Cholesterol biosynthesis inhibiting pyrazole analogs of mevalonolactone and its derivatives

This invention relates to compounds of the formula ##STR3## wherein R.sub.1 is C.sub.1-6 alkyl not containing an asymmetric carbon atom,
each of R.sub.2 and R.sub.5 is independently hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy,
each of R.sub.3 and R.sub.6 is independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
each of R.sub.4 and R.sub.7 is independently hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, not more than one of R.sub.2 and R.sub.3 is benzyloxy, not more than one of R.sub.5 and R.sub.6 is trifluoromethyl, not more than one of R.sub.5 and R.sub.6 is phenoxy, and not more than one of R.sub.5 and R.sub.6 is benzyloxy,
X is --(CH.sub.2).sub.m --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--, wherein m is 0, 1, 2 or 3, and ##STR4## wherein R.sub.10 is hydrogen or C.sub.1-3 alkyl, and R.sub.11 is hydrogen, R.sub.12 or M, wherein
R.sub.12 is a physiologically acceptable and hydrolyzable ester group, and
M is a pharmaceutically acceptable cation,
with the provisos that (i) the --X--Z group is in the 4- or 5-position of the pyrazole ring, and (ii) the R.sub.1 group and the --X--Z group are ortho to each other,
processes for and intermediates in the synthesis thereof, pharmaceutical compositions comprising a compound of Formula I and the use of the compounds of Formula I for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.
By the term "physiologically acceptable and hydrolyzable ester group" is meant a group which, together with the --COO-- radical to which it is attached, forms an ester group which is physiologically acceptable and hydrolyzable under physiological conditions to yield a compound of Formula I wherein R.sub.11 is hydrogen and an alcohol which itself is physiologically acceptable, i.e., non-toxic at the desired dosage level, and which, preferably, is free of centers of asymmetry. Examples of such groups are C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl and benzyl, collectively referred to as R.sub.12 '.
For the avoidance of doubt, throughout this application it is the right-hand side of the X radical that is attached to the Z group.
The compounds of Formula I may be divided into four groups, viz., those of Formulae IA, IB, IC and ID: ##STR5##
The compounds of each of Groups IA-ID may be divided into two subgroups based upon the significance of Z, viz., Group IAa (the compounds of Group IA wherein Z is a group of Formula a), Group IAb (the compounds of Group IA wherein Z is a group of Formula b), Group IBa (the compounds of Group IB wherein Z is a group of Formula a), Group IBb (the compounds of Group IB wherein Z is a group of Formula b), Group ICa (the compounds of Group IC wherein Z is a group of Formula a), Group ICb (the compounds of Group IC wherein Z is a group of Formula b), Group IDa (the compounds of Group ID wherein Z is a group of Formula a) and Group IDb (the compounds of Group ID wherein Z is a group of Formula b).
As is self-evident to those in the art, each compound of Formula I (and every subscope and species thereof) has two centers of asymmetry (the two carbon atoms bearing the hydroxy groups in the group of Formula a and the carbon atom bearing the hydroxy group and the carbon atom having the free valence in the group of Formula b) and, therefore, there are four stereoisomeric forms (enantiomers) of each compound (two racemates or pairs of diastereoisomers), provided that R.sub.11 does not contain any center of asymmetry. The four stereoisomers may be designated as the R,R, R,S, S,R and S,S enantiomers, all four stereoisomers being within the scope of this invention. When R.sub.11 contains one or more centers of asymmetry, there are eight or more stereoisomers. Since it is preferred that R.sub.11 not contain a center of asymmetry and for reasons of simplicity any additional stereoisomers resulting from the presence of one or more centers of asymmetry in R.sub.11 usually will be ignored, it being assumed that R.sub.11 is free of centers of asymmetry.
R.sub.1 is preferably R.sub.1 ', where R.sub.1 ' is C.sub.1-3 alkyl, n-butyl or i-butyl, more preferably R.sub.1 ", where R.sub.1 " is C.sub.1-3 alkyl, and most preferably isopropyl.
R.sub.2 is preferably R.sub.2 ', where R.sub.2 ' is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro or chloro, more preferably R.sub.2 ", where R.sub.2 " is hydrogen or fluoro, and most preferably hydrogen.
R.sub.3 is preferably R.sub.3 ', where R.sub.3 ' is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and most preferably hydrogen.
R.sub.4 is preferably R.sub.4 ', where R.sub.4 ' Is hydrogen or methyl, and most preferably hydrogen.
The R.sub.2 -bearing phenyl group is preferably unsubstituted.
R.sub.5 is preferably R.sub.5 ', where R.sub.5 ' is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro or chloro, more preferably R.sub.5 ", where R.sub.5 " is hydrogen or fluoro, and most preferably fluoro.
R.sub.6 is preferably R.sub.6 ', where R.sub.6 ' is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, more preferably R.sub.6 ", where R.sub.6 " is hydrogen or methyl, and most preferably hydrogen.
R.sub.7 is preferably R.sub.7 ', where R.sub.7 ' is hydrogen or methyl, and most preferably hydrogen.
Preferably, when two of R.sub.5 (R.sub.5 ', etc.), R.sub.6 (R.sub.6 ', etc.) and R.sub.7 (R.sub.7 ', etc.) are other than hydrogen and one is hydrogen, at least one of the two that are other than hydrogen is in a meta or para position and not more than one of them is a member of the group consisting of t-butyl, trifluoromethyl, phenyl, phenoxy and benzyloxy; more preferably, the two that are other than hydrogen are not ortho to each other when neither of them is a member of the group consisting of methyl, methoxy, fluoro and chloro.
Preferably, when each of R.sub.5 (R.sub.5 ', etc.), R.sub.6 (R.sub.6 ', etc.) and R.sub.7 (R.sub.7 ', etc.) is other than hydrogen, at least two of them are in meta or para positions, and not more than one of them is a member of the group consisting of t-butyl, trifluoromethyl, phenyl, phenoxy and benzyloxy; more preferably, no two of them are ortho to each other unless at least one member of each pair of substituents that are ortho to each other is a member of the group consisting of methyl, methoxy, fluoro and chloro.
The R.sub.5 -bearing phenyl group is preferably 4-fluorophenyl or 3,5-dimethylphenyl, preferably the former.
R.sub.10 is preferably R.sub.10 ', where R.sub.10 ' is hydrogen or methyl, and most preferably hydrogen.
R.sub.11 is preferably R.sub.11 ', where R.sub.11 ' is hydrogen, R.sub.12 ' or M, more preferably R.sub.11 ", where R.sub.11 " is hydrogen, C.sub.1-3 alkyl or M, even more preferably R.sub.11 '", where R.sub.11 '" is hydrogen, C.sub.1-2 alkyl or M, and most preferably M, especially sodium.
R.sub.12 is preferably R.sub.12 ', where R.sub.12 ' is C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl or benzyl, more preferably C.sub.1-3 alkyl, and most preferably C.sub.1-2 alkyl, especially ethyl.
Any --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH-- as X is preferably trans, i.e., (E).
X is preferably X', where X' is --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--, more preferably --CH.dbd.CH--, and most preferably ##STR6## (i.e., (E)--CH.dbd.CH--).
Z is preferably a group of Formula a wherein R.sub.10 is R.sub.10 ' (especially hydrogen), and R.sub.11 is R.sub.11 ' or a group of Formula b, more preferably a group of Formula a wherein R.sub.10 is hydrogen, and R.sub.11 is R.sub.11 " or a group of Formula b, even more preferably a group of Formula a wherein R.sub.10 is hydrogen, and R.sub.11 is R.sub.11 '" or a group of Formula b, and most preferably a group of Formula a wherein R.sub.10 is hydrogen, and R.sub.11 is M (especially sodium).
m is preferably m', where m' is 2 or 3, most preferably 2.
M is preferably free from centers of asymmetry and is more preferably M', i.e., sodium, potassium or ammonium, and most preferably sodium. For simplicity, each formula in which M appears has been written as if M were monovalent and, preferably, it is. However, it may also be divalent or trivalent and, when it is, balances the charge of two or three carboxy groups, respectively. Thus, Formula I and every other formula containing an M embraces compounds wherein M is divalent or trivalent, i.e., compounds containing two or three carboxylate-containing anions per cation M.
As between otherwise identical compounds of Formula I, those wherein Z is a group of Formula a are generally preferred over those wherein Z is a group of Formula b.
Insofar as the compounds of Groups IAa, IBa, ICa and IDa and each of the subgroups thereof are concerned, the erythro isomers are preferred over the threo isomers, erythro and threo referring to the relative positions of the hydroxy groups in the 3- and 5-positions of the group of Formula a.
Insofar as the compounds of Groups IAb, IBb, ICb and IDb and each of the subgroups thereof are concerned, the trans lactones are generally preferred over the cis lactones, cis and trans referring to the relative positions of R.sub.10 and the hydrogen atom in the 6-position of the group of Formula b.
The preferred stereoisomers of the compounds of Formula I having only two centers of asymmetry wherein X is a direct bond, --CH.dbd.CH-- or --CH.sub.2 --CH.dbd.CH--, and Z is a group of Formula a are the 3R,5S isomer and the racemate of which it is a constituent, i.e., the 3R,5S-3S,5R (erythro) racemate.
The preferred stereoisomers of the compounds of Formula I having only two centers of asymmetry wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--CH.sub.2 --, and Z is a group of Formula a are the 3R,5R isomer and the racemate of which it is a constituent, i.e., the 3R,5R-3S,5S (erythro) racemate.
The preferences set forth in the preceding two paragraphs also apply to the compounds of Formula I having more than two centers of asymmetry and represent the preferred configurations of the indicated positions.
The preferred stereoisomers of the compounds of Formula I wherein X is a direct bond, --CH.dbd.CH-- or --CH.sub.2 --CH.dbd.CH--, and Z is a group of Formula b are the 4R,6S and 4R,6R isomers and the racemate of which each is a constituent, i.e., the 4R,6S-4S,6R (trans lactone) and 4R,6R-4S,6S (cis lactone) racemates, with the 4R,6S isomer and the racemate of which it is a constituent being more preferred and the 4R,6S isomer being most preferred.
The preferred stereoisomers of the compounds of Formula I wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--CH.sub.2 --, and Z is a group of Formula b are the 4R,6R and 4R,6S isomers and the racemate of which each is a constituent, i.e., the 4R,6R-4S,6S (trans lactone) and 4R,6S-4S,6R (cis lactone) racemates, with the 4R,6R isomer and the racemate of which it is a constituent being more preferred and the 4R,6R isomer being most preferred.
Each of the preferences set forth above applies, not only to the compounds of Formula I, but also to the compounds of Formulae IA, IB, IC and ID and those of Groups IAa, IAb, IBa, IBb, ICa, ICb, IDa and IDb as well as to every other subgroup thereof set forth in the specification, e.g., Groups (i) et seq., unless otherwise indicated. When any preference or group contains a variable, the preferred significances of that variable apply to the preference in question, unless otherwise indicated.
Preferred groups of compounds of Formulae IAa and IAb include the compounds
(i) of Group IAa wherein R.sub.1 is R.sub.1 ', R.sub.2 is R.sub.2 ', R.sub.3 is R.sub.3 ', R.sub.4 is R.sub.4 ', R.sub.5 is R.sub.5 ', R.sub.6 is R.sub.6 ', R.sub.7 is R.sub.7 ', R.sub.10 is R.sub.10 ', R.sub.11 is R.sub.11 ', and X is X',
(ii) of (i) wherein R.sub.2 is R.sub.2 ", R.sub.3 is hydrogen, R.sub.4 is hydrogen, R.sub.5 is R.sub.5 ", R.sub.6 is R.sub.6 ", R.sub.10 is hydrogen, R.sub.11 is R.sub.11 ", and X is (E)--CH.dbd.CH--,
(iii) of (ii) wherein R.sub.1 is R.sub.1 ",
(iv)-(vi) of (i)-(iii) wherein R.sub.11 is M, especially sodium,
(vii)-(xii) of (i)-(vi) wherein the hydrogen groups in the 3- and 5-positions of the group of Formula a have the erythro configuration.
(xiii)-(xviii) the 3R,5S enantiomers of the compounds of (vii)-(xii) wherein X is --CH.dbd.CH-- and the 3R,5R enantiomers of those wherein X is --CH.sub.2 CH.sub.2 --,
(xix) of Group IAb wherein R.sub.1 is R.sub.1 ', R.sub.2 is R.sub.2 ', R.sub.3 is R.sub.3 ', R.sub.4 is R.sub.4 ', R.sub.5 is R.sub.5 ', R.sub.6 is R.sub.6 ', R.sub.7 is R.sub.7 ', R.sub.10 is R.sub.10 ', and X is X',
(xx) of (xix) wherein R.sub.2 is R.sub.2 ", R.sub.3 is hydrogen, R.sub.4 is hydrogen, R.sub.5 is R.sub.5 ", R.sub.6 is R.sub.6 ", R.sub.10 is hydrogen, and X is (E)--CH.dbd.CH--,
(xxi) of (xx) wherein R.sub.1 is R.sub.1 ",
(xxii)-(xxiv) of (xix)-(xxi) wherein R.sub.10 and the hydrogen atom in the 6-position of the group of Formula b are trans to each other (i.e., the trans lactones), and
(xxv)-(xxvii) the 4R,6S enantiomers of the compounds of (xxii)-(xxiv) wherein X is --CH.dbd.CH-- and the 4R,6R enantiomers of those wherein X is --CH.sub.2 CH.sub.2 --.
Groups (viii)-(xii) embrace the 3R,5S-3S,5R racemate and the 3R,5S and 3S,5R enantiomers, the 3S,5R enantiomer being least preferred.
Groups (xxiii) and (xxiv) embrace the 4R,6S-4S,6R racemate and the 4R,6S and 4S,6R enantiomers, the 4S,6R enantiomer being least preferred.
Insofar as Groups IBa, IBb, ICa, ICb, IDa and IDb are concerned, the preferred subgroups are those that correspond to Groups (i)-(xxvii). As should be self-evident, the preferred groups of compounds of Groups IBa, ICa and IDa are those that correspond to Groups (i)-(xviii), i.e., Groups (xxviii)-(xlv), (lv)-(lxxii) and (lxxxii)-(xcix), respectively, and the preferred groups of compounds of Groups IBb, ICb and IDb are those that correspond to Groups (xix)-(xxvii), i.e., Groups (xlvi)-(liv), (lxxiii)-(lxxxi) and (c)-(cviii), respectively.
The compounds of Formula I may be synthesized as follows:
Reaction Scheme I
The compounds of Formula I wherein X is --CH.dbd.CH-- and Z is a group of Formula b having the 4R,6S configuration or X is --CH.sub.2 CH.sub.2 -- and Z is a group of Formula b having the 4R,6R configuration may be synthesized by the following series of reactions: ##STR7##
Reaction Scheme II
The compounds of Formula I wherein X is --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--, and Z is a group of Formula a wherein R.sub.11 is R.sub.12 ' may be synthesized by the following series of reactions: ##STR8##
Reaction Scheme III
The compounds of Formula I wherein X is --(CH.sub.2).sub.m -- or (E)--CH.dbd.CH--, and Z is a group of Formula a wherein R.sub.10 is hydrogen, and R.sub.11 is R.sub.12 ' or R.sub.10 is R.sub.10a and R.sub.11 is M.sub.2.sup..sym. may be synthesized by the following series of reactions: ##STR9##
Reaction Scheme IV
The compounds of Formula I wherein Z is a group of Formula a wherein R.sub.11 is R.sub.12 ' or a group of Formula b may be converted into the corresponding compounds of Formula I wherein Z has a different significance by the following series of reactions: ##STR10##
Reaction Scheme V
The compounds of Formulae II and CCI wherein Py is PyA may be synthesized by the following series of reactions: ##STR11##
Reaction Scheme VI
The compounds of Formulae II and CCI wherein Py is PyB may be synthesized by the following series of reactions: ##STR12##
Reaction Scheme VII
The compounds of Formulae II and CCI wherein Py is PyC may be synthesized by the following series of reactions: ##STR13##
Reaction Scheme VIII
The compounds of Formulae II and CCI wherein Py is PyD may be synthesized by the following series of reactions: ##STR14##
Reaction Scheme IX
The compound of Formula IV may be synthesized by the following series of reactions: ##STR15##
Reaction Scheme X
The compounds of Formula X may be synthesized by the following series of reactions: ##STR16##
Reaction Scheme XI
The compounds of Formula XV wherein X.sub.5 is --(CH.sub.2).sub.m -- or (E)--CH.dbd.CH and those of Formula IX wherein X.sub.1 is --CH.sub.2 CH.sub.2 -- may be synthesized by the following series of reactions: ##STR17##
In the foregoing reaction schemes,
R.sub.10a is C.sub.1-3 alkyl, preferably methyl,
each R.sub.13 is independently C.sub.1-3 alkyl, preferably n-C.sub.1-3 alkyl and most preferably C.sub.1-2 alkyl,
R.sub.14 is C.sub.1-2 alkyl,
Py is ##STR18## wherein R.sub.1 -R.sub.7 are as defined above, with the provisos that (i) the free valence is in the 4- or 5-position of the pyrazole ring, and (ii) the R.sub.1 group is ortho to the free valence,
PyA-PyD are as defined in Reaction Schemes V-VIII, respectively,
X.sub.1 is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --,
X.sub.2 is a direct bond or --CH.sub.2 --,
X.sub.3 is --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--, preferably (E)--CH.dbd.CH--, (E)--CH.dbd.CH--CH.sub.2 -- or (E)--CH.sub.2 --CH.dbd.CH-- and especially (E)--CH.dbd.CH--,
X.sub.4 is --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2 --, especially --CH.sub.2 CH--,
X.sub.5 is --(CH.sub.2).sub.m -- or (E)--CH.dbd.CH--, especially (E)--CH.dbd.CH--, wherein m is 0, 1, 2 or 3,
Y is chloro, bromo or iodo,
Y.sup..crclbar. is chloride, bromide or iodide,
Y' is chloro or bromo,
M.sub.2.sup..sym. is sodium or potassium, and each of the other variables is as defined above.
Inert Reaction/Type Reagents, Molar Ratios and Comments Temperature Time Solvent Atmosphere A 1-1.3 moles triphenylphosphine per 60.degree. C.-reflux, 0.5-24 hrs., AIO, pref. HC Yes mole II pref. .ltoreq. 150.degree. C., pref. 0.75-2 such as benzene, esp. 75.degree.-90.degree. C. hrs. toluene or xylene, or a mixture thereof B (Wittig) (1) 1-2 moles strong base, e.g., -40.degree.-5.degree.C., pref. 5-60 min. AIO, e.g., HC Yes sodium hydride or pref. n-butyl- -35.degree.--20.degree. C. such as toluene or, lithium (pref. as 1.3-1.7 M. solu- pref., ES such as THF tion in hexane), per mole III. Pref., slowly add n-butyllithium solution to solution of III. (2) 0.65-1.5 moles IV per mole III. -55.degree.-25.degree. C., pref. 0.75-18 hrs., Same as Step 1 Yes The product (V) is a mixture of -35.degree.--5.degree. C. pref. 1- 4 hrs. the (Z) and (E) (cis and trans, respectively) isomers which may be separated by chromatography. See, for example, Part d of Step 7 of Example 1. C (Deprotection) 1-4 moles, pref. 2-4 moles, fluoride 20.degree.-60.degree. C., pref. 2-30 hrs. AIO, e.g., ES, -- reagent, esp. tetra-n-butylammonium 20.degree.-25.degree. C. pref. THF fluoride, per mole V and 1-2 moles, pref. 1.2-1.5 moles, glacial acetic acid per mole fluoride reagent. First add glacial acetic acid to solution of V, then add fluoride reagent. D (Hydrogenation) Excess hydrogen (more than 1 mole 20.degree.-25.degree. C. Until 1 mole Lower alkanol, -- per mole V) and catalytic amount of hydrogen per e.g., ethanol platinum dioxide (e.g., 1-5 g. per mole V is taken mole V). Initial hydrogen pressure up is conveniently 30-60 p.s.i. E (Deprotection) Same as Reaction C (Molar quantities Same as C Same as C Same as C -- are per mole VII). F (Wittig) Same as Reaction B. (Reactant in Step Same as B Same as B Same as B Yes 2 is X.) The product (XI) is a mixture of the (Z) and (E) (cis and trans, re- spectively) isomers which may be sepa- rated by chromatography. See, for example, Part d of Step 7 of Example 1. G (Deprotection) Same as Reaction C except utilize Same as C Same as C Same as C -- 2-8 moles, pref. 4-8 moles, fluoride reagent per mole XI. H (Hydrogenation) Same as Reaction D (Molar quantities Same as D Same as D Same as D -- are per mole XI). I (Deprotection) Same as Reaction C except utilize Same as C Same as C Same as C -- 2-8 moles, pref. 4-8 moles, fluoride reagent per mole XIII. J (1) Generation of dianion of XIX: 1 mole -50.degree.-10. degree. C., 0.3-1.5 AIO, e.g., ES, Yes XIX and 2-2.2 equivalents strong pref. -20.degree.-5.degree. C. hrs., pref. THF base, pref. 1-1.1 moles sodium hydride then 1-1.1 moles n-butyl- lithium or 2-2.2 moles lithium diisopropylamide. n-butyllithium is preferably employed as a 1.3-1.7 M solution in hexane and lithium diisopropylamide is prepared in situ from n-butyllithium and diisopropyl- amine. (2) 1-2.5 moles, pref. 1.2-2.2 moles, -80.degree.-0.degree. C., pref. 0.3-4 hrs. Same as Step Yes more pref. 1.3-2.1 moles, of dianion -50.degree.-0.degree. C., pref. 0.3-1.5 1 of XIX (assuming 100% conversion of more pref. hrs. XIX to its dianion) per mole XV. -30.degree.--10.degree. C. Product (XX) is racemic. K (Reduction) (a) Non-stereoselective: 1-4, pref. -10.degree.-30.degree. C. 1-8 hrs. IO, e.g., Yes 2-4, equivalents of transferable lower hydride per mole XX, pref. sodium alkanol, borohydride or complex of t-butyl- exp. ethanol amine and borane. When a racemic XX is utilized, product (XXI) is a mixture of all four possible stereoisomers (the erythro and threo racemates), the ratio of the erythro racemate to the threo racemate generally being 3:2 to 2:3. (b) Stereoselective: (1) 1-2.2 moles, pref. 1.02-2 0.degree.-50.degree. C., pref. 0.5-6 hrs., AIO, pref. -- moles, tri-(primary or 0.degree.-25. degree. C. pref. 1-3.5 ES, esp. secondary C.sub.2-4 alkyl)borane, hrs. THF pref. triethylborane or tri-n- butylborane, and, optionally, 0.5-8 liters, e.g., 0.75-6.5 liters, air (at 25.degree. C. and 760 mm. Hg.) per mole XX. (2) 0.4-7.5 moles, pref. 2-5 -100.degree.--40.degree. C., 2-48 hrs., Same as Step 1 -- moles, sodium borohydride per pref. -90.degree.--70.degree. C. pref. 10-40 mole XX. After the reaction hrs. quench the reaction mixture with, for example, 10% hydro- chloric acid and isolate the crude product by extracting with a suitable inert organic solvent (e.g., diethyl ether) and evaporating the solvent at reduced pressure. (3) Large excess of anhydrous 20.degree.-60.degree. C., 0.2-5 hrs., Neat -- methanol, e.g., 50-100 moles pref. 20.degree.-30.degree. C. pref. 0.5-4 per mole XX, or use mixture of hrs. methanol, hydrogen peroxide and aqueous phosphate buffer having a pH of 7-7.2. See Step 3 of Alternative b of Reaction FB. (c) Alternative stereoselective: (p) Preparation of zinc borohy- 20.degree.-25.degree. C. 16-18 hrs. Anhydrous Yes dride/diethyl ether: Add diethyl ether 1 mole zinc chloride to 51. anhydrous diethyl ether followed by 2 moles sodium borohydride. Stir for 16-18 hrs. and decant off the solution (a 0.15-0.2 M solution of zinc borohydride in diethyl ether). N.B. The solid should be decomposed very care- fully. (1) 1 mole zinc borohydride (in -80.degree.--50.degree. C., 0.5-5 hrs., AIO, pref. ES, Yes form of solution produced in pref. -80.degree.- pref. 1-2 esp. diethyl Step p) per mole XX -75.degree. C. hrs. ether or mix- ture of diethyl ether with another ES (2) Add excess methanol (e.g., -80.degree.--50.degree. C., 1-2 hrs. Same as Step 1 -- 10-100 moles per mole XX) and pref. -80.degree.- allow to slowly warm to 20.degree.-25.degree. C. -75.degree. C., .fwdarw. 20.degree.-25.degree. C. (3) Add excess dilute aqueous acetic 20.degree.-25.degree. C. -- Same as Step 1 -- acid to quench the reaction mix- ture When a racemic XX is utilized in Alterna- tive b or c, product (XXI) is a mixture of the four possible stereoisomers wherein the ratio of the erythro isomers (racemate) to the threo isomers (racemate) is about 4-20:1, usually 5-15:1. Repeated recrystallization of the cyclic boron ester produced in Step 2 of Alternative b, if a solid, may raise the ratio or even yield pure erythro racemate and mother liquors en- riched with the threo racemate from which pure threo racemate may be obtained. L (1) Generation of monoanion of XVI: 1-1.1 -80.degree.--40.deg ree. C., 0.25-1.5 AIO, e.g., ES, Yes equivalents strong base, pref. lithium pref. -80.degree.- hrs. pref. THF diisopropylamide, per mole XVI. -75.degree. C. (2) 1-4 moles, pref. 3 moles, of monoanion -80.degree.--40.degree. C., 0.25-1.5 Same as Step 1 Yes of XVI (assuming 100% conversion of VI pref. -80.degree.- hrs. to its monoanion) per mole XV. -75.degree. C. Product (XVII) is a racemate. M (Acylation) 1-3 moles, pref. 2 moles, XVIIA or XVIIB per -10.degree.-50.degree. C., 2-18 hrs., Pyridine or Yes mole XVII. When an ES is used as the solvent, pref. 20-30.degree. C. pref. 4-12 anhydrous ES, also use 1-4 moles, pref. 2.5-3 moles, of a hrs. pref. THF tertiary amine, e.g., pyridine or, pref., 4-dimethylamin opyridine, per mole XVII. N (1) Generation of monoanion of XVIID: 1-1.1 -80.degree.-0.degree. C. 0.25-1 hr. AIO, e.g., ES, Yes equivalents strong base, pref. lithium pref. THF diisopropylamide, per mole XVIID. (2) 1-4 moles, pref. 3 moles, of monoanion of -80.degree.--40.deg ree. C., 0.25-1.5 Same as Step 1 Yes XVIID (assuming 100% conversion of XVIID pref. -80.degree.- hrs. to its monoanion) per mole XVIIC. -70.degree. C. NA (Hydrolysis) 2-2.3 moles, pref. 2-2.2 moles, XXIII per 0.degree. C.-reflux, 1-4 hrs. Inert aqueous -- mole XVIIE. pref. 0.degree.-75.degree. C., organic, e.g., esp. 20.degree.-50.degree. C. mixture of water and lower alkanol, pref. mixture of water and methanol or, esp., ethanol O (Hydrolysis) 1-1.3 equivalents XXIII per mole XXII 0.degree. C.-reflux, 1-4 hrs. Inert aqueous -- or, if it is desired to isolate XXIV, pref. 0.degree.-75.degr ee. C., organic, e.g., 0.95-0.99 equivalents XXIII per mole esp. 20.degree.-70.degree. C. mixture of water XXII. and lower alkanol, pref. mixture of water and methanol or, esp., ethanol P (Acidification) At least 1 equivalent, e.g., 1-1.25 0.degree.-25.degree. C. 1-5 min. Water or mixture -- equivalents, acid, e.g., 2N. hydro- of water and water- chloric acid, per mole XXIV. miscible inert organic solvent, e.g., methanol, ethanol, diethyl ether or THF Q (Esterification) At least 2 moles, e.g., 2-10 moles, 0.degree.-70.d egree. C., 2-12 hrs. IO, e.g., ES such as -- pref. 2.05-2.5 moles, XXVIII per mole pref. 20.degree.-25.degree. C. THF or alcohol of the XXX. formula R.sub.12 --OH (R.sub.12 same as in XXXVIII), if a liquid R (Neutralization) 0.95-0.99 equivalents, pref. 0.96-0.98 0.degree.-25.degree. C., pref. 2-10 min. Same as O -- equivalents, XXVI per mole XXV. 20.degree.-25.degree. C. S (Lactonization) (a) Use of catalytic amount of strong 75.degree. C.-reflux, 3-18 hrs., AIO, pref. HC, -- acid such as p-toluenesulfonic pref. 75.degree.- pref. 4-7 e.g., benzene, acid is optional but usually 150.degree. C., esp. hrs. toluene or xylene omit. Use of Dean-Stark apparatus 80.degree.-120.degree. C. or mixture thereof is pref. if solvent forms azeotrope with water. (b) 1-1.5 moles of a lactonization agent, 10-35.degree. C., 2-8 hrs., AIO, pref. HLA, -- e.g., a carbodiimide, pref. a water- pref. 20.degree. -25.degree. C. pref. 3-4 esp. methylene soluble carbodiimide such as N--cyclo- hrs. chloride hexyl-N'--[2'-(N"--methylmorpholinium)- ethyl]carbodiimide p-toluenesulfonate per mole XXV. Alternative b often results in higher yields of XXX than Alternative a. Racemic erythro XXV yields racemic trans (lactone) XXX, racemic threo XXV yields racemic cis (lactone) XXX, mixture of racemic erythro and threo XXV yields mixture of racemic trans and cis (lactones) XXX and single enantiomer of XXV yields single enantiomer of XXX, e.g., 3R,5S erythro XXV yields 4R,6S trans XXX. T (Hydrolysis) 1-1.3 equivalents XXIII per mole XXX 0.degree. C.-reflux, pref. 1-6 hrs., Same as O -- or, if it is desired to isolate XXIV, 0.degree.- 75.degree. C., more pref. pref. 1-4 0.95-1 equivalent, preferably 20.degree.-75.degree. C., esp. hrs. 0.97-0.99 equivalent, XXIII per 40.degree.-60.degree. C. mole XXX. Racemic trans (lactone) XXX yields racemic erythro XXIV, racemic cis (lactone) XXX yields racemic threo XXIV, mixture of racemic trans and cis (lactones) XXX yields mixture of racemic erythro and threo XXIV and single enantiomer of XXX yields single enantiomer of XXIV, e.g., 4R,6S trans XXX yields 3R,5S erythro XXIV. AA (Grignard) (1) 0.9-1 mole magnesium turnings per 10.degree. C.-reflux, Until mag- Anhydrous Yes mole XXXI. Pref., slowly add mag- pref. 30.degree.-38.degree. C. nesium com- inert ES, nesium turnings to solution of XXXI pletely dis- esp. diethyl at rate such that the reaction mix- solves, e.g., ether or ture refluxes gently. 0.5-2 hrs. THF (2) 1-2 moles, pref. 1.2-1.5 moles, 10.degree. C.-reflux, 2-20 hrs., Same as Step 1 Yes Grignard reagent (produced in Step 10.degree.-75.degree. C., pref. 3-5 (1) per mole XXXII. pref. 20.degree.-40.degree. C., hrs. esp. 20.degree.-25.degree. C. (Hydrolysis) (3) Excess aqueous inorganic acid, e.g., 0.degree.-25.degree. C. 1-30 min., Inert aqueous -- 10% hydrochloric acid. Pref., pour e.g., 1-5 organic, pref. ice cold aqueous inorganic acid into min. mixture of water solution resulting from Step 2 and solvent stirred at 0.degree.-25.degree. C. utilized in Steps 1 and 2 AB 1-3 moles, pref. 1.5-2.5 moles, 60.degree.-100.degree. C., pref. 1-4 hrs., pref. IO optionally -- XXXIV and a catalytic amount (e.g., 70.degree.-90.degree. C. 1.25-3 hrs. containing a 0.05-0.5 moles) acetic acid per small amount mole XXXIII. (.ltoreq.10%) of water, pref. a lower alkanol such as methanol or ethanol, e.g., 95% ethanol AC (Acylation) 1-1.8 moles, pref. 1.1-1.5 moles, 0.degree.-25.degree. C. 1-3 hrs. AIO, e.g., HC -- acetyl chloride and 1-3 moles, such as benzene pref. 1.5-2 moles, of a tertiary or toluene or amine, e.g., a tri(C.sub.1-3 alkyl)amine, ES, pref. THF pref. triethylamine, per mole XXXV, (at least one mole tertiary amine per mole acetyl chloride). Commence reaction at 0.degree.-5.degree. C. and allow temperature to gradually rise to 20.degree.-25.degree. C. as reaction proceeds. AD (Cyclization) 2-6 moles sodium hydroxide or, 50.degree.-90.degree. C., pref. 3-10 hrs. AIO, e.g., Yes preferably, potassium hydroxide 70.degree.-80.degree. C. higher boiling per mole XXXVI. Can commence ES, pref. bis- reaction at 70.degree.-80.degree. C. and, after (2-methoxyethyl)- 2-3 hrs., allow reaction mixture to ether or bis- cool to 20.degree.-25.degree. C. and stir at this (2-ethoxyethyl)- temperature for 8-24 hrs. ether AE 1-1.1 moles lead tetraacetate per 20.degree.-80.degree. C. 8-15 hrs. Glacial acetic Yes mole XXXVII. acid or benzene AF (Hydrolysis) 1-1.5 equivalents, pref. 1.1-1.3 20.degree.-50.degree. C. 3-5 hrs. Same as O -- equivalents, sodium hydroxide or potassium hydroxide per mole XXXVIII. AG (Halogenation) 1-2 moles, pref. 1.5-1.8 moles, -10.degree.-80 .degree. C. 2-18 hrs. AIO, pref. ES, -- XLI or XLII per mole XXXIX. Y e.g., diethyl in product is Y'. ether or THF, HLA, e.g., methylene chloride, or HC, e.g., benzene AH (Halogenation) 1-1.5 moles, pref. 1.1-1.3 moles, 50.degree.-100.degree. C., pref. 0.5-1.5 hrs., AIO, pref. HLA, Yes N--bromo-, N--chloro- or N--iodo- 70.degree.-90.degree. C. pref. 0.6-1 esp. carbon succinimide and catalytic amount hr. tetrachloride of an organic peroxide, e.g., di- benzoyl peroxide. BA 1-3 moles, pref. 1.1-1.5 moles, Same as AB Same as AB Same as AB Yes LII and a catalytic amount of acetic acid (e.g., 0.05-0.5 mole) per mole LI. BB (Acylation) Same as Reaction AC. (Molar Same as AC Same as AC Same as AC -- quantities are per mole LIII). BC (Cyclization) Same as Reaction AD. (Molar Same as AD Same as AD Same as AD Yes quantities are per mole LIV). BD Same as Reaction AE. (Molar Same as AE Same as AE Same as AE Yes quantities are per mole LV). BE (Hydrolysis) Same as Reaction AF. (Molar Same as AF Same as AF Same as AF -- quantities are per mole LVI). BF (Halogenation) Same as Reaction AG. (Molar Same as AG Same as AG Same as AG -- quantities are per mole LVII). BG (Halogenation ) Same as Reaction AH. (Molar Same as AH Same as AH Same as AH Yes quantities are per mole LV). CA (Acylation) 1-1.01 moles LXI and 1-2 moles of a -10.degree.-0.degree. C. .fwdarw. 2-4 hrs. AIO, e.g., -- tertiary amine, e.g., a tri(C.sub.1-3 alkyl)- 20.degree.-25.degree. C. ES, pref. amine, pref. triethylamine, per mole diethyl ether LXII (at least one mole tertiary or THF amine per mole LXI). Commence reaction at -10.degree.-0.degree. C. and allow temperature to gradually rise to 20.degree.-25.degree. C. as reaction proceeds. CB 1-1.5 moles, pref. 1.2 moles, phosphorus 30.degree.-40.degree. C., 8-16 hrs., AIO, e.g., ES, Yes pentachloride per mole LXIII. pref. 35.degree. C. pref. 10-14 pref. diethyl hrs. ether CC 1-1.05 moles LXV and 1-1.05 20.degree.-25.degree. C. 3-6 hrs., Anhydrous lower Yes moles base, pref. sodium ethoxide, pref. 4 hrs. alkanol, pref. per mole LXIV. absolute ethanol CD (Reduction) 0.5-3.2 moles, pref. 0.75-3 moles, -5.degree.-25.degree. C., 2-6 hrs., AIO, e.g., ES, Yes lithium aluminum hydride per mole pref. -5.degree.-5.degre e. C. pref. 2-4 pref. diethyl LXVI. Pref. commence at -5.degree.-5.degree. C. .fwdarw. 20.degree.-25.degree. C. hrs. ether and allow reaction mixture to warm to 20.degree.-25.degree. C. as reaction proceeds. CE (Halogenation) Same as Reaction AG. (Molar quantities Same as AG Same as AG Same as AG -- are per mole LXVII). DA (1) 2-2.2 moles strong base, pref. -5.degree.-5.degree. C. 0.5-1 hr. AIO, pref. ES, Yes sodium hydride, per mole LXXI. esp. THF (2) 1-2 moles, pref. 1.5-1.7 moles, -5.degree.-5.degree. C. .fwdarw.2.5-4 hrs. Same as Step Yes LXXII per mole LXXI. 20.degree.-25.degree. C. 1 Add LXXII dropwise (if a liquid) or as a solution in the reaction solvent to the solution of the anion produced in Step 1 at -5.degree.-5.degree. C., stir for 5-30 min., allow temperature to slowly rise to 20.degree.-25.degree. C. and stir at this temperature for the balance of the reaction time. DB (Cyclizati on) 1-2.2 moles, pref. 1.5 moles, LXII 20.degree.-40.degree. C., pref. 12-24 hrs. Glacial acetic Yes per mole LXXIII. Product may be 20.degree. -25.degree. C. acid or dimethyl a mixture of LXXIV and LXVI, with sulfoxide the former usually being the major product. The relative amounts of the two compounds depends upon, among other things, the significance of R.sub.1 and the significances and posi- tions of R.sub.2 -R.sub.7. The mixture may be separated by conventional means. DC (Reduction) Same as Reaction CD. (Molar quantities Same as CD Same as CD Same as CD Yes are per mole LXXIV). DD (Halogenation) Same as Reaction AG. (Molar quantities Same as AG Same as AG Same as AG -- are per mole LXXV). DE Same as Reaction DA. (Molar quantities Same as DA Same as DA Same as DA Yes are per mole LXV). EA (1) Catalytic amount of sodium, e.g., 20.degree.-25.degree. C. 1.5 hrs. Methanol Yes 0.026 mole per mole LXXXI. Add sodium to methanol, stir for 15 min., add LXXXI portionwise over 15 min. period and stir for 1 hr. (2) 1-1.01 moles mercuric acetate per mole 20.degree.-25.degree. C. 5 hrs. Methanol Yes LXXXI. EB (1) 1.55-1.6 moles sodium chloride per mole 20.degree.-25.degre e. C. 30 min. Methanol Yes LXXXII. (2) 1-1.1 moles, esp. 1.08 moles, sodium -5.degree.-0.degree. C. .fwdarw. 5 hrs. 3:2 mixture Yes borohydride per mole LXXXII. Add sodium 20.degree.-25.degree. C. of methanol and borohydride portionwise over 1.5 hr. isopropanol period at 0.degree.-5.degree. C. adding isopropanol after each portion (in amounts such that final solvent is 3:2 mixture of methanol and isopropanol) and stir at 20.degree.-25.degree. C. for 3.5 hours. EC (Etherifica- 0.8-1 mole, pref. 0.84 mole, triphenylmethyl 35.degree.-40.d egree. C. 30-32 hrs. 10-15:1, pref. Yes tion) chloride per mole LXXXIII. Add triphenyl- 12-14:1, mix- methyl chloride portionwise over 15 min. ture of period at 20.degree.-25.degree. C. and stir at 20.degree.-25.degree. C. pyridine and for 1 hr. and at 35.degree.-40.degree. C. for 30-31 hrs. methylene chloride ED (1) 4-5 moles, pref. 4.75 moles, sodium 20.degree.-30.degree. C. 3.5 hrs. Hexamethylphos- Yes hydride per mole LXXXIV. Over 30 min. phoramide or, period add solution of LXXXIV in THF to pref., dry THF sodium hydride stirred in THF (some cooling is necessary to maintain tempera- ture at 25.degree.-30.degree. C.) and stir at 20.degree.-25.degree. C. for 3 hrs. (2) 1 mole of LXXXIVA per mole LXXXIV. Over -30.degree. C. .fwdarw. 2.5 hrs. Same as Step 1 -- 30 min. period add solution of LXXXIVA 20.degree.-25.degree. C. to reaction mixture stirred at -30.degree. C. and allow reaction mixture to slowly warm to 20.degree.-25.degree. C. over 2 hr. period. EE (Reduction) 1.8-1.9 moles, pref. 1.85 moles, lithium -10.degree.-10.de gree. C. 16.5-18.5 Dry methyl Yes aluminum hydride per mole LXXXV. Over 1.5 hrs. t-butyl ether hr. period add lithium aluminum hydride to or diethyl solution of LXXXV stirred at -10.degree.-0.degree. C. and ether stir at -10.degree.-10.degree. C. for 15-17 hrs. EF (Silylation) 1-2 moles, pref. 1.1 moles, LXXXVIA per 20.degree.-32.degree. C. 16-19 hrs. Dry dimethyl- Yes mole LXXXVI and 2 moles imidazole per mole formamide LXXXVIA. Add LXXXVIA to solution of LXXXVI and imidazole over 30 min. period (maintain maximum temperature of 32.degree. C.) and stir for 15.5-18.5 hrs. at 20.degree.-25.degree. C. EG (Hydrolysis) 125-130 ml. 70% (v/v) aqueous trifluoroacetic -55.degree.--50.degree. C. 5 hrs. Methylene Yes acid per mole LXXXVII. Over 1 hr. period .fwdarw. -10.degree.-0.degree. C. chloride add aqueous trifluoroacetic acid dropwise to solution of LXXXVII stirred at -55.degree.--50.degree. C., allow to warm to -10.degree. C. over 1 hr. period and stir at -10.degree.-0.degree. C. for 3 hrs. EH (Oxidation) 2 moles pyridinium chlorochromate or 6-10 20.degree.-25.de gree. C. 2.25-3.5 Dry methylene Yes moles, pref. 8 moles, chromium trioxide hrs. chloride (pref. complexed with pyridine, more pref. 2 moles pyridine per mole chromium trioxide) and 700-1000 g. crushed molecular sieves (pref. 4.ANG.. size) per mole LXXXVIII. When pyridiniu m chlorochromate is used, add it portionwise over 15-30 min. period to balance of reaction mixture, and when chromium trioxide is used, add solution of LXXXVIII to balance of reaction mixture over 15-30 min. period and, in each case, stir for 2-3 hrs. EI (Wittig) (p) Synthesis of LXXXIXA: 1 mole methyl- -30.degree.-25.degree. C., 1.16-1.33 Dry THF Yes triphenylphosphonium bromide or, pref., pref. -5.degree.-5.degree. C. hrs. iodide and 1-1.03 moles n-butyllithium. Add solution of n-butyllithium, pref. 1.3-1.7 M. in hexane, dropwise over 10-20 min. period to slurry of phosphonium compound and stir for 1 hr. (1) 1-1.5 moles, pref. 1.1-1.45 moles, -10.degree.-10.degree. C., 16-19 hrs. Dry THF Yes LXXXIXA per mole LXXXIX. Add solution of pref. -5.degree.-5.degr ee. C. LXXXIX in dry THF dropwise over 30 min. .fwdarw. 20.degree.-25.degree. C. period to product of Step p stirred at -10.degree.-10.degree. C., allow reaction mixture to warm to 20.degree.-25.degree. C. and stir for balance of reaction time. EJ (Hydrolysis) Heat XC in large excess of the solvent. 60.degree.-70.degree. C. 2-3 hrs. Mixture of -- Pref., quantity of solvent is such that glacial acetic reaction mixture contains 40-60 moles acetic acid, THF and acid per mole XC. water, pref. a 3:2:2 mixture EK (Oxidation) 2-4 moles pyrdinium chlorochromate per 20.degree.-25.degree. C. 16-24 hrs., Dry methylene -- mole XCI. pref. 17- chloride 19 hrs. EL (Ozonolysis) Excess ozone. Bubble ozone through solution -80.degree.--70.degree. C., 2-30 min. C.sub.1-3 alkanol, -- of XCII until a bluish coloration persists perf. -78.degree. C. esp. methanol, and then quench reaction mixture with or HLA, esp. dimethyl sulfide or triphenylphosphine. methylene chloride, or ethyl acetate FA (1) Generation of dianion of XIX: 1 mole -50.degree.-10.degree. C., 0.3-1.5 AIO, e.g., ES, Yes XIX and 2-2.2 equivalents strong pref. -10.degree.- hrs., pref. pref. THF base, e.g., 2-2.2 moles lithium 10.degree. C. 0.5-1 hr. diisopropylamide or, pref., 1-1.1 moles sodium hydride followed by 1-1.1 moles n-butyllithiu m (pref. as 1.3-1.7 M. solution in hexane). (2) 1-1.2 moles dianion of XIX (assuming -80.degree.-0.degree. C., 2.5 hrs. Same as Step 1 Yes 100% conversion of XIX to its dianion) pref. -40.degree.- per mole XCIII. Slowly add solution of -20.degree. C., esp. XCIII in, pref., dry THF to solution of -35.degree.--30.degree. C., dianion stirred at -80.degree.-0.degree. C., pref. -40.degree.- .fwdarw. 20.degree.-25.degree. C. -20.degree. C., esp. -35.degree.--30.degree. C., stir at same temperature for 30 min. and allow to warm to 20.degree .-25.degree. C. over a 2 hr. period. Product (XCIV) is a racemate. FB (Reduction) (a) Non-stereoselective: Same as Reaction K, Same as K, a Same as K, Same as K, a Yes Altenative a (Molar quantities are per a mole of XCIV). Product (XCV) is a mixture of all four possible stereoiso mers (the erythro and threo racemates), the erythro to threo ratio being approximately 3:2 to 2:3. (b) Stereoselective: (1) 1-1.25 moles, pref. 1.05-1.25 moles, 0.degree.-50.degree. C., pref. 1-6 hrs., AIO, pref. ES, -- esp. 1.2-1.25 moles, tri-(primary 20.degree.-25.degree . C. pref. 1.5- esp. THF or secondary C.sub.2-4 alkyl)borane, pref. 3 hrs. triethylborane or tri-n-butylborane, esp. the latter, per mole XCIV. Use of air as in Step 1 of Alternative b of Reaction K is optional. (2) 0.4-1.5 moles, pref. 1-1.25 moles, -100.degree.--40.degree . C., 2-60 hrs., Same as Step 1 -- sodium borohydride per mole XCIV. pref. -90.degree.- pref. 24- After the reaction, reaction -70.degree. C., esp. 48 hrs. mixture is quenched with, for example, -90.degree.--78. degree. C. 10% hydrochloric acid and crude product is isolated by extraction with, for example, diethyl ether and evaporation of the solvent. (3) Large excess of methanol (e.g., 0.degree.-25.degree. C., pref. 0.7-5 hrs., As indicated -- 50-100 moles per mole XCIV) or 0.degree.-10.degree. C., when pref. 2-4 mixture of methanol (e.g., 10-20 1. using a mixture hrs. per mole XCIV), hydrogen peroxide of methanol, (e.g., 4-8 1. of 30% aqueous hydrogen hydrogen per- peroxide per mole XCIV) and a pH oxide and buffer 7-7.2 aqueous phosphate buffer (pref. and 20.degree.-60.degree. C. 6-10 1. of a pH 7 aqueous phosphate when using buffer (e.g., 0.054 M. sodium, 0.024 M. methanol alone potassium and 0.047 M. phosphate) per mole XCIV). The amount of buffer must be sufficient to maintain a pH of 7-7.2. Dissolve product of Step 2 in methanol and add buffer and aqueous hydrogen peroxide. Use of methanol alone is preferred. (c) Alternative stereoselective: Same as Same as K, c Same as K, Same as K, c Same as Reaction K, Alternative c c K, c FC (Silylation) 2-8 moles, pref. 4 moles, LXXXVIA per mole 20.degree.-30.degree. C., pref. 16-19 hrs. Dry dimethyl- Yes XCV and 2 moles imidazole per mole LXXXVIA. 20.degree.-25.degree. C. formamide Slowly add LXXXVIA to solution of XCV and imidazole (at rate such that temperature does not exceed 30.degree. C.) and stir at, pref., 20.degree.-25.degree. C. for balance of reaction time. FD (Gridnard) (1) 1.8-2.1 moles, pref. 2 moles, XCIX per -70.degree.-25.degree. C., 1-15 hrs., AIO, pref. Yes mole XCIV. pref. -50.degree.-0.degree. C. pref. 2-8 ES, esp. THF hrs. (2) Quench with, for example, saturated -20.degree.-25.degree. C. 5-15 min. -- -- ammonium chloride solution. FE (Silylation) Same as Reaction FC (Molar quantities of Same as FC Same as FC Same as FC Yes LXXXVIA are per mole C). FF (Ozonolysis) Same as Reaction EL. Same as EL Same as EL Same as EL -- FG (Wittig) Same as Reaction GC (Molar quantities are Same as GC Same as GC Same as GC -- per mole XCVII). GA (Oxidation) 1-3.5 moles, pref. 1.2-3 moles, pyridiniu m 20.degree.-30.degree. C., pref. 2-18 hrs., AIO, pref. HLA, Yes chlorochromate or pyridinium dichromate, 20.degree.-25.degree. C. pref. 3-12 exp. methylene 5-10 moles, pref. 6-8 moles, chromium hrs., with chloride, for trioxide (pref. complexed with pyridine, pyridinium pyridinium more pref. 2 moles pyridine per mole chrom- chloro- chlorochromate, ium trioxide) or 5-50 moles, pref. 10-20 chromate or chromium moles, manganese dioxide, pref. activated chromium trioxide or manganese dioxide, per mole CCI. trioxide, pyridinium 8-24 hrs., dichromate and pref. 15- pref. HLA or 18 hrs., ES, esp. with pyri- diethyl ether, dinium for manganese dichromate dioxide and 4-48 hrs., pref. 10-24 hrs., with manganese dioxide GB (p1) Preparation of cis-1-ethoxy-2-tri-n- 50.degree.-55.degree. C. for 5 hrs. Neat Yes butylstannylethylene: 1 mole 4 hrs. and 60.degree.- ethoxyacetylene and 1 mole tri-n-butyltin 70.degree. C. for 1 hr. hydride. Add ethoxyacetylene to tri-n-butyltin hydride at 50.degree. C. over 1 hr. period and stir at 50.degree.-55.degree. C. for 3 hrs. and at 60.degree.-70.degree. C. for 1 hr. (p2) Preparation of CCIII: 1-1.08 moles -80.degree.--75.degree. C. 1-3 hrs., AIO, e.g., ES, Yes n-butyllithium and 1 mole cis-1- pref. 2 pref. THF ethoxy-2-tri-n-butylstannylethylene. hrs. Add n-butyllithium (pref. as 1.3-1.7 M. solution in hexane) dropwise to solution of stannyl compound at -78.degree. C. (Addition) (1) 1-1.15 moles CCIII (assuming 100% yield -80.degree.--40.degree. C., 1-8 hrs., Same as Step Yes from Step p2) per mole CCII. Crude enol pref. -80.degre e.- pref. 1.5- (p2) ether product of this step may be used -60.degree. C. 5 hrs. in next step without isolation and/or purification but isolation and purifica- tion of enol ether intermediate may improve yield of CCIV from next step. (Hydrolysis) (2) Catalytic amount of p-toluenesulfonic 20.degree.-40.degree. C., 1-5 hrs., Mixture of ES -- acid or monohydrate thereof (e.g., 0.5- pref. 20.degree.-25.degree. C. pref. 1.5-4 and water, 2 g., pref. 1.2-1.8 g., per mole CCII hrs. pref. mixture used in Step 1) and water. of THF and water GC (Wittig) (1) Synthesis of ylide: 1-1.05 moles strong -40.degree.-0.degree . C., 1-4 hrs. AIO, pref. ES, Yes base, e.g., sodium hydride, phenyllithi um pref. -35.degree.- e.g., THF or, pref., n-butyllithium (esp. as 1.3- -20.degree. C. 1.7 M. solution in hexane) per mole CCV. Pref., slowly add solution of strong base to solution of CCV. (2) Synthesis of enol ether: Ylide from -30.degree.-0.degree. C., 1-4 hrs. Same as Step 1 Yes 1-1.05 moles CCV per mole CCII. pref. -20.degree.-0.degree. C. (3) Hydrolysis of enol ether: Large molar 0.degree.-30.degree. C. 8-24 hrs. Mixture of -- excess, e.g., 2-20 moles, strong acid, aqueous acid e.g., 70% perchloric acid, per mole CCII an ES, e.g., used in Step 2. mixture of 70% perchloric acid and THF GD (Wittig) Same as Reaction GC (Molar quantities in Same as GC Same as GC Same as GC Same as Steps 2 and 3 are per mole CCVI). GC GE (Wittig) Same as Reaction GC (Molar quantities in Same as GC Same as GC Same as GC Same as Steps 2 and 3 are per mole CCVII). GC GF (Wittig) Alternative a: 1-2 moles, pref. 1-1.7 moles, CCIX per 80.degree. C.-reflux, 6-18 hrs. AIO, pref. HC, Yes mole CCII. esp. refluxing esp. toluene toluene Alternative b: (1) Synthesis of ylide: 1-1.07 moles strong -20.degree.-25.degree. C., 0.75-2 hrs. AIO, pref. ES, Yes base, pref. sodium hydride, per mole pref. -20.degree.-0.degree. C. esp. THF CCX. Pref., add small amount of CCX to suspension of sodium hydride in THF stirred at 20.degree.-25.degree. C., cool to -20.degree.--15.degree. C. once reaction commences and complete reaction at -20.degree.--15.degree. C. (2) 1-1.25 moles ylide from CCX (assuming -20.degree.-25.degree. C. 0.75-18 Same as Step 1 Yes 100% conversion of CCX to ylide) per mole hrs. CCII. Add solution of CCII to ylide solution at -20.degree.--15.degree. C. and stir at -20.degree.-25.degree. C. for balance of reaction. GG (Reduction) (1) At least 2 equivalents of transferable 0.degree.-25.degree. C., pref. 0.7-3 hrs. AIO, pref. ES, Yes hydride from a metal hydride reducing 0.degree.- 10.degree. C. e.g., THF agent, e.g., lithium aluminum hydride or diisobutylaluminum hydride, per mole CCXI, pref. 3.8-6 moles diisobutyla luminum hydride per mole CCXI. (2) Quench with, for example, saturated 0.degree.-25.degree. C. 5-15 min. -- -- aqueous ammonium chloride or sodium sulfate solution. GH (Oxidation) 5-50 moles, pref. 10-30 moles, manganese 20.degree. C.-reflux, 3-24 hrs., AIO, pref. HC -- dioxide, pref. activated manganese dioxide, pref. 20.degree.-40.degree. C. pref. 10- or ES, pref. per mole CCXII. 18 hrs. diethyl ether GI (Reduction) (a) Same as Reaction K, Alternative a (Molar Same as K, a Same as K, Same as K, a -- quantities are per mole CCVI). a (b) Same as Reaction CD or GG utilizing half Same as CD or Same as CD Same as CD or Yes the indicated molar quantities (Molar GG or GG GG quantities are per mole CCVI). GJ (Halogena- Same as Reaction AG (Molar quantities are Same as AG Same as AG Same as AG -- tion per mole CCXIII). GK Same as Reaction A (Molar quantities are per Same as A Same as A Same as A Yes mole CCXIV).
In the preceding table,
AIO=anhydrous inert organic solvent
ES=ether solvent, for example, diethyl ether, 1,2-diethoxyethane, 1,2-dimethoxyethane, tetrahydrofuran and mixtures thereof
esp.=especially
HC=hydrocarbon solvent, for example, benzene, toluene, xylene and mixtures thereof
HLA=halogenated lower alkane solvent, for example, carbon tetrachloride, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, methylene chloride and 1,1,2-trichloroethane, usually preferably methylene chloride
hr. (hrs.)=hours(s)
IO=inert organic solvent
min.=minutes
pref.=preferably, preferred
THF=tetrahydrofuran
Most of the molar amounts (ratios) given in the preceding table are merely exemplary and may be varied, as is evident to one of ordinary skill in the art. For example, in a reaction of two compounds one of which is readily available and one of which isn't, an excess of the readily available compound may be used to drive the reaction further towards completion (unless the use of an excess would increase the synthesis of an undesired compound).
Likewise, most of the temperature ranges given in the preceding table are merely exemplary, and it is within the ability of one of ordinary skill in the art to vary those that are not critical.
The reaction times set forth in the preceding table are also merely exemplary and may be varied. As is wellknown, the reaction time is often inversely related to the reaction temperature. Generally, each reaction is monitored by, for example, thin layer chromatography and is terminated when at least one starting material is no longer present, when it appears that no more of the desired product is being formed, etc.
Conventional work-up procedures have generally been omitted from the preceding table.
As utilized in the preceding table, the term "solvent" embraces mixtures of solvents and implies that the reaction medium is a liquid at the desired reaction temperature. It should, therefore, be understood that not all of the solvents listed for a particular reaction may be utilized for the entire recited temperature range. It should also be understood that the solvent must be at least substantially inert to the reactants employed, intermediates generated and end products under the reaction conditions utilized.
The term "inert atmosphere", as utilized in the preceding table, means an atmosphere that does not react with any of the reactants, intermediates or end products or otherwise interfere with the reaction. While a carbon dioxide atmosphere is suitable for certain reactions, the inert atmosphere is usually nitrogen, helium, neon, argon or krypton, or a mixture thereof, and most often dry nitrogen to maintain anhydrous conditions. Most reactions, including those where the use of an inert atmosphere is not specified, are carried out under an inert atmosphere, usually dry nitrogen, for convenience.
Reactions analogous to Reactions A-C, E-G, I-T, AG, BF, CD, CE, DC, DD, GA-GE and GG-GK are described in detail in copending application Ser. No. 06/722,288, filed by Faizulla G. Kathawala on Apr. 11, 1985 and titled Indole Analogs Of Mevalonolactone And Derivatives Thereof. These reactions may be carried out analogously to the corresponding reactions of said application. Also disclosed in said application are Reactions EA-EH of this application. Said application, particularly pages 14-21, 24-26, 28-52, 65-76, 82-96, 98-102, 106, 107 and 116-122 thereof, is hereby incorporated by reference. Generally, where the reaction conditions set forth in said application differ from those set forth in this application, the reaction conditions set forth in said application may also be utilized for the compounds of this application.
Reactions EA-EF and EI-EL are described in further detail in copending application Ser. No. 06/563,945, filed by me and Charles F. Jewell, Jr. on Dec. 21, 1983 and titled Derivatives Of Tetrahydropyran-2-One. Also described in said application is an alternate procedure for carrying out Reactions EG and EH. Said application, particularly pages 15-28 thereof, is hereby incorporated by reference.
Reactions FA-FC and FF are described in further detail in copending application Ser. No. 06/596,411, filed by me and Charles F. Jewell, Jr. on Apr. 3, 1984 and titled Preparation Of Olefinic Compounds. Pages 16-19 of said application are hereby incorporated by reference.
The product of each reaction may, if desired, be purified by conventional techniques such as recrystallization (if a solid), column chromatography, preparative thin layer chromatography, gas chromatography (if sufficiently volatile), fractional distillation under high vacuum (if sufficiently volatile) or high pressure (performance) liquid chromatography (HPLC). Often, however, the crude product of one reaction may be employed in the following reaction without purification.
Some of the reactions described above yield mixtures of two or more products only one of which leads to the desired compound of Formula I. For example, Reactions AE and AH may yield mixtures when, for example, at least one of R.sub.2 -R.sub.7 is primary or secondary alkyl, Reactions BD and BG may yield mixtures when, for example, at least one of R.sub.1 -R.sub.7 is methyl and, as set forth above, Reaction DB usually results in a mixture. Any obtained mixture may be separated by conventional techniques such as those set forth in the preceding paragraph.
As is evident to those in the art, each of the compounds of Formulae XVII, XVIIC, XX, LXXIII and XCIV has a single center of asymmetry and, therefore, may be resolved into two optically active isomers. When a compound of Formula XVIIC, XX or XCIV is converted into a compound of Formula XVIIE, XXI or XCV or C, respectively, an additional center of asymmetry is generated. Consequently, when a racemic compound of Formula XVIIC, XX or XCIV is utilized, four stereoisomers (two pairs of diastereoisomers) of the resulting compound of Formula XVIIE, XXI or XCV or C are formed, whereas when an optically pure compound of Formula XVIIC, XX or XCIV is utilized, two diastereoisomers of the compound of Formula XVIIE, XXI or XCV or C are formed. The center of asymmetry of each compound of Formula LXXIII may be ignored since it is destroyed in the following reaction (Reaction DB).
The compounds of Formulae I (including those of Formulae IA-ID, XII, XIV, XXI, etc.), X, XI, XIII, XVIIE, XCV, XCVI and C have two centers of asymmetry and, therefore, may exist in four stereoisomeric forms. Except where the compound is formed from an optically pure precursor already having both chiral carbon atoms or where the reaction involves the use of a stereospecific reagent that gives an optically pure product, the compound is obtained as a mixture of two (if formed from an optically pure compound having one cneter of asymmetry) or four (if formed from a racemic compound having one center of asymmetry) stereoisomers.
The obtained mixtures of stereoisomers may be separated by conventional means. For example, diastereoisomers may be separated by fractional crystallization, column chromatography, preparative thin layer chromatography and HPLC. Each mixture of four stereoisomers of a compound of Formula XXX may, for example, be separated by HPLC into its cis and trans (lactone) components, each of which is a racemate that may be resolved into two optically active enantiomers.
Techniques for separating a racemate into its two optically active enantiomers are known. For example, a racemic compound having a carboxylic acid group may be reacted with an optically pure organic base having at least one center of asymmetry to form a mixture of diastereoisomeric salts that may be separated by fractional crystallization, column chromatography, etc. or it may be reacted with an optically pure alcohol having at least one center of asymmetry to form a mixture of diastereoisomeric esters which may be separated by conventional techniques such as those set forth above or below. Likewise, a racemic compound having a carboxylic acid, acyl halide, ester or lactone group may be reacted with an optically pure organic base, i.e., an amine, to form a mixture of diastereoisomeric amides that may be separated by conventional means, e.g., fractional crystallization, column chromatography and/or HPLC. For example, a racemic lactone of Formula XXX may be reacted with an excess of R-(+)-.alpha.-methylbenzylamine (or the corresponding S-(-) compound) to form a mixture of two diastereoisomeric .alpha.-methylbenzylamides which may be separated by, for example, column chromatography on a silica gel column and/or by HPLC using a Partisil column. Often it is desirable to utilize both techniques, i.e., to partially separate the diastereoisomers by column chromatography and to purify each fraction by HPLC. Typically, the .alpha.-methylbenzylamides are synthesized by reacting the racemic lactone with a large molar excess of the amine at 20.degree.-25.degree. C. for 16-24 hours. The reaction is run neat, with the excess amine serving as the solvent. After the reaction, the excess amine is removed by vacuum distillation at 25.degree.-35.degree. C. After separation, each chiral amide may be hydrolyzed to the corresponding, for example, sodium, salt by, for example, refluxing with 1.5-3, preferably 2-2.2, equivalents of a base such as sodium hydroxide for 5-25 hours in a mixture of water and ethanol. The resulting salts may be converted to the corresponding free acids, esters, lactones and other salts by conventional means such as the reactions set forth in Reaction Scheme IV. On the other hand, a racemic compound having a hydroxy group may be esterified with an optically pure carboxylic acid having at least one center of asymmetry to form a mixture of diastereoisomeric esters or it may be reacted with an optically pure trisubstituted silyl halide, e.g., (-)-.alpha.-naphthylphenylmethylchlorosilane (Sommer et al., J. Am. Chem. Soc. 80, 3271 (1958).), to form a mixture of two diastereoisomeric silyloxy compounds, which mixture may be separated by conventional techniques. For example, diastereoisomeric (-)-.alpha.-naphthylphenylmethylsilyl derivatives of a lactone of Formula XXX may be separated on a silica column having covalently bound L-phenylglycine. After separation, the optically pure salts, amides, esters or silyloxy compounds are reconverted to the corresponding carboxy group- or hydroxy group-containing compounds with retention of optical purity. For example, the process conditions disclosed for Reactions C, E, G and I may be utilized to cleave (-)-.alpha.-naphthylphenylmethylsilyl and other silyl groups.
The compounds of Formulae XVI, XVIIA, XVIIB, XVIID, XIX, XXIII, XXVI, XXVIII, XXXI, XXXII, XXXIV, XLI, XLII, LI, LII, LXI, LXII, LXV, LXXI, LXXII, LXXXI-LXXXVIII, XCIII, XCIX, CCV, CCIX and CCX and the reagents not designated by a Roman numeral are known or, if unknown, may be synthesized by processes analogous to those described in the literature for similar known compounds. For example, Compound LXXXI is commercially available tri-O-acetyl-D-glucal and Compounds LXXXV-LXXXVIII are disclosed in Yang et al., Tetrahedron Letters 23, 4305-4308 (1982).
A preferred process for the synthesis of the erythro racemate of the compound of Formula XCVII wherein R.sub.10 is hydrogen, and R.sub.12 ' is methyl is disclosed in Kapa, Tetrahedron Letters 25, 2435-2438 (1984). The other compounds of Formula XCVII wherein R.sub.10 is hydrogen in racemic erythro form may be synthesized similarly. See also U.S. Pat. No. 4,571,428. Said patent, particularly column 3, line 3-column 6, line 23 and column 7, line 27-column 11, line 22 is hereby incorporated by reference.
Since any compound of Formula I wherein Z is a group of Formula a wherein R.sub.11 is a cation other than M may be converted into the corresponding compound wherein R.sub.11 is hydrogen, M or R.sub.12 by the processes of Reaction Scheme IV, the compounds of Formula I wherein Z is a group of Formula a and R.sub.11 is a pharmaceutically unacceptable cation are also within the scope of this invention since they are useful as intermediates. However, such compounds are not compounds of Formula I as utilized in this application, except where indicated to the contrary.
Also within the scope of this invention are the intermediates of Formulae V, VII, XI, XIII, XVII, XVIIC, XVIIE, XX, XCVIII, C, CCIV, CCXI and CCXII and those of Formulae XCVI and XCVII wherein R.sub.10 is C.sub.1-3 alkyl. The preferences for each variable are the same as those set forth for the compounds of Formula I, with the preferred groups of such compounds including those that correspond to Groups (xix)-(xxvii), (xlvi)-(liv), (lxxiii)-(lxxxi) and (c)-(cviii) (for Formulae V and VII) and Groups (i)-(xviii), (xxviii)-(xlv), (lv)-(lxxii) and (lxxxii)-(xcix) (for each of the others) to the extent consistent therewith.
The entire specification of parent application Serial No. 06/623,393, particularly pages 1-9 and 55-60 thereof, is hereby incorporated by reference, as if set forth herein in its entirety.
Besides having the utility set forth below, every compound of Formula I is useful as an intermediate in the synthesis of one or more other compounds of Formula I utilizing the reactions set forth in Reaction Scheme IV.
The compounds of Formula I are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in chloesterol biosynthesis, and, therefore, they are inhibitors of cholesterol biosynthesis. Consequently, they are useful for lowering the blood cholesterol level in animals, e.g., mammals, especially larger primates such as humans, and, therefore, as hypolipoproteinemic and anti-atherosclerotic agents. The biological activity of the compounds of Formula I may be demonstrated in the following two tests:
Test A. In Vitro Microsomal Assay of HMG-CoA Reductase Inhibition:
200 .mu.l. aliquots (1.08-1.50 mg./ml.) of rat liver microsomal suspensions, freshly prepared from male Sprague-Dawley rats (150-225 g. body weight), in Buffer A with 10 mmol. dithiothreitol are incubated with 10 .mu.l. of a solution of the test substance in dimethylacetamide and assayed for HMG-CoA reductase activity as described in Ackerman et al., J. Lipid Res. 18, 408-413 (1977), the concentration of the test substance in the assay system being 0.0001-2,000 .mu.molar. In the assay the microsomes are the source of the HMG-CoA reductase enzyme which catalyzes the reduction of HMG-CoA to mevalonate. The assay employs a chloroform extraction to separate the product, [.sup.14 C]mevalonolactone, formed by the HMG-CoA reductase recution of the substrate, [.sup.14 C]HMG-CoA. [.sup.3 H]mevalonolactone is added as an internal reference. Inhibition of HMG-CoA reductase is calculated from the decrease in specific activity ([.sup.14 C/.sup.3 H]mevalonate) of test groups compared to controls.
Test B. In Vivo Cholesterol Biosynthesis Inhibition Test:
In vivo studies utilize male Wistar Royal Hart rats weighing 150.+-.20 g. which have been kept for 7-10 days on an altered light cycle (6:30 A.M.-6:30 P.M. dark) housed two per cage and fed powdered Purina Rat Chow and water ad libitum. Three hours before the diurnal maximum of cholesterol synthesis at mid-dark, the rats are orally administered the test substance (e.g., 0.01-200 mg./kg. body weight) dissolved or as a suspension in 0.5% carboxymethylcellulose in a volume of 1 ml./100 g. body weight. Controls receive vehicle alone. One hour after receiving the test substance (or the vehicle alone), the rats are injected intraperitoneally with about 25 .mu.Ci/100 g. body weight of sodium [1-.sup.14 C]acetate 1-3 mCi/mmol. Two hours after mid-dark, blood samples are obtained under sodium hexobarbitol anesthesia, and the serum is separated by centrifugation.
Serum samples are saponified and neutralized, and the 3.beta.-hydroxysterols are precipitated with digitonin basically as described in Sperry et al., J. Biol. Chem. 187, 97 (1950). The [.sup.14 C]digitonides are then counted by liquid scintillation spectrometry. After correcting for efficiencies, the results are calculted in nCi (nanocuries) of 3.beta.-hydroxysterol formed per 100 ml. of serum. Inhibition of 3.beta.-hydroxysterol synthesis is calculated from the reduction in the nCi of 3.beta.-hydroxysterols formed from test groups compared to controls.
The following results were obtained:
______________________________________Test A: Example 1 IC.sub.50 = 0.08 .mu.molar Example 2 IC.sub.50 = 103 .mu.molar Example 3 IC.sub.50 = 0.06 .mu.molar Example 7 IC.sub.50 = 0.04 .mu.molar Example 11 IC.sub.50 = 0.26 .mu.molar Example 14 IC.sub.50 = 0.02 .mu.molar Compactin IC.sub.50 = 0.77 .mu.molar Mevinolin IC.sub.50 = 0.14 .mu.molar______________________________________
IC.sub.50 is the concentration of the test substance in the assay system calculated or observed to produce a 50% inhibition of HMG-CoA reductase activity.
______________________________________Test B: Example 3 ED.sub.50 = 0.05 mg./kg. Example 7 ED.sub.50 = 0.06 mg./kg. Example 14 ED.sub.50 = 0.013 mg./kg. Compactin ED.sub.50 = 3.5 mg./kg. Mevinolin ED.sub.50 = 0.41 mg./kg.______________________________________
ED.sub.50 is the dose of the test substance calculated or observed to produce a 50% inhibition of 3.beta.-hydroxysterol synthesis.
As set forth above, the compounds of formula I (including each and every subgroup thereof set forth in the specification and/or the claims) inhibit cholesterol biosynthesis and are useful for lowering the blood cholesterol level in animals, particularly mammals and more particularly larger primates, and, therefore, as hypolipoproteinemic and anti-atherosclerotic agents.
The compounds of Formula I may be formulated into conventional pharmaceutical compositions and administered by conventional modes of administration. The compounds of each and every subgroup thereof in the specification and/or claims may likewise be formulated into conventional pharmaceutical compositions.
The compounds of Formula I may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered orally in the form of tablets, dispersible powders, granules, capsules, elixirs, suspensions and the like or parenterally in the form of sterile injection solutions or suspensions. The compositions may be prepared by conventional means. The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and capsules.
The precise dosage of the compounds of Formula I to be employed for inhibiting cholesterol biosynthesis depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration and the particular compound employed. However, in general, suitable daily oral dosages of the compounds of Formula I for the satisfactory inhibition or reduction of cholesterol biosynthesis (i.e., the satisfactory reduction of the blood cholesterol level and satisfactory treatment of hyperlipoproteinemia and atherosclerosis) are indicated to be 0.01-100, e.g., 0.01-5, mg./kg. body weight or, for most larger primates, a daily dosage of 0.1-2000 mg., suitably 0.1-150 mg., e.g., 0.1-20 mg. for the more active compounds. For the compound of Example 3, the oral daily dosage is indicated to be 0.05-2.5 mg./kg. body weight or, for most larger primates, it is indicated to be 0.5-20 mg. For the compound of Example 14, the oral daily dosage is indicated to be 0.01-1 mg./kg. body weight or, for most larger primates, it is indicated to be 0.1-20, preferably 1-20, mg.
The daily dosage may be divided into two to four equal portions or administered in a single dose. A typical oral dosage of the compounds of Examples 3 and 14 is indicated to be 1 mg. three times a day. Usually, a small dosage is administered initially, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. For administration by injection, a dosage somewhat lower than would be used for oral administration of the same compound to the same host having the same condition is usually employed. However, the above dosages are also typically used for i.v. administration.
A typical dosage unit for oral administration may contain 0.05-500 mg. of a compound of Formula I. Preferred dosage units contain 0.05-2.5 mg. of a compound of Formula I such as the compounds of Examples 3, 7 and 14.
The compounds of Formula I (including those of each and every subgroup thereof) may be formulated into such pharmaceutical compositions containing an amount of the active substance that is effective for inhibiting cholesterol biosynthesis, such compositions in unit dosage form and such compositions comprising a solid pharmaceutically acceptable carrier.
Representive formulations prepared by conventional techniques for encapsulation in a hard gelatin capsule are:
______________________________________A. Compound of Formula I, e.g., the compound of 0.5 mg. Example 3 Corn starch 248 mg. Magnesium stearate 1.5 mg.B. Compound of Formula I, e.g., the compound of 1 mg. Example 14 Corn starch 248 mg. Magnesium stearate 1 mg.______________________________________
A representative formulation suitable for preparing tablets by conventional means is:
______________________________________Compound of Formula I, e.g., the compound of 1 mg.Example 7Polyvinylpyrrolidone USP 5 mg.Powdered lactose 183 mg.Corn starch 10 mg.Magnesium stearate 1 mg.______________________________________
The following examples show representative compounds encompassed by this invention and their synthesis. However, it should be understood that they are for purposes of illustration only.

EXAMPLE 1
(E)-Trans-6S-(2'-[4"-(4'"-fluorophenyl)-1"-(1'"-methylethyl)-3"-phenyl-1H-pyrazol-5"-yl]ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one ##STR19##
Step 1 (Reaction AA)
.alpha.-(4-Fluorophenyl)acetophenone (Compounds CII)
5.27 ml. (42 mmoles) of 4-fluorobenzyl bromide (Compound CI) is slowly added to 928 mg. (38 mmoles) of magnesium turnings stirred in 38 ml. of anhydrous diethyl ether under nitrogen over a period of 45 minutes at a rate such that the reaction mixture gently refluxes. The reaction mixture is allowed to cool to 20.degree.-25.degree. C., 2.96 ml. (29 mmoles) of benzonitrile in 5 ml. of anhydrous diethyl ether is added over a period of 5 minutes, and the reaction mixture is stirred at 20.degree.-25.degree. C. for 3 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is slowly poured into ice cold 10% hydrochloric acid, and the organic phase is separated. The aqueous phase is extracted five times with diethyl ether and twice with ethyl acetate, and the organic phases are combined, washed once with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The residue is dissolved in 450 ml. of hot petroleum ether, and the solution is filtered and cooled to obtain the product as an off-white solid (3.5 g.), m.p. 109.degree.-110.degree. C. A second crop is also obtained (0.39 g.).
Step 2 (Reaction AB)
1-[2'-(4"-Fluorophenyl)-1'-phenylethylidene]-2-(1'-methylethyl)-hydrazine (Compound CIII)
A mixture of 3 g. (14.0 mmoles) of Compound CII, 2.45 ml. (28 mmoles) of isopropylhydrazine and 0.5 ml. of acetic acid in 23 ml. of 95% ethanol is stirred at 80.degree. C. for 1.4 hours. The reaction mixture is cooled, most of the solvent is evaporated at reduced pressure and methylene chloride is added. The methylene chloride solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. Toluene is added to the residue, and the mixture is evaporated to dryness at reduced pressure to obtain the product (3.97 g.) as a somewhat cloudy yellow liquid.
Isopropylhydrazine is synthesized as follows: 9.39 ml. (0.1 mole) of 2-bromopropane is slowly added over a period of 2 hours to 48.4 ml. (1 mole) of hydrazine.hydrate stirred under nitrogen at 20.degree.-25.degree. C. During the addition the temperature rises to as high as 40.degree. C. The reaction mixture is stirred under nitrogen at 60.degree. C. for 3.25 hours, cooled to 20.degree.-25.degree. C. and continuously extracted with diethyl ether for 20 hours. The diethyl ether is evaporated at reduced pressure to obtain the crude product (4.03 g.) which is used as is. B.p. 106.degree.-107.degree. C. (742 mm. Hg.)
Step 3 (Reaction AC)
1-Acetyl-2-[2'-(4"-fluorophenyl)-1'-phenylethylidene]-1-(1'-methylethyl)hydrazine (Compound CIV)
3.9 ml. (28 mmoles) of triethylamine is added to a solution of 3.97 g. (.ltoreq.14 mmoles) of crude Compound CIII in 140 ml. of toluene, the mixture is cooled to 0.degree.-5.degree. C., 1.24 ml. (17.5 mmoles) of acetyl chloride is added, and the reaction mixture is stirred for 1.5 hours with gradual warming to 20.degree.-25.degree. C. 500 ml. of diethyl ether is added, and the solution is filtered through anhydrous sodium sulfate and evaporated to dryness at reduced pressure. Toluene is added, and the mixture is evaporated to dryness at reduced pressure. The residue is chromatographed on 160 g. of silica gel utilizing 75% diethyl ether/n-hexane as the eluant. The fractions containing the product (as determined by thin layer chromatography) are combined and evaporated at reduced pressure to obtain the product as a yellow oil (3.6 g. (82%)).
Step 4 (Reaction AD)
4-(4'-Fluorophenyl)-5-methyl-1-(1'-methylethyl)-3-phenyl-1H-pyrazole (Compound CV)
A mixture of 1.6 g. (5.1 mmoles) of Compound CIV and 0.656 g. (10.2 mmoles) of potassium hydroxide in 51 ml. of bis-(2-methoxyethyl) ether is stirred at 80.degree. C. under nitrogen for 2 hours, an additional 0.75 g. of potassium hydroxide is added, and the reaction mixture is stirred under nitrogen at 80.degree. C. for 2 hours and at 20.degree.-25.degree. C. for 16 hours and poured into 300 ml. of distilled water. The mixture is extracted three times with 150 ml. portions of diethyl ether and once with 200 ml. of ethyl acetate. The organic extracts are combined, washed with 500 ml. of ice cold 3% hydrochloric acid and twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated at reduced pressure, and heated at 90.degree.-100.degree. C. for a few minutes. A small amount of chloroform and n-hexane is added, and the solution is cooled in a sealed container at -78.degree. C. to obtain the crystalline product (0.92 g. (61%)), m.p. 139.degree.-140.degree. C.
Step 5 (Reaction AH)
5-Bromomethyl-4-(4'-fluorophenyl)-1-(1'-methylethyl)-3-phenyl-1H-pyrazole (Compound CVI)
A mixture of 0.9 g. (3.06 mmoles) of Compound CV, 654 mg. (3.67 mmoles) of N-bromosuccinimide and 37 mg. of 5 molar % dibenzoyl peroxide in 61.2 ml. of carbon tetrachloride is stirred at 80.degree. C. under nitrogen for 45 minutes. The reaction mixture is cooled to 20.degree.-25.degree. C., filtered and evaporated to dryness at reduced pressure to obtain the crude product as a pale yellow oil. Petroleum ether is added to partially crystalline the product. 0.393 g. of crystalline product and 0.66 g. of oily product are obtained. An analytical sample is recrystallized from petroleum ether, m.p. 93.degree.-95.degree. C.
Step 6 (Reaction A)
4-(4'-Fluorophenyl)-1-(1'-methylethyl)-3-phenyl-5-triphenylphosphoniummethyl-1H-pyrazole (Compound CVII)
A mixture of 0.6 g. (1.77 mmoles) of Compound CVI (the oily product of the preceding step) and 0.58 g. (2.21 mmoles) of triphenylphosphine in 42 ml. of toluene is stirred at 80.degree. C. under nitrogen for 45 minutes. The reaction mixture is allowed to cool to 20.degree.-25.degree. C., and the solid white product is collected by filtration and washed with diethyl ether (0.7 g. (62.5%)).
Step 7 (Reaction EL and B)
(E)-Trans-4R-(1',1'-dimethylethyl-diphenylsilyloxy)-6S-(2'-[4"-(4'"-fluorophenyl)-1"-(1'"-methylethyl)-3"-phenyl-1H-pyrazol-5"-yl]ethenyl)-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound CVIII and its (Z) isomer (Compound CIX)
(a) Trans-4R-(1',1'-dimethylethyl-diphenylsilyloxy)-6S-formyl-2H-pyran-2one (Compound IV): Ozone is bubbled through a solution of 200 mg. (0.526 mmole) of trans-4R-(1',1'-dimethylethyl-diphenylsilyloxy-6S-vinyl-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound XCII) in 26 ml. of methylene chloride stirred at -78.degree. C. until the solution has a bluish tint (about 5 minutes), and 0.5 ml. of dimethyl sulfide is added by syringe to quench the reaction mixture. The mixture is warmed to 20.degree.-25.degree. C., the solvent is evaporated at reduced pressure, and any remaining solvent is evaporated under high vacuum to obtain the product as an oil.
(b) 501 mg. (0.789 mmole) of Compound CVII is dried under high vacuum for 2 hours (to remove any trace of solvent present) and dissolved in 7.89 ml. of dry tetrahydrofuran. The solution is stirred at -30.degree. C. under nitrogen and 570 .mu.l. of 1.7M. n-butyllithium/n-hexane (0.969 mmole) is added by syringe to obtain a solution of the ylide (Compound of Formula CVII having a --CH.dbd.P(C.sub.6 H.sub.5).sub.3 group in lieu of the --CH.sub.2 P.sup..sym. (C.sub.6 H.sub.5).sub.3 Br.sup..crclbar. group).
(c) The ylide solution of Part (b) is added by syringe to a solution of Compound IV (from Part (a)) in 5.26 ml. of dry tetrahydrofuran stirred at -30.degree. C. under nitrogen, and the reaction mixture is stirred under the same conditions for 1 hour and quenched with 5 ml. of saturated ammonium chloride solution. The mixture is extracted with 150 ml. of diethyl ether, and the diethyl ether extract is washed twice with saturated sodium chloride solution, dried over anydrous magnesium sulfate, filtered and evaporated to dryness at reduced pressure to obtain the crude product as a brown foam (439.6 mg.).
(d) The brown foam from Part (c) is triturated three times with 50% diethyl ether/n-hexane, and the diethyl ether/n-hexane solutions are combined and evaporated at reduced pressure to an oil (.about.110 mg.). The oil is chromatographed on 40 g. of silica gel utilizing 50% diethyl ether/n-hexane as the eluant, and the fractions containing each product are combined and evaporated at reduced pressure to obtain the (E) olefin (Compound CVIII) (45.1 (13%)) and the (Z) olefin (Compound CIX) (38.0 mg. (11%)) as oils. The (E) olefin is eluted prior to the (Z) olefin.
Step 8 (Reaction C)
(E)-Trans-6S-(2'-[4"-(4'"-fluorophenyl)-1"-(1'"-methylethyl)-3"-phenyl-1H-pyrazol-5"-yl]ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound CX)
16.2 .mu.l. (0.28 mmole) of glacial acetic acid is added dropwise by syringe to a solution of 36.6 mg. (0.056 mmole) of Compound CVIII in 2.8 ml. of tetrahydrofuran stirred at 20.degree.-25.degree. C. under nitrogen. 224 .mu.l. of 1M. tetra-n-butylammonium fluoride/tetrahydrofuran (0.224 mmole) is added by syringe, and the reaction mixture is stirred at 20.degree.-25.degree. C. under nitrogen for 3.75 hours and poured into 20 ml. of ice cold water. The mixture is extracted four times with diethyl ether, and the diethyl ether extracts are combined, washed with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness at reduced pressure. The residue is washed with 50% diethyl ether/petroleum ether to obtain the product as a white solid (15.4 mg.), m.p. 216.degree. C. (yellows and shrinks at 214.degree. C.). [.alpha.].sub.D.sup.25 =-6.86.degree. (CH.sub.3 COCH.sub.3, c=0.35)
N.M.R. (CDCl.sub.3): 1.59 (d (J=6.5 Hz.), 6H), 1.87 (m, 2H), 2.69 (m, 2H), 4.35 (m, 1H), 4.62 (m (J=6.5 Hz.), 1H, 5.2 (m, 1H), 5.6 (dd (J.sub.1 =16 Hz., J.sub.2 =5 Hz.), 1H), 6.58 (d (J=16 Hz.), 1H), 7.0-7.5 (m, 9H).
EXAMPLE 2
(Z)-Trans-6S-(2'-[4"-(4'"-fluorophenyl)-1"-(1'"-methylethyl)-3"-phenyl-1H-pyrazol-5"-yl]ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound CXI) ##STR20##
The product is obtained from 34 mg. (0.052 mmole) of Compound CIX by the process of Step 8 of Example 1 utilizing 15.0 .mu.l. (0.26 mmole) of glacial acetic acid, 208 .mu.l. of 1M. tetra-n-butylammonium fluoride/tetrahydrofuran (0.208 mmole) and, as the solvent, 26 ml. of tetrahydrofuran except that the reaction time is 24-28 hours (14.5 mg., m.p. 190.degree. C. [.alpha.].sub.D.sup.25 =+171.37.degree. (CH.sub.2 Cl.sub.2, c=0.51)
N.M.R. (CDCl.sub.3): 0.72 (m, 1H), 1.27 (m, 1H), 1.46 (m, 1H), 1.58 (d (J=6.5 Hz.), 6H), 2.52 (m, 2H), 4.1 (m, 1H), 4.5 (m (J=6.5 Hz.), 1H), 4.95 (m, 1H), 5.83 (dd (J.sub.1 =11 Hz., J.sub.2 =10 Hz.), 1H), 6.5 (d (J=11 Hz.), 1H), 6.95-7.45 (m, 9H).
EXAMPLE 3
Sodium erythro-(E)-3R,5S-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-3'-phenyl-1H-pyrazol-5'-yl]hept-6-enoate ##STR21##
50.16 .mu.l. of 0.5N. sodium hydroxide solution (0.0251 mmole) is added by syringe to a solution of 11.1 mg. (0.0264 mmole) of Compound CX in 2 ml. of methanol stirred at 20.degree.-25.degree. C., and the reaction mixture is stirred under nitrogen at this temperature for 3 hours. The methanol is evaporated at reduced pressure, and the residue is dissolved in 2 ml. of water. The aqueous solution is carefully extracted with diethyl ether, and the last traces of diethyl ether are removed at reduced pressure. The aqueous solution is cooled to -78.degree. C. and freeze-dried under high vacuum to obtain the product as a free-flowing pale yellow foam (10.2 mg.), m.p. begins to darken at 166.degree. C.; almost completely a black char at 215.degree. C.
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): 1.53 (d (J=6.5 Hz.), 6H), 1.5 (m, 2H), 2.3 (m, 2H), 4.1 (bm, 1H), 4.3 (bm, 1H), 4.65 (m (J=6.5 Hz.), 1H), 5.62 (dd (J.sub.1 =16 Hz., J.sub.2 =5 Hz.), 1H), 6.48 (d (J=16 Hz.), 1H), 6.9-7.4 (m, 9H).
EXAMPLE 4
Sodium erythro-(Z)-3R,5S-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-3'-phenyl-1H-pyrazol-5'-yl]hept-6enoate ##STR22##
The product is obtained from Compound CXI substantially in accordance with the process of Example 3.
EXAMPLES 5 AND 6
Methyl erythro-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-3'-phenyl-1H-pyrazol-5'-yl]hept-6-enoate and (E)-Trans-6-(2'-[4"-(4'"-fluorophenyl)-1"-(1'"-methylethyl)-3"-phenyl-1H-pyrazol-5"-yl]ethenyl)-4-hydroxy-3,4,5,6-tetrahydro2H-pyran-2-one ##STR23##
Step 1 (Reaction F)
Methyl erythro-(E)-3,5-[di-(1',1'-dimethylethyl-diphenylsilyloxy)]-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-3'-phenyl-1H-pyrazol-5'-yl]hept-6-enoate (Compound CXV)
The product is obtained from 0.7 g. (1.1 mmoles) of Compound CVII (Example 1, Step 6), 0.7 g. (1.1 mmoles) of methyl erythro-3,5-di-(1',1'-dimethylethyl-diphenylsilyloxy)-6-oxohexanoate (Compound CXIV, Example 1, Step F of said application U.S. Pat. No. 4,571,428 flash chromatographed on a silica gel column utilizing 1:1 chloroform/n-hexane as the eluant prior to use), 1.4 ml. of 1.6M. n-butyllithium/n-hexane (2.2 mmoles) and 25 ml. of dry tetrahydrofuran as the solvent substantially in accordance with Parts (b) and (c) of Step 7 of Example 1, the principal differences being that the solution of Compound CXIV in dry tetrahydrofuran is added dropwise to the solution of the ylide produced from Compound CVII and the reaction time is 16 hours. The crude oily product is flash chromatographed on a silica gel column (2.5 cm..times.15.3 cm.) utilizing 25% diethyl ether/n-hexane as the eluant to obtain the crude product as an oil (0.83 g.).
Step 2 (Reaction G)
Methyl erythro-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"methylethyl)-3'-phenyl-1H-pyrazol-5'-yl]hept-6-enoate (Compound CXVI) and
(E)-Trans-6-(2'-[4"-(4'"-fluorophenyl)-1"(1'"-methylethyl)-3"-phenyl-1H-pyrazol-5"-yl]ethenyl)-4-hydroxy-3,4,5,6-tetrahydro2H-pyran-2-one (Compound CXVII)
(a) 3.6 ml. of 1M. tetra-n-butylammonium fluoride/tetrahydrofuran (3.6 mmoles) is added to a mixture of 0.83 g. (0.9 mmole) of crude Compound CXV (from the preceding step), 0.42 ml. (7.2 mmoles) of glacial acetic acid and 20 ml. of tetrahydrofuran, and the reaction mixture is stirred at 20.degree.-25.degree. C. for 24 hours and poured into saturated sodium bicarbonate solution. The mixture is extracted with diethyl ether, the diethyl ether extract is dried over anhydrous magnesium sulfate, and the diethyl ether is evaporated at reduced pressure. The residue is chromatographed on a silica gel column (2.5 cm..times.20.3 cm.) utilizing 7:2:1 methyl t-butyl ether/n-hexane/acetone as the eluant. The fractions containing the first component of the major product (as determined by thin layer chromatography) are combined and evaporated at reduced pressure to obtain Compound CXVI as an oil (30 mg.).
N.M.R. (CDCl.sub.3): 1.46-1.58 (m, 2H), 1.58 (d, 6H), 2.46 (d, 2H), 3.10-3.70 (bm, 2H), 3.72 (s, 3H), 4.20 (m, 1H), 4.42 (m, 1H), 4.65 (m, 1H), 5.60 (dd, 1H), 6.52 (d, 1H), 7.00 (t, 2H), 7.12-7.25 (m, 5H), 7.35-7.40 (m, 2H).
The product is a racemate that may be resolved to obtain the 3R,5S and 3S,5R enantiomers.
(b) The fractions containing the second component of the major product (see Part (a)) are combined and evaporated at reduced pressure to obtain Compound CXVII as crystalline needles (11 mg.).
The product is a racemate that may be resolved to obtain the 4R,6S and 4S,6R enantiomers.
EXAMPLE 7
Sodium erythro-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-1'-(1"-methylethyl)-3'-phenyl-1H-pyrazol-5'-yl]hept-6-enoate ##STR24##
A mixture of 11 mg. (0.026 mmole) of Compound CXVII, 0.05 ml. of 0.5N. sodium hydroxide (0.25 mmole) and 5 ml. of 95% ethanol is stirred at 20.degree.-25.degree. C. for 2 hours and evaporated to dryness at reduced pressure. The residue is dissolved in about 3 ml. of water, and the solution is washed twice with diethyl ether and freeze dried to obtain the product as a solid foam (15 mg.).
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): 1.4-1.5 (m, 2H), 1.58 (d, 6H), 2.18-2.5 (m, 2H), 4.1 (m, 1H), 4.36 (m, 1H), 4.68 (m, 1H), 5.65 (dd, 1H), 6.51 (d, 1H), 6.92-7.05 (m, 2H), 7.10-7.40 (m, 7H).
The product is a racemate that may be resolved to obtain the 3R,5S and 3S,5R enantiomers.
EXAMPLE 8
Ethyl (E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-5'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate ##STR25##
Step 1 (Reaction CA)
4-Fluorobenzoic acid-N'-phenylhydrazide (Compound CXXI)
30 ml. (0.25 mole) of 4-fluorobenzoyl chloride is added dropwise over a 30 minute period to a mixture of 25 ml. (0.25 mole) of phenylhydrazine and 35 ml. (0.25 mole) of triethylamine in 500 ml. of anhydrous diethyl ether stirred at -10.degree. C. under nitrogen. The reaction mixture is allowed to warm to 20.degree.-25.degree. C. and stirred under nitrogen for 3 hours. The obtained solids are collected by filtration, washed with diethyl ether and dissolved in about 600 ml. of methylene chloride. The methylene chloride solution is filtered and evaporated at reduced pressure to near dryness, and n-hexane is added to obtain the crude solid product (26 g.). The crude product is dissolved in tetrahydrofuran and filtered to remove the triethylamine hydrochloride, the tetrahydrofuran is evaporated at reduced pressure, and the obtained product is recrystallized from acetone (12 g.), m.p. 181.degree.-186.degree. C. A second crop is also obtained (6 g.).
Step 2 (Reaction CB)
4-Fluoro-N-phenylbenzenecarbohydrazonoyl chloride (Compound CXXII)
A mixture of 8.6 g. (41 mmoles) of phosphorus pentachloride, 8.0 g. (35 mmoles) of Compound CXXI and 60 ml. of anhydrous diethyl ether is refluxed under nitrogen for 16 hours and cooled to 20.degree.-25.degree. C., a solution of 15 g. of phenol in 20 ml. of diethyl ether is added, the mixture is stirred for 5 minutes, 15 ml. of methanol is added very slowly (exothermic reaction), and the mixture is concentrated at 70.degree.-75.degree. C. and cooled for 16 hours in a refrigerator to obtain the crystalline product which is washed with cold 5% water/acetone (3 g.), m.p. 118.degree.-121.degree. C.
Step 3 (Reaction CC)
Ethyl 3-(4'-fluorophenyl)-5-(1'-methylethyl)-1-phenyl-1H-pyrazole-4-carboxylate (Compound CXXIV)
0.28 g. (12.0 mmoles) of sodium is dissolved in 40 ml. of absolute ethanol stirred at 20.degree.-25.degree. C., 2.0 ml. (12.0 mmoles) of ethyl isobutyrylacetate (Compound CXXIII) is added dropwise with stirring at 20.degree.-25.degree. C., the mixture is stirred at 20.degree.-25.degree. C. for 15 minutes, 3.0 g. (12.0 mmoles) of Compound CXXII is added positionwise as a solid (the temperature increases to 35.degree. C.), and the reaction mixture is stirred at 20.degree.-25.degree. C. for 4 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is quenched with 10 ml. of 10% hydrochloric acid, and the mixture is concentrated at reduced pressure (which results in dehydration of an intermediate). The residue is extracted with diethyl ether, and the diethyl ether extract is washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The residue is flash chromatographed on a silica gel column (2.5 cm..times.20.3 cm.) utilizing chloroform as the eluant, and the chloroform is evaporated at reduced pressure to obtain the crude product as a red oil (3.1 g. (75%)).
Step 4 (Reaction CD)
3-(4'-Fluorophenyl)-5-(1'-methylethyl)-1-phenyl-1H-pyrazole-4-methanol (Compound CXXV)
A solution of 3.0 g. (8.5 mmoles) of Compound CXXIV in 20 ml. of anhydrous diethyl ether is added to a suspension of 0.65 g. (17.1 mmoles) of lithium aluminum hydride in 30 ml. of anhydrous diethyl ether stirred at 0.degree.-5.degree. C. under nitrogen, and the reaction mixture is stirred under the same conditions for 3 hours. The reaction mixture is quenched with about 5 ml. of ethyl acetate, and 10 ml. of 10% hydrochloric acid is added. The organic phase is separated, and the aqueous phase is extracted with diethyl ether. The organic phases are combined, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The solid residue is recrystallized from 5:1 n-hexane/chloroform to obtain the crystalline product (2.2 g. (84%)), m.p. 144.degree.-147.degree. C.
Step 5 (Reaction CE)
4-Chloromethyl-3-(4'-fluorophenyl)-5-(1'-methylethyl)-1-phenyl-1H-pyrazole (Compound CXXVI)
A mixture of 2.0 g. (6.5 mmoles) of Compound CXXV, 0.6 ml. (8.2 mmoles) of thionyl chloride and 20 ml. of benzene (reagent grade) is refluxed under nitrogen for 4 hours and stirred at 20.degree.-25.degree. C. under nitrogen for 16 hours. The excess thionyl chloride and the benzene are evaporated at reduced pressure, additional benzene is added, the mixture is evaporated at reduced pressure twice, and the residue is dried under high vacuum. Petroleum ether is added to crystalline the product (2.1 g.), m.p. 124.degree.-128.degree. C.
Step 6 (Reaction A)
3-(4'-Fluorophenyl)-5-(1'-methylethyl)-1-phenyl-4-triphenylphosphoniummethyl-1H-pyrazole chloride (Compound CXXVII)
A mixture of 2.0 g. (6.1 mmoles) of Compound CXXVI, 2.1 g. (7.9 mmoles) of triphenylphosphine and 80 ml. of toluene is refluxed for 2 hours, stirred at 20.degree.-25.degree. C. for 64 hours, refluxed for 20 hours and cooled to 20.degree.-25.degree. C., the reaction mixture being maintained under nitrogen throughout. The product is collected by filtration and washed with diethyl ether (2.7 g.).
Step 7 (Reaction F)
Ethyl 3,5-di-(1',1'-dimethylethyl-diphenylsilyloxy)-7-[3'-(4"-fluorophenyl)-5'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate (Compound CXXIX)
The product is obtained from 1.0 g. (1.7 mmoles) of Compound CXXVII, 1.0 g. (1.5 mmoles) of ethyl 3,5-di-(1',1'-dimethylethyl-diphenylsilyloxy)-6-oxohexanoate (a mixture of isomers wherein the erythro:threo ratio is about 4:1 produced substantially as described in Steps A-D of Example 1 of said application Ser. No. 596,411, the principal difference being the use of triethylborane in Step B rather than tri-(n-butyl)borane) and 2.1 ml. of 1.65M. n-butyllithium/n-hexane (3.47 mmoles) according to the process of Step 1 of Examples 5 and 6. The product is obtained as a solid foam (0.53 mg. (36%)).
The product is a mixture of the (E)-erythro, (E)-threo, (Z)-erythro and (Z)-threo racemates wherein the ratio of the (E) isomers to the (Z) isomers is about 2:1 and the ratio of the erythro isomers to the threo isomers is about 4:1. The four isomers may be separated by conventional means. Each erythro racemate may be resolved to obtain the 3R,5S and 3S,5R enantiomers, and each threo racemate may be resolved to obtain the 3R,5R and 3S,5S enantiomers.
Step 8 (Reaction G)
Ethyl (E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-5'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate
2 ml. of 1M. tetra-n-butylammonium fluoride/tetrahydrofuran (2 mmoles) is added to a mixture of 0.5 g. (0.51 mmoles) of Compound CXXIX (from the preceding step), 0.23 ml. (4 mmoles) of glacial acetic acid and 50 ml. of tetrahydrofuran (distilled prior to use), and the reaction mixture is stirred at 20.degree.-25.degree. C. for 3 days and at 40.degree. C. for 1 day, additional 1M. tetra-n-butylammonium fluoride/tetrahydrofuran being added periodically. The reaction mixture is poured onto a mixture of ice and sodium bicarbonate solution, and the mixture is extracted with diethyl ether. The diethyl ether extract is washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated at reduce pressure. The residue is chromatographed on a silica gel column (2.5 cm..times.20.3 cm.) utilizing 7:2:1 methyl t-butyl ether/n-hexane/acetone as the eluant. The fractions containg the product are combined and evaporated at reduced pressure to obtain the product (65 mg.).
The product is an about 4:1 mixture of the (E)-erythro and (E)-threo racemates which may be separated by conventional means. The former may be resolved to obtain the 3R,5S and 3S,5R enantiomers, and the latter may be resolved to obtain the 3R,5R and 3S,5S enantiomers.
EXAMPLES 9-11
(E)-Trans-6-(2'-[3"-(4'"-fluorophenyl)-5"-(1'"-methylethyl)-1"-phenyl-1H-pyrazol-4"-yl]ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one ##STR26##
(a) A mixture of 65 mg. (0.14 mmole) of Compound CXXX (from Example 8), 0.32 ml. of 0.5N. sodium hydroxide solution (0.16 mmole) and 10 ml. of ethanol is stirred at 20.degree.-25.degree. C. for 2 hours and evaporated to near dryness at reduced pressure. An about 4:1 mixture of the erythro and threo racemates of Compound CXXXI is present (Example 9).
(b) The product of Part (a) is dissolved in water and acidified with 10% hydrochloric acid, the solution is extracted with diethyl ether, and the diethyl ether extract is dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to an oil, an about 4:1 mixture of the erythro and threo racemates of Compound CXXXII (Example 10).
(c) The product of Part (b) is dissolved in 10 ml. of methylene chloride (reagent grade), 100 mg. of N-cyclohexyl-N'-[2'-(N"-methylmorpholinium)ethyl]carbodiimide p-toluenesulfonate is added, and the reaction mixture is stirred at 20.degree.-25.degree. C. for 3 hours and poured into sodium chloride solution. The mixture is extracted with a 1:1 mixture of diethyl ether and tetrahydrofuran, and the extract is dried over anhydrous magnesium sulfate and evaporated at reduced pressure to a yellow oil. The oil is flash chromatographed on a silica gel column (1.25 cm..times.20.3 cm.) utilizing 7:2:1 methyl t-butyl ether/n-hexane/acetone as the eluant to obtain the product.
N.M.R. (CDCl.sub.3): 1.23 (d,6H), 1.50-2.0 (m,2H), 2.21 (s,1H), 2.42-2.74 (m,2H), 3.08 (m,1H), 4.28 (m,1H), 5.15 (m,1H), 5.50 (dd, 1H), 6.68 (d,1H), 7.00 (t,2H), 7.31-7.58 (m,7H).
The product is a racemate that may be resolved to obtain the 4R,6S and 4S,6R enantiomers.
EXAMPLE 12
Sodium erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-5'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate ##STR27##
The product may be obtained by the process of Example 7. It is a racemate that may be resolved to obtain the 3R,5S and 3S,5R enantiomers.
EXAMPLE 13
Ethyl (.+-.)-erythro-(E)-3,5-dihydroxy-7-[5'-(4"-fluorophenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate ##STR28##
Step 1
Ethyl 3-(4'-fluorophenyl)-3-oxopropanoate (Compound CXXXVII)
57.92 g. (1.448 moles) of 60% sodium hydride/mineral oil is washed twice with pentane, the pentane is decanted, the sodium hydride is dried in a stream of nitrogen, 171 g. (1.448 moles) of diethyl carbonate is added neat at 20.degree.-25.degree. C., and the dropwise addition of a solution of 100 g. (0.724 mole) of 4-fluoroacetophenone in 100 ml of dry diethyl ether is commenced, the reaction mixture being stirred at 20.degree.-25.degree. C. under nitrogen throughout. After about 10% of the diethyl ether solution is added, 10 drops of ethanol is added (gas evolution commences immediately), and the balance of the solution is added dropwise over a period 1 hour at a rate such that the reaction mixture refluxes, the reaction mixture being stirred under nitrogen throughout. 1 kg. of dry diethyl ether is added to facilitate stirring, and the reaction mixture is refluxed under nitrogen for 3 hours and cooled to 0.degree. C., water is carefully added (to destroy the excess sodium hydride) until all solids dissolve (the addition being exothermic), the diethyl ether phase is separated, the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid and extracted twice with diethyl ether, and the three diethyl ether phases are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain an orange oil. The orange oil is fractionally distilled at about 1 mm. Hg. to obtain the product as a colorless liquid (117.8 g. (77%)). B.p. 117.degree.-125.degree. C..lambda.1 mm. Hg.
Step 2 (Reaction DA)
Ethyl 2-(4'-fluorobenzoyl)-4-methyl-3-oxopentanoate (Compound CXXXIX)
21.0 g. (524 mmoles) of 60% sodium hydride/mineral oil is washed twice with hexane, the hexane is decanted, the sodium hydride is dried in a stream of nitrogen and suspended in 500 ml. of dry tetrahydrofuran, the suspension is cooled to 0.degree. C., 50.0 g. (238 mmoles) of Compound CXXXVII is added dropwise over a period of 20 minutes at 0.degree. C., the reaction mixture is allowed to warm to 20.degree.-25.degree. C., stirred at this temperature for 30 minutes and cooled to 0.degree. C., 38.0 g. (357 mmoles) of isobutyryl chloride is added dropwise with stirring at 0.degree. C., and the reaction mixture is allowed to warm to 20.degree.-25.degree. C., stirred at 20.degree.-25.degree. C. for 3 hours and cooled to 0.degree. C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is quenched at 0.degree. C. with water, sufficient water being added to form a homogeneous mixture, the tetrahydrofuran is evaporated at reduced pressure, and the aqueous solution is acidified to pH 1 with 10% hydrochloric acid and extracted twice with 200 ml. portions of diethyl ether. The diethyl ether extracts are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as an orange oil (72.99 g.).
Step 3 (Reaction DB)
Ethyl 5-(4"-fluorophenyl)-3-(1'-methylethyl)- 1-phenyl-1H-pyrazole-4-carboxylate (Compound CXL)
38.6 g. (357 mmoles) of phenylhydrazine is added portionwise to a solution of 72.99 g. (.ltoreq.238 mmoles) of crude Compound CXXXIX (from Step 2) in 300 ml. of glacial acetic acid stirred at 20.degree.-25.degree. C. under nitrogen (the addition being slightly exothermic) and the reaction mixture is stirred at 20.degree.-25.degree. C. under nitrogen for 16 hours and poured into 700 ml. of water. The mixture is extracted twice with 200 ml. portions of diethyl ether, and the diethyl ether extracts are combined, extracted with saturated sodium bicarbonate solution (until the aqueous phase remains basic), washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain an orange gel. The gel is triturated with petroleum ether to obtain the product as a yellow powder (29.57 g.). The mother liquor is evaporated at reduced pressure, and the residue is purified on a Waters Prep-500 high pressure liquid chromatograph (HPLC) having a silica gel column and utilizing methylene chloride as the solvent to obtain additional solid which is recrystallized from diethyl ether/hexane to obtain additional product (8.47 g.). Total yield: 38.04 g. (43% Steps 2 and 3 combined). M.p. 91.5.degree.-93.degree. C.
Step 4 (Reaction DC)
5-(4'-Fluorophenyl)-3-(1'-methylethyl)-1-phenyl-1H-pyrazole-4-methanol (Compound CXLI)
A solution of 42.0 g. (115 mmoles) of Compound CXL in 500 ml. of dry diethyl ether is added dropwise over a period of 1.5 hours to a suspension of 13.1 g. (345 mmoles) of lithium aluminum hydride in 250 ml. of dry diethyl ether stirred at 0.degree. C. under nitrogen, and the resulting green suspension is allowed to warm to 20.degree.-25.degree. C. over a period of 1.5 hours with stirring under nitrogen. The reaction mixture is cooled to 0.degree. C. and quenched by carefully adding water until the evolution of gas ceases, the resulting precipitate is collected by filtration and washed with ethyl acetate, the ethyl acetate washing is combined with the diethyl ether filtrate, and the organic solution is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as a tan powder (33.95 g. (95%)).
Step 5 (Reaction GA)
5-(4'-Fluorophenyl)-3-(1'-methylethyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (Compound CXLII)
A solution of 33.95 g. (.ltoreq.109 mmoles) of crude Compound CXLI (from Step 4) in 250 ml. of methylene chloride is added rapidly dropwise to a solution of 70.75 g. (328 mmoles) of pyridinium chlorochromate in 350 ml. of methylene chloride stirred at 20.degree.-25.degree. C., and the reaction mixture is stirred at 20.degree.-25.degree. C. for 4 hours. 2.5 l. of diethyl ether is added, and the mixture is filtered through a 12.7 cm. pad of silica gel and evaporated at reduced pressure to obtain a brown solid which is recrystallized from diethyl ether to obtain the product as a white solid (24.46 g.). The mother liquor is chromatographed on a silica gel column utilizing 20% diethyl ether/hexane as the eluant to obtain additional product (3.66 g.). Total yield: 28.12 g. (83% Steps 4 and 5 combined). M.p. 110.degree.-112.degree. C.
Step 6 (Reaction GF)
Ethyl (E)- 3-[5'-(4"-fluorophenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]propenoate (Compound CXLIV)
761 mg. (19 mmoles) of 60% sodium hydride/mineral oil is washed twice with hexane, the hexane is decanted, the sodium hydride is dried in a stream of nitrogen and suspended in 50 ml. of dry tetrahydrofuran, the suspension is cooled to -15.degree. C., 4.06 g. (18 mmoles) of triethyl phosphonoacetate is added dropwise with stirring at -15.degree. C., the reaction mixture is stirred at -15.degree. C. for 45 minutes, a solution of 5.59 g. (18 mmoles) of Compound CXLII in 50 ml. of dry tetrahydrofuran is added dropwise with stirring at -15.degree. C., and the reaction mixture is stirred at -15.degree. C. for 45 minutes and allowed to warm to 20.degree.-25.degree. C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is quenched at 20.degree.-25.degree. C. by the dropwise addition of saturated ammonium chloride solution, the tetrahydrofuran is evaporated at reduced pressure, and the solid residue is partitioned between ethyl acetate and water. The organic phase is separated, washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as a yellow solid (6.59 g.).
Step 7 (Reaction GG)
(E)-3-[5'-(4"-Fluorophenyl)-3' -(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]prop-2-en-1-ol (Compound CXLV)
46.4 ml. of 1.5M. diisobutylaluminum hydride/toluene (69.6 mmoles) is added dropwise to a solution of 6.59 g. (.ltoreq.17 mmoles) of crude Compound CXLIV (from Step 6) in 150 ml. of dry tetrahydrofuran stirred at 0.degree. C. under nitrogen, the reaction mixture is stirred at 0.degree. C. under nitrogen for 45 minutes, quenched at 0.degree. C. by the dropwise addition of saturated sodium sulfate solution and allowed to warm to 20.degree.-25.degree. C., and sufficient 10% hydrochloric acid is added to dissolve the resulting gel. The organic phase is separated, the aqueous phase is extracted with diethyl ether, and the organic phase and diethyl ether extract are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain the crude product as a yellow foam (6.13 g.).
Step 8 (Reaction GH)
(E)-3-[5'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4' -yl]propenal (Compound CXLVI)
A mixture of 36.8 g. (423 mmoles) activated manganese dioxide and a solution of 6.13 g. (.ltoreq.17 mmoles) of crude Compound CXLV (from Step 7) in 150 ml. of diethyl ether is stirred at 20.degree.-25.degree. C. for 16 hours and filtered through a 5.1 cm. pad of Celite filter aid. The Celite is washed with ethyl acetate, and the ethyl acetate washing and the diethyl ether filtrate are combined and evaporated at reduced pressure to obtain a yellow solid which is recrystallized from diethyl ether to obtain the product as a yellow solid (1.59 g.). The mother liquor is evaporated at reduced pressure, and the residue is chromatographed on a silica gel column utilizing 30% diethyl ether/hexane as the eluant to obtain additional product (2.0 g.). Total yield: 3.59 g. (59% Steps 6, 7 and 8 combined). M.p. 146.degree.-150.degree. C.
Step 9 (Reaction J)
Ethyl (.+-.)-(E)-7-[5'-(4"-fluorophenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]-5-hydroxy-3-oxohept-6-enoate (Compound CXLVIII)
1.355 g. (33.88 mmoles) of 60% sodium hydride/mineral oil is washed with hexane, the hexane is decanted, the sodium hydride is suspended in 100 ml. of dry tetrahydrofuran, the suspension is cooled to -15.degree. C., 4.01 g. (30.8 mmoles) of ethyl acetoacetate is added dropwise with stirring at -15.degree. C., the reaction mixture is stirred at -15.degree. C., for 30 minutes, 20.2 ml. of 1.6M. n-butyllithium/hexane (32.3 mmoles) is added dropwise with stirring at -15.degree. C., the reaction mixture is stirred at -15.degree. C. for 15 minutes, a solution of 5.14 g. (15.4 mmoles) of Compound CXLVI in 50 ml. of dry tetrahydrofuran is added dropwise with stirring at -15.degree. C., and the reaction mixture is stirred at -15.degree. C. for 1 hour, the reaction mixture being stirred under nitrogen throughout. The reaction mixture is quenched at -15.degree. C. with saturated ammonium chloride solution and warmed to 20.degree.-25.degree. C., the tetrahydrofuran is evaporated at reduced pressure, and the residue is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, and the diethyl ether extract and diethyl ether phase are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a yellow foam which is chromatographed on a silica gel column (350 g.) utilizing 1:1 diethyl ether/hexane as the eluant to obtain the product as a yellow oil (5.42 g. (76%)).
The product is a racemate that may be resolved to obtain the R and S enantiomers.
Step 10 (Reaction K)
Ethyl (.+-.)-erythro-(E)-3,5-dihydroxy-7-[5'-(4"-fluorophenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate (Compound CXLIX)
23.34 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (23.34 mmoles) is added via syringe to a solution of 5.42 g. (11.67 mmoles) of Compound CXLVIII in 100 ml. of dry tetrahydrofuran stirred at 20.degree.-25.degree. C., air is bubbled through the reaction mixture of 2 minutes with stirring, the reaction mixture is stirred at 20.degree.-25.degree. C. for 1 hour and cooled to -78.degree. C., 2.21 g. (58.35 mmoles) of sodium borohydride is added, the reaction mixture is stirred at -55.degree. C. for 16 hours and at 0.degree. C. for 1 hour and, if thin layer chromatography reveals the presence of some starting material, the reaction mixture is cooled to -55.degree. C., an additional 1.1 g. (29.1 mmoles) of sodium borohydride is added, and the reaction mixture is stirred at -55.degree. C. for 16 hours and warmed to 0.degree. C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is quenched at 0.degree. C. by the addition of 10% hydrochloric acid (until bubbling ceases), warmed to 20.degree.-25.degree. C. and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, and the diethyl ether extract and the diethyl ether phase are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to a clear oil. The oil is dissolved in 10 ml. of isopropanol and the solution is evaporated at reduced pressure, this procedure is repeated to obtain a pale green wax, the wax is dissolved in a minimum amount of hot isopropanol, and the solution is allowed to cool to 20.degree.-25.degree. C. and stored at -30.degree. C. for 64 hours. The resulting waxy solid is collected by filtration and vacuum dried to obtain a white powder (erythro:threo=.about.9:1). The powder is recrystallized from isopropanol to obtain a waxy solid which is vacuum dried to obtain a white poweder (erythro:threo=.about.19:1). The white powder is warmed in methanol at 40.degree.-60.degree. C. for 2 minutes, the methanol is evaporated at reduced pressure, the residue is warmed in methanol at 40.degree.-60.degree. C. for 2 minutes and the methanol is evaporated at reduced pressure, and this procedure is repeated once more to obtain a white foam which is recrystallized from benzene/hexane to obtain the product as a white solid (1.05 g. (19%)), m.p. 101.degree.-104.degree. C.
N.M.R. (CDCl.sub.3): 1.28 (t (J=7.5 Hz.), 3H), 1.40 (d (J=7 Hz.), 6H), 1.65 (m, 2H), 2.48 (m, 2H), 3.11 (bs, 1H), 3.22 (m, 1H), 3.70 (bs, 1H), 4.18 (q (J=7.5 Hz.), 2H), 4.24 (m, 1H), 4.42 (m, 1H), 5.68 (dd (J.sub.1 =15.5 Hz., J.sub.2 =5.5 Hz.), 1H), 6.38 (d (J=15.5 Hz.), 1H), 7.05 (t (J=7.5 Hz.), 2H), 7.20 (m, 7H).
The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is .about.19:1 and which, if desired, may be separated by conventional means to obtain the pure erythro and threo racemates. The former may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which the former is preferred, and the latter may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a non-stereoselective reduction would afford a mixture of all four enantiomers wherein the ratio of the erythro isomers to the threo isomers ranges from 3:2 to 2:3.
EXAMPLE 14
Sodium erythro-(.+-.)-(E)-3,5-dihydroxy-7-[5'-(4"-fluorophenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate ##STR29##
4.2 ml. of 0.5N. sodium hydroxide solution (2.1 mmoles) is added to a solution of 1.02 g. (2.2 mmoles) of Compound CXLIX (Step 10 of Example 13) in 25 ml. of 95% ethanol, the mixture is stirred at 20.degree.-25.degree. C. under nitrogen for 5 hours, the ethanol is evaporated at reduced pressure, and the residue is partitioned between diethyl ether and water. The aqueous phase is washed twice with diethyl ether and lyophilized at -78.degree. C. for 16 hours. The residue is warmed to 20.degree.-25.degree. C. and lyophilized at -78.degree. C. for another 16 hours to obtain the product as a flocculant white solid (861 mg. (85%)), m.p. 205.degree.-210.degree. C. (dec.).
N.M.R. (CDCl.sub.3 +CD.sub.3 O.sub.D): 1.35 (d (J=7.5 hz.), 6H), 1.52 (m), 3.18 (m, 1H), 4.11 (m, 1H), 4.25 (m, 1H), 5.64 (dd (J.sub.1 =15 Hz., J.sub.2 =5 Hz.), 1H), 6.32 (d (J=15.5 Hz), 1H), 6.95 (t (J=9.5 Hz.), 2H), 7.16 (m, 7H).
The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is .about.19:1 and which, if desired, may be separated by conventional means to obtain the pure erythro and threo racemates. The former may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which the former is preferred, and the latter may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a starting material obtained by utilizing a non-stereoselective reduction in Step 10 of Example 13 would afford a mixture of all four enantiomers wherein the ratio of the erythro isomers to the threo isomers ranges from 3:2 to 2:3.
EXAMPLE 15
Ethyl (.+-.)-erythro-(E)-3,5-dihydroxy-7-[5'-(3",5"-dimethylphenyl)-3'-(1"-methylethyl-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate ##STR30##
The product may be obtained as a solid foam by the processes of Steps 3-10 of Example 13 from ethyl 2-(3',5'-dimethylbenzoyl)-4-methyl-3-oxopentanoate. Said compound is synthesized from ethyl 4-methyl-3-oxopentanoate and 3,5-dimethylbenzoyl chloride by Reaction DE carried out analogously to Step 2 of Example 13.
N.M.R. (CDCl.sub.3): 1.28 (t (J=7.5 Hz.), 3H), 1.4 (d (J=7.5 Hz.), 6H), 1.68 (m, 2H), 2.25 (s, 6H), 2.46 (m, 2H), 2.98 (bs, 1H), 3.22 (m, 1H), 3.74 (d (J=2.5 Hz.), 1H), 4.16 (q (J=7.5 Hz.), 2H), 4.22 (m, 1H), 4.39 (m, 1H), 5.69 (dd (J.sub.1 =17.5 Hz., J.sub.2 =7.5 Hz), 1H), 6.38 (d (J=17.5 Hz.), 1H), 6.79 (bs, 2H), 6.95 (bs, 1H), 7.2 (m, 5H).
The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is .about.9:1 and which, if desired, may be separated by conventional means to obtain the pure erythro and threo racemates. The former may be resolved to obtain the 3R,SS and 3S,5R enantiomers, of which the former is preferred, and the latter may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a non-stereoselective reduction would afford a mixture of all four enantiomers wherein the ratio of the erythro isomers to the threo isomers ranges from 3:2 to 2:3.
EXAMPLE 16
Sodium (.+-.)-erythro-(E)-3,5-dihydroxy-7-[5'-(3",5"-dimethylphenyl)-3'-(1"-methylethyl)-1'-phenyl-1H-pyrazol-4'-yl]hept-6-enoate ##STR31##
The product may be obtained from Compound CLI by the process of Example 14. M.p. 203.degree.-210.degree. C. (dec.).
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): 1.40 (d (J=7 Hz.)), 1.55 (bm), 2.12 (s, 6H), 2.26 (bm), 3.18 (m, 1H), 4.11 (bm, 1H), 4.22 (bm, 1H), 5.64 (dd (J.sub.1 =15 Hz., J.sub.2 =5 Hz.), 1H), 6.30 (d (J=15 Hz.), 1H), 6.70 (s, 2H), 6.82 (s, 1H), 7.15 (m, 5H).
The product is a mixture of the erythro and threo racemates wherein the ratio of the former to the latter is .about.9:1 and which, if desired, may be separated by conventional means to obtain the pure erythro and threo racemates. The former may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which the former is preferred, and the latter may be resolved to obtain the 3R,5R and 3S,5S enantiomers. The use of a starting material prepared by the process of Example 15 but wherein the last step is non-stereoselective reduction would afford a mixture of all four enantiomers wherein the ratio of the erythro isomers to the threo isomers ranges from 3:2 to 2:3.
TABLE__________________________________________________________________________Examples 17-19The following compounds of Group IDa may be synthesized by the processesset forth above:R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.10 R.sub.11 X Isomer M.P.__________________________________________________________________________Ex. 17 i-C.sub.3 H.sub.7 H H H H H H H C.sub.2 H.sub.5 (E)--CH.dbd.CH-- >90% E oilEx. 18 i-C.sub.3 H.sub.7 H H H H H H H Na.sup..sym. (E)--CH.dbd.CH-- >90% E 206.degree.-210.degree. C. (dec.)Ex. 19 i-C.sub.3 H.sub.7 H H H 4-F H H H Na.sup..sym. --CH.sub.2 CH.sub.2 -- >90% E 198.degree.-210.degree. C.__________________________________________________________________________ (dec.) E = erythro racemate
N.M.R. DATA: Ex. 17 (CDCl.sub.3): 1.26 (t, 3H), 1.41 (d, 6H), 1.72 (m, 2H), 2.49 (m, 2H), 2.96 (bs, 1H), 3.25 (m, 1H), 3.69 (bs, 1H), 4.18 (q, 2H), 4.25 (m, 1H), 4.42 (m, 1H), 5.68 (dd, 1H), 6.4 (d, 1H), 7.24 (m, 10H). Ex. 19 (CD.sub.3 OD): 1.36 (d, 6H), 1.55 (m, 4H), 2.34 (m, 4H), 3.66 (m, 1H), 4.08 (m, 1H), 7.2 (m, 9H).
Throughout the examples, the term "reduced pressure" denotes aspirator pressure. Where no solvent is specified in connection with a solution, the solvent is water, and all solvent mixtures are by volume. When a reaction is carried out under nitrogen, dry nitrogen is used to maintain anhydrous conditions (except where the reaction medium contains water).
All nuclear magnetic resonance spectra were taken at ambient temperature on a 200 MHz. spectrometer. All chemical shits are given in p.p.m. (.delta.) relative to tetramethylsilane and where a single .delta. value is given for anything other than a sharp singlet, it is its center point. In the N.M.R. data:
______________________________________bm = broad multiplet bs = broad singletd = doublet dd = doublet of a doubletm = multiplet q = quartets = singlet t = triplet______________________________________
In the optical rotation data, the concentrations (c) are given in g./100 ml.
Each of the compounds of the examples wherein Z is a group of Formula a wherein R.sub.11 is a cation may be converted into the corresponding compounds wherein R.sub.11 is hydrogen or a different cation M, particularly the latter, especially M', by the processes set forth in Reaction Scheme IV.
Each of the compounds of Examples 1-19 (including each of the possible optical isomers of the examples not directed to single isomers) may be administered to an animal, e.g., a larger primate, to inhibit cholesterol biosynthesis and thereby lower the blood cholesterol level for, for example, the treatment of atherosclerosis and hyperlipoproteinemia. The dosages are those set forth supra.

Number	Name	Date
3983140	Endo et al.	Sep 1976
4198425	Mitsui et al.	Apr 1980
4248889	Oka et al.	Feb 1981
4255444	Oka et al.	Mar 1981
4308378	Stokker	Dec 1981
4351844	Patchett et al.	Sep 1982
4361515	Terahara et al.	Nov 1982
4375475	Willard et al.	Mar 1983
4376863	Lam	Mar 1983
4387242	Lam	Jun 1983
4440927	Prugh	Apr 1984
4474971	Wareing	Oct 1984
4503072	Hoffman et al.	Mar 1985

Number	Date	Country
895445	Apr 1983	BEX
38061	Oct 1981	EPX
68038	Jan 1983	EPX
56-7775	Jan 1981	JPX
WO8402131	Jun 1984	WOX
WO8402903	Aug 1984	WOX

Cholesterol biosynthesis inhibiting pyrazole analogs of mevalonolactone and its derivatives

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Hulcher, Arch. Biochem. Biophys. 146, 422-427 (1971).
Sato et al., Chem. Pharm. Bull. 28, 1509-1525 (1980).
Singer et al., Proc. Soc. Exp. Biol. Med. 102, 370-373 (1959).