JP6980315B2 - ラタノプロステンブノドの製造方法及びそのための中間体 - Google Patents
ラタノプロステンブノドの製造方法及びそのための中間体 Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims description 27
- 239000000543 intermediate Substances 0.000 title description 5
- 238000000034 method Methods 0.000 title description 3
- 239000000126 substance Substances 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 150000004682 monohydrates Chemical class 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 101710134784 Agnoprotein Proteins 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 9
- -1 4- (nitrooxy) butyl Chemical group 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KPSZWAJWFMFMFF-UHFFFAOYSA-N hept-5-enoic acid Chemical compound CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 description 3
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- HNPFPERDNWXAGS-LZCJLJQNSA-N (e)-7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl]hept-5-enoic acid Chemical compound C=1C=CC=CC=1CCC(O)CCC1C(O)CC(O)C1C\C=C\CCCC(O)=O HNPFPERDNWXAGS-LZCJLJQNSA-N 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 2
- IKDHVMDABUMCLO-UHFFFAOYSA-N 4-bromobutyl nitrate Chemical compound [O-][N+](=O)OCCCCBr IKDHVMDABUMCLO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000009739 binding Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KSRNMZVGEYUNEO-JNAAKWLTSA-N COC(CCC/C=C\C[C@H]([C@@H](CC[C@H](CCc1ccccc1)O)[C@@H](C1)O)[C@H]1O)=O Chemical compound COC(CCC/C=C\C[C@H]([C@@H](CC[C@H](CCc1ccccc1)O)[C@@H](C1)O)[C@H]1O)=O KSRNMZVGEYUNEO-JNAAKWLTSA-N 0.000 description 1
- 208000035484 Cellulite Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- LOVMMUBRQUFEAH-UIEAZXIASA-N Latanoprostene bunod Chemical compound C([C@@H](O)CCC=1C=CC=CC=1)C[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OCCCCO[N+]([O-])=O LOVMMUBRQUFEAH-UIEAZXIASA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- HNPFPERDNWXAGS-NFVOFSAMSA-N O[C@H](CC[C@H]([C@@H](C/C=C\CCCC(O)=O)[C@H](C1)O)[C@@H]1O)CCc1ccccc1 Chemical compound O[C@H](CC[C@H]([C@@H](C/C=C\CCCC(O)=O)[C@H](C1)O)[C@@H]1O)CCc1ccccc1 HNPFPERDNWXAGS-NFVOFSAMSA-N 0.000 description 1
- 206010049752 Peau d'orange Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000036232 cellulite Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/02—Preparation of esters of nitric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C203/00—Esters of nitric or nitrous acid
- C07C203/02—Esters of nitric acid
- C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(i)下記化学式3で表される化合物を、下記化学式4で表される化合物とエステル化反応させて、下記化学式5で表される化合物を収得する段階;及び
(ii)下記化学式5で表される化合物のブロミドをニトロ化反応させる段階を含む。
化学式5で表される化合物は、化学式3で表される化合物を化学式4で表される化合物と塩基の存在下でエステル化反応させて製造することができる。
化学式1で表される化合物は、化学式5で表される化合物のブロミドをニトロ化反応させて製造することができる。
(i)下記化学式3で表される化合物を下記化学式4で表される化合物とエステル化反応させる段階を含む。
ラタノプロスト(2)(30g)をメタノール(600mL)に溶かした後、水(120mL)と水酸化リチウム・一水和物(14.55g)を加え、室温で約15時間撹拌した。反応の進行を薄層クロマトグラフィー(エチルアセテート:メタノール=15:1)にて観測した。反応完了後、反応溶媒を濃縮し、1M塩化アンモニウム(300mL)、2M硫酸水素ナトリウム(300mL)及びエチルアセテート(300mL)を加え、約15〜20分間撹拌した。有機層を分離し無水硫酸ナトリウムを加えて乾燥し、ろ過後に減圧濃縮した。得られた残留物をシリカゲルを用いたクロマトグラフィー(エチルアセテート:メタノール=5:1)にて精製して、純粋なラタノプロスト酸((Z)−7−((1R,2R,3R,5S)−3,5−ジヒドロキシ−2−((R)−3−ヒドロキシ−5−フェニルペンチル)シクロペンチル)ヘプト−5−エン酸)(3)(23.9g、88%)を収得した。
13C NMR (300 MHz, CDCl3) : δ = 177.5, 142.2, 129.6, 129.5, 128.6, 126.0, 78.7, 74.6, 71.7, 52.6, 51.9, 42.6, 38.9, 35.3, 33.2, 32.2, 29.2, 26.8, 26.5, 24.8, 14.3.。
化学式3で表される化合物(22.8g)をジメチルホルムイミド(342mL)に溶かした後、炭酸カリウム(24.2g)及び1,4−ジブロモブタン(4)(37.8g)を加え、約40〜50℃で約2時間加熱撹拌した。反応の進行を薄層クロマトグラフィー(エチルアセテート100%)にて観測した。反応完了後、飽和塩化ナトリウム水溶液(684mL)及びエチルアセテート(684mL)を加え、約15〜20分間撹拌した。有機層を分離して飽和塩化ナトリウム水溶液(456mL)で洗浄した。有機層を分離し、無水硫酸ナトリウムを加えて乾燥し、ろ過後に減圧濃縮した。得られた残留物をシリカゲルを用いたクロマトグラフィー(エチルアセテート100%)にて精製して、純粋な4−ブロモブチル(Z)−7−((1R,2R,3R,5S)−3,5−ジヒドロキシ−2−((R)−3−ヒドロキシ−5−フェニルペンチル)シクロペンチル)ヘプト−5−エノエート(5)(25.5g、83%)を収得した。
13C NMR (300 MHz, CDCl3) : δ = 174.0, 142.2, 129.6, 129.5, 128.6, 128.5, 126.0, 79.0, 74.9, 71.4, 69.6, 53.1, 52.0, 42.7, 39.2, 35.9, 33.8, 33.2, 32.3, 29.8, 29.4, 27.4, 27.1, 26.8, 25.0.。
化学式5で表される化合物(25.5g)をアセトニトリル(382mL)に溶かした後、硝酸銀(16.5g)を加え、約30〜40℃で約40〜50時間加熱撹拌した。反応の進行を薄層クロマトグラフィー(ヘキサン:エタノール=5:1)にて観測した。反応完了後、反応物の温度を室温に冷却させ、不溶性固体をセルライトろ過を施して除去した。ろ過液を減圧濃縮し、エチルアセテート(382mL)及び水(382mL)を加え、約15〜20分間撹拌した。有機層を分離し、飽和塩化ナトリウム水溶液(382mL)を加え、約10〜15分間撹拌した。有機層を分離し、無水硫酸ナトリウムを加えて乾燥し、ろ過後に減圧濃縮した。得られた残留物をシリカゲルを用いたクロマトグラフィー(ヘキサン:エタノール=5:1)にて精製して、純粋な4−(ニトロオキシ)ブチル(Z)−7−((1R,2R,3R,5S)−3,5−ジヒドロキシ−2−((R)−3−ヒドロキシ−5−フェニルペンチル)シクロペンチル)ヘプト−5−エノエート(1)(14.0g、56.8%)を収得した。
13C NMR (300 MHz, CDCl3) : δ = 173.9, 142.2, 129.6, 129.5, 128.5, 128.5, 125.9, 78.9, 74.9, 72.7, 71.4, 63.6, 53.0, 52.0, 42.6, 39.2, 35.9, 33.9, 32.2, 29.7, 27.1, 26.7, 25.1, 24.9, 23.8.。
Claims (7)
- 段階(i)におけるエステル化反応は、塩基の存在下で行なわれる、請求項1に記載の製造方法。
- 前記塩基は、炭酸カリウムである、請求項2に記載の製造方法。
- 前記加水分解反応は、水酸化リチウム・一水和物を用いて行われる、請求項4に記載の製造方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2017-0101252 | 2017-08-09 | ||
KR1020170101252A KR102069205B1 (ko) | 2017-08-09 | 2017-08-09 | 라타노프로스틴 부노드의 제조 방법 및 그를 위한 중간체 |
PCT/KR2018/008854 WO2019031774A1 (ko) | 2017-08-09 | 2018-08-03 | 라타노프로스틴 부노드의 제조 방법 및 그를 위한 중간체 |
Publications (2)
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JP2020530010A JP2020530010A (ja) | 2020-10-15 |
JP6980315B2 true JP6980315B2 (ja) | 2021-12-15 |
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JP2020506760A Active JP6980315B2 (ja) | 2017-08-09 | 2018-08-03 | ラタノプロステンブノドの製造方法及びそのための中間体 |
Country Status (5)
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US (1) | US10870621B2 (ja) |
EP (1) | EP3666751A4 (ja) |
JP (1) | JP6980315B2 (ja) |
KR (1) | KR102069205B1 (ja) |
WO (1) | WO2019031774A1 (ja) |
Families Citing this family (1)
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US11332433B2 (en) * | 2020-07-24 | 2022-05-17 | Chirogate International Inc. | Process for the preparation of latanoprostene bunod and intermediate thereof and compositions comprising the same |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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CO4960662A1 (es) | 1997-08-28 | 2000-09-25 | Novartis Ag | Ciertos acidos 5-alquil-2-arilaminofenilaceticos y sus derivados |
NZ548271A (en) | 2004-01-05 | 2010-01-29 | Nicox Sa | Prostaglandin nitrooxyderivatives |
US7091231B2 (en) * | 2004-12-10 | 2006-08-15 | Allergan, Inc. | 12-Aryl prostaglandin analogs |
US7396829B2 (en) * | 2005-02-24 | 2008-07-08 | Nitromed, Inc. | Nitric oxide enhancing diuretic compounds, compositions and methods of use |
WO2007000641A2 (en) * | 2005-06-29 | 2007-01-04 | Pfizer Inc. | Prostaglandin derivatives |
US8211996B2 (en) * | 2008-12-01 | 2012-07-03 | The Regents Of The University Of California | Well-defined donor-acceptor rod-coil diblock copolymer based on P3HT containing C60 |
AU2011279909A1 (en) | 2010-07-19 | 2013-01-24 | Inspire Pharmaceuticals, Inc. | Bifunctional rho kinase inhibitor compounds, composition and use |
CN109528721B (zh) * | 2013-03-15 | 2021-10-01 | 爱瑞制药公司 | 联合治疗 |
HU231175B1 (hu) * | 2015-12-04 | 2021-06-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Tetszőleges, előre meghatározott minőségű Latanoprostene bunod előállítása gravitációs kromatográfiával |
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- 2017-08-09 KR KR1020170101252A patent/KR102069205B1/ko active IP Right Grant
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2018
- 2018-08-03 JP JP2020506760A patent/JP6980315B2/ja active Active
- 2018-08-03 US US16/636,955 patent/US10870621B2/en active Active
- 2018-08-03 EP EP18845115.7A patent/EP3666751A4/en active Pending
- 2018-08-03 WO PCT/KR2018/008854 patent/WO2019031774A1/ko unknown
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Publication number | Publication date |
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EP3666751A4 (en) | 2021-04-28 |
US20200165199A1 (en) | 2020-05-28 |
KR20190016820A (ko) | 2019-02-19 |
JP2020530010A (ja) | 2020-10-15 |
EP3666751A1 (en) | 2020-06-17 |
WO2019031774A1 (ko) | 2019-02-14 |
KR102069205B1 (ko) | 2020-01-22 |
US10870621B2 (en) | 2020-12-22 |
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