CN103183650A - Preparation method of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole - Google Patents
Preparation method of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole Download PDFInfo
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- CN103183650A CN103183650A CN2011104600449A CN201110460044A CN103183650A CN 103183650 A CN103183650 A CN 103183650A CN 2011104600449 A CN2011104600449 A CN 2011104600449A CN 201110460044 A CN201110460044 A CN 201110460044A CN 103183650 A CN103183650 A CN 103183650A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- VVPFOYOFGUBZRY-LURJTMIESA-N n-[(6s)-2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]propanamide Chemical compound C1[C@@H](NC(=O)CC)CCC2=C1SC(N)=N2 VVPFOYOFGUBZRY-LURJTMIESA-N 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 110
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 30
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 150000002170 ethers Chemical class 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 3
- 230000000737 periodic effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000011218 segmentation Effects 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 2
- 239000012279 sodium borohydride Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 11
- SMWAOXCEPHEGFV-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine Chemical compound C1CCCC2=C1N=C(N)S2 SMWAOXCEPHEGFV-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 229910000085 borane Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012451 post-reaction mixture Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 229960002652 pramipexole dihydrochloride Drugs 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- VQMNWIMYFHHFMC-UHFFFAOYSA-N tert-butyl 4-hydroxyindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1O VQMNWIMYFHHFMC-UHFFFAOYSA-N 0.000 description 4
- 229910015900 BF3 Inorganic materials 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003637 basic solution Substances 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000007605 air drying Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention provides a preparation method of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole. According to the preparation method, (S)-(-)2-amino-6- propionamido-4,5,6,7-tetrahydrobenzothiazole is adopted as raw material and is reduced through I2 and sodium borohydride to prepare the (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole. The preparation method has the advantages that the raw material is easy to obtain, the reaction condition is mild, the control is easy and the reaction safety is high; and the preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of 2-amino-6-of (S)-(-) third amino-4,5,6, the preparation method of 7-tetrahydro benzothiazol.
Background technology
(S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol, its dihydrochloride are body of Pramipexole dihydrochloride, and wherein (S) is expressed as the S configuration, and (-) is expressed as levo form, and its structural formula is as follows:
Body of Pramipexole dihydrochloride can be used as medical material, is used for the treatment of parkinsonian medicine, and body of Pramipexole dihydrochloride must be the S configuration, left-handed just have a medical effect.Prepare the 2-amino-6-of (S)-(-) third amino-4,5,6 in the synthetic hydrochloric acid pramipexole at present, the method for 7-tetrahydro benzothiazol mainly contains:
J.Med.chem.1987,30,494-498 disclose a kind of preparation method of body of Pramipexole dihydrochloride, and this method is with the 2-of (S)-(-) amino-6-propionamido-4,5,6, and the 7-tetrahydro benzothiazol is raw material, logical N in tetrahydrofuran (THF)
2Protection down obtains the 2-amino-6-of (S)-(-) third amino-4,5,6, the 7-tetrahydro benzothiazol with the borine solution reaction of tetrahydrofuran (THF).This preparation method's particular content is: at the logical N of room temperature
2Protection is containing the 2-of (S)-(-) amino-6-propionamido-4,5,6 down, dropwise adds the borine solution of tetrahydrofuran (THF) in the tetrahydrofuran solution of 7-tetrahydro benzothiazol, stirs 1 hour down and cooling at 50 ℃ then, adds water and concentrated hydrochloric acid again.Evaporate tetrahydrofuran (THF) and add 25% sodium hydroxide solution to aqueous phase, filter precipitation (the 2-amino-6-of (S)-(-) third amino-4,5,6 that obtain then, the 7-tetrahydro benzothiazol), the precipitation that obtains is washed and it is dissolved in the ethyl acetate of heat.The moisture of removing in the solution also concentrates, and filters and obtains precipitation, uses the ethyl acetate washing precipitation, obtains the 2-amino-6-of (S)-(-) third amino-4,5,6, the 7-tetrahydro benzothiazol.The shortcoming of this method is the borine solution manufacture method complexity of tetrahydrofuran (THF), is not suitable for suitability for industrialized production, and because the colourless severe toxicity of borine is inflammable and explosive, the facile hydrolysis poor stability be difficult for preserving transportation, so production security is poor.
Chinese patent CN1834092B replaces borine with the diethyl ether solution of boron trifluoride, because the diethyl ether solution of boron trifluoride also is highly toxic product, inflammable and explosive, and the diethyl ether solution of boron trifluoride is met moisture hydrolysis immediately in air, generate the fluorochemical smog of severe toxicity, severe reaction conditions also is unfavorable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to be difficult for making in order to overcome aforesaid method, the low shortcoming that is unfavorable for suitability for industrialized production of reaction safety, provide a kind of raw material be simple and easy to, the 2-amino-6-of (S)-(-) third amino-4 that reaction safety is high, the preparation method of 5,6,7-tetrahydro benzothiazol.
Preparation method provided by the invention is with the 2-of (S)-(-) amino-6-propionamido-4,5,6, and the 7-tetrahydro benzothiazol is raw material, passes through I
2And sodium borohydride reduction, the preparation 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol.This preparation method's raw material is simple and easy to, and the reaction conditions gentleness is easy to control, and this preparation method's reaction safety is improved.
2-amino-the 6-of (S)-(-) third amino-4,5,6 provided by the invention, the preparation method of 7-tetrahydro benzothiazol can be represented by following reaction equation:
In reaction equation, the described 2-of (S)-(-) amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4And I
2Mol ratio be 1: 2: 1-1: 15: 8, be preferably 1: 5: 2-1: 9: 4.
Described solvent can be the mixture of tetrahydrofuran (THF), organic ether, tetrahydrofuran (THF) and organic ether, and its volumetric usage is NaBH
4The 10-25 of weight is (volume/weight, unit is mL/g) doubly.
Described rare gas element refers to not the gas with reactant generation chemical reaction, as in the gas of zero group in nitrogen, the periodic table of elements one or more, is preferably nitrogen.
In when reaction, (S)-(-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4And I
2Order be preferably, earlier with NaBH
4Join in the reaction solvent, and then add the 2-of (S)-(-) amino respectively-6-propionamido-4,5,6,7-tetrahydro benzothiazol and I
2Under the preferable case, in the adition process of three kinds of reactants, constantly stir, and remain on below 10 ℃, be preferably 0-5 ℃.
Described I
2With I
2With tetrahydrofuran (THF) or I
2With organic ethers or I
2Add with the solution form of the mixed solution of tetrahydrofuran (THF) and organic ether, described organic ether is preferably ether.
Described I
2With tetrahydrofuran (THF) or I
2With organic ethers or I
2With the concentration of tetrahydrofuran (THF) and organic ether be the 0.4-1.5 mol, be preferably the 0.8-1.0 mol.Organic ethers and tetrahydrofuran (THF) volume ratio are preferably 1: 1-1: 2.
After above-mentioned reactant mixes, (S)-(-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4And I
2Catalytic temperature of reaction is 0-80 ℃, is preferably 0-50 ℃, and the reaction times is 10-36 hour, is preferably 12-36 hour, more preferably 24-30 hour.Under the preferable case, adopt the mode of segmentation reaction, namely reacted 10-14 hour down at 0-5 ℃, 30-50 ℃ of reaction 6-10 hour, reaction was finished, and cooled off down at 0-5 ℃.
The described 2-amino-6-of (S)-(-) third amino-4,5,6, the separation of 7-tetrahydro benzothiazol can be adopted known method, as add hydrochloric acid soln, hydrochloric acid and (S)-(-) 2-amino-6-third amino-4,5,6, the reaction of 7-tetrahydro benzothiazol generates the 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol one hydrochloride and/or dihydrochloride evaporate tetrahydrofuran (THF) then.The resistates that evaporates behind the tetrahydrofuran (THF) is soluble in water, add basic solution, as sodium hydroxide solution, sodium carbonate solution or ammoniacal liquor, the solution pH value is adjusted to 9-10,2-amino-the 6-of (S)-(-) third amino-4 at this moment, 5,6,7-tetrahydro benzothiazol, one hydrochloride and/or dihydrochloride and basic solution reaction generate the 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol is used organic solvent extraction, add anhydrous sodium sulfate drying, evaporating solvent obtains the 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol, drying obtains solid product.The volume of described hydrochloric acid soln is NaBH
415-25 doubly (volume/weight, unit is mL/g), the concentration of described hydrochloric acid soln is 15-25%; Described solvent is one or more in ethyl acetate, methylene dichloride, the ether, is preferably ethyl acetate; Described drying can adopt known method and technology, as seasoning, heat drying, forced air drying, vacuum-drying etc.
According to the 2-amino-6-of (S)-(-) third amino-4,5,6 that preparation method provided by the invention obtains, 7-tetrahydro benzothiazol, product yield 60%.
Embodiment
The following examples will be done to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
Embodiment 1
With 0.18 mole of NaBH
4Join in three mouthfuls of reaction flasks of the anhydrous tetrahydro furan that fills 50 milliliters; feed nitrogen protection; under 0-5 ℃ of continuous stirring condition; the 2-of (S)-(-) amino-6-propionamido-4 that adds 0.02 mole; 5; 6,7-tetrahydro benzothiazol slowly splashes into 100 milliliters of 0.08 mole of I after the mixing back is even again
2Tetrahydrofuran solution (0.08 mole of I
2), being incubated to the 0-5 ℃ of condition reaction 10 hours, again reaction mixture is heated to 50 ℃ of reactions 10 hours then.Under ice bath, cool off then.
Add 350 ml concns in the above-mentioned post reaction mixture and be 10% hydrochloric acid soln, NaOH solution with 20% is regulated pH value to 10, extract with the ethyl acetate gradation, add anhydrous sodium sulfate drying in the extracting solution, evaporating solvent obtains solid product, and vacuum-drying obtains the 2.54 gram 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol, product yield 60%.
(
1H-NMR(400MHz，DMSO)；δ(PPm)：δ6.57(s，2H)，δ2.806-2.755(m，1H)，δ2.719-2.681(dd，1H)，δ2.522-2.486(t，2H)，δ2.454-2.349(m，2H)，δ2.219-2.160(q，1H)，δ1.902-1.870(m，1H)，δ1.506-1.457(m，2H)，δ1.449-1.365(m，2H)，δ0.875-0.837(t，3H)。
Embodiment 2
With 0.18 mole of NaBH
4Join in three mouthfuls of reaction flasks of the anhydrous tetrahydro furan that fills 50 milliliters; feed nitrogen protection; under 0-5 ℃ of continuous stirring condition; the 2-of (S)-(-) amino-6-propionamido-4 that adds 0.02 mole; 5; 6,7-tetrahydro benzothiazol mixes the I that the back slowly splashes into 100 milliliters 0.08 mole after evenly again
2Tetrahydrofuran (THF), diethyl ether solution (0.08 mole of I
2, tetrahydrofuran (THF) and ether volume ratio are 1: 1), be incubated then to 0-5 ℃ of continuous stirring condition and reacted 6 hours, again reaction mixture is heated to 35 ℃ of reactions 12 hours.Under ice bath, cool off then.
Add 360 ml concns in the above-mentioned post reaction mixture and be 10% hydrochloric acid soln, NaOH solution with 20% is regulated pH value 9-10, extract with the ethyl acetate gradation, add anhydrous sodium sulfate drying in the extracting solution, evaporating solvent obtains solid product, and vacuum-drying obtains the 2.75 gram 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol, product yield 65%.
(
1H-NMR(400MHz，DMSO)；δ(PPm)：δ6.57(s，2H)，δ2.806-2.755(m，1H)，δ2.719-2.681(dd，1H)，δ2.522-2.486(t，2H)，δ2.454-2.349(m，2H)，δ2.219-2.160(q，1H)，δ1.902-1.870(m，1H)，δ1.506-1.457(m，2H)，δ1.449-1.365(m，2H)，δ0.875-0.837(t，3H)。
Embodiment 3
With 0.04 mole of NaBH
4Join in three mouthfuls of reaction flasks of the anhydrous tetrahydro furan that fills 50 milliliters; feed nitrogen protection; under 0-5 ℃ of continuous stirring condition; the 2-of (S)-(-) amino-6-propionamido-4 that adds 0.02 mole; 5; 6,7-tetrahydro benzothiazol mixes the I that the back slowly splashes into 100 milliliters 0.16 mole after evenly again
2Tetrahydrofuran (THF), diethyl ether solution (0.16 mole of I
2, tetrahydrofuran (THF) and ether volume ratio are 1: 4), reaction is 12 hours under the 0-5 ℃ of continuous stirring condition, reaction mixture is heated to 40 ℃ of reactions 20 hours again, cools off under ice bath then.
Add 360 ml concns in the above-mentioned post reaction mixture and be 10% hydrochloric acid soln, NaOH solution with 20% is regulated pH value to 9-10, extract with the ethyl acetate gradation, add anhydrous sodium sulfate drying in the extracting solution, evaporating solvent obtains solid product, and vacuum-drying obtains the 2.33 gram 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol, product yield 55%.
(
1H-NMR(400MHz，DMSO)；δ(PPm)：δ6.57(s，2H)，δ2.806-2.755(m，1H)，δ2.719-2.681(dd，1H)，δ2.522-2.486(t，2H)，δ2.454-2.349(m，2H)，δ2.219-2.160(q，1H)，δ1.902-1.870(m，1H)，δ1.506-1.457(m，2H)，δ1.449-1.365(m，2H)，δ0.875-0.837(t，3H)。
Embodiment 4
With 0.3 mole of NaBH
4Join in three mouthfuls of reaction flasks of the anhydrous tetrahydro furan that fills 50 milliliters; feed nitrogen protection; under 0-5 ℃ of continuous stirring condition; the 2-of (S)-(-) amino-6-propionamido-4 that adds 0.02 mole; 5; 6,7-tetrahydro benzothiazol slowly splashes into 100 milliliters of 0.12 mole of I after the mixing back is even again
2Tetrahydrofuran solution (0.12 mole of I
2), the time is 3-4 hour.Control temperature 0-5 ℃ of continuous stirring reaction 10 hours then, again reaction mixture is heated to 70 ℃ of reactions 10 hours.Under ice bath, cool off then.
Add 350 ml concns in the above-mentioned post reaction mixture and be 10% hydrochloric acid soln, NaOH solution with 20% is regulated pH value to 9-10, extract with the ethyl acetate gradation, add anhydrous sodium sulfate drying in the extracting solution, evaporating solvent obtains solid product, and vacuum-drying obtains the 2.46 gram 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol, product yield 58%.
(
1H-NMR(400MHz，DMSO)；δ(PPm)：δ6.57(s，2H)，δ2.806-2.755(m，1H)，δ2.719-2.681(dd，1H)，δ2.522-2.486(t，2H)，δ2.454-2.349(m，2H)，δ2.219-2.160(q，1H)，δ1.902-1.870(m，1H)，δ1.506-1.457(m，2H)，δ1.449-1.365(m，2H)，δ0.875-0.837(t，3H)。
Embodiment 5
With 0.1 mole of NaBH
4Join in three mouthfuls of reaction flasks of the anhydrous tetrahydro furan that fills 50 milliliters; feed nitrogen protection; under 0-5 ℃ of continuous stirring condition; the 2-of (S)-(-) amino-6-propionamido-4 that adds 0.02 mole; 5; 6,7-tetrahydro benzothiazol slowly splashes into 100 milliliters of 0.04 mole of I after the mixing back is even again
2Tetrahydrofuran solution (0.04 mole of I
2), the time is 3-4 hour.Control temperature 0-5 ℃ of continuous stirring reaction 10 hours then, again reaction mixture is heated to 80 ℃ of reactions 24 hours.Under ice bath, cool off then.
Add 350 ml concns in the above-mentioned post reaction mixture and be 10% hydrochloric acid soln, NaOH solution with 20% is regulated pH value to 9-10, extract with the ethyl acetate gradation, add anhydrous sodium sulfate drying in the extracting solution, evaporating solvent obtains solid product, and vacuum-drying obtains the 2.2 gram 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol, product yield 52%.
(
1H-NMR(400MHz，DMSO)；δ(PPm)：δ6.57(s，2H)，δ2.806-2.755(m，1H)，δ2.719-2.681(dd，1H)，δ2.522-2.486(t，2H)，δ2.454-2.349(m，2H)，δ2.219-2.160(q，1H)，δ1.902-1.870(m，1H)，δ1.506-1.457(m，2H)，δ1.449-1.365(m，2H)，δ0.875-0.837(t，3H)。
Claims (10)
1. the 2-amino-6-of (S)-(-) third amino-4,5,6, the preparation method of 7-tetrahydro benzothiazol is characterized in that, under protection of inert gas, with the 2-of (S)-(-) amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4And I
2Contact reacts in reaction solvent is isolated the 2-amino-6-of (S)-(-) third amino-4,5,6, the 7-tetrahydro benzothiazol.
2. method according to claim 1 is characterized in that, the described 2-of (S)-(-) amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4And I
2Mol ratio be 1: (2-15): (1-8).
3. method according to claim 2 is characterized in that, the described 2-of (S)-(-) amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4And I
2Mol ratio be 1: (5-9): (2-4).
4. method according to claim 1 is characterized in that, described reaction solvent is selected from any of mixed solution of tetrahydrofuran (THF), organic ethers, tetrahydrofuran (THF) and organic ethers; The consumption of reaction solvent and NaBH
4Envelope-bulk to weight ratio be 10-25, unit is mL/g.
5. method according to claim 1 is characterized in that, described rare gas element is one or more in the gas of zero group in nitrogen, the periodic table of elements, is preferably nitrogen.
6. method according to claim 1 is characterized in that, the described 2-of (S)-(-) amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4And I
2Addition sequence be earlier with NaBH
4Join in the reaction solvent, and then add the 2-of (S)-(-) amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and I
2, and keep 0-10 ℃ of temperature.
7. method according to claim 6 is characterized in that, described I
2With I
2With tetrahydrofuran (THF), I
2With organic ethers, I
2Add with any solution form of the mixed solution of tetrahydrofuran (THF) and organic ether; Described organic ether and tetrahydrofuran (THF) volume ratio are 1: 1-1: 4, and described I
2The concentration of solution is the 0.4-1.5 mol.
8. method according to claim 1 is characterized in that, (S)-(-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4And I
2The contact reacts temperature be 0-80 ℃, the reaction times is 8-36 hour.
9. according to claim 1 or 8 described methods, it is characterized in that (S)-(-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4And I
2Contact reacts be the mode of segmentation reaction, 0-35 ℃ of reaction 2-10 hour, 35-80 ℃ of reaction 8-24 hour.
10. according to claim 4 or 7 described methods, it is characterized in that described organic ethers is for containing C
4-C
10, O
1-O
2In the organic ether one or more are preferably ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104600449A CN103183650A (en) | 2011-12-31 | 2011-12-31 | Preparation method of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005092871A2 (en) * | 2004-03-19 | 2005-10-06 | Dipharma S.P.A. | Intermediates for the preparation of pramipexole |
| CN101585818A (en) * | 2009-06-08 | 2009-11-25 | 上海医药工业研究院 | A kind of preparation method for the intermediate of pramipexole hydrochloride |
| CN101676272A (en) * | 2008-09-17 | 2010-03-24 | 北京德众万全药物技术开发有限公司 | preparation method of pramipexole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005092871A2 (en) * | 2004-03-19 | 2005-10-06 | Dipharma S.P.A. | Intermediates for the preparation of pramipexole |
| CN101676272A (en) * | 2008-09-17 | 2010-03-24 | 北京德众万全药物技术开发有限公司 | preparation method of pramipexole |
| CN101585818A (en) * | 2009-06-08 | 2009-11-25 | 上海医药工业研究院 | A kind of preparation method for the intermediate of pramipexole hydrochloride |
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