CN104557935B - Preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification - Google Patents
Preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification Download PDFInfo
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- CN104557935B CN104557935B CN201510041466.0A CN201510041466A CN104557935B CN 104557935 B CN104557935 B CN 104557935B CN 201510041466 A CN201510041466 A CN 201510041466A CN 104557935 B CN104557935 B CN 104557935B
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- base
- amino piperidine
- xanthine
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- purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Abstract
The invention discloses one and prepare (R) 8 (3 amino piperidine 1 base) xanthic method of purification, comprise the steps: that 8 (3 amino piperidine 1 base) the xanthine crude product obtained carries out into salt with suitable acid reaction to be purified, making beating, then obtain highly purified (R) 8 (3 amino piperidine 1 base) xanthine with the neutralization of suitable alkali.Product not only productivity obtained by the method for purification that the present invention provides is higher and operation is simpler, and the time, shorter being conducive to was commercially produced, and most importantly product purity is higher, and products obtained therefrom can guarantee that in API that all lists are miscellaneous and is held at 0.1% level below.
Description
Technical field
Present invention relates particularly to one and prepare (R)-8-(3-amino piperidine-1-base)-xanthic method of purification.
Background technology
Patent WO 04/018468 discloses a kind of 8-(3-amino piperidine-1-base)-xanthine and utilizes tertbutyloxycarbonyl
Prepared by the derivant deprotection of protection, and tertbutyloxycarbonyl protection group is made into by patent CN101048409A
Use phthalic acid anhydride group.
But this patent has simply focused on the improvement on route, and is not absorbed in the improvement of method of purification, it purifies
Method has to pass through twice recrystallization and operation complexity, and purification time is long, is not suitable for industrialized great production equipment
Operation.And (R)-8-obtained (3-amino piperidine-1-base) is although-xanthine meets drug registration requirement at that time,
But along with people drug safety is required more and more higher, during drug registration prescription the strictest
For under background, (R)-8-(3-amino piperidine-1-the base)-xanthine using this method of purification to obtain can not meet to be wanted
Ask, still its method of purification is improved.
Summary of the invention
Goal of the invention: the present invention provides one to prepare (R)-8-(3-amino piperidine-1-base)-xanthic method of purification.
Technical scheme: one prepares (R)-8-(3-amino piperidine-1-base)-xanthic method of purification, including as follows
Step: 8-(3-amino piperidine-1-the base)-xanthine crude product obtained is carried out into suitable acid reaction salt and purifies,
Making beating, then obtain highly purified (R)-8-(3-amino piperidine-1-base)-xanthine with the neutralization of suitable alkali.
As optimization: described acid is: hydrochloric acid, hydrobromic acid, benzenesulfonic acid, benzoic acid, glycolic, malonic acid,
Pyroglutamic acid, salicylic acid, maleic acid, oxalic acid, benzoic acid, citric acid, L-TARTARIC ACID and D-tartaric acid.
As preferably, described acid is hydrochloric acid, maleic acid, D-tartaric acid.
As optimization: in described salification process organic solvent mainly select methanol, ethanol, normal propyl alcohol, isopropanol,
One or more in ethyl acetate, dichloromethane, acetone；Reaction temperature selects 20-80 DEG C.
As optimization: described organic solvent preferred alcohol；Reaction temperature is preferably 70-80 DEG C.
As optimization: in described pulping process, organic solvent is: methanol, ethanol, ethyl acetate, dichloromethane,
One or more in acetone；Making beating temperature is 20-80 DEG C.
As optimization: organic solvent preferred alcohol in described pulping process, or, ethanol: ethyl acetate=1:1；
Making beating temperature is preferably 70-80 DEG C.
As optimization: in described N-process, solvent has: the one or several in water, methanol, ethanol and acetone etc.
Kind；Reaction temperature-10-50 DEG C；Alkali is: sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine,
One or more in N, N-diisopropylethylamine.
As preferably, in described N-process, solvent is water；Reaction temperature 5-10 DEG C；Alkali is: triethylamine and
N, N-diisopropylethylamine.
As optimization: preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification:
A. salt-forming reaction pulling an oar:
Synthesis is obtained (R)-8-(3-amino piperidine-1-base)-xanthine 1kg, ethanol 18kg and adds 50L reactor
In, be back to molten clearly, by D-(-)-tartaric acid 0.32kg be dissolved in 2.5kg ethanol stir molten clear after, be added dropwise to
In above-mentioned reactant liquor, within one hour, drip off, back flow reaction 1 hour, close heating and naturally cool to room temperature, mistake
Filter, 500ml ethanol rinse；Filter cake is transferred in 50L reactor, addition methanol 8kg, ethyl acetate 8kg,
Backflow making beating 1 hour, is cooled to 30 DEG C, filters, filter cake 60 DEG C of drying under reduced pressure 12 hours, obtain white extremely
Faint yellow solid；
B. in and reaction:
Upper step gained (R)-8-(3-amino piperidine-1-base)-xanthine tartrate 1.12kg is added 50L reactor
In, add water 30L, is cooled to 5-10 DEG C after stirring and dissolving, and dropping triethylamine 0.65kg drips off for mono-hour, surveys
About pH=10, add methylene chloride 10L, extraction, and aqueous phase extracts with dichloromethane 5L again, merges organic facies,
It is evaporated to 2L, methylate tertbutyl ether 3L, is concentrated into 2L, methylate tertbutyl ether 5L, backflow 1
Hour, naturally cooling to room temperature, filter, filter cake, 60 DEG C of drying under reduced pressure 12 hours, obtains white to faint yellow
Solid.
Beneficial effect: the product not only productivity obtained by the method for purification that the present invention provides is higher and operation is simpler
Single, the time, shorter being conducive to was commercially produced, and most importantly product purity is higher, and products obtained therefrom can guarantee that
In API, all lists are miscellaneous is held at 0.1% level below.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be described in detail.
Summary:
One prepares (R)-8-(3-amino piperidine-1-base)-xanthic method of purification, and comprising the steps: must
To 8-(3-amino piperidine-1-base)-xanthine crude product carry out into salt with suitable acid reaction and purify, making beating, then with
Suitably alkali neutralizes and obtains highly purified (R)-8-(3-amino piperidine-1-base)-xanthine.
Described acid is: hydrochloric acid, hydrobromic acid, benzenesulfonic acid, benzoic acid, glycolic, malonic acid, pyroglutamic acid,
Salicylic acid, maleic acid, oxalic acid, benzoic acid, citric acid, L-TARTARIC ACID and D-tartaric acid.As preferably,
Described acid is hydrochloric acid, maleic acid, D-tartaric acid.
In described salification process organic solvent mainly select methanol, ethanol, normal propyl alcohol, isopropanol, ethyl acetate,
One or more in dichloromethane, acetone；Reaction temperature selects 20-80 DEG C.As optimization: described organic
Solvent preferred alcohol；Reaction temperature is preferably 70-80 DEG C.
In described pulping process, organic solvent is: in methanol, ethanol, ethyl acetate, dichloromethane, acetone
One or more；Making beating temperature is 20-80 DEG C.As optimization: the preferred second of organic solvent in described pulping process
Alcohol, or, ethanol: ethyl acetate=1:1；Making beating temperature is preferably 70-80 DEG C.
In described N-process, solvent has: one or more in water, methanol, ethanol and acetone etc.；Reaction temperature
Spend-10-50 DEG C；Alkali is: sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, N, and N-bis-is different
One or more in propylethylamine.
As preferably, in described N-process, solvent is water；Reaction temperature 5-10 DEG C；Alkali is: triethylamine and N, N-
Diisopropylethylamine.
Specific embodiment:
Preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification:
A. salt-forming reaction pulling an oar:
Synthesis is obtained (R)-8-(3-amino piperidine-1-base)-xanthine 1kg, ethanol 18kg and adds 50L reactor
In, be back to molten clearly, by D-(-)-tartaric acid 0.32kg be dissolved in 2.5kg ethanol stir molten clear after, be added dropwise to
In above-mentioned reactant liquor, within one hour, drip off, back flow reaction 1 hour, close heating and naturally cool to room temperature, mistake
Filter, 500ml ethanol rinse；Filter cake is transferred in 50L reactor, addition methanol 8kg, ethyl acetate 8kg,
Backflow making beating 1 hour, is cooled to 30 DEG C, filters, filter cake 60 DEG C of drying under reduced pressure 12 hours, obtain white extremely
Faint yellow solid；
B. in and reaction:
Upper step gained (R)-8-(3-amino piperidine-1-base)-xanthine tartrate 1.12kg is added 50L reactor
In, add water 30L, is cooled to 5-10 DEG C after stirring and dissolving, and dropping triethylamine 0.65kg drips off for mono-hour, surveys
About pH=10, add methylene chloride 10L, extraction, and aqueous phase extracts with dichloromethane 5L again, merges organic facies,
It is evaporated to 2L, methylate tertbutyl ether 3L, is concentrated into 2L, methylate tertbutyl ether 5L, backflow 1
Hour, naturally cooling to room temperature, filter, filter cake, 60 DEG C of drying under reduced pressure 12 hours, obtains white to faint yellow
Solid.
Product not only productivity obtained by the method for purification that the present invention provides is higher and operation is simpler, and the time is shorter
Being conducive to commercially producing, most importantly product purity is higher, and products obtained therefrom can guarantee that all lists in API
Miscellaneous it is held at 0.1% level below.
Claims (1)
1. prepare (R)-8-(3-amino piperidine-1-base)-xanthic method of purification, its feature
It is: comprise the steps: 8-(3-amino piperidine-1-the base)-xanthine crude product that will obtain
Carry out into salt to purify with suitable acid reaction, making beating, then obtain with the neutralization of suitable alkali
(R)-8-(3-amino piperidine-1-base)-xanthine；
Concrete operations are as follows:
A. salt-forming reaction pulling an oar:
Synthesis obtains (R)-8-(3-amino piperidine-1-base)-xanthine 1kg, and ethanol 18kg adds
Enter in 50L reactor, be back to molten clearly, by D-(-)-tartaric acid 0.32kg is dissolved in
2.5kg ethanol stirs molten clear after, be added dropwise in above-mentioned reactant liquor, within one hour, drip off, return
Stream reaction 1 hour, closes heating and naturally cools to room temperature, filter, 500ml ethanol rinse；
Filter cake is transferred in 50L reactor, adds methanol 8kg, ethyl acetate 8kg, backflow
Pull an oar 1 hour, be cooled to 30 DEG C, filter, filter cake 60 DEG C of drying under reduced pressure 12 hours,
Obtain white to faint yellow solid；
B. in and reaction:
Upper step gained (R)-8-(3-amino piperidine-1-base)-xanthine tartrate 1.12kg is added
In 50L reactor, add water 30L, is cooled to 5-10 DEG C after stirring and dissolving, drips triethylamine
0.65kg drips off for mono-hour, surveys pH=10, and add methylene chloride 10L, and extraction, aqueous phase is used again
Dichloromethane 5L extracts, and merges organic facies, is evaporated to 2L, methylate tertbutyl ether 3L,
It is concentrated into 2L, methylate tertbutyl ether 5L, refluxes 1 hour, naturally cool to room temperature,
Filtering, filter cake, 60 DEG C of drying under reduced pressure 12 hours, obtains white to faint yellow solid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510041466.0A CN104557935B (en) | 2015-01-27 | 2015-01-27 | Preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification |
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| CN201510041466.0A CN104557935B (en) | 2015-01-27 | 2015-01-27 | Preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification |
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| CN104557935A CN104557935A (en) | 2015-04-29 |
| CN104557935B true CN104557935B (en) | 2016-08-17 |
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Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101150449B1 (en) * | 2002-08-21 | 2012-06-01 | 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 | 8-3---1-- 8-[3-Amino-piperidin-1-yl]-xanthines the production thereof and the pharmaceutical composition containing the same |
| DE102004054054A1 (en) * | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
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