CN110128401B - Simple preparation method of alogliptin benzoate - Google Patents
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Abstract
The invention relates to a preparation method of alogliptin benzoate, which comprises the steps of reacting 3, 3-dihalogen-N-methacrylamide with (R) -3-Boc-aminopiperidine and 2-cyanobenzylamine in sequence to prepare (R) -3- (3-Boc amino) piperidine-1-yl-3- (2-cyano) benzylamine-N-methacrylamide, then reacting with a carbonylation reagent to prepare alogliptin, and salifying benzoic acid to prepare alogliptin benzoate. The method has the advantages of cheap and easily-obtained raw materials, simple and convenient operation and small amount of waste water, and is beneficial to the industrial production of alogliptin benzoate.
Description
Technical Field
The invention relates to a simple preparation method of alogliptin benzoate, belonging to the technical field of medical chemistry.
Background
Alogliptin benzoate (Alogliptin benzoate), chemically known as 2- ({6- [ (3R) -3-amino-1-piperidinyl ] -3-methyl-2, 4-dioxo-3, 4-dihydropyrimidyl-1- (2H) -yl } methyl) benzonitrile benzoate, is a dipeptidyl peptidase iv (DPP-iv) inhibitor developed by wutian corporation of japan and marketed in 9 months 2011. It is used for treating type II diabetes, is a high-selectivity DPP-IV activity inhibitor, can maintain the level of glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), promotes the secretion of insulin, and exerts the effect of reducing blood sugar. The structural formula of alogliptin benzoate is as follows:
at present, the synthetic routes of alogliptin mainly comprise the following steps:
patent documents CN102134231(WO2005095381) and US20110212982 disclose a preparation method of alogliptin benzoate, which comprises the steps of taking 6-chlorouracil as a raw material, carrying out substitution reaction with 2-cyanobenzyl bromide, carrying out methylation, carrying out nucleophilic substitution reaction with (R) -3-aminopiperidine dihydrochloride to obtain alogliptin, and then salifying with benzoic acid to obtain alogliptin benzoate, wherein the synthetic route is as shown in a scheme 1:
the total yield of the scheme is less than 25%, and a DMF/DMSO mixed solvent is used in the process, so that the post-treatment is difficult and the recycling is difficult; the hazardous reagent NaH is used, anhydrous reaction conditions are required, and the method is not suitable for industrial production; in addition, a methylation reagent methyl iodide belongs to highly toxic products and has higher price; the (R) -3-aminopiperidine dihydrochloride is used as a raw material, the 3-amino is not protected, the disubstituted side reaction is easy to occur, and the reaction selectivity is general.
Chinese patent documents CN103980249, CN104193726, CN104672210 and CN104592195, etc. report an improved method based on the above route: the preparation method comprises the following steps of carrying out substitution reaction on 6-chloro-3-methyl uracil which is used as a raw material and 2-cyanobenzyl bromide to obtain 1, 3-disubstituted uracil, carrying out substitution on the 1, 3-disubstituted uracil and (R) -3-aminopiperidine dihydrochloride to obtain alogliptin, and finally salifying the alogliptin with benzoic acid in methanol or ethanol to obtain alogliptin benzoate. The method avoids the use of a methylating agent, but the reaction selectivity is not high by using (R) -3-aminopiperidine dihydrochloride as an initial raw material.
Patent CN102942556 reports a synthetic route of alogliptin benzoate: taking 6-chloro-3-methyluracil as a raw material, sequentially reacting with 2-cyanobenzyl bromide and (R) -3-Boc-aminopiperidine for substitution reaction, then carrying out tert-butyloxycarbonyl removal protection to obtain alogliptin, and finally carrying out salt formation with benzoic acid to obtain alogliptin benzoate, wherein the synthetic route is as shown in a route 2:
the route uses toluene, ethanol and the like as reaction solvents, is easier to treat than DMF/DMSO, is more environment-friendly, has higher yield in each step, and reduces the occurrence of side reactions by using aminopiperidine protected by tert-butyloxycarbonyl (Boc); however, ethanol is used as a solvent when the (R) -3-Boc-aminopiperidine is substituted, and potassium carbonate is almost insoluble in ethanol, so that the reaction time is too long, namely 10 hours, and the reaction is carried out after repeated extraction and washing, so that the process is complicated, and the method is not suitable for industrialization. In addition, CN10303063 and CN103524483 reported a similar process to that of route 2, but using phthalic anhydride instead of Boc anhydride as the amino protecting reagent, the same problems as in route 2.
Patent document CN104086527 reports a new synthesis method of alogliptin benzoate, in which monoethyl malonate is used as raw material, to generate acyl chloride under the action of thionyl chloride, and then reacts with (R) -3-Boc-aminopiperidine to obtain intermediate (R) -3- (3-Boc-aminopiperidine-1-yl) -3-oxopropanoic acid ethyl ester, and then closes with 1- (2-cyanobenzyl) -3-methylurea under the action of sodium alkoxide or sodium hydride, followed by acidic deprotection to obtain free alogliptin, and finally forms a salt with benzoic acid to obtain alogliptin benzoate, the synthesis method is shown in scheme 3:
the route uses the ethyl malonate to replace 6-chlorouracil or 6-chloro-3-methyluracil in the current mainstream process, so that the cost is reduced, the whole process avoids the use of high-boiling-point and high-toxicity solvents, and the ethyl malonate is environment-friendly and easy to recover. However, the route is too long, the operation is complicated, the source of the raw material 1- (2-cyanobenzyl) -3-methylurea is few, the raw material is not easy to be directly purchased and generally needs to be automatically synthesized, so that the process is more complicated, and the method is not suitable for industrialization.
WO2010109468(US20120029000) reports two routes of preparation of alogliptin: in the 1 st route, 2-cyanobenzylamine is used as a raw material, 1, 3-disubstituted uracil is obtained through three steps of substitution, ring closing and chlorination, then (R) -3-Boc-aminopiperidine is substituted and deprotected to obtain alogliptin, and finally the alogliptin and benzoic acid are salified to obtain a final product, wherein the synthesis steps are as shown in the following step 4:
the process route uses a phosphorus oxychloride reagent, is toxic, can generate a large amount of waste acid and wastewater, and is not suitable for industrialization; the total route is too long, the total yield is less than 20 percent, and no cost advantage exists.
In the 2 nd route, 1- (2-cyanobenzyl) -3-methylurea is used as a raw material, reacts with cyanoacetic acid, is hydrolyzed in one step, then reacts with (R) -3-Boc-aminopiperidine to obtain a Boc protected compound, and finally, under the action of benzoic acid, a protecting group is removed, and the Boc protected compound and benzoic acid are salified to obtain alogliptin benzoate, wherein the reaction is described as a route 5:
the method uses cyanoacetic acid as a high-toxicity reagent, and uses sodium hydroxide solution for hydrolysis, so that products are easy to damage, and the purity of hydrolysis products is low; the intermediate with Boc protection directly reacts with benzoic acid to form a salt, and because benzoic acid is weak in acidity and difficult to deprotect, completely deprotected alogliptin benzoate is difficult to obtain.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a simple preparation method of alogliptin benzoate with safety, greenness, low cost and high purity.
Description of terms:
in the specification, the Roman numerals after the names of the compounds are consistent with the Roman numerals of the corresponding structural formulas in number, and the Chinese names are based on the structural formulas. For example:
compound v: (R) -3- (3-Boc amino) piperidin-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (v);
the technical scheme of the invention is as follows:
a preparation method of alogliptin benzoate with a formula I,
the method comprises the following steps:
(1) carrying out 1, 4-addition reaction on 3, 3-dihalogen-N-methacrylamide (II) and (R) -3-Boc-aminopiperidine (III) in a solvent, and then carrying out substitution and elimination reaction on the 3, 3-dihalogen-N-methacrylamide (II) and 2-cyanobenzylamine (IV) in the presence of alkali to prepare a compound V;
in formula II, X is Cl or Br;
(2) reacting compound v with a carbonylation reagent in a solvent to produce alogliptin (vi) by two reaction routes:
a. when the carbonylation reagent is triphosgene, the solvent is one or the combination of dichloromethane, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, chloroform, acetonitrile and toluene, the reaction temperature is 10-80 ℃, and the tert-butyloxycarbonyl group is removed during carbonylation to prepare alogliptin (VI); alternatively, the first and second electrodes may be,
b. when the carbonylation reagent is one or a combination of diphenyl carbonate, di-tert-butyl dicarbonate (Boc anhydride), dimethyl dicarbonate or diethyl dicarbonate, the solvent is one or a combination of N, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), tetrahydrofuran, 2-methyltetrahydrofuran and toluene, the carbonylation is performed to form a pyrimidine ring in the presence of alkali, the reaction temperature is 20-100 ℃, and then the tert-butyloxycarbonyl (Boc) protective group is removed in an acid solution to prepare alogliptin (VI);
(3) in a solvent, alogliptin (VI) and benzoic acid are salified to prepare alogliptin benzoate (I).
According to the method of the present invention, the preferred process conditions and amounts in the steps are as follows:
preferably, in the step (1), the solvent is one of diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile or a mixture thereof in any proportion; more preferably, the mass ratio of the solvent to the 3, 3-dichloro-N-methacrylamide (II) is (3-15): 1; particularly preferably, the mass ratio is (5-10): 1.
Preferably, in step (1), the 3, 3-dihalo-N-methacrylamide (II) is selected from 3, 3-dichloro-N-methacrylamide 3, 3-dibromo-N-methacrylamide, preferably 3, 3-dichloro-N-methacrylamide; the base is inorganic base or organic base, the organic base is one or a combination of N, N-diisopropylethylamine, triethylamine and pyridine, and the inorganic base is one or a combination of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and calcium carbonate; the molar ratio of the alkali to the 3, 3-dihalo-N-methacrylamide (II) is (2-5): 1.
Preferably, in the step (1), the molar ratio of the 3, 3-dihalo-N-methacrylamide (II), (R) -3-Boc-aminopiperidine (III) and 2-cyanobenzylamine (IV) is 1.0 (0.9-1.2) to (0.9-1.5). The molar ratio can effectively reduce the generation amount of byproducts formed by two molecules of the compound III and the compound II, and can ensure that the generated intermediate and the compound IV are reacted and completely converted into the target product.
Preferably, in the step (1), the temperature of the 1, 4-addition reaction is from-50 ℃ to 25 ℃, and more preferably, the temperature of the 1, 4-addition reaction is from-30 ℃ to 0 ℃. The reaction time is 6-12 hours.
Preferably, in the step (1), the substitution and elimination reaction is carried out at a reaction temperature of 0 to 100 ℃, and more preferably at a reaction temperature of 10 to 40 ℃. The reaction time is 5 to 18 hours.
In the step (2), the mass ratio of the solvent to the compound V is preferably (3-15): 1, and more preferably (5-10): 1.
Preferably, in the step (2), the molar ratio of the carbonylation reagent to the compound V is (0.5-3.0): 1. The inventors have unexpectedly found that when triphosgene carbonylation reagent is used, compound V does not react completely and deprotection is not complete when it is used in an equivalent amount of less than 0.5 equivalent; when other carbonylating agents are used, the amount of carbonylating agent used is less than 1 equivalent, and the reaction of compound V is incomplete.
In the step (2) a, under the condition that the carbonylation reagent is triphosgene, the deprotection step is not needed after the triphosgene is used for carbonylation under the alkali-free condition; the reaction temperature for carbonylation by using triphosgene and removal of the tert-butyloxycarbonyl protection is preferably 20-60 ℃; the reaction time is 2-10 hours.
In the step (2) b, the alkali is organic alkali or inorganic alkali; the organic base is one of N, N-diisopropylethylamine, triethylamine and pyridine or a combination of any proportion, the inorganic base is one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate and potassium carbonate or a combination of any proportion, and further preferably, the molar ratio of the base to the compound V is (1-3): 1. The inventor has surprisingly found that when the molar equivalent of the base is less than 1, the reaction raw material remains and the reaction is incomplete. Further preferably, the reaction temperature is 40-80 ℃. The reaction time is 1-6 hours.
Preferably, in the step (2) b, the acid in the acid solution subjected to the tert-butoxycarbonyl protection is hydrogen chloride, p-toluenesulfonic acid or trifluoroacetic acid, and the molar ratio of the acid to the compound V is (2-10): 1; the solvent in the acid solution is one or a combination of dichloromethane, methanol, ethanol, tetrahydrofuran and isopropanol; the acid solution is 1-3mol/L acid solution. The preferred ratio of acid to compound V of the present invention allows for complete deprotection.
Most preferably, in step (2) b, the acid solution is a dichloromethane-methanol solution of the acid; wherein the ratio of dichloromethane: methanol 3-4: 1 volume ratio.
Preferably, in the step (2) b, the reaction temperature of the protection of the removed tert-butyloxycarbonyl group is 20-80 ℃, and further preferably, the reaction temperature is 25-50 ℃; the reaction time is 2-8 hours.
Preferably, in step (3), the solvent is one of methanol, ethanol, tetrahydrofuran, isopropanol and dichloromethane or a combination thereof in any proportion; the mass ratio of the solvent to the alogliptin (VI) is (4-10) to 1; in the step (3), the reaction temperature is 25-100 ℃, and the preferable temperature is 40-80 ℃; the reaction time is 1-5 hours.
The work-up of the products of the individual steps of the process according to the invention is effected in accordance with the prior art. The present invention is preferably as follows:
post-treating a product in the step (1): and adding water into the system, filtering, washing a filter cake with water, and drying to obtain a compound V. The purity is more than or equal to 99 percent.
Post-treating a product in the step (2): and (3) filtering, dissolving the filter cake in water, adding dichloromethane, adjusting the pH value of a water layer to 9-10 by using NaOH aqueous solution, stirring, layering organic phases, extracting a water phase by using dichloromethane, combining the organic phases, drying, filtering, evaporating the solvent under reduced pressure to obtain an alogliptin crude product, and pulping and washing by using methyl tert-butyl ether to obtain the alogliptin pure product. The purity is more than or equal to 99 percent.
And (3) post-treating a product: filtering, washing a filter cake with methanol, and drying to obtain the alogliptin benzoate. The purity is more than or equal to 99.9 percent.
The preparation method of alogliptin benzoate of the present invention is described by taking 3, 3-dichloro-N-methacrylamide as an example, as reaction scheme 6:
the invention has the technical characteristics and excellent effects that:
the invention provides a new synthesis route of alogliptin benzoate, which is characterized in that 3, 3-dihalogen-N-methacrylamide is sequentially subjected to 1, 4-addition with (R) -3-Boc-aminopiperidine, then the (R) -3- (3-Boc amino) piperidine-1-yl-3- (2-cyano) benzylamino-N-methacrylamide is synthesized by substitution and elimination with 2-cyanobenzylamine, the (R) -3- (3-Boc amino) piperidine-1-yl-3- (2-cyano) benzylamino-N-methacrylamide reacts with carbonylation reagent to generate pyrimidine ring, removing the tert-butyloxycarbonyl protecting group to generate alogliptin, and then synthesizing alogliptin benzoate (I) by the alogliptin and benzoic acid in a solvent.
The invention takes 3, 3-disubstituted-N-methacrylamide as a raw material, utilizes the characteristic that the molecular structure of the acrylamide is easy to generate 1, 4-addition reaction and further eliminate and dehydrochlorinate to replace, constructs a basic framework (compound V) of alogliptin benzoate, and has easy operation of subsequent carbonylation reaction and benzoic acid salt-forming reaction and high yield. The raw material 3, 3-disubstituted-N-methacrylamide is preferably 3, 3-dichloro-N-methacrylamide, is easy to obtain, each step of reaction involved in a reaction route has single selectivity, is easy to carry out, and has high yield of intermediate products.
The method has the advantages of cheap and easily-obtained raw materials, mild process conditions, high product yield and purity, and high total yield of the final product which can reach more than 70 percent and is far higher than the total yield of the product in the prior art. On the other hand, the method has the advantages of small wastewater amount, environmental protection and contribution to the industrial production of alogliptin benzoate.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
Example 1: preparation of (R) -3- (3-Boc amino) piperidin-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (V)
100 g of methyl tert-butyl ether and 15.4 g (0.1 mol) of 3, 3-dichloro-N-methacrylamide (II) are sequentially added into a 500 ml four-neck flask which is connected with a stirring thermometer and a constant-pressure low-liquid funnel, stirred, cooled to-5 ℃, kept at the temperature of-5 ℃ to 0 ℃, and a solution of 20.1 g (0.1 mol) of (R) -3-Boc-aminopiperidine and 30 g of methyl tert-butyl ether is dropwise added within 2 hours and stirred for 6 hours at the temperature of 0 ℃ to 5 ℃. Then 27.5 g (0.2 mol) of N, N-Diisopropylethylamine (DIPEA) and 13.9 g (0.1 mol) of 2-cyanobenzylamine (IV) were added, and the mixture was stirred at 35 to 40 ℃ for 8 hours, 50 g of water was added to the system, and the mixture was filtered, and the filter cake was washed with 20 g of water and dried to obtain 34.1 g of (R) -3- (3-Boc amino) piperidin-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (V), which was 82.5% in yield and 98.9% in purity.
Example 2: preparation of (R) -3- (3-Boc amino) piperidin-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (V)
120 g of diethyl ether and 15.4 g (0.1 mol) of 3, 3-dichloro-N-methacrylamide (II) are sequentially added into a 500 ml four-neck flask which is connected with a stirring thermometer and a constant-pressure low-liquid funnel, stirred, cooled to-15 ℃, kept at the temperature of-15 ℃ to-10 ℃, and a solution of 20.1 g (0.1 mol) of (R) -3-Boc-aminopiperidine and 40 g of diethyl ether is dropwise added within 2 hours and stirred for 8 hours at-15 ℃. Then, 15.8 g (0.2 mol) of pyridine and 14.5 g (0.11 mol) of 2-cyanobenzylamine (IV) were added thereto, and the mixture was stirred at 35 ℃ for 8 hours to complete the reaction, and 50 g of water was added to the system, followed by filtration, washing of the cake with 20 g of water and drying to obtain 36.2 g of (R) -3- (3-Boc-amino) piperidin-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (V) in 87.6% yield and 99.1% purity.
Example 3: preparation of alogliptin (VI)
Dissolving 20.7 g (50 mmol) of (R) -3- (3-Boc amino) piperidine-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (V) in 50 ml tetrahydrofuran in a 250 ml reaction bottle, dissolving 14.8 g (50 mmol) of triphosgene in 30 ml tetrahydrofuran at room temperature, dropwise adding the triphosgene tetrahydrofuran solution into the compound V tetrahydrofuran solution while stirring within 30 minutes, heating to 45 ℃, reacting for 5 hours, precipitating solids in the reaction, cooling, filtering, dissolving a filter cake in water, adding 100 ml dichloromethane, adjusting the pH of a water layer to 9-10 with NaOH aqueous solution, stirring for 30 minutes, layering an organic phase, extracting an aqueous phase with 50 ml dichloromethane, combining the organic phases, drying, filtering, evaporating the solvent under reduced pressure, the crude alogliptin product is obtained and is pulped by methyl tert-butyl ether to obtain 14.7 g (43.3 mmol) of the product, the yield is 86.5 percent, and the purity is 99.3 percent.
Example 4: preparation of alogliptin (VI)
To a 250 ml reaction flask were added in sequence 60 ml of N, N-dimethylformamide, (R) -3- (3-Boc amino) piperidin-1-yl-3- (2-cyano) benzylamino-N-methacrylamide (V) 20.7 g (50 mmol), cooled to 0-5 deg.C, added 5.4 g (100 mmol) sodium methoxide, stirred for 15 minutes, added 11.8 g (55 mmol) diphenyl carbonate to the system, heated to 50 deg.C, reacted for 2 hours, cooled, added 200 mmol water, stirred for 30 minutes, filtered, dried to obtain Boc protected alogliptin 21.1 g, yield 96.0%, and the next step was carried out without purification.
Preparing a dichloromethane/methanol solution of 2mol/LHCl (dichloromethane: methanol is 4: 1 volume ratio), taking 200 ml of the solution, adding the solution into a flask, stirring the solution at 0-5 ℃, adding 21.1 g (48 mmol) of the Boc-protected alogliptin into a reaction bottle, keeping the temperature and stirring the solution for 4 hours, finishing the reaction, adding 150 ml of water, separating an organic layer, washing an aqueous layer by 100 ml of dichloromethane, layering the aqueous layer, adding 100 ml of dichloromethane into the aqueous layer, adjusting the pH of the aqueous layer to 9-10 by using 2mol/l NaOH aqueous solution, stirring the aqueous layer for 30 minutes, separating the organic layer, extracting the aqueous layer by using 100 ml of dichloromethane, combining organic phases, drying, filtering, evaporating the solvent, pulping the rest substance by using methyl tert-butyl ether to obtain 20.0 g of alogliptin, wherein the yield is 91.0% and the purity is 99.8%.
Example 5: preparation of alogliptin benzoate (I)
To a 500 ml four-neck flask equipped with a stirring thermometer, constant pressure low liquid funnel, 250 g ethanol, 50 g (147 mmol) alogliptin, 21 g (172 mmol) benzoic acid were added, stirred, heated to 78 ℃ (reflux), stirred for 2 hours, cooled to room temperature, filtered, the filter cake was washed with 100 g ethanol, dried to obtain 63.3 g alogliptin benzoate, yield 93.1%, purity 99.9%.
The product sample NMR data is as follows, 1H NMR (400MHz, D)2O)
δ7.83–7.72(m,2H),7.71–7.65(m,1H),7.59–7.52(m,1H),7.47–7.40(m,1H),7.40–7.31(m,3H),7.30–7.22(m,1H),5.47(s,1H),5.25–5.09(m,2H),3.46–3.29(m,2H),3.06(s,3H),3.02–2.66(m,3H),2.01(s,1H),1.83–1.71(m,1H),1.68–1.49(m,2H).
Example 6: preparation of alogliptin benzoate (I)
300 g of methanol, 50 g (147 mmol) of alogliptin and 19.8 g (162 mmol) of benzoic acid are added into a 500 ml four-neck flask which is connected with a stirring thermometer and a constant-pressure low-liquid funnel, the mixture is stirred, the temperature is raised to 65 ℃ (reflux), the mixture is stirred and reacted for 2.5 hours, the temperature is reduced to room temperature, the mixture is filtered, a filter cake is washed by 120 g of methanol and dried to obtain 60.7 g of alogliptin benzoate, the yield is 89.3 percent and the purity is 99.9 percent.
Claims (14)
1. A preparation method of alogliptin benzoate with a formula I,
the method comprises the following steps:
(1) carrying out 1, 4-addition reaction on 3, 3-dihalogen-N-methacrylamide (II) and (R) -3-Boc-aminopiperidine (III) in a solvent, and then carrying out substitution and elimination reaction on the 3, 3-dihalogen-N-methacrylamide (II) and 2-cyanobenzylamine (IV) in the presence of alkali to prepare a compound V;
in formula II, X = Cl, Br;
(2) reacting compound v with a carbonylation reagent in a solvent to produce alogliptin (vi) by two reaction routes:
a. when the carbonylation reagent is triphosgene, the solvent is one or the combination of dichloromethane, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, chloroform, acetonitrile and toluene, the reaction temperature is 10-80 ℃, and the tert-butyloxycarbonyl group is removed during carbonylation to prepare alogliptin (VI); alternatively, the first and second electrodes may be,
b. when the carbonylation reagent is one or a combination of diphenyl carbonate, di-tert-butyl dicarbonate (Boc anhydride), dimethyl dicarbonate or diethyl dicarbonate, the solvent is one or a combination of N, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), tetrahydrofuran, 2-methyltetrahydrofuran and toluene, the carbonylation is performed to form a pyrimidine ring in the presence of alkali, the reaction temperature is 20-100 ℃, and then the tert-butyloxycarbonyl (Boc) protective group is removed in an acid solution to prepare alogliptin (VI);
(3) in a solvent, alogliptin (VI) and benzoic acid are salified to prepare alogliptin benzoate (I).
2. The process for the preparation of alogliptin benzoate according to claim 1, wherein the reaction in the step (1) comprises one or more of the following conditions:
i. the solvent is one of diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran and acetonitrile or a mixture of the diethyl ether, the methyl tertiary butyl ether, the tetrahydrofuran, the 2-methyl tetrahydrofuran and the acetonitrile in any proportion;
said 3, 3-dihalo-N-methacrylamide (II) being selected from 3, 3-dichloro-N-methacrylamide or 3, 3-dibromo-N-methacrylamide;
the base is inorganic base or organic base, wherein the organic base is one or a combination of N, N-diisopropylethylamine, triethylamine and pyridine, and the inorganic base is one or a combination of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and calcium carbonate;
the molar ratio of the base to the 3, 3-dihalo-N-methacrylamide (II) is (2-5): 1;
v. the molar ratio of the 3, 3-dihalo-N-methacrylamide (II), (R) -3-Boc-aminopiperidine (III) and 2-cyanobenzylamine (IV) is 1 (0.9-1.2) to (0.9-1.5);
the temperature of the 1, 4-addition reaction is-50 ℃ to 25 ℃;
and vii, the substitution and elimination reaction is carried out at the reaction temperature of 0-100 ℃.
3. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (1), the 3, 3-dihalo-N-methacrylamide (II) is selected from 3, 3-dichloro-N-methacrylamide, and the mass ratio of the solvent to the 3, 3-dichloro-N-methacrylamide is (3-15): 1.
4. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (1), the temperature of the 1, 4-addition reaction is-30 ℃ to 0 ℃; the substitution and elimination reaction is carried out at the reaction temperature of 10-40 ℃.
5. The process for the preparation of alogliptin benzoate according to claim 1, wherein the reaction in the step (2) comprises one or more of the following conditions:
i. the mass ratio of the solvent to the compound V is (3-15) to 1;
the molar ratio of the carbonylation reagent to the compound V is (0.5-3.0): 1.
6. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) a, the reaction temperature for carbonylation with triphosgene and removal of t-butyloxycarbonyl protection is 20-60 ℃.
7. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) b, the base is an organic base or an inorganic base; wherein the organic base is one of N, N-diisopropylethylamine, triethylamine and pyridine or the combination of any proportion, and the inorganic base is one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate and potassium carbonate or the combination of any proportion.
8. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) b, the molar ratio of the base to the compound V is (1-3): 1; the reaction temperature is 40-80 ℃.
9. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) b, the acid in the acid solution subjected to the protection by t-butoxycarbonyl is hydrogen chloride, p-toluenesulfonic acid or trifluoroacetic acid; the molar ratio of the acid to the compound V is (2-10): 1.
10. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) b, the solvent in the acid solution is one or a combination of dichloromethane, methanol, ethanol, tetrahydrofuran and isopropanol.
11. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) b, the acid solution is 1 to 3 mol/L.
12. The method for preparing alogliptin benzoate according to claim 1, wherein in the step (2) b, the reaction temperature for removing the tert-butoxycarbonyl protection is 25 to 50 ℃.
13. The process for the preparation of alogliptin benzoate according to claim 1, wherein the reaction in the step (3) comprises one or more of the following conditions:
i. the solvent is one of methanol, ethanol, tetrahydrofuran, isopropanol and dichloromethane or the combination of any proportion;
the mass ratio of the solvent to the alogliptin (VI) is (4-10) to 1;
and iii, the reaction temperature is 25-100 ℃.
14. The method for preparing alogliptin benzoate according to claim 1, wherein the reaction temperature in the step (3) is 40 to 80 ℃.
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| CN102361557A (en) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | Process for the preparation of alogliptin |
| CN105037325A (en) * | 2015-07-01 | 2015-11-11 | 合肥信风科技开发有限公司 | Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102361557A (en) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | Process for the preparation of alogliptin |
| CN105037325A (en) * | 2015-07-01 | 2015-11-11 | 合肥信风科技开发有限公司 | Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin |
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Denomination of invention: A simple preparation method of agliptin benzoate Effective date of registration: 20221213 Granted publication date: 20200428 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |