CN110734413A - Preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole - Google Patents
Preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole Download PDFInfo
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- CN110734413A CN110734413A CN201911211957.XA CN201911211957A CN110734413A CN 110734413 A CN110734413 A CN 110734413A CN 201911211957 A CN201911211957 A CN 201911211957A CN 110734413 A CN110734413 A CN 110734413A
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- tetrahydrobenzothiazole
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- acetamido
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
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- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, which takes 4-acetamido cyclohexanol as a starting material, hydrobromic acid as an oxidant and a brominating agent, hydrogen peroxide as an auxiliary oxidant to generate 2-bromo-4-acetamido cyclohexanone aqueous solution, and then cyclizes with thiourea, and is hydrolyzed by sulfuric acid to prepare the 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole.
Description
Technical Field
The invention relates to a preparation method of pramipexole intermediates (2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole), belonging to the technical field of organic synthesis.
Background
With the aging of society, the incidence of parkinson's disease increases year by year, pramipexole dihydrochloride is used as line medicine for treating parkinson's disease, the market prospect is broad, pramipexole dihydrochloride is a selective non-ergot dopamine receptor agonist, is successfully developed by the germany bristleger bergham company, the U.S. FDA is firstly approved for treating idiopathic parkinson's disease in 5 months in 1997, and is marketed in china in 2007 under the tradename of forest foro, and is used for treating signs and symptoms of idiopathic parkinson's disease, alone (without levodopa) or in combination with levodopa.
The current -synthesis method (such as EP0186087) of 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole comprises the steps of firstly oxidizing 4-acetamido cyclohexanol into 4-acetamido cyclohexanone, then adopting glacial acetic acid as a solvent, reacting the 4-acetamido cyclohexanone with bromine (as a brominating agent) to prepare the 2-bromo-4-acetamido cyclohexanone, and then cyclizing and hydrolyzing the 2-bromo-4, 5,6, 7-tetrahydrobenzothiazole with thiourea.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, wherein 4-acetamido cyclohexanol is used as a starting material, hydrobromic acid is used as an oxidant and a brominating agent, hydrogen peroxide is used as an auxiliary oxidant to generate 2-bromo-4-acetamido cyclohexanone aqueous solution, and the 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole is prepared by cyclization with thiourea and hydrolysis of sulfuric acid.
The technical scheme of the invention is a preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, which is characterized in that,
1) adding 4-acetamido cyclohexanol and hydrobromic acid (serving as an oxidant and a brominating agent) into water for dissolving, heating to 30-40 ℃, dropwise adding hydrogen peroxide (serving as an auxiliary oxidant), and continuing to react until the reaction is complete (the reaction time is 20-25 h) after dropwise adding is finished to obtain an aqueous solution of 2-bromo-4-acetamido cyclohexanone;
2) adding thiourea into the aqueous solution of 2-bromo-4-acetamido cyclohexanone, heating to reflux reaction (reaction time is 1-3 h) to prepare 6-acetamido-2-amino-4, 5,6, 7-tetrahydrobenzothiazole, and then carrying out acidolysis and post-treatment to prepare the 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole.
The reaction equation is as follows:
the molar ratio of the 4-acetamido-cyclohexanol, the hydrobromic acid and the hydrogen peroxide in the step 1) is 1: 1.0-1.1: 2.0-3.0, and preferably 1:1: 2.
The molar ratio of the 4-acetamido-cyclohexanol to the thiourea in the step 1) is 1:1.0 to 1.1.
The acidolysis in the step 2) uses inorganic acid, preferably sulfuric acid.
The post-treatment of the step 2) comprises the following steps: decolorizing, cooling, crystallizing, pulping the crystal with water, adjusting pH to 12 or above with alkali, filtering, and oven drying to obtain 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole.
The invention has the beneficial effects that: the method has the advantages of easily available raw materials, mild reaction conditions, simple operation process, no pollution, safety, environmental protection, high reaction yield (not less than 75%), high product purity (not less than 99.5%), and suitability for industrial mass production.
Detailed Description
The following example is illustrative of the present invention at step , but the present invention is not limited thereto.
Example 1:
to a 1000ml reaction flask were added 314g of water, 157g of 4-acetamidocyclohexanol (1mol), and 202.5g of hydrobromic acid (40% concentration, 1mol), and the mixture was dissolved under stirring and heated to 30 ℃ and 194.3g (2mol) of 35% hydrogen peroxide was added dropwise. Dropping the mixture in about 2 hours, controlling the temperature to be 30-40 ℃ for reaction for 23 hours, detecting the disappearance of raw materials by TLC, detecting the non-oxidability by using starch potassium iodide test paper, adding 76g of thiourea, heating to reflux for reaction for 2 hours, adding 105g of concentrated sulfuric acid, continuously refluxing for 12 hours, after the reaction is finished, adding 10g of activated carbon, stirring and decoloring for 30 minutes, performing suction filtration, cooling to 5-10 ℃ for crystallization for 12 hours, performing suction filtration, washing, pulping crystals by using 200ml of water, adjusting the pH value to be more than 12 by using sodium hydroxide, performing suction filtration, and drying to obtain 134g of 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, wherein the yield is 79.3 percent and the.
Example 2:
to a 1000ml reaction vessel were added 314g of water, 157g of 4-acetamidocyclohexanol (1mol), and 222.8g of hydrobromic acid (40% concentration, 1.1mol), and the mixture was dissolved under stirring and heated to 30 ℃ and 194.3g (2mol) of 35% hydrogen peroxide was added dropwise. Dropping the mixture in about 2 hours, controlling the temperature to be 30-40 ℃ for reaction for 23 hours, detecting the disappearance of raw materials by TLC, detecting the non-oxidability by using starch potassium iodide test paper, adding 76g of thiourea, heating to reflux for reaction for 2 hours, adding 105g of concentrated sulfuric acid, continuously refluxing for 12 hours, after the reaction is finished, adding 10g of active carbon, stirring and decoloring for 30 minutes, performing suction filtration, cooling to 5-10 ℃ for crystallization for 12 hours, performing suction filtration, washing, pulping crystals by using 200ml of water, adjusting the pH value to be more than 12 by using sodium hydroxide, performing suction filtration, and drying to obtain 130g of 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, wherein the yield is 76.9 percent and the.
Example 3:
to a 1000ml reaction vessel were added 314g of water, 157g of 4-acetamidocyclohexanol (1mol), and 202.5g of hydrobromic acid (40% concentration, 1mol), and the mixture was dissolved under stirring and heated to 30 ℃ and 291.5g (3mol) of 35% hydrogen peroxide was added dropwise. Dropping the mixture in about 2 hours, controlling the temperature to be 30-40 ℃ for reaction for 24 hours, detecting the disappearance of raw materials by TLC, detecting the non-oxidability by using starch potassium iodide test paper, adding 76g of thiourea, heating to reflux for reaction for 2 hours, adding 105g of sulfuric acid, continuously refluxing for 12 hours, adding 10g of activated carbon after the reaction is finished, stirring and decoloring for 30 minutes, performing suction filtration, cooling to 5-10 ℃ for crystallization for 12 hours, performing suction filtration, washing, pulping crystals by using 200ml of water, adjusting the pH value to be more than 12 by using sodium hydroxide, performing suction filtration, and drying to obtain 127g of 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, wherein the yield is 75.1 percent and the purity is.
Claims (7)
- A process for the preparation of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, which is characterized in that,1) adding 4-acetamido cyclohexanol and hydrobromic acid into water for dissolving, heating to 30-40 ℃, dropwise adding hydrogen peroxide, and continuing to react until the reaction is complete after dropwise adding to obtain an aqueous solution of 2-bromo-4-acetamido cyclohexanone;2) adding thiourea into the aqueous solution of 2-bromo-4-acetamido cyclohexanone, heating to reflux reaction to prepare 6-acetamido-2-amino-4, 5,6, 7-tetrahydrobenzothiazole, and then carrying out acidolysis and post-treatment to prepare the 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole.
- 2. The method for preparing pramipexole intermediates, namely 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, according to claim 1, wherein the molar ratio of 4-acetamido-cyclohexanol, hydrobromic acid and hydrogen peroxide in step 1) is 1: 1.0-1.1: 2.0-3.0.
- 3. The process for preparing pramipexole intermediates, 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, as claimed in claim 2, wherein the molar ratio of 4-acetamido-cyclohexanol, hydrobromic acid and hydrogen peroxide in step 1) is 1:1: 2.
- 4. The method for preparing pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole as claimed in claim 1, wherein the molar ratio of 4-acetamido cyclohexanol to thiourea in step 1) is 1: 1.0-1.1.
- 5. The process for producing pramipexole intermediates, 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, according to claim 1, wherein an inorganic acid is used for the acid hydrolysis in the step 2).
- 6. The process for preparing pramipexole intermediates, 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, according to claim 5, wherein said inorganic acid is sulfuric acid.
- 7. The process for preparing pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole as claimed in any of claims 1-6, wherein the post-treatment in step 2) includes decoloring, cooling and crystallizing, pulping the crystals with water, adjusting pH to greater than 12 with alkali, suction filtering, and drying to obtain 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0186087A1 (en) * | 1984-12-22 | 1986-07-02 | Dr. Karl Thomae GmbH | Tetrahydro-benzothiazoles, their production and their use as intermediates or drugs |
| WO2006003677A1 (en) * | 2004-07-01 | 2006-01-12 | Alembic Limited | Improved process for the preparation of biologically active tetrahydrobenzthiazole derivative |
| CN1735604A (en) * | 2002-11-04 | 2006-02-15 | 希普拉有限公司 | Process for preparing 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole |
| CN102675243A (en) * | 2012-04-28 | 2012-09-19 | 铜陵凯顺生物科技有限公司 | Process for synthesizing intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of anti-parkinson drug |
| CN103613562A (en) * | 2013-11-25 | 2014-03-05 | 浙江美诺华药物化学有限公司 | Preparation method of pramipexole |
-
2019
- 2019-12-02 CN CN201911211957.XA patent/CN110734413A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0186087A1 (en) * | 1984-12-22 | 1986-07-02 | Dr. Karl Thomae GmbH | Tetrahydro-benzothiazoles, their production and their use as intermediates or drugs |
| CN1735604A (en) * | 2002-11-04 | 2006-02-15 | 希普拉有限公司 | Process for preparing 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole |
| WO2006003677A1 (en) * | 2004-07-01 | 2006-01-12 | Alembic Limited | Improved process for the preparation of biologically active tetrahydrobenzthiazole derivative |
| US20070123573A1 (en) * | 2004-07-01 | 2007-05-31 | Alembic Limited | Process for the preparation of biologically active tetrahydrobenzthiazole derivative |
| CN102675243A (en) * | 2012-04-28 | 2012-09-19 | 铜陵凯顺生物科技有限公司 | Process for synthesizing intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of anti-parkinson drug |
| CN103613562A (en) * | 2013-11-25 | 2014-03-05 | 浙江美诺华药物化学有限公司 | Preparation method of pramipexole |
Non-Patent Citations (5)
| Title |
|---|
| AJDA PODGORSEK等: "Bromination of ketones with H2O2-HBr "on water"", 《GREEN CHEMISTRY》 * |
| BANOTHU RAMMURTHY 等: "A new and versatile one-pot strategy to synthesis alpha-bromoketones from secondary alcohols using ammonium bromide and oxone", 《NEW JOURNAL OF CHEMISTRY》 * |
| TRIVIKRAM REDDY GUNDALA 等: "Citric acid-catalyzed synthesis of 2,4-disubstituted thiazoles from ketones via C-Br, C-S, and C-N bond formations in one pot: a green approach", 《JOURNAL OF THE CHINESE CHEMICAL SOCIETY》 * |
| 李凯 等: "2,6-二氨基-4,5,6,7-四氢苯并噻唑的合成工艺改进", 《浙江化工》 * |
| 王悦伟: "盐酸普拉克索中间体(S)-2,6-二氨基-4,5,6,7-四氢苯并噻唑合成的工艺改进", 《天津化工》 * |
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