WO2021053690A1 - An improved process for the preparation of baricitinib - Google Patents

An improved process for the preparation of baricitinib Download PDF

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Publication number
WO2021053690A1
WO2021053690A1 PCT/IN2020/050793 IN2020050793W WO2021053690A1 WO 2021053690 A1 WO2021053690 A1 WO 2021053690A1 IN 2020050793 W IN2020050793 W IN 2020050793W WO 2021053690 A1 WO2021053690 A1 WO 2021053690A1
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formula
compound
hcl
baricitinib
acetonitrile
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PCT/IN2020/050793
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French (fr)
Inventor
Shankar Reddy BUDIDETI
Srinivasan ABAYEE KALIYAPERUMAL
Srinivasa Krishna Murthy Konduri
Nagalingam SAMATHAM
Jayakrishna KASUGANTI
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
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Natco Pharma Limited
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Publication of WO2021053690A1 publication Critical patent/WO2021053690A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for the preparation of Baricitinib of Formula- 1 having structure depicted below.
  • Baricitinib is a Janus kinase (JAK) inhibitor. It is chemically designated as JK
  • Baricitinib (Ethyl sul ronyl)-3-[4-(7/7-pyrrolo[2,3-i/]pyn midi n-4-yl)-l/7-pyrazol-l-yl]azctidin-3 yl ⁇ acetonitrile of Formula-I.
  • Baricitinib (trade name Olumiant) is a drug for the treatment of rheumatoid arthritis (RA), being developed by Incyte and Eli Lilly. European approval is granted in February 2017 and FDA Advisory Committee recommended approval of Baricitinib 2mg for the treatment of rheumatoid arthritis in April 2018.
  • US 8158616 discloses a process for the preparation of Baricitinib (as depicted in scheme-1). According to process, diethyl cyanomethylphosphonate of Formula-II is condensed with tert- butyl-3 -oxoaztidine-l-carboxylate of Formula-Ill in the presence of sodium hydride in THF to afford compound of Formula-IV which is later condensed with compound of Formula-V in the presence of DBU in Acetonitrile followed purification by flash column chromatography to afford compound of Formula- VI. Thereafter, compound of Formula- VI is subjected to de -protection under 4M HC1 in 1,4-dioxane to afford compound of Formula- VII.
  • compound of Formula- VII is condensed with compound of Formula- VIII in the presence of V, V- d i i s o p ro p y 1 c t h y 1 a m i n c in THF to afford compound of Formula- IX.
  • compound of Formula-IX is de-protected in the presence of TFA in methylene chloride followed by purification using preparative HPLC to afford Baricitinib of Formula- 1 as TFA salt. The overall yield is found to be about 21%.
  • US ‘616 also discloses an alternate process for the preparation of Baricitinib (as shown in scheme-2).
  • diethyl cyanomethylphosphonate of Formula- II is condensed with t-butyl-3-oxoaztidine-l-carboxylate of formula (III) in the presence of potassium ieri-butoxide in THF solution at sub-zero conditions to afford compound of Formula- IV.
  • which is later subjected to de-protection in the presence of aq. HC1 followed by condensation with ethane sulfonyl chloride of Formula- VIII followed by purification using column chromatography to afford mixture of compounds of Formula-X and Formula-XI.
  • US ‘616 also discloses an alternate process for the preparation of Baricitinib (as depicted in scheme-3), According to the process, compound of Formula-V is condensed with compound of Formula-X in the presence of DBU in acetonitrile to afford compound of Formula- IX which is further subjected to two stage de -protection using L1BF4 followed by aq. Ammonia which is further purified by column chromatography to afford Baricitinib of Formula-I.
  • US ‘616 also discloses an alternate process for the preparation of Baricitinib (as depicted in scheme-4), According to the process, compound of Formula-XIII is reacted with POM-C1 in the presence of sodium hydride in 1,2-dimethoxyethane. Later the POM protected compound of Formula- XIV is condensed with compound of Formula-XV in the presence of tetrakis (triphenylphosphine)palladium (0) and potassium carbonate as base to afford compound of Formula-XVI. Later, the compound of Formula-XVI is subjected to de-protection in the presence of aqueous HC1 to afford compound of Formula-XVII.
  • WO 2016205487 A1 discloses a process for the preparation of Baricitinib (as depicted in scheme-5), According to the process, compound of Formula-XIX is condensed with ethanesulfonylchloride of Formula- VIII in the presence of potassium phosphate to afford compound of Formula-XX, which is later oxidized in the presence for TEMPO under pressurized air to afford compound of Formula -XXL Later, the compound is further condensed with compound of Formula-II to afford compound of Formula-X. The compound of Formula -X is further condensed with compound of Formula- XXII to afford compound of formula -XIII. This intermediate further condensed with compound of Formula-XTTT to afford Baritinib of Formula-I.
  • the output quantity would be very low and is unviable on commercial scale to meet the market demand.
  • the main objective of the present invention is to provide an improved process for the preparation of Baricitinib of Formula-I, which comprises simple, safe, economical and commercially viable process which surpasses the above mentioned disadvantages.
  • the present invention provides an improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of: (i) condensing the compound of Formula-IV Formula- IV with compound of Formula-XXII or compound of Formula-XXIIa in the presence of organic base in an organic solvent to obtain compound of Formula- XXIV or compound of Formula-XXIVa.
  • the present invention provides an improved process for the preparation of Baricitinib of Formula- 1 having more than 99% purity by HPLC, comprising the steps of: (i) condensing the compound of Formula-IV with compound of Formula- XXII or compound of Formula-XXIIa under in the presence of organic base in an organic solvent to obtain compound of Formula- XXIV or compound of Formula- XXIVa;
  • the organic base used in the condensation of compound of Formula-IV with compound of Formula-XXTT is 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) or any organic or inorganic base.
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • the organic solvent used in the condensation of compound of Formula-IV with compound of Formula-XXTT is selected from acetonitrile, isopropyl alcohol, N, N- d i m c t h y 1 fo m a m i dc , /V,/V-dimethylacetamide or mixture thereof preferably isopropyl alcohol or mixture thereof.
  • the temperature at which the condensation of compound of Formula- IV with compound of Formula-XXII is performed in the range from 0-85°C preferably 75-82°C.
  • the condensed product of Formula- XXIV is optionally purified from organic solvent selected from methanol, acetone, ethyl acetate, isopropyl alcohol, toluene, acetonitrile, n-heptane preferably from isopropyl alcohol or mixture thereof.
  • the catalyst used in the condensation of compound of Formula-XXIV with compound of formula-XIII is Tetrakis(triphenylphosphine) palladium(O) or any other palladium derived catalyst.
  • the organic solvent used in the condensation of compound of Formula-XXIV with compound of Formula-XIII is selected from 1,2- dimethoxyethane, V, V- d i in c t h y 1 fo m a m i dc , n-butanol, water, tertiary butanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetonitrile or mixture thereof preferably water or mixture of isopropyl alcohol/water.
  • the base used in the condensation of compound of Formula -XXIV with compound of Formula-XIII is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as N,N-diisopropylethylamine, triethylamine, DBU, Diisopropyl amine or any equivalent organic base; preferably potassium carbonate.
  • inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as N,N-diisopropylethylamine, triethylamine, DBU, Diisopropyl amine or any equivalent organic base; preferably potassium carbonate.
  • step (ii) of the present invention the temperature at which condensation of compound of Formula-XXIV with compound of Formula-XIII is in the range of 20-85°C preferably 80-85°C.
  • the condensed product of Formula-XXV is optionally purified from organic solvent selected from ethyl acetate, n-heptane, methanol, toluene, acetonitrile or mixture thereof.
  • an acid used to selectively de-protect compound of Formula-XXV is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile- HC1, ethylacetate-HCl preferably isopropyl alcohol-HCl in the presence of solvents like MeOH, Ethanol, Isopropanol, THF etc, preferably MeOH.
  • the temperature at which selective de protection of compound of Formula-XXV is ranging from 10-65°C preferably 25-35°C.
  • the isolated product of Formula-XXVI is optionally purified from solvent, selected from water, acetonitrile, methanol, N,N- dimethylformamide, alcoholic solvents or mixture thereof preferably from water.
  • the base used in the condensation of compound of Formula-XXVI with compound of Formula- VIII is selected from organic bases such as /V,/V-diisopropylcthyl amine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
  • the solvent used in the condensation of compound of Formula-XXVI with compound of Formula- VIII is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof preferably acetonitrile-water.
  • step (v) of the present invention optionally Baricitinib of Formula-I is purified by crystallization or trituration using solvent selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, n- propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, /V,/V-dimethylformamide, A, A-di methyl acetamide, DMSO, acetone or mixture thereof.
  • solvent selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, n- propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, /V,/V-dimethylformamide, A, A-di
  • Another embodiment of present invention provides an improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of:
  • step (iv) de-protection of compound of Formuia-XXVIII obtained in step (ii) in the presence of a base in an organic solvent to obtain compound of Formu!a- XXVIa
  • the catalyst used in the condensation of compound of Formula-XXIV with compound of Formula- XXVII is Tetrakis(triphenylphosphine) palladium(O) or any other palladium derived catalyst.
  • the organic solvent used in the condensation of compound of Formula-XXIV with compound of Formula-XXVII is selected from 1,2- dimethoxyethane, V, V- d i m c t h y 1 fo m a m i dc , n-butanol, water, tertiary butanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetonitrile or mixture thereof preferably water or mixture of isopropyl alcohol/water.
  • the base used in the condensation of compound of Formula -XXIV with compound of Formula-XXVII is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as /V,/V-diisopropylcthyl amine, triethylamine, DBU, Diisopropyl amine or any equivalent organic base; preferably potassium carbonate.
  • inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as /V,/V-diisopropylcthyl amine, triethylamine, DBU, Diisopropyl amine or any equivalent organic base; preferably potassium carbonate.
  • step (i) of the present invention the temperature at which condensation of compound of Formula-XXIV with compound of Formula-XXVII is in the range of 20- 85°C preferably 80-85°C.
  • the condensed product of Formula- VI is optionally purified from organic solvent selected from ethyl acetate, n-heptane, methanol, toluene, acetonitrile or mixture thereof.
  • the acid used to selectively de -protect compound of Formula- VI is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile-HCl, ethylacetate-HCl preferably isopropyl alcohol-HCl in the presence of solvents like MeOH, Ethanol, Isopropanol, THF etc, preferably with Methanol.
  • the temperature at which selective de -protection of compound of Formula- VI is ranging from 10-65°C preferably 25-45°C.
  • the isolated product of Formula- XXVIII is optionally purified from solvent, selected from water, acetonitrile, methanol, N,N- dimethylformamide, alcoholic solvents or mixture thereof preferably from water.
  • the base used in the condensation of compound of Form ul a-XX VIII with compound of Formula- VIII is selected from organic bases such as VX-diisopropylcthyl amine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
  • solvent used in the condensation of compound of Formula- XXVIII with compound of Formula- VIII is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof preferably acetonitrile- w ater .
  • step (iii) of the present invention the temperature at which the condensation of compound of Formula- XXVIII with compound of Formula- VIII is ranging from -10 to 50°C preferably -5 to 5°C.
  • step (iv) of the present invention the de-protection of compound of Formula- XXVIII obtained in step (ii) with base is selected from organic bases such as N,N- diisopropylethylamine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably ammonia.
  • organic bases such as N,N- diisopropylethylamine, triethylamine, DBU
  • inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably ammonia.
  • step (iv) of the present invention the reduction of compound of Formula- XXVIII obtained in step (ii) in organic solvent is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof preferably acetonitrile- water.
  • step (iv) of the present invention the temperature at which the de-protection of compound of Formula- XXVIII is ranging from 0 to 80°C preferably 25-30°C.
  • the base used in the condensation of compound of formula-XXVIa with compound of Formula- VIII is selected from organic bases such as VX-diisopropylcthyl amine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
  • organic bases such as VX-diisopropylcthyl amine, triethylamine, DBU
  • inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
  • the solvent used in the condensation of compound of Formula- XXVIa with compound of Formula- VIII is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, toluene, water or mixture thereof preferably acetonitrile-water.
  • step (v) of the present invention the temperature at which the condensation of compound of Formula-XXVIa with compound of Formula- VIII is ranging from -10 to 50°C preferably -5 to 5°C.
  • step (v) of the present invention optionally Baricitinib of Formula-I is purified by crystallization or trituration using solvent selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, «-propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, /V,/V-dimethylformamide, /V,/V-di methyl acetamide, DMSO, acetone or mixture thereof.
  • solvent selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, «-propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, /V,/V-dimethylformamide, /V,/
  • the present invention does not require usage of pyrophoric reagent like sodium hydride.
  • the present invention does not require purification techniques like preparative HPLC / column chromatography / flash chromatography purification techniques to purify the product thereby reducing the environmental pollution load and improve the productivity.
  • the overall yield is greatly improved.
  • Successfully avoided prolonged reaction times thereby improve the product time cycle.
  • Example- 1 Process for the preparation of tert-butyl-3-(cyanomethyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl) azetidine-l-carboxylate of Formula-XXIV.
  • Example-2 Process for the preparation of 1,1-Dimethylethyl 3-(cyanomethyl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-l-azetidinecarboxylate compound of Formula-XXV.
  • Example-3 Preparation of 2-[3-[4-(7//-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]azetidin-3-yl]acetonitrile dihydrochloride compound of Formula-XXVI.
  • Example-4 Process for the preparation of Baricitinib of Formula-I.
  • Example-5 Preparation of 4-Chloro-7-[[2-(trimethylsilyl)ethoxy]methyl]-7//- pyrrolo[2,3-rf]pyrimidine compound of Formula-XXVII.
  • Example-6 Process for the Preparation of tert-Butyl 3-(cyanomethyl)-3-[4-[7-[[2- (trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-lH-pyrazol-l-yl] azetidine-l-carboxylate compound of Formula- VI.
  • Example-7 A Process for the preparation of 3-[4-[7-(Hydroxymethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-lH-pyrazol-l-yl]-3-azetidineacetonitrile dihydrochloride compound of Formula-XXVIII.
  • Example-8 A Process for the preparation of Baricitinib of Formula-I.
  • Example-9 Process for the preparation of Baricitinib of Formula-I. Into the RBF a solution of acetonitrile, Formula- XXVIa (0.43 moles) and

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

The present invention provides an improved process for the preparation of Baricitinib of formula (I),

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF BARICITINIB
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Baricitinib of Formula- 1 having structure depicted below.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Baricitinib is a Janus kinase (JAK) inhibitor. It is chemically designated as
(Ethyl sul ronyl)-3-[4-(7/7-pyrrolo[2,3-i/]pyn midi n-4-yl)-l/7-pyrazol-l-yl]azctidin-3 yl } acetonitrile of Formula-I. Baricitinib (trade name Olumiant) is a drug for the treatment of rheumatoid arthritis (RA), being developed by Incyte and Eli Lilly. European approval is granted in February 2017 and FDA Advisory Committee recommended approval of Baricitinib 2mg for the treatment of rheumatoid arthritis in April 2018.
US 8158616 discloses a process for the preparation of Baricitinib (as depicted in scheme-1). According to process, diethyl cyanomethylphosphonate of Formula-II is condensed with tert- butyl-3 -oxoaztidine-l-carboxylate of Formula-Ill in the presence of sodium hydride in THF to afford compound of Formula-IV which is later condensed with compound of Formula-V in the presence of DBU in Acetonitrile followed purification by flash column chromatography to afford compound of Formula- VI. Thereafter, compound of Formula- VI is subjected to de -protection under 4M HC1 in 1,4-dioxane to afford compound of Formula- VII. Later, compound of Formula- VII is condensed with compound of Formula- VIII in the presence of V, V- d i i s o p ro p y 1 c t h y 1 a m i n c in THF to afford compound of Formula- IX. Finally, compound of Formula-IX is de-protected in the presence of TFA in methylene chloride followed by purification using preparative HPLC to afford Baricitinib of Formula- 1 as TFA salt. The overall yield is found to be about 21%.
Figure imgf000003_0001
Scheme- 1
The process disclosed in US 8158616 suffers from the following drawbacks: a) Process requires pyrophoric reagent like sodium hydride. b) Process needs flash and preparative HPLC purification techniques to purify the product. On higher scale production, flash and preparative HPLC purifications techniques are time consuming and not viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale to meet the market demand. c) Isolation and work-up procedures are very cumbersome and tedious. d) The overall yield is only -21% from compound of Formula- III. e) Process does not describe regeneration of Baricitinib base from Baricitinib. TFA salt.
US ‘616 also discloses an alternate process for the preparation of Baricitinib (as shown in scheme-2). According to the process, diethyl cyanomethylphosphonate of Formula- II is condensed with t-butyl-3-oxoaztidine-l-carboxylate of formula (III) in the presence of potassium ieri-butoxide in THF solution at sub-zero conditions to afford compound of Formula- IV. Which is later subjected to de-protection in the presence of aq. HC1 followed by condensation with ethane sulfonyl chloride of Formula- VIII followed by purification using column chromatography to afford mixture of compounds of Formula-X and Formula-XI. The mixture of compound of formulae-X and XI is then condensed with compound of Formula- V to afford compound of Formula- IX. Thereafter, compound of formula- IX is subjected to two stage de-protection using lithium tetrafluoro borate and aqueous ammonia followed by purification using column chromatography to afford Baricitinib of Formula-I.
Figure imgf000004_0001
Scheme-2
The above process disclosed in US ‘616 suffers from the following de-merits: i) Process requires flash and chromatographic purification techniques to purify the product. On higher scale production, flash and chromatographic purification techniques are time consuming and not viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale to meet the market demand. ii) Isolation and work-up procedures are cumbersome. iii) The overall yield is only -17% from compound of Formula- III. US ‘616 also discloses an alternate process for the preparation of Baricitinib (as depicted in scheme-3), According to the process, compound of Formula-V is condensed with compound of Formula-X in the presence of DBU in acetonitrile to afford compound of Formula- IX which is further subjected to two stage de -protection using L1BF4 followed by aq. Ammonia which is further purified by column chromatography to afford Baricitinib of Formula-I.
Figure imgf000005_0001
Scheme-3
The above process disclosed in US ‘616 suffers with the following disadvantages: i) Process requires column chromatography purification techniques to purify the product. On higher scale production, chromatographic purification techniques are time consuming and not viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale to meet the market demand. ii) Isolation and work-up procedures are cumbersome.
US ‘616 also discloses an alternate process for the preparation of Baricitinib (as depicted in scheme-4), According to the process, compound of Formula-XIII is reacted with POM-C1 in the presence of sodium hydride in 1,2-dimethoxyethane. Later the POM protected compound of Formula- XIV is condensed with compound of Formula-XV in the presence of tetrakis (triphenylphosphine)palladium (0) and potassium carbonate as base to afford compound of Formula-XVI. Later, the compound of Formula-XVI is subjected to de-protection in the presence of aqueous HC1 to afford compound of Formula-XVII. This is further condensed with compound of Formula-X in the presence of DBU in DMF to afford compound of Formula-XVIII. Finally MOM water de-protected from compound of Formula-XVIII with aqueous sodium hydroxide to afford Baricitinib of Formula-I.
Figure imgf000006_0001
Scheme-4
The above process disclosed in US 8158616 suffers from the following weaknesses: a) Process requires pyrophoric reagent like sodium hydride b) Isolation and work-up procedures are very cumbersome and tedious.
WO 2016205487 A1 discloses a process for the preparation of Baricitinib (as depicted in scheme-5), According to the process, compound of Formula-XIX is condensed with ethanesulfonylchloride of Formula- VIII in the presence of potassium phosphate to afford compound of Formula-XX, which is later oxidized in the presence for TEMPO under pressurized air to afford compound of Formula -XXL Later, the compound is further condensed with compound of Formula-II to afford compound of Formula-X. The compound of Formula -X is further condensed with compound of Formula- XXII to afford compound of formula -XXIII. This intermediate further condensed with compound of Formula-XTTT to afford Baritinib of Formula-I.
Figure imgf000007_0001
The above process disclosed in WO2016205487 suffers from the following weaknesses: a) Isolation and work-up procedures are very cumbersome and tedious. b) Prolonged reaction times increases the product time cycle.
However, in spite of having the choice of variety of methods for the preparation of Baricitinib of Formula-I, there is still need to have a simple, minimize the time cycle, cost effective and commercially viable process for the preparation of Baricitinib of Formula-I on large scale operations, since, in general, the following common disadvantages are associated with the existing processes for the preparation of Baricitinib. a) Process requires pyrophoric reagent like sodium hydride. b) Process needs preparative HPLC / column chromatography / flash chromatography purification techniques to purify the product. On higher scale production, purification by chromatographic techniques are not commercially viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale to meet the market demand. c) Isolation and work-up procedures are very cumbersome and tedious. d) The overall yield are very low. e) Prolonged reaction times increases the product time cycle. Hence there is a need for a simple, cost effective and commercially viable process for the preparation of Baricitinib of Formula-I on large scale to meet the market demand. Accordingly, the process should be circumventing the following disadvantages like: a) Avoiding usage of pyrophoric reagents like sodium hydride. b) Avoiding purification of product by chromatographic techniques like preparative HPLC / column chromatography / flash chromatography purification techniques to purify the product. On higher scale production, purification by chromatographic techniques are not commercially viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale to meet the market demand. c) Adopting simple work-up and isolation procedures. d) Improve the overall yield of the Baricitinib. e) Controlling the related substances to acceptable level. f) Avoiding prolonged reaction times and improve the output per-cycle.
BJECTIVE OF THE INVENTION
Keeping in view of the above disadvantages associated with the prior art processes disclosed in the literature for the preparation of Baricitinib of Formula-I, the inventors of the present invention have developed a simple, economical and commercially viable process for commercial production of Baricitinib of Formula-I by circumventing the above mentioned disadvantages.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of Baricitinib of Formula-I, which comprises simple, safe, economical and commercially viable process which surpasses the above mentioned disadvantages.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of: (i) condensing the compound of Formula-IV Formula- IV
Figure imgf000009_0001
with compound of Formula-XXII or compound of Formula-XXIIa
Figure imgf000009_0003
in the presence of organic base in an organic solvent to obtain compound of Formula- XXIV or compound of Formula-XXIVa.
Figure imgf000009_0004
(ii) condensing the compound of Formula- XXIV or compound of Formula-XXIV a with compound of Formula- XIII.
Figure imgf000009_0002
in the presence of a catalyst in an aqueous organic solvent medium to obtain compound of Formula- XXV.
Figure imgf000010_0001
(iii) de-protecting the compound of Formula- XXV in the presence of acid environment to obtain compound of Formula- XXVI.
Formula- XXVI
Figure imgf000010_0002
(iv) reacting the compound of Formula- XXVI with compound of Formula- VIII
Formula- VIII
Figure imgf000010_0003
under basic conditions to obtain Baricitinib of Formula-I
Figure imgf000010_0004
(v) optionally purifying the Baricitinib of Formula-I from suitable solvent medium wherein the obtained Baricitinib of formula (I) having more than 99% of HPLC purity. Another embodiment of present invention provides an improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of:
(i) condensing the compound of Formula-XXIV
Formula-XXIV
Figure imgf000011_0001
with compound of Formula- XXVII in the presence of a catalyst in an organic solvent medium
Formula- XXVII
Figure imgf000011_0002
to obtain compound of Formula- VI
Formula- VI
Figure imgf000011_0003
(ii) deprotecting the compound of Formula- VI in the presence of acid to obtained compound of Formula- XXVIII
Formula- XXVIII.
Figure imgf000012_0001
(iii) reacting the compound of Formula- XXVIII with compound of Formula- VIII
Formula- VIII
Figure imgf000012_0002
under basic conditions to obtain Baricitinib of Formula (I); or (iv) de-protection of compound of Form id a -XX VITT obtained in step (ii) in the presence of a base in an organic solvent to obtain compound of Formula-XXVIa.
Formula-XXVIa
Figure imgf000012_0003
(vi) reacting the compound of formula-XXVIa with compound of formula- VIII
Formula- VIII
Figure imgf000012_0004
under basic conditions to obtain Baricitinib of Formula-I
Figure imgf000013_0001
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Baricitinib of Formula- 1 having more than 99% purity by HPLC, comprising the steps of: (i) condensing the compound of Formula-IV with compound of Formula- XXII or compound of Formula-XXIIa under in the presence of organic base in an organic solvent to obtain compound of Formula- XXIV or compound of Formula- XXIVa;
(ii) condensing the compound of Formula- XXIV or compound of Formula-XXIVa with compound of Formula- XIII in the presence of a catalyst in an aqueous organic solvent medium to obtain compound of Formula- XXV;
(iii) de-protecting the compound of Formula-XXV in the presence of acid environment to obtain compound of Formula-XXVI;
(iv) reacting the compound of Formula-XXVI with compound of Formula- VIII under basic conditions to obtain Baricitinib of Formula-I; (v) optionally purifying the Baricitinib of Formula-I from suitable solvent medium wherein the obtained Baricitinib of Formula-I have more than 99% of HPLC purity.
In step (i) of the present invention, the organic base used in the condensation of compound of Formula-IV with compound of Formula-XXTT is 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) or any organic or inorganic base.
In step (i) of the present invention, the organic solvent used in the condensation of compound of Formula-IV with compound of Formula-XXTT is selected from acetonitrile, isopropyl alcohol, N, N- d i m c t h y 1 fo m a m i dc , /V,/V-dimethylacetamide or mixture thereof preferably isopropyl alcohol or mixture thereof. In step (i) of the present invention, the temperature at which the condensation of compound of Formula- IV with compound of Formula-XXII is performed in the range from 0-85°C preferably 75-82°C.
In step (i) of the present invention, the condensed product of Formula- XXIV is optionally purified from organic solvent selected from methanol, acetone, ethyl acetate, isopropyl alcohol, toluene, acetonitrile, n-heptane preferably from isopropyl alcohol or mixture thereof.
In step (ii) of the present invention, the catalyst used in the condensation of compound of Formula-XXIV with compound of formula-XIII is Tetrakis(triphenylphosphine) palladium(O) or any other palladium derived catalyst.
In step (ii) of the present invention, the organic solvent used in the condensation of compound of Formula-XXIV with compound of Formula-XIII is selected from 1,2- dimethoxyethane, V, V- d i in c t h y 1 fo m a m i dc , n-butanol, water, tertiary butanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetonitrile or mixture thereof preferably water or mixture of isopropyl alcohol/water.
In step (ii) of the present invention, the base used in the condensation of compound of Formula -XXIV with compound of Formula-XIII is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as N,N-diisopropylethylamine, triethylamine, DBU, Diisopropyl amine or any equivalent organic base; preferably potassium carbonate.
In step (ii) of the present invention, the temperature at which condensation of compound of Formula-XXIV with compound of Formula-XIII is in the range of 20-85°C preferably 80-85°C.
In step-ii of the present invention, the condensed product of Formula-XXV is optionally purified from organic solvent selected from ethyl acetate, n-heptane, methanol, toluene, acetonitrile or mixture thereof.
In step-iii of the present invention, an acid used to selectively de-protect compound of Formula-XXV is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile- HC1, ethylacetate-HCl preferably isopropyl alcohol-HCl in the presence of solvents like MeOH, Ethanol, Isopropanol, THF etc, preferably MeOH. In step (iii) of the present invention, the temperature at which selective de protection of compound of Formula-XXV is ranging from 10-65°C preferably 25-35°C.
In step (iii) of the present invention, the isolated product of Formula-XXVI is optionally purified from solvent, selected from water, acetonitrile, methanol, N,N- dimethylformamide, alcoholic solvents or mixture thereof preferably from water.
In step (iv) of the present invention, the base used in the condensation of compound of Formula-XXVI with compound of Formula- VIII is selected from organic bases such as /V,/V-diisopropylcthyl amine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
In step (iv) of the present invention, the solvent used in the condensation of compound of Formula-XXVI with compound of Formula- VIII is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof preferably acetonitrile-water.
In step (iv) of the present invention, the temperature at which the condensation of compound of Formula-XXVI with compound of Formula- VIII is ranging from -10 to 50°C preferably -5 to 5°C.
In step (v) of the present invention, optionally Baricitinib of Formula-I is purified by crystallization or trituration using solvent selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, n- propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, /V,/V-dimethylformamide, A, A-di methyl acetamide, DMSO, acetone or mixture thereof.
Another embodiment of present invention provides an improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of:
(i) condensing the Formula-XXIV with compound of Formula- XXVII in the presence of a catalyst in an organic solvent medium to obtain compound of Formula- VI;
(ii) deprotecting the compound of Formula- VI in the presence of acid to obtained compound of Formula-XXVIII; (iii) reacting the compound of Formula- XXVIII with compound of Formula- VIII under basic conditions to obtain Baricitinib of Formula-I; or
(iv) de-protection of compound of Formuia-XXVIII obtained in step (ii) in the presence of a base in an organic solvent to obtain compound of Formu!a- XXVIa
(v) reacting the compound of Formula-XXVIa with compound of Formula- VIII under basic conditions to obtain Baricitinib of Formula-I.
In step (i) of the present invention, the catalyst used in the condensation of compound of Formula-XXIV with compound of Formula- XXVII is Tetrakis(triphenylphosphine) palladium(O) or any other palladium derived catalyst.
In step (i) of the present invention, the organic solvent used in the condensation of compound of Formula-XXIV with compound of Formula-XXVII is selected from 1,2- dimethoxyethane, V, V- d i m c t h y 1 fo m a m i dc , n-butanol, water, tertiary butanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetonitrile or mixture thereof preferably water or mixture of isopropyl alcohol/water.
In step (i) of the present invention, the base used in the condensation of compound of Formula -XXIV with compound of Formula-XXVII is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as /V,/V-diisopropylcthyl amine, triethylamine, DBU, Diisopropyl amine or any equivalent organic base; preferably potassium carbonate.
In step (i) of the present invention, the temperature at which condensation of compound of Formula-XXIV with compound of Formula-XXVII is in the range of 20- 85°C preferably 80-85°C.
In step (i) of the present invention, the condensed product of Formula- VI is optionally purified from organic solvent selected from ethyl acetate, n-heptane, methanol, toluene, acetonitrile or mixture thereof.
In step (ii) of the present invention, the acid used to selectively de -protect compound of Formula- VI is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile-HCl, ethylacetate-HCl preferably isopropyl alcohol-HCl in the presence of solvents like MeOH, Ethanol, Isopropanol, THF etc, preferably with Methanol. In step (ii) of the present invention, the temperature at which selective de -protection of compound of Formula- VI is ranging from 10-65°C preferably 25-45°C.
In step (ii) of the present invention, the isolated product of Formula- XXVIII is optionally purified from solvent, selected from water, acetonitrile, methanol, N,N- dimethylformamide, alcoholic solvents or mixture thereof preferably from water.
In step (iii) of the present invention, the base used in the condensation of compound of Form ul a-XX VIII with compound of Formula- VIII is selected from organic bases such as VX-diisopropylcthyl amine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
In step (iii) of the present invention, solvent used in the condensation of compound of Formula- XXVIII with compound of Formula- VIII is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof preferably acetonitrile- w ater .
In step (iii) of the present invention, the temperature at which the condensation of compound of Formula- XXVIII with compound of Formula- VIII is ranging from -10 to 50°C preferably -5 to 5°C.
In step (iv) of the present invention, the de-protection of compound of Formula- XXVIII obtained in step (ii) with base is selected from organic bases such as N,N- diisopropylethylamine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably ammonia.
In step (iv) of the present invention, the reduction of compound of Formula- XXVIII obtained in step (ii) in organic solvent is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof preferably acetonitrile- water.
In step (iv) of the present invention, the temperature at which the de-protection of compound of Formula- XXVIII is ranging from 0 to 80°C preferably 25-30°C.
In step (v) of the present invention, the base used in the condensation of compound of formula-XXVIa with compound of Formula- VIII is selected from organic bases such as VX-diisopropylcthyl amine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate preferably /V,/V-diisopropylethylamine.
In step (v) of the present invention, the solvent used in the condensation of compound of Formula- XXVIa with compound of Formula- VIII is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, toluene, water or mixture thereof preferably acetonitrile-water.
In step (v) of the present invention, the temperature at which the condensation of compound of Formula-XXVIa with compound of Formula- VIII is ranging from -10 to 50°C preferably -5 to 5°C.
In step (v) of the present invention, optionally Baricitinib of Formula-I is purified by crystallization or trituration using solvent selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, «-propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, /V,/V-dimethylformamide, /V,/V-di methyl acetamide, DMSO, acetone or mixture thereof.
Advantages: a) The present invention does not require usage of pyrophoric reagent like sodium hydride. b) The present invention does not require purification techniques like preparative HPLC / column chromatography / flash chromatography purification techniques to purify the product thereby reducing the environmental pollution load and improve the productivity. c) The overall yield is greatly improved. d) Simple work-up and isolation procedures. e) Successfully avoided prolonged reaction times thereby improve the product time cycle.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention. Example- 1: Process for the preparation of tert-butyl-3-(cyanomethyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl) azetidine-l-carboxylate of Formula-XXIV.
Into the RBF, a suspension of Isopropyl alcohol, tert-Butyl 3-(cyanomethylene) azetidine-l-carboxylate compound of Formula-IV (1.28 moles.), and 4-(4, 4,5,5- Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole compound of Formula-XXII (1.28 moles) and DBU (0.12 moles) were added. Later reaction mass was heated to reflux. The reaction was monitored by HPLC after completion of reaction, reaction mass was cooled to 0-5 °C while cooling at 55°C Heptane was added. The precipitated material was filtered and dried afforded Formula-XXIV. Yield: 80%; Purity: > 98 %
Example-2: Process for the preparation of 1,1-Dimethylethyl 3-(cyanomethyl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]-l-azetidinecarboxylate compound of Formula-XXV.
Into the RBF, a solution of 1,4-dioxane and DM water 4-Chloro- 1 //-indole compound of Formula-XIII (0.65 moles) and tert- Butyl 3-(cyanomethyl)-3-[4-(4, 4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 /7-pyrazol- 1 -yl] azetidine- 1 -carboxylate compound of Formula-XXIV (0.71 moles) and potassium carbonate (1.95 moles) were added. The mixture was degassed with Nitrogen for an hour and added tetrakis(triphenylphosphine)palladium(0) (0.006 moles). Later the reaction mixture was refluxed. The reaction was monitored by HPLC. After completion of reaction the reaction mass was filtered with charcoal the reaction mass was diluted with DM water and obtained solid was filtered and washed with DM water afforded Formula-XXV without any purification proceeded for next step.
Example-3: Preparation of 2-[3-[4-(7//-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]azetidin-3-yl]acetonitrile dihydrochloride compound of Formula-XXVI.
Into the RBF, a suspension of of 1,4-dioxane and Formula-XXV were added. The mixture was cooled to 15-20°C and added Conc.HCl and the reaction mixture was stirred room temperature. The reaction was monitored by HPLC. After completion of reaction the reaction mass was diluted 1,4-dioxane and acetonitrile obtained solid was filtered and washed with acetonitrile. The attained crude material was once again leached with 1,4- dioxane and DM water and dried the material afforded as a pure Formula-XXVI. Yield: 85% Purity: > 99%
Example-4: Process for the preparation of Baricitinib of Formula-I.
Into the RBF a solution of acetonitrile, XXVI (0.05 moles) and N,N- Diisopropylethylamine (0.20 moles) were added and cooled to 0-5°C. Then Ethane sulphonyl chloride compound of Formula- VIII (0.06 moles) was added slowly and stirred for 6 hours at same temperature. After that aqueous ammonia (0.50 moles) was added allowed the reaction mass to room temperature and maintained for 4 hours. Finally, reaction mass was diluted with DM water and obtained solid material was filtered and dried afforded Baricitinib. Pure material was obtained by recrystallizing in acetonitrile DM water medium. Yield: 65%; Purity: > 99%
Example-5: Preparation of 4-Chloro-7-[[2-(trimethylsilyl)ethoxy]methyl]-7//- pyrrolo[2,3-rf]pyrimidine compound of Formula-XXVII.
Into the RBF, a suspension Dimethylformamide, 4-Chloro- IH- indole compound of Formula-XTTT (0.54 moles), potassium carbonate (1.54 moles) were added. The mixture was stirred for an hour and cooled to 0-5 °C added 2- (Trimethylsilyl)ethoxymethyl chloride (0.66 moles) reaction mixture slowly. The reaction was monitored by HPLC. Upon completion of the reaction, the reaction mass was diluted with water and extracted with Methyl-t-butyl ether. Organic layer was washed with DM water. The obtained organic layer dried over sodium sulphate. After concentration under reduced pressure afforded Formula-XXVII as a liquid without further purification proceed for next step.
Example-6: Process for the Preparation of tert-Butyl 3-(cyanomethyl)-3-[4-[7-[[2- (trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-lH-pyrazol-l-yl] azetidine-l-carboxylate compound of Formula- VI.
Into the RBF, a solution of Isopropyl alcohol and DM water and 2-[(4- Chloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethylsilane compound of Formula-XXVII (0.52 moles) and tert-Butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl] azetidine- 1 -carboxylate compound of
Formula- XXIV (0.52 moles) and potassium carbonate (1.55 moles) were added. The mixture was degassed with Nitrogen for an hour and added tetrakis(triphenylphosphine)palladium(0) (0.0025 moles). Later the reaction mixture was refluxed. The reaction was monitored by HPLC. After completion of reaction the reaction mass was filtered with charcoal. The reaction mass was diluted with water and extracted with Ethyl acetate. Organic layer was washed with DM water and sodium chloride solution. The obtained organic layer dried over sodium sulphate. After concentration under reduced pressure afforded crude material was co-distilled with Toluene. The crude material was purified by Toluene, n-Heptane and ethyl acetate. The obtained material was filtered and dried afforded Formula- VI without any further purification proceed for next step.
Example-7: A Process for the preparation of 3-[4-[7-(Hydroxymethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-lH-pyrazol-l-yl]-3-azetidineacetonitrile dihydrochloride compound of Formula-XXVIII.
Into the RBF, a solution of Methanol and compound of Formula- VI (0.38 moles) were added. The mixture was cooled to 20-25°C and added IPA-HCl (2.33 moles). Eater the reaction mixture was stirred for overnight. The reaction was monitored by HPFC. After completion of reaction the reaction mass was filtered and washed with acetonitrile. The obtained crude material was recrystallized with hot water and dried the material without any further purification proceed for next step. Into the another RBF, a solution of acetonitrile, above material 10 g (0.02 moles) and methanesulphonic acid (0.12 moles) were added. The mixture was stirred at RT for overnight to 20-25°C and added IPA-HCl (0.36 moles). After completion of reaction the reaction mass was filtered and washed with acetonitrile and dried Formula-XXVIII and found it is degrading over the period of time and gave Formula- XXVI. Yield: 35% Purity: 90%.
Example-8: A Process for the preparation of Baricitinib of Formula-I.
Into the RBF a solution of acetonitrile, XXVIII (0.05 moles) and N, N- Diisopropylethylamine (0.20 moles) were added and cooled to 0-5°C. Then Ethane sulphonyl chloride of Formula- VIII (0.06 moles) was added slowly and stirred for 6 hours at same temperature. After that aqueous ammonia (0.50 moles) was added allowed the reaction mass to room temperature and maintained for 4 hours. Finally, reaction mass was diluted with DM water and obtained solid material was filtered and dried afforded Baricitinib. Pure material was obtained by recrystallizing in acetonitrile DM water medium. Yield: 65% Purity: > 99%
Example-9: Process for the preparation of Baricitinib of Formula-I. Into the RBF a solution of acetonitrile, Formula- XXVIa (0.43 moles) and
N, /V-Diisopropylethylamine (1.92 moles) were added and cooled to 0-5°C. Then Ethane sulphonyl chloride of compound of Formula- VIII (0.52 moles) was added slowly and stirred for 5 hours at same temperature. The reaction was monitored by HPLC. After completion of reaction the reaction mass was diluted with DM water and obtained solid was filtered. Washed with aqueous acetonitrile and DM water, dried the material afforded Formula- I. Pure material was obtained by recrystallizing in acetonitrile DM water medium. Yield: 65% Purity: > 99%.

Claims

CLAIMS:
1. An improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of:
(i) condensing the compound of Formula- IV
Formula- IV
Figure imgf000023_0001
with compound of Formula-XXII or compound of Formula-XXIIa
Figure imgf000023_0003
in the presence of organic base in an organic solvent to obtain compound of Formula- XXIV or compound of Formula-XXIVa.
Figure imgf000023_0002
in the presence of a base and catalyst in an aqueous organic solvent medium to obtain compound of Formula-XXV.
Formula-XXV
Figure imgf000024_0001
(iii) de-protecting the compound of Formula- XXV in the presence of acid environment to obtain compound of Formula- XXVI.
Formula-XXVI
Figure imgf000024_0002
(iv) reacting the compound of Formula-XXVI with compound of Formula- VIII
Formula- VIII
Figure imgf000024_0003
under basic conditions to obtain Baricitinib of Formula-I
Formula-I
Figure imgf000025_0001
(v) optionally purifying the Baricitinib of Formula-I from suitable solvent medium wherein the obtained Baricitinib of formula (I) having more than 99% of HPLC purity.
2. The process as claimed in claim 1, wherein the organic base used in step (i) is
Diazabicyclo[5.4.0]undec-7-ene (DBU).
3. The process as claimed in claim 1, wherein, the solvent used in step (i) is selected from acetonitrile, isopropyl alcohol, /V,/V-dimethylformamide, N, N-d\ met h y 1 acct a m i dc or mixture thereof preferably isopropyl alcohol or mixture thereof.
4. The process as claimed in claim 1, wherein the catalyst used in step (ii) is Tetrakis(triphenylphosphine) palladium(O) or any other palladium derived catalyst. And the organic solvent is selected from 1,2-dimethoxyethane, N,N- dimethylformamide, n-butanol, water, tertiary butanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetonitrile or mixture thereof.
5. The process as claimed in claim 1, wherein the base used in step (ii) is selected from organic or inorganic base.
6. The process as claimed in claim 1, wherein an acid used in step (iii) is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile-HCl, ethylacetate-HCl.
7. The process as claimed in claim 1, wherein the solvent used in step (iv) is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof.
8. The process as claimed in claim 1, wherein the solvent used in step (v) is selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, «-propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, N,N- dimethylformamide, VV-dimethylacetamide, DMSO, acetone or mixture thereof.
9. An improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of: (i) condensing the compound of Formula-XXIV or compound of Formula- XXIVa
Figure imgf000026_0002
Formula- XXIV Formula- XXIVa with compound of Formula-XIII.
Formula-XIII
Figure imgf000026_0001
in the presence of a base and catalyst in an aqueous organic solvent medium to obtain compound of Formula-XXV.
Figure imgf000027_0001
(ii) de-protecting the compound of Formula- XXV in the presence of acid environment to obtain compound of Formula-XXVI.
Formula-XXVI
Figure imgf000027_0002
(iii) reacting the compound of Formula-XXVI with compound of Formula- VIII
Formula- VIII
Figure imgf000027_0003
under basic conditions to obtain Baricitinib of Formula-I
Figure imgf000027_0004
(iv) optionally purifying the Baricitinib of Formula-I from suitable solvent medium wherein the obtained Baricitinib of formula (I) having more than 99% of HPLC purity.
10. The process as claimed in claim 9, wherein the catalyst used in step (i) is
Tetrakis(triphenylphosphine) palladium(O) or any other palladium derived catalyst. And the organic solvent is selected from 1,2-dimethoxyethane, N,N- dimethylformamide, n-butanol, water, tertiary butanol, isopropyl alcohol, n- propanol, tetrahydrofuran, acetonitrile or mixture thereof.
11. The process as claimed in claim 9, wherein the organic base used in step (i) is Diazabicyclo[5.4.0]undec-7-ene (DBU).
12. The process as claimed in claim 9, wherein an acid used in step (ii) is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile-HCl, ethylacetate-HCl.
13. The process as claimed in claim 9, wherein the solvent used in step (iii) is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof.
14. The process as claimed in claim 9, wherein the solvent used in step (iv) is selected from methanol, ethanol, isopropyl alcohol, tertiary butanol, n- propanol, toluene, ethylacetate, acetonitrile, diisopropylether, n-heptane, water, tetrahydrofuran, N,N- dimethylformamide, A,A-dimcthylacctamidc, DMSO, acetone or mixture thereof.
15. An improved process for the preparation of Baricitinib of Formula-I having more than 99% purity by HPLC, comprising the steps of:
(i) condensing the compound of Formula-XXIV Formula- XXIV
Figure imgf000029_0001
with compound of Formula-XXVII in the presence of a base and catalyst in an organic solvent medium
Figure imgf000029_0002
to obtain compound of Formula- VI
Figure imgf000029_0003
(ii) deprotecting the compound of Formula- VI in the presence of acid to obtain compound of Formula- XXVIII
Formula- XXVIII
Figure imgf000030_0001
(iii) reacting the compound of Formula- XXVIII with compound of Formula- VIII
Formula- VIII
Figure imgf000030_0002
under basic conditions to obtain Baricitinib of formula (I); or
(iv) de-protection of compound of Formula-XXVIII obtained in step (ii) in the presence of a base in an organic solvent to obtain compound of Formula-XXVIa
Formula-XXVIa
Figure imgf000030_0003
(v) reacting the compound of formula-XXVIa with compound of Formula- VIII
Formula- VIII
Figure imgf000030_0004
under basic conditions to obtain Baricitinib of Formula-I
16. The process as claimed in claim 15, wherein the base used in step (i) is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, potassium acetate, sodium acetate, aq. ammonia or organic bases such as /V,/V-diisopropylethylamine, triethylamine, DBU, Diisopropyl amine.
17. The process as claimed in claim 15, wherein the acid used in step (i) is selected from isopropyl alcoholic. HC1, methanolic.HCl, ethanolic HC1, isopropyl alcohol-HCl, methanol-HCl, ethanol-HCl, 1,4-dioxane-HCl, acetonitrile-HCl, ethylacetate-HCl.
18. The process as claimed in claim 15, wherein the solvent used in step (iii) is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof.
19. The process as claimed in claim 15, wherein the base used in step (iv) is selected from organic bases such as /V,/V-diisopropylethylamine, triethylamine, DBU and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate.
20. The process as claimed in claim 15, wherein, the solvent used in step (iv) is selected from tetrahydrofuran, acetonitrile, dichloromethane, ethylacetate, toluene, water or mixture thereof.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016125080A2 (en) * 2015-02-02 2016-08-11 Sun Pharmaceutical Industries Limited Process for the preparation of baricitinib and an intermediate thereof
AU2018102141A4 (en) * 2017-12-13 2019-10-03 Jiangsu Zhongbang Pharmaceutical Co., Ltd. Method for preparing Baricitinib

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016125080A2 (en) * 2015-02-02 2016-08-11 Sun Pharmaceutical Industries Limited Process for the preparation of baricitinib and an intermediate thereof
AU2018102141A4 (en) * 2017-12-13 2019-10-03 Jiangsu Zhongbang Pharmaceutical Co., Ltd. Method for preparing Baricitinib

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