JP6876708B2 - エフィナコナゾールの合成方法 - Google Patents
エフィナコナゾールの合成方法 Download PDFInfo
- Publication number
- JP6876708B2 JP6876708B2 JP2018533860A JP2018533860A JP6876708B2 JP 6876708 B2 JP6876708 B2 JP 6876708B2 JP 2018533860 A JP2018533860 A JP 2018533860A JP 2018533860 A JP2018533860 A JP 2018533860A JP 6876708 B2 JP6876708 B2 JP 6876708B2
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- JP
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- Prior art keywords
- efinaconazole
- reaction
- water
- temperature
- ethanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- NFEZZTICAUWDHU-RDTXWAMCSA-N efinaconazole Chemical compound N1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)CCC(=C)CC1 NFEZZTICAUWDHU-RDTXWAMCSA-N 0.000 title claims description 30
- 229960003937 efinaconazole Drugs 0.000 title claims description 30
- 238000000034 method Methods 0.000 title claims description 10
- 230000002194 synthesizing effect Effects 0.000 title description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 15
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 11
- 239000012458 free base Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- LPKIGDXRQSIQBA-UHFFFAOYSA-N 4-methylidenepiperidine Chemical compound C=C1CCNCC1 LPKIGDXRQSIQBA-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 22
- 239000000725 suspension Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- CLASDMKBOIFHNY-UHFFFAOYSA-N 2-methylidenepiperidine Chemical compound C=C1CCCCN1 CLASDMKBOIFHNY-UHFFFAOYSA-N 0.000 description 12
- ISPQVMBOGGGEAV-UHFFFAOYSA-N 2-methylidenepiperidine;hydrochloride Chemical compound Cl.C=C1CCCCN1 ISPQVMBOGGGEAV-UHFFFAOYSA-N 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000002441 X-ray diffraction Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 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 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- -1 alkyl hydrocarbons Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 230000020169 heat generation Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- UNFJWHIOPXIYGO-UHFFFAOYSA-N 2-methylidenepiperidine hydrobromide Chemical compound Br.C=C1CCCCN1 UNFJWHIOPXIYGO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 241001365789 Oenanthe crocata Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 1
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Description
1−[[(2R,3S)−2−(2,4−ジフルオロフェニル)−3−メチルオキシラニル]メチル]−1H−1,2,4−トリアゾール(172.5g、0.6866mol)のアセトニトリル(690ml)溶液に、メチレンピペリジン塩酸塩(119.27g、0.8926mol)を加える。
0〜5℃に冷却した、メチレンピペリジン塩酸塩(3.45g、25.9mmol)の無水テトラヒドロフラン(20ml)懸濁液に、テトラヒドロフラン中の2.0Mイソプロピルマグネシウムクロリド(12.3g、25.2mmol)を約1時間かけて加える。
メチレンピペリジン塩酸塩(119.27g、0.8926モル)、アセトニトリル(690ml)およびジイソプロピルエチルアミン(124.2g、0.961モル)の懸濁液を調製する。
予め0〜5℃に冷却したメチレンピペリジン塩酸塩(3.45g、25.9mmol)の無水テトラヒドロフラン(20ml)懸濁液に、テトラヒドロフラン中の2.0Mイソプロピルマグネシウムクロリド(12.3g、25.2mmol)を約1時間かけて加える。次いで、得られた懸濁液を、1−[[(2R,3S)−2−(2,4−ジフルオロフェニル)−3−メチルオキシラニル]メチル]−1H−1,2,4−トリアゾール中間体(5.00g、19.9mmol)のアセトニトリル(10ml)懸濁液に加える。
粗製エフィナコナゾール(354.0g)をエタノール(1580ml)に溶解する。
エフィナコナゾールp−トルエンスルホン酸塩(454.0g、0.873mol)をエタノール(870ml)と水(500ml)の混合物に溶解する。
Claims (4)
- 非プロトン性有機溶媒中、無水条件下、中和剤および反応を促進するアルキルマグネシウムハライドおよび無水塩化マグネシウムから選択される金属種の存在下で、1−[[(2R,3S)−2−(2,4−ジフルオロフェニル)−3−メチルオキシラニル]メチル]−1H−1,2,4−トリアゾールを、遊離塩基または塩酸塩としての4−メチレンピペリジンと反応させることを含む、エフィナコナゾールの合成方法。
- 前記非プロトン性有機溶媒がアセトニトリルまたはテトラヒドロフランまたは2−メチルテトラヒドロフランである、請求項1に記載の方法。
- 前記中和剤が、有機アミンおよびアルキルマグネシウムハライドから選択される、請求項1又は2に記載の方法。
- 前記中和剤が、N,N−ジイソプロピルエチルアミン(DIPEA)およびイソプロピルマグネシウムブロミドまたはクロリドから選択される、請求項3に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITUB2015A009795A ITUB20159795A1 (it) | 2015-12-30 | 2015-12-30 | Processo per la sintesi di efinaconazolo |
IT102015000089243 | 2015-12-30 | ||
PCT/EP2016/082345 WO2017114743A1 (en) | 2015-12-30 | 2016-12-22 | Process for the synthesis of efinaconazol |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019501913A JP2019501913A (ja) | 2019-01-24 |
JP6876708B2 true JP6876708B2 (ja) | 2021-05-26 |
Family
ID=55858824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018533860A Active JP6876708B2 (ja) | 2015-12-30 | 2016-12-22 | エフィナコナゾールの合成方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US10626102B2 (ja) |
EP (1) | EP3397628B1 (ja) |
JP (1) | JP6876708B2 (ja) |
ES (1) | ES2749171T3 (ja) |
IT (1) | ITUB20159795A1 (ja) |
WO (1) | WO2017114743A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018212333A1 (ja) | 2017-05-19 | 2018-11-22 | 科研製薬株式会社 | エフィナコナゾールの製造及び精製方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1046278C (zh) * | 1993-05-10 | 1999-11-10 | 科研制药株式会社 | 吡咯胺衍生物 |
DK2612859T3 (en) * | 2010-08-31 | 2015-10-19 | Kaken Pharma Co Ltd | PROCEDURE FOR PREPARING 1-TRIAZOL-2-BUTANOL DERIVATE. |
WO2016079728A1 (en) * | 2014-11-23 | 2016-05-26 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of efinaconazole |
AU2016261273A1 (en) * | 2015-05-12 | 2017-12-07 | Lupin Limited | Process for the preparation of efinaconazole |
EP3112360A1 (en) * | 2015-06-29 | 2017-01-04 | Dipharma Francis S.r.l. | Process for the preparation of efinaconazole |
-
2015
- 2015-12-30 IT ITUB2015A009795A patent/ITUB20159795A1/it unknown
-
2016
- 2016-12-22 WO PCT/EP2016/082345 patent/WO2017114743A1/en active Application Filing
- 2016-12-22 JP JP2018533860A patent/JP6876708B2/ja active Active
- 2016-12-22 US US16/066,328 patent/US10626102B2/en active Active
- 2016-12-22 EP EP16825421.7A patent/EP3397628B1/en active Active
- 2016-12-22 ES ES16825421T patent/ES2749171T3/es active Active
Also Published As
Publication number | Publication date |
---|---|
US20190010141A1 (en) | 2019-01-10 |
ES2749171T3 (es) | 2020-03-19 |
JP2019501913A (ja) | 2019-01-24 |
EP3397628A1 (en) | 2018-11-07 |
WO2017114743A1 (en) | 2017-07-06 |
ITUB20159795A1 (it) | 2017-06-30 |
US10626102B2 (en) | 2020-04-21 |
EP3397628B1 (en) | 2019-09-18 |
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