DESC: “PREPARATION OF 1-[(BENZYLOXY)CARBONYL]-4-ETHYL-2,5-DIHYDRO-1H-PYRROLE-3-CARBOXYLIC ACID”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid with high yield and purity.

BACKGROUND OF THE INVENTION

1-[(Benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid as a key intermediate for the preparation of Janus kinase inhibitors, also known as JAK inhibitors or Jakinibs, this intermediate is also used in the preparation of Upadacitinib (JAK inhibitors), which is treated rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, psoriatic arthritis, axial SpA and Giant Cell Arteritis.

1-[(Benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid, is represented by structural Formula (I).

1-[(Benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid of formula (I), which is a key intermediate for the preparation of Upadacitinib.

WO2017066775 discloses a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I), which comprises compound of formula (II) is reacted with ethyl acrylate in presence of t-BuONa/THF to obtain the compound of formula (III). The compound of formula (III) is reacted with trifluoromethanesulfonic anhydride in presence of DIPEA /diisopropyl ether to obtain the compound of formula (IV). The compound of formula (IV) is reacted with ethyl boronic acid (EtB(OH)2) in presence of Potassium carbonate/PdCl2(dppf)/toluene to obtain the compound of formula (V). The compound of formula (V) is reacted with NaOH/THF/H2O to obtain the compound of formula (I).
The above process is schematically shown as below:

However, the above said process is analogously disclosed. So, our inventors have developed a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I). The present invention is providing industrial applicable process with high purity and good yield.

OBJECT OF THE INVENTION

The present invention relates to a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I) with high yield and purity

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I), comprising the steps of;

a) reacting compound of formula (II) with methyl acrylate in presence of t-BuONa and solvent to obtain the compound of formula (III),

b) reacting compound of formula (III) with trifluoromethanesulfonic anhydride in presence of triethylamine and solvent to obtain compound of formula (IV),

c) reacting compound of formula (IV) with ethylboronic acid in present of PdCl2(dppf), K2CO3 and solvent to obtain compound of formula (V), and

d) hydrolysing compound of formula (V) with NaOH in presence of solvent to obtain compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I) with high yield and purity

The present invention provides a process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I), comprising the steps of;

a) reacting compound of formula (II) with methyl acrylate in presence of t-BuONa and solvent to obtain the compound of formula (III),

b) reacting compound of formula (III) with trifluoromethanesulfonic anhydride in presence of triethylamine and solvent to obtain compound of formula (IV),

c) reacting compound of formula (IV) with ethylboronic acid in presence of PdCl2(dppf), K2CO3 and solvent to obtain compound of formula (V), and

d) hydrolysing compound of formula (V) with NaOH in presence of solvent to obtain compound of formula (I).

In an embodiment of the present invention, compound of formula (II) is reacting with methyl acrylate in presence of t-BuONa and solvent and the reaction is carried out at room temperature for 10-12 hours to obtain the compound of formula (III). compound of formula (III) is reacting with trifluoromethanesulfonic anhydride in presence of triethylamine and solvent and the reaction is carried out at room temperature for 2-3 hours to obtain the compound of formula (IV). compound of formula (IV) is reacting with ethylboronic acid in presence of PdCl2(dppf), K2CO3 and solvent and the reaction is carried out at 70-85°C for 2-4 hours to obtain the compound of formula (V), and compound of formula (V) is hydrolysing with NaOH in presence of solvent and the reaction is carried out at 30-45°C for 2-3 hours to obtain the compound of formula (I).

According to an embodiment of the present invention provides 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I) having HPLC purity = 99.5%.

According to an embodiment of the present invention, wherein the solvent is selected from tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform or mixtures thereof.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:
Preparation of 1-benzyl 3-methyl 4-hydroxy-1H-pyrrole-1,3(2H,5H)- dicarboxylate (III)
Methyl acrylate (6 g) in THF (100 mL), Carboxybenzyl-glycine ethyl ester (10 g) (II) at 0 °C were added into RB flask, followed by addition of NatOBu (5g) portionwise over 2 hours. The resulting mixture was warmed to room temperature and stirred 10 hours. After completion of the reaction, the reaction was quenched with water (60 mL), the pH adjusted to 5.0 with concentrated HCl. The product was extracted into DCM (80 mL) and the organic layer washed with water (30 mL). After removal of the DCM the product was crystallized from methanol get title compound, which is used directly in the next step.

Yield: 95% (17.5 gr)

Example-2:
Preparation of 1-benzyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,3(2H,5H)-dicarboxylate (IV)
1-benzyl 3-methyl 4-hydroxy-1H-pyrrole-1,3(2H,5H)-dicarboxylate (10g) in toluene (100 mL) was added at 0 °C trifluoromethanesulfonic anhydride (12g), followed by a slow addition of trimethylamine (5g) over 15 min. The resulting mixture was warmed to room temperature and stirred 2 hours. Upon completion, the reaction was carefully quenched with 1M HCl (100 ml), additional toluene (75 ml) was added and the layers separated. The organic layer was washed twice with water (100 ml) and concentrated. The residue was chased with toluene to obtain tile compound and used directly in the next step.

Yield: 97% (14.5 gr)

Example-3:
Preparation of 1-benzyl 3-methyl 4-ethyl-1H-pyrrole-1,3(2H,5H)- dicarboxylate
Toluene (60 mL), water (10 mL), ethyl boronic acid (EtB(OH)2) (2.2 g), potassium carbonate (6g) were added to above toluene solution (14.5g) was added additional and the resulting mixture was added with PdCl2(dppf) (735 mg), the resulting mixture heated to 70-85 °C and stirred for 4 hours. Upon completion, the mixture was cooled to room temperature, filtered and the layers separated. The organic layer was washed with water and concentrated, diluted with toluene (60 mL), filtered and concentrated to obtain titled product.
Yield: 92% (6.5 gr)

Example-4:
1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid
1-benzyl 3-methyl 4-ethyl-1H-pyrrole-l,3(2H,5H)-dicarboxylate (10g) and THF (30 mL) were added in RB flask, followed by added solution of 20% aqueous NaOH (30 g). The resulting mixture was warmed to 40 °C and stirred 3 hours. After competition of the reaction, the mixture was cooled to room temperature, additional water (25mL) was added and the pH adjusted to 6.5 with concentrated HCl. The aqueous layer was cooled to room temperature and the pH adjusted to 3.5 with concentrated HC1. The resulting slurry of product was stirred for 2 hours before collecting the solids by filtration. The cake was washed with water (30 mL) and dried in a vacuum oven. The product was then dissolved in EtOAc (200 mL) at 55°C, filtered. The product crystallized upon cooling to 0 °C, was collected by filtration, washed with EtOAc (130 mL), and dried in a vacuum oven to afford the title compound.
Yield: 96% (9.2 gr)
Purity: 99.79%.
,CLAIMS:1. A process for the preparation of 1-[(benzyloxy)carbonyl]-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (I), comprising the steps of:

a) reacting compound of formula (II) with methyl acrylate in presence of t-BuONa and solvent to obtain the compound of formula (III),

b) reacting compound of formula (III) with trifluoromethanesulfonic anhydride in presence of triethylamine and solvent to obtain compound of formula (IV),

c) reacting compound of formula (IV) with ethylboronic acid in presence of PdCl2(dppf), K2CO3 and solvent to obtain compound of formula (V), and

d) hydrolysing compound of formula (V) with NaOH in presence of solvent to obtain compound of formula (I).

2. The process as claimed in claim 1, wherein the solvent is selected from tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform or mixtures thereof.