US20080281093A1 - Novel Process For Preparation of Cefprozil Intermediate - Google Patents
Novel Process For Preparation of Cefprozil Intermediate Download PDFInfo
- Publication number
- US20080281093A1 US20080281093A1 US10/595,544 US59554404A US2008281093A1 US 20080281093 A1 US20080281093 A1 US 20080281093A1 US 59554404 A US59554404 A US 59554404A US 2008281093 A1 US2008281093 A1 US 2008281093A1
- Authority
- US
- United States
- Prior art keywords
- cefprozil
- process according
- formula
- compound
- dimethylformamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229960002580 cefprozil Drugs 0.000 title claims abstract description 33
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 title claims abstract 15
- 238000000034 method Methods 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 18
- -1 3-methoxy-1-methyl-3-oxo-1-propenyl Chemical group 0.000 claims abstract description 11
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 9
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims abstract description 9
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960003424 phenylacetic acid Drugs 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000006884 silylation reaction Methods 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 4
- WDLWHQDACQUCJR-WTBJWPOVSA-N (6r,7r)-7-[[2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(z)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)\C=C/C)C(O)=O)C(=O)C(N)C1=CC=C(O)C=C1 WDLWHQDACQUCJR-WTBJWPOVSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 3
- 238000001914 filtration Methods 0.000 claims 3
- 238000003756 stirring Methods 0.000 claims 3
- 230000001376 precipitating effect Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 abstract description 4
- ALYUMNAHLSSTOU-CIRGZYLNSA-N (6r,7r)-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 ALYUMNAHLSSTOU-CIRGZYLNSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- IYRKMTPJECPERP-OUKQBFOZSA-N CCOC(=O)OC(=O)C(N/C(C)=C/C(=O)OC)C1=CC=C(O[Si](C)(C)C)C=C1 Chemical compound CCOC(=O)OC(=O)C(N/C(C)=C/C(=O)OC)C1=CC=C(O[Si](C)(C)C)C=C1 IYRKMTPJECPERP-OUKQBFOZSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- MMYFWIKVPRLCFD-MDZDMXLPSA-N CCOC(=O)OC(=O)C(N/C(C)=C/C(=O)OC)C1=CC=C(O)C=C1 Chemical compound CCOC(=O)OC(=O)C(N/C(C)=C/C(=O)OC)C1=CC=C(O)C=C1 MMYFWIKVPRLCFD-MDZDMXLPSA-N 0.000 description 2
- VXLHFWHJVCLKPT-BQYQJAHWSA-N COC(=O)/C=C(\C)NC(C(=O)O)C1=CC=C(O)C=C1 Chemical compound COC(=O)/C=C(\C)NC(C(=O)O)C1=CC=C(O)C=C1 VXLHFWHJVCLKPT-BQYQJAHWSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WDLWHQDACQUCJR-AGGBKSKLSA-N [H][C@@]1(NC(=O)[C@H](N)C2=CC=C(O)C=C2)C(=O)N2C(C(=O)O)=C(/C=C\C)CS[C@@]21[H] Chemical compound [H][C@@]1(NC(=O)[C@H](N)C2=CC=C(O)C=C2)C(=O)N2C(C(=O)O)=C(/C=C\C)CS[C@@]21[H] WDLWHQDACQUCJR-AGGBKSKLSA-N 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- KFCMZNUGNLCSJQ-GWQXNCQPSA-N (4-methoxyphenyl)methyl (6r)-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)C2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-GWQXNCQPSA-N 0.000 description 1
- RJFPBECTFIUTHB-INEUFUBQSA-N (6r,7r)-7-azaniumyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 RJFPBECTFIUTHB-INEUFUBQSA-N 0.000 description 1
- 0 *=NCOC(N)=O Chemical compound *=NCOC(N)=O 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- HNECZOPHAZRMFX-HJWRWDBZSA-N C/C=C\C1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)C2SC1 Chemical compound C/C=C\C1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)C2SC1 HNECZOPHAZRMFX-HJWRWDBZSA-N 0.000 description 1
- BWDUZTOAQJNYFU-JVFKZUMRSA-N C/C=C\C1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)C2SC1.CCOC(=O)OC(=O)C(N/C(C)=C/C(=O)OC)C1=CC=C(O[Si](C)(C)C)C=C1.[H][C@@]1(NC(=O)C(N/C(C)=C/C(=O)OC)C2=CC=C(O[Si](C)(C)C)C=C2)C(=O)N2C(C(=O)O[Si](C)(C)C)=C(/C=C\C)CS[C@@]21[H].[H][C@@]1(NC(=O)[C@H](N)C2=CC=C(O)C=C2)C(=O)N2C(C(=O)O)=C(/C=C\C)CS[C@@]21[H] Chemical compound C/C=C\C1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)C2SC1.CCOC(=O)OC(=O)C(N/C(C)=C/C(=O)OC)C1=CC=C(O[Si](C)(C)C)C=C1.[H][C@@]1(NC(=O)C(N/C(C)=C/C(=O)OC)C2=CC=C(O[Si](C)(C)C)C=C2)C(=O)N2C(C(=O)O[Si](C)(C)C)=C(/C=C\C)CS[C@@]21[H].[H][C@@]1(NC(=O)[C@H](N)C2=CC=C(O)C=C2)C(=O)N2C(C(=O)O)=C(/C=C\C)CS[C@@]21[H] BWDUZTOAQJNYFU-JVFKZUMRSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- SMSBZLYVLAATSM-RGXPKUQQSA-N [H][C@@]1(NC(=O)C(N/C(C)=C/C(=O)OC)C2=CC=C(O[Si](C)(C)C)C=C2)C(=O)N2C(C(=O)O[Si](C)(C)C)=C(/C=C\C)CS[C@@]21[H] Chemical compound [H][C@@]1(NC(=O)C(N/C(C)=C/C(=O)OC)C2=CC=C(O[Si](C)(C)C)C=C2)C(=O)N2C(C(=O)O[Si](C)(C)C)=C(/C=C\C)CS[C@@]21[H] SMSBZLYVLAATSM-RGXPKUQQSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 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
- C07D501/14—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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
Definitions
- the present invention relates to a process for preparing a key intermediate of cefprozil and provides less expensive and commercially viable process for preparing cefprozil.
- U.S. Pat. No. 4,520,022 disclosed 3-[(Z)-1-propen-1-yl]-7-acylamido cephalosporins. These compounds are antibacterial agents.
- Cefprozil chemically (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid is an orally effective cephalosporin antibiotic having a broad spectrum of antibacterial activity against both gram-positive and gram-negative organisms.
- Cefprozil is represented by the following structure:
- Mixed anhydride of formula V can be prepared by reacting the compound of formula III or a salt thereof with ethyl chloroformate in an organic solvent such as a chlorinated solvent, optionally in the presence of another solvent such as dimethylformamide.
- organic solvent such as a chlorinated solvent
- another solvent such as dimethylformamide.
- catalytic quantities of N-methyl morpholine and methanesulfonic acid may also be used.
- the reaction is carried out below about ⁇ 20° C., preferably below about ⁇ 40° C.
- Silylation of the mixed anhydride is carried out in an organic solvent such as a chlorinated solvent using N,O-bis(trimethylsilyl)acetamide.
- organic solvent such as a chlorinated solvent using N,O-bis(trimethylsilyl)acetamide.
- Other common silylating reagents such as hexamethyldisilazane and trimethylsilyl iodide etc., failed to silylate the anhydride. This is contrary to the observation (U.S. Pat. No.
- silylation of [R-(Z)]-[4-hydroxy- ⁇ -[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt (amoxydane salt) can be done properly with hexamethyldisilazane and trimethylsilyl iodide and the use of N,O-bis(trimethylsilyl)acetamide results in the development of color which cannot be removed.
- silylation of amoxydane salt is different from the silylation of the mixed anhydride of formula II.
- the compound of formula III used as starting material is commercially available.
- silylated mixed anhydride of formula II in the preparation of cefprozil and pharmaceutically acceptable salts thereof is also novel and provides another aspect of the present invention.
- Cefprozil and pharmaceutically acceptable salts also include their hydrates or solvates.
- the use of the silylated compound of formula V in the preparation of cefprozil is known but the problem with the use of the compound is the self-acylation resulting in the formation of the corresponding impurity. So, this requires strict control of relative quantity of this compound and strict control of addition of the compound to the compound of formula VI in order to avoid the self-acylation.
- silyl protected compound of formula II avoids the self-acylation and so, strict control of quantity of silyl protected intermediate is not required and controlled addition of the reactant is not required; and so, the use of the silyl protected compound of formula II in the preparation of cefprozil is practically advantageous.
- the use of formula II in the preparation of cefprozil may be formulated in the scheme shown below.
- the reaction between the silylated compound of formula II and the compound of formula VI is carried out in chlorinated solvents such as methylene chloride.
- chlorinated solvents such as methylene chloride.
- the reaction is carried out at ⁇ 50° C. to 40° C., more preferably at ⁇ 40° C. to 25° C.
- silylated mixed anhydride of formula II does not react with compound of formula VI in solvents such as acetonitrile or hydrocarbon solvent such as cyclohexane.
- the deprotection of silyl protected and N-protected group of the compound of formula VII obtained above may preferably be carried out with aqueous hydrochloric acid solution to obtain compound of formula I.
- Compound of formula I (cefprozil) may be isolated and converted to hydrates, solvates and pharmaceutically acceptable salts by known methods.
- the compound of formula I is preferably precipitated from the reaction mass as dimethylformamide solvate (cefprozil DMF solvate) by adjusting the pH of the reaction mass to about 5.5 to 7.0 with a base such as ammonia in the presence of dimethylformamide.
- Cefprozil DMF solvate may be converted to cefprozil hydrates or solvates; or to a pharmaceutically acceptable salt by a known method.
- the compound of formula VI used as starting materials may be prepared by known methods for example as described in U.S. Pat. No. 4,694,079.
- p-Methoxybenzyl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate 100 gm is suspended in a mixture of methylene chloride (600 ml) and water (600 ml), then sodium iodide (32.32 gm) and triphenylphosphine (56.5 gm) are added at 25° C. and the contents are stirred for 1 hour 30 minutes at 25° C. Then the layers are separated, the resulting organic layer is cooled to 0° C. and then 1.5% sodium hydroxide solution (600 ml) is added.
- Phosphorous pentachloride (136 gm) is added to methylene chloride (625 ml) at 25° C. to 30° C., cooled to 15° C. under N 2 atmosphere and then pyridine (45 gm) is added for 30 minutes at 15-20° C. The contents are stirred for 5 minutes, cooled to ⁇ 12° C. and then stirred for 20 minutes at ⁇ 12° C. Then p-Methoxybenzyl 7-phenylacetamido-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylate (125 gm, obtained as in example 2) is added to the reaction mass at ⁇ 12° C., stirred for 1 hour 30 minutes at ⁇ 12° C.
- 1,3-Propanediol (125 ml) is added to the reaction mass for 30 minutes at ⁇ 25° C., stirred for 30 minutes at ⁇ 25° C. and phenol (500 gm) in methylene chloride (125 ml) is added at ⁇ 25° C.
- the reaction mass is stirred for 2 hours at ⁇ 25° C. to ⁇ 15° C., water (500 ml) is added at ⁇ 15° C. to ⁇ 10° C. and stirred for 15 minutes. Then separated the layers and the organic layer is extracted with 2N HCl (2 L).
- the total aqueous layer is washed with methylene chloride (500 ml), pH is adjusted to 2.0 with 25% sodium hydroxide at 0-5° C. and stirred for 1 hour at the same temperature. Then the separated solid is filtered and washed with acetone (250 ml) to give 41.25 gm of 7-Amino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid (containing 8.8% E-isomer).
- N,O-bis(trimethylsilyl)acetamide (39 ml) is added to the reaction mass, stirred for 30 minutes and [7-trimethylsilylamino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid]trimethylsilyl ester obtained in step-I is added to this solution.
- the contents are stirred for 3 hours, 2N hydrochloric acid (120 ml) is added and the layers are separated. Then the mixture of dimethylformamide (300 ml) and acetone (75 ml) is added to the reaction mass, carbon (3 gm) is added and stirred for 30 minutes.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Magnetic Heads (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
Abstract
The present invention relates to a process for preparing a key intermediate of cefprozil and use of this intermediate in the preparation of cefprozil thereby avoiding impurity-causing self-acylation. [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt is reacted with ethyl chloroformate to obtain mixed anhydride which is then silylated with N,O-bis(trimethylsilyl)acetamide. The silylated compound obtained is reacted with [7-trimethylsilylamino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid]trimethylsilyl ester and deprotected with aqueous hydrochloric acid to give cefprozil.
Description
- The present invention relates to a process for preparing a key intermediate of cefprozil and provides less expensive and commercially viable process for preparing cefprozil.
- U.S. Pat. No. 4,520,022 disclosed 3-[(Z)-1-propen-1-yl]-7-acylamido cephalosporins. These compounds are antibacterial agents. Among them Cefprozil, chemically (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid is an orally effective cephalosporin antibiotic having a broad spectrum of antibacterial activity against both gram-positive and gram-negative organisms. Cefprozil is represented by the following structure:
- Processes for the preparations of cefprozil, it's hydrates and related compounds were described in U.S. Pat. No. 4,727,070, WO 98/04732, U.S. Pat. No. 4,694,079 and GB 2173798. U.S. Pat. No. 4,694,079 disclosed a process for the preparation of DMF solvate of cefprozil. U.S. Pat. No. 5,608,055 disclosed a process for the preparation of 7-α-acylamino-cephalosporin by acylating 7-amino-3-cephem-4-carboxylic acid or a derivative thereof in a halogen-free solvent. According to U.S. Pat. No. 4,148,817 the silylation of [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt (amoxydane salt) can be done properly with hexamethyldisilazane and trimethylsilyl iodide and the silylated salt is converted into a mixed anhydride; and the patent also disclosed that the use of N,O-bis(trimethylsilyl)acetamide in the silylation results in the development of color which cannot be removed. Moreover the process as per U.S. Pat. No. 4,148,817 requires isolation of silylated amoxydane salt intermediate before converting to silylated anhydride.
- All the aforesaid patents are incorporated herein by reference.
- According to one aspect of the present invention, there is provided a process for preparing silylated mixed anhydride of formula II:
- which comprises reacting the compound of formula III or a salt thereof:
- with ethyl chloroformate of formula IV:
- to obtain mixed anhydride of formula V:
- then silylating the mixed anhydride of formula V obtained above with N,O-bis(trimethylsilyl)acetamide to obtain the compound of formula II:
- Mixed anhydride of formula V can be prepared by reacting the compound of formula III or a salt thereof with ethyl chloroformate in an organic solvent such as a chlorinated solvent, optionally in the presence of another solvent such as dimethylformamide. Preferably, catalytic quantities of N-methyl morpholine and methanesulfonic acid may also be used.
- The reaction is carried out below about −20° C., preferably below about −40° C.
- Silylation of the mixed anhydride is carried out in an organic solvent such as a chlorinated solvent using N,O-bis(trimethylsilyl)acetamide. Other common silylating reagents such as hexamethyldisilazane and trimethylsilyl iodide etc., failed to silylate the anhydride. This is contrary to the observation (U.S. Pat. No. 4,148,817) that silylation of [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt (amoxydane salt) can be done properly with hexamethyldisilazane and trimethylsilyl iodide and the use of N,O-bis(trimethylsilyl)acetamide results in the development of color which cannot be removed. Thus, silylation of amoxydane salt is different from the silylation of the mixed anhydride of formula II.
- Moreover, the novel process does not require isolation of intermediates whereas the prior art process (U.S. Pat. No. 4,148,817) requires isolation of silylated amoxydane salt intermediate before converting to silylated anhydride.
- The compound of formula III used as starting material is commercially available.
- Use of silylated mixed anhydride of formula II in the preparation of cefprozil and pharmaceutically acceptable salts thereof is also novel and provides another aspect of the present invention. Cefprozil and pharmaceutically acceptable salts also include their hydrates or solvates. The use of the silylated compound of formula V in the preparation of cefprozil is known but the problem with the use of the compound is the self-acylation resulting in the formation of the corresponding impurity. So, this requires strict control of relative quantity of this compound and strict control of addition of the compound to the compound of formula VI in order to avoid the self-acylation. The use of the silyl protected compound of formula II avoids the self-acylation and so, strict control of quantity of silyl protected intermediate is not required and controlled addition of the reactant is not required; and so, the use of the silyl protected compound of formula II in the preparation of cefprozil is practically advantageous. The use of formula II in the preparation of cefprozil may be formulated in the scheme shown below.
- The reaction between the silylated compound of formula II and the compound of formula VI is carried out in chlorinated solvents such as methylene chloride. Preferably the reaction is carried out at −50° C. to 40° C., more preferably at −40° C. to 25° C.
- It has been found that the silylated mixed anhydride of formula II does not react with compound of formula VI in solvents such as acetonitrile or hydrocarbon solvent such as cyclohexane.
- The deprotection of silyl protected and N-protected group of the compound of formula VII obtained above may preferably be carried out with aqueous hydrochloric acid solution to obtain compound of formula I.
- Compound of formula I (cefprozil) may be isolated and converted to hydrates, solvates and pharmaceutically acceptable salts by known methods.
- The compound of formula I is preferably precipitated from the reaction mass as dimethylformamide solvate (cefprozil DMF solvate) by adjusting the pH of the reaction mass to about 5.5 to 7.0 with a base such as ammonia in the presence of dimethylformamide.
- Cefprozil DMF solvate may be converted to cefprozil hydrates or solvates; or to a pharmaceutically acceptable salt by a known method.
- The compound of formula VI used as starting materials may be prepared by known methods for example as described in U.S. Pat. No. 4,694,079.
- The invention will now be further described by the following examples, which are illustrative rather than limiting.
- p-Methoxybenzyl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (100 gm) is suspended in a mixture of methylene chloride (600 ml) and water (600 ml), then sodium iodide (32.32 gm) and triphenylphosphine (56.5 gm) are added at 25° C. and the contents are stirred for 1 hour 30 minutes at 25° C. Then the layers are separated, the resulting organic layer is cooled to 0° C. and then 1.5% sodium hydroxide solution (600 ml) is added. The contents are stirred for 1 hour at 0° C., separated the layers and washed the resulting organic layer with saturated sodium chloride solution (2 L). Then the organic layer is cooled to −10° C., isopropyl alcohol (700 ml), water (500 ml) and acetaldehyde (90.65 gm) are added and stirred for 20 hours. The reaction mass is treated with sodium metabisulfite, stirred for 10 minutes and separated. Distilled off methylene chloride, isopropyl alcohol (400 ml) and water (200 ml) are added to the reaction mass and stirred for 2 hours at 0-5° C. Then the separated solid is filtered and dried under vacuum to give 70 gm of p-methoxybenzyl 7-phenylacetamido-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylate.
- Phosphorous pentachloride (136 gm) is added to methylene chloride (625 ml) at 25° C. to 30° C., cooled to 15° C. under N2 atmosphere and then pyridine (45 gm) is added for 30 minutes at 15-20° C. The contents are stirred for 5 minutes, cooled to −12° C. and then stirred for 20 minutes at −12° C. Then p-Methoxybenzyl 7-phenylacetamido-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylate (125 gm, obtained as in example 2) is added to the reaction mass at −12° C., stirred for 1 hour 30 minutes at −12° C. and then cooled to −25° C. 1,3-Propanediol (125 ml) is added to the reaction mass for 30 minutes at −25° C., stirred for 30 minutes at −25° C. and phenol (500 gm) in methylene chloride (125 ml) is added at −25° C. The reaction mass is stirred for 2 hours at −25° C. to −15° C., water (500 ml) is added at −15° C. to −10° C. and stirred for 15 minutes. Then separated the layers and the organic layer is extracted with 2N HCl (2 L). The total aqueous layer is washed with methylene chloride (500 ml), pH is adjusted to 2.0 with 25% sodium hydroxide at 0-5° C. and stirred for 1 hour at the same temperature. Then the separated solid is filtered and washed with acetone (250 ml) to give 41.25 gm of 7-Amino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid (containing 8.8% E-isomer).
- To a slurry of 7-Amino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid (30 gm, obtained as in preparative example 2) in methylene chloride (120 ml) is added hexamethyl disilazane (19.8 ml), trimethyl chlorosilane (12.6 ml) and imidazole (300 mg) and the contents are heated to reflux for 4 hours. Then the resulting solution is cooled to −15° C. under nitrogen atmosphere to give [7-trimethylsilylamino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid]trimethylsilyl ester.
- Methylene chloride (180 ml) is added to [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt (43.5 gm), cooled to −20° C. and dimethylformamide (160 ml) is added at −20° C. Then methanesulfonic acid (0.4 ml) and N-methylmorpholine (0.44 ml) are added. The contents are cooled to −50° C. to −60° C., ethyl chloroformate (14 ml) is added and stirred for 1 hour 30 minutes. N,O-bis(trimethylsilyl)acetamide (39 ml) is added to the reaction mass, stirred for 30 minutes and [7-trimethylsilylamino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid]trimethylsilyl ester obtained in step-I is added to this solution. The contents are stirred for 3 hours, 2N hydrochloric acid (120 ml) is added and the layers are separated. Then the mixture of dimethylformamide (300 ml) and acetone (75 ml) is added to the reaction mass, carbon (3 gm) is added and stirred for 30 minutes. Filtered the reaction mass, washed with 150 ml of dimethylformamide and the pH is adjusted to 6-6.5 with NH3 solution. Then the precipitated solid is filtered, washed with dimethylformamide and acetone and dried under vacuum at 40° C. to give 58 gm of cefprozil dimethylformamide solvate (1.5 mole dimethylformamide per mole of cefprozil.
- The mixture of Cefprozil dimethylformamide solvate (58 gm, obtained in step-II) and water (100 ml) is stirred for 1 hour, filtered, washed with acetone (100 ml) and dried under vacuum at 40-45° C. to give 40 gm of cefprozil monohydrate (containing 10% E-isomer).
Claims (18)
1. A process for preparing silylated mixed anhydride of formula II:
which comprises reacting the compound of formula III or a salt thereof:
with ethyl chloroformate of formula IV:
to obtain mixed anhydride of formula V:
then silylating the mixed anhydride of formula V obtained above with N,O-bis(trimethylsilyl)acetamide to obtain the compound of formula II.
2. The process according to claim 1 , wherein the mixed anhydride of formula V is prepared by reacting [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt (amoxydane salt) with ethyl chloroformate in a chlorinated solvent.
3. The process according to claim 2 , wherein the chlorinated solvent is methylene chloride.
4. The process according to claim 2 , wherein the reaction is carried out in the presence of dimethylformamide along with the said chlorinated solvent.
5. The process according to claim 2 , wherein the catalytic quantities of N-methyl morpholine and methanesulfonic acid are used.
6. The process according to claim 1 , wherein the reaction between the compound of formula III or salt thereof and ethyl chloroformate is carried out below about −20° C.
7. The process according to claim 6 , wherein the reaction is carried out below −40° C.
8. The process according to claim 1 , wherein the silylation of the mixed anhydride is carried out in a chlorinated solvent.
9. The process according to claim 8 , wherein the chlorinated solvent is methylene chloride.
10. The process for preparing (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid of formula I (cefprozil) or hydrate; or a pharmaceutically acceptable salt thereof.
with the compound of formula II:
b) deprotecting the compound obtained above with an aqueous hydrochloric acid to give cefprozil of formula I;
c) precipitating cefprozil as dimethylformamide solvate from the reaction mass obtained in step (b) and
d) converting the solvate of step (c) into cefprozil or cefprozil hydrate; or
pharmaceutically acceptable salt.
11. The process according to claim 10 , wherein the chlorinated solvent is methylene chloride.
12. The process according to claim 10 , wherein the solvate is precipitated from the reaction mass at a pH of above 5.5 to 7.0 in the presence of dimethylformamide.
13. The process according to claim 10 , wherein cefprozil hydrate is prepared in step (d) by stirring dimethylformamide solvate in water, filtering the de-solvated cefprozil and drying.
14. The process according to claim 3 , wherein the catalytic quantities of N-methyl morpholine and methanesulfonic acid are used.
15. The process according to claim 4 , wherein the catalytic quantities of N-methyl morpholine and methanesulfonic acid are used.
16. The process according to claim 11 , wherein the solvate is precipitated from the reaction mass at a pH of above 5.5 to 7.0 in the presence of dimethylformamide.
17. The process according to claim 11 , wherein cefprozil hydrate is prepared in step (d) by stirring dimethylformamide solvate in water, filtering the de-solvated cefprozil and drying.
18. The process according to claim 12 , wherein cefprozil hydrate is prepared in step (d) by stirring dimethylformamide solvate in water, filtering the de-solvated cefprozil and drying.
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EP (2) | EP1809638B1 (en) |
AT (1) | ATE457990T1 (en) |
DE (1) | DE602004025631D1 (en) |
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US7230097B2 (en) * | 2003-03-10 | 2007-06-12 | Lupin Ltd. | Process for preparation of 7-[α-Amino (4-hydroxyphenyl) acetamido]-3-substituted-3-cephem-4-carboxylic acid |
WO2006048887A1 (en) | 2004-11-01 | 2006-05-11 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
CN102408438B (en) * | 2010-09-26 | 2015-01-07 | 石药集团中奇制药技术(石家庄)有限公司 | Preparation method of cefprozil monohydrate |
CN102911187B (en) * | 2012-10-11 | 2015-03-11 | 南通康鑫药业有限公司 | Recovery method of cefprozil |
CN103910749B (en) * | 2014-03-14 | 2016-06-29 | 中节能万润股份有限公司 | A kind of preparation method of cefotiam hydrochloride |
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KR820001564B1 (en) * | 1981-05-09 | 1982-09-02 | 동신제약 주식회사 | Process for preparing cephalosporin derivatives |
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GB0118764D0 (en) * | 2001-08-01 | 2001-09-26 | Biochemie Gmbh | Organic compounds |
CA2519853A1 (en) * | 2003-03-21 | 2004-09-30 | Neera Tewari | Process for the preparation of 7-amino (p-hydroxyphenylglycylamido) cephem compounds |
WO2006048887A1 (en) | 2004-11-01 | 2006-05-11 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
-
2004
- 2004-11-01 WO PCT/IN2004/000337 patent/WO2006048887A1/en active Application Filing
- 2004-11-01 PL PL04806740T patent/PL1809638T3/en unknown
- 2004-11-01 US US10/595,544 patent/US20080281093A1/en not_active Abandoned
- 2004-11-01 EP EP04806740A patent/EP1809638B1/en not_active Not-in-force
- 2004-11-01 ES ES04806740T patent/ES2338335T3/en active Active
- 2004-11-01 AT AT04806740T patent/ATE457990T1/en not_active IP Right Cessation
- 2004-11-01 EP EP09177637A patent/EP2213676A1/en not_active Withdrawn
- 2004-11-01 DE DE602004025631T patent/DE602004025631D1/en active Active
-
2008
- 2008-10-24 US US12/257,738 patent/US7629482B2/en not_active Expired - Fee Related
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US3940354A (en) * | 1973-01-31 | 1976-02-24 | Roussel-Uclaf | Cephalosporan compounds |
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US7230097B2 (en) * | 2003-03-10 | 2007-06-12 | Lupin Ltd. | Process for preparation of 7-[α-Amino (4-hydroxyphenyl) acetamido]-3-substituted-3-cephem-4-carboxylic acid |
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WO2006048887A1 (en) | 2006-05-11 |
EP1809638B1 (en) | 2010-02-17 |
DE602004025631D1 (en) | 2010-04-01 |
EP2213676A1 (en) | 2010-08-04 |
US20090048460A1 (en) | 2009-02-19 |
ES2338335T3 (en) | 2010-05-06 |
ATE457990T1 (en) | 2010-03-15 |
EP1809638A1 (en) | 2007-07-25 |
US7629482B2 (en) | 2009-12-08 |
PL1809638T3 (en) | 2010-07-30 |
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