PENDYAM DR KRISHNAIAH (IN)
KALLEPALLY MR SUDHEER (IN)
AVULA MR SUDARSHAN REDDY (IN)
GOTTAPU MR VENKATA NAIDU (IN)
PAPPULA MR VIJAYENDAR REDDY (IN)
| WO2018198086A1 | 2018-11-01 | |||
| WO2019115019A1 | 2019-06-20 |
| US8765948B2 | 2014-07-01 | |||
| US7056927B2 | 2006-06-06 |
| We Claim: 1. An improved process for the preparation of Elagolix sodium of formula-I which comprises: a) coupling of compound of formula-II with compound of formula-III in presence of a base, ligand, catalyst and coupling agent to obtain compound of formula-IV ; b) condensation of compound of formula-IV with compound of formula-V in presence of a base and solvent to obtain compound of formula-V(a) in in-situ; c) deprotection of compound of formula- V(a) in presence of an acid to obtain pure compound of formula- VI; d) condensation of compound of formula-VI with ethyl-4-bromo butyrate in presence of a base and solvent to obtain compound of formula- VII; e) conversion of compound of formula- VII in presence of base and solvent followed by treatment with sodium source to obtain Elagolix sodium of formula-I. 2. The process as claimed in step-d) of claim 1, wherein said sodium source is selected from sodium hydroxide, sodium carbonate or sodium bicarbonate. 3. An improved process for the preparation of Elagolix sodium of formula-IV which comprises: coupling of compound of formula-II with compound of formula-III in presence of a base, ligand, catalyst and coupling agent to obtain compound of formula-IV. 4. A process for the preparation of Elagolix sodium of formula-I which comprises: a) coupling of compound of formula-II with compound of formula-III in presence of potassium hydroxide, potassium iodide, tri tert-butyl phosphonium tetra fluoroborate and palladium acetate to obtain compound of formula-IV ; b) condensation of compound of formula-IV with compound of formula- V(i) in presence of 1 , 1 ,3,3-tetramethyl guanidine and N,N-dimethylformamide to obtain compound of formula-V(b); c) deprotection of compound of formula- V(b) in presence of methane sulfonic acid to obtain pure compound of formula- VI as a solid; d) condensation of compound of formula- VI with ethyI-4-bromo butyrate in presence of a diisopropyl ethyl amine and N,N-dimethyI form amide to obtain compound of formula- VII; e) conversion of compound of formula- VII in presence of sodium hydroxide and ethanol to obtain Elagolix sodium of formula-I. 5. An improved process for the preparation of pure compound of formula- VI. which comprises: a) coupling of compound of formula-II with compound of formula-III in presence of base, catalyst and coupling agent to obtain compound of formula-IV; b) condensation of compound of formula-IV with compound of formula-V in presence of base and solvent to obtain compound of formula- V(b) in in-situ; c) deprotection of compound of formula- V(b) in presence of an acid to obtain compound of formula- VI as a solid. 6. The process as claimed in claim 1, claim 3 and claim 4, wherein said coupling agent is selected from the group consisting of palladium acetate, palladium chloride, bis(acetonitrile) palladium dichloride, bis (triphenyl phosphene) palladium chloride, palladium bis (acetyl acetonate) or Tetrakis (triphenyl phosphine) palladium; wherein said ligand is Tri-tert- butylphosphonium tetrafluoroborate (TTB-HBF4); wherein said catalyst is selected from the group consisting of potassium iodide, dimethyl amino pyridine or quaternary ammonium salt; wherein said acid is selected from the group consisting of acetic acid, trifluoroacetic acid or methane sulfonic acid. 7. The process as claimed in claim 1, claim 3 and claim 4, wherein said base is selected from the group consisting of inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; organic base such as triethylamine (TEA), diisopropylethylamine (DIPEA), diisopropyl amine, diisobutylamine, piperidine, pyridine, 4-dimethyl aminopyridine (DMAP), N-methyl morpholine (NMM), N-methyl pyrrolidone (NMP) or tetra methyl guanidine. 8. The process as claimed in claim 1 , claim 3 and claim 4, wherein said solvent is selected from the group consisting of alcoholic solvent such as methanol, ethanol or isopropanol; ketonic solvents such as acetone or methyl isobutyl ketone; ester solvent such as ethyl acetate or isopropyl acetate; polar aprotic solvent such as N,N-dimethyI form amide or dimethyl sulfoxide; ether solvent such as tetrahydrofuran; hydrocarbon solvent such as toluene, xylene, hexane or heptane; water or its mixture. 9. Crystalline form-N of compound of formuIa-IV characterized by its powder x-ray diffractogram having peaks at about 7.9, 9.7, 10.4, 10.8, 11.8, 12.4, 13.3, 14.5, 14.7, 15.2, 15.9, 16.2, 16.6, 17.2, 17.8, 18.5, 18.8, 19.7, 20.5, 21.3, 22.7, 23.5, 24.3, 25.5, 27.9, 28.7, 29.8, 31.7, 33.6, 34.7, 36.3 and 40.1 ± 0.2 degree two theta 10. Highly pure compound of formula- VI as a solid having HPLC purity of 99.9 % used in the preparation of Elagolix sodium. |
Field of The Invention
The present invention relates to an improved process for the preparation of Elagolix Sodium having the structural formula (I).
Background of the Invention
Elagolix Sodium is chemically known as Sodium 4-({(lR)-2-[5-(2-fluoro-3-methoxyphenyl) -3- { [2-fluoro-6-(trifluoro methyl) phenyl] methyl }-4-methyl-2, 6-dioxo-3,6-dihydropyrimidin- 1(2 H) -yl]-1-phenylethyl} amino) butanoate. Food and Drug Administration granted marketing Authorisation for Elagolix Sodium in United States under the brand name “ORILISSA” for the treatment of endometriosis-associated pain. Elagolix is the first and currently the only marketed member of a new class of GnRH modulators, which is described as "second-generation" due to their non-peptide and small-molecule nature and oral activity.
Elagolix Sodium is a gonadotropin releasing hormone antagonist (GnRH antagonist) used in the treatment of pain associated with endometriosis in women. It is also in phase III clinical trials for the treatment of uterine fibroids in women. Endometriosis is a frequent cause of infertility, connected with a chronic pelvic and pre-menstrual pain.
Elagolix was first disclosed in WO 2005007165 Al. In example-1H of this patent application, Elagolix free acid is described as a white gel and it is passed through a DOWEX MSC-1 macroporous strong cation exchange column to convert the free acid to sodium salt. Finally, lyophilization gives the Elagolix Sodium as a white solid. The reported process for the preparation of Elagolix Sodium utilizes cation exchange column which makes it difficult for bulk manufacturing as well as it effects the overall yield making the process uneconomical.
Various procedures for the preparation of Elagolix sodium is disclosed in US 7015226, US 7419983, US 8765948 and WO 2018198086 A1. These procedures involves column chromatography separations, costly raw materials, large amount of ligand, reagent for Suzuki coupling reaction and usage of acid-base treatments for purification which make these procedures commercially not viable.
In view of all these disadvantages, there is a significant need to develop a stable, simple, commercially viable process for the preparation of highly pure Elagolix Sodium with good yield.
Summary of The Invention
The present invention provides cost effective and efficient process for the preparation of Elagolix Sodium with higher yield and purity.
In one embodiment, the present invention provides a process for the preparation of Elagolix Sodium of formula-I. which comprises: a) coupling of compound of formula-II with compound of formula-III in presence of a base, ligand, catalyst and coupling agent to obtain compound of formula-IV ; b) condensation of compound of formula-IV with compound of formula-V in presence of a base and solvent to obtain compound of formula-V[a] in in-situ; c) deprotection of compound of formula- V(a) in presence of an acid to obtain compound of formula- VI ;
d) condensation of compound of formula- VI with ethyI-4-bromo butyrate in presence of a base and solvent to obtain compound of formula- VII; e) conversion of compound of formula- VII in presence of sodium source and solvent to obtain Elagolix sodium of formula-I.
In another embodiment, the present invention provides an improved process for the preparation of Elagolix sodium of formula-I which comprises: a) coupling of compound of formula-II
with compound of formula-III in presence of potassium hydroxide, potassium iodide, tri tert-butyl phosphonium tetra fluoro borate and palladium diacetate to obtain compound of formula-IV ; b) condensation of compound of formula-IV with compound of formula- V(i) in presence of 1,1,3,3-tetramethyl guanidine and N,N-dimethylformamide to obtain compound of formula-V[b] in in-situ;
c) deprotection of compound of formula- V(b) in presence of Methanesulfonic acid to obtain compound of formula- VI as a solid; d) condensation of compound of formula- VI with ethyl-4-bromo butyrate in presence of a diisopropyl ethyl amine and N,N-dimethyl form amide to obtain compound of formula- VII; e) conversion of compound of formula- VII in presence of sodium hydroxide and ethanol to obtain Elagolix sodium of formula-I.
In yet another embodiment, the present invention provides an improved process for the preparation of pure compound of formula- VI.
which comprises: a) coupling of compound of formula-II with compound of formula-III in presence of a base, catalyst and coupling agent to obtain compound of formula-IV ; b) condensation of compound of formula-IV with compound of formula- V(i)
in presence of base and solvent to obtain compound of formula-V[b] in in-situ; c) deprotection of compound of formula- V(b) with methane sulfonic acid to obtain compound of formula- VI.
In yet another embodiment, the present invention provides pure compound of formula- VI which is isolated as a solid with HPLC purity of 99.9 %
In yet another embodiment, the present invention provides novel crystalline form of compound of formula- VI which is further designated as from-N. It is characterized by powder x-ray diffractogram having peaks about 7.9, 9.7, 10.4, 10.8, 11.8, 12.4, 13.3, 14.5, 14.7, 15.2, 15.9, 16.2, 16.6, 17.2, 17.8, 18.5, 18.8, 19.7, 20.5, 21.3, 22.7, 23.5, 24.3, 25.5, 27.9, 28.7, 29.8, 31.7, 33.6, 34.7, 36.3 and 40.1 + 0.2 degree two theta. PXRD spectrum and DSC thermogram of novel crystalline form-N of compound of formula- VI substantially as shown in figure- 1 and -2.
Detailed Description of the Invention
Accordingly, the present invention provides a novel process for the preparation of Elagolix Sodium of formula-I.
The main embodiment of the present invention provides a process for the preparation of Elagolix Sodium of formula (I) as shown in the Scheme-I given below.
Scheme-I
In step-1, coupling of compound of formula-II with compound of formula-III in presence of a base, catalyst, ligand and a reagent to obtain compound of formuIa-IV.
The base used in the reaction is selected from the group consisting of inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as triethylamine, diisopropylethylamine or pyridine, preferably using potassium hydroxide.
The coupling reagent used in the reaction is selected from the group consisting of Tetrakis (triphenyl phosphine) palladium, palladium acetate or Tris (dibenzylidene acetone) dipalladium, preferably using Palladium acetate.
The amount of coupling agent used in the reaction may be in the range of 0.02 to 2.0 molar equivalents: preferably using 0.04 to 1.0 molar equivalents. Usage of palladium and tri-tert-butyl phosphine complex as a catalyst results carbon-carbon bond formation. Ligand used in the reaction is Tri-tert-butyl phosphine complex like tri-tert-butyl phosphonium tetra fluoroborate. Catalyst used in this reaction is selected from the group consisting of potassium iodide, quaternary ammonium salt like tetra butyl ammonium bromide or dimethyl amino pyridine.
The catalyst used in the reaction is preferably potassium iodide. Usage of potassium iodide reduces the time of reaction and increases the rate of reaction. It also decreases the usage of quantity of ligand and coupling agent in this coupling reaction.
The reaction temperature may range from 50-80 °C and preferably at a temperature in the range from 65-75 °C. The duration of the reaction may range from 6-12 hours, preferably for a period of 8-10 hours.
Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; ketone solvents such as acetone or methyl tert-butyl ketone; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide; water or its mixture thereof; preferably using acetone-water mixture.
In step-2, condensation of compound of formuIa-IV with compound of formuIa-V in presence of a base and solvent to obtain compound of formuIa-V[a] in in-situ manner. Further, it is deprotected by using an acid in a solvent to obtain highly pure compound of formula- VI as a solid. Compound of formula- VI is isolated as a solid from a solvent system of isopropyl acetate and methyl tert butyl ether.
Acid used for amino deprotection is selected from hydrochloric acid, acetic acid, trifluoro acetic acid and methane sulfonic acid; preferably using methane sulfonic acid.
Base used in the reaction is selected from the group consisting of inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as triethylamine, diisopropylethylamine, tetramethyl guanidine or pyridine, preferably using 1 ,1 ,3,3- tetramethyl guanidine.1,1,3,3-tetramethyl guanidine used in the reaction may be in the range of 0.5 to 1.5 molar equivalents; preferably using 0.5 to 1.0 molar equivalents. Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl sulfoxide or dimethyl formamide; preferably using dimethyl form amide. The reaction temperature may range from 30-50 °C and preferably at a temperature in the range from 40-45 °C. The duration of the reaction may range from 30-50 hours, preferably for a period of 35-45 hours.
In the reported literature, cumbersome workup procedures and multiple acid-base treatments required to get compound of formula- VI as a residue. The present invention provides simple workup procedures which is useful in bulk manufacturing. The present invention also provides highly pure compound of formula- VI which is isolated as a solid with HPLC purity of 99.9%. Highly pure compound of formula- VI involves major role in the preparation of pure Elagolix sodium.
Hydroxy protecting group used in the reaction may be selected from the group consisting of benzyloxycarbonyl, C 1 -C 6 straight chain or branched chain alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl, tert-butyloxycarbonyl, acetyl, trichloroacetyl, trifluoroacetyl, 1 -ethoxy ethyl, benzoyl, benzyl, p-methoxybenzyl, methylthiomethyl, pivaloyl, trityl (triphenylmethyl), methoxy-iso-propanyl, tri ( C 1 -C 6 straight chain or branched chain alkyl) silyl groups such as trimethyl silyl (TMS), tri-ethyl silyl, triisopropylsilyl, tri-iso-propylsilyloxy methyl, tert-butyl-dimethylsilyl, tert-butyl- biphenylsilyl, furanidinyl, dihydropyran, tetrahydropyran, trichloroethoxy carbonyl or methane sulfonyl; preferably using methane sulfonyl group.
Amino protecting group used in the reaction may be selected from the group consisting of tetra butyl oxy carbonyl, carbo benzyloxy, 9-fluorenyImethyIoxy carbonyl (Fmoc), benzyl, acetyl, tosyl, tri chloroethyl or benzoyl; preferably using tert-butyloxy carbonyl group.
In step-3, condensation of compound of formula- VI with aIkyI-4-haIo butyrate in presence of a base and solvent to obtain compound of formula- VII.
Solvent used in this reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide or dimethyl sulfoxide; ether solvent such as tetrahydrofuran; preferably dimethyl formamide.
Alkyl-4-halo butyrate used in this step may be selected from the group consisting of ethyl-4- bromo butyrate, methyl-4-chloro butyrate or isopropyl-4-bromo butyrate; preferably using ethyl- 4-bromo butyrate.
Ethyl-4-bromo butyrate used in the reaction may be in the range of 0.5 to 2.5 molar equivalents: preferably using 1.0 to 2.0 molar equivalents.
The base used in the reaction is selected from the group consisting of inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as triethylamine, diisopropylethylamine or pyridine, preferably using potassium carbonate.
The reaction temperature may range from 40-60 °C and preferably at a temperature in the range from 50-55 °C. The duration of the reaction may range from 10-18 hours, preferably for a period of 11-12 hours.
In step-4, compound of formula- VII undergoes ester hydrolysis in presence of a base to provide Elagolix free acid in in-situ manner which is converts to its sodium salt using sodium source.
The base used in the reaction is selected from the group consisting of inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as triethylamine, diisopropylethylamine or pyridine, preferably using sodium hydroxide.
Sodium source used in this step is selected from the group consisting of sodium hydroxide, sodium carbonate or sodium bicarbonate; preferably using sodium hydroxide.
Sodium hydroxide used in the reaction may be in the range of 1.0 to 3.0 molar equivalents: preferably using 2.0 to 2.5 molar equivalents.
Solvent used in this reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol, industrial methylated spirit (IMS) or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide or dimethyl sulfoxide; ether solvent such as tetrahydrofuran; preferably using ethanol. The reaction temperature may range from 20- 50 °C and preferably at a temperature in the range from 30-50 °C. The duration of the reaction may range from 1-4 hours, preferably for a period of 2-4 hours.
Elagolix sodium can be isolated by different isolation techniques like filtration, distillation, chromatographic techniques, and solvent-anti solvent techniques where solvent is selected from methyl iso butyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate and anti-solvent is selected from non-polar solvent such as heptane or hexane. Preferably using isopropyl acetate and heptane solvent system used for Elagolix sodium isolation.
In yet another embodiment, the present invention provides an improved process for the preparation of Elagolix Sodium of formula (I) as shown in the Scheme-II given below:
Scheme-II In step-1, coupling of compound of formula-11 with compound of formula-111 in presence of potassium hydroxide, potassium iodide and palladium acetate combined with tri-tert-butyl phosphonium tetra fluoroborate to obtain compound of formuIa-IV. Usage of potassium iodide reduces the time of reaction and increases the rate of reaction. It also decreases the usage of quantity of ligand and coupling agent in this coupling reaction.
The reaction temperature may range from 50-70 °C; preferably at a temperature in the range from 60-65 °C. The duration of the reaction may range from 6-12 hours, preferably for a period of 8- 10 hours.
Solvent used in the reaction is selected from the group consisting of alcoholic solvents; chlorinated solvents; nitrile solvent; ester solvents; ketone solvents; aromatic organic solvents; polar aprotic solvent; water or its mixture thereof; preferably using acetone-water mixture.
In step-2, condensation of compound of formula-IV with compound of formula-V(i) in presence of 1,1,3,3-tetra methyl guanidine and solvent to obtain compound of formula-V(b) in in-situ manner. Further, it is deprotected by using methane sulfonic acid to obtain highly pure compound of formula- VI which is isolated as a solid. Compound of formula- VI having HPLC purity of 99.9% which shows high impact on the purity of Elagolix sodium.
Solvent used in the reaction is selected from the group consisting of alcoholic solvents; chlorinated solvents; nitrile solvent; ester solvents; aromatic organic solvents; polar aprotic solvent; preferably using dimethyl formamide.
The reaction temperature may range from 30-50 °C and preferably at a temperature in the range from 40-45 °C. The duration of the reaction may range from 30-60 hours, preferably for a period of 35-40 hours.
In the reported literature, cumbersome workup procedures and multiple acid-base treatments required to get compound of formula- VI which is isolated as a residue. Then it is converted to salt by using an acid. Further, it is neutralized to get compound of formula- VI. The present invention provides simple workup procedures which is useful in bulk manufacturing. The present invention also provides highly pure compound of formula- VI in solid form is developed. Compound of formula- VI having HPLC purity of 99.9% which shows high impact on the purity of Elagolix sodium. In step-3, condensation of compound of formula- VI with ethyl-4-bromo butyrate in presence of a diisopropyl ethyl amine and solvent to obtain compound of formula- VII.
Solvent used in this reaction is selected from the group consisting of alcoholic solvents; chlorinated solvents; nitrile solvent; ester solvents; aromatic organic solvents; polar aprotic solvent; ether solvent; preferably using dimethylformamide.
The reaction temperature may range from 40-60 °C and preferably at a temperature in the range from 50-55 °C. The duration of the reaction may range from 10-18 hours, preferably for a period of 10-12 hours.
In step-4, compound of formula- VII undergoes ester hydrolysis in presence of sodium hydroxide to provide Elagolix free acid in in-situ manner which is converts to its sodium salt using sodium source such as sodium hydroxide.
Solvent used in this reaction is selected from the group consisting of alcoholic solvents; chlorinated solvents; nitrile solvent; ester solvents; aromatic organic solvents; polar aprotic solvent; ether solvent; preferably using ethanol.
The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-30 °C. The duration of the reaction may range from 1-4 hours, preferably for a period of 2-4 hours.
Elagolix sodium can be isolated by different isolation techniques like filtration, distillation, chromatographic techniques, and solvent-anti solvent techniques where solvent is selected from methyl iso butyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate and anti-solvent is selected from non-polar solvent such as heptane or hexane. Preferably using isopropyl acetate and heptane solvent system used for Elagolix sodium isolation.
In yet another embodiment, the present invention provides an improved process for the preparation of compound of formula- VI as shown in the Scheme-Ill given below:
Scheme-Ill
In step-1, coupling of compound of formula-11 with compound of formula-111 in presence of potassium hydroxide, potassium iodide and palladium acetate combined with tri-tert-butyl phosphonium tetra fluoroborate to obtain compound of formuIa-IV. Usage of potassium iodide reduces the time of reaction and increases the rate of reaction. It also decreases the usage of quantity of ligand and coupling agent in this coupling reaction.
The reaction temperature may range from 50-80 °C and preferably at a temperature in the range from 60-70 °C. The duration of the reaction may range from 14-24 hours, preferably for a period of 10-12 hours.
Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; ketone solvents such as acetone or methyl tert-butyl ketone; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide; water or its mixture thereof; preferably using acetone-water mixture.
In step-2, condensation of compound of formula-IV with compound of formula-V(i) in presence of 1,1,3,3-tetra methyl guanidine and solvent to obtain compound of formula-V(b). Further, it is deprotected in presence of methane sulfonic acid to obtain compound of formula- VI. Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl sulfoxide or dimethyl formamide; preferably using dimethyl form amide.
The reaction temperature may range from 30-60 °C and preferably at a temperature in the range from 50-55 °C. The duration of the reaction may range from 30-60 hours, preferably for a period of 35-40 hours.
In yet another embodiment, the present invention provides pure compound of formula- VI which is isolated as a solid with HPLC purity of 99.9 %
In yet another embodiment, the present invention provides novel crystalline form of compound of formula- VI which is further designated as from-N. It is characterized by powder x-ray diffractogram having peaks about 7.9, 9.7, 10.4, 10.8, 11.8, 12.4, 13.3, 14.5, 14.7, 15.2, 15.9, 16.2, 16.6, 17.2, 17.8, 18.5, 18.8, 19.7, 20.5, 21.3, 22.7, 23.5, 24.3, 25.5, 27.9, 28.7, 29.8, 31.7, 33.6, 34.7, 36.3 and 40.1 + 0.2 degree two theta as illustrated in figure-1. Novel crystalline form- N of compound of formula- VI having DSC endotherm of about 152.3°C.
The present invention provides simple workup procedures to get compound of formula- VI as a solid which is useful in bulk manufacturing.
Compounds of formulae-II, -III and -V(i) used in the present invention is prepared from the any known methods disclosed in the prior art.
EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Example-1: Process for the preparation of (R)-2-((tert-butoxycarbonyl) amino)-2-phenyl ethyl methane sulfonate [compound of formula-V(i)] - Keep as Example-1
Methyl sulfonyl chloride (53.8 mL) is slowly added to a mixture of N, N-dimethyl formamide (73 mL), triethyl amine (76.7 mL) and tert-butyl (R)-(2-hydroxy-1-phenylethyl) carbamate (150 grams) at 0-5 °C and stirred for 15 minutes at the same temperature. Raised the temperature of reaction mixture to 25-30 °C and stirred for 3 hours at the same temperature. Acetone and water were added to the resulting reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5 °C and stirred for 3 hours at the same temperature. Filtered the reaction mixture and washed with acetone: water mixture to get the title compound.
Yield: 91.1 %.
Example-2: Process for the preparation of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3- methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)- dione [compound of formula-VI]
Stage-1: Synthesis of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)- 6-methylpyrimidine-2,4(1H,3H)-dione [compound of formula-IV]
Aqueous potassium hydroxide solution is added to a mixture of (2-fluoro-3-methoxyphenyl) boronic acid [compound of formula-III] (199.8 grams), potassium iodide (65.3 grams), acetone (900 mL) and water (900 mL) at 25-30 °C under nitrogen atmosphere and stirred for 10 minutes at the same temperature. 1 -(2-fluoro-6-(trifluoromethyl) benzyl)-5-bromo-6-methyl-1H- pyrimidine-2,4-dione [Compound of formula-II] (150 grams) and tri tert-butyl phosphonium tetrafluoroborate (1.14 grams) were added to the resulting reaction mixture at 25-30 °C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45 °C and stirred for 20 minutes at the same temperature, palladium acetate (2.94 grams) was added to the resulting reaction mixture at 40-45°C. Heated the reaction mixture to 65-75 °C and stirred for 8 hours at the same temperature. Acetic acid was slowly added drop wise to the reaction mixture at 60-65 °C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30 °C and stirred for 2 hours at the same temperature. Filtered the reaction mixture and washed with water followed by methanol. Dissolve the obtained wet material in methanol at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid, washed with water followed by methanol and dried to get the title compound.
Yield: 79.2 %
Stage-2: Synthesis of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1 -(2- fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione [compound of formula-VI]
A mixture of N, N-dimethyl form amide (180 mL), 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- (trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (120 grams, obtained from stage-1), (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methane sulfonate [compound of formula-V(i)] (133 grams) and tetramethyl guanidine (97.4 grams) were stirred for 15 minutes at 25-30 °C. Heated the resulting reaction mixture to 40-45 °C and stirred for 36 hours at the same temperature. Cooled the reaction mixture to 25-30 °C. Isopropyl acetate and phosphoric acid solution was added to the resulting reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with phosphoric acid solution. Separate the organic layer and washed twice with water. Both the layers were separated and water was added to the organic layer at 25-30 °C. Methane sulfonic acid was added to the obtained reaction mixture at 25-30 °C. Heated the reaction mixture to 40-45 °C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30 °C. Aqueous potassium carbonate solution was slowly added to the reaction mixture at 25-30 °C and stirred for 10 minutes at the same temperature. Both the aqueous and organic layers were separated. Organic layer was washed with ortho phosphoric acid solution. Aqueous layer was separated and washed twice with isopropyl acetate. Both the aqueous and organic layers were separated, and organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure. Co-distilled the obtained compound with isopropyl acetate. Cool the reaction mixture to 25-30°C. Isopropyl acetate and methyl tert butyl ether were added to the obtained compound at 25-30°C and stirred for 4 hours at the same temperature. Filtered the precipitated solid and washed with methyl tert-butyl ether.
Isopropyl acetate (120 mL) added to the obtained wet compound at 25-30°C and stirred for 15 minutes at the same temperature. Heated the resulting reaction mixture to 45-50°C and stirred for 30 minutes at the same temperature, reaction mixture and stirred for 15 minutes. Cooled the reaction mixture to 25-30°C. Methyl tert-butyl ether was added to the resulting reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. Filtered the precipitated solid and washed with methyl tert-butyl ether to get the title compound.
Yiled: 76.5 %
Example-3: Process for the preparation of Elagolix Sodium
Stage-1: Synthesis of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)- 6-methylpyrimidine-2,4(1H,3H)-dione [compound of formula-IV]
Aqueous potassium hydroxide solution is added to a mixture of (2-fluoro-3-methoxyphenyI) boronic acid [compound of formula-ill] (199.8 grams), potassium iodide (65.3 grams), acetone (900 mL) and water (900 mL) at 25-30 °C under nitrogen at6mosphere and stirred for 10 minutes at the same temperature. 1 -(2-fluoro-6-(trifluoromethyl) benzyI)-5-bromo-6-methyI-1H- pyrimidine-2,4-dione [Compound of formula-11] (150 grams) and tri tert-butyl phosphonium tetrafluoroborate (1.14 grams) were added to the resulting reaction mixture at 25-30 °C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45 °C and stirred for 20 minutes at the same temperature, palladium acetate (0.44 grams) was added to the resulting reaction mixture at 40-45°C. Heated the reaction mixture to 65-75 °C and stirred for 8 hours at the same temperature. Acetic acid was slowly added drop wise to the reaction mixture at 60-65 °C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30 °C and stirred for 2 hours at the same temperature. Filtered the reaction mixture and washed with water followed by methanol. Dissolve the obtained wet material in methanol at 25-30°C and stirred for 30 minutes at the same temperature. Water was added to the resulting reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid, washed with mixture of methanol, water and dried to get the title compound.
Yield: 79.2 %
Stage-2: Synthesis of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1 -(2- fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione [compound of formula- VI]
A mixture of N, N-dimethyl form amide (180 mL), 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- (trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (120 grams, obtained from stage-1), (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methane sulfonate [compound of formula-V(i)] (133 grams) and tetramethyl guanidine (97.4 mL) were stirred for 15 minutes at 25-30 °C. Heated the resulting reaction mixture to 40-45 °C and stirred for 36 hours at the same temperature. Cooled the reaction mixture to 25-30 °C. Isopropyl acetate and phosphoric acid solution was added to the resulting reaction mixture at 25-30 °C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with phosphoric acid solution. Separate the organic layer and washed twice with water. Both the layers were separated and water was added to the organic layer at 25-30 °C. Methane sulfonic acid was added to the obtained reaction mixture at 25-30 °C. Heated the reaction mixture to 60-65 °C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30 °C. Aqueous potassium carbonate solution was slowly added to the reaction mixture at 25-30 °C and stirred for 10 minutes at the same temperature. Both the aqueous and organic layers were separated. Organic layer was washed with ortho phosphoric acid solution. Aqueous layer was separated and washed twice with isopropyl acetate. Both the aqueous and organic layers were separated and organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure. Co-distilled the obtained compound with isopropyl acetate. Cool the reaction mixture to 25-30 °C. Isopropyl acetate and methyl tert butyl ether were added to the obtained compound at 25-30 °C and stirred for 4 hours at the same temperature. Filtered the precipitated solid and washed with methyl tert-butyl ether.
Isopropyl acetate (120 mL) added to the obtained wet compound at 25-30 °C and stirred for 15 minutes at the same temperature. Heated the resulting reaction mixture to 45-50 °C and stirred for 30 minutes at the same temperature, reaction mixture and stirred for 15 minutes. Cooled the reaction mixture to 25-30 °C. Methyl tert-butyl ether (240 mL) was added to the resulting reaction mixture at 25-30 °C and stirred for 4 hours at the same temperature. Filtered the precipitated solid and washed with methyl tert-butyl ether to get the title compound.
Yiled: 76.5%; Purity by HPLC: 99.9 %.
Stage-3: Synthesis of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifl uoro methyl) benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-1- phenylethyl) amino) butanoate [compound of formula- VII]
Diisopropyl ethyl amine (49.6 grams) is added to a mixture of (R)-3-(2-amino-2-phenylethyl)-5- (2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)be nzyl)-6-methylpyrimidine- 2,4(1H,3H)-dione [compound of formula- VI] (70 grams, obtained in stage-2) and N, N-Dimethyl form amide (105 mL) at 25-30 °C and stirred for 10 minutes at the same temperature. Ethyl-4- bromo butyrate (37.4 grams) is slowly added to the resulting reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 50-55°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Isopropyl acetate (350 mL) and water (350 mL) were added to the resulting reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Organic layer was washed twice with ortho phosphoric acid solution. Aqueous layer was separated and washed twice with isopropyl acetate. Aqueous potassium carbonate solution was added to a mixture of aqueous layer and isopropyl acetate at 25-30°C and stirred for 15 minutes at the same temperature. Both the layers were separated and distilled off the solvent completely from the organic layer, co-distilled the obtained compound with isopropyl acetate to get the title compound.
Yield: 84.4 %.
Stage-4: Synthesis of Elagolix Sodium [compound of formula-I]
Aqueous sodium hydroxide solution (130 mL) is added to a mixture of ethanol (220 mL) and compound of formula- VII (44 grams, obtained in stage-3) at 25-30°C. Heated the reaction mixture to 40-45 °C and stirred for 3 hours at the same temperature. After consumption of starting material, volatiles were removed from the reaction mixture under reduced pressure. Isopropyl acetate (220 mL) is added to the obtained residue at 25-30 °C and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were separated and aqueous layer was washed twice with isopropyl acetate. Aqueous sodium hydroxide solution was added to the aqueous layer and stirred for 15 minutes at the same temperature. Extracted the reaction mixture with isopropyl acetate at 25-30 °C. Organic layer was separated and distilled off the solvent from the organic layer under reduced pressure.
Toluene (88 mL) was added to the obtained compound at 25-30 °C and stirred for 10 minutes at the same temperature. Volatiles were evaporated from the reaction mixture under reduced pressure. Co-distilled the reaction mixture with isopropyl acetate. The obtained compound was dissolved in isopropyl acetate at 40-50 °C and stirred for 30 minutes at the same temperature. The resulting reaction mixture was added to heptane at 25-30 °C and stirred for 5-10 hours at the same temperature. Filtered the precipitated solid, washed with heptane and dried to get the title compound.
Yiled: 80 %.
1 H NMR (DMSO D6): δ 1.43-1.45 (d, 2H), 1.78 (s, 2H), 2.08 (s, 3H), 2.19-2.27 (m, 2H), 3.88 (s, 3H), 3.95 (m, 3H), 5.33 (s, 2H), 6.59-6.62 (m, 1H), 7.1-7.25 (m, 7H), 7.56-7.66 (m, 3H).
The present invention has the following advantages:
1. The process is efficient and atom economic.
2. Simplified workup procedure by avoiding the stage wise column purifications.
3. Usage of potassium iodide in step-1 reduces the time of reaction and increases the rate of reaction.
4. Highly pure compound of formula- VI is isolated as a solid which is suitable for large scale manufacturing.
5. Lactam impurity is controlled as per ICH guidelines and N-oxide impurity is not detected in final API.
6. Improved the purity of Elagolix sodium.