Claims:

1) A process for preparation of pyrrolo[2,3-b]pyrazine compound of Formula (I),

the process comprising the steps of;
i) reacting 3,5-dihalopyrazine-2-amine compound of formula (IV) with trimethylsilyl acetylene (TMS-Ac) in presence of palladium catalyst in a solvent to form 5-halo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (III);

ii) forming insitu compound of formula (II), by cyclization of compound of formula (III) in presence of a base in a solvent;

iii) reacting the insitu formed compound of Formula (II) with benzene sulfonyl halide of formula (V) in a base to form compound of formula (I),
wherein X is a halogen selected from chlorine, fluorine, bromine, iodine; and
R1 is (1-4C) alkyl, -NO2.

2) The process as claimed in claim 1, wherein palladium catalyst in stage (i) is selected from bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2], Trisdipalladium [Pd2(dba)3] and Palladium(II)acetate [Pd(OAc)2].

3) The process as claimed in claim 1 or 2 wherein catalyst is bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2].

4) The process as claimed in claim 1, wherein the catalyst used is 0.003 - 0.007 mol equivalent.

5) The process as claimed in claim 1 or 4, wherein the catalyst is 0.005 mol equivalent.

6) The process as claimed in claim 1, wherein the stage (i) is carried out in presence of copper co-catalyst and an amine base.

7) The process as claimed in claim 6, wherein the copper co-catalyst is copper iodide.

8) The process as claimed in claim 6, wherein the amine base is selected from triethylamine, di-isopropylethylamine and di-isopropylamine.

9) The process as claimed in claim 1, wherein the solvent used in stage (i) is selected from tetrahydrofuran, toluene and acetonitrile.

10) The process as claimed in claim 1 or 9, wherein the solvent used in stage (i) is tetrahydrofuran.

11) The process as claimed in claim 1, wherein the solvent used in stage (i) is 4-8 volumes (V).

12) The process as claimed in claim 1 or 11, wherein the solvent used in stage (i) is 5-7 volumes (V).

13) The process as claimed in claim 1, wherein stage (i) is carried out at -10 to 10°C.

14) The process as claimed in claim 1 or 13, wherein stage (i) is carried out at 0-5°C.

15) The process as claimed in claim 1, wherein Trimethyltrimethyl silyl acetylene used is 1 - 1.1 mol equivalent.

16) The process as claimed in claim 1 or 15, wherein trimethyl silyl acetylene used is 1.05 mol equivalent.

17) The process as claimed in claim 1, wherein base used in stage (ii) is selected from alkali metal hydroxide and alkali metal alkoxide.

18) The process as claimed in claim 17, wherein alkali metal hydroxide is selected from potassium hydroxide, sodium hydroxide; and alkali metal alkoxide is selected from potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide.

19) The process as claimed in claim 1, wherein the solvent used in stage (ii) is selected from dioxane, dimethyl formamide and tetrahydrofuran.

20) The process as claimed 1, wherein the stage (ii) is carried out at 20-40°C.

21) The process as claimed 1 or 19, wherein the stage (ii) is carried out at 25-30 ?.
22) The process as claimed in claim 1, wherein the base used in stage (iii) is selected from alkali metal hydroxide and alkali metal alkoxide.

23) The process as claimed in claim 22, wherein alkali metal hydroxide is selected from potassium hydroxide, sodium hydroxide; and alkali metal alkoxide is selected from potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide.

24) The process as claimed in claim 1, wherein the solvent used in stage (ii) and stage (iii) is selected from dioxane, dimethyl formamide and tetrahydrofuran.

25) The process as claimed in claim 1, wherein

compound of Formula I is represented by compound of Formula VI,

compound of Formula III is represented by compound of Formula VIII,

compound of Formula II is represented by compound of Formula VII

and compound of Formula V is represented by compound of Formula X
.

26) The process as claimed in claim 1 or 25, wherein compound of Formula VI, wherein the process comprises the steps:

ii) reacting 3,5-dibromopyrazine-2-amine of formula (IX) with trimethylsilyl acetylene (TMS-Ac) in presence of a palladium catalyst selected from bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2], Trisdipalladium [Pd2(dba)3] and Palladium(II)acetate [Pd(OAc)2] to form 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (VIII);


ii) forming in situ compound of formula (VII), by cyclization of compound of formula (VIII) in presence of base selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide in a solvent selected from dioxane, dimethyl formamide and tetrahydrofuran;

iii) reacting compound of formula (VII) with tosyl chloride of formula (X) in a base selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide to form compound of formula (VI).
, Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See Section 10, Rule 13]

IMPROVED PROCESS FOR PREPARATION OF SUBSTITUTED PYRROLO[2,3-B]PYRAZINE COMPOUNDS

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.
Field of the invention
The present invention relates to a process for preparation of substituted pyrrolo[2,3-b]pyrazine compound.

Background of the invention

Substituted pyrrolo[2,3-b]pyrazine compound of formula I, is well-known in the art as an important intermediate in the manufacturing of Upadacitinib. The structure of substituted pyrrolo[2,3-b]pyrazine compound of formula I is illustrated below-

Formula I
Processes are known in the art for the preparation of Formula I. Reference may be made to U.S. Patent No. 8,426,411 which discloses a process for the preparation of pyrrolo[2,3-b]pyrazine compound. The reference particularly discloses preparation of 2-bromo-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine intermediate (IA). The process comprises the reaction of 3,5-dibromopyrazin-2-amine with (trimethylsilyl)acetylene in THF in presence of triethylamine, copper iodide and bis(triphenylphosphine)palladium dichloride to give
5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine. The yield of this stage reported is 93% and the purity is 93%. Bromo ethylene pyrazine derivative compound obtained is cyclized by reacting with sodium hydride (60% dispersion in mineral oil) and further N-tosyl protection is done in situ by reacting with p-toluenesulfonyl chloride. The yield of this stage reported is 52% and time required for the completion of the reaction is 16 hours.
The process involves use of sodium hydride which is pyrophoric in nature. In 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine preparation, the catalyst bis(triphenylphosphine) palladium dichloride used is 0.01 eq and solvent THF used is 11-12 volumes. The process involves use of 10V DMF and the amount of water required for quenching is very high.

Formation of pyrrolo pyrazine ring involves three stages, deprotection, cyclization and N-tosyl protection and the overall yield of these three stages is 52%. The time required for the completion of the reaction is 16 hours.
Thus, due to high catalyst and solvent consumption the process becomes costly especially at higher scale. Also, time required for the reaction completion being higher, there is need for process which is feasible at plant scale.

Accordingly, there is a need of efficient and industrially feasible process for the preparation of Pyrrolo[2,3-b]pyrazine compound that overcomes the above mentioned drawbacks of the prior art.

Objects of the invention

An object of the present invention is to provide an improved process for preparation of pyrrolo[2,3-b]pyrazine compound that is suitable for industrial production.

Another object of the present invention is to provide the improved process for the preparation of pyrrolo[2,3-b]pyrazine compound having higher yield and better purity.

Another object of the present invention is to provide an improved process for the preparation of pyrrolo[2,3-b]pyrazine compound which avoids use of pyrophoric reagents like sodium hydride.

Yet another object of the present invention is to provide the improved process for the preparation of pyrrolo[2,3-b]pyrazine compound which avoids use of higher solvent and trimethylsilyl acetylene consumption.

Summary of the invention

The present invention teaches a process for preparation of pyrrolo[2,3-b]pyrazine compound of Formula I.

The process comprises reacting 3,5-dihalopyrazine-2-amine compound of formula (IV) with trimethyl silyl acetylene at low temperature in the presence of suitable palladium catalyst in a solvent to form 5-halo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (III), wherein addition of trimethyl silyl acetylene is carried out over optimum period of time. The reaction is carried out in presence of 0.01 mol eq of catalyst and 5-7 V of solvent.

The pyrazine-2-amine derivative of formula (III) is further cyclized and converted to pyrrolo[2,3-b]pyrazine compound of Formula I in presence of suitable alkali, wherein trimethyl silyl deprotection, cyclization and sulfonyl protection is carried out using a single alkali.

Detailed description of the invention

The foregoing objects of the present invention are accomplished, and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
In one aspect, the present invention relates to a process for preparation of Pyrrolo[2,3-b]pyrazine compound of Formula I, comprising the steps of;

i) reacting 3,5-dihalopyrazine-2-amine compound of formula (IV) with trimethylsilyl acetylene (TMS-Ac) at low temperature in presence of palladium catalyst in a solvent to form 5-halo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (III);

ii) forming insitu compound of formula (II), by cyclization of compound of formula (III) in presence of an alkali in a solvent;

iii) reacting the said insitu formed compound (II) with benzene sulfonyl halide of formula
(V) in a alkali to form compound of formula (I),
wherein X is a halogen selected from chlorine, fluorine, bromine, iodine; and
R1 is (1-4C) alkyl, -NO2.

The palladium catalyst in stage (i) is selected from bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2], Trisdipalladium [Pd2(dba)3] and Palladium(II)acetate [Pd(OAc)2]. In a preferred embodiment the palladium catalyst is bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2].
The catalyst used is preferably 0.003 - 0.007 mol equivalent, preferably 0.005 mol equivalent.

The reaction in stage (i) is carried out in presence of copper co-catalyst and an amine base.

The copper cocatalyst is Copper(I) halide preferably copper iodide.
Amine base used in stage (i) is selected from triethylamine, di-isopropylethylamine and di-isopropylamine, preferably triethylamine.

The solvent used in stage (i) is selected from Tetrahydrofuran, toluene and acetonitrile, preferably tetrahydrofuran.

The reaction proceeds in 4-8 volumes (V) of the solvent, preferably 5-7 volumes (V) of the solvent.

The addition of TMS-AC in the reaction in stage (i) is carried out slowly by maintaining the temperature of the reaction mixture at -10 to 10°C, preferably at 0-5°C. The addition of TMS-AC in controlled manner is important.

It is observed that in the typical reaction conditions, there is formation of III-imp. One molar equivalent of 2-amino-3,6-dihalopyrazine reacts with >1.1 molar equivalents of trimethyl silyl acetylene. The reaction proceeds in presence of 0.02 mol equivalents of catalyst Pd(PPh3)2Cl2, 0.03 molar equivalent cocatalyst copper iodide and an amine base in the solvent (10 volume). The formation of III-imp observed in ~70-75%.
The impurity is isolated and characterized by NMR.

1H NMR(300 MHZ, DMSO): 8.19 (S, 1H), 7.02 (brs, 2H), 0.23 (S, 9H), 0.21 (S,9H).

The temperature of the reaction also plays very important role on the purity of compound (III). At higher temperature, formation of dimer impurity 3,5-bis(2-trimethylsilylethynyl) pyrazin-2-amine of formula (III-imp) is higher.

If the (III-imp) impurity is formed in the higher amount, it is carry forwarded in the next stage (ii) and (iii) and also in the compound (I). Thus, to achieve the purity of compound (I), the additional purifications are required, which results in yield loss.
Due to the structural similarity, the solubility of the impurity is similar to product. Thus, purification is challenging to isolate pure product.
The process of the present invention provides controlled conversion of compound (IV) to compound (III). This is achieved by controlled charging of TMS-Ac to the reaction mixture.

To the reaction mixture containing 3,5-dihalopyrazine-2-amine, palladium catalyst, copper cocatalyst and an amine base in the solvent, TMS-Ac is charged at -10 to 10°C.

TMS-Ac used is 1.0 - 1.05 molar equivalent with respect to 1.01 mol equivalent of compound of formula (IV).

The rate and time of addition of TMS-Ac is adjusted such that the temperature of the reaction mixture is maintained at 0-5°C.

It is observed that the dimer impurity is minimized in the reaction conditions optimized according to the process of the present invention.

In stage (ii), compound of formula (III) is cyclized insitu to 5-halo-5H-pyrrolo[2,3-b]pyrazine of formula (II) with suitable alkali in a solvent.

The alkali used in stage (ii) is selected from alkali metal hydroxide and alkali metal alkoxide. Alkali metal hydroxide is preferably potassium hydroxide, sodium hydroxide; and alkali metal alkoxide is potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide.
The stage (ii) is carried out by adding the solution of compound of formula (III) in a solvent to the alkali. The addition is performed in a controlled manner to avoid temperature rise. The solvent is selected from dioxane, dimethyl formamide and tetrahydrofuran, preferably dimethyl formamide.

The reaction is carried out at 20-40°C, preferably at 25-30°C.

The alkali used in stage (iii) is selected from alkali metal hydroxide and alkali metal alkoxide. The alkali metal hydroxide is preferably potassium hydroxide, sodium hydroxide, and alkali metal alkoxide is potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, preferably sodium methoxide.

The reaction is carried out in the solvent selected from dioxane, dimethyl formamide and tetrahydrofuran, preferably dimethyl formamide.

A preferred embodiment of the present invention is a process for preparation of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine of Formula (VI),

the process comprising the steps of;
i) i) reacting 3,5-dibromopyrazine-2-amine of formula (IX) with trimethylsilyl acetylene (TMS-Ac) in presence of a palladium catalyst selected from bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2], Trisdipalladium [Pd2(dba)3] and Palladium(II)acetate [Pd(OAc)2] to form 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (VIII);

ii) forming in situ compound of formula (VII), by cyclization of compound of formula (VIII) in presence of base selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide in a solvent selected from dioxane, dimethyl formamide and tetrahydrofuran;

iii) reacting compound of formula (VII) with tosyl chloride of formula (X) in a base selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide to form compound of formula (VI).

EXAMPLES:
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine [Formula (VIII)]
3,5-dibromopyrazin-2-amine of formula (IX) (100 g) was charged to THF (400 ml) at 25-30°C and the mixture was stirred for 15 - 20 minutes.

[PdCl2(PPh3)2] (1.38 gm) was charged to the mixture and stirred for 30 minutes. Copper iodide (3.76 gm) was charged to the mixture at 25-30°C and stirred for 30 minutes. The mixture was cooled to 15-20°C and triethylamine (200 gm) was added slowly. The mixture was cooled to 0-5°C. Separately prepared solution of trimethyl silyl acetylene (39.2 gm) in THF (200 ml) was charged slowly to the cooled reaction mixture over 5-6 hours. The mixture was stirred for 2-3 hours. The mixture was filtered and the solid was washed with THF. The organic layer was distilled under vacuum. The toluene strippings (100 ml x 2) were given to the mass. Toluene (500 ml) was charged and charcoal (20 gm) was added to the mixture at 70-75°C. The mixture was filtered and the organic layer was distilled under vacuum below 50°C.
The reaction mass was stripped out with cyclohexane (200 ml) at 50-55°C and further cyclohexane (600 ml) was charged to the reaction mass. The temperature of the reaction mass was raised to 70-75°C and stirred for 1.5-2 hours. The mass was gradually cooled to 30-35°C, further chilled to 5-10°C and stirred for 1-2 hours. The solid precipitated was filtered and washed with (100 ml) cyclohexane cooled to 5-10°C. The compound 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (VIII) was suck dried and further dried in the oven at 45-50°C.

Yield = 90%
Dimer impurity 1%
HPLC Purity = 99.65%
LCMS: M+1 = 261

Example 2
Preparation of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine [Formula (VI)]
Potassium tert-butoxide (45 gms) was charged to dimethyl formamide (100 ml) and stirred at 25-30°C. Separately prepared solution of 5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-amine of formula (VIII) (100 gm in 150 ml dimethyl formamide) was charged slowly with constant stirring over 3-4 hours at 20-25°C.
Tosyl chloride of formula (X) (77.5 gm) was charged lotwise in 5 equal lots to the reaction mixture at 20-25°C in 1-2 hours.

Ethyl acetate (800 ml) was charged to the reaction mass at 25-30°C and stirred well for 30-60 minutes. The reaction mixture was filtered and water (800 ml) was charged to the filtrate. The mixture of aqueous and organic layers was mixed well and heated to 50-55°C. The mixture was maintained with constant stirring for 30-40 minutes. The layers were separated and aqueous layer was extracted twice with ethyl acetate (200 ml).
The combined organic layer was washed with water (200 ml) and brine solution (200 ml) at hot conditions. The organic layer was treated with 15% charcoal (15 g) and filtered.
The organic layer was distilled under vacuum at 50-55°C and stripping of methanol ((2x100 ml) was given and methanol (300 ml) was charged to the solution. The temperature of the reaction mass was raised to 65-70°C and maintained for 1-2 hours, The reaction mass was cooled gradually to 30-35°C and chilled to 10-15°C. The mass was filtered and washed with chilled methanol (50 ml). The solid wet compound 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine of formula (VI) obtained was analyzed for purity.

Dimer impurity 0.6%

The solid wet 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine of formula (VI) (100 gm) was charged to ethyl acetate (1000 ml) and temperature was raised to 65-70°C. Charcoal (10 gm ) was added to the reaction mixture and the mass was maintained for 1-2 hours for 65-70°C. The mass was filtered and the solvent was distilled under vacuum at 45-50°C to retain 4V solvent. The mass was stirred well and maintained at 65-70°C for 1-2 hours. The heating was stopped and the mas was cooled gradually to 30-35°C and further chilled to 10-15°C. The mass was filtered and washed with chilled ethyl acetate (50 ml). The solid was dried at 50-55°C for 4-5 hours. Yield: 90 gm (90%)
Dimer impurity 0.25%