CN87105873A - 二氢吲哚的制备方法 - Google Patents
二氢吲哚的制备方法 Download PDFInfo
- Publication number
- CN87105873A CN87105873A CN87105873.1A CN87105873A CN87105873A CN 87105873 A CN87105873 A CN 87105873A CN 87105873 A CN87105873 A CN 87105873A CN 87105873 A CN87105873 A CN 87105873A
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- hydrogen
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- alkyl
- reduction
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- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title abstract description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims abstract description 4
- 230000029936 alkylation Effects 0.000 claims abstract description 3
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 3
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000852 hydrogen donor Substances 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WMUZDBZPDLHUMW-UHFFFAOYSA-N (2-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1[N+]([O-])=O WMUZDBZPDLHUMW-UHFFFAOYSA-N 0.000 description 1
- CHZFWRYSGOZSAU-UHFFFAOYSA-N 1,3-dihydroindol-2-one Chemical class C1=CC=C2NC(=O)CC2=C1.C1=CC=C2NC(=O)CC2=C1 CHZFWRYSGOZSAU-UHFFFAOYSA-N 0.000 description 1
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- XDXHAEQXIBQUEZ-UHFFFAOYSA-N Ropinirole hydrochloride Chemical compound Cl.CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 XDXHAEQXIBQUEZ-UHFFFAOYSA-N 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal cation Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Iron Core Of Rotating Electric Machines (AREA)
- Glass Compositions (AREA)
Abstract
制备结构(I)的化合物或其药物上可接受的盐的方法，其包含：还原结构(II)的化合物。接着环化所形成的中间体，并随意地，烷基化以形成其中R1为C1-6烷基的结构(I)的化合物，以及随意地形成其药物上可接受的盐，其特征在于结构(II)的化合物的还原是在作为溶剂的水中经催化转移氢化而进行。
Description
本发明是关于制备取代二氢吲哚酮（indolidone）衍生物的改良方法。在EP 0113694中，描述该化合物用于心脏血管治疗。
EP 0113694A描述了制备取代二氢吲哚酮衍生物的方法，其包含用催化氢化法还原2-硝基苯醋酸前体，接着自发环化所形成的中间体。该氢化是低至中压下于例如乙醇的有机溶剂中进行。
现已意外地发现，可在作为溶剂的水中以转移氢化法进行还原，而得到高得率和高纯度的所需的取代二氢吲哚酮。在大规模地制造供治疗的化合物时，产品的质量和得率尤为重要。
因此，本发明提供一种制备结构（Ⅰ）的化合物或其药物上可接受盐的方法
式中，
每一基团R为氢，C1-6烷基，C3-6烯丙基，苯基C1-6烷基或4-羟基苯基C1-6烷基;
R1、R2及R3为氢或C1-6烷基;
R4为氢或羟基;且
n为1至3，
其包含还原结构（Ⅱ）的化合物
式中R、R2至R4如同结构（Ⅰ）所描述，R5为氢或阳离子，接着环化所形成的中间体，及随意地烷基化以形成其中R1为C1-6烷基的化合，以及随意地形成药物上可接受的盐，其特征在于结构（Ⅱ）的化合物的还原是在作为溶剂的水中经催化转移氢化而进行。
此制法能合适地用于制备其中每个R为C1-6烷基，较佳为正丙基的结构（Ⅰ）化合物。此制法特别可用于制备4-（2-二丙基氨基乙基）-2-二氢吲哚酮或其盐酸盐。
此反应可适合于在其中R5为氢的结构（Ⅱ）化合物，即游离酸前体上进行;此反应较佳在其中R5为阳离子的结构（Ⅱ）化合物，即酸的盐上进行。合适地此阳离子为碱金属阳离子，较佳为铵（Na+）。
还原是在氢给体存在下，在合适催化剂上氢化进行。合适的催化剂包括，例如，阮内镍（Raney Nickle）或稀有金属催化剂如在碳上的铂或钯。合适的氢给体包括例如水合肼或次磷酸钠。该还原较佳地在水合肼存在下，于稀有金属催化剂，特别是钯/碳上氢化进行。
还原合适在介于0℃及50℃间的温度，较佳在约环境温度或稍高，即15至25℃下进行。
因此，还原较佳在作为溶剂的水中，在15至25℃，有水合肼的存在下，于在钯/碳催化剂上经氢化而进行。
已发现当按照本发明进行结构（Ⅱ）化合物的还原以及随后的环化反应时，可制得高得率（约80-85%）和非常高纯度（HPLC 测得＞99%）的结构（Ⅱ）的化合物。
实例1
4-（2-二丙基氨基乙基）-2-二氢吲哚酮盐酸盐的制备
将1-2-（2-二-正-丙基氨基乙基）-6-硝基苯基）醋酸盐酸盐（1.13公斤，3摩尔）加入到氢氧化钠（240克，6摩尔）的水（6升）溶液中。再加入10%在钯/碳（225克），并搅拌此混合物20分钟同时冷却使温度降至20℃。
以氮气清洗烧瓶，并小心地加入水合肼（300克，6摩尔）。混合物的温度开始上升，并使用冷却将在加料时的温度维持至16及22℃间。加料约在1小时后完成，并在约20℃下搅拌此混合物达1.15小时。
过滤此反应混合物，并且用水（600毫升）洗涤滤饼。然后用浓盐酸（600毫升）酸化滤液，且将所得的混合物加热至70℃。随后将烧瓶从热源中移开，并于冰-水浴中冷却，然后在环境温度中静置过夜。
在搅拌下，将氢氧化钠（150克）加入混合物中得到pH值9的溶液。用醋酸乙酯（1.4升，然后2×800毫升）萃取产物。乾燥（MgSO4，40克），过滤合并萃取液，然后将其加入正一丙醇（13升）中。搅拌下加入盐酸（300毫升），5分钟后形成沉淀物。
将混合物冷却至10℃（冰/盐）并且于10℃下静置1小时。滤出所产生的固体，用正一丙醇（2×500毫升）清洗，并乾燥，得到灰白色固体的标题化合物，735克，82.5%，熔点245-247℃。
Claims (7)
1、制备结构(Ⅰ)的化合物或其药物上可接受盐的方法
其中，
每一基团R为氢，C1-6烷基，C3-6烯丙基，苯基C1-6烷基或4-羟基苯基C1-6烷基；
R1、R2及R3为氢或C1-6烷基；
R4为氢或羟基；且
n为1至3，
其包含还原结构(Ⅱ)的化合物
其中R、R2至R4及n如上所述，且R5为氢或阳离子，接着环化所形成的中间体，及随意地，烷基化以形成其中R1为C1-6烷基的结构(Ⅰ)的化合物，以及随意地，形成其药物上可接受盐，其特征在于结构(Ⅱ)的化合物的还原是在作为溶剂的水中经催化转移氢化而进行。
2、根据权利要求1的方法，其中基团R均为C1-6烷基。
3、根据权利要求2的方法，其中结构（Ⅰ）的化合物为4-（2-二丙基氨基乙基）-2-二氢吲哚酮或其盐酸盐。
4、根据权利要求1至3的任何一项的方法，其中转移还原是在水合肼的存在下于稀有金属催化剂上氢化进行。
5、根据权利要求4的方法，其中稀有金属催化剂为钯/碳。
6、根据权利要求1至5的任何一项的方法，其中反应是在约20℃的温度下进行。
7、根据权利要求的任一项的方法，其中R5为Na+。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8621040 | 1986-08-30 | ||
| GB868621040A GB8621040D0 (en) | 1986-08-30 | 1986-08-30 | Process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN87105873A true CN87105873A (zh) | 1988-03-09 |
| CN1016342B CN1016342B (zh) | 1992-04-22 |
Family
ID=10603475
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87105873A Expired CN1016342B (zh) | 1986-08-30 | 1987-08-24 | 二氢吲哚酮的制备方法 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4950765A (zh) |
| EP (1) | EP0266033B1 (zh) |
| JP (1) | JPH0768212B2 (zh) |
| KR (1) | KR100233397B1 (zh) |
| CN (1) | CN1016342B (zh) |
| AT (1) | ATE107631T1 (zh) |
| AU (1) | AU593130B2 (zh) |
| CA (1) | CA1305711C (zh) |
| DE (1) | DE3750117T2 (zh) |
| DK (1) | DK170372B1 (zh) |
| ES (1) | ES2054681T3 (zh) |
| GB (1) | GB8621040D0 (zh) |
| HK (1) | HK1004550A1 (zh) |
| HU (1) | HU199414B (zh) |
| IE (1) | IE64176B1 (zh) |
| PT (1) | PT85585B (zh) |
| ZA (1) | ZA876397B (zh) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW457233B (en) * | 1996-10-11 | 2001-10-01 | Bristol Myers Squibb Co | Preparation of 3-fluoro oxindole derivatives |
| WO2005074387A2 (en) * | 2003-12-30 | 2005-08-18 | Sun Pharmaceutical Industries Limited | Novel crystal forms of 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone hydrochloride |
| WO2005105741A1 (en) * | 2004-02-11 | 2005-11-10 | Sun Pharmaceutical Industries Limited | Substantially pure 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone hydrochloride |
| WO2011072704A1 (en) | 2009-12-16 | 2011-06-23 | Pharmathen S.A. | Process for the preparation of ropinirole and salts thereof |
| EP3012310B8 (en) | 2014-10-24 | 2018-11-14 | Neste Oyj | Method for ketonisation of biological material |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
-
1986
- 1986-08-30 GB GB868621040A patent/GB8621040D0/en active Pending
-
1987
- 1987-08-24 CA CA000545203A patent/CA1305711C/en not_active Expired - Lifetime
- 1987-08-24 US US07/088,774 patent/US4950765A/en not_active Expired - Lifetime
- 1987-08-24 CN CN87105873A patent/CN1016342B/zh not_active Expired
- 1987-08-25 DE DE3750117T patent/DE3750117T2/de not_active Expired - Lifetime
- 1987-08-25 PT PT85585A patent/PT85585B/pt unknown
- 1987-08-25 AT AT87307510T patent/ATE107631T1/de not_active IP Right Cessation
- 1987-08-25 EP EP87307510A patent/EP0266033B1/en not_active Expired - Lifetime
- 1987-08-25 ES ES87307510T patent/ES2054681T3/es not_active Expired - Lifetime
- 1987-08-25 DK DK443587A patent/DK170372B1/da not_active IP Right Cessation
- 1987-08-26 JP JP62212628A patent/JPH0768212B2/ja not_active Expired - Lifetime
- 1987-08-27 AU AU77615/87A patent/AU593130B2/en not_active Expired
- 1987-08-27 KR KR1019870009359A patent/KR100233397B1/ko not_active IP Right Cessation
- 1987-08-27 ZA ZA876397A patent/ZA876397B/xx unknown
- 1987-08-28 IE IE230987A patent/IE64176B1/en not_active IP Right Cessation
- 1987-08-28 HU HU873793A patent/HU199414B/hu unknown
-
1998
- 1998-04-29 HK HK98103672A patent/HK1004550A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HUT45012A (en) | 1988-05-30 |
| KR100233397B1 (ko) | 2000-02-01 |
| IE64176B1 (en) | 1995-07-12 |
| EP0266033A2 (en) | 1988-05-04 |
| CN1016342B (zh) | 1992-04-22 |
| EP0266033A3 (en) | 1989-01-25 |
| DK443587D0 (da) | 1987-08-25 |
| DK170372B1 (da) | 1995-08-14 |
| PT85585A (en) | 1987-09-01 |
| GB8621040D0 (en) | 1986-10-08 |
| PT85585B (pt) | 1990-05-31 |
| CA1305711C (en) | 1992-07-28 |
| EP0266033B1 (en) | 1994-06-22 |
| JPH0768212B2 (ja) | 1995-07-26 |
| US4950765A (en) | 1990-08-21 |
| DE3750117T2 (de) | 1994-10-06 |
| AU7761587A (en) | 1988-03-03 |
| IE872309L (en) | 1988-02-29 |
| ES2054681T3 (es) | 1994-08-16 |
| HU199414B (en) | 1990-02-28 |
| DE3750117D1 (de) | 1994-07-28 |
| JPS6363658A (ja) | 1988-03-22 |
| ZA876397B (en) | 1988-02-25 |
| ATE107631T1 (de) | 1994-07-15 |
| DK443587A (da) | 1988-03-01 |
| KR880002825A (ko) | 1988-05-11 |
| HK1004550A1 (en) | 1998-11-27 |
| AU593130B2 (en) | 1990-02-01 |
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