CN102675243A - Process for synthesizing intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of anti-parkinson drug - Google Patents
Process for synthesizing intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of anti-parkinson drug Download PDFInfo
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- CN102675243A CN102675243A CN2012101305309A CN201210130530A CN102675243A CN 102675243 A CN102675243 A CN 102675243A CN 2012101305309 A CN2012101305309 A CN 2012101305309A CN 201210130530 A CN201210130530 A CN 201210130530A CN 102675243 A CN102675243 A CN 102675243A
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- tetrahydro benzothiazol
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000000939 antiparkinson agent Substances 0.000 title claims abstract description 12
- 229940035678 anti-parkinson drug Drugs 0.000 title abstract 2
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000002131 composite material Substances 0.000 claims abstract description 8
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 238000005893 bromination reaction Methods 0.000 claims abstract description 7
- HWAFCRWGGRVEQL-UHFFFAOYSA-N n-(4-hydroxycyclohexyl)acetamide Chemical compound CC(=O)NC1CCC(O)CC1 HWAFCRWGGRVEQL-UHFFFAOYSA-N 0.000 claims abstract description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims abstract 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 230000000648 anti-parkinson Effects 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- DRRYZHHKWSHHFT-BYPYZUCNSA-N (6s)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Chemical compound C1[C@@H](N)CCC2=C1SC(N)=N2 DRRYZHHKWSHHFT-BYPYZUCNSA-N 0.000 claims description 8
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000007790 solid phase Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 230000031709 bromination Effects 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- DRRYZHHKWSHHFT-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Chemical compound C1C(N)CCC2=C1SC(N)=N2 DRRYZHHKWSHHFT-UHFFFAOYSA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Substances Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- -1 tetramethyl piperidine oxide compound Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses process for synthesizing an intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of an anti-parkinson drug. 4-acetamidocyclohexanol is used as a raw material, and a novel composite oxidant TEMPO/DBDMH is adopted. In the process, the novel composite oxidant TEMPO/DBDMH is adopted, reaction time is greatly shortened, reaction selectivity is good, a toxic reagent is prevented from being used, quality is good, operation is easy, and the process is environment-friendly. The process uses DBDMH (dibromohydantoin) to replace liquid bromine to conduct bromination, product positioning is good, and operation is safe.
Description
Technical field
The present invention relates to the medicine synthesising process field, exactly is a kind of anti-Parkinson pharmaceutical intermediate (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique.
Background technology
Anti-Parkinson pramipexole midbody, i.e. (S)-2,6-diamino--4,5; 6, the 7-tetrahydro benzothiazol, CN1772744A introduces; Use the 4-Trans-4-Amino Cyclohexanol to be raw material, implement amido protecting through the N-acetylization reaction, the Jones reagent oxidation makes 4-kharophen pimelinketone.Thiazole Cheng Huan, HBr hydrolysis, the five steps reaction of tartrate chiral separation make then.Complex operation, reaction time is long, and uses the strong raw materials of corrodibility such as Jones reagent, bromine, HBr, and is harmful to environment.TEMPO (tetramethyl piperidine oxide compound) has been proved to be a kind of effective friendly process to the oxidation of secondary alcohol, but not to the report of 4-acetamido-cyclohexanol oxidation, adopts the oxidation of TEMPO/DBDMH composite oxidant not appear in the newspapers especially.
Summary of the invention
The purpose of this invention is to provide a kind of environmental protection anti-Parkinson pharmaceutical intermediate (S)-2 simultaneously easy and simple to handle, 6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique.
Above-mentioned purpose realizes through following scheme:
A kind of anti-Parkinson pharmaceutical intermediate (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique is characterized in that:
May further comprise the steps:
(1) get in the mixing solutions that 4-acetamido-cyclohexanol about 100g drops into acetone and the water about 200ml about 800ml, stirring and dissolving is lowered the temperature; Slowly add about TEMPO/DBDMH composite oxidant 20g, control reaction temperature adds the back insulation reaction about 6 hours below 30 ℃; Filter, suction filtration is to doing, and acetone is reclaimed in the filtrate decompression distillation; Add re-crystallizing in ethyl acetate, get the acetparaminosalol pimelinketone;
(2) get step (1) about 30g and make the acetparaminosalol pimelinketone and join in the ETHYLE ACETATE about 450ml, slowly add under the room temperature about DBDMH 55g, add in 2 hours, be incubated about 2 hours complete again to bromination reaction; Heat up gradually, controlled temperature is at 40-50 ℃, and the back adds about thiocarbamide 35g, adds continued and is heated to backflow; Stirred about 5 hours, and after ETHYLE ACETATE is reclaimed in underpressure distillation, in residuum, added the water about 300ml; Regulate PH=2 with the vitriol oil then, PH is regulated with about 30% NaOH solution in about the 3 hours backs of refluxing>10, to there being solid to separate out; Stir about 1 hour after-filtration, 60 ℃ of left and right sides vacuum-dryings promptly get 2,6-diamino--4; 5,6, the 7-tetrahydro benzothiazol;
(3) get 2 of step (2) gained about 35g, 6-diamino--4,5,6; The 7-tetrahydro benzothiazol is put in 10～12 times the water, is heated to 70～80 ℃, add the clarification of L (+)-tartrate to solution becomes after, 70～80 ℃ were stirred about 12 hours down; Be cooled to 0～5 ℃ then and stirred about 2 hours, filter out solid,, the tartrate of gained is dissolved in the dilute hydrochloric acid solution the solid washing; Remove by filter insolubles, filtrating is regulated PH with about 30% liquid caustic soda>8, remain on 0-5 ℃ and stirred 2～3 hours down; Filter, washing, vacuum-drying promptly gets pale powder shape solid phase prod.
Described a kind of anti-Parkinson pharmaceutical intermediate (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique is characterized in that: the described bromination reaction degree of depth of step (2) detects control by TLC.
Described a kind of anti-Parkinson pharmaceutical intermediate (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique is characterized in that: described TEMPO/DBDMH composite oxidant is to be composited by the mol ratio of 1:0.4-0.6 by TEMPO/DBDMH.
Beneficial effect of the present invention is:
1, route of the present invention adopts novel oxygenant TEMPO/DBDMH, has shortened the reaction times greatly, and the selectivity of reaction is good, has avoided the use of poisonous reagent, and quality is good, and is easy to operate and environmentally friendly;
2, the present invention replaces the liquid bromine to carry out bromination with DBDMH (C5H6Br2N2O2), and product orientation property is better, operates safer.
Embodiment
(1) the acetparaminosalol pimelinketone is synthetic
The 100g4-acetamido-cyclohexanol drops in 800ml acetone and the 200ml water, stirring and dissolving, and cooling slowly adds TEMPO/DBDMH composite oxidant 20g, and control reaction temperature added the back insulation reaction 6 hours below 30 ℃, filtered, and suction filtration is to doing.Acetone is reclaimed in the filtrate decompression distillation, adds re-crystallizing in ethyl acetate, gets acetparaminosalol pimelinketone 96.75g, yield 98%.
(2) (±)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol
30g product of last step joins in the 450ml ETHYLE ACETATE, slowly adds DBDMH55g under the room temperature, adds in 2 hours; Be incubated 2 hours again and detect bromination reaction to TLC complete, heat up gradually, controlled temperature is at 40-50 ℃; Add continued to the 35g thiocarbamide and be heated to backflow, stirred 5 hours.ETHYLE ACETATE is reclaimed in underpressure distillation, and residuum adds 300ml water, regulates PH=2 with the 35ml vitriol oil then, refluxes 3 hours.Regulate PH with 30%NaOH solution>10, there is solid to separate out, stir 1 hour after-filtration, 60 ℃ of vacuum-dryings get 25g 2,6-diamino--4,5,6,7-tetrahydro benzothiazol, its content are 98%, 223～225 ℃ of fusing points.
(3) (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol
35g 2, and 6-diamino--4,5,6,7-tetrahydro benzothiazol are put in 10～12 times of water, are heated to 70～80 ℃, add 31.2g L-(+)-tartrate, and solution becomes clarification at once.70～80 ℃ were stirred 12 hours down, were cooled to 0～5 ℃ then and stirred 2 hours, filtered out solid, washing; The tartrate of gained is dissolved in the dilute hydrochloric acid solution, removes by filter insolubles, filtrating is regulated PH with 30% liquid caustic soda>8; Remain on 0-5 ℃ and stirred 2～3 hours down, filter washing.Vacuum-drying gets pale powder shape solid phase prod 14g, and wherein product content is 99.6%, [a] d=-95 °～-104 ° (C=2, CH
3OH).
Claims (3)
1. an anti-Parkinson pharmaceutical intermediate (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique is characterized in that:
May further comprise the steps:
(1) get in the mixing solutions that 4-acetamido-cyclohexanol about 100g drops into acetone and the water about 200ml about 800ml, stirring and dissolving is lowered the temperature; Slowly add about TEMPO/DBDMH composite oxidant 20g, control reaction temperature adds the back insulation reaction about 6 hours below 30 ℃; Filter, suction filtration is to doing, and acetone is reclaimed in the filtrate decompression distillation; Add re-crystallizing in ethyl acetate, get the acetparaminosalol pimelinketone;
(2) get step (1) about 30g and make the acetparaminosalol pimelinketone and join in the ETHYLE ACETATE about 450ml, slowly add under the room temperature about DBDMH 55g, add in 2 hours, be incubated about 2 hours complete again to bromination reaction; Heat up gradually, controlled temperature is at 40-50 ℃, and the back adds about thiocarbamide 35g, adds continued and is heated to backflow; Stirred about 5 hours, and after ETHYLE ACETATE is reclaimed in underpressure distillation, in residuum, added the water about 300ml; Regulate PH=2 with the vitriol oil then, PH is regulated with about 30% NaOH solution in about the 3 hours backs of refluxing>10, to there being solid to separate out; Stir about 1 hour after-filtration, 60 ℃ of left and right sides vacuum-dryings promptly get 2,6-diamino--4; 5,6, the 7-tetrahydro benzothiazol;
(3) get 2 of step (2) gained about 35g, 6-diamino--4,5,6; The 7-tetrahydro benzothiazol is put in 10～12 times the water, is heated to 70～80 ℃, add the clarification of L (+)-tartrate to solution becomes after, 70～80 ℃ were stirred about 12 hours down; Be cooled to 0～5 ℃ then and stirred about 2 hours, filter out solid,, the tartrate of gained is dissolved in the dilute hydrochloric acid solution the solid washing; Remove by filter insolubles, filtrating is regulated PH with about 30% liquid caustic soda>8, remain on 0-5 ℃ and stirred 2～3 hours down; Filter, washing, vacuum-drying promptly gets pale powder shape solid phase prod.
2. a kind of anti-Parkinson pharmaceutical intermediate according to claim 1 (S)-2,6-diamino--4,5,6,7-tetrahydro benzothiazol synthesis technique is characterized in that: the described bromination reaction degree of depth of step (2) detects control by TLC.
3. a kind of anti-Parkinson pharmaceutical intermediate according to claim 1 (S)-2; 6-diamino--4,5,6; 7-tetrahydro benzothiazol synthesis technique is characterized in that: described TEMPO/DBDMH composite oxidant is to be composited by the mol ratio of 1:0.4-0.6 by TEMPO/DBDMH.
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| CN201210130530.9A CN102675243B (en) | 2012-04-28 | 2012-04-28 | Process for synthesizing intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of anti-parkinson drug |
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| CN201210130530.9A CN102675243B (en) | 2012-04-28 | 2012-04-28 | Process for synthesizing intermediate of (S)-2,6-diamino-4,5,6,7-tetralinbenzothiazole of anti-parkinson drug |
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| CN102675243B CN102675243B (en) | 2014-08-27 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110669024A (en) * | 2019-10-30 | 2020-01-10 | 福建福瑞明德药业有限公司 | Alkali precipitation method of (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole L-tartrate |
| CN110734413A (en) * | 2019-12-02 | 2020-01-31 | 山东铂源药业有限公司 | Preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole |
| CN110878067A (en) * | 2019-11-13 | 2020-03-13 | 上海星酶生物科技有限公司 | Crystallization process of diamino-4, 5,6, 7-tetrahydrobenzothiazole |
| CN111362884A (en) * | 2018-12-26 | 2020-07-03 | 江苏神龙药业股份有限公司 | Industrial preparation method of 2, 6-diamino-4, 5,6, 7-tetrahydro-benzothiazole |
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2012
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Patent Citations (3)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111362884A (en) * | 2018-12-26 | 2020-07-03 | 江苏神龙药业股份有限公司 | Industrial preparation method of 2, 6-diamino-4, 5,6, 7-tetrahydro-benzothiazole |
| CN110669024A (en) * | 2019-10-30 | 2020-01-10 | 福建福瑞明德药业有限公司 | Alkali precipitation method of (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole L-tartrate |
| CN110878067A (en) * | 2019-11-13 | 2020-03-13 | 上海星酶生物科技有限公司 | Crystallization process of diamino-4, 5,6, 7-tetrahydrobenzothiazole |
| CN110734413A (en) * | 2019-12-02 | 2020-01-31 | 山东铂源药业有限公司 | Preparation method of pramipexole intermediates 2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole |
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Address after: 235232 Jicun Industrial Park, Xiao County, Suzhou City, Anhui Province Patentee after: Anhui Dongkai Biotechnology Co.,Ltd. Address before: 235200 Jicun Industrial Park, Xiao County, Suzhou City, Anhui Province Patentee before: EASTSKY PHARM (ANHUI) TECHNOLOGY Co.,Ltd. |
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Denomination of invention: Synthesis process of an intermediate (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole for anti Parkinson's drugs Granted publication date: 20140827 Pledgee: Bank of China Limited Suzhou Branch Pledgor: Anhui Dongkai Biotechnology Co.,Ltd. Registration number: Y2024980001524 |
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