WO2015019238A1 - Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one - Google Patents

Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one Download PDF

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WO2015019238A1
WO2015019238A1 PCT/IB2014/063486 IB2014063486W WO2015019238A1 WO 2015019238 A1 WO2015019238 A1 WO 2015019238A1 IB 2014063486 W IB2014063486 W IB 2014063486W WO 2015019238 A1 WO2015019238 A1 WO 2015019238A1
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formula
compound
thiazolidin
pyrrolidin
protected
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PCT/IB2014/063486
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French (fr)
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WO2015019238A8 (en
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Prabhat GIRI
Achyut TENDOLKAR
Ashwini Kumar Kapoor
Dhiren Chandra BARMAN
Asok Nath
Mohan Prasad
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Ranbaxy Laboratories Limited
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 an N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III.
  • the present invention also provides a process for the preparation of ⁇ (25',45)-4-[4-(3-methyl-l-phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl ⁇ ( 1 ,3 -thiazolidin-3 -yl)methanone, or salts thereof, using the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III.
  • U.S. Patent Nos. 7,074,794 and 8,003,790 disclose processes 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, comprising the steps of condensing N-tert-butoxycarbonyl-L-trans-4-hydroxyproline with thiazolidine to obtain 3- [(2S,4R)- 1 -tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]- 1 ,3-thiazolidine, followed by its oxidation using a sulfur trioxide pyridine complex in dimethylsulfoxide to obtain 3-(( ⁇ S)- 1 -tert-butoxycarbonyl-4-oxo-2-pyrrolidinecarbonyl)- 1 ,
  • the present inventors have found that carrying out the oxidation step prior to the condensation step results in better yield and purity of the N-protected (5 ⁇ S)-5-(l,3- thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III, and the ⁇ (25 * ,45)-4-[4-(3 ⁇ 1- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl ⁇ ( 1 ,3-thiazolidin-3-yl)methanone of Formula II, or salts thereof.
  • the present invention provides improved processes for the preparation of ⁇ (2S, 4 ⁇ S)- 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, and N-protected (5 ⁇ S)-5-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidin-3-one of Formula III.
  • a first aspect of the present invention provides a process for the preparation of an N-protected (55)-5-(l,3-thiazolidin-3- lcarbonyl)pyrrolidin-3-one of Formula III
  • a second aspect of the present invention provides 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, wherein the process comprises the steps of:
  • a third aspect of the present invention provides ⁇ (25 * ,45)-4-[4-(3-methyl-l-phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl ⁇ ( 1 ,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate of Formula I having an HPLC purity greater than 99%.
  • protecting group (Pro) refers to an amino-protecting group.
  • amino-protecting groups include Fmoc, Troc, Boc, Teoc, Alloc, Cbz, trifluoroacetamide, benzylamine, allylamine, and tritylamine.
  • salts refer 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 methane sulfonic acid, benzene sulfonic 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 oxidation of the compound of Formula IV to the compound of Formula V is carried out using a pyridine-sulfur trioxide complex in DMSO, an alkaline solution of potassium permanganate, oxalyl chloride in DMSO and a tertiary amine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in dichloromethane, sodium hypochlorite, or a mixture of TCCA and TEMPO.
  • the condensation of the compound of Formula V with thiazolidine is carried out using a condensing agent selected from the group comprising of DCC, EDC, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride.
  • a condensing agent selected from the group comprising of DCC, EDC, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride.
  • additives examples include HONSu, HOBT, HOOBT, and DMAP.
  • the oxidation of the compound of Formula IV is carried out using a mixture of TCCA and TEMPO to obtain a 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 III.
  • the conversion of the compound of Formula III into the compound of Formula II, or salts thereof, is carried out by reacting the compound of Formula III with the compound of Formula VI in the presence of a metal hydrogen complex to obtain a compound of Formula VII, which is then deprotected to obtain the compound of Formula II.
  • metal hydrogen complexes include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.
  • the compound of Formula VI may be prepared by the processes disclosed in U.S. Patent Nos. 7,074,794 and 8,003,790.
  • the reaction of the compound of Formula III with the compound of Formula VI may also be carried out in the presence of an acid catalyst.
  • acid catalysts may include acetic acid, p-toluenesulfonic acid, and borotriflouride.
  • Deprotection of the compound of Formula VII may be carried out using conventional methods disclosed in Greene, T.Q. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 4th Edition, 2006.
  • HPLC purity was determined using a Gemini ® C18 (250 x 4.6) mm, 5 ⁇ column with a flow rate of l .OmL/minute with gradient elution; Column oven temperature 35°C; Sample tray temperature: 25°C to 30°C; Detector UV: 215 nm; Injection volume: 10 ⁇ ; Run time: 65 minutes.
  • Di-tert-butyldicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in tetrahydrofuran (500 mL). The reaction mixture was cooled to a temperature of 5°C to 10°C. A solution of sodium hydroxide (prepared by adding 30.5 g sodium hydroxide to 305 mL deionized water) was added slowly to the reaction mixture over 10 minutes to 20 minutes. The reaction mixture was allowed to warm to a temperature of 20°C to 25°C, and stirred at the same temperature for 20 hours to 24 hours. The reaction mixture was cooled to a temperature of 5°C to 10°C.
  • sodium hydroxide prepared by adding 30.5 g sodium hydroxide to 305 mL deionized water
  • 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, and 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; prepared by adding 40 g sodium hydroxide to 200 mL deionized water).
  • the organic layer was concentrated at a temperature of about 50°C to 55°C under reduced pressure to obtain a residue.
  • the residue was dissolved in ethyl acetate (500 mL), and again concentrated at 50°C to 55°C under reduced pressure.
  • Trichloroisocyanuric acid (75.6 g) was added to a solution of ( R)- ⁇ -(tert- butoxycarbonyl)-4-hydroxy-L-proline (Formula IV, prepared according to the process of Example 1 ; 100 g) in ethyl acetate (1000 mL). The solution was cooled to 0°C to -5°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, and the reaction mixture was stirred at the same temperature for 20 minutes. The reaction mixture was heated to a temperature of 25°C to 30°C, and stirred at the same temperature for 60 minutes.
  • reaction mixture was quenched with deionized water (200 mL), and stirred for 60 minutes at a temperature of about 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 (prepared by adding 40 g sodium hydroxide to 200 mL deionized water). The organic layer was concentrated at a temperature of about 50°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate ( 100 mL).
  • the reaction mixture was allowed to warm to a temperature of 0°C to 5°C, and stirred at the same temperature for 60 minutes.
  • the reaction mixture was quenched with deionized water (20 mL), and stirred at 20°C to 25°C for 30 minutes.
  • the resulting mixture was filtered through a Hyflo® bed. The filtrate was washed with aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water).
  • the organic layer was separated and 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, and the reaction mixture was stirred at 25°C to 30°C for 30 minutes.
  • the reaction mixture was filtered through a Hyflo® bed, and concentrated at a temperature of 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 1 to 2 hours.
  • the reaction mixture was further cooled to a temperature of 0°C to 5°C, and 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 stirred for 10 minutes. The reaction mixture was allowed to settle for about 15 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate (60 g sodium bicarbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), and concentrated at a temperature of about 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 a temperature of about 50°C under reduced pressure, and used as such in the next step.
  • deionized water 600 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 a temperature of 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 a temperature of 20°C to 25 °C, and 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), and dried at 50°C under reduced pressure for 15 hours to obtain crude ⁇ (25 * ,45)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl ⁇ ( 1 ,3 -thiazolidin-3 -yl)methanone
  • Example 6 Purification of ⁇ (2 ⁇ '.4 ⁇ )-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl ⁇ ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)
  • hemipentahydrobromide hydrate (100 g; prepared according to the process of Example 5) in ethanol (700 mL) was heated at 70°C to 75°C to obtain a solution.
  • the solution was filtered at the same temperature.
  • the filtrate was allowed to cool to a temperature of 65 °C to 68°C, and deionized water (10 mL) was added at the same temperature.
  • the solution was cooled to a temperature of 55°C to 60°C, and stirred at the same temperature for 2 hours.
  • the solution was further cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes to obtain a solid.

Abstract

The present invention provides a process for the preparation of an N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. The invention also provides a process for the preparation of {(25',45)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin-l-yl]pyrrolidin-2-yl}(l,3-thiazolidin-3-yl)methanone, or salts thereof, using the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. (III)

Description

PROCESS FOR THE PREPARATION OF N-PROTECTED (5S)-5-(l,3- THIAZOLIDIN-3-YLCARBONYL)PYRROLIDIN-3-ONE
Field of the Invention
The present invention provides a process for the preparation of an N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. The present invention also provides a process for the preparation of {(25',45)-4-[4-(3-methyl-l-phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone, or salts thereof, using the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III.
Figure imgf000002_0001
Formula III
Background of the Invention
{ (2S, 4S) -4- [4-(3 -Methyl- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2- yl} (1,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate of Formula I is marketed in Japan for the treatment of Type 2 Diabetes Mellitus.
Figure imgf000002_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- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl} ( 1,3- thiazolidin-3-yl)methanone of Formula II, or salts thereof, comprising the steps of condensing N-tert-butoxycarbonyl-L-trans-4-hydroxyproline with thiazolidine to obtain 3- [(2S,4R)- 1 -tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]- 1 ,3-thiazolidine, followed by its oxidation using a sulfur trioxide pyridine complex in dimethylsulfoxide to obtain 3-((<S)- 1 -tert-butoxycarbonyl-4-oxo-2-pyrrolidinecarbonyl)- 1 ,3 -thiazolidine .
Figure imgf000003_0001
Formula II
The process disclosed in U.S. Patent No. 7,074,794 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, involves carrying out the condensation step prior to the oxidation step.
The present inventors have found that carrying out the oxidation step prior to the condensation step results in better yield and purity of the N-protected (5<S)-5-(l,3- thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III, and the {(25*,45)-4-[4-(3^ε^1- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3-thiazolidin-3-yl)methanone of Formula II, or salts thereof.
Summary of the Invention
The present invention provides improved processes for the preparation of {(2S, 4<S)- 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, and N-protected (5<S)-5-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidin-3-one of Formula III.
Figure imgf000003_0002
Formula II Formula III A first aspect of the present invention provides a process for the preparation of an N-protected (55)-5-(l,3-thiazolidin-3- lcarbonyl)pyrrolidin-3-one of Formula III
Figure imgf000004_0001
Formula III
wherein the process comprises the steps of:
a) oxidizing a compound of Formula IV
Figure imgf000004_0002
Formula IV
to obtain a compound of Formula V; and
Figure imgf000004_0003
Formula V
b) condensing the compound of Formula V with thiazolidine to obtain the N- protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III wherein 'Pro' is a protecting group.
A second aspect of the present invention provides 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, wherein the process comprises the steps of:
a) oxidizing a compound of Formula IV
Figure imgf000005_0001
Formula IV
to obtain a compound of Formula V;
Figure imgf000005_0002
Formula V
b) condensing the compound of Formula V with thiazolidine to obtain N- protected (55)-5-(l,3-thiazolidin-3- lcarbonyl)pyrrolidin-3-one of Formula III;
Figure imgf000005_0003
Formula III
c) reacting the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III with a compound of Formula VI or salts thereof
Figure imgf000005_0004
Formula VI
to obtain a compound of Formula VII; and
Figure imgf000006_0001
Formula VII
d) deprotecting the compound of Formula VII to obtain {(25*,45)-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
wherein 'Pro' is a protecting group.
A third aspect of the present invention provides {(25*,45)-4-[4-(3-methyl-l-phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate of Formula I having an HPLC purity greater than 99%.
The following ; abbreviations are used in the present invention:
Alloc Allyl carbamate
Boc tert-Butyloxycarbonyl
Cbz Carboxybenzyl
CDI Carbodiimidazole
DCC Ν,Ν' -Dicyclohexylcarbodiimide
DIC N, N '-diisopropylcarbodiimide
DMAP 4-Dimethylaminopyridine
DEPC Diethylphosphoryl cyanide
DMSO Dimethyl sulfoxide
DPPA Diphenylphosphoryl azide
EEDQ 2-Ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroxyquinoline
EDCI N-(3 -dimethylaminopropyl) -N ' -ethy lcarbodiimide
Fmoc 9-Fluorenylmethyl carbamate
HONSu N-hydroxysuccinimide
HOBT Hydroxybenzotriazole HOOBT 3-Hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine
PyBOP Benzotriazol- 1 -yl-oxytrispyrrolidinophosphonium
hexafluorophosphate
KMn04 Potassium permanganate
NaCIO Sodium hypochlorite
Troc 2,2,2-Trichloroethyl carbamate
TCCA Trichloroisocyanuric
Teoc 2-(Trimethylsilyl)ethyl carbamate
TEMPO (2,2,6,6-Tetramethylpiperidin
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.
The term "protecting group (Pro)", as used herein, refers to an amino-protecting group. Examples of the amino-protecting groups include Fmoc, Troc, Boc, Teoc, Alloc, Cbz, trifluoroacetamide, benzylamine, allylamine, and tritylamine.
In the context of the present invention, salts refer 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 methane sulfonic acid, benzene sulfonic 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 oxidation of the compound of Formula IV to the compound of Formula V is carried out using a pyridine-sulfur trioxide complex in DMSO, an alkaline solution of potassium permanganate, oxalyl chloride in DMSO and a tertiary amine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in dichloromethane, sodium hypochlorite, or a mixture of TCCA and TEMPO. The condensation of the compound of Formula V with thiazolidine is carried out using a condensing agent selected from the group comprising of DCC, EDC, 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 HONSu, 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 TCCA and TEMPO to obtain a 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 III.
The conversion of the compound of Formula III into {(25*,45)-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, is carried out by following the processes disclosed in U.S. Patent Nos. 7,074,794 and 8,003,790, which are incorporated herein by reference.
In general, the conversion of the compound of Formula III into the compound of Formula II, or salts thereof, is carried out by reacting the compound of Formula III with the compound of Formula VI in the presence of a metal hydrogen complex to obtain a compound of Formula VII, which is then deprotected to obtain the compound of Formula II. Examples of metal hydrogen complexes include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.
The compound of Formula VI may be prepared by the processes disclosed in U.S. Patent Nos. 7,074,794 and 8,003,790.
The reaction of the compound of Formula III with the compound of Formula VI may also be carried out in the presence of an acid catalyst. Examples of acid catalysts may include acetic acid, p-toluenesulfonic acid, and borotriflouride.
Deprotection of the compound of Formula VII may be carried out using conventional methods disclosed in Greene, T.Q. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 4th Edition, 2006.
Method
The HPLC purity was determined using a Gemini® C18 (250 x 4.6) mm, 5 μιη column with a flow rate of l .OmL/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
Example 1 : Preparation of (4 i?)-l-(fer^butoxycarbonyl)-4-hvdroxy-L-proline (Formula
Di-tert-butyldicarbonate (183 g) was added to a solution of trans-4-hydroxy-L- proline (100 g) in tetrahydrofuran (500 mL). The reaction mixture was cooled to a temperature of 5°C to 10°C. A solution of sodium hydroxide (prepared by adding 30.5 g sodium hydroxide to 305 mL deionized water) was added slowly to the reaction mixture over 10 minutes to 20 minutes. The reaction mixture was allowed to warm to a temperature of 20°C to 25°C, and stirred at the same temperature for 20 hours to 24 hours. The reaction mixture was cooled to a temperature of 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, and 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; prepared by adding 40 g sodium hydroxide to 200 mL deionized water). The organic layer was concentrated at a temperature of about 50°C to 55°C under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (500 mL), and again 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 this solution over a period of 20 minutes to 30 minutes. The reaction mixture was stirred at 20°C to 25°C for 60 minutes. Hexanes (700 mL) were again slowly added to the reaction mixture over a period of 60 minutes. The reaction mixture was stirred at 20°C to 25°C for 2 hours. The reaction mixture was cooled to a temperature of about 0°C to 5°C, and stirred at the same temperature for 2 hours to obtain a solid. The solid was filtered, then washed with a pre-cooled mixture of ethyl acetate and hexanes (0°C to 5°C; 2 x 100 mL, prepared by mixing 40 mL ethyl acetate and 160 mL hexanes). The solid was dried at 40°C to 45 °C under reduced pressure to obtain ( R)-\-(tert- butoxycarbonyl)-4-hydroxy-L-proline.
Yield: 95.4%
Example 2: Preparation of l-(fer -butoxycarbonyl)-4-oxo-L-proline (Formula V)
Trichloroisocyanuric acid (75.6 g) was added to a solution of ( R)-\-(tert- butoxycarbonyl)-4-hydroxy-L-proline (Formula IV, prepared according to the process of Example 1 ; 100 g) in ethyl acetate (1000 mL). The solution was cooled to 0°C to -5°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, and the reaction mixture was stirred at the same temperature for 20 minutes. The reaction mixture was heated to a temperature of 25°C to 30°C, and stirred at the same temperature for 60 minutes. After completion of the reaction, the reaction mixture was quenched with deionized water (200 mL), and stirred for 60 minutes at a temperature of about 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 (prepared by adding 40 g sodium hydroxide to 200 mL deionized water). The organic layer was concentrated at a temperature of about 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 of ethyl acetate. 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), and 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 ferf-Butyl (2^)-4-oxo-2-(1.3-thiazolidin-3- ylcarbonvDpyrrolidine-l-carboxylate (Formula III)
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 IV, prepared according to the process of Example 2; 100 g) in toluene (900 mL) at -5°C to - 10°C, and the reaction mixture was stirred for 30 minutes at the same temperature. Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at a temperature of about -6°C to -2°C over a period of about 15 to 20 minutes. The reaction mixture was allowed to warm to a temperature of 0°C to 5°C, and stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), and stirred at 20°C to 25°C for 30 minutes. The resulting mixture was filtered through a Hyflo® bed. The filtrate was washed with aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated and 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, and the reaction mixture was stirred at 25°C to 30°C for 30 minutes. The reaction mixture was filtered through a Hyflo® bed, and concentrated at a temperature of 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 1 to 2 hours. The reaction mixture was further cooled to a temperature of 0°C to 5°C, and stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solid was washed with a pre-cooled (0°C to 5°C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), and dried at a temperature of 40°C to 45°C under reduced pressure to obtain fert-Butyl (25)-4-oxo-2-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidine- l-carboxylate.
Yield: 81.7%
HPLC Purity: 98.97%
Example 4: Preparation of ferf-butyl (2<SV4-r4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin-l-yll-2-(1.3-thiazolidin-3-ylcarbonyl)pyrrolidine- l-carboxylate (Formula VII)
A solution of sodium triacetoxy borohydride (98.8 g) in toluene (300 mL) was added to a mixture of fert-butyl (25)-4-oxo-2-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidine-l- carboxylate (Formula III, prepared according to the process of Example 3; 100 g) and 1- (3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine acetate (Formula VI; 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 stirred for 10 minutes. The reaction mixture was allowed to settle for about 15 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate (60 g sodium bicarbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), and concentrated at a temperature of about 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 a temperature of about 50°C under reduced pressure, and used as such in the next step.
Example 5: Preparation of {(2^,.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -vHpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)
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 a temperature of 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 a temperature of 20°C to 25 °C, and 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), and dried at 50°C under reduced pressure for 15 hours to obtain crude {(25*,45)-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%
Example 6: Purification of {(2^'.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)
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 the process of Example 5) in ethanol (700 mL) was heated at 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to a temperature of 65 °C to 68°C, and deionized water (10 mL) was added at the same temperature. The solution was cooled to a temperature of 55°C to 60°C, and stirred at the same temperature for 2 hours. The solution was further cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, washed with ethanol (100 mL), and 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-l- 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 an N-protected (5,S 5-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidin-3-one of Fo
Figure imgf000014_0001
Formula III
wherein the process comprises the steps of:
a) oxidizing a compound of Formula IV
Figure imgf000014_0002
Formula IV
a compound of Formula V; and
Figure imgf000014_0003
Formula V
b) condensing the compound of Formula V with thiazolidine to obtain the N- protected (5iS)-5-(1.3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III wherein 'Pro' is a protecting group.
2. A process for the preparation of {(25*,45)-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, wherein the process comprises the steps of:
a) oxidizing a compound of Formula IV
Figure imgf000015_0001
Formula IV
to obtain a compound of Formula V;
Figure imgf000015_0002
Formula V
b) condensing the compound of Formula V with thiazolidine to obtain an N- protected (55)-5-(l,3-thiazolidin-3- lcarbonyl)pyrrolidin-3-one of Formula III;
Figure imgf000015_0003
Formula III
c) reacting the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III with a compound of Formula VI, or salts thereof,
Figure imgf000015_0004
Formula VI
to obtain a compound of Formula VII; and
Figure imgf000016_0001
Formula VII
d) deprotecting the compound of Formula VII to obtain {(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
wherein 'Pro' is a protecting group.
3. The process according to claims 1 and 2, wherein the oxidation of the compound of Formula IV is carried out using pyridine-sulfur trioxide complex in DMSO, an alkaline solution of potassium permanganate, oxalyl chloride in DMSO and a tertiary amine, acetic anhydride in DMSO, EDCI in DMSO, chromium oxide pyridine complex in
dichloromethane, sodium hypochlorite, or a mixture of TCCA and TEMPO.
4. The process according to claims 1 and 2, wherein the condensation of the compound of Formula V with thiazolidine is carried out in the presence of a condensing agent and an additive.
5. The process according to claim 4, wherein the condensing agent is selected from the group comprising of DCC, EDC, EEDQ, CDI, DEPC, PyBOP, DPPA, isobutyl chloroformate, diethylacetyl chloride, and trimethylacetyl chloride.
6. The process according to claim 4, wherein the additive is selected from the group consisting of HONSu, HOBT, HOOBT, and DMAP.
7. The process according to claims 1 and 2, wherein condensation is carried out using DCC and DMAP.
8. { (2S,4S)-4- [4-(3-methyl- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2- yl} (1,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate having an HPLC purity greater than 99%.
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