The present invention provides a process for desilylation of carbapenem intermediates.
Carbapenem compounds are known for their broad and potent antibacterial activity. A large number of derivatives have been prepared and investigated for clinical efficacy. Imipenem, faropenem, meropenem, ertapenem and doripenem are some of the carbapenem antibiotics available in the market for treating various bacterial infections.
The silyl protected intermediates of Formula I or its analogues are useful in the preparation of carbapenem antibiotics,
(Formula Removed)
FORMULA I
wherein R1, R2 and R3 are same or different and are C1-5 alkyl.
The silyl protecting groups of the compounds of Formula I or its analogues must eventually be removed during the preparation of carbapenem antibiotics. US Patent No 4,683,296 provides a desilylation process for carbapenem intermediates of Formula I and related compounds by using aqueous hydrochloric acid. Similarly US Patent No 5,340,927 provides a desilylation process using methanesulfonic acid. A similar process is provided in US Patent No 4,783,453 wherein desilylation is carried out using potassium phosphate.
The prior art methods involve the use of strong reaction conditions and excess quantity of desilylating agents. The desilylating methods that involve the use of mineral or sulfonic acids also require considerable amount of base for neutralization.
Carbapenem ring system being sensitive to such acidic or basic conditions, it usually results in reduced yield and increased impurity level.
The present inventors have developed an efficient method for desilylation of carbapenem intermediates using an acetyl chloride, silica chloride, oxalyl chloride or thionyl chloride. The present method employs only a catalytic quantity of these chloride compounds and does not require excessive base for neutralization. Thus, by employing the present method, the process becomes facile, eco-friendly and high yielding with improved purity.
The term "protecting group" in the present invention refers to those used in the art and serve the function of blocking the carboxyl or amino groups while the reactions are carried out at other sites of the molecule. Examples of a carboxyl protecting group include, but not limited to, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-C19 aralkyl, optionally substituted C6-C12 aryl, optionally substituted C1-C12 amino, optionally substituted C3-C12 hydrocarbonated silyl, optionally substituted C3-C12 hydrocarbonated stannyl, and a pharmaceutically active ester forming group. Examples of amino protecting groups include, but not limited to, lower alkylsilyl groups, lower alkoxymethyl groups, aralkyl groups, acetyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
A first aspect of the present invention provides a process for the preparation of the compound of the Formula II,
(Formula Removed)
wherein R4 is selected from a group comprising of,
(Formula Removed)
wherein P1 is hydrogen or a carboxyl protecting group, P2 is hydrogen or an amino protecting group, R6 is hydrogen or C1-5 alkyl, R7 and R8 are same or different and are hydrogen, C1.5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, X is oxygen atom or sulfur atom, Y is oxygen atom, sulfur atom, substituted or unsubstituted methylene group or an imino group and Z is a substituted or unsubstituted methylene group, and R5 is hydrogen, or R4 and R5 are joined together so as to form a resultant compound of Formula III,
wherein R6 and P1 are as defined above, A is selected from a group comprising of a)

wherein P2, R7 and R8 are as defined above, by desilylating the compound of Formula IV,
(Formula Removed)
FORMULA IV
wherein R1, R2 and R3 are same or different and are C1-5 alkyl, and R4 and R5 are as defined above, in the presence of acetyl chloride or silica chloride or thionyl chloride or oxalyl chloride.
Starting materials of the present invention can be prepared by any of the methods known in the art. The compound of Formula IV is treated with an organic solvent selected from a group comprising of C1-5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester and ether in the presence of acetyl chloride or silica chloride or thionyl chloride or oxalyl chloride. The reaction mixture was stirred for sufficient time to affect desilylation. The desilylated compound can be isolated from the reaction mixture by layer separation or by drying the solid obtained from the reaction mixture. The isolation can also be accompanied by neutralization of the reaction mixture.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1 PREPARATION OF Ha:
(Formula Removed)
Acetyl chloride (2.7 g) was added to a mixture of the compound IVa (50 g) in toluene (500 ml) and methanol (100 ml). The reaction mixture was stirred for 2 h at 20° to 25°C. The reaction was monitored by thin layer chromatography and the solid was separated by filtration. The separated solid was washed with methanol and dried to obtain lla. Yield: 36 g HPLC Purity: 98%
PMR: 1.29 (d, 3H), 2.85 (dd, 1H), 3.2 (m, 2H), 3.93 (m, 1H), 4.1 (m, 2H), 5.37 (s, 2H), 7.56 (d, 2H), 8.24 (d, 2H)
EXAMPLE 2 PREPARATION OF Mb:
(Formula Removed)
The compound IVb (100 g) was suspended in methanol (300 ml) at ambient temperature. Acetyl chloride (3.1 g) was added to the suspension and stirred for 2 h.
After the completion of reaction, the homogeneous solution was poured into a mixture of dichloromethane (1 L) and water (700 ml), followed by the adjustment of pH to 7.0. The dichloromethane layer was separated, concentrated under vacuum and the residue was crystallized with toluene to obtain Mb.
Yield: 74 g
HPLC Purity: 99%
PMR (CDCI3): 8.28 (d, 2H), 7.54 (d. 2H), 6.16 (1H, NH), 5.36 (s, 2H), 4.13 (m, 1H),
3.86 (m, 2H), 3.78 (m, 1H), 2.91 (m, 1H), 1.30 (d, 3H),1.22(d, 3H)
EXAMPLE 3 PREPARATION OF lla:
Using the procedure set forth in Example 1, acetyl chloride was replaced with thionyl chloride (4.1 g) to obtain lla.
Yield: 35 g HPLC Purity: 97%
EXAMPLE 4 PREPARATION OF Mb:
Using the procedure set forth in Example 2, acetyl chloride was replaced with silica chloride (25 g) to obtain lib.
Yield: 73 g HPLC Purity: 99%
EXAMPLE 5 PREPARATION OF lib:
Using the procedure set forth in Example 2, acetyl chloride was replaced with thionyl chloride (4.7 g) to obtain Mb.
Yield: 70 g HPLC Purity: 99%
EXAMPLE 6 PREPARATION OF lie:
(Formula Removed)
The compound IVc (20 g) was suspended in methanol (60 ml) at ambient temperature. Acetyl chloride (0.65 g) was added to the suspension so obtained and stirred for 2 h. After the completion of the reaction, the homogeneous solution was poured into a mixture of dichloromethane (1 L) and water (700 ml), followed by the adjustment of pH to 7.0. The dichloromethane layer was separated, concentrated under vacuum and the residue was crystallized with a mixture of ethyl acetate and hexane (1:1) to obtain llc.
Yield: 12.7 g
HPLC Purity: 99%
PMR (CDCI3): 8.23 (d, 2H), 7.54 (d. 2H), 6.1 (1H, NH), 5.31 (s, 2H), 4.14 (m, 1H), 3.81
(m, 1H), 3.66 (s, 2H), 2.93 (m, 1H), 2.45 (m, 1H), 1.29 (d, 3H), 1.25 (d, 3H)
EXAMPLE 7
PREPARATION OF lld:

(Formula Removed)
(2R)-2-[3-(1 -{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]propanoic acid (10 g) was suspended in dichloromethane (100 ml) and cooled to -15°C. Ethyl chloroformate (4.4 g) was added to the suspension, followed by the addition of triethylamine (4.3 g) at -15° to -10°C and stirred for 60 minutes. 4-Nitrobenzyl 2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-1-carboxylate (11.7 g) was added to the reaction mixture -10°C and stirred for 60 minutes. Water (50 ml) was added to the reaction mixture and the pH was adjusted to 7.0 followed by washing with water (50 ml). The organic layer was separated and concentrated under vacuum to obtain a solid residue containing the compound IVd. The residue so obtained was dissolved in methanol (30 ml), followed by the addition of acetyl chloride (0.65 g). The reaction mixture was stirred for 60 minutes at 20° to 25°C and subsequently it was poured into a mixture of dichloromethane (100 ml) and water (100 ml), followed by the adjustment of pH to 5.0. The dichloromethane layer was separated and concentrated to obtain lid.
Yield: 7.0 g Purity by NMR : 95%
EXAMPLE 8 PREPARATION OF lld:
Using the procedure set forth in Example 7, acetyl chloride was replaced with silica chloride (2 g) to obtain lld.
Yield: 6.5 g
EXAMPLE 9 PREPARATION OF lie:
(Formula Removed)
Compound IVe (5 g) was added to methanol (20 ml), followed by the addition of acetyl chloride (0.2 g). The reaction mixture was stirred for 2 h and subsequently poured into a mixture of dichloromethane (50 ml) and water (50 ml). The dichloromethane layer was separated and concentrated, followed by recrystallization with a mixture of toluene and hexane to obtain lle.
Yield: 3.2 g
EXAMPLE 10 PREPARATION OF lle:
Using the procedure set forth in Example 9, acetyl chloride was replaced with silica chloride (1.0 g) to obtain lle.

WE CLAIM:
1. A process for the preparation of the compound of the Formula II,
(Formula Removed)
wherein R4 is selected from a group comprising of,

(Formula Removed)
wherein P1 is hydrogen or a carboxyl protecting group, P2 is hydrogen or an amino protecting group, R6 is hydrogen or C1-5 alkyl, R7 and R8 are same or different and are hydrogen, C1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, X is oxygen atom or sulfur atom, Y is oxygen atom, sulfur atom, substituted or unsubstituted methylene group or an imino group and Z is a substituted or unsubstituted methylene group, and R5 is hydrogen, or R4 and R5 are joined together so as to form a resultant compound of Formula III,
(Formula Removed)
wherein R6 and P1 are as defined above, A is selected from a group comprising of
a)
(Formula Removed)
wherein P2, R7 and R8 are as defined above, by desilylating the compound of Formula IV,

(Formula Removed)
FORMULA IV
wherein R1, R2 and R3 are same or different and are C1-5 alkyl, and R4 and R5 are as defined above, in the presence of acetyl chloride or silica chloride or thionyl chloride or oxalyl chloride.
2. A process as claimed in claim 1, wherein the process is carried out in the presence of acetyl chloride.
3. A process as claimed in claim 1, wherein the process is carried out in the presence of silica chloride.
4. A process as claimed in claim 1, wherein the process is carried out in the presence
of thionyl chloride.
5. A process as claimed in claim 1, wherein the process is carried out in the presence
of an organic solvent.
6. A process as claimed in claim 5, wherein the organic solvent is selected from a
group comprising of C1-5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester and ether.
7. A process as claimed in claim 6, wherein the organic solvent is a C1-5 alkanol.
8. A process as claimed in claim 1, wherein the process comprises neutralization of
the reaction mixture.
9. A process as claimed in claim 1, wherein the compound of Formula II is isolated
from the reaction mixture by layer separation.
10. A process as claimed in claim 1, wherein the process is carried out at a
temperature of about 0° to about 80°C.