EA009985B1 - Новый способ получения рофлумиласта - Google Patents
Новый способ получения рофлумиласта Download PDFInfo
- Publication number
- EA009985B1 EA009985B1 EA200501350A EA200501350A EA009985B1 EA 009985 B1 EA009985 B1 EA 009985B1 EA 200501350 A EA200501350 A EA 200501350A EA 200501350 A EA200501350 A EA 200501350A EA 009985 B1 EA009985 B1 EA 009985B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- cyclopropylmethoxy
- amino
- activated
- dichloropyridine
- roflumilast
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 61
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960002586 roflumilast Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- IGFDIFLMMLWKKY-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid Chemical class OC(=O)C1=CC=C(OC(F)F)C(OCC2CC2)=C1 IGFDIFLMMLWKKY-UHFFFAOYSA-N 0.000 claims abstract description 43
- ISIQAMHROGZHOV-UHFFFAOYSA-N 3,5-dichloropyridin-4-amine Chemical compound NC1=C(Cl)C=NC=C1Cl ISIQAMHROGZHOV-UHFFFAOYSA-N 0.000 claims abstract description 42
- 150000001450 anions Chemical class 0.000 claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 48
- -1 4-amino-3,5-dichloropyridine anion Chemical class 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- LBLBOIFGYPHXGS-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride Chemical compound FC(F)OC1=CC=C(C(Cl)=O)C=C1OCC1CC1 LBLBOIFGYPHXGS-UHFFFAOYSA-N 0.000 claims description 6
- 201000004624 Dermatitis Diseases 0.000 claims description 6
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- 230000001154 acute effect Effects 0.000 claims description 5
- 239000006227 byproduct Substances 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- IJTMJUHUWQHBEA-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide Chemical compound OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 IJTMJUHUWQHBEA-UHFFFAOYSA-N 0.000 claims description 3
- 208000030090 Acute Disease Diseases 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 210000002345 respiratory system Anatomy 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 208000014085 Chronic respiratory disease Diseases 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- ABSOPIACDNJKKU-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl bromide Chemical compound FC(F)OC1=CC=C(C(Br)=O)C=C1OCC1CC1 ABSOPIACDNJKKU-UHFFFAOYSA-N 0.000 claims 1
- 208000017667 Chronic Disease Diseases 0.000 claims 1
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- 239000000443 aerosol Substances 0.000 description 9
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
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- 208000010668 atopic eczema Diseases 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- IJOHVNWQLHGGTA-UHFFFAOYSA-N 2-(3,5-dichloropyridin-4-yl)-4-methoxybenzamide Chemical compound ClC=1C=NC=C(C=1C1=C(C(=O)N)C=CC(=C1)OC)Cl IJOHVNWQLHGGTA-UHFFFAOYSA-N 0.000 description 5
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- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- OWWHXPWJCDTADU-UHFFFAOYSA-N 3-cyclopentyloxy-4-methoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC1CCCC1 OWWHXPWJCDTADU-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- RRRUXBQSQLKHEL-UHFFFAOYSA-N piclamilast Chemical compound COC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OC1CCCC1 RRRUXBQSQLKHEL-UHFFFAOYSA-N 0.000 description 2
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- ROLSWOAJNMKBLK-UHFFFAOYSA-N 2-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid Chemical compound OC(=O)C1=CC=C(OC(F)F)C=C1OCC1CC1 ROLSWOAJNMKBLK-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JLWMMYZWEHHTFF-UHFFFAOYSA-N 2-[6-(3-carbamimidoylphenoxy)-4-[di(propan-2-yl)amino]-3,5-difluoropyridin-2-yl]oxy-5-(2-methylpropylcarbamoyl)benzoic acid Chemical compound OC(=O)C1=CC(C(=O)NCC(C)C)=CC=C1OC1=NC(OC=2C=C(C=CC=2)C(N)=N)=C(F)C(N(C(C)C)C(C)C)=C1F JLWMMYZWEHHTFF-UHFFFAOYSA-N 0.000 description 1
- OICRLZODQDWPMK-UHFFFAOYSA-N 3-cyclopentyl-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1C1CCCC1 OICRLZODQDWPMK-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- PUPKPAZSFZOLOR-UHFFFAOYSA-N n,n-dimethylformamide;toluene Chemical group CN(C)C=O.CC1=CC=CC=C1 PUPKPAZSFZOLOR-UHFFFAOYSA-N 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- Chemical & Material Sciences (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03005245 | 2003-03-10 | ||
| PCT/EP2004/050272 WO2004080967A1 (en) | 2003-03-10 | 2004-03-08 | Novel process for the preparation of roflumilast |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200501350A1 EA200501350A1 (ru) | 2006-04-28 |
| EA009985B1 true EA009985B1 (ru) | 2008-04-28 |
Family
ID=32981730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200501350A EA009985B1 (ru) | 2003-03-10 | 2004-03-08 | Новый способ получения рофлумиласта |
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| JP (1) | JP4742026B2 (enExample) |
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| AT (1) | ATE447555T1 (enExample) |
| AU (1) | AU2004220357B2 (enExample) |
| BR (1) | BRPI0406427B8 (enExample) |
| CA (1) | CA2503290C (enExample) |
| CY (1) | CY1109580T1 (enExample) |
| DE (1) | DE602004023921D1 (enExample) |
| DK (1) | DK1606261T3 (enExample) |
| EA (1) | EA009985B1 (enExample) |
| ES (1) | ES2335498T3 (enExample) |
| HR (1) | HRP20050399B1 (enExample) |
| IL (1) | IL168170A (enExample) |
| IS (1) | IS2723B (enExample) |
| ME (1) | ME00524B (enExample) |
| MX (1) | MXPA04008070A (enExample) |
| NO (1) | NO329301B1 (enExample) |
| NZ (1) | NZ539542A (enExample) |
| PL (1) | PL1606261T3 (enExample) |
| PT (1) | PT1606261E (enExample) |
| RS (2) | RS52908B (enExample) |
| SI (1) | SI1606261T1 (enExample) |
| TW (1) | TWI340741B (enExample) |
| WO (1) | WO2004080967A1 (enExample) |
| ZA (1) | ZA200503191B (enExample) |
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| EP1755595A1 (en) * | 2004-05-10 | 2007-02-28 | Altana Pharma AG | Use of roflumilast for the prophylaxis or treatment of emphysema |
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| CN102617457A (zh) * | 2011-01-28 | 2012-08-01 | 天津药物研究院 | 一种制备罗氟司特的新方法 |
| WO2012147098A2 (en) * | 2011-04-28 | 2012-11-01 | Glenmark Generics Limited | Novel process for the preparation of 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide |
| CN102775345A (zh) * | 2011-05-13 | 2012-11-14 | 上海特化医药科技有限公司 | 制备罗氟司特的方法及中间体 |
| CN102336703B (zh) * | 2011-07-20 | 2013-09-25 | 华润赛科药业有限责任公司 | 一种制备罗氟司特的方法 |
| CN102351787B (zh) * | 2011-08-18 | 2014-08-13 | 天津市汉康医药生物技术有限公司 | 高生物利用度的罗氟司特化合物 |
| CN103012255B (zh) * | 2011-09-21 | 2014-06-11 | 天津康鸿医药科技发展有限公司 | 罗氟司特晶型化合物、其制备方法、组合物及应用 |
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| CN103570610B (zh) * | 2012-07-18 | 2017-08-11 | 重庆华邦制药有限公司 | 一种罗氟司特微粒的制备方法 |
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| CN103319333B (zh) * | 2013-07-15 | 2014-12-10 | 天津南开允公医药科技有限公司 | 一种制备3-环丙基甲氧基-4-二氟甲氧基苯甲酰氯化合物的方法 |
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| AU2019281888B2 (en) | 2018-06-04 | 2024-05-02 | Arcutis Biotherapeutics, Inc. | Method and formulation for improving roflumilast skin penetration lag time |
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