WO2014045294A1 - A novel process for the preparation of rosuvastatin calcium using novel intermediates - Google Patents
A novel process for the preparation of rosuvastatin calcium using novel intermediates Download PDFInfo
- Publication number
- WO2014045294A1 WO2014045294A1 PCT/IN2013/000164 IN2013000164W WO2014045294A1 WO 2014045294 A1 WO2014045294 A1 WO 2014045294A1 IN 2013000164 W IN2013000164 W IN 2013000164W WO 2014045294 A1 WO2014045294 A1 WO 2014045294A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- substituted
- isopropyl
- solvents
- Prior art date
Links
- PSWGUZCMWYGVNV-UQECUQMJSA-N CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2I)c1/C=C/[C@H]1OC(C)(C)O[C@@H](CC(OC(C)(C)C)=O)C1 Chemical compound CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2I)c1/C=C/[C@H]1OC(C)(C)O[C@@H](CC(OC(C)(C)C)=O)C1 PSWGUZCMWYGVNV-UQECUQMJSA-N 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Definitions
- the present invention relates to novel process for the preparation of [(E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidi
- Rosuvastatin which is an antihypercholesterolemic drug, is chemically known as (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5- dihydroxyhept-6-enoic acid calcium (2: 1 ) salt of formula L
- Rosuvastatin was for the first time disclosed in US5260440. Rosuvastatin is being marketed under the proprietary name CRESTOR, as an oral tablet, for the treatment of hypercholesterolemia. In view of the importance of Rosuvastatin as a lipid-lowering agent, several synthetic methods have been reported in the literature to prepare rosuvastatin, some of which as summarized below:
- the US'437B 1 patent also discloses a process for the preparation of Rosuvastatin or a saltthereo-Lwhich-is-iLlustrated-b-y-SGheme-below-f-
- the present invention relates to novel intermediate compounds and process for the selective synthesis of Rosuvastatin calcium of the formula (I) using these novel intermediate compounds.
- the present invention relates to a process for the preparation of
- R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions, with a suitable reagent to give the compound of formula I.
- R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions, comprising:
- R and R' are hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, nitro, amino substitutions.
- R is hydrogen, alkyl, alkyl substituted, sul foxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions.
- In another aspect of the present invention is to provide a novel acetonide anilide compound of formula lllb an amorphous form.
- the present invention provides novel compound or a salt thereof selected from the compounds of formula (II), (III), (Ilia)
- Figure 1 &2 are the schematic representation of a process preparation of compound of formula V
- Figure 3 is a schematic representation of a process of present invention.
- Figure 1 is an XRPD pattern of the crystalline acetonide anilide compound of formula lllb.
- Figure 2 is a DSC thermogram of the crystalline acetonide anilide compound of formula lllb.
- Figure 3 is an FTIR spectrum of the crystalline acetonide anilide compound of formula lllb.
- Figure 4 is an XRPD pattern of the crystalline Diol anilide compound of formula Ila.
- Figure 5 is a DSC thermogram of the crystalline Diol anilide compound of formula Ila.
- Figure 6 is a FTI R spectrum of the crystalline Diol anilide compound of formula Ila.
- the present invention provides new compounds and intermediates as well as process that can oe used directly for the selective synthesis of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- isopi pyl-2-[methyl(methylsLilfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6- enoicacid] calcium salt of the formula (I)
- R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions, with a suitable reagent to give the compound of formula I.
- the bases that can be used include inorganic or organic bases.
- Organic bases such as triethylamine, tripropyl amine, pyridine, diisopropylamine, diisopropylethylamine, DBU and the like.
- Inorganic bases such as ammonia, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride.
- Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal bi carbonates such as sodium bi carbonate, potassium bi carbonate and the like or mixtures thereof.
- the solvents that can be used include water, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert butanol and the like.
- Water miscible polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitri le, dimethylsul foxide, propylele carbonate and the like.
- Water immiscible solvents such as toluene, MTBE (Methyl t-butyl ether), DIPE and the like. Preferable toluene, MTBE, acetonitrile, methanol.
- the salts that can be used calcium source which is not limited to calcium chloride di hydrate and calcium acetate.
- reaction can be performed in the absence of solvent(s) i.e., neat.
- the reaction can be performed at temperature typically from about 0°C to about 70°C or boiling point of the solvent(s) used. Preferably from about 20°C to about 45°C.
- 48hours preferably from about 12 hours to about 14 hours.
- the present invention provides a process for the preparation of diol ani lide compound or a pharmaceutically acceptable salt thereof of formula II.
- R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions,
- R and ' are hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl,- aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, nitro, amino substitutions.
- R is hydrogen, alkyl, alkyl substituted, sul foxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions.
- Organic bases such as triethylamine, tripropyl amine, pyridine, diisopropylamine, diisopropylethylamine, DBU, dimethylaminopyridine and the like.
- Inorganic bases such as ammonia, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride.
- Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal bi carbonates such as sodium bi carbonate, potassium bi carbonate and the like or mixtures thereof.
- solvents that can be used in step a) include but are not limited to Non polar solvents such as hexane, cyclohexane, pentane, cyclopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like.
- the polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide and the like.
- the polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like.
- hexane, cyclohexane, toluene, dichloromethane, methanol is being used.
- reaction can be performed in the absence of solvent(s) i.e., neat.
- the reaction can be performed at temperature typically from about 20°C to about 100°C or boiling point of the solvent(s) used. Preferably from about 50°C to about 55°C.
- the reaction time required for the completion may range from about 5 hours to about 48 hours, preferably from about 12 hours to about 15 hours.
- the formates of compound of formula VIII that can be used in step b) include but are not limited to chloro formates such as ls.o,b_utyLchloro.£orm —
- the bases that can be used in step b) include but are not limited to organic bases such as triethylamine, tripropyl amine, pyridine, diisopropylamine, diisopropylethylamine, DBU, N- methylmorpholine and anilines compound of formula IX such as ani line, 4-fluoroaniline, 4- bromoaniline, 4-nitroanil ine and the like. Preferable N-methylmorpholine, 4-fluoro, bromo, and nitroanilines are being used.
- the solvents that can be used in step b) include but are not limited to Non polar solvents such as hexane, cyclohexane, pentane, cyclopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like.
- the polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethyl formamide, acetonitrile, dimethylsulfoxide and the like.
- the polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like.
- Ethers such as tetrahydrofuran, diisopropylether, diethylether, methylisobutylether and the like.
- dichloromethane, tetrahydrofuran, hexane, cyclohexane is being used.
- reaction can be performed in the absence of solvent(s) i.e., neat.
- the reaction can be performed at temperature typically from about -70°C to about 80°C boiling point of the solvent(s) used. Preferably from about -5°C to about 30 °C
- the reaction time required for the completion may range from about 5 hours to about 48 hours, preferably from about 2 hours.
- the acids that can be used in step c) include but are not limited to organic acids or inorganic acids.
- Organic acids such as phosphonic acid, para toluene sulfonic acid, pyridinium para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid and the like.
- Inorganic acids such as hydrochloric acid, hydrobroraic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
- hydrochloric acid, pyridinium para toluene sulfonic acid is being used.
- the solvents that can be used in step c) include but are not limited to Non polar solvents such as hexane, cyclohexane, pentane, cyciopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like.
- the polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide and the like.
- the polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like.
- Ethers such as tetrahydrofuran, diisopropylether, diethylether, methylisobutylether and the like.
- reaction can be performed in the absence of solvent(s) i.e., neat.
- the reaction can be performed at temperature typically from about 0°C to about 70°C or boiling point of the solvent(s) used. Preferably from about 40°C to about 45°C.
- the reaction time required for the completion may range from about 1 hours to about 20 hours, preferably from about 2 hours to about 4 hours.
- In another embodiment of the present invention is to provide a novel diol anilide compound of formula Ila an amorphous form.
- In another embodiment of the present invention is to provide a novel acetonide anilide compound of formula Hlb an amorphous form.
- In further embodiment of the present invention is to provide a novel diol anilide compound of formula Ha in crystalline form characterized by XRPD (Bruker) pattern showing characteristic peaks at 3.2, 4.3, 9.1 , 13.2, 13.7, 14.6, 16.9, 17.4, 18.4, 19.0, 19.7, 20.1 , 20.8, 22.5, 23.7, 24.7, 25.8, 26.7, and 29.8.
- a novel diol anilide compound of formula II in crystalline form characterized by DSC (TA instrument) thermogram showing characteristic peaks at 132.91°C.
- a novel diol anilide compound of formula II in crystalline form characterized by FT-IR (KBr, Perkin Elmer) spectrum shown the absorption bands at 3521 , 3362, 2972, 1669, 1603, 1 139, 503 cm " 1 .
- In further embodiment of the present invention is to provide a novel of acetonide anilide compound of formula III in crystalline form characterized by XRPD (Bruker) showing the peaks at 5.7, 9.3, 10.0, 1 .4, 12.4, 13.4, 14.1 , 14.4, 14.8, 16.6, 17.6, 19.3, 19.6, 20.2, 20.6, 21.0, 21.3, 22.0, 22.7, 23.7, 24.2, 24.6, 24.9, 25.5, 26.6, 27. 1 , 27.9, 28.6, 29.8, 3 1.3, 32.5, 33.5, 34.6 and 36.8.
- In further embodiment of the present invention is to provide a novel of acetonide anilide compound of formula III in crystalline form characterized by DSC (TA instrument) thermogram showing characteristic peaks at 126.19°C.
- acetonide anilide compound of formula III in crystalline form characterized by FT-IR (KBr, Perkin Elmer) spectrum shown the absorption bands at 3382, 2966. 1677, 1596, 1 15 1. 504_cml_
- the present invention provides novel compound or a salt thereof selected from the compounds of formula (Hi), (II), (Ilia)
- reaction mixtures especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
- the reaction mixture was heated to a temperature in the range of from about 50°C to about 55°C for about 12 - 15 hours. After completion of the reaction as determined by HPLC, disti lled off solvent completely under reduced pressure water bath at a temperature of about 50°C. After distillation, DCM (300 ml) and purified _ water-(-300-ml-)-were-ad d ed-to-the-res id ue-and-the-react ;i o n-m-ix-ture-was-cooled-to-the-range-of— from about 15°C to about 20°C.
- a solution of 40% acetic acid solution were added at a temperature of about 15°C to about 20°C to achieve the pH in the range of from about 7.0 to about 7.5.
- the mixture was stirred for about 1 0 to about . 1 5 minutes.
- the mixture was allowed to settle for about 10 minutes at a temperature of about 20°C, resulting in two layers.
- the bottom organic layer was separated and washed with 5% sodium chloride solution at a temperature of about 20°C, organic layer dried over sodium sulphate.
- reaction mixture was -cooled— to-a— temperature-in— the-range- of— from— about— -S-G-to-about—O-G— under— nitrogen— atmosphere.
- N-methyl morpholine was added at a temperature in the range of from about -
- Purified water 180 ml was added and stirred for 10 to 15 minutes and allowed to settle ' the layers for 10 to 15 minutes,, separated the organic layer and twice washed with purified water ( 100 ml). Distilled the solvent completely under reduced pressure water bath at a temperature of from about 40°C to about 50°C to get residue and co-distilled with toluene ( 120 ml) in water bath at a temperature of from about 40°C to about 50°C. Toluene (480 ml) was added and stirred to get complete dissolution at a temperature of from about 55°C to about 60°C. Slowly cooled to temperature o from about 25°C to about 30°C, separated solid was maintained for 3 hours.
- Diol anilide (Compound Ila) is isolated by distillation of Acetonitrile at below 45 °C under vacuum, which is obtained by reaction of N-(4-bromophenyl)-2- ((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl- l ,3-dioxan-4-yl)acetamide (1 Mole Eq , Compound Ilia) with dilute hydrochloric acid (1.5 Mole Eq, l Molar dilution in water ) at 25-45 °C for 2-6 hrs till to absences of Acetonide anilides (Compound Ilia) by
- FT-IR (KBr) spectrum shown the absorption bands at 3521 , 3362, 2972, 1669, 1603, 1 139, 503 cm “ 1 .
Abstract
The present invention relates to novel process for the preparation of [(E)-7-[4-(4-fluorophenyl)-6-isopropy 1-2-isopropyl-2-[methyl (methyllsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt using novel intermediates. Novel intermediate compounds and processes for the selective synthesis of Rosuvastatin calcium of the formula (I) using these novel intermediate compounds are disclosed. In one aspect, the present invention relates to a process for the preparation of Rosuvastatin or a pharmaceutically acceptable salt thereof of Formula I.
Description
A NOVEL PROCESS FOR THE PREPARATION OF ROSUVASTATIN CALCIUM
USING NOVEL INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to novel process for the preparation of [(E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidi
(3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt using novel intermediates.
BACKGROUND OF THE INVENTION
Rosuvastatin, which is an antihypercholesterolemic drug, is chemically known as (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5- dihydroxyhept-6-enoic acid calcium (2: 1 ) salt of formula L
Rosuvastatin was for the first time disclosed in US5260440. Rosuvastatin is being marketed under the proprietary name CRESTOR, as an oral tablet, for the treatment of hypercholesterolemia. In view of the importance of Rosuvastatin as a lipid-lowering agent, several synthetic methods have been reported in the literature to prepare rosuvastatin, some of which as summarized below:
U.S. Patent No. US 5,260,440 describes Rosuvastatin or pharmaceutically acceptable acid addition salts thereof.
US'440 also discloses a process for the preparation of Rosuvastatin which is illustrated by scheme below:
Rosuvastatin calcium
U.S. Patent No. US 6,844,437B 1 describes Rosuvastatin or pharmaceutically acceptable cation salts thereof.
The US'437B 1 patent also discloses a process for the preparation of Rosuvastatin or a saltthereo-Lwhich-is-iLlustrated-b-y-SGheme-below-f-
Rosuvastatin calcium salt
P.C.T Patent No. WO2008/044243A2 describes a synthesis of Rosuvastatin calcium which i llustrated by scheme below:
Amorphous Rosuvastatin ca
The final steps of aforementioned processes have several disadvantages like:
The processes reported in the prior art are expensive, difficulty to handle on commercial scale, requires additional purification steps intermediately thus ending up with Lower yields.
Thus there is a need in the art to provide a process which can overcome the aforesaid disadvantages and hence the present invention is simple, eco-friendly, inexpensive, reproducible, robust and is well suited on an industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to novel intermediate compounds and process for the selective synthesis of Rosuvastatin calcium of the formula (I) using these novel intermediate compounds.
In one aspect, the present invention relates to a process for the preparation of
I
comprising:
reacting the diol anilide compound of formula II
- II
wherein R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions, with a suitable reagent to give the compound of formula I.
anilide compound or a pharmaceutically acceptable salt thereof of formula II.
II
wherein R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions, comprising:
reacting the compound of formula (V) with a suitable reagent to obtain acetonide acid compound of formula (IV)
V
reacting the acetonide acid compound of formula (IV) with the compound of formula VIII to obtain an insitu of isobutyl carbonic compound of formula Ilia which is reacted with Formula IX to give acetonide anilide compound or a pharmaceutically acceptable salt thereof of formula Ι Π.
Ilia
wherein R and R' are hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, nitro, amino substitutions.
reacting the acetonide anilide compound of formula III with suitable reagent to obtain a diol anilide compound or a pharmaceutically acceptable salt thereof of formula II.
Wherein R is hydrogen, alkyl, alkyl substituted, sul foxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions.
In another aspect of the present invention is to provide a novel diol anilide compound of formula Ila an amorphous form.
In another aspect of the present invention is to provide a novel acetonide anilide compound of formula lllb an amorphous form.
In further aspect of the present invention is to provide a novel diol anilide compound of formula Ila in crystalline form.
In further aspect of the present invention is to provide a novel of acetonide anilide compound of formula lllb in crystalline form.
In yet another aspect, the present invention provides novel compound or a salt thereof selected from the compounds of formula (II), (III), (Ilia)
BRIEF SCHEMATIC DESCRIPTION OF THE FIGURES
Figure 1 &2: are the schematic representation of a process preparation of compound of formula V Figure 3 is a schematic representation of a process of present invention.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an XRPD pattern of the crystalline acetonide anilide compound of formula lllb.
Figure 2 is a DSC thermogram of the crystalline acetonide anilide compound of formula lllb.
Figure 3 is an FTIR spectrum of the crystalline acetonide anilide compound of formula lllb.
Figure 4 is an XRPD pattern of the crystalline Diol anilide compound of formula Ila.
Figure 5 is a DSC thermogram of the crystalline Diol anilide compound of formula Ila. Figure 6 is a FTI R spectrum of the crystalline Diol anilide compound of formula Ila.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new compounds and intermediates as well as process that can oe used directly for the selective synthesis of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- isopi pyl-2-[methyl(methylsLilfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6- enoicacid] calcium salt of the formula (I)
I
in one embodiment, there is provide a process for the preparation of Rosuvastatin or a pharmaceutically acceptable salt thereof of formula I
I
comprising:
reacting the diol ani lide compound of formula II
II
wherein R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions, with a suitable reagent to give the compound of formula I.
The bases that can be used include inorganic or organic bases. Organic bases such as triethylamine, tripropyl amine, pyridine, diisopropylamine, diisopropylethylamine, DBU and the like. Inorganic bases such as ammonia, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride. Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal bi
carbonates such as sodium bi carbonate, potassium bi carbonate and the like or mixtures thereof. Preferable sodium hydroxide
The solvents that can be used include water, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert butanol and the like. Water miscible polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitri le, dimethylsul foxide, propylele carbonate and the like. Water immiscible solvents such as toluene, MTBE (Methyl t-butyl ether), DIPE and the like. Preferable toluene, MTBE, acetonitrile, methanol.
The salts that can be used calcium source which is not limited to calcium chloride di hydrate and calcium acetate.
Optional ly the reaction can be performed in the absence of solvent(s) i.e., neat.
The reaction can be performed at temperature typically from about 0°C to about 70°C or boiling point of the solvent(s) used. Preferably from about 20°C to about 45°C.
The reaction_tinie_r.e.q.uii:e.d_for-the-co.mpleti.o
48hours, preferably from about 12 hours to about 14 hours.
in another embodiment, the present invention provides a process for the preparation of diol ani lide compound or a pharmaceutically acceptable salt thereof of formula II.
wherein R is hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions,
comprising:
a) reacting the compound of formula (V) with a suitable reagent to obtain acetonide acid compound of formula (IV)
. V
b) reacting the acetonide acid compound of formula (IV) with the compound of formula VIII to obtain an insitu of isobutyl carbonic compound of formula Ilia which is reacted with Formula IX to give acetonide anilide compound or a pharmaceutically acceptable salt thereof of formula III.
Ilia
wherein R and ' are hydrogen, halogen, alkyl, alkyl substituted, sulfoxy, aryl,- aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, nitro, amino substitutions.
reacting the acetonide anilide compound of formula III with suitable reagent to give diol anilide compound or a pharmaceutically acceptable salt thereof of formula II.
wherein R is hydrogen, alkyl, alkyl substituted, sul foxy, aryl, aryl substitutions like hydrogen, halogen, alkyl, alkyl substituted, alkoxy, sulfoxy, amino substitutions.
The bases that can be used in step a) included but are not limited to inorganic or organic bases. Organic bases such as triethylamine, tripropyl amine, pyridine, diisopropylamine, diisopropylethylamine, DBU, dimethylaminopyridine and the like. Inorganic bases such as ammonia, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride. Alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal bi carbonates such as sodium bi carbonate, potassium bi carbonate and the like or mixtures thereof. Preferable triethylamine, diisopropylamine, dimethylaminopyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate is being used.
The solvents that can be used in step a) include but are not limited to Non polar solvents such as hexane, cyclohexane, pentane, cyclopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like. The polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide and the like. The polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like. Preferably hexane, cyclohexane, toluene, dichloromethane, methanol is being used.
Optionally the reaction can be performed in the absence of solvent(s) i.e., neat.
The reaction can be performed at temperature typically from about 20°C to about 100°C or boiling point of the solvent(s) used. Preferably from about 50°C to about 55°C.
The reaction time required for the completion may range from about 5 hours to about 48 hours, preferably from about 12 hours to about 15 hours.
The formates of compound of formula VIII that can be used in step b) include but are not limited to chloro formates such as ls.o,b_utyLchloro.£orm — The bases that can be used in step b) include but are not limited to organic bases such as triethylamine, tripropyl amine, pyridine, diisopropylamine, diisopropylethylamine, DBU, N- methylmorpholine and anilines compound of formula IX such as ani line, 4-fluoroaniline, 4- bromoaniline, 4-nitroanil ine and the like. Preferable N-methylmorpholine, 4-fluoro, bromo, and nitroanilines are being used.
The solvents that can be used in step b) include but are not limited to Non polar solvents such as hexane, cyclohexane, pentane, cyclopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like. The polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethyl formamide, acetonitrile, dimethylsulfoxide and the like. The polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like. Ethers such as tetrahydrofuran, diisopropylether, diethylether, methylisobutylether and the like. Preferably dichloromethane, tetrahydrofuran, hexane, cyclohexane is being used.
Optionally the reaction can be performed in the absence of solvent(s) i.e., neat.
The reaction can be performed at temperature typically from about -70°C to about 80°C boiling point of the solvent(s) used. Preferably from about -5°C to about 30 °C
The reaction time required for the completion may range from about 5 hours to about 48 hours, preferably from about 2 hours.
The acids that can be used in step c) include but are not limited to organic acids or inorganic acids. Organic acids such as phosphonic acid, para toluene sulfonic acid, pyridinium para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid and the like. Inorganic acids such as hydrochloric acid, hydrobroraic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Preferably hydrochloric acid, pyridinium para toluene sulfonic acid is being used.
The solvents that can be used in step c) include but are not limited to Non polar solvents such as hexane, cyclohexane, pentane, cyciopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like. The polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide and the like. The polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like. Ethers such as tetrahydrofuran, diisopropylether, diethylether, methylisobutylether and the like. Preferably acetQni.trile..-rae.thanoLis-bein.g-used.—
Optionally the reaction can be performed in the absence of solvent(s) i.e., neat.
The reaction can be performed at temperature typically from about 0°C to about 70°C or boiling point of the solvent(s) used. Preferably from about 40°C to about 45°C.
The reaction time required for the completion may range from about 1 hours to about 20 hours, preferably from about 2 hours to about 4 hours.
In another embodiment of the present invention is to provide a novel diol anilide compound of formula Ila an amorphous form.
In another embodiment of the present invention is to provide a novel acetonide anilide compound of formula Hlb an amorphous form.
In further embodiment of the present invention is to provide a novel diol anilide compound of formula Ha in crystalline form characterized by XRPD (Bruker) pattern showing characteristic peaks at 3.2, 4.3, 9.1 , 13.2, 13.7, 14.6, 16.9, 17.4, 18.4, 19.0, 19.7, 20.1 , 20.8, 22.5, 23.7, 24.7, 25.8, 26.7, and 29.8.
In further embodiment of the present invention is to provide a novel diol anilide compound of formula II in crystalline form characterized by DSC (TA instrument) thermogram showing characteristic peaks at 132.91°C.
In further embodiment of the present invention is to provide a novel diol anilide compound of formula II in crystalline form characterized by FT-IR (KBr, Perkin Elmer) spectrum shown the absorption bands at 3521 , 3362, 2972, 1669, 1603, 1 139, 503 cm" 1.
In further embodiment of the present invention is to provide a novel of acetonide anilide compound of formula III in crystalline form characterized by XRPD (Bruker) showing the peaks at 5.7, 9.3, 10.0, 1 .4, 12.4, 13.4, 14.1 , 14.4, 14.8, 16.6, 17.6, 19.3, 19.6, 20.2, 20.6, 21.0, 21.3, 22.0, 22.7, 23.7, 24.2, 24.6, 24.9, 25.5, 26.6, 27. 1 , 27.9, 28.6, 29.8, 3 1.3, 32.5, 33.5, 34.6 and 36.8.
In further embodiment of the present invention is to provide a novel of acetonide anilide compound of formula III in crystalline form characterized by DSC (TA instrument) thermogram showing characteristic peaks at 126.19°C.
In further embodiment of the present invention is to provide a novel of acetonide anilide compound of formula III in crystalline form characterized by FT-IR (KBr, Perkin Elmer) spectrum shown the absorption bands at 3382, 2966. 1677, 1596, 1 15 1. 504_cml_
In yet another embodiment, the present invention provides novel compound or a salt thereof selected from the compounds of formula (Hi), (II), (Ilia)
III
For example, the vvorking-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
Advantageously,
1) The process of present invention provides chemically and stereochemically pure Rosuvasatain calcium.
2) The present invention yield contribution in the final step is very imported in industry likewise this invention is better than prior arts both in yield and cost in final step.
3) The process of present invention provides Economical and industrially viable production of Producing Rosuvastain calcium.
4) Intermediates and it's pharmaceutically acceptable salts resulted from this process may leads the discovery of new drugs.
xamples:
Example: 1
Preparation of 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)aceticacid (Compound IV).
In to a 2 L 4-necked round bottom flask, Tert-Butyl6-[(lE)-2-[4-(4-fluorophenyl)-6-(l- methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-l,3- dioxane-4-acetate compound of formula V (100 g), methanol ( 1000 ml) and sodium hydroxide solution (24.26 g) in water (50 ml) were added at a temperature in the range of 25°C to about 30°C under stirring. The reaction mixture was heated to a temperature in the range of from about 50°C to about 55°C for about 12 - 15 hours. After completion of the reaction as determined by HPLC, disti lled off solvent completely under reduced pressure water bath at a temperature of about 50°C. After distillation, DCM (300 ml) and purified _ water-(-300-ml-)-were-ad d ed-to-the-res id ue-and-the-react ;i o n-m-ix-ture-was-cooled-to-the-range-of— from about 15°C to about 20°C. A solution of 40% acetic acid solution were added at a temperature of about 15°C to about 20°C to achieve the pH in the range of from about 7.0 to about 7.5. The mixture was stirred for about 1 0 to about .1 5 minutes. The mixture was allowed to settle for about 10 minutes at a temperature of about 20°C, resulting in two layers. The bottom organic layer was separated and washed with 5% sodium chloride solution at a temperature of about 20°C, organic layer dried over sodium sulphate. Filtered the sodium sulphate and washed with dichloromethane ( 100 ml), collected the solution in to a RB flask and cyclohexane (1200 ml) were added under stirring at a temperature in the range of from about 25°C to about 30°C, precipitated mass maintained for about 30 minutes. The mass was heated to temperature in the range of from about 35°C to about 40°C, maintained for about 30 minutes, then cooled to a temperature of from about 25°C to about 30°C and maintained for about 12 hours, filtered the solid material and washed with cyclohexane (200 ml). The isolated solid was obtained 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2-dimethyl- l ,3-dioxan-4-yl) acetic acid compound of formula I V. It was dried at temperature range of from about 40°C to about 45°C under vacuum. The dried product appeared as an off- white crystalline solid weighing about 72.0 g. The yield was about 79.74 %, and HPLC purity about 98.34 %.
The IR (KBr) spectrum shown the absorption bands at 3482,2967, 1698, 1605, 1 155 cm'1 Mass Value: [M+l ] 522.2 (Molecular weight: 521.6).
H NMR (400 MHz, CD30D) 5 (ppm): 7.7-7.6(2H,dd), 7.18-7.14(2H,dd), 6.63-6.58( lH,d), 5.5-5.4( l H,dd), 4.55-4.50( l H,m), 4.38-4.32(lH,m), 3.4(3H,s), 3.5(3H,s), 3.2(lH,m), ' 1 .28(6H,s), 1.26(6H,s).
Example: 2
Preparation of. N-(4-bromophenyl)-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl- 2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetamide (Compound Illb)
In to a 1 L 4-necked round bottom flask, 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsLi l fonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- t ,3-dioxan-4- yl)acetic acid compound of formula IV (60 g), Dichloro methane (480 ml) were added at a temperature in the range of 25°C to about 30°C under stirring. The reaction mixture was -cooled— to-a— temperature-in— the-range- of— from— about— -S-G-to-about—O-G— under— nitrogen— atmosphere. N-methyl morpholine was added at a temperature in the range of from about -
5°C to about 0°C for about 30minutes, maintained for 30 minutes. Isobutyl chloroformate was added at a temperature in the range of from about -5°C to about 0°C for about 20 minutes, maintained for 2 hours. In another round bottom flask, 4-bromo aniline and dichloromethane ( 120 ml) were added at a temperature in the range of from about 25°C to about 30°C. The above reaction mass was added to this solution at a temperature in the range of from about 25°C to about 30°C, maintained for 2 hours. After completion of the reaction as determined by TLC, Purified water (180 ml) was added and stirred for 10 to 15 minutes and allowed to settle'the layers for 10 to 15 minutes,, separated the organic layer and twice washed with purified water ( 100 ml). Distilled the solvent completely under reduced pressure water bath at a temperature of from about 40°C to about 50°C to get residue and co-distilled with toluene ( 120 ml) in water bath at a temperature of from about 40°C to about 50°C. Toluene (480 ml) was added and stirred to get complete dissolution at a temperature of from about 55°C to about 60°C. Slowly cooled to temperature o from about 25°C to about 30°C, separated solid was maintained for 3 hours. Filtered the solid and washed with toluene (120 ml) The isolated solid was N-(4-bromophenyl)-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- l ,3-dioxan-4-
yl)acetamide compound of formula Illb. It was dried at temperature range of from about 50°C to about 55°C under vacuum. The dried product appeared as an off- white crystalline solid weighing about 57.0 g. The yield was about 73 %, Melting point from about 124°C to about 126°C and HPLC purity about 97.6 %.
Mass Value: [M+l] 677 (Molecular weight: 675.6).
DSC 126.19°C
II NMR (400 MHz, CDC13) δ (ppm): 8.3 (lH,s), 7.6 (2H,m), 7.4(4H,m), 7(2H,t), 6.57(lH,d), 5.4(lH,dd), 4.4(lH,bd), 4.3(lH,m), 3.57(3H,d), 3.51( 3H,s), 3.3(lH,m), 2.5 (2H,d) , 1.5(6H,d), 1.3(lH,s), l,2(6H,m)
XRPD with specific peaks 2-theta = 5.7, 9.3, 10.0, 11.4, 12.4, 13.4, 14.1, 14.4, 14.8, 16.6,
17.6, 19.3, 19.6, 20.2, 20.6, 21.0, 21.3, 22.0, 22.7, 23.7, 24.2, 24.6, 24.9, 25.5, 26.6, 27.1, 27.9, 28.6, 29.8, 31.3, 32.5, 33.5, 34.6 and 36.8.
FT-IR (KBr) spectrum shows absorption bands at 3382, 2966), 1677, 1596, 1151, 504 cmll
Few of the related compounds are prepared and by H-NMR and Mass Spectroscopic data
R: CIO (Methyl):
Mass Value:. [M+l] 535.3 (Molecular weight: 534.2)
II NMR (400 MHz, CDCI3) δ (ppm): 7.7-7.6,(2H,dd), 7.18-7.14(2H,dd), 6.5-6.4(lH,d), 6 (lH,bd), 5.5-5.4(1 H,'dd), 4.55-4.50 (lH,m), 4.38-4.32(1 H,m), 3.57(3H,s), 3.51(3,s), 3.3(lH,m), 2.8(3H,d), 2.4(2H,m), 1.6(lH,s), 1.5(3H,bs), 1.2(3H,bs), 1.26(6H,s), 1.19(lH,m).
R: C6H5 (Phenyl):
Mass Value: [M+l] 597.3 (Molecular weight: 596.7)
II NMR (400 MHz, CD30D) δ (ppm): 8.2 (lH,s), 7.7-7.6,(2H,dd), 7.5 (2H,d) 7.3(2H,t), 7.1(lH,t) 7.0(2H,t), 6.5(ll-l,dd), 5.5(lH,dd), 4.4(lH,m), 4.3(lH,m), 3.5(3H,s), 3.39(3H,s), 3.35(lH,m), 2.5(2H,d), 1.6(lH,m), 1.5(6H,s), 1.3(lH,s), 1.2(6H,m).
R: C6II4-F (4-fluoro Phenyl);
Mass Value: [M+l] 615.2 (Molecular weight: 614.2)
II NMR (400 MHz, CDC13) δ (ppm): 8.2 (lH,s), 7.7-7.6(2H,dd), 7.5 (2H,d), 7.3(lH,m), 7.l(4H,m) 6.80(1 H,t), 6.7(1 H,m), 6.5(lH,dd), 5.4 (lH,dd), 4.4(lH,m), 4.3(lH,m), 4.3 (3H,t) 3.9 (4H,m), 3.5 (3H,s), 3.4 (3H,s) , 3.3 (4H,m), 2.9 (3H,bt), 2.8 (5H,s),.2.5 (2H,d), 2(lH,s),
1.5(3H,s), 1.50(3H,s) 1.27(lH,s), 1.26(6H,s), 0.9(3H,s), 0.85(lH,m).
Example: 3
Preparation of (3R,5S,E)-N-(4-bromophenyl)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl methylsulfonylamido)pyrimidin-5-yI)-3,5-dihydroxyhept-6-enamide (Compound Ila)
General procedure: Diol anilide (Compound Ila) is isolated by distillation of Acetonitrile at below 45 °C under vacuum, which is obtained by reaction of N-(4-bromophenyl)-2- ((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl- l ,3-dioxan-4-yl)acetamide (1 Mole Eq , Compound Ilia) with dilute hydrochloric acid (1.5 Mole Eq, l Molar dilution in water ) at 25-45 °C for 2-6 hrs till to absences of Acetonide anilides (Compound Ilia) by
TLC monitoring.
Mass Value: [M+ l ] 636 (Molecular weight: 635-5).
DSC value 1 32.9 l °C.
— X-Rl¾-w*t-h~spec4fic--pea^
19.7, 20.1 , 20.8, 22.5, 23.7, 24.7, 25.8, 26.7, and 29.8
II NMR (400 MHz, CDC13) δ (ppm): 8. 1 ( 1 H,S), 7.6(2H,mm), 7.4(3H,m), 7.3( l H,s), 7. 1 (2H,m), 6.6( l H,d), 5.5( lH,d), 4.5( lH,m), 4.3(1 H,m), 3.6(3 H,S),3.5 (3H,S), 3.3(l H,m), 2.6(2H,d), 1 .8(2H,m), 1.6 (2H,s), 1.3(6H,s).
FT-IR (KBr) spectrum shown the absorption bands at 3521 , 3362, 2972, 1669, 1603, 1 139, 503 cm" 1.
Example: 4
Preparation of Rosuvastatin Calcium (Compound I):
20 gm (3R,5S,E)-N-(4-bromophenyl)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( -methyl methyl sulfonylamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide (Compound Ila) was dissolved in 7-8 volume of Methanol in to a RJBF, slowly added 60 ml sodium hydroxide (1M solution in water) 25-30°C. Maintained reaction temperature at 40-45°C till to get the absence of Diol anilides (Compound Ila) by TLC Monitoring, Distilled the methanol after adjusting pH to 8.5-9.0 with di l HCI, the obtained residue was dissolved in 140 ml purified water and washed with Toluene and MTBE solvent. Rosuvastatin Calcium was isolated by filtration of the slurry which was obtained by adding Calcium chloride dihydrate (~20 % solution in water) in to the above aqueous layer which was obtained from charoclisation using l gm activated
charcoal. Isolated Rosuvastatin Calcium was dried at 40-45 °C under vacuum till to get constant weight. The obtained Rosuvastain calcium has been characterized by H-NMR and mass.
Spectroscopic data as follows.
Mass Value: [M+l] 482 (Molecular weight: 480.56).
II NMR (400 MHz, DMSO-d6) δ (ppm): 7.68(2H,t), 7.26(2H,t), 6.4(lH,d),
5.4 (lH,dd), 5.0(lH,m), 4.l9(lH,m), 3.76(lH,s), 3.54(3H,s), 3.44(3H,s), 3.33(1H,S), l.96(2H,dd), l.27(2H,m), 1.19(6H,d).
Claims
Claims
1. A compound of general formula-Ill
and a pharmaceutically acceptable acid addition salts,
wherein P represents amino substituted or ester substituted
compound as claimed in Cl. l , which represented by
wherein Q represents hydrogen, alkyl, alkyl substituted, alkoxy, alkoxy substituted, sulfoxy, sulfoxy substituted, aryl, aryl substituted.
3. compound as claimed in CI.2, which represented by
Wherein R represents hydrogen, halogen, alkyl, alkyl substituted, alkoxy, alkoxy substituted, amino, amino substituted, sulfoxy, sulfoxy substituted, aryl, aryl substituted,
4. compound as laimed in cl. l , which represented by
wherein Rl represents hydrogen, Ci-Ci0 alkyl, aryl, substituted aryl.
compound as claimed in cl.4, where Ci-CI0 represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl. Pentyl, hexyl, isopentyl, isohexyl.
compound of general formula ΓΠ
7. compound of formula Illb, which represented by N-(4-bromophenyl)-2-((4R, 6S)-6-((E)- 2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl- l ,3-dioxan-4-yl)acetamide.
compound of formula Ilia, which represented by 2-((4R,6S)-6-((E)-2-(4-(4- fluoiOphenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2- dimethyl- l ,3-dioxan-4-yl)acetic (isobutyl carbonic)anhydride.
8. Novel crystalline form of N-(4-bromophenyl)-2-((4R, 6S)-6-((E)-2-(4-(4-fluorophenyl)- 6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l ,3- dioxan-4-yl)acetamide compound of formula Illb characterized by its X-ray powder diffraction pattern with peaks at 5.7, 9.3, 10.0, 1 1.4, 12.4, 13.4, 14.1, 14.4, 14.8, 16.6, 17.6, 19.3, 19.6, 20.2, 20.6, 21.0, 21.3, 22.0, 22.7, 23.7, 24.2, 24.6, 24.9, 25.5, 26.6, 27.1, 27.9, 28.6, 29.8, 31 .3, 32.5, 33.5, 34.6 and 36.8 ±2 deg. 2Θ. FT-IR (KBr) spectrum shows the absorption bands at 3382, 2966, 1677, 1596, 1 15 1 , 504 cm" 1. DSC 126.19°C.
9. compound of general formula II.
and a pharmaceutically acceptable acid addition salts. wherein P represents amino substituted or ester substituted
compound as claimed in CI.12, which represented by
Wherein Q represents hydrogen, alkyl, alkyl substituted, alkoxy, alkoxy substituted, sulfoxy, sulfoxy substituted, aryl, aryl substituted,
compound as claimed in claim 14, which represented by
Wherein R represents hydrogen, halogen, alkyl, alkyl substituted, alkoxy, alkoxy substituted, amino, amino substituted, sulfoxy, sulfoxy substituted, aryl, aryl substituted,
12. compound of general formula Ila
compound of general formula I la, which represented by (3R,5S,E)-N-(4-bromo phenyl)- 7-(4-(4-fluoropheny[)-6-isopropyl-2-(N-methylmethylsulfonylamido)pyrimidin-5-yl)-3,5- dihydroxyhept-6-enamide
Novel crystalline form of (3R,5S,E)-N-(4-bromophenyl)-7-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonylamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6- enamide compound of formula lla characterized by its X-ray powder diffraction pattern with peaks at 3.2, 4.3, 9. i 13.2, 13.7, 14.6, 16.9, 17.4, 18.4, 19.0, 1 9.7, 20.1 , 20.8, 22.5,
23.7, 24.7, 25.8, 26.7, and 29.8±2 deg. 2Θ., FT-IR ( Br) spectrum shows the absorption bands at 352 1 , 3362, 2972, 1669, 1603, 1 139 and 503 cm' 1, DSC 132.91°C.
a process for the preparation of (3R,5S,E)-N-(4-bromo phenyl)-7-(4-(4-fluorophenyl)-6- isopropyI-2-(N-methylmethylsuIfonylamido)pyrimidin-5-yI)-3,5-dihydroxyhept-6- enamide compound of formula Ha.
Comprising:
a) reacting Tert-Butyl 6-[ΟΕ1^2÷Γ. ^(^ί^ — (methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl- l ,3-dioxane-4-acetate compound of formula V in presence of base and solvent to give 2-((4R,6S)-6-((E)-2-(4- (4-nuoi phenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yI)vinyl)-2,2- dimethyl- 1 ,3-dioxan-4-yl)acetic acid compound of formula IV.
b) converting a 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- l ,3-dioxan-4-yl)acetic acid compound of formula IV with the compound of formula VII to obtain an insitu of 2-((4R,6S)-6- ((E)-2-(4-(4-fluoiOphenyl)-6-isopropyl-2-(N-methylmethylsul fonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetic(isobutylcarbonic)anhydride compound of formula Ilia which is reacted with Formula IX to give N-(4-bromophenyl)-2-((4R,6S)-6- ((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl- l ,3-dioxan-4-yl)acetamide compound or a pharmaceutically acceptable salt thereof of formula Illb.
c) reacting the above step b compound of formula Illb with an acid, solvent and suitable base to obtain (3R,5S,E)-N-(4-bromophenyl)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonylamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide compound or a pharmaceutically acceptable salt thereof of formula lla.
15. a process according to claim 18 in step a, wherein the bases are an inorganic, organic bases.
16. a process according to claim 19, wherein the inorganic bases are ammonia, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, sodium bi carbonate, potassium bi carbonate, the organic bases are triethylamine, tripropylamine, pyridine, di isopropylamine, di isopropylethylatnine, DBU, dimethylaminopyridine.
1 8. process according to claim 18 in step a, wherein the solvents are non polar, polar protic, polar aprotic solvents.
1 9. process according to claim 18 in step a, wherein the solvents are water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert butanol, dichloromethane, tetra hydrofuran, ethylacetate, acetone, dimethylformamide, aetonitrile, dimethyl sulfoxide, propylene carbonate, toluene, MTBE, DIPE.
20. a process according to claim 18 in step a, wherein the_reac.tion_is-car-r ed-out— at— a- temperature in the range of between 20°C and 100°C.
2 1 . a process according to claim 8 in step b, wherein the formats are chloro formats such as isobutyl chloroformate, benzyl chloroformate, the bases are triethylamine, triporpylamine, pyridine, diisopropylamine, diisopropylethylamine, DBU, N- methylmorpholine.
22. a process according to claim 18 in step b, wherein aniline, 4-fluoroaniline, 4- bromoaniline, 4-nitroanilines.
23. a process according to claim 18 in step b, wherein the solvents are Non polar solvents such as hexane, cyclohexane, pentane, cyclopentane, benzene, toluene, 1 ,4-dioxane, chloroform, diethylether and the like. The polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide and the like. The polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water and the like. Ethers such as tetrahydrofuran, di isopropylether, diethylether, methyl isobutylether and the like.
24. a process according to claim 18 in step b, wherein the reaction is carried out at a temperature in the range of between -70°C and 80°C.
25. a process according to claim 18 in step c, wherein the acids are organic acids or inorganic acids. Organic acids such as phosphonic acid, para toluene sulfonic acid, pyridinium para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid and the like, inorganic acids such as hydrochloric acid, hydrobromic acid, sul furic acid, nitric acid, phosphoric acid and the like.
26. a process according to claim 18 in step c, wherein the solvents are Non polar solvents such as hexane, cyclohexane, pentane, cyclopentane, benzene, toluene, 1,4-dioxane, chloroform, diethylether. The polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsul foxide. The polar protic solvents such as formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water. Ethers such as tetrahydrofuran, diisopropylether, diethylether, methyl isobutylether.
27. a process according to claim 18 in step b, wherein the reaction is carried out at a temperature in_the-r.ange_af_b.etw.een-0-C-and-7-Q-C —
28. a process for the preparation of rosuvastatin of formula I comprising reacting N-(4- bromophenyl)-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(Tsi-methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- l ,3-dioxan-4-yI)acetamide of compound of formula Ila with a salts, solvents.
29. a process according to claim 24, wherein the salts are calcium chloride, calcium dihydrate.
30. a process according to claim 25, wherein the solvents are organic and inorganic solvents.
3 1 . use of compounds of formula 111 of cl.1 in the synthesis of rosuvastatin or salts thereof.
32. use of compounds of formula II of cl.9 in the synthesis of rosuvastatin or salts thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3905/CHE/2012 | 2012-09-20 | ||
IN3905CH2012 | 2012-09-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014045294A1 true WO2014045294A1 (en) | 2014-03-27 |
Family
ID=50340674
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2013/000164 WO2014045294A1 (en) | 2012-09-20 | 2013-03-18 | A novel process for the preparation of rosuvastatin calcium using novel intermediates |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2014045294A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104529908A (en) * | 2014-12-12 | 2015-04-22 | 浙江京新药业股份有限公司 | Method for preparing rosuvastatin calcium |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100056783A1 (en) * | 2006-10-09 | 2010-03-04 | Manne Satyanarayana Reddy | Novel Process for the Preparation of Statins and their Pharmaceutically Acceptable Salts thereof |
WO2010103320A1 (en) * | 2009-03-10 | 2010-09-16 | Bradford Pharma Limited | Use of rosuvastatin lactols as medicaments |
WO2011104725A2 (en) * | 2010-02-23 | 2011-09-01 | Cadila Healthcare Limited | Hmg-coa reductase inhibitors and process for the preparation thereof |
WO2012038785A1 (en) * | 2010-09-21 | 2012-03-29 | Biocon Limited | Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt |
-
2013
- 2013-03-18 WO PCT/IN2013/000164 patent/WO2014045294A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100056783A1 (en) * | 2006-10-09 | 2010-03-04 | Manne Satyanarayana Reddy | Novel Process for the Preparation of Statins and their Pharmaceutically Acceptable Salts thereof |
WO2010103320A1 (en) * | 2009-03-10 | 2010-09-16 | Bradford Pharma Limited | Use of rosuvastatin lactols as medicaments |
WO2011104725A2 (en) * | 2010-02-23 | 2011-09-01 | Cadila Healthcare Limited | Hmg-coa reductase inhibitors and process for the preparation thereof |
WO2012038785A1 (en) * | 2010-09-21 | 2012-03-29 | Biocon Limited | Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104529908A (en) * | 2014-12-12 | 2015-04-22 | 浙江京新药业股份有限公司 | Method for preparing rosuvastatin calcium |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5273587B2 (en) | Process for producing phenylalanine derivative having quinazolinedione skeleton and production intermediate | |
EP2451786B1 (en) | Improved process for the preparation of ambrisentan and novel intermediates thereof | |
CN1989111A (en) | Method for the production of 3-phenyl(thio)uracils and dithiouracils | |
EP2072503A2 (en) | Process for the preparation of bosentan | |
WO2014152752A1 (en) | Methods for the synthesis of chiral kynurenine compounds | |
US20110263623A1 (en) | Process for preparation of bosentan | |
US11434238B2 (en) | Method for producing triazolopyridine compound | |
KR101368974B1 (en) | New Rosuvastatine intermediate, the preparation method thereof and the preparation method of Rosuvastatine hemicalcium salt using the same | |
WO2014045294A1 (en) | A novel process for the preparation of rosuvastatin calcium using novel intermediates | |
WO2012011129A2 (en) | Novel polymorph of bis[(e)-7-[4-(4-fluorophenyl)-6-iso-propyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid] calcium salt | |
WO2013059572A1 (en) | Process for the preparation of etravirine and intermediates in the synthesis thereof | |
WO2016046833A2 (en) | Improved processes for the preparation of agomelatine using novel intermediates | |
US20140275535A1 (en) | Acid addition salts of bosentan | |
US20230025246A1 (en) | Process for preparing chroman compounds | |
JP6183053B2 (en) | Method for producing tetrahydropyranylpyrimidine compound | |
JP4968066B2 (en) | Process for producing 4-amino-2-alkylthio-5-pyrimidinecarbaldehyde | |
KR102441327B1 (en) | Novel processes for preparing a diaminopyrimidine derivative or acid addition salt thereof | |
JP5034277B2 (en) | Of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide Production method | |
JP6797839B2 (en) | New manufacturing method of teriflunomide | |
WO2007086559A1 (en) | Method for producing tetrahydropyran compound | |
WO2017179065A1 (en) | Improved process for the preparation of apremilast | |
US20040116709A1 (en) | Process for producing optically active n-aryl-1-amino-2-propanol derivatives | |
EP2332923A1 (en) | 5-ý2-(methylthio)ethoxy¨pyrimidine-2-amine manufacturing method | |
WO2008152514A2 (en) | Process for the preparation of alfuzosin and salts thereof | |
JPWO2002070482A1 (en) | Method for producing optically active N-aryl-1-amino-2-propanol derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13839574 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 13839574 Country of ref document: EP Kind code of ref document: A1 |