WO2001072706A1 - Synthesis of [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) - Google Patents

Synthesis of [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) Download PDF

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WO2001072706A1
WO2001072706A1 PCT/IN2000/000030 IN0000030W WO0172706A1 WO 2001072706 A1 WO2001072706 A1 WO 2001072706A1 IN 0000030 W IN0000030 W IN 0000030W WO 0172706 A1 WO0172706 A1 WO 0172706A1
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formula
compound
give
chosen
reacting
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PCT/IN2000/000030
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Ganesh Sambasivan
Madhavan Sridharan
Sathyashanker Padudevastana
Acharya Poornaprajna
Joy Mathew
Sumithra Srinath
Satheesh Nair
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Biocon India Limited
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Priority to AU2000254249A priority patent/AU2000254249A1/en
Publication of WO2001072706A1 publication Critical patent/WO2001072706A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

  • This invention relates to a process for manufacturing R- (R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy-5-(l -methylethyl)-3- phenyl-4-[( ⁇ henylamino) carbonyl]-lH-pyrrole-l-heptanoic acid 0 hemi calcium salt, atorvastatin and the novel intermediates produced during the course of manufacture.
  • the said compound is useful as inhibitors of the enzyme HMG-CoA reductase and are thus useful as hypolipidemic and hypocholesterolemic agents.
  • the object of the present invention is to disclose an inexpensive, simple and scalable route for the synthesis of atorvastatin.
  • this invention provides a process involves the synthesis of compound R-(R*,R*)]-2-(4-fluorophenyl)- B,D-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-l H-pyrrole-l-heptanoic acid hemi calcium salt (formula XXII ) comprising: a) reacting of compound of formula XVII with a compound of structure XIV in a non-polar solvent to give an intermediate of structure XXI, b) deprotection, followed by hydrolysis of the compound of structure XXI follo ed by cyciization m ethyl acetate to give the lactone, c) treating the lactone with NH 3 to give the ammonium salt, and d) reacting the ammonium salt with CaCl 2 gives the corresponding calcium salt of formula XXII.
  • the de-protecting agent in step (b) is selected from moist silica or PTSA.
  • the ammonium salt in step (c) is prepared by treating with aqueous NH 3 or methanolic NH 3 or by passing NH 3 gas to the compound taken in EtOAc, MeOH. isopropvl alcohol, diisopropvl ether or cyclohexane.
  • the compound of formula XVII is prepared by: a) reacting meldrum acid with isobutyryi chloride in the presence of base in CH 2 CI 2 to give an intermediate of formula XVIII, b) reacting the intermediate of formula XVIII with base in CH 2 C1 2 to give an intermediate of formula XIX, c) reacting the intermediate of formula XIX with benzaldehyde in the presence of base and toluene to give a compound of formula XX, and d) reacting of compound of formula XX with 4- fluorobenzaldehyde with a metal cyanide and polar solvent in the presence of a base to give the compound of formula XVII.
  • step (b) the base is selected from aniline, pyridinc, triethylamine, dimethylanili ⁇ e, diethylisopropylamine.
  • step (c) the base is selected from piperidine, pyrrolidine or diisopropylethylamine.
  • metal cyanide in step (d) is selected from NaCN, CuCN, KCN, AgCN or tetraalkyl ammonium cyanide.
  • the polar solvent in step (d) is selected from DMSO. DMF, CH 3 CN.
  • the base in step (d) is selected from diisopropylethyl amine, 1- methylimidazole, pyridine.
  • the compound of (4R)-methyl 6-(2-aminoethyl)-2,2-dimethyl- l,3-dioxane-3-acetate(Formula XIV) used in step ( ⁇ is prepared by: a) reacting a compound of formula II with meldrum ' s acid followed by hydrolysis to give a compound of formula III. b) reacting a compound of formula III with thionyl chloride to give an acid chloride which is then reacted with a meldrum ' s acid followed by alcoholosis to give a compound of formula IV, c) reducing a compound of formula IV to give a compound of formula V. d) reducing a compound of formula V to give a dihydroxy ester of formula VI.
  • the alcohol in step (b) is chosen from methanol. ethanol. isopropanol. benzyl alcohol.
  • the reducing agent in step (c) is baker ' s yeast or a reagent of formula R* 2 BC1 wher* R* 2 is chosen from (- ) ⁇ pinene or (-t -) - ⁇ - pinene.
  • the reducing agent in step (d) is chosen from dimethoxvethylboron or triethoxyboron and sodium borohydride.
  • the protecting group for conversion in step (e) is chosen from acetone, benzophenone, acetophenone or benzaldehyde.
  • the reagent for ammonolysis in step (f) is chosen from aqueous NH 3 .
  • the phthalimide sail in step ( g) is chosen from potassium, sodium or lithium.
  • the compound of (4R)-methyl 6-(2-aminoethyl)-2,2-dimethyl- l,3-dioxane-3-acetate( Formula XIV) used in step (a) is prepared by: a) reacting a compound of formula II with meldrum ' s acid followed by hydrolysis to give a compound of formula IX, b) reacting a compound of formula IX with tert-butyl acetate with a base at -30 to -80°C to give a compound of formula X, c) reducing a compound of formula X to give a compound of formula XI, d) reducing a compound of formula XI to give a dihydroxy ester of formula XII, e) Converting a compound of formula XII to give a compound of formula XIII, f) ammonoiysis of a compound of formula
  • R 4 in step (a) is chosen from, OMs, OTs, Br, Cl or I.
  • the reducing agent in step (c) is baker's yeast or a reagent of formula R* 2 BC1 where R* 2 is chosen form (-) ⁇ pinene or (+) - ⁇ - pinene.
  • the reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxyboron and sodium borohydride.
  • the protecting group for conversion in step (e) is chosen from acetone, benzophenone. acetophenone or
  • the reagent for ammonolysis in step (f) is chosen from aqueous NHn. methanolic NH 3 or gaseous NH 3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyl ether.
  • the phthalimide salt in step (g) is chosen from potassium, sodium or lithium.
  • the process of the present invention in its first aspect is a new. improved, economical, and commercially feasible method for preparing HMG Co A reductase inhibitors of Formula XXII which are useful as inhibitors of the enzyme HMG CoA reductase and are thus useful as hypolipidemic or hypocholesterolemic agents is outlined in Scheme 5.
  • Structure XXII The synthetic scheme for the synthesis of the amino ester of formula VIII is outlined in scheme 1 Scheme - 1
  • PCK etc in the presence of a base chosen from Et 3 N, pyridine, N,N-dimethylaniline, N,N-diisopropylethyl amine. etc., in a solvent like, CH 2 C1 2 , CH 3 CN, DMF etc., to give a compound of formula II, which is subsequently treated with meldrum 's acid in presence of pyridine and CH 2 C1 2 to give an acyl meldrum acid which is hydrolyzed to give a compound of formula III.
  • a base chosen from Et 3 N, pyridine, N,N-dimethylaniline, N,N-diisopropylethyl amine. etc.
  • a solvent like, CH 2 C1 2 , CH 3 CN, DMF etc. to give a compound of formula II, which is subsequently treated with meldrum 's acid in presence of pyridine and CH 2 C1 2 to give an acyl meldrum acid which is hydrolyzed to give a compound
  • a ⁇ -keto acid of formula III is then converted to its acid chloride by reacting with a reagent chosen from PC1 5 , oxalyl chloride, thionyl chloride etc., in the presence of a base chosen from pyridine, Et 3 N. dusopropylethyl amine, N,N-dimethylaniline etc., in a solvent chosen from CH 2 CI 2 , CH 3 CN, DMF etc.
  • the diketo ester compound of formula IV is then reduced either with baker's yeast or with a reagent of formula R* 2 BC1 Where R* 2 is chosen from (-)- ⁇ -pinene, (+)- ⁇ -pinene, etc.. to give a hydroxy keto ester of formula V.
  • a hydroxy ketone ester of Formula V is treated with a borane reagent of formula R 2 10 BOCH 3 wherein R 10 is a alkyl group of Cl to 3, for example, methoxydiethylborane in the absence of air and subsequent treatment with a metal hydride, such as. for example, sodium borohvdride in a solvent, such as. for example, methanol, tetrahydrofuran.
  • the reaction is carried out with methoxydiethylborane under a nitrogen atmosphere and subsequent treatment with sodium borohydride in a mixture of methanol and tetrahydrof ⁇ iran at about - 20°C. to about -78°C. for about 5 hours followed by the addition of glacial acetic acid.
  • a 3,5-dihydroxy ester of Formula VI is treated with a ketal- forming reagent of R COR 2 wherein R 1 or R" is independent ⁇ from Ci to C 3 alkyl, phenyl. benzyl, substituted phenyl etc., for example, a ketal-forming reagent selected from acetone. 2.2-dimethoxypropane. 2-methoxypropene. cyclopentanone. cyclohexanone. 1.1 -dimethoxycyclopentane. 1, 1 - dimethoxycyclohexane. and the like or optionally an acetai forming reagent, for example, benzaldehyde.
  • reaction is carried out with a ketone forming reagent of Formula VII, for example, 2,2- dimethoxypropane and acetone in the presence of methanesulfonic acid at room temperature.
  • an acid such as, for example, methanesulfonic acid, camphorsulfonic acid, paratoluenesulfonic acid, and the like
  • an inert solvent such as, for example, dichloromethane, and the like at about 0°C. to about the reflux temperature of the reagent or solvent to afford a compound of Formula VI wherein R 1 and R" are as defined above.
  • the reaction is carried out with a ketone forming reagent of Formula VII, for example, 2,2- dimethoxypropane and acetone in the presence of methanesulfonic acid at room temperature.
  • a compound of formula VII which is then taken up in a solvent like, methanol, EtOAc, hexane or a mixture of these solvents and is converted to a compound of formula VIII by treating with gaseous NH 3 . or by treating with aqueous NH 4 OH solution or methanolic ammonia to give a compound of formula VIII
  • a compound of formula XIV can be prepared as described in scheme 2
  • the diketo ester compound of formula X is then reduced either with baker's yeast or with a reagent of formula R* : BC1 Where R* 2 is chosen from ( -)- ⁇ -pinene, (+)- ⁇ -pinene. etc.. to give a hydroxy keto ester of formula XI.
  • a hydroxy ketone ester of Formula XI is treated with a borane reagent of formula R 2 l ⁇ BOCH wherein R 10 is a alkyl group of Cl to 3, for example, methoxydiethylborane in the absence of air and subsequent treatment with a metal hydride, such as, for example, sodium borohydride in a soh ent, such as, for example, methanol.
  • telrahydrofuran mixtures thereof, and the like at about 0°C. to about 1 10°C. for about 5 hours followed subsequent treatment with an acid, like glacial acetic acid, and the like to afford a compound of Formula XII.
  • the reaction is carried out with melhoxvdiethvlborane under a 11
  • R COR 2 wherein R 1 or R 2 is independently from Cj to C 3 alkyl. phenyl. benzyl, substituted phenyl etc., for example, a ketal-forming reagent selected from the group consisting of acetone. 2.2-dimethoxypropane.
  • a compound of formula XIII which is then taken up in a solvent like, methanol, EtOAc, hexane or a mixture of these solvents and is converted to a compound of formula XIV by treating with gaseous NH 3 . or by treating with aqueous NH OH solution or methanolic ammonia.
  • the intermediate of formula VII or XIII can be converted to VIII and XIV respectively as sho n in scheme 3 Scheme - 3 where R ⁇ is chosen from Li. K, Na, quaternary ammonium etc., to give the substituted phthalimide of formula XV or XVI which on treatment with hydrazine hydrate gives the desired amino compound.
  • R ⁇ is chosen from Li. K, Na, quaternary ammonium etc.
  • a amino ester of Formula VIII or XIV is reacted with a diketone of Formula XVII wherein the process for the preparation of the compound of formula XVII is described in scheme 4
  • Scheme - 4 A compound of formula XVII is prepared as described in scheme 6. which comprises of reacting isobutyryl chloride and meldrum ' s acid in the presence of a base chosen from pyridine. triethylamine. dusopropylethyl amine. dimethylaniline etc in CH C!; at 0-5°C for about 18h to give an intermediate of formula XVIII.
  • a base chosen from pyridine. triethylamine. dusopropylethyl amine. dimethylaniline etc in CH C!; at 0-5°C for about 18h to give an intermediate of formula XVIII.
  • the reaction is done in pyridine and CH 2 CL at 0°C.
  • the acyl meldrum acid so obtained is then reacted with aniline in a solvent chosen from CH 2 C1 2 , acetonitrile, toluene etc., at the reflux temperature of the solvent for about 12h to afford the amide of formula XIX.
  • a solvent chosen from CH 2 C1 2 , acetonitrile, toluene etc.
  • the reaction is carried out in CH 2 CI by stirring at room temperature.
  • keto amide is then reacted with benzaldehyde in the presence of a base chosen from aqueous NaOH in acetic acid, sodium acetate and acetic acid, p> ⁇ rolidine and acetic acid, piperdine and toluene, pyrrolidine and toluene etc., at the reflux temperature and by removal of water for about 26h to give the methylenephenyl intermediate of formula XX.
  • a base chosen from aqueous NaOH in acetic acid, sodium acetate and acetic acid, p> ⁇ rolidine and acetic acid, piperdine and toluene, pyrrolidine and toluene etc.
  • the compound of formula XX is treated with 4- fluorobenzaldehyde in the presence of a catalyst chosen from metallic cvanide where the metal is A2. K. Na. Cu. tetraalkvlammonium etc . or trimethylsilyl cyanide in a polar solvent chosen from DMSO, DMF, acetonitrile etc.. at the reflux temperature of the solvent to give a compound of formula XVII.
  • a catalyst chosen from metallic cvanide where the metal is A2.
  • K. Na. Cu. tetraalkvlammonium etc . or trimethylsilyl cyanide in a polar solvent chosen from DMSO, DMF, acetonitrile etc.. at the reflux temperature of the solvent to give a compound of formula XVII.
  • the reaction is carried out by reacting 4-fluorobenzaldehyde and sodium cyanide in DMSO at reflux temperature.
  • the diketone of formula XVII is reacted with the amino ester of formula VIII or XIV as described in Scheme 5 in the presence of a catalyst of Formula Rj 2 C0 2 H wherein R n is chosen from trifluoromethane sulfonic acid, methane sulfonic acid, p-toleue sulfonic acid and a solvent or mixtures thereof such as, for example, acetonitrile, xylene, diisopropvl ether and the like for about 24 to about 48 hours from 5 to 10°C to about the reflux temperature of the solvent with the removal of water to afford a compound of Formula VII.
  • the reaction is carried out in the presence of methanesulfonic acid and a mixture of xylene-hexane at reflux for about 48 hours with the removal of water.
  • the intermediate of formula XXI is de-protected using moist silica in CI-LCL at room temperature over a period of 24h and is then hydrolyzed using methanolic sodium hydroxide and acidified using dil HC1 to give the free acid which is converted to its ammonium salt by passing gaseous NH 3 in EtOAc. The ammonium salt is then treated with calcium acetate to give atorvastatin calcium.
  • Example 1 Preparation of 4-methyI-3-oxo-N-phenylpetaj ⁇ amide (Formula XIX).
  • the reaction was quenched by addition of acetic acid and concentrated under reduced pressure to afford an oily residue.
  • the crude oil was taken up in acetone and 2,2- dimethoxypropane was added followed by cataKtic amount of trifluoromethanesulfonic acid.
  • the contents were stirred at room temperature for 4h and after the completion of the reaction was washed with bicarbonate solution.
  • the organic extracts was washed with water and was concentrated to give an oil which was crystallized from hexane.
  • the solution was diluted with diisopropyl ether and methanol and was washed with dilute methanolic sodium hydroxide solution, dilute HCl and the solvent was then removed under vacuum.
  • the crude oil was stirred with moist silica in CH : C1 2 and was stirred at room temperature for 18h.
  • a solution of aqueous NaOH was then added at room temperature and was stirred for 4h.
  • the reaction mixture was diluted with water and was washed with diisopropyl ether.
  • the aqueous layer was acidified with HCl and was taken up in diisopropvl ether.
  • the crude acid intermediate was then taken up in EtOAc and NH 3 gas was bubbled.

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Abstract

The present invention discusses a novel process for the synthesis of [R-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt by using 4-fluoro-α-[2-methyl-1-oxopropyl]η-oxo-N-β-diphenylbenzene butaneamide with (4R)-methyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-3-acetate. The compound so prepared is useful as inhibitors of the enzyme HMG-CoA reductase and are thus used as hypolipidemic and hypocholesterolemic agents.

Description

TITLE OF THE INVENTION:
SYNTHESIS OF [R-(R*,R*)]-2-(4-FLU0R0PHENYL)-jBETA,DELTA-DIHYDR0XY-5- (l-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMIN0)CARB0NYL]-lH-PYRR0LE-l-HEPTAN0IC ACID HEMI CALCIUM SALT (ATORVASTATIN)
5
FILED OF THE INVENTION:
This invention relates to a process for manufacturing R- (R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy-5-(l -methylethyl)-3- phenyl-4-[(ρhenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid 0 hemi calcium salt, atorvastatin and the novel intermediates produced during the course of manufacture. The said compound is useful as inhibitors of the enzyme HMG-CoA reductase and are thus useful as hypolipidemic and hypocholesterolemic agents. BACKGROUND OF THE INVENTION 5 US Patent. No. 4,681,893, discloses a route using resolution of the racemic product using R (+) α-methyl benzyl amine. US patent No. 5,003,080 discloses a synthetic route for the preparation of the chiral form of atorvastatin. The patent discloses a process for the preparation of the lactone or its salts by coupling an ester of (4R)-6- 0 (2-aminoethyI)-2,2-dialkyl-l,3-dioxane-3-acetate with 4-fluoro-α-[2- methyl- 1 -oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide followed by deprotection and hydrolysis to give the product. The product suffers from the fact ozonolysis is required as one of the steps for the synthesis of the amino ketal intermediate, which is hazardous 5 for large scale preparation. The patent describes an alternate procedure wherein 4-fluoro-α-[2-methyl-l -oxopropyl]γ-oxo-N-β- diphenylbenzenebutaneamide is reacted with 3-amino propinaldehyde acetal followed by conventional procedures to give atorvastatin. US patent No. 5.216,174. No. 5,097,045. No. 5,103,024, No. 5,124,482, No. 5.149.837, No. 5,155.251, No. 5.216.174. No. 5.245,047, No. 5,273,995, No.5,248,793, and No.5.397,792 describes various minor modifications in the procedure for the preparation of
5 atorvastatin calcium salt.
Synthesis of esters of (4R)-6-(2-aminoethyl)-2.2-dialkyl-1.3- dioxane-3 -acetate is an important part of the preparation of atorvastatin calcium. US patent 5,155,251 also discloses a synthetic route for the synthesis of (3R)-4-cyano-3-hydroxy butyric acid esters
10 from (S)-3-hydroxy butyrolact&ne, which in turn is synthesized from a suitable carbohydrate substrate.
Other patents like 5.292,939, 5,319, 1 10 and 5,374,773 discloses the preparation of 3,4-dihydroxybutyric acid. However, isolation of this highly water soluble compound or its lactone is not
15 attempted.
Another multi step procedure starting from (S)-malic acid (J. org. Chem., 1981 , 46, 4319) is reported. Esters of (S)-malic acid have also been used (Chem. Lett., 1984. 1389) for the synthesis of the hydroxy lactone involving B S-NaBH4 reduction, followed by
20 lactonization. While a six step procedure from D-isoascorbic acid is also reported (Syn., 1987, 570) but this process requires a silica gel chromatographic separation of the diasteromic mixtures.
Optical resolution of the racemic hydroxylactones using lipase * is disclosed in US patent 5,084,392 but this method suffers from poor
■> enatiomeric excess and loss of the other active isomer.
Thus, these prior art procedures involves cumbersome reaction conditions or expensive starting materials, reagents which are difficult to handle or hazardous for scale up. coupled with a multi step procedure which results in poor overall yield. The object of the present invention is to disclose an inexpensive, simple and scalable route for the synthesis of atorvastatin.
To achieve the said objective, this invention provides a process involves the synthesis of compound R-(R*,R*)]-2-(4-fluorophenyl)- B,D-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-l H-pyrrole-l-heptanoic acid hemi calcium salt (formula XXII ) comprising: a) reacting of compound of formula XVII with a compound of structure XIV in a non-polar solvent to give an intermediate of structure XXI, b) deprotection, followed by hydrolysis of the compound of structure XXI follo ed by cyciization m ethyl acetate to give the lactone, c) treating the lactone with NH3 to give the ammonium salt, and d) reacting the ammonium salt with CaCl2 gives the corresponding calcium salt of formula XXII. The non-polar solvent in step (a) is selected from xylene or acetonitrile.
The de-protecting agent in step (b) is selected from moist silica or PTSA.
The ammonium salt in step (c) is prepared by treating with aqueous NH3 or methanolic NH3 or by passing NH3 gas to the compound taken in EtOAc, MeOH. isopropvl alcohol, diisopropvl ether or cyclohexane.
The compound of formula XVII is prepared by: a) reacting meldrum acid with isobutyryi chloride in the presence of base in CH2CI2 to give an intermediate of formula XVIII, b) reacting the intermediate of formula XVIII with base in CH2C12 to give an intermediate of formula XIX, c) reacting the intermediate of formula XIX with benzaldehyde in the presence of base and toluene to give a compound of formula XX, and d) reacting of compound of formula XX with 4- fluorobenzaldehyde with a metal cyanide and polar solvent in the presence of a base to give the compound of formula XVII. In step (b) the base is selected from aniline, pyridinc, triethylamine, dimethylaniliαe, diethylisopropylamine. In step (c) the base is selected from piperidine, pyrrolidine or diisopropylethylamine.
In the metal cyanide in step (d) is selected from NaCN, CuCN, KCN, AgCN or tetraalkyl ammonium cyanide.
The polar solvent in step (d) is selected from DMSO. DMF, CH3CN.
The base in step (d) is selected from diisopropylethyl amine, 1- methylimidazole, pyridine.
The compound of (4R)-methyl 6-(2-aminoethyl)-2,2-dimethyl- l,3-dioxane-3-acetate(Formula XIV) used in step (β is prepared by: a) reacting a compound of formula II with meldrum's acid followed by hydrolysis to give a compound of formula III. b) reacting a compound of formula III with thionyl chloride to give an acid chloride which is then reacted with a meldrum's acid followed by alcoholosis to give a compound of formula IV, c) reducing a compound of formula IV to give a compound of formula V. d) reducing a compound of formula V to give a dihydroxy ester of formula VI. e) converting a compound of formula VI to give a compound of formula VII, f) ammonolysis of a compound of formula VII to gπ e a compound of formula VIII. g) alternatively reacting the compound of formula VII w ith phthaltmide salt to give a compound of formula XVI, h) reacting a compound of formula XVI with hydrazine hydrate to give the compound of formula VIII. and i) where R5 = tei-butyi in formula VIII, formula XIV is obtained R4 in step (a) is chosen from. OMs. OTs. Br, Cl or I.
The alcohol in step (b) is chosen from methanol. ethanol. isopropanol. benzyl alcohol.
The reducing agent in step (c) is baker's yeast or a reagent of formula R*2BC1 wher* R*2 is chosen from (- ) α pinene or (-t -) -α- pinene. The reducing agent in step (d) is chosen from dimethoxvethylboron or triethoxyboron and sodium borohydride.
The protecting group for conversion in step (e) is chosen from acetone, benzophenone, acetophenone or benzaldehyde.
The reagent for ammonolysis in step (f) is chosen from aqueous NH3. methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc. cyclohexane. methanol. isopropanol or diisopropvl ether.
The phthalimide sail in step ( g) is chosen from potassium, sodium or lithium. The compound of (4R)-methyl 6-(2-aminoethyl)-2,2-dimethyl- l,3-dioxane-3-acetate( Formula XIV) used in step (a) is prepared by: a) reacting a compound of formula II with meldrum' s acid followed by hydrolysis to give a compound of formula IX, b) reacting a compound of formula IX with tert-butyl acetate with a base at -30 to -80°C to give a compound of formula X, c) reducing a compound of formula X to give a compound of formula XI, d) reducing a compound of formula XI to give a dihydroxy ester of formula XII, e) Converting a compound of formula XII to give a compound of formula XIII, f) ammonoiysis of a compound of formula XIII to give a compound of formula XIV, g) alternatively reacting the compound of formula XIII with phthalimide salt to give a compound of formula XV and h) reacting a compound of formula XV with hydrazine hydrate to give the compound of formula VIII
R4 in step (a) is chosen from, OMs, OTs, Br, Cl or I.
The reducing agent in step (c) is baker's yeast or a reagent of formula R*2BC1 where R*2 is chosen form (-) α pinene or (+) -α- pinene.
The reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxyboron and sodium borohydride.
The protecting group for conversion in step (e) is chosen from acetone, benzophenone. acetophenone or
Figure imgf000007_0001
The reagent for ammonolysis in step (f) is chosen from aqueous NHn. methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyl ether.
The phthalimide salt in step (g) is chosen from potassium, sodium or lithium.
The inteπnediate compounds of formula XVIII. XIV, XV. VII & IX whenever prepared by the above process.
The intermediate of formula VII. wherein R5 is chosen from C1-C5 alkyl, benzyl, isopropvl, cyclohexyl or tert-butyl. The intermediate of formula IX, wherein R is chosen from
CH:Br. CH2C1, CH2I- CH OMs or CH20ts. DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention in its first aspect is a new. improved, economical, and commercially feasible method for preparing HMG Co A reductase inhibitors of Formula XXII which are useful as inhibitors of the enzyme HMG CoA reductase and are thus useful as hypolipidemic or hypocholesterolemic agents is outlined in Scheme 5. Structure XXII The synthetic scheme for the synthesis of the amino ester of formula VIII is outlined in scheme 1 Scheme - 1
Thus, a halo acetic acid of formula I, where X = Cl, Br or I is treated with sodium or potassium salt of trifluoromethane sulfonic acid or p-toluenesul tonic acid in the presence oC base chosen from Et3N, pyridine, N,N-dimethylaniline. N.N-diisopropylethyl amine. etc.. in a solvent like. CH CI , CH3CN. DMF etc.. to give an intermediate which is then converted to an acid chloride by choosing a rea ent from thionvl chloride, oxalvl chloride. PCK etc in the presence of a base chosen from Et3N, pyridine, N,N-dimethylaniline, N,N-diisopropylethyl amine. etc., in a solvent like, CH2C12, CH3CN, DMF etc., to give a compound of formula II, which is subsequently treated with meldrum 's acid in presence of pyridine and CH2C12 to give an acyl meldrum acid which is hydrolyzed to give a compound of formula III.
A β-keto acid of formula III is then converted to its acid chloride by reacting with a reagent chosen from PC15, oxalyl chloride, thionyl chloride etc., in the presence of a base chosen from pyridine, Et3N. dusopropylethyl amine, N,N-dimethylaniline etc., in a solvent chosen from CH2CI2, CH3CN, DMF etc. to give an acid chloride which is then reacted with meldrum acid as described earlier to give an acyl meldrum acid which on subsequent reaction with an alcohol R5OH Where R5 = Cι-C6 alkyl, C3 to C6-cycloalkyl, benzyl etc., to give an intermediate of formula IV.
The diketo ester compound of formula IV is then reduced either with baker's yeast or with a reagent of formula R*2BC1 Where R*2 is chosen from (-)-α-pinene, (+)-α-pinene, etc.. to give a hydroxy keto ester of formula V. A hydroxy ketone ester of Formula V is treated with a borane reagent of formula R2 10BOCH3 wherein R10 is a alkyl group of Cl to 3, for example, methoxydiethylborane in the absence of air and subsequent treatment with a metal hydride, such as. for example, sodium borohvdride in a solvent, such as. for example, methanol, tetrahydrofuran. mixtures thereof and the like at about 0°C. to about -1 10°C. for about 5 hours follo ed by subsequent treatment with an acid, such as, for example, glacial acetic acid, and the like to afford a compound of Formula VI. Preferably, the reaction is carried out with methoxydiethylborane under a nitrogen atmosphere and subsequent treatment with sodium borohydride in a mixture of methanol and tetrahydrofϊiran at about - 20°C. to about -78°C. for about 5 hours followed by the addition of glacial acetic acid.
A 3,5-dihydroxy ester of Formula VI is treated with a ketal- forming reagent of R COR2 wherein R1 or R" is independent^ from Ci to C3 alkyl, phenyl. benzyl, substituted phenyl etc., for example, a ketal-forming reagent selected from acetone. 2.2-dimethoxypropane. 2-methoxypropene. cyclopentanone. cyclohexanone. 1.1 -dimethoxycyclopentane. 1, 1 - dimethoxycyclohexane. and the like or optionally an acetai forming reagent, for example, benzaldehyde. and the like in the presence of an acid, such as, for example, methanesulfonic acid, camphorsulfonic acid, paratoluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent, such as, for example, dichloromethane, and the like at about 0°C. to about the reflux temperature of the reagent or solvent to afford a compound of Formula VI wherein R1 and R" are as defined above. Preferably, the reaction is carried out with a ketone forming reagent of Formula VII, for example, 2,2- dimethoxypropane and acetone in the presence of methanesulfonic acid at room temperature.
A compound of formula VII, which is then taken up in a solvent like, methanol, EtOAc, hexane or a mixture of these solvents and is converted to a compound of formula VIII by treating with gaseous NH3. or by treating with aqueous NH4OH solution or methanolic ammonia to give a compound of formula VIII Optionally a compound of formula XIV can be prepared as described in scheme 2
Scheme - 2 Thus a compound of formula II where, R = CH2Br, CH2C1,
CH2I. CH2OMs, CH OTs, etc.. with meldrum acid in the presence of a base chosen from pyridine. Et3N. N.N-di ethy (aniline. N.N- diisopropylethylamine etc in CFLCL to give an acyl meldrum acid of formula IX. The acyl meldrum acid is taken in a solvent selected from hexane. THF. ether, or a mixture of hexane. THF or ether and was cooled to -30 to -80°C. A solution of tertiary butyl acetate and a base chosen from n-BuLi. LDA. Lithium pyrrolidide. etc.. is added at a temperature between -30 to - 80°C to afford the diketo ester compound of formula X.
The diketo ester compound of formula X is then reduced either with baker's yeast or with a reagent of formula R*:BC1 Where R*2 is chosen from ( -)-α-pinene, (+)-α-pinene. etc.. to give a hydroxy keto ester of formula XI. A hydroxy ketone ester of Formula XI is treated with a borane reagent of formula R2 lϋBOCH wherein R10 is a alkyl group of Cl to 3, for example, methoxydiethylborane in the absence of air and subsequent treatment with a metal hydride, such as, for example, sodium borohydride in a soh ent, such as, for example, methanol. telrahydrofuran. mixtures thereof, and the like at about 0°C. to about 1 10°C. for about 5 hours followed
Figure imgf000011_0001
subsequent treatment with an acid, like glacial acetic acid, and the like to afford a compound of Formula XII. Preferably, the reaction is carried out with melhoxvdiethvlborane under a 11
nitrogen atmosphere and subsequent treatment with sodium borohydride in a mixture of methanol and tetrahydrofuran at about
20°C. to about -78°C. for about 5 hours followed by the addition of glacial acetic acid. A 3,5-dihydroxy ester of Formula XII is treated with a ketal- forming reagent of
R COR2 wherein R1 or R2 is independently from Cj to C3 alkyl. phenyl. benzyl, substituted phenyl etc., for example, a ketal-forming reagent selected from the group consisting of acetone. 2.2-dimethoxypropane.
2-methoxypropene. cyclopentanone, cvclohexanone. 1.1 - dimethoxycyclopentane, 1 ,1-dimethoxycycIohexane, and the like or optionally an acetal forming reagent, for example, benzaldehyde. and the like in the presence of an acid, such as methanesulfonic acid. camphorsulfonic acid, paratoluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent, such as, for example. dichloromethane. and the like at about 0°C. to about the reflux temperature of the reagent or solvent to afford a compound of
Formula XIII wherein R1 and R2 are as defined above. Preferably, the reaction is carried out with a ketone forming reagent for example.
2.2-dimethoxypropane and acetone in the presence of methanesulfonic acid at about room temperature.
A compound of formula XIII, which is then taken up in a solvent like, methanol, EtOAc, hexane or a mixture of these solvents and is converted to a compound of formula XIV by treating with gaseous NH3. or by treating with aqueous NH OH solution or methanolic ammonia.
Alternatively, the intermediate of formula VII or XIII can be converted to VIII and XIV respectively as sho n in scheme 3 Scheme - 3 where R^ is chosen from Li. K, Na, quaternary ammonium etc., to give the substituted phthalimide of formula XV or XVI which on treatment with hydrazine hydrate gives the desired amino compound. A amino ester of Formula VIII or XIV is reacted with a diketone of Formula XVII wherein the process for the preparation of the compound of formula XVII is described in scheme 4
Scheme - 4 A compound of formula XVII is prepared as described in scheme 6. which comprises of reacting isobutyryl chloride and meldrum's acid in the presence of a base chosen from pyridine. triethylamine. dusopropylethyl amine. dimethylaniline etc in CH C!; at 0-5°C for about 18h to give an intermediate of formula XVIII. Preferably the reaction is done in pyridine and CH2CL at 0°C. The acyl meldrum acid so obtained is then reacted with aniline in a solvent chosen from CH2C12, acetonitrile, toluene etc., at the reflux temperature of the solvent for about 12h to afford the amide of formula XIX. Preferably the reaction is carried out in CH2CI by stirring at room temperature.
The keto amide is then reacted with benzaldehyde in the presence of a base chosen from aqueous NaOH in acetic acid, sodium acetate and acetic acid, p>τrolidine and acetic acid, piperdine and toluene, pyrrolidine and toluene etc., at the reflux temperature and by removal of water for about 26h to give the methylenephenyl intermediate of formula XX.
The compound of formula XX is treated with 4- fluorobenzaldehyde in the presence of a catalyst chosen from metallic cvanide where the metal is A2. K. Na. Cu. tetraalkvlammonium etc . or trimethylsilyl cyanide in a polar solvent chosen from DMSO, DMF, acetonitrile etc.. at the reflux temperature of the solvent to give a compound of formula XVII. Preferably the reaction is carried out by reacting 4-fluorobenzaldehyde and sodium cyanide in DMSO at reflux temperature.
The diketone of formula XVII is reacted with the amino ester of formula VIII or XIV as described in Scheme 5 in the presence of a catalyst of Formula Rj2C02H wherein Rn is chosen from trifluoromethane sulfonic acid, methane sulfonic acid, p-toleue sulfonic acid and a solvent or mixtures thereof such as, for example, acetonitrile, xylene, diisopropvl ether and the like for about 24 to about 48 hours from 5 to 10°C to about the reflux temperature of the solvent with the removal of water to afford a compound of Formula VII. Preferably, the reaction is carried out in the presence of methanesulfonic acid and a mixture of xylene-hexane at reflux for about 48 hours with the removal of water.
Scheme - 5
The compound of formula XXI is converted to atorvastatin calcium as shown in scheme 6
Scheme - 6
Which involves the deprotection of the ketal followed by hydrolysis of the ester to give the free acid which is converted to its ammonium salt by reacting with either NH4OH, methanolic NH3 or by bubbling gaseous NH3 to the solution of carboxylic acid in a solvent chosen from a mixture of EtOAc, hexane, diisopropyl ether, isopropanol, cyclohexane and methanol. Preferably the intermediate of formula XXI is de-protected using moist silica in CI-LCL at room temperature over a period of 24h and is then hydrolyzed using methanolic sodium hydroxide and acidified using dil HC1 to give the free acid which is converted to its ammonium salt by passing gaseous NH3 in EtOAc. The ammonium salt is then treated with calcium acetate to give atorvastatin calcium.
The invention will now be described with reference to the following example. Example 1 1.1 Preparation of 4-methyI-3-oxo-N-phenylpetajιamide (Formula XIX).
To a suspension of malonic acid ( 104g) in acetic anhydride (120mL) at room temperature, Cone. H2S04 (3mL) was added. The mixture was cooled to 20°C followed by the addition of acetone (80mL) drop wise. The contents were stirred at room temperature (15min) and kept at 0-5°C overnight and filtered. The solid was washed with cold water and cold acetone and dried. The crude material was recrystallized from acetone-hexane mixture.
Meldrum 's acid (59g) was dissolved in CH2C12 (200 mL) and cooled to 0°C. Pyridine (73mL) was added drop wise over a period of 30 min and the mixture was stirred for an additional 10 min. Isobutyryl chloride (44g) was added drop wise over a period of 30 min. and the mixture was stirred at 0°C for lh followed by stirring at room temperature over night. The mixture was poured into 1.5N HC1 containing crushed ice. The layers were separated and the aqueous layer was extracted with CH2C12 (2xl00mL). The combined extracts were washed with 1.5N HC1 (2xl00mL) followed by saturated NH4CI solution (2xl00mL) and dried over Na2S04 and concentrated under reduced pressure to afford the crude acyl meldrum s acid which was used for the next step. The crude acyl meldrum "s acid (84g) was taken in benzene (300mL) and aniline ( 1 1 I mL) was added. The mixture was retluxed for 4h. Cool the reaction mixture to room temperature and wash with 2N HCl (5xl00mL) and benzene was removed under reduced s pressure to get formula XIX.
1.2 Preparation of 4-methyI-3-oxo-N-phenyl-2- (phenylmethylene) pentanamide (Formula XX).
The crude amide was taken in acetic acid and piperdine. To this 0 mixture at room temperature benzaldehvde was added. The contents ere allowed to stir under reflux for 2h. Pour the contents into water and extract with CH2CI2. The organic extracts were washed with bicarbonate, bisulfite solution, dried and concentrated under reduced pressure to afford the crude compound of formula XX. 5
1.3 Preparation of 4-fluoro-α-[2-methyI-l-oxopropyl]y-oxo-N- β-diphenylbenzenebutaneamide (Formula XVII).
To 4-fluorobenzaldehyde in anhydrous DMF, sodium cyanide as added and the contents were retluxed for 4h. To this the inteπnediate from example 3 was added and the contents were stirred for an additional 18h. Usual work up affords the crude diketo compound of formula XVII.
1.4 Preparation of 4-trifluoromethanesιdfonyl-3-oxo-butyric acid (Formula III).
To a solution of chloroacetic acid in pyridine at 0°C and CILCL, tritluoromethane sulfonyl chloride was added slowh . After the reaction was complete, oxalyl chloride was added and the contents were relluxed for 3h and the solvent was removed- under reduced pressure to give the crude acid chloride.
Meldrum's acid (59g) was dissolved in CH2C12 (200 mL) and cooled to 0°C. Pyridine (73mL) was added drop wise over a period of 30 min and the mixture was stirred for an additional 10 min. Trifluromethanesulfonyl acetylchloride (44g) was added drop wise over a period of 30 min. and the mixture was stirred at 0°C for lh followed by stirring at room temperature over night. The mixture was poured into 1.5N HCl containing crushed ice. The layers were separated and the aqueous layer was extracted with CI CL (2xl 00mL). The combined extracts were washed with 1.5N HCl (2xl 00mL) followed by saturated NH4CI solution (2xl00mL) and dried over Na S0 and concentrated under reduced pressure to afford the crude acyl meldrum's acid was hydrolyzed to give the title compound of formula III.
1.5 Preparation of methyl 6-trifluoromethane sulfonyI-5,3- dioxo-butryate (Formula IV).
The crude compound from example 5 was taken in CH2CL and pyridine and was cooled to 0-5°C. Oxalyl chloride was slowly introduced and the contents were refluxed for 6h. The solvent was removed under reduced pressure to afford the crude acid chloride.
Meldrum's acid (59g) was dissolved in CH2C12 (200 mL) and cooled to 0°C. Pyridine (73mL) was added drop wise over a period of 30 min and the mixture was stirred for an additional 10 min. The acid chloride (44g) was added drop wise over a period of 30 min. and the mixture was stirred at 0°C for l h followed by stirring at room temperature over night. The mixture was poured into 1.5N HCl containing crushed ice. The layers were separated and the aqueous layer was extracted with CHjCL (2xl 00mL). The combined extracts were washed with 1.5N HCl (2xl 00mL) followed by saturated NH4C1 solution (2xl 00mL) and dried over Na2S04 and concentrated under reduced pressure to afford the crude acyl meldrum's acid was 5 refluxed in methanol to give the title compound of formula IV
1.6 reparation of methyl 6-trifluoromethane sulfonyl-5-oxo-3- hydroxybutr ate (Formula V).
To a mixture of dry bakers' yeast and glucose in boiled w?ater 0 was stirred at ambient temperature. The crude diketo ester from example 5 was then added and the reaction mixture was stirred for an additional period 8-13h at ambient temperature. Celite was added to the reaction mixture and filtered. The celite bed was washed thoroughly with ethyl acetate and the combined ethyl acetate extracts 5 was dried and concentrated under reduced pressure to afford the title product which was used for the next step without further purification.
1.7 Preparation of (4R)-methyl 6-trifluoromethyl sulfonyl methyl-2,2-dimethyI-l,3-dioxane-4-acetate (Formula VII). 0 The crude product from example 6 was taken up in dry THF and isopropanol under nitrogen atmosphere. The solution was cooled to -78°C and a solution of diethylmethoxyborane was added. The reaction mixture was cooled to -80°C and sodium borohvdride was added in portion over a period of 4h. The temperature was maintained ^ between -70 to -85oC and was allowed to warm to room temperature and stand for 18h. The reaction was quenched by addition of acetic acid and concentrated under reduced pressure to afford an oily residue. The crude oil was taken up in acetone and 2,2- dimethoxypropane was added followed by cataKtic amount of trifluoromethanesulfonic acid. The contents were stirred at room temperature for 4h and after the completion of the reaction was washed with bicarbonate solution. The organic extracts was washed with water and was concentrated to give an oil which was crystallized from hexane.
1.8 Preparation of (4R)-methyl 6-(2-aminoethyI)-2,2-dimethyl- l,3-dioxane-3-acetate (Formula VIII)
The crude mesylate from example 8 was taken up in methanol and NH3 gas was bubbled. The contents were then stirred for 6-14h at room temperature. After the reaction was complete, solvent was removed under reduced pressure to afford the crude title compound of formula VIII.
1.9 Preparation of (R-(R*,R*)]-2-(4-fluorophenyI)-β,δ- dihydroxy-5-(l -methylethyI)-3-phenyl-4- [ phenylaminocarbonv 11 - lH-pyrrole-1-heptanoic acid, hemi calcium salt (Formula XXII) A solution of (4R)-methyl 6-(2-aminoethyl)-2.2-dimethyl-l,3- dioxane-3 -acetate (of formula XIV) and 4-fluoro-α-[2-methyl-l - oxoρroρyl]γ-oxo-N-β-diρhenyIbenzenebutaneamide (formula XVII) and acetic acid in xylene were heated to reflux to 44h. The solution was diluted with diisopropyl ether and methanol and was washed with dilute methanolic sodium hydroxide solution, dilute HCl and the solvent was then removed under vacuum. The crude oil was stirred with moist silica in CH:C12 and was stirred at room temperature for 18h. A solution of aqueous NaOH was then added at room temperature and was stirred for 4h. The reaction mixture was diluted with water and was washed with diisopropyl ether. The aqueous layer was acidified with HCl and was taken up in diisopropvl ether. The crude acid intermediate was then taken up in EtOAc and NH3 gas was bubbled. The contents were stirred for completion of the reaction and solvent was removed upon which the product crystallized. The crude ammonium salt is then taken up in diisopropyl ether-isopropanol mixture and a solution of calcium acetate was added at room temperature upon which the calcium salt precipitated from the solution. The product was filtered and dried under vacuum to get formula XXII of acceptable pharmaceutical purity.
The invention has been described by reference to specific embodiments, this was for the purpose of illustration only. Numerous alternative embodiments will be apparent to those skilled in the art and are considered within the scope of these claims.
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
Figure imgf000021_0004
Figure imgf000021_0005
21
Figure imgf000022_0001
XIII
Figure imgf000022_0002
Figure imgf000023_0001
PhNHCO
Figure imgf000023_0002
XXI
Figure imgf000023_0003
Scheme -1
Figure imgf000024_0001
Scheme - 2
Figure imgf000024_0002
R*2BC1
Figure imgf000024_0003
Scheme - 3
Figure imgf000025_0001
Scheme - 4
Figure imgf000025_0002
Scheme - 5
Figure imgf000026_0001
Scheme - 6
Figure imgf000026_0002

Claims

26We claim:
1. The process involves the synthesis of compound R-(R*,R*)]-2- (4-fluorophenyl)-B,D-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l -heptanoic acid hemi calcium salt (formula XXII) which comprising: a) reacting of compound of formula XVII with a compound of structure XIV in a non-polar solvent, to give an intermediate of structure XXI, b) deprotection, followed by hydrolysis of the compound of structure XXI followed by cyclization in ethyl acetate to give the lactone, c) treating the lactone with NH3 to give the ammonium salt, and d) reacting the ammonium salt with CaCl2 gives the corresponding calcium salt of formula XXII.
2. A process as claimed in claim 1, wherein the non-polar solvent in step (a) is selected from xylene or acetonitrile.
3. A process as claimed in claim 1, wherein the de-protecting agent in step (b) is selected from moist silica or PTSA.
4. A process as claimed in claim 1, wherein the ammonium salt in step (c) is prepared by treating with aqueous NH3 or methanolic NH3 or by passing NH3 gas to the compound taken in EtOAc, MeOH, isopropyl alcohol, diisopropyl ether or cyclohexane.
5. A process as claimed in claim 1, wherein the compound of compound of formula XVII is prepared by: a) reacting meldrum acid with isobutyryl chloride in the presence of base in CH2C12 to give an intermediate of formula XVIII, b) reacting the intermediate of formula XVIII with base in CH2C12 to give an intermediate of formula XIX, c) reacting the intermediate of formula XIX with benzaldehyde in the presence of base and toluene to give a compound of formula XX, and d) reacting of compound of formula XX with 4- fluorobenzaldehyde with a metal cyanide and polar solvent in the presence of a base to give the compound of formula XVII.
6. A process as claimed in claim 5 where in step (b) the base is selected from aniline, pyridine, triethylamine, dimethylaniline, diethylisopropylamine.
7. A process as claimed in claim 5 where in step (c) the base is selected from piperidine, pyrrolidine or diisopropylethylamine.
8. A process as claimed in claim 5 where in the metal cyanide in step (d) is selected from NaCN, CuCN, KCN, AgCN or tetraalkyl ammonium cyanide.
9. A process as claimed in claim 5 wherein the polar solvent in step (d) is selected from DMSO, DMF, CH3CN.
10. A process as claimed in claim 5 wherein the base in step (d) is selected from dusopropylethyl amine, 1-methylimidazole, pyridine.
11. A process as claimed in claim 1 wherein compound of (4R)- methyl 6-(2-aminoethyl)-2,2-dimethyl-l ,3-dioxane-3-acetate(Formula XIV) used in step (a) is prepared by: a) reacting a compound of formula II with meldrum's acid followed by hydrolysis to give a compound of formula III, b) reacting a compound of formula III with thionyl chloride to give an acid chloride which is then reacted with a meldrum's acid followed by alcoholosis to give a compound of formula IV, c) reducing a compound of formula IV to give a compound of formula V, d) reducing a compound of formula V to give a dihydroxy ester of formula VI, e) Converting a compound of formula VI to give a compound of formula VTI, f) ammonolysis of a compound of formula VII to give a compound of formula VIII, g) alternatively reacting the compound of formula VII with phthalimide salt to give a compound of formula XVI, h) reacting a compound of formula XVI with hydrazine hydrate to give the compound of formula VIII, and i) where R5 = ter-butyl in formula VIII, formula XIV is obtained
12. A process as claimed in claim 11 wherein R4 in step (a) is chosen from, OMs, OTs, Br, Cl or I.
13. A process as claimed in claim 11 wherein, the alcohol in step (b) is chosen from methanol, ethanol, isopropanol, benzyl alcohol.
14. A process as claimed in claim 11 wherein the reducing agent in step (c) is baker's yeast or a reagent of formula R*2BC1 where R*2 is chosen from (-) α pinene or (+) -α- pinene.
15. A process as claimed in claim 11 wherein the reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxyboron and sodium borohydride.
16. A process as claimed in claim 1 1 wherein the protecting group for conversion in step (e) is chosen from acetone, benzophenone, acetophenone or benzaldehyde.
17. A process as claimed in claim 11 wherein the reagent for ammonolysis in step (f) is chosen from aqueous NH3, methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyl ether.
18. A process as claimed in claim 1 1 wherein the phthalimide salt in step (g) is chosen from potassium, sodium or lithium.
19. A process as claimed in claim 1 wherein compound of (4R)- methyl 6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-3-acetate(Formula
XIV) used in step (a) is prepared by: a) reacting a compound of formula II with meldrum's acid followed by hydrolysis to give a compound of formula IX, b) reacting a compound of formula IX with tert-butyl acetate with a base at -30 to -80°C to give a compound of formula X, c) reducing a compound of formula X to give a compound of formula XI, d) reducing a compound of formula XI to give a dihydroxy ester of formula XII, e) Converting a compound of formula XII to give a compound of formula XIII, f) ammonolysis of a compound of formula XIII to give a compound of formula XIV g) alternatively reacting the compound of formula XIII with phthalimide salt to give a compound of formula XV and h) reacting a compound of formula XV with hydrazine hydrate to give the compound of formula XIV.
20. A process as claimed in claim 19 wherein R4 in step (a) is chosen from, OMs, OTs, Br, Cl or I.
21. A process as claimed in claim 19 wherein the reducing agent in step (c) is baker's yeast or a reagent of formula R*2BC1 where R*2 is chosen from (-) α pinene or (+) -α- pinene.
22. A process as claimed in claim 19 wherein the reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxyboron and sodium borohydride.
23. A process as claimed in claim 19 wherein the protecting group for conversion in step (e) is chosen from acetone, benzophenone, acetophenone or benzaldehyde.
24. A process as claimed in claim 19 wherein the reagent for ammonolysis in step (f) is chosen from aqueous NH3, methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyl ether.
25. A process as claimed in claim 19 wherein the phthalimide salt in step (g) is chosen from potassium, sodium or lithium.
26. The intermediate compound of formula XVIII as claimed in claim 5.
27. The intermediate of formula XIV as claimed in claim 1.
28. The intermediate of formula XV as claimed in claim 19.
29. The intermediate of formula VII, wherein R5 is chosen from C C5 alkyl, benzyl, isopropyl, cyclohexyl or tert-butyl as claimed in claim 11.
30. The intermediate of formula IX, wherein R is chosen from CH2Br, CH2C1, CH2I, CH2OMs or CH2Ots as claimed in claim 19.
AMENDED CLAIMS
[received by the International Bureau on 16 February 2001 (16.02.01); original claims 1-30 replaced by new claims 1-21 (5 pages)]
1. The process for the manufacture of compound R-(R*, R*)]-2-) 4-fluorophenyl )- β,δ-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH- pyrrole-1 -heptanoic acid hemi calcium salt (formula XX11) which comprises:
a) reacting of compound of formula XVII with a compound of structure
XIV or a compound of structure VIII in a mixture of solvents chosen from xylene, cyclohexane,methyl tert-butyl ether, diisopropyl ether, acetonitrile. in the presence of catalyst chosen from trifluromethyl sulfonic acid, methane sulfonic acid, p-toluene sulfonic acid (PTSA) or pyridine p-toluene sulphonic acid (PPTS). to give an intermediate of structure XXL. where R) or R2 is independently from H: Cj to C? alkyl. phenyl. benzyl, substituted phenyl and R5 is chosen from Ci-C n-alkyl. C3- C6 Cycloalkyl, benzyl or ter-butyl,
b) deprotection followed by hydrolysis of the compound of structure XXI followed by cyclization in ethyl acetate to give the lactone,
c) treating the lactone with NH3 to give the ammonium salt, and
d) reacting the ammonium salt with Ca+" salts gives the corresponding calcium salt of formula XXII.
2. A process as claimed in claim 1, wherein the ammonium salt in step (c) is prepared by treating with aqueous NH3 or methanolic NH3 or by passing NH? gas to the compound taken in EtOAc, MeOH, Isopropyl alcohol, diisopropyl ether or cyclohexane.
3. A process as claimed in claim 1, wherein the compound of formula XVII is prepared by:
a) reacting meldrum acid with isobutyryl chloride in the presence of base in CH2C12 to give an intermediate of formula XVIII.
b) reacting the intermediate of formula XVIII with aniline in CH2C1 to give an intermediate of formula XIX. c) reacting the intermediate of formula XIX with benzaldehyde in the presence of catalyst and toluene to give a compound of formula XX, and
d) reacting of compound of formula XX with 4-flurobenzaldehyde with a cyanide reagent and solvent in the presence of a base to give the compound of formula XVII.
4. A process as claimed in claim 3 wherein step (c) the catalyst is selected from piperidine, pyrrolidine, dissopropylethylamine, PTSA or PPTS.
5. A process as claimed in claim 3 where in the cyanide reagent in step (d) is selected from NaCN, CuCN, KCN, AgCN, tetra-alkyl ammonium cyanide or trimethyl silyl cynaide.
6. A process as claimed in claim 3 wherein the solvent in step (d) is selected from DMSO, DMF, CH3CN.
7. A process as claimed in claim 3 wherein the base in step (d) is selected from dusopropylethyl amine, 1-methylimidazole, pyridine.
8. A process as claimed in claim 1 wherein compound of formula XIV used in step (a); where R) or R2 is independently from H, Cj to C3 alkyl, phenyl, benzyl, substituted phenyl and R4 is chosen from CH2OMs,CH2OTs, CH C1, CH2Br or CH2I; is prepared by:
a) reacting a compound of formula II, with meldrum's acid followed by hydrolysis to give a compound of formula IX,
b) reacting a compound of formula IX with ter-butyl acetate with a base at -30 to -80 °C to give a compound of formula X,
c) reducing a compound of formula X to give a compound of formula XI.
d) reducing a compound of formula XI to give a dihydroxy ester of formula XII,
e) converting a compound of formula XII to give a compound of formula
XIII.
27 f) ammonolysis of a compound of formula XIII to give a compound of formula XIV.
g) alternatively reacting the compound of formula XIII with phthalimide salt to give a compound of formula XV, and
h) reacting a compound of formula XV with hydrazine hydrate to give the compound of formula XIV.
9. A process as claimed in claim 8 wherein the reducing agent in step (c) is derived from yeast or a reagent of formula R* BC1, where R*2 is chosen from pinene.
10. A process as claimed in claim 8 wherein the reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxyboron and sodium borohydride.
11. A process as claimed in claim 8 wherein the reagent for ammonolysis in step (f) is chosen from aqueous NH3, methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyl ether.
12. A process as claimed in claim 8 wherein the phthalimide salt in step (g) is chosen from potassium, sodium or lithium.
13. A process as claimed in claim 1 wherein compound of formula VIII used in step (a); where Rj or R2 is independently from H, Ci to C3, alkyl, phenyl, benzyl, substituted phenyl R4 is chosen from CH2OMs, CH2OTs, CH2C1, CH2Br or CH2I and R5 is Cι-C6 n-alkyl, C3-C6 cycloalkyl, benzyl or ter-butyl; is prepared by:
a) reacting a compound of formula II, with meldrum's acid followed by hydrolysis to give a compound of formula III,
b) reacting a compound of formula III with thionyl chloride to give an acid chloride which is then reacted with a meldrum's acid followed by alcholysis to give a compound of formula IV,
c) reducing a compound of formula IV to give a compound of formula V. d) reducing a compound of formula V to give a dihydroxy ester of formula VI,
e) converting a compound of formula VI to give a compound of formula VII.
f) ammonolysis of a compound of formula VII to give a compound of formula VIII.
g) alternatively reacting the compound of formula VII with phthalimide salt to give a compound of formula XVI, and
h) reacting a compound of formula XVI with hydrazine hydrate to give the compound of formula VIII.
14. A process as claimed in claim 13 wherein the reducing agent in step (c) is derived from yeast or a reagent of formula R*2BC1, where R* is chosen from α pinene.
15. A process as claimed in claim 13 wherein the reducing agent in step (d) is chosen from dimethoxyethylboron or tietoxyboron and sodium borohydride.
16. A process as claimed in claim 13 wherein the reagent for ammonolysis in step (f) is chosen from aqueous NH3, methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyl ether.
17. A process as claimed in claim 13 wherein the phthalimide salt in step (g) is chosen from potassium, sodium or lithium.
18. The intermediate of formula XVI, where Ri or R2 is independently from H, Ci to C3 alkyl, phenyl, benzyl, substituted phenyl and R5 is chosen from - C6n- alkyl, C -C6 cycloalkyl, benzyl or ter-butyl.
19. The intermediate of formula XV, where Ri or R2 is independently from H, Ci to C3 alkyl, phenyl, benzyl, substituted phenyl.
20. The intermediate of formula VII, where Ri or R2 is independently from H, Ci to C3 alkyl, phenyl, benzyl, substituted phenyl and R4 is chosen from CH2Br, CH2C1, CH2I, CH2OMs or CH2OTs and R5 is chosen from d - C6 n alkyl, C3- C6 cycloalkyl, benzyl or ter-butyl.
21. The intermediate of formula IX, wherein R4 is chosen from CH2Br, CH2C1, CH2I, CH2OMs or CH2OTs.
PCT/IN2000/000030 2000-03-28 2000-03-28 Synthesis of [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) WO2001072706A1 (en)

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