CN105481792A

CN105481792A - Synthetic method with respect to pramipexole impurity C

Info

Publication number: CN105481792A
Application number: CN201410498904.1A
Authority: CN
Inventors: 赵孝杰; 刘远慧
Original assignee: SHANDONG BOYUAN PHARMACEUTICAL CO Ltd
Current assignee: Shandong Ailan Pharmaceutical Co.,Ltd.
Priority date: 2014-09-25
Filing date: 2014-09-25
Publication date: 2016-04-13
Anticipated expiration: 2034-09-25
Also published as: CN105481792B

Abstract

The invention discloses a synthetic method with respect to a pramipexole impurity C and belongs to the field of drug synthesis. The method comprises the steps of: by taking a compound I 2-amino-6-propionyl amine-4,5,6,7-tetrahydrobenzothiazole as a raw material, generating a compound II 6-nitrogen[2-amino-4,6-tetrahydro1,3-benzothiazole-6-yl]-1-ethyl-2-methyl-3- carbonyl propyl hydrocarbyl]-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine under the action of sodium methylate, then performing a reaction on the compound II and dithioglycol to obtain a compound III 6-nitrogen[2-amino-4,6-tetrahydro1,3-benzothiazole-6-yl]-1-ethyl-2-methyl-3-ketone thioacetal propyl hydrocarbyl]-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine; and then by taking nickel as a catalyst, performing hydrogenation reduction to obtain a mixed isomer of a compound IV: (6S)-6-nitrogen[3-(6S)-2-amino-4,6-tetrahydro1,3-benzothiazole-6-yl]-1-ethyl-2-methyl propyl]-4,5,6,7-tetrahydro1,3-benzothiazole-2,6-diamine. The compound prepared by the method is relatively high in purity, and the method is simple to operate.

Description

A kind of synthetic method about pramipexole impurity C

Technical field

The present invention relates to the synthetic method of a kind of pramipexole impurity C.

Technical background

Pramipexole is used to the S&S for the treatment of idiopathic parkinsonism, and pramipexole is a kind of non-ergot class dopamine agonist.In vitro study shows, and the specificity of pramipexole to D2 acceptor is higher and have intrinsic activity completely, to the avidity of D3 acceptor higher than D2 and D4 acceptor.Pramipexole oral absorption is complete rapidly.

Mixed isomers (6S)-6-nitrogen [3-(6S)-2-amino-4,6-tetrahydrochysene 1,3-benzothiazol-6-yl)-1-Ethyl-2-Methyl propyl group]-4,5,6,7-tetrahydrochysene 1,3-benzothiazole-2,6-diamines is impurity contained in pramipexole finished product, does not also report its synthetic method in existing patent, document.

Summary of the invention

Introduction of the present invention be the synthetic method of a kind of impurity C of pramipexole

The synthetic route of pramipexole impurity C provided by the invention is as follows:

Compound I 2-amino-6-propionyl amine-4, 5, 6, 7-tetrahydro benzothiazol generates Compound II per 6-nitrogen [2-amino-4 under the effect of sodium methylate, 6-tetrahydrochysene 1, 3-benzothiazol-6-yl)-1-Ethyl-2-Methyl-3-carbonyl third alkyl]-4, 5, 6, 7-tetrahydrochysene-1, 3-benzothiazole-2, 6-diamines, Compound II per reacts to obtain compound III 6-nitrogen [2-amino-4 again with dithioglycol, 6-tetrahydrochysene 1, 3-benzothiazol-6-yl)-1-Ethyl-2-Methyl-3-contracting thioketones third alkyl]-4, 5, 6, 7-tetrahydrochysene-1, 3-benzothiazole-2, 6-diamines, compound III is that catalyst hydrogenation reduces and to obtain compound IV mixed isomers (6S)-6-nitrogen [3-(6S)-2-amino-4 with nickel, 6-tetrahydrochysene 1, 3-benzothiazol-6-yl)-1-Ethyl-2-Methyl propyl group]-4, 5, 6, 7-tetrahydrochysene 1, 3-benzothiazole-2, 6-diamines.

Preferably, alkaline reagents used in step a is the one in sodium methylate, sodium ethylate, sodium hydroxide or potassium hydroxide.

Preferably, solvent used in step a is the one in methyl alcohol, ethanol or Virahol.

Preferably, the range of reaction temperature in step b is 0-50 DEG C.

Preferably, in step c, used catalyst is nickel, Raney's nickel, or the one in palladium charcoal.

Preferably, the range of reaction temperature in step c is 0-50 DEG C.

Preferably, the mol ratio of Compound I and alkali is 1:1.0-1.4.

Preferably, the mol ratio of Compound I and dithioglycol is 1:1.0-1.1.

Preferred version is, comprises the following steps:

A, Compound I 2-amino-6-propionyl amine-4,5,6,7-tetrahydro benzothiazol add in reaction flask, then add methyl alcohol, add sodium methylate under stirring, are heated to backflow, are then cooled to room temperature.

B, slowly drip dithioglycol, dropwise rear temperature control stirring and react 3 hours, then concentrating under reduced pressure solvent evaporated, add wherein methylene dichloride stir molten clear after, add purified water agitator treating, point water-yielding stratum, in methylene dichloride, add magnesium sulfate stir dry, filtering siccative, evaporated under reduced pressure methylene dichloride.

C, add dehydrated alcohol wherein, stir molten clear after reaction solution is transferred to autoclave, add catalyzer, pressure 0.1mpa is kept with passing into hydrogen after nitrogen replacement, temperature control stirring reacts 3 hours, filtering reacting liquid, be evaporated to dry, add recrystallisation from isopropanol and obtain compound IV mixed isomers (6S)-6-nitrogen [amino-4, the 6-tetrahydrochysenes 1 of 3-(6S)-2-, 3-benzothiazol-6-yl)-1-Ethyl-2-Methyl propyl group]-4,5,6,7-tetrahydrochysene 1,3-benzothiazole-2,6-diamines.

Embodiment

In order to understand the present invention better, illustrate content of the present invention further below in conjunction with embodiment, but content of the present invention is not only confined to the following examples, embodiment should not regard as limiting the scope of the present invention.

Below in conjunction with example, the present invention will be further described:

Implement 1

Get 50g Compound I 2-amino-6-propionyl amine-4, 5, 6, 7-tetrahydro benzothiazol adds in 500ml there-necked flask, then methyl alcohol 200ml is added, 14.4g sodium methylate is added under stirring, be heated to back flow reaction 2 hours, then room temperature is cooled to, slow dropping 22g dithioglycol, dropwise rear temperature control 25 DEG C of stirring reactions 3 hours, then water-bath 40 DEG C of concentrating under reduced pressure solvent evaporated, add wherein 200ml methylene dichloride stir molten clear after, add purified water 200ml agitator treating, divide water-yielding stratum, 200ml purified water is added again in methylene dichloride, agitator treating, divide water-yielding stratum, in methylene dichloride, add 5g magnesium sulfate stir dry 1 hour, filtering siccative, temperature control less than 40 DEG C evaporated under reduced pressure methylene dichloride, add 200ml dehydrated alcohol wherein, stir molten clear after reaction solution is transferred to 500ml autoclave, add 65g nickel, pressure 0.1mpa is kept with passing into hydrogen after nitrogen replacement, temperature control 25 DEG C of stirring reactions 3 hours, filtering reacting liquid, be evaporated to dry, add 270ml recrystallisation from isopropanol and obtain compound IV mixed isomers (6S)-6-nitrogen [3-(6S)-2-amino-4, 6-tetrahydrochysene 1, 3-benzothiazol-6-yl)-1-Ethyl-2-Methyl propyl group]-4, 5, 6, 7-tetrahydrochysene 1, 3-benzothiazole-2, 6-diamines 29.0g, purity 98.2%, yield 61.0%.

Embodiment 2

Get 50g Compound I 2-amino-6-propionyl amine-4, 5, 6, 7-tetrahydro benzothiazol adds in 500ml there-necked flask, then ethanol 200ml is added, 18.2g sodium ethylate is added under stirring, be heated to back flow reaction 2 hours, then room temperature is cooled to, slow dropping 22g dithioglycol, dropwise rear temperature control 20 DEG C of stirring reactions 4 hours, then water-bath 40 DEG C of concentrating under reduced pressure solvent evaporated, add wherein 200ml methylene dichloride stir molten clear after, add purified water 200ml agitator treating, divide water-yielding stratum, 200ml purified water is added again in methylene dichloride, agitator treating, divide water-yielding stratum, in methylene dichloride, add 5g magnesium sulfate stir dry 1 hour, filtering siccative, temperature control 40 DEG C of evaporated under reduced pressure methylene dichloride, add 200ml dehydrated alcohol wherein, stir molten clear after reaction solution is transferred to 500ml autoclave, add 65g nickel, pressure 0.2mpa is kept with passing into hydrogen after nitrogen replacement, temperature control 30 DEG C of stirring reactions 2 hours, filtering reacting liquid, be evaporated to dry, add 270ml recrystallisation from isopropanol and obtain compound IV mixed isomers (6S)-6-nitrogen [3-(6S)-2-amino-4, 6-tetrahydrochysene 1, 3-benzothiazol-6-yl)-1-Ethyl-2-Methyl propyl group]-4, 5, 6, 7-tetrahydrochysene 1, 3-benzothiazole-2, 6-diamines 28.1g, purity 98.4%, yield 59.2%.

The above is the preferred embodiment of the present invention; for the practical study technician of the art; under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modifications are also regarded as protection scope of the present invention.

Claims

1. the present invention relates to a kind of synthetic method of pramipexole impurity C, it is characterized in that, comprise the following steps:

A), Compound I reacting by heating in alkaline environment obtains chemical combination II;

B), Compound II per and dithioglycol react to obtain compound III;

C), compound III obtains compound IV by hydro-reduction.

2., in synthetic method according to claim 1, alkaline reagents used in step a is sodium methylate, sodium ethylate, sodium hydroxide or potassium hydroxide.

3., in synthetic method according to claim 1, solvent used in step a is methyl alcohol, ethanol or Virahol.

4., in synthetic method according to claim 1, the range of reaction temperature in step b is 0-50 DEG C.

5., in synthetic method according to claim 1, in step c, used catalyst is nickel, Raney's nickel or palladium charcoal.

6., in synthetic method according to claim 1, the range of reaction temperature in step c is 0-50 DEG C.

7., in synthetic method according to claim 1, the mol ratio of Compound I and alkali is 1:1.0-1.4.

8., in synthetic method according to claim 1, the mol ratio of Compound I and dithioglycol is 1:1.0-1.1.

9., according to the synthetic method of the arbitrary described pramipexole impurity C of claim 1-8, it is characterized in that, comprise the following steps:

A, Compound I 2-amino-6-propionyl amine-4,5,6,7-tetrahydro benzothiazol add in reaction flask, then add methyl alcohol, add sodium methylate under stirring, are heated to backflow, are then cooled to room temperature;

B, slowly drip dithioglycol, dropwise rear temperature control stirring and react 3 hours, then concentrating under reduced pressure solvent evaporated, add wherein methylene dichloride stir molten clear after, add purified water agitator treating, point water-yielding stratum, in methylene dichloride, add magnesium sulfate stir dry, filtering siccative, evaporated under reduced pressure methylene dichloride;