CN104447685A - Preparation method of alogliptin - Google Patents
Preparation method of alogliptin Download PDFInfo
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- CN104447685A CN104447685A CN201310440067.2A CN201310440067A CN104447685A CN 104447685 A CN104447685 A CN 104447685A CN 201310440067 A CN201310440067 A CN 201310440067A CN 104447685 A CN104447685 A CN 104447685A
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- VKXJOQVLADBJKD-GOSISDBHSA-N CC(C)(C)OC(N[C@H](CCC1)CN1C(N(Cc(cccc1)c1C#N)C(N1C)=O)=CC1=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1)CN1C(N(Cc(cccc1)c1C#N)C(N1C)=O)=CC1=O)=O VKXJOQVLADBJKD-GOSISDBHSA-N 0.000 description 1
- SGLXGFAZAARYJY-UHFFFAOYSA-N CN(C(C=C(N1)Cl)=O)C1=O Chemical compound CN(C(C=C(N1)Cl)=O)C1=O SGLXGFAZAARYJY-UHFFFAOYSA-N 0.000 description 1
- VEAUABSQMYGLJY-MRXNPFEDSA-N CN(C(C=C(N1Cc(cccc2)c2C#N)N(CCC2)C[C@@H]2N=C)=O)C1=O Chemical compound CN(C(C=C(N1Cc(cccc2)c2C#N)N(CCC2)C[C@@H]2N=C)=O)C1=O VEAUABSQMYGLJY-MRXNPFEDSA-N 0.000 description 1
- BVUJISIVAHYNLI-UHFFFAOYSA-N CN(C(C=C(N1Cc2ccccc2C#N)Cl)=O)C1=O Chemical compound CN(C(C=C(N1Cc2ccccc2C#N)Cl)=O)C1=O BVUJISIVAHYNLI-UHFFFAOYSA-N 0.000 description 1
- ZSBOMTDTBDDKMP-UHFFFAOYSA-N CN(C(C=C(N1Cc2ccccc2C#N)N(CCC2)CC2N)=O)C1=O Chemical compound CN(C(C=C(N1Cc2ccccc2C#N)N(CCC2)CC2N)=O)C1=O ZSBOMTDTBDDKMP-UHFFFAOYSA-N 0.000 description 1
- DCGGMHIZEAHUJL-UHFFFAOYSA-N CN(C(CC(N1)=O)=O)C1=O Chemical compound CN(C(CC(N1)=O)=O)C1=O DCGGMHIZEAHUJL-UHFFFAOYSA-N 0.000 description 1
- QGXNHCXKWFNKCG-UHFFFAOYSA-N N#Cc1c(CBr)cccc1 Chemical compound N#Cc1c(CBr)cccc1 QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of alogliptin. The preparation method comprises the following steps: performing cyclization by taking N-methylurea which is low in price and easy to obtain as a raw material to obtain a compound shown in the formula III, introducing a leaving group to obtain a compound shown in the formula IV, reacting with a compound shown in the formula V to obtain a compound shown in the formula VI, then performing reaction on the compound shown in the formula VI and (R)-3-Boc aminopiperidine to obtain a compound shown in the formula VII, and performing deprotection on the compound shown in the formula VII to form a salt, thereby obtaining alogliptin or the salt thereof. Compared with a traditional method, the method has the advantages of low cost, easiness in control of reaction, simple post-treatment operation and the like, and is suitable for industrial production of alogliptin or the salt thereof.
Description
Technical field
The present invention relates to chemical and medicine industry field, particularly, relate to a kind of medicine A Luoliting: 2-[[6-[(3R)-3-amino-piperidino]-3 treating type II diabetes, 4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] preparation method of cyanobenzene or its salt.
Background technology
Diabetes are considered to one of chief threat of 21 century human death, and as far back as 2006, the World Health Organization (WHO) estimated that there are 1.8 hundred million diabeticss in the whole world, and will double to this numeral of the year two thousand thirty.The main harm of diabetes was to destroy heart, blood vessel, eye, kidney and nerve, and the complication produced result in about 1,100,000 people and dies from diabetes in 2005.WHO estimates that the death that coming 10 years diabetes are relevant can increase above 50%, therefore will produce great burden on society.
Diabetes are divided into two classes according to the cause of disease: I type and II type, wherein type II diabetes accounts for whole diabetic subject's 90%, I type is characterized as insulin deficit, and the islet p-cell destruction of mainly autoimmunization mediation causes, and II type is characterized as insulopathic and consequent insulin resistant.Oral hypoglycaemic conventional clinically at present will mainly comprise biguanides, sulfonylurea, thiazolidinediones and alpha-glucosidase inhibitor etc.
In the last few years, along with the further investigation to type II diabetes pathophysiological mechanism, the research and development of new oral antidiabetic drug are that the treatment of type II diabetes provides how better selection.Serine protease dipeptidyl peptidase (DPP-IV) belongs to proteolytic enzyme S9b peptidase families, present research confirms, DPP-IV is by controlling the insulinotropic activity of glucagon-like peptide (GLP-1) and glucose-dependent-insulinotropic polypeptide (GIP), play a key effect in maintenance blood glucose balance, DPP-IV inhibitor can promote the level of endogenous secretin, promote insulin secretion, therefore DPP-IV inhibitor is considered to the medicine of new treatment type II diabetes.
Recently, be developed a series of DPP-IV inhibitor, wherein A Luoliting (alogliptin) and analogue thereof demonstrate challenging effect (WO2005/095381; WO2007/035379).A Luoliting is the DPP-IV inhibitor of Japanese Takeda company development, and obtained the approval listing of Japanese MHLW in 2010, clinical being mainly used in treats type II diabetes, and tolerance is good, and its structural formula is as follows:
EP1586571 disclose a kind of with 6-chlorouracil for raw material, replace with 2-cyano group benzyl bromine, then methyl iodide methylates, then carries out replacement with amine and obtain A Luoliting.The method polystep reaction in building-up process uses the dimethyl formamide/dimethyl sulfoxide (DMSO) (DMF/DMSO) being difficult to separation and purification, and solvent is difficult to recycle, trade effluent is many, directly substitution reaction is carried out, poor selectivity, product purification difficulty with (R)-3-amino piperidine, yield is low, three step total recoverys are 27%, and the price of starting raw material 6-chlorouracil is also higher, limit its application in industrialization.
CN102361557A discloses the preparation method of a kind of A Luoliting and derivative thereof, with 1-(2-cyanobenzyls)-3-MU for raw material, after reacting with cyanoacetic acid, ring is closed in hydrolysis, react with (R)-3-Boc amino piperidine again, obtain A Luoliting through de-Boc.Raw material 1-(2-cyanobenzyls)-3-MU is easy to get degree difference, expensive, is difficult to ensure raw material supply, is hydrolyzed Guan Huanshi simultaneously, has by product and produces, and is difficult to the quality ensureing product.
CN102942556A discloses one with 3-methyl-6-chlorouracil for raw material, and replace with 2-cyano group benzyl bromine, then react with (R)-3-Boc amino piperidine, the de-Boc of warp obtains A Luoliting.Starting raw material 3-methyl-6-chlorouracil in this method is expensive, is difficult to apply in suitability for industrialized production.
Therefore, still needing in this area provides a kind of raw material to be easy to get, the preparation method of the A Luoliting that cost is low.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of A Luoliting, utilize raw material that is cheap, that be easy to get, through controlled reaction process, come by simple post-processing operation, ensure that yield simultaneously, can suitability for industrialized production.
A first aspect of the present invention, provides the preparation method of a kind of A Luoliting or its pharmacy acceptable salt, comprises the following steps:
A () in organic solvent, propanedioic acid, diethyl malonate, dimethyl malonate, malonyl chloride or its mixture and formula II compound are obtained by reacting formula III compound;
B () in organic solvent, in the presence of a base, substituted or unsubstituted sulphonic acid anhydride or substituted or unsubstituted SULPHURYL CHLORIDE and formula III compound are obtained by reacting formula IV compound, in formula, and L
1for leavings group, be selected from: sulphonate, substituted sulfonic acid ester, wherein said replacement refers to and to be replaced by following group: C
1-C
4alkyl, phenyl, trifluoromethyl, to phenmethyl, p-nitrophenyl;
C () in organic solvent, in the presence of a base, formula IV compound and formula V compound are obtained by reacting formula VI compound, in formula, and L
2for leavings group, be selected from: chlorine, bromine, iodine or sulphonate;
D () in organic solvent, in the presence of a base, formula VI compound and (R)-3-Boc amino piperidine are obtained by reacting formula VII compound;
E () in organic solvent, adopts acid treatment formula VII compound, obtains A Luoliting or its pharmacy acceptable salt.
In another preference, the organic solvent in described step (a) is polar solvent, is selected from: acetic acid, ethanol, diacetyl oxide, dioxane, Virahol, methyl alcohol; And/or
Organic solvent in described step (b) is selected from: toluene, dimethyl formamide (DMF), methylene dichloride, chloroform, THF, pyridine; Described alkali is selected from triethylamine, DIPEA (DIPEA), Trimethylamine 99, pyridine, 4-picoline, 2,6-lutidine; And/or
Organic solvent in described step (c) is selected from: DMF, N-Methyl pyrrolidone, tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, toluene, acetonitrile; Alkali used is selected from: salt of wormwood, cesium carbonate, sodium carbonate, NaH, sodium hydroxide, potassium hydroxide, sodium methylate sodium ethylate, triethylamine, DIPEA, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU); And/or
In described step (d), organic solvent is selected from: toluene, acetonitrile, ethanol, acetone, DMF, N-Methyl pyrrolidone, THF, 2-methyltetrahydrofuran; Alkali used is salt of wormwood, cesium carbonate, sodium carbonate, triethylamine, DIPEA, DBU; And/or
In described step (e), organic solvent is selected from: methylene dichloride, methyl alcohol, ethanol, Virahol, ethyl acetate, the tertiary ether of first.
In another preference, the mol ratio of propanedioic acid described in described step (a), diethyl malonate, dimethyl malonate, malonyl chloride or its mixture and described formula II compound is 1-1.5:1; The temperature added is 0-30 DEG C; Temperature of reaction is 70-120 DEG C.
In another preference, the mol ratio of alkali described in described step (b) and described formula III compound is 1-3:1;
The mol ratio of described substituted or unsubstituted sulphonic acid anhydride or substituted or unsubstituted SULPHURYL CHLORIDE and described formula III compound is 1.1-2.0:1, and the temperature added is 0-30 DEG C; Temperature of reaction is 0-30 DEG C.
In another preference, the SULPHURYL CHLORIDE of described replacement is selected from: methylsulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, benzene sulfonyl chloride; And/or
The sulphonic acid anhydride of described replacement is trifluoromethanesulfanhydride anhydride.
In another preference, the mol ratio of described step (c) compound of formula IV and formula V compound is 0.9-1:1; The mol ratio of described alkali and formula V compound is 1.1-5.0:1; The temperature added is 0-30 DEG C; Temperature of reaction is 70-120 DEG C.
In another preference, the mol ratio of alkali and formula VI described in described step (d) is 1.1-5.0:1; (R) mol ratio of-3-Boc amino piperidine and formula VI compound is 1.0-1.1:1; The temperature added is 0 ~ 30 DEG C; Temperature of reaction is 50 ~ 90 DEG C.
In another preference, adopt acid treatment to refer in described step (e) and adopt hydrochloric acid or trifluoroacetic acid (TFA) process; Or hydrogen chloride gas is passed in reaction system.
In another preference, acid described in described step (e) is 10-50:1 with the mol ratio of formula VII compound, and the temperature added and temperature of reaction are 0 ~ 30 DEG C.
In another preference, described step (c), described step (d) and described step (e) are carried out continuously, without the need to processing intermediate product.
Preparation method of the present invention, low raw-material cost, reacts controlled, simple to operate, on average often walks yield about 90%, selects suitable solvent can operate continuously, is a kind of economical, the method for feasible suitability for industrialized production A Luoliting.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Specific embodiments
Present inventor is through extensively and in depth studying, and the unexpected preparation method developing a kind of new A Luoliting first, utilizes N-MU that is cheap, that be easy to get to be raw material, have with low cost, easy control of reaction, the advantages such as post-processing operation is simple, are applicable to suitability for industrialized production.On this basis, the present invention is completed.
Preparation method
Synthetic route of the present invention is as follows:
In a preferred implementation of the present invention, described method specifically comprises the following steps:
(1) preparation of 1-methylbarbituric acid (formula III compound)
N-MU (formula II compound) is dissolved in solvent, add propanedioic acid or diethyl malonate, dimethyl malonate, malonyl chloride or its mixture, after reacting completely, through aftertreatment, obtain 1-methylbarbituric acid (formula III compound); Wherein
Described raw material is N-MU; Solvent be polar solvent as acetic acid, ethanol, diacetyl oxide, dioxane, Virahol, methyl alcohol, be preferably acetic acid, ethanol, diacetyl oxide; The mol ratio of propanedioic acid or diethyl malonate, dimethyl malonate, malonyl chloride or its mixture and N-MU is 1.5:1 ~ 1:1, is preferably 1.2:1 ~ 1:1; The temperature added is 0 ~ 30 DEG C, is preferably 0 ~ 25 DEG C; Temperature of reaction is 70 ~ 120 DEG C, is preferably 70 ~ 110 DEG C.
(2) preparation of formula IV compound
1-methylbarbituric acid (formula III compound) is dissolved in solvent, adds alkali and SULPHURYL CHLORIDE or replace SULPHURYL CHLORIDE or acid anhydrides or substituted sulfonic acid acid anhydride, after reacting completely, through aftertreatment, obtain formula IV compound; Wherein:
Described solvent is toluene, DMF, methylene dichloride, chloroform, THF, pyridine etc., is preferably toluene, methylene dichloride, chloroform, THF, pyridine;
Described alkali is triethylamine, DIPEA, Trimethylamine 99, pyridine, 4-picoline, 2,6-lutidine etc., is preferably triethylamine, DIPEA, pyridine, 4-picoline, 2,6-lutidine;
The mol ratio of the consumption of alkali and 1-methylbarbituric acid (formula III compound) is 1:1 ~ 3:1, is preferably 1.2:1 ~ 2:1;
Described SULPHURYL CHLORIDE is preferably methylsulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, benzene sulfonyl chloride, or trifluoromethanesulfanhydride anhydride, is more preferably methylsulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, or trifluoromethanesulfanhydride anhydride;
The mol ratio of the consumption of SULPHURYL CHLORIDE or sulphonic acid anhydride and 1-methylbarbituric acid (formula III compound) is 2.0:1 ~ 1.1:1, and be preferably 1.5:1 ~ 1.1:1, the temperature added is 0 ~ 30 DEG C, is preferably 0 ~ 25 DEG C;
Temperature of reaction is 0 ~ 30 DEG C, is preferably 0 ~ 25 DEG C.
(3) preparation of formula VI compound
Formula VI compound is dissolved in solvent, adds alkali and formula V compound, after reacting completely, through aftertreatment, obtain formula VI compound; Wherein:
Solvent for use is DMF, N-Methyl pyrrolidone, THF, 2-methyltetrahydrofuran, toluene, acetonitrile etc., is preferably DMF, THF, 2-methyltetrahydrofuran, toluene, acetonitrile;
Alkali used is salt of wormwood, cesium carbonate, sodium carbonate, NaH, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, triethylamine, DIPEA, DBU etc., is preferably salt of wormwood, cesium carbonate, sodium carbonate, NaH, triethylamine, DIPEA, DBU etc.;
The consumption of alkali and the mol ratio of formula V compound are 5.0:1 ~ 1.1:1, are preferably 4.0:1 ~ 1.1:1;
The mol ratio of formula IV compound and formula V compound is 1.0:1 ~ 0.9:1; The temperature added is 0 ~ 30 DEG C;
Temperature of reaction is 70 ~ 120 DEG C.
(4) (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) preparation of t-butyl carbamate (formula VII compound):
Formula VI compound is dissolved in solvent, adds alkali and (R)-3-Boc amino piperidine (Boc is tertbutyloxycarbonyl) herein, after reacting completely, through aftertreatment, obtain formula VII compound; Wherein:
Solvent for use is acetonitrile, ethanol, acetone, DMF, N-Methyl pyrrolidone, toluene, THF, 2-methyltetrahydrofuran etc., is preferably toluene, acetonitrile, ethanol, acetone, DMF, THF, 2-methyltetrahydrofuran;
Alkali used is salt of wormwood, cesium carbonate, sodium carbonate, triethylamine, DIPEA, DBU etc., is preferably salt of wormwood, cesium carbonate, sodium carbonate, triethylamine, DIPEA;
The consumption of alkali and the mol ratio of formula VI compound are 5.0:1 ~ 1.1:1, are preferably 4.0:1 ~ 1.1:1; (R) consumption of-3-Boc amino piperidine and the mol ratio of formula VI compound are 1.0:1 ~ 1.1:1; The temperature added is 0 ~ 30 DEG C;
Temperature of reaction is 50 ~ 90 DEG C.
(5) 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, the i.e. preparation of A Luoliting or its salt (formula I)
By (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) is dissolved in solvent, adds acid, and temperature control is to after reacting completely, through aftertreatment, obtain formula I or its salt; Wherein:
Solvent is methylene dichloride, methyl alcohol, ethanol, Virahol, ethyl acetate, the tertiary ether of first etc., is preferably methylene dichloride, methyl alcohol, ethanol, ethyl acetate, the tertiary ether of first; Suitable acid is hydrochloric acid, or other solution of HCl gas, or TFA; Consumption and (R)-(1-(3-(2-the cyanobenzyls)-1-methyl-2 of acid, 6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) mol ratio of t-butyl carbamate is 50:1 ~ 10:1, the temperature added and temperature of reaction are 0 ~ 30 DEG C.
In another preference, step (3), step (4) do not need aftertreatment directly to carry out next step reaction, as selected toluene when step (3), step (4), 2-methyltetrahydrofuran equal solvent can operate continuously, when step (4) adopts ethyl acetate equal solvent can with step (5) operate continuously.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature disclosed in specification sheets, anyly can be provided identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Usefulness of the present invention is:
(1) raw material is easy to get, with low cost;
(2) easy control of reaction, post-processing operation is simple, does not even need aftertreatment;
(3) yield is high, is applicable to suitability for industrialized production.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment 1
(1) preparation of 1-methylbarbituric acid (formula III compound)
0.74kgN-MU joins in 5L Glacial acetic acid, temperature control 0 ~ 30 DEG C, add dimethyl malonate 1.4kg, be heated to 90 DEG C of insulations to reacting completely, reclaim under reduced pressure acetic acid, adds 3L95% ethanol, crystallization obtains 1-methylbarbituric acid (formula III compound) yellow solid 1.29kg, yield 91%, fusing point 130 ~ 133 DEG C
1h NMR (DMSO-d
6, 300 MHz): δ=11.31 (s, 1H), 3.56 (s, 2H), 3.03 (s, 3H) ppm.
(2) preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates formula IV
1-methylbarbituric acid (formula III compound) 1kg, is dissolved in methylene dichloride 5L, adds DIPEA 1kg, temperature control 0 ~ 30 DEG C, drip methylsulfonyl chloride 0.9kg, temperature control is to reacting completely, add 5L water, separatory, organic layer is through anhydrous sodium sulfate drying, filter, decompression and solvent recovery obtains 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates (formula IV compound) 1.39kg, yield 90%
1h NMR (DMSO-d
6, 300MHz): δ=5.92 (s, 3H) 3.43 (s, 3H), 3.15 (s, 3H), ppm.
(3) preparation of 3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates (formula VI compound)
1kg1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates (formula VI compound) joins in 7L toluene, add 2-cyano group benzyl bromine 0.9kg, temperature control 0 ~ 30 DEG C, adds triethylamine 0.5kg, be warming up to 70 DEG C, insulation, to reacting completely, adds 7L water, separatory, organic over anhydrous dried over sodium sulfate, filter, obtain 3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2, the toluene solution of 3,6-tetrahydropyrimidine-4-base methanesulfonates (formula VI compound), directly carries out the next step without the need to processing;
(4) preparation of (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate formula (VII)
By the solution that upper step is obtained by reacting, temperature control 0 ~ 30 DEG C, add DIPEA 0.65kg, (R)-3-Boc amino piperidine 1kg, temperature rising reflux, insulation is to reacting completely, add 5L washing, separatory, organic over anhydrous dried over sodium sulfate, filters, recycling design, obtain (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) 1.7kg, yield 84.5%
1h-NMR (400MHz, DMSO-d
6): δ 8.02(s, 1H) 7.82 (d, 1H), 7.65 (t, 1H), 7.46 (t, 1H), 7.23 (d, 1H), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H), 1.42 (s, 9H) .MS (ES) [m+H] 440.2..
(5) 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, the i.e. preparation of A Luoliting or its salt (formula I)
By (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) 1kg joins in saturated ethanolic hydrogen chloride solution 5L, temperature control 0 ~ 30 DEG C is to reacting completely, be spin-dried for and obtain 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] benzonitrile hydrochloride, i.e. A Luoliting hydrochloride 0.73kg, yield 95%.
1H-NMR(400MHz,DMSO-d
6):δ7.82(d,1H,J=7.6Hz),7.65(t,1H,J=7.6Hz),7.46(t,1H,J=7.6Hz),7.23(d,1H,J=8.0Hz),5.42(s,1H),5.50-5.00(ABq,2H,J=41.6,15.2Hz),3.30(m,2H),3.16(s,3H),2.91(m,1H),2.76(m,2H),1.93(m,1H),1.79(m,1H),1.51(m,2H).MS(ES)[m+H]340.2。
Embodiment 2
(1) preparation of 1-methylbarbituric acid (formula III compound)
0.74kgN-MU joins in 3L Glacial acetic acid, temperature control 0 ~ 30 DEG C, adding propanedioic acid 1.1kg, diacetyl oxide 2kg, being heated to 90 DEG C of insulations to reacting completely, reclaim under reduced pressure acetic acid, add 3L 95% ethanol, crystallization obtains 1-methylbarbituric acid (formula III compound) yellow solid 1.32kg, yield 93%, fusing point 132 ~ 135 DEG C
1hNMR (DMSO-d
6, 300MHz): δ=11.31 (s, 1H), 3.56 (s, 2H), 3.03 (s, 3H) ppm.
(2) preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base p-toluenesulfonic esters (formula IV compound)
1-methylbarbituric acid (formula III compound) 1kg, is dissolved in pyridine 3L, temperature control 0 ~ 30 DEG C, add Tosyl chloride 1.5kg, reaction solution, to reacting completely, is added in 10L frozen water by temperature control, stir and separate out solid, obtain 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base p-toluenesulfonic esters (formula IV compound) 1.98kg, yield 95.1%
1h NMR (DMSO-d
6, 300MHz): δ=7.74 (d, 2H), 7.40 (d, 2H), 5.74 (s, 1H), 3.20 (s, 3H), 2.33 (s, 3H) ppm.
(3) preparation of 3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base p-toluenesulfonic esters (formula VI compound)
1kg1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base p-toluenesulfonic esters (formula IV compound) joins in 8L acetonitrile, add 2-cyano group benzyl bromine 0.7kg, temperature control 0 ~ 30 DEG C, add salt of wormwood 1kg, be warming up to 70 DEG C, insulation is to reacting completely, filtered and recycled solvent, add water and each 4L water of ethyl acetate, separatory, organic over anhydrous dried over sodium sulfate, filtered and recycled solvent, obtain 3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base p-toluenesulfonic esters (formula VI compound) 1.2kg, yield 87%,
1h NMR (DMSO-d
6, 300MHz): δ=7.74-7.34 (m, 8H), 5.74 (s, 1H), 5.40 (s, 2H), 3.40 (s, 3H), 2.13 (s, 3H) ppm.
(4) preparation of (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound)
3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base p-toluenesulfonic esters (formula VI compound) 1kg joins in 6L acetonitrile, temperature control 0 ~ 30 DEG C, add cesium carbonate 1kg, (R)-3-Boc amino piperidine 0.5kg, be warming up to backflow, insulation is to reacting completely, filter, add water and each 4L water of ethyl acetate, separatory, organic over anhydrous dried over sodium sulfate, filter, obtain (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-base) ethyl acetate solution of t-butyl carbamate (formula VII compound), do not need process.
(5) 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, the i.e. preparation of A Luoliting or its salt (formula I)
(R) that upper step is obtained-(1-(3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) ethyl acetate solution, temperature control 0 ~ 30 DEG C, pass into dry HCl gas to saturated, be stirred to and react completely, filtration obtains 2-[[6-[(3R)-3-amino-piperidino]-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H)-pyrimidyl] methyl] benzonitrile hydrochloride, i.e. A Luoliting hydrochloride 0.93kg, two step yields 90%,
1h-NMR (400MHz, DMSO-d
6): δ 7.82 (d, 1H, J=7.6Hz), 7.65 (t, 1H, J=7.6Hz), 7.46 (t, 1H, J=7.6Hz), 7.23 (d, 1H, J=8.0Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6,15.2Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H) .MS (ES) [m+H] 340.2.
Embodiment 3
(1) preparation of 1-methylbarbituric acid (formula III compound)
0.74kg N-MU joins in 3L dehydrated alcohol, temperature control 0 ~ 30 DEG C, add diethyl malonate 1.6kg, reflux, insulation, to reacting completely, is cooled to 0 ~ 5 DEG C, crystallization obtains 1-methylbarbituric acid (formula III compound) yellow solid 1.35kg, yield 95%, fusing point 131 ~ 133 DEG C
1h NMR (DMSO-d
6, 300MHz): δ=11.31 (s, 1H), 3.56 (s, 2H), 3.03 (s, 3H) ppm.
(2) preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base triflate (formula IV compound)
1-methylbarbituric acid (formula III compound) 0.1kg, is dissolved in 0.5L 2-methyltetrahydrofuran, temperature control 0 ~ 30 DEG C, add triethylamine 0.1kg, drip trifluoromethanesulfanhydride anhydride 0.2kg, temperature control is to reacting completely, be added to by reaction solution in 0.5L frozen water, stir separatory, organic layer is dry, filter, obtain 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base triflate (formula IV compound) 2-methyltetrahydrofuran solution.
(3) preparation of 3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base triflate (formula VI compound)
By the 1-methyl-2 that step (2) obtains, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base triflate (formula IV compound) 2-methyltetrahydrofuran, be cooled to 0 ~ 10 DEG C and add 60%NaH0.042kg, stir after 30 minutes, add 2-cyanobenzyls triflate 0.18kg, temperature control 0 ~ 30 DEG C, stir after 30 minutes, be warming up to 70 DEG C, insulation is to reacting completely, filter, add water 4L, separatory, organic over anhydrous dried over sodium sulfate, filtered and recycled solvent, obtain 3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base triflate (formula VI compound) 0.23kg, yield 87%,
1h NMR (DMSO-d
6, 300MHz): δ=7.74-7.34 (m, 4H), 5.84 (s, 1H), 5.30 (s, 2H), 3.20 (s, 3H) ppm.
(4) (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) preparation of t-butyl carbamate (formula VII compound)
3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base triflate (formula VI compound) 0.1kg joins in 0.5L acetone, temperature control 0 ~ 30 DEG C, add sodium carbonate 1kg, (R)-3-Boc amino piperidine 0.051kg, temperature rising reflux is to reacting completely, filter, add water and each 0.4L water of ethyl acetate, separatory, organic over anhydrous dried over sodium sulfate, filter, obtain (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-base) ethyl acetate solution of t-butyl carbamate (formula VII compound), do not need process.
(5) 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, the i.e. preparation of A Luoliting or its salt (formula I)
(R) that upper step is obtained-(1-(3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) ethyl acetate solution, temperature control 0 ~ 30 DEG C, pass into dry HCl gas to saturated, be stirred to and react completely, filtration obtains 2-[[6-[(3R)-3-amino-piperidino]-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H)-pyrimidyl] methyl] benzonitrile hydrochloride, i.e. A Luoliting hydrochloride 0.7kg, two step yields 80%,
1h-NMR (400MHz, DMSO-d
6): δ 7.82 (d, 1H, J=7.6Hz), 7.65 (t, 1H, J=7.6Hz), 7.46 (t, 1H, J=7.6Hz), 7.23 (d, 1H, J=8.0Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6,15.2Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H) .MS (ES) [m+H] 340.2.
Embodiment 4
(1) preparation of 1-methylbarbituric acid (formula III compound)
0.74kgN-MU joins in 6L acetic acid, temperature control 0 ~ 30 DEG C, adds propanedioic acid 1.2kg, reflux, insulation is to reacting completely, recovery of acetic acid, adds 6L95% ethanol, is cooled to 0 ~ 5 DEG C, crystallization obtains 1-methylbarbituric acid (formula III compound) yellow solid 1.26kg, yield 89%, fusing point 130 ~ 133 DEG C
1hNMR (DMSO-d
6, 300MHz): δ=11.31 (s, 1H), 3.56 (s, 2H), 3.03 (s, 3H) ppm.
(2) preparation of 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates (formula IV compound)
1-methylbarbituric acid (formula III compound) 0.1kg, is dissolved in 0.3L pyridine, temperature control 0 ~ 30 DEG C, drip methylsulfonic acid acid anhydride 0.09kg, reaction solution, to reacting completely, is added in 1L ethyl acetate by temperature control, add frozen water 1L again, stir separatory, organic layer is dry, filtered and recycled solvent, obtains 1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates (formula IV compound) 0.142kg, yield 91.6%
1h NMR (DMSO-d
6, 300MHz): δ=5.92 (s, 3H) 3.43 (s, 3H), 3.15 (s, 3H), ppm.
(3) preparation of 3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base methanesulfonates (formula VI compound)
1-methyl-2 will be obtained, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base methanesulfonates (formula IV compound) 0.1kg is dissolved in the THF of 1L, be cooled to 0 ~ 10 DEG C and add salt of wormwood 0.12kg, stir after 30 minutes, add 2-cyanobenzyls triflate 0.2kg, stir after 30 minutes, be warming up to 70 DEG C, insulation is to reacting completely, filtered and recycled solvent, add methylene dichloride and each 4L water of water, separatory, organic over anhydrous dried over sodium sulfate, filtered and recycled solvent, obtain 3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base methanesulfonates (formula VI compound) 0.146kg, yield 96%,
1h NMR (DMSO-d
6, 300MHz): δ=7.74-7.34 (m, 4H), 5.64 (s, 1H), 5.20 (s, 2H), 3.40 (s, 3H), 2.33 (s, 3H) ppm.
(4) preparation of (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound)
3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base methanesulfonates (formula VI compound) 0.1kg joins in 0.3L DMF, temperature control 0 ~ 30 DEG C, add DIPEA0.07kg, (R)-3-Boc amino piperidine 0.06kg, heat up 100 degree of insulations to reacting completely, add water and each 1L water of ethyl acetate, separatory, organic over anhydrous dried over sodium sulfate, filtered and recycled solvent, obtain (R)-(1-(3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) 0.1kg, yield 76%,
1h-NMR (400MHz, DMSO-d
6): δ 8.02(s, 1H) 7.82 (d, 1H), 7.65 (t, 1H), 7.46 (t, 1H), 7.23 (d, 1H), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H), 1.42 (s, 9H) .MS (ES) [m+H] 440.2.
(5) 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, the i.e. preparation of A Luoliting (formula I)
(R) that upper step is obtained-(1-(3-(2-cyanobenzyls)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-base) t-butyl carbamate (formula VII compound) 0.1kg is dissolved in 300ml methylene dichloride, temperature control 0 ~ 30 DEG C, drip 100ml trifluoroacetic acid, be stirred to and react completely, add salt of wormwood and regulate PH to 11, separatory, organic layer is dry, filtered and recycled solvent, obtain 2-[[6-[(3R)-3-amino-piperidino]-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, i.e. A Luoliting 0.069kg, yield 90%,
1h-NMR (400MHz, DMSO-d
6): δ 7.82 (d, 1H, J=7.6Hz), 7.65 (t, 1H, J=7.6Hz), 7.46 (t, 1H, J=7.6Hz), 7.23 (d, 1H, J=8.0Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6,15.2Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H) .MS (ES) [m+H] 340.2.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the preparation method of Yi Zhong A Luoliting or its pharmacy acceptable salt, is characterized in that, comprises the following steps:
A () in organic solvent, propanedioic acid, diethyl malonate, dimethyl malonate, malonyl chloride or its mixture and formula II compound are obtained by reacting formula III compound;
B () in organic solvent, in the presence of a base, substituted or unsubstituted sulphonic acid anhydride or substituted or unsubstituted SULPHURYL CHLORIDE and formula III compound are obtained by reacting formula IV compound, in formula, and L
1for leavings group, be selected from: sulphonate, substituted sulfonic acid ester, wherein said replacement refers to and to be replaced by following group: C
1-C
4alkyl, phenyl, trifluoromethyl, to phenmethyl, p-nitrophenyl;
C () in organic solvent, in the presence of a base, formula IV compound and formula V compound are obtained by reacting formula VI compound, in formula, and L
2for leavings group, be selected from: chlorine, bromine, iodine or sulphonate;
D () in organic solvent, in the presence of a base, formula VI compound and (R)-3-Boc amino piperidine are obtained by reacting formula VII compound;
E () in organic solvent, adopts acid treatment formula VII compound, obtains A Luoliting or its pharmacy acceptable salt.
2. the method for claim 1, is characterized in that, the organic solvent in described step (a) is polar solvent, is selected from: acetic acid, ethanol, diacetyl oxide, dioxane, Virahol, methyl alcohol; And/or
Organic solvent in described step (b) is selected from: toluene, dimethyl formamide (DMF), methylene dichloride, chloroform, THF, pyridine; Described alkali is selected from triethylamine, DIPEA (DIPEA), Trimethylamine 99, pyridine, 4-picoline, 2,6-lutidine; And/or
Organic solvent in described step (c) is selected from: DMF, N-Methyl pyrrolidone, tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, toluene, acetonitrile; Alkali used is selected from: salt of wormwood, cesium carbonate, sodium carbonate, NaH, sodium hydroxide, potassium hydroxide, sodium methylate sodium ethylate, triethylamine, DIPEA, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU); And/or
In described step (d), organic solvent is selected from: toluene, acetonitrile, ethanol, acetone, DMF, N-Methyl pyrrolidone, THF, 2-methyltetrahydrofuran; Alkali used is salt of wormwood, cesium carbonate, sodium carbonate, triethylamine, DIPEA, DBU; And/or
In described step (e), organic solvent is selected from: methylene dichloride, methyl alcohol, ethanol, Virahol, ethyl acetate, the tertiary ether of first.
3. method as claimed in claim 1 or 2, it is characterized in that, the mol ratio of propanedioic acid described in described step (a), diethyl malonate, dimethyl malonate, malonyl chloride or its mixture and described formula II compound is 1-1.5:1; The temperature added is 0-30 DEG C; Temperature of reaction is 70-120 DEG C.
4. method as claimed in claim 1 or 2, it is characterized in that, the mol ratio of alkali described in described step (b) and described formula III compound is 1-3:1;
The mol ratio of described substituted or unsubstituted sulphonic acid anhydride or substituted or unsubstituted SULPHURYL CHLORIDE and described formula III compound is 1.1-2.0:1, and the temperature added is 0-30 DEG C; Temperature of reaction is 0-30 DEG C.
5. the method for claim 1, is characterized in that, the SULPHURYL CHLORIDE of described replacement is selected from: methylsulfonyl chloride, Tosyl chloride, 4-Nitrobenzenesulfonyl chloride, benzene sulfonyl chloride; And/or
The sulphonic acid anhydride of described replacement is trifluoromethanesulfanhydride anhydride.
6. method as claimed in claim 1 or 2, it is characterized in that, the mol ratio of described step (c) compound of formula IV and formula V compound is 0.9-1:1; The mol ratio of described alkali and formula V compound is 1.1-5.0:1; The temperature added is 0-30 DEG C; Temperature of reaction is 70-120 DEG C.
7. method as claimed in claim 1 or 2, it is characterized in that, the mol ratio of alkali and formula VI described in described step (d) is 1.1-5.0:1; (R) mol ratio of-3-Boc amino piperidine and formula VI compound is 1.0-1.1:1; The temperature added is 0 ~ 30 DEG C; Temperature of reaction is 50 ~ 90 DEG C.
8. the method for claim 1, is characterized in that, adopts acid treatment to refer to and adopt hydrochloric acid or trifluoroacetic acid (TFA) process in described step (e); Or hydrogen chloride gas is passed in reaction system.
9. the method as described in claim 1 or 8, is characterized in that, acid described in described step (e) is 10-50:1 with the mol ratio of formula VII compound, and the temperature added and temperature of reaction are 0 ~ 30 DEG C.
10. the method for claim 1, is characterized in that, described step (c), described step (d) and described step (e) are carried out continuously, without the need to processing intermediate product.
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| WO2016178246A1 (en) * | 2015-05-04 | 2016-11-10 | Indoco Remedies Limited | Process for the preparation of alogliptin |
| CN106336396A (en) * | 2016-08-25 | 2017-01-18 | 合肥立方制药股份有限公司 | Alogliptin benzoate preparation method |
| CN108586360A (en) * | 2018-06-13 | 2018-09-28 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of the chloro- 3- methyluracils of 6- |
| CN109503551A (en) * | 2018-11-21 | 2019-03-22 | 安阳师范学院 | The preparation method of one koji Ge Lieting |
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| CN102361557A (en) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | Process for the preparation of alogliptin |
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| WO2016178246A1 (en) * | 2015-05-04 | 2016-11-10 | Indoco Remedies Limited | Process for the preparation of alogliptin |
| CN105801490A (en) * | 2016-05-05 | 2016-07-27 | 青岛辰达生物科技有限公司 | Method for preparing alogliptin midbody |
| CN106336396A (en) * | 2016-08-25 | 2017-01-18 | 合肥立方制药股份有限公司 | Alogliptin benzoate preparation method |
| CN106336396B (en) * | 2016-08-25 | 2019-04-09 | 合肥立方制药股份有限公司 | A kind of preparation method of alogliptin benzoate |
| CN108586360A (en) * | 2018-06-13 | 2018-09-28 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of the chloro- 3- methyluracils of 6- |
| CN108586360B (en) * | 2018-06-13 | 2021-07-30 | 峨眉山宏昇药业股份有限公司 | Preparation method of 6-chloro-3-methyl uracil |
| CN109503551A (en) * | 2018-11-21 | 2019-03-22 | 安阳师范学院 | The preparation method of one koji Ge Lieting |
| CN112250664A (en) * | 2020-09-30 | 2021-01-22 | 辰欣药业股份有限公司 | Preparation method of alogliptin benzoate |
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