Patent Application
20120142897
Provided herein are synthons useful for the synthesis of phosphonates compounds or derivatives showing better bioavailability, processes for their preparation and their use in the synthesis of phosphonates compounds or derivatives showing better bioavailability.
Several biologically active molecules are bearing a phosphonate moiety. As for instance, certain aryl-substituted ketophosphonates have been reported to have bone anabolic activity (see, e.g., WO 2004/026245) or to function as thyroid receptor ligands (see, e.g., US 2006/0046980), meanwhile bisphosphonic acids (also known as diphosphonic acids) and their salts are a class of compounds that are cytotoxic to osteoclasts and act to prevent bone resorption; when conjugated with alkylating moieties, bis-phosphonates have been reported to have antitumor activity (see, e.g., WO 9843987). The pyrazolopyrimidine and pyrimidinyl bisphosphonic esters are anti-inflammatory agents (see, e.g., U.S. Pat. No. 5,397,774), meanwhile macrocyclic phosphonates and amidophosphates have been reported to inhibit HCV (see, e.g., WO 2008096002); several phosphonate analogs of HIV protease inhibitors have an improved cellular accumulation properties (see, e.g., WO 2003090690); some heteroaromatic phosphonates were tested for a variety of biological activities including inhibition of fructose 1,6-bisphosphatase (FBPase) and activity toward AMP binding enzymes, such as adenosine kinase, and are useful in the treatment of diabetes and other diseases where inhibition of gluconeogenesis, control of blood glucose levels, reduction in glycogen storage, or reduction in insulin levels is beneficial (see, e.g., US 1998-135504P); dihydropyridine-5-phosphonate derivatives are effective Ca antagonists (see, e.g., JP 60069089); some pyrimidyl phosphonates act as brain performance disturbance and depression treatment agents (see, e.g., DE 1993-4343599); some phosphonates with alkenes derivatives are known as antibacterial (DE 18 05 677 A1) and antibiotics (DE 20 02 807); Other compounds, such as nucleoside derivatives or analogs, are active agents that are administered in non-phosphorylated form, but are phosphorylated in vivo in the form of metabolic monophosphate or triphosphate to become active. Thus, nucleoside derivatives having antitumor activity, such as 5-fluorouridine, 5-fluoro-2′-deoxyuridine or antiviral activity (in the treatment of AIDS, hepatitis B or C), such as 2′,3′-dideoxynucleosides, acyclonucleoside phosphonates, exert their activity in phosphorylated form as phosphate or phosphonates analogs.
Compounds bearing a phosphonate group have a negatively charged ionic nature at physiological pH. The therapeutic activity of such compounds is consequently limited, on account of the low diffusion of negatively charged compounds across biological lipid membranes. In particular, charged compounds do not diffuse efficiently across cell membranes, or indeed across the cerebral barrier, which are lipidic in nature. Thus, one solution to drug delivery and/or bioavailability issues in pharmaceutical development is converting known phosphonate drugs to phosphonate prodrugs. Typically, in a phosphonate prodrug, the polar functional group is masked by a pro-moiety, which is labile under physiological conditions. Accordingly, prodrugs are usually transported through hydrophobic biological barriers such as membranes and typically possess superior physicochemical properties in comparison to the parent drug. For instance, in the nucleoside domain, numerous studies showed the importance of having monophosphates or phosphonates of said nucleosides in order to present a better bioavailability (pro-nucleosides). Several compounds without any biological activity became also active when converted to monophosphate or phosphonate derivatives (Somogyi Gabor et al. <<Targeted drug delivery to the brain via phosphonates derivatives>>, IJP 166, 2008, p. 15-26 and Gong-Xin et al: <<Chapter 3.6. Prodrugs of Phosphonates, Phosphinates and Phosphates>>, Prodrugs Challenges and Reward Part1. Springer New York, US, vol. 5.1, 2007, p. 923-964).
Generally, most of the methods, which are use for introducing a biolabile moiety onto a phosphonate group, comprise several steps (e.g., deprotection of a dimethyl, diethyl or diisopropyl phosphonate under harsh conditions, its activation and its substitution by a biolabile group), poor yields, purification on reverse phase column and structural restrictions to the use of the synthons.
Thus, the present invention satisfies these and other needs by providing synthons useful for the synthesis of phosphonates derivatives showing better bioavailability, processes for their preparation and their use in the synthesis of phosphonates derivatives showing better bioavailability. The inventors discovered new processes for synthesizing phosphonate synthons bearing a biolabile moiety which can be used to (a) either transform a said compound into its phosphonate analogue, (2) to synthesize a phosphonate compound. They prepared several phosphonates derivatives which bear independently of each other either (a) an ester function or analogous, said function being optionally bio-labile, and/or lipidic chain, (b) an unsaturated (alkene, alyne, allene) function or analogous (c) a nucleofuge or (d) a hydrogen atom or (e) a methyl group directly linked to a phosphate group. Use of such derivatives in (a) olefin cross metathesis route, (b) nucleophilic substitution reaction (c) dipolar [1,3]-cycloaddition, (d) amination, (e) ring-opening, (f) addition of carbonyl and analogues, (g) organometallic cross-coupling, especially catalyzed by Pd(0), for instance, permit to convert a compound into its phosphonate diester, unsymmetrical diester, or monoester said phosphonate presenting a better bioavailability. The synthons according to the invention show several advantages: convergent synthesis on high scale, easy purification, and easy transformation of product with a better bioavailability.
Thus an object of the instant invention is a compound of formula (I)
wherein
In an advantageous embodiment of the invention, the compounds are those of formula
corresponding to a compound of formula (I) wherein
is a group
with R1 is as defined before.
In another advantageous embodiment of the invention the compounds are those of formula
corresponding to a compound of formula (I) wherein R is equal to R2 as defined above.
More advantageously, the compounds are selected from the group comprising
or from the group comprising
The compounds according to the invention may be prepared by any methods known from the one skilled in the art.
Another object of the invention is a process for making lipophilic pro-drugs comprising the step of contacting a drug D with a compound of formula (I) according to the invention.
In an advantageous embodiment of the invention, said process is an olefin-metathesis reaction comprising the step of contacting at least one compound of formula (I), with a drug D which bears an olefin group as shown in the following scheme
In an advantageous embodiment of the invention, said process is the step of contacting at least one compound according to anyone of claims 2, 4 and 5 with a drug D which bears a leaving group such as halogen, TfO, sulfones . . . .
In a more advantageous embodiment of the invention said process is a process for making a compound of formula (II-1)
D-A (5)
In an advantageous embodiment of the invention the process is a process for making a compound of formula (II-2)
D-OH (6)
When D is a phosphonate derivative, the synthon according to the invention will be introduced by any reaction known from the one skilled in the art, for example by Diels and Alder reaction, Arbuzov reaction, olefin metathesis, nucleophilic substitution
In another embodiment according to the invention, the prodrugs may be prepared by a Mitsunobu reaction of an alcohol according to the following scheme.
wherein R′ and R″ are as disclosed above
According to the invention, halogen stands for fluorine, chlorine, bromine and iodine.
The term straight or branched (C1-C6)alkyl group stands for a straight-chain or branched hydrocarbon residue containing 1-6 C-atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-hexyl.
The term (C1-C6)alkoxy group stands for alkyl-O— with alkyl as defined above, e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy and hexoxy.
The term straight or branched (C2-C6)alkenyl groups stands for straight-chain or branched hydrocarbon residue containing one or more olefinic bonds and up to 6, preferably up to 4 C-atoms. Olefin and olefine may also be used to design an alkenyl group.
The term lipophilic chain or long-chain refers to the cyclic, branched or straight chain chemical groups that when covalently linked to a phosphonic acid to form a phosphonate ester increase oral bioavailability and enhance activity as for instance for some nucleoside phosphonates when compared with the parent nucleoside. These lipophilic groups include, but are not limited to aryl, alkyl, alkoxyalkyl, and alkylglyceryl (such as hexadecyloxypropyl (HDP)-, octadecyloxyethyl-, oleyloxypropyl-, and oleyloxyethyl-esters).
The term aromatic ring stands for, but is not limited to aryl, e.g. phenyl, benzyl, naphtyl or indanyl, said aryl group being optionally substituted.
The term leaving groups is an ion (metal) or substituent with the ability to detach itself from a molecule e.g. halogen, sulfonyl group for example p-toluensulfonyloxy group and the like.
The term carbonyl group stands for a group composed of a carbon atom double-bonded to an oxygen atom: C═O e.g. formyl, acetyl, propionyl, butyryl and the like.
D is selected from a compound having a biological activity such as but not limited to neurotransmitters, stimulants, dopaminergic agents, tranquilizers, antidepressants, narcotic analgesics, narcotic antagonists, sedatives, hypnotics, anesthetics, antiepileptics/anticonvulsants, hormones such as the male and female sex hormones, peptides, anti-inflammatory steroids, non-steroidal anti-inflammatory agents/non-narcotic analgesics, memory enhancers, antibacterials/antibiotics, antineoplastics (anticancer/antitumor agents) and antiviral agents.
POM states for pivaloyl oxymethyl and POC states for isopropyloxymethylcarbonate. Molecules bearing bis-POM and/or bisPOC are directly usable to be biologically tested. Molecules bearing a HDP group should be first deprotected before being tested.
Another object of the invention is the use of compounds according to the invention as intermediates in the synthesis of phosphonates derivatives useful as pro-drugs.
Another object of the invention are compounds of formula
for their use as drugs, in particular the compounds of examples 16 to 48.
Still another object of the invention is a method of treating a disease comprising the administration to a patient in need thereof of a compound of formula
Another object of the invention is a method of making phosphonates derivatives useful as pro-drugs comprising a step involving the compounds according to the invention as intermediates.
Thus with the synthons according to the invention, it is possible to synthesize bis-POM/POC acyclonucleosides phosphonates prodrugs by direct Cross Metathesis of allyl bis-POM/POC allylphosphonates, on free nucleosides. They permit to introduce in a same step the phosphorus and the POM/POC prodrug part.
The following figures and examples are provided for illustrative purposes.
Examples 1 to 15 illustrate the synthesis of the synthons according to the invention.
Examples 16 to 48 illustrate the synthesis of prodrugs from said synthons.
1.1. Introduction of Lipophilic Chain on Dialkyl Alkylphosphonate
To a dichloromethane (DCM) (5 mL/mmol) solution of dialkyl allylphosphonate (1 eq.) was added oxalyl chloride (3 eq.), and gently reflux for 24 h under positive pressure of dry argon. This solution was evaporated under reduced pressure and diluted in DCM (5 mL/mmol). Lipophilic alcohol (1.05 eq.) and dry triethylamine (1.5 eq.) were then added and the solution was refluxed for 48 h under positive pressure of dry argon. Volatiles were evaporated and the residue purified by chromatography on silica gel to give the corresponding alkyl/lipophilic chain alkylphosphonate.
1.2. Conversion of Dimethyl Alkylphosphonate into Bis-(POM) or Bis-(POC) Form.
To an acetonitrile ACN (1 mL/mmol) solution of dimethyl alkylphosphonate (1 eq.) and anhydrous sodium iodide (2 eq.), was added chloromethyl pivalate POMC1 (2.5 eq.) or chloromethyl isopropyl carbonate (2.5 eq.). This solution was stirred at reflux for 48 h under positive pressure of dry argon. After cooling, diethyl ether was added (10 mL/mmol) and the solution was washed with water (2 mL/mmol). The organic layer was dried on magnesium sulfate, evaporated and purified by chromatography on silica gel to give the corresponding Bis-(POM) or Bis-(POC) alkylphosphonate.
1.3. Conversion of Methyl/Prodrug Group Alkylphosphonate into Mixt POM or POC/Prodrug Group Alkylphosphonate
To an ACN (1 mL/mmol) solution of methyl/prodrug group alkylphosphonate (1 eq.) and anhydrous sodium iodide (1 eq.), was added chloromethyl pivalate POMC1 (1.5 eq.) or chloromethyl isopropyl carbonate (1.5 eq.). This solution was stirred at reflux for 48 h under positive pressure of dry argon. After cooling, diethyl ether was added (10 mL/mmol) and the solution was washed by water (2 mL/mmol). The organic layer was dried on magnesium sulfate, evaporated and purified by chromatography on silica gel to give corresponding Bis-(POM) or Bis-(POC) alkylphosphonate.
1.4. Conversion of Dialkyl H-Phosphonate into Alkyl/Lipophilic Chain H-Phosphonate.
To a tetrahydrofuran (THF) (1 mL/mmol) solution of 1,3-bis(cycicohexyl) imidazolium tetrafluoroborate (IcyHBF4) salt (0.05 eq.) and molecular sieves (0.5 g/mmol), under argon, is added tBuOK (0.9 eq.) and stirred for 10 min. Lipophilic alcohol (1 eq.) and dialkyl H-phosphonate (2 eq.) are added and the reaction stirred at room temperature for 24 h. The reaction is quenched with a saturated solution of ammonium chloride (5 mL/mmol) and filtrate on celite. Ethylacetate (AcOEt) (10 mL/mmol) is added to the solution then the organic and aqueous layers are separated. Aqueous phase is then extracted with AcOEt (10 mL/mmol) and the combinated organic layers are evaporated under vacuum. The corresponding alkyl/lipophilic chain H-phosphonate is finally purified by chromatography on silica gel.
Compound 1 is synthesized according to procedure 1.4. from dibenzylphosphite as reported by the scheme 1.
1H NMR (400 MHz, CDCl3) δ=7.74 (s, 0.5H, H—P), 7.41-7.33 (m, 5H, HAr), 5.99 (s, 0.5H, H—P), 5.11 (d, J=9.5 Hz, 3H, OCH3), 4.20-4.07 (m, 2H, P—O—CH2—CH2—CH2—O), 3.46 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.37 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.90 (p, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.53 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.35-1.19 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.87 (t, J=6.4 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3) δ=136.6, 128.7, 128.6, 127.9, 126.9 (CAr), 71.2 (O—CH2—CH2—(CH2)13—CH3), 67.2 (2C, CH2-Ph), 66.3 (P—O—CH2—CH2—CH2—O), 63.1, 63.0 (P—O—CH2—CH2—CH2—O), 31.9, 30.6 (2C), 29.7, 29.6 (2C), 29.5, 29.3, 26.1, 22.7 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=10.05.
Compound 2 is synthesized according to procedure 1.2. from dimethyl methylphosphonate as reported by the scheme 2
1H NMR (400 MHz, CDCl3) δ=5.59-5.50 (m, 4H, O—CH2—O), 1.47 (d, J=15.9, 3H, CH3—P), 1.11 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3) δ=176.5 (C═O), 81.1, 81.0 (O—CH2—O), 38.4 (C(CH3)3), 26.6 (C(CH3)3), 12.9, 11.5 (CH3—P).
31P NMR (162 MHz, CDCl3): δ=31.54
Compound 3 is synthesized according to procedure 1.1. from dibenzyl methylphosphonate as reported by the scheme 3.
1H NMR (400 MHz, CDCl3) δ=7.41-7.28 (m, 1H), 5.11-4.99 (m, 2H, CH2-Ph), 4.15-3.99 (m, 2H, P—O—CH2—CH2—CH2—O), 3.45 (t, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.36 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.87 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.53 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.46 (d, J=17.6 Hz, 3H, CH3—P), 1.32-1.20 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.87 (t, J=6.4 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3) δ=136.4 (2C), 128.5, 128.3, 127.8 (CAr), 71.2 (O—CH2—CH2—(CH2)13—CH3), 67.0 (2C, CH2-Ph), 66.5 (P—O—CH2—CH2—CH2—O), 62.9, 62.8 (P—O—CH2—CH2—CH2—O), 31.9, 30.8, 30.7, 30.3 (2C), 29.7, 29.6 (3C), 29.5, 29.3, 26.1, 22.6 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3), 11.9, 10.4 (CH3—P).
31P NMR (162 MHz, CDCl3): δ=31.23
Compound 4 is synthesized according to procedure 1.2. from dimethyl vinylphosphonate as reported by the scheme 4.
1H NMR (400 MHz, CDCl3): δ=6.45-6.03 (m, 3H, CH2═CH), 5.72-5.63 (m, 4H, O—CH2—O), 4.92 (sept., J=6.2 Hz, 2H, CH(CH3)2), 1.31 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=153.1 (C═O), 136.9, 136.8 (CH2═CH), 125.6, 123.7 (CH2═CH), 84.1, 84.0 (O—CH2—O), 73.2 (CH(CH3)2), 21.6 (CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=16.89.
Compound 5 is synthesized according to procedure 1.2. from dimethyl vinylphosphonate as reported by the scheme 5
1H NMR (400 MHz, CDCl3) δ=6.43-5.99 (m, 3H, CH2═CH), 5.74-5.60 (m, 4H, O—CH2—O), 1.21 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3) δ=176.7 (C═O), 136.6 (2C, CH2═CH), 126.0, 124.1 (CH2═CH), 81.5, 81.4 (O—CH2—O), 38.7, 38.4 (C(CH3)3), 27.0, 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3) δ=17.14.
Compound 6 is synthesized according to procedure 1.1. from dimethyl vinylphosphonate as reported by the scheme 6.
1H NMR (400 MHz, CDCl3): δ=6.37-5.93 (m, 3H, CH2═CH), 4.11 (q, J=6.5 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.70 (d, J=11.1 Hz, 3H, OCH3), 3.48 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.37 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.92 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.57-1.49 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.34-1.20 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.86 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3) δ=136.0 (2C, CH2═CH), 126.0, 124.1 (CH2═CH), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.5 (P—O—CH2—CH2—CH2—O), 63.2 (2C, P—O—CH2—CH2—CH2—O), 52.3 (2C, OCH3), 31.9, 30.8 (2C), 29.7, 29.6 (3C), 29.5, 29.3, 26.1, 22.6 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=18.80.
Compound 7 is synthesized according to procedure 1.2. from dimethyl allylphosphonate as reported by the scheme 7.
1H NMR (400 MHz, CDCl3) δ=5.74-5.57 (m, 5H, O—CH2—O, CH2═CH), 5.22-5.14 (m, 2H, CH2═CH), 2.64 (dd, J=22.6 Hz, J=7.3 Hz, 2H, P—CH2), 1.16 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3) δ=176.6 (C═O), 125.8, 125.7 (CH2═CH), 121.0, 120.9 (CH2═CH), 81.4, 81.3 (O—CH2—O), 38.6 (C(CH3)3), 32.7, 31.3 (CH2—P), 26.7 (C(CH3)3).
31P NMR (162 MHz, CDCl3) δ=27.71.
Compound 8 is synthesized according to procedure 1.2. from dimethyl allylphosphonate as reported by the scheme 8
1H NMR (400 MHz, CDCl3) δ=5.82-5.71 (m, 1H, CH2═CH), 5.68 (dd, 2H, J=5.4 Hz, 11.6 Hz, O—CH2—O), 5.65 (dd, 2H, J=5.4 Hz, 11.6 Hz, O—CH2—O), 5.30-5.22 (m, 2H, CH2═CH), 4.94 (sept., J=6.2 Hz, 2H, CH(CH3)2), 2.74 (tdd, J=22.8, 7.4, 1.1 Hz, 2H, P—CH2), 1.33 (d, J=6.28 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3) δ=153.2 (C═O), 125.7, 125.6 (CH2═CH), 121.3, 121.2 (CH2═CH), 84.1, 84.0 (O—CH2—O), 73.2 (CH(CH3)2), 32.9, 31.5 (CH2—P), 21.6 (CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=27.99.
Compound 9 is synthesized according to procedure 1.1. from dimethyl allylphosphonate as reported by the scheme 9.
1H NMR (400 MHz, CDCl3) δ=5.85-5.71 (m, 1H, CH2═CH), 5.26-5.16 (m, 2H, CH2═CH), 4.13 (dt, J=6.5, 1.7 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.73 (d, J=10.9 Hz, 3H, OCH3), 3.48 (t, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.38 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.62 (ddt, J=22.0, 7.4, 1.1 Hz, 2H, CH2—P), 1.91 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.54 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.32-1.22 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.86 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3) δ=127.3, 127.2 (CH2═CH), 120.1, 120.0 (CH2═CH), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.5 (P—O—CH2—CH2—CH2—O), 63.3 (2C, P—O—CH2—CH2—CH2—O), 52.6, 52.5 (OCH3), 31.9, 31.8, 30.9, 30.8, 30.4, 29.7, 29.6 (3C), 29.5, 29.3, 26.1, 22.7 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3) δ=28.3.
Compound 10 is synthesized according to procedure 1.3. from methyl HDP allylphosphonate obtained in example 9, as reported by the scheme 10.
1H NMR (400 MHz, CDCl3) δ=5.82-5.68 (m, 1H, CH2═CH), 5.68-5.58 (m, 1H, O—CH2—O), 5.26-5.17 (m, 2H, CH2═CH), 4.91 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.24-4.07 (m, 2H, P—O—CH2—CH2—CH2—O), 3.47 (t, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.37 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.67 (dd, J=22.4, 7.4 Hz, 2H, CH2—P), 1.91 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.57-1.49 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.33-1.20 (m, 32H, O—CH2—CH2—(CH2)13—CH3, CH(CH3)2), 0.86 (t, J=6.7 Hz, 3H, O—CH2—CH2—(CH2)13—CH3)
13C NMR (100 MHz, CDCl3) δ=153.2 (C═O), 126.6, 126.5 (CH2═CH), 120.6, 120.5 (CH2═CH), 84.4, 84.3 (O—CH2—O), 73.0, 71.2 (CH(CH3)2), 66.5 (P—O—CH2—CH2—CH2—O), 63.3 (2C, P—O—CH2—CH2—CH2—O), 32.7, 31.9, 31.3, 30.7 (2C), 29.7, 29.6 (2C), 29.5, 29.3, 26.1, 22.7, 21.6 (CH(CH3)2, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3) δ=26.7.
Compound 11 is synthesized according to procedure 1.2. from dimethylbenzyloxyphosphonate, as reported by the scheme 11.
1H NMR (400 MHz, CDCl3) δ=7.40-7.26 (m, 5H, HAr), 5.74-5.68 (d, J=12.7 Hz, 4H, O—CH2—O), 4.64 (s, 2H, Ph-CH2), 3.83 (d, J=8.2 Hz, 2H, O—CH2—P), 1.22 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3) δ=176.7 (C═O), 136.5, 128.4, 128.1, 128.0 (CAr), 81.6 (2C, O—CH2—O), 75.0, 74.9 (Ph-CH2), 64.7, 63.0 (O—CH2—P), 38.6 (C(CH3)3), 26.7 (C(CH3)3).
31P NMR (162 MHz, CDCl3) δ=21.79.
Compound 12 is synthesized according to the following scheme 12.
To a THF (5 mL/mmol) solution of bis-(POM)benzyloxymethylphosphonate prepared according to example 11.1. is added 5% Pd on activated carbon (0.05 eq. of Pd), and stirred under an hydrogen atmosphere for 12 h. The mixture is then filtrated, evaporated and purified by chromatography on silica gel (50% AcOEt/EP) to give pure bis-(POM)hydroxymethylphosphonate.
1H NMR (400 MHz, CDCl3) δ ppm 5.72-5.55 (m, 4H, O—CH2—O), 3.97 (d, J=5.3 Hz, 2H, O—CH2—P), 1.22 (s, 18H, (C(CH3)3).
13C NMR (100 MHz, CDCl3) δ ppm 177.0 (C═O), 81.8, 81.7 (O—CH2—O), 58.2, 56.6 (O—CH2—P), 38.7 (C(CH3)3), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3) δ=24.07.
Compound 13 is synthesized according to the following scheme 14 from compound 7 as reported by the scheme 13.
To a dichloromethane (20 mL/mmol) solution of bis-(POM)allylphosphonate and 2-buten-1,4-diol under argon is added ImesRuCl2(PPh3)2 (0.05 eq.) and reflux for 12 h. After evaporation of all volatiles, the residue is purified by chromatography on silica gel (50% AcOEt/EP) to give pure bis-(POM) 1-hydroxymethyl-allylphosphonate.
1H NMR (400 MHz, CDCl3) δ ppm=5.88-5.79 (m, 1H, CH═CH), 5.73-5.55 (m, 5H, CH═CH, O—CH2—O), 4.11 (t, J=7.4 Hz, HOCH2, 2H), 2.68 (dd, J=22.4, 7.3 Hz, 2H, CH2—P), 2.03 (s, 1H, OH), 1.22 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3) δ ppm=176.9 (C═O), 135.9, 135.7 (CH═CH), 119.0, 118.9 (CH═CH), 81.6, 81.5 (O—CH2—O), 62.9 (2C, HOCH2), 38.7 (C(CH3)3), 31.4, 30.1 (CH2—P), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=27.54.
Compound 14 is synthesized according to the following scheme 14 from compound 7.
1H NMR (400 MHz, CDCl3) δ ppm=5.93-5.83 (m, 1H, CH═CH), 5.74-5.62 (m, 5H, CH═CH, O—CH2—O), 3.92 (dd, J=7.5, 3.5 Hz, BrCH2, 2H), 2.70 (dd, J=22.7, 7.3 Hz, CH2—P, 2H), 1.23 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3) δ ppm=176.9 (C═O), 135.9, 135.7 (CH═CH), 119.0, 118.9 (CH═CH), 81.6, 81.5 (O—CH2—O), 62.9 (2C, HOCH2), 38.7 (C(CH3)3), 31.4, 30.1 (CH2—P), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.77.
Compound 15 is synthesized according to the following scheme 15 from compound 12.
To a dichloromethane (2 mL/mmol) solution of bis-(POM) hydroxymethylphosphonate obtained in example 12.2 and 2,6 lutidine under argon is added trifluoromethanesulfonic anhydride at −50° C. at stirred 10 minutes. The mixture is then allowed to warm to 0° C. and stirred for 2 h. The mixture is then diluted in diethyl ether (15 ml/mmol), washed with water (5 mL/mmol). After evaporation of volatiles, the residue is purified by chromatography on silica gel (15% AcOEt/EP) to give pure bis-(POM) trifluoromethanesulfonic oxymethylphosphonate.
1H NMR (400 MHz, CDCl3) δ=5.78 (dd, J=12.1, 5.2 Hz, 2H), 5.69 (dd, J=12.1, 5.2 Hz, 2H), 4.70 (d, J=9.2 Hz, 2H), 1.23 (s, 18H).
13C NMR (100 MHz, CDCl3) δ=176.9 (C═O), 118.4 (q, J=318 Hz, CF3), 82.2 (2C, O—CH2—O), 67.0, 65.3 (CH2—P), 38.7 (C(CH3)3), 26.7 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=12.17.
To a CH2Cl2 (25 mL/mmol) solution of N1-crotyl-5-substituted uracil (1 eq.) and bis-(POM)allylphosphonate (1.3 eq.) prepared in example 8, IMes Catalyst (0.05 eq.) was added. This solution was gently refluxed for indicated time under positive pressure of dry argon. After evaporation of all volatiles, the residue was purified by chromatography on silica gel (EtOAc/EP).
The procedure is illustrated in the following scheme
Compounds of the following examples 17 to 21 are prepared according to this general procedure.
1H NMR (400 MHz, CDCl3) δ=8.73 (s, 1H, NH), 7.17 (d, J=7.9 Hz, 1H, H6), 5.75-5.61 (m, 7H, O—CH2—O, CH═CH, H5), 4.32 (t, J=4.1 Hz, 2H, U—CH2), 2.72 (dd, J=22.4 Hz, 5.0 Hz, 2H, P—CH2), 1.23 (s, 18H, tBu).
13C NMR (100 MHz, CDCl3) δ=176.8 (C═O), 163.2 (C═O), 150.5 (C═O), 143.4 (C6), 129.5, 129.3 (CH═CH), 124.1, 124.0 (CH═CH), 102.6 (C5), 81.6, 81.5 (O—CH2—O), 49.1, 49.0 (U—CH2), 38.7 (C(CH3)3), 31.5, 30.1 (P—CH2), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3) δ=26.4.
IR ν cm−1: 2977; 1751; 1685; 1459; 1242; 1138; 956; 855.
1H NMR (400 MHz, CDCl3) δ=8.32 (s, 1H, NH), 7.47 (d, J=7.9 Hz, 1H, H6), 5.77-5.60 (m, 7H, O—CH2—O, CH═CH, H5), 4.44 (t, J=4.7 Hz, 2H, U—CH2), 2.82 (dd, J=23.4, 6.7 Hz, 2H, P—CH2), 1.24 (s, 18H, tBu).
13C NMR (100 MHz, CDCl3) δ=177.0 (C═O), 163.2 (C═O), 150.6 (C═O), 144.4 (C6), 129.1, 128.9 (CH═CH), 122.1, 122.0 (CH═CH), 102.5 (C5), 81.6, 81.5 (O—CH2—O), 44.8, 44.7 (U—CH2), 38.8 (C(CH3)3), 27.0 and 25.6 (P—CH2), 26.9 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.6.
1H NMR (400 MHz, CDCl3): δ=9.58 (s, 1H, NH), 7.28 (d, J=5.5 Hz, 1H, H6), 5.77-5.61 (m, 6H, O—CH2—O, CH═CH), 4.31 (t, J=4.9 Hz, 2H, U—CH2), 2.72 (dd, J=22.6 Hz, 5.3 Hz, 2H, P—CH2), 1.22 (s, 18H, tBu).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 157.2, 156.9 (C═O), 149.3 (C═O), 141.7, 139.3 (C5), 129.1, 128.9 (CH═CH), 127.7, 127.4 (C6), 124.7, 124.6 (CH═CH), 81.6, 81.5 (O—CH2—O), 49.3 (2C, U—CH2), 38.6 (C(CH3)3), 31.4, 30.0 (P—CH2), 26.7 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.3.
IR ν cm−1: 2977; 2361; 1752; 1702; 1480; 1238; 1137; 965; 871
1H NMR (400 MHz, CDCl3): δ=8.59 (s, 1H, NH), 7.73 (d, J=5.8 Hz, 1H, H6), 5.75-5.61 (m, 6H, O—CH2—O, CH═CH), 4.44 (t, J=4.7 Hz, 2H), 2.80 (dd, J=6.8 Hz, 23.5 Hz, 2H, P—CH2), 1.23 (s, 18H, tBu).
13C NMR (100 MHz, CDCl3): δ=177.0 (C═O), 157.0, 156.7 (C═O), 149.2 (C═O), 141.7, 139.4 (C5), 128.9, 128.7, 128.6 (2C, CH═CH, and C6), 122.6, 122.5 (CH═CH), 81.7, 81.6 (O—CH2—O), 44.9 (2C, U—CH2), 38.8 (C(CH3)3), 26.9 and 25.5 (P—CH2), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.4.
1H NMR (400 MHz, CD3OD): δ=7.37 (d, J=0.9 Hz, 1H, H6), 5.85-5.74 (ttd, J=5.1 Hz, 11.2 Hz, 15.4 Hz, 1H, CH═CH), 5.66 (m, 5H, O—CH2—O, CH═CH), 4.32 (t, J=5.2 Hz, 2H, T-CH2), 2.82 (dd, J=22.5 Hz, 7.2 Hz, 2H, P—CH2), 1.87 (s, 3H, CH3—U) 1.23 (s, 18H, tBu).
13C NMR (100 MHz, CD3OD): δ=178.1 (C═O), 166.8 (C═O), 152.7 (C═O), 142.4 (C6), 131.8, 131.6 (CH═CH), 123.7, 123.6 (CH═CH), 111.5 (C5), 83.2, 83.1 (O—CH2—O), 49.9 (2C, U—CH2), 39.7 (C(CH3)3), 31.8, 30.4 (P—CH2), 27.2 (C(CH3)3), 12.3 (CH3—U).
31P NMR (162 MHz, CD3OD): δ=27.3.
IR ν cm−1: 2929; 1678; 1453, 1396; 1196; 986; 751
1H NMR (400 MHz, CD3OD): δ ppm 7.46 (d, J=1.2 Hz, 1H, H6), 5.78-5.60 (m, 7H, O—CH2—O, CH═CH), 4.40 (dd, J=3.8 Hz, 5.5 Hz, 2H), 3.01 (dd, J=23.2, 7.8 Hz, 2H, P—CH2), 1.88 (d, J=1.11 Hz, 3H, CH3—U), 1.24 (d, J=3.16 Hz, 18H, tBu).
13C NMR (100 MHz, CD3OD): δ=178.2 (C═O), 166.9 (C═O), 152.9 (C═O), 142.7 (C6), 130.6, 130.4 (CH═CH), 123.0, 122.8 (CH═CH), 111.5 (C5), 83.2, 83.1 (O—CH2—O), 45.6 (U—CH2), 39.8 (C(CH3)3), 27.7 and 26.3 (P—CH2), 27.3 (C(CH3)3), 12.3 (CH3—U).
31P NMR (162 MHz, CD3OD): δ=27.6.
1H NMR (400 MHz, CDCl3): δ=8.73 (s, 1H, NH), 7.42 (s, 1H, H6), 5.80-5.60 (m, 6H, O—CH2—O, CH═CH), 4.33 (t, J=4.5 Hz, 2H, U—CH2), 2.72 (dd, J=5.7 Hz, 22.6 Hz, 2H, P—CH2), 1.23 (s, 18H, tBu).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 158.8 (C═O), 149.4 (C═O), 140.3 (C6), 129.0, 128.8 (CH═CH), 125.0, 124.9 (CH═CH), 109.0 (C5), 81.6 (2C, O—CH2—O), 49.5 (2C, U—CH2), 38.7 (C(CH3)3), 31.5, 30.1 (P—CH2), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.1.
IR ν cm−1: 2976; 1752; 1692; 1452; 1236; 1135; 963; 853.
1H NMR (400 MHz, CDCl3): δ=8.48 (s, 1H, NH), 7.79 (s, 1H, H6), 5.74-5.62 (m, 6H, O—CH2—O, CH═CH), 4.47 (t, J=4.63 Hz, 2H, U—CH2), 2.82 (dd, J=23.5 Hz, 6.9 Hz, 2H, P—CH2), 1.24 (s, 18H).
13C NMR (100 MHz, CDCl3): δ=177.0 (C═O), 158.9 (C═O), 149.7 (C═O), 141.3 (C6), 128.6, 128.4 (CH═CH), 122.7, 122.6 (C6), 108.9 (C5), 81.7, 81.6 (O—CH2—O), 45.1 (2C, U—CH2), 38.8 (C(CH3)3), 27.0 and 25.6 (P—CH2), 26.8 (C(CH3)3).
1H NMR (400 MHz, CD3OD): δ=7.98 (s, 1H, H6), 5.85-5.76 (m, 1H, CH═CH), 5.75-5.62 (m, 5H, O—CH2—O, CH═CH), 4.36 (t, J=5.1 Hz, 2H, U—CH2), 2.82 (dd, J=22.5 Hz, 6.9 Hz, 2H, P—CH2), 1.23 (s, 18H, tBu).
13C NMR (100 MHz, CD3OD): δ=178.1 (C═O), 162.1 (C═O), 152.0 (C═O), 146.2 (C6), 131.4, 131.3 (CH═CH), 124.5, 124.4 (CH═CH), 96.8 (C5), 83.3, 83.2 (O—CH2—O), 50.6, 50.5 (U—CH2), 39.8 (C(CH3)3), 31.9, 30.5 (P—CH2), 27.2 (C(CH3)3).
31P NMR (162 MHz, CD3OD): δ=27.1.
IR ν cm−1: 2976; 2361; 1751; 1693; 1441; 1235; 1137; 965; 854, 768.
1H NMR (400 MHz, CD3OD): δ=8.06 (s, 1H, H6), 5.70-5.52 (m, 6H, O—CH2—O, CH═CH), 4.45 (dd, J=6.8 Hz, 3.7 Hz, 2H), 3.01 (dd, J=23.4, 7.8 Hz, 2H), 1.24 (s, 18H).
13C NMR (100 MHz, CD3OD): δ=178.2 (C═O), 162.2 (C═O), 152.1 (C═O), 146.3 (C6), 130.1, 129.9 (CH═CH), 123.5, 123.4 (CH═CH), 96.7 (C5), 83.2, 83.1 (O—CH2—O), 46.2 (2C, U—CH2), 39.8 (C(CH3)3), 27.7 and 26.3 (P—CH2), 27.3 (C(CH3)3).
31P NMR (100 MHz, CD3OD): δ=27.5.
To a CH2Cl2 (25 mL/mmol) solution of N1-crotyl-5-substituted uracil (1 eq.) and bis-(POC) allylphosphonate (1.3 eq.) prepared according to example 9, IPr Catalyst (0.05 eq.) was added. This solution was stirred at room temperature for indicated time under positive pressure of dry argon. After evaporation of all volatiles, the residue was purified by chromatography on silica gel (EtOAc/EP).
The procedure is illustrated in the following scheme
Compounds of the following examples 23 to 27 are prepared according this general procedure.
1H NMR (400 MHz, CDCl3) δ=8.94 (s, 1H, NH), 7.19 (d, J=7.9 Hz, 1H, H6), 5.74-5.61 (m, 7H, O—CH2—O, CH═CH, H5), 4.92 (sept., J=6.2 Hz, 2H, CH(CH3)2), 4.33 (t, J=4.4 Hz, 2H, U—CH2), 2.76 (dd, J=22.8, 5.6 Hz, 2H, P—CH2), 1.32 (d, J=6.3 Hz, 12H, CH(CH3)2). 13C NMR (100 MHz, CDCl3) δ=163.3 (C═O), 153.0 (C═O), 150.6 (C═O), 143.4 (C6), 129.7, 129.6 (CH═CH), 123.8, 123.7 (CH═CH), 102.5 (C5), 84.1, 84.0 (O—CH2—O), 73.4 (CH(CH3)2), 48.9 (2C, U—CH2), 31.3, 29.9 (P—CH2), 21.6 (CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.8.
IR ν cm−1: 2896; 1755; 1679; 1457; 1257; 1152; 1100; 981; 949; 830.
1H NMR (400 MHz, CDCl3): δ=8.36 (s, 1H, NH), 7.30 (d, J=5.6 Hz, 1H, H6), 5.80-5.60 (m, 7H, O—CH2—O, CH═CH, H5), 4.93 (sept, J=6.3 Hz, 2H, CH(CH3)2), 4.32 (t, J=4.17 Hz, 2H, U—CH2), 2.77 (dd, J=22.9, 5.5 Hz, 2H, P—CH2), 1.33 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=163.5 (C═O), 153.1 (C═O), 148.8 (C═O), 141.7 (C6), 129.2, 129.1 (CH═CH), 127.8, 127.5 (CH═CH), 124.6, 124.5 (CH═CH), 84.2, 84.1 (O—CH2—O), 73. (CH(CH3)2), 49.3 (2C, U—CH2), 31.3, 29.9 (P—CH2), 21.6 (2C, CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.6.
1H NMR (400 MHz, CDCl3): δ=9.06 (s, 1H, NH), 7.00 (d, J=1.0 Hz, 1H, H6), 5.76-5.60 (m, 6H, O—CH2—O, CH═CH), 4.91 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.30 (t, J=4.6 Hz, 2H, U—CH2), 2.74 (dd, J=22.6 Hz, 5.9 Hz, 2H, P—CH2), 1.90 (d, J=0.7 Hz, 3H, CH3—U), 1.31 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=164.0 (C═O), 153.0 (C═O), 150.7 (C═O), 139.4 (C6), 130.1, 130.0 (CH═CH), 123.3, 123.1 (CH═CH), 111.0 (C5), 84.1, 84.0 (O—CH2—O), 73.3 (CH(CH3)2), 48.7 (2C, U—CH2), 31.3, 29.9 (P—CH2), 21.5 (2C, CH(CH3)2), 12.2 (CH3—U).
31P NMR (162 MHz, CDCl3): δ=27.0.
IR ν cm−1: 2985; 1756; 1679; 1467; 1257; 1152; 1101; 982; 950; 831; 788.
1H NMR (400 MHz, CDCl3): δ=8.13 (s, 1H, NH), 7.23 (d, J=1.2 Hz, 1H, H6), 5.76-5.61 (m, 6H, O—CH2—O, CH═CH), 5.00-4.87 (sept, J=6.3 Hz, 2H, CH(CH3)2), 4.41 (t, J=4.6 Hz, 2H, U—CH2), 2.88 (dd, J=23.2, 6.3 Hz, 2H, P—CH2), 1.92 (s, 3H, CH3—U), 1.33 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=163.7 (C═O), 153.1 (C═O), 150.6 (C═O), 140.1 (C6), 129.4, 129.3 (CH═CH), 121.6, 121.5 (CH═CH), 110.9 (C5), 84.1 (2C, O—CH2—O), 73.4 (CH(CH3)2), 44.4 (2C, U—CH2), 27.0, 25.6 (P—CH2), 21.6 (CH(CH3)2), 12.2 (CH3—U).
31P NMR (162 MHz, CDCl3): δ=26.8.
1H NMR (400 MHz, CDCl3): δ=9.44 (s, 1H, NH), 7.31 (d, J=5.5 Hz, 1H, H6), 5.78-5.61 (m, 6H, O—CH2—O, CH═CH), 4.92 (sept, J=6.3 Hz, 2H, CH(CH3)2), 4.32 (t, J=4.6 Hz, 2H, U—CH2), 2.77 (dd, J=23.0, 5.1 Hz, 2H, P—CH2), 1.31 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=157.2, 156.9 (C═O), 153.1 (C═O), 149.3 (C═O), 141.8, 139.4 (C5), 129.4, 129.2 (CH═CH), 127.8, 127.5 (C6), 124.4, 124.3 (CH═CH), 84.2 (2C, O—CH2—O), 73.5 (CH(CH3)2), 49.3, 49.2 (U—CH2), 31.3, 29.9 (P—CH2), 21.6 (2C, CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.8.
IR ν cm−1: 2987; 1756; 1694; 1468; 1259; 1152; 1101; 981; 949; 870; 831; 787.
1H NMR (400 MHz, CDCl3): δ=8.40 (s, 1H, NH), 7.70 (d, J=5.8 Hz, 1H, H6), 5.78-5.61 (m, 6H, O—CH2—O, CH═CH), 4.94 (sept, J=6.3 Hz, 2H, CH(CH3)2), 4.45 (t, J=4.8 Hz, 2H, U—CH2), 2.93-2.79 (dd, J=23.7, 6.8 Hz, 2H, P—CH2), 1.33 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=157.2, 156.9 (C═O), 153.178 (C═O), 149.2 (C═O), 128.9, 128.7 (CH═CH), 122.4, 122.2 (CH═CH), 84.3 (2C, O—CH2—O), 73.5 (CH(CH3)2), 44.9 (2C, U—CH2), 26.9, 25.5 (P—CH2), 21.6 (CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.6.
1H NMR (400 MHz, CDCl3): δ=9.31 (s, 1H, NH), 7.45 (s, 1H, H6), 5.76-5.61 (m, 6H, O—CH2—O, CH═CH), 4.92 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.34 (t, J=4.2 Hz, 2H, U—CH2), 2.77 (dd, J=22.8, 5.6 Hz, 2H, P—CH2), 1.31 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=159.1 (C═O), 153.0 (C═O), 149.7 (C═O), 140.4 (C6), 129.3, 129.2 (CH═CH), 124.5, 124.4 (CH═CH), 109.0 (C5), 84.2, 84.1 (O—CH2—O), 73.4 (CH(CH3)2), 49.4 (2C, U—CH2), 31.3, 29.9 (P—CH2), 21.6, 21.5 (CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.7.
IR ν cm−1: 2986; 1756; 1686; 1451; 1348; 1258; 1152; 1186; 981; 949; 903; 869; 831; 787.
1H NMR (400 MHz, CDCl3): δ=8.79 (s, 1H, NH), 7.76 (s, 1H, H6), 5.74-5.61 (m, 6H, O—CH2—O, CH═CH), 4.93 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.47 (t, J=4.7 Hz, 2H, U—CH2), 2.87 (dd, J=23.6, 6.7 Hz, 2H, P—CH2), 1.32 (d, J=6.3 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=159.0 (C═O), 153.1 (C═O), 149.7 (C═O), 141.3 (C6), 128.7, 128.6 (CH═CH), 122.4, 122.3 (CH═CH), 108.9 (C5), 84.2, 84.1 (O—CH2—O), 73.5 (CH(CH3)2), 45.1, 45.0 (U—CH2), 26.9, 25.5 (P—CH2), 21.6 (CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.6.
1H NMR (400 MHz, CDCl3): δ=9.45 (s, 1H, NH), 7.51 (s, 1H, H6), 5.75-5.55 (m, 6H, O—CH2—O, CH═CH), 4.87 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.29 (t, J=4.1 Hz, 2H, U—CH2), 2.72 (dd, J=22.4, 5.2 Hz, 2H, P—CH2), 1.26 (d, J=6.27 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=159.3 (C═O), 153.1 (C═O), 150.0 (C═O), 143.0 (C6), 129.4, 129.3 (CH═CH), 124.5, 124.4 (CH═CH), 96.7 (C5), 84.2 (2C, O—CH2—O), 73.4 (CH(CH3)2), 49.4 (2C, U—CH2), 31.3, 29.9 (P—CH2), 21.6 (2C, CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.8.
IR ν cm−1: 2986; 1756; 1691; 1442; 1347; 1260; 1153; 1186; 1029; 983; 951; 871; 832; 789.
1H NMR (400 MHz, CDCl3): δ=8.40 (s, 1H, NH), 7.86 (s, 1H, H6), 5.76-5.61 (m, 6H, O—CH2—O, CH═CH), 4.94 (sept, J=6.3 Hz, 2H, CH(CH3)2), 4.47 (t, J=4.6 Hz, 2H, U—CH2), 2.87 (dd, J=23.6, 6.8 Hz, 2H, P—CH2), 1.33 (d, J=6.2 Hz, 12H, CH(CH3)2).
13C NMR (100 MHz, CDCl3): δ=159.0 (C═O), 153.2 (C═O), 149.9 (C═O), 143.9 (C6), 128.7, 128.6 (CH═CH), 122.5, 122.4 (CH═CH), 96.5 (C5), 84.3, 84.2 (O—CH2—O), 73.5 (CH(CH3)2), 45.1 (2C, U—CH2), 27.0, 25.6 (P—CH2), 21.6 (2C, CH(CH3)2).
31P NMR (162 MHz, CDCl3): δ=26.6.
28.1. General Procedure for Cross-Metathesis with IPr NHC Catalysts
To a CH2Cl2 (25 mL/mmol) solution of N1-crotyl-5-substituted uracil (1 eq.) and HDP-POC-allylphosphonate (1.3 eq.) prepared according to example 11, IPr Catalyst (0.05 eq.) was added. This solution was stirred a room temperature for indicated time under positive pressure of dry argon. After evaporation of all volatiles, the residue was purified by chromatography on silica gel (EtOAc/EP).
To N1-[(E)-O-hexadecyloxypropyl isopropyloxycarbonyloxymethyl-phosphinyl-2-butenyl]-5-substituted uracil prepared in example 28.1 was added a 0.1M solution (1 ml) of sodium hydroxide in demineralized water. This solution was stirred a room temperature for 4 h. The basic solution is neutralized with acidic DOWEX resin 50w8 and washed two times with DCM (1 ml). Pure product is directly obtain after evaporation of all volatiles,
Compounds of examples 29 to 38 are synthesized according to said general procedure
1H NMR (400 MHz, CDCl3): δ=8.93 (s, 1H, NH), 7.18 (d, 1H, J=7.9 Hz, H6), 5.73-5.68 (m, 3H, CH═CH, H5), 5.63 (td, J=13.9, 5.3 Hz, 2H, O—CH2—O) 4.92 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.39-4.26 (m, 2H, U—CH2), 4.25-4.08 (m, 2H, P—O—CH2—CH2—CH2—O), 3.46 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.38 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.69 (dd, J=22.0, 5.2 Hz, 2H, CH2—P), 1.91 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.54 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.34-1.20 (m, 32H, O—CH2—CH2—(CH2)13—CH3, CH(CH3)2), 0.87 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3): δ=163.3 (C═O), 153.1 (C═O), 150.5 (C═O), 143.4 (C6), 129.0, 128.9 (CH═CH), 124.7, 124.6 (CH═CH), 102.5 (C5), 84.4, 84.3 (O—CH2—O), 73.2 (CH(CH3)2), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.3 (P—O—CH2—CH2—CH2—O), 63.5 (2C, P—O—CH2—CH2—CH2—O), 49.0 (2C, U—CH2), 31.8, 31.1, 30.7, 30.6, 29.7, 29.6 (3C), 29.5, 29.4, 29.3, 26.1, 22.6, 21.6 (CH2—P, CH(CH3)2, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.0 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=26.7.
1H NMR (400 MHz, CDCl3): δ=9.44 (s, 1H, NH), 7.43 (s, 1H, H6), 5.80-5.60 (m, 4H, CH═CH, O—CH2—O), 4.91 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.38-4.29 (m, 2H, U—CH2), 4.23-4.10 (m, 2H, P—O—CH2—CH2—CH2—O), 3.46 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.37 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.71 (dd, J=22.5, 6.6 Hz, 2H, CH2—P), 1.91 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.53 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.32-1.22 (m, 32H, O—CH2—CH2—(CH2)13—CH3, CH(CH3)2), 0.86 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3): δ=159.1 (C═O), 153.2 (C═O), 149.8 (C═O), 140.3 (C6), 128.6, 128.5 (CH═CH), 125.6, 125.5 (CH═CH), 109.0 (C5), 84.5, 84.4 (O—CH2—O), 73.2 (CH(CH3)2), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.4 (P—O—CH2—CH2—CH2—O), 63.7, 63.6 (P—O—CH2—CH2—CH2—O), 49.5, 49.4 (U—CH2), 31.9, 31.1, 30.7, 30.6, 29.7 (2C), 29.6 (2C), 29.5, 29.3, 26.1, 22.6, 21.6 (2C)(CH2—P, CH(CH3)2, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=26.6.
1H NMR (400 MHz, CDCl3): δ=8.58 (s, 1H, NH), 7.54 (s, 1H, H6), 5.84-5.59 (m, 4H, CH═CH, O—CH2—O), 4.93 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.40-4.30 (m, 2H, U—CH2), 4.26-4.08 (m, 2H, P—O—CH2—CH2—CH2—O), 3.47 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.39 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.72 (dd, J=22.5, 6.8 Hz, 2H, CH2—P), 1.92 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.55 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.34-1.22 (m, 32H, O—CH2—CH2—(CH2)13—CH3, CH(CH3)2), 0.88 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3): δ=158.9 (C═O), 153.2 (C═O), 149.7 (C═O), 142.9 (C6), 128.6, 128.4 (CH═CH), 125.8, 125.7 (CH═CH), 96.7 (C5), 84.5 (2C, O—CH2—O), 73.3 (CH(CH3)2), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.4 (P—O—CH2—CH2—CH2—O), 63.7, 63.6 (P—O—CH2—CH2—CH2—O), 49.5 (2C, U—CH2), 31.9, 31.2, 30.7 (2C), 29.8, 29.7, (2C), 29.6 (2C), 29.5, 29.3, 26.2, 22.7, 21.7, 21.6 (CH2—P, CH(CH3)2, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=26.5
1H NMR (400 MHz, CDCl3): δ=9.08 (s, 1H, NH), 7.02 (d, J=3.9 Hz, 1H, H6), 5.73-5.48 (m, 4H, CH═CH, O—CH2—O), 4.92 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.52 (t, J=4.4 Hz, 2H, U—CH2), 4.22-4.08 (m, 2H, P—O—CH2—CH2—CH2—O), 3.47 (t, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.39 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.64 (dd, J=22.2, 5.9 Hz, 2H, CH2—P), 1.91 (m, 5H, P—O—CH2—CH2—CH2—O, CH3—U), 1.53 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.34-1.24 (m, 32H, O—CH2—CH2—(CH2)13—CH3, CH(CH3)2), 0.88 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3): δ=163.6 (C═O), 153.2 (C═O), 152.2 (C═O), 134.3 (C6), 129.6 (2C, CH═CH), 122.6, 122.5 (CH═CH), 110.0 (C5), 84.5 (2C, O—CH2—O), 77.2 (C5), 73.1 (CH(CH3)2), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.5 (P—O—CH2—CH2—CH2—O), 63.5, 63.4 (P—O—CH2—CH2—CH2—O), 41.8 (2C, U—CH2), 31.9, 31.3, 30.8, 30.7, 29.9, 29.7 (2C), 29.6 (2C), 29.5, 29.4, 26.2, 22.7, 21.7 (CH2—P, CH(CH3)2, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.1 (O—CH2—CH2—(CH2)13—CH3), 12.9 (CH3—U).
31P NMR (162 MHz, CDCl3): δ=26.6
1H NMR (400 MHz, CDCl3): δ=8.67 (d, J=3.6 Hz, 1H, NH), 7.29 (d, J=5.5 Hz, 1H, H6), 5.82-5.59 (m, 4H CH═CH, O—CH2—O), 4.93 (sept., J=6.3 Hz, 2H, CH(CH3)2), 4.38-4.26 (m, 2H, U—CH2), 4.25-4.11 (m, 2H, P—O—CH2—CH2—CH2—O), 3.47 (t, J=6.10 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.38 (t, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.72 (dd, J=22.4, 6.6 Hz, 2H, CH2—P), 1.92 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.53 (p, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.35-1.19 (m, 32H, O—CH2—CH2—(CH2)13—CH3, CH(CH3)2), 0.88 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3): δ=156.9, 156.6 (C═O), 153.2 (C═O), 149.0 (C═O), 141.7, 139.3 (C6), 128.6, 128.4 (CH═CH), 127.7, 127.4 (C6), 125.7, 125.6 (CH═CH), 84.5, 84.4 (O—CH2—O), 73.3 (CH(CH3)2), 71.2 (O—CH2—CH2—(CH2)13—CH3), 66.4 (P—O—CH2—CH2—CH2—O), 63.7, 63.6 (P—O—CH2—CH2—CH2—O), 49.4, 49.3 (U—CH2), 31.9 (2C), 31.2, 30.7 (2C), 29.8, 29.7, 29.6 (2C), 29.5 (2C), 29.3 (2C), 26.2, 22.7, 21.6 (2C)(CH2—P, CH(CH3)2, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3) 14.1 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=26.5
1H NMR (400 MHz, CD3OD): δ=7.54 (d, 1H, J=7.9 Hz, H6), 5.78-5.72 (m, 2H, CH═CH), 5.66 (dd, J=7.8, 1.9 Hz, 1H, H5), 4.35 (t, J=4.1 Hz, 2H, U—CH2), 4.07 (q, J=6.5 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.51 (t, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.42 (t, J=6.6 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.64 (dd, J=22.0, 5.3 Hz, 2H, CH2—P), 1.88 (p, J=6.24 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.56 (p, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.38-1.25 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.90 (t, J=6.9 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CDCl3): δ=166.7 (C═O), 152.7 (C═O), 146.7 (C6), 129.9, 129.8 (CH═CH), 126.6, 126.5 (CH═CH), 102.5 (C5), 72.2 (O—CH2—CH2—(CH2)13—CH3), 67.8 (P—O—CH2—CH2—CH2—O), 64.0, 63.9 (P—O—CH2—CH2—CH2—O), 50.3 (2C, U—CH2), 33.1, 32.0, 30.8 (2C), 30.7, 30.5, 27.3, 23.8 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.5 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CDCl3): δ=25.9.
1H NMR (400 MHz, CD3OD): δ=7.89 (s, 1H, H6), 5.85-5.68 (m, 2H, CH═CH), 4.35 (t, J=4.2 Hz, 2H, U—CH2), 4.07 (q, J=6.5 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.51 (t, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.42 (t, J=6.6 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.64 (dd, J=21.6, 5.9 Hz, 2H, CH2—P), 1.89 (p, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.56 (p, 1H, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.39-1.25 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.90 (t, J=6.9 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CD3OD): δ=161.9 (C═O), 151.8 (C═O), 143.6 (C6), 129.6, 129.4 (CH═CH), 127.2, 127.1 (CH═CH), 109.0 (C5), 72.2 (O—CH2—CH2—(CH2)13—CH3), 67.8 (P—O—CH2—CH2—CH2—O), 63.9 (2C, P—O—CH2—CH2—CH2—O), 50.6 (2C, U—CH2), 33.1, 32.1, 32.0, 30.8 (2C), 30.7, 30.5, 27.3, 23.8 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.5 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CD3OD): δ=25.4.
1H NMR (400 MHz, CD3OD): δ=7.98 (s, 1H, H6), 5.83-5.70 (m, 2H, CH═CH), 4.36 (t, J=3.9 Hz, 2H, U—CH2), 4.08 (q, J=6.5 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.51 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.42 (t, J=6.6 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.65 (dd, J=21.6, 5.4 Hz, 2H, CH2—P), 1.89 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.55 (p, 2H, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.40-1.23 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.90 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CD3OD): δ=152.1 (C═O), 146.2 (C═O, C6), 129.8, 129.6 (CH═CH), 127.0, 126.9 (CH═CH), 96.7 (C5), 72.2 (O—CH2—CH2—(CH2)13—CH3), 67.7 (P—O—CH2—CH2—CH2—O), 64.0 (2C, P—O—CH2—CH2—CH2—O), 50.6 (2C, U—CH2), 33.1, 32.0 2C), 31.9, 30.8 (2C), 30.7, 30.5, 27.4, 23.8 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.5 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CD3OD): δ=25.7.
1H NMR (400 MHz, CD3OD): δ=7.78 (d, J=6.2 Hz, 1H, H6), 5.83-5.69 (m, 1H, CH═CH)), 4.31 (t, J=4.2 Hz, 2H, U—CH2), 4.07 (q, J=6.4 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.51 (t, J=6.2 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.42 (t, J=6.6 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.64 (dd, J=21.6, 6.0 Hz, 2H, CH2—P), 1.89 (p, J=6.3 Hz, 2H, P—O—CH2—CH2—CH2—O), 1.55 (p, J=6.7 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.35-1.25 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.90 (t, J=6.8 Hz, 3H, O—CH2—CH2—(CH2)13—CH3).
13C NMR (100 MHz, CD3OD): δ=159.9, 159.7 (C═O), 151.3 (C═O), 142.9, 140.6 (C5), 130.7, 130.4 (C6), 129.5, 129.4 (CH═CH), 127.2, 127.1 (CH═CH), 72.2 (O—CH2—CH2—(CH2)13—CH3), 67.8 (P—O—CH2—CH2—CH2—O), 63.9, 63.8 (P—O—CH2—CH2—CH2—O), 50.4 (2C, U—CH2), 33.1, 32.0 (3C), 30.8 (2C), 30.7, 30.5, 27.3, 23.8 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 14.5 (O—CH2—CH2—(CH2)13—CH3).
31P NMR (162 MHz, CD3OD): δ=25.4.
1H NMR (400 MHz, CD3OD): δ=7.22 (d, J=1.1 Hz, 1H, H6), 5.78-5.64 (m, 2H, CH═CH), 4.50 (m, 2H, U—CH2), 4.05 (m, 2H, P—O—CH2—CH2—CH2—O), 3.50 (t, J=6.1 Hz, 2H, P—O—CH2—CH2—CH2—O), 3.43 (dt, J=6.5 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 2.59 (d, J=18.4 Hz, 2H), 1.94-1.83 (m, 5H, P—O—CH2—CH2—CH2—O, CH3—U)), 1.60-1.51 (p, 2H, J=6.9 Hz, 2H, O—CH2—CH2—(CH2)13—CH3), 1.37-1.24 (m, 26H, O—CH2—CH2—(CH2)13—CH3), 0.90 (t, J=6.9 Hz, 3H, CH3—U).
13C NMR (100 MHz, CD3OD): δ=166.0 (C═O), 153.2 (C═O), 137.5 (C6), 110.0 (C5), 72.2 (O—CH2—CH2—(CH2)13—CH3), 67.8 (P—O—CH2—CH2—CH2—O), 64.0, 63.9 (P—O—CH2—CH2—CH2—O), 42.8 (2C, U—CH2), 33.1, 32.0 (2C), 30.8, 30.7 (2C), 30.5, 27.3, 23.8 (CH2—P, P—O—CH2—CH2—CH2—O, O—CH2—CH2—(CH2)13—CH3), 15.9, 14.5 (O—CH2—CH2—(CH2)13—CH3), 12.9 (CH3—U).
To a dioxane (5 mL/mmol) solution of Bis-(POM) 1-hydroxymethyl-allylphosphonate (1 eq.) prepared according to example 13, heterocyclic base (1.5 eq.), triphenylphosphine (1.5 eq.) was added diisopropylazodicarboxylate (1.5 eq). under argon at 10° C. This solution was stirred a room temperature for 20 h. After evaporation of all volatiles, the residue was purified by chromatography on silica gel (MeOH/DCM).
The compounds of examples 40 to 42 are synthesized according to said general procedure.
1H NMR (400 MHz, CDCl3): δ=8.36 (s, 1H, H2), 7.81 (s, 1H, H8), 5.95-5.85 (m, 1H, CH═CH), 5.74-5.60 (m, 7H, CH═CH, O—CH2—O, NH2), 4.80 (t, J=5.0 Hz, 2H, B—CH2), 2.72 (dd, J=22.6, 7.3 Hz, 2H, CH2—P), 1.23 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 155.4 (C6), 153.1 (C2), 149.9 (C4), 140.1 (C8), 130.0, 129.8 (CH═CH), 123.4, 123.2 (CH═CH), 119.6 (C5), 81.6 (2C, O—CH2—O), 44.9 (2C, B—CH2), 38.7 (C(CH3)3), 31.5, 30.1 (CH2—P), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.50
1H NMR (400 MHz, CDCl3): δ=8.73 (s, 1H, H2), 8.14 (s, 1H, H8), 5.94-5.85 (m, 1H, CH═CH), 5.80-5.71 (m, 1H, CH═CH), 5.71-5.67 (m, 4H, O—CH2—O), 4.88 (t, J=5.2 Hz, 2H, B—CH2), 2.71 (dd, J=22.8, 7.1 Hz, 2H, CH2—P), 1.21 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 152.0 (C2), 151.6, 151.1 (C4 and C6), 144.7 (C8), 131.6 (C5), 128.9, 128.7 (CH═CH), 124.6, 124.5 (CH═CH), 81.6, 81.5 (O—CH2—O), 45.5, 45.4 (B—CH2), 38.7 (C(CH3)3), 31.4, 30.0 (CH2—P), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.05.
1H NMR (400 MHz, CDCl3): δ=7.74 (s, 1H, H2), 5.88-5.79 (m, 1H, CH═CH), 5.72-5.59 (m, 5H, CH═CH, O—CH2—O), 5.28 (s, 2H, NH2), 4.65 (t, J=5.1 Hz, 2H, B—CH2), 2.70 (dd, J=22.7, 7.2 Hz, 2H, CH2—P), 1.20 (s, 18H, C(CH3)3).
13C NMR (162 MHz, CDCl3): δ=176.8 (C═O), 159.1 (C6), 153.6 (C4), 151.3 (C2), 141.8 (C8), 129.4, 129.3 (CH═CH), 125.1 (C5), 123.6, 123.5 (CH═CH), 81.6, 81.5 (O—CH2—O), 44.9 (B—CH2), 38.7 (C(CH3)3), 31.4, 30.0 (CH2—P), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.35.
A solution of 6-chloropurine in 1:9 mixture of cyclopropylamine and dichloromethane (20 mL/mmol) is stirred for 20 h at 40° C. After evaporation of all volatiles, the residue was purified by chromatography on silica gel (MeOH/DCM).
The compounds of examples 44 and 45 are prepared according this procedure.
1H NMR (400 MHz, CDCl3): δ=8.47 (s, 1H, H2), 7.75 (s, 1H, H8), 5.95 (s, 1H, NH), 5.93-5.84 (m, 1H, CH═CH), 5.69-5.61 (m, 5H, CH═CH, O—CH2—O), 4.78 (t, J=5.1 Hz, 2H, B—CH2), 3.04 (d, J=3.0 Hz, 1H, NHCH), 2.70 (dd, J=22.6, 7.3 Hz, 2H, CH2—P), 1.21 (s, 18H, C(CH3)3), 0.94 (td, J=8.4 Hz, 6.9 Hz, 2H, NHCHCH2), 0.68-0.64 (m, 2H, NHCHCH2).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 155.8 (C6), 153.3 (C2), 149.0 (C4), 139.5 (C8), 130.1, 129.9 (CH═CH), 123.2, 123.0 (CH═CH), 119.8 (C5), 81.6, 81.5 (O—CH2—O), 44.8 (2C, B—CH2), 38.7 (C(CH3)3), 31.5, 30.1 (CH2—P), 26.8 (C(CH3)3), 23.7 (NHCH), 7.4 (NHCHCH2).
31P NMR (162 MHz, CDCl3): δ=26.57
1H NMR (400 MHz, CDCl3): δ=7.44 (s, 1H, H2), 5.89-5.81 (m, 1H, CH═CH), 5.76 (s, 1H, NH), 5.67-5.57 (m, 5H, CH═CH, O—CH2—O), 4.79 (s, 2H, NH2), 4.61 (t, J=5.1 Hz, 2H, B—CH2), 3.05-2.95 (m, 1H, NHCH), 2.69 (dd, J=23.0, 7.0 Hz, 2H, CH2—P), 1.22 (s, 18H, C(CH3)3), 0.85 (td, J=6.9, 5.4 Hz, 2H, NHCHCH2), 0.63-0.58 (m, 2H, NHCHCH2).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 160.1, 156.3 (C6 and C2), 151.0 (C4), 136.9 (C8), 130.6, 130.4 (CH═CH), 122.4, 122.3 (CH═CH), 114.6 (C5), 81.6 (2C, O—CH2—O), 44.4, 44.3 (2C, B—CH2), 38.7 (C(CH3)3), 31.4, 30.0 (CH2—P), 26.8 (C(CH3)3), 23.7 (NHCH), 7.4 (NHCHCH2).
31P NMR (162 MHz, CDCl3): δ=26.77.
A solution of 6-chloropurine in 1:1 mixture of demineralized water and formic acid (20 mL/mmol) is stirred for 20 h at 40° C. After evaporation of all volatiles, the residue was purified by chromatography on silica gel (MeOH/DCM).
Compounds of examples 47 and 48 are synthesized according to this procedure.
1H NMR (400 MHz, CDCl3): δ=12.94 (s, 1H, NH), 8.17 (s, 1H, H2), 7.81 (s, 1H, H8), 5.94-5.83 (m, 1H, CH═CH), 5.78-5.60 (m, 5H, CH═CH, O—CH2—O), 4.78 (t, J=5.2 Hz, 2H, B—CH2), 2.72 (dd, J=22.7, 7.2 Hz, 2H), 1.21 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3): δ=176.8 (C═O), 159.1 (C6), 148.9 (C4), 145.0 (C2), 139.7 (C8), 129.7, 129.5 (CH═CH), 124.5 (C5), 123.8, 123.7 (CH═CH), 81.6 (2C, O—CH2—O), 45.3 (2C, B—CH2), 38.7 (C(CH3)3), 31.4, 30.0 (CH2—P), 26.8 (C(CH3)3).
31P NMR (162 MHz, CDCl3): δ=26.40.
1H NMR (400 MHz, CDCl3): δ=12.11 (s, 1H, NH), 7.60 (s, 1H, H8), 6.65 (s, 2H, NH2), 5.95-5.84 (m, 1H, CH═CH), 5.73-5.62 (m, 5H, CH═CH, O—CH2—O), 4.60 (t, J=4.7 Hz, 2H, B—CH2), 2.72 (dd, J=22.6, 7.3 Hz, 2H), 1.20 (s, 18H, C(CH3)3).
13C NMR (100 MHz, CDCl3): δ=176.9 (C═O), 159.0 (C6), 153.9 (C2), 151.4 (C4), 137.2 (C8), 130.6, 130.4 (CH═CH), 122.7, 122.6 (CH═CH), 116.8 (C5), 81.7, 81.6 (O—CH2—O), 44.8 (B—CH2), 38.7 (C(CH3)3), 31.4, 30.0 (CH2—P), 26.8 (C(CH3)3).
31P NMR (100 MHz, CDCl3): δ=27.04.
Log D (pH=7.4) was calculated using MarvinSketch 5.3 (Method Weighter) from ChemAxon.
Results are given in
The greater is the Log D, the more the compound will be lipophilic and so the better will be its bioavailability.
The compounds according to the invention (examples 16 to 48) with the claimed formula R=R′=POM; R=R′=POC; R=POC and R′=HDP, and R=H and R′=HDP) all have a much greater Log D than the corresponding phosphoric acid (R=R′=H).
| Number | Date | Country | Kind |
|---|---|---|---|
| 09305562.2 | Jun 2009 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2010/058567 | 6/17/2010 | WO | 00 | 2/24/2012 |
