WO2016079699A1 - Process for the preparation of (4r)-1-(tert-butoxycarbonyl)-4-hydroxy-l-proline - Google Patents

Process for the preparation of (4r)-1-(tert-butoxycarbonyl)-4-hydroxy-l-proline Download PDF

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WO2016079699A1
WO2016079699A1 PCT/IB2015/058944 IB2015058944W WO2016079699A1 WO 2016079699 A1 WO2016079699 A1 WO 2016079699A1 IB 2015058944 W IB2015058944 W IB 2015058944W WO 2016079699 A1 WO2016079699 A1 WO 2016079699A1
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formula
compound
salts
thiazolidin
fert
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PCT/IB2015/058944
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French (fr)
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Rajesh Kumar
Dhiren Chandra BARMAN
Asok Nath
Mohan Prasad
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Sun Pharmaceutical Industries Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides a process for the preparation of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
  • the present invention also provides a process for the preparation of ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-l-(teri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
  • Tenelegliptin hydrobromide hydrate chemically ⁇ (2S,4S)-4-[4-(3-Methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate of Formula I, is marketed in Japan for the treatment of type 2 diabetes mellitus.
  • U.S. Patent Nos. 7,074,794 and 8,003,790 disclose processes for the preparation of ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3- thiazolidin-3-yl) methanone of Formula II, or salts thereof, comprising the steps of condensing (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV with thiazolidine to obtain fert-butyl (2S,4R)-4-hydroxy-2-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidine-l-carboxylate, followed by its oxidation using a pyridine-sulfur trioxide complex in dimethylsulfoxide to obtain fert-butyl (2S)-4-oxo-2-(l,3-thiazolidin-3
  • (4R)-l-(fert-Butoxycarbonyl)-4-hydroxy-L-proline of Formula IV is a key raw material for the preparation of ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof.
  • the prior art process for the preparation of the compound of Formula IV involves the reaction of trans-4-hydroxy-L-proline with di-fert-butyl dicarbonate in the presence of a base in a mixture of water and an organic solvent.
  • the insolubility of di-fert-butyl dicarbonate in water necessitates the use of an organic solvent in the reaction.
  • the present invention involves the reaction of trans-4-hydroxy-L-proline with di-fert-butyl dicarbonate in water alone.
  • the present inventors have found that eliminating the organic solvent reduces the time taken for the reaction without compromising the purity of the product.
  • the present invention provides a process for the preparation of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
  • the present invention also provides a process for the preparation of ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-l-(teri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
  • a first aspect of the present invention provides a process for the preparation of (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV
  • a second aspect of the present invention provides a process for the preparation of ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3- thiazolidin-3-yl) methanone of Formula II, or salts thereof,
  • a third aspect of the present invention provides a process for the preparation of ⁇ (2S,4S)-4-[4-(3-methyl- l-phenyl- lH-pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-yl ⁇ (l,3- thiazolidin-3 -yl) methanone of Formula II, or salts thereof,
  • salts refers to inorganic acid addition salts, organic acid addition salts, and salts formed with amino acids.
  • inorganic acid addition salts include salts formed with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acid addition salts include salts formed with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, and methylsulfuric acid.
  • amino acid salts include salts formed with glutamic acid and aspartic acid.
  • the reaction of the compound of Formula III with di-fert-butyl dicarbonate is carried out in the presence of a base in water to obtain a compound of Formula IV.
  • the base is selected from organic or inorganic bases. Examples of organic bases include methylamine, ethylamine, diethylamine, triethylamine, diisopropylamine, and
  • inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • the compound of Formula III is reacted with di-fert-butyl dicarbonate using sodium hydroxide in water to obtain the compound of Formula IV.
  • the oxidation of the compound of Formula IV to obtain a compound of Formula V is carried out using an oxidizing agent.
  • oxidizing agents include a pyridine- sulfur trioxide complex in DMSO, an alkaline solution of KMnO/t, oxalyl chloride in DMSO and triethylamine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in dichloromethane, NaCIO, a mixture of NaCIO and TEMPO, and a mixture of TCCA and TEMPO.
  • the condensation of the compound of Formula V with thiazolidine to obtain a compound of Formula VI is carried out using a condensing agent.
  • the condensing agent is selected from the group comprising of DCC, EDCI, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride.
  • the condensation reaction is carried out in the presence of an additive.
  • additives include NHS, HOBT, HOOBT, and DMAP.
  • the oxidation of the compound of Formula IV is carried out using a mixture of NaClO and TEMPO to obtain the compound of Formula V, followed by condensation of the compound of Formula V with thiazolidine in the presence of DCC and DMAP to obtain the compound of Formula VI.
  • the reaction of the compound of Formula VI with the compound of Formula VII to obtain a compound of Formula VIII is carried out in the presence of an acid catalyst.
  • acid catalysts include acetic acid, p-toluenesulfonic acid, and borotriflouride etherate.
  • HPLC High Performance Liquid Chromatography
  • Di-fert-butyl dicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in tetrahydrofuran (500 mL) to obtain a reaction mixture.
  • the reaction mixture was cooled to 5°C to 10°C.
  • a solution of sodium hydroxide (30.5 g sodium hydroxide in 305 mL deionized water) was added slowly to the reaction mixture over a period of 10 minutes to 20 minutes.
  • the reaction mixture was allowed to warm to 20°C to 25 °C, and then stirred at the same temperature for 20 hours to 24 hours.
  • the reaction mixture was cooled to 5°C to 10°C.
  • the pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (290 mL; 3M).
  • the reaction mixture was stirred for 10 minutes, then allowed to settle for 15 minutes.
  • the layers were separated.
  • the aqueous layer was extracted with ethyl acetate (3 x 200 mL).
  • the combined organic layers were washed with an aqueous solution of sodium chloride (200 mL; 40 g sodium chloride in 200 mL deionized water).
  • the organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue.
  • the residue was dissolved in ethyl acetate (500 mL), then concentrated at 50°C to 55°C under reduced pressure.
  • the solid obtained was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, mixture of 40 mL ethyl acetate and 160 mL hexanes).
  • the solid was dried at 40°C to 45°C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)- 4-hydroxy-L-proline .
  • the solution was stirred for 10 minutes, then allowed to settle for 15 minutes. The layers were separated.
  • the aqueous layer was extracted with ethyl acetate (3 x 200 mL).
  • the combined organic layers were washed with an aqueous solution of sodium chloride (200 mL; 40 g sodium chloride in 200 mL deionized water).
  • the organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue.
  • the residue was dissolved in ethyl acetate (500 mL), then concentrated at 50°C to 55°C under reduced pressure.
  • the residue obtained was dissolved in ethyl acetate (200 mL) to obtain a solution.
  • Di-fert-butyl dicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in water (200 mL).
  • a solution of sodium hydroxide (33.6 g sodium hydroxide in 100 mL deionized water) was added slowly to the reaction mixture over a period of 10 minutes to 20 minutes.
  • the reaction mixture was allowed to warm to 40°C to 45 °C, then was stirred at the same temperature for 3 hours to 4 hours.
  • the reaction mixture was cooled to 25°C to 30°C.
  • Ethyl acetate 1000 mL was added to the reaction mixture, and then the mixture was cooled to 0°C to 5°C.
  • the pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (275 mL; 3M).
  • the reaction mixture was stirred for 10 minutes, and then allowed to settle for 15 minutes.
  • the layers were separated.
  • the aqueous layer was extracted with ethyl acetate (4 x 200 mL) at 15°C to 20°C.
  • the combined organic layers were washed with an aqueous solution of sodium chloride (100 mL; 20 g sodium chloride in 100 mL deionized water).
  • the organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue.
  • the residue was dissolved in ethyl acetate (200 mL), then stirred at 40°C to 45°C for 20 minutes.
  • Hexanes 100 mL were slowly added to the solution over a period of 20 minutes to 30 minutes at 25 °C to 30°C, and then the mixture was stirred at the same temperature for 60 minutes to obtain a solid.
  • Hexanes 700 mL were slowly added to the solid to obtain a slurry, and then the mixture was stirred over a period of 60 minutes. The slurry was cooled to 0°C to 5°C, then stirred at the same temperature for 2 hours.
  • the solid was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, a mixture of 40 mL ethyl acetate and 160 mL hexanes).
  • the solid was dried at 40°C to 45 °C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L- proline.
  • Trichloroisocyanuric acid (75.6 g) was added to a solution of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline (Formula IV, prepared according to Example 1; 100 g) in ethyl acetate (1000 mL). The solution was cooled to -5°C to 0°C. A solution of TEMPO in ethyl acetate (3.38 g in 50 mL ethyl acetate) was slowly added to the reaction mixture at -5°C to 10°C, then the reaction mixture was stirred at the same temperature for 20 minutes. The reaction mixture was heated to 25 °C to 30°C, then stirred at the same temperature for 60 minutes.
  • reaction mixture was quenched with deionized water (200 mL), then stirred for 60 minutes at 25°C to 30°C.
  • the reaction mixture was filtered through a Hyflo ® bed. The filtrate was washed with deionized water (2 x 200 mL). The layers were separated. The organic layer was washed with an aqueous solution of sodium chloride (40 g sodium hydroxide in 200 mL deionized water). The organic layer was concentrated at 50°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (100 mL). Hexanes (400 mL) were slowly added to the solution.
  • reaction mixture was stirred at 25°C to 30°C for 30 minutes.
  • the reaction mixture was filtered to obtain a solid.
  • the solid was washed with a mixture of ethyl acetate (20 mL) and hexanes (80 mL), then dried at 40°C to 45°C under reduced pressure to obtain l-(fert-butoxycarbonyl)-4-oxo-L-proline.
  • reaction mixture was quenched with deionized water (20 mL), then stirred at 20°C to 25°C for 30 minutes.
  • the resulting mixture was filtered through a Hyflo ® bed. The filtrate was washed with an aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water).
  • the organic layer was separated, then washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water).
  • Activated carbon (10 g) was added to the organic layer, then the reaction mixture was stirred at 25 °C to 30°C for 30 minutes.
  • the reaction mixture was filtered through a Hyflo ® bed, then concentrated at 50°C under reduced pressure.
  • the residue obtained was dissolved in ethyl acetate (200 mL) at 50°C to 55°C.
  • Hexanes (800 mL) were added at 50°C to 55°C over a period of one hour to 2 hours.
  • the reaction mixture was further cooled to 0°C to 5°C, then stirred at the same temperature for 3 hours.
  • the reaction mixture was filtered to obtain a solid.
  • reaction mixture was quenched with deionized water (600 mL), and then stirred for 10 minutes. The reaction mixture was allowed to settle for 15 minutes. The organic layer was separated, then washed with aqueous sodium bicarbonate (60 g sodium bicarbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), then concentrated at 50°C under reduced pressure to obtain a residue. The residue was dissolved in isopropyl alcohol (500 mL) to obtain a solution. The solution was concentrated at 50°C under reduced pressure, and used as such in the next step.
  • deionized water 600 mL
  • isopropyl alcohol 500 mL
  • Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C.
  • the reaction mixture was filtered through a Hyflo ® bed. The filtrate was heated to 70°C to 75°C.
  • Hydrobromic acid 48 %; 168 g was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes.
  • the reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 20°C to 25°C, and then stirred at the same temperature for 60 minutes.
  • reaction mixture was filtered to obtain a solid.
  • the solid obtained was washed with isopropyl alcohol (2 x 200 mL), then dried at 50°C under reduced pressure for 15 hours to obtain crude ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl ⁇ (l,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate.
  • the solution was cooled to 55°C to 60°C, and then stirred at the same temperature for 2 hours.
  • the solution was further cooled to 20°C to 25°C, and then stirred at the same temperature for 60 minutes to obtain a solid.
  • the solid was filtered, then washed with ethanol (100 mL), and then dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-yl ⁇ (1,3 -thiazolidin-3 -yl) methanone hemipentahydrobromide hydrate.

Abstract

The present invention provides a process for the preparation of (4R)-1-(tert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-yl}(1,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.

Description

PROCESS FOR THE PREPARATION OF (4R)-l-(TERT-BUTOXYCARBONYL)-
4-HYDROXY-L-PROLINE
Field of the Invention
The present invention provides a process for the preparation of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-l-(teri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
Figure imgf000003_0001
Formula IV
Background of the Invention
Tenelegliptin hydrobromide hydrate, chemically {(2S,4S)-4-[4-(3-Methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate of Formula I, is marketed in Japan for the treatment of type 2 diabetes mellitus.
Figure imgf000003_0002
Formula I
U.S. Patent Nos. 7,074,794 and 8,003,790 disclose processes for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3- thiazolidin-3-yl) methanone of Formula II, or salts thereof, comprising the steps of condensing (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV with thiazolidine to obtain fert-butyl (2S,4R)-4-hydroxy-2-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidine-l-carboxylate, followed by its oxidation using a pyridine-sulfur trioxide complex in dimethylsulfoxide to obtain fert-butyl (2S)-4-oxo-2-(l,3-thiazolidin-3- ylcarbonyl)pyrroli
Figure imgf000004_0001
Formula II
(4R)-l-(fert-Butoxycarbonyl)-4-hydroxy-L-proline of Formula IV is a key raw material for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof. The prior art process for the preparation of the compound of Formula IV involves the reaction of trans-4-hydroxy-L-proline with di-fert-butyl dicarbonate in the presence of a base in a mixture of water and an organic solvent. The insolubility of di-fert-butyl dicarbonate in water necessitates the use of an organic solvent in the reaction.
In a step towards green chemistry, the present invention involves the reaction of trans-4-hydroxy-L-proline with di-fert-butyl dicarbonate in water alone. The present inventors have found that eliminating the organic solvent reduces the time taken for the reaction without compromising the purity of the product.
Summary of the Invention
The present invention provides a process for the preparation of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-l-(teri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.
Figure imgf000004_0002
Formula IV A first aspect of the present invention provides a process for the preparation of (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV
Figure imgf000005_0001
Formula IV
wherein the process comprises reacting a compound of Formula III
Figure imgf000005_0002
Formula III
with di-fert-butyl dicarbonate in water.
A second aspect of the present invention provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3- thiazolidin-3-yl) methanone of Formula II, or salts thereof,
Figure imgf000005_0003
Formula II
wherein the process comprises the steps of:
a) reacting a compound of Formula III
Figure imgf000005_0004
Formula III with di-fert-butyl dicarbonate in water to obtain a compound of Formula IV; and
Figure imgf000006_0001
Formula IV
b) converting the compound of Formula IV to {(2S,4S)-4-[4-(3-methyl- l-phenyl- lH-pyrazol-5 -yl) piperazin- 1 -yl] pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl) methanone of Formula II, or salts thereof.
A third aspect of the present invention provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl- l-phenyl- lH-pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-yl}(l,3- thiazolidin-3 -yl) methanone of Formula II, or salts thereof,
Figure imgf000006_0002
Formula II
wherein the process comprises the steps of:
a) reacting a compound of Formula III
Figure imgf000006_0003
Formula III
with di-fert-butyl dicarbonate in water to obtain a compound of Formula IV;
Figure imgf000007_0001
Formula IV
b) oxidizing the compound of Formula IV to obtain a compound of Formula V;
Figure imgf000007_0002
Formula V
c) condensing the compound of Formula V with thiazolidine to obtain a
compound of Formula VI;
Figure imgf000007_0003
Formula VI
d) reacting the compound of Formula VI with a compound of Formula VII or salts thereof
Figure imgf000007_0004
Formula VII
to obtain a compound of Formula VIII; and
Figure imgf000008_0001
Formula VIII
e) deprotecting the compound of Formula VIII to obtain {(2S,4S)-4-[4-(3-methyl- 1 -phenyl- lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3- yl) methanone of Formula II, or salts thereof.
The following abbreviations are used in the present invention:
Boc tert-Butyloxycarbonyl
CDI Ι,Γ-Carbodiimidazole
DCC N,N'-Dicyclohexylcarbodiimide
DIC N,N'-Diisopropylcarbodiimide
DMAP 4-Dimethylaminopyridine
DEPC Diethyl phosphoryl cyanide
DMSO Dimethyl sulfoxide
DPPA Diphenylphosphoryl azide
EEDQ 2-Ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline
EDCI N-(3-Dimethylaminopropyl)-N'-etliylcarbodiimide
NHS N-Hydroxysuccinimide
HOBt Hydroxybenzotriazole
HOOBT 3-Hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine
PyBOP Benzotriazol-l-yl-ox rispyrrolidinophosphonium
hexafluorophosphate
KMn04 Potassium permanganate NaCIO Sodium hypochlorite
TCCA Trichloroisocyanuric acid
TEMPO (2,2,6,6-Tetramethylpiperidin- 1 -yl)oxyl
Detailed Description of the Invention
Various embodiments and variants of the present invention are described herein.
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
In the context of the present invention, "salts" refers to inorganic acid addition salts, organic acid addition salts, and salts formed with amino acids. Examples of inorganic acid addition salts include salts formed with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acid addition salts include salts formed with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, and methylsulfuric acid. Examples of amino acid salts include salts formed with glutamic acid and aspartic acid.
The reaction of the compound of Formula III with di-fert-butyl dicarbonate is carried out in the presence of a base in water to obtain a compound of Formula IV. The base is selected from organic or inorganic bases. Examples of organic bases include methylamine, ethylamine, diethylamine, triethylamine, diisopropylamine, and
diisopropylethylamine. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
In general, the compound of Formula III is reacted with di-fert-butyl dicarbonate using sodium hydroxide in water to obtain the compound of Formula IV.
The oxidation of the compound of Formula IV to obtain a compound of Formula V is carried out using an oxidizing agent. Examples of oxidizing agents include a pyridine- sulfur trioxide complex in DMSO, an alkaline solution of KMnO/t, oxalyl chloride in DMSO and triethylamine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in dichloromethane, NaCIO, a mixture of NaCIO and TEMPO, and a mixture of TCCA and TEMPO. The condensation of the compound of Formula V with thiazolidine to obtain a compound of Formula VI is carried out using a condensing agent. The condensing agent is selected from the group comprising of DCC, EDCI, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride. The condensation reaction is carried out in the presence of an additive. Examples of additives include NHS, HOBT, HOOBT, and DMAP.
In an embodiment of the present invention, the oxidation of the compound of Formula IV is carried out using a mixture of NaClO and TEMPO to obtain the compound of Formula V, followed by condensation of the compound of Formula V with thiazolidine in the presence of DCC and DMAP to obtain the compound of Formula VI.
The reaction of the compound of Formula VI with the compound of Formula VII to obtain a compound of Formula VIII is carried out in the presence of an acid catalyst. Examples of acid catalysts include acetic acid, p-toluenesulfonic acid, and borotriflouride etherate.
The deprotection of the compound of Formula VIII is carried out using conventional methods, such as those disclosed in Greene and Wuts, 2006. Greene 's Protective Groups in Organic Synthesis, 4th Edition.
The preparation and conversion of the compound of Formula VII into {(2S,4S)-4- [4-(3-methyl- 1 -phenyl- lH-pyrazol-5 -yl) piperazin- 1 -yl] pyrrolidin-2-yl} ( 1 ,3 -thiazolidin- 3-yl) methanone of Formula II, or salts thereof, is carried out by following the processes disclosed in U.S. Patent Nos. 7,074,794 and 8,003,790 or our co-pending Indian Patent Application Nos. 2347/DEL/2013, 3229/DEL/2013, and 2350/DEL/2013, which are incorporated herein by reference.
Method
The High Performance Liquid Chromatography (HPLC) purity was determined using an Agilent® Atlantis® T3 (250 x 4.6 mm), 5 μιη column with a flow rate of 1.0 mL/minute with gradient elution; Column oven temperature: 35°C; Sample tray temperature: 25°C to 30°C; Detector UV: 215 nm; Injection volume: 10 μί; Run time: 65 minutes.
The examples are set forth to aid the understanding of the invention but are not intended to and should not be construed to limit its scope in any way. Examples
Comparative Example 1 : Preparation of (4R)-l-(fer -butoxycarbonyl)-4-hvdroxy-L- proline (Formula IV) according to Example 1 of WO 2006/038119
Di-fert-butyl dicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in tetrahydrofuran (500 mL) to obtain a reaction mixture. The reaction mixture was cooled to 5°C to 10°C. A solution of sodium hydroxide (30.5 g sodium hydroxide in 305 mL deionized water) was added slowly to the reaction mixture over a period of 10 minutes to 20 minutes. The reaction mixture was allowed to warm to 20°C to 25 °C, and then stirred at the same temperature for 20 hours to 24 hours. The reaction mixture was cooled to 5°C to 10°C. The pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (290 mL; 3M). The reaction mixture was stirred for 10 minutes, then allowed to settle for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with an aqueous solution of sodium chloride (200 mL; 40 g sodium chloride in 200 mL deionized water). The organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (500 mL), then concentrated at 50°C to 55°C under reduced pressure. The residue obtained was again dissolved in ethyl acetate (200 mL) to obtain a solution. Hexanes (100 mL) were slowly added to the solution over a period of 20 minutes to 30 minutes. The reaction mixture was stirred at 20°C to 25°C for 60 minutes to obtain a solid. Hexanes (700 mL) were again slowly added to the slurry over a period of 60 minutes. The slurry was cooled to 0°C to 5°C, and then stirred at the same temperature for 2 hours. The solid obtained was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, mixture of 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45°C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)- 4-hydroxy-L-proline .
Yield: 95.4 %
HPLC purity: 99.53 %
Comparative Example 2: Preparation of (4R)-l-(ferZ-butoxycarbonyl)-4-hvdroxy-L- proline (Formula IV) according to J Ors. Chem., 61(10):3534-3541 (1996)
Di-fert-butyl dicarbonate (332.6 g) and triethylamine (92.5 g) were added to a solution of trans-4-hydroxy-L-proline (100 g) in methanol (1000 mL) to obtain a reaction mixture. The reaction mixture was allowed to warm to 65°C to 68°C, then stirred at the same temperature for 2 hours to 3 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (1000 mL) and water (300 mL) were added to the residue and then the mixture was cooled to 0°C to 5°C. The pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (200 mL; 2.5 M). The solution was stirred for 10 minutes, then allowed to settle for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with an aqueous solution of sodium chloride (200 mL; 40 g sodium chloride in 200 mL deionized water). The organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (500 mL), then concentrated at 50°C to 55°C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) to obtain a solution. Hexanes (100 mL) were slowly added to the solution over a period of 20 minutes to 30 minutes. The reaction mixture was stirred at 20°C to 25°C for 60 minutes to obtain a solid. Hexanes (700 mL) were again slowly added to the solid to obtain a slurry, which was then stirred for 60 minutes. The slurry was cooled to 0°C to 5°C, then stirred at the same temperature for 2 hours. The solid was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45°C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)- 4-hydroxy-L-proline.
Yield: 88.5 %
HPLC Purity: 99.24 %
Example 1 : Preparation of (4R)-l-(fer^-butoxycarbonyl)-4-hvdroxy-L-proline (Formula IV]
Di-fert-butyl dicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in water (200 mL). A solution of sodium hydroxide (33.6 g sodium hydroxide in 100 mL deionized water) was added slowly to the reaction mixture over a period of 10 minutes to 20 minutes. The reaction mixture was allowed to warm to 40°C to 45 °C, then was stirred at the same temperature for 3 hours to 4 hours. The reaction mixture was cooled to 25°C to 30°C. Ethyl acetate (1000 mL) was added to the reaction mixture, and then the mixture was cooled to 0°C to 5°C. The pH of the reaction mixture was adjusted to 2.0 to 2.5 using aqueous hydrochloric acid (275 mL; 3M). The reaction mixture was stirred for 10 minutes, and then allowed to settle for 15 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (4 x 200 mL) at 15°C to 20°C. The combined organic layers were washed with an aqueous solution of sodium chloride (100 mL; 20 g sodium chloride in 100 mL deionized water). The organic layer was concentrated at 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (200 mL), then stirred at 40°C to 45°C for 20 minutes. Hexanes (100 mL) were slowly added to the solution over a period of 20 minutes to 30 minutes at 25 °C to 30°C, and then the mixture was stirred at the same temperature for 60 minutes to obtain a solid. Hexanes (700 mL) were slowly added to the solid to obtain a slurry, and then the mixture was stirred over a period of 60 minutes. The slurry was cooled to 0°C to 5°C, then stirred at the same temperature for 2 hours. The solid was filtered, then washed with a precooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, a mixture of 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45 °C under reduced pressure to obtain (4R)-l-(fert-butoxycarbonyl)-4-hydroxy-L- proline.
Yield: 95.8 %
HPLC Purity: 99.93 %
Example 2: Preparation of l-(ferf-butoxycarbonyl)-4-oxo-L-proline (Formula V)
Trichloroisocyanuric acid (75.6 g) was added to a solution of (4R)-l-(fert- butoxycarbonyl)-4-hydroxy-L-proline (Formula IV, prepared according to Example 1; 100 g) in ethyl acetate (1000 mL). The solution was cooled to -5°C to 0°C. A solution of TEMPO in ethyl acetate (3.38 g in 50 mL ethyl acetate) was slowly added to the reaction mixture at -5°C to 10°C, then the reaction mixture was stirred at the same temperature for 20 minutes. The reaction mixture was heated to 25 °C to 30°C, then stirred at the same temperature for 60 minutes. After completion of the reaction, the reaction mixture was quenched with deionized water (200 mL), then stirred for 60 minutes at 25°C to 30°C. The reaction mixture was filtered through a Hyflo® bed. The filtrate was washed with deionized water (2 x 200 mL). The layers were separated. The organic layer was washed with an aqueous solution of sodium chloride (40 g sodium hydroxide in 200 mL deionized water). The organic layer was concentrated at 50°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (100 mL). Hexanes (400 mL) were slowly added to the solution. The reaction mixture was stirred at 25°C to 30°C for 30 minutes. The reaction mixture was filtered to obtain a solid. The solid was washed with a mixture of ethyl acetate (20 mL) and hexanes (80 mL), then dried at 40°C to 45°C under reduced pressure to obtain l-(fert-butoxycarbonyl)-4-oxo-L-proline.
Yield: 95.9 %
Example 3: Preparation of fert-butyl (2S)-4-oxo-2-(1.3-thiazolidin-3- ylcarbonyl)pyrrolidine-l-carboxylate (Formula VI)
A solution of DCC (107.8 g) in toluene (300 mL) was added to a solution of 1- (fert-butoxycarbonyl)-4-oxo-L-proline (Formula V, prepared according to Example 2; 100 g) in toluene (900 mL) at -10°C to -5°C. The reaction mixture was stirred for 30 minutes at -10°C to -5°C. 4-Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at -6°C to -2°C over a period of 15 minutes to 20 minutes. The reaction mixture was allowed to warm to 0°C to 5°C, then stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), then stirred at 20°C to 25°C for 30 minutes. The resulting mixture was filtered through a Hyflo® bed. The filtrate was washed with an aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated, then washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water). Activated carbon (10 g) was added to the organic layer, then the reaction mixture was stirred at 25 °C to 30°C for 30 minutes. The reaction mixture was filtered through a Hyflo® bed, then concentrated at 50°C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) at 50°C to 55°C. Hexanes (800 mL) were added at 50°C to 55°C over a period of one hour to 2 hours. The reaction mixture was further cooled to 0°C to 5°C, then stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solid was washed with a precooled (0°C to 5°C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), then dried at 40°C to 45°C under reduced pressure to obtain fert-butyl (2S)-4- oxo-2-( 1 ,3 -thiazolidin-3 -ylcarbonyl)pyrrolidine- 1 -carboxylate .
Yield: 81.7 %
HPLC Purity: 98.97 % Example 4: Preparation of fert-butyl (2S.4S)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yll-2-(1.3-thiazolidin-3-ylcarbonyl) pyrrolidine- 1-carboxylate (Formula VIII)
A solution of sodium triacetoxy borohydride (98.8 g) in toluene (300 mL) was added to a mixture of fert-butyl (2S)-4-oxo-2-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidine-l- carboxylate (Formula VI, prepared according to Example 3; 100 g) and 1 -(3 -methyl- 1- phenyl-lH-pyrazol-5-yl)piperazine acetate (Formula VII; 100.7 g) in toluene (800 mL) at 5°C to 10°C. The reaction mixture was stirred at 20°C to 25°C for 3 hours. The progress of the reaction was monitored by HPLC. After the reaction was complete, the reaction mixture was quenched with deionized water (600 mL), and then stirred for 10 minutes. The reaction mixture was allowed to settle for 15 minutes. The organic layer was separated, then washed with aqueous sodium bicarbonate (60 g sodium bicarbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), then concentrated at 50°C under reduced pressure to obtain a residue. The residue was dissolved in isopropyl alcohol (500 mL) to obtain a solution. The solution was concentrated at 50°C under reduced pressure, and used as such in the next step.
Example 5: Preparation of {(2S.4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1-vH pyrrolidin-2-yl}(1.3-thiazolidin-3-yl)methanone hemipentahydrobromide hydrate (Formula I)
Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was filtered through a Hyflo® bed. The filtrate was heated to 70°C to 75°C. Hydrobromic acid (48 %; 168 g) was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes. The reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 20°C to 25°C, and then stirred at the same temperature for 60 minutes. The reaction mixture was filtered to obtain a solid. The solid obtained was washed with isopropyl alcohol (2 x 200 mL), then dried at 50°C under reduced pressure for 15 hours to obtain crude {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate.
Yield: 90 % Example 6: Purification of {(2S.4S)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1-vH pyrrolidin-2-yl}(1.3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate (Formula I)
A reaction mixture containing {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl) methanone hemipentahydrobromide hydrate (100 g; prepared according to Example 5) in ethanol (700 mL) was heated to 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to 65°C to 68°C, then deionized water (10 mL) was added at the same temperature. The solution was cooled to 55°C to 60°C, and then stirred at the same temperature for 2 hours. The solution was further cooled to 20°C to 25°C, and then stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, then washed with ethanol (100 mL), and then dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-yl} (1,3 -thiazolidin-3 -yl) methanone hemipentahydrobromide hydrate.
Yield: 90 %
HPLC Purity: 99.93 %

Claims

We claim:
1. A process for the preparation of (4R)-l-(feri-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV,
Figure imgf000017_0001
Formula IV
wherein the process comprises reacting a compound of Formula III
Figure imgf000017_0002
Formula III
with di-fert-butyl dicarbonate in water.
A process for the preparation of {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof,
Figure imgf000017_0003
Formula II
wherein the process comprises the steps of:
a) reacting a compound of Formula III
Figure imgf000018_0001
Formula III
with di-fert-butyl dicarbonate in water to obtain a compound of Formula IV; and
Figure imgf000018_0002
Formula IV
b) converting the compound of Formula IV to {(2S,4S)-4-[4-(3-methyl-l-phenyl- lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}(l,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof.
A process for the preparation of {(2S,4S)-4-[4-(3-methyl- 1-phenyl- lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl) methanone of Formula II, or salts thereof
Figure imgf000018_0003
Formula II
wherein the process comprises the steps of:
a) reacting a compound of Formula III
Figure imgf000019_0001
Formula III
with di-fert-butyl dicarbonate in water to obtain a compound of Formula IV;
Figure imgf000019_0002
Formula IV
b) oxidizing the compound of Formula IV to obtain a compound of Formula V;
Figure imgf000019_0003
c) condensing the compound of Formula V with thiazolidine to obtain a
compound of Formula VI;
Figure imgf000019_0004
Formula VI
d) reacting the compound of Formula VI with a compound of Formula VII or salts thereof
Figure imgf000020_0001
Formula VII
to obtain a compound of Formula VIII; and
Figure imgf000020_0002
Formula VIII
e) deprotecting the compound of Formula VIII to obtain {(2S,4S)-4-[4-(3-methyl- 1 -phenyl- lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl}( l,3-thiazolidin-3- yl) methanone of Formula II, or salts thereof.
4. The process according to claim 2 or claim 3, wherein the oxidizing agent is selected from the group consisting of pyridine-sulfur trioxide complex in DMSO, an alkaline solution of KMnOzt, oxalyl chloride in DMSO and a triethylamine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in dichloromethane, NaClO, a mixture of NaClO and TEMPO, and a mixture of TCCA and TEMPO. 5. The process according to claim 4, wherein the oxidizing agent is a mixture of NaClO and TEMPO.
6. The process according to claim 2 or claim 3, wherein the condensation is carried out in the presence of a condensation agent and an additive.
7. The process according to claim 6, wherein the condensation agent is selected from the group consisting of DCC, EDCI, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride.
8. The process according to claim 6, wherein the additive is selected from the group consisting of NHS, HOBT, HOOBT, and DMAP.
9. The process according to claim 7, wherein the condensation agent is DCC.
10. The process according to claim 8, wherein the additive is DMAP.
PCT/IB2015/058944 2014-11-19 2015-11-18 Process for the preparation of (4r)-1-(tert-butoxycarbonyl)-4-hydroxy-l-proline WO2016079699A1 (en)

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