FIELD OF THE INVENTION
The present invention relates to novel and industrially advantageous process for the preparation of rosuvastatin of formula I,
(Formula Removed)
or pharmaceutically acceptable salts thereof. BACKGROUND OF THE INVENTION
Rosuvastatin of formula-I, chemically known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy hept-6-enoic acid is commercially available in calcium salt form, is HMG-CoA reductase inhibitor.
(Formula Removed)
Rosuvastatin was first disclosed in US patent 5,260,440 as a useful hypocholesterolemic agent for treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Rosuvastatin is prepared by process as shown below:
(Formula Removed)
Process involves isolation of most of intermediates using silica gel chromatography which is considered as cumbersome and time consuming process and thus not

suitable for industrial synthesis. In addition to this, product, obtained by following above process is found to contain number of impurities which are difficult to remove. Several synthetic methods have been reported in literature to prepare rosuvastatin; some of them have been incorporated here.
US patent 6,844,437 discloses a process for preparation of rosuvastatin by reaction of diphenyl-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-ylmethyl}phosphineoxide with t-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl -l,3-dioxan-4-yl]acetate in presence of strong base to form acetonide t-butyl rosuvastatin ester. Above intermediate is then hydrolyzed using an acid followed by treatment with a solution of sodium hydroxide to form sodium salt of rosuvastatin which is neutralized to form rosuvastatin and purified via methylamine salt. US patent 7,312,329 discloses a process for preparation of rosuvastatin by making use of Wittig reaction which is as shown below:
(Formula Removed)
This process suffers from the quality aspect as process results in the product containing approximately 20 % of Z-isomer after Wittig reaction. Removal of Z-isomer requires tedious purification and also results in loss of yields thus makes the process uneconomical from the industrial point of view.
US patent 7,566,782 discloses a process for preparation of rosuvastatin using intermediates containing cyanide functionality. The process involves reaction of pyrimidine aldehyde intermediate with l-cyano(2S)-2-[(tert-butyldimethylsilyl)oxy]-4-oxo-5-triphenylphosphorylidene pentane to give hydroxyl protected cyano keto intermediate which is purified by silica gel chromatography. Above intermediate is then reacted with methanesulfonic acid to deprotect hydroxyl protecting group to give cyano keto alcohol intermediate which is purified using silica gel chromatography. Cyano keto alcohol intermediate is then reduced with sodium borohydride & diethyl

methoxy borane to give cyano diol intermediate which is finally hydrolyzed and converted to rosuvastatin calcium salt. Process is as shown below:
(Formula Removed)
Process requires purification of intermediates using chromatographic techniques which is very time consuming and cumbersome process. Further process involves use of an intermediate having cyanide functionality, which needs special handling and extra care due to its toxic nature. Use of chromatographic techniques and highly toxic cyanide intermediate makes process unattractive for industrial synthesis. US patent application 2008/0091014 discloses preparation of rosuvastatin calcium starting from pyrimidine aldehyde by sequence of reaction steps as shown below:
(Formula Removed)
Process involves incorporation of side chain in two steps, first by converting aldehyde pyrimidine intermediate to corresponding acrylonitrile and then to corresponding 5-acryaldehyde. Resulting intermediate is then reacted with 1,3-bis(trimethyl siloxane)-l-ethoxy-l,3-butadiene, thus process involves more number of steps which adds to cost of API. In addition to this, process involves use of cyanide intermediate which require special handling. Another disadvantage of this process is

that during conversion of acrylonitrile intermediate to corresponding 5-acryaldehyde intermediate, number of impurities is formed along with unwanted cis-isomer. US patent application 20080161560 discloses a process for the preparation of rosuvastatin as shown below:
(Formula Removed)
Process involves more number of steps and also involves resolution at intermediate stage which is not considered to be suitable for the industrial synthesis. US patent application 2009/0124803 discloses a process for preparation of rosuvastatin by reacting pyrimidine aldehyde intermediate with carbethoxy methylene)triphenylphosphorane to form corresponding ethyl acrylate intermediate, purified by silica gel chromatography. This intermediate is reduced to convert ester moiety to alcohol followed by its oxidation and condensation with 1-tert-butoxy-ethenol to form t-butyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl}3-hydroxy-4-pentenoate which is then converted to rosuvastatin calcium of steps: hydrolysis of tert-butyl ester, resolution, esterification, condensation with 1-tert-butoxy-ethenol, reduction followed by saponification.

US patent application 2010/156783 discloses a process for the preparation of rosuvastatin or salts thereof by the process as described below:
(Formula Removed)
Process involves synthesis of olefinic bond via Wittig reaction using a Wittig reagent which comprises pyrimidine core of rosuvastatin molecule. Preparation of such Wittig reagent is disadvantageous as the synthesis of fully substituted pyrimidine compound is very expensive task and also results in low yield thus adds to the cost of final product and makes the process not suitable from commercial point of view. Various other strategies to prepare rosuvastatin are disclosed in several patent applications such as US 2005/0222415, US 2008/0207903, US 2008/0255170, US 2008/0300406, US 2010/048899, US 2010/0228028, WO 2006/106526, WO 2008/093205, WO 2009/024323 and WO 2009/143776, etc.
In addition to this, many different strategies to prepare statin compounds are given in literature, for example US 6,777,552, US 7,371,865 and the like. US patent 7,371,865 discloses a process to prepare statins using amide intermediates but specifically describes the synthesis of only fluvastatin and pitvastatin. Each intermediate has its own characteristic properties and it is not possible to employ the same strategy for all the statin molecules. As nature of other functional group has great impact on reaction progress as well product of the reaction. So it is possible to get different results for

different statins as they have only common feature related to side chain but main
moiety is different.
As mentioned above though there are a number of processes available, which have
their own advantages and disadvantages still there is a continuing need to develop
alternative process for the manufacture of rosuvastatin and its pharmaceutically
acceptable salts. In most of the reference olefinic bond in rosuvastatin has been
generated using Wittig reaction by employing different strategies and using different
Wittig reagent. In prior art references, either side chain intermediate containing ester
or cyanide functionality is used as Wittig reagent or expensive Wittig reagent having
pyrimidine core is used for the reaction. We have not found any reference wherein
olefinic bond in the rosuvastatin has been generated using side chain intermediate
having aralkyl amide functionality as a Wittig reagent, which is found to be highly
useful for the synthesis of rosuvastatin. Such process is found to be more convenient
to use, provides product in a better yield, reduces the number of steps involved, and
uses intermediates which are novel when compared to previously known processes.
OBJECTIVE OF THE INVENTION
The foremost objective of the present invention is to provide a novel and industrially
advantageous process for the preparation of rosuvastatin or its lactone or
pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide an enantioselective synthesis of
rosuvastatin or its lactone or pharmaceutically acceptable salt thereof.
Still another object of the present invention is to provide a process for the preparation
of rosuvastatin or salts thereof using novel amide intermediates.
Yet another object of the present invention is to provide novel amide intermediates,
which serve as industrially useful intermediates for the efficient synthesis of
rosuvastatin or its lactone or pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
Accordingly, present invention provides a novel, efficient and industrially
advantageous process for the preparation of rosuvastatin of formula I,

(Formula Removed)
or its lactone or pharmaceutically acceptable salts thereof, comprising the steps of: a), reacting an intermediate of formula II,
(Formula Removed)
wherein R1, R2, and R3 are same or different and can be independently selected from
alkyl or aryl, alkoxy and the like; or any one of R1, R2 and R3 can be an oxo group;
R4 can be selected from hydrogen, alkyl, aryl, aralkyl and the like;
P1 is hydroxyl protecting group
or reactive derivative or salts thereof with methyl benzylamine in presence of suitable
base to form amide intermediate of formula III,
(Formula Removed)
wherein R1, R2, R3 and P1 are as defined above
b). condensing amide intermediate of formula III with pyrimidine aldehyde intermediate of formula IV,
(Formula Removed)
in suitable solvent to give intermediate of formula V,
(Formula Removed)
c). deprotecting hydroxyl group of intermediate of formula V using a suitable reagent to form keto hydroxy intermediate of formula VI,
(Formula Removed)
d). reducing keto hydroxy intermediate of formula VI using a suitable reducing reagent in the presence of a suitable chelating agent to form dihydroxy intermediate of formula VII,
(Formula Removed)
e). converting dihydroxy intermediate of formula VII in to rosuvastatin or its lactone
or pharmaceutically acceptable salts thereof. According to another embodiment, present invention provides a process for the preparation of rosuvastatin of formula I or its lactone or pharmaceutically acceptable salts thereof, comprising the steps of: a), providing dihydroxy intermediate of formula VII, b). protecting hydroxyl groups of intermediate of formula VII to form dihydroxy
protected intermediate of formula VIII, and
(Formula Removed)
wherein P1 and P2 are hydroxyl protecting group and both can be same or different; or taken together with the oxygen atom to which each is bonded to form a hydrolysable cyclic protecting group
c). converting dihydroxy protected intermediate of formula VIII to form rosuvastatin
or its lactone or pharmaceutically acceptable salts thereof. According to another embodiment, present invention provides a process for the preparation of rosuvastatin of formula I or its lactone or pharmaceutically acceptable salts thereof, comprising the steps of: a), providing dihydroxy intermediate of formula VII, and b). hydrolyzing dihydroxy intermediate of formula VII to form rosuvastatin or its
lactone or pharmaceutically acceptable salts thereof. According to yet another embodiment, present invention provides novel aralkyl amide intermediates of formulae V, VI, VII and VIII which are useful in the synthesis of rosuvastatin or its lactone or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used here in, the term "hydroxyl protecting group" includes but not limited to a silyl group, of general formula Si(R)3 where each R is independently selected from a C1-6 linear or branched aliphatic or aromatic group. Preferably can be selected from triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl and the like
As used here in, the term "cyclic protecting groups" includes dioxane, cyclic sulfate, cyclic phosphate or borylidene which are optionally substituted with alkyl or aryl group, preferably cyclic protecting group can be dioxane and the like. The present invention provides novel and industrially advantageous process for the preparation of rosuvastatin or its lactone or pharmaceutically acceptable salts thereof using novel amide intermediates.
According to one embodiment, present invention provides a process for the preparation of rosuvastatin initially by converting intermediate of formula II or reactive derivative thereof in to intermediate of formula III.
Generally, process involves the reaction of intermediate of formula II or reactive derivative thereof with methyl benzylamine in the presence of a suitable base at a temperature of-50 to 0 °C for few minutes to several hours. Suitable base used for the
reaction can be organic or inorganic base. Organic base includes primary, secondary or tertiary amine such as JV-methylmorpholine, triethylamine and the like; and inorganic base includes alkali or alkaline metal hydroxide, alkoxide, hydride, carbonate, bicarbonate thereof such as lithium hydroxide, lithium hydroxide monohydrate, barium hydroxide, sodium methoxide, sodium hydroxide, potassium hydroxide and the like. Preferably amide formation is carried out using (S)-methyl benzylamine, however another isomer or mixture of two can be used for the reaction. The reaction can be carried out in a solvent that includes but not limited to water, ethers such as tetrahydrofuran; alcohols such as methanol, ethanol, isopropanol; ketones such as acetone; nitriles such as acetonitrile and the like or mixture thereof. Usually, reaction is carried out at a temperature of -30 °C to -10 °C for 2 to 3 hours, preferably till the completion of the reaction. After completion of the reaction, amide intermediate of formula III can be isolated from the reaction mixture by using any conventional technique known in the art or can be used as such for the further condensation reaction with pyrimidine aldehyde intermediate of formula IV. Preferably, intermediate of formula III can be isolated from the reaction mixture by adding water to the reaction mixture followed by extraction with a suitable solvent. Suitable solvent used for the extraction purpose can be water immiscible solvent which includes but not limited to esters such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof. Resulting solution can be optionally washed with an aqueous solution of a base and/or brine. Amide intermediate of formula III can be recovered from the resulting solution by removal of solvent using suitable techniques, preferably by evaporation, or distillation.
Alternatively, amidation reaction can be carried out by first converting intermediate of formula II (wherein R4 is hydrogen) in to its reactive derivative which is then employed for the amidation reaction.
Reactive derivative of intermediate of formula II can be prepared by the reaction of intermediate of formula II (wherein R4 is hydrogen) with a suitable activating agent at
-40 to -10 °C for 3 hours. Suitable activating agent includes but not limited to organic acid anhydrides; alkyl chloroformate or aryl chloroformate, such as methylchloroformate, ethylchloroformate, isobutylchloroformate; diimide reagent such as l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, N,N'-dicyclohexyl carbodiimide and the like or combination thereof. Suitable solvents used for the reaction can be same as used for further amidation reaction or different and can be selected from the solvents as defined above. The reactive derivative of acid intermediate of formula II, can be isolated from the reaction mixture or can be proceeded in situ to undergo reaction with methylbenzyl amine. In another alternate way, intermediate of formula II (wherein R4 is hydrogen) can be prepared from the respective ester intermediate of formula II (wherein R4 is other than hydrogen) by hydrolysis using a suitable base and then acid intermediate of formula II is converted to intermediate of formula III.
Generally, hydrolysis reaction can be carried using a suitable base at a temperature of 0 to 100 °C for 30 minutes to 20 hours, preferably at a temperature of 5 to 30 °C for 2-3 hours. More preferably reaction can be carried out till the completion of the reaction. Suitable base used for the reaction include alkali or alkaline metal hydroxide, carbonate, bicarbonate, hydride, alkoxide thereof such as lithium hydroxide, barium hydroxide, magnesium hydroxide, sodium hydroxide, potassium hydroxide sodium methoxide and the like. The reaction can be carri' ' in a suitable solvent which includes, but not limited to water, alcohol such as methanol, ethanol, isopropanol, n-butanol, 1-propanol; ether such as tetrahydrofuran; ketone such as acetone; nitriles such as acetonitrile and the like or mixture thereof. After completion of the reaction, resulting product can be isolated from reaction mixture or can be used as such for the further amidation reaction with methylbenzyl amine. Intermediate of formula II (wherein R4 is hydrogen) can be isolated from reaction mixture using suitable method known in the art or specifically by addition of suitable acid to reaction mixture followed by extraction with a suitable solvent. Suitable acid can be selected from organic acid such as acetic acid, formic acid; or inorganic acid such as
hydrochloric acid, nitric acid, sulfuric acid and the like. Suitable solvent used for extraction purpose can be water immiscible solvent selected from halogenated solvent such as dichloromethane, chloroform; ester such as ethyl acetate; ethers such as isopropyl ether, methyl tert-butyl ether; ketones such as methyl isobutyl ketone; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof. Intermediate of formula II (wherein R4 is hydrogen) can be recovered from resulting solution by removal of solvent using suitable techniques, preferably by evaporation, or distillation. Intermediate of formula II thus prepared is then converted to amide intermediate of formula III using suitable base and other reaction conditions as described above.
In another way, intermediate of formula II (wherein R4 is hydrogen) can be converted to its acid addition salt using a suitable base and then reacted with methyl benzylamine to form intermediate of formula III or intermediate of formula II (wherein R4 is hydrogen) can be purified using base acid treatment before reaction with methyl benzylamine.
Generally, intermediate of formula II (wherein R4 is hydrogen) can be treated with a suitable base at a temperature of 0 to 40 °C for 1 to 5 hours, preferably till complete formation of salt. Suitable base employed for salt formation can be a organic or inorganic base. Organic base includes but not limited to primary, secondary or tertiary amine of general formula NR'R"R'" (wherein R', R", and R'" can be same or different and can be independently selected from alkyl, aryl, aralkyl, cycloalkyl, heteroaryl and the like), preferably amine can be selected from dicyclohexylamine, methylamine, ethanolamine, diethanolamine, benzylamine, triethylamine and the like or mixture thereof. Inorganic base includes alkali or alkaline metal hydroxide, alkoxide thereof such as lithium hydroxide or its monohydrate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, lithium bromide and the like or mixture thereof. Salt formation can be carried in a suitable solvent for providing the reaction media and can be selected from alcohol such as methanol, ethanol; ethers such as tetrahydrofuran; ketone such as acetone; nitrile such as
acetonitrile and the like or mixture thereof. After completion of salt formation, resulting salt can be isolated from reaction mixture or can be in situ condensed with methyl benzylamine or alternatively can be neutralized to form pure acid intermediate of formula II.
Intermediate of formula II or salts thereof can be optionally purified prior to condensation reaction to enhance the purity and/or remove impurities present in the product. Any suitable purification method can be employed for purification, such as crystallization, slurry wash, base acid treatment and the like. Suitable solvent used for purification of intermediate of formula II or salts thereof can be selected from ethers such as methyl tert-butyl ether, isopropyl ether; aliphatic or aromatic hydrocarbon such as cyclohexane, n-hexane, heptane and the like or mixture thereof depending upon nature of intermediate of formula II or salts thereof.
Amide intermediate of formula III can be condensed with pyrimidine aldehyde intermediate of formula IV to form intermediate of formula V, which also forms a novel part of the invention.
Generally, process involves condensation of amide intermediate of formula III with pyrimidine aldehyde intermediate of formula IV in a suitable solvent at a temperature of 0 °C to reflux temperature of solvent for few minutes to several hours. Suitable solvent employed for the reaction includes aliphatic or aromatic hydrocarbon such as toluene, benzene, xylene; nitriles such as acetonitrile; aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide; ether such as diethyl ether, tetrahydrofuran, isopropyl ether, methyl tert-butyl ether and the like or mixture thereof. The reaction can be optionally carried out using a suitable base which includes inorganic base such as alkali or alkaline metal such as butyl lithium; alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride, alkoxide thereof such as sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydride and the like; or organic base such as trialkylamine such as triethylamine, diisopropylethylamine, l,5-diazabicyclo[4.3.0]non-5-ene; 1,8-diaza-bicyclo[5.4.0]undec-7-ene and the like. Usually reaction can be carried out at 80 to
100 °C for 10 to 15 hours. The reaction completion can be monitored by suitable chromatographic techniques such as high pressure liquid chromatography (HPLC), gas chromatography (GC), ultra pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and the like. After completion of reaction, intermediate of formula V can be isolated from the reaction mixture using a suitable method or can be used as such for further reaction.
It is optional to add a suitable metal halide to the reaction mixture to remove by product such as triphenyl phosphonium oxide, if present, from the reaction mixture. Metal halide includes magnesium halide such as magnesium chloride, cobalt chloride, copper chloride, calcium chloride, lithium chloride, ferrous chloride and the like. Triphenylphosphine oxide makes a complex with metal halide and can be removed by suitable techniques such as filtration, centrifugation from reaction mixture. Intermediate of formula V free from by products can be recovered from the resulting reaction mixture by the removal of the solvent using suitable techniques such as distillation, evaporation and the like.
It is found by present inventors that use of intermediate of formula III having aralkyl amide functionality as Wittig reagent is highly advantageous as intermediate of formula III having aralkyl amide functionality is found to be more stable and suitable for reaction as compared to the Wiitig reagent having pyrimidine core as reported in prior art.
Intermediate of formula V thus prepared can be optionally purified to enhance the purity and/or to minimize the impurities using any suitable purification method such as crystallization, slurry wash, acid base treatment, salt formation etc. to provide pure intermediate of formula V.
Hydroxy group of intermediate of formula V can be deprotected using a suitable deprotecting reagent to form intermediate of formula VI, which also forms a novel feature of the invention.
Generally, process involves reaction of intermediate of formula V with a suitable deprotecting reagent at a temperature of 0 °C to reflux temperature of the solvent for
few minutes to several hours, preferably for 15 to 60 °C till the completion of the reaction. Deprotecting reagent can be selected from any reagent known in the art that effectively serves purpose of deprotection of hydroxyl group. Specifically, deprotecting reagent can be selected from but not limited to acid such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, sulfonic acid such as methanesulfonic acid; fluoride salts such as tetrabutylammonium fluoride, hydrogen fluoride and the like. Usually, deprotection reaction completes in 1 to 2 hours at a temperature of 25 to 50 °C. After the completion of the reaction, intermediate of formula VI can be isolated from the reaction or can be used as such for the further reduction reaction. Intermediate of formula VI can be isolated from the reaction mixture by using suitable techniques, preferably intermediate of formula VI can be isolated from the reaction mixture by first neutralization of the reaction mixture by the addition of a suitable base followed by extraction of the resulting product with a suitable solvent. Suitable base employed for the reaction can be organic or inorganic base. Organic base includes methylamine, triethylamine, diisopropylethylamine, and the like. Inorganic base includes alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride, alkoxide thereof such as sodium carbonate, sodium bicarbonate, sodium methoxide and the like. Suitable solvent used for the extraction includes halogenated solvent such as dichloromethane, chloroform; ester such as ethyl acetate; ether and the like. Resulting organic layer can be optionally further treated with a suitable base and/or saturated with brine solution. Intermediate of formula VI can be isolated from the resulting organic layer by using suitable techniques such as evaporation, distillation and the like.
Intermediate of formula VI can be reduced stereoselectively using a suitable reducing agent to form dihydroxy intermediate of formula VII.
Generally, process involves the reaction of intermediate of formula VI with a suitable reducing agent in the presence of suitable chelating agent at a temperature of -90 to 0 °C for few minutes to several hours, preferably till completion of reduction reaction. Reduction can be carried out using catalytic hydrogenation in the presence of

hydrogenation catalyst such as ruthenium catalyst such as (Ru(cod)(nu-3-(2-methylally))2; hydrides which includes borohydride, aluminoborohydride such as diisobutyl aluminium borohydride, lithium aluminium hydride; alkali or alkaline metal hydride such as sodium borohydride, lithium borohydride; alkali metal cyanoborohydride such as sodium cyanoborohydride; diborane; diisopinocampheyl chloroborane; CBS-oxazaborolidines and the like. Chelating agent used for the reaction includes but not limited to trialkyl borane or boronates selected from dialkyl alkoxy borane such as diethyl-methoxy-borane, diethyl ethoxy borane, dimethyl methoxy borane and the like. Reduction can be carried out using an inert solvent which includes ether such as tetrahydrofuran; nitrile such as acetonitrile; halogenated solvent such as dichloromethane, chloroform; protic solvent such as alcohol (methanol) and the like or mixture thereof. Further reduction can be effectively accomplished at a temperature of -70 to -80 °C for 1 to 2 hours, preferably till completion of reaction. After completion of reaction, reaction mixture can be optionally quenched with a suitable quenching agent. Suitable quenching agent includes acid such as acetic acid, citric acid and the like or mixture thereof. After completion of reaction, dihydroxy intermediate of formula VII can be isolated from reaction mixture using suitable techniques or can be used as such for further reaction. Preferably, dihydroxy intermediate of formula VII can be isolated from reaction mixture by removal of solvent using evaporation or distillation and the like. It is optional to add a suitable solvent such as alcohol selected from methanol, ethanol and the like to resulting residue followed by removal of solvent to remove the traces of previous solvent. Dihydroxy intermediate of formula VII can be recovered from the resulting residue by adding water and water immiscible solvent followed by layer separation. Water immiscible solvent includes but not limited to ester such as ethyl acetate; halogenated solvent such as dichloromethane; ethers and the like or mixture thereof. Product can be isolated from resulting solution using suitable techniques such as evaporation, distillation and the like.
Dihydroxy intermediate of formula VII can be converted directly to rosuvastatin or its lactone or pharmaceutically acceptable salts thereof or through dihydroxy protected intermediate of formula VIII.
According to one method, present invention provides direct conversion of dihydroxy intermediate of formula VII to rosuvastatin or its lactone or pharmaceutically acceptable salts thereof by hydrolysis.
Generally, process involves reaction of intermediate of formula VII with a suitable base at a temperature of 25 to 100 °C for few minutes to several hours. Preferably hydrolysis reaction can be carried out at a temperature of 60 to 85 °C for 10 to 20 hours, more preferably till the completion of hydrolysis. Suitable base used for reaction is inorganic base which can be selected from alkali or alkaline metal hydroxide, carbonate, bicarbonate, hydride, alkoxide thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like or combination thereof. Reaction can be carried out using a suitable solvent selected from, but not limited to alcohol such as methanol, ethanol; ethers such as tetrahydrofuran; aprotic solvent such as tetrahydrofuran, dimethyldulfoxide; ketone such as acetone; nitriles such as acetonitrile and the like. After completion of hydrolysis, rosuvastatin can be isolated from reaction mass using conventional methods known in the art or can be used in situ for the lactone or salt formation. According to another method, dihydroxy intermediate of formula VII can be first converted to dihydroxy protected intermediate of formula VIII and then to rosuvastatin or pharmaceutically acceptable salts thereof.
Generally, process involves reaction of dihydroxy intermediate of formula VII with a suitable reagent in a solvent at a temperature of 0 to 50 °C to 1 to 5 hours. Preferably reaction can be carried out at a temperature of 25 to 30 °C for 1 to 2 hours, more preferably till completion of the reaction. Suitable reagent employed for reaction can be selected from the reagent known in the art that can effectively protect the two hydroxyl group present in the intermediate of formula VII provided no effect on the other functionalities and can be selected depending upon the protecting group to be
incorporated in intermediate of formula VII. Preferably suitable reagent includes but not limited to ketone such as acetone; dialkoxy alkane such as 2,2-dimethoxy propane and the like or combination thereof. Reaction can be carried out in the presence of a suitable catalyst to enhance the reaction kinetics. Suitable catalyst includes acid such as methanesulfonic acid, triflic acid and the like. Solvent used for reaction can be selected from ketones and the like or mixture thereof. After completion of reaction, dihydroxy protected intermediate of formula VIII can be isolated from the reaction mixture using suitable conventional methods or can be used as such for further reaction. Preferably, dihydroxy protected intermediate of formula VIII can be isolated from the reaction by extraction of the resulting product with a suitable solvent. Suitable solvent used for extraction purpose can be selected from halogenated solvent such as dichloromethane, chloroform; ester such as ethyl acetate; aliphatic or aromatic hydrocarbon such as toluene; ether such as isopropyl ether, methyl tert-butyl ether and the like. Resulting organic layer can be optionally washed with aqueous solution of suitable base as defined above and/or brine solution. Intermediate of formula VIII can be recovered from the resulting organic layer by the removal of solvent using suitable techniques, preferably evaporation, distillation and the like. Intermediate of formula VIII can be further converted to rosuvastatin or its lactone or pharmaceutically acceptable salts thereof.
Generally, process involves deprotection of intermediate of formula VIII with a suitable deprotecting reagent, in a solvent, at a temperature of 0 to 50 °C for few minutes to several hours, preferably till completion of reaction. Specifically deprotection reaction can be carried out using a suitable acid which includes organic acid such as acetic acid, oxalic acid, formic acid, and the like; or inorganic acid such as hydrochloric acid, sulfuric acid, ortho-phosphoric acid; sulfonic acid such as para-toluene sulfonic acid; methane sulfonic acid; and the like or combination thereof. The reaction can be carried out in a suitable solvent selected from but not limited to ketone, alcohol such as methanol, ethanol; ketone such as acetone; ester, nitriles, ether such as tetrahydrofuran and the like or mixture thereof. After completion of
reaction, dihydroxy intermediate of formula VII generated in situ can be optionally isolated from the reaction mixture or can be in situ hydrolyzed using a suitable base to form rosuvastatin or its lactone or pharmaceutically acceptable salts thereof. Suitable base and other reaction condition for hydrolysis are same as described above for the similar reaction.
Dihydroxy intermediate of formula VII or dihydroxy protected intermediate of formula VIII can be converted to rosuvastatin free acid or lactone which may or may not be isolated in solid form, from which the pharmaceutically acceptable salts can be formed directly or via other alkaline salt such as sodium salt. Pharmaceutically acceptable salts includes an alkali metal salt for example sodium or potassium salt; an alkaline earth metal salt for example calcium or magnesium salt; an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example methylamine, ethylamine, dimethylamine, morpholine, diethanolamine, and the like. The salt preparation can be carried out using methods known in the art. Preferably rosuvastatin calcium salt can be prepared.
Preferably, formation of pharmaceutically acceptable salts, such as rosuvastatin calcium, can be carried out by reacting a solution of rosuvastatin sodium with a source of calcium ion. Suitable source of calcium ion includes calcium hydroxide, calcium acetate, calcium chloride dihydrate, and the like. Solvent used for such transformation can be selected from water, alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof.
Rosuvastatin can be converted to corresponding lactone can be carried out in the presence of an acid. Acid used can be organic or inorganic acid. Lactone formation can be carried out in protic or aprotic solvent selected from but not limited to alcohol, nitrile and the like or mixture thereof. The conversion can be carried out at varying temperature depending upon the nature of acid used.
Starting material used for the present can be procured from the commercial sources or can be prepared by the processes known in the art.
Novel amide intermediates of the present invention can be characterized using suitable techniques such as Nuclear magnetic resonance spectroscopy ('H-NMR and/ or C-NMR), Infra-red spectroscopy (IR), melting point, mass analysis (MS), and the like. Other techniques such as powder X-ray diffraction pattern (PXRD), differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA), karl-fischer (KF) and the like can be employed to check the nature of intermediates of present invention. Present invention provides novel amide intermediate of formula V, VI, VII and VIII which are useful in the synthesis of rosuvastatin or its lactone or pharmaceutically acceptable salts thereof.
Intermediates as well as final compound of the present invention may be optionally purified to enhance the purity of the product. Any suitable purification procedure such as, for example, crystallization, derivatisation, slurry wash, salt preparation, various chromatographic techniques, solvent anti-solvent system or combination of these procedures, may be employed to get the purified material. However, other equivalent procedures such as acid-base treatment or acid-acid treatment could, also be used, to purify the intermediates as well as final product. The solvents used for the purification of final compound may be selected amongst nitriles such as acetonitrile, ether such as tetrahydrofuran; esters such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; aliphatic or aromatic hydrocarbon such as toluene; ketone such as methyl isobutyl ketone; alcohols such as methanol, ethanol, isopropanol and the like or mixtures thereof in suitable proportion. As used herein the term "conventional methods for the isolation of intermediates as well as final product" may be varied depending upon the nature of the reactions, nature product of the reaction, medium of the reaction and the like, the suitable conventional methods can be selected amongst but not limited to distillation of the solvent, addition of water to the reaction mixture followed by extraction with water immiscible solvents, removal of the insoluble particles from the reaction mixture, if present, by filtration or centrifugation or by decantation, addition of water immiscible organic solvent, addition
of a solvent to the reaction mixture which precipitate the product, neutralizing the
reaction mixture with a suitable acid or base whichever is applicable.
The order and manner of combining the reactants at any stage of the process are not
critical and may be varied. The reactants may be added to the reaction mixture as
solids, or may be dissolved individually and combined as solutions. Further, any of
the reactants may be dissolved together as sub-groups, and those solutions may be
combined in any order. The time required for the completion of the reaction may also
vary widely, depending on many factors, notably the reaction temperature and the
nature of the reagents and solvents employed. Wherever required, progress of the
reaction may be monitored by suitable chromatographic techniques such as High
performance liquid chromatography (HPLC), gas chromatography (GC), ultra
pressure liquid chromatography (UPLC) or thin layer chromatography (TLC).
The major advantage of present invention is to provide a novel, efficient and
industrially advantageous process for preparation of rosuvastatin of formula I, or its
lactone or pharmaceutically acceptable salts thereof using novel amide intermediates.
Process of present invention is useful as it provides an alternative method to prepare
rosuvastatin or its lactone or pharmaceutically acceptable salts thereof which
circumvent disadvantages of already existing processes and is convenient and easy to
employ at industrial level.
Although, the following examples illustrate the practice of the present invention in
some of its embodiments, the examples should not be construed as limiting the scope
of the invention. Other embodiments will be apparent to one skilled in the art from
consideration of the specification and examples.
EXAMPLES
Example 1: Preparation of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-
-phosphanylidene)-hexanoic acid
Method A: To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-
phosphanylidene)-hexanoic acid methyl ester (50 g) in aqueous methanol (200 ml),
lithium hydroxide monohydrate (11.5 g) was added at 5 to 10 °C and stirred for 3
hours. After completion of reaction, reaction mixture was cooled to 0 to 5 °C followed by addition of aqueous hydrochloric acid. The resulting reaction mixture was extracted with dichloromethane and organic layer was concentrated under vacuum to give 49 g of the title compound.
Method B: To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphanylidene)-hexanoic acid methyl ester (10 g) in aqueous methanol (40 ml), lithium hydroxide monohydrate (2.3 g) was added at 5 °C to 10 °C and stirred for 3 hours. After completion of reaction, solvent was evaporated and the product was crystallized from methyl tert-butyl ether (25 ml) and washed with water (10 ml). Solid thus obtained was suspended in water (100 ml), cooled to 0 to 5°C and dilute aqueous hydrochloric acid was added to the reaction mixture. Thereafter, reaction mass was extracted with dichloromethane and organic layer was concentrated under vacuum to give 6 g of the title compound.
Example 2: Preparation of lithium salt of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphanylidene)-hexanoic acid
To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphanylidene)-hexanoic acid methyl ester (10 g) in aqueous methanol (40 ml), lithium hydroxide monohydrate (2.3 g) was added and stirred for 3 hours at ambient temperature. After completion of reaction, solvent was evaporated and resulting product was crystallized from methyl tert-butyl ether (30 ml), washed with water (10 ml) and dried to give 7 g of the title compound having purity 98.9 % by HPLC. Example 3: Preparation of dicyclohexyl amine salt of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphanylidene)-hexanoic acid To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphany lidene)-hexanoic acid methyl ester (5g) in methanol (20ml), lithium hydroxide monohydrate (1.15 g) was added and stirred for 3 hours at ambient temperature. After completion of reaction, solvent was evaporated and ethyl acetate was added to the resulting residue followed by addition of solution of dicyclohexyl amine salt in ethyl acetate. Reaction mixture was stirred for 5 hours to give 5 g of the title compound.
Example 4: Preparation of 3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphanylidene)-hexanoic acid (l-phenyl-ethyl)-amide
3-(tert-Butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-5-phosphanylidene)-hexanoic acid (50 g) in tetrahydrofuran (0.5 L) was cooled to -25°C and N-methyl morpholine (9 g) followed by isobutylchloroformate (13 g) was added to reaction mixture and stirred for 30 minutes. S (-) methylbenzylamine (14 g) in tetrahydrofuran (25 ml) was added to above reaction mixture and stirred at -25 °C for 2 hours. After completion of reaction, demineralised water (150 ml) was added to reaction mixture and reaction mass was extracted with ethyl acetate (50 ml). Organic layer was washed with sodium bicarbonate solution and saturated with brine solution. Resulting organic layer was concentrated under vacuum to give 58 g of the title compound. Example 5: Preparation of 3-(tert-butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid (l-phenyl-ethyl)-amide
To 3 -(tert-butyl-dimethyl-silanyloxy)-5 -oxo-6-(triphenyl-5-phosphanylidene)-
hexanoic acid (l-phenyl-ethyl)-amide in toluene (1.0 L), N-[4-(4-fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (20 g) was added and mixture stirred at 100 °C for 15 hours. After completion of reaction, magnesium chloride (23 g) was added to the reaction mixture and stirred for 2 hours at 100°C. Reaction mixture was cooled to 0 to 5 °C and filtered. Resulting filtrate was concentrated under vacuum to give 62 g of the title compound. A portion of the resulting product was purified.
Example 6: Preparation of 7-[4-(4-fiuoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid (l-phenyl-ethyl)-amide
3-(Tert-butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methane sulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid (1 -phenyl-ethyl)-amide was dissolved in methanol (400 ml) and aqueous methane sulphonic acid (20 g in 50 ml water) was added to the reaction mixture. Reaction mixture was stirred at
ambient temperature for 2 hours. After completion of reaction, reaction mixture was neutralized by the addition of aqueous sodium bicarbonate solution (10 %) and the reaction mass was extracted with dichloromethane (480 ml). Sodium bicarbonate (5%, 250 ml) was again added to the organic layer and saturated with brine solution. Resulting organic layer was concentrated under vacuum to give 47 g of the title compound.
Example 7: Preparation of 7-[4-(4-fiuoro-phenyl)-6-isopropyl-2-(methane sulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid (1-phenyl-ethyl)-amide
Tetrahydrofuran (150 ml) was cooled to -78°C under nitrogen atmosphere, sodium borohydride (3.8 g) was added followed by the addition of diethyl-methoxyborane (80 g, 50% solution in tetrahydrofuran). Reaction mixture was stirred for 10 minutes and 7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin -5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid (l-phenyl-ethyl)-amide (48 g) in tetrahydrofuran (400 ml) was added to the reaction mixture. Reaction mixture was stirred for 1 hour at -78 °C. After completion of reaction, acetic acid (38 ml) was added to the reaction mixture and stirred for 15 minutes. Reaction mass was distilled out completely. Methanol (100 ml) was added to resulting residue and distilled off. Water (250 ml) and ethyl acetate (300 ml) were added to the residue thus obtained and stirred for 15 minutes. Layers were separated and organic layer was concentrated under vacuum to give 42 g of the title compound. Example 8: Preparation of rosuvastatin calcium
Method A: Step I: Preparation of 2-(6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l,3] dioxan-4-yl)-N-(l-phenyI-ethyl)-acetamide: 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid (l-phenyl-ethyl)-amide (20 g) was dissolved in acetone (200 ml) and then 2,2-dimethoxypropane (200 ml) was added to the reaction mixture. Reaction mixture was stirred till clear solution. Reaction mass was cooled to 10-15°C, methanesulfonic acid
(2.8 g) was added and stirred for 60 minutes. After completion of reaction, ethyl acetate (400 ml) and water (200 ml) were added and stirred for 15 minutes followed by layer separation. Aqueous layer was extracted with ethyl acetate (200 ml) and combined organic layer was washed with brine. Organic layer was concentrated and crystallized from aqueous isopropanol (40 ml) to give 15 g of the title compound. Step II: preparation of rosuvastatin calcium: 2-(6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-N-(l-phenyl-ethyl)-acetamide (15 g) in tetrahydrofuran (180 ml) and methanol (70 ml) was stirred till clear solution and cooled to 15 °C. Aqueous hydrochloric acid (30 ml) was added to the reaction and stirred for 6 hours at 25-30°C. After completion of the reaction, aqueous sodium hydroxide (10%) was added to the reaction mixture till pH 12.0-12.5 and stirred for 1 hour. The reaction mixture was filtered and concentrated under vacuum. Water (30ml) was added to the resulting residue and stirred. Aqueous layer was neutralized by adding dilute hydrochloric acid. Calcium chloride solution (1.95g in 20 ml water) was added to the resulting reaction mixture and stirred for 2 hours. Product thus obtained was filtered, washed with water and dried under vacuum to give 10 g of the title compound. Method B: 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid (l-phenyl-ethyl)-amide was dissolved in ethanol (350 ml) and sodium hydroxide solution (8.4 g in 80 ml in water) was added to the reaction mixture. The reaction mixture was heated at 80 °C for 18 hours. Solvent was distilled out from the reaction mixture and water (300 ml) was added to the resulting residue followed by addition of calcium chloride (2.25g). Reaction mixture was stirred, filtered, washed with cold water and dried under vacuum to give 8.4 g of the title compound as amorphous solid.

We Claim:
1). A process for the preparation of rosuvastatin of formula I,
(Formula Removed)
or its lactone or pharmaceutically acceptable salts thereof, comprising the steps of: a), reacting an intermediate of formula II,
(Formula Removed)
wherein R1, R2, and R3 are same or different and can be independently selected
from alkyl or aryl, alkoxy and the like; or any one of R1, R2 and R3 can be an oxo
group; R4 can be selected from hydrogen, alkyl, aryl, aralkyl and the like;
P1 is hydroxyl protecting group
or reactive derivative or salts thereof with methyl benzylamine in presence of
suitable base to form amide intermediate of formula III,
(Formula Removed)
wherein R1, R2, R3 and P1 are as defined above b). condensing amide intermediate of formula III with pyrimidine aldehyde intermediate of formula IV,
(Formula Removed)
in suitable solvent to give intermediate of formula V,
(Formula Removed)
wherein P1 is as defined above c). deprotecting hydroxyl group of intermediate of formula V using a suitable reagent to form keto hydroxy intermediate of formula VI,
(Formula Removed)
d). reducing keto hydroxy intermediate of formula VI using a suitable reducing reagent in the presence of a suitable chelating agent to form dihydroxy intermediate of formula VII,
(Formula Removed)
e). converting dihydroxy intermediate of formula VII in to rosuvastatin or its lactone or pharmaceutically acceptable salts thereof.
2). The process according to claim 1, wherein in step a) suitable base is organic base or inorganic base.
3). The process according to claim 2, wherein organic base is selected from primary, secondary or tertiary amine such as N-methylmorpholine, triethylamine and the like; inorganic base is selected from alkali or alkaline metal hydroxide, alkoxide, hydride, carbonate, bicarbonate thereof and the like such as lithium hydroxide, lithium hydroxide monohydrate, barium hydroxide, sodium methoxide, sodium hydroxide, potassium hydroxide and the like.
4). The process according to claim 1, wherein in step b) suitable solvent is selected from aliphatic or aromatic hydrocarbon, nitriles; aprotic solvent, ether and the like or mixture thereof.
5). The process according to claim 1, wherein step b) is optionally carried out using a suitable base.
6). The process according to claim 5, wherein in step b) suitable base is inorganic base or organic base.
7). The process according to claim 6, wherein inorganic base is selected from alkali or alkaline metal, alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride, alkoxide thereof; organic base is selected from trialkylamine, 1,5-diazabicyclo[4.3.0]non-5-ene; l,8-diaza-bicyclo[5.4.0]undec-7-ene and the like.
8). The process according to claim 1, wherein in step c) suitable reagent is selected from acid such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, sulfonic acid such as methanesulfonic acid; fluoride salts such as tetrabutylammonium fluoride, hydrogen fluoride and the like.
9). The process according to claim 1, wherein in step d) suitable reducing agent is selected from hydrogenation catalyst such as ruthenium catalyst; hydrides; alkali or alkaline metal hydride; alkali metal cyanoborohydride; diborane; diisopinocampheyl chloroborane; CBS-oxazaborolidines and the like.
10). The process according to claim 1, wherein in step d) chelating agent is selected from trialkyl borane or boronates including dialkyl alkoxy borane such as diethyl-methoxy-borane, diethyl ethoxy borane, dimethyl methoxy borane and the like.