CN107540633A - A kind of industrialized process for preparing of Pramipexole and its hydrochloride - Google Patents
A kind of industrialized process for preparing of Pramipexole and its hydrochloride Download PDFInfo
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- CN107540633A CN107540633A CN201610473501.0A CN201610473501A CN107540633A CN 107540633 A CN107540633 A CN 107540633A CN 201610473501 A CN201610473501 A CN 201610473501A CN 107540633 A CN107540633 A CN 107540633A
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Abstract
The present invention relates to a kind of preparation method of S () Pramipexole, it comprises the following steps：(1) by the diaminourea 4,5 of S () 2,6,6,7 tetrahydro benzothiazols dissolve in the mixed solvent, stirring, add base catalyst and p-methyl benzenesulfonic acid n-propyl, finish, heat, stirring reaction, after reaction terminates, filtering, dry, obtain white S () Pramipexole tosilate solid；(2) S () Pramipexole tosilate is added in the aqueous solution of salt, under stirring, adds inorganic base, finish, be stirred at room temperature, filter, dry, obtain white S () Pramipexole solid；Wherein, organic solvent is free of in step (2).
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of suitable for industrial Pramipexole and its hydrochloride
Preparation method.
Background technology
Pramipexole, it is non-ergot bases D2 and the D3 dopamine-receptor stimulant of a new generation, for early and late pa
The gloomy sick treatment of gold.In actual applications, preferably pramipexole dihydrochloride monohydrate is as the chemical combination for treating Parkinson's
Thing, referred to as pramipexole dihydrochloride monohydrate and body of Pramipexole dihydrochloride or Pramipexole hydrochloride.Pramipexole disalt
Hydrochloride-hydrate molecular formula is C11H17N3S·2HCl·H2O, chemical name are (S)-(-) -2- amino -6- (the third amino) -4,
5,6,7- tetrahydro benzothiazol dihydrochloride monohydrates, wherein (S) represents that body of Pramipexole dihydrochloride is S configurations, (-) represents hydrochloric acid
The optical activity of Pramipexole is left-handed.It is reported that Pramipexole S (-) isomers is approximately R to the affinity of d2 dopamine receptor
8-10 times of (+) isomers, it is 2 times of racemic modification, Pramipexole S (-) isomers is also bright to the therapeutic effect of Parkinson's
It is aobvious to be better than R (+) isomers and racemic modification.The chemical structural formula of body of Pramipexole dihydrochloride is as follows：
A kind of S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzos are disclosed in international patent application WO2007075095
Thiazole passes through the method that S- (-) Pramipexole and its hydrochloride is prepared in alkylated reaction, and this method includes：(1)S-(-)-
2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols and p-methyl benzenesulfonic acid n-propyl are not adding base catalysis using DMF as solvent
Under conditions of agent, S- (-) Pramipexole tosilate is prepared；(2) S- (-) Pramipexole tosilate can be with
With concentrated hydrochloric acid or excess acetyl chloride, S- (-) Pramipexole hydrochloride is directly prepared；(3) S- (-) Pramipexole is to toluene sulphur
Hydrochlorate can also be dissociated in the NaOH aqueous solution, CH2Cl2Extraction, concentrate, S- (-) pula gram of free state is prepared
Rope；Then using isopropanol as solvent, hydrochloric acid is added, S- (-) pramipexole dihydrochloride is prepared.In this method step (1)
Using DMF as solvent, because such solvent solubility is good, the salt of majority of compounds can part be dissolved in DMF, so S-
The yield of (-) Pramipexole tosilate is low, is not suitable for industrialized production；Step (2) although in concentrated hydrochloric acid or
Chloroacetic chloride, which carries out reaction, can directly be prepared S- (-) pramipexole dihydrochloride, but yield is relatively low, be unsuitable for industrializing big life
Production；Needed in step (3) by the step such as extracting, concentrating, extraction, concentration not only need to consume substantial amounts of manpower, improve production
Cost, and substantial amounts of organic reagent can be wasted, it is unfriendly to environment and producers.
Disclosed in international patent application WO2013096816 with R- (+) -6- diaminourea -4,5,6,7- tetrahydro benzothiazols
The method for preparing R- (+) pramipexole dihydrochloride monohydrate as raw material with p-methyl benzenesulfonic acid n-propyl, this method include：
(1) R- (+) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols and p-methyl benzenesulfonic acid n-propyl are prepared by base catalysis
R- (+) Pramipexole tosilate；(2) and then using 2- methyltetrahydrofurans, salting liquid as mixed solvent, NaOH's
Lower R- (+) Pramipexole p-methyl benzenesulfonic acid salt hydrolysis of effect obtain R- (+) Pramipexole of free state, with 2- methyltetrahydrofurans
R- (+) Pramipexole of free state is extracted for extractant, the 2- methyltetrahydrofurans for obtaining R- (+) Pramipexole are molten
Liquid；(3) aqueous isopropanol, stirring are added in the 2- methyltetrahydrofuran solution of R- (+) Pramipexole, is added under stirring state
Hydrochloric acid aqueous isopropanol, to reaction substantially completely, stand, filter to obtain R- (+) pramipexole dihydrochloride monohydrate.
2- methyltetrahydrofurans largely are used as solvent and extractant, 2- methyltetrahydrofuran toxicity in the above method
It is larger unfriendly to environment and producers, and 2- methyltetrahydrofurans are highly inflammable, can generate explosive peroxides, pacifying
There is larger potential safety hazard in all round process.2- methyltetrahydrofurans are used to be passed through as extractant in the other above method
Cross and R- (+) Pramipexole is obtained by extraction, extraction can take substantial amounts of manpower, improve production cost, be not suitable for industrialization amplification
Production, and substantial amounts of organic reagent can be wasted.In summary, the preparation of above-mentioned R- (+) pramipexole dihydrochloride monohydrate
Method, production cost is high, can use substantial amounts of toxic solvent, unfriendly to environment and producers, and safety is hidden in production process
Suffer from big, unsuitable industrialized production.
The content of the invention
It is an object of the invention to provide a kind of preparation method of S- (-) Pramipexole suitable for industrialized production.This method
Extraction, concentration step are needed not move through in preparation process is produced, the organic solvent amount used greatly reduces, and also saves simultaneously
Human cost, substantially reduce production cost, S- (-) Pramipexole high income, the purity that this method is prepared are good, suitable for work
Industry metaplasia is produced.
It is general obtained by this method it is a further object of the present invention to provide the method that one kind prepares S- (-) Pramipexole hydrochloride
Clarke rope hydrochloride high income, purity are good.
The present invention relates to a kind of preparation method of S- (-) Pramipexole, it comprises the following steps：
(1) S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols are dissolved in into the mixed solvent, stirs, add alkalescence
Catalyst and p-methyl benzenesulfonic acid n-propyl, are finished, heating, stirring reaction, after reaction terminates, are filtered, are dried, obtain white S-
(-) Pramipexole tosilate solid；
(2) S- (-) Pramipexole tosilate is added in the aqueous solution of salt, under stirring, adds inorganic base, add
Finish, be stirred at room temperature, filter, dry, obtain white S- (-) Pramipexole solid；
Wherein, organic solvent is free of in step (2).
The specific route of S- (-) the Pramipexole preparation method, it is as follows：
Foregoing S- (-) Pramipexole preparation method, wherein, mixed solvent described in step (1) is acetonitrile, water, different
The mixed solvent that two or more combination obtains in propyl alcohol；It is preferred that acetonitrile/water combines obtained mixed solvent；It is molten when mixing
When agent is acetonitrile/water, the volume ratio of acetonitrile and water is 49:1-9:1, preferably 30:1-19:1.
Foregoing S- (-) Pramipexole preparation method, wherein, base catalyst described in step (1) is selected from triethylamine, N,
N- diisopropylethylamine (DIPEA), pyridine, the carbon -7- alkene (DBU) of 1,8- diazabicylos 11, preferably N, N- diisopropyls
Ethamine (DIPEA)；The mol ratio of S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols and base catalyst is 1:
0.3-1:1.0, preferably 1:0.4-1:0.6.
Foregoing S- (-) Pramipexole preparation method, wherein, S- (-) -2,6- diaminourea -4,5 described in step (1), 6,
The mol ratio of 7- tetrahydro benzothiazols and p-methyl benzenesulfonic acid n-propyl is 1:1.1-1:2.5, preferably 1:1.4-1:1.6；It is described
Stirring reaction temperature is 70-77 DEG C, preferably 74-76 DEG C.
Foregoing S- (-) Pramipexole preparation method, wherein, the aqueous solution of the salt described in step (2) is selected from NaCl water
Solution, the KCl aqueous solution, preferably the NaCl aqueous solution；The concentration of the aqueous solution of described salt is to be less than to satisfy more than 20.1% (w/w%)
With the concentration of solution, when the aqueous solution of the salt is the NaCl aqueous solution, its concentration is 20.1-26.5% (w/w%), further
Preferably 23-25% (w/w%).
Foregoing S- (-) Pramipexole preparation method, wherein, S- (-) Pramipexole described in step (2) is to toluene sulphur
The amount of aqueous solution used of hydrochlorate and salt ratio is 1:2-1:9 (g/ml), preferably 1:5-1:7(g/ml).
Foregoing S- (-) Pramipexole preparation method, wherein, inorganic base described in step (2) be selected from NaOH, KOH,
Na2CO3、K2CO3, preferably NaOH；The inorganic base can be configured to aqueous solution addition, directly can also add in solid form；
The mol ratio of S- (-) Pramipexole tosilate and inorganic base is 1:1-1:1.3.
Organic solvent is free of in step (2) of the present invention, " organic solvent " here includes those skilled in the art
All organic solvents that can be known according to prior art and general knowledge.
The invention further relates to a kind of preparation method of S- (-) Pramipexole hydrochloride, it comprises the following steps：
(1) S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols are dissolved in into the mixed solvent, stirs, add alkalescence
Catalyst and p-methyl benzenesulfonic acid n-propyl, are finished, heating, stirring reaction, after reaction terminates, are filtered, are dried, obtain white S-
(-) Pramipexole tosilate solid；
(2) S- (-) Pramipexole tosilate is added in the aqueous solution of salt, under stirring, adds inorganic base, add
Finish, be stirred at room temperature, filter, dry, obtain white S- (-) Pramipexole solid；
(3) S- (-) Pramipexole is dissolved in isopropanol, stirred, hydrochloric acid is added dropwise, room temperature reaction, reacts after terminating, mistake
Filter, dry, obtain white S- (-) Pramipexole hydrochloride.
Wherein, organic solvent is free of in step (2).
The specific route of S- (-) the Pramipexole hydrochloric acid salt production process, it is as follows：
Foregoing S- (-) Pramipexole preparation method, wherein, mixed solvent described in step (1) is acetonitrile, water, different
The mixed solvent that two or more combination obtains in propyl alcohol；It is preferred that acetonitrile/water combines obtained mixed solvent；It is molten when mixing
When agent is acetonitrile/water, the volume ratio of acetonitrile and water is 49:1-9:1, more preferably 30:1-19:1.
Foregoing S- (-) Pramipexole preparation method, wherein, base catalyst described in step (1) is selected from triethylamine, N,
N- diisopropylethylamine (DIPEA), pyridine, the carbon -7- alkene (DBU) of 1,8- diazabicylos 11, preferably N, N- diisopropyls
Ethamine (DIPEA)；The mol ratio of S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols and base catalyst is 1:
0.3-1:1.0, preferably 1:0.4-1:0.6.
Foregoing S- (-) Pramipexole preparation method, wherein, S- (-) -2,6- diaminourea -4,5 described in step (1), 6,
The mol ratio of 7- tetrahydro benzothiazols and p-methyl benzenesulfonic acid n-propyl is 1:1.1-1:2.5, preferably 1:1.4-1:1.6；It is described
Stirring reaction temperature is 70-77 DEG C, preferably 74-76 DEG C.
Foregoing S- (-) Pramipexole preparation method, wherein, the aqueous solution of the salt described in step (2) is selected from NaCl water
Solution, the KCl aqueous solution, preferably the NaCl aqueous solution；The concentration of the aqueous solution of described salt is to be less than to satisfy more than 20.1% (w/w%)
With the concentration of solution, when the aqueous solution of the salt is the NaCl aqueous solution, its concentration is 20.1-26.5% (w/w%), further
Preferably 23-25% (w/w%).
Foregoing S- (-) Pramipexole preparation method, wherein, S- (-) Pramipexole described in step (2) is to toluene sulphur
The amount of aqueous solution used of hydrochlorate and salt ratio is 1:2-1:9 (g/ml), preferably 1:5-1:7(g/ml).
Foregoing S- (-) Pramipexole preparation method, wherein, inorganic base described in step (2) be selected from NaOH, KOH,
Na2CO3、K2CO3, preferably NaOH；The inorganic base can be configured to aqueous solution addition, directly can also add in solid form；
The mol ratio of S- (-) Pramipexole tosilate and inorganic base is 1:1-1:1.3.
Organic solvent is free of in step (2) of the present invention, " organic solvent " here includes those skilled in the art
All organic solvents that can be known according to prior art and general knowledge.
Foregoing S- (-) Pramipexole hydrochloric acid salt production process, wherein, S- (-) Pramipexole and salt described in step (3)
The mol ratio of acid is 1:2-1:3, the hydrochloric acid can be commercially available concentrated hydrochloric acid or the hydrochloric acid by dilution.
The advantage of the invention is that：Compared with international patent application WO2007075095, the present invention is preparing S- (-) pula
Boiling point is high, dissolubility is good DMF is not used during gram rope tosilate as solvent, and S- produced by the present invention
The purity of (-) Pramipexole and S- (-) Pramipexole hydrochloride is high, high income, suitable for industrialized production.With international patent application
WO2013096816 is compared, and the present invention is preparing S- (-) Pramipexole process to toluene sulphur salt using S- (-) Pramipexole as raw material
In, without using organic solvent 2- methyltetrahydrofurans highly inflammable, that explosive peroxides can be generated, without being extracted
And concentration process, reduce the potential safety hazard in production process, it is friendly to environment and producers, greatly reduce and be produced into
This.And S- (-) Pramipexole of the invention being prepared and S- (-) Pramipexole hydrochloride high income, purity are good, suitable for industry
Metaplasia is produced.
Embodiment
With reference to embodiment, the present invention is further elaborated, but these embodiments are definitely not any limit to the present invention
System.
The preparation of S- (-) Pramipexole tosilate
Embodiment 1
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 240mL, stir
Mix, add isopropanol 10mL, triethylamine (88.6mmol, 9.0g), p-methyl benzenesulfonic acid n-propyl (324.9mmol, 69.6g), finish,
70 DEG C of stirring reaction 16h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 95.4g, yield 84.2%.
Embodiment 2
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), isopropanol 240mL, stir
Mix, add purified water 10mL, pyridine (118.2mmol, 9.3g), p-methyl benzenesulfonic acid n-propyl (384.0mmol, 82.3g).Finish,
72 DEG C of stirring reaction 14h, reaction terminate.Filter, isopropanol washing, 50 DEG C of forced air dryings, obtain white solid 95.8g, yield
84.6%.Embodiment 3
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 200mL, isopropyl
Alcohol 40ml, stirring, add purified water 10mL, DBU (147.7mmol, 22.5g), p-methyl benzenesulfonic acid n-propyl (413.6mmol,
88.6g).Finish, 76 DEG C of stirring reaction 10h, reaction terminates.Filter, acetonitrile washing.Dry, obtain white solid 96.2g, yield
84.9%.Embodiment 4
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 245mL, stir
Mix, add purified water 5mL, DIPEA (88.6mmol, 11.4g), p-methyl benzenesulfonic acid n-propyl (354.5mmol, 76.0g).Finish,
70 DEG C of stirring reaction 9h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 96.5g, yield 85.2%.
Embodiment 5
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 244mL, stir
Mix, add purified water 6mL, DIPEA (118.2mmol, 15.3g), p-methyl benzenesulfonic acid n-propyl (413.6mmol, 88.6g).Finish,
74 DEG C of stirring reaction 8h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 97.2g, yield 85.8%.
Embodiment 6
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 242mL, stir
Mix, add purified water 8mL, DIPEA (147.7mmol, 19.1g), p-methyl benzenesulfonic acid n-propyl (443.1mg, 94.9g).Finish, 75
DEG C stirring reaction 7h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 99.6g, yield 87.9%.
Embodiment 7
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 240mL, stir
Mix, add purified water 10mL, DIPEA (177.2mmol, 22.9g), p-methyl benzenesulfonic acid n-propyl (472.6mg, 101.3g).Finish,
76 DEG C of stirring reaction 6h, reaction terminate.Filter, acetonitrile washing.Dry, obtain white solid 99.9g, yield 88.2%.
Embodiment 8
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 237.5mL, stir
Mix, add purified water 12.5mL, DIPEA 25mL (177.2mmol, 22.9g), p-methyl benzenesulfonic acid n-propyl (472.6mg,
101.3g).Finish, 75 DEG C of stirring reaction 6h, reaction terminates.Filter, acetonitrile washing, dry, obtain white solid 99.5g, yield
87.8%.Embodiment 9
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 225mL, stir
Mix, add purified water 25mL, DIPEA (206.8mmol, 26.7g), p-methyl benzenesulfonic acid n-propyl SM2 (443.3mg, 95g).Finish,
77 DEG C of stirring reaction 5h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 95.4g, yield 84.2%.
Embodiment 10
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 242mL, stir
Mix, add purified water 8mL, DIPEA (265.9mmol, 34.4g), p-methyl benzenesulfonic acid n-propyl (443.1mg, 94.9g).Finish, 75
DEG C stirring reaction 5h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 94.9g, yield 83.8%.
Embodiment 11
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 240mL, stir
Mix, add purified water 10mL, DIPEA (295.4mmol, 38.2g), p-methyl benzenesulfonic acid n-propyl (472.6mg, 101.3g).Finish,
76 DEG C of stirring reaction 5h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 93.6g, yield 82.6%.
Embodiment 12
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 242mL, stir
Mix, add purified water 8mL, DIPEA (147.7mmol, 19.1g), p-methyl benzenesulfonic acid n-propyl (561.3mg, 120.3g).Finish,
75 DEG C of stirring reaction 4h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 93.2g, yield 82.3%.
Embodiment 13
Add S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols (295.4mmol, 50g), acetonitrile 240mL, stir
Mix, add purified water 10mL, DIPEA (177.2mmol, 22.9g), p-methyl benzenesulfonic acid n-propyl (738.5mg, 158.2g).Finish,
75 DEG C of stirring reaction 4h, reaction terminate.Filter, acetonitrile washing, dry, obtain white solid 92.0g, yield 81.2%.
The preparation of S- (-) Pramipexole
Embodiment 14
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 20.1%NaCl aqueous solution 80mL, stir
Under, 2N NaOH aqueous solution 52.2mL (104.3mmol) are added dropwise.Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid
18.9g, yield 85.6%.
Embodiment 15
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 21%NaCl aqueous solution 120mL, stir
Under, 4N NaOH aqueous solution 27.5mL (110mmol) are added dropwise.Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid
19.0g, yield 86.2%.
Embodiment 16
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 22%NaCl aqueous solution 160mL, stir
Under, 6N NaOH aqueous solution 19.2mL (115mmol) are added dropwise.Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid
19.35g, yield 87.8%.
Embodiment 17
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 23%NaCl aqueous solution 200mL, stir
Under, 8N NaOH aqueous solution 15.0mL (119.9mmol) are added dropwise.Finish, 30min is stirred at room temperature.Filter, 50 DEG C of forced air dryings, obtain
White solid 20.2g, yield 91.5%.
Embodiment 18
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 24%NaCl aqueous solution 240mL, stir
Under, add NaOH (125.2mmol, 5.0g).Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid 21.0g, yield
95.2%.
Embodiment 19
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 25%NaCl aqueous solution 280mL, stir
Under, add NaOH (130.4mmol, 5.2g).Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid 20.8g, yield
94.3%.
Embodiment 20
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 26.5%NaCl aqueous solution 360mL, stir
Under, add NaOH (135.6mmol, 5.4g).Finish, 30min is stirred at room temperature.Filter, 50 DEG C of forced air dryings, obtain white solid
19.5g, yield 88.5%.
Embodiment 21
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 25%NaCl aqueous solution 320mL, stir
Under, add NaOH (110mmol, 4.4g).Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid 20.4g, yield
92.6%.
Embodiment 22
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 23%KCl aqueous solution 240mL, under stirring,
Add KOH (125.2mmol, 7.0g).Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid 19.9g, yield
90.2%.
Embodiment 23
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 24%NaCl aqueous solution 200mL, stir
Under, 8N Na are added dropwise2CO3Aqueous solution 15.0mL (119.9mmol).Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid
Body 19.7g, yield 89.6%.
Embodiment 24
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 23%NaCl aqueous solution 280mL, stir
Under, 4N K are added dropwise2CO3Aqueous solution 27.5mL (110mmol).Finish, 30min is stirred at room temperature.Filter, dry, obtain white solid
19.4g, yield 88.2%.
The preparation of S- (-) Pramipexole hydrochloride
Embodiment 25
Add S- (-) Pramipexole II (47.3mmol, 10g), isopropanol 100mL, stirring and dissolving, 6N hydrochloric acid isopropanols are added dropwise
Solution 15.8mL.It is added dropwise, reacts at room temperature 2h.Reaction terminates, and filters, and dries, obtains white solid 13.2g, yield 92.4%,
Chemical purity 100%, optical purity 100%.
Embodiment 26
Add S- (-) Pramipexole II (47.3mmol, 10g), isopropanol 100mL, stirring and dissolving, concentrated hydrochloric acid 8.5mL is added dropwise.
It is added dropwise, reacts at room temperature 2h.Reaction terminates, and filters, and dries, obtains white solid 13.7g, yield 95.8%, chemical purity
100%, optical purity 100%.
Embodiment 27
Add S- (-) Pramipexole II (47.3mmol, 10g), isopropanol 100mL, stirring and dissolving, concentrated hydrochloric acid is added dropwise
10.2mL.It is added dropwise, reacts at room temperature 2h.Reaction terminates, and filters, and dries, and obtains white solid 13.6g, yield 95.2%, chemistry
Purity 100%, optical purity 100%.
Embodiment 28
Add S- (-) Pramipexole II (47.3mmol, 10g), isopropanol 100mL, stirring and dissolving, concentrated hydrochloric acid is added dropwise
11.8mL.It is added dropwise, reacts at room temperature 2h.Reaction terminates, and filters, and dries, and obtains white solid 13.0g, yield 90.6%, chemistry
Purity 100%, optical purity 100%.
Comparative example
The preparation of S- (-) Pramipexole
Comparative example 1 (according to the WO2013096816 method one of embodiment 3)
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 2- methyltetrahydrofurans 360ml, 12%
NaCl aqueous solution 200mL, mixed solution are stirred under 125rpm, dropwise addition 2N NaOH aqueous solution 55ml (110mmol,
1.04).Finish, stirring reaction to all solids dissolves (about 20min).After reaction terminates, stratification, liquid separation, aqueous phase 2-
Methyltetrahydrofuran is extracted, and merges organic phase, isopropanol washing gained organic phase.By 2- methyltetrahydrofuran solution decompressions
Evaporation, obtains thick white solid 15.8g, yield 71.5%.
Comparative example 2 (according to the WO2013096816 method two of embodiment 3)
Add S- (-) Pramipexole tosilate (104.3mmol, 40g), 2- methyltetrahydrofurans 360ml, 12%
NaCl aqueous solution 200mL, mixed solution are stirred under 125rpm, dropwise addition 2N NaOH aqueous solution 55ml (110mmol,
1.04).Finish, stirring reaction to all solids dissolves (about 20min).After reaction terminates, stratification, liquid separation, aqueous phase 2-
Methyltetrahydrofuran is extracted, and merges organic phase, washing gained organic phase.Organic phase is evaporated under reduced pressure, thick white is obtained and consolidates
Body 15.9g, yield 72.3%.
Claims (10)
1. a kind of preparation method of S- (-) Pramipexole, it comprises the following steps：
(1) S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols are dissolved in into the mixed solvent, stirs, add base catalysis
Agent and p-methyl benzenesulfonic acid n-propyl, are finished, heating, stirring reaction, after reaction terminates, are filtered, are dried, it is general to obtain white S- (-)
Clarke rope tosilate solid；
(2) S- (-) Pramipexole tosilate is added in the aqueous solution of salt, under stirring, adds inorganic base, finish, room
Temperature stirring, is filtered, and is dried, is obtained white S- (-) Pramipexole solid；
Wherein, organic solvent is free of in step (2).
2. preparation method according to claim 1, wherein, the mixed solvent described in step (1) is acetonitrile, water, isopropyl
The mixed solvent that two or more combination obtains in alcohol.
3. preparation method according to claim 2, wherein, the mixed solvent described in step (1) combines for acetonitrile/water
The mixed solvent arrived；When mixed solvent is acetonitrile/water, the volume ratio of acetonitrile and water is 49:1-9:1.
4. preparation method according to claim 3, wherein, when the mixed solvent described in step (1) is acetonitrile/water, second
The volume ratio of nitrile and water is 30:1-19:1.
5. preparation method according to claim 1, wherein, base catalyst described in step (1) is selected from triethylamine, N, N-
One kind in diisopropylethylamine, pyridine, the carbon -7- alkene of 1,8- diazabicylos 11, the S- (-) -2,6- diaminourea -4,5,
The mol ratio of 6,7- tetrahydro benzothiazols and base catalyst is 1:0.3-1:1.0；S- (-) -2,6- diaminourea -4,5,6,
The mol ratio of 7- tetrahydro benzothiazols and p-methyl benzenesulfonic acid n-propyl is 1:1.1-1:2.5；The stirring reaction temperature is 70-
77℃。
6. preparation method according to claim 5, wherein, base catalyst described in step (1) is N, N- diisopropyls
The mol ratio of ethamine, the S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols and base catalyst is 1:0.4-1:
0.6；The mol ratio of S- (-) -2,6- diaminourea -4,5,6,7- tetrahydro benzothiazols and p-methyl benzenesulfonic acid n-propyl is preferred
For 1:1.4-1:1.6, the stirring reaction temperature is 74-76 DEG C.
7. preparation method according to claim 1, wherein, the aqueous solution of the salt described in step (2) is water-soluble selected from NaCl
One kind in liquid, the KCl aqueous solution；The concentration of the aqueous solution of described salt is to be less than saturated solution more than 20.1% (w/w%)
Concentration；Described S- (-) Pramipexole tosilate and the amount of aqueous solution used ratio of salt are 1:2-1:9(g/ml).
8. preparation method according to claim 7, wherein, the aqueous solution of the salt described in step (2) is the NaCl aqueous solution,
Its concentration is 20.1-26.5% (w/w%)；Described S- (-) Pramipexole tosilate and the amount of aqueous solution used ratio of salt
For 1:5-1:7(g/ml).
9. preparation method according to claim 8, wherein, the concentration of the NaCl aqueous solution is 23-25% (w/ in step (2)
W%).
10. preparation method according to claim 1, wherein, the inorganic base described in step (2) be selected from NaOH, KOH,
Na2CO3、K2CO3In one kind；The mol ratio of S- (-) Pramipexole tosilate and inorganic base is 1:1-1:1.3.
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| CN111072593A (en) * | 2019-12-31 | 2020-04-28 | 江苏天和制药有限公司 | Preparation method of pramipexole dihydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007075095A1 (en) * | 2005-12-29 | 2007-07-05 | Instytut Farmaceutyczny | Process for the preparation of pramipexole base and/or its salts |
| WO2011109596A1 (en) * | 2010-03-03 | 2011-09-09 | Knopp Neurosciences | Synthesis of chirally purified substituted benzothiazole diamines |
| WO2013096816A1 (en) * | 2011-12-22 | 2013-06-27 | Biogen Idec Ma Inc. | Improved synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
-
2016
- 2016-06-24 CN CN201610473501.0A patent/CN107540633A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007075095A1 (en) * | 2005-12-29 | 2007-07-05 | Instytut Farmaceutyczny | Process for the preparation of pramipexole base and/or its salts |
| WO2011109596A1 (en) * | 2010-03-03 | 2011-09-09 | Knopp Neurosciences | Synthesis of chirally purified substituted benzothiazole diamines |
| WO2013096816A1 (en) * | 2011-12-22 | 2013-06-27 | Biogen Idec Ma Inc. | Improved synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072593A (en) * | 2019-12-31 | 2020-04-28 | 江苏天和制药有限公司 | Preparation method of pramipexole dihydrochloride |
| CN111072593B (en) * | 2019-12-31 | 2022-11-08 | 江苏天和制药有限公司 | Preparation method of pramipexole dihydrochloride |
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