CN107602535A - The preparation method of SYR-322 - Google Patents
The preparation method of SYR-322 Download PDFInfo
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- CN107602535A CN107602535A CN201710867988.5A CN201710867988A CN107602535A CN 107602535 A CN107602535 A CN 107602535A CN 201710867988 A CN201710867988 A CN 201710867988A CN 107602535 A CN107602535 A CN 107602535A
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Abstract
The present invention relates to a kind of preparation method of SYR-322, belong to pharmaceutical chemistry technical field.The present invention comprises the following steps：(1) with 6 chlorine 3 methylpyrimidine 2,4 (1H, 3H) diketone for raw material, reacted with 2 bromomethyl cyanophenyls, TM1 is made；(2) TM1 is in the basic conditions, using polar aprotic material and water as solvent, reacted with (R) 3 amino piperidine dihydrochloride, (R) 2 ((6 (base of 3 amino piperidine 1) 3 methyl 2 are made, 4 dioxo 3,4 dihydro-pyrimidin 1 (2H) base) methyl) cyanophenyl (TM2)；(3) TM2 and benzoic acid, described SYR-322 is made.The present invention is simple and convenient, reduces the generation of side reaction, the purity of reaction yield and target product is improved, beneficial to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of SYR-322, belong to pharmaceutical chemistry technical field.
Background technology
SYR-322 (Alogliptin benzoate), chemistry are entitled：2- [[6- [(3R) -3- amino -1- piperazines
Piperidinyl]-(the 2H)-pyrimidine radicals of 3,4- dihydro -3- methyl -2,4- dioxo -1] methyl] benzonitrile benzoic acid salt, chemical constitution is such as
Under：
SYR-322 is the serine protease DPP IV (DPP-IV) of Japanese Takeda companies research and development
Inhibitor, there is high selectivity, internal glucagon-like peptide 1 (GLP-1) and glucose dependency pancreotropic hormone can be maintained more
The level of peptide (GIP), promotes the secretion of insulin, and so as to play hypoglycemic curative effect, in April, 2010 obtains Japanese MHLW
Listing approval, be current China's approved the 5th DPP-4 inhibitor, the glycemic control for diabetes B patient.
For the synthetic route of SYR-322, it has been disclosed that a variety of routes, but due to the generation of impurity, shadow
The purity for having arrived target product and yield are rung, it is necessary to be optimized to synthesis technique.
The content of the invention
It is an object of the invention to provide a kind of preparation method of SYR-322, its is simple and convenient, reduces
The generation of side reaction, the purity of reaction yield and target product is improved, beneficial to industrialized production.
The preparation method of SYR-322 of the present invention, comprises the following steps：
(1) it is anti-with 2- bromomethyls cyanophenyl (SM2) with the chloro- 3- methylpyrimidines -2,4 (1H, 3H) of 6--diketone (SM1) for raw material
Should, TM1 2- ((chloro- 3- methyl -2,4- dioxo -3,4- dihydro-pyrimidin -1 (the 2H)-yls of 6-) methyl) cyanophenyl is made；
(2) TM1 in the basic conditions, using polar aprotic material and water as solvent, with (R) -3- amino piperidine disalts
Hydrochlorate (SM3) react, be made (R) -2- ((6- (3- amino piperidine -1- bases) -3- methyl -2,4- dioxos -3,4- dihydro-pyrimidin -
1 (2H)-yl) methyl) cyanophenyl (TM2)；
(3) TM2 reacts with benzoic acid (SM4), and described SYR-322 (TP) is made.
Reaction equation is as follows：
In step (1), react and carried out under the conditions of existing for diisopropylethylamine, reaction solvent for use is toluene and N- first
Base pyrrolidones.The volume ratio of 1-METHYLPYRROLIDONE and toluene is 0.8-1.2:1.
The diisopropylethylamine and the mol ratio of 2- bromomethyl cyanophenyls are 1-2:1.
The 2- bromomethyls cyanophenyl and the mol ratio of chloro- 3- methylpyrimidines -2,4 (1H, the 3H)-diketone of 6- are 1-1.5:1.
In step (1), reaction temperature is 68-73 DEG C, and the reaction time is 1-3 hours.
In step (2), alkalescence condition is that sodium acid carbonate and TM1 mol ratio are 5- under the conditions of existing for sodium acid carbonate
10:1；The volume ratio of polar aprotic material and water is 3-5:10.
In step (2), described polar aprotic material is acetonitrile, acetone, tetrahydrofuran or N, N- dimethyl formyl
Amine.
In step (2), reaction temperature is 68-73 DEG C, and the reaction time is 8-16 hours.
In step (3), solvent for use is ethanol, and benzoic acid and TM2 mass ratio are 1-2：1.
In step (3), reaction temperature is 68-73 DEG C, and the reaction time is 2-6 hours.
The present invention compared with prior art, has the advantages that：
(1) the preparation method simple operation described in, reaction condition are gently controllable；
(2) generation of side reaction is reduced, and reduces the generation of accessory substance, the content of object is by original in crude product
91% brings up to 94%, and then reduces the difficulty of purifying, reduces the loss in purge process, improves reaction yield, by
60% originally brings up to 87%.
Embodiment
With reference to embodiment, the present invention is further illustrated, but it is not intended to limit the implementation of the present invention.
Embodiment 1
It is at (1) 25 DEG C that 10.0g (62.3mmol) SM1,40mL 1-METHYLPYRROLIDONE, 12.1g (93.6mmol) two is different
Propylethylamine is added sequentially in 500mL there-necked flasks, is added dropwise again into reaction bulb dissolved with 13.4g (68.4mmol) under agitation
SM2 40mL toluene solutions, after being added dropwise, 70 DEG C are warming up to, is reacted 1.5 hours.Reaction system is down to room temperature, adds thereto
Enter 40mL water, stirred 30 minutes at 25 DEG C, be cooled to 0 DEG C, stir 1 hour, filter.Dried after filter cake is eluted with 10mL isopropanols
It is dry to obtain 15.5g off-white powders, yield 90.2%.1HNMR(400MHz,DMSO-d6) δ ppm 7.90 (d, J=7.6Hz,
1H), 7.71 (t, J=7.8Hz, 1H), 7.52 (t, J=7.8Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 6.24 (s, 1H),
5.39(s,2H),3.19(s,3H)。
11.3g (65.3mmol) SM3,22.5mL water, 39.5g (470.2mmol) sodium acid carbonate are added successively at (2) 25 DEG C
Enter to 500mL reaction bulbs, stirring reaction 30 minutes at a temperature of this.Add 75mL N, N- dimethyl at 25 DEG C into reaction bulb again
Formamide, 15.0g (54.4mmol) TM1 are added.70 DEG C are warming up to react 12 hours.It is concentrated under reduced pressure and removes N, N- dimethyl formyls
Amine, thick liquid is obtained, adds 450mL dichloromethane, 225mL water at 25 DEG C into system, stirring separates organic after 30 minutes
Phase, aqueous phase add the extraction of 225mL dichloromethane, merge organic phase.Organic phase uses 450mL, 225mL 1M hydrochloric acid solutions successively
Extraction, merge aqueous phase.Sodium bicarbonate solid 60g regulations pH=7~8 are added into aqueous phase, successively using 450mL, 225mL dichloro
Methane is extracted twice, and merges organic phase, organic phase is washed through saturated nacl aqueous solution, after anhydrous sodium sulfate drying, is rotated to molten
Liquid residue about 45mL, 225mL normal heptane is added dropwise under stirring thereto, 2 DEG C are stirred 1 hour, there is solid precipitation, are filtered, filter cake
Drying obtains 16.0g white solids, yield 86.6%.1HNMR(400MHz,D2O) δ ppm 7.61 (d, J=7.6Hz, 1H),
7.49 (t, J=7.6Hz, 1H), 7.30 (t, J=7.6Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 5.42 (s, 1H), 5.11
(dd,J1=34.0Hz, J2=15.2Hz, 2H), 3.57 (t, J=6.6Hz, 2H), 3.25-3.35 (m, 2H), 2.99 (s, 3H),
2.65-2.95(m,3H),1.90-2.00(m,1H),1.65-1.75(m,3H),1.45-1.60(m,2H)。
(3) 25 DEG C are added sequentially to 10.0g (29.5mmol) TM2,40mL absolute ethyl alcohol in 250mL there-necked flasks, stirring
All dissolved to solid, be warming up to 70 DEG C, the anhydrous second dissolved with 5.4g (44.2mmol) benzoic acid is added dropwise under stirring thereto again
Alcoholic solution 20mL, after being added dropwise, 70 DEG C of stirring reactions 3 hours.0 DEG C is cooled to, is stirred 2 hours, is filtered, filter cake is with 10mL's
Water wash, filter cake dry to obtain 12.2g white solids, yield 89.6%.1HNMR(400MHz,DMSO-d6)δppm 7.90
(d, J=6.8Hz, 2H), 7.82 (d, J=7.6Hz, 1H), 7.63 (t, J=7.8Hz, 1H), 7.42-7.48 (m, 2H), 7.38
(t, J=7.2Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 5.37 (s, 1H), 5.18 (dd, J1=35.0Hz, J2=15.8Hz,
2H), 3.5 (d, J=10.8Hz, 1H), 3.08 (s, 3H), 3.01-3.10 (m, 1H), 2.8-2.99 (m, 1H), 2.65-2.75
(m,2H),1.82-1.94(m,1H),1.70-1.80(m,1H),1.30-1.53(m,2H)。
Embodiment 2
By 10.0g (62.3mmol) SM1,48mL 1-METHYLPYRROLIDONE, 16.1g (124.6mmol) two at (1) 25 DEG C
Wopropyl ethyl amine is added sequentially in 500mL there-necked flasks, is added dropwise again into reaction bulb dissolved with 18.3g (93.5mmol) under agitation
SM2 40mL toluene solutions, after being added dropwise, 73 DEG C are warming up to, is reacted 3 hours.Reaction system is down to room temperature, adds thereto
40mL water, stir 30 minutes at 25 DEG C, be cooled to 0 DEG C, stir 1 hour, filter.Dried after filter cake is eluted with 10mL isopropanols
Obtain 14.5g off-white powders, yield 84.4%.
11.3g (65.3mmol) SM3,30mL water, 54.9g (653.0mmol) sodium acid carbonate are sequentially added at (2) 25 DEG C
To 500mL reaction bulbs, stirring reaction 30 minutes at a temperature of this.Add 75mL tetrahydrofurans, 15.0g at 25 DEG C into reaction bulb again
(54.4mmol) TM1 is added.73 DEG C are warming up to react 16 hours.It is concentrated under reduced pressure and removes tetrahydrofuran, obtains thick liquid, 25 DEG C
Lower that 450mL dichloromethane, 225mL water are added into system, stirring separates organic phase after 30 minutes, and aqueous phase adds 225mL bis-
Chloromethanes extracts, and merges organic phase.Organic phase is extracted with 450mL, 225mL 1M hydrochloric acid solutions successively, merges aqueous phase.To aqueous phase
Middle addition sodium bicarbonate solid 60g regulations pH=7~8, are extracted twice using 450mL, 225mL dichloromethane, are associated with successively
Machine phase, organic phase are washed through saturated nacl aqueous solution, after anhydrous sodium sulfate drying, are rotated to solution residue about 45mL, under stirring
225mL normal heptane is added dropwise thereto, 2 DEG C are stirred 1 hour, there is solid precipitation, are filtered, and filter cake dries to obtain 15.4g whites admittedly
Body, yield 83.4%.
(3) 25 DEG C are added sequentially to 10.0g (29.5mmol) TM2,40mL absolute ethyl alcohol in 250mL there-necked flasks, stirring
All dissolved to solid, be warming up to 70 DEG C, the anhydrous second dissolved with 7.2g (59.0mmol) benzoic acid is added dropwise under stirring thereto again
Alcoholic solution 20mL, after being added dropwise, 73 DEG C of stirring reactions 6 hours.0 DEG C is cooled to, is stirred 2 hours, is filtered, filter cake is with 10mL's
Water wash, filter cake dry to obtain 11.7g white solids, yield 85.9%.
Embodiment 3
It is at (1) 25 DEG C that 10.0g (62.3mmol) SM1,32mL 1-METHYLPYRROLIDONE, 8.1g (62.3mmol) two is different
Propylethylamine is added sequentially in 500mL there-necked flasks, is added dropwise again into reaction bulb dissolved with 12.2g (62.3mmol) under agitation
SM2 40mL toluene solutions, after being added dropwise, 68 DEG C are warming up to, is reacted 1 hour.Reaction system is down to room temperature, adds thereto
40mL water, stir 30 minutes at 25 DEG C, be cooled to 0 DEG C, stir 1 hour, filter.Dried after filter cake is eluted with 10mL isopropanols
Obtain 11.6g off-white powders, yield 67.5%.
11.3g (65.3mmol) SM3,15mL water, 22.8g (272.0mmol) sodium acid carbonate are sequentially added at (2) 25 DEG C
To 500mL reaction bulbs, stirring reaction 30 minutes at a temperature of this.Add 75mL acetonitriles, 15.0g at 25 DEG C into reaction bulb again
(54.4mmol) TM1 is added.68 DEG C are warming up to react 8 hours.Be concentrated under reduced pressure and remove acetonitrile, obtain thick liquid, at 25 DEG C to
450mL dichloromethane, 225mL water are added in system, stirring separates organic phase after 30 minutes, and aqueous phase adds 225mL dichloromethanes
Alkane extracts, and merges organic phase.Organic phase is extracted with 450mL, 225mL 1M hydrochloric acid solutions successively, merges aqueous phase.Add into aqueous phase
Enter sodium bicarbonate solid 60g regulations pH=7~8, be extracted twice successively using 450mL, 225mL dichloromethane, merge organic phase,
Organic phase is washed through saturated nacl aqueous solution, after anhydrous sodium sulfate drying, is rotated to solution residue about 45mL, under stirring thereto
225mL normal heptane is added dropwise, 2 DEG C are stirred 1 hour, there is solid precipitation, are filtered, and filter cake dries to obtain 12.8g white solids, yield
For 69.3%.
(3) 25 DEG C are added sequentially to 10.0g (29.5mmol) TM2,40mL absolute ethyl alcohol in 250mL there-necked flasks, stirring
All dissolved to solid, be warming up to 70 DEG C, the anhydrous second dissolved with 3.6g (29.5mmol) benzoic acid is added dropwise under stirring thereto again
Alcoholic solution 20mL, after being added dropwise, 68 DEG C of stirring reactions 2 hours.0 DEG C is cooled to, is stirred 2 hours, is filtered, filter cake is with 10mL's
Water wash, filter cake dry to obtain 9.8g white solids, yield 72.0%.
Claims (10)
1. a kind of preparation method of SYR-322, it is characterised in that comprise the following steps：
(1) with chloro- 3- methylpyrimidines -2,4 (1H, the 3H)-diketone of 6- for raw material, reacted with 2- bromomethyls cyanophenyl, TM1 2- are made
((chloro- 3- methyl -2,4- dioxos -3,4- dihydro-pyrimidins -1 (the 2H)-yls of 6-) methyl) cyanophenyl；
(2) TM1 in the basic conditions, using polar aprotic material and water as solvent, with (R) -3- amino piperidine dihydrochlorides
Reaction, be made TM2 (R) -2- ((6- (3- amino piperidine -1- bases) -3- methyl -2,4- dioxos -3,4- dihydro-pyrimidin -1 (2H) -
Base) methyl) cyanophenyl；
(3) TM2 and benzoic acid, described SYR-322 is made.
2. the preparation method of SYR-322 according to claim 1, it is characterised in that：In step (1), react
Carried out under the conditions of diisopropylethylamine is existing, reaction solvent for use is toluene and 1-METHYLPYRROLIDONE.
3. the preparation method of SYR-322 according to claim 2, it is characterised in that：1-METHYLPYRROLIDONE with
The volume ratio of toluene is 0.8-1.2:1；Diisopropylethylamine and the mol ratio of 2- bromomethyl cyanophenyls are 1-2:1.
4. the preparation method of SYR-322 according to claim 1, it is characterised in that：2- bromomethyls cyanophenyl and 6-
The mol ratio of chloro- 3- methylpyrimidines -2,4 (1H, 3H)-diketone is 1-1.5:1.
5. the preparation method of SYR-322 according to claim 1, it is characterised in that：In step (1), reaction temperature
Spend for 68-73 DEG C, the reaction time is 1-3 hours.
6. the preparation method of SYR-322 according to claim 1, it is characterised in that：In step (2), alkaline bar
Part is that sodium acid carbonate and TM1 mol ratio are 5-10 under the conditions of existing for sodium acid carbonate:1；Polar aprotic material and water
Volume ratio be 3-5:10.
7. the preparation method of the SYR-322 according to claim 1 or 6, it is characterised in that：In step (2), pole
Property aprotic material is acetonitrile, acetone, tetrahydrofuran or DMF.
8. the preparation method of SYR-322 according to claim 1, it is characterised in that：In step (2), reaction temperature
Spend for 68-73 DEG C, the reaction time is 8-16 hours.
9. the preparation method of SYR-322 according to claim 1, it is characterised in that：It is used molten in step (3)
Agent is ethanol, and benzoic acid and TM2 mass ratio are 1-2：1.
10. the preparation method of SYR-322 according to claim 1, it is characterised in that：In step (3), reaction
Temperature is 68-73 DEG C, and the reaction time is 2-6 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109810094A (en) * | 2019-01-31 | 2019-05-28 | 深圳市第二人民医院 | A kind of preparation method of Egelieting |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592195A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | A preparing process of alogliptin benzoate |
| CN105367546A (en) * | 2014-08-18 | 2016-03-02 | 北京博时安泰科技发展有限公司 | A preparing process of alogliptin benzoate |
| CN105646446A (en) * | 2014-11-14 | 2016-06-08 | 海正辉瑞制药有限公司 | An alogliptin purifying method |
-
2017
- 2017-09-22 CN CN201710867988.5A patent/CN107602535A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592195A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | A preparing process of alogliptin benzoate |
| CN105367546A (en) * | 2014-08-18 | 2016-03-02 | 北京博时安泰科技发展有限公司 | A preparing process of alogliptin benzoate |
| CN105646446A (en) * | 2014-11-14 | 2016-06-08 | 海正辉瑞制药有限公司 | An alogliptin purifying method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109810094A (en) * | 2019-01-31 | 2019-05-28 | 深圳市第二人民医院 | A kind of preparation method of Egelieting |
| CN109810094B (en) * | 2019-01-31 | 2021-11-12 | 深圳市第二人民医院 | Preparation method of alogliptin |
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