JPS643182B2 - - Google Patents
Info
- Publication number
- JPS643182B2 JPS643182B2 JP5528280A JP5528280A JPS643182B2 JP S643182 B2 JPS643182 B2 JP S643182B2 JP 5528280 A JP5528280 A JP 5528280A JP 5528280 A JP5528280 A JP 5528280A JP S643182 B2 JPS643182 B2 JP S643182B2
- Authority
- JP
- Japan
- Prior art keywords
- dioxane
- mixture
- formula
- product
- chloride
- 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.)
- Expired
Links
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 30
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 28
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 27
- 239000007789 gas Substances 0.000 claims description 22
- MRFJAULKKHVIGF-OGFXRTJISA-N (2r)-2-amino-2-(4-hydroxyphenyl)acetyl chloride;hydrochloride Chemical compound Cl.ClC(=O)[C@H](N)C1=CC=C(O)C=C1 MRFJAULKKHVIGF-OGFXRTJISA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 12
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 4
- 150000001983 dialkylethers Chemical class 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- KPEQETAUMLUASP-XCUBXKJBSA-N O1CCOCC1.Cl.OC1=CC=C(C=C1)[C@@H](N)C(=O)Cl Chemical compound O1CCOCC1.Cl.OC1=CC=C(C=C1)[C@@H](N)C(=O)Cl KPEQETAUMLUASP-XCUBXKJBSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims 2
- 150000002012 dioxanes Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- 239000000047 product Substances 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- RHZVXAJWBLWUJL-SNVBAGLBSA-N (2R)-2-(4-hydroxyphenyl)-2-(propan-2-yloxycarbonylamino)acetic acid Chemical compound C(C)(C)OC(=O)N[C@H](C1=CC=C(C=C1)O)C(=O)O RHZVXAJWBLWUJL-SNVBAGLBSA-N 0.000 description 9
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- -1 n-hexane) Chemical class 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000010899 nucleation Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- 229930186147 Cephalosporin Natural products 0.000 description 4
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- GSUXBGBMKIAZGI-MRVPVSSYSA-N (2R)-2-(4-hydroxyphenyl)-2-(methoxycarbonylamino)acetic acid Chemical compound COC(=O)N[C@H](C1=CC=C(C=C1)O)C(=O)O GSUXBGBMKIAZGI-MRVPVSSYSA-N 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 150000002960 penicillins Chemical class 0.000 description 3
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- OFZQDADMXNKALJ-SECBINFHSA-N (2R)-2-(ethoxycarbonylamino)-2-(4-hydroxyphenyl)acetic acid Chemical compound C(C)OC(=O)N[C@H](C1=CC=C(C=C1)O)C(=O)O OFZQDADMXNKALJ-SECBINFHSA-N 0.000 description 1
- RJUHFEYASOTUCG-SNVBAGLBSA-N (2R)-2-phenyl-2-(propan-2-yloxyamino)acetic acid Chemical compound C(C)(C)ON[C@H](C1=CC=CC=C1)C(=O)O RJUHFEYASOTUCG-SNVBAGLBSA-N 0.000 description 1
- CGDQNVNWDDEJPY-CQSZACIVSA-N (2r)-2-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)acetic acid Chemical compound N([C@@H](C(=O)O)C=1C=CC(O)=CC=1)C(=O)OCC1=CC=CC=C1 CGDQNVNWDDEJPY-CQSZACIVSA-N 0.000 description 1
- GVVFCAFBYHYGEE-OGFXRTJISA-N (2r)-2-amino-2-phenylacetyl chloride;hydron;chloride Chemical compound Cl.ClC(=O)[C@H](N)C1=CC=CC=C1 GVVFCAFBYHYGEE-OGFXRTJISA-N 0.000 description 1
- CUSUMDVSPPALSO-SNVBAGLBSA-N (2r)-2-phenyl-2-(propan-2-yloxycarbonylamino)acetic acid Chemical compound CC(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 CUSUMDVSPPALSO-SNVBAGLBSA-N 0.000 description 1
- RHZVXAJWBLWUJL-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-2-(propan-2-yloxycarbonylamino)acetic acid Chemical compound CC(C)OC(=O)NC(C(O)=O)C1=CC=C(O)C=C1 RHZVXAJWBLWUJL-UHFFFAOYSA-N 0.000 description 1
- WQTBOSUELVDJHH-UHFFFAOYSA-N 2-(hydroxyamino)-2-phenylacetyl chloride hydrochloride Chemical compound C1=CC=C(C=C1)C(C(=O)Cl)NO.Cl WQTBOSUELVDJHH-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 1
- 229950004030 cefaloglycin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- UXZAJSZFFARTEI-GUMHCPJTSA-N methyl (2R,3S)-3-(methanesulfonamido)-2-[(4-phenylcyclohexyl)oxymethyl]piperidine-1-carboxylate Chemical compound COC(=O)N1CCC[C@H](NS(C)(=O)=O)[C@@H]1COC1CCC(CC1)c1ccccc1 UXZAJSZFFARTEI-GUMHCPJTSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
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ã®ååç©ã®è£œé æ³ã«é¢ãããDETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula [In the formula, R is hydrogen or hydroxy, especially 4-
It is hydroxy. ] Concerning a method for producing the compound.
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éå®ããããã®ã§ã¯ãªãã A compound of formula has an asymmetric carbon atom and is racemic
It may exist in the DL form or in the isomeric D or L form. The invention particularly relates to, but is not limited to, the D isomer.
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ãã®ã§ãç¹ã«æçšãªãã®ã§ããã Compounds of the formula are known as intermediates for the production of β-lactam antibiotics. The compound may have, for example, formula A of formula B [In the formula, R has the same meaning as above. ] can be used to prepare useful penicillins or salts or protected forms thereof, which may be deprotected in a subsequent step or in the reaction solution.
The use of such compounds in this method has been described in many publications. The compound in which R is hydrogen or 4-hydroxy in the D isomer,
It is particularly useful because it can be converted into the well-known semi-synthetic penicillins ampicillin and amoxicillin by the above method.
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ããããšãã§ããã®ã§ãç¹ã«æçšãªãã®ã§ããã Similarly, the compound has the formula C [wherein X is hydrogen, acetoxy, or other group used in known cephalosporin antibiotics, such as -SZ (Z is a heterocycle, such as 1,2,3-triazol-5-yl)]. ] with the 7-aminocephalosporanic acid or its derivative, or its salt or protected form to form [In the formula, R and X have the same meanings as above. ] can be used to prepare useful cephalosporins or salts or protected forms thereof, which may be deprotected in a subsequent step or in the reaction solution. The use of such compounds in this method has also been described in a number of publications. Compounds of the formula in which R is hydrogen or 4-hydroxy in the D isomer are, for example, the well-known semi-synthetic cephalosporin antibiotics cephalexin (R=H, X=H), cephaloglycin (R=H, X=acetoxy) or cefatridine (R=4-OH, X=1,2,3
-triazol-5-yl) by the above method, and is therefore particularly useful.
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ãã Compounds of the formula, especially those in which R is hydrogen, especially 4-hydroxy, present some difficulties in their preparation. A commonly used known method is Helv.Chim.Acta 39 . pp. 1525-1528 (1958)
The reaction proceeds according to the following reaction formula.
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ã«é瀺ãç¹èš±è«æ±ãããŠããã [Wherein, Y is an amino acid residue. ] The method used for the preparation of D-(-)-4-hydroxyphenylglycyl chloride hydrochloride is disclosed and claimed in DE 2364192, which is carried out under anhydrous conditions and Excess phosgene is removed from the reaction mixture after formation of Leuck anhydride F and a large excess of hydrogen chloride gas is used. The same process is disclosed and claimed in DE 25 27 235 for the preparation of D-(-)-4-hydroxyphenylglycyl chloride hydrochloride dioxane hemisolvate.
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äœäžãããåŸåã«ããããšã§ããã This known method has several drawbacks. The first is the difficulty of having to respond using Hosgen (which is high toxicity), and second is Leuck anhydride F (this is unstable in the existence of Hosgen. Thirdly, relatively strong conditions (preferably 60-80 °C for the formation of intermediate F) must be employed; First, this tends to reduce the yield and purity of the final product.
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äœãã The prior art is also disclosed, for example, in British Patent No. 1241844, in which free glycine is reacted with phosphorus pentachloride and then with hydrogen chloride gas.
This is a method for obtaining hydroxyphenylglycyl chloride hydrochloride. However, as explained in DE 25 27 235 mentioned above, this process forms products with such poor physical properties that they cannot be used for large scale production of penicillins and cephalosporins. Furthermore, the yield is necessarily low.
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ã«ããã The object of the present invention is to eliminate these drawbacks.
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ãšããæããåŒã®ååç©ã®è£œé æ³ãæäŸããã More specifically, the present invention provides the formula [In the formula, R has the same meaning as above. R 1 is straight or branched lower alkyl or benzyl. A process for preparing a compound of the formula comprises reacting the compound with thionyl chloride and reacting the resulting product with hydrogen chloride gas.
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ãã When R 1 is lower alkyl, it preferably has 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. More preferred is branched, especially isopropyl.
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ïŒæéã§ããã The first step of the process of the invention is carried out under anhydrous conditions in an inert organic solvent such as a hydrocarbon (e.g. n-hexane), a chlorinated hydrocarbon (e.g. methylene chloride), an ester or an ether (e.g. dioxane). It is appropriate to do so. Preferably, the step comprises trichloroacetic acid, trifluoroacetic acid,
It is carried out in the presence of strong acids such as p-toluenesulfonic acid or methanesulfonic acid. Advantageously, the acid is present in a catalytic to equivalent amount. Advantageously, thionyl chloride is added to a mixture of the compound of formula, an inert solvent and strength at a temperature of about 0°C. The reaction mixture is then suitably maintained at a temperature between 30° C. and the reflux temperature of the mixture until the reaction is complete. Reaction times typically range from about 1 to
It is 4 hours.
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åœã§ããã The resulting intermediate product can be separated from the reaction mixture and purified using known methods. However, on the other hand, it may also be used in the second stage of the method without purification. In this step, the intermediate or the mixture containing it is dissolved in an inert solvent, preferably an ether (e.g. tetrahydrofuran, dioxane), a dialkyl ether (e.g. diethyl ether, diisopropyl ether, di-n-butyl ether, anisole, tetrahydrofuran),
Suitable solutions are aromatic hydrocarbons (eg toluene), esters (eg butyl acetate) or chlorinated hydrocarbons (eg methylene chloride).
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¥ããã It is then appropriate to introduce hydrogen chloride gas into this mixture. This step is advantageously carried out at temperatures from 0° C. to room temperature. Preferably,
Hydrogen chloride is introduced for a first short period of time until the mixture is saturated at a relatively low temperature, for example -5 to +10°C. If desired, the mixture may then be seeded with the desired product. Preferably, then a weak flow
HCl gas is introduced at room temperature over a suitable period of time, for example up to 15 hours.
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ãïŒããŸãã¯ãããã®æ··åç©ã§ããã The resulting product may be separated and purified by conventional methods. When the reaction mixture of the second stage of the process contains dioxane as a solvent or cosolvent, the product results in the formation of a dioxane hemisolvate.
However, when dioxane is not present and the solvent consists of, for example, dialkyl ethers, tetrahydrofuran, anisole, aromatic hydrocarbons, esters or chlorinated hydrocarbons, solvate-free products are obtained. Preferred solvents for producing solvate-free products are dialkyl ethers (especially diethyl-, diisopropyl- or di-n-butyl-ether), tetrahydrofuran, anisole, esters (preferably butyl acetate), and chlorine. hydrocarbons (eg methylene chloride), or mixtures thereof.
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çŽãªçæç©ã§åŸãããã Relatively pure or crystalline, solvate-free D-(-)-4-hydroxyphenylglycyl chloride hydrochloride, this product is at first glance described in DE 2364192 However, it is believed that the procedures specifically mentioned therein are all operated with dioxane and that the products obtained are in all cases considered to be dioxane hemi-solvated products, so that they are in fact new. Other known products are obtained in amorphous/impure products.
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å€ã®ããšã§ããã The method of the invention is especially useful when applied to compounds of the formula in which R is hydroxy, especially 4-hydroxy, and more particularly when applied to the compound D-(-)-4-hydroxyphenylglycyl chloride hydrochloride. , is new and unexpected. Although processes for the preparation of acid chloride hydrochlorides of phenylglycine and substituted phenylglycines using thionyl chloride or phosphorous pentachloride are known, this process is unsatisfactory, at least for hydroxy-substituted phenylglycines. It is described in West German Patent Publication No. 2364192. Thus, in the first stage for example thionyl chloride and in the second stage
It is unexpected that the process of the present invention using HCl gas provides the final product in good yield and purity.
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ã«æ¯ã¹æããã«æå©ã§ããã The process of the invention also has a clear advantage over the above-mentioned process using phosgene, in that it does not use the highly toxic substance phosgene and does not require removal of this agent after the first stage.
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代ã䜿çšããŠãåå¿ããªãã The process of the invention is even more surprising since it has been found that neither the prior art phosgene process nor the process of the invention can exchange phosgene for thionyl chloride. In the conventional method, no reaction occurs even if phosgene is replaced with thionyl chloride. In the method of the present invention, no reaction occurs even if phosgene is used in place of thionyl chloride.
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¥æããŒã¿ã«ãã€ãŠç€ºãããã In fact, the method of the present invention is believed to have a different mechanism and reaction route than the phosgene method. Although the exact nature of the intermediates involved in the process of the invention has not been established, it is available that they are not the same as the Leuck anhydride formed in the phosgene process, at least when applied to the preparation of compounds in which R is hydroxy. Indicated by the data.
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ã®ååç©ãšåå¿ãããŠè£œé ããŠãããã Certain compounds of the formula used as starting materials are novel, especially those in which R 1 is isopropyl. A compound of the formula may be, for example, a compound of the formula [In the formula, R has the same meaning as above. ] A salt of a compound of the formula X-CO-O-R 1 [wherein R 1 has the same meaning as above. X is a residue (eg chlorine, bromine, iodine, azide or tosyl). ] It may be produced by reacting with the compound.
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ãExample 1: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product) 25 g of D-(-)-N-isopropoxycarbonyl-4-hydroxyphenylglycine was added to 250 ml.
of methylene chloride and add 16 g of trichloroacetic acid to the mixture. 16 ml of thionyl chloride are added with ice cooling and stirring, and after 10 minutes the mixture is allowed to warm to room temperature and stirred for 2-3 hours, after which time the starting material is no longer visible by TLC.
After evaporation of the solvent, the residue is taken up in 300 ml of alkyl acetate and the solution is shaken once with 150 ml of water and then with 100 ml of brine. After drying with Na 2 SO 4 the mixture was evaporated and the residue was dissolved in 160 ml of dry dioxane and
Collect in 80 ml of toluene. While cooling with ice,
HCl gas is introduced into the mixture until saturation. Crystallization begins shortly after seeding and stirring at room temperature. After stirring overnight, crystals of the title compound are collected and confirmed by IR. Yield 28%.
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ãExample 2: D-(-)-phenylglycyl chloride hydrochloride (dioxane semisolvate) 2.5 g D-(-)-N-isopropoxyphenylglycine, 25 ml methylene chloride, 0.8 g trichloroacetic acid and 1.2 ml of thionyl chloride are subjected to a reaction similar to that described in Example 1. After 3 hours of reaction, the mixture is cooled, 5 ml of dioxane are added and HCl gas is introduced into the mixture until saturation. After seeding, the mixture is stirred for several hours at room temperature and the product is then isolated. Yield 60%.
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ãExample 3: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semisolvate) 2.5 g D-(-)-N-isopropoxycarbonyl-4-hydroxyphenylglycine, 0.8
g of trichloroacetic acid and 25 ml of n-hexane are mixed with 1.2 ml of thionyl chloride with ice cooling, and the mixture is then refluxed for 1 hour. The mixture is evaporated on a rotary evaporator and the residue is taken up in 16 ml of dioxane and 8 ml of toluene. After saturation with HCl gas, seeding with cooling and stirring for several hours at room temperature, the product is taken up, washed with dioxane/toluene (1:1) and then with a little methylene chloride and dried. The product is confirmed by IR and methyl ester formation (TLC). Yield 27%.
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ç©ã®äžæŽ»æ§ã¬ã¹æµãã€ã«ã¿ãŒïŒgasâflushed
filterïŒã§åããå°éã®å¡©åã¡ãã¬ã³ã§æŽãã
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ãExample 4: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product) 12.5 g of D-(-)-N-isopropoxycarbonyl-4-hydroxyphenylglycine was dissolved in 125
Suspend in ml of methylene chloride and add 4 g of trichloroacetic acid and 8 ml of thionyl chloride. The mixture is heated under suitable reflux for 5 hours with stirring and dehydration, then cooled to 5°C. Add 25 ml of dioxane and introduce HCl gas for 30 minutes. After seeding, the mixture is stirred at room temperature until crystallization begins. A weak stream of HCl gas is then blown for 6 hours. Inert gas-flushed filters for listed compounds
filter), wash with a small amount of methylene chloride,
Dry with P2O5 . Yield 78%.
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ãExample 5: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product) 2.25 g of D-(-)-N-methoxycarbonyl-4-hydroxyphenylglycine was dissolved in 20 ml of dioxane. and add 0.02 g of trichloroacetic acid. After dropwise addition of 0.8 ml of thionyl chloride in 5 ml of dioxane, the mixture is stirred at 50° C. for 4 hours with dehydration. The mixture is then mixed with 8 ml of toluene, cooled to about 0° C. and HCl gas is introduced for 1 hour. The cooling means are removed and the mixture is stirred at room temperature for several hours after seeding. The precipitate is removed, washed with methylene chloride, and dried. Yield 27%.
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ãExample 6: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semisolvate) 2.25 g of D-(-)-N-methoxycarbonyl-4-hydroxyphenylglycine was chlorinated with 25 ml of chloride. Suspend in methylene, add 0.8 ml trichloroacetic acid and add 1.4 ml thionyl chloride dropwise at room temperature with stirring. The mixture is dehydrated and heated under suitable reflux for 4-5 hours with stirring. The mixture is cooled and mixed with 7 ml of dioxane, then hydrogen chloride gas is introduced for 30 minutes. After seeding, the mixture is stirred at 20-25 °C until crystallization begins. Then,
A weak stream of HCl gas is blown in for several hours, and the product is removed under moisture protection, washed with methylene chloride, and dried in a desiccator over P 2 O 5 and silica gel. Yield 52%.
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ãExample 7: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product) 2.4 g of D-(-)-N-ethoxycarbonyl-4-hydroxyphenylglycine was mixed with 0.8 g The reaction and operation were carried out in the same manner as in Example 6, except that 1.6 g of trichloroacetic acid was used instead of .
Yield 30%.
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ãExample: 8 D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product) 2.7 g of D-(-)-tert-butoxycarbonyl-4-hydroxyphenylglycine,
The reaction is carried out as described in Example 6. Yield 70%.
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ãExample 9: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product) 3 g of D-α-benzyloxycarbonylamino-α-4-hydroxyphenyl acetic acid was dissolved in 20 ml of dioxane. Dissolve, add 0.05 g trichloroacetic acid and 0.8 ml thionyl chloride, and keep the mixture at 50° C. for 1 hour with dehydration and magnetic stirring. After addition of 8 ml of toluene, the mixture is cooled to -5 DEG C. and dry HCl gas is introduced for 1 hour. After sowing,
The mixture is stirred at room temperature for 4 hours and the title compound separates, which is isolated and dried over P 2 O 5 and silica gel in a vacuum desiccator. Yield 56
%.
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ãExample 10: D-(-)-4-Hydroxyphenylglycyl chloride-hydrochloride 12.5 g D-(-) in 125 ml methylene chloride
-N-isopropoxycarbonyl-4-hydroxyphenylglycine is reacted with 8 g of trichloroacetic acid and 8 ml of thionyl chloride at 40° C. for 3 hours. The mixture is cooled with ice water, 100 ml of diisopropyl ether are added and HCl gas is introduced into the mixture for 1.5 hours. Stir overnight at room temperature to obtain a well-crystalline, unsolvated product. Yield 80%.
å®æœäŸ11ïŒ
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ãExample 11: D-(-)-4-Hydroxyphenylglycyl chloride hydrochloride Thionyl chloride and D- as described in Example 10
The mixture resulting from the reaction of (-)-N-isopropoxycarbonyl-4-hydroxyphenylglycine is mixed with 100 ml of di-N-butyl ether and then converted to the title compound by introducing HCl gas. Yield 81%.
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ã§ãè¡šèšååç©ãåŸããExample 12: D-(-)-4-hydroxyphenylglycyl chloride-hydrochloride Instead of 100 ml of diisopropyl ether,
The title compound is obtained in a similar manner to that described in Example 10, but using either 75 ml of anisole, 50 ml of tetrahydrofuran or 75 ml of diethyl ether.
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ãYield: a Anisole: 47% b Tetrahydrofuran: 72% c Diethyl ether: 83% Example 13: D-(-)-4-hydroxyphenylglycyl chloride hydrochloride 38 g p-toluenesulfonic acid, 125 ml of methylene chloride and 15 ml of thionyl chloride,
Heat at reflux for 1-1.5 hours. 50g of D-(-)-
N-isopropoxycarbonyl-4-hydroxyphenylglycine and 30 ml of thionyl chloride are added and the mixture is heated to gentle boiling for 2 hours.
After adding 200 ml of dry butyl acetate, HCl gas is introduced with cooling. The mixture was then heated at 5°C for 1
Stir for an hour and repeat the HCl introduction (30 min).
After stirring for a further 30 minutes at 5 DEG C. and addition of 400-500 ml of dry methylene, the mixture is stirred for 15 hours at room temperature and the reaction product is then taken up on a glass fritted filter with protection from moisture. After washing with methylene chloride, the product is dried in a vacuum desiccator at room temperature. Yield 85%.
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ãExample 14: D-(-)-4-Hydroxyphenylglycyl chloride hydrochloride (dioxane semisolvate) 190 g of p-toluenesulfonic acid/water in 625 ml of methylene chloride is briefly combined with 119 g of thionyl chloride. Stir. 253 g of D-(-)-N-isopropoxycarbonyl-4-hydroxyphenylglycine and 238 g of thionyl chloride are added and the mixture is refluxed for 2.5-3 hours, after some time a clear solution forms. Cool the mixture to 0 °C and incubate at 500 °C.
After addition of ml of dioxane, approximately 170 g of HCl gas is introduced with external cooling to bring the HCl content to 100
Set as mg/ml. Finally, the mixture is stirred at room temperature for 10 hours, the precipitated product is taken, washed with dioxane/methylene chloride (1:1) then methylene chloride, and dried under vacuum for 24 hours. Yield 86%.
次ã®å®æœäŸã¯ãåŒããã®åºçºåæã®è£œé ã瀺
ãã The following examples demonstrate the preparation of starting materials of formula [].
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ããa D-(-)-N-isopropoxycarbonyl-4-hydroxyphenylglycine (1) Suspend 40g of D-(-)-4-hydroxyphenylglycine in 320ml of water, and suspend 9.6g in 80ml of water. of sodium hydroxide at room temperature. A clear solution with a pH value of 9.7 is produced.
Furthermore, 9.9 g of sodium hydroxide in 80 ml of water and 29.2 ml of isopropyl chloroformate in 50 ml of acetone have a pH of 9.5.
The two solutions are prepared simultaneously by adding dropwise so that the temperature remains between 9.7 and 25°C. The mixture is stirred at room temperature for 2 hours. Final
PH9.6. The acetone was evaporated, the aqueous solution was extracted with 50 ml of ether and acidified with hydrochloric acid (1:1), and the acylated product was collected in a total volume of 250 ml.
Extract with 3 portions of ethyl acetate. The purified extract is dried and ethyl acetate is evaporated as much as possible. The residue is taken up in chloroform, dissolved by heating, and the mixture is evaporated to remove as much ethyl acetate as possible. The residue is taken up in 150 ml of chloroform, heated again and 60 ml of hexane is added to complete the crystallization. The product exhibits an mp of 163-164°C after drying.
(2) äžèšå®æœäŸïœïŒïŒã®æ¹æ³ããã¢ã»ãã³ã®èž
çºãŸã§ç¹°è¿ããçæ溶液ãéãã40mlã®æ¿
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ã滎å®ããã³IRã§ç¢ºèªããã (2) Repeat the method of Example a) 1 above until the acetone evaporates. The resulting solution is filtered, mixed with 40 ml of concentrated ammonia or an equivalent amount of sodium hydroxide, and kept at room temperature for 1-2 hours. The mixture was then acidified with hydrochloric acid (1:1) to pH 1.5 while cooling and stirring at low speed.
~2 and sow when cloudy in appearance. Continue stirring until crystallization is complete. Confirm the product by titration and IR.
(3) 500ïœã®ïŒ€âïŒâïŒâïŒâããããã·ããš
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ããã (3) Suspend 500 g of D-(-)-4-hydroxyphenylglycine in 4 of water, cool the suspension to 2-5°C, and
G of sodium hydroxide solution is slowly added dropwise. Maintain temperature at 5°C or below. Then add 900 ml of isopropyl chloroformate. Again, maintain a temperature of 5°C. The mixture is stirred for 1 hour with ice cooling and then 780 ml of 10N NaOH are added.
After 30 minutes at 20°C, the mixture is filtered and acidified with sulfuric acid until the liquid becomes cloudy. After 5-10 minutes of crystallization time, add more sulfuric acid with stirring,
Let it reach a pH of 2.0. The mixture is stirred with ice cooling for 15-30 minutes to complete crystallization. The mixture was washed with water and then first heated to 50°C.
Then, dry in a dryer with a vacuum drying shelf at 80 to 90°C. The title compound thus obtained is pure according to TLC, exhibiting a melting point of 162-164°C and a specific rotation of [α] 20 D = -155° (c = 1, in methanol). has.
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ç¹134ã137âãb D-(-)-N-methoxycarbonyl-4-
Hydroxyphenylglycine 40g of D-(-)-4-hydroxyphenylglycine in 320ml of water is mixed with 9.6g of D-(-)-4-hydroxyphenylglycine in 80ml of water.
Mix with a solution of NaOH. To this is added a mixture of 9.6 g NaOH in 80 ml water and 19.8 ml methyl chloroformate in 40 ml acetone dropwise with water cooling to maintain a pH of 9.5-9.8. Additionally, 35 ml of 3N-NaOH are required. 2 at room temperature
After stirring for an hour, the final pH is 9.5. The acetone is evaporated, the mixture is filtered and the aqueous layer is acidified with hydrochloric acid (1:1) and extracted with ethyl acetate.
The mixture is evaporated and the residue is recrystallized from chloroform/hexane to give the pure title compound. Melting point 134-137â.
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žãšãã«ããïŒãc D-(-)-N-isopropoxycarbonyl-phenylglycine 113.1g of D-(-)-phenylglycine 1
of water and adjust the pH to 10.2-10.4 by adding 50% NaOH with cooling (cold water) and stirring. Add 225ml of isopropyl chloroformate and 50% sodium hydroxide at the same time and adjust the above pH.
maintain. The reaction mixture is then made alkaline to a pH of 12-13 and stirred at this pH for 40 minutes. In practice, a clear solution is acidified with concentrated hydrochloric acid while cooling until it becomes cloudy. The mixture begins to seed and crystallize, and after 20 minutes the PH further drops to 2.0. 30
After a crystallization time of 1 min, filter the mixture and remove 100 ml of the residue.
of water five times and dried on silica gel in a dryer with a vacuum drying shelf at 50-60°C. After rubbing, it is further dried at 60-70°C for 16-17 hours. M.p116ïœ120
°C (from ethyl acetate).
å
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ã®æ¹æ³ã§åŸãŠãããã Other compounds of formula [ ] used in the previous examples may be obtained in analogous manner to those described in Examples a) to c) above.
âïŒâïŒâïŒâããããã·ããšãã«ã°ãªã·ã«
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ãαã20 DïŒâ95ãïŒïœïŒïŒïŒ1NâHClïŒã Characteristics of D-(-)-4-hydroxyphenylglycyl chloride hydrochloride (dioxane semi-solvated product): [α] 20 D = -95° (c = 1,1N-HCl).
溶åªéïŒgcïŒïŒãžãªããµã³16ïŒ ïŒCH2Cl20.2ïŒ ãSolvent amount (gc) = dioxane 16%, CH 2 Cl 2 0.2%.
IRããŒã¯cm-1ïŒ3280ïŒïœïŒïŒ1770ïŒïœïŒïŒ1735ïŒïœïŒïŒ
1210ïŒïœïŒïŒ1170ïŒïœïŒïŒ865ïŒïœïŒãIR peak cm -1 : 3280 (s), 1770 (s), 1735 (s),
1210(s), 1170(s), 865(s).
é溶åªåç©çµæ¶ã®ïŒ€âïŒâïŒâããããã·ããš
ãã«ã°ãªã·ã«ã¯ãã©ã€ãâå¡©é
žå¡©ã®ç¹æ§è¡šç€ºïŒ
ãαã20 DïŒâ112ïŒïœïŒïŒïŒ1NâHClïŒã Characteristics of unsolvated crystalline D-(-)-hydroxyphenylglycyl chloride-hydrochloride: [α] 20 D = -112 (c = 1, 1N-HCl).
溶åªéïŒgcïŒïŒé ¢é žããã«0.5ïŒ ïŒCH2Cl20.2ïŒ ãSolvent amount (gc) = butyl acetate 0.5%, CH 2 Cl 2 0.2%.
IRããŒã¯cm-1ïŒ3000ïŒBrïŒïŒ1735ïŒïœïŒïŒ1170ïŒïœïŒïŒ
830ãIR peak cm -1 = 3000 (Br), 1735 (s), 1170 (s),
830.
M.pã¯å解ã®ãã枬å®äžå¯èœã M.p cannot be measured due to decomposition.
Claims (1)
éãŸãã¯åæç¶äœçŽã¢ã«ãã«ãŸãã¯ãã³ãžã«ã§ã
ããã ã®ååç©ãããªãã«ã¯ãã©ã€ããšåå¿ããããã
ãŠçæç©ãå¡©åæ°ŽçŽ ã¬ã¹ãšåå¿ãããããšããæ
ãåŒ ãåŒäžãã¯åèšãšåæ矩ãã ã®ååç©ã®è£œé æ³ã ïŒ ããªãã«ã¯ãã©ã€ããšã®åå¿ãåŒ·é žã®ååšäž
ã«å®æœããäžèšç¬¬ïŒé ã®æ¹æ³ã ïŒ åŒ·é žãããªã¯ããé ¢é žãããªãã«ãªãé ¢é žã
ïœâãã«ãšã³ã¹ã«ãã³é žãŸãã¯ã¡ã¿ã³ã¹ã«ãã³é ž
ã§ããäžèšç¬¬ïŒé ã®æ¹æ³ã ïŒ å¡©åæ°ŽçŽ ã¬ã¹ãšã®åå¿ãäžæŽ»æ§ãžãªããµã³å«
æ溶åªåç©äžã§å®æœããŠããžãªããµã³å溶åªåç©
ã®åœ¢æ ã§çæç©ãåŸãäžèšç¬¬ïŒé ã第ïŒé ã®ãã
ããäžã®æ¹æ³ã ïŒ ïŒ€âïŒâïŒâïŒâããããã·ããšãã«ã°ãªã·
ã«ã¯ãã©ã€ãå¡©é žå¡©ãžãªããµã³å溶åªåç©ã®è£œé
ã®ããã®äžèšç¬¬ïŒé ã®æ¹æ³ã ïŒ å¡©åæ°ŽçŽ ã¬ã¹ãšã®åå¿ããžãªããµã³ãå«æã
ãªãäžæŽ»æ§æº¶åªäžã§å®æœããŠã溶åªåç©ã®ãªã圢
æ ã§çæç©ãåŸãäžèšç¬¬ïŒé ã第ïŒé ã®ãããã
äžã®æ¹æ³ã ïŒ äžæŽ»æ§æº¶åªããžã¢ã«ãã«ãšãŒãã«ãããã©ã
ãããã©ã³ãã¢ããœãŒã«ãè³éŠæçåæ°ŽçŽ ããšã¹
ãã«ãŸãã¯å¡©çŽ åçåæ°ŽçŽ ããæãäžèšç¬¬ïŒé ã®
æ¹æ³ã ïŒ æº¶åªåç©ã®ãªãâïŒâïŒâïŒâããããã·
ããšãã«ã°ãªã·ã«ã¯ãã©ã€ãå¡©é žå¡©ã®è£œé ã®ãã
ã®äžèšç¬¬ïŒé ãŸãã¯ç¬¬ïŒé ã®æ¹æ³ã[Claims] 1 formula [In the formula, R is hydrogen or hydroxy, and R 1 is linear or branched lower alkyl or benzyl. ] consisting of reacting the compound with thionyl chloride and reacting the product with hydrogen chloride gas [In the formula, R has the same meaning as above. ] Method for producing the compound. 2. The method of item 1 above, wherein the reaction with thionyl chloride is carried out in the presence of a strong acid. 3 Strong acids include trichloroacetic acid, trifluoroacetic acid,
The method according to the above item 2, which is p-toluenesulfonic acid or methanesulfonic acid. 4. The method according to any one of items 1 to 3 above, wherein the reaction with hydrogen chloride gas is carried out in an inert dioxane-containing solvate to obtain the product in the form of a dioxane hemi-solvate. 5. The method of item 4 above for producing D-(-)-4-hydroxyphenylglycyl chloride hydrochloride dioxane hemisolvate. 6. The method according to any one of paragraphs 1 to 3 above, wherein the reaction with hydrogen chloride gas is carried out in an inert solvent that does not contain dioxane to obtain the product in a solvate-free form. 7. The method of item 6 above, wherein the inert solvent comprises a dialkyl ether, tetrahydrofuran, anisole, aromatic hydrocarbon, ester or chlorinated hydrocarbon. 8. The method of item 6 or 7 above for the production of solvate-free D-(-)-4-hydroxyphenylglycyl chloride hydrochloride.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT308979A ATA308979A (en) | 1979-04-25 | 1979-04-25 | METHOD FOR PRODUCING (D) -PHENYLGLYCYLCHLORIDE HYDROCHLORYD DERIVATIVES |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS55145646A JPS55145646A (en) | 1980-11-13 |
JPS643182B2 true JPS643182B2 (en) | 1989-01-19 |
Family
ID=3545153
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5528280A Granted JPS55145646A (en) | 1979-04-25 | 1980-04-24 | Manufacture of penicilins |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS55145646A (en) |
AT (1) | ATA308979A (en) |
ZA (1) | ZA802523B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR780000197B1 (en) * | 1972-12-26 | 1978-05-26 | Bristol Myers Co | Method for preparing antibacterial agent |
-
1979
- 1979-04-25 AT AT308979A patent/ATA308979A/en not_active Application Discontinuation
-
1980
- 1980-04-24 JP JP5528280A patent/JPS55145646A/en active Granted
- 1980-04-25 ZA ZA00802523A patent/ZA802523B/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA802523B (en) | 1981-12-30 |
JPS55145646A (en) | 1980-11-13 |
ATA308979A (en) | 1982-01-15 |
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