WO2010082108A1 - Improved process for preparation of key intermediate of cephalosporins - Google Patents
Improved process for preparation of key intermediate of cephalosporins Download PDFInfo
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- WO2010082108A1 WO2010082108A1 PCT/IB2010/000036 IB2010000036W WO2010082108A1 WO 2010082108 A1 WO2010082108 A1 WO 2010082108A1 IB 2010000036 W IB2010000036 W IB 2010000036W WO 2010082108 A1 WO2010082108 A1 WO 2010082108A1
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- acid
- reaction mixture
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 7
- 229940124587 cephalosporin Drugs 0.000 title abstract description 7
- 150000001780 cephalosporins Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000011541 reaction mixture Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims 1
- 229940107816 ammonium iodide Drugs 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000007239 Wittig reaction Methods 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 3
- 229960002129 cefixime Drugs 0.000 description 3
- -1 cephalosporin compounds Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GQLGFBRMCCVQLU-XCGJVMPOSA-N (6r)-7-amino-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(C=C)=C(C(O)=O)N2C(=O)C(N)[C@H]21 GQLGFBRMCCVQLU-XCGJVMPOSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 2
- 229960003719 cefdinir Drugs 0.000 description 2
- QHTOIDKCEPKVCM-ZCFIWIBFSA-N cepham Chemical compound S1CCCN2C(=O)C[C@H]21 QHTOIDKCEPKVCM-ZCFIWIBFSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006886 vinylation reaction Methods 0.000 description 2
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 description 1
- ZYLDQHILNOZKIF-OXLALJFOSA-N (6r,7r)-7-azaniumyl-8-oxo-3-[(z)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(\C=C/C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 ZYLDQHILNOZKIF-OXLALJFOSA-N 0.000 description 1
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
Definitions
- the present invention relates to an improved process for the preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I) using a compound of formula (A); wherein R represents hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted.
- cephalosporin compounds referred to in this specification are generally named with reference to cepham which is described in J. Am. Chem. Soc. 1962, 84, 3400.
- cephem refers to the basic cepham structure with a single double bond.
- Compounds referred to in this specification are useful for the manufacturing of cephalosporins having antibacterial activity against a range of gram-positive and gram-negative organisms and are of value in human and veterinary medicine. They may also be of value in the preparation of other 3-substituted cephalosoporin compounds.
- the compound of formula (I) is one of the key intermediate of cephalosporin antibiotics such as Cefixime and Cefdinir and is extremely useful in their synthesis.
- a compound of formula (I) may be prepared by Wittig reaction using the alkali metal halide such has sodium iodide, potassium iodide, sodium bromide and the like in a conventional solvent which does not adversely influence the reaction such as N,N-dimethylformamide, dimethylsulfoxide, methylene chloride, tetrahydrofuran, ethyl acetate, etc., or a mixture thereof.
- the said patent '214 further discloses that the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- Patent IN 961 /MUM/2004 discloses and claims an improved process for the preparation of 7-Amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA) and for (Z)-isomer enriched (7-amino-8-oxo-3-[(lZ)-prop-l-enyl]-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-APCA) by carrying out multi-step reactions in one pot and utilizing sodium bromide in Wittig reaction.
- the said patent discloses and claims an improved process for the preparation of 7-Amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA) and for (Z)-isomer enriched (7-amino-8-oxo-3-[(lZ)-prop-l-enyl]-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7
- the process makes use of a suspension of the reagents in a reaction, because of which the reaction goes slow and it takes more time to complete.
- the use of additional hydrobromic acid and aqueous sodium thiosulfate in Wittig reaction makes the procedure complex in larger commercial scale.
- the role of temperature and addition of methanol is very critical and crucial.
- the procedure disclosed according to example 3 of the said patent '961 results in low yields and surprisingly the said patent is silent about the purity of a compound of formula (I).
- the main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
- Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s),which makes the present invention eco-friendly as well.
- Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
- Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
- the present invention provides a process for the preparation of compound of formula (I), which comprises the steps of:
- R Hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted II]
- X Any halogen 1
- the triphenylphosphonium halide formation and vinylation steps are carried out in an in-situ manner without isolating the compound of formula (III), which makes the process easier.
- the organic solvent used in step (i) is preferably N,N-dimethylformamide or N, N-dimethylacetamide or mixture thereof.
- R is represented hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted, more preferably R is hydrogen.
- X is represented by any halogen, preferably bromine or iodine, more preferably bromine.
- step (ii) of said reaction is carried out preferably in the range of 0.2 to 5 equivalents of a compound of formula (A).
- the step (ii) of said reaction is preferably with 1 to 2 equivalents of triphenylphosphine.
- the step (ii) of said reaction is completed in the range of 1 hr to 6 hrs, preferably in 2 hrs.
- the organic solvent used for the preparation of compound of formula (I) in step (iii) is preferably methylene chloride.
- the formaldehyde used in step (v) is preferably in the range of 3 to 50 equivalents.
- the base used in step (v) is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide.
- the acid used in step (vi) is preferably hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
- the alcoholic solvent used in step (viii) is preferably methanol.
- step (ix) the role of addition of water in step (ix) is a very essential and crucial feature of the present invention. By doing this way it results in better quality of a compound of formula (I) along with good yield.
- the addition of water during this step takes care of the inorganics or by-products formed during the reaction.
- all the steps are preferably performed at a temperature in the range of (-) 10 0 C to reflux temperature of the solvent used.
- process for preparation of a compound of formula (I) can be extended further in the making of cephalosporin antibiotics such as Cefixime and Cefdinir by conventional methods.
- T-phenylacetamido-S-chloromethyl-S-cephem ⁇ -carboxylic acid-p-methoxybenzyl ester (10Og, 0.205mol) was dissolved in N,N dimethylformamide (15OmL) in a four necked round bottom flask at room temperature and triphenylphosphine (55g, 0.21 mol), ammonium bromide (19.46g, 0.205 mol) were added under stirring and the temperature raised slightly to facilitate the reaction. After the completion of reaction in 2.5 hrs, methylene chloride (50OmL) was added and the reaction mixture was cooled to 12 0 C to 14 0 C. The reaction mixture was filtered and washed with methylene chloride (10OmL).
- reaction mixture was cooled down to 1O 0 C, stirred for one hour and the solid was filtered and washed with aqueous methanol and dried at temperature 37 0 C to yield 78g of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxy benzyl ester, with a chemical purity of more than 96.46 % by HPLC.
- the process of the present invention provides higher yield with greater purity of Wittig product.
- the use of alkali metal iodides such as sodium iodide in Wittig reaction leads to tendency of product to pick up color for which it requires additional purification procedures. Therefore, the present invention uses substantially cheaper reagent(s) in substantially lower amounts and less organic solvent(s) thereby achieving better quality Wittig product that is substantially free of colored impurities forming in the said reaction.
- the process of the present invention avoids excessive use of reagents like sodium bromide, sodium iodide, triphenylphosphine, formaldehyde and large amounts of organic solvent(s) such as N,N-dimethylformamide and methylene chloride, thereby reducing the reaction bulk that facilitates scaling up for an industrial production.
- reagents like sodium bromide, sodium iodide, triphenylphosphine, formaldehyde and large amounts of organic solvent(s) such as N,N-dimethylformamide and methylene chloride, thereby reducing the reaction bulk that facilitates scaling up for an industrial production.
- the process has effectively less number of steps that result in shortening of reaction time and lowering of labour.
- the process of the present invention avoids excess usages of reagent(s) and organic solvent(s),and thereby promotes green chemistry and ensures a cleaner surrounding by putting less load on environment.
- the by-products formed during the reaction can be reusable and recyclable, which makes the process industrially and commercially viable.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
An improved process for the preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I), which is a key intermediate of cephalosporin antibiotics and is extremely useful in their synthesis, is provided. More particularly, an improved process for the preparation of a compound of formula (I) by using a compound of formula (A) is provided, wherein, R represents hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted, making it a substantially cost effective and eco-friendly procedure.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF A KEY INTERMEDIATE FOR CEPHALOSPORINS
Field of the invention
The present invention relates to an improved process for the preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I) using a compound of formula (A); wherein R represents hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted.
Background of the invention The cephalosporin compounds referred to in this specification are generally named with reference to cepham which is described in J. Am. Chem. Soc. 1962, 84, 3400. The term "cephem" refers to the basic cepham structure with a single double bond.
Compounds referred to in this specification are useful for the manufacturing of cephalosporins having antibacterial activity against a range of gram-positive and gram-negative organisms and are of value in human and veterinary medicine. They may also be of value in the preparation of other 3-substituted cephalosoporin compounds. The compound of formula (I) is one of the key intermediate of cephalosporin antibiotics such as Cefixime and Cefdinir and is extremely useful in their synthesis.
According to the product patent of Cefixime US 4,409,214 (henceforth '214), the route of synthesis of 7-phenylacetamido-3-vinyl cephalosporanic acid-p- methoxybenzyl ester of compound of formula (I) is generically disclosed. The preparation of compound of formula (I) is specifically neither disclosed nor described in the said patent '214. According to the general disclosure of '214 a compound of
formula (I) may be prepared by Wittig reaction using the alkali metal halide such has sodium iodide, potassium iodide, sodium bromide and the like in a conventional solvent which does not adversely influence the reaction such as N,N-dimethylformamide, dimethylsulfoxide, methylene chloride, tetrahydrofuran, ethyl acetate, etc., or a mixture thereof. The said patent '214 further discloses that the reaction temperature is not critical and the reaction is usually carried out under cooling to warming. When we have carried out the general procedures described in the said patent '214 for equivalent compound(s) of a compound of formula (I) we have got substantially low yield and low purity of the products. Hence the present inventors attempted to do the experiment in a substantially different way, which has resulted in a good yield and purity of the compound of formula (I) by using a compound of formula (A) in a simple and economical process.
Patent IN 961 /MUM/2004 (henceforth '961) discloses and claims an improved process for the preparation of 7-Amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA) and for (Z)-isomer enriched (7-amino-8-oxo-3-[(lZ)-prop-l-enyl]-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-APCA) by carrying out multi-step reactions in one pot and utilizing sodium bromide in Wittig reaction. The said patent
'961 discloses in example 3 the process for the preparation of a compound of formula (I) which is a complex manufacturing procedure, and therefore commercially not preferred.
According to the disclosure of example 3 of the said patent '961 , the process makes use of a suspension of the reagents in a reaction, because of which the reaction goes slow and it takes more time to complete. Moreover, the use of additional hydrobromic acid and aqueous sodium thiosulfate in Wittig reaction makes the procedure complex in larger commercial scale. During the isolation of Wittig product, the role of temperature and addition of methanol is very critical and crucial. The procedure disclosed according to example 3 of the said patent '961 results in low yields and surprisingly the said patent is silent about the purity of a compound of formula (I). Because the process disclosed in the said patent '961 may be suffering from unwanted by-products or is accompanied by impurity formation during the formation of Wittig product; this ultimately results in the low yield mentioned.
Accordingly therefore, there is an urgent need to develop a process for the preparation of a compound of formula (I), which is readily amenable to scale-up. Hence, we focused our research to simplify the process for the preparation of a compound of formula (I) with greater yield and higher chemical purity by using a compound of formula (A) in a substantially cost effective and eco-friendly manner and to obviate the problems associated with the prior art process(s).
Objective of the invention
The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s),which makes the present invention eco-friendly as well.
Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of compound of formula (I), which comprises the steps of:
M
(i) dissolving 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid-p- methoxybenzyl ester of formula (II) in an organic solvent to get a solution;
(ii) reacting triphenylphosphine and a compound of formula (A) with a solution obtained from step (i) to get a compound of formula (III); (Hi) adding an organic solvent after the completion of reaction;
(iv) filtering the reaction mixture;
(v) treating the filtrate with aqueous formaldehyde and a base;
(vi) adjusting the pH of reaction mixture with acid;
(vii) separating and concentrating the organic layer; (viii) precipitating the reaction mixture by using an alcoholic solvent;
(ix) adding water to the reaction mixture; and
(x) isolating the 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I).
The above process is illustrated in the following synthetic scheme
Formation of trlphenylohosphonlum halide step
[W [III]
Aqueous formaldehyde
Vinylation step Base
Organic solvent(s)
R = Hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted II] X = Any halogen 1
Detailed description of the invention
Accordingly in an embodiment of the present invention, the triphenylphosphonium halide formation and vinylation steps are carried out in an
in-situ manner without isolating the compound of formula (III), which makes the process easier.
In another embodiment of the present invention, the organic solvent used in step (i) is preferably N,N-dimethylformamide or N, N-dimethylacetamide or mixture thereof.
In another embodiment of the present invention, in a compound of formula (A). R is represented hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted, more preferably R is hydrogen.
In another embodiment of the present invention, in a compound of formula (III) and formula (A). X is represented by any halogen, preferably bromine or iodine, more preferably bromine.
In another embodiment of the present invention, the step (ii) of said reaction is carried out preferably in the range of 0.2 to 5 equivalents of a compound of formula (A).
In another embodiment of the present invention, the step (ii) of said reaction is preferably with 1 to 2 equivalents of triphenylphosphine.
In another embodiment of the present invention, the step (ii) of said reaction is completed in the range of 1 hr to 6 hrs, preferably in 2 hrs.
In another embodiment of the present invention, the organic solvent used for the preparation of compound of formula (I) in step (iii) is preferably methylene chloride.
In another embodiment of the present invention, the formaldehyde used in step (v) is preferably in the range of 3 to 50 equivalents.
In another embodiment of the present invention, the base used in step (v) is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide.
In another embodiment of the present invention, the acid used in step (vi) is preferably hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
In another embodiment of the present invention, the alcoholic solvent used in step (viii) is preferably methanol.
In another embodiment of the present invention, the role of addition of water in step (ix) is a very essential and crucial feature of the present invention. By doing this way it results in better quality of a compound of formula (I) along with good yield. The addition of water during this step takes care of the inorganics or by-products formed during the reaction.
In another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 100C to reflux temperature of the solvent used.
In yet another embodiment of the present invention, process for preparation of a compound of formula (I) can be extended further in the making of cephalosporin antibiotics such as Cefixime and Cefdinir by conventional methods.
In the present invention starting material(s) for the preparation a compound of formula (I), were prepared according to the known processes in the prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Example
Preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxy benzyl ester of formula (T)
T-phenylacetamido-S-chloromethyl-S-cephem^-carboxylic acid-p-methoxybenzyl ester (10Og, 0.205mol) was dissolved in N,N dimethylformamide (15OmL) in a four necked round bottom flask at room temperature and triphenylphosphine (55g, 0.21 mol), ammonium bromide (19.46g, 0.205 mol) were added under stirring and the temperature
raised slightly to facilitate the reaction. After the completion of reaction in 2.5 hrs, methylene chloride (50OmL) was added and the reaction mixture was cooled to 120C to 140C. The reaction mixture was filtered and washed with methylene chloride (10OmL). After 10 minutes of stirring, 36% aqueous formaldehyde solution (108.0 g, 1.29 mol) and sodium hydroxide solution (lOg/lOOmL, 0.25 mol) were added. After 40 mins of further stirring of the reaction mixture, water (80OmL) and hydrochloric acid (5 mL, 36%) were added to this, so that the pH becomes less than 2.0. The organic layer was separated and aqueous layer was extracted with methylene chloride (2 x 100mL).The mixed organic layer was concentrated by distilling out methylene chloride. Methanol (120OmL) was added to the concentrated mass and stirred for one hour to complete the precipitation. Remaining methylene chloride was distilled out and water (35OmL) was added. The reaction mixture was cooled down to 1O0C, stirred for one hour and the solid was filtered and washed with aqueous methanol and dried at temperature 37 0C to yield 78g of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxy benzyl ester, with a chemical purity of more than 96.46 % by HPLC.
Substantial Advantages
(1) The process of the present invention provides higher yield with greater purity of Wittig product. (2) The use of alkali metal iodides such as sodium iodide in Wittig reaction leads to tendency of product to pick up color for which it requires additional purification procedures. Therefore, the present invention uses substantially cheaper reagent(s) in substantially lower amounts and less organic solvent(s) thereby achieving better quality Wittig product that is substantially free of colored impurities forming in the said reaction.
(3) The process of the present invention avoids excessive use of reagents like sodium bromide, sodium iodide, triphenylphosphine, formaldehyde and large amounts of organic solvent(s) such as N,N-dimethylformamide and methylene chloride, thereby reducing the reaction bulk that facilitates scaling up for an industrial production. (4) The process has effectively less number of steps that result in shortening of reaction time and lowering of labour.
(5) The process of the present invention avoids excess usages of reagent(s) and organic solvent(s),and thereby promotes green chemistry and ensures a cleaner surrounding by putting less load on environment.
(6) In the process of the present invention, the by-products formed during the reaction can be reusable and recyclable, which makes the process industrially and commercially viable.
Claims
We claim:
(I) A process for the preparation of a compound of formula (I), comprising the steps of;
(i) dissolving 7-phenylacetamido-3-chloromethyl-3-cephern-4-carboxylic acid-p- methoxybenzyl ester of formula (II) in an organic solvent to get a solution;
(ii) reacting triphenylphosphine and a compound of formula (A), with a solution obtained from step (i) to get a compound of formula (III);
Wherein R is preferably represented by hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted and X is represented by any halogen selected from bromine or iodine
(iii) adding an organic solvent after the completion of reaction; (iv) filtering the reaction mixture;
(v) treating the filtrate with aqueous formaldehyde and a base;
(vi) adjusting the pH of reaction mixture with acid;
(vii) separating and concentrating the organic layer;
(viii) precipitating the reaction mixture by using an alcoholic solvent; (ix) adding water to the reaction mixture; and
(x) isolating the 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I).
(2) A process according to claim no. 1 wherein, the said organic solvent in step (i) is N,N-dimethylformamide or N, N-dimethylacetamide or mixture thereof.
(3) A process according to claim no.l wherein, the said compound of formula (A) is ammonium bromide or ammonium iodide.
(4) A process according to claim no. 1 wherein, the said organic solvent in step (iii) is methylene chloride.
(5) A process according to claim no. 1 wherein, the said base in step (v) is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide.
(6) A process according to claim no. 1 wherein, the pH of reaction mixture in step (vi) is adjusted below 2.0.
(7 A process according to claim no. 1 wherein, the said acid in step (vi) is preferably hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
(8) A process according to claim no. 1 wherein, the said alcoholic solvent in step (viii) is methanol.
(9) A process according to claim no. 1 wherein, all the steps are preferably performed at a temperature in the range of (-) 100C to reflux temperature of the solvent used.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN78/DEL/2009 | 2009-01-16 | ||
| IN78DE2009 | 2009-01-16 |
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| WO2010082108A1 true WO2010082108A1 (en) | 2010-07-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IB2010/000036 WO2010082108A1 (en) | 2009-01-16 | 2010-01-12 | Improved process for preparation of key intermediate of cephalosporins |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898440A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester |
| CN105440053A (en) * | 2015-12-24 | 2016-03-30 | 湖北凌晟药业有限公司 | Method for recycling GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acidp-methoxybenzyl ester) crystallization barren liquor |
| CN103923104B (en) * | 2014-04-25 | 2016-04-13 | 湖北凌晟药业有限公司 | 7-phenylacetylamino-3-vinyl-4-cephemcarboxylic acid is to the preparation method of methoxy benzyl ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5401841A (en) * | 1991-03-08 | 1995-03-28 | Sandoz Ltd. | Process for the production of cephalosporines |
| US6417351B1 (en) * | 1997-06-04 | 2002-07-09 | Otsuka Kagaku Kabushiki Kaisha | Process for producing 3-alkenylcephem compounds |
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2010
- 2010-01-12 WO PCT/IB2010/000036 patent/WO2010082108A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5401841A (en) * | 1991-03-08 | 1995-03-28 | Sandoz Ltd. | Process for the production of cephalosporines |
| US6417351B1 (en) * | 1997-06-04 | 2002-07-09 | Otsuka Kagaku Kabushiki Kaisha | Process for producing 3-alkenylcephem compounds |
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| Title |
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| WANG, YONGJIN ET AL.: "Synthesis of Intermediate of Cefixime: 7-Amino-3-Vinyl Cephalosporanic Acid-p-Methoxybenzyl Ester Hydrochloride.", SHANDONG HUAGONG, vol. 34, no. 4, August 2005 (2005-08-01), pages 9 - 10, 13 * |
| YOUSUKE KATSURA ET AL.: "A Convenient Protective Method for the 7-Amino Function on a Cephem Derivative in Wittig Vinylation.", TETRAHEDRON LETTERS, vol. 35, no. 51, 1994, pages 9601 - 9604 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898440A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester |
| CN103923104B (en) * | 2014-04-25 | 2016-04-13 | 湖北凌晟药业有限公司 | 7-phenylacetylamino-3-vinyl-4-cephemcarboxylic acid is to the preparation method of methoxy benzyl ester |
| CN105440053A (en) * | 2015-12-24 | 2016-03-30 | 湖北凌晟药业有限公司 | Method for recycling GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acidp-methoxybenzyl ester) crystallization barren liquor |
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