CN106608853A - Preparation method of dipeptidyl peptidase IV inhibitor - Google Patents
Preparation method of dipeptidyl peptidase IV inhibitor Download PDFInfo
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- CN106608853A CN106608853A CN201510702131.9A CN201510702131A CN106608853A CN 106608853 A CN106608853 A CN 106608853A CN 201510702131 A CN201510702131 A CN 201510702131A CN 106608853 A CN106608853 A CN 106608853A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- C07—ORGANIC CHEMISTRY
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- 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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Abstract
The invention provides a preparation method of a dipeptidyl peptidase IV inhibitor. The preparation method utilizes isopropanol and water as solvents and a volume ratio of isopropanol to water is 1-8: 1 so that a product yield and product purity are greatly improved and reaction time is shortened. An intermediate is subjected to beating and purification under action a poor solvent. The purification method is simple in operation, a product yield and product purity are high, and the production process is easy to control and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation and purification method of dipeptidy peptidase in inhibitors, and in particular to the preparation and purification method of bent Ge Lieting and Egelieting.
Background technology
Bent Ge Lieting (Trelagliptin), chemical name is：[[6- [(3R) -3- amino-piperidino] -3- methyl -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls] fluoro- benzonitriles of -4-, its structural formula is 2-：
；
Egelieting（Alogliptin）, chemical name is：[[6- [(3R) -3- amino-piperidino] -3- methyl -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls]-benzonitrile, its structural formula is 2-：
。
Bent Ge Lieting and Egelieting belong to dipeptidy peptidase in inhibitors, are researched and developed by Japanese Takeda companies, for treating type Ⅱdiabetes mellitus.Both medicines structure is similar, and its preparation method is also similar.Preparation method as disclosed in patent CN101360723A is：
。
The purification process of compound III has following several：One is crude product to be beaten in isopropanol, washed, is dried, and obtains sterling；Two is that crude product is obtained into sterling by column chromatography eluting；Three is, with N-Methyl pyrrolidone (NMP) as reaction dissolvent, after the completion of reaction, to be directly added into pure water, carries out beating purification, and isopropanol washing is dried 16h sterlings derived above under vacuum.
Compound III is soluble in isopropanol and NMP, water insoluble.Method one is beaten purification for crude product in single good solvent, but Jing studies compound III yield that the purification process obtains and purity is all relatively low, and purification effect is bad；Method two is cumbersome, and product yield is low, is not suitable for large-scale production；Method three is beaten purification for crude product in the mixed solvent of good solvent-poor solvent, has used the difficult solvent NMP of high boiling point so that solvent is easily remained, not easy-clear.
Compound III reacts prepare compound V with compounds Ⅳ, is mixed as solvent with water with alcohols, or isopropanol.When alcohols is used as solvent, reaction system need to be carried out in the pipe of sealing, and reaction temperature is 80-110 DEG C, and the reaction condition is high to equipment requirements, is not suitable for industrialized production；Isopropyl alcohol and water disclosed in patent CN101360723A is with volume ratio 138:1 used as solvent, it has been investigated that the response time is long, at least wants 16h, and product yield and purity are all relatively low.
Accordingly, it would be desirable to a kind of succinct method for effectively preparing and purifying dipeptidy peptidase in inhibitors, make product reach high-purity, in high yield while technological process it is simple, be conducive to large-scale production.It is an object of the invention to provide a kind of preparation and purification method of new dipeptidy peptidase in inhibitors.
The content of the invention
The present invention provides a kind of purification process of dipeptidy peptidase in inhibitors intermediate, comprises the following steps：
A. with compound ii in the basic conditions, reaction is obtained compound III crude product to compounds I；
B. carry out beating to compound III crude product with poor solvent to purify；
Wherein R1For F or H, R2For Br or Cl.
Compounds I reacts prepare compound III with compound ii, is the alkylated reaction of amine.The alkylating of amine can be carried out under conditions known in the art, including using a kind of alkali, such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, cesium carbonate, triethylamine, DIPEA, tri-n-butylamine etc.；Its reaction dissolvent is common solvent, including single solvent and mixed solvent, such as DMSO, NMP, DMF, THF or its mixing.
The preparation of chemicalses includes organic synthesiss and isolates and purifies.Always with more or less by-product and unreacted completely raw material during organic synthesis, therefore, reacted process step is very crucial, and whether this is related to can isolate pure and high income finished product from reaction mixture.Same reaction, the step of isolate and purify adopted, solvent, method it is different, will result directly in its yield and purity be also different.
Chemicalses isolate and purify including：Extraction, fractional distillation, recrystallization, beating, adsorbing separation, membrance separation, column chromatography, sedimentation method etc..Column chromatography is not suitable for large-scale production, it is industrial it is more for recrystallization, be beaten and the sedimentation method.Beating is that a small amount of solvent is added in raw material so as to obtain the state of slurry, filters after stirring or is centrifuged, and removes the process of impurity.Beating can typically remove the impurity for being attached to its surface, and solvent load is few, and product loss is little；But beating is typically only used as the preliminary purification of product, the purity of its product does not often reach the requirement of sterling, subsequently also needs to carry out further purification by other purification process, such as carry out recrystallization, column chromatography etc. again after being beaten.The solvent of beating purification can be the mixing of good solvent, poor solvent, or good solvent and poor solvent.Because good solvent can preferably lysate so that impurity of the absorption on product also dissolves more, therefore the purity for being beaten product after purification using good solvent can be higher.Beating purification is all, using good solvent, product purity highest, yield is minimum；Using the mixing of good solvent and poor solvent, product purity and yield take second place；Using poor solvent, product purity is minimum, yield highest.
The present invention is studied the physicochemical properties of product Compound III, be finally found that and do not combine other purification process, and carry out beating purification to compound III crude product only with poor solvent, the yield for not only making product is improved, and the purity of product is also improved.Good solvent in the present invention refers to that compound can be dissolved in well in the solvent, and poor solvent refers to that compound can not very well dissolve or can not be dissolved in the solvent.Through inventor's numerous studies, determining the good solvent of compound III has：DMF、DMSO、CHCl3、CH2Cl2, ethanol, tetrahydrofuran, methanol, isopropanol, acetonitrile etc.；Poor solvent has：Ethyl acetate, isopropyl acetate, normal heptane, normal hexane, methyl tertiary butyl ether(MTBE), petroleum ether, n-butyl acetate, hexamethylene, ether etc..
The present invention carries out the poor solvent ethyl acetate of purification employing, isopropyl acetate, normal heptane, normal hexane, methyl tertiary butyl ether(MTBE), petroleum ether, n-butyl acetate, hexamethylene, one or more in ether to compound III crude product；More preferably ethyl acetate.
The temperature of purification is preferred 15-35 DEG C, and the purified product yield of its compound III for obtaining and purity are higher.
The quality of compound III crude product and the volume ratio of poor solvent preferably 1：2-10（g/ml）, the purified product yield of its compound III for obtaining and purity it is higher.
The present invention also provides a kind of preparation method of dipeptidy peptidase in inhibitors, and synthetic route is as follows：
Comprise the following steps：Compound III reacts in the basic conditions prepare compound V with compounds Ⅳ, and reaction dissolvent is isopropyl alcohol and water, wherein, the volume ratio of isopropyl alcohol and water is 1-8:1；R1For F or H.
Compound III reacts prepare compound V with compounds Ⅳ, is the alkylated reaction of amine.Compounds Ⅳ can participate in reaction in the form of free state or its hydrochlorate.It is understood that the alkylating of amine can be carried out under conditions known in the art, including using a kind of alkali, such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, cesium carbonate, triethylamine, DIPEA, tri-n-butylamine etc..
Inventor has found that the ratio of the isopropyl alcohol and water in above-mentioned reaction can directly affect the effect reacted, including response time, the yield and purity of product Compound V.Therefore, inventor's research is drawn when reaction dissolvent is isopropyl alcohol and water, and solvent ratio is 1-8:When 1, the yield and purity for obtaining the crude product of compound V is all greatly improved, and its response time shortens.
The ratio of preferred solvent isopropyl alcohol and water is 5:1, reaction temperature is preferably 55-65 DEG C, and faster, the yield and purity for obtaining the crude product of compound V is higher for its reaction rate.
The yield and purity of the crude product of compound V directly affect the yield and purity of sterling, and the crude product of compound V prepared by the present invention, Jing is further purified the sterling that can obtain higher purity.The preparation of dipeptidy peptidase in inhibitors described above or purification process, R1For F or H.Work as R1For H when, compound V be Egelieting；Work as R1For F when, compound V be song Ge Lieting.
Specific embodiment
Embodiment
1
By 7.27g 2- cyano group -5- fluorine bromobenzyl (R1For F, R2For Br), 6.00g 3- methyl -6- chloro uracil, 5.10g potassium carbonate are dissolved in the mixed solution of 78ml DMSO and THF, stirring reaction 1h at being warming up to 50 DEG C, reaction is cooled to room temperature, 80ml frozen water is slowly added dropwise, drop to finish and stir 1h, sucking filtration under ice bath, compound III crude product 8.84g is obtained, yield is 88.60%.At 20 DEG C, compound III crude product is beaten with 17.7ml normal heptane, is filtered, washing, dry compound III sterling 8.54g, purification yield 96.61%.Compound III total recovery 85.59%, purity 99.20%.
Embodiment
2
By 6.34g 2- cyano group -5- fluorobenzyl chloride (R1For F, R2For Cl), 6.00g 3- methyl -6- chloro uracil, 4.40g sodium carbonate are dissolved in 78ml DMSO solutions, stirring reaction 1h at being warming up to 60 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, and drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 9.73g, and yield is 88.66%.At 35 DEG C, compound III crude product is beaten with 48.6ml petroleum ether and 48.7ml isopropyl acetates mixed solvent, is filtered, washing, dry compound III sterling 8.96g, purification yield 92.09%.Compound III total recovery 81.64%, purity 99.00%.
Embodiment
3
By the fluorine-based bromobenzyl (R of 8.42g 2- cyanogen -5-1For F, R2For Br), 6.00g 3- methyl -6- chloro uracil, 3.50g sodium bicarbonate are dissolved in 78ml nmp solutions, stirring reaction 1h at being warming up to 65 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, and drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 9.77g, and yield is 89.02%.At 25 DEG C, compound III crude product is beaten with 39.0ml ethyl acetate, is filtered, washing, dry compound III sterling 9.56g, purification yield 97.85%.Compound III total recovery 87.11%, purity 99.5%.
Embodiment
4
By 6.66g 2- cyano-benzyl bromide (R1For H, R2For Br), 6.00g 3- methyl -6- chloro uracil, 3.80g potassium bicarbonates are dissolved in 78ml DMF solutions, stirring reaction 1h at being warming up to 65 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, and drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 8.27g, and yield is 88.30%.At 30 DEG C, compound III crude product is beaten with 41.3ml normal hexane, is filtered, washing, dry compound III sterling 7.95g, purification yield 96.13%.Compound III total recovery 84.88%, purity 99.30%.
Embodiment
5
By 5.66g 2- cyano group benzyl chloride (R1For H, R2For Cl), 6.00g 3- methyl -6- chloro uracil, 5.30gN, N- diisopropylethylamine is dissolved in the solution of 78ml DMSO, stirring reaction 1h at being warming up to 60 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 9.08g, and yield is 88.14%.At 15 DEG C, compound III crude product is beaten with 72.6ml ether, is filtered, washing, dry compound III sterling 8.82g, purification yield 97.14%.Compound III total recovery 85.62%, purity 99.10%.
Embodiment
6
By 7.71g 2- cyano-benzyl bromide (R1For H, R2For Br), 6.00g 3- methyl -6- chloro uracil, 4.20g triethylamines are dissolved in the mixed solution of 78ml DMSO and THF, stirring reaction 1h at being warming up to 50 DEG C, reaction is cooled to room temperature, 80ml frozen water is slowly added dropwise, drop to finish and stir 1h, sucking filtration under ice bath, compound III crude product 9.15g is obtained, yield is 88.81%.At 35 DEG C, compound III crude product is beaten with 9.2ml methyl tertiary butyl ether(MTBE)s and 18.3ml n-butyl acetates, is filtered, washing, dry compound III sterling 8.83g, purification yield 96.50%.Compound III total recovery 85.70%, purity 99.20%.
Comparative example
1
By 8.42g 2- cyano group -5- fluorine bromobenzyl (R1For F, R2For Br), 6.00g 3- methyl -6- chloro uracil, 3.50g sodium bicarbonate are dissolved in 78ml nmp solutions, stirring reaction 1h at being warming up to 65 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, and drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 9.78g, and yield is 89.11%.At 30 DEG C, compound III crude product ethyl acetate-CHCl3Mixed solvent be beaten, filter, washing, dry compound III sterling 6.60g, purification yield 67.48%.Compound III total recovery 60.14%, purity 90.80%.
Comparative example
2
By 5.66g 2- cyano group benzyl chloride (R1For H, R2For Cl), 6.00g 3- methyl -6- chloro uracil, 5.30gN, N- diisopropylethylamine is dissolved in the mixed solution of 78ml DMSO, stirring reaction 1h at being warming up to 60 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 9.08g, and yield is 88.14%.At 20 DEG C, compound III crude product is beaten with a small amount of isopropanol, is filtered, washing, dry compound III sterling 6.03g, purification yield 66.41%.Compound III total recovery 58.53%, purity 92.60%.
Comparative example
3
By 7.27g 2- cyano group -5- fluorine bromobenzyl (R1For F, R2For Br), 6.00g 3- methyl -6- chloro uracil, 5.10g potassium carbonate are dissolved in the mixed solution of 78ml DMSO and THF, stirring reaction 1h at being warming up to 50 DEG C, reaction is cooled to room temperature, 80ml frozen water is slowly added dropwise, drop to finish and stir 1h, sucking filtration under ice bath, compound III crude product 8.82g is obtained, yield is 88.40%.At 50 DEG C, compound III crude product ethanol dissolves, and being cooled to 10 DEG C carries out recrystallization, filters, washing, dry compound III sterling 4.28g.Purification yield 48.53%.Compound III total recovery 42.90%, purity 97.50%.
Comparative example
4
By 6.34g 2- cyano group -5- fluorobenzyl chloride (R1For F, R2For Cl), 6.00g 3- methyl -6- chloro uracil, 4.40g sodium carbonate are dissolved in 60ml DMSO solutions, stirring reaction 1h at being warming up to 60 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, and drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 9.75g, and yield is 88.84%.At 40 DEG C, compound III crude product CH2Cl2- heptane dissolves, and being cooled to 10 DEG C carries out recrystallization, filters, washing, dry compound III sterling 6.36g.Purification yield 65.23%.Compound III total recovery 57.95%, purity 97.20%.
Comparative example
5
By 6.66g 2- cyano-benzyl bromide (R1For H, R2For Br), 6.00g 3- methyl -6- chloro uracil, 3.80g potassium bicarbonates are dissolved in 78ml DMF solutions, stirring reaction 1h at being warming up to 65 DEG C, reaction is cooled to room temperature, is slowly added dropwise 80ml frozen water, and drop to finish and stir 1h under ice bath, sucking filtration, obtains compound III crude product 8.27g, and yield is 88.30%.165ml ethyl acetate is added in compound III crude product, is dissolved under reflux state, being cooled to 15 DEG C carries out recrystallization, filtered, washing, dry compound III sterling 6.85g, purification yield 82.83%.Compound III total recovery 73.14%, purity 99.10%.
Comparative example
6
By 7.71g 2- cyano-benzyl bromide (R1For H, R2For Br), 6.00g 3- methyl -6- chloro uracil, 4.20g triethylamines are dissolved in the mixed solution of 78ml DMSO and THF, stirring reaction 1h at being warming up to 50 DEG C, reaction is cooled to room temperature, 80ml frozen water is slowly added dropwise, drop to finish and stir 1h, sucking filtration under ice bath, compound III crude product 9.15g is obtained, yield is 88.81%.At 25 DEG C, the ethyl acetate drip washing of compound III crude product is filtered, washing, dry compound III sterling 8.94, purification yield 97.90%.Compound III total recovery 86.77%, purity 89.70%.
According to the difference of above-described embodiment, purification solvent and way of purification, the yield and purity of the purified product of its compound III are summarized as follows table：
Embodiment 1-6 carries out beating purification using single or mixing poor solvent, comparative example 1 is good solvent-poor solvent mixing beating purification, comparative example 2 is that good solvent is beaten purification, comparative example 3-5 is respectively good solvent, good solvent-poor solvent, the recrystallization purifying of poor solvent, and comparative example 6 is poor solvent drip washing purification.Different way of purification and the solvent of employing is different, and the yield and purity of its purification is different.By the above results as can be seen that when being beaten purification, poor solvent is higher than good solvent, the yield of the purified product of good solvent-poor solvent and purity；Poor solvent purified product is all, beating is higher than the yield of recrystallization, higher than the purity of drip washing.
Embodiment
7
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ -4- fluorobenzonitriles（Compound III, R1For F）, 3.09g (R) -3- amino piperidines dihydrochloride and 10.40g potassium carbonate be dissolved in the mixed solution of 50ml isopropanols and 10ml water, stirring reaction 12h at being warming up to 55 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 5.41g of compound V, and yield is 88.91%, and purity is 96.50%.By the crude product ethyl alcohol recrystallization of compound V, filter, washing, dry sterling 4.79g of compound V, purification yield 88.54%.The total recovery 78.72% of compound V, purity 99.80%.
Embodiment
8
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ -4- fluorobenzonitriles（Compound III, R1For F）, 3.24g (R) -3- amino piperidines dihydrochloride and 7.94g sodium carbonate be dissolved in the mixed solution of 56ml isopropanols and 7ml water, heat up stirring reaction 14h at 65 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 5.19g of compound V, and yield is 85.30%, and purity is 96.40%.The crude product of compound V is dissolved in into a small amount of ethanol, adds trifluoroacetic acid acidifying, stirring to separate out crystal.Slurry is filtered, and is washed filter cake, is dried to obtain the trifluoroacetate 5.80g of compound V, purification yield 84.72%.The total recovery 72.27% of compound V, purity 99.60%.
Embodiment
9
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ -4- fluorobenzonitriles（Compound III, R1For F）, 2.95g (R) -3- amino piperidines dihydrochloride and 24.40g cesium carbonates be dissolved in the mixed solution of 30ml isopropanols and 30ml water, stirring reaction 12h at being warming up to 65 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 5.24g of compound V, and yield is 86.12%, and purity is 95.20%.By the crude product methanol of compound V and re-crystallizing in ethyl acetate, filter, washing, dry sterling 4.68g of compound V, purification yield 89.31%.The total recovery 76.91% of compound V, purity 99.90%.
Embodiment
10
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ benzonitrile（Compound III, R1For H）, 3.30g (R) -3- amino piperidines dihydrochloride and 8.00g triethylamines be dissolved in the mixed solution of 60ml isopropanols and 1ml water, stirring reaction 13h at being warming up to 60 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 5.23g of compound V, and yield is 84.97%, and purity is 95.80%.By the crude product recrystallisation from isopropanol of compound V, filter, washing, dry sterling 4.48g of compound V, purification yield 85.66%.The total recovery 72.79% of compound V, purity 99.50%.
Embodiment
11
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ benzonitrile（Compound III, R1For H）, 3.45g (R) -3- amino piperidines dihydrochloride and 14.80g tri-n-butylamines be dissolved in the mixed solution of 45ml isopropanols and 15ml water, stirring reaction 13h at being warming up to 60 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 5.26g of compound V, and yield is 85.46%, and purity is 95.50%.The crude product of compound V is dissolved in into a small amount of ethanol solution, adds hydrochloric acid acidifying, stirring to separate out crystal.Slurry is filtered, and is washed filter cake, is dried to obtain the hydrochlorate 4.89g of compound V, purification yield 83.95%.The total recovery 71.74% of compound V, purity 99.50%.
Comparative example
7
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ benzonitrile（Compound III, R1For H）, 3.14g (R) -3- amino piperidines dihydrochloride and 11.0g potassium carbonate be dissolved in the mixed solution of 60ml isopropanols and 4ml water, stirring reaction 40h at being warming up to 65 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 4.16g of compound V, and yield is 67.58%, and purity is 89.40%.By the crude product ethanol of compound V and the mixed solvent recrystallization of methanol, filter, washing, dry sterling 3.49g of compound V, purification yield 83.89%.The total recovery 56.69% of compound V, purity 99.40%.
Comparative example
8
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ -4- fluorobenzonitriles（Compound III, R1For F）, 3.24g (R) -3- amino piperidines dihydrochloride and 7.94g sodium carbonate be dissolved in the mixed solution of 54ml isopropanols and 6ml water, stirring reaction 36h at being warming up to 60 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 4.21g of compound V, and yield is 69.19%, and purity is 89.80%.The crude product of compound V is dissolved in into a small amount of THF solution, adds trifluoroacetic acid acidifying, stirring to separate out crystal.Slurry is filtered, and is washed filter cake, is dried to obtain the trifluoroacetate 4.73g of compound V, purification yield 85.17%.The total recovery 58.93% of compound V, purity 99.60%.
Comparative example
9
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ benzonitrile（Compound III, R1For H）, 3.14g (R) -3- amino piperidines dihydrochloride and 26.00g cesium carbonates be dissolved in the mixed solution of 20ml isopropanols and 40ml water, stirring reaction 42h at being warming up to 55 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 3.71g of compound V, and yield is 60.27%, and purity is 88.60%.By the crude product ethyl alcohol recrystallization of compound V, filter, washing, dry sterling 3.28g of compound V, purification yield 88.41%.The total recovery 53.28% of compound V, purity 99.50%.
Comparative example
10
By 5.0g 2- [(chloro- 3,4- dihydros -3- methyl -2 of 6-, 4- dioxo -1 (2H)-pyrimidine radicals) methyl ］ benzonitrile（Compound III, R1For H）, 3.45g (R) -3- amino piperidines dihydrochloride and 8.00g triethylamines be dissolved in the mixed solution of 10ml isopropanols and 50ml water, stirring reaction 48h at being warming up to 65 DEG C.Reaction is cooled to room temperature, is slowly added dropwise the mixed solution of 60ml acetonitriles and heptane, and drop to finish and stir 1h under ice bath, and sucking filtration obtains the crude product 3.49g of compound V, and yield is 56.70%, and purity is 88.20%.The crude product of compound V is dissolved in into a small amount of ethanol solution, adds hydrochloric acid acidifying, stirring to separate out crystal.Slurry is filtered, and is washed filter cake, is dried to obtain the hydrochlorate 3.24g of compound V, purification yield 83.83%.The total recovery 47.53% of compound V, purity 99.20%.
According to above-described embodiment, compound III prepare compound V, its response time, the product yield of crude product and purity affect such as following table with the volume ratio of solvent isopropyl alcohol and water：
When reaction dissolvent is isopropyl alcohol and water, and its volume ratio is 1-8:When 1, the response time shortens, and the yield and purity of crude product all improve a lot.With the raising of crude yield and purity, the yield and purity of its end-product sterling are also improved.
Claims (8)
1. a kind of purification process of dipeptidy peptidase in inhibitors intermediate, it is characterised in that comprise the following steps：
A. with compound ii in the basic conditions, reaction is obtained compound III crude product to compounds I；
B. carry out beating to compound III crude product with poor solvent to purify；
Wherein R1For F or H, R2For Br or Cl.
2. the purification process of dipeptidy peptidase in inhibitors intermediate according to claim 1, it is characterised in that poor solvent is ethyl acetate, isopropyl acetate, normal heptane, normal hexane, methyl tertiary butyl ether(MTBE), petroleum ether, n-butyl acetate, hexamethylene, one or more in ether.
3. the purification process of dipeptidy peptidase in inhibitors intermediate according to claim 2, it is characterised in that poor solvent is ethyl acetate.
4. the purification process of dipeptidy peptidase in inhibitors intermediate according to claim 1, it is characterised in that cleansing temp is 15-35 DEG C.
5. the purification process of dipeptidy peptidase in inhibitors intermediate according to claim 1, it is characterised in that the quality of compound III crude product is 1 with the volume ratio of poor solvent：2-10（g/ml）.
6. a kind of preparation method of dipeptidy peptidase in inhibitors, it is characterised in that comprise the following steps：
Compound III reacts in the basic conditions prepare compound V with compounds Ⅳ, and reaction dissolvent is isopropyl alcohol and water, wherein, the volume ratio of isopropyl alcohol and water is 1-8:1;R1For F or H.
7. the preparation method of dipeptidy peptidase in inhibitors according to claim 6, it is characterised in that the volume ratio of isopropyl alcohol and water is 5:1.
8. the preparation method of dipeptidy peptidase in inhibitors according to claim 6, it is characterised in that reaction temperature is 55-65 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109705089A (en) * | 2019-02-27 | 2019-05-03 | 浙江华贝药业有限责任公司 | The purification process of compound |
| CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
| CN111349075A (en) * | 2018-12-21 | 2020-06-30 | 浙江万晟药业有限公司 | Preparation method of trelagliptin succinate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
| CN101616673A (en) * | 2006-09-13 | 2009-12-30 | 武田药品工业株式会社 | 2-[6-(3-amino-piperadine-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl]-purposes of 4-fluoro-benzonitrile |
-
2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
| CN101616673A (en) * | 2006-09-13 | 2009-12-30 | 武田药品工业株式会社 | 2-[6-(3-amino-piperadine-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl]-purposes of 4-fluoro-benzonitrile |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111349075A (en) * | 2018-12-21 | 2020-06-30 | 浙江万晟药业有限公司 | Preparation method of trelagliptin succinate |
| CN109705089A (en) * | 2019-02-27 | 2019-05-03 | 浙江华贝药业有限责任公司 | The purification process of compound |
| CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
| CN109705089B (en) * | 2019-02-27 | 2020-04-10 | 浙江华贝药业有限责任公司 | Method for purifying compound |
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