KR102299990B1 - METHOD FOR PREPARATION OF 4-((3-amino-2-hydroxypropyl)-aminocarbony)-pheylboronic acid - Google Patents
METHOD FOR PREPARATION OF 4-((3-amino-2-hydroxypropyl)-aminocarbony)-pheylboronic acid Download PDFInfo
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- KR102299990B1 KR102299990B1 KR1020140150857A KR20140150857A KR102299990B1 KR 102299990 B1 KR102299990 B1 KR 102299990B1 KR 1020140150857 A KR1020140150857 A KR 1020140150857A KR 20140150857 A KR20140150857 A KR 20140150857A KR 102299990 B1 KR102299990 B1 KR 102299990B1
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- amino
- hydroxypropyl
- carboxyphenylboronic acid
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- 238000000034 method Methods 0.000 title claims abstract description 13
- -1 3-amino-2-hydroxypropyl Chemical group 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000002253 acid Substances 0.000 title 1
- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 claims abstract description 25
- XQAGTGNEKHHSKQ-UHFFFAOYSA-N [4-[(3-amino-2-hydroxypropyl)carbamoyl]phenyl]boronic acid Chemical compound NCC(O)CNC(=O)C1=CC=C(B(O)O)C=C1 XQAGTGNEKHHSKQ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- NCJZCJCCZMJSPI-UHFFFAOYSA-N P.S1C=NC2=CC=CC=C12 Chemical compound P.S1C=NC2=CC=CC=C12 NCJZCJCCZMJSPI-UHFFFAOYSA-N 0.000 claims abstract description 11
- UYBWIEGTWASWSR-UHFFFAOYSA-N 1,3-diaminopropan-2-ol Chemical compound NCC(O)CN UYBWIEGTWASWSR-UHFFFAOYSA-N 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 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 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OVVDFORZEGKEJM-UHFFFAOYSA-N 1-methylindazole-3-carboxylic acid Chemical compound C1=CC=C2N(C)N=C(C(O)=O)C2=C1 OVVDFORZEGKEJM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 229960003607 granisetron hydrochloride Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- QYZRTBKYBJRGJB-UHFFFAOYSA-N hydron;1-methyl-n-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)indazole-3-carboxamide;chloride Chemical compound Cl.C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 QYZRTBKYBJRGJB-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- UQKAOOAFEFCDGT-UHFFFAOYSA-N n,n-dimethyloctan-1-amine Chemical compound CCCCCCCCN(C)C UQKAOOAFEFCDGT-UHFFFAOYSA-N 0.000 description 1
- MGOXMUZCJGPUAN-UHFFFAOYSA-N phosphane;1,3-thiazole Chemical compound P.C1=CSC=N1 MGOXMUZCJGPUAN-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- GNFABDZKXNKQKN-UHFFFAOYSA-N tris(prop-2-enyl)phosphane Chemical compound C=CCP(CC=C)CC=C GNFABDZKXNKQKN-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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
본 발명은 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법에 관한 것으로, 4-카복시페닐보로닉산과 벤조티아졸 포스핀염을 반응시켜 4-카복시페닐 보로닉산의 활성형 에스테르화물인 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르를 제조하는 단계; 및 상기 4-카복시페닐보로닉산 S-벤조티아졸-2-일 에스테르와 1,3-디아미노-2-프로판올을 유기용매 하에서 아실화 반응시켜 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 제조하는 단계;를통해, 공업적으로 간편하고 경제적일 뿐 아니라 고순도를 보장할 수 있는 신규한 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 제조하는 방법을 제공한다.The present invention relates to a method for preparing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid by reacting 4-carboxyphenylboronic acid with a benzothiazole phosphine salt. preparing 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester, which is an active ester product of 4-carboxyphenyl boronic acid; and 4-((3-amino-2-hydroxyl) by acylating the 4-carboxyphenylboronic acid S-benzothiazol-2-yl ester with 1,3-diamino-2-propanol in an organic solvent. A novel 4-((3-amino-2-hydroxypropyl) that can ensure high purity as well as industrially simple and economical through; producing propyl)-aminocarbonyl)-phenylboronic acid )-Aminocarbonyl)-phenylboronic acid is provided.
Description
본 발명은 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법에 관한 것으로, 더욱 상세하게는 XC-DAPOL-CPBA를 합성하기 위한 중요 중간체인 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 신규한 제조 방법에 관한 것이다.The present invention relates to a method for preparing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid, and more particularly, an important intermediate for synthesizing XC-DAPOL-CPBA. It relates to a novel process for the preparation of 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid.
미국 특허 제5,631,364호에서는 당화혈색소(HbA1c)를 측정하기 위한 시약으로서 XC-DAPOL-CPBA를 개시한다. 상기 XC-DAPOL-CPBA를 합성하기 위한 중요 중간체로서 하기 화학식으로 표시되는 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산이 사용된다.US Patent No. 5,631,364 discloses XC-DAPOL-CPBA as a reagent for measuring glycated hemoglobin (HbA1c). As an important intermediate for synthesizing the XC-DAPOL-CPBA, 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid represented by the following formula is used.
미국 특허 제5,631,364호에서는 하기 반응식에 표시된 바와 같이, DCC와 HOBt 또는 NHS를 사용하여 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 합성했다.In US Patent No. 5,631,364, 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid was synthesized using DCC and HOBt or NHS, as shown in the following scheme.
그러나, 상기와 같은 방법은 반응 중에 부산물인 유레아(urea)가 발생되어 이를 정제하기 위한 단계가 추가되고, 최종 화합물의 정제법 또한 대량 생산에 적합하지 않은 실리카 칼럼을 통한 정제법일 뿐만 아니라, 반응 수율이 저조하고 일정한 순도를 보장할 수 없다는 문제점이 있다. 또한 반응 용매로 사용되는 N,N-디메틸포름아미드(N,N-dimethylformamide, DMF)는 제거하기가 어렵다는 문제점이 있다.However, in the above method, a by-product urea is generated during the reaction and a step for purifying it is added, and the purification method of the final compound is not only a purification method through a silica column that is not suitable for mass production, but also the reaction yield There is a problem in that it is poor and cannot guarantee a constant purity. In addition, N,N-dimethylformamide (N,N-dimethylformamide, DMF) used as a reaction solvent has a problem in that it is difficult to remove.
본 발명은 공업적으로 간편하고 경제적일 뿐 아니라 고순도를 보장할 수 있는 신규한 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 제조하는 방법을 제공한다.The present invention provides a method for preparing a novel 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid that is industrially simple and economical as well as guaranteeing high purity do.
상술한 과제를 해결하기 위하여, 본 발명에 따른 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법은, 4-카복시페닐보로닉산과 벤조티아졸 포스핀염을 반응시켜 4-카복시페닐 보로닉산의 활성형 에스테르화물인 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르를 제조하는 단계; 및 상기 4-카복시페닐보로닉산 S-벤조티아졸-2-일 에스테르와 1,3-디아미노-2-프로판올을 유기용매 하에서 아실화 반응시켜 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 제조하는 단계;를 포함하는 것을 특징으로 한다.In order to solve the above problems, the method for producing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid according to the present invention, 4-carboxyphenylboronic acid and benzoic acid preparing 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester which is an active ester product of 4-carboxyphenylboronic acid by reacting a thiazole phosphine salt; and 4-((3-amino-2-hydroxyl) by acylating the 4-carboxyphenylboronic acid S-benzothiazol-2-yl ester with 1,3-diamino-2-propanol in an organic solvent. Propyl) -aminocarbonyl) -preparing phenylboronic acid; characterized in that it comprises a.
바람직하게는, 상기 벤조티아졸 포스핀염은 트리페닐포스핀과 2,2'-디티오비스(벤조티아졸)로부터 제조하는 것을 특징으로 한다.Preferably, the benzothiazole phosphine salt is characterized in that it is prepared from triphenylphosphine and 2,2'-dithiobis(benzothiazole).
바람직하게는, 상기 4-카복시페닐보로닉산 S-벤조티아졸-2-일 에스테르의 제조 시, 반응 용매는 디클로로메탄, 클로로포름, 1,2-디클로로에탄에서 선택되는 어느 하나 또는 혼합 용매인 것을 특징으로 한다.Preferably, when preparing the 4-carboxyphenylboronic acid S-benzothiazol-2-yl ester, the reaction solvent is any one selected from dichloromethane, chloroform, and 1,2-dichloroethane, or a mixed solvent. characterized.
바람직하게는, 상기 아실화 반응의 유기용매는 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 테트라하이드로퓨란, N,N'-디메틸아세트아미드, N,N'-디메틸포름아미드에서 선택되는 어느 하나 또는 혼합 용매인 것을 특징으로 한다.Preferably, the organic solvent for the acylation reaction is any one selected from dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, N,N'-dimethylacetamide, and N,N'-dimethylformamide. or a mixed solvent.
또한, 본 발명에 따른 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법은, 그라니세트론 염산염을 제조하기 위한 중간체로서 신규 물질인 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르를 제공하는 것을 특징으로 한다.In addition, the method for producing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid according to the present invention is a novel material 4 as an intermediate for preparing granisetron hydrochloride. -Carboxyphenylboronic acid-S-benzothiazol-2-yl ester is characterized.
본 발명에 의한 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법은 저렴하고 취급이 용이한 합성 원료를 사용함으로써 전체 생산 비용을 절감할 수 있다.The method for producing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid according to the present invention can reduce the overall production cost by using an inexpensive and easy-to-handle synthetic raw material. have.
또한 본 발명은 4-카복시페닐보로닉산을 출발물질로 하여 온화한 반응 조건 하에서 재결정을 통한 간편하면서도 고수율로 제조할 수 있는 효율성 높은 제조 방법을 제공할 수 있다.In addition, the present invention can provide a high-efficiency manufacturing method that can be prepared in a simple and high yield through recrystallization under mild reaction conditions using 4-carboxyphenylboronic acid as a starting material.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 및 실험예를 제시한다. 그러나 하기의 실시예 및 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 이들에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples and experimental examples are presented to help the understanding of the present invention. However, the following Examples and Experimental Examples are provided for easier understanding of the present invention, and the content of the present invention is not limited thereto.
본 발명은 하기 화학식1로 표시되는 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산(DAPOL-CPBA)의 신규한 제조 방법을 제안한다.The present invention proposes a novel method for preparing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid (DAPOL-CPBA) represented by the following formula (1).
본 발명에 따른 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산(DAPOL-CPBA)의 반응 단계를 하기 반응식들로 표시하였다.The reaction steps of 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid (DAPOL-CPBA) according to the present invention are shown in the following schemes.
출발물질로 사용되는 하기 화학식2의 4-카복시페닐보로닉산은 공지된 화합물로서, 상업적으로 쉽게 취득 가능한 화합물이다.4-carboxyphenylboronic acid of the following formula (2) used as a starting material is a known compound, and is a commercially available compound.
본 발명의 방법에서 하기 화학식3으로 표시되는 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르(4-카복시페닐 보로닉산의 활성형 에스테르화물)의 제조는 화학식7로 표시되는 벤조티아졸 포스핀염과 화학식2의 4-카복시페닐보로닉산과의 반응에 의하여 제조된다.In the method of the present invention, the preparation of 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester (active esterified product of 4-carboxyphenylboronic acid) represented by the following formula (3) is represented by the formula (7) It is prepared by reaction of a benzothiazole phosphine salt with 4-carboxyphenylboronic acid of the formula (2).
화학식7의 벤조티아졸 포스핀염은 적절한 유기용매에 하기 화학식6의 포스핀 화합물을 용해시킨 후 하기 화학식5의 2,2'-디티오비스(벤조티아졸)을 가하여 제조되며, 제조된 화학식7의 벤조티아졸 포스핀염을 분리하지 않고 상기 화학식2의 4-카복시페닐보로닉산과의 반응에 직접 사용된다.The benzothiazole phosphine salt of Formula 7 is prepared by dissolving the phosphine compound of Formula 6 in an appropriate organic solvent and then adding 2,2'-dithiobis(benzothiazole) of Formula 5, The benzothiazole phosphine salt is directly used in the reaction with 4-carboxyphenylboronic acid of the above formula (2) without separation.
상기 반응에 사용되는 포스핀 화합물로서, 트리(저급알킬)포스핀 또는 트리알릴포스핀, 트리알킬(또는 알릴)포스파이트 등이 사용될 수 있다. 바람직하게는 트리페닐포스핀이 사용될 수 있는데, 사용되는 트리페닐포스핀의 당량은 4-카복시페닐보로닉산에 대하여 2 내지 3 당량이며, 바람직하게는 2.5 당량일 수 있다.As the phosphine compound used in the above reaction, tri (lower alkyl) phosphine or triallylphosphine, trialkyl (or allyl) phosphite, etc. may be used. Preferably, triphenylphosphine may be used, and the equivalent of triphenylphosphine used is 2 to 3 equivalents based on 4-carboxyphenylboronic acid, and may preferably be 2.5 equivalents.
이때 사용되는 반응 용매로는 디클로로메탄, 클로로포름, 1,2-디클로로에탄 등이 적합하며, 바람직하게는 디클로로메탄이 사용될 수 있다. 반응 온도는 0℃ 내지 60℃이며, 20℃ 내지 25℃가 바람직하다.As the reaction solvent used at this time, dichloromethane, chloroform, 1,2-dichloroethane, etc. are suitable, and dichloromethane may be preferably used. The reaction temperature is 0°C to 60°C, preferably 20°C to 25°C.
제조된 벤조티아졸 포스핀염의 반응혼합물에 직접 화학식2의 4-카복시페닐보로닉산을 가하여 20℃ 내지 25℃에서 24시간 내지 48시간 동안 교반하여 화학식3의 4-카복시페닐보로닉산의 활성형 에스테르화물인 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르를 제조할 수 있다.4-carboxyphenylboronic acid of Formula 2 was added directly to the reaction mixture of the prepared benzothiazole phosphine salt and stirred at 20° C. to 25° C. for 24 hours to 48 hours to activate 4-carboxyphenylboronic acid of Formula 3 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester, which is a type esterified product, can be prepared.
상기 혼합 용액에 첨가하는 상기 화학식2의 1-메틸인다졸-3-카르복실산의 당량은 2,2'-디티오비스(벤조티아졸)에 대하여 0.2 내지 0.5 당량이고, 0.4 당량이 바람직하다.The equivalent of 1-methylindazole-3-carboxylic acid of Formula 2 added to the mixed solution is 0.2 to 0.5 equivalent, preferably 0.4 equivalent, based on 2,2'-dithiobis(benzothiazole).
상기 화학식3의 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르와 하기 화학식4의 1,3-디아미노-2-프로판올(그라나탄 아민)을 유기용매 하에서 아실화 반응하여 고순도, 고수율로 화학식1의 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 합성한다.Acylation reaction of 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester of Formula 3 with 1,3-diamino-2-propanol (granathan amine) of Formula 4 in the presence of an organic solvent 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid of Formula 1 is synthesized with high purity and high yield.
본 발명의 아실화 반응에 사용되는 유기용매로는 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 테트라하이드로퓨란, 아세톤, N,N'-디메틸아세트아미드, N,N'-디메틸포름아미드, 메탄올, 에탄올 등의 단독 또는 혼합 용매가 사용될 수 있으며, 바람직하게는 에탄올일 수 있다.Examples of the organic solvent used in the acylation reaction of the present invention include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, acetone, N,N'-dimethylacetamide, N,N'-dimethylformamide, and methanol. , a single or mixed solvent such as ethanol may be used, and preferably ethanol.
1,3-디아미노-2-프로판올에 대한 활성형 에스테르화물(4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르)의 당량비는 1 내지 2당량이고, 1.5당량이 바람직하다. 아실화 반응의 온도는 10℃ 내지 30℃이며, 20℃ 내지 25℃가 바람직하다. 반응온도가 30℃ 이상인 경우 아실화 반응의 부반응이 증가하게 되고, 10℃ 이하인 경우는 반응 속도가 느린 단점이 있다.The equivalent ratio of the active esterified product (4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester) to 1,3-diamino-2-propanol is 1 to 2 equivalents, preferably 1.5 equivalents . The temperature of the acylation reaction is 10°C to 30°C, preferably 20°C to 25°C. When the reaction temperature is 30° C. or higher, side reactions of the acylation reaction increase, and when the reaction temperature is 10° C. or lower, the reaction rate is slow.
상기 아실화된 반응 혼합물은 감압건조한 뒤에 유기용매를 제거한다. 유기용매 제거 후, 수용성 유기용매를 사용하여 결정을 형성한 후 여과하여, 본 발명의 목적 화합물인 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 결정화한다.After the acylated reaction mixture is dried under reduced pressure, the organic solvent is removed. After the organic solvent is removed, crystals are formed using a water-soluble organic solvent and filtered to obtain 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid, the target compound of the present invention. crystallize
4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르(화학식3)의 제조Preparation of 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester (Formula 3)
트리페닐포스핀 43.57g(166mmol)을 염화메틸렌 350㎖에 용해시키고 2,2'-디티오비스(벤조티아졸) 55.2g(166mmol)을 상온에서 첨가한 후 30분간 교반한다.43.57 g (166 mmol) of triphenylphosphine is dissolved in 350 ml of methylene chloride, and 55.2 g (166 mmol) of 2,2'-dithiobis (benzothiazole) is added at room temperature, followed by stirring for 30 minutes.
상기 교반에 따른 반응 혼합물에 4-카복시페닐보로닉산 19.5g(110mmol)을 서서히 첨가하고 상온에서 24시간 동안 교반한다. 이후 반응물을 감압 농축하여 염화메틸렌을 제거한다. 농축 잔사에 메탄올 350㎖를 첨가하고 상온에서 1시간 동안 교반한 후, 여과 및 건조하여 표제 화합물 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르 22.2g(85%)을 얻는다.19.5 g (110 mmol) of 4-carboxyphenylboronic acid was slowly added to the reaction mixture according to the stirring, and the mixture was stirred at room temperature for 24 hours. Thereafter, the reaction product is concentrated under reduced pressure to remove methylene chloride. 350 ml of methanol was added to the concentrated residue, stirred at room temperature for 1 hour, filtered and dried to obtain 22.2 g (85%) of the title compound 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester .
융점: 105℃ 내지 108℃Melting Point: 105°C to 108°C
4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산(DAPOL-CPBA)(화학식1)의 제조Preparation of 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid (DAPOL-CPBA) (Formula 1)
1,3-디아미노-2-프로판올 1.85g(11.17mmol)을 에탄올 40㎖에 용해시키고 25℃에서 2시간 동안 교반시킨다. 상온에서 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르 4.3g(12.29mmol)을 첨가한 후 상온에서 1시간 동안 교반한다. 반응 혼합물을 40℃에서 감압농축하고, 농축 잔사에 이소프로판올 50㎖를 첨가하고 1시간 동안 환류시킨다. 25℃에서 2시간, 5℃에서 2시간 동안 교반시킨 후 생성된 결정을 여과하고 에탄올 25㎖로 세척 후 건조하여 표제 화합물인 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산(DAPOL-CPBA) 2.5g(65%)을 얻는다.1.85 g (11.17 mmol) of 1,3-diamino-2-propanol was dissolved in 40 ml of ethanol and stirred at 25° C. for 2 hours. After adding 4.3 g (12.29 mmol) of 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester at room temperature, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure at 40°C, 50 ml of isopropanol was added to the concentrated residue, and refluxed for 1 hour. After stirring at 25°C for 2 hours and at 5°C for 2 hours, the resulting crystals were filtered, washed with 25 ml of ethanol, and dried to obtain the title compound, 4-((3-amino-2-hydroxypropyl)-aminocarbonyl. )-Phenylboronic acid (DAPOL-CPBA) 2.5 g (65%) is obtained.
융점: 201℃ 내지 205℃Melting Point: 201°C to 205°C
1H NMR(CDCl3): δ2.80(d, 2H), 3.35(d,2H)m, 4.08(t,1H), 7.4(m, 2H), 7.9(m, 2H) 1 H NMR (CDCl 3 ): δ2.80 (d, 2H), 3.35 (d, 2H) m, 4.08 (t, 1H), 7.4 (m, 2H), 7.9 (m, 2H)
<HPLC 조작 조건><HPLC operating conditions>
디텍터: 자외부 흡광 광도계Detector: Ultraviolet Absorbance Photometer
칼럼: 5㎛, 25㎝, ODS 칼럼(Hypersil)Column: 5 μm, 25 cm, ODS column (Hypersil)
유량: 1.5㎖/minFlow rate: 1.5ml/min
감도: A.U.F.S.0.1Sensitivity: A.U.F.S.0.1
주입량: 10㎕Injection volume: 10 μl
이동상: 디메틸옥틸아민 용액과 테트라하이드류란을 97.5:2.5의 비율로 섞은 후, 여과하여 사용한다.Mobile phase: After mixing dimethyloctylamine solution and tetrahydrulan in a ratio of 97.5:2.5, filtration is used.
Claims (4)
하기의 화학식 2의 4-카복시페닐보로닉산을 하기 화학식 7의 벤조티아졸 포스핀염과 반응시켜 하기 화학식 3의 4- 카복시페닐보로닉산 S-벤조티아졸-2-일 에스테르를 제조하는 단계;
상기 화학식 3의 4-카복시페 닐보로닉산 S-벤조티아졸-2-일 에스테르와 하기 화학식 4의 1,3-디아미노-2-프로판올을 유기용매 하에서 아실화 반응시켜 상기 화학식 1 의 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산을 제조하는 단계;를 포함하고,
상기 화학식 7의 벤조티아졸 포스핀염은 하기 화학식 6의 트리페닐포스핀을 제1 유기 용매로 용해시킨 후 하기 화학식 5로 표시되는 2,2'-디티오비스(벤조티아졸)을 가하여 제조하고,
사용되는 트리페닐포스핀의 당량은 4-카복시페닐보로닉산에 대하여 2 내지 3 당량이고,
제조된 화학식7의 벤조티아졸 포스핀염을 분리하지 않고 상기 화학식2의 4-카복시페닐보로닉산과의 반응에 직접 사용하고,
제조된 벤조티아졸 포스핀염의 반응혼합물에 직접 화학식2의 4-카복시페닐보로닉산을 가하여 20℃ 내지 25℃에서 24시간 내지 48시간 동안 교반하여 화학식3의 4-카복시페닐보로닉산의 활성형 에스테르화물인 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르를 제조하고,
제조된 벤조티아졸 포스핀염의 반응혼합물에 직접 화학식2의 4-카복시페닐보로닉산을 첨가한 반응물을 감압 농축하여 상기 제1 유기용매를 제거하고, 농축 잔사에 메탄올을 첨가하고 교반한 후, 여과 및 건조하여 화학식 3의 4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르을 얻고,
1,3-디아미노-2-프로판올에 대한 활성형 에스테르화물(4-카복시페닐보로닉산-S-벤조티아졸-2-일 에스테르)의 당량비는 1 내지 2당량이고,
상기 아실화 반응의 온도는 10℃ 내지 30℃인 것을 특징으로 하는 4-((3-아미노-2-히드록시프로필)-아미노카보 닐)-페닐보로닉산의 제조 방법.
Preparing 4-carboxyphenylboronic acid S-benzothiazol-2-yl ester of Formula 3 by reacting 4-carboxyphenylboronic acid of Formula 2 with a benzothiazole phosphine salt of Formula 7 below ;
4-carboxyphenylboronic acid S-benzothiazol-2-yl ester of Formula 3 and 1,3-diamino-2-propanol of Formula 4 below are acylated in an organic solvent to react 4- ((3-amino-2-hydroxypropyl)-aminocarbonyl)- preparing phenylboronic acid;
The benzothiazole phosphine salt of Formula 7 is prepared by dissolving triphenylphosphine of Formula 6 in a first organic solvent and then adding 2,2'-dithiobis(benzothiazole) represented by Formula 5 below,
The equivalent of triphenylphosphine used is 2-3 equivalents based on 4-carboxyphenylboronic acid,
It is used directly in the reaction with 4-carboxyphenylboronic acid of Formula 2 without separating the prepared benzothiazole phosphine salt of Formula 7,
4-carboxyphenylboronic acid of Formula 2 was added directly to the reaction mixture of the prepared benzothiazole phosphine salt and stirred at 20° C. to 25° C. for 24 hours to 48 hours to activate 4-carboxyphenylboronic acid of Formula 3 To prepare 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester, which is an esterified product,
The reaction product obtained by adding 4-carboxyphenylboronic acid of Formula 2 directly to the reaction mixture of the prepared benzothiazole phosphine salt was concentrated under reduced pressure to remove the first organic solvent, methanol was added to the concentrated residue, and stirred, Filtration and drying to obtain 4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester of Formula 3,
The equivalent ratio of the active esterified product (4-carboxyphenylboronic acid-S-benzothiazol-2-yl ester) to 1,3-diamino-2-propanol is 1 to 2 equivalents,
That the temperature of the acylation reaction is 10 ℃ to 30 ℃ A process for preparing 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid, characterized in that.
상기 화학식 3의 4-카복시페닐보로닉산 S-벤조티아졸-2-일 에스테르의 제조 시, 반응 용매로 상기 제1 유기 용매는 디클로로메탄, 클로로포름, 1,2-디클로로에탄에서 선택되는 어느 하나 또는 혼합 용매인 것을 특징으로 하는 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법.The method according to claim 1
When preparing 4-carboxyphenylboronic acid S-benzothiazol-2-yl ester of Formula 3, the first organic solvent as a reaction solvent is any one selected from dichloromethane, chloroform, and 1,2-dichloroethane or 4-((3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid, characterized in that it is a mixed solvent.
디클로로메탄, 클로로포름, 1,2-디클로로에탄, 테트라하이드로퓨란, N,N'-디메틸아세트아미드, N,N'-디메틸포름아미드에서 선택되는 어느 하나 또는 혼합 용매인 것을 특징으로 하는 4-((3-아미노-2-히드록시프로필)-아미노카보닐)-페닐보로닉산의 제조 방법.
The method according to claim 1, wherein the organic solvent of the acylation reaction is
Dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, N,N'-dimethylacetamide, 4-(( A process for the preparation of 3-amino-2-hydroxypropyl)-aminocarbonyl)-phenylboronic acid.
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