WO2015019239A1 - Process for the preparation of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine - Google Patents

Process for the preparation of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine Download PDF

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WO2015019239A1
WO2015019239A1 PCT/IB2014/063487 IB2014063487W WO2015019239A1 WO 2015019239 A1 WO2015019239 A1 WO 2015019239A1 IB 2014063487 W IB2014063487 W IB 2014063487W WO 2015019239 A1 WO2015019239 A1 WO 2015019239A1
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formula
compound
phenyl
methyl
pyrazol
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PCT/IB2014/063487
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French (fr)
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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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms

Definitions

  • the present invention provides a process for the preparation of l-(3-methyl-l- phenyl- lH-pyrazol-5-yl)piperazine of Formula III, or salts thereof.
  • the 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, or salts thereof, using 1 -(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III, or salts thereof.
  • U.S. Patent No. 7,074,794 discloses 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, or salts thereof, comprising the steps of: reaction of 1-tert- butoxycarbonylpiperazine with a diketene to obtain l-acetoacetyl-4-tert- butoxycarbonylpiperazine; reaction of the l-acetoacetyl-4-tert-butoxycarbonylpiperazine with phenylhydrazine in the presence of methane sulfonic acid, followed by the addition of pyridine and cyclization with phosphorus oxy chloride to obtain l-tert-butoxycarbonyl-4- (3-methyl-l-phenyl-5-pyr
  • the present invention provides an improved, economical, and industrially advantageous process for the preparation of ⁇ (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, and 1 -(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III.
  • the process of the present invention circumvents the use of a diketene and hazardous chemicals such as phosphorus oxychloride, pyridine, and trifluoroacetic acid.
  • a first aspect of the present invention provides a process for the preparation of 1- (3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III, or salts thereof,
  • 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, wherein the process comprises the steps of:
  • protecting group (Pro) refers to an amino-protecting group.
  • amino-protecting groups include 9-fluorenylmethyl carbamate (Fmoc), 2,2,2-trichloroethyl carbamate (Troc), ethyl carbamate, t-butyl carbamate (Boc), 2-(trimethylsilyl)ethyl carbamate (Teoc), allyl carbamate (Alloc), carboxybenzyl (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 methane sulfonic acid.
  • amino acid salts include salts formed with glutamic acid and aspartic acid.
  • alkylacetoacetates examples include ethylacetoacetate, n-propylacetoacetate, iso-propylacetoacetate, n-butylacetoacetate, and t-butylacetoacetate.
  • the compound of Formula IV is reacted with an alkylacetoacetate in the presence of phenylhydrazine to obtain a compound of Formula V.
  • the compound of Formula V is cyclized using a dehydrating agent in the presence of a base to obtain a compound of Formula VI.
  • dehydrating agents include phosphorus pentoxide and phosphorus pentasulphide.
  • bases include inorganic and organic bases. Examples of inorganic bases include sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Examples of organic bases include methyl amine, ethylamine, and triethylamine.
  • the compound of Formula VI is deprotected to obtain a compound of Formula III, which is reacted with a compound of Formula VII in the presence of a metal hydrogen complex to obtain a compound of Formula VIII.
  • metal hydrogen complexes include sodium borohydride, sodium cyanoborohydride, and sodium
  • the compound of Formula VII 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 VII may also be carried out in the presence of an acid catalyst.
  • acid catalysts include acetic acid, p-toluenesulfonic acid, and boron trifluoride.
  • the compound of Formula VIII is deprotected 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, using conventional methods disclosed in Greene, T.Q. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 4th Edition, 2006.
  • the compound of Formula III may also be converted into ⁇ (2S,4S)-4-[4-(3-methyl-
  • HPLC purity was determined using a Gemini ® C18 (250 x 4.6) mm, 5 ⁇ column with a flow rate of 1.0 mL/minute with gradient elution; Column oven
  • Ethylacetoacetate (82.2 g) was added to a solution of ethyl piperazine-1- carboxylate (Formula IV; 100 g) in toluene (1000 mL), and the reaction mixture was heated at 100°C to 110°C for 24 hours. The reaction mixture was cooled to a temperature of 0°C to 5°C. Phenyl hydrazine (68.4 g) was slowly added to the reaction mixture at 0°C to 10°C over a period of 15 minutes to 20 minutes. The reaction mixture was heated to 20°C to 25°C, and stirred at the same temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated at a temperature of about 55°C under reduced pressure to obtain a residue.
  • Formula IV ethyl piperazine-1- carboxylate
  • the reaction mixture was stirred at 35°C to 40°C for 30 minutes. The reaction mixture was allowed to settle for about 15 minutes. The organic layer was separated and the aqueous layer was extracted with toluene (2 x 200 mL) at 35°C to 40°C. The combined organic layers were washed with deionized water (500 mL) at 25°C to 30°C. The organic layer was concentrated at a temperature of about 55°C under reduced pressure to obtain a residue. The residue was dissolved in methanol (200 mL), and concentrated at 55°C under reduced pressure to obtain a residue. The residue was again dissolved in methanol (500 mL). Deionized water (250 mL) was added.
  • Potassium hydroxide (301.4 g) was added to the above reaction mixture, and the reaction mixture was heated to a temperature of about 80°C to 85°C for 2 hours to 3 hours.
  • the reaction mixture was allowed to cool to a temperature of 50°C to 55°C, and quenched with toluene (500 mL) and deionized water (100 mL).
  • the reaction mixture was allowed to settle for 15 minutes, and the layers were separated at a temperature of about 50°C to 55°C.
  • the aqueous layer was extracted with toluene (2 x 200 mL) at a temperature of 50°C to 55°C.
  • the organic layers were combined and washed with an aqueous solution of sodium chloride (3 x 200 mL; prepared by adding 120 g sodium chloride to 600 mL deionized water) at 50°C to 55°C.
  • the organic layer was separated, washed with deionized water (100 mL) at 52°C to 55°C, and concentrated at 100°C to 110°C under atmospheric pressure to a volume of about 560 mL.
  • the concentrated solution was cooled to a temperature of 50°C to 55 °C, and glacial acetic acid (28.5 g) was slowly added at 50°C to 55°C.
  • the reaction mixture was stirred at the same temperature for 60 minutes, allowed to cool to a temperature of 20°C to 25°C, and stirred at the same temperature for 60 minutes.
  • the reaction mixture was then cooled to a temperature of about 0°C to about 5°C, and stirred at the same temperature for 60 minutes.
  • the reaction mixture was filtered.
  • the solid obtained was washed with toluene (100 mL) at 0°C to 5°C, and then dried in an air oven at 40°C to 45°C for 15 hours to 20 hours to obtain l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine acetate.
  • 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 an aqueous sodium bicarbonate solution (60 g sodium carbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), and concentrated at about 50°C under reduced pressure to obtain a residue.
  • deionized water 600 mL
  • aqueous sodium bicarbonate solution 60 g sodium carbonate in 600 mL deionized water
  • Activated carbon (10 g) was added to a solution of the residue (Formula VIII; prepared according to the process of Example 2) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was stirred at the same temperature for 30 minutes. 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 at 70°C to 77°C for 2 hours to 3 hours. The progress of the reaction was monitored by HPLC.
  • 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 ⁇ (2S,4S)-4-[4-(3 -methyl- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2- yl ⁇ (l,3-thiazolidin-3-yl)methanone hemipentahydrobromide hydrate.
  • 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.

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Abstract

The present invention provides a process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine of Formula (III), or salts thereof. The 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, or salts thereof, using 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula (III), or salts thereof.

Description

PROCESS FOR THE PREPARATION OF 1 -(3-METHYL- 1-PHENYL- 1H- PYRAZOL-5-YL)PIPERAZINE
Field of the Invention
The present invention provides a process for the preparation of l-(3-methyl-l- phenyl- lH-pyrazol-5-yl)piperazine of Formula III, or salts thereof. The 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, or salts thereof, using 1 -(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III, or salts thereof.
Figure imgf000002_0001
Formula III
Background of the Invention
{(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 represented by Formula I, is marketed in Japan for the treatment of Type 2 Diabetes Mellitus.
Figure imgf000002_0002
Formula I
U.S. Patent No. 7,074,794 discloses 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, or salts thereof, comprising the steps of: reaction of 1-tert- butoxycarbonylpiperazine with a diketene to obtain l-acetoacetyl-4-tert- butoxycarbonylpiperazine; reaction of the l-acetoacetyl-4-tert-butoxycarbonylpiperazine with phenylhydrazine in the presence of methane sulfonic acid, followed by the addition of pyridine and cyclization with phosphorus oxy chloride to obtain l-tert-butoxycarbonyl-4- (3-methyl-l-phenyl-5-pyrazolyl)piperazine as an oil; and its deprotection with trifluoroacetic acid to obtain l-(3-methyl-l-phenyl-5-pyrazolyl)piperazine of Formula III.
Due to the unstable nature of diketenes, their use for the preparation of l-(3- methyl-1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III on a large scale results in decreased yield and purity of the l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine of Formula III, and {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l- yl]pyrrolidin-2-yl}(l,3-thiazolidin-3- l)methanone of Formula II, or salts thereof.
Figure imgf000003_0001
Formula II
Summary of the Invention
The present invention provides an improved, economical, and industrially advantageous process for the preparation of {(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, and 1 -(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III. The process of the present invention circumvents the use of a diketene and hazardous chemicals such as phosphorus oxychloride, pyridine, and trifluoroacetic acid.
Figure imgf000003_0002
Formula II Formula III A first aspect of the present invention provides a process for the preparation of 1- (3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine of Formula III, or salts thereof,
Figure imgf000004_0001
Formula III
wherein the process comprises the steps of:
a) reacting a compound of Formula IV
Pro— N NH Formula IV
with an alkylacetoacetate and phenylhydrazine to obtain a compound of Formula V;
Figure imgf000004_0002
Formula V
b) cyclizing the compound of Formula V to obtain a compound of Formula VI; and
Figure imgf000004_0003
Formula VI c) deprotecting the compound of Formula VI to obtain l-(3-methyl-l -phenyl- 1H- pyrazol-5-yl)piperazine 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-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) reacting a compound of Formula IV
Pro— N j r ΝΗ
Formula IV
with an alkylacetoacetate and phenylhydrazine to obtain a compound of Formula V;
Figure imgf000005_0001
Formula V
b) cyclizing the compound of Formula V to obtain a compound of Formula VI;
Figure imgf000005_0002
Formula VI
c) deprotecting the compound Formula VI to obtain a compound of Formula III;
Figure imgf000006_0001
Formula III
d) reacting the compound of Formula III, or a salt thereof, with a compound of Formula VII
Figure imgf000006_0002
Formula VII
to obtain a compound of Formula VIII; and
Figure imgf000006_0003
Formula VIII
e) deprotecting the compound of Formula VIII 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.
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 amino-protecting groups include 9-fluorenylmethyl carbamate (Fmoc), 2,2,2-trichloroethyl carbamate (Troc), ethyl carbamate, t-butyl carbamate (Boc), 2-(trimethylsilyl)ethyl carbamate (Teoc), allyl carbamate (Alloc), carboxybenzyl (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 methane sulfonic acid. Examples of amino acid salts include salts formed with glutamic acid and aspartic acid.
Examples of alkylacetoacetates include ethylacetoacetate, n-propylacetoacetate, iso-propylacetoacetate, n-butylacetoacetate, and t-butylacetoacetate.
The compound of Formula IV is reacted with an alkylacetoacetate in the presence of phenylhydrazine to obtain a compound of Formula V.
The compound of Formula V is cyclized using a dehydrating agent in the presence of a base to obtain a compound of Formula VI. Examples of dehydrating agents include phosphorus pentoxide and phosphorus pentasulphide. Examples of bases include inorganic and organic bases. Examples of inorganic bases include sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Examples of organic bases include methyl amine, ethylamine, and triethylamine.
The compound of Formula VI is deprotected to obtain a compound of Formula III, which is reacted with a compound of Formula VII in the presence of a metal hydrogen complex to obtain a compound of Formula VIII. Examples of metal hydrogen complexes include sodium borohydride, sodium cyanoborohydride, and sodium
triacetoxyborohydride . The compound of Formula VII 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 VII may also be carried out in the presence of an acid catalyst. Examples of acid catalysts include acetic acid, p-toluenesulfonic acid, and boron trifluoride.
The compound of Formula VIII is deprotected 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, using conventional methods disclosed in Greene, T.Q. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 4th Edition, 2006.
The compound of Formula III may also be converted 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, by following the processes disclosed in U.S. Patent Nos. 7,074,794 and 8,003,790.
{(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 of Formula I, obtained by the process of the present invention, has an HPLC purity greater than 99%.
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.
Methods
The HPLC purity was determined using a Gemini® C18 (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 35°C; Detector UV: 215 nm; Injection volume: 10 μί; Run time: 65 minutes.
EXAMPLES
Example 1 : Preparation of l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine acetate (Formula IIP
Ethylacetoacetate (82.2 g) was added to a solution of ethyl piperazine-1- carboxylate (Formula IV; 100 g) in toluene (1000 mL), and the reaction mixture was heated at 100°C to 110°C for 24 hours. The reaction mixture was cooled to a temperature of 0°C to 5°C. Phenyl hydrazine (68.4 g) was slowly added to the reaction mixture at 0°C to 10°C over a period of 15 minutes to 20 minutes. The reaction mixture was heated to 20°C to 25°C, and stirred at the same temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated at a temperature of about 55°C under reduced pressure to obtain a residue. The residue was dissolved in tetrahydrofuran (350 mL), and sodium carbonate (67 g) was added to it at 20°C to 22°C. Phosphorus pentasulphide (70.2 g) was slowly added to the above solution over a period of 30 minutes to 45 minutes. The reaction mixture was stirred at 35°C to 40°C for 90 minutes. The reaction mixture was heated to a temperature of 50°C to 55°C, and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool to a temperature of 35°C to 40°C. The reaction mixture was quenched with toluene (500 mL) and deionized water (500 mL). The reaction mixture was stirred at 35°C to 40°C for 30 minutes. The reaction mixture was allowed to settle for about 15 minutes. The organic layer was separated and the aqueous layer was extracted with toluene (2 x 200 mL) at 35°C to 40°C. The combined organic layers were washed with deionized water (500 mL) at 25°C to 30°C. The organic layer was concentrated at a temperature of about 55°C under reduced pressure to obtain a residue. The residue was dissolved in methanol (200 mL), and concentrated at 55°C under reduced pressure to obtain a residue. The residue was again dissolved in methanol (500 mL). Deionized water (250 mL) was added. Potassium hydroxide (301.4 g) was added to the above reaction mixture, and the reaction mixture was heated to a temperature of about 80°C to 85°C for 2 hours to 3 hours. The reaction mixture was allowed to cool to a temperature of 50°C to 55°C, and quenched with toluene (500 mL) and deionized water (100 mL). The reaction mixture was allowed to settle for 15 minutes, and the layers were separated at a temperature of about 50°C to 55°C. The aqueous layer was extracted with toluene (2 x 200 mL) at a temperature of 50°C to 55°C. The organic layers were combined and washed with an aqueous solution of sodium chloride (3 x 200 mL; prepared by adding 120 g sodium chloride to 600 mL deionized water) at 50°C to 55°C. The organic layer was separated, washed with deionized water (100 mL) at 52°C to 55°C, and concentrated at 100°C to 110°C under atmospheric pressure to a volume of about 560 mL. The concentrated solution was cooled to a temperature of 50°C to 55 °C, and glacial acetic acid (28.5 g) was slowly added at 50°C to 55°C. The reaction mixture was stirred at the same temperature for 60 minutes, allowed to cool to a temperature of 20°C to 25°C, and stirred at the same temperature for 60 minutes. The reaction mixture was then cooled to a temperature of about 0°C to about 5°C, and stirred at the same temperature for 60 minutes. The reaction mixture was filtered. The solid obtained was washed with toluene (100 mL) at 0°C to 5°C, and then dried in an air oven at 40°C to 45°C for 15 hours to 20 hours to obtain l-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazine acetate.
Yield: 68%
HPLC Purity: 99.75%
Example 2: Preparation of fert-butyl (2^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin-l-yll-2-(1.3-thiazolidin-3-ylcarbonyl)pyrrolidine-l-carboxylate (Formula VHP
A solution of sodium triacetoxy borohydride (98.8 g) in toluene (300 mL) was added to a mixture of fert-butyl (2<S)-4-oxo-2-(l,3-thiazolidin-3-yl carbonyl)pyrrolidine-l- carboxylate (100 g) and 1 -(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazine acetate (100.7 g; prepared according to Example 1) 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 completion of the reaction, 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 an aqueous sodium bicarbonate solution (60 g sodium carbonate in 600 mL deionized water). The organic layer was washed with deionized water (600 mL), and concentrated at about 50°C under reduced pressure to obtain a residue. The residue was dissolved in isopropyl alcohol (500 mL) and the solution was concentrated at 50°C under reduced pressure to obtain fert-butyl (2<S)-4-[4-(3 -methyl- 1 -phenyl- lH-pyrazol-5 -yl)piperazin-l- yl]-2-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidine-l-carboxylate. The residue was used as such in the next step.
Example 3: Preparation of {(2S.4S)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula I)
Activated carbon (10 g) was added to a solution of the residue (Formula VIII; prepared according to the process of Example 2) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was stirred at the same temperature for 30 minutes. 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 at 70°C to 77°C for 2 hours to 3 hours. 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 { (2S,4S)-4-[4-(3 -methyl- 1 -phenyl- lH-pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2- yl}(l,3-thiazolidin-3-yl)methanone hemipentahydrobromide hydrate.
Yield: 90%
Example 4: Purification of {(2S.4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula I)
A mixture of {(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 (100 g; Formula I; prepared according to the process of Example 3) in ethanol (700 mL) was heated to a temperature of 70°C to 75°C to obtain a clear solution. The solution was filtered at the same temperature, and the residue was washed with hot ethanol (100 mL; 70°C to 75°C). 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 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-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 1 -(3 -methyl- 1 -phenyl- lH-pyrazol-5 -yl)piperazine of Formula III, or salts thereof,
Figure imgf000012_0001
Formula III
wherein the process comprises the steps of:
a) reacting a compound of Formula IV
Pro— N NH Formula IV
with an alkylacetoacetate and phenylhydrazine to obtain a compound of Formula V;
Figure imgf000012_0002
Formula V
b) cyclizing the compound of Formula V to obtain a compound of Formula VI; and
Figure imgf000012_0003
Formula VI c) deprotecting the compound of Formula VI to obtain l-(3-methyl-l -phenyl- 1H- pyrazol-5-yl)piperazine of Formula III
wherein 'Pro' is a protecting group.
2) 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, wherein the process comprises the steps of:
a) reacting a compound of Formula IV
Pro— N ΝΗ
_y
Formula IV
with an alkylacetoacetate and phenylhydrazine to obtain a compound of Formula V;
Figure imgf000013_0001
Formula V
b) cyclizing the compound of Formula V to obtain a compound of Formula VI;
Figure imgf000013_0002
Formula VI
c) deprotecting the compound Formula VI to obtain a compound of Formula III;
Figure imgf000014_0001
Formula III
d) reacting the compound of Formula III, or a salt thereof, with a compound of Formula VII
Figure imgf000014_0002
Formula VII
to obtain a compound of Formula VIII; and
Figure imgf000014_0003
Formula VIII
e) deprotecting the compound of Formula VIII 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 claim 1 or 2, wherein the alkylacetoacetate is selected from the group consisting of ethylacetoacetate, n-propylacetoacetate, iso- propylacetoacetate, n-butylacetoacetate, and t-butylacetoacetate.
4. The process according to claim 1 or 2, wherein the compound of Formula V is cyclized in the presence of a dehydrating agent and a base.
5. The process according to claim 4, wherein the dehydrating agent is phosphorus pentoxide or phosphorus pentasulfide.
6. The process according to claim 4, wherein the base is selected from the group consisting of inorganic and organic bases.
7. The process according to claim 6, wherein the base is sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate.
PCT/IB2014/063487 2013-08-06 2014-07-28 Process for the preparation of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine WO2015019239A1 (en)

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WO2015173779A1 (en) 2014-05-16 2015-11-19 Micro Labs Limited Process for the preparation of teneligliptin and its novel intermediates
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CN108727364A (en) * 2017-04-18 2018-11-02 乳源东阳光药业有限公司 A kind of hydrobromic acid is unformed and preparation method thereof for Ge Lieting
WO2019205021A1 (en) * 2018-04-25 2019-10-31 乳源东阳光药业有限公司 Amorphous teneligliptin hydrobromide and preparation method thereof

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