CN109705089A - The purification process of compound - Google Patents
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- CN109705089A CN109705089A CN201910145195.1A CN201910145195A CN109705089A CN 109705089 A CN109705089 A CN 109705089A CN 201910145195 A CN201910145195 A CN 201910145195A CN 109705089 A CN109705089 A CN 109705089A
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Abstract
The invention discloses a kind of 2- [[6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo -1 (2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile, that is, compound 1 of -4- purification process: 2- [(6- chloro- 3,4- dihydro -3- methyl -2,4- dioxo -1 (2H)-pyrimidine radicals) methyl] -4- fluorobenzonitrile and (R) -3- amino piperidine dihydrochloride be raw material, ethanol as solvent, in the presence of alkali, reaction generates 1 reaction solution of compound, after reaction, purifying obtains 1 product of compound.The improved technique of the present invention, after reaction, filtering, filtrate is concentrated into prescribed volume, and cooling crystallization obtains crude product, and crude product ethyl alcohol is once recrystallized to give finished product, for its purity up to 99.5% or more, yield reaches 85% or more, wherein the process impurity of a more difficult purifying is effectively removed.Reaction and purifying have used identical etoh solvent, not only small toxicity, but also are conducive to the recovery of solvent.The preparation and purification technological operation is easier, it can be achieved that recycled solvent, manufacturing cost is lower, and waste discharge is less, environmental-friendly, is suitble to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, specifically a kind of compound 2- [[6- [(3R) -3- amino -1-
Piperidyl] -1 (2H)-pyrimidine radicals of -3,4- dihydro -3- methyl -2,4- dioxo] methyl] and the fluoro- benzonitrile of -4- purification process.
Technical background
The amber love song Ge Lieting (compound 2) of Wu Tian company exploitation, is a kind of oral long-acting anti-diabetes B medicine
Object, it obtains the listing approval of Japanese PMDA on March 26th, 2015, and May is with trade nameLog in a day this city
?.
He is a kind of Long-acting selective two peptidyl enzyme -4 (DPP-4) inhibitor, can effectively inhibit DPP-4 active, is made postprandial
The glucagon-like-peptide-1 (GLP-1) and GIP of secretion are not degraded by DPP-4, extend GLP-1 and GIP action time, promote pancreas
The release of island element, reduces postprandial blood sugar.Since the secretion of GLP-1 and GIP is to rely on postprandial blood sugar concentration to increase, so song Ge Lieting
Blood sugar reducing function be also rely on postprandial blood sugar it is raised, cause the risk of hypoglycemia relatively small.
2- [[- 1 (2H)-pyrimidine radicals of 6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo]
Methyl] the fluoro- benzonitrile of -4- (compound 1) be ambroin love song Ge Lieting important intermediate.
The patent (WO2007035629) of Wu Tian company is reported with 2- [(the chloro- 3,4- dihydro -3- methyl -2,4- dioxy of 6-
- 1 (2H)-pyrimidine radicals of generation) methyl] -4- fluorobenzonitrile (compound 3) and (R) -3- amino piperidine dihydrochloride (compound 4)
For raw material, ethanol as solvent, under sodium bicarbonate effect, reaction obtains 1 crude product of compound, and crude product prepares salt in methylene chloride
Hydrochlorate, then dissociate and retrieve 1 finished product of compound.
The technique needs hydrochloric acid salt to dissociate again and obtains 1 finished product of compound after obtaining 1 crude product of compound, cumbersome, system
It makes at high cost, generates a large amount of wastes, the practicability is poor for process economics.
Patent (CN07337664) is reported with compound 3 and compound 4 as raw material, and molecular sieve, ethyl alcohol (EtOH) is added
Make solvent, under sodium bicarbonate effect, reaction obtains 1 reaction solution of compound, filters, and filtrate cooling crystallization obtains crude product, crude product
It is recrystallized to give 1 finished product of compound.
The technique has used molecular sieve, because molecular sieve activation regenerates difficulty, can not effectively realize recycling, manufacturing cost
Height is not suitable for industrialized production.
Patent (CN106608853) is reported with compound 3 and compound 4 as raw material, and isopropanol (IPA) and water are made molten
Agent, under potassium carbonate effect, reaction obtains 1 reaction solution of compound, and reaction terminates, and acetonitrile and heptane mixed solvent, ice bath is added dropwise
Crystallization obtains crude product, and crude product ethyl alcohol recrystallization once obtains 1 finished product of compound.Yield 78.72%, purity 99.80%.
The technique is not only in reaction using the mixed solvent of IPA and water, but also in purification process into reaction solution
The mixed solvent that joined acetonitrile and heptane causes solvent to be difficult to recycle, and yield is relatively low, and manufacturing cost is high, generates a large amount of
Waste is not suitable for industrialized production.
It is raw material, IPA and water as solvent that patent (105968093), which reports compound 3 and compound 4, in sodium carbonate and
Under potassium iodide effect, reaction obtains 1 reaction solution of compound, and reaction terminates, filtering, and filtrate is concentrated to dryness to obtain crude product, and crude product is used
Petroleum ether (PE) and ethyl acetate (EA) mixed solvent recrystallization obtain 1 product of compound twice.Yield 76.9%, purity
98.7%.
The technique this not only reaction when using IPA and water mixed solvent, but also crude product need to PE and EA mixing it is molten
Agent recrystallizes twice, causes solvent to be difficult to recycle, generates a large amount of wastes, cumbersome.It need to concentrate the filtrate to simultaneously
Dry to obtain solid crude product, reaction kettle can not stir, therefore be not suitable for industrialized production.
Patent (CN105541793) is reported with compound 3 and compound 4 as raw material, and isopropanol (IPA) and water are made molten
Agent, under potassium carbonate effect, reaction obtains 1 reaction solution of compound, and reaction terminates, and filtering, filtrate is concentrated to dryness to obtain crude product, slightly
Product once obtain 1 product of compound with 95% ethyl alcohol recrystallization.Yield 72%, purity 99.6%.
The technique this not only reaction when using IPA and water mixed solvent, cause solvent to be difficult to recycle, generate
A large amount of wastes, at the same need to concentrate the filtrate to it is dry obtain solid crude product, reaction kettle can not stir, therefore it is big raw to be not suitable for industrialization
It produces.Test discovery is carried out using the technique, finished product has process impurity (compound 5) residual of a more difficult removing more, affects
The quality of finished product compound 2, thus it is speculated that reason may are as follows: it is concentrated to dryness to obtain the technique of crude product to compound 5 without purification effect,
Only the impurity can not be effectively removed by 95% ethyl alcohol recrystallization.
Therefore, it is easy to operate to find one kind, process impurity compound 5, solvent recoverable, economic ring can be effectively removed
It protects, it is necessary for being conducive to the purification process of the compound 1 of industrialized production.
Summary of the invention
It is an object of the invention to 5 hardly possiblies of process impurity compound in the finished product in order to solve existing prepare compound 1 to remove,
Solvent is difficult to recycle, at high cost, seriously polluted, is not suitable for the defect of industrialized production, and provides a kind of 2- [[6-
- 1 (2H)-pyrimidine radicals of [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo] methyl] the fluoro- benzene of -4-
The purification process of formonitrile HCN, comprising the following steps:
With 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile
(compound 3) and (R) -3- amino piperidine dihydrochloride (compound 4) is raw material, and ethanol as solvent reacts in the presence of alkali
Generate 2- [[- 1 (2H)-pyrimidine radicals of 6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo] first
Base] the fluoro- benzonitrile of -4- (compound 1) reaction solution, after reaction, filtering, filtrate is concentrated, and cooling crystallization obtains crude product, slightly
Product ethyl alcohol recrystallization once obtains finished product.
Reaction principle of the present invention is schematically as follows:
The present invention has redesigned its purification process in the method for existing prepare compound 1, after reaction, filtering,
Filtrate is concentrated into prescribed volume, and cooling crystallization obtains crude product, and crude product ethyl alcohol recrystallization once obtains finished product.The purification process step
Simply, process impurity compound 5 can effectively remove, and solvent can realize recycling, and product purity is high, high income, be suitble to industry
Change application.
Preferably, filtrate volume is concentrated into 2- [(chloro- 3,4- dihydro -3- methyl -2, the 4- dioxo-of 6- in above-mentioned steps
1 (2H)-pyrimidine radicals) methyl] -4- fluorobenzonitrile inventory volume mass ratio be -10~20 DEG C, preferably 5.5~7.0V/W；
Preferably, crystallization temperature is -5~5 DEG C after being concentrated into prescribed volume in above-mentioned steps；
Preferably, crude product recrystallization uses in above-mentioned steps ethyl alcohol and 2- [[6- [(3R) -3- amino -1- piperidines
Base] -1 (2H)-pyrimidine radicals of -3,4- dihydro -3- methyl -2,4- dioxo] methyl] the fluoro- benzonitrile volume mass ratio of -4- are as follows:
8:1~20:1, preferably 8:1~10:1；
Preferably, the crystallization temperature of ethyl alcohol recrystallization is -10~20 DEG C, preferably 0~10 DEG C in above-mentioned steps.
The invention has the benefit that filtering, filtrate is concentrated into prescribed volume present invention employs after reaction, drop
Warm crystallization obtains crude product, and crude product alcohols solvent recrystallization once obtains the purification process of finished product, and filtrate is concentrated into prescribed volume, drop
Warm crystallization obtains the technique of crude product, and the technique for the crystallization that directly cools down compared to filtrate improves product yield, dense compared to filtrate
It is reduced to the dry technique for obtaining crude product, enhances the removal effect to process impurity compound 5.Crude product is using consistent with reaction dissolvent
Ethyl alcohol recrystallization it is primary, not only solvent can realize recycling, but also further enhance the removal effect of impurity so that at
The control of product compound 5 is in reasonable limit hereinafter, improve product purity, and products obtained therefrom purity is up to 99.5% or more, yield
Reach 85% or more, purity and yield all improve.The purifying process has to 5 removal effect of process impurity compound
It is good, it is easy to operate, preparation cost is low and environmental-friendly, is suitble to the advantages that industrialized production.
Specific embodiment
Below in conjunction with specific embodiment, the present invention will be further explained:
In raw material used in the present invention, compound 3 is self-control, other to be commercially available.
Embodiment 1: the synthesis of compound 3
By the chloro- 3- methyluracil (compound 6) (3.00Kg) of 6- and 2- cyano -5- fluorine bromobenzyl (compound 7)
(4.20Kg) is added in tetrahydrofuran (9L), and diisopropylethylamine (DIPEA) (2.66Kg) is slowly added dropwise under stirring, 65~
It is stirred 6 hours at 75 DEG C.It is cooled to 0~5 DEG C, filtering.Filter cake is added in water (8.4L), is beaten 1 hour at 10~15 DEG C, mistake
Filter.The drying 6~10 hours of 60~70 DEG C of filter cake, obtains 5.28Kg off-white powder compound 1, yield 96.3%, purity
99.3%.ESI:m/z, 294 [M+H]+.1H NMR (400MHz, CDCl3): δ (ppm) 7.72-7.75 (m, 1H), 7.12-7.17
(m, 1H), 6.92-6.95 (m, 1H), 6.04 (s, 1H), 5.49 (s, 1H), 3.40 (s, 1H)
Embodiment 2: the synthesis of compound 1
By 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile
Dehydrated alcohol (50mL) is added in (compound 3) (5.00 g) and (R) -3- amino piperidine dihydrochloride (compound 4) (3.83g)
In, it is added with stirring sodium carbonate (5.41g), is warming up at 75~85 DEG C and stirs 5 hours.Filtering, filtrate volume are concentrated under reduced pressure into
35mL is cooled to -10~-5 DEG C of stirring 1h, filtering.Filter cake is added in dehydrated alcohol (100mL), is warming up to 60~65 DEG C of dissolved clarifications,
It is cooled to and stirs 1h at -10~-5 DEG C, filter.The drying 6~10 hours of 60~70 DEG C of filter cake, obtains 5.24g off-white powder
Compound 1, yield 86.1%, purity 99.6%.ESI:m/z, 358 [M+H]+.1H NMR (400MHz, CDCl3): δ(ppm)
7.79-7.83 (m, 1H), 7.19-7.24 (m, 1H), 7.08-7.11 (m, 1H), 5.41 (s, 1H), 5.27 (s, 2H), 3.57-
7.63 (m, 1H), 3.24 (s, 3H), 3.16-3.19 (m, 1H), 3.01-3.04 (m, 1H), 2.80-2.87 (m, 1H), 2.61-
2.67 (m, 1H), 2.42-2.47 (m, 1H), 1.92-1.97 (m, 1H), 1.73-1.78 (m, 1H), 1.52-1.64 (m, 1H),
1.15-1.19 (t, 2H)
Embodiment 3: the synthesis of compound 1
By 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile
Dehydrated alcohol (50mL) is added in (compound 3) (5.00 g) and (R) -3- amino piperidine dihydrochloride (compound 4) (3.09g)
In, it is added with stirring sodium carbonate (4.51g), is warming up at 75~85 DEG C and stirs 5 hours.Filtering, filtrate volume are concentrated under reduced pressure into
28mL is cooled to 15~20 DEG C of stirring 1h, filtering.Filter cake is added in dehydrated alcohol (40mL), is warming up to 60~65 DEG C of dissolved clarifications, drops
Temperature is filtered to 1h is stirred at 15~20 DEG C.The drying 6~10 hours of 60~70 DEG C of filter cake, obtains 5.19g off-white powder chemical combination
Object 1, yield 85.3%, purity 99.7%.
Embodiment 4: the synthesis of compound 1
By 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile
Dehydrated alcohol is added in (compound 3) (20.00g) and (R) -3- amino piperidine dihydrochloride (compound 4) (12.97g)
In (200mL), it is added with stirring sodium carbonate (12.99g), is warming up at 75~85 DEG C and stirs 5 hours.Filtering, filtrate volume subtract
Pressure is concentrated into 125mL, is cooled to 0~5 DEG C of stirring 1h, filters.Filter cake is added in dehydrated alcohol (300mL), is warming up to 60~65
DEG C dissolved clarification, is cooled to and stirs 1h at 0~5 DEG C, filters.The drying 6~10 hours of 60~70 DEG C of filter cake, it is white to obtain 21.13g class
Color solid chemical compound 1, yield 86.8%, purity 99.5%.
Embodiment 5: the synthesis of compound 1
By 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile
Dehydrated alcohol is added in (compound 3) (20.00g) and (R) -3- amino piperidine dihydrochloride (compound 4) (12.97g)
In (200mL), it is added with stirring sodium carbonate (12.99g), is warming up at 75~85 DEG C and stirs 5 hours.Filtering, filtrate volume subtract
Pressure is concentrated into 130mL, is cooled to 0~5 DEG C of stirring 1h, filters.Filter cake is added in dehydrated alcohol (200mL), is warming up to 60~65
DEG C dissolved clarification, is cooled to and stirs 1h at 15~20 DEG C, filters.The drying 6~10 hours of 60~70 DEG C of filter cake, obtains 20.86g class
Compound as white solid 1, yield 85.7%, purity 99.7%.
Embodiment 6: the synthesis of compound 1
By 2- [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile
Dehydrated alcohol is added in (compound 3) (2.50 Kg) and (R) -3- amino piperidine dihydrochloride (compound 4) (1.62Kg)
In (22.5L), it is added with stirring sodium carbonate (1.98Kg), is warming up at 75~85 DEG C and stirs 5 hours.Filtering, filtrate volume subtract
Pressure is concentrated into 15.5L, is cooled to 0~5 DEG C of stirring 1h, filters.Filter cake is added in dehydrated alcohol (25.0L), is warming up to 60~65
DEG C dissolved clarification, is cooled to and stirs 1h at 0~5 DEG C, filters.The drying 6~10 hours of 60~70 DEG C of filter cake, it is white to obtain 2.66Kg class
Color solid chemical compound 1, yield 87.4%, purity 99.6%.
Claims (8)
1. a kind of 2- [[- 1 (2H)-pyrimidine of 6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo
Base] methyl] the fluoro- benzonitrile of -4- purification process, with 2-, [(chloro- 3,4- dihydro -3- methyl -2, the 4- dioxo -1 (2H)-of 6- is phonetic
Piperidinyl) methyl] -4- fluorobenzonitrile and (R) -3- amino piperidine dihydrochloride be raw material, ethanol as solvent, in the presence of alkali,
Reaction generates 2- [[- 1 (2H)-pyrimidine radicals of 6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo]
Methyl] the fluoro- benzonitrile reaction solution of -4-, after reaction, filtering, filtrate is concentrated, and cooling crystallization obtains crude product, and crude product ethyl alcohol is molten
Agent recrystallization is primary, obtains 2- [[6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo -1
(2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile finished product of -4-.
2. a kind of 2- according to claim 1 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile of -4- purification process, which is characterized in that filtrate volume is concentrated into 2-
The 5.5 of [(chloro- -1 (the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo of 6-) methyl] -4- fluorobenzonitrile inventory~
7.0V/W。
3. a kind of 2- according to claim 1 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile of -4- purification process, which is characterized in that filtrate concentration after, crystallization
Temperature is -10~20 DEG C.
4. a kind of 2- according to claim 3 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile of -4- purification process, which is characterized in that crystallization temperature be -5~5
℃。
5. a kind of 2- according to claim 1 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] -4- fluoro- benzonitrile purification process, which is characterized in that crude product recrystallization uses
Ethyl alcohol and 2- [[- 1 (2H)-pyrimidine radicals of 6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo] first
Base] the fluoro- benzonitrile volume mass ratio of -4- are as follows: 8:1~20:1.
6. a kind of 2- according to claim 5 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] -4- fluoro- benzonitrile purification process, which is characterized in that crude product recrystallization uses
Ethyl alcohol and 2- [[- 1 (2H)-pyrimidine radicals of 6- [(3R) -3- amino -1- piperidyl] -3,4- dihydro -3- methyl -2,4- dioxo] first
Base] the fluoro- benzonitrile volume mass ratio of -4- are as follows: 8:1~10:1.
7. a kind of 2- according to claim 1 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile of -4- purification process, which is characterized in that the crystallization of ethyl alcohol recrystallization
Temperature are as follows: -10~20 DEG C.
8. a kind of 2- according to claim 6 [[6- [(3R)-3- amino-1- piperidyl] methyl-2-3,4- dihydro-3-,
4- dioxo -1 (2H)-pyrimidine radicals] methyl] the fluoro- benzonitrile of -4- purification process, which is characterized in that the crystallization of ethyl alcohol recrystallization
Temperature is 0~10 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114364668A (en) * | 2019-06-21 | 2022-04-15 | 甘李药业股份有限公司 | CDK4/6 inhibitors, salts and intermediates thereof |
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| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| CN105541793A (en) * | 2016-01-04 | 2016-05-04 | 河北国龙制药有限公司 | Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate |
| CN105968093A (en) * | 2016-06-29 | 2016-09-28 | 郑州明泽医药科技有限公司 | Preparation method for trelagliptin succinate |
| CN106608853A (en) * | 2015-10-27 | 2017-05-03 | 北京万生药业有限责任公司 | Preparation method of dipeptidyl peptidase IV inhibitor |
| CN107337664A (en) * | 2016-05-03 | 2017-11-10 | 上海现代制药股份有限公司 | One koji Ge Lieting preparation method |
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2019
- 2019-02-27 CN CN201910145195.1A patent/CN109705089B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| CN106608853A (en) * | 2015-10-27 | 2017-05-03 | 北京万生药业有限责任公司 | Preparation method of dipeptidyl peptidase IV inhibitor |
| CN105541793A (en) * | 2016-01-04 | 2016-05-04 | 河北国龙制药有限公司 | Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate |
| CN107337664A (en) * | 2016-05-03 | 2017-11-10 | 上海现代制药股份有限公司 | One koji Ge Lieting preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114364668A (en) * | 2019-06-21 | 2022-04-15 | 甘李药业股份有限公司 | CDK4/6 inhibitors, salts and intermediates thereof |
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