CN1479730A - 氨基噻唑衍生物的无水物的制备方法 - Google Patents
氨基噻唑衍生物的无水物的制备方法 Download PDFInfo
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- thiazolamine
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- 150000008064 anhydrides Chemical class 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 title description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000013078 crystal Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- -1 amino cepham compound Chemical class 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- OXSKAHWTPGWWRZ-UHFFFAOYSA-N 2-iminoacetyl chloride hydrochloride Chemical compound Cl.N=CC(=O)Cl OXSKAHWTPGWWRZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 229950003476 aminothiazole Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 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 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- VKFHPXSFQRCNQW-UHFFFAOYSA-N 4-chloro-2-(2-methoxy-2-oxoethoxy)imino-3-oxobutanoic acid Chemical compound COC(=O)CON=C(C(O)=O)C(=O)CCl VKFHPXSFQRCNQW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
提供2－(2－氨基噻唑－4－基)－2－羟基化合物的无水物的新型工业制备方法。
Description
本发明涉及2-(2-氨基噻唑-4-基)-2-羟基化合物的无水物的制备方法。更详细地说，本发明涉及由下述通式表示的2-(2-氨基噻唑-4-基)-2-羟基化合物的水合物高收率地制备无水物的新型制备方法。
(式中，R1表示酰基、被保护的羧基(低级)烷基或烷基。)
氨基噻唑衍生物通常具有1分子或2分子的结晶水。为了合成氨基噻唑衍生物的酰氯，需要有效除去作为阻碍的结晶水。
也就是说，本发明的目的在于提供2-(2-氨基噻唑-4-基)-2-羟基化合物的无水物的新型工业制备方法。
以前，使用2-(2-氨基噻唑-4-基)-2-羟基化合物(I)的水合物合成酰氯，对于仅1或2分子结晶水的当量数，有必要大量使用卤化剂，通常使用约3当量。但是，按照本发明，通过除去化合物(I)的结晶水制成无水物，可以将卤化剂的用量降低至约1～1.2当量。通过这种卤化剂的减量，可以减轻环境负荷。
本发明的发明人等悉心研究了2-(2-氨基噻唑-4-基)-2-羟基化合物的工业制备方法，结果成功地完成了能够由2-(2-氨基噻唑-4-基)-2-羟基化合物的含结晶水的晶体容易地除去结晶水的新型制备方法。
通过本发明的制备方法得到的2-(2-氨基噻唑-4-基)-2-羟基化合物(I)的无水物对于与五氯化磷等卤化剂反应，形成酰氯·盐酸盐(A)，与7-氨基头孢化合物反应，得到抑制包括革兰氏阳性菌和革兰氏阴性菌在内的广泛病原菌的繁殖的抗菌药有用。
以下详细叙述本说明书中上述记载的R1的优选实例和说明。
作为优选的“酰基”，可以例举脂肪族酰基以及含有芳香族环或杂环的酰基。作为这些酰基的优选实例，可以例举甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、草酰基、琥珀酰基、新戊酰基等低级烷酰基；
甲氧基羰基、1-环丙基乙氧基羰基、异丙氧基羰基、丁氧基羰基、叔丁氧基羰基、戊氧基羰基、己氧基羰基等低级烷氧基羰基；
甲磺酰基、乙磺酰基、丙磺酰基、1-甲基乙磺酰基、丁磺酰基等低级烷烃磺酰基；
苯磺酰基、甲苯磺酰基等芳烃磺酰基；
苯甲酰基、甲苯甲酰基、二甲苯酰基、萘酰基、邻苯二甲酰基、二氢化茚羰基等芳酰基；
苯基乙酰基、苯基丙酰基等芳基(低级)烷氧基羰基等。
上述酰基部分也可以具有至少1个氯、溴、氟和碘的卤素等适当的取代基。
作为优选的“被保护的羧基(低级)烷基”，可以例举酯化的羧基(低级)烷基，更优选甲氧基羰基甲基、叔丁氧基羰基乙基等低级烷氧基羰基(低级)烷基，二苯甲氧基羰基甲基等单或二或三苯基(低级)烷氧基羰基(低级)烷基，氯甲氧基羰基甲基、2-碘乙氧基羰基甲基等单或二或三氯(低级)烷氧基羰基(低级)烷基等。
作为优选的“烷基”，可以例举甲基、乙基等。
以下详细说明本发明的目的化合物(I)的制备方法。制备方法1
在丙酮、甲乙酮、甲基异丁基酮等酮溶剂中或乙腈中，加热回流或悬浊化合物(I)的晶体后，过滤晶体，减压干燥，可以得到不含结晶水的晶体。以下，通过制备例和实施例说明本发明。
制备例1-(1)
在乙醇(216ml)中悬浊2-(2-氨基噻唑-4-基)-2-羟基亚氨基乙酸乙酯(顺式异构体)(24.0g)，在搅拌条件下，在45℃用1小时滴加1N氢氧化钠水溶液(125ml)。滴加结束后，在相同温度下搅拌2小时。将反应混合物冷却至5℃，搅拌1小时。过滤收集沉淀物，用乙醇洗涤后，真空干燥，得到2-(2-氨基噻唑-4-基)-2-羟基亚氨基乙酸钠·2水合物(顺式异构体)(24.6g)。mp：130-131℃(分解)IR(液体石蜡(Nujol))：3520，3300，1600，1530cm-1NMR(DMSO-d6，δ)：6.97(2H，br s)，7.33(1H，s)制备例1-(2)
将2-(2-氨基噻唑-4-基)-2-羟基亚氨基乙酸钠·2水合物(顺式异构体)(24.6g)加入到水(160ml)中，在20-30℃下搅拌。用60分钟滴加醋酸酐(28.7g)。滴加过程中，使用20％碳酸钠水溶液，将pH控制在6.0±0.2。滴加结束后，搅拌30分钟，然后用6N盐酸将pH调节为2.5。将反应液冷却至5℃后，过滤析出的晶体，依次用异丙醇和丙酮洗涤。减压干燥得到的湿晶体，得到含有2分子结晶水的2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酸(顺式异构体)(2 3.9g)。IR(液体石蜡)：3400，3100，1760，1630cm-1NMR(DMSO-d6，δ)：2.16(3H，s)，7.21(1H，s)水分：14％
实施例1
将2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酸·2水合物(顺式异构体)(20.0g)悬浊于丙酮(200ml)中，搅拌，在55-56℃下加热回流1小时。冷却至5℃后，过滤晶体，用丙酮洗涤后，减压干燥，得到2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酸·无水晶体(16.4g)。IR(液体石蜡)：3400，3100，1750，1600cm-1NMR(DMSO-d6，δ)：2.16(3H，s)，7.21(1H，s)水分：0.5％粉末X射线衍射(峰角度：2θ)：具有在2θ＝14.7°附近、16.0°附近、19.0°附近、19.5°附近、20.5°附近、21.4°附近、24.5°附近、25.5°附近、25.8°附近、27.2°附近、30.2°附近具有衍射峰，并在8.9°附近、14.3°附近、15.3°附近、17.2°附近、18.4°附近、19.6°附近、21.0°附近、22.3°附近、24.3°附近、26.7°附近、27.5°附近、28.5°附近、29.0°附近不具有衍射峰的X射线衍射图像。制备例2
在水(400ml)中加入4-氯-2-(甲氧基羰基甲氧基亚氨基)-3-氧代丁酸(200g)，在5℃下悬浊，搅拌。使用碳酸氢钠(71.2g)，溶解晶体。加入硫脲(70.5g)，30℃下使用氨水溶液使pH保持在5.5，同时反应60分钟。使用稀释盐酸将pH调节为2后，冷却至5℃，搅拌30分钟。过滤收集析出的晶体，用冷水洗涤。在减压条件下干燥，得到2-(2-氨基噻唑-4-基)-2-甲氧基羰基甲氧基亚氨基乙酸·1水合物(顺式异构体)(225.2g)(收率96.5％)。IR(液体石蜡)：3400，1770，1740，1660，1610cm-1NMR(DMSO-d6，δ)：3.68(3H，s)，4.72(2H，s)，6.87(1H，s)，7.26(2H，s)KF法(水分)：6.7％
实施例2
在丙酮(100ml)中，悬浊2-(2-氨基噻唑-4-基)-2-甲氧基羰基甲氧基亚氨基乙酸·1水合物(顺式异构体)(10.0g)，搅拌，加热回流120分钟。过滤收集析出的晶体后，减压干燥，得到2-(2-氨基噻唑-4-基)-2-甲氧基羰基甲氧基亚氨基乙酸·无水物(顺式异构体)(9.0g)(收率96％)。IR(液体石蜡)：3350，1760，1740，1655cm-1NMR(DMSO-d6，δ)：3.68(3H，s)，4.72(2H，s)，6.87(1H，s)，7.26(2H，s)KF法(水分)：0.5％
接着，通过以下的参考例，以高收率得到最终产物。参考例1-(1)
将2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酸·无水晶体(顺式异构体)(12.5g)悬浊于二氯甲烷(125ml)中并搅拌，冷却至-20～-25℃。加入五氯化磷(13.6g)，在相同温度下反应15小时。过滤析出的晶体，用二氯甲烷洗涤后，减压干燥，得到2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酰氯·盐酸盐(顺式异构体)(14.6g)。mp：128-130℃(分解)IR(液体石蜡)：3300，1800，1780，1640，1590cm-1参考例1-(2)
将7-氨基-3-乙烯基-3-头孢烯-4-甲酸(4.52g)和1，3-二(三甲基甲硅烷基)脲(10.2g)悬浊于乙酸乙酯(80ml)中，加热回流120分钟，进行甲硅烷基化，使之溶解。将反应液冷却至-20℃，加入2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酰氯盐酸盐(顺式异构体)(6.25g)，使之反应30分钟。在反应液中加入冷水(90ml)，接着过滤收集生成的沉淀，用冷水洗涤后，减压干燥，得到7-〔2-氨基噻唑-4-基〕-2-乙酰氧基亚氨基乙酰氨基〕-3-乙烯基-3-头孢烯-4-甲酸(顺式异构体)(8.32g)(收率95％)。IR(液体石蜡)：3250，1770，1750，1705，1650，1590，1540cm-1NMR(DMSO-d6，δ)：2.33(3H，s)，3.60，3.87(2H，Abq，J＝18Hz)，5.23(1H，d，J＝10Hz)，5.60(1H，d，J＝17Hz)，58.2((1H，dd，J＝8Hz，J＝5Hz)，6.92(1H，dd，J＝10Hz，J＝17Hz)，7.17(1H，s)，9.97(1H，d，J＝8Hz)参考例1-(3)
将7-〔2-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酰氨基〕-3-乙烯基-3-头孢烯-4-甲酸(顺式异构体)(1.3g)悬浊于水(13ml)中，在5℃下搅拌。用碳酸钠水溶液溶解晶体，加入氯化铵(670mg)，使用碳酸钠水溶液将pH调节为8.5，维持相同温度、相同pH，反应60分钟。使用稀释盐酸将pH调节为2.5，过滤收集生成的沉淀，用冷水洗涤，接着在减压条件下干燥，得到7-〔2-(2-氨基噻唑-4-基)-羟基亚氨基乙酰氨基〕-3-乙烯基-3-头孢烯-4-甲酸(顺式异构体)(1.12g)(收率95％)。IR(液体石蜡)：3300，1780，1660，1605cm-1NMR(DMSO-d6，δ)：3.53，3.80(2H，Ab q，J＝18Hz)，5.17(1H，d，J＝5Hz)，5.28(1H，D，J＝10Hz)，5.57(1H，d，J＝17Hz)，5.75(1H，dd，J＝17Hz，J＝10Hz)，7.07(2H，br s)，9.42(1H，d，J＝8Hz)，11.25(1H，br s)
Claims (2)
1.式(I)的无水物的制备方法，其特征在于，在酮溶剂中、在乙腈中处理式(I)表示的2-(2-氨基噻唑-4-基)-2-羟基化合物的水合物，式中，R1表示酰基、被保护的羧基(低级)烷基或烷基。
2.式(I)表示的2-(2-氨基噻唑-4-基)-2-羟基化合物的无水物，式中，R1表示酰基、被保护的羧基(低级)烷基或烷基。
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| WO2004016623A1 (en) * | 2002-08-13 | 2004-02-26 | Sandoz Ag | A cefdinir intermediate |
| WO2004046154A1 (en) * | 2002-11-15 | 2004-06-03 | Orchid Chemicals & Pharmaceuticals Ltd | Novel amorphous hydrate of a cephalosporin antibiotic |
| AU2004224045A1 (en) * | 2003-03-24 | 2004-10-07 | Sandoz Ag | Novel crystal of 7-[2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetamido-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) and method for preparation thereof |
| US7105659B2 (en) * | 2003-06-02 | 2006-09-12 | Aurobind - Pharma Ltd. | Process for preparing cefdinir |
| US20050137182A1 (en) * | 2003-06-02 | 2005-06-23 | Ramesh Dandala | Novel crystalline form of cefdinir |
| US20040242556A1 (en) * | 2003-06-02 | 2004-12-02 | Ramesh Dandala | Novel crystalline form of cefdinir |
| US20050059818A1 (en) * | 2003-09-12 | 2005-03-17 | Duerst Richard W. | Polymorph of a pharmaceutical |
| US20050209211A1 (en) * | 2004-03-16 | 2005-09-22 | Devalina Law | Trihemihydrate, anhydrate and novel hydrate forms of Cefdinir |
| US20060069079A1 (en) * | 2004-09-27 | 2006-03-30 | Sever Nancy E | Stable amorphous cefdinir |
| US20050245738A1 (en) * | 2004-05-03 | 2005-11-03 | Lupin Ltd | Stable bioavailable crystalline form or cefdinir and a process for the preparation thereof |
| GB0416379D0 (en) * | 2004-07-22 | 2004-08-25 | Sandoz Ag | Organic compounds |
| US20070128268A1 (en) * | 2005-12-07 | 2007-06-07 | Herwig Jennewein | Pharmaceutical compositions comprising an antibiotic |
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| US1961542A (en) * | 1929-08-09 | 1934-06-05 | Bataafsche Petroleum | Process for the manufacture of acetic anhydride |
| US4426528A (en) | 1982-04-01 | 1984-01-17 | Eli Lilly And Company | Purification of syn-(2-aminothiazol-4-yl)methoxyimino)acetic acid |
| DE3419015A1 (de) | 1984-05-22 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von cephalosporinen |
| JPH0253782A (ja) | 1988-08-12 | 1990-02-22 | Sankyo Co Ltd | ホルミルアミノチアゾール酢酸誘導体の製法 |
| AU2394302A (en) * | 2000-12-04 | 2002-06-18 | Pfizer Prod Inc | Coupling process and intermediates useful for preparing cephalosphorins |
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| EP1340751A1 (en) | 2003-09-03 |
| KR20030051895A (ko) | 2003-06-25 |
| US20040034233A1 (en) | 2004-02-19 |
| JP4192599B2 (ja) | 2008-12-10 |
| EP1340751A4 (en) | 2005-07-27 |
| CN1232512C (zh) | 2005-12-21 |
| WO2002046175A1 (fr) | 2002-06-13 |
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