FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of carbapenem derivative of formula I.

COOH wherein R2 represents:

BACKGROUND OF THE INVENTION

Carbapenems are a broad class of antibiotic compounds useful for the treatment of infectious diseases including gram positive and negative aerobic and anaerobic bacteria. Meropenem, Ertapenem, and Doripenem are some of the commercially available pyrrolidylthiocarbapenem compounds.
Doripenem is a pyrrolidylthiocarbapenem derivative chemically known as (4R,5S,6S)-3-[((3S,5S)-5-[[(aminosulfonyl)amino]-methyl]-3-pyrrolidinyl)thio]-6-[(lR)-l-hydroxy ethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is marketed in the form of monohydrate by Janssen as DORIBAX®. Doripenem monohydrate is used as antibiotic agent in the treatment of complicated intraabdominal infections. It is also used in the treatment of urinary tract infections including pyelonephritis. In view of the importance, several synthetic procedures to prepare carbapenems have been reported.

US 5,317,016 discloses a process for the preparation of pyrrolidylthiocarbapenem compounds, which comprises condensation of compound of formula III with compound of formula Ila in the presence of base.
wherein R3 is a carboxy protecting group and Pi is amino protecting group selected from p-nitrobenzyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyl, p-methoxybenzyloxycarbonyl or tert-butoxycarbonyl.
In US '016 the thiol side chain compound of formula Ila is prepared by deprotection of compound of formula IVa in presence of strong acid or strong base.


wherein Ri is thiol protecting group selected from acetyl or benzoyl; Pi and P2 are same or different amino protecting groups selected from p-nitrobenzyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyl, p-methoxybenzyloxycarbonyl or tert-butoxycarbonyl

Japanese patent JP 4274739 also discloses a similar process for the preparation of Doripenem wherein compound of formula Ila is prepared by deprotection of compound of formula IVa in presence of sulfuric acid.

Formula IV Formula II

Similar processes for the preparation of carbapenem derivatives have been reported in Journal of Antibiotics 1996, 49 (5), pp 478-484; Organic Process Research & Development 2003, 7, pp846-850 and Zhongguo Kagshengsu Zazhi 2006, 31 (12), pp746-748.

PCT application WO 2007/029084 A2 also discloses a process for the preparation of pyrrolidinylthiocarbapenem compounds wherein side chain compound of formula II is prepared by deprotection of compound of formula IV in presence of acetyl chloride, silica chloride and thionyl chloride.
wherein Pi and R2 are same as defined above wherein R2 represents:

wherein R] represnts acetyl group, P] represents hydrogen or amino protecting group selected from p-
nitrobenzyloxycarbonyl or tert-butoxycarbonyl and R2a represents:

P2 represents hydrogen or amino protecting group selected from p-nitrobenzyloxy¬carbonyl or tert-butoxycarbonyl.

The prior art processes involve the preparation of compound of formula II by deprotection of compound of formula IV in presence of acids or bases, which leads to the formation of unknown impurities during deprotection and consequently results in lower yield of desired compound of formula II. Further, conversion of compound of formula II to carbapenem derivatives of formula I results in formation of about 0.7% of dimeric impurities with total impurities up to 5 %, which requires repeated purification thus resulting in lower yield. Hence, there is a need to develop a simple, industrially feasible cost effective process for the preparation of carbapenems containing less than 0.10% of dimeric impurity.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple, commercially viable, and industrially scalable process for the preparation of carbapenem derivative of formula I with greater than 99.9% purity.
Another objective of the present invention is to provide a process for the preparation of carbapenem derivative of formula I containing less than 0.10% of dimeric impurities.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of carbapenem derivative of formula I,
which comprises:

a) treating compound of formula IV,

wherein R] represnts acetyl group, Pi represents hydrogen or amino protecting group selected from p-nitrobenzyloxycarbonyl or tert-butoxycarbonyl and R2a represents:

P2 represents hydrogen or amino protecting group selected from p-nitrobenzyloxy-carbonyl or tert-butoxycarbonyl with valeryl chloride to obtain compound of formula II;

wherein Pi and R2 are same as defined above

b) condensing compound of formula II with compound of formula III,

wherein R3 is p-nitrobenzyl group to obtain compound of formula V,

wherein R2, R3 and P1 are same as defined above

c) deprotecting the compound of formula V to obtain a compound of formula I,
d) optionally, purifying the compound of formula I; and
e) isolating the carbapenem of formula I.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides a process for the preparation of compound of formula II,

wherein P1 is amino protecting groups selected from p-nitrobenzyloxycarbonyl or tert-butoxycarbonyl wherein R2 represents:

P2 represents amino protecting group or hydrogen, which comprises treating the compound of formula IV, with valeryl chloride in an organic solvent to obtain compound of formula II. The organic solvent is selected from C1-C5 alcohols or mixtures thereof; preferably methanol. The compound of formula II is extracted from the reaction mixture by adding water immiscible organic solvent selected from esters, ethers, halogenated hydrocarbons and hydrocarbons or mixtures thereof; preferably methylene chloride.
In another embodiment, present invention provides a process for the preparation of carbapenem of formula I, which comprises treating compound of formula IV with valeryl chloride to obtain compound of formula II, which is thereafter condensed with compound of formula III to obtain protected carbapenem of formula V in presence of an organic base selected from secondary amines or tertiary amines; preferably N,N-diisopropylethylamine.

Water is added to the reaction mass and protected carbapenem of Formula V is extracted with an organic solvent selected from esters, ethers, halogenated hydrocarbons and hydrocarbons or mixtures thereof; preferably ethyl acetate.

Deprotection of compound of formula V to obtain carbapenem of formula I is carried out by hydrogenation using hydrogen and metal catalyst, which is optionally pre-reduced selected from Palladium on carbon (Pd/C), Platinum or Raney nickel in the presence of a buffer having pH 4-8. The buffer is selected from N-methylmorpholineacetate, N-methylmorpholineformate, morpholinehydrochloride, 3-(N-morpholino)propanesulfonate (MOPS), 2-(N-morpholino)ethanesulfonate (MES) or mixtures thereof; preferably N-methylmorpholineacetate.

The reaction mass containing carbapenem of formula I is washed with water immiscible organic solvents selected from esters, ethers, halogenated hydrocarbons and hydrocarbons or mixtures thereof; preferably ethyl acetate and then added C1-C5 alcohols, preferably isopropyl alcohol to obtain carbapenem of formula I. The isolated carbapenem is dried at temperature in the range of 20-40°C and is optionally purified.

In a preferred embodiment, present invention relates to process for the preparation of Doripenem, which comprises treating compound of formula IVa with valeryl chloride in C1.5 alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof to obtain compound of formula Ila,

wherein Ri is acetyl group, Pi and P2 are same or different amino protecting groups selected from p-nitrobenzyloxycarbonyl or tert-butoxycarbonyl, thereafter condensed with compound of formula III in the presence of organic base selected from secondary amine or tertiary amine to obtain protected Doripenem and is subsequently deprotected by catalytic hydrogenation to obtain Doripenem.

In yet another embodiment of the present invention, Doripenem obtained according to present invention is in the form of monohydrate which is in crystalline or amorphous form; preferably in crystalline form. The crystalline Doripenem is obtained by seeding with crystals of Doripenem monohydrate or without seeding.
In one more embodiment, present invention provides a process to prepare pure Doripenem monohydrate, which comprises; a. dissolving crude Doripenem in water;

b. optionally, treating the aqueous solution with carbon enoanticromos and passing
through 0.22 u filters;

c. optionally, seeding the reaction mass;

d. cooling to precipitate the Doripenem;

e. optionally, adding water miscible organic solvent; and

f. isolating and drying the pure Doripenem monohydrate.

The water miscible organic solvent is selected from C1-C5 alcohols, acetone or mixtures thereof; preferably isopropanol.

The Doripenem monohydrate obtained according to present invention contains less than 0.10% of dimeric impurities with greater than 99.9% purity. The dimeric impurities of Doripenem are as follows:

The compounds of formula III and formula IV used herein are prepared by the processes known in the prior-art.

The present invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF CRUDE CRYSTALLINE DORIPENEM

STEP A: DEPROTECTION OF DORIPENEM SIDE CHAIN
4-Nitrobenzyl(2S,4S)-4-acetylthio-2-[(N-sulfamoyl-N-(tert-butoxycarbonyl)amino]-methyl-pyrrolidine-1-carboxylate (114 g) was suspended in methanol (500 ml) and valeryl chloride (12.90 g) was added to the above suspension at 20-30°C. Reaction mass was heated to 48-52°C and stirred for 16h to complete the deprotection. DM water (1000 ml) was added to the reaction mass, extracted with methylene chloride (1000 ml) at 20-30°C and concentrated. The resulting concentrate was dissolved in N,N-dimethylformamide (200 ml) for the preparation of protected Doripenem.

STP B: PREPARATION OF PROTECTED DORIPENEM
(4-Nitrophenyl)methyl[4R,5R,6S]-3-[(diphenoxyphosphinyl)oxy]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate [100 g] was dissolved in N,N-dimethylformamide (300 ml) and cooled to -40°C. The reaction mass obtained in step-A and N,N-diisopropylethylamine (30.2 g) were added to the reaction mass at -40°C to -10°C and stirred for 6 h. Ethyl acetate (1000 ml) and DM water (600 ml) were added to the reaction mass and adjusted the pH to 3 with hydrochloric acid. Organic layer was separated, washed with DM water and concentrated under reduced pressure. The concentrated reaction mass was dissolved in tetrahydrofuran and the solution as such was taken for the preparation of crude Doripenem.

STEP C: PREPARATION OF CRUDE CRYSTALLINE DORIPENEM
N-Methylmorpholine (17.0 g) was added to DM water (800 ml), adjusted the pH to 7 with acetic acid and added to the reaction mass obtained in step-B at 15-25°C. 10% w/w

Palladium on charcoal was added to reaction mass and hydrogenated at 8-10 kg/cm2 for 2 h. The reaction mass was filtered and washed with ethyl acetate. To the aqueous portion, seeds of crystalline Doripenem followed by isopropyl alcohol (2700 ml) was added over a period of 5 h at 20-30°C, cooled to 0-3°C and stirred for 5 h. The product was filtered, washed with aqueous isopropanol (20% v/v, 100 ml) and dried at 30-35°C to yield title compound.

Yield: 50 g
Chromatographic purity: 99.22% (By HPLC)
Dimeric impurity: 0.06%

EXAMPLE 2
PREPARATION OF PURE CRYSTALLINE DORIPENEM MONOHYDRATE
Crude Doripenem (30 g) was added to hot DM water (50-53°C) and stirred at this temperature for 2-3 min. The resulting solution was cooled rapidly to 33-37°C, treated with activated carbon (3 g), filtered and passed through 0.22 u. filters. Seeds of crystalline Doripenem followed by isopropanol (300 ml) were added to the filtrate at 15-20°C over a period of 1 h to crystallize the product. The slurry was cooled to 0-5°C and stirred for 3 h. The product was filtered, washed with aqueous isopropanol (20% v/v, 30 ml) and dried under reduced pressure at 30-50°C to obtain title compound. Yield: 21 g
Chromatographic purity: 99.94% (By HPLC) Doripenem Dimer impurity: Not detected

EXAMPLE 3
PREPARATION OF CRUDE CRYSTALLINE DORIPENEM
STEP A: DEPROTECTION OF DORIPENEM SIDE CHAIN
4-nitrobenzyl (2S,4S)-4-acetylthio-2-[(N-sulfamoyl-N-(tert-butoxycarbonyl)amino]-
methyl-pyrrolidine-1-carboxylate (28.5 g) was suspended in methanol (125 ml) and valeryl chloride (3.2 g) was added to the above suspension at 20-30°C. Reaction mass was heated to 48-52°C and stirred for 16h to complete the deprotection. DM water

(250 ml) was added to the reaction mass, extracted with methylene chloride (250 ml) at 20-30°C and concentrated. The resulting concentrate was dissolved in N,N-dimethylformamide (50 ml) and used as such in the preparation of protected Doripenem.

STEP B: PREPARATION OF PROTECTED DORIPENEM
(4-nitrophenyl)methyl[4R,5R,6S]-3-[(diphenoxyphosphinyl)oxy]-6-[(lR)-l-hydroxyethyl ]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate [25 g] was dissolved in N,N-dimethylformamide (75 ml) and cooled to -40°C. The reaction mass obtained in step-A and N,N-diisopropylethylamine (7.55 g) were added to the reaction mass at -40°C to -10°C and stirred for 6 h. Ethyl acetate (250 ml) and DM water (150 ml) were added to the reaction mass and adjusted pH to 3 with hydrochloric acid. Organic layer was separated, washed with DM water and concentrated under reduced pressure. The concentrated reaction mass was dissolved in Tetrahydrofuran and the solution as such was taken for the preparation of crude Doripenem.

STEP C: PREPARATION OF CRUDE CRYSTALLINE DORIPENEM
N-Methylmorpholine (4.25 g) was added to DM water (200 ml), adjusted pH to 7 with acetic acid and added to the reaction mass obtained in step-B at 15-25°C. 10% w/w Palladium on charcoal was added to reaction mass and hydrogenated at 8-10 kg/cm for 2 h. The reaction mass was filtered and washed with ethyl acetate. To the aqueous portion, isopropyl alcohol (675 ml) was added over a period of 5 h at 20-30°C, cooled to 0-3°C and stirred for 5 h. The product was filtered, washed with aqueous isopropanol (20% v/v, 25 ml) and dried at 30-35°C to yield title compound. Yield: 12.5 g
Chromatographic purity: 99.26% (By HPLC) Dimeric impurity: 0.04%

EXAMPLE 4
PREPARATION OF PURE CRYSTALLINE DORIPENEM MONOHYDRATE
Crude Doripenem (5 g) was added to hot DM water (50-53°C) and stirred at this temperature for 2-3 min. The resulting solution was cooled rapidly to 33-37°C, treated with activated carbon (0.5 g), filtered and passed through 0.22 filters. Isopropanol (50 ml) was added to the filtrate at 15-20°C over a period of 1 h to crystallize the product.

The slurry was cooled to 0-5°C and stirred for 3 h. The product was filtered, washed with aqueous isopropanol (20% v/v, 5 ml) and dried under reduced pressure at 30-50°C to obtain title compound.
Yield: 3.3 g
Chromatographic purity: 99.92% (By HPLC)
Dimeric impurity: 0.05%.

WE CLAIM:

1. A process for the preparation of compound of formula I, OH

wherein R2 represents:

which comprises:
a) treating compound of formula IV,

wherein R1 represnts acetyl group, P1 represents hydrogen or amino protecting group selected from the group consisting of p-nitrobenzyloxycarbonyl and tert-butoxycarbonyl, R2a represents:

P2 represents hydrogen or amino protecting group selected from the group consisting of p-nitrobenzyloxy- carbonyl or tert-butoxycarbonyl with valeryl chloride to obtain compound of formula II;

wherein Pi and R2 are same as defined above b) condensing compound of formula II with compound of formula III,

COOR3 wherein R3 is p-nitrobenzyl group to obtain compound of formula V;

wherein R2, R3 and P1 are same as defined above

c) deprotecting the compound of formula V to obtain a compound of formula I;
d) optionally, purifying the compound of formula I; and
e) isolating the compound of formula I.

2. The process according to claim 1, wherein step (a) is carried out in a solvent selected from C1-C5 alcohols or mixtures thereof.

3. The process according to claim 1, wherein step (b) is carried out in presence of organic base selected from secondary amines or tertiary amines.

4. The process according to claim 1, wherein compound of formula V is deprotected by hydrogenation using hydrogen in the presence of metal catalyst, which is optionally pre-reduced selected from palladium on carbon (Pd/C), Platinum or Raney nickel and in the presence of buffer having pH about 4 to 8.

5. The process according to claim 4, wherein the buffer is selected from the group consisting of N-methylmorpholineacetate, N-methylmorpholineformate, morpholinehydrochloride, 3-(N-morpholino)propanesulfonate (MOPS), 2-(N-morpholino)ethanesulfonate (MES) and mixtures thereof.

6. The process for the preparation of Doripenem, which comprises: a) treating compound of formula IVa,

wherein R1 is acetyl group, Pi and P2 are same or different amino protecting groups selected from p-nitrobenzyloxycarbonyl or tert-butoxycarbonyl. with valeryl chloride in methanol to obtain compound of formula IIa;

wherein Pi is same as defined above.

b) condensing compound of formula IIa with compound of formula III,

wherein R2 is p-nitrobenzyl group.
in presence of organic base selected from secondary amines or tertiary amines to obtain protected Doripenem of formula Va,

wherein R2 and Pi are same as defined above

c) deprotecting the compound of formula Va by catalytic hydrogenation to obtain Doripenem;
d) optionally, purifying the compound obtained in step (c); and
e) isolating Doripenem.

7. Carbapenem obtained according to any of the preceding claims, containing dimeric impurities less than 0.10 % (by HPLC).

8. A process to prepare pure Doripenem monohydrate, which comprises;

a) dissolving crude Doripenem in water;
b) optionally, treating the aqueous solution with carbon enoanticromos and passing through 0.22 n filters;
c) optionally, seeding the reaction mass;
d) cooling to precipitate the Doripenem;
e) optionally, adding water miscible organic solvent; and
f) isolating and drying the pure Doripenem monohydrate.

9. The process according to claim 8, wherein water miscible organic solvent is selected from the group consisting of C1-C5 alcohols, acetone or mixtures thereof.

10. A process for the preparation of Doripenem substantially same as described herein.