KR20200088570A - Process for Preparation of Fimasartan and Intermediate for Preparing the Same - Google Patents
Process for Preparation of Fimasartan and Intermediate for Preparing the Same Download PDFInfo
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- KR20200088570A KR20200088570A KR1020190004981A KR20190004981A KR20200088570A KR 20200088570 A KR20200088570 A KR 20200088570A KR 1020190004981 A KR1020190004981 A KR 1020190004981A KR 20190004981 A KR20190004981 A KR 20190004981A KR 20200088570 A KR20200088570 A KR 20200088570A
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- fimasartan
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 239000005475 Fimasartan Substances 0.000 title claims abstract description 25
- 229960003489 fimasartan Drugs 0.000 title claims abstract description 25
- AMEROGPZOLAFBN-UHFFFAOYSA-N fimasartan Chemical compound CCCCC1=NC(C)=C(CC(=S)N(C)C)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 AMEROGPZOLAFBN-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 8
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 7
- -1 amide salt Chemical class 0.000 claims description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 6
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- 230000002862 amidating effect Effects 0.000 claims description 5
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 229960000281 trometamol Drugs 0.000 claims description 4
- 238000007126 N-alkylation reaction Methods 0.000 claims description 3
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- 239000000126 substance Substances 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 0 *[n]1nnnc1-c(cccc1)c1-c1ccc(CBr)cc1 Chemical compound *[n]1nnnc1-c(cccc1)c1-c1ccc(CBr)cc1 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- OAMDXZTUOHORAO-UHFFFAOYSA-N 2-(2-butyl-6-methyl-4-oxo-1h-pyrimidin-5-yl)-n,n-dimethylacetamide Chemical compound CCCCC1=NC(=O)C(CC(=O)N(C)C)=C(C)N1 OAMDXZTUOHORAO-UHFFFAOYSA-N 0.000 description 1
- JDXQWYKOKYUQDN-UHFFFAOYSA-N 3-hydroxypyrrolidine-2,5-dione Chemical compound OC1CC(=O)NC1=O JDXQWYKOKYUQDN-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241000219492 Quercus Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- PUNKBDMMPFKQMA-UHFFFAOYSA-N ethyl 2-(2-butyl-6-methyl-4-oxo-1h-pyrimidin-5-yl)acetate Chemical compound CCCCC1=NC(C)=C(CC(=O)OCC)C(O)=N1 PUNKBDMMPFKQMA-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000005980 thioamidation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
Abstract
Description
본 발명은 피마살탄 및 그의 제조 중간체의 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 간단하고 경제적으로 피마살탄 및 그의 제조 중간체를 제조하는 방법에 관한 것이다. The present invention relates to a method for producing fimasartan and its intermediate. More specifically, the present invention relates to a simple and economical method for preparing fimasartan and its intermediates.
하기 화학식 1의 피마살탄(fimasartan)은 안지오텐신 II 수용체 길항제(Angiotensin II Receptor Blocker, ARB) 계열의 혈압 강하제로 알려져 있다. Fimasartan of Formula 1 is known as an angiotensin II receptor antagonist (ARB)-based blood pressure lowering agent.
[화학식 1] [Formula 1]
피마살탄의 제조방법은 대한민국 등록 특허 제10-521980호에 하기 반응식 1에서 볼 수 있는 바와 같이, 하기 화학식 2의 화합물을 N-히드록시벤조트리아졸(HOBt), N-메틸모폴린(NMM) 및 디시클로헥실카보디이미드(DCC)의 존재 하에 아민과 반응시켜 하기 화학식 3의 화합물을 수득하고, 하기 화학식 3의 화합물과 하기 화학식 4의 화합물을 수소화 리튬의 존재 하에 반응시켜 하기 화학식 5의 화합물을 수득한 다음, 하기 화학식 5의 화합물을 로손 시약(Lawesson's reagent)를 사용하여 티오아미드화 반응시킨 후, 보호기를 제거하여 제조할 수 있는 것으로 개시되어 있다.The production method of fimasartan is as shown in the following Reaction Scheme 1 in Korean Patent Registration No. 10-521980, N-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM) And reacting with an amine in the presence of dicyclohexylcarbodiimide (DCC) to obtain a compound of Formula 3, and reacting a compound of Formula 3 with a compound of Formula 4 in the presence of lithium hydride: After obtaining, it is disclosed that the compound of Formula 5 can be prepared by reacting a thioamide reaction using a Lawesson's reagent and then removing a protecting group.
[반응식 1][Scheme 1]
그러나, 상기 제조방법은 N,N'-디시클로헥실카보디이미드(DCC)로부터 반응 부산물로 수분을 함습하는 성질이 커서 일반적인 원심분리로 여과하기 어려운 N,N'-디시클로헥실우레아(DCU)가 다량 생성 되는 문제점이 있다. However, the manufacturing method has a property of moisturizing moisture from N,N'-dicyclohexylcarbodiimide (DCC) as a reaction by-product, making it difficult to filter by general centrifugation. There is a problem that a large amount is generated.
또한, 로손 시약은 가격이 비싸고, 분리의 어려움이 있으며, 제조 시 반응 부산물로 다량의 황화수소(H2S)을 발생하므로 환경적인 문제점이 있다. In addition, Lawson's reagent is expensive, has difficulty in separation, and generates a large amount of hydrogen sulfide (H 2 S) as a by-product of the manufacturing process, thereby causing environmental problems.
따라서, 반응 부산물인 우레아가 생성되지 않으며 경제적이고 간단한 공정으로 피마살탄을 고수율로 제조할 수 있는 방법의 개발이 절실히 요구되어 왔다. Therefore, the development of a method capable of producing fimasartan in a high yield in an economical and simple process without generating reaction by-product urea has been urgently required.
본 발명의 한 목적은 피마살탄을 간단하고 경제적으로 제조할 수 있는 방법을 제공하는 것이다.One object of the present invention is to provide a simple and economical method for producing fimasartan.
본 발명의 다른 목적은 피마살탄의 제조 중간체인 화학식 3의 화합물을 반응 부산물로서 우레아의 생성을 억제하면서 고수율로 제조할 수 있는 방법을 제공하는 것이다. Another object of the present invention is to provide a method capable of producing a compound of formula 3, which is an intermediate for the production of fimasartan, as a reaction by-product while suppressing the production of urea with high yield.
본 발명의 또 다른 목적은 피마살탄 트로메타민염 이수화물을 상업적으로 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for commercially preparing fimasartan tromethamine salt dihydrate.
본 발명의 일 실시형태는 하기 화학식 1의 피마살탄의 제조방법에 관한 것으로, 본 발명의 제조방법은 One embodiment of the present invention relates to a method for preparing fimasartan of the following Chemical Formula 1,
(i) 하기 화학식 2의 화합물을 N,N‘-디이소프로필카보디이미드, N-하이드록시숙신이미드와 염기의 존재 하에 디메틸아민염산염과 아미드화 반응시켜 하기 화학식 3의 화합물을 수득하는 단계;(i) amidating the compound of formula 2 with N,N'-diisopropylcarbodiimide, N-hydroxysuccinimide with dimethylamine hydrochloride in the presence of a base to obtain a compound of formula 3 ;
(ii) 하기 화학식 3의 화합물을 염기의 존재 하에 하기 화학식 4의 화합물과 N-알킬화 반응시켜 하기 화학식 5의 화합물을 수득하는 단계;(ii) subjecting the compound of formula 3 to N-alkylation reaction with the compound of formula 4 in the presence of a base to obtain a compound of formula 5;
(iii) 하기 화학식 5의 화합물을 P2S5-피리딘 시약으로 티오아미드화 반응시켜 하기 화학식 6의 화합물을 수득하는 단계; 및(iii) subjecting the compound of formula 5 to a thioamide reaction with a P 2 S 5 -pyridine reagent to obtain a compound of formula 6; And
(iv) 하기 화학식 6의 화합물을 산 존재 하에 탈보호화 반응시키는 단계를 포함한다. (iv) deprotecting the compound of Formula 6 in the presence of an acid.
[화학식 2][Formula 2]
[화학식 3] [Formula 3]
[화학식 4] [Formula 4]
[화학식 5] [Formula 5]
[화학식 6] [Formula 6]
[화학식 1] [Formula 1]
이하, 본 발명의 제조방법을 하기 반응식 2를 참조로 보다 상세히 설명한다. 하기 반응식 2에 기재된 방법은 대표적으로 사용된 방법을 예시한 것일 뿐 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다. Hereinafter, the production method of the present invention will be described in more detail with reference to Scheme 2 below. The method described in Scheme 2 below is merely an example of a method used, and reaction reagents, reaction conditions, and the like may be changed as many times as necessary.
[반응식 2][Scheme 2]
제1단계: 화학식 3의 화합물의 합성 Step 1: Synthesis of Compound of Formula 3
화학식 3의 화합물은 화학식 2의 화합물을 N,N‘-디이소프로필카보디이미드(DIC), N-하이드록시숙신이미드(NHS)와 염기의 존재 하에 디메틸아민염산염과 아미드화 반응시켜 제조할 수 있다.The compound of Formula 3 is prepared by amidating a compound of Formula 2 with N,N'-diisopropylcarbodiimide (DIC), N-hydroxysuccinimide (NHS) and dimethylamine hydrochloride in the presence of a base. Can.
화학식 2의 화합물과 N,N‘-디이소프로필카보디이미드(DIC)의 몰비는 1:1 내지 1:3이 바람직하며, 1:2가 보다 더 바람직하다.The molar ratio of the compound of Formula 2 and N,N'-diisopropylcarbodiimide (DIC) is preferably 1:1 to 1:3, and more preferably 1:2.
화학식 2의 화합물과 N-하이드록시숙신이미드(NHS)의 몰비는 1:1 내지 1:2가 바람직하며, 1:1.3이 보다 더 바람직하다.The molar ratio of the compound of Formula 2 and N-hydroxysuccinimide (NHS) is preferably 1:1 to 1:2, more preferably 1:1.3.
상기 염기로는 트리에틸아민, 트리메틸아민, 트리이소프로필아민, 디이소프로필에틸아민 등이 사용될 수 있으며, 트리에틸아민이 바람직하다. As the base, triethylamine, trimethylamine, triisopropylamine, diisopropylethylamine and the like can be used, and triethylamine is preferred.
화학식 2의 화합물과 염기의 몰비는 1:1 내지 1:5가 바람직하며, 1:3이 보다 더 바람직하다.The molar ratio between the compound of Formula 2 and the base is preferably 1:1 to 1:5, and more preferably 1:3.
반응용매는 디클로로메탄, 아세톤, DMF 단독 또는 이들의 혼합물이며, 반응용매의 사용량은 화학식 2의 화합물의 사용 중량당 약 5 내지 20배 부피비(ml/g)를 사용하는 것이 바람직하며, 10 배가 보다 더 바람직하다.The reaction solvent is dichloromethane, acetone, DMF alone or a mixture thereof, and the amount of the reaction solvent is preferably about 5 to 20 times the volume ratio (ml/g) per use weight of the compound of Formula 2, more than 10 times More preferred.
반응온도는 0~35℃, 반응시간은 1 내지 5시간이 바람직하다. The reaction temperature is preferably 0 to 35°C, and the reaction time is preferably 1 to 5 hours.
화학식 2의 화합물은 상업적으로 입수하거나, 당해 기술분야에 공지된 방법에 따라 용이하게 제조할 수 있다.Compounds of Formula 2 are commercially available or can be readily prepared according to methods known in the art.
반응 후의 후처리 공정은 생성된 고체를 여과하고 여과물을 이소프로필알콜로 재결정하여 수행하며, 단순 여과 및 재결정에 의해 순도 95% 이상의 화학식 3의 화합물을 수득할 수 있다. The post-treatment process after the reaction is carried out by filtering the resulting solid and recrystallizing the filtrate with isopropyl alcohol, and a compound of Formula 3 having a purity of 95% or more can be obtained by simple filtration and recrystallization.
상기 화학식 3의 화합물의 제조 단계는 기존 방법에서 생성되는 우레아 부산물을 억제할 수 있으며, 반응 후 단순 여과 및 결정화 과정으로 후처리 공정을 간소화 하여 생산 비용을 감소시킬 수 있다. The preparation step of the compound of Chemical Formula 3 can suppress the urea by-product generated in the existing method, and can reduce the production cost by simplifying the post-treatment process by a simple filtration and crystallization process after the reaction.
제2단계: 화학식 5의 화합물의 합성 Step 2: Synthesis of Compound of Formula 5
화학식 5의 화합물은 화학식 3의 화합물을 염기의 존재 하에 하기 화학식 4의 화합물과 N-알킬화 반응시켜 제조할 수 있다.The compound of Formula 5 may be prepared by reacting the compound of Formula 3 with an N-alkylation reaction with the compound of Formula 4 in the presence of a base.
상기 염기로는 알칼리 금속의 탄산염, 아마이드염, 히드록시염 등을 사용할 수 있으며, 리튬히드록사이드(LiOH)가 가장 바람직하다. As the base, carbonates, amide salts, and hydroxy salts of alkali metals can be used, and lithium hydroxide (LiOH) is most preferred.
화학식 3의 화합물과 염기의 몰비는 1:1 내지 1:2가 바람직하며, 1:1.1이 보다 더 바람직하다. The molar ratio of the compound of Formula 3 and the base is preferably 1:1 to 1:2, more preferably 1:1.1.
반응용매로는 디메틸포름아미드와 톨루엔의 혼합 용매를 사용하는 것이 바람직하며, 디메틸포름아미드와 톨루엔의 혼합비는 1:9 내지 1:30이 바람직하며, 1:9가 보다 더 바람직하다. As a reaction solvent, it is preferable to use a mixed solvent of dimethylformamide and toluene, and the mixing ratio of dimethylformamide and toluene is preferably 1:9 to 1:30, more preferably 1:9.
반응온도는 50 내지 70℃, 반응시간은 15 내지 30시간이 바람직하다. The reaction temperature is preferably 50 to 70°C, and the reaction time is 15 to 30 hours.
제3단계: 화학식 6의 화합물의 합성 Step 3: Synthesis of Compound of Formula 6
화학식 6의 화합물은 화학식 5의 화합물을 P2S5-피리딘 시약으로 티오아미드화 반응시켜 제조할 수 있다. The compound of Formula 6 can be prepared by subjecting the compound of Formula 5 to a thioamide reaction with a P 2 S 5 -pyridine reagent.
화학식 5의 화합물과 P2S5-피리딘 시약의 몰비는 1:1 내지 1:3이 바람직하며, 1:1.2가 보다 더 바람직하다. The molar ratio of the compound of Formula 5 and P 2 S 5 -pyridine reagent is preferably 1:1 to 1:3, 1:1.2 is more preferred.
상기 P2S5-피리딘 시약은 문헌 [J. Org . Chem. 2011, 76, 1546-1553]에 기재된 방법으로 용이하게 제조할 수 있다.The P 2 S 5 -pyridine reagent is described in J. Org . Chem . 2011, 76 , 1546-1553] can be easily prepared.
반응용매로는 톨루엔, 자이렌과 같은 유기 용매를 사용할 수 있으며, 톨루엔이 바람직하다. Examples of the reaction solvent are toluene, xylene and The same organic solvent can be used, and toluene is preferred.
반응 후의 후처리 공정은 정제수를 투입하여 추출과정을 거쳐 수층으로 P2S5-피리딘 시약의 반응 부산물인 피리딘 등을 제거하고 유기층을 농축하여 수행할 수 있다. The post-treatment process after the reaction can be performed by removing purified pyridine, a by-product of P 2 S 5 -pyridine reagent, and concentrating the organic layer through an extraction process by adding purified water.
반응온도는 80 내지 120℃, 반응시간은 1 내지 5시간이 바람직하다. The reaction temperature is preferably 80 to 120°C, and the reaction time is 1 to 5 hours.
종래의 티오아미드화 반응에 사용되는 로손 시약(Lawesson's reagent)은 110℃ 이상의 높은 온도에서 안정성이 낮아 분해 되기 쉽다. 이에 반해 P2S5-피리딘 시약은 110℃ 이상의 높은 온도에서도 안정성이 우수하여 본 발명에서는 높은 끊는점을 갖고 있는 톨루엔 및 자이렌과 같은 유기 용매에서 가열 환류하여 단시간 내에 티오아미드화 반응을 진행할 수 있다. 아울러, 반응 종결 후 반응액에 정제수을 투입하여 P2S5-피리딘 시약의 반응 부산물인 피리딘 등을 용의하게 제거 가능하여 컬럼 크로마토그램 과정을 거치 않아도 된다. Lawesson's reagent used in the conventional thioamidation reaction has a low stability at a high temperature of 110° C. or higher and is easily decomposed. On the other hand, the P 2 S 5 -pyridine reagent has excellent stability even at a high temperature of 110° C. or higher, and in the present invention, it can be heated to reflux in an organic solvent such as toluene and xylene having a high breaking point to carry out a thioamide reaction within a short time. have. In addition, after the completion of the reaction, purified water is added to the reaction solution to easily remove pyridine, which is a by-product of the P 2 S 5 -pyridine reagent, and does not require a column chromatography process.
제4단계: 화학식 1의 Step 4: Formula 1 피마살탄의Fimasartan 합성 synthesis
화학식 1의 피마살탄은 화학식 6의 화합물을 산 존재 하에 탈보호화 반응시켜 제조할 수 있다. Fimasartan of Formula 1 can be prepared by deprotecting the compound of Formula 6 in the presence of an acid.
상기 산으로는 염산, 아세트산, 트리플루오르아세트산 등이 사용될 수 있으며, 염산이 바람직하다. As the acid, hydrochloric acid, acetic acid, trifluoroacetic acid, and the like can be used, and hydrochloric acid is preferred.
화학식 6의 화합물과 산의 몰비는 1:1 내지 1:10이 바람직하며, 1:1이 보다 더 바람직하다.The molar ratio of the compound of Formula 6 and the acid is preferably 1:1 to 1:10, and more preferably 1:1.
반응용매로는 알코올류, 테트라하이드로퓨란과 같은 유기 용매를 사용할 수 있으며, 메탄올이 바람직하다.As the reaction solvent, an organic solvent such as alcohols or tetrahydrofuran may be used, and methanol is preferred.
반응온도는 60 내지 70℃, 반응시간은 3 내지 6시간이 바람직하다. The reaction temperature is preferably 60 to 70°C, and the reaction time is 3 to 6 hours.
본 발명의 일 실시형태는 상기에서 제조된 화학식 1의 피마살탄에 트로메타민과 물을 첨가하여 피마살탄 트로메타민염 이수화물을 제조하는 방법에 관한 것이다. One embodiment of the present invention relates to a method for preparing fimasartan tromethamine salt dihydrate by adding tromethamine and water to the fimasartan of Formula 1 prepared above.
본 발명에 따른 피마살탄 트로메타민염 이수화물의 제조방법은 Method for producing fimasartan tromethamine salt dihydrate according to the present invention
(v) 피마살탄 및 트로메타민을 유기 용매에 용해시키는 단계;(v) dissolving fimasartan and tromethamine in an organic solvent;
(vi) 물을 추가하는 단계; 및(vi) adding water; And
(vii) 반응물을 교반하여 생성된 고체를 여과하는 단계를 포함한다.(vii) filtering the resulting solid by stirring the reactants.
상기 유기 용매로는 메탄올, 에탄올, 2-프로판올, 아세토니트릴 및 아세톤으로 구성된 군에서 선택된 1종 이상이 사용될 수 있다.As the organic solvent, one or more selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile and acetone may be used.
상기 단계(vi)에서 물로는 정제수를 사용하는 것이 바람직하며, 물의 사용량은 화학식 1의 화합물의 중량 당 0.1 내지 10배 부피비(ml/g)가 바람직하다. In step (vi), it is preferable to use purified water as water, and the amount of water used is preferably 0.1 to 10 times the volume ratio (ml/g) per weight of the compound of Formula 1.
본 발명의 일 실시형태는 하기 화학식 3의 화합물의 제조방법에 관한 것으로, 본 발명의 제조방법은 One embodiment of the present invention relates to a method for preparing a compound represented by the following Chemical Formula 3,
(i) 하기 화학식 2의 화합물을 N,N‘-디이소프로필카보디이미드, N-하이드록시숙신이미드와 염기의 존재 하에 디메틸아민염산염과 아미드화 반응시키는 단계를 포함한다. (i) a step of amidating the compound of Formula 2 with N,N'-diisopropylcarbodiimide, N-hydroxysuccinimide and dimethylamine hydrochloride in the presence of a base.
[화학식 2][Formula 2]
[화학식 3] [Formula 3]
상기 화학식 3의 화합물의 제조방법에 대한 상세한 설명은 상기 피마살탄의 제조방법과 관련하여 상술한 제1단계와 동일하므로, 중복을 피하기 위해 구체적인 설명을 생략한다.The detailed description of the method for preparing the compound of Formula 3 is the same as the first step described above with respect to the method for preparing the fimasartan, so a detailed description is omitted to avoid duplication.
본 발명의 제조방법에 따르면, 피마살탄 및 그의 제조 중간체를 우레아 부산물 생성을 억제하면서 간단한 공정으로 저렴한 원료를 사용하여 제조할 수 있다. 아울러, 반응시간을 단축하며 후처리 공정을 단순화할 수 있다. 따라서, 본 발명의 제조방법은 피마살탄의 상업적 생산 공정에 효과적으로 적용될 수 있다. According to the production method of the present invention, fimasartan and its intermediates can be produced using inexpensive raw materials in a simple process while suppressing the production of urea byproducts. In addition, it is possible to shorten the reaction time and simplify the post-treatment process. Therefore, the manufacturing method of the present invention can be effectively applied to the commercial production process of fimasartan.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.Hereinafter, the present invention will be described in more detail by examples. It is apparent to those skilled in the art that these examples are only for describing the present invention, and the scope of the present invention is not limited to these examples.
제조예Manufacturing example 1 : 21: 2 -부틸-1,6--Butyl-1,6- 디히드로Dehydro -4--4- 메틸methyl -6--6- 옥스Oaks -5--5- 피리미딘아세트산의Pyrimidineacetic acid 제조 Produce
2-n-부틸-5-에톡시카르보닐메틸-4-히드록시-6-메틸피리미딘 95 g, 메탄올 240 mL, 테트라하이드로푸란 700 mL을 투입하였다. 10 % 수산화나트륨 수용액 1,000 g을 투입하고 실온에서 3 시간 교반하였다. 반응액을 0 ~ 5 ℃로 냉각한 후 10% 염산 수용액으로 pH 4.0으로 맞추고 1 시간 교반하여 생성된 고체를 여과한 후 정제수로 세척하였다. 50 ~ 55 ℃에서 12 시간 진공 건조하여 2-부틸-1,6-디히드로-4-메틸-6-옥스-5-피리미딘아세트산 79 g(수율 95%)을 수득하였다. 95 g of 2-n-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine, 240 mL of methanol and 700 mL of tetrahydrofuran were added. 1,000 g of a 10% aqueous sodium hydroxide solution was added and stirred at room temperature for 3 hours. After cooling the reaction solution to 0 ~ 5 ℃ to pH 4.0 with a 10% hydrochloric acid aqueous solution and stirred for 1 hour to filter the resulting solid was washed with purified water. Vacuum drying at 50-55° C. for 12 hours yielded 79 g of 2-butyl-1,6-dihydro-4-methyl-6-ox-5-pyrimidineacetic acid (95% yield).
1H NMR (400MHz, DMSO-d6): δ 3.33(s, 2H), 2.43(m, 2H), 2.10(s, 3H), 1.57(m,2H), 1.26(m, 2H), 0.85(t, 3H) 1 H NMR (400MHz, DMSO-d 6 ): δ 3.33(s, 2H), 2.43(m, 2H), 2.10(s, 3H), 1.57(m,2H), 1.26(m, 2H), 0.85( t, 3H)
실시예Example 1 : 21: 2 -(2-n-부틸-4-히드록시-6--(2-n-butyl-4-hydroxy-6- 메틸피리미딘Methylpyrimidine -5-일)--5 days)- N,NN,N -디메틸아세트아미드의 제조-Preparation of dimethylacetamide
제조예 1에서 얻은 2-부틸-1,6-디히드로-4-메틸-6-옥스-5-피리미딘아세트산 79 g, 디메틸아민염산염 57 g, N-히드록시숙신이미드 53 g, N,N’-디이소프로필카보디이미드 89 g, 트리에틸아민 96 g, 디클로로메탄 800 mL을 투입하고 30 ~ 35 ℃에서 3 시간 교반하였다. 반응액을 0 ~ 5 ℃로 냉각하고 2 시간 교반하였다. 생성된 고체를 여과하고 이소프로필알콜에서 재결정화 한 후, 50 ~ 55 ℃에서 12 시간 이상 진공 건조하여 2-(2-n-부틸-4-히드록시-6-메틸피리미딘-5-일)-N,N-디메틸아세트아미드 75 g (수율 85%)을 수득하였다. 2-butyl-1,6-dihydro-4-methyl-6-ox-5-pyrimidineacetic acid obtained in Preparation Example 1 79 g, dimethylamine hydrochloride 57 g, N-hydroxysuccinimide 53 g, N, 89 g of N'-diisopropylcarbodiimide, 96 g of triethylamine, and 800 mL of dichloromethane were added and stirred at 30 to 35°C for 3 hours. The reaction solution was cooled to 0-5 °C and stirred for 2 hours. The resulting solid was filtered and recrystallized from isopropyl alcohol, followed by vacuum drying at 50 to 55°C for at least 12 hours to 2-(2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl) 75 g (85% yield) of -N,N-dimethylacetamide was obtained.
1H NMR (400MHz, DMSO-d6): δ 3.40(s, 2H),3.03(s, 3H),2.78(s, 3H), 2.45(m, 2H), 2.05(s, 3H), 1.58(m,2H), 1.26(m, 2H), 0.85(t, 3H) 1 H NMR (400MHz, DMSO-d 6 ): δ 3.40(s, 2H), 3.03(s, 3H), 2.78(s, 3H), 2.45(m, 2H), 2.05(s, 3H), 1.58( m,2H), 1.26(m, 2H), 0.85(t, 3H)
실시예Example 2 : 22: 2 -n-부틸-5--n-butyl-5- 디메틸아미노카르보닐메틸Dimethylaminocarbonylmethyl -6--6- 메틸methyl -3-[[2′-(N--3-[[2′-(N- 트리페닐메틸테트라졸Triphenylmethyltetrazole -5-일)비페닐-4-일]메틸]-피리미딘-4(3H)-온의 제조Preparation of -5-yl)biphenyl-4-yl]methyl]-pyrimidin-4(3H)-one
실시예 1에서 얻은 2-(2-n-부틸-4-히드록시-6-메틸피리미딘-5-일)-N,N-디메틸아세트아미드 75 g, 5-(4'-브로모메틸-1,1'-비페닐-2-일)-1-트리페닐메틸-1H-테트라졸 180 g, 디메틸포름아미드 75 mL, 톨루엔 680 mL, 리튬히드록사이드 8 g을 투입하고 60 ~ 65 ℃에서 24 시간 교반하였다. 생성된 고체를 여과한 후 톨루엔으로 세척하였다. 50 ~ 55 ℃에서 12 시간 이상 진공 건조하여 2-n-부틸-5-디메틸아미노카르보닐메틸-6-메틸-3-[[2′-(N-트리페닐메틸테트라졸-5-일)비페닐-4-일]메틸]-피리미딘-4(3H)-온 153 g (수율 70%)을 수득하였다. 75 g of 2-(2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide obtained in Example 1, 5-(4'-bromomethyl- 180 g of 1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole, 75 mL of dimethylformamide, 680 mL of toluene, and 8 g of lithium hydroxide were added thereto at 60 to 65°C. Stir for 24 hours. The resulting solid was filtered and washed with toluene. 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2′-(N-triphenylmethyltetrazol-5-yl) ratio by vacuum drying at 50 to 55° C. for at least 12 hours Phenyl-4-yl]methyl]-pyrimidine-4(3H)-one 153 g (yield 70%) was obtained.
1H NMR (400MHz, CDCl3): δ 7.89(m, 1H), 7.44(m, 2H), 7.31(m, 4H), 7.24(m, 6H), 7.07(m, 2H), 6.91(m, 8H), 5.16(s, 2H), 3.61(s, 2H), 3.14(s, 3H), 2.95(s, 3H), 2.50(m, 2H), 2.32(s, 3H), 1.57(m, 2H), 1.25(m, 2H), 0.83(t, 3H) 1 H NMR (400 MHz, CDCl 3 ): δ 7.89 (m, 1H), 7.44 (m, 2H), 7.31 (m, 4H), 7.24 (m, 6H), 7.07 (m, 2H), 6.91 (m, 8H), 5.16(s, 2H), 3.61(s, 2H), 3.14(s, 3H), 2.95(s, 3H), 2.50(m, 2H), 2.32(s, 3H), 1.57(m, 2H) ), 1.25 (m, 2H), 0.83 (t, 3H)
실시예Example 3 : 23: 2 -n-부틸-5--n-butyl-5- 디메틸아미노티오카르보닐메틸Dimethylaminothiocarbonylmethyl -6--6- 메틸methyl -3-[[2′-(1H--3-[[2′-(1H- 테트라졸Tetrazole -5-일)비페닐-4-일]-5-yl)biphenyl-4-yl] 메틸methyl ]-피리미딘-4(3H)-온(피마살탄)의 제조 ]-Preparation of pyrimidine-4(3H)-one (fimasartan)
실시예 2에서 얻은 2-n-부틸-5-디메틸아미노카르보닐메틸-6-메틸-3-[[2′-(N-트리페닐메틸테트라졸-5-일)비페닐-4-일]메틸]-피리미딘-4(3H)-온 153 g, P2S5-피리딘 시약 96 g, 톨루엔 1,500 mL을 투입하고 3시간 가열환류한 후 실온으로 냉각하여 물로 세척하였다. 유기층을 분리하고 농축 후 진한 염산 22 g, 메탄올 700 mL을 투입하였다. 반응액을 3시간 가열환류하고 실온으로 냉각하였다. 반응액을 농축하고 에틸아세테이트를 투입하여 실온에서 6시간 교반하였다. 생성된 고체를 여과하고 에틸아세테이트로 세척하였다. 50 ~ 55 ℃에서 12시간 이상 진공 건조하여 2-n-부틸-5-디메틸아미노티오카르보닐메틸-6-메틸-3-[[2′-(1H-테트라졸-5-일)비페닐-4-일]메틸]-피리미딘-4(3H)-온 85 g (수율 80%)을 수득하였다. 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2′-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl] obtained in Example 2] Methyl]-pyrimidine-4(3H)-one 153 g, P 2 S 5 -pyridine reagent 96 g, toluene 1,500 mL was added, heated to reflux for 3 hours, cooled to room temperature, and washed with water. After separating and concentrating the organic layer, 22 g of concentrated hydrochloric acid and 700 mL of methanol were added. The reaction solution was heated to reflux for 3 hours and cooled to room temperature. The reaction solution was concentrated and ethyl acetate was added thereto, followed by stirring at room temperature for 6 hours. The resulting solid was filtered and washed with ethyl acetate. 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl- by vacuum drying at 50-55°C for at least 12 hours 4-yl]methyl]-pyrimidine-4(3H)-one 85 g (yield 80%) was obtained.
1H NMR (400MHz, DMSO-d6): δ 7.45(m, 1H), 7.30(m, 3H), 7.02(m, 2H), 6.92(m, 2H), 5.21(s, 2H), 3.75(s, 2H), 3.46(s, 3H), 3.38(s, 3H), 2.57(m, 2H), 2.13(s, 3H), 1.53(m, 2H), 1.25(m, 2H), 0.79(t, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.45 (m, 1H), 7.30 (m, 3H), 7.02 (m, 2H), 6.92 (m, 2H), 5.21 (s, 2H), 3.75 ( s, 2H), 3.46 (s, 3H), 3.38 (s, 3H), 2.57 (m, 2H), 2.13 (s, 3H), 1.53 (m, 2H), 1.25 (m, 2H), 0.79 (t , 3H)
실시예Example 4 : 4 : 피마살탄Fimasartan 트로메타민염Tromethamine salt 이수화물의 제조 Preparation of dihydrate
실시예 3에서 얻은 2-n-부틸-5-디메틸아미노티오카르보닐메틸-6-메틸-3-[[2′-(1H-테트라졸-5-일)비페닐-4-일]메틸]-피리미딘-4(3H)-온 85 g, 트로메타민 21 g, 이소프로판올 900 mL을 넣고 가열환류하여 용해시켰다. 반응액을 20 ~ 30 ℃로 냉각하고 반응액에 정제수 160 mL을 투입하였다. 상기 반응액을 0 ~ 5 ℃로 냉각하고 2 시간 동안 교반한 다음 생성된 고체를 여과하고 50 ~ 55 ℃에서 12시간 이상 진공 건조하여 피마사탄 트로메타민염 이수화물 100 g (수율 90%)을 수득하였다.2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl obtained in Example 3] -Pyrimidine-4(3H)-one 85 g, tromethamine 21 g, isopropanol 900 mL was added thereto, and heated to reflux to dissolve. The reaction solution was cooled to 20 to 30°C, and 160 mL of purified water was added to the reaction solution. The reaction solution was cooled to 0-5° C., stirred for 2 hours, and then the resulting solid was filtered and vacuum dried at 50-55° C. for 12 hours or more to obtain 100 g of pimasartan tromethamine salt dihydrate (90% yield). Did.
1H NMR (400MHz, DMSO-d6): δ 7.50(m, 1H), 7.33(m, 3H), 7.02(d, 2H), 6.94(d,2H), 5.21(br, 2H), 3.75(s, 3H), 3.41(m, 12H), 2.58(m, 2H), 2.47(m,3H), 2.13(s, 3H), 1.53(m, 2H), 1.24(m, 2H), 0.78(t, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.50 (m, 1H), 7.33 (m, 3H), 7.02 (d, 2H), 6.94 (d, 2H), 5.21 (br, 2H), 3.75 ( s, 3H), 3.41 (m, 12H), 2.58 (m, 2H), 2.47 (m, 3H), 2.13 (s, 3H), 1.53 (m, 2H), 1.24 (m, 2H), 0.78 (t , 3H)
수분 (KF법) : 5.60% Moisture (KF method): 5.60%
Claims (9)
(ii) 하기 화학식 3의 화합물을 염기의 존재 하에 하기 화학식 4의 화합물과 N-알킬화 반응시켜 하기 화학식 5의 화합물을 수득하는 단계;
(iii) 하기 화학식 5의 화합물을 P2S5-피리딘 시약으로 티오아미드화 반응시켜 하기 화학식 6의 화합물을 수득하는 단계; 및
(iv) 하기 화학식 6의 화합물을 산 존재 하에 탈보호화 반응시키는 단계를 포함하는 하기 화학식 1의 피마살탄의 제조방법:
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[화학식 6]
[화학식 1]
(ii) subjecting the compound of formula 3 to N-alkylation reaction with the compound of formula 4 in the presence of a base to obtain a compound of formula 5;
(iii) subjecting the compound of formula 5 to a thioamide reaction with a P 2 S 5 -pyridine reagent to obtain a compound of formula 6; And
(iv) a method for preparing fimasartan of formula 1, which comprises the step of deprotecting the compound of formula 6 in the presence of an acid:
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
[Formula 6]
[Formula 1]
(vi) 물을 추가하는 단계; 및
(vii) 반응물을 교반하여 생성된 고체를 여과하는 단계를 포함하는 피마살탄 트로메타민염 이수화물의 제조방법. (v) dissolving fimasartan and tromethamine prepared by the manufacturing method according to any one of claims 1 to 7 in an organic solvent;
(vi) adding water; And
(vii) A method for preparing fimasartan tromethamine salt dihydrate comprising the step of filtering the resulting solid by stirring the reactants.
[화학식 2]
[화학식 3]
[Formula 2]
[Formula 3]
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| KR100521980B1 (en) | 2002-10-10 | 2005-10-17 | 보령제약 주식회사 | The preparation method for pyrimidinone compound and trihydrate of the salt of the pyrimidinone compound |
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| CN113336709B (en) * | 2021-06-25 | 2022-06-03 | 上海立科化学科技有限公司 | Preparation method of N, N-dimethylacetamide |
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