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  • Patent Application
  • 20200165283
  • Publication Number
    20200165283
  • Date Filed
    July 04, 2018
    6 years ago
  • Date Published
    May 28, 2020
    4 years ago
Information
Abstract
The present invention provides a metallocenyl compound of formula (I). Ra, Rb, Rc, Rd, Re, Rf, M, m, n, j, k, Y and Z and * are as described in the specification. The invention also provides a process for the preparation of the complexes, a process for increasing the optical purity of a compound of formula (II) and a process for the asymmetric transfer hydrogenation (ATH) of a metallocenyl compound of formula (V) to a metallocenyl compound of formula (IV).
Description

The present invention relates to quaternary ammonium salts of metallocenyl-containing amines and a process for the preparation thereof. In particular, the invention relates to optically active quaternary ammonium salts of metallocenyl-containing amines, wherein the anion is non optically active. The present invention also relates to an improved process for the preparation of a metallocenyl alcohol. In particular, the invention relates to the preparation of optically active metallocenyl alcohols by asymmetric transfer hydrogenation (ATH).


Enantioenriched N,N-dimethyl-α-ferrocenylethylamine (Ugi amine) is a versatile starting material for the synthesis of various chiral ligands used in asymmetric catalysis. U.S. Pat. No. 5,760,264 (to Lonza) describes the synthesis of enantioenriched N,N-dimethyl-α-ferrocenylethylamine (B) by a multi-step procedure (Scheme 1), starting from acetylferrocene, which is reduced in the presence of a chiral borane to obtain (R)-(1-hydroxyethyl)ferrocene (D), followed by acetylation, to obtain (R)-(1-acetoxyethyl)ferrocene (C) in 88% ee. This product is subsequently treated with dimethylamine to obtain (R)-[1-dimethylamino)ethyl]ferrocene (N,N-dimethyl-α-ferrocenylethylamine, Ugi amine, B). Presuming that the amination step is carried out without erosion of optical purity, the maximum ee of the product is 88%.




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N,N-dimethyl-α-ferrocenylethylamine (B) was obtained optically pure by resolution with a chiral anion. In one example by Gokel et al (J. Chem. Ed., 1972, 49, 294), racemic N,N-dimethyl-α-ferrocenylethylamine was treated with R-(+)-tartaric acid. However, the described salt resolution can yield a single desired enantiomer in a theoretical yield of 50%.


In addition to their use in obtaining optically active metallocenyl-containing amines, optically active metallocenyl alcohols are useful as intermediates in the preparation of bis-phosphorus-containing metallocenyl ligands, such as Bophoz, Josiphos and Xyliphos ligands.


SUMMARY OF THE INVENTION

The present invention provides quaternary ammonium salts of metallocenyl-containing amines in high purity and/or high enantiomeric excess, which are obtained in high yields. In certain embodiments the quaternary ammonium salts of metallocenyl-containing amines have high chemical purity. In certain embodiments the quaternary ammonium salts of metallocenyl-containing amines have high enantiomeric excess.


The present invention is also more suited to the large-scale manufacture of optically active metallocenyl alcohols. In certain embodiments, the ATH process produces the optically active metallocenyl alcohol in high yields. In certain embodiments, the ATH process produces the optically active metallocenyl alcohol in high enantiomeric excess.


Accordingly, the invention provides a metallocenyl compound of formula (I),




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wherein:


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5 and k is 1 or 2;


when j=1, n is an integer from 0 to 4 and k is 1;


Y is (j+1) Zk− or Z(j+1)k−;


Z is a non optically active anion; and


* denotes an optically active carbon atom.


In another aspect, the invention provides a process for the preparation of a metallocenyl compound of formula (I)




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comprising mixing a compound of formula (II) with an acid Hk(j+1)Z in a solvent to form a compound of formula (I),


wherein


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5 and k is 1 or 2;


when j=1, n is an integer from 0 to 4 and k is 1;


Y is (j+1) Zk− or Z(j+1)k−;


Z is a non optically active anion; and


* denotes an optically active carbon atom.


In yet another aspect, it is provided a process for increasing the optical purity of a compound of formula (II),




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comprising the steps of:


a) mixing a metallocenyl compound of formula (I) with a solvent to obtain a suspension of solid particles in a liquid, wherein the mixing is carried out at about the boiling point of the solvent;


b) separating metallocenyl compound of formula (I) as a solid from the suspension of step a).


c) obtaining the compound of formula (II) from the metallocenyl compound of formula (I) of step b) in the presence of a base,


wherein


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5 and k is 1 or 2;


when j=1, n is an integer from 0 to 4 and k is 1;


Y is (j+1) Zk− or Z(j+1)k−;


Z is a non optically active anion; and


* denotes an optically active carbon atom.


In another aspect, the invention provides a process for the asymmetric transfer hydrogenation (ATH) of a metallocenyl compound of formula (V) to a metallocenyl compound of formula (IV),




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wherein:


the asymmetric transfer hydrogenation is carried out in an aqueous solvent at a temperature greater than 60° C. in the presence of an asymmetric transfer hydrogenation catalyst and activated formic acid; wherein:


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5;


when j=1, n is an integer from 0 to 4; and


* denotes an optically active carbon atom.


Definitions

The point of attachment of a moiety or substituent is represented by “-”. For example, —OH is attached through the oxygen atom.


“Activated formic acid” refers to a mixture of formic acid, a tertiary amine base and optionally water which forms a liquid reducing agent for an ATH reaction.


“Alkyl” refers to a straight-chain or branched saturated hydrocarbon group. In certain embodiments, the alkyl group may have from 1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, in certain embodiments, 1-8 carbon atoms. The alkyl group may be unsubstituted. Alternatively, the alkyl group may be substituted. Unless otherwise specified, the alkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Typical alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.


The term “cycloalkyl” is used to denote a saturated carbocyclic hydrocarbon group. In certain embodiments, the cycloalkyl group may have from 3-15 carbon atoms, in certain embodiments, from 3-10 carbon atoms, in certain embodiments, from 3-8 carbon atoms. The cycloalkyl group may be unsubstituted. Alternatively, the cycloalkyl group may be substituted. Unless otherwise specified, the cycloalkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.


“Alkoxy” refers to an optionally substituted group of the formula alkyl-O— or cycloalkyl-O—, wherein alkyl and cycloalkyl are as defined above.


“Aryl” refers to an aromatic carbocyclic group. The aryl group may have a single ring or multiple condensed rings. In certain embodiments, the aryl group can have from 5-20 carbon atoms, in certain embodiments from 6-15 carbon atoms, in certain embodiments, 6-12 carbon atoms. The aryl group may be unsubstituted. Alternatively, the aryl group may be substituted. Unless otherwise specified, the aryl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl and the like.


“Arylalkyl” refers to an optionally substituted group of the formula aryl-alkyl-, where aryl and alkyl are as defined above.


“Aryloxy” refers to an optionally substituted group of the formula aryl-O—, where aryl is as defined above.


“Halo”, “hal” or “halide” refers to —F, —Cl, —Br and —I.


“Heteroalkyl” refers to a straight-chain or branched saturated hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certain embodiments, the heteroalkyl group may have from 1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, in certain embodiments, 1-8 carbon atoms. The heteroalkyl group may be unsubstituted. Alternatively, the heteroalkyl group may substituted. Unless otherwise specified, the heteroalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heteroalkyl groups include but are not limited to ethers, thioethers, primary amines, secondary amines, tertiary amines and the like.


“Heterocycloalkyl” refers to a saturated cyclic hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certain embodiments, the heterocycloalkyl group may have from 2-15 carbon atoms, in certain embodiments from 2-10 carbon atoms, in certain embodiments, 2-8 carbon atoms. The heterocycloalkyl group may be unsubstituted. Alternatively, the heterocycloalkyl group may be substituted. Unless otherwise specified, the heterocycloalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heterocycloalkyl groups include but are not limited to epoxide, morpholinyl, piperadinyl, piperazinyl, thirranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, thiomorpholinyl and the like.


“Heteroaryl” refers to an aromatic carbocyclic group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certain embodiments, the heteroaryl group may have from 4-20 carbon atoms, in certain embodiments from 4-15 carbon atoms, in certain embodiments, 4-8 carbon atoms. The heteroaryl group may be unsubstituted. Alternatively, the heteroaryl group may be substituted. Unless otherwise specified, the heteroaryl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heteroaryl groups include but are not limited to thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, thiophenyl, oxadiazolyl, pyridinyl, pyrimidyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, indolyl, quinolinyl and the like.


“Substituted” refers to a group in which one or more hydrogen atoms are each independently replaced with substituents (e.g. 1, 2, 3, 4, 5 or more) which may be the same or different. The group may be substituted with one or more substituents up to the limitations imposed by stability and the rules of valence. The substituents are selected such that they are not adversely affected under the ATH, acylation, amination or salt formation reaction conditions. Examples of substituents include but are not limited to -halo, —CF3, —Ra, —O—Rm, —S—Rm, —NRmRn, —CN, —C(O)—Rm, —COORm, —C(S)—Rm, —C(S)ORm, —S(O)2OH, —S(O)2—Rm, —S(O)2NRmRn and —CONRmRn, preferably -halo, —CF3, —Rm, —O—Rm, —NRmRn, —COORm, —S(O)2OH, —S(O)2—Rm, —S(O)2NRmRn and —CONRmRn. Rm and Rn are independently selected from the groups consisting of H, alkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or Rm and Rn together with the atom to which they are attached form a heterocycloalkyl group, and wherein Rm and Rn may be unsubstituted or further substituted as defined herein.


“Metallocenyl” refers to a transition metal complex group wherein a transition metal atom or ion is “sandwiched” between two rings of atoms. The metallocenyl group may be substituted or unsubstituted. Unless otherwise specified, the metallocenyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of transition metal atoms or ions include but are not limited to ruthenium, osmium, nickel and iron. An example of a suitable ring of atoms is a cyclopentadienyl ring. An example of a metallocenyl group includes but is not limited to ferrocenyl, which comprises a Fe(II) ion sandwiched between two cyclopentadienyl rings, wherein each cyclopentadienyl ring may be independently unsubstituted or substituted.


“Optically active” means capable of rotating the plane of vibration of polarized light to the right or left.


“Halide anion” refers to F−, Cl−, Br− and I−.


An “oxy-anion” means an anion containing one or more oxygen atoms bonded to another element.


A “monoanion” is an ion having a single negative charge. A “dianion” is an anion carrying two negative charges.


An “acyl group” is a moiety derived by the removal of one or more hydroxyl groups from a carboxylic acid.


A “suspension” is a heterogeneous mixture that contains solid particles sufficiently large for sedimentation on standing.


An “aqueous solvent” refers to water or a mixture of water and water-miscible solvents.







DETAILED DESCRIPTION

Metallocenyl Compounds of Formula (I) and (II)


In one aspect the invention provides a metallocenyl compound of formula (I),




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wherein:


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5 and k is 1 or 2;


when j=1, n is an integer from 0 to 4 and k is 1;


Y is (j+1) Zk− Or Z(j+1)k-;


Z is a non optically active anion; and


* denotes an optically active carbon atom.


Ra may be selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Ra is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. Ra may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (e.g. n-pentyl or neopentyl), hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3-10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 4-methoxy-3,5-dimethylphenyl and 3,5-di(trifluoromethyl)phenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used. In one embodiment, Ra is methyl.


Rb may be selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Rb is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Rb is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. Rb may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (e.g. n-pentyl or neopentyl), hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3-10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 4-methoxy-3,5-dimethylphenyl and 3,5-di(trifluoromethyl)phenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used.


Rb may be present or absent. When absent, m is 0 i.e. the Rb-containing Cp ring is not further substituted. When Rb is present, m may be 1, 2, 3 or 4. The or each Rb may be the same or different. In one embodiment, Rb is absent i.e. m is 0.


Rc may be selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Rc is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Rc is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. Rc may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (e.g. n-pentyl or neopentyl), hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3-10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 4-methoxy-3,5-dimethylphenyl and 3,5-di(trifluoromethyl)phenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used.


Rc may be present or absent. When absent, n is 0 i.e. the Rc-containing Cp ring is not substituted.


When Rc is present, n may be 1, 2, 3, 4 or 5 when j is 0 or n may be 1, 2, 3 or 4 when j is 1.


The or each Rc may be the same or different. In one embodiment, Rc is absent i.e. n is 0.


Rd may be selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Rd is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. Rd may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (e.g. n-pentyl or neopentyl), hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3-10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 4-methoxy-3,5-dimethylphenyl and 3,5-di(trifluoromethyl)phenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used.


In one embodiment, Rd is absent and j is 0.


In one embodiment, Rd is methyl and j is 1.


Re may be selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl. In one embodiment, Re is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl. Re may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (e.g. n-pentyl or neopentyl), hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3-10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 4-methoxy-3,5-dimethylphenyl and 3,5-di(trifluoromethyl)phenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used. In one embodiment, Re is methyl.


Rf may be selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl. In one embodiment, Rf is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl. In one embodiment, Rf is selected from the group consisting of unsubstituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. Rf may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (e.g. n-pentyl or neopentyl), hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents each of which may be the same or different such as halide (F, Cl, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3-10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 4-methoxy-3,5-dimethylphenyl and 3,5-di(trifluoromethyl)phenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used. In one embodiment, Rf is methyl.


M may be selected from the group consisting of Fe, Ru, Os and Ni. In one embodiment, M is Fe and the compound of formula (I) is a ferrocenyl compound. In another embodiment, M is Ru. In another embodiment, M is Os. In another embodiment, M is Ni. Preferably, M is Fe.


In one embodiment, j is 0, n is an integer from 1 to 5, k is 1 or 2 and the metallocenyl compound of formula (I), is represented by the formula (Ia):




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Z is a non-optically active anion and suitably may be selected from:

    • a) a monoatomic anion, such as a halide anion, in which case k=1; or
    • b) an oxyanion, such as (H2PO4)− (k=1) or (HPO4)2− (k=2); or
    • c) a non optically active organic anion, such as:
      • when k=1: CH3CO2− (acetate), C6H5CO2− (benzoate), CH3SO3− (mesylate), CH3C6H4SO2− (tosylate), HO2CCH═CHCO2− (monoanionic fumarate), HO2C(CH2)4CO2− (monoanionic adipate), HO2C—CO2− (monoanionic oxalate),
      • when k=2: −O2CCH═CHCO2− (dianionic fumarate), −O2C(CH2)4CO2− (dianionic adipate), −O2C—CO2− (dianionic oxalate).


In one embodiment Z may be a monoanion (in which case k=1) or a dianion (in which case k=2).


In another embodiment, j is 1, n is an integer from 1 to 4, k is 1 and the metallocenyl compound of formula (I) is represented by the formula (Ib):




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Z is a non-optically active anion and suitably may be selected from:

    • a) a monoatomic anion, such as a halide anion; or
    • b) an oxyanion, such as (H2PO4)− or (HPO4)2−; or
    • c) a non optically active organic anion, such as:
      • CH3CO2− (acetate), C6H5CO2− (benzoate), CH3SO3− (mesylate), CH3C6H4SO2− (tosylate), HO2CCH═CHCO2− (monoanionic fumarate), HO2C(CH2)4CO2− (monoanionic adipate), HO2C—CO2− (monoanionic oxalate),
      • −O2CCH═CHCO2− (dianionic fumarate), −O2C(CH2)4CO2− (dianionic adipate), −O2C—CO2− (dianionic oxalate).


Suitable metallocenyl compounds of formula (I) are salts of the N,N-dimethyl-α-ferrocenylethylammonium cation (A*), such as A*(H2PO4), A*2(HPO4) or mixtures thereof, A*(OAc), A*(benzoate), A*(mesylate), A*(tosylate), A*(fumarate), A*(adipate), A*(oxalate):




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Preferred metallocenyl compounds of formula (I) are N,N-dimethyl-α-ferrocenylethylammonium dihydrogenphosphate (A*(H2PO4)), di(N,N-dimethyl-α-ferrocenylethylammonium monohydrogenphosphate (A*2(HPO4)) or mixtures thereof.


In another aspect, the present invention provides a process for the preparation of a metallocenyl compound of formula (I)




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comprising mixing a compound of formula (II) with an acid Hk(j+1)Z in a solvent to form a compound of formula (I),


wherein


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5 and k is 1 or 2;


when j=1, n is an integer from 0 to 4 and k is 1;


Y is (j+1) Zk− Or Z(j+1)k−;


Z is a non optically active anion; and


* denotes an optically active carbon atom.


The acid Hk(j+1)Z may be a corresponding acid of the non-optically active anion Z− or Z2− in the compound of formula (I). In one embodiment, the acid Hk(j+1)Z may be H3PO4, fumaric acid, adipic acid, oxalic acid, benzoic acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid. In one preferred embodiment, the acid Hk(j+1)Z may be H3PO4.


The process according to the invention may be carried out in the presence of a solvent. Preferably, the solvent comprises, an alcohol, an ether (cyclic or open chain, such as tetrahydrofuran (THF) or methyl tert-butylether (MTBE)), an aromatic solvent (such as benzene or toluene), an ester (such as ethyl acetate) or a combination thereof. When the solvent comprises an alcohol, preferred alcohols have boiling points at atmospheric pressure (i.e. 1.0135×105 Pa) below 160° C., more preferably below 120° C. and even more preferably below 100° C. Preferred examples are methanol, ethanol, n-propanol, isopropanol, n-butanol or combinations thereof. More preferably, the alcohol is methanol, isopropanol or a combination thereof. Particular preference is given to methanol.


The concentration of compound of formula (II) may be in the range of. 0.1-5 M, preferably 0.9 M to about 1.2 M. In one embodiment, the concentration of compound of formula (II) is about 1.1 M. The concentration of Hk(j+1)Z may be in the range of 0.5 M to about 1 M. In one embodiment, the concentration of Hk(j+1)Z is about 0.9 M. In another embodiment, the concentration of Hk(j+1)Z is about 0.6 M.


The reactants may be added in any suitable order, but in a preferred process of the invention a diluted aqueous solution of the Hk(j+1)Z is added to a solution of the compound of formula (II) in the solvent. It is desirable that the diluted aqueous solution of the Hk(j+1)Z is added to the solution of the compound of formula (II) slowly in order to avoid an uncontrollable exotherm.


In the present invention, the ratio between the compound of formula (II) and Hk(j+1)Z determines the composition and purity of the metallocenyl compound of formula (I). When j=0 and k=1 the ratio between the compound of formula (II) and the number of equivalents of Hk(j+1)Z may be in the range of about 0.8:1 to about 1.25:1 and a mixture of unreacted compound of formula (II) and a compound of formula (I) wherein k=1 may be formed. Suitable ratios between compound of formula (II) and the number of equivalents of Hk(j+1)Z include but are not limited to 0.80:1, 0.85:1, 0.90:1, 0.95:1, 1.00:1, 1.05:1, 1.10:1, 1.15:1, 1.20:1, 1.25:1.


Where j=0 and k is 2 or where j=1 and k=1 the ratio between the compound of formula (II) and the number of equivalents of Hk(j+1)Z may be in the range of about 1.15:1 to about 2.20:1 and a mixture of a compound of formula (I) wherein k=1 and a compound of formula (I) wherein k=2 may be formed. Suitable ratios between compound of formula (II) and the number of equivalents of Hk(j+1)Z include but are not limited to 1.15:1, 1.20:1, 1.25:1, 1.30:1, 1.35:1, 1.40:1, 1.45:1, 1.50:1, 1.55:1, 1.60:1, 1.65:1, 1.70:1, 1.75:1, 1.80:1, 1.85:1, 1.90:1, 1.95:1, 2.00:1, 2.05:1, 2.10:1, 2.15:1, 2.20:1.


While Hk(j+1)Z is added to the compound of formula (II), it is preferred that the temperature range of the reaction mixture may be maintained at one or more temperatures between about −15° C. to about 35° C. In one embodiment the reaction mixture is maintained at a temperature of between about −10° C. to about 10° C. In another embodiment, the reaction mixture is maintained at a temperature of less than about 5° C. In one preferred embodiment, the reaction mixture is maintained at 0° C.


The reaction may be continued for a period of from about 30 minutes to about 2 hours, preferably about 1 hour. During this time, the reaction temperature may be varied one or more times between about −10° C. and about 60° C.


Alternatively, Hk(j+1)Z may be added to the compound of formula (II) at a temperature below 160° C., more preferably below 120° C. and even more preferably below 100° C. The reaction may be continued for a period of from about 30 minutes to about 2 hours, preferably about 1 hour. During this time, the reaction temperature may be varied one or more times between about 160° C. and about 15° C.


On completion of the reaction, the compound of formula (I) may be separated from the reaction mixture by any appropriate method.


Purification of the complex of formula (I) is not normally required, although if necessary it is possible to purify the complex using conventional procedures.


In one embodiment, the present invention further comprises the step of treating the metallocenyl complex of formula (I) with a base to form the complex of formula (II). The metallocenyl complex of formula (I) is preferably mixed with a solvent to obtain a suspension. The solvent may be any suitable solvent, for example an aromatic hydrocarbon (such as toluene). The base is preferably an aqueous solution of an alkali hydroxide. The base may be added until the pH of the liquid will be in the range of about 10 to about 11. On completion of the reaction, the compound of formula (II) may be separated from the reaction mixture by any appropriate method. Determination of the enantiomeric excess is carried out on a sample of the compound of formula (II) by analysing it by HPLC.


In another aspect, the present invention provides a process for increasing the optical purity of a compound of formula (II),




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comprising the steps of:


a) mixing a metallocenyl compound of formula (I) with a solvent to obtain a suspension of solid particles in a liquid, wherein the mixing is carried out at about the boiling point of the solvent;


b) separating metallocenyl compound of formula (I) as a solid from the suspension of step a).


c) obtaining the compound of formula (II) from the metallocenyl compound of formula (I) of step b) in the presence of a base,


wherein


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5 and k is 1 or 2;


when j=1, n is an integer from 0 to 4 and k is 1;


Y is (j+1) Zk− or Z(j+1)k−;


Z is a non optically active anion; and


* denotes an optically active carbon atom.


In one embodiment, the process for the preparation of a metallocenyl compound of formula (I) previously described further comprises a process for increasing the optical purity of the compound of formula (II),




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comprising the steps of:


a) mixing the metallocenyl compound of formula (I) with a solvent to obtain a suspension of solid particles in a liquid, wherein the mixing is carried out at about the boiling point of the solvent;


b) separating metallocenyl compound of formula (I) as a solid from the suspension of step a).


c) obtaining the compound of formula (II) from the metallocenyl compound of formula (I) of step b) in the presence of a base.


Ra, Rb, Rc, Rd, Re, Rf, M, Y, Z, m, n, j and k are as generally described above.


A preferred compound of formula (I) is compound A*(H2PO4) and a preferred compound of formula (II) is compound B:




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When compound of formula (I) is compound A*(H2PO4) and compound of formula (II) is compound B, the solvent comprises an alcohol. Preferred alcohols have boiling points at atmospheric pressure (i.e. 1.0135×105 Pa) below 160° C., more preferably below 120° C. and even more preferably below 100° C. Preferred examples are methanol, ethanol, n-propanol, isopropanol, n-butanol or combinations thereof. More preferably, the alcohol is methanol, isopropanol or a combination thereof. Particular preference is given to a mixture of isopropanol/methanol 99/1.


Compound A*(H2PO4) is separated as a solid from the suspension and isolated using conventional procedures, such as filtration.


Isolated compound A*(H2PO4) is treated in a suitable solvent, such as toluene, with a base.


The preferred base is NaOH 2M. The base may be added until the pH of the liquid will be in the range of about 10 to about 11. On completion of the reaction, compound B may be separated from the reaction mixture by any appropriate method, such as separating the organic layer from the aqueous layer and isolating compound B from the organic layer.


Determination of the enantiomeric excess is carried out on a sample of the compound B by analysing it by HPLC. The enantiomeric excess of compound B may be ≥99% ee.


In an embodiment, the compound of formula (II) is prepared by mixing a compound of formula (III) with a compound of formula HNReRf in a solvent to form the compound of formula (II),




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wherein


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C1Pa-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5;


when j=1, n is an integer from 0 to 4; and


* denotes an optically active carbon atom.


The molar ratio of compound of formula (III):HNReRf when j=0 may be in the range of about 1:10 to about 1:4, preferably of about 1:6 to about 1:4. In one embodiment, the molar ratio of compound of formula (III):HNReRf may be in the range of about 1:5.5 to 1:4.5. In one preferred embodiment, the ratio is about 1:5. When j=1, the molar ratio of compound of formula (III):HNReRf may be in the range of about 1:20 to about 1:8, preferably of about 1:12 to about 1:8. In one embodiment, the molar ratio of compound of formula (III):HNReRf may be in the range of about 1:11 to 1:9. In one preferred embodiment, the ratio is about 1:10.


The process according to the invention may be carried out in the presence of a solvent. Preferably, the solvent comprises a mixture of alcohol and a C1-C8 alkane. The solvent may further comprise water. Preferred alcohols have boiling points at atmospheric pressure (i.e. 1.0135×105 Pa) below 160° C., more preferably below 120° C. and even more preferably below 100° C. Preferred examples are methanol, ethanol, n-propanol, isopropanol, n-butanol or combinations thereof. More preferably, the alcohol is methanol, isopropanol or a combination thereof. Particular preference is given to isopropanol. The C1-C8 alkane may be a linear alkane, a branched alkane or a cycloalkane. Suitable alkanes are pentane (all isomers), hexane (all isomers), heptane (all isomers), octane (all isomers) or mixtures thereof. The most preferred alkanes are heptane and cyclohexane.


The ratio alcohol:C1-C8 alkane may be in the range of about 1:3 to about 1:8 preferably about 1:4 to about 1:7, most preferably 1:5.


The reactants may be added in any suitable order, but in a preferred process of the invention a solution of the compound of formula HNReRf in water or alcohol is added to the solution of the compound of formula (III) in the solvent. It is desirable that the solution of the HNReRf is added to the solution of the compound of formula (III) slowly in order to avoid an uncontrollable exotherm.


While HNReRf is added to the compound of formula (III), it is preferred that the temperature range of the reaction mixture may be maintained at one or more temperatures between about −15° C. to about 35° C. In one embodiment the reaction mixture is maintained at a temperature of between about −10° C. to about 10° C. In another embodiment, the reaction mixture is maintained at a temperature of less than about 5° C. In one preferred embodiment, the reaction mixture is maintained at 0° C.


The reaction may be continued for a period of from about 30 minutes to about 24 hours, preferably about 10 hours. During this time, the reaction temperature may be varied one or more times between about −10° C. and about 65° C., preferably about 50° C. On completion of the reaction, the compound of formula (II) may be separated from the reaction mixture by any appropriate method. Purification of the complex of formula (II) is not normally required, although if necessary it is possible to purify the complex using conventional procedures.


In an embodiment, the compound of formula (III) is prepared by mixing a compound of formula (IV) with a compound of formula acyl-LG in the presence of a base to form a compound of formula (III), wherein LG is a leaving group:




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The compound of formula acyl-LG is preferably a carboxylic anhydride or an acyl chloride. In these instances, LG may be —O-acyl (for carboxylic anhydride), or —Cl (for acyl chloride). The most preferred compound of formula acyl-LG is acetic anhydride.


The base may be an organic or an inorganic base. Preferably, the base is sodium acetate. The most preferred base is sodium acetate trihydrate (NaOAc-3.H2O).


The reaction may be carried out in the absence of a solvent (neat). In these instances, the compound of formula acyl-LG acts as a solvent. Suitable compounds of formula acyl-LG are preferably a carboxylic anhydride.


Alternatively, the reaction may be carried out in the presence of a solvent. The solvent may be any suitable aprotic solvent. The solvent may be selected from the group consisting of an aromatic solvent (such as benzene or toluene), an ether (cyclic, such as tetrahydrofuran (THF) or open chain, such as methyl tert-butylether (MTBE)), an ester (such as ethyl acetate, isopropyl acetate), a C1-C8 alkane (such as pentane, hexane, heptane, octane or mixtures thereof), dichloromethane, acetonitrile, acetone or a combination thereof. In a preferred embodiment the solvent is heptane.


The compound of formula (IV) and the compound of formula acyl-LG may be added in any suitable order. In a preferred process of the invention, however, the compound of formula (IV) and the base is placed in a reaction vessel, together with the solvent (if used), and then the compound of formula acyl-LG is added.


When j=0, the molar ratio between the compound of formula (IV) and the compound of formula acyl-LG may be in the range of about 1:1 to about 1:5. Preferably the molar ratios between compound of formula (IV) and the compound of formula acyl-LG may be in the range of about 1:1.5 to about 1:2 When j=1, the molar ratio between the compound of formula (IV) and the compound of formula acyl-LG may be in the range of about 1:2.2-1:8. Preferably the molar ratios between compound of formula (IV) and the compound of formula acyl-LG may be in the range of about 1:2.2-1:2.6.


The base may be added in a molar ratio compound of formula (IV) to the base of between about 1:0.1 to 1:5.


Alternatively, the base is dimethylaminopyridine (DMAP).


In one embodiment, the compound of formula (IV) is prepared by asymmetric transfer hydrogenation (ATH) of a metallocenyl compound of formula (V)




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wherein:


the asymmetric transfer hydrogenation is carried out in an aqueous solvent at a temperature greater than 60° C. in the presence of an asymmetric transfer hydrogenation catalyst and activated formic acid; wherein


Ra, Rb, Rc and Rd are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl, unsubstituted C4-C20-heteroaryl, substituted C4-C20-heteroaryl, wherein the heteroatoms in the C4-C20-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen;


Re and Rf are independently selected from the group consisting of unsubstituted C1-C20-alkyl, substituted C1-C20-alkyl, unsubstituted C3-C15-cycloalkyl, substituted C3-C15-cycloalkyl, unsubstituted C5-C20-aryl, substituted C5-C20-aryl;


M is selected from the group consisting of Fe, Ru, Os and Ni;


m is an integer from 0 to 4;


j is 0 or 1; and


when j=0, n is an integer from 0 to 5;


when j=1, n is an integer from 0 to 4; and


* denotes an optically active carbon atom.


A preferred compound of formula (I) is compound A*(H2PO4), a preferred compound of formula (II) is compound B, a preferred compound of formula (III) is compound C and a preferred compound of formula (IV) is compound D:




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In one embodiment, the compound of formula (III) is compound C, the compound of formula (IV) is compound D and dimethylaminopyridine (DMAP) may be used as a base in the process of preparing compound C from compound D.


In this instance, compound A*(H2PO4) can be isolated free of impurities, such as DMAP-H3PO4 and DMAP-HOAc, by further purification comprising the steps of:

    • a) adding methanol to a compound A*(H2PO4) containing DMAP-H3PO4 and DMAP-HOAc, to produce a solid-liquid mixture;
    • b) separating the liquid containing the compound A*(H2PO4) and DMAP-HOAc from the solid-liquid mixture of step a);
    • c) isolating the compound A*(H2PO4) containing DMAP-HOAc from the liquid of step b);
    • d) adding dichloromethane or acetonitrile to the isolated compound A*(H2PO4) containing DMAP-HOAc of step c), to produce a second solid-liquid mixture;
    • e) isolating the solid from the second solid-liquid mixture of step d) to produce a compound A*(H2PO4) of higher purity than before the steps a) to e).


In one embodiment, the compound of formula (III) is obtained in situ, therefore without further isolation, before reaction with the compound of formula HNReRf.


Metallocenyl Compounds of Formula (IV) and (V)


The metallocenyl carbonyl compound of formula (V) is asymmetrically reduced to the metallocenyl alcohol of formula (IV):




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Ra, Rb, Rc, Rd, M, m, n and j are as generally described above.


Asymmetric Transfer Hydrogenation Catalyst


The asymmetric transfer hydrogenation catalyst may be a complex of formula (VI). The complex of formula (VI) may be referred to herein as a tethered complex.




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wherein,


R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl, optionally substituted C6-20 aryloxy, —OH, CN, —NR20R21, —COOH, COOR20, —CONH2, —CONR20R21 and —CF3 wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR30R31, —COOR30, —CONR30R31 and —CF3; and/or


R1 and R2, R2 and R3, R3 and R4 or R4 and R5 together form an aromatic ring composed of 6 to 10 carbon atoms which is optionally substituted with one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3;


R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl and optionally substituted C6-20 aryloxy wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3, or


R6 and R7 together with the carbon atom to which they are bound and/or R8 and R9 together with the carbon atom to which they are bound form an optionally substituted C3-20 cycloalkyl or an optionally substituted C2-20 cycloalkoxy, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3, or one of R6 and R7 and one of R8 and R9 together form an optionally substituted C5-10 cycloalkyl or an optionally substituted C5-10 cycloalkoxy, wherein the substituents are independently selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3,


provided R6 and R7 and/or R8 and R9 are not the same,


¤ represents an optically active carbon atom;


R10 is an optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, an optionally substituted C6-10 aryl or —NR11R12 wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, -Hal, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3;


R11 and R12 are independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl and optionally substituted C6-10 aryl, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl groups, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3, or


R11 and R12 together with the nitrogen atom to which they are bound form an optionally substituted C2-10 cycloalkyl-amino group, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3;


R20 and R21 are independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl, optionally substituted C6-20 aryloxy, —OH, —CN, —NR30R31, —COOR30, —CONR30R31 and —CF3, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3;


R30 and R31 are independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl, optionally substituted C6-20 aryloxy, —OH, —CN and —CF3, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3;


A is an optionally substituted straight- or branched-chain C2-5 alkyl wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl and C6-10 aryloxy, or


A is a group of formula (VII):




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wherein p is an integer selected from 1, 2, 3 or 4;


each R40 is independently selected from the group consisting of straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN or —CF3;


q and r are independently integers selected from 0, 1, 2 or 3 wherein q+r=1, 2 or 3; each R41 is independently selected from the group consisting of hydrogen, straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3; or


A is a group of formula (VIII):




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X is O or S;

s and t are independently integers selected from 0, 1, 2 or 3 wherein s+t=1, 2 or 3;


each R42 is independently selected from the group consisting of hydrogen, straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3;


and


Hal is a halogen.


The carbon atoms to which R6 and R7 and/or R8 and R9 are bound are asymmetric when R6 and R7 and/or R8 and R9 are not the same groups. In one embodiment, R6 and R7 are not the same groups. In another embodiment, R8 and R9 are not the same groups. The asymmetric carbon atoms are represented by the symbol “n”. The complex of formula (VI) therefore is chiral (optically active) and the transfer hydrogenation process of the invention is an asymmetric transfer hydrogenation process.


R1, R2, R3, R4 and R5 may each be independently selected from the group consisting of hydrogen, straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR20R21, —COOH, COOR20, —CONH2, —CONR20R21 and —CF3. In another embodiment, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH. Preferably, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, straight-chain C1-10 alkyl and branched-chain C1-10 alkyl. R1, R2, R3, R4 and R5 may be each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. For example, R1, R2, R3, R4 and R5 may each be hydrogen. In another embodiment, R3 may be methyl and R1, R2, R4 and R5 may each be hydrogen.


In yet another embodiment, R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, optionally substituted straight- or branched-chain C1-10 alkyl, optionally substituted straight- or branched-chain C1-10 alkoxy, optionally substituted C6-10 aryl and optionally substituted C6-10 aryloxy wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH. The groups R6, R7, R8 and R9 may be each independently selected from the group consisting of hydrogen and optionally substituted C6-10 aryl. For example, R6, R7, R8 and R9 may each be independently selected from the group consisting of hydrogen or phenyl. In one embodiment, one of R6 and R7 is phenyl and the other of R6 and R7 is hydrogen. In one embodiment, one of R8 and R9 is phenyl and the other of R8 and R9 is hydrogen.


In another embodiment, R6 and R7 together with the carbon atom to which they are bound and/or R8 and R9 together with the carbon atom to which they are bound form an optionally substituted C5-10 cycloalkyl or an optionally substituted C5-10 cycloalkoxy, wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


In yet another embodiment, one of R6 and R7 and one of R8 and R9 together form an optionally substituted C5-10 cycloalkyl or an optionally substituted C5-10 cycloalkoxy, wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


In yet another embodiment, R10 is an optionally substituted straight, branched or cyclic C1-10 alkyl, an optionally substituted C6-10 aryl wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, -Hal, —OH, —CN, —NR20R21, —COOR20, —CONR20R21 and —CF3. In another embodiment, the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, -Hal, or —CF3. In another embodiment, R10 is a straight- or branched-chain C1-10 alkyl or a C6-10 aryl optionally substituted with one or more straight- or branched-chain C1-10 alkyl groups. Examples of R10 include, but are not limited to, p-tolyl, methyl, p-methoxyphenyl, p-chlorophenyl, trifluoromethyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, pentamethylphenyl and 2-naphthyl. R10 may be methyl or a tolyl group.


In another embodiment, R10 is —NR11R12 wherein R11 and R12 are independently selected from the group consisting of straight- or branched-chain C1-10 alkyl and C6-10 aryl optionally substituted with one or more straight- or branched-chain C1-10 alkyl groups. —NR11R12 may be —NMe2.


In yet another embodiment, R11 and R12 together with the nitrogen atom to which they are bound form an optionally substituted C5-10 cycloalkyl-amino group wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


In one embodiment, A is an optionally substituted straight- or branched-chain C2-5 alkyl, preferably an optionally substituted straight- or branched-chain C3-5 alkyl, wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl and C6-10 aryloxy. A may be selected from —(CH2)2—, —(CH2)3—, —(CH2)4— or —(CH2)5—, for example, —(CH2)3— or —(CH2)4—.


Alternatively, A can be a group of formula (VII) i.e. the —[C(R41)2]q— and —[C(R41)2]r— groups are ortho to each other.




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wherein p is an integer selected from 1, 2, 3 or 4;


each R40 is independently selected from the group consisting of straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN or —CF3;


q and r are independently integers selected from 0, 1, 2 or 3 wherein q+r=1, 2 or 3; and


each R41 is independently selected from the group consisting of hydrogen, straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN or —CF3.


In one embodiment, p is 0. The phenyl ring therefore is not substituted by any R40 groups.


In another embodiment, each R41 are independently selected from the group consisting of hydrogen, straight-chain C1-10 alkyl and branched-chain C1-10 alkyl. More preferably, each R41 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. In one embodiment, each R41 is hydrogen.


In one embodiment, q+r is 1. In another embodiment, q+r is 2. In yet another embodiment, q+r is 3.


Examples of A include, but are not limited to, the following:




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In another embodiment, A is a group of formula (VIII):




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wherein X is O or S;


s and t are independently integers selected from 0, 1, 2 or 3 wherein s+t=1, 2 or 3;


each R42 is independently selected from the group consisting of hydrogen, straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3.


In one embodiment, s+t may be 1. In another embodiment, s+t may be 2. In yet another embodiment, s+t may be 3.


In one embodiment, X is O i.e. an oxygen atom. In another embodiment, X is S i.e. a sulfur atom.


In another embodiment, each R42 are independently selected from the group consisting of hydrogen, straight-chain C1-10 alkyl and branched-chain C1-10 alkyl. More preferably, each R42 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. In one embodiment, each R42 is hydrogen.


Examples of A include, but are not limited to, the following:




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In one embodiment, A includes but is not limited to:




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In one embodiment, Hal is chlorine, bromine or iodine, preferably chlorine.


The metal complexes of formula (VI) may be selected from the group consisting of:




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The metal complexes of formula (VI) may be selected from the group consisting of:




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The preparation of the metal complexes of formula (VI) is given in WO2010/106364, WO2016/042298 and EP2609103.


The asymmetric transfer hydrogenation catalyst may be a complex of formula (IX):




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wherein,


R101, R102, R103, R104, R105 and R106 are each independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl, optionally substituted C6-20 aryloxy, —OH, CN, —NR200R201, —COOH, COOR200, —CONH2, —CONR200R201 and —CF3 wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR300R301, —COOR300, —CONR300R301 and —CF3; and/or


R101 and R102, R102 and R103, R103 and R104, R104 and R105 or R105 and R106 together form an aromatic ring composed of 6 to 10 carbon atoms which is optionally substituted with one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3;


R107, R108, R109 and R110 are each independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl and optionally substituted C6-20 aryloxy wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3, or


R107 and R108 together with the carbon atom to which they are bound and/or R109 and R110 together with the carbon atom to which they are bound form an optionally substituted C3-20 cycloalkyl or an optionally substituted O2-20 cycloalkoxy, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3, or


one of R107 and R108 and one of R109 and R110 together form an optionally substituted C5-10 cycloalkyl or an optionally substituted C5-10 cycloalkoxy, wherein the substituents are independently selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic O3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3,


provided R107 and R108 and/or R109 and R110 are not the same,


¤ represents an optically active carbon atom;


R111 is an optionally substituted straight, branched or cyclic C1-10 alkyl, an optionally substituted C6-10 aryl or —NR112R113 wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, -Hal, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3;


R112 and R113 are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C1-10 alkyl and optionally substituted C6-10 aryl, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl groups, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3, or


R112 and R113 together with the nitrogen atom to which they are bound form an optionally substituted C2-10 cycloalkyl-amino group, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3;


R200 and R201 are independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl, optionally substituted C6-20 aryloxy, —OH, —CN, —NR300R301, —COOR300, —CONR300R301 and —CF3, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3;


R300 and R301 are independently selected from the group consisting of hydrogen, optionally substituted straight C1-20 alkyl, branched or cyclic C3-20 alkyl, optionally substituted straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, optionally substituted C6-20 aryl, optionally substituted C6-20 aryloxy, —OH, —CN and —CF3, wherein the substituents are selected from the group consisting of one or more straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN and —CF3;


and


Hal′ is a halogen.


The carbon atoms to which R107 and R108 and/or R109 and R110 are bound are asymmetric when R107 and R108 and/or R109 and R110 are not the same groups. In one embodiment, R107 and R108 are not the same groups. In another embodiment, R108 and R109 are not the same groups. The asymmetric carbon atoms are represented by the symbol “n”. The complex of formula (IX) therefore is chiral (optically active) and the transfer hydrogenation process of the invention is an asymmetric transfer hydrogenation process.


In one embodiment, R101, R102, R103, R104, R105 and R106 are each independently selected from the group consisting of hydrogen, straight C1-20 alkyl, branched or cyclic C3-20 alkyl, straight C1-20 alkoxy, branched or cyclic C3-20 alkoxy, C6-20 aryl, C6-20 aryloxy, —OH, —CN, —NR200R201, —COOH, COOR200, —CONH2, —CONR200R201 and —CF3. In another embodiment, R101, R102, R103, R104, R105 and R106 are each independently selected from the group consisting of hydrogen, straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH. For example, R101, R102, R103, R104, R105 and R106 may each independently selected from the group consisting of hydrogen, straight-chain C1-10 alkyl and branched-chain C1-10 alkyl. R101, R102, R103, R104, R105 and R106 may be each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. For example, R101, R102, R103, R104, R105 and R106 may each be hydrogen i.e. the aryl ring coordinated to the Ru atom is benzene. In another embodiment, R102 may be methyl, R105 may be i-propyl, and R101, R103, R104 and R106 may each be hydrogen i.e. the aryl ring coordinated to the Ru atom is p-cymene. In another embodiment, R101, R103 and R105 are each methyl, and R102, R104 and R106 are each hydrogen i.e. the aryl ring coordinated to the Ru atom is mesitylene.


In yet another embodiment, R107, R108, R109 and R110 are each independently selected from the group consisting of hydrogen, optionally substituted straight- or branched-chain C1-10 alkyl, optionally substituted straight- or branched-chain C1-10 alkoxy, optionally substituted C6-10 aryl and optionally substituted C6-10 aryloxy wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


The groups R107, R108, R109 and R110 may be each independently selected from the group consisting of hydrogen and optionally substituted C6-10 aryl. For example, R107, R108, R109 and R110 may each be independently selected from the group consisting of hydrogen or phenyl. In one embodiment, one of R107 and R108 is phenyl and the other of R107 and R108 is hydrogen. In one embodiment, one of R109 and R110 is phenyl and the other of R109 and R110 is hydrogen.


In another embodiment, R107 and R108 together with the carbon atom to which they are bound and/or R109 and R110 together with the carbon atom to which they are bound form an optionally substituted C5-10 cycloalkyl or an optionally substituted C5-10 cycloalkoxy, wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


In yet another embodiment, one of R107 and R108 and one of R1109 and R110 together form an optionally substituted C5-10 cycloalkyl or an optionally substituted C5-10 cycloalkoxy, wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


In yet another embodiment, R111 is an optionally substituted straight, branched or cyclic C1-10 alkyl, an optionally substituted C6-10 aryl wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, -Hal, —OH, —CN, —NR200R201, —COOR200, —CONR200R201 and —CF3. In another embodiment, the substituents are selected from the group consisting of one or more straight, branched or cyclic C1-10 alkyl, straight, branched or cyclic C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy, -Hal, or —CF3. In another embodiment, R111 is a straight- or branched-chain C1-10 alkyl or a C6-10 aryl optionally substituted with one or more straight- or branched-chain C1-10 alkyl groups. Examples of R111 include, but are not limited to, p-tolyl, methyl, p-methoxyphenyl, p-chlorophenyl, trifluoromethyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, pentamethylphenyl and 2-naphthyl. R111 may be methyl or a tolyl group.


In another embodiment, R111 is —NR112R113 wherein R112 and R113 are independently selected from the group consisting of straight- or branched-chain C1-10 alkyl and C6-10 aryl optionally substituted with one or more straight- or branched-chain C1-10 alkyl groups. —NR112R113 may be —NMe2.


In yet another embodiment, R112 and R113 together with the nitrogen atom to which they are bound form an optionally substituted C5-10 cycloalkyl-amino group wherein the substituents are selected from the group consisting of straight- or branched-chain C1-10 alkyl, straight- or branched-chain C1-10 alkoxy, C6-10 aryl, C6-10 aryloxy and —OH.


Hal′ may be chlorine, bromine or iodine, for example, chlorine.


The metal complexes of formula (IX) may be selected from the group consisting of:




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The preparation of the metal complexes of formula (IX) is given in EP0916637B (to Takasago International Corporation and others).


Asymmetric Transfer Hydrogenation Reaction


Transfer hydrogenation is the addition of hydrogen to a molecule from a source other than hydrogen gas. An asymmetric transfer hydrogen reaction reduces a prochiral molecule (such as the metallocenyl compound of formula (V)) to an optically active product (such as the metallocenyl compound of formula (IV)).


In the present invention, the ATH reaction is carried out in an aqueous solvent in the presence of an ATH catalyst and activated formic acid.


The ATH catalyst and activated formic acid are combined in the aqueous solvent. In one embodiment, the aqueous solvent is water. Water may be introduced to the ATH reaction in its own right or as part of the activated formic acid mixture. In another embodiment, the aqueous solvent is water and at least one water-miscible solvent. Any suitable water-miscible solvent may be used which is capable of dissolving the ATH catalyst and activated formic acid, and does not adversely affect either the chemical conversion of compound (V) to compound (IV) and/or enantiomeric purity of compound (IV)). When the ATH catalyst is a complex of formula (VI), the aqueous solvent may be selected from the group consisting of water, amide solvents, cyclic ether solvents and ester solvents. Examples of amide solvents include but are not limited to dimethylformamide (DMF) and dimethylacetamide (DMA). Examples of cyclic ether solvents include but are not limited to tetrahydrofuran (THF) and 1,4-dioxane. Mixtures of water and water-miscible solvents include but are not limited to water and THF, water and 1,4-dioxane, water and DMF, or water and DMA. Certain ester solvents are water-soluble in small quantities. These ester solvents include but are not limited to ethyl acetate and propyl acetate (i- or n-).


The ATH reaction may be monophasic (i.e. homogeneous) or biphasic. The ATH reaction may be biphasic if the aqueous phase contains measurable amounts of organic solvents dissolved.


The ATH reaction may be carried out at a temperature greater than 60° C. and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the aqueous solvents used. In one embodiment, the ATH reaction is carried out at one or more temperatures in the range of >about 60° C. to about ≤about 100° C. In some embodiments, the hydrogenation is carried out at one or more temperatures ≥about 65° C. In some embodiments, the hydrogenation is carried out at one or more temperatures ≥about 70° C. In some embodiments, the hydrogenation is carried out at one or more temperatures ≥about 75° C. In some embodiments, the hydrogenation is carried out at one or more temperatures ≤about 95° C. In some embodiments, the hydrogenation is carried out at one or more temperatures ≤about 90° C. In some embodiments, the hydrogenation is carried out at one or more temperatures ≤about 85° C. In one preferred embodiment, the hydrogenation is carried out at one or more temperatures in the range of ≥about 77° C. to about ≤85° C., such as about 80° C.


The hydrogen donor in the ATH reaction is activated formic acid. “Activated formic acid” refers to a mixture of formic acid, a tertiary amine base and optionally water which forms a liquid reducing agent for an ATH reaction. When water is added to the ATH reaction as an individual component of the reaction, the activated formic acid may be a mixture of formic acid and a tertiary organic base. Alternatively, or in addition, the activated formic acid may be a mixture of formic acid, tertiary amine base and water. In this instance, it may not be necessary to add further water to the reaction mixture as an individual component. The tertiary amine base includes but is not limited to NR′R″R′″ wherein R′, R″, and R′″ are independently substituted or unsubstituted C1-20-alkyl groups. Tertiary amines include but are not limited to trimethylamine and triethylamine, for example, triethylamine. In one embodiment, the activated formic acid is a mixture of concentrated formic acid, triethylamine and water. The activated formic acid may be deoxygenated before use e.g. by bubbling an inert gas, such as argon or nitrogen, through the liquid.


The molar ratio of formic acid:tertiary amine may be in the range of about 1:1 to about 1.5:1 moles i.e. the formic acid may be in slight excess. In one embodiment, the molar ratio of formic acid:tertiary amine is about 1:1 moles. In another embodiment, the molar ratio of formic acid:tertiary amine is about 1.1:1 moles. In yet another embodiment, the molar ratio of formic acid:tertiary amine is about 1.2:1 moles. In yet another embodiment, the molar ratio of formic acid:tertiary amine is about 1.4:1 moles.


When the formic acid:tertiary amine liquid is diluted with water, the concentration of formic acid:tertiary amine may be in the range of 1 M:1 M to about 1.2 M:1 M. In one embodiment, the molar ratio is about 1 M:1 M. In another embodiment, the molar ratio is about 1.1 M:1M. In yet another embodiment, the molar ratio is about 1.2 M:1M.


When the molar ratio of formic acid:tertiary amine in water is in the range of about 1 M:1 M to about 1.2 M:1 M, the pH of the liquid will in the range of about 4 to about 10. It has been found that slight variations in the concentration of formic acid:tertiary amine results in a major change in pH. In one embodiment, the pH of formic acid:triethylamine 1M:1M in water is about pH 6.5.


In certain embodiments, the activated formic acid is not an azeotropic mixture of formic acid and triethylamine i.e. formic acid:triethylamine in a ratio of 5 M:2 M.


The molar ratio of activated formic acid per carbonyl group to be reduced (i.e. —CORa or —CORd) may be in the range of about 1:1 to about 1.5:1 moles i.e. the activated formic acid may be in slight excess.


In one embodiment, the molar ratio of activated formic acid per carbonyl group to be reduced is about 1:1 moles. In another embodiment, the molar ratio of activated formic acid per carbonyl group to be reduced is about 1.1:1 moles. In yet another embodiment, the molar ratio of activated formic acid per carbonyl group to be reduced is about 1.2:1 moles. In yet another embodiment, the molar ratio of activated formic acid per carbonyl group to be reduced is about 1.4:1 moles.


The substrate/catalyst (S/C) molar ratio of the metallocenyl compound of formula (V) to ATH catalyst may in the range of about 100:1 to about 2000:1. In some embodiments, the S/C molar ratio may be ≥about 150:1. In some embodiments, the S/C molar ratio may be ≥about 200:1. In some embodiments, the S/C molar ratio may be ≥about 250:1. In some embodiments, the S/C molar ratio may be ≥about 300:1. In some embodiments, the S/C molar ratio may be ≥about 350:1. In some embodiments, the S/C molar ratio may be ≥about 400:1. In some embodiments, the S/C molar ratio may be ≥about 450:1. In some embodiments, the S/C molar ratio may be ≥about 500:1. In some embodiments, the S/C molar ratio may be ≥about 550:1. In some embodiments, the S/C molar ratio may be ≥about 600:1. In some embodiments, the S/C molar ratio may be ≤about 2000:1. In some embodiments, the S/C molar ratio may be ≤about 1750:1. In some embodiments, the S/C molar ratio may be ≤about 1500:1. In some embodiments, the S/C molar ratio may be ≤about 1250:1. In some embodiments, the S/C molar ratio may be ≤about 1000:1. In some embodiments, the S/C molar ratio may be ≤about 750:1. In some embodiments, the S/C molar ratio may be ≤about 700:1. In one embodiment, the S/C molar ratio may be in the range of >600:1 to ≤about 700:1, such as about 620:1 or 645:1. It is believed that the synthesis of compound (IV) (e.g. chiral ferrocenyl ethanol) has not been previously described at S/C molar ratios of >100:1 or higher, in particular at high S/C molar ratios of ≥600:1. The ability to perform the ATH reaction at high S/C molar ratios permits the development of a commercially-viable industrial process for the preparation of compounds (IV).


The ATH reaction may be conducted under an inert atmosphere, such as nitrogen or argon. In this instance, it is desirable for the reaction to be run in an open system, e.g. using a bubbler, to release the CO2 by-product. The inert gas purges the CO2 out of the reaction.


The ATH reaction is carried out for a period of time until it is determined that the reaction is complete. Completion of the reaction may be determined by in-process analysis e.g. by taking a sample of the reaction mixture and analysing it by HPLC to determine conversion and enantiomeric excess. In certain embodiments, the conversion of compound (V) to compound (IV) is >about 50%. In certain embodiments, the conversion is ≥about 60%. In certain embodiments, the conversion is ≥about 70%. In certain embodiments, the conversion is ≥about 80%. In certain embodiments, the conversion is ≥about 85%. In certain embodiments, the conversion is ≥about 90%. In certain embodiments, the conversion is ≥about 95%. In certain embodiments, the conversion is ≥about 97%. In certain embodiments, the conversion is substantially 100%. Typically, the reaction is complete within about 48 hours. The enantiomeric excess of compound (B) may be ≥90% ee, ≥91% ee, ≥92% ee, ≥93% ee, ≥94% ee, ≥95% ee, ≥96% ee, ≥97% ee, ≥98% ee, ≥99% ee or higher.


The reagents may be added in any suitable order. In this respect, a reactor may be charged with the compound (V), followed by the activated formic acid and ATH catalyst. The activated formic acid may be added in one portion. Alternatively, the activated formic acid may be added slowly and continuously over a period of time (e.g. using a syringe pump) and/or portionwise during the course of the reaction. As the ATH reaction produces 1 mole of CO2 per 1 mole of reduced carbonyl, a significant amount of gas is released. As such, the slow/continuous and/or portionwise addition of the activated formic acid helps control the build-up of gas by limiting the amount of reducing agent present in the reactor vessel. The ATH catalyst may be added to the reaction mixture as a solid or as a solution in one of the water-miscible solvent described above (e.g. THF). The reaction mixture may be stirred for a suitable period of time and at a suitable temperature.


On completion of the reaction, the reaction vessel may be cooled to ambient temperature and optionally purged with one or more inert gas/vacuum cycles (e.g. one, two, three, four or five cycles) to remove excess carbon dioxide. The reaction mixture may be treated with an ester solvent (such as ethyl acetate), washed one or more times (e.g. one, two, three or more times) with water or brine, dried (e.g. over magnesium sulfate), and filtered (e.g. through a pad of silica and magnesium sulfate). The product, the compound (IV), may be obtained by the removal of the organic solvents, such as by increasing the temperature or reducing the pressure using distillation or stripping methods well known in the art.


The compound (IV) may be further treated with a hot alkane solvent (such as pentane, hexane or heptane) which causes the compound (IV) to precipitate or crystallise. The solid compound (IV) may then be washed with further alkane solvent and dried. Drying may be performed using known methods, for example, at temperatures in the range of about 10-60° C., such as 20-40° C., under 0.1-30 mbar for about 1 hour to about 5 days.


The isolated yield of compound (IV) may be ≥70%, ≥71%, ≥72%, ≥73%, ≥74%, ≥75% or higher. In certain embodiments, the isolated yield of compound (B) is ≥76%. In certain embodiments, the isolated yield of compound (IV) is ≥80%. In certain embodiments, the isolated yield of compound (IV) is ≥83%. In certain embodiments, the isolated yield of compound (IV) is ≥85%. In certain embodiments, the isolated yield of compound (IV) is ≥90%.


The compounds (IV) prepared by the process of the present invention are pure. In certain embodiments, the chemical purity of the compound (IV) is ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95% or higher. In certain embodiments, the chemical purity of the compound (IV) is ≥95%. In certain embodiments, the chemical purity of the compound (IV) is ≥96%. In certain embodiments, the chemical purity of the compound (IV) is ≥97%. In certain embodiments, the chemical purity of the compound (IV) is ≥98%. In certain embodiments, the chemical purity of the compound (IV) is ≥99%.


The enantiomeric excess of isolated compound (IV) may be ≥90% ee, ≥91% ee, ≥92% ee, ≥93% ee, ≥94% ee, ≥95% ee, ≥96% ee, ≥97% ee, ≥98% ee, ≥99% ee or higher.


Compounds of formula (V) are obtainable for example by the method described by Gokel et al (J. Chem. Ed. 1972, 49, 4, 294).


Conversion of the Metallocenyl Alcohol of Formula (IV) to Ligands Useful in Asymmetric Catalysis


The metallocenyl alcohols of formulae (IV) are key intermediates in the preparation of various chiral metallocenyl ligands by methods known in the art (see, for example, Schaarschmidt and Lang, Organometallics, 2013, 32, 5668-5704).


For example, the metallocenyl alcohol of formula (IV) may transformed to Bophoz ligands or Josiphos ligands. In this instance, M is Fe, and m is 0, 1, 2 or 3 (but not 4), and at least one of the carbon atoms ortho to the —RaC*H(OH) group must be unsubstituted (i.e. —H). At least one of carbon atoms ortho to the —RaC*H(OH) group must be unsubstituted (i.e. —H) in order for a phosphorus-containing group to be chemically incorporated into the ferrocenyl compound by methods known in the art.


When the ligand is a Josiphos ligand, the ligand may be of formula (La) or (Lb):




embedded image


wherein,


Rw and Rx are independently selected from the group consisting of unsubstituted C1-20-alkyl, substituted C1-20-alkyl, unsubstituted C3-20-cycloalkyl, substituted C3-20-cycloalkyl, unsubstituted C1-20-alkoxy, substituted C1-20-alkoxy, unsubstituted C5-20-aryl, substituted C5-20-aryl, unsubstituted C1-20-heteroalkyl, substituted C1-20-heteroalkyl, unsubstituted C2-20-heterocycloalkyl, substituted C2-20-heterocycloalkyl, unsubstituted C4-20-heteroaryl and substituted C4-20-heteroaryl;


Ry and Rz are independently selected from the group consisting of unsubstituted C1-20-alkyl, substituted C1-20-alkyl, unsubstituted C3-20-cycloalkyl, substituted C3-20-cycloalkyl, unsubstituted C1-20-alkoxy, substituted C1-20-alkoxy, unsubstituted C5-20-aryl, substituted C5-20-aryl, unsubstituted C1-20-heteroalkyl, substituted C1-20-heteroalkyl, unsubstituted C2-20-heterocycloalkyl, substituted C2-20-heterocycloalkyl, unsubstituted C4-20-heteroaryl and substituted C4-20-heteroaryl; and


Ra is as defined above.


In one embodiment, Ra is selected from the group consisting of unsubstituted C1-20-alkyl and substituted C1-20-alkyl. In one embodiment, Ra is an unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl. Preferably, Ra is methyl.


In one embodiment, Rw and Rx are independently selected from the group consisting of substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, aryl groups such as phenyl, naphthyl or anthracyl and heteroaryl groups such as furyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (—F, —Cl, —Br or —I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). The heteroaryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino or tri(halo)methyl (e.g. F3C—). Preferably, Rw and Rx are the same and are selected from the group consisting of tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl, 3,5-xylyl, 2-methylphenyl and 2-furyl, most preferably tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl and 2-furyl.


In one embodiment, Ry and Rz are independently selected from the group consisting of substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, aryl groups such as phenyl, naphthyl or anthracyl and heteroaryl groups such as furyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (—F, —Cl, —Br or —I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). The heteroaryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino or tri(halo)methyl (e.g. F3C—). Preferably, Ry and Rz are the same and are selected from the group consisting of tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl, 3,5-xylyl, 2-methylphenyl and 2-furyl, most preferably tert-butyl, cyclohexyl, phenyl, 3,5-xylyl and 2-methylphenyl.


In one embodiment, the ligand of formula (La) is selected from the group consisting of:

  • (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine,
  • (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (R)-1-[(S)-2-(di-3,5-bis(trifluoromethyl)phenylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (R)-1-[(S)-2-(di-4-methoxy-3,5-dimethylphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (R)-1-[(S)-2-(di-3,5-bis(trifluoromethyl)phenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (R)-1-[(S)-2-(di-(4-trifluoromethyl)phenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (R)-1-[(S)-2-(di-4-methoxy-3,5-dimethylphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (R)-1-[(S)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (R)-1-[(S)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (R)-1-[(S)-2-(di-1-naphthylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (R)-1-[(S)-2-(di-1-naphthylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (R)-1-[(S)-2-(di-4-methoxy-3,5-dimethylphenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (R)-1-[(S)-2-(di-4-methoxy-3,5-dimethylphenylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine,
  • (R)-1-[(S)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine,
  • (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine,
  • (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine,
  • (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldiphenylphosphine,
  • (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi(adamantyl)phosphine, and
  • (R)-1-[(S)-2-(di(adamantyl)phosphino)ferrocenyl]ethyldiphenylphosphine.


In one embodiment, the ligand of formula (Lb) is selected from the group consisting of:

  • (S)-1-[(R)-2-di(phenylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (S)-1-[(R)-2-di(phenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (S)-1-[(R)-2-di(cyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (S)-1-[(R)-2-di(cyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine,
  • (S)-1-[(R)-2-di(phenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (S)-1-[(R)-2-di-(3,5-bis(trifluoromethyl)phenylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (S)-1-[(R)-2-di-(4-methoxy-3,5-dimethyl)phenylphosphino)ferrocenyl]ethyldicyclohexylphosphine,
  • (S)-1-[(R)-2-di-(3,5-bis(trifluoromethyl)phenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (S)-1-[(R)-2-di(cyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (S)-1-[(R)-2-di-((4-trifluoromethyl)phenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (S)-1-[(R)-2-di-(4-methoxy-3,5-dimethyl)phenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (S)-1-[(R)-2-di-(2-furyl)phosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (S)-1-[(R)-2-di-(2-furyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (S)-1-[(R)-2-di(1-naphthyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine,
  • (S)-1-[(R)-2-di(1-naphthyl)phosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (S)-1-[(R)-2-di-(4-methoxy-3,5-dimethyl)phenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine,
  • (S)-1-[(R)-2-di-(4-methoxy-3,5-dimethyl)phenylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine,
  • (S)-1-[(R)-2-di-(2-furyl)phosphinoferrocenyl]ethyldi-(2-methylphenyl)phosphine,
  • (S)-1-[(R)-2-di(tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine,
  • (S)-1-[(R)-2-di(tert-butylphosphino)ferrocenyl]ethyldi-(2-methylphenyl)phosphine,
  • (S)-1-[(R)-2-diphenylphosphinoferrocenyl]ethyldiphenylphosphine,
  • (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi(adamantyl)phosphine, and
  • (S)-1-[(R)-2-(di(adamantyl)phosphino)ferrocenyl]ethyldiphenylphosphine.


When the ligand is a Bophoz ligand, the ligand may be of formula (Lc) or (Ld):




embedded image


wherein,


Rw and Rx are independently selected from the group consisting of unsubstituted C1-20-alkyl, substituted C1-20-alkyl, unsubstituted C3-20-cycloalkyl, substituted C3-20-cycloalkyl, unsubstituted C1-20-alkoxy, substituted C1-20-alkoxy, unsubstituted C5-20-aryl, substituted C5-20-aryl, unsubstituted C1-20-heteroalkyl, substituted C1-20-heteroalkyl, unsubstituted C2-20-heterocycloalkyl, substituted C2-20-heterocycloalkyl, unsubstituted C4-20-heteroaryl and substituted C4-20-heteroaryl;


Ry is selected from the group consisting of unsubstituted C1-20-alkyl, substituted C1-20-alkyl, unsubstituted C3-20-cycloalkyl, substituted C3-20-cycloalkyl, unsubstituted C1-20-alkoxy, substituted C1-20-alkoxy, unsubstituted C5-20-aryl, substituted C5-20-aryl, unsubstituted C1-20-heteroalkyl, substituted C1-20-heteroalkyl, unsubstituted C2-20-heterocycloalkyl, substituted C2-20-heterocycloalkyl, unsubstituted C4-20-heteroaryl and substituted C4-20-heteroaryl;


Rz and Rz′ are independently selected from the group consisting of unsubstituted C1-20-alkyl, substituted C1-20-alkyl, unsubstituted C3-20-cycloalkyl, substituted C3-20-cycloalkyl, unsubstituted C1-20-alkoxy, substituted C1-20-alkoxy, unsubstituted C5-20-aryl, substituted C5-20-aryl, unsubstituted C1-20-heteroalkyl, substituted C1-20-heteroalkyl, unsubstituted C2-20-heterocycloalkyl, substituted C2-20-heterocycloalkyl, unsubstituted C4-20-heteroaryl and substituted C4-20-heteroaryl; and


Ra is as defined above.


In one embodiment, Ra is selected from the group consisting of unsubstituted C1-20-alkyl and substituted C1-20-alkyl. In one embodiment, Ra is an unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl. Preferably, Ra is methyl.


In one embodiment, Rw and Rx are independently selected from the group consisting of substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, aryl groups such as phenyl, naphthyl or anthracyl and heteroaryl groups such as furyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (—F, —Cl, —Br or —I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). The heteroaryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino or tri(halo)methyl (e.g. F3C—). Preferably, Rw and Rx are the same and are selected from the group consisting of tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl, 3,5-xylyl, 2-methylphenyl and 2-furyl, most preferably tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl and 2-furyl.


In one embodiment, Ry is selected from the group consisting of substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, aryl groups such as phenyl, naphthyl or anthracyl and heteroaryl groups such as furyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (—F, —Cl, —Br or —I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). The heteroaryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino or tri(halo)methyl (e.g. F3C—). Ry may be selected from the group consisting of methyl, tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl, 3,5-xylyl, 2-methylphenyl and 2-furyl, most preferably, methyl, tert-butyl, cyclohexyl, phenyl, 3,5-xylyl and 2-methylphenyl.


In one embodiment, Rz and Rz′ are independently selected from the group consisting of substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, aryl groups such as phenyl, naphthyl or anthracyl and heteroaryl groups such as furyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (—F, —Cl, —Br or —I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C—). The heteroaryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (—F, —Cl, —Br or —I), straight- or branched-chain C1-C10-alkyl (e.g. methyl), C1-C10 alkoxy, straight- or branched-chain C1-C10-(dialkyl)amino or tri(halo)methyl (e.g. F3C—). Preferably, Rz and Rz′ are the same and are selected from the group consisting of tert-butyl, cyclohexyl, phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-methoxy-3,5-dimethylphenyl, 4-trifluoromethylphenyl, 1-naphthyl, 3,5-xylyl, 2-methylphenyl and 2-furyl, most preferably tert-butyl, cyclohexyl, phenyl, 3,5-xylyl and 2-methylphenyl.


In one embodiment, the ligand (Lc) may be (R)-Me-Bophoz.


In one embodiment, the ligand (Ld) may be (S)-Me-Bophoz.


The metallocenyl alcohol of formula (IV) where j=1 may be transformed into optically active metallocenyl ligands such as those described in U.S. Pat. No. 5,760,264 (to Lonza, AG). In this instance, M is Fe, Ru or Ni, m is 0, 1, 2 or 3 (but not 4) and n is 0, 1, 2, or 3 (but not 4), and at least one of the carbon atoms ortho to each of the —RaC*H(OH) and —RdC*H(OH) groups must be unsubstituted (i.e. —H). At least one of carbon atoms ortho to the —RaC*H(OH) and —RdC*H(OH) groups must be unsubstituted (i.e. —H) in order for phosphorus-containing groups to be chemically incorporated into the metallocenyl compound.


Other Preferences


Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.


Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.


“and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example “A and/or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.


Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.


Certain aspects and embodiments of the invention will now be described by the way of the following non-limiting Examples.


EXAMPLES
Abbreviations















DCM
dichloromethane


DMF
dimethylformamide


Et3N
triethylamine


IPA
isopropanol


THF
tetrahydrofuran


MTBE
methyl t-butyl ether


DEA
diethylamine


DMAP
dimethylaminopyridine


En
ethylenediamine


eq.
equivalent


EtOAc
ethyl acetate


HOOH
formic acid


H
hour


L
Litre


MEK
2-butanone


mL
millilitre


RT
Room Temperature





Ts = tosylate


embedded image







Ms = mesylate


embedded image







[RuCl (R,R)-TsDPEN p-cymene]


embedded image







[RuCl (R,R)-TsDPEN p-cymene]


embedded image











General


All reactions were carried out under argon or nitrogen atmosphere.


NMR measurements were recorded on Bruker AC 200 and Bruker Advance 400 spectrometers and the chemical shifts, in ppm, are relative to TMS for 1H.


HPLC Chiral Method for Determining the Optical Purity of Metallocenyl Compound B:


AD-H column, 80:20 Heptane:EtOH+0.1% DEA, Flow: 1 ml/min, temp=25° C., detection at 254 nm. The peaks of the N,N-dimethyl-α-ferrocenylethylamine (B) enantiomers are baseline separated: (S)-enantiomer 4.4 min, (R)-enentiomer 3.8 min


HPLC Chiral Method for Metallocenyl Compounds of Formula (IV) and (V):


AS-H column, IPA/n-Heptane 30/70 with addition of small amounts of trifluoroacetic acid as modifier, Flow: 1 mL/min, detection at 205 nm. The peaks of the 1-Ferrocenyl Ethanol enantiomers are baseline separated: (S)-enantiomer 4.8 min, (R)-enentiomer 6.7 min.


The reaction sample was diluted with EtOAc to a concentration of 5 mg/1 mL. 1 mL of the resulting solution was further diluted with 4 mL of n-heptane and 2-5 μL of this solution was injected.


XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively. All data were processed within Diffrac Plus EVA using the Enhance background model; threshold=0.25, and the curvature varied to model baseline features sufficiently.


Samples were run under ambient conditions as flat plate specimens. The material was gently ground using pestle and mortar. The sample was prepared on a polished, zero-background (510) silicon wafer by gently packing the material into a cut cavity. The sample was rotated in its own plane.


The details of the standard collection method are:

    • Angular range: 4.5 to 42.0° 2θ
    • Step size: 0.01° 2θ
    • Collection time: 3.0 s/step (total collection time: 234 min)


Example 1

Synthesis of Enantioenriched (R)—N,N-Dimethyl-α-Ferrocenylethyl Ammonium Dihydrogenphosphate (A*(H2PO4)) Starting from Enantioenriched Ferrocenylethanol (D) Using NaOAc.3H2O as a Base




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(R)-Ferrocenylethanol (D, 8.06 g, 35.06 mmol, 1 eq., 97% ee) and NaOAc-3H2O (4.77 g, 35.06 mmol, 1 eq.) were placed into a 250 mL round bottom flask equipped with magnetic stirrer and heptane (34 mL) was added. Ac2O (6.53 mL, 70.12 mmol, 2 eq.) was added in one portion at room temperature.


The mixture was stirred at 40° C. for 4 h.


The reaction mixture was cooled down to 0° C. and an aqueous solution of Me2NH (40% aq., 22.08 mL, 5 eq.) was added dropwise followed by IPA (7 mL). The reaction was stirred overnight at 50° C. The organic phase was separated from the aqueous layer, concentrated by distillation and dried at 40° C./10 mbar.


The residue was dissolved in MeOH (30 mL) and H3PO4 (85% wt) (1.91 mL, 28.04 mmol, 0.8 eq.) was added dropwise at 0° C. The solution was stirred at room temperature for 1 h, concentrated in vacuum and acetone was added as anti-solvent to give a yellow-orange crystalline powder (10.6 g, 86% yield) that was collected by filtration.



1H-NMR (A*(H2PO4)): 1H NMR (400 MHz, CD3OD): δ=1.81 (3H, d, J=6.72 Hz), 2.59 (6H, s), 4.26 (5H, s), 4.32-4.58 (5H, m).









TABLE







XRPD peak listing for A*(H2PO4).










Angle (° 2θ)
Intensity (%)














 8.9
2.9



 9.2
5.3



13.1
3.8



13.8
4.9









14.0
(14.0)
15.4


14.2
(14.25)
23.7










14.4
8.0



14.9
10.3









15.3
(15.3)
30.8










16.4
10.0



17.0
6.3



17.5
12.3









17.9
(17.95)
100.0










18.2
10.4



18.4
7.0









18.7
(18.7)
14.8










19.0
9.6



19.3
8.8



20.4
4.2



21.5
4.3









22.0
(22.04)
13.9










22.5
5.9



22.7
7.5



22.8
6.3



23.8
8.0



24.0
8.3



24.6
5.1



25.0
6.1



25.2
8.3



28.2
4.8







Data in brackets are from a calculation using the single X-ray structure analysis data.






A single X-ray structure analysis confirms the identity of A(H2PO4). The calculated XPRD peak list is in high agreement with the measured XPRD peaklist reported above.


Thermal analysis (DSC, TGA) give an onset of decomposition of 125° C.


Recovery of the Free N, N-Dimethyl-α-Ferrocenylethylamine (B, Ugi Amine). Enantiomeric Excess Determination


Phosphate salt A*(H2PO4) (8.70 g, 24.5 mmol) was placed into a 50 mL round bottom flask and toluene (15 mL) was added. Then, NaOH (2M) was added to the suspension until pH 10-11 was reached. The organic phase was separated from the aqueous layer. After distillation of solvent compound N,N-dimethyl-α-ferrocenylethylamine (B) was obtained as a yellow-orange liquid (6.11 g, 97% yield). (R)-B: 97.2% ee by HPLC.


Example 2

Synthesis of Enantioenriched (R)—N,N-Dimethyl-α-Ferrocenylethyl Ammonium Dihydrogenphosphate (A*(H2PO4)) Starting from Enantioenriched Ferrocenylethanol (D) Using NaOAc-3H2O as a Base Followed by Purification


(R)—N,N-dimethyl-α-ferrocenylethyl ammonium dihydrogenphosphate (A*(H2PO4)) was obtained following the procedure of Example 1. The crude N,N-dimethyl-α-ferrocenylethyl ammonium dihydrogenphosphate (A*(H2PO4)) was slurried in DCM (50 mL). The slurry was stirred at room temperature for 30 min and then filtered to obtain compound A*(H2PO4) (8.58 g) in 68% yield.


After isolation of free N,N-dimethyl-α-ferrocenylethylamine (B, Ugi amine) following the procedure of example 1 a yellow-orange oil was obtained. Assayed as (R)-B of 97.2% ee by HPLC.


Example 3

Synthesis of Enantioenriched (R)—N,N-Dimethyl-α-Ferrocenylethyl Ammonium Dihydrogenphosphate (A*(H2PO4)) Starting from Enantioenriched Ferrocenylethanol (D) Using NaOAc Anhydrous


(R)-Ferrocenylethanol (D, 1.21 g, 5.26 mmol, 1 eq., 97% ee) and NaOAc (432 mg, 5.26 mmol, 1 eq.) were placed into a 100 mL round bottom flask equipped with magnetic stirrer and heptane (5 mL) was added followed by the addition of Ac2O (0.99 mL, 10.52 mmol, 2 eq.) at room temperature. The mixture was stirred at 40° C. for 4 h (a small sample from the reaction mixture was taken and analysed by 1H-NMR showing only 15% conversion to product). Then, H2O (0.30 mL, 16 mmol) was added and the reaction was stirred at 40° C. for 2 h more (1H-NMR data shows 85% mol product).


The reaction mixture was cooled down to 0° C. and an aqueous solution of Me2NH (40% aq., 3.31 mL, 5 eq.) was added dropwise followed by IPA (1 mL). The reaction was stirred overnight at 50° C. The organic phase was separated from the aqueous layer and distilled.


The residue was dissolved in MeOH (5 mL) and H3PO4 (85% wt) (0.25 mL, 4.33 mmol, 0.7 eq.) was added dropwise at 0° C. The solution was stirred at room temperature for 1 h, the solvent was distilled and the residue washed with acetone affording 1.36 g (73% yield) of the corresponding salt A*(H2PO4). After isolation of the N,N-dimethyl-α-ferrocenylethylamine (B) following the procedure of Example 1 a yellow-orange oil was obtained. (R)-B: 97.1% ee by HPLC.


Example 4

Synthesis of enantioenriched di-(N,N-dimethyl-α-ferrocenylethylammonium) monohydrogenphosphate ((R)-A*2(HPO4))




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(R)—N,N-dimethyl-α-ferrocenylethyl amine (B, 7.20 g, 28 mmol, 97% ee) was dissolved in MeOH (25 mL) and H3PO4 (85% wt) (0.95 mL, 14 mmol) was added dropwise at 0° C. The solution was stirred at room temperature for 1 h, concentrated in vacuum and salt (R)-A*2(HPO4) was precipitated by adding acetone as anti-solvent affording a yellow-orange crystalline powder (5.90 g, 70% yield) that was collected by filtration.



1H-NMR ((R)-A*2(HPO4)): 1H NMR (400 MHz CD3OD): δ 1.66 (3H, d, J=6.88 Hz), 2.35 (6H, s), 4.07 (1H, q, J=6.84 Hz), 4.19 (5H, s), 4.25-4.38 (4H, m).









TABLE







XRPD peak listing for ((R)-A*2(HPO4)).










Angle (° 2θ)
Intensity (%)














5.6
3.0



6.0
4.0



8.9
2.5



9.2
5.1



11.9
3.4



14.0
12.0



14.2
16.3



14.4
5.8



14.9
9.5



15.3
27.2



16.4
9.8



17.0
7.6



17.5
14.0



17.9
100.0



17.9
76.6



18.2
13.0



18.4
5.7



18.7
10.3



19.0
9.8



19.3
15.5



22.0
24.5



22.5
8.8



22.7
5.4



22.8
5.2



23.7
5.5



24.0
25.4



25.0
11.9



25.2
9.1



28.1
4.1



32.6
10.7










Thermal analysis (DSC, TGA) give a melting point of 173° C. followed by decomposition at higher temperatures


Example 5 (Comparative)

Synthesis of Racemic Di-(N,N-Dimethyl-α-Ferrocenylethylammonium) Monohydrogenphosphate (Rac-A2(HPO4))


rac-N,N-dimethyl-α-ferrocenylethyl amine (rac-B, 4.69 g, 18 mmol) was dissolved in MeOH (18 mL) and H3PO4 (85% wt) (0.61 mL, 9 mmol) was added dropwise at 0° C. The solution was stirred at room temperature for 1 h. In contrast to the salt obtained from 97% ee amine (R)-B, this time some solid precipitated and it was collected by filtration in vacuum (697 mg of a yellow-orange crystalline powder). All the volatiles from the mother liquors were removed under reduced pressure affording some more yellow-orange powder (4.42 g) (total amount: 5.11 g).



1H-NMR (rac-A2(HPO4)): 1H NMR (400 MHz CD3OD): δ 1.78 (3H, d, J=6.76 Hz), 2.56 (6H, s), 4.24 (5H, s), 4.29-4.54 (5H, m).









TABLE







XRPD peak listing for ((rac)-A2(HPO4)).










Angle (° 2θ)
Intensity (%)














5.5
5.9



8.9
6.4



11.0
2.0



13.0
13.6



13.4
4.6



14.1
8.3



15.2
33.6



15.5
88.7



16.5
12.5



17.1
13.0



17.9
52.6



19.0
37.0



19.8
9.3



21.1
6.9



22.0
100.0



21.7
6.3



22.2
6.4



23.9
9.6



24.4
6.1



25.8
4.3



26.2
4.8



26.4
4.3



27.0
4.4



28.5
6.2



30.8
7.2



33.3
12.9










Thermal analysis (DSC, TGA) give an onset of decomposition of 160° C.


Example 6

General Procedure for the Synthesis of Enantioenriched (R)—N,N-Dimethyl-α-Ferrocenylethyl Ammonium Salts (Compounds of Formula I, Table 1, Entries 3-9)


(R)—N,N-dimethyl-α-ferrocenylethylamine B (8.6 mL, 40.9 mmol) was dissolved in MeOH (20 mL) and cooled down to 0° C. The corresponding acid (40.9 mmol) was added slowly over the MeOH solution and the mixture was stirred at room temperature for 1 h. Then, the volume was reduced in half and the corresponding anti-solvent was added in order to precipitate the salt (Table 1, entries 1, 2 and 4-7) affording yellow to orange solids in 70-98% yields. Compounds in entries 3, 8 and 9 were obtained as brown ionic liquids after removal of the solvent under high vacuum.









TABLE 1







N,N-dimethyl-α-ferrocenylethyl ammonium salts:


recovery yields and precipitation conditions














Acid







(ratio
Yield

Solvent/anti-


Entry
Compound
A*:acid)
(%)
Appearance
solvent






 1a
N,N-dimethyl-α-
H3PO4
86%
Yellow-
MeOH/Acetone



ferrocenylethylammonium
(1:1)

orange solid



dihydrogenphosphate (A*(H2PO4))



 2b
Di-(N,N-dimethyl-α-
H3PO4
70%
Yellow solid
MeOH/Acetone



ferrocenylethylammonium)
(2:1)



monohydrogenphosphate



(A*2(HPO4))


3
N,N-dimethyl-α-
AcOH
99%
Brown liquid
—



ferrocenylethylammonium acetate
(1:1)



(A*(acetate))


4
N,N-dimethyl-α-
Fumaric
98%
Yellow solid
MeOH/THF



ferrocenylethylammonium
acid



fumarate (A*(fumarate))
(1:1)


5
N,N-dimethyl-α-
Adipic
96%
Yellow solid
MeOH/THF



ferrocenylethylammonium adipate
acid



(A*(adipate))
(1:1)


6
N,N-dimethyl-α-
Oxalic
98%
Yellow solid
MeOH/THF



ferrocenylethylammonium oxalate
acid



(A*(oxalate))
(1:1)


7
N,N-dimethyl-α-
Benzoic
89%
Yellow solid
MeOH/MTBE



ferrocenylethylammonium
acid



benzoate (A*(benzoate))
(1:1)


8
N,N-dimethyl-α-
Mesylic
99%
Brown liquid
—



ferrocenylethylammonium
acid



mesylate (A*(mesylate))
(1:1)


9
N,N-dimethyl-α-
Tosylic
99%
Brown liquid
—



ferrocenylethylammonium tosylate
acid



(A*(tosylate))
(1:1)






aaccording to Example 1;



baccording to Example 4



1H-NMR data


A*(acetate) (entry 3): 1H NMR (400 MHz, CDCl3): δ 1.62 (3H, d, J = 6.92 Hz), 2.01 (3H, s), 2.29 (6H, s), 4.11 (1H, q, J = 6.83 Hz), 4.15 (5H, s), 4.15-4.19 (1H, q, J = 2.43 Hz), 4.19-4.30 (3H, m, J = 3.62 Hz).


A*(fumarate) (entry 4): 1H NMR (400 MHz, CD3OD): δ 1.77 (3H, d, J = 6.84 Hz), 2.61 (6H, s), 4.24 (5H, s), 4.31-4.52 (5H, m), 6.70 (2H, s).


A*(adipate) (entry 5): 1H NMR (400 MHz, CD3OD): δ 4.57-4.71 (4H, m), 1.78 (3H, d, J = 6.88 Hz), 2.28 (4H, m), 2.58 (6H, s), 4.26 (5H, s), 4.33-4.51 (5H, m).


A*(oxalate) (entry 6): 1H NMR (400 MHz, CD3OD): δ 1.79 (3H, d, J = 6.44 Hz), 2.64 (6H, s), 4.27 (5H, s), 4.32-4.57 (5H, m).


A*(benzoate) (entry 7): 1H NMR (400 MHz, CDCl3): δ 1.72 (3H, d, J = 6.92 Hz), 2.43 (6H, s), 4.16 (5H, s), 4.19-4.29 (3H, m), 4.30-4.40 (2H, m), 7.33-7.48 (3H, m), 8.04-8.13 (2H, m).


A*(mesylate) (entry 8): 1H NMR (400 MHz, CD3OD): δ 1.79 (3H, d, J = 6.88 Hz), 2.65 (3H, s), 2.66 (3H, s), 2.73 (3H, s), 4.28 (5H, s), 2.52-2.72 (5H, m).


A*(tosylate) (entry 9): 1H NMR (400 MHz, CD3OD): δ 1.78 (3H, d, J = 6.88 Hz), 2.39 (3H, s), 2.64 (3H, s), 2.65 (3H, s), 4.27 (5H, s), 4.36-4.55 (5H, m), 7.26 (2H), 7.73 (2H).






Example 7

Process for Increasing the Optical Purity of N,N-Dimethyl-α-Ferrocenylethyl Amine B


N,N-dimethyl-α-ferrocenylethyl ammonium dihydrogenphosphate (A*(H2PO4)) (5-10 g scale) was placed into a 250 mL round bottom flask equipped with magnetic stirrer and it was heated in a solvent or solvent mixture for the time and the temperature shown in Table 2. Then, the slurry was filtered under vacuum affording a yellow powder.


After isolation of the N,N-dimethyl-α-ferrocenylethyl amine B (Ugi amine) following the procedure of examples 1 or 2 a yellow-orange oil was obtained. Assayed as (R)-B of final ee (%) as indicated in Table 2.









TABLE 2







Recrystallisation of N,N-dimethyl-α-ferrocenylethyl


ammonium dihydrogenphosphate A*(H2PO4) - solvent screening














Entry
Solvent
C (g/mL)
T (ext.)
Time
Initial ee(%)
Final ee(%)
Yield

















1
IPA
0.15
82° C.
 2 h
97.2%
98.2%
94%


2
EtOH
0.30
68° C.
72 h
98.2%
98.2%
33%


3
EtOH
0.10
65° C.
24 h
98.2%
99.3%
55%


4
IPA:MeOH(1%)
0.05
82° C.
24 h
97.2%
99.4%
83%









Example 8

Synthesis of Enantioenriched (S)—N,N-Dimethyl-α-Ferrocenylethyl Ammonium Dihydrogenphosphate (A*(H2PO4)) Starting from Enantioenriched (S)-Ferrocenylethanol (D) Using NaOAc-3H2O as a Base-Solvent Screening1 1 M. M. Mojtahedi, S. Samadian, “Efficient and Rapid Solvent-Free Acetylation of Alcohols, Phenols and Thiols Using Catalytic Amounts of Sodium Acetate Trihydrate”, Journal of Chemistry, 2013, Hindawi Publishing Corporation.


(S)-1-Ferrocenylethanol (D, 1 g, 3.8 mmol, 97.0% ee), NaOAc-3H2O (517 mg, 3.8 mmol, 1 equiv), Ac2O (1.1 mL, 11.4 mmol, 3 equiv) and the corresponding solvent (Table 3) were introduced in a carousel screening reaction tube and the reaction mixture was stirred at 40° C. for 18 h. Then, a sample was taken in order to analyse the mixtures by 1H-NMR.









TABLE 3







Solvent screening (conversions as determined by 1H-NMR)













Conversion to




Concentration
Product C


Entry
Solvent
(g D/mL solvent)
(% mol)













1
Neat
0.25a
98.3% 


2
Tolueneb
0.1
35%


3
EtOAc
0.1
22%


4
MTBE
0.1
19%


5
MeCN
0.1
45%


6
Acetone
0.1
15%


7
Heptanec
0.1
79%


8
Heptanec,d
0.25
85%






aExcess of Ac2O was employed (4 mL, 12 equiv).



b3 equiv. of NaOAc•3H2O were added.



cThe acetate C was transformed into amine B in order to confirm that the enantiomeric excess of 97.0% ee was retained;



dThe reaction time was 2 h.






Example 9

Synthesis of N,N-Dimethyl-α-Ferrocenylethyl Ammonium Dihydrogenphosphate (A*(H2PO4)) with Loss of Optical Purity Starting from Enantioenriched Ferrocenylethanol (D) Using AcOH/iPrOAc as Acetylating Agent (Comparative)




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(R)-1-Ferrocenylethanol (D, 69.0 g, 0.30 mol, 97% ee) was dissolved in iPrOAc (500 mL) and AcOH (20 mL) was added. The mixture was refluxed for 24 h using a Dean-Stark in order to remove generated H2O from the reaction media (4.5 mL of H2O were collected). Then, all the volatiles were distilled in vacuum adding small amounts of iPrOAc to remove remaining AcOH and H2O.


The residue was dissolved in MeOH (500 mL) and Me2NH (40% aq., 163 mL) was added. The reaction was stirred at RT for 24 h. The mixture was concentrated in vacuo to remove a significant amount of unreacted Me2NH affording a dark red oil.


The residue was dissolved in MeOH (500 mL) and H3PO4 (20.3 mL) was added dropwise. The mixture was allowed to stir at RT for 1 h. The solvent was removed in vacuo and toluene was employed in order to dry the residue (azeotropic distillation of remaining H2O). The phosphate salt A*(H2PO4) was precipitated from MeOH/Acetone obtaining a yellow-orange solid (64 g, 0.18 mol, 63% yield).


After isolation of the corresponding amine B following the procedure of Example 1 a yellow-orange oil was obtained. Assayed as (R)-B of 80% ee by HPLC.


Example 10

Synthesis of DMAP-H3PO4


DMAP (5.00 g mL, 40.9 mmol) was dissolved in MeOH (30 mL) and cooled down to 0° C. H3PO4 (85% wt.) (2.8 mL, 40.9 mmol) was added slowly over the MeOH solution and the mixture was stirred at room temperature for 1 h. Then, precipitate was filtered off and washed with MeOH affording DMAP.H3PO4 as a white solid (8.82 g, 98% yield).


Example 11

Synthesis of DMAP-HOAc


DMAP (5.00 g mL, 40.9 mmol) was dissolved in MeOH (30 mL) and cooled down to 0° C. AcOH (2.35 mL, 40.9 mmol) was added slowly over the MeOH solution and the mixture was stirred at room temperature for 1 h. Then, the solvent was removed in vacuo and the residue was slurried in acetone and filtered off affording DMAP-HOAc as a white hygroscopic solid (6.78 g, 91% yield).


Example 12

Solubility Comparison Between N,N-Dimethyl-α-Ferrocenylethyl Ammonium Dihydrogenphosphate (a*(H2PO4)), DMAP.H3PO4 and DMAP.HOAc


In cases where DMAP is used as catalyst for the acetylation of ferrocenylethanol (D), DMAP-containing impurities are carried over in the subsequent steps of the synthesis of N,N-dimethyl-α-ferrocenylethyl ammonium dihydrogenphosphate (A*(H2PO4)). Purification of the crude product mixture is, therefore required.


As shown in Table 4 the solubilities of the Ugi ammonium dihydrogen phosphate ((A*(H2PO4)), DMAP-H3PO4 and DMAP.HOAc are different in dichloromethane, methanol and acetonitrile.

    • a) In order to separate compounds A*(H2PO4) and DMAP.H3PO4, the sample is dissolved in MeOH and the solids filtered off to obtain A*(H2PO4) (potentially contaminated with DMAP.HOAc) after distillation of the mother liquor.
    • b) The removal of DMAP.HOAc can be achieved dissolving the material of step a) either in DCM or MeCN. The mixture is filtered in vacuo to afford A*(H2PO4) as a solid.









TABLE 4







Solubility comparison between (A*(H2PO4)), DMAP•H3PO4 and DMAP•HOAc in various


solvents




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Example 13

Preparation of HCOOH.Et3N 2M:2M Mixture


The HCOOH.Et3N 2M:2M mixture was prepared by dissolving HCOOH (400 mmol, 18.412 g, 15.7 mL of 96%) in water (10 mL) and neutralizing it with Et3N (400 mL, 40.48 g, 56.02 mL). Finally, pH was adjusted to 6.5 using a calibrated pH meter and the volume was topped up with water to 200 mL. The obtained mixture was a viscous colourless liquid. The reagent was deoxygenated by bubbling Argon though the liquid for 30 min.


Example 14

Small Scale Procedure 1: One Pot Reaction




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Ts-DPEN Ru Cl (p-cym) MW: 636.2


A 500 mL round bottom flask equipped with reflux condensed and large stirring bar was charged with acetyl ferrocene (51 g, 223 mmol) and placed under argon atmosphere by three vacuum/refill cycles. 130 mL of the solution of HCOOH.Et3N (260 mmol, 1.2 eq.) of Example 13 was added, followed by a solution of [RuCl (S,S)-TsDPEN p-cymene (228 mg, 0.36 mmol, S/C 620/1) in THF (45 mL). The reaction mixture was heated to 80° C. for 16 h. After cooling, a sample was taken and analysed by HPLC to determine conversion and enantiomeric excess (95% conversion, 95% ee). The reaction mixture was diluted with EtOAc (200 mL) and transferred to 500 mL separating funnel. The organic phase was washed with brine. The aqueous phases were extracted back with EtOAc and the combined organic extracts were dried (MgSO4) and filtered over glass sinter containing pad of silica gel (2 cm) and MgSO4 (1 cm). Solvents were evaporated to give crude (S)-1-ferrocenyl ethanol as a red solid. This was crystallized from hot heptane (300 mL) to give orange to yellow crystalline material. This was collected by filtration, washed with cold heptane (50 mL), transferred to a round bottom flask and dried in vacuo to give (S)-1-ferrocenyl ethanol as a yellow solid (isolated yield: 37.9 g, 76% yield, 95% purity by 1H NMR, 95% ee).


Example 15

Large Scale Procedure 1: One Pot Reaction


The above procedure was repeated in a 20 L flask with an efficient reflux condenser connected to a silicon oil filled bubbler as a pressure reliever, using acetyl ferrocene (312 g, 1.368 mol), HCOOH.Et3N (795 mL, 1.587 mol, 1.2 eq.), [RuCl (R,R)-TsDPEN p-cymene (1.4 g, 0.0022 mol, S/C 620/1), THF (275 mL). The reaction was heated to 80° C. for a total of 20 hours, until HPLC analysis showed only 1.6% starting material left. A vigorous evolution of gas was detected during the first two hours at 80° C. After work up (no filtration required to achieve phase separation) and recrystallization, (R)-1-ferrocenyl ethanol was obtained in 89% isolated yield (280 g, >99% purity by HPLC, >98% purity by 1H NMR, 98.3% ee).


Example 16

Small-Scale Procedure 2: Slow Addition of HCOOH.Et3N


A 250 mL two neck round bottom flask equipped with reflux condensed and large stirring bar was charged with acetyl ferrocene (29.4 g, 129 mmol) and placed under argon atmosphere by three vacuum/refill cycles. A solution of HCOOH.Et3N 2M:2M (25 mL, 50 mmol, 0.42 eq.) was added, followed by a solution of [RuCl (R,R)-TsDPEN p-cymene (127 mg, 0.2 mmol, S/C 645/1) in THF (26 mL). The reaction mixture was deoxygenated by three vacuum/refill cycles and heated up to 80° C. After 30 minutes, slow addition of reagent was commenced using a syringe pump. The remaining 50 mL of HCOOH.Et3N 2M:2M (0.84 eq.) were added over 3 h. When the addition was completed, a sample of the reaction mixture was and analysed by HPLC to determine conversion and enantiomeric excess (68% conversion, 91% ee). Heating was continued overnight. In the morning, HPLC analysis showed 96% conversion and 95% enantiomeric excess.


Example 17

Large-Scale Procedure 2: Slow Addition of HCOOH.Et3N


The above procedure was repeated in the 20 L reactor of Example 15 using acetyl ferrocene (312 g, 1.368 mol), HCOOH.Et3N 2M:2M (initial amount: 286 mL, 0.572 mol, 0.42 eq.), [RuCl (R,R)-TsDPEN p-cymene (1.4 g, 0.0022 mol, S/C 620/1) and THF (275 mL). HCOOH.Et3N 2M:2M (574 mL, 0.148 mmol, 0.84 eq.) was added over six hours at 80° C. causing a steady evolution of gas from the reaction. The reaction was heated to 80° C. for a total over 16 hours (including addition time), until HPLC analysis showed only 1.4% starting material left. After work up and recrystallization, (R)-1-ferrocenyl ethanol was obtained in 83% isolated yield (261 g, >99% purity by HPLC, >99% purity by 1H NMR, 97.4% ee).


Example 18

Small-Scale Procedure 3: Slow Addition of HCOOH


A 500 mL two neck round bottom flask equipped with reflux condenser was charged with acetyl ferrocene (41.5 g, 181.5 mmol) and placed under argon atmosphere by three vacuum/refill cycles. A solution of HCOOH.Et3N 2M:2M (36.4 mL 72.8 mmol, 0.33 eq.) was added, followed by a solution of [RuCl (R,R)-TsDPEN p-cymene] (192 mg, 0.302 mmol, S/C 600/1) in THF (25.7 mL). The reaction mixture was deoxygenated by three vacuum/refill cycles and heated to 80° C. After 30 minutes, slow addition of HCOOH was commenced using a syringe pump. HCOOH (5.46 mL, 145 mmol, 0.8 eq) was added over 4 hours. When the addition was completed, a sample of the reaction mixture was taken and analysed by HPLC to determine conversion and enantiomeric excess (83% conversion, 95% ee). Heating was continued overnight. In the morning, a sample of the reaction mixture was taken and analysed by HPLC to determine conversion and enantiomeric excess (96% conversion, 95% ee).


Example 19

Large-Scale Procedure 3: Slow Addition of HCOOH.Et3N


The above procedure was repeated in a 20 L flask using acetyl ferrocene (312 g, 1.368 mol), HCOOH.Et3N 2M:2M (initial amount: 274 mL, 0.548 mol, 0.4 eq.), [RuCl (R,R)-TsDPEN p-cymene] (1.4 g, 0.0022 mol, S/C 620/1) and THF (193 mL). HCOOH (50 g, 1.086 mol, 0.8 eq.) was added over four hours at 80° C. causing a steady evolution of gas from the reaction. The reaction was heated to 80° C. for a total over 14 hours (including addition time), until HPLC analysis showed only 2.1% starting material left. After work up (filtration was required to achieve phase separation) and recrystallization, (R)-1-ferrocenyl ethanol was obtained in 90% isolated yield (282 g, >97% purity by HPLC, >99% purity by 1H NMR, 98.3% ee).

Claims
  • 1. A metallocenyl compound of formula (I),
  • 2. The metallocenyl compound according to claim 1, wherein Ra is methyl.
  • 3. The metallocenyl compound according to claim 1 wherein j is 0.
  • 4. The metallocenyl compound according to claim 1, wherein m is 0.
  • 5. The metallocenyl compound according claim 1, wherein n is 0.
  • 6. The metallocenyl compound according to claim 1, wherein Ra is methyl and m, n and j are 0.
  • 7. The metallocenyl compound according to claim 1, wherein j is 1.
  • 8. The metallocenyl compound according to claim 1, wherein Rd is methyl.
  • 9. The metallocenyl compound according to claim 1, wherein Re and Rf are methyl.
  • 10. The metallocenyl compound according to claim 1, wherein M is Fe, Ru or Os.
  • 11. The metallocenyl compound according to claim 1, wherein Z is selected from the group consisting of a monoatomic anion, an oxyanion and an organic anion.
  • 12. The metallocenyl compound according to claim 11, wherein the oxyanion is (H2PO4)− or (HPO4)2−.
  • 13. The metallocenyl compound according to claim 11, wherein Z is a monoanion or a dianion.
  • 14. A process for the preparation of a metallocenyl compound of formula (I):
  • 15. The process according to claim 14, wherein Hk(j+1)Z is H3PO4, fumaric acid, adipic acid, oxalic acid, benzoic acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • 16. The process according to claim 14, wherein the solvent is selected from the group consisting of an alcohol, an ether, an aromatic solvent, and an ester or a combination thereof.
  • 17. The process according to claim 16, wherein the solvent is an alcohol.
  • 18. The process according to claim 17, wherein the alcohol is methanol.
  • 19. The process according to claim 14, further comprising obtaining the metallocenyl compound of formula (II) from the metallocenyl compound of formula (I) in the presence of a base.
  • 20. A process for increasing the optical purity of a compound of formula (II),
  • 21. The process according to claim 14, further comprising a process for increasing the optical purity of the compound of formula (II),
  • 22. The process according to claim 20, wherein the compound of formula (I) is compound A*(H2PO4) and the compound of formula (II) is compound B:
  • 23. The process according to claim 20, wherein the solvent comprises an alcohol.
  • 24. The process according to claim 23, wherein the alcohol is selected from the group consisting of methanol, n-propanol, and isopropanol or combinations thereof.
  • 25. The process according to claim 20, wherein the base is sodium hydroxide.
  • 26. The process according to claim 22, wherein the enantiomeric excess of compound B is ≥99% ee.
  • 27. The process according to claim 14, wherein the compound of formula (II) is prepared by mixing a compound of formula (III) with a compound of formula HNReRf in a solvent to form the compound of formula (II),
  • 28. The process according to claim 27, wherein the solvent comprises a mixture of alcohol and a C1-C8 alkane.
  • 29. The process according to claim 28, wherein the alcohol is a mixture of isopropanol and heptane or a mixture of isopropanol and cyclohexane.
  • 30. The process according to claim 27, wherein the compound of formula (III) is prepared by mixing a compound of formula (IV) with a compound of formula acyl-LG in the presence of a base to form a compound of formula (III), wherein LG is a leaving group:
  • 31. The process according to claim 30, wherein the compound of formula acyl-LG is a carboxylic anhydride or an acyl chloride.
  • 32. The process according to claim 30, wherein the compound of formula acyl-LG is acetic anhydride.
  • 33. The process according to claim 30, wherein the base is sodium acetate.
  • 34. The process according to claim 33, wherein the sodium acetate is NaOAc.3H2O.
  • 35. The process according to claim 30, further comprising a solvent.
  • 36. The process according to claim 35, wherein the solvent is an aprotic solvent.
  • 37. The process according to claim 36, wherein the aprotic solvent is heptane.
  • 38. The process according to claim 30, wherein the base is dimethylaminopyridine (DMAP).
  • 39. The process according to claim 30, wherein the compound of formula (IV) is prepared by asymmetric transfer hydrogenation (ATH) of a metallocenyl compound of formula (V)
  • 40. The process according to claim 14, wherein the compound of formula (I) is compound A*(H2PO4), the compound of formula (II) is compound B, the compound of formula (III) is compound C, the compound of formula (IV) is compound D:
  • 41. The process according to claim 38, further comprising the steps of: a) adding methanol to a compound A*(H2PO4) containing DMAP-H3PO4 and DMAP-HOAc, to produce a solid-liquid mixture;b) separating the liquid containing the compound A*(H2PO4) and DMAP-HOAc from the solid-liquid mixture of step a);c) isolating the compound A*(H2PO4) containing DMAP-HOAc from the liquid of step b);d) adding dichloromethane or acetonitrile to the isolated compound A*(H2PO4) containing DMAP-HOAc of step c), to produce a second solid-liquid mixture;e) isolating the solid from the second solid-liquid mixture of step d) to produce a compound A*(H2PO4) of higher purity than before the steps a) to e).
  • 42. The process according to claim 27, wherein the compound of formula (III) is obtained in situ before reaction with the compound of formula HNReRf.
  • 43. A process for the asymmetric transfer hydrogenation (ATH) of a metallocenyl compound of formula M to a metallocenyl compound of formula (IV),
  • 44. The process according to claim 43, wherein Ra is methyl.
  • 45. The process according to claim 43 wherein j is 0.
  • 46. The process according to claim 43, wherein m is 0.
  • 47. The process according to claim 43, wherein n is 0.
  • 48. The process according to claim 43, wherein Ra is methyl and m, n and j are 0.
  • 49. The process according to claim 43, wherein j is 1.
  • 50. The process according to claim 43, wherein Rd is methyl.
  • 51. The process according to claim 43, wherein Re and Rf are methyl.
  • 52. The process according to claim 43, wherein the asymmetric transfer hydrogenation catalyst is a complex of formula (VI):
  • 53. The process according to claim 43, wherein the asymmetric transfer hydrogenation catalyst is a complex of formula (IX):
  • 54. The process according to claim 43, wherein the aqueous solvent is water or a mixture of water and water-miscible solvents.
  • 55. The process according to claim 43, wherein the asymmetric transfer hydrogen reaction is carried out at one or more temperatures in the range of ≥about 60° C. to about ≤about 100° C.
  • 56. The process according to claim 43, wherein the activated formic acid is a mixture of formic acid, a tertiary amine base and optionally water.
  • 57. The process according to claim 56, wherein the tertiary amine base is triethylamine.
  • 58. The process according to claim 57, wherein the molar ratio of formic acid:tertiary amine is in the range of about 1:1 to about 1.2:1 moles.
  • 59. The process according to claim 57, wherein the activated formic acid is a mixture of formic acid, a tertiary amine and water, and the concentration of formic acid:tertiary amine is in the range of 1 M:1 M to about 1.2 M:1 M.
  • 60. The process according to claim 43, wherein the molar ratio of the metallocenyl compound of formula (V) to asymmetric transfer hydrogenation catalyst is in the range of about 100:1 to about 2000:1.
  • 61. The process according to claim 60, wherein the molar ratio is ≥about 600:1.
  • 62. The process according to claim 43, wherein M is Fe, and m is 0, 1, 2 or 3, and at least one of the carbon atoms ortho to the —RaC*H(OH) group is unsubstituted, and further comprising transforming the metallocenyl alcohol of formula (IV) into a Bophoz or Josiphos ligand.
  • 63. The process according to claim 14, wherein the enantiomeric excess of the compound of formula (II) is ≥97%.
Priority Claims (2)
Number Date Country Kind
1710954.7 Jul 2017 GB national
1807243.9 May 2018 GB national
PCT Information
Filing Document Filing Date Country Kind
PCT/GB2018/051886 7/4/2018 WO 00