Title of Invention

METHOD OF PREPARATION OF B-LACTAM COMPOUNDS USING POLY-3-HYDROXYBUTYRATES

Abstract The present application has disclosed usage of poly-3-hydroxyalkanoates (P(3HB)) in preparation of β-lactam compounds. The present application has disclosed preparation method of β-lactam compounds of formula (I) by using P(3HB), in which definitions of the substitutents of formula (I) are the same as description. It is convenient to obtain compounds of formula (I) by utilizing the present method as it has shorter steps and higher yield, as well as avoids using agents which pollute environment or are expensive agents. So it is cost-effective and decreases pollution.
Full Text FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
& THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
USAGE OF POLY-3-HYDROXYBUTYRATES IN PREPARATION OF β-LACTAM COMPOUNDS;
TIANJIN GREENBIO MATERIAL CO. LTD, A
CORPORATION ORGANIZED AND
EXISTING UNDER THE LAWS OF CHINA, WHOSE ADDRESS IS, B7 HIGH-TECH PARK OF TJANJJN UNJVERSITY 80#, 4TH STREET TEDA TIANJIN, 300457, CHINA
THE FOLLOWING SPECIFICATION
PARTICULARLY DESCRIBES THE
INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.



Fields of the Invention
This invention relates to the preparation of β-lactam compounds. More particularly, the usage of Poly-3-hydroxybutyrates P (3HB) in the preparation of β-lactam compounds of formula (I) is disclosed:





wherein:

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Therefore, there is a persistent need for a skilled person in the art to seek for a suitable starting material and to optimize the synthesis process, so as to cut the use of the high cost reagents and to reduce pollution.
Summary of the Invention
Through a great deal of experiments, the inventors of this invention have discovered poly-3-hydroxybutyrate as the starting material for the preparation of compound of formula (I)

, and developed procedures suitable for production of synthesizing abovementioned compounds on large scale as well, which comprises, abtaining substituted (3R)-3-hydroxybutyrateane acid methyl ester from P(3HB), getting substituted (3R)-3-hydroxy butyraldehyde by reduction, after enolization and reacting with chlorosulfonyl isocyanate to abtain the
compound of formula(l), wherein are lower linear
or branched C1-C4alkyl. The reactint The new method, which has routines as follows:

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(I)

1, The usage of P(3HB) in the preparation of compounds of formula(l):

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5, The method according to item 4, wherein the reflux lasts for 3
days.
6, The method according to item 3, wherein
(3R)-3-RO-CH(CH3)CH2COOCH3 is (3R)-3-t-butyl-dimethylsiloxy methyl
butyrate.
7, The method according to item 3, wherein the enolization
procedure in the step c is reacting (3R)-3-RO-CH(CH3)CH2CHO with
isopropenyl acetate and p-toluenesulfonic acid by heating refluxing.
8, The method according to item 3, wherein the reducing agent used
in the step c is sodium bisulfite.
Poiy-3-hydroxybutyrates P(3HB) as the starting material used in the
present invention is a kind of thermoplastic resins, with favorable
biodegradability and biocompatibility, and is mainly used as a
biodegradable material. In the present invention, compared with
synthesizing substituted (3R)-3-RO-CH(CH3)CH2COOCH3 with
(3R)-3-hydroxymethylbutyrate, it is very convenient to obtain P(3HB) as
the starting material with a lower price for preparation of β-lactam
compounds having formula (I), to synthesize
(3R)-3-RO-CH(CH3)CH2COOCH3, wherein the 3-hydroxy group is substituted by RO. Furthermore, the condition of the reaction is to reflux

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P(3HB) with methanol and sulphuric acid, post-processing to obtain initial product, then reacting with substitutional methylsilyl chloride to obtain (3R)-3-RO-CH(CH3)CH2COOCH3.
(3R)-3-RO-CH(CH3)CH2CHO can be synthesized from (3R)-3-RO-CH(CH3)CH2COOCH3 started by P(3HB) with traditional reactions, for example, react with iBu2AIH under low temperature, then the mixture is poured into saturated potassium sodium tartrate solution, ether is added, after that the mixture is extracted, dried, evaporated to dryness, finally subjected to silica gel column for purification.
The enolate obtained from enolization of (3R)-3-RO-CH(CH3)CH2CHO is subjected with chlorosulfonyl isocyanate, reduced by gentle reducing agent sodium bisulfite, purified on silica gel column to yield final product with 99%ee.
Preferred Embodiments
The following examples are meant to illustrate the present invention in detail, and should not be known as the limitation of it in any way. The yields are molar yields, the reagents are commercial chemical pure reagents, unless stated otherwise , the solvents of all the solutions are water if not mentioned specially.

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P(3HB) a product is from Tianjin Green Biosciences Limited Company
Polarimeter model : WZZ-1, Shanghai Precision Instruments Co., Ltd.
NMR spectrometer model: Bruker AVANCE DRX-500, Bruker Optics
Melting point instrument model: WRS-2A, Shanghai Precision Instruments Co., Ltd.
Example 1: Preparation of (3R)-3-t-butyI-dimethylsiloxymethyl butyrate
80g P(3HB) is dissolved in 1L absolute dichloroethane. The mixture is at reflux for 1h, 20ml concentrated sulfuric acid and 400ml absolute methanol are added, the whole is at reflux for three more days and then cooled to room temperature. 200ml saturated NaCI solution is added to the reaction mixture, then the whole is stirred for 30minutes. The aqueous phase is separated, washed for three times with 500ml chloroform in total. The combined organic layers are washed for three times with 200ml saturated NaCI solution\200ml saturated sodium bicarbonate solution and 200ml saturated NaCI solution respectively. Dried over magnesium sulfate, the mixture is evaporated under reduced pressure to remove the solvent. The residue is subjected to reduced pressure distillation. The fractions of 61-62 centi-degree/18mHg are collected to get 104g product. That product is added into a three-necked flask, 400ml dichloroethane

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and 50g imidazole are added, the whole is stired uniformly. Then 120g 3-t-butyl-dimethyl methylsilyl chloride is added slowly into the mixture, 5 hours later, filtration is carried out. The filtrate is washed with saturated sodium bicarbonate solution\ HCI and saturated NaCI solution respectively. The organic layer is separated and dried over magnesium sulfate for the whole night, concentrated under reduced pressure to obtain 200g (3R)-3-t-butyl-dimethylsiloxy methyl butyrate with yield 92.5%.
Example 2: The preparation of (3R)-triisopropylsiloxymethyl butyrate
The procedure is the same as that in example 1, replacing 3-t-butyl-dimethyl methylsilyl chloride with triisopropyl methylsilyl chloride to obtain 200g (3R)-triisopropylsiloxymethyl butyrate with yield 87.2%.
Example 3: The preparation of (3R)-3-t-butyl-dimethylsiloxy butyraldehyde
46.4g (3R)-3-t-butyl-dimethylsiloxymethyl butyrate is dissolved in 200ml N-hexane, cooled to -78□, 240ml solution of 1mol/L iBu2AIH in N-hexane is slowly added dropwise. After the addition, the reaction mixture is kept under the same temperature to react for 2 hours. After reaction is completed, the temperature is raised slowly, and then the mixture is

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poured into 1L saturated potassium sodium tartrate solution, then 1.5L ether and 0.5L water are added, the whole is stirred vigorously for 1hour. After the separation, the organic phase is washed with saturated NaCI solution, the aqueous phase is washed three times with 1.2L ether in total, the resulting organic phases are combined, dried over sodium sulfate for the whole night and evaporated under reduced pressure to remove the solvent. The resulting crude product is purified on silica gel column chromatography (the eluent: ethyl acetate: hexane=1:1), and 39.7g (3R)-3-t-butyl-dimethylsiloxy butyraldehyde with yield 98.3% is obtained.
Example 4: The preparation of (3R)-triisopropylsiloxy butyraldehyde
The procedure is the same as that in example 3, replacing
(3R)-3-t-butyl-dimethylsiloxy methyl butyrate with
(3R)-triisopropylsiloxymethyi butyrate with amount of 54.8g, to obtain 44g (3R)-triisopropylsiloxy butyraldehyde with yield 90.2%.
Example 5: The preparation of
3R,4R)-4-acetoxy-3-[(R)-1-t-butyl-dimethyl
methylsilyloxylethyl]-azetidine-2-one
20.2g (3R)-3-t-butyl-dimethylsiloxy butyraldehyde, 15g isopropenyl acetate and 1g p-toiuenesulfonic acid are heated at reflux, the mixture is subjected to Vigreux Column, so as to remove acetone generated in the

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system completely. The residual liquid is neutralized with saturated sodium bicarbonate solution until the pH value is neutrality, then the whole is evaporated under reduced pressure to remove the azeotropic mixture of water and raw material, to obtain 17.2g enolization product with yield 70.5%.
4.90g above-mentioned crude product is dissolved in 25ml dichloromethane, cooled to 0D in ice bath, 3.40g chlorosulfonyl isocyanate is added slowly, the system temperature is maintained below On. After the whole reacts for 2h, a reddish brown reaction mixture is obtained, then is cooled to . The cooled solution is slowly added
dropwise into vigorously stired 200ml saturated sodium sulfite solution;
the whole is neutralized with saturated sodium hydroxide solution until pH
is 8-10. The reaction procedure is monitored by Thin-layer
Chromatography. When the raw material is completely reacted, the
organic phase is separated, dried over magnesium sulfate over night,
evaporated under reduced pressure to remove the solvent, and purified
on silica gel column chromatography (the eluent: ethyl acetate ;
hexane=1:10), to obtain
(3R,4R)-4-acetoxy-3-[(R)-1-t-butyl-dimethylmethy--lsilyloxylethyl]-azetidine-2-one, which is recrystallized in N-hexane to obtain 3.40g white acicular crystal with yield 59.0%. Such white acicular crystal is the final product. This process includes three steps in total, with

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an overall yield 37.8%.
Optical rotation of the product: 53-57°(c=0.5 . CHCI3) NMR ( 500MHz , CDCI3)
:0.08(6H,s) ,0.84(9H,s) ,1.20(3H,d) ,2.01 (3H,s) ,3.04(1H,dd) , 4.12(1H,m) , 5.76(1 H,d) , 6.73(NH) Melting point: 106-110
Example 6: The preparation of
(3R,4R)-4-acetoxy-3-[(R)-triisopropylsiloxylethyl]-azetidine-2-one
The procedure is the same as that in example 5, replacing
(3R)-3-t-butyl-dimethylsiloxy butyraldehyde with 24.4g
(3R)-triisopropylsiloxy butyraldehyde, to obtain 10.9g final product, with yield 33.1%.
The melting point, optical rotation and NMR data of the final product in the present invention are in accordance with those of the products disclosed in Chinese Patent application number 85105097.

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We Claim:
1. The usage of P(3HB) in preparation of compounds of formula(l):



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5. The method according to claim 4, wherein the reflux lasts for 3 days.
6. The method according to claim 3, wherein
(3R)-3-RO-CH(CH3)CH2COOCH3 is (3R)-3-t-butyl-dimethylsiloxy methyl butyrate.
7. The method according to claim 3, wherein the enolization procedure in the step c is reacting (3R)-3-RO-CH(CH3)CH2CHO with isopropenyl acetate and p-toluenesulfonic acid by heating refluxing.
8. The method according to claim 3, wherein the reducing agent used in the step c is sodium bisulfite.
Dated this 29th day of August, 2008


Documents:

1873-MUMNP-2008-ABSTRACT(23-6-2011).pdf

1873-MUMNP-2008-ABSTRACT(29-8-2008).pdf

1873-MUMNP-2008-ABSTRACT(GRANTED)-(26-8-2011).pdf

1873-mumnp-2008-abstract.doc

1873-mumnp-2008-abstract.pdf

1873-MUMNP-2008-CANCELLED PAGES(23-6-2011).pdf

1873-MUMNP-2008-CLAIMS(AMENDED)-(23-6-2011).pdf

1873-MUMNP-2008-CLAIMS(GRANTED)-(26-8-2011).pdf

1873-mumnp-2008-claims.doc

1873-mumnp-2008-claims.pdf

1873-MUMNP-2008-CORRESPONDENCE(12-8-2011).pdf

1873-MUMNP-2008-CORRESPONDENCE(21-10-2008).pdf

1873-MUMNP-2008-CORRESPONDENCE(29-8-2008).pdf

1873-MUMNP-2008-CORRESPONDENCE(IPO)-(26-8-2011).pdf

1873-mumnp-2008-correspondence.pdf

1873-mumnp-2008-description(complete).doc

1873-mumnp-2008-description(complete).pdf

1873-MUMNP-2008-DESCRIPTION(GRANTED)-(26-8-2011).pdf

1873-MUMNP-2008-FORM 1(21-10-2008).pdf

1873-mumnp-2008-form 1(29-8-2008).pdf

1873-mumnp-2008-form 1.pdf

1873-mumnp-2008-form 13(23-6-2011).pdf

1873-mumnp-2008-form 18(29-8-2008).pdf

1873-mumnp-2008-form 18.pdf

1873-MUMNP-2008-FORM 2(GRANTED)-(26-8-2011).pdf

1873-MUMNP-2008-FORM 2(TITLE PAGE)-(GRANTED)-(26-8-2011).pdf

1873-mumnp-2008-form 2(title page).pdf

1873-mumnp-2008-form 2.doc

1873-mumnp-2008-form 2.pdf

1873-mumnp-2008-form 3(21-10-2008).pdf

1873-MUMNP-2008-FORM 3(23-6-2011).pdf

1873-mumnp-2008-form 3.pdf

1873-mumnp-2008-form 5.pdf

1873-MUMNP-2008-GENERAL POWER OF ATTORNEY(23-6-2011).pdf

1873-MUMNP-2008-MARKED COPY(23-6-2011).pdf

1873-MUMNP-2008-PETITION UNDER RULE 137(12-8-2011).pdf

1873-MUMNP-2008-REPLY TO EXAMINATION REPORT(23-6-2011).pdf

1873-MUMNP-2008-SPECIFICATION(AMENDED)-(23-6-2011).pdf

1873-MUMNP-2008-US DOCUMENT(23-6-2011).pdf

1873-MUMNP-2008-VERIFICATION OF TRANSLATION(21-10-2008).pdf

abstract1.jpg


Patent Number 248814
Indian Patent Application Number 1873/MUMNP/2008
PG Journal Number 35/2011
Publication Date 02-Sep-2011
Grant Date 26-Aug-2011
Date of Filing 29-Aug-2008
Name of Patentee TIANJIN GREENBIO MATERIAL CO. LTD
Applicant Address B7, HIGH-TECH PARK OF TIANJIN UNIVERSITY 80#, 4TH STREET TEDA TIANJIN, 300457,
Inventors:
# Inventor's Name Inventor's Address
1 LU, WEICHUAN B7, HIGH-TECH PARK OF TIANJIN UNIVERSITY 80#, 4TH STREET TEDA TIANJIN, 300457,
2 ZHANG QIAN B7, HIGH-TECH PARK OF TIANJIN UNIVERSITY 80#, 4TH STREET TEDA TIANJIN, 300457,
3 CHEN XIN B7, HIGH-TECH PARK OF TIANJIN UNIVERSITY 80#, 4TH STREET TEDA TIANJIN, 300457,
PCT International Classification Number C07D205/08
PCT International Application Number PCT/CN2006/002707
PCT International Filing date 2006-10-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 200610013223.7 2006-02-28 China