CN105646446A - An alogliptin purifying method - Google Patents
An alogliptin purifying method Download PDFInfo
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Abstract
The invention relates to an alogliptin purifying method through separating an alogliptin dimer impurity, and an alogliptin preparing method including the purifying method. The purifying method includes (1) providing an ethanol solution of 2-[6-[(3R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl-methyl]benzonitrile, (2) adsorbing the alogliptin dimer impurity through adsorption, and filtering, and (3) crystallizing the filtrate and separating to obtain crystals. The purifying method is characterized by being simple, convenient and efficient in operation, low in cost, environmental friendly, and outstanding in effects, and is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to the purification process of Egelieting, in particular to the method carrying out purification Egelieting by separation Egelieting dimer impurity, and the preparation method comprising the Egelieting of this purification process.
Background technology
In recent years, the sickness rate of diabetes presents the trend of constantly rising, it is believed that be one of the chief threat of 21 century human death. In 2006, World Health Organization (WHO) (WHO) estimated that the whole world has more than 1.8 hundred million people and suffers from diabetes, and this is predicted to the year two thousand thirty for several times and can double. Elapsing over time, the diabetes being not controlled by can damage body system, including heart, blood vessel, eye, kidney and nerve. According to WHO, about 1,100,000 people within 2005, are had to die from diabetes, it is contemplated that the death that in following 10 years, diabetes are relevant can increase above 50%. In worldwide, the social economical burden of diabetes is very considerable.
In numerous Remedies for diabetes, serine protease DPP IV (DPP-IV) inhibitor compounds is considered as the type ii diabetes medicine that good effect toxicity is low, and it is by maintaining the level of internal glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic polypeptide (GLP), promote that the secretion of insulin plays blood sugar lowering curative effect. In recent years, it is developed a series of DPP-IV inhibitor. Wherein, SYR-322 is the DPP-IV inhibitor of Takeda company of Japan research and development, obtains the listing approval of MHLW of Japan in April, 2010, obtains the listing approval of U.S. FDA in January, 2013. Clinic is mainly used in treatment type ii diabetes, and toleration is good.
The chemistry of SYR-322 is called: (R)-2-[(6-(3-amino piperidine-1-base)-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-Ji) methyl] benzonitrile benzoate, or 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile benzoate, English by name Alogliptinbenzoate, its chemical constitution shown in formula I:
The record in CN200680042863.9 is applied for according to China, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile (i.e. Egelieting, Alogliptin) preferably in adopt isopropanol and water as solvent by 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) after the synthetic method that starts of-benzonitrile and (R)-3-amino piperidine dihydrochloride with acid-addition salts (such as hydrochlorate, benzoate, trifluoroacetate or toluene fulfonate) isolated in form.The reaction scheme of this synthetic method is as follows:
In the method, owing in (R)-3-amino piperidine dihydrochloride, the active sites of ammonia is equipped with two, so be easy to occur substitution reaction to produce the dimer impurity as shown in formula (B) in the position of two ammonia simultaneously, it is difficult to from target product to remove, therefore easily affects purity and the quality of medicinal Egelieting raw material:
In order to remove this dimer impurity, fulfilling medicinal standard, CN200680042863.9 employs extremely complex post-processing approach, such as its description the 66th page record, after reaction terminates, first be filtered to remove in course of reaction produce inorganic salt, again with another kind of organic solvent tetrahydrofuran dilution after filtrate concentration, with hcl acidifying to prepare Egelieting hydrochlorate, again that hydrochlorate is soluble in water, dimer is removed with isopropyl acetate washing, add potassium carbonate from water layer to free-basing organic layer, water layer is separated with organic layer, water layer extracts with isopropyl acetate again. merge organic layer and remove remaining potassium salt with aqueous NaCl wash. again organic solvent is concentrated, then carry out the salt-forming reaction of lower step.
The process employs the complex steps that first acidifying dissociates, repeatedly extracts, and repeatedly use multiple organic solvent, wherein isopropyl acetate is not only inflammable and explosive, and be inhaled into, take in or after skin absorption, health be harmful to, eyes, skin and mucosa there is stimulation, and larynx, bronchitis, spasm, chemical pneumonitis, pulmonary edema etc. can be caused after sucking, be not suitable for large-scale use in commercial production. Additionally repeatedly use the strong acid and strong bases such as hydrochloric acid/potassium carbonate, not only production equipment is caused corrosion, also add the discharge of waste water and waste liquid. Therefore, the method complicated operation, high expensive, environment is unfriendly, is not suitable for the big production of industry.
The preparation method describing the compound F similar with Egelieting structure in China application CN200780049086.5, its structure is as follows. The method is similar with the preparation method of above-mentioned Egelieting, by 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2-H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-and (R)-3-amino piperidine dihydrochloride reaction, same in order to remove the dimer impurity being easier to produce in this reaction, this application uses the method purification end product of HPLC, obtains the trifluoroacetate of end-product.
Although the method for HPLC purification can obtain highly purified product, but the method is only used for laboratory and prepares a small amount of sample on a small scale, because of its inefficiency, with high costs, it is impossible to suitable in large-scale industrial production.
Chinese patent application CN200980152029.9 discloses a kind of method purifying Egelieting, first 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 is wherein provided, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in chlorohydrocarbon (preferred dichloromethane), then to 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in add ether (such as symmetrically or non-symmetrically C2-C6 alkyl ether, especially selected from diisopropyl ether, the ether of dimethyl ether and methyl tertiary butyl ether(MTBE)) or aliphatic hydrocarbon (especially pentane, hexane or heptane) as anti-solvent so that 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile crystallization, then 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 of fractional crystallization form again, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile.The method can isolate dimer impurity, but first its requirement obtains chlorohydrocarbon solution, then use the anti-solvent different from chlorohydrocarbon carry out crystallization, thus production cost height and to use the disagreeableness organic solvent of environment.
Liu Shao Wen et al. (synthesis of SYR-322, Strait Pharmaceutical Journal, 2011,23rd volume the 9th phase, 214-215 page) propose a kind of method synthesizing Egelieting, wherein adopting n-butyl alcohol is solvent, and tri-n-butylamine makes acid binding agent, can directly precipitate out Egelieting after having reacted, and then adopt 75% ethyl alcohol recrystallization to be purified. Although the yield of the method is greatly improved, but still only have about 56.1%.
In order to solve the separation purification difficult problem that dimer impurity brings, also have tried to avoid the generation of dimer impurity from source, namely first with protection base, a reactive amines in 3-amino piperidine is closed, then reacts. As China has applied for disclosed in CN201080013649.7 the preparation method of a kind of Egelieting and derivant thereof; by 2-(the chloro-3-methyl-2 of 6-; 4-dioxo-3; 4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-BOC-amido piperidine hydrochlorate react and obtain the Egelieting free alkali that tertbutyloxycarbonyl (BOC) is protected; finally become salt Deprotection simultaneously again with benzoic acid, prepare SYR-322.
But adding BOC in the method protects base and de-BOC to protect the step of base, in industry produces greatly, adds cost and operation easier. And, when final step benzoic acid is as deprotecting regent, owing to its acidity is more weak, it is impossible to make the oxygen of carbamate effectively protonate, thus BOC cannot be removed smoothly and protect base, have impact on the purity of end-product.
In sum, in prior art, preparation is suitable for the method for medicinal high-purity SYR-322 substantially all to there is operating procedure complexity manufacturing cycle long, and production cost is high, uses the disagreeableness organic solvent of multiple environment, is not suitable for the defects such as industrialized great production. Therefore, need exploitation preparation 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] improved method of benzonitrile acid-addition salts, especially effectively remove the dimer impurity of formula (B) and be suitable for simultaneously by low cost, environmental friendliness, easy and simple to handle in the way of carry out the method for large-scale production.
Summary of the invention
The above-mentioned problems in the prior art is conducted in-depth research by the present inventor, has carefully studied Egelieting and dimeric character thereof, finally found that, Egelieting and dimer impurity dissolution properties difference in ethanol is very big. Under dimer impurity exists, Egelieting not easily precipitates out in ethanol. And dimer precipitates out in ethanol easily by absorption under adsorbent effect, and just not readily dissolve after precipitation, and Egelieting adds a large amount of ethanol again and can again dissolve after precipitating out in ethanol, such that it is able to remove dimer. Thus, the present invention is completed.
In addition, inventor it is also surprising that, the method its not only can remove the dimer impurity as shown in previously described formula (B), also eliminate unexpectedly simultaneously and preparing intermediate 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile process is produced and is taken to C, the N-dibenzyl cyanogen impurity as shown in following formula (C) in follow-up Egelieting synthesis step:
According to an aspect of the invention, it is provided a kind of method of purification Egelieting, described method comprises the steps:
(1) 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol is provided;
(2) adsorb the dimer impurity as shown in above formula (B) by adsorption, and filter;
(3) filtrate crystallize separating obtained crystal are made.
In described step (1), described 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile is construed as 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 comprising impurity, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile crude product, such as include but not limited to, comprise 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 of the dimer impurity shown in above formula (B), 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile crude product. additionally, for providing 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] method of benzonitrile solution in ethanol is not particularly limited, as long as described solution can be obtained. such as, can pass through to make 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reacts the Egelieting crude product of the oily obtained or solid, shaped and is dissolved in ethanol and provides 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile solution in ethanol. or, can pass through to make 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reacts in ethanol and provides 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile solution in ethanol. preferably employ later approach to provide described solution.
Make 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile can for any 2-(chloro-3-methyl-2 of 6-that can make with the method that (R)-3-amino piperidine or its salt (such as dihydrochloride) react, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reacts and obtains 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] method of benzonitrile, such as at Chinese patent application CN200680042863.9, CN200780049086.5, the method recorded in CN200980152029.9 etc., method disclosed in research paper, or their variant or the like.
In step (1), to 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] content of Egelieting dimer impurity in benzonitrile solution in ethanol is not particularly limited. Generally speaking, at 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) in the reaction solution that obtains after-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reaction, the content of Egelieting dimer impurity is typically in about more than 2.5%, even at about more than 3%, based on the gross weight of all solids in solution.
The absorption of described step (2) can adopt any adsorbent that can adsorb Egelieting dimer impurity to adsorb. For example, it is possible to adsorb dimer impurity with inorganic salt, such that it is able to be filtered to remove.Herein, described inorganic salt can be synthesis 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile reaction in produce inorganic salt, it is also possible to be the inorganic salt that it is possible to additionally incorporate. Or, it is possible to adsorb by it is possible to additionally incorporate adsorbent in described alcoholic solution. Described adsorbent can be activated carbon etc.
In described step (2), described filtration can adopt any feasible method and available filter plant in this area to carry out, for instance can be filtered with filter paper, buchner funnel etc., it is also possible to adopt the methods such as sucking filtration.
In one embodiment, described step (2) can be carried out as follows: by described 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile solution in ethanol is at the temperature of about-10 DEG C to about 10 DEG C, more preferably at the temperature of about-5 DEG C to about 5 DEG C, stir most preferably at the temperature of about 0 DEG C to about 5 DEG C, then filter.
Carry out described stirring in order that allow the dimer impurity in solution fully be adsorbed on inorganic salt and to precipitate out. Therefore, the time carrying out described stirring is not particularly limited, as long as so that the precipitation of dimer impurity and absorption, the loss of Egelieting can not caused simultaneously as far as possible. Although product quality is not affected by long mixing time, but meeting is consuming time and causes meaningless waste. Those skilled in the art can readily determine that mixing time by optimization process. Preferably, the time of described stirring can be, for instance, more than about 10 minutes, about more than half an hour, more than about 1 hour or more than about 2 hours. Additionally, the time of stirring is typically about less than 6 hours, less than about 4 hours, or less than about 3 hours.
After Egelieting dimer impurity is adsorbed onto on inorganic salt, it is possible to be filtered to remove.
In another embodiment, described step (2) can be carried out as follows: stirs after adding activated carbon in described alcoholic solution, then filters. In solution, add activated carbon can adsorb a part of Egelieting dimer impurity, such that it is able to dimer impurity is filtered to remove. Those skilled in the art can readily determine that required activated carbon content by optimization process. Preferably, the consumption of described activated carbon is the about 5%-about 20% based on Egelieting quality, more preferably based on the about 5%-about 15% of Egelieting quality, it is most preferred that for based on about the 10% of Egelieting quality. To carrying out the temperature and time of described stirring all without special restriction, as long as so that activated carbon adsorption dimer impurity, the loss of Egelieting can not caused simultaneously as far as possible. Preferably, described stirring can carry out at the temperature of about-10 DEG C to about 40 DEG C, carries out more preferably at the temperature of about-5 DEG C to about 35 DEG C, still carries out more preferably at the temperature of about 0 DEG C to about 30 DEG C, it is most preferred that at room temperature carry out. Although product quality is not affected by long mixing time, but meeting is consuming time and causes meaningless waste. Those skilled in the art can readily determine that mixing time by optimization process. Preferably, the time of described stirring can be, for instance, more than about 10 minutes, about more than half an hour, more than about 1 hour or more than about 2 hours. Additionally, the time of stirring is typically about less than 6 hours, less than about 4 hours, or less than about 3 hours.
After described step (2), it is possible to the content of the dimer impurity in the filtrate containing Egelieting is reduced to about less than 0.4%, even about less than 0.3%.
In step (3), described in make the step of filtrate crystallize that any suitable Crystallization method in this area can be adopted to carry out. For example, it is possible to after filtrate being concentrated, brought out crystallize by cooling solution, or, it is possible to be concentrate the filtrate to dry after, add ethanol crystallize, or, it is possible to bring out crystallize by adding anti-solvent. The anti-solvent being suitable for can be readily determined by optimization process according to conventional methods by those skilled in the art. In Crystallization Process, it is possible to add kind of crystalline substance to bring out crystallization, to avoid supersaturation.
In step (3), the step of described separating obtained crystal can adopt any suitable method in this area to carry out. It is for instance possible to use Filtration, centrifuging etc.
The method of the purification Egelieting according to the present invention, after step (2), can further include before step (3):
A () makes filtrate concentration crystallize; With
B () adds the crystal of ethanol solution modeling, then filter.
In one preferred embodiment, described step (a) is carried out as follows: filtrate is concentrated into after doing, and adds ethanol crystallize. Step (b) adds the ethanol Egelieting for solution modeling again. Egelieting dimer impurity not easily re-dissolved in ethanol after precipitation, such that it is able to be filtered to remove. The addition of described ethanol is not particularly limited, so that Egelieting can fully be dissolved as suitable. But, the addition of ethanol is unsuitable too high, in order to avoid a large amount of solvents are wasted in impact, increases the process time of step (3) simultaneously. Preferably, the addition of described ethanol is so that the ratio of Egelieting and ethanol is about 1:1-20 (g:ml), preferably about 1:5-15 (g:ml), more preferably from about 1:8-13 (g:ml), it is most preferred that about 1:10 (g:ml).
In step (b), it is preferable that be additionally may included in and filter the step adding activated carbon in forward direction solution. In solution, add activated carbon can adsorb Egelieting dimer impurity, such that it is able to be easy to the dimer impurity being filtered to remove in solution. Being preferably based on the quality of Egelieting, the consumption of described activated carbon is about 20wt% for about 5wt%-, more preferably about 5wt%-is about 15wt%, it is most preferred that for about 10wt%.
In one preferred embodiment, the method for the purification Egelieting of the present invention comprises the steps:
(c1) 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol (particularly dehydrated alcohol) is provided;
(c2) described solution is stirred at about 0-5 DEG C, filter;
(c3) filtrate is concentrated crystallize;
(c4) ethanol is added, particularly dehydrated alcohol, the crystal of solution modeling, add activated carbon stirring, filter;
(c5) filtrate concentration crystallize, and filter, dry gained crystal.
In one preferred embodiment, step (c3) is carried out as follows: concentrate the filtrate to dry after, add ethanol, particularly dehydrated alcohol, crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution.
Being preferably carried out in mode at one, step (c5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
Another preferred embodiment in, the method for the purification Egelieting of the present invention comprises the steps:
(d1) 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol (particularly dehydrated alcohol) is provided;
(d2) stir after adding activated carbon in described solution, filter;
(d3) filtrate is concentrated crystallize;
(d4) ethanol is added, particularly dehydrated alcohol, the crystal of solution modeling, stirs after adding activated carbon, filters;
(d5) filtrate concentration crystallize, and filter, dry gained crystal.
In one preferred embodiment, in step (d2) and (d4), described stirring can carry out at the temperature of about-10 DEG C to about 40 DEG C, carry out more preferably at the temperature of about-5 DEG C to about 35 DEG C, still carry out more preferably at the temperature of about 0 DEG C to about 30 DEG C, it is most preferred that at room temperature carry out.
In one preferred embodiment, step (d3) is carried out as follows: concentrate the filtrate to dry after, add ethanol, particularly dehydrated alcohol, crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution.
In one preferred embodiment, step (d5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
According to a further aspect in the invention, provide one and prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] method of benzonitrile or its salt, described method comprises the employing above-mentioned purification 2-according to the present invention [6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] method of benzonitrile carrys out purification 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] step of benzonitrile.
More specifically, include according to preparation 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3, the 4-tetrahydropyrimidine-1-ylmethyls] benzonitrile of the present invention or the method for its salt:
(1) 2-(the chloro-3-methyl-2 of 6-is made, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reacts to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile;
(2) method according to purification 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile of the present invention is adopted to be purified;
(3) not necessarily, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 that will finally give in (2), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile crystal and acid reaction obtain 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] acid-addition salts of benzonitrile.
At preparation 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 according to the present invention, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile or its salt method in, described step (1), even if 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reacts to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile, can use and any can make 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) reacts and obtains 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] method of benzonitrile, such as at Chinese patent application CN200680042863.9, CN200780049086.5, the method recorded in CN200980152029.9 etc., method disclosed in research paper, or their variant or the like.In step (3), described acid can be any applicable inorganic or organic acid, for instance hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, propanoic acid, butanoic acid, ethanedioic acid, malonic acid, succinic acid, methanesulfonic acid, benzene methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, malic acid, succinic acid, benzoic acid, maleic acid, fumaric acid etc. Preferably, the acid-addition salts of described 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile is benzoate. In an embodiment of the invention, include according to preparation 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3, the 4-tetrahydropyrimidine-1-ylmethyls] benzonitrile of the present invention or the method for its salt:
(e1) 2-(the chloro-3-methyl-2 of 6-is made, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) is in ethanol (particularly dehydrated alcohol), react to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 under sodium bicarbonate exists, 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile;
(e2) after reaction terminates, described solution is stirred at about 0-is about 5 DEG C, filter;
(e3) filtrate concentration crystallize;
(e4) ethanol is added, particularly dehydrated alcohol, the crystal of solution modeling, add activated carbon stirring, filter;
(e5) filtrate concentration crystallize, and filter, dry gained crystal;
(e6) not necessarily, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 that will finally give in (e5), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile crystal and acid reaction obtain 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] acid-addition salts of benzonitrile.
In one preferred embodiment, step (e3) is carried out as follows: concentrate the filtrate to dry after, add ethanol, particularly dehydrated alcohol, crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution.
Being preferably carried out in mode at one, step (e5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
In an embodiment of the invention, include according to preparation 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3, the 4-tetrahydropyrimidine-1-ylmethyls] benzonitrile of the present invention or the method for its salt:
(f1) 2-(the chloro-3-methyl-2 of 6-is made, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt (such as dihydrochloride) is in ethanol (particularly dehydrated alcohol), react to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 under sodium bicarbonate exists, 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile;
(f2), after reaction terminates, stir after adding activated carbon in described solution, filter;
(f3) filtrate concentration crystallize;
(f4) ethanol is added, particularly dehydrated alcohol, the crystal of solution modeling, stirs after adding activated carbon, filters;
(f5) filtrate concentration crystallize, and filter, dry gained crystal;
(f6) not necessarily, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 that will finally give in (f5), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile crystal and acid reaction obtain 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] acid-addition salts of benzonitrile.
In one preferred embodiment, in step (f2) and (f4), described stirring can carry out at the temperature of about-10 DEG C to about 40 DEG C, carry out more preferably at the temperature of about-5 DEG C to about 35 DEG C, still carry out more preferably at the temperature of about 0 DEG C to about 30 DEG C, it is most preferred that at room temperature carry out.
In one preferred embodiment, step (f3) is carried out as follows: concentrate the filtrate to dry after, add ethanol, particularly dehydrated alcohol, crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution.
In one preferred embodiment, step (f5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
In the present invention, make the step of filtrate concentration crystallize described in, it is possible to be, after filtrate being concentrated, brought out crystallize by cooling solution, or, it is possible to be concentrate the filtrate to dry after, add ethanol crystallize. Or, it is also possible to be concentrate the filtrate to dry after be made directly next step without crystallize. Concentrate the filtrate to dry after, when adding ethanol crystallize, it is possible to Egelieting and Egelieting dimer impurity are all fully precipitated out, in order to carry out next step separation. Now, the addition of described ethanol is not particularly limited, so that Egelieting can fully precipitate out, but less dissolving is advisable in ethanol. Preferably, the addition of described ethanol is so that the ratio of Egelieting and ethanol is about 1:0.5-3 (g:ml), preferably about 1:0.8-2 (g:ml), more preferably from about 1:0.8-1.5 (g:ml), it is most preferred that about 1:1 (g:ml). In Crystallization Process, it is possible to add kind of crystalline substance to bring out crystallization, to avoid supersaturation.
In the present invention, term " ethanol " refers to ethanol content and is at least about more than 95%, it is preferable that about more than 97%, more preferably from about the alcohol solvent of more than 99%, it is preferred to use dehydrated alcohol.
In the present invention, term " filtrate is concentrated into dry " refers to and concentrates the filtrate to remove after major part solvent in dope or the state substantially near solid.
In the present invention, unless otherwise specified, all disclosed all numerical rangies all include arbitrary point value therein and arbitrary subrange.
In the present invention, although " Egelieting ", " 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2; 4-dioxo-1; 2; 3; 4-tetrahydropyrimidine-1-ylmethyl] benzonitrile ", " (R)-2-[(6-(3-amino piperidine-1-base)-3-methyl-2; 4-dioxo-3 have been used alternatingly, 4-dihydro-pyrimidin-1 (2H)-Ji) methyl] benzonitrile " and " Egelieting free alkali "; but it will be appreciated by those skilled in the art that; these terms in this article all referring to same compound, i.e. the free alkali of the compound of Formulas I.
In the present invention, although " dimer impurity " and " Egelieting dimer impurity " is used alternatingly, it will be appreciated by a person skilled in the art that these terms all refer to same compound in this article, namely structural formula is the compound of B.
In the present invention, room temperature refers to the indoor ambient temperature implementing the inventive method, generally at about 25 �� 5 DEG C, namely between about 20 to about 30 DEG C.
In the present invention, term " about " refers to described numerical value and allows there is certain error, it is preferable that described error �� 15%, or �� 10%, or in the scope of �� 5%.
Beneficial effect
Present invention have an advantage that first, only using a kind of eco-friendly alcohol solvent in purge process, and each operating procedure all refers to the conventional means by this area, operation is simple, with low cost, it is further purified or directly salt-forming steps is provided convenience for follow-up.
Secondly, instant invention overcomes in existing purification process as separating dimer impurity and adopt first Egelieting free alkali is prepared into the first salt (example hydrochloric acid salt or trifluoroacetate), prepare into, after free, the complicated operation that the process means of benzoate are brought again, (as utilized HPLC purification trifluoroacetate) with high costs, environmental pollution is (as being used for into the trifluoroacetic acid of salt, or first become the poisonous and harmful extractant isopropyl acetate used in salt free process again, dichloromethane, oxolane etc.), the defects such as equipment corrosion (as being used for into the hydrochloric acid of salt and for free potassium carbonate).
Again; present invention, avoiding in existing preparation method as reducing the generation of dimer impurity; the upper protection base replacing (R)-3-amino piperidine dihydrochloride to prepare Egelieting with (R)-3-amido piperidine hydrochlorate of BOC protection and to increase and the step of Deprotection; simplify production process, decrease the chance of contaminating impurity.
Additionally, the present invention not removing only dimer impurity, also eliminate front step unexpectedly simultaneously and prepare intermediate 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile synthetic reaction in the C that gets off of institute's band, N-dibenzyl cyanogen impurity, is ensureing on the basis of reaction yield, is namely being met medicinal standard requires, highly purified Egelieting crude drug by simple purification process.
Therefore, purification process provided by the present invention has efficient, with low cost, environmental friendliness, remarkably productive feature easy and simple to handle, is suitable for industrialized great production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described. There is provided the following example only to facilitate those skilled in the art are more fully understood that the present invention, it is not intended to the present invention is carried out any restriction. It should be appreciated that what the present invention provided is typical case or preferred process condition (including reaction temperature, time, the mol ratio of reactant, solvent, charging process or order etc.), however, it is also possible to use other process conditions. Optimum reaction condition can change with concrete raw material used, intermediate, reagent, solvent, but these conditions can be determined by routine optimization process by those skilled in the art.
Except as otherwise noted, raw material used in the embodiment of the present invention, reagent, solvent etc. are commercially available commodity, or with chemosynthesis standard method well known to those skilled in the art synthesis. The record method that the raw material " 2-(the chloro-3-methyl-2 of 6-; 4-dioxo-3,4-dihydro-2-H-pyrimidine-1-ylmethyl) benzonitrile (AG-101) " that such as present invention uses is referred in China application CN200680042863.9 is easily prepared.
Embodiment 1
By AG-101 (580g under room temperature, 2.11mol), (R)-3-amino piperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and dehydrated alcohol (5800ml) add in the there-necked flask of 10000ml, stir. Being warmed up to about 70-about 80 DEG C reaction, about 5-6h reacts completely (HPLC monitors AG-101 content less than 0.1%).
Above-mentioned reactant liquor is cooled to about 0 DEG C of-Yue 5 DEG C, stirs 2 hours, filter, and with dehydrated alcohol (1160ml) washing leaching cake, obtain filtrate 1.
Filtrate 1 is evaporated to dry in water-bath about 50 DEG C, and residue adds dehydrated alcohol (580ml) about 5 hours (adding 1g crystal seed if any supersaturation) of stirring and crystallizing under room temperature. A large amount of solids add dehydrated alcohol (5220ml) after precipitating out, and under room temperature, stir about has partial suspended solid insoluble with dissolved solid in 20 minutes. Add activated carbon (58g) stir about 10 minutes under room temperature. Filtration under diminished pressure, filter cake dehydrated alcohol (290ml) washs, and obtains filtrate 2.
Filtrate 2 is evaporated to about the 20% of original volume at water-bath about 50 DEG C, a large amount of white solid is had to precipitate out, place crystallize 1 hour, filter, filter cake is with after about 0 DEG C of dehydrated alcohol 5 DEG C cold for-Yue (280ml) washing, within 4 hours, obtaining off-white color solid, molar yield 88.7% in about 60 DEG C of forced air dryings, HPLC detects purity.
Embodiment 2
By AG-101 (580g under room temperature, 2.11mol), (R)-3-amino piperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and dehydrated alcohol (5800ml) add in the there-necked flask of 10000ml, stir. Being warmed up to about 70-about 80 DEG C reaction, about 5-6h reacts completely (HPLC monitors AG-101 content less than 0.1%).
Above-mentioned reactant liquor is cooled to about 0 DEG C of-Yue 5 DEG C, stir about 2 hours, filters, and with dehydrated alcohol (1160ml) washing leaching cake, obtain filtrate 1.
Filtrate 1 is evaporated to dry in water-bath about 50 DEG C, and residue adds dehydrated alcohol (5800ml), and under room temperature, stir about has partial suspended solid insoluble with dissolved solid in 20 minutes. Add activated carbon (58g) stir about 10 minutes under room temperature. Filtration under diminished pressure, filter cake dehydrated alcohol (290ml) washs, and obtains filtrate 2.
Filtrate 2 is evaporated to about the 20% of original volume at water-bath about 50 DEG C, a large amount of white solid is had to precipitate out, place crystallize about 1 hour, filter, filter cake is with after about 0 DEG C of dehydrated alcohol 5 DEG C cold for-Yue (280ml) washing, within about 4 hours, obtaining off-white color solid in about 60 DEG C of forced air dryings, molar yield about 89%, HPLC detects purity.
Embodiment 3
By AG-101 (580g under room temperature, 2.11mol), (R)-3-amino piperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and dehydrated alcohol (5800ml) add in the there-necked flask of 10000ml, stir. Being warmed up to about 70-80 DEG C of reaction, about 5-6h reacts completely (HPLC monitors AG-101 content less than 0.1%).
Above-mentioned reactant liquor is cooled to room temperature, is added thereto to 58g activated carbon, stir 2 hours, filter, and with dehydrated alcohol (1160ml) washing leaching cake, obtain filtrate 1.
Filtrate 1 is dense to about the 20% of original volume in water-bath about 50 DEG C decompression, a large amount of solid is had to precipitate out, it is added thereto to dehydrated alcohol (4640ml) dissolve, has partial suspended solid insoluble, add activated carbon (58g) stir about 10 minutes under room temperature. Filtration under diminished pressure, filter cake dehydrated alcohol (290ml) washing leaching cake, obtain filtrate 2.
Filtrate 2 is evaporated to about the 20% of original volume at water-bath about 50 DEG C, a large amount of white solid is had to precipitate out, place crystallize about 1 hour, filter, filter cake is with after about 0 DEG C of dehydrated alcohol 5 DEG C cold for-Yue (280ml) washing, within 4 hours, obtaining off-white color solid in about 60 DEG C of forced air dryings, molar yield about 87%, HPLC detects purity.
Embodiment 4
By AG-101 (580g under room temperature, 2.11mol), (R)-3-amino piperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and dehydrated alcohol (5800ml) add in the there-necked flask of 10000ml, stir. Being warmed up to about 70-80 DEG C of reaction, about 5-6h reacts completely (HPLC monitors AG-101 content less than 0.1%).
Above-mentioned reactant liquor is cooled to room temperature, is added thereto to 58g activated carbon, stir about 2 hours, filters, and with dehydrated alcohol (1160ml) washing leaching cake, obtain filtrate 1.
Filtrate 1 is dense to dry in about 50 DEG C of decompressions of water-bath, is added thereto to dehydrated alcohol (5800ml) and dissolves, has partial suspended solid insoluble, add activated carbon (58g) stir about 10 minutes under room temperature. Filtration under diminished pressure, filter cake dehydrated alcohol (290ml) washing leaching cake, obtain filtrate 2.
Filtrate 2 is evaporated to about the 20% of original volume at water-bath about 50 DEG C, a large amount of white solid is had to precipitate out, place crystallize about 1 hour, filter, filter cake is with after about 0 DEG C of dehydrated alcohol 5 DEG C cold for-Yue (280ml) washing, within 4 hours, obtaining off-white color solid in about 60 DEG C of forced air dryings, molar yield about 89.5%, HPLC detects purity.
Comparative example 1
By AG-101 (580g under room temperature, 2.11mol), (R)-3-amino piperidine dihydrochloride (400.2g, 2.33mol), sodium bicarbonate (881.6g, 10.50mol) and dehydrated alcohol (5800ml) add in the there-necked flask of 10000ml, stir. Being warmed up to about 70-80 DEG C of reaction, about 5-6h reacts completely (HPLC monitors AG-101 content less than 0.1%).
Above-mentioned reactant liquor is cooled to room temperature, filters, and with dehydrated alcohol (1160ml) washing leaching cake, obtain filtrate 1.
Filtrate 1 dense has solid to precipitate out to about the 20% of original volume in water-bath about 50 DEG C decompression, is added thereto to dehydrated alcohol (4640ml) dissolving, has partial suspended solid insoluble. Filtration under diminished pressure, filter cake dehydrated alcohol (290ml) washs, and obtains filtrate 2.
Filtrate 2 is evaporated to about the 20% of original volume at water-bath about 50 DEG C, white solid is had to precipitate out, place crystallize about 1 hour, filter, filter cake is with after about 0 DEG C of dehydrated alcohol 5 DEG C cold for-Yue (280ml) washing, within 4 hours, obtaining off-white color solid in about 60 DEG C of forced air dryings, molar yield about 65%, HPLC detects purity.
The used herein conventional method that HPLC detection method is this area, concrete measuring condition simple example is as follows:
Filtrate 1 in embodiment 1��4 and comparative example 1, filtrate 2 and prepared Egelieting free alkali (AG-102) purity and impurity content and final yield are as shown in table 1:
Table 1
Claims (10)
1. the method for purification 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3, a 4-tetrahydropyrimidine-1-ylmethyls] benzonitrile, described method comprises the steps:
(1) 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol is provided;
(2) adsorb the dimer impurity shown in following facial B by adsorption, and filter;
(3) filtrate crystallize separating obtained crystal are made,
Preferably, after described step (2), the content of the dimer impurity in gained filtrate is reduced to less than 0.4%, and even less than 0.3%;
Preferably, the absorption of described step (2) adopts synthesis 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile reaction in the inorganic salt that produces or the adsorbent that it is possible to additionally incorporate, it is preferred to activated carbon, adsorb;
It is highly preferred that
Described step (2) is carried out as follows: by described 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol is at the temperature of-10 DEG C to 10 DEG C, more preferably at the temperature of-5 DEG C to 5 DEG C, it is most preferred that stir at the temperature of 0 DEG C to 5 DEG C, then filter; Or to 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol adds stirring after activated carbon, then filter, wherein it is preferred to, based on 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] quality of benzonitrile, the consumption of described activated carbon is 5%-20%, more preferably 5%-10%, it is most preferred that be 10%; And/or
Crystallize in described step (3) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution; Or concentrate the filtrate to dry after, add ethanol crystallize.
2. method according to claim 1, wherein, after step (2), also includes before step (3):
A () makes filtrate concentration crystallize;With
B () adds the crystal of ethanol solution modeling, then filter;
Preferably, described step (a) is carried out as follows: filtrate is concentrated into after doing, and adds ethanol crystallize; And/or
Preferably, in step (b), the addition of described ethanol for make 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] ratio of benzonitrile and ethanol is 1:1-20, it is preferable that 1:5-15, more preferably 1:8-13, most preferably 1:10, in g:ml; And/or
Preferably, in step (b), it is additionally included in and filters the step adding activated carbon in forward direction solution, wherein, it is preferably based on 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] quality of benzonitrile, the consumption of described activated carbon is 5%-20%, it is more preferably 5%-10%, it is most preferred that be 10%.
3. method according to claim 1, wherein, described method comprises the steps:
(c1) 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol is provided;
(c2) described solution is stirred at 0-5 DEG C, filter;
(c3) filtrate is concentrated crystallize;
(c4) add the crystal of ethanol solution modeling, add activated carbon stirring, filter;
(c5) filtrate concentration crystallize, and filter, dry gained crystal,
Preferably, described step (c3) is carried out as follows: concentrate the filtrate to dry after, add ethanol crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution; And/or
Step (c5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
4. method according to claim 1, wherein, described method comprises the steps:
(d1) 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile solution in ethanol is provided;
(d2) stir after adding activated carbon in described solution, filter;
(d3) filtrate is concentrated crystallize;
(d4) add the crystal of ethanol solution modeling, stir after adding activated carbon, filter;
(d5) filtrate concentration crystallize, and filter, dry gained crystal,
Preferably,
In step (d2) and (d4), described stirring carries out at the temperature of-10 DEG C to 40 DEG C, it is preferable that carries out at the temperature of-5 DEG C to 35 DEG C, carries out more preferably at the temperature of 0 DEG C to 30 DEG C, it is most preferred that at room temperature carry out; And/or
Step (d3) is carried out as follows: concentrate the filtrate to dry after, add ethanol crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution; And/or
Step (d5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
5. the method according to any one of claim 1-4, wherein, described ethanol is that ethanol content is at least more than 95%, it is preferable that more than 97%, the more preferably alcohol solvent of more than 99%, it is preferred to dehydrated alcohol.
6. prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 for one kind, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] method of benzonitrile or its salt, described method comprises purification 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 adopted according to any one of claim 1-5, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] method of benzonitrile carrys out purification 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-1-ylmethyl] step of benzonitrile.
7. method according to claim 6, wherein, described method includes:
(1) 2-(the chloro-3-methyl-2 of 6-is made, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt reacts to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile;
(2) method of purification 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile according to any one of claim 1-5 is adopted to be purified;
(3) not necessarily, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 that will finally give in (2), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile crystal and acid reaction obtain 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] acid-addition salts of benzonitrile, it is preferred to benzoate.
8. method according to claim 7, wherein, described method includes:
(e1) 2-(the chloro-3-methyl-2 of 6-is made, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt are in ethanol, react to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 under sodium bicarbonate exists, 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile;
(e2) after reaction terminates, described solution is stirred at 0-5 DEG C, filter;
(e3) filtrate concentration crystallize;
(e4) add the crystal of ethanol solution modeling, add activated carbon stirring, filter;
(e5) filtrate concentration crystallize, and filter, dry gained crystal;
(e6) not necessarily, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 that will finally give in (e5), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile crystal and acid reaction obtain 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] acid-addition salts of benzonitrile, it is preferred to benzoate.
Preferably,
Step (e3) is carried out as follows: concentrate the filtrate to dry after, add ethanol crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution; And/or
Step (e5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
9. method according to claim 7, wherein, described method includes:
(f1) 2-(the chloro-3-methyl-2 of 6-is made, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile and (R)-3-amino piperidine or its salt are in ethanol, react to prepare 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 under sodium bicarbonate exists, 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile;
(f2), after reaction terminates, stir after adding activated carbon in described solution, filter;
(f3) filtrate concentration crystallize;
(f4) add the crystal of ethanol solution modeling, stir after adding activated carbon, filter;
(f5) filtrate concentration crystallize, and filter, dry gained crystal;
(f6) not necessarily, 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 that will finally give in (f5), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] benzonitrile crystal and acid reaction obtain 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] acid-addition salts of benzonitrile, it is preferred to benzoate.
Preferably,
In step (f2) and (f4), described stirring carries out at the temperature of-10 DEG C to 40 DEG C, carries out more preferably at the temperature of-5 DEG C to 35 DEG C, still carries out more preferably at the temperature of 0 DEG C to 30 DEG C, it is most preferred that at room temperature carry out;And/or
Step (f3) is carried out as follows: concentrate the filtrate to dry after, add ethanol crystallize; Or, after filtrate being concentrated, brought out crystallize by cooling solution; And/or
Step (f5) is carried out as follows: after filtrate being concentrated, brought out crystallize by cooling solution.
10. the method according to any one of claim 7-9, wherein, described ethanol is that ethanol content is at least more than 95%, it is preferable that more than 97%, the more preferably alcohol solvent of more than 99%, it is preferred to dehydrated alcohol.
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| CN107602535A (en) * | 2017-09-22 | 2018-01-19 | 山东淄博新达制药有限公司 | The preparation method of SYR-322 |
| CN109810094A (en) * | 2019-01-31 | 2019-05-28 | 深圳市第二人民医院 | A kind of preparation method of Egelieting |
| CN111253324A (en) * | 2020-03-17 | 2020-06-09 | 湖北扬信医药科技有限公司 | Preparation method of alogliptin impurity |
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| CN106496194A (en) * | 2016-09-13 | 2017-03-15 | 合肥拓锐生物科技有限公司 | A kind of dimeric preparation method of Egelieting |
| CN107602535A (en) * | 2017-09-22 | 2018-01-19 | 山东淄博新达制药有限公司 | The preparation method of SYR-322 |
| 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 |
| CN111253324A (en) * | 2020-03-17 | 2020-06-09 | 湖北扬信医药科技有限公司 | Preparation method of alogliptin impurity |
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