FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: "An Efficient Process for the Preparation of Beta Lactams Used as an
Intermediate in the Synthesis of Carbapenem Antibiotics"


2. Applicants):
(a) NAME:
(b) NATIONALITY:
(c) ADDRESS:

ARCH PHARMALABS LIMITED
An Indian Company
"H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri (East), Mumbai-400 072, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.


TECHNICAL FIELD OF THE INVENTION
Present invention relates to a very safe and economical process that can be used for the purpose of the ring closure or cyclisation of the compound of the formula II to form the compound of the formula I which is an important intermediate for carbapenem.

Wherein R is selected from the group of C1-C4alkyl group
Rl is selected from the group of H, C1-C4 straight chain or branched alkyl group, Secondary alcoholic group or protected thereof, and Secondary thioalcoholic group or protected thereof
R2 is selected from the group of H, C1-C4 alkyl group or aryl group or substituted aryl group where substituents could be chosen from the group of OR', halogens, wherein R' is C1-C4 alkyl, cycloalkyl group.


Prior art references disclose following reagents which can be used for the ring closure or cyclisation of the compound of the formula II to form the compound of the formula I:
1. Dipyridylsulphide, complex of dipyridylsulphide and triphenylphosphene
2. Triphenylphosphene-mercaptopyridine-mangnesedioxide complex.
3. Dibenzothiazolyldisulphide in combination with triphenyl phosphene
4. Grignard reagent
5. Dialkyl Zinc in combination with lithium diisopropyl amide
6. Lithium diethylamide comprising the use of unsafe, pyrophoric and hazardous n-butyl lithium prepared under cryogenic reaction conditions.
7. Methane sulphonyl chloride, potassium carbonate using phase transfer catalyst optionally in aqueous medium
Disadvantages of the reagents disclosed in the prior art for the ring closure or cyclisation of the compound of the formula II to form the compound of the formula I are:
- high cost
- Industrial waste
- Lower yield
- Cryogenic reaction conditions to prepare lithium diisopropyl amide using n-butyl lithium
- Pyrophoric nature of n-butyl lithium
Present invention discloses a very safe and economical method that can be used for the purpose of the ring closure or cyclisation of the compound of the formula II to form the compound of the formula I which is an important intermediate for carbapenem.
3 -7 OCT 2009

BACKGROUND OF THE INVENTION
Carbapenem antibiotics are well known for treating a broad spectrum of gram positive and gram negative bacterial infections. In order to develop safe, less expensive and better methods for their production, research is being carried out in this area continuously. One focus in this field has been on different modes for the synthesis of the starting azetidinone intermediate of the formula I.
Beta lactam type antimicrobial agents such as carbapenem type agents have currently been attracting the greatest interest as antimicrobial substances which all have azetidine-2-one unit as common base structure.
The ring closure i.e. cyclodehydration of compound of formula II to prepare a beta lactam of formula I can be affected by using the prior art procedures.
H. Huang et.al. Chemical Letters, p. 1465 (1984) discloses a process comprising use of 2-chloro-l-methylpyridinium iodide as cyclising agent for cyclisation of the compound of the formula II to form the compound of formula I.
T.Kametani et.al. in JACS, 102, p.2060 (1980) discloses a process comprising use of dicyclohexyldimide as a cyclising agent for cyclisation of the compound of the formula II to form the compound of formula I.
Noyori et. al.in JACS, 111,9134 (1989) and Japanese published application (Kokai) Hei 2-134349 by Takasago International Corporation discloses the formation of beta lactam comprising using dipyridylsulphide and triphenylphosphene as a cyclising agent as shown below.

Japanese published application Hei 4-173795 and by Takasago International Corporation discloses the formation of beta lactam by cyclization of hydroxyl protected amino acid using dipyridylsulphide and triphenylphosphene as shown below.

OSBT
dipyridylsulphide and / triphenylphosphene.

COOH

TBSCI/ base

COOH

TBSO

Japanese published application Hei 4-173776 application by Takasago International Corporation discloses the formation of beta lactam using sulphenamide derivative and triphenyl phosphene

Japanese published application Hei 4-173776 by Takasago International Corporation discloses the formation of beta lactam by cyclising beta amino ester using grignard reagent as shown below.



US4927507 (Japanese published application Sho 63-297360) by Ciba Geigy co. Ltd. Discloses the formation of beta lactam using pyridine thiol, triphenyl phosphene and Mn02 as shown below.

y.Watanabe et.al., Chem. Letters, 1981, pp443-4444 discloses the formation of beta lactam ring comprising employing two phase liquid-liquid phase transfer system of methylene chloride/water, tetrabutylammonium hydrogen sulphate as a phase transfer catalyst and methanesulphonyl chloride, potassium bicarbonate as the cyclising agent.

US5037974 discloses the formation of beta lactam using methane sulphonyl chloride and sodium bi carbonate as cyclising agent in an organic solvent.



JPO1056686 disclose the ring closure for the preparation of beta lactam using diethyl zinc and lithium diisopropyl amide in combination. However there is no mention of the process used for the preparation of lithium diisopropyl amide. EP0742223 Bl discloses the formation of beta lactam by the cyclization of beta amino ester comprising using Lithium diethyl amide which is prepared by using hazardous pyrophilic n-butyl lithium at cryogenic reaction conditions. The crude product (80%) is purified by column chromatography. There is no mention of purity of the product purified by column chromatography.

Draw back associated with prior art:
Disadvantages in the prior art for the ring closure of an amino acid or its derivative to prepare the corresponding beta lactam are associated with, relative high cost of dipyridyldisulphide, increased industrial waste in using triphenylphosphene-dipyridyldisulphide complex, triphenylphosphenemercaptopyridinemagnesedioxide complex, dibenzothiazolyldisulphide and triphenylphosphene thereby bringing the limitation on production scale, higher process cost in using grignard reagent as cyclising agent, use of hazardous and pyrophoric n-butyl lithium which is used under cryogenic reaction conditions, chromatographic separation, instability of amino acid


or its derivatives in aqueous basic phase when cyclisation is carried out using methane sulphonyl chloride and potassium bicarbonate, higher O-mesylation observed when cyclisation is carried out using methane sulphonyl chloride and potassium bicarbonate in organic solvent than reported in the prior art.
Therefore, there is a dire need to develop a safe industrially viable process that can eliminate the problems described in the prior art for the cyclization of amino acids or derivative for the preparation of corresponding beta lactams which is a key intermediate for the synthesis of carbapenem antibiotics.
OBJECT OF THE INVENTION
Main aspect of the present invention is to provide a safe, efficient, convenient and inexpensive process of cyclisation to convert beta amino acid or its ester of the formula II into beta lactam of the formula I as shown in scheme-I

Wherein R is selected from the group of C1-C4 straight chain or branched alkyl group
Rl is selected from the group of H, C1-C4 straight chain or branched alkyl group, Secondary alcoholic group or protected thereof, and Secondary thioalcoholic group or protected thereof


R2 is selected from the group of H, C1-C4 alkyl group or aryl group or substituted aryl group where substituents could be chosen from the group of OR', halogens, wherein R' is C1-C4 alkyl, cycloalkyl group.
Another aspect of the invention is to provide a safe, efficient, convenient and inexpensive process for the preparation of compound of formula I comprising cyclisation of the compound of Formulae II comprising alkali metal preferably lithium and alkyl amine preferably diisopropyl amine in the presence of a catalyst such as isoprene, styrene,anthracene or a-methyl styrene at ambient temperature replacing n-butyl lithium which is unsafe, hazardous, expensive, pyrophoric which as per the prior art is used under cryogenic reaction conditions.
One more aspect of the invention is to provide a safe, efficient, convenient and inexpensive process for the preparation of compound of formula III comprising cyclisation of the compound of Formulae IV comprising alkali metal preferably lithium and alkyl amine preferably diisopropyl amine of formula IX resulting into compound of formula X in the presence of a catalyst such as isoprene, styrene, anthracene or a-methyl styrene at ambient temperature replacing n-butyl lithium which is unsafe, hazardous,expensive,pyrophoric which as per the prior art is used under cryogenic reaction conditions.

£*^ OCT 'iilUk

Advantages of the present invention:
1. Minimising industrial waste.
2. Reducing the cost by avoiding costly chemicals.
3. Comparatively simpler operations with better yield and higher enatiomeric excess with required specific optical rotation.
4. Cost reduction over the process using Grignard's reagent as cyclising agent for converting beta amino acid/ester to the corresponding beta lactam.
5. Avoiding use of n-butyl lithium which is unsafe, hazardous to use, pyrophoric and also requiring cryogenic reaction conditions.
6. Lithium metal is much safer to use as it is available in wax coated cubes, less expensive than n-butyl lithium which in turn also reduces the cost of preparing compound of formula I.


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7. Replacing n-BuLi with lithium metal avoids low temperature conditions, thereby saving energy cost.
8. Process is suitable on production scale.
9. Eliminating the use of dialkyl zinc in combination with n-butyl lithium as
described in JP01056686.
10. Avoiding the chromatographic separation as reported in the prior art making it
feasible at production level as described in EP0742223 Bl
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of beta lactams of formula I which is a key intermediate for the synthesis of carbapenem antibiotics. Disclosed herein is an efficient, inexpensive,safe, less hazardous and industrially viable process for the preparation of beta lactams of formula I comprising ring closure or cyclisation of compound of formula II comprising alkali metal preferably lithium and alkyl amine preferably diisopropyl amine in the presence of a catalyst such as isoprene, styrene,anthracene or a-methyl styrene at ambient temperature replacing n-butyl lithium which is unsafe, hazardous,expensive,pyrophoric which as per the prior art EP0742223 Bl is used under cryogenic reaction conditions to prepare the compound of formula I by ring closure or cyclisation of compound of formula II.

Wherein R is selected from the group of C1-C4 straight chain or branched alkyl group
Rl is selected from the group of H, C1-C4 straight chain or branched alkyl group, Secondary alcoholic group, and Secondary thioalcoholic group
R2 is selected from the group of H, C1-C4 alkyl group or aryl group or substituted aryl group where substituents could be chosen from the group of OR', halogens, wherein R' is C1-C4 alkyl, cycloalkyl group.
DETAILED DESCRIPTION OF THE INVENTION
"Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process."
The present invention relates to a process for preparing beta lactams of formula I comprising ring closure or cyclisation of compound of formula II comprising alkali metal preferably lithium and alkyl amine preferably diisopropyl amine of formula IX resulting into compound of formula X in the presence of a catalyst such as isoprene, styrene,anthracene or a-methyl styrene at ambient temperature replacing n-butyl

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QCTflJl

lithium which is unsafe, hazardous, expensive, pyrophoric which as per the prior art EP0742223 Bl is used under cryogenic reaction conditions to prepare the compound of formula I by ring closure or cyclisation of compound of formula II.

Wherein R is selected from the group of C1-C4 straight chain or branched alkyl group,
Rl is selected from the group of H, C1-C4 straight chain or branched alkyl group, Secondary alcoholic group or protected thereof, and Secondary thioalcoholic group or protected thereof.
R2 is selected from the group of H, C1-C4 alkyl group or aryl group or substituted aryl group where substituents could be chosen from the group of OR', halogens, wherein R' is C1-C4 alkyl, cycloalkyl group.

13

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In an embodiment compound of formula I is prepared comprising reacting the alkali metal with alkyl amine of formula III in the presence of a catalyst at ambient temperature followed by the addition of beta amino acid or beta amino ester of formula II at up to -50°C, The process is summarized in scheme-I

Scheme-I
The alkali metal is sodium, potassium or lithium. Preferably the alkali metal is lithium.
Wherein R is selected from the group of C1-C4 straight chain or branched alkyl group
Rl is selected from the group of H, C1-C4 straight chain or branched alkyl group, Secondary alcoholic group or protected thereof, and Secondary thioalcoholic group or protected thereof
R2 is selected from the group of H, C1-C4 alkyl group or aryl group or substituted aryl group where substituents could be chosen from the group of OR', halogens, wherein R' is C1-C4 alkyl, cycloalkyl group.
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R4 and R5 may be the same or different and each represents any of an alkyl group branched or straight chain 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms. Specifically there can be mentioned methyl, ethyl, isopropyl, tert-butyl, n-octyl, phenyl, naphthyl, p-methoxyphenyl, benzyl and p-nitrobenzyl, trimethylsilyl, triethyl silyl and phenyldimethylsilyl among others. Preferably R4 and R5 are methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. More preferably R4 and R5 are isopropyl.
The catalyst may be isoprene, styrene, anthracene, a-methyl styrene and the like.
The ambient temperature may be between about 10°C to about 50°C.
In a preferred embodiment Azitidinone derivatives (R )-3-(S)-l-
(tertbutyldimethylsilyloxy)-ethylazetidine-2-one of formula IV can be prepared comprising adding alkali metal and dialkyl amine and a catalyst in a suitable organic solvent system at ambient temperature to form alkali metal dialkyl amide. The catalyst can be isoprene, styrene, a-methyl styrene or antharacene and the like. Preferably the catalyst can be isoprene or styrene. The ambient temperature can be about 10°C to about 50°C. The organic solvent system can be aliphatic or aromatic hydrocarbon, carboxylic acid ester, halogenated hydrocarbon, ether or a mixture thereof. Preferably the solvent system may be hexane, cyclohexane, THF or a mixture thereof.


The reaction scheme can be depicted in Scheme-II

The compound of formula V is added to a solution prepared hereinbefore at temperature up to -50°C.
In a more preferred embodiment (R )-3-(S)-l-(tertbutyldimethylsilyloxy)-
ethylazetidine-2-one can be prepared comprising reacting lithium metal with
disopropylamine in the presence of a catalyst in a suitable solvent system at ambient
temperature followed by addition of (2S,3S)-methyl-2-(aminomethyl)-3-tertbutyl-
dimethylsilyloxy) butanoate of formula V at a temperature upto -50°C to give a
compound of formula IV. The catalyst can be isoprene, styrene, a-methyl styrene or
antharacene. Preferably the catalyst can be isoprene or styrene. The ambient
temperature can be about 10°C to about 50°C. The solvent system can be
hydrocarbon, carboxylic acid ester, halogenated hydrocarbon and ether or a mixture
thereof. Preferably the solvent system may be hexane, cyclohexane, THF or a mixture
thereof. The compound (2S,3S)-methyl-2-(aminomethyl)-3-tertbutyl-
dimethylsilyloxy) butanoate of formula IV is added to a solution prepared hereinbefore at temperature up to -50°C.
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The solvent which can be used for this reaction may be an aprotic organic solvent. The organic solvent mentioned hereinbefore includes hydrocarbon solvents such as benzene, toluene, n-hexane, cyclohexane etc., ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert butyl ether, dimethoxymethane, ethylene glycol dimethyl ether etc., halogen containing solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloro ethane etc. These solvents may be used each alone or two or more of them in combination. Preferred are hydrocarbon solvents such as benzene, toluene, n-hexane, cyclohexane etc and ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert butyl ether dimethoxymethane and ethylene glycol dimethyl ether. More preferred are hexane and tetrahydrofuran.
The invention can be further illustrated by the following non-limiting examples:
Preparation of (R )-3-(S)-1-(tertbutyldimethylsi!yloxy)-ethylazetidine-2-one:
Example 1:
Under the nitrogen gas, a solution composed of 238.36g (2.36 mol) isopropyl amine and 18 ml tetrahydrofuran was charged with freshly cut 17.63g (2.55 mol) lithium metal followed by addition of 374 ml hexane at ambient temperature (32°C). The contents were stirred well and contents were heated upto 40°C. This was added with drop wise addition of solution composed of 122.79(1.17mol) isoprene and 175 ml tetrahydrofuran over a time period of about one hour keeping the temperature in the


range of 35-50°C. The reaction was them maintained for 3 hours to prepare lithium diisopropyl amide.
The solution containing LDA was chilled to -30°C and 200g (0.76 mol) of (2S.3S)-methyl-2-(aminomethyl)-3-tertbutyl-dimethylsilyloxy) butanoate were added in about 30 - 45 minutes maintaining the temperature in the range of -30 to -25°C. Contents were stirred for an hour and reaction was monitored on TLC. After the completion of the reaction mass was diluted with hexane and was quenched by IN HC1. Organic layer was separated and washed 10% bicarbonate solution. Hexane was removed under vacuum to dryness yielding 162 g of crude product of technical grade that can be used further without any purification.
Example 2: Example 1 was repeated with change of catalyst as isoprene in place of styrene.
Example 3:
Under the nitrogen gas, a solution composed of 271.48g (2.69mol) isopropyl amine and 20.5 ml tetrahydrofuran was charged with freshly cut 18.5 (2.69 mol) lithium metal followed by addition of 380 ml hexane at ambient temperature (32°C). The contents were stirred well and contents were heated upto 40°C. This was added with drop wise addition of solution composed of 139(1.33mol) isoprene and 180 ml tetrahydrofuran over a time period of about one hour keeping the temperature in the range of 35-50°C. The reaction was them maintained for 3 hours to prepare lithium diisopropyl amide.
The solution containing LDA was chilled to -30°C and 200g (0.76 mol) of (2S,3S)-methyl-2-(aminomethyl)-3-tertbutyl-dimethylsilyloxy) butanoate were added in about 30 - 45 minutes maintaining the temperature in the range of -30 to -25°C. Contents were stirred for an hour and reaction was monitored on TLC. After the completion of

the reaction mass was diluted with hexane and was quenched bylN HC1. Organic layer was separated and washed 10% bicarbonate solution. Hexane was removed under vacuum to dryness yielding 155 g of product with GC purity of 95.0%, SOR of -66.49°in — of technical grade that can be used further without any purification.


Claim:
1. A process for the preparation of compound of formula-1
wherein R is selected from the group of C1-U4 alkyl group;
wherein Rl and R2 are as defined hereinbefore in the specification;
comprising:
a) reacting an alkali metal with dialkylamine of formula VI wherein R4 and R5 are as defined hereinbefore in the specification, in the presence of a catalyst at ambient temperature in an organic solvent;

b) to a reaction mass of (a) is added compound of formula-II wherein Rl and R2 is as defined hereinbefore in the specification, at temperature up to -50°C;
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Wherein R is selected from the group of C1-C4 straight chain or branched
alkyl group
to obtain a compound of formula-I
2. A process of claim 1 wherein the alkali metal can be sodium, potassium or lithium and more preferably the alkali metal is lithium.
3. A process of claim 1 wherein organic solvent is hydrocarbon, carboxylic acid ester, ether, halogenated hydrocarbon or a mixture thereof and more preferably organic solvent is hexane, cyclohexane, THF or a mixture thereof.
4. A process of claim 1 wherein dialkylamine is diisopropyl amine.
5. A process of claim 1 wherein catalyst is selected from the group of isoprene, styrene, a-methyl styrene or anthracene.
6. A process of claim 1 wherein ambient temperature is about 10°C to about 50°C.
7. A process for the preparation of compound of Formula III
21


Comprising
a) reacting lithium metal with diisopropyl amine of formula IX in the presence
of a catalyst at ambient temperature in an organic solvent;

b) to a reaction mass of (a) is added compound of formula-VII at temperature upto -50°C;

22

"7 OCT 2009

8. A process of claim 7 wherein organic solvent is hydrocarbon, carboxylic acid ester, ether, halogenated hydrocarbon or a mixture thereof and more preferably organic solvent is hexane, cyclohexane, THF or a mixture thereof..
9. A process of claim 7 wherem catalyst is isoprene, styrene, a-methyl styvene or anthracene.
10. A process of claim 7 wherein ambient temperature is about 10°C to about 50°C.

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