DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF BARICITINIB

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Baricitinib and its intermediates.

BACKGROUND OF THE INVENTION

Baricitinib is chemically known as {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, as shown below a Compound of Formula (1). Baricitinib is marketed under the brand name of Olumiant®. Olumiant is a Janus Kinase (JAK) inhibitor to treat Rheumatoid arthritis.

Formula 1

Baricitinib (1) first disclosed in US Patent 8,158,616, which discloses different processes for the preparation of Baricitinib, which are shown below:

Compound of Formula (A) is reacted with Boron compound by Suzuki coupling reaction in presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) / K2CO3 in DMF to produce a Compound of Formula (B), which is treated with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (Azetidine compound) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile to produce Compound of Formula (C). The resulting compound is treated with hydrochloric acid to produce Boc deprotected Compound of Formula (D). Further, Compound (D) is treated with ethanesulfonyl chloride to produce Compound of Formula (E). Finally, Compound of Formula (E) is treated with trifluoroacetic acid (TFA) in methylene chloride to give Baricitinib TFA salt.

The process as shown in Scheme-I below:

Scheme-I

In another disclosure, compound of Formula (A) is reacted with 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Boron compound) (2) in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) / potassium carbonate (K2CO3) to produce a Compound of Formula (F), which is treated with aqueous hydrochloric acid to produce Compound of Formula (B). The resulting compound (B) is treated with 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (Azetidinylidene derivative) (3) in the presence of DBU to produce Compound of Formula (E). Compound (E) is treated with lithium tetrafluoroborate (LiBF4) to produce Compound of Formula (G), which is in-situ treated with aqueous ammonium hydroxide to produce Baricitinib, which is purified by column chromatography.

The process is as shown in Scheme-II below:


Scheme-II

In another disclosure, compound of Formula (A) is reacted with 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Boron compound) (2) in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) / K2CO3 to produce a Compound of Formula (4), which is treated with aqueous hydrochloric acid to produce Compound of Formula (5). The resulting compound (5) is treated with 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (Azetidine derivative) (3) in the presence of DBU in DMF to produce Compound of Formula (6). Compound (6) is hydrolyzed using aqueous sodium hydroxide or lithium hydroxide to produce Baricitinib, which is purified by column chromatography.

The process is as shown in Scheme-III below:

Scheme-III

Considering the importance of Baricitinib (1), there is always a need for an alternative and improved preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

In view of this, our inventors have developed the present invention; it has now surprisingly been found that the pure Baricitinib have numerous advantages over the reported processes.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is an improved process for the preparation of Baricitinib and its intermediates with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of Baricitinib (1):

1
which comprises:
(i) Providing a reaction mixture containing compound of formula (9)

Formula 9

wherein R1 is a protecting group,
(ii) isolating the obtained Compound of Formula (9) from an aromatic solvent; and
(iii) deprotecting a Compound of Formula (9) to obtain Baricitinib (1).

In another embodiment, the present invention provides an improved process for the preparation of Baricitinib (1):

Formula 1
which comprises:
(i) Providing a reaction mixture containing a compound of formula (8A);

Formula 8A

(ii) isolating obtained Compound of Formula (8A) from an aromatic solvent;
(iii) converting a Compound of Formula (8A) to Baricitinib (1).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of Baricitinib (1):

Formula 1
which comprises:
(i) Providing a reaction mixture containing a compound of formula (8A);

Formula 8A

(ii) isolating obtained Compound of Formula (8A) from an aromatic solvent;
(iii) Conversion of compound of Formula (8A) to a compound of formula (9) by known methods;

Formula 9

(iv) isolating obtained Compound of Formula (9) from an aromatic solvent; and
(v) deprotecting Compound of Formula (9) to obtain Baricitinib (1).

In still another embodiment, R1 is independently a protecting group comprising of pivaloyloxymethyl, benzyloxycarbonyl, allyl, benzyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, p-methoxybenzyl, hydroxymethyl and/or tert-butoxycarbonyl.

In still another embodiment, wherein, R2 is a hydrogen or independently a protecting group comprising of pivaloyloxymethyl, benzyloxycarbonyl, allyl, benzyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, p-methoxybenzyl, hydroxymethyl and/or tert-butoxycarbonyl.

Compounds (8A) and (9) of the present invention are obtained by methods known in the art.

In another embodiment, the reaction mixture containing the compound of formula (8A) is in a solvent or a mixture of solvents comprising water, acetonitrile, THF and 1,4-dioxane.

In another embodiment, isolating the obtained Compound of Formula (8A) from an aromatic solvent.

In another embodiment, aromatic solvent used is step (ii) comprises toluene, benzene, xylene and/or ethylbenzene.

The advantage of using aromatic solvent like toluene in step (ii) is ~15% of higher yield is obtained for isolation of product from aromatic solvent than alcohol / ester solvent.

In another embodiment, isolation of Compound of Formula (9) in step (iv) from an aromatic solvent or mixture of aromatic and water solvent.

In another embodiment, aromatic solvent used is step (iv) comprises toluene, benzene, xylene and/or ethylbenzene.

The advantage of using aromatic solvent like toluene in step (iv) is ~15% of higher yield is obtained for isolation of product from aromatic solvent than alcohol / ester solvent.

In still another embodiment, after adding suitable aromatic solvent and water to the reaction mass and maintained for 2 h at 20-30°C. Filtering the reaction mixture and dried at 30-55°C under reduced pressure.

In another embodiment, purification of Baricitinib is done by conventional methods like crystallization using a solvent or mixture of solvents.

In another embodiment, the present invention provides Baricitinib obtained is in crystalline form.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Isolation of (4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)methyl pivalate (4):

A reaction mixture containing (4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)methyl pivalate in acetonitrile and water was cooled to 20-30°C and diluted with purified water (1500 ml) and toluene (3000 ml). The organic layer was separated, and the aqueous layer was extracted with toluene (600 ml) at 20-30oC. The combined organic layer was washed with 25% w/w aqueous sodium chloride solution (600 ml) at 20-30°C. The obtained combined organic layer (~5200 ml) contains (4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)methyl pivalate with Chromatographic Purity (by HPLC): ~95%. It was taken as such for acidic hydrolysis without any purifications/isolations.

Example 2: Isolation of [4-(1H-Pyrazol-4yl-)7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5):
Combined organic layer (4) (as obtained from Example-1) was hydrolyzed by process known in the art, the resulting product was filtered and washed with pre-cooled toluene (2 x 300 ml, 0-10°C). The wet filtered mass (~500 g) was dried at 40-50°C under reduced pressure for 10 h to obtain [4-(1H-pyrazol-4yl-)7H-pyrrolo [2,3-d]pyrimidin-7-yl]methyl pivalate (288 g, 86% yield) with Chromatographic Purity (by HPLC): 99.6%.

Example 3: Isolation of [4-[1-[3-(cyanomethyl)-1-(Ethylsulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (6):

A reaction mixture containing [4-[1-[3-(cyanomethyl)-1-(Ethylsulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate was diluted with toluene (2000 ml) and purified water (4500 ml) and stirring was continued for 1 hour. The product was filtered and washed with toluene (1 x 500 ml) and with purified water (2 x 375 ml). The wet filtered mass (~580 g) dried at 35-45°C under reduced pressure for 10h to obtain [4-[1-[3-(Cyanomethyl)-1-(Ethylsulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d] pyrimidin-7-yl]methyl pivalate (375 g, 92% yield) with Chromatographic Purity (by HPLC): ~99.6%. ,CLAIMS:WE CLAIM:
1. An improved process for the preparation of Baricitinib (1):

1

which comprises:
(i) providing a reaction mixture containing the compound of formula (9);

Formula 9

wherein, R1 is a protecting group,
(ii) isolating the obtained Compound of Formula (9) from an aromatic solvent; and
(iii) deprotecting Compound of Formula (9) to obtain Baricitinib (1).

2. The process as claimed in claim 1, wherein step (i), R1 is independently a protecting group comprising of pivaloyloxymethyl, benzyloxycarbonyl, allyl, benzyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, p-methoxybenzyl, hydroxymethyl and/or tert-butoxycarbonyl.
3. The process as claimed in claim 1, step (ii), aromatic solvent comprises toluene, benzene, xylene and/or ethylbenzene and/or mixtures thereof.

4. An improved process for the preparation of Baricitinib (1):

Formula 1
which comprises:
(i) Providing a reaction mixture containing the compound of formula (8A);

Formula 8A

(ii) isolating Compound of Formula (8A) from an aromatic solvent;
(iii) Converting the Compound of Formula (8A) to Baricitinib (1).

5. The process as claimed in claim 4, wherein, R1 is independently a protecting group comprising of pivaloyloxymethyl, benzyloxycarbonyl, allyl, benzyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, p-methoxybenzyl, hydroxymethyl and/or tert-butoxycarbonyl; R2 is a hydrogen or independently a protecting group comprising of pivaloyloxymethyl, benzyloxycarbonyl, allyl, benzyl, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, p-methoxybenzyl, hydroxymethyl and/or tert-butoxycarbonyl and X is a leaving group comprises tosylate group, a triflate group, iodo, chloro, or bromo.
6. The process as claimed in claim 4 step (ii), aromatic solvent comprises toluene, benzene, xylene and/or ethylbenzene and/or mixtures thereof.