KR100531668B1 - 4-Hydroxyphenylglycine derivatives and processes for the preparation thereof - Google Patents
4-Hydroxyphenylglycine derivatives and processes for the preparation thereof Download PDFInfo
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- KR100531668B1 KR100531668B1 KR10-2003-0076354A KR20030076354A KR100531668B1 KR 100531668 B1 KR100531668 B1 KR 100531668B1 KR 20030076354 A KR20030076354 A KR 20030076354A KR 100531668 B1 KR100531668 B1 KR 100531668B1
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- hydroxyphenylglycine
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- 238000000034 method Methods 0.000 title claims abstract description 16
- LJCWONGJFPCTTL-ZETCQYMHSA-N L-4-hydroxyphenylglycine Chemical class OC(=O)[C@@H](N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-ZETCQYMHSA-N 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 11
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- -1 n-tributylamine Chemical compound 0.000 claims description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical group 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229930186147 Cephalosporin Natural products 0.000 abstract description 9
- 229940124587 cephalosporin Drugs 0.000 abstract description 9
- 150000001780 cephalosporins Chemical class 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940124588 oral cephalosporin Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- 125000001950 (p-hydroxyphenyl)glycinamido group Chemical group 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- AUKCYOUETBBMFV-UHFFFAOYSA-N 3-trimethylsilyl-1,3-oxazolidin-2-one Chemical compound C[Si](C)(C)N1CCOC1=O AUKCYOUETBBMFV-UHFFFAOYSA-N 0.000 description 1
- NVIAYEIXYQCDAN-UHFFFAOYSA-N 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)C(N)C12 NVIAYEIXYQCDAN-UHFFFAOYSA-N 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- IQZXALHQIKIUHS-UHFFFAOYSA-N [2-amino-2-(4-hydroxyphenyl)acetyl] 2-amino-2-(4-hydroxyphenyl)acetate Chemical compound OC1=CC=C(C(N)C(=O)OC(C(N)C2=CC=C(C=C2)O)=O)C=C1 IQZXALHQIKIUHS-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229940053198 antiepileptics succinimide derivative Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- ACXMTAJLYQCRGF-PBFPGSCMSA-N cefatrizine Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC1=CN=N[N]1 ACXMTAJLYQCRGF-PBFPGSCMSA-N 0.000 description 1
- 229960002420 cefatrizine Drugs 0.000 description 1
- 229960002580 cefprozil Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5463—Compounds of the type "quasi-phosphonium", e.g. (C)a-P-(Y)b wherein a+b=4, b>=1 and Y=heteroatom, generally N or O
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
Abstract
본 발명은 세팔로스포린계 화합물의 제조용 중간체로서 유용한 하기 화학식 1의 4-히드록시페닐글리신 유도체 및 그의 제조방법을 제공한다:The present invention provides 4-hydroxyphenylglycine derivatives of the general formula (1) useful as intermediates for the preparation of cephalosporin-based compounds and methods for their preparation:
<화학식 1><Formula 1>
식 중, R은 아미노 보호기이다.In the formula, R is an amino protecting group.
Description
본 발명은 세팔로스포린계 화합물의 제조용 중간체로서 유용한 신규의 4-히드록시페닐글리신 유도체 및 그의 제조방법에 관한 것이다.The present invention relates to novel 4-hydroxyphenylglycine derivatives useful as intermediates for the preparation of cephalosporin-based compounds and methods for their preparation.
세프프로질, 세파트리진 및 세파드록실 등의 경구용 세팔로스포린계 항생제는 하기에 나타낸 바와 같이, 4-히드록시페닐글리신 기를 공통적으로 포함한다. Oral cephalosporin-based antibiotics such as cefprozil, cepatrizine, and cepadroxyl commonly include 4-hydroxyphenylglycine groups, as shown below.
상기에서, A가 -C=CH-CH3일 경우 세프프로질이며, A가 1H-1,2,3-트리아졸-4-일-티오메틸일 경우 세파트리진이고, A가 -CH3일 경우 세파드록실을 나타낸다.In the above, A is -C = CH-CH 3 is ceprozil, A is 1H-1,2,3-triazol-4-yl-thiomethyl, and is sephatrizin, A is -CH 3 In the case of cephadroxyl.
종래에 4-히드록시페닐글리신의 반응성 유도체를 3-세펨 화합물과 반응시켜 세프프로질, 세파트리진 및 세파드록실 등의 경구용 세팔로스포린계 항생제를 제조하는 다양한 방법이 알려져 있다.Conventionally, various methods for preparing oral cephalosporin-based antibiotics such as ceproprozil, cephatrizin, and cephadoxyl are known by reacting a reactive derivative of 4-hydroxyphenylglycine with a 3-cefem compound.
예를 들어, 미국특허 제3,985,741호는 4-히드록시페닐글리신과 에틸클로로포메이트를 N-메틸모포린과 반응시켜 무수물로 제조한 후 7-아미노-디아세톡시-세팔로스포란산(7-ADCA)과 반응시켜 세파드록실을 제조하는 방법을 개시한 바 있으나, 수율 및 품질이 떨어져 사용하기 어려운 문제점이 있다.For example, US Pat. No. 3,985,741 discloses anhydrous by reacting 4-hydroxyphenylglycine and ethylchloroformate with N-methylmorpholine to prepare 7-amino-diacetoxy-cephalosporanic acid (7 -ADCA) has been disclosed a method for producing a Sephadex siloxane, but has a problem in that the yield and quality are difficult to use.
미국특허 제4,520,022호, 제4,591,641호 및 제4,661,590호는 N,N'-디시클로헥실카보디이미드를 아미노기가 보호된 4-히드록시페닐글리신과 세펨화합물의 반응 축합제로 사용하는 것을 개시하고 있으나, 반응 후 생성되는 N,N'-디시클로헥실우레아를 제거하기 어려워 공업적으로 사용하기 어려운 문제점이 있다.U.S. Pat.Nos. 4,520,022, 4,591,641 and 4,661,590 disclose the use of N , N' -dicyclohexylcarbodiimide as a reaction condensation agent of 4-hydroxyphenylglycine and cefem compound protected with amino groups. N , N'- dicyclohexyl urea produced after the reaction is difficult to remove, there is a problem difficult to use industrially.
미국특허 제4,336,376호는 아미노기가 보호된 4-히드록시페닐글리신 염을 트리메틸실릴-2-옥사졸리디논과 반응시켜 4-히드록시기를 보호한 후 아실클로라이드와 다시 반응시켜 4-히드록시페닐글리신 무수물을 제조한 후 7-아미노-디아세톡시-세팔로스포란산(7-ADCA)과 반응시켜 세파드록실을 제조하는 방법을 개시하고 있으나 먼저 실릴화를 실시해야하는 점과 반응의 불편함 등으로 산업화에 적용하기 어려운 문제점이 있다.U.S. Patent No. 4,336,376 discloses a 4-hydroxyphenylglycine salt with an amino group protected by trimethylsilyl-2-oxazolidinone to protect the 4-hydroxy group and then reacted again with an acyl chloride to react 4-hydroxyphenylglycine anhydride. The present invention discloses a method for preparing cephadoxyl by reacting with 7-amino-diacetoxy-cephalosporranic acid (7-ADCA), but it has been industrialized due to the silylation and the inconvenience of reaction. There is a problem that is difficult to apply to.
미국특허 제4,708,825호는 아미노기가 치환된 4-히드로시페닐글리신을 티오닐클로라이드와 염화수소 가스를 이용하여 4-히드록시페닐글리실 클로라이드 염산염을 제조한 후 세펨화합물과 반응시키는 방법을 개시하고 있으나 티오닐클로라이드와 염화수소 가스의 취급상의 문제점으로 산업화에 적용하기에는 쉽지 않다.U.S. Patent No. 4,708,825 discloses a method for preparing 4-hydroxyphenylglycosyl chloride hydrochloride using an amino group-substituted 4-hydrocyphenylglycine using thionyl chloride and hydrogen chloride gas, followed by reaction with a cefem compound. Problems in handling of onyl chloride and hydrogen chloride gas are not easy to apply to industrialization.
미국특허 제3,925,418호, 제4,243,819호, 제4,464,307호 등은 4-히드록시페닐글리신을 제조하는 방법으로 과량의 포스겐을 사용하는 것을 개시하고 있으나 고독성인 포스겐의 취급, 반응 후 과량의 잔류 포스겐의 제거 및 반응조건 등의 작업상의 문제점으로 대량 생산에 적용하기에 어려움이 있다.U.S. Pat. And it is difficult to apply to mass production due to operational problems such as reaction conditions.
또한, 4-히드록시페닐글리신을 반응성 무수물로 제조하기 위한 방법으로 포스포러스 펜타클로라이드, 포스포러스 옥시클로라이드 및 티오닐 클로라이드 등을 이용한 산 염화물의 제조, 이미다졸, 머캅토벤조티아졸 및 히드록시 벤조트리아졸 등을 이용한 활성 에스테르의 제법 등이 개시된 바 있으나, 산 염화물의 경우 히드록시기의 영향에 의해 반응성이 떨어지며, 활성 에스테르의 경우에는 반응성이 떨어지며, 부반응이 일어나는 문제점이 있다. In addition, preparation of acid chlorides using phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, and the like as a method for preparing 4-hydroxyphenylglycine as a reactive anhydride, imidazole, mercaptobenzothiazole and hydroxy benzo Although the preparation of active esters using triazoles and the like have been disclosed, in the case of acid chlorides, the reactivity decreases under the influence of the hydroxyl group, and in the case of the active esters, the reactivity decreases and side reactions occur.
기타, 대한민국 특허공개 제2002-69431호, 제2002-69432호, 제2002-69437호, 제2002-69440호에서는 4-히드록시페닐글리신의 피발로일 또는 숙신이미드 유도체의 제조방법 및 이를 사용하여 세프프로질 등의 세펨 화합물을 제조하는 방법이 개시된 바 있다.In addition, Korean Patent Publication Nos. 2002-69431, 2002-69432, 2002-69437, and 2002-69440 disclose methods for preparing pivaloyl or succinimide derivatives of 4-hydroxyphenylglycine and the use thereof. There has been disclosed a method for producing a cefem compound such as cefeprozil.
본 발명은 상기 선행기술의 문제점을 해결하기 위한 것으로, 본 발명은 세팔로스포린계 항생제를 고수율 및 고순도로 간편히 제조할 수 있는 반응성 중간체 즉, 신규의 4-히드록시페닐글리신 유도체 및 그의 제조방법을 제공한다.The present invention is to solve the problems of the prior art, the present invention is a reactive intermediate that can easily prepare cephalosporin-based antibiotics in high yield and high purity, that is a novel 4-hydroxyphenylglycine derivative and a method for preparing the same To provide.
따라서, 본 발명은 세팔로스포린계 화합물의 제조용 중간체로서 유용한 신규의 4-히드록시페닐글리신 유도체를 제공하는 것을 목적으로 한다.It is therefore an object of the present invention to provide novel 4-hydroxyphenylglycine derivatives useful as intermediates for the preparation of cephalosporin compounds.
또한, 본 발명의 목적은 상기 화합물을 제조하는 방법을 제공하는 것을 포함한다.It is also an object of the present invention to provide a method for preparing the compound.
본 발명의 일 태양에 따라, 세프프로질, 세파드록실, 세파트리진 등의 4-히드록시페닐글리신 기를 갖는 세팔로스포린계 화합물의 제조용 중간체로서 유용한 화합물이 제공된다. 즉, 본 발명은 하기 화학식 1의 화합물을 제공한다:According to one aspect of the present invention, a compound useful as an intermediate for producing a cephalosporin-based compound having a 4-hydroxyphenylglycine group such as ceprozyl, cephadoxyl, cepatrizine, etc. That is, the present invention provides a compound of the formula:
식 중, R은 아미노 보호기이다.In the formula, R is an amino protecting group.
상기 본 발명의 화합물은 바람직하게는 무수물 형태이며, 무수물 형태의 화학식 1의 화합물은 최종적으로 세팔로스포린계 항생제를 제조하는데 유용하게 사용될 수 있다.The compound of the present invention is preferably in the anhydride form, the compound of formula (1) in the anhydride form can finally be usefully used to prepare cephalosporin-based antibiotics.
상기 아미노 보호기는 세팔로스포린계 항생제 제조시 통상적으로 사용될 수 있는 아미노 보호기를 포함하며, 예를 들어 포밀, 아세틸, 벤질, 벤질리덴, 디페닐메틸, 트리페닐메틸, 트리클로로에톡시카보닐, t-부톡시카보닐, 2-메톡시카보닐-1-메틸-비닐, 2-에톡시카보닐-1-메틸-비닐 등을 포함한다. 상기 본 발명에 따른 화합물 중, R은 2-에톡시카보닐-1-메틸-비닐인 화합물이 경제성, 취급성, 및 최종 생성물의 수율 등의 측면에서 더욱 바람직하며, 에틸 아세토아세테이트를 사용하여 2-에톡시카보닐-1-메틸-비닐 기를 도입할 수 있다.The amino protecting group includes an amino protecting group that can be commonly used in the preparation of cephalosporin-based antibiotics, for example formyl, acetyl, benzyl, benzylidene, diphenylmethyl, triphenylmethyl, trichloroethoxycarbonyl, t -Butoxycarbonyl, 2-methoxycarbonyl-1-methyl-vinyl, 2-ethoxycarbonyl-1-methyl-vinyl and the like. Among the compounds according to the present invention, R is 2-ethoxycarbonyl-1-methyl-vinyl compound, which is more preferable in terms of economic efficiency, handleability, yield of the final product, etc., using ethyl acetoacetate -Ethoxycarbonyl-1-methyl-vinyl groups can be introduced.
상기 본 발명에 따른 화학식 1의 화합물은 세팔로스포린계 화합물 합성시 사용되는 통상의 유기용매, 예를 들어 메틸렌클로라이드, 아세토니트릴등에 대한 용해도가 매우 우수하므로, 별도로 여과 및 건조 등의 분리공정을 거치지 않고 직접 반응용액상으로 다음 공정(예를 들어, 아실화 반응)을 수행할 수 있다.The compound of Chemical Formula 1 according to the present invention has excellent solubility in common organic solvents used in synthesizing cephalosporin-based compounds, for example, methylene chloride, acetonitrile, and the like. The next step (eg, acylation reaction) can be carried out directly in the reaction solution phase without.
본 발명의 다른 태양에 따라, 상기 화학식 1의 화합물을 제조하는 방법이 제공된다. 즉, 화학식 2의 화합물과 디클로로트리페닐포스포란을 염기 존재하에서 반응시키는 단계를 포함하는 화학식 1의 화합물의 제조방법이 제공된다:According to another aspect of the present invention, a method of preparing the compound of Formula 1 is provided. That is, there is provided a process for preparing a compound of formula 1 comprising reacting a compound of formula 2 with dichlorotriphenylphosphorane in the presence of a base:
<화학식 1><Formula 1>
식 중, R은 아미노 보호기이고, R1은 수소, 나트륨, 또는 포타슘이다.Wherein R is an amino protecting group, and R 1 is hydrogen, sodium, or potassium.
상기 화학식 2의 화합물은 4-히드록시페닐글리신에 통상의 아미노 보호 반응을 수행함으로써, 원하는 아미노 보호기(예를 들어, 상기에서 언급한 아미노 보호기)를 갖는 화합물로 제조할 수 있다.The compound of Formula 2 may be prepared as a compound having a desired amino protecting group (for example, the amino protecting group mentioned above) by performing a conventional amino protecting reaction on 4-hydroxyphenylglycine.
본 발명의 제조방법에 있어서, 디클로로트리페닐포스포란은 화학식 2의 화합물 1 당량에 대하여 1 ∼ 5 당량, 바람직하게는 1.1 ∼ 1.5 당량을 반응시키는 것이 바람직하다. 또한, 화학식 2의 화합물과 디클로로트리페닐포스포란과의 반응은 디클로로메탄, 아세토니트릴, 테트라하이드로퓨란, 및 이들의 혼합물로 이루어진 군으로부터 선택된 유기용매 중에서 반응시키는 것이 바람직하다. 또한, 상기 반응은 -30 ∼ 20 ℃, 바람직하게는 -5 ∼ 5℃의 반응온도에서 1 ∼ 5 시간, 바람직하게는 1 ∼ 2 시간 동안 수행할 수 있다.In the production method of the present invention, dichlorotriphenylphosphorane is preferably reacted with 1 to 5 equivalents, preferably 1.1 to 1.5 equivalents, relative to 1 equivalent of the compound of formula (2). In addition, the reaction of the compound of formula (2) with dichlorotriphenylphosphorane is preferably carried out in an organic solvent selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, and mixtures thereof. In addition, the reaction may be carried out for 1 to 5 hours, preferably 1 to 2 hours at a reaction temperature of -30 to 20 ℃, preferably -5 to 5 ℃.
본 발명의 제조방법에서 사용가능한 염기는 트리에틸아민, 디에틸아민, n-트리부틸아민, N,N-디메틸아닐린, 또는 피리딘을 포함하며, 이중 트리에틸아민이 바람직하게 사용될 수 있다. 염기의 사용량은 상기 화학식 2의 화합물 1당량에 대하여 약 1 ∼ 1.5 당량일 수 있으며, 1.1 ∼ 1.3 당량이 더욱 바람직하다.Bases that can be used in the production method of the present invention include triethylamine, diethylamine, n-tributylamine, N, N-dimethylaniline, or pyridine, of which triethylamine can be preferably used. The base may be used in an amount of about 1 to 1.5 equivalents, more preferably 1.1 to 1.3 equivalents, based on 1 equivalent of the compound of Formula 2.
상기 디클로로트리페닐포스포란은 트리페닐포스핀과 헥사클로로에탄을 반응시켜 얻어질 수 있으며, 이를 반응식으로 나타내면 다음 반응식 1과 같다.The dichlorotriphenylphosphorane may be obtained by reacting triphenylphosphine and hexachloroethane, which is represented by the following Scheme 1.
상기 반응식 1에 따른 반응은 유기용매 중에서 약 -5 ∼ 5 ℃ (바람직하게는 약 0 ℃)에서 약 1 ∼ 3 시간 (바람직하게는 약 2시간) 동안 수행할 수 있다. 사용가능한 유기용매는 테트라하이드로퓨란, 디클로로메탄, 클로로포름, 사염화탄소, 디메틸포름아미드, 디메틸아세트아미드, 1,4-디옥산, 또는 아세토니트릴 등을 포함하며, 이 중 디클로로메탄 또는 디메틸아세트아미드가 바람직하게 사용될 수 있다.The reaction according to Scheme 1 may be performed at about −5 to 5 ° C. (preferably about 0 ° C.) in an organic solvent for about 1 to 3 hours (preferably about 2 hours). Organic solvents that can be used include tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylacetamide, 1,4-dioxane, acetonitrile and the like, of which dichloromethane or dimethylacetamide is preferable. Can be used.
상기 트리페닐포스핀과 헥사클로로에탄을 반응시키는 단계 및 화학식 2의 화합물과 디클로로트리페닐포스포란을 염기 존재하에서 반응시키는 단계는 별도의 분리공정 없이 동일 반응용기에서 수행되는 것(즉, 동일-반응용기 반응, one-pot reaction)이 바람직하다. 이를 반응식으로 나타내면 반응식 2와 같다.The step of reacting the triphenylphosphine and hexachloroethane and the step of reacting the compound of formula (2) with dichlorotriphenylphosphorane in the presence of a base is carried out in the same reaction vessel without a separate separation step (ie, the same-reaction A one-pot reaction is preferred. If this is represented by the reaction scheme shown in Scheme 2.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이들 실시예는 본 발명을 예시하기 위한 것으로 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are intended to illustrate the invention and do not limit the scope of the invention.
실시예 1. (2-에톡시카보닐-1-메틸-비닐아미노)-(4-히드록시페닐)-아실옥시포스포니움 클로라이드의 제조Example 1 Preparation of (2-Ethoxycarbonyl-1-methyl-vinylamino)-(4-hydroxyphenyl) -acyloxyphosphonium chloride
단계 AStep A
트리페닐포스핀 9.9g (0.038mol)과 헥사클로로에탄 8.8g (0.038mol)을 메틸렌클로라이드 100ml에 차례로 투입하고 0 ℃에서 2시간 동안 반응시킨 후, 반응온도를 -5 ℃로 냉각하고 포타슘 (2-에톡시카보닐-1-메틸-비닐아미노)-(4-히드록시페닐)-아세테이트 10g (0.031mol) 및 트리에틸아민 8g을 차례로 투입하고 2시간 동안 교반하였다. 9.9 g (0.038 mol) of triphenylphosphine and 8.8 g (0.038 mol) of hexachloroethane were sequentially added to 100 ml of methylene chloride and reacted at 0 ° C. for 2 hours. The reaction temperature was cooled to −5 ° C. and potassium (2 10 g (0.031 mol) of -ethoxycarbonyl-1-methyl-vinylamino)-(4-hydroxyphenyl) -acetate and 8 g of triethylamine were sequentially added and stirred for 2 hours.
단계 BStep B
단계 A에서 석출된 결정을 여과하여 메틸렌클로라이드 20ml로 세척한 후, 얻어진 여과액을 감압증류하여 용매를 제거한 다음, 석출된 결정을 여과하고 진공건조하여 백색의 표제화합물 17.5g (96.7%)을 수득하였다.The precipitated crystals were filtered off and washed with 20 ml of methylene chloride, and the obtained filtrate was distilled under reduced pressure to remove the solvent. The precipitated crystals were filtered and dried in vacuo to yield 17.5 g (96.7%) of the white title compound. It was.
H-NMR(δ, CHCl3-d1) 1.31(3H, d, 8.6Hz, -OCH2 CH 3 ), 1.75(1H, m, -NHCHCHCO-), 4.23(2H, m, -OCH 2 CH3), 4.51(1H, d, 8.3Hz, -NHCHCHCO-), 4.81(1H, d, 8.0Hz, -NHCH(Ph)CO-), 6.63(2H, d, 8.0Hz), 6.91(2H, d, 8.1Hz), 7.31(6H, m), 7.65(9H, m)H-NMR (δ, CHCl 3 -d 1 ) 1.31 (3H, d, 8.6 Hz, -OCH 2 CH 3 ), 1.75 (1H, m, -NH CH CHCO-), 4.23 (2H, m, -O CH 2 CH 3 ), 4.51 (1H, d, 8.3 Hz, -NHCH CH CO-), 4.81 (1H, d, 8.0 Hz, -NH CH (Ph) CO-), 6.63 (2H, d, 8.0 Hz), 6.91 (2H, d, 8.1 Hz), 7.31 (6H, m), 7.65 (9H, m)
실시예 2. 7-[2-아미노-2-(4-히드록시페닐)아세트아미도]-3-[프로펜-1-일]-3-세펨-4-카르복실산(세프프로질)의 제조Example 2. 7- [2-Amino-2- (4-hydroxyphenyl) acetamido] -3- [propen-1-yl] -3-cepem-4-carboxylic acid (sephprozyl) Manufacture
실시예 1의 단계 A에서 얻어진 반응액을 -40 ℃로 냉각하고, 7-아미노-3-[프로펜-1-일]-3-세펨-4-카르복실산 6.88g (0.029mol)을 메틸렌클로라이드 40ml, 물 10ml와 트리에틸아민 6.5g에 용해시킨 용액을 상기 -40 ℃로 냉각된 용액에 천천히 1시간 동안 적가하였다. The reaction solution obtained in step A of Example 1 was cooled to −40 ° C., and 6.88 g (0.029 mol) of 7-amino-3- [propen-1-yl] -3-cefe-4-carboxylic acid was added to methylene. A solution dissolved in 40 ml of chloride, 10 ml of water and 6.5 g of triethylamine was slowly added dropwise to the solution cooled to −40 ° C. for 1 hour.
적가가 완료된 후, 같은 온도에서 2시간 동안 반응시킨 후 반응액의 온도를 0 ℃로 조절하고 생성된 불용성 고체를 여과하였다. 여액을 반응기로 이송하여 6N HCl 20ml를 가한 후 1시간 교반하였다. 반응액에 10% NaOH를 가하여 pH를 3.2로 조절하여 2시간 동안 0 ℃에서 교반한 후 여과하여 백색의 표제화합물 9.6g(83%)을 수득하였다.After the dropwise addition was completed, the reaction was carried out at the same temperature for 2 hours, and then the temperature of the reaction solution was adjusted to 0 ° C. and the resulting insoluble solid was filtered. The filtrate was transferred to the reactor and 20 ml of 6N HCl was added thereto, followed by stirring for 1 hour. 10% NaOH was added to the reaction solution, the pH was adjusted to 3.2, and the mixture was stirred at 0 ° C. for 2 hours, followed by filtration to obtain 9.6 g (83%) of the white title compound.
H-NMR(δ, D2O-d2) : 1.65(3H, d, 8.6Hz, -CH=CHCH 3 ( cis)), 1.81(0.21H, d, 8.6Hz, -CH=CHCH 3 (trans)), 3.22(1H, d, 18Hz, 2-H), 3.55(1H. d. 18Hz, 2-H), 5.15(1H, d, 4.6Hz, 6-H), 5.66(1H, d, 4.6Hz, 7-H), 5.75(1H, m, vinyl-H), 5.96(1H, m, vinyl-H), 6.91(2H, d, 8.0Hz, phenyl-H), 7.38(2H, d, 8.0Hz, phenyl-H)H-NMR (δ, D 2 Od 2 ): 1.65 (3H, d, 8.6Hz, -CH = CH CH 3 ( cis)), 1.81 (0.21H, d, 8.6Hz, -CH = CH CH 3 (trans )), 3.22 (1H, d, 18 Hz, 2-H), 3.55 (1H.d. 18 Hz, 2-H), 5.15 (1H, d, 4.6 Hz, 6-H), 5.66 (1H, d, 4.6 Hz, 7-H), 5.75 (1H, m, vinyl-H), 5.96 (1H, m, vinyl-H), 6.91 (2H, d, 8.0 Hz, phenyl-H), 7.38 (2H, d, 8.0 Hz, phenyl-H)
본 발명에 따른 4-히드록시페닐글리신 유도체는 일반적인 반응조건에서 쉽게 제조할 수 있으며, 추가의 분리나 정제과정을 거치지 않고 고수율 및 고순도로 세팔로스포린계 항생제 제조용 중간체로 사용할 수 있다.The 4-hydroxyphenylglycine derivative according to the present invention can be easily prepared under general reaction conditions, and can be used as an intermediate for preparing cephalosporin-based antibiotics in high yield and high purity without undergoing further separation or purification.
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| KR10-2003-0076354A KR100531668B1 (en) | 2003-10-30 | 2003-10-30 | 4-Hydroxyphenylglycine derivatives and processes for the preparation thereof |
| EP04793627A EP1678186A4 (en) | 2003-10-30 | 2004-10-30 | Processes for the preparation of cephem derivatives |
| US10/577,552 US7544797B2 (en) | 2003-10-30 | 2004-10-30 | Processes for the preparation of cephem derivatives |
| PCT/KR2004/002770 WO2005042543A1 (en) | 2003-10-30 | 2004-10-30 | Processes for the preparation of cephem derivatives |
| US12/436,619 US20090221815A1 (en) | 2003-10-30 | 2009-05-06 | Processes for the preparation of cephem derivatives |
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