JP2022166243A - オメカムティブメカルビルの合成 - Google Patents
オメカムティブメカルビルの合成 Download PDFInfo
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- JP2022166243A JP2022166243A JP2022130911A JP2022130911A JP2022166243A JP 2022166243 A JP2022166243 A JP 2022166243A JP 2022130911 A JP2022130911 A JP 2022130911A JP 2022130911 A JP2022130911 A JP 2022130911A JP 2022166243 A JP2022166243 A JP 2022166243A
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- omecamtive
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 5
- RFUBTTPMWSKEIW-UHFFFAOYSA-N omecamtiv mecarbil Chemical compound C1CN(C(=O)OC)CCN1CC1=CC=CC(NC(=O)NC=2C=NC(C)=CC=2)=C1F RFUBTTPMWSKEIW-UHFFFAOYSA-N 0.000 title abstract description 6
- 229950001617 omecamtiv mecarbil Drugs 0.000 title abstract 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 66
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 claims abstract description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000005270 trialkylamine group Chemical group 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims description 101
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 97
- 239000000243 solution Substances 0.000 claims description 95
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 91
- UENBBJXGCWILBM-UHFFFAOYSA-N 6-methylpyridin-3-amine Chemical compound CC1=CC=C(N)C=N1 UENBBJXGCWILBM-UHFFFAOYSA-N 0.000 claims description 85
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- 238000002156 mixing Methods 0.000 claims description 48
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 41
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 38
- 239000012458 free base Substances 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 36
- TWHXWYVOWJCXSI-UHFFFAOYSA-N phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O TWHXWYVOWJCXSI-UHFFFAOYSA-N 0.000 claims description 36
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 35
- 229940011051 isopropyl acetate Drugs 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- 229910019142 PO4 Inorganic materials 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 31
- 239000010452 phosphate Substances 0.000 claims description 29
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- 238000006243 chemical reaction Methods 0.000 claims description 24
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 22
- NBCNUIXYBLFJMI-UHFFFAOYSA-N 2-fluoro-1-methyl-3-nitrobenzene Chemical compound CC1=CC=CC([N+]([O-])=O)=C1F NBCNUIXYBLFJMI-UHFFFAOYSA-N 0.000 claims description 21
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
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- WNYADZVDBIBLJJ-UHFFFAOYSA-N N-Nitrosopyrrolidine Chemical compound O=NN1CCCC1 WNYADZVDBIBLJJ-UHFFFAOYSA-N 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 10
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 8
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- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 7
- 238000002955 isolation Methods 0.000 claims description 6
- QPDHXGBVJICHLM-UHFFFAOYSA-N methyl 4-[(3-amino-2-fluorophenyl)methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC)CCN1CC1=CC=CC(N)=C1F QPDHXGBVJICHLM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 6
- OSHVGUAPPIYWIS-UHFFFAOYSA-N piperazin-1-ium;acetate Chemical compound CC(O)=O.C1CNCCN1 OSHVGUAPPIYWIS-UHFFFAOYSA-N 0.000 claims description 6
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 6
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- MIESICVJNXXYKC-UHFFFAOYSA-N 1-(bromomethyl)-2-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(CBr)=C1F MIESICVJNXXYKC-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 5
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 5
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- 238000010924 continuous production Methods 0.000 claims description 4
- QBSLBISOVGGPJO-UHFFFAOYSA-N methyl 4-[(2-fluoro-3-nitrophenyl)methyl]piperazine-1-carboxylate Chemical compound COC(=O)N1CCN(Cc2cccc(c2F)[N+]([O-])=O)CC1 QBSLBISOVGGPJO-UHFFFAOYSA-N 0.000 claims description 4
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- 238000005292 vacuum distillation Methods 0.000 description 1
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- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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Abstract
Description
Claims (33)
- 工程(a)で生成された前記PMECを、メチレンクロリド、ジクロロエタン、2-メチルテトラヒドロフラン、又はこれらの混合物の溶液として単離する工程をさらに含む、請求項2に記載の方法。
- 前記単離は、
(i)前記工程(a)で得られたPMECを有機溶媒で洗浄する工程;
(ii)塩基を加えてpHを8~14に変更することにより、塩基性水溶液を生成する工程;及び
(iii)メチレンクロリド、ジクロロエタン、2-メチルテトラヒドロフラン、又はこれらの混合物によって、前記工程(ii)の塩基性水溶液から前記PMECを抽出する工程
により行われる、請求項3に記載の方法。 - 工程(a)は水溶液中で行われる、請求項2に記載の方法。
- 工程(a)は、20~55℃の温度で1~12時間行われる、請求項2~5のいずれか一項に記載の方法。
- 前記FNBは、チオ硫酸ナトリウム水溶液及び塩化ナトリウム水溶液で洗浄される、請求項7に記載の方法。
- FNBはトルエンで抽出され、水酸化ナトリウム水溶液で洗浄される、請求項9に記載の方法。
- 前記PIPNは塩酸塩として生成される、請求項7~10のいずれか一項に記載の方法。
- 前記PMECリン酸塩水和物は、請求項2~6のいずれか一項に記載の方法によって調製される、請求項7~11のいずれか一項に記載の方法。
- 前記トリアルキルアミン塩基は、ジイソプロピルエチルアミン又はトリエチルアミンを含む、請求項7~12のいずれか一項に記載の方法。
- 前記FNB、前記トリアルキルアミン塩基、及び前記PMECリン酸塩水和物を混合する前に、ジエチルホスファイト及びトリアルキルアミンを加え、得られた混合物を30~65℃の温度で混合することをさらに含む、請求項7~13のいずれか一項に記載の方法。
- 前記混合は15~30℃の温度で1~15時間行われる、請求項15に記載の方法。
- 前記PCARは塩酸塩として生成される、請求項15又は16に記載の方法。
- 工程(i)の前に、イソプロピルアセテート中のNPYRを水酸化ナトリウム水溶液で洗浄し、続いて前記イソプロピルアセテート中の洗浄済みNPYRを木炭と混合する工程をさらに含む、請求項18に記載の方法。
- APYRとフェニルクロロホルメートを混合する前に、
(i)粗APYRのイソプロピルアセテート溶液であって、前記粗APYRは10重量%までのAPYR塩酸塩を含むもの、を水酸化ナトリウム水溶液で洗浄し、前記洗浄済みAPYRを木炭と混合して、ろ過後にAPYR溶液を生成する工程;並びに
(ii)前記工程(i)のAPYR溶液から、イソプロピルアセテート及びヘプタンによりAPYRを結晶化する工程
を含む方法によりAPYRを精製する工程をさらに含む、請求項15~17のいずれか一項に記載の方法。 - PCARを結晶化させる工程をさらに含む、請求項15~20のいずれか一項に記載の方法。
- 前記無機塩基は水酸化ナトリウムを含む、請求項22に記載の方法。
- オメカムティブメカルビル二塩酸塩水和物を調製する方法であって、
(a)アセトニトリル及びテトラヒドロフラン中でメチル4-(3-アミノ-2-フルオロベンジル)ピペラジン-1-カルボキシレート
(b)前記粗オメカムティブメカルビル溶液からオメカムティブメカルビル遊離塩基を単離する工程;並びに
(c)前記単離されたオメカムティブメカルビル遊離塩基を、イソプロパノール及び水中で2~3モル当量の塩酸と混合して、オメカムティブメカルビル二塩酸塩水和物
を含む方法。 - 前記トリアルキルアミンは、ジイソプロピルエチルアミン又はトリエチルアミンを含む、請求項24に記載の方法。
- 前記工程(b)の単離は、前記工程(a)からの粗オメカムティブメカルビルの溶液に水を加えることによって、オメカムティブメカルビル遊離塩基を結晶化させる工程、及び前記結晶化したオメカムティブメカルビル遊離塩基をろ過する工程を含む、請求項24又は25に記載の方法。
- イソプロパノール及び水から前記オメカムティブメカルビル二塩酸塩水和物を結晶化させる工程をさらに含む、請求項24~26のいずれか一項に記載の方法。
- 前記PCARは、請求項15~21のいずれか一項に記載の方法によって調製される、請求項24~27のいずれか一項に記載の方法。
- オメカムティブメカルビル二塩酸塩水和物を調製する方法であって、
(a)メチル4-(3-アミノ-2-フルオロベンジル)ピペラジン-1-カルボキシレート
(b)前記PIPAイソシアネートと5-アミノ-2-メチルピリジン
(c)前記オメカムティブメカルビル遊離塩基を、イソプロパノール及び水中で2~3モル当量の塩酸と混合して、オメカムティブメカルビル二塩酸塩水和物を生成する工程
を含む方法。 - 工程(a)は、PIPA及び前記トリアルキルアミンをアセトニトリル中に含む第1の溶液と、トリホスゲンをテトラヒドロフラン中に含む第2の溶液とを、マイクロミキサーチップ及び反応ループを用いて混合して、前記PIPAイソシアネートを生成する工程を含む連続製造により行われる、請求項29に記載の方法。
- 工程(b)は、前記PIPAイソシアネートを含む溶液と前記AYPRを含む溶液とを、Yミキサー及び反応ループを用いて混合する工程を含む連続製造により行われる、請求項29又は30に記載の方法。
- 前記APYRは、前記請求項18~21のいずれか一項に記載の方法によって調製される、請求項29~31のいずれか一項に記載の方法。
- 前記PIPAは、前記請求項21~23のいずれか一項に記載の方法によって調製される、請求項24~32のいずれか一項に記載の方法。
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