# US 6,294,680 B1 · Process for the production of semi synthetic statins via novel intermediates

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- Number: US 6,294,680 B1
- Document ID: US6294680B1
- Status: Granted
- Kind: B1
- Application number: 09/341,809
- Filed: 2000-01-05
- Granted: 2001-09-25
- Earliest claimed: 1997-01-28
- Assignees: Plus Chemicals SA
- Inventors: Ton Rene Vries; Hans Wijnberg; Wijnand Sjourd Faber; Venetka Ivanova Kalkman-Agayn; Mieke Ivanova Sibeyn
- Web page: https://patentgrep.com/patent/US6294680B1

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 309/30: Oxygen atoms, e.g. delta-lactones
- C07F 9/65742: {non-condensed with carbocyclic rings or heterocyclic rings or ring systems}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A process has been provided to produce semi synthetic statins, as for instance simvastatin with a high yield, for another statin, preferably a naturally occurring statin, as for instance lovastatin. Also a number of novel intermediate compounds, prepared during said process, has been provided.

## Claims

### Claim 1

A compound of formula II,
wherein R1, and R2, are independently selected from the group consisting of a hydrogen atom, a hydroxyl, C1-10alkyl and C6-14aryl and C6-14arylC1-3alkyl, and wherein R3 is R9-C═O or hydrogen, and wherein each of R9, R4 and R5 are independently selected from the group consisting of:
(1) C1-15alkyl, straight or branched,
(2) C3-15cycloalkyl,
(3) C2-15alkenyl, straight or branched,
(4) C2-15alkynyl, straight or branched,
(5) phenyl and
(6) phenylC1-6,alkyl-
and R9 may also be each of the definitions mentioned under (1) to (6) substituted with one or more of the substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6,alkoxy and C6-14aryl, and R4 and R5 may also be hydrogen or form with the nitrogen to which they are attached, a 5, 6 or 7 membered heterocycle moiety, and wherein R6 and R7 are also independently selected from the group consisting of:
(1) a dioxane moiety,
wherein R10 and R11 are independently selected from the group consisting of:
(1) C1-15 alkyl, straight or branched,
(2) C3-15cycloalkyl,
(3) C2-15alkenyl, straight or branched,
(4) C2-15,alkynyl, straight or branched,
(5) phenyl, and
(6) phenylC1-6alkyl-,
all optionally substituted with one or more of the substituents independently selected from the group consisting of halogen C1-6alkyl, C1-6alkoxy or C6-14aryl,
(7) hydrogen, with the proviso that R10 is not hydrogen,
(8) R10 and R11 form an optionally substituted 5, 6, 7 or 8 membered cyclic moiety, in which one or more of the substituents; is selected from the group consisting of halogen and a lower alkyl in any combination,
(2) a cyclic sulfate,
(3) or a cyclic phosphate,
in which R12 is selected from the group consisting of:
(1) C1-15 alkyl, straight or branched,
(2) C3-15cycloalkyl,
(3) phenyl,
(4) phenylC1-6alkyl-,
(5) hydrogen,
(6) primary amines, and
(7) secondary amines, and with the proviso that when R3 is hydrogen, R6 and R7 may also form a
(1) borylidene group,
in which R8 is a phenyl optionally substituted by one to five substituents, halogen or lower alkyl in any combination, or (2) R6 and R7 are both hydrogen,
and wherein the dotted lines at x, y and z represent possible double bonds, when any are present, being either x and z in combination or x, y or z alone or none; or a corresponding stereoisomer thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein independently R1 is methyl, R2 is methyl, R3 is 2-methylbutyrate, R4 is n-butyl, R5 is selected form the group consisting of hydrogen, 1 -methylpropyl and 1, 1-dimethylpropyl, R6 and R7 form to
R8 is phenyl or parafluoro phenyl. and x and z are double bonds.

### Claim 3 (depends on 1)

A compound of formula IV,
wherein R1, R2, R3, R4, R6 and R7 and x, y and z are defined as for a compound of formula II in claim 1, or a corresponding stereoisomer thereof,
with the proviso that R3 and R4 are not hydrogen, and R6 and R7 may also form a borylidene group, as defined in claim 1.

### Claim 4 (depends on 1)

A process for the preparation of a compound of formula II as defined in claim 1 comprising reacting a compound of formula I,
wherein R1, R2 and R3 and x, y and z are defined as for a compound of formula II in claim 1, with the proviso that R3 is not hydrogen and R1, R2, x, y and z are the same for the starting material and the end product, or a corresponding stereoisomer thereof, with a corresponding amine, followed by the protection of the hydroxyl groups formed upon opening of the lactone ring in the compound of formula I, by reaction with a protective group forming agent.

### Claim 5 (depends on 4)

The process according to claim 4 wherein R3 is 2-methylbutylrate in both formula I and formula II.

### Claim 6 (depends on 4, 5)

The process according to claim 4 or 5, wherein the amine is selected from the group consisting of:
(1) ammonia,
(2) primary amines, and
(3) secondary amines,
and the protective group forming agent is selected from the group consisting( of:
(1) ketones,
(2) aldehydes,
(3) acetals,
(4) sulfonyl chloride, followed by oxidation with sodium periodate,
(5) phosphonyl chloride, followed by reaction with an alcohol, amine or water and
(6) boronic acid.

### Claim 7 (depends on 1)

A process for the preparation of a compound of formula II as defined in claim 1, with the proviso that R3 is hydrogen, and wherein both R6 and R7 may also be hydrogen or a silyl protecting group, comprising reacting a compound of formula II as defined in claim 1, with the proviso that R3 is not hydrogen, and wherein both R6 and R7 may also be hydrogen or a silyl protecting group or form a boiylidene moiety, and where all the parameters R, x, y and z are the same for the starting material and the end product except for R3, with at least one suitable agent to remove the R3 ester moiety.

### Claim 8 (depends on 7)

The process according to claim 7 wherein the at least one agent is selected from the group consisting of:
(1) lithiumaluniliumhydride,
(2) aluminiumhydride,
(3) diisobutylaluminiumhydride
(4) LiY and wherein Y is C1-6alkyl or C6-14aryl, and
(5) ZMgCl, and
(6) ZMgBr wherein Z is C1-6alkyl or C6-14aryl.

### Claim 9 (depends on 1)

A process for the preparation of a compound of formula II as defined in claim 1, with the proviso that R3 is hydrogen, and wherein both R6 and R7 may also be hydrogen or a silyl protecting group, comprising reacting a compound of formula II as defined in claim 1, with the proviso that R3 is not hydrogen, and wherein both R6 and R7 may also be hydrogen or a silyl protecting group or form a boiylidene moiety, and where R, x, y and z are the same for the starting~ material and the end product except for R3+with a primary amine of the formula R4NH2 with R4 as defined in claim 1, with the proviso that R4 is not part of a heterocycle moiety.

### Claim 10 (depends on 1, 4, 9)

A process for the preparation of a compound of formula II as defined in claim 1, with the proviso that R3, R5, R6 and R7 are hydrogen, and R1, R2, x, y and z are the same for the starting material and the endproduct, comprising reacting a compound of formula I as defined in claim 4, with an excess of a primary amine of the formula R4NH2 as defined in claim 9 at a temperature between about 1000° C. and 250° C.

### Claim 11 (depends on 3, 5)

A process for the preparation of a compound of formula IV as defined in claim 3, comprising the step of reacting a compound of formula III, or the corresponding stereoisomer thereof,
wherein R1, R2, R4, R6, and R7 are as defined for formula II in claim 5, and R5 is hydrogen, and with the proviso that R6 and R7 are not hydrogen, and where R, x, y and z are the same for the starting material and the end product, with a suitable corresponding acylation agent.

### Claim 12 (depends on 1)

A process for the preparation of a compound of formula II as defined in claim 1, with the proviso that R3, R5, R6, R7 are not hydrogen, comprising the step of reacting a compound of formula II wherein R1, R2, R4, R5, R6 and R7 are as defined in claim 1 and R3 is hydrogen, with the proviso that R5, R6 and R7 are not hydrogen, and where R, x, y and z are the same the for starting material and the end product except for R3, with a suitable corresponding acylation agent.

### Claim 13 (depends on 8, 9)

The process according to claim 8 or 9 wherein the acylation agent is selected form the group consisting of:
(1) acid chloride of the corresponding acyl group,
(2) free acid of the corresponding acyl group, and
(3) acid anhydride of the corresponding acyl group.

### Claim 14 (depends on 1, 3, 4, 7, 11, 12)

A process for the preparation of the compound of formula I as defined in claim 4, from a compound of formula I as defined in claim 4, with the proviso that the R3 moiety of the compound as prepared may be different from the R3 moiety of the starting compound and where the other parameters are the same for starting material and end product, comprising the following steps:
a) ring opening of the lactone by formation of an amide bond and forming a protective group according to claim 4,
b) reduction of the R3 moiety of formula II according to claim 7,
c) acylation of the compound of formula III according to claim 11 or a compound of formula II according to claim 12,
d) removal of the acetal moiety and hydrolysis of the amide group of formula IV as defined in claim 3, or of a compound of formula II as defined in claim 1, into formula V, wherein M forms any pharmaceutically acceptable salt, acid or ester, and
e) lactonization of formula V into formula I by heating.

### Claim 15 (depends on 1, 3, 4, 9, 12)

A process for the preparation of the compound of formula I as defined in claim 4, from a compound of formula I as defined in claim 4, with the proviso that tile R3 moiety of the compound as prepared may be different from the R3 moiety of the starting compound and where the other parameters are the same for the starting material and the end product, comprising the following steps:
a) reacting the compound of formula I with an amine R4NH2 as defined in claim 9,
b) formation of a protective group according to claim 4,
c) acylation of the compound of formula III according to claim II or a compound of formula 11 according to claim 12,
d) removal of the acetal moiety and hydrolysis of the amide groups of formula IV as defined in claim 3, or of a compound of formula II as defined in claim 1, into formula V, wherein M forms any pharmaceutically acceptable salt, acid or ester, and
e) lactonization of formula V into formula I by heating.

### Claim 16 (depends on 12)

A process to prepare simvastatin from lovastatin according to claim 12, comprising the following steps:
a) ring opening of the lactone of lovastatin by formation of an amide bond with n-butylamine, followed by dioxane forming with acetone or dimethoxypropane;
b) removal of the 2-methylbutyrate ester group of the compound formed in step a) by reaction with an agent selected from the group consisting of,
(1) lithiumaluminumhydride,
(2) aluminiumhydride,
(3) diisobutylaluminiumhydride,
(4) LiY and wherein Y is C1-6alkyl or C5-14aryl,
(5) ZMgCl, and
(6) ZMgBr wherein Z is C1-6alkyl or C6-14aryl;
c) acylation of the compound formed in step b) by reaction with 2,2-dimethylbutyl chloride in the presence of para-toluene sulphonic acid, hydrogen chloride or sulfuric acid;
d) removal of the dioxane moiety and of the amide group of the compound formed in step c) by hydrolysis, optionally followed by reaction with ammonium hydroxide to form ammonium salt of simvastatin and
e) lactonization of the ammonium salt or sodium salt of simvastatin or by heating in toluene to form simvastatin, followed by crystallization.

### Claim 17

A process to prepare simvastatin from lovastatin, comprising the following steps:
a) ring opening of the lactone of lovastatin, by formation of an amide bond with n-butylamine, followed by dioxane forming with acetone or dimethoxypropane,
b) α-methylation of the 2-methylbutyrate side chain of the compound formed in step a) with methyl iodide,
c) removal of the dioxane moiety and of the amide group of the compound formed in step a) by hydrolysis, optionally followed by reaction with ammonium hydroxide to form ammonium salt of simvastatin,
d) lactonization of the ammonium salt or sodium salt of simvastatin or by heating in toluene to form simvastatin, followed by crystallization.

### Claim 18 (depends on 16, 17)

A process for preparing simvastatin according to claim 16 or 17 from a crude lovastatin, which contains no more than about 30% of impurities.

### Claim 19 (depends on 1)

The compound of claim 1, wherein the 5, 6 or 7 membered heterocyclic moiety is selected from the group consisting of pyrrolidine, piperidine and a homopiperidine.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R12 is a primary amine when R6 and R7 form a cyclic phosphate.

### Claim 21 (depends on 20)

The compound of claim 20, wherein said primary amine is selected from the group consisting of cyclohexylamine and n-butylamine.

### Claim 22 (depends on 1)

The compound of claim 1, wherein R8 is selected from the group consisting of phenyl and para-fluorophenyl when R6 and R7 form a borylidene group.

### Claim 23 (depends on 4)

The process of claim 4, wherein said reaction with a protective group forming agent takes place in the presence of at least one catalytic agent.

### Claim 24 (depends on 23)

The process of claim 23, wherein said at least one catalytic agent is selected from the group consisting of para-toluene sulfonic acid and sulfuric acid.

### Claim 25 (depends on 1)

A process for the preparation of a compound of formula II as defined in claim wherein R1 is methyl; R2 is hydrogen or methyl; R3 is 2-methylbutyryl; R4 is C1-15 straight or branched alkyl; R5 is hydrogen; R6 and R7 are as defined in claim 1 with the proviso that both R6 and R7 are not hydrogen; and, x and z are both double bonds; comprising reacting a compound of formula 11 wherein R1, R2, R3, R4, R5, x and z are as defined above, and R6 and R7 are both hydrogen with a protective group forming agent.

### Claim 26 (depends on 25)

The process of claim 25 wherein the protective group forming agent is selected from the group consisting of:
(1) ketones,
(2) aldehydes,
(3) acetals,
(4) sulfonyl chloride, followed by oxidation with sodium periodate,
(5) phosphonyl chloride, followed by reaction with an alcohol, amine or water, and
(6) boronic acid.

### Claim 27 (depends on 26)

The process of claim 26, wherein said reaction with a protective group forming agent takes place in the presence of at least one catalytic agent.

### Claim 28 (depends on 27)

The process of claim 27, wherein said at least one catalytic agent is selected from the group consisting of para-toluene sulfonic acid and sulfuric acid.

### Claim 29 (depends on 1, 6)

The process of claim 6, wherein R1 is methyl and R2 is hydrogen or methyl in both formulas I and II, and wherein R4 is straight or branched C1-15 alkyl, R5 is hydrogen, R6 and R7 are as defined in claim 1, with the proviso that R6 and R7 are not both hydrogen, and x and z are double bonds.

### Claim 30 (depends on 29)

The process of claim 29 wherein R2 is methyl.

### Claim 31 (depends on 30)

The process of claim 30 wherein R4 is n-butyl or cyclohexyl.

### Claim 32 (depends on 31)

The process of claim 31 wherein R4 is n-butyl.

### Claim 33 (depends on 6)

The process of claim 6, wherein the protective group forming agent is acetone.

### Claim 34 (depends on 7)

The process of claim 7, wherein both R6 and R7 are t-butyl dimethyl silyl.

### Claim 35 (depends on 8)

The process of claim 8, wherein the agent is LiY and Y is n-butyl.

### Claim 36 (depends on 8)

The process of claim 8, wherein the agent is ZMgCl and Z is methyl.

### Claim 37 (depends on 8)

The process of claim 8, wherein the reducing agent is ZMgBr and Z is methyl.

### Claim 38 (depends on 9)

The process of claim 9, wherein both R6, and R7 are t-butyl dimethyl silyl.

### Claim 39 (depends on 1)

A compound of formula II as defined in claim 1 wherein R1 is methyl; R2 is hydrogen or methyl; R3 is 2-methylbutyryl; R4 is C1-15 straight or branched alkyl; R5 is hydrogen; R6 and R7 are as defined in claim 1; and, x and z are both double bonds.

### Claim 40 (depends on 39)

The compound of claim 39 wherein R6 and R7 are both hydrogen.

### Claim 41 (depends on 39)

The compound of claim 39 wherein R6 and R7 are not both hydrogen.