CN106496194A - A kind of dimeric preparation method of Egelieting - Google Patents
A kind of dimeric preparation method of Egelieting Download PDFInfo
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- CN106496194A CN106496194A CN201610822990.6A CN201610822990A CN106496194A CN 106496194 A CN106496194 A CN 106496194A CN 201610822990 A CN201610822990 A CN 201610822990A CN 106496194 A CN106496194 A CN 106496194A
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- Prior art keywords
- egelieting
- preparation
- methyl
- benzonitrile
- chloro
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- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 48
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims abstract description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 40
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 34
- 239000000706 filtrate Substances 0.000 claims abstract description 30
- 239000000539 dimer Substances 0.000 claims abstract description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000605 extraction Methods 0.000 claims abstract description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- AKQXKEBCONUWCL-MRVPVSSYSA-N tert-butyl (3r)-3-aminopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC[C@@H](N)C1 AKQXKEBCONUWCL-MRVPVSSYSA-N 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 238000010926 purge Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- KEKKOBDBXZTFAR-SSDOTTSWSA-N tert-butyl (3r)-3-aminopiperazine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCN[C@@H](N)C1 KEKKOBDBXZTFAR-SSDOTTSWSA-N 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000009413 insulation Methods 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000460 chlorine Substances 0.000 abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 abstract 2
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 abstract 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 12
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 10
- 239000012535 impurity Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 6
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 5
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 5
- 125000003963 dichloro group Chemical group Cl* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 3
- 229960005095 pioglitazone Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229940117337 nesina Drugs 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- KEJICOXJTRHYAK-XFULWGLBSA-N alogliptin benzoate Chemical compound OC(=O)C1=CC=CC=C1.C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 KEJICOXJTRHYAK-XFULWGLBSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229940103513 kazano Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229960004329 metformin hydrochloride Drugs 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229940103456 oseni Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention discloses a kind of dimeric preparation method of Egelieting, comprises the steps：S1, preparation intermediate A：1 (6 chlorine, 3 methyl, 2,4 dioxo, 3,4 dihydro 2H pyrimidines, 1 ylmethyl) benzonitrile, 3 amino piperidine of (R) 1 N tertbutyloxycarbonyls, sodium acid carbonate, isopropanol are mixed, backflow takes filtrate and is concentrated to give intermediate A；S2, preparation intermediate B：The intermediate A obtained in S1 is added in dichloromethane and is dissolved, trifluoroacetic acid is added dropwise, stir 1 5h, concentration is obtained by extraction intermediate B；S3, preparation Egelieting dimer：Intermediate B, 1 (6 chlorine, 3 methyl, 2,4 dioxo, 3,4 dihydro 2H pyrimidines, 1 ylmethyl) benzonitrile, potassium carbonate, N will be obtained in S2, N dimethylformamides are mixed, and are heated up, insulated and stirred, filtrate is filtered to take, is purified, is recrystallized to give Egelieting dimer.
Description
Technical field
The present invention relates to SYR-322 impurity preparing technical field, more particularly to a kind of Egelieting is dimeric
Preparation method.
Background technology
Chemical entitled 2- ({ 6- [(3R) -3- amino piperidines -1- bases] -3- methyl -2, the 4- dioxies of SYR-322
- 1 (2H)-yl of generation -3,4- dihydro-pyrimidins } methyl)-benzonitrile list benzoate, its molecular formula is C18H21N5O2·C7H6O2, point
Son amount is 461.51, and No. CAS is 850649-62-6, and its structural formula is as follows：
SYR-322 is a kind of selective dipeptidyl peptidase-IV (DPP-IV) inhibitor of military field pharmaceutical development,
SYR-322 can effectively reduce glucose level in health volunteer and diabetes B patient's body, increase its internal pancreas
Island element level, and tolerance is good, is a kind of high selectivity dipeptidyl peptidase IV (DPP-IV) inhibitor, with very strong
Targeting specific, when glucose is normal, the medicine does not have activity, is not result in hypoglycemia.In April, 2010, in Japanese quilt
Ratify for treating diabetes B, and become the best-selling at present DPP-4 inhibitor products for diabetes B of Japan
(Nesina).Which also goes through this in July, 2011 with the combination formulations Liovel (Egelieting/Pioglitazone) of Pioglitazone
Idicatio.Early in 2008, military field just proposed application for quotation to FDA, and on January 25th, 2013, U.S. FDA have approved DPP-IV
3 kinds of preparation listings of inhibitor Egelieting, for improving the blood sugar level of adult's diabetes B.This 3 kinds of preparations be respectively Ah
Ge Lieting pieces, Egelieting and Metformin hydrochloride fixed dosage complex tablet and Egelieting and Pioglitazone complex tablet,
Its trade name is followed successively by Nesina, Kazano and Oseni).2013 Nian Yuanyan producers are in Chinese granted listing.
In the preparation process of SYR-322, following 8 kinds of impurity are easily produced, its structural formula is respectively：
In order to reach high-quality SYR-322, need to control impurity content therein.Main by height at present
Effect liquid phase chromatogram method is monitoring the quality of SYR-322, quantitative to impurity more accurate using external standard method (impurity Standard reference)
Really.Therefore a kind of easy method for preparing high-purity impurity is provided, for the quality of monitoring SYR-322, improves its matter
Amount standard, it is ensured that people's safe medication is significant.
Content of the invention
The technical problem that basic background technology is present, the present invention propose a kind of dimeric preparation method of Egelieting,
Egelieting dimeric structural formula such as impurity E, high income of the present invention, the Egelieting dimer purity for preparing are high, into
This is low, simple to operate, is suitable for industrialized production.
A kind of dimeric preparation method of Egelieting proposed by the present invention, comprises the steps：
S1, preparation intermediate A：By 1- (the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- Ji Jia of 6-
Base)-benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, sodium acid carbonate, isopropanol mix, backflow, filter to take filtrate, dense
Contracting obtains intermediate A；
S2, preparation intermediate B：The intermediate A obtained in S1 is added in dichloromethane and is dissolved, trifluoroacetic acid is added dropwise, stirs
1-5h is mixed, after concentration, intermediate B is obtained by extraction；
S3, preparation Egelieting dimer：To obtain in S2 intermediate B, 1- (chloro- 3- methyl -2,4- dioxo -3 of 6-,
4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate, DMF mix, heat up, insulated and stirred, filter
Filtrate is taken, is purified, is recrystallized to give Egelieting dimer.
Preferably, in S1, by 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls) -
Benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, sodium acid carbonate, isopropanol are mixed, and flow back 3-24h, filters to take filter while hot
Liquid, is concentrated to give intermediate A.
Preferably, in S1,1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzyl
Nitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, the weight ratio of sodium acid carbonate are 1：0.8-0.9：0.4-0.5.
Preferably, in S1,1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzyl
Nitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, the weight ratio of sodium acid carbonate are 1：0.87：0.46.
Preferably, in S1,1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzyl
The bulking value (g/ml) of nitrile and isopropanol is than being 1：5.4-6.
Preferably, in S2, in extraction process, after concentration, water dissolves are added, plus ethyl acetate is mixed, extraction water intaking
Phase, adds dichloromethane in Xiang Shuixiang, adjusts pH=11-12, takes organic phase, be concentrated to give intermediate B.
Preferably, in S2, in extraction process, after concentration, water dissolves are added, plus ethyl acetate is mixed, extraction water intaking
Phase, adds dichloromethane, adjusts pH=11-12 with sodium hydrate aqueous solution, take organic phase in Xiang Shuixiang, reduced pressure concentration is obtained
Arrive intermediate B.
Preferably, in S2, intermediate A, the bulking value (g/ml) of trifluoroacetic acid are than being 1：1.9-2.1.
Preferably, in S3, will obtain in S2 intermediate B, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydros -
2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate, DMF mix, be warming up to 60-70 DEG C, insulated and stirred 2-
8h, filters to take filtrate while hot, purifying, is recrystallized to give Egelieting dimer.
Preferably, in S3, in purge process, filtering to take filtrate while hot, being cooled to room temperature, precipitation is added in filtrate
Agent is mixed, and filters to take filter cake, after drying, is recrystallized to give Egelieting dimer.
Preferably, precipitating reagent is water.
Preferably, in S3, in recrystallization process, after drying, DMF is added, 50-70 is warming up to
DEG C, insulated and stirred 1-2h is cooled to room temperature, filters to take filter cake, is washed with ethyl acetate, is dried to obtain Egelieting dimer.
Preferably, in S3, intermediate B, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydro -2H- pyrimidine -1- bases
Methyl)-benzonitrile, potassium carbonate weight ratio be 1：0.75-0.85：0.8-1.2；Preferably, in S3, (6- is chloro- for intermediate B, 1-
3- methyl -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate weight ratio be 1：0.82：1.
In above-mentioned S1, do not specify reflux temperature, state can be maintained the reflux for, reflux temperature is determined according to concrete operations.
In above-mentioned S2, dichloromethane, the effect of water are to dissolve and extract, and the effect of ethyl acetate is extraction, does not specify which
Consumption, determines its consumption according to concrete operations.
In above-mentioned S2, the effect of sodium hydrate aqueous solution is to adjust pH, does not specify its concentration, determines which according to concrete operations
Concentration.
In above-mentioned S3, in purge process, do not specify the consumption of precipitating reagent, its consumption is determined according to concrete operations.
In above-mentioned S3, DMF is used as reaction dissolvent and recrystallization solvent, ethyl acetate
Effect is washing, does not specify its consumption, determines its consumption according to concrete operations.
Above-mentioned isopropanol, dichloromethane, water, ethyl acetate, DMF are both needed to recovered process, then profit
With.
The present invention from 1- (the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- ylmethyls of 6-)-benzonitrile,
(R) -1-N- tertbutyloxycarbonyls -3- amino piperidines are main material, protect the secondary amine on piperidine ring with tertbutyloxycarbonyl, promote primary amine
React with chlorine so that reaction selectivity is high, impurity is few, high income；Other auxiliary material sodium acid carbonate, trifluoroacetic acid, potassium carbonate
Deng, cheap and easy to get, cost-saved；Reaction condition is gentle, and energy saving can be further cost-effective, and convenient operation, keeps away
Exempt from potential safety hazard；Simple to operate, suitable industrialized production, and of the present invention high income, the Egelieting dimerization that prepare respectively are walked
Body purity is high.
Description of the drawings
Fig. 1 is a kind of synthetic route chart of the dimeric preparation method of Egelieting proposed by the present invention.
Specific embodiment
As shown in figure 1, Fig. 1 is a kind of synthetic route chart of the dimeric preparation method of Egelieting proposed by the present invention.
With reference to Fig. 1, a kind of dimeric preparation method of Egelieting proposed by the present invention comprises the steps：
S1, preparation intermediate A：By 1- (the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- Ji Jia of 6-
Base)-benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, sodium acid carbonate, isopropanol mix, backflow, filter to take filtrate, dense
Contracting obtains intermediate A；
S2, preparation intermediate B：The intermediate A obtained in S1 is added in dichloromethane and is dissolved, trifluoroacetic acid is added dropwise, stirs
1-5h is mixed, after concentration, intermediate B is obtained by extraction；
S3, preparation Egelieting dimer：To obtain in S2 intermediate B, 1- (chloro- 3- methyl -2,4- dioxo -3 of 6-,
4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate, DMF mix, heat up, insulated and stirred, filter
Filtrate is taken, is purified, is recrystallized to give Egelieting dimer.
Below, technical scheme is described in detail by specific embodiment.
Embodiment 1
A kind of dimeric preparation method of Egelieting, comprises the steps：
S1, preparation intermediate A：By 1- (the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- Ji Jia of 6-
Base)-benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, sodium acid carbonate, isopropanol mix, backflow, filter to take filtrate, dense
Contracting obtains intermediate A；
S2, preparation intermediate B：The intermediate A obtained in S1 is added in dichloromethane and is dissolved, trifluoroacetic acid is added dropwise, stirs
3h is mixed, after concentration, intermediate B is obtained by extraction；
S3, preparation Egelieting dimer：To obtain in S2 intermediate B, 1- (chloro- 3- methyl -2,4- dioxo -3 of 6-,
4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate, DMF mix, heat up, insulated and stirred, filter
Filtrate is taken, is purified, is recrystallized to give Egelieting dimer.
Embodiment 2
A kind of dimeric preparation method of Egelieting, comprises the steps：
S1, preparation intermediate A：By 1 part of 1-, (the chloro- 3- methyl -2,4- dioxos -3,4- dihydro -2H- of 6- are phonetic by weight
Pyridine -1- ylmethyls)-benzonitrile, 0.8 part of (R) -1-N- tertbutyloxycarbonyl -3- amino piperidine, 0.5 part of sodium acid carbonate, isopropanol mix
Even, flow back 3h, filters to take filtrate while hot, is concentrated to give intermediate A, wherein, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4-
Dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile and isopropanol bulking value (g/ml) than being 1：5.4；
S2, preparation intermediate B：By weight the intermediate A obtained in 1 part of S1 is added in dichloromethane and is dissolved, be added dropwise
Trifluoroacetic acid, stirs 5h, after concentration, adds water dissolves, plus ethyl acetate is mixed, and extraction water intaking phase adds dichloro in Xiang Shuixiang
Methane, adjusts pH=12, takes organic phase, be concentrated to give intermediate B, wherein, intermediate A, the bulking value of trifluoroacetic acid
(g/ml) than being 1：1.9；
S3, preparation Egelieting dimer：Intermediate B, 0.75 part 1- (6- chloro- 3- first will be obtained in 1 part of S2 by weight
Base -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, 1.2 parts of potassium carbonate, DMFs mix
Even, 70 DEG C are warming up to, insulated and stirred 2h filters to take filtrate while hot, purifying, is recrystallized to give Egelieting dimer.
Embodiment 3
A kind of dimeric preparation method of Egelieting, comprises the steps：
S1, preparation intermediate A：By 1 part of 1-, (the chloro- 3- methyl -2,4- dioxos -3,4- dihydro -2H- of 6- are phonetic by weight
Pyridine -1- ylmethyls)-benzonitrile, 0.9 part of (R) -1-N- tertbutyloxycarbonyl -3- amino piperidine, 0.4 part of sodium acid carbonate, isopropanol mix
Even, flow back 24h, filters to take filtrate while hot, is concentrated to give intermediate A, wherein, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4-
Dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile and isopropanol bulking value (g/ml) than being 1：6；
S2, preparation intermediate B：By weight the intermediate A obtained in 1 part of S1 is added in dichloromethane and is dissolved, be added dropwise
Trifluoroacetic acid, stirs 1h, after concentration, adds water dissolves, plus ethyl acetate is mixed, and extraction water intaking phase adds dichloro in Xiang Shuixiang
Methane, adjusts pH=11 with sodium hydrate aqueous solution, takes organic phase, be concentrated under reduced pressure to give intermediate B, wherein, intermediate
A, the bulking value (g/ml) of trifluoroacetic acid are than being 1：2.1；
S3, preparation Egelieting dimer：Intermediate B, 0.85 part 1- (6- chloro- 3- first will be obtained in 1 part of S2 by weight
Base -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, 0.8 part of potassium carbonate, DMF mix
Even, 60 DEG C are warming up to, insulated and stirred 8h filters to take filtrate while hot, is cooled to room temperature, adds water and mixes, filter to take in filtrate
Filter cake, after drying, is recrystallized to give Egelieting dimer.
Embodiment 4
A kind of dimeric preparation method of Egelieting, comprises the steps：
S1, preparation intermediate A：By 1 part of 1-, (the chloro- 3- methyl -2,4- dioxos -3,4- dihydro -2H- of 6- are phonetic by weight
Pyridine -1- ylmethyls)-benzonitrile, 0.85 part of (R) -1-N- tertbutyloxycarbonyl -3- amino piperidine, 0.48 part of sodium acid carbonate, isopropanol mix
Even, flow back 10h, filters to take filtrate while hot, is concentrated to give intermediate A, wherein, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4-
Dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile and isopropanol bulking value (g/ml) than being 1：5.6；
S2, preparation intermediate B：By weight the intermediate A obtained in 1 part of S1 is added in dichloromethane and is dissolved, be added dropwise
Trifluoroacetic acid, stirs 4h, after concentration, adds water dissolves, plus ethyl acetate is mixed, and extraction water intaking phase adds dichloro in Xiang Shuixiang
Methane, adjusts pH=11.8 with sodium hydrate aqueous solution, takes organic phase, be concentrated under reduced pressure to give intermediate B, wherein, middle
Body A, the bulking value (g/ml) of trifluoroacetic acid are than being 1：1.95；
S3, preparation Egelieting dimer：Intermediate B, 0.8 part 1- (6- chloro- 3- first will be obtained in 1 part of S2 by weight
Base -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, 1.1 parts of potassium carbonate, DMFs mix
Even, 67 DEG C are warming up to, insulated and stirred 4h filters to take filtrate while hot, is cooled to room temperature, adds water and mixes, filter to take in filtrate
Filter cake, after drying, adds DMF, is warming up to 50 DEG C, and insulated and stirred 2h is cooled to room temperature, filters to take filter cake,
Washed with ethyl acetate, be dried to obtain Egelieting dimer.
Embodiment 5
A kind of dimeric preparation method of Egelieting, comprises the steps：
S1, preparation intermediate A：By 1 part of 1-, (the chloro- 3- methyl -2,4- dioxos -3,4- dihydro -2H- of 6- are phonetic by weight
Pyridine -1- ylmethyls)-benzonitrile, 0.89 part of (R) -1-N- tertbutyloxycarbonyl -3- amino piperidine, 0.42 part of sodium acid carbonate, isopropanol mix
Even, flow back 16h, filters to take filtrate while hot, is concentrated to give intermediate A, wherein, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4-
Dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile and isopropanol bulking value (g/ml) than being 1：5.8；
S2, preparation intermediate B：By weight the intermediate A obtained in 1 part of S1 is added in dichloromethane and is dissolved, be added dropwise
Trifluoroacetic acid, stirs 2h, after concentration, adds water dissolves, plus ethyl acetate is mixed, and extraction water intaking phase adds dichloro in Xiang Shuixiang
Methane, adjusts pH=11.2 with sodium hydrate aqueous solution, takes organic phase, be concentrated under reduced pressure to give intermediate B, wherein, middle
Body A, the bulking value (g/ml) of trifluoroacetic acid are than being 1：2.05；
S3, preparation Egelieting dimer：Intermediate B, 0.84 part 1- (6- chloro- 3- first will be obtained in 1 part of S2 by weight
Base -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, 0.9 part of potassium carbonate, DMF mix
Even, 63 DEG C are warming up to, insulated and stirred 6h filters to take filtrate while hot, is cooled to room temperature, adds water and mixes, filter to take in filtrate
Filter cake, after drying, adds DMF, is warming up to 70 DEG C, and insulated and stirred 1h is cooled to room temperature, filters to take filter cake,
Washed with ethyl acetate, be dried to obtain Egelieting dimer.
Embodiment 6
A kind of dimeric preparation method of Egelieting, comprises the steps：
S1, preparation intermediate A：By 1 part of 1-, (the chloro- 3- methyl -2,4- dioxos -3,4- dihydro -2H- of 6- are phonetic by weight
Pyridine -1- ylmethyls)-benzonitrile, 0.87 part of (R) -1-N- tertbutyloxycarbonyl -3- amino piperidine, 0.46 part of sodium acid carbonate, isopropanol mix
Even, flow back 13h, filters to take filtrate while hot, is concentrated to give intermediate A, wherein, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4-
Dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile and isopropanol bulking value (g/ml) than being 1：5.44；
S2, preparation intermediate B：By weight the intermediate A obtained in 1 part of S1 is added in dichloromethane and is dissolved, be added dropwise
Trifluoroacetic acid, stirs 3h, after concentration, adds water dissolves, plus ethyl acetate is mixed, and extraction water intaking phase adds dichloro in Xiang Shuixiang
Methane, adjusts pH=11.5 with sodium hydrate aqueous solution, takes organic phase, be concentrated under reduced pressure to give intermediate B, wherein, middle
Body A, the bulking value (g/ml) of trifluoroacetic acid are than being 1：1.97；
S3, preparation Egelieting dimer：Intermediate B, 0.82 part 1- (6- chloro- 3- first will be obtained in 1 part of S2 by weight
Base -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, 1 part of potassium carbonate, DMF mix,
65 DEG C are warming up to, insulated and stirred 5h filters to take filtrate while hot, is cooled to room temperature, are added water and mixed in filtrate, filter to take filter
Cake, after drying, adds DMF, is warming up to 60 DEG C, and insulated and stirred 1h is cooled to room temperature, filters to take filter cake, uses
Ethyl acetate is washed, and is dried to obtain Egelieting dimer.
The yield of each step reaction in embodiment 2-6 is calculated, as a result such as following table：
High income of the present invention as can be seen from the above table, purity are good.
The above, the only present invention preferably specific embodiment, but protection scope of the present invention is not limited thereto,
Any those familiar with the art the invention discloses technical scope in, technology according to the present invention scheme and its
Inventive concept equivalent or change in addition, should all be included within the scope of the present invention.
Claims (10)
1. the dimeric preparation method of a kind of Egelieting, it is characterised in that comprise the steps：
S1, preparation intermediate A：By 1- (the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- ylmethyls of 6-)-benzyl
Nitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperidines, sodium acid carbonate, isopropanol are mixed, backflow, are filtered to take filtrate, are concentrated to give
Intermediate A；
S2, preparation intermediate B：The intermediate A obtained in S1 is added in dichloromethane and is dissolved, trifluoroacetic acid is added dropwise, stir 1-
5h, after concentration, is obtained by extraction intermediate B；
S3, preparation Egelieting dimer：Intermediate B, 1- (the chloro- 3- methyl -2,4- dioxos -3,4- two of 6- will be obtained in S2
Hydrogen -2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate, DMF mix, heat up, and insulated and stirred filters to take filter
Liquid, purifying, is recrystallized to give Egelieting dimer.
2. the dimeric preparation method of Egelieting according to claim 1, it is characterised in that in S1, (6- is chloro- by 1-
3- methyl -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperazines
Pyridine, sodium acid carbonate, isopropanol are mixed, and flow back 3-24h, filters to take filtrate while hot, is concentrated to give intermediate A.
3. the dimeric preparation method of Egelieting according to claim 1 or claim 2, it is characterised in that in S1, (6- is chloro- for 1-
3- methyl -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3- amino piperazines
Pyridine, the weight ratio of sodium acid carbonate are 1：0.8-0.9：0.4-0.5.
4. the dimeric preparation method of Egelieting according to any one of claim 1-3, it is characterised in that in S1,1-
(the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- ylmethyls of 6-)-benzonitrile, (R) -1-N- tertbutyloxycarbonyl -3-
Amino piperidine, the weight ratio of sodium acid carbonate are 1：0.87：0.46.
5. the dimeric preparation method of Egelieting according to any one of claim 1-4, it is characterised in that in S1,1-
(the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- ylmethyls of 6-)-benzonitrile and the bulking value (g/ of isopropanol
Ml) than being 1：5.4-6.
6. the dimeric preparation method of Egelieting according to any one of claim 1-5, it is characterised in that in S2,
In extraction process, after concentration, water dissolves are added, plus ethyl acetate are mixed, extraction water intaking phase adds dichloromethane in Xiang Shuixiang,
PH=11-12 is adjusted, organic phase is taken, is concentrated to give intermediate B.
7. the dimeric preparation method of Egelieting according to any one of claim 1-6, it is characterised in that in S2,
In extraction process, after concentration, water dissolves are added, plus ethyl acetate are mixed, extraction water intaking phase adds dichloromethane in Xiang Shuixiang,
PH=11-12 is adjusted with sodium hydrate aqueous solution, organic phase is taken, is concentrated under reduced pressure to give intermediate B.
8. the dimeric preparation method of Egelieting according to any one of claim 1-7, it is characterised in that in S2, in
Mesosome A, the bulking value (g/ml) of trifluoroacetic acid are than being 1：1.9-2.1.
9. the dimeric preparation method of Egelieting according to claim 3 or 4, it is characterised in that in S3, will be in S2
Intermediate B, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate, N is arrived,
Dinethylformamide is mixed, and is warming up to 60-70 DEG C, and insulated and stirred 2-8h filters to take filtrate while hot, purifying, is recrystallized to give
Egelieting dimer；Preferably, in S3, in purge process, filter to take filtrate while hot, be cooled to room temperature, in filtrate
Add precipitating reagent to mix, filter to take filter cake, after drying, be recrystallized to give Egelieting dimer；Preferably, precipitating reagent is water；
Preferably, in S3, in recrystallization process, after drying, DMF is added, 50-70 DEG C is warming up to, insulation is stirred
1-2h is mixed, room temperature is cooled to, filter cake is filtered to take, is washed with ethyl acetate, be dried to obtain Egelieting dimer.
10. the dimeric preparation method of Egelieting according to claim 3 or 4, it is characterised in that in S3, intermediate
B, 1- (the chloro- 3- methyl -2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- ylmethyls of 6-)-benzonitrile, the weight ratio of potassium carbonate are
1：0.75-0.85：0.8-1.2；Preferably, in S3, intermediate B, 1- (chloro- 3- methyl -2 of 6-, 4- dioxo -3,4- dihydros -
2H- pyrimidine -1- ylmethyls)-benzonitrile, potassium carbonate weight ratio be 1：0.82：1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104725349A (en) * | 2013-12-23 | 2015-06-24 | 湖北华世通生物医药科技有限公司 | Polycrystalline A-type crystal of alogliptin polycrystalline, preparation method and production purpose thereof |
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| CN104725349A (en) * | 2013-12-23 | 2015-06-24 | 湖北华世通生物医药科技有限公司 | Polycrystalline A-type crystal of alogliptin polycrystalline, preparation method and production purpose thereof |
| CN105646446A (en) * | 2014-11-14 | 2016-06-08 | 海正辉瑞制药有限公司 | An alogliptin purifying method |
| WO2016139677A1 (en) * | 2015-03-02 | 2016-09-09 | Msn Laboratories Private Limited | Improved process for the preparation of 2-({6-[(3r)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihvdropvrimidin-1(2h)-yl}methyl)benzonitrile and pharmaceutically acceptable salts thereof |
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