CN105418580A - New trelagliptin preparation process - Google Patents

New trelagliptin preparation process Download PDF

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Publication number
CN105418580A
CN105418580A CN201410462005.6A CN201410462005A CN105418580A CN 105418580 A CN105418580 A CN 105418580A CN 201410462005 A CN201410462005 A CN 201410462005A CN 105418580 A CN105418580 A CN 105418580A
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compound
acid
lieting
bent
organic solvent
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陈武
刘相奎
季宗德
朱雪焱
袁哲东
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The present invention provides a trelagliptin preparation process, which comprises that: 1) a compound 4 and a compound 5 are adopted as raw materials, and are subjected to a condensation reaction in an organic solvent in the presence of an alkali to obtain a compound 6; 2) the compound 6 reacts with an acid HA in an organic solvent to remove the t-butyloxy carbonyl so as to obtain a trelagliptin.HA salt; and 3) the trelagliptin.HA salt is subjected to alkali neutralization treatment and purification to obtain the trelagliptin, wherein the reaction route is defined in the specification. According to the present invention, in the improved preparation process, the 2-site amino of the compound 5 is protected by the t-butyloxy carbonyl, such that the selectivity of the nucleophilic substitution reaction is improved, and the impurity production caused by primary amine substitution is avoided so as to improve the nucleophilic substitution yield and improve the trelagliptin purity.

Description

Prepare the novel process of bent Ge Lieting
Technical field
The invention belongs to chemicals synthesis field, the new preparation process being specifically related to the bent Ge Lieting of a kind of ofhypoglycemic medicine and the new intermediate obtained in this new preparation process.
Background technology
Diabetes (DiabetesMellitus, DM) are a kind of metabolic diseases of multi-pathogenesis, are because the absolute of Regular Insulin or relative deficiency cause blood sugar increasing and cause organism metabolic disorder.It can be divided into insulin-dependent diabetes mellitus (insulindependentdiabetesmellitus, IDDM, also referred to as insulin-dependent diabetes mellitus (IDDM)) and non insulin dependent diabetes (non ?insulindependentdiabetesmellitus, NIDDM, also referred to as type II diabetes), wherein type II diabetes is the most common, accounts for more than 90% of diabetic.
DPP IV (DPP ?IV) is a kind of serine protease, and it has expression in a lot of tissue in vivo, as intestines, liver, lung, kidney etc., and in T lymphocyte in circulation.It is responsible for the metabolic cleavage of some endogenous peptide (GLP ?1 (7 ?36), hyperglycemic-glycogenolytic factor) in body, and the verified protein decomposing activity having external antagonism other peptide multiple (GHRH, NPY, GLP ?2, VIP).
GLP ?1 (7 ?36) be a kind of peptide be made up of 30 amino acid, derived by the post translational processing process of front glucagon in small intestine.GLP ?1 (7 ?36) there is effect in multiple body, comprise and stimulate insulin secretion, suppress glucagon to secrete, promote satiety and delay stomach emptying etc.Based on its physiology behavior, believe GLP ?the effects beneficial of I (7 ?36) in prevention and therapy type ii diabetes and obesity.Such as, have been found that GLP ?the exogenous administration of 1 (7 ?36) in diabetic subject (inputting continuously) be effective to this kind of patient group.Unfortunately, GLP ?1 (7 ?36) degrade rapidly in vivo, there is the very short transformation period ((t1/2<1.5min).The DPP cultivated based on heredity ?IV reject the research of mouse and selective d PP ?IV inhibitor body in/in vitro study, shown DPP ?IV be in body GLP ?the primary degrading enzyme of 1 (7 ?36).GLP ?1 (7 ?36) by DPP ?IV efficient degradation be GLP ?1 (9 ?36), the latter by supposition serve as GLP ?the physiological antagonist of 1 (7 ?36).Therefore believe in body suppress DPP ?IV can be used for strengthening endogenous GLP ?1 (7 ?36) level and weaken its antagonist GLP ?the generation of 1 (9 ?36).DPP ?IV inhibitor available treatment by DPP ?IV mediate illness or prevention, delay its progress, these illnesss as diabetes, especially type II diabetes.
Bent Ge Lieting is the effective DPP IV of one (the DPP ?4) inhibitor of Japanese Takede Chemical Industries Ltd exploitation, suppresses DPP ?4, control glucose level by selectivity, persistence.The submission of bent Ge Lieting new drug application, is based on the efficacy and saferry data of the several III clinical trial phases carried out in Japanese patients with NIDDM.The curative effect of bent Ge Lieting all obtains confirmation in all tests, has good security and tolerance simultaneously.Bent Ge Lieting Per-Hop behavior once just effectively can control glucose level, is expected to the compliance improving patient.It is reported, DPP ?the novel type II diabetes medicine of 4 inhibitor to be first classes by improving body self-ability control glucose level, can be used as single medicine, also can with other oral antidiabetic drug coupling.Its mechanism of action is unique, has not produce hypoglycemia, do not cause body weight to increase, and the unique advantage such as side effect is little, causes the incidence of gastrointestinal side effect also very low.Bent Ge Lieting, chemical name: 2 ?[{ 6 ?[(3R) ?3 ?ammonia base piperazine pyridine ?1 ?yl] ?3 ?first base ?2,4 ?bis-oxygen for ?3,4 ?bis-hydrogen phonetic pyridine ?1 (2H) ?yl } methyl] ?4 ?fluorine ?benzyl cyanogen; Chemical formula: C 18h 20fN 5o 2.C 4h 6o 4; No. CAS be 865759 ?25 ?7.Its structural formula is as follows:
The method preparing bent Ge Lieting is disclosed, shown in following route in Chinese patent CN102675221:
In above-mentioned route, starting raw material 2 ?Xiu ?5 ?toluene fluoride (1) in DMF, under the effect of cuprous cyanide, directly there is nucleophilic substitution reaction, replace bromine by cyano group and obtain compound 2, yield is 60%.Compound 2 in CCl4 at reflux with AIBN (Diisopropyl azodicarboxylate) for initiator, under the effect of NBS (N-bromo-succinimide), there is benzyl position bromine substitution reaction obtain compound 3.Thick product 3 is without to be further purified directly and 3-methyl-6-chloro uridylic generation substitution reaction obtains compound 4, and yield is 60%.Compound 4 obtains the bent Ge Lieting of compound again in EtOH under 100 DEG C of conditions with 2 ?amido piperidine hydrochlorate generation nucleophilic substitution reactions.Prepare the total recovery of bent Ge Lieting about 17% by this synthesis technique, yield is lower.In the final step nucleophilic substitution reaction of this route, due to 2 ?in amido piperidine hydrochlorate structure simultaneously with primary amine and secondary amine, the product of the nucleophilic substitution of two kinds of different positionss is generated in reaction, thus causing the bent Ge Lieting purity of order mark product thing ? not high, needs preparation liquid phase is further purified process just can obtain highly purified applicable medicinal bent Ge Lieting.Therefore, for this route, in the urgent need to finding the higher technique being more suitable for the bent Ge Lieting of industrial preparation or its salt of yield; Especially need to find the technique improving final step.
Summary of the invention
The invention provides a kind of bent Ge Lieting preparation technology newly, comprise step:
1) compound 5 and compound 4 are raw material, in organic solvent and under alkali existence condensation reaction occur, obtain compound 6,
2) compound 6 is in organic solvent, reacts remove tertbutyloxycarbonyl with sour HA, obtains bent Ge Lieting .HA salt,
3) bent Ge Lieting .HA salt is through alkali neutralizing treatment and purification operations, obtains bent Ge Lieting; Reaction scheme is shown in following:
In step 1) in, the organic solvent used has no particular limits, and object is to dissolve above-claimed cpd, and described organic solvent comprises sulfone and sulfoxide, preferred methyl-sulphoxide, tetramethylene sulfone; Alcoholic solvent, preferred alcohol, Virahol; Amide solvent, preferred N, N ?dimethyl formamide, N, N ?N,N-DIMETHYLACETAMIDE, ether solvent, excellent dioxane; Nitrile solvents, preferred acetonitrile.
In step 1) in, described alkali comprises mineral alkali and organic bases, and mineral alkali is selected from sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate or magnesiumcarbonate, preferred sodium bicarbonate, salt of wormwood; The preferred tri-n-butylamine of organic bases, triethylamine.
In step 1) in, suitable temperature of reaction be 50 DEG C ?100 DEG C.
In step 2) in, described organic solvent comprises draws together sulfone and sulfoxide, alcoholic solvent, amide solvent, ether solvent.Preferred alcohols kind solvent and ether solvent, preferred alcohol in alcoholic solvent, Virahol, preferred tetrahydrofuran (THF) in ether solvent.
In step 2) in, described acid comprises organic acid and mineral acid, and mineral acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, preferred hydrochloric acid; Organic acid comprises acetic acid, Phenylsulfonic acid, tosic acid, toxilic acid, succsinic acid, phenylformic acid, preferred tosic acid.
In step 3) in, described alkali neutralizing treatment and purification operations are by step 2) the bent Ge Lieting .HA salt that obtains is placed in water and organic solvent, adds alkali, and stirrings, separatory, extraction, concentrate and obtain bent Ge Lieting.
Bent Ge Lieting is prepared, in a preferred embodiment, step 2 by above-mentioned technique) the bent Ge Lieting .HA salt that obtains is without any separating-purifying process, directly the reaction solution containing bent Ge Lieting .HA salt is added alkali, stir, separatory, extract, concentrate and obtain bent Ge Lieting.
By above-mentioned technique, as bent Ge Lieting .HA salt prepared by needs, then only need to carry out above-mentioned steps 1) and step 2) operation step.
Therefore, on the other hand, present invention also offers a kind of bent Ge Lieting preparation technology .HA salt newly, comprise step:
1) compound 5 and compound 4 are raw material, under existing in organic solvent, condensation reaction occurs, obtain compound 6 with alkali,
2) compound 6 in organic solvent, reacts remove tertbutyloxycarbonyl with sour HA, and obtain bent Ge Lieting .HA salt, wherein the reaction conditions of step 2 and step 3 is same as above.
On the other hand, by the new preparation process of above-mentioned bent Ge Lieting, present invention also offers new compound 6.
In preparation technology of the present invention; compound 4 and 2 ?the primary amine group on amino piperidine is first optionally protected with tertbutyloxycarbonyl before amino piperidine structure generation nucleophilic substitution; so can improve the selectivity of nucleophilic substitution reaction; avoid primary amine to occur replace and produce impurity; and then improve the yield of nucleophilic substitution, also improve the purity of bent Ge Lieting.It also avoid original text offers in CN102675221 technique simultaneously, due to most product purity not high and need with preparation liquid phase come this of purifying loaded down with trivial details, the aftertreatment that is unfavorable for the large production of technology.
Following abbreviations has following implication in patent specification full text of the present invention: g (gram); Mg (milligram); L (liter); ML (milliliter); M (volumetric molar concentration); MM (millimolar concentration); Hz (hertz); MHz (megahertz); Mmol (mmole); Mol (mole); Min (minute); H (hour); TLC (tlc); RT (room temperature); MeOH (methyl alcohol); EtOH (ethanol); EtOAc (ethyl acetate); DCM (methylene dichloride); THF (tetrahydrofuran (THF)); DMSO (methyl-sulphoxide); DMF (DMF); DMAc (N,N-dimethylacetamide); CuCN (cuprous cyanide); NBS (N-bromo-succinimide); AIBN (Diisopropyl azodicarboxylate); CCl 4(tetracol phenixin); K 2cO 3(salt of wormwood); Na 2cO 3(sodium carbonate); NaHCO 3(sodium bicarbonate); MgSO 4(magnesium sulfate).
By the following examples to illustrate the present invention further; It should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise, can also make some improvements and modifications, these improvements and modifications also should be considered within the scope of protection of the present invention.
Embodiment
If no special instructions, the reagent used in the embodiment of the present invention and solvent commercially obtain, according to reaction needed, and unprocessed or use after suitably processing.
the synthesis (with reference to Chinese patent CN102675221) of embodiment 1, compound 4:
Step 1. prepares the fluoro-2-methyl-benzonitrile of 4-(compound 2)
By bromo-for 2-5-toluene fluoride (35g, 185mmol) with CuCN (20g, mixture 220mmol) in DMF (500mL) refluxes 24 hours, dilute with water reacts and uses hexane extraction, by the dry organic phase of MgS04 also except desolventizing obtains product 2 (yield 60%).1H-NMR(400MHz,CDC13):s7.60(dd,J＝5.6,8.8Hz，1H)，6.93-7.06(m,2H)，2.55(s，3H)。Step 2. prepares 2-brooethyl-4-fluorine benzonitrile (compound 3)
Under nitrogen protection by compound 2 (20g, 148mmol), NBS (26.4g, 150mmol) and AIBN (1g) mixture in CCl4 refluxes 2 hours, and reaction is cooled to room temperature.Solids removed by filtration, concentrated organic solution, obtains the crude product of oily, uses it in next step under not being further purified.1H-NMR(400MHz,CDC13):s7.68(dd,J＝5.2,8.4Hz,1H)，7.28(dd,J＝2.4,8.8Hz,1H)，7.12(m,1H)，4.6(s，2H)。
Step 3. prepares 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-(compound 4)
At 60 DEG C by 3-methyl-6-chloro uridylic (12g, 76mmol), compound 3 (17.2g, 80mmol) and K2CO3 (10g, mixture 80mmol) in DMSO (100mL) stirs 2 hours, and dilute with water reaction also extracts with EtOAc.By the dry organic phase of MgSO4 and except desolventizing.Column chromatography eluting acquisition product 4,13.2g (yield is 60%).1H-NMR(400MHz,CDC13):δ.7.73(dd,J＝7.2,8.4Hz,1H)，7.26(d,J-4.OHz,1H)，7.11-7.17(m,1H)，6.94(dd,J＝2.0,9.OHz，1H)，6.034(s，2H)，3.39(s，3H)。MS(ES)[m+H]294。
embodiment 2, prepare compound 6
By compound 4 (7.5g, 25.5mmol), 2-t-butoxycarbonyl amino piperidines (compound 5,7.3g, 36.5mmol) and NaHCO 3(7.3g, 36.5mmol) joins in EtOH (120ml), stirs 4.5h at reflux, after having reacted, and filtering NaHCO 3water (100ml) is at room temperature dripped with the NaCl generated, separate out a large amount of solid, continue to stir 2h, suction filtration under ice bath, solid use water (50ml) drip washing, obtains the compound 69.7g (yield 83%) of faint yellow solid after drying.1H-NMR(400MHz,DMSO+D 2O):δ：7.96-7.92(dd,J＝8.0,8.0Hz,1H),7.34-7.29(m,1H),7.23-7.20(d,J＝12.0Hz,1H),6.86-6.84(d,J＝8.0Hz,1H),5.32(s,1H),5.12(S,2H),3.09(s,3H),3.05-3.02(d,J＝12.0,1H),2.95-2.92(d,J＝12.0,1H),2.70-2.62(m,1H),2.39(s,1H),1.74(s,2H),1.38(s,3H),1.32(s,9H)。MS(ES)[m+H]458。
embodiment 3, prepare compound 6
By compound 4 (1.0g), compound 5 (0.77g) and K 2cO 3(0.93g) join in DMAc (10ml), 2h is reacted under being warming up to 50 DEG C of conditions, at room temperature drip water (20ml) after reacting completely and separate out a large amount of solid, continue to stir 2h under ice bath, suction filtration, solid 10ml water wash, obtains the compound 61.1g (yield 70%) of faint yellow solid after drying.
embodiment 4, prepare compound 6
By compound 4 (1.0g), compound 5 (0.77g) and K 2cO 3(0.95g) join in DMF (10ml), 2h is reacted under being warming up to 75 DEG C of conditions, at room temperature drip water (20ml) after having reacted and separate out a large amount of solid, continue to stir 2h under ice bath, suction filtration, solid 10ml water wash, obtains the compound 61.0g (yield 63%) of faint yellow solid after drying.
embodiment 5, prepare compound 6
By compound 4 (1.0g), compound 5 (0.77g) and K 2cO 3(0.93g) join in DMSO (10ml), 100min is reacted under being warming up to 50 DEG C of conditions, at room temperature drip water (20ml) after having reacted and separate out a large amount of solid, continue to stir 2h under ice bath, suction filtration, solid 10ml water wash, obtains the compound 60.8g (yield 50%) of faint yellow solid after drying.
embodiment 6, prepare compound 6
By compound 4 (0.5g), compound 5 (0.5g) and NaHCO 3(0.93g) join in EtOH (5ml), 2h is reacted under 100 DEG C of conditions, at room temperature drip water (10ml) after having reacted and separate out a large amount of solid, continue to stir 2h under ice bath, suction filtration, solid 10ml water wash, obtains the compound 61.2g (yield 75%) of faint yellow solid after drying.
embodiment 7, prepare compound 6
By compound 4 (0.5g), compound 5 (0.5g) and NaHCO 3(0.93g) 1 is joined, in 4-dioxane (5ml), 2h is reacted under being warming up to 101 DEG C of conditions, at room temperature drip water (10ml) after having reacted and separate out a large amount of solid, continue to stir 1.5h under ice bath, suction filtration, solid 10ml water wash, obtains the compound 60.9g (yield 56%) of faint yellow solid after drying.
embodiment 8, prepare compound 6
By compound 4 (0.5g), compound 5 (0.5g) and NaHCO 3(0.93g) join in acetonitrile (5ml), 2h is reacted under being warming up to reflux conditions, at room temperature drip water (10ml) after having reacted and separate out a large amount of solid, continue to stir 1.5h under ice bath, suction filtration, solid 10ml water wash, obtains faint yellow solid I 0.8g (yield 50%) after drying.
embodiment 9, prepare compound 6
By compound 4 (0.5g), 1-1 (0.5g) and tri-n-butylamine (0.6ml) join in ethanol (5ml), 2h is reacted under being warming up to reflux conditions, at room temperature drip water (10ml) after having reacted and separate out a large amount of solid, continue to stir 1.5h under ice bath, suction filtration, solid 10ml water wash, obtains faint yellow solid compound 60.9g (yield 56%) after drying.
embodiment 10, prepare bent Ge Lieting
Compound 6 (1.0g, 2.2mmol) is dissolved in THF (10ml), at room temperature drips 6M hydrochloric acid (15ml, 90mmol), at room temperature continue after dropwising to stir 1.5h, be cooled to 0 DEG C, filter, dry and obtain bent Ge Lieting hydrochloride 0.8g.Thick for the hydrochloride obtained product is dissolved in 30ml water, with potash solid, the aqueous solution is adjusted pH>9.Aqueous phase methylene dichloride/Virahol (3/1) mixed extractant solvent (50mlx4).Merge organic layer saturated common salt washing (150mlx2), after anhydrous sodium sulfate drying, concentrate to obtain pale yellow oil product.Under oil product ice bath, cooling leaves standstill has the precipitation of a large amount of white solid to obtain bent Ge Lieting 0.7g (yield 90%) of white solid product.1H-NMR(400MHz,DMSO+D2O):δ.7.95-7.93(dd,J＝8.0,8.0Hz,1H),7.36-7.32(m,1H),7.19-7.16(d,J＝12.0Hz,1H),5.32(s,1H),5.17-5.08(m,2H),3.07(s,3H),3.04(s,1H),2.90-2.89(d,J＝4Hz,1H),2.87(s,1H),2.60-2.55(t,J＝8Hz,12Hz,1H),2.45-2.40(t,J＝8Hz,12Hz,1H),1.81-1.78(m,1H),1.68-1.64(m,1H),1.46-1.37(m,1H),1.19-1.17(d,J＝8Hz,1H)MS(ES)[m+Na]380。
embodiment 11, prepare bent Ge Lieting
Compound 6 (2g) is dissolved in THF (20ml), add concentrated hydrochloric acid (5.6ml), at room temperature stir 1h, after having reacted, THF is steamed, add 50ml water, with potash solid, the aqueous solution is adjusted pH>9.Aqueous phase methylene dichloride/Virahol (3/1) mixed extractant solvent (50mlx4).Merge organic layer saturated common salt washing (100mlx2), after anhydrous sodium sulfate drying, concentrate to obtain pale yellow oil product.Under oil product ice bath, cooling leaves standstill has a large amount of white solid to separate out, and obtains bent Ge Lieting 1.1g (73%) of white solid product.
embodiment 12, prepare bent Ge Lieting
Compound 6 (2g) is dissolved in ethanol (20ml), at room temperature slowly add tosic acid monohydrate (1.4g), continue to stir under reaction being warming up to after adding reflux state, a large amount of solid is had to separate out in reaction process, 0 DEG C is cooled to after having reacted, filtration drying obtains tosilate 11.8g and adds 50ml water, with potash solid, the aqueous solution is adjusted pH>9.Aqueous phase methylene dichloride/Virahol (3/1) mixed extractant solvent (50mlx4).Merge organic layer saturated common salt washing (100mlx2), after anhydrous sodium sulfate drying, concentrate to obtain pale yellow oil product.Under oil product ice bath, cooling leaves standstill has a large amount of white solid to separate out, and obtains bent Ge Lieting 1.2g (80%) of white solid product.

Claims (8)

1. a preparation technology of bent Ge Lieting, comprises the following steps:
1) compound 5 and compound 4 are raw material, in organic solvent and under alkali existence condensation reaction occur, obtain compound 6,
2) compound 6 is in organic solvent, reacts remove tertbutyloxycarbonyl with sour HA, obtains bent Ge Lieting .HA salt,
3) bent Ge Lieting .HA salt is through alkali neutralizing treatment and purification operations, obtains bent Ge Lieting; Reaction scheme is shown in following:
2. preparation technology according to claim 1, is characterized in that, described step 1) described in alkali be selected from sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate, magnesiumcarbonate, tri-n-butylamine or triethylamine; Described organic solvent is selected from sulfone, sulfoxide, alcohols, amides, ethers and nitrile solvents.
3. preparation technology according to claim 2, is characterized in that, described step 1) described in alkali be selected from sodium bicarbonate, salt of wormwood, tri-n-butylamine or triethylamine; Described organic solvent be selected from methyl-sulphoxide, tetramethylene sulfone, ethanol, Virahol, N, N ?dimethyl formamide, N, N ?N,N-DIMETHYLACETAMIDE, dioxane, acetonitrile; State step 1) temperature of reaction be 50 DEG C ?100 DEG C.
4. preparation technology according to claim 1, is characterized in that, described step 2) described in alkali be selected from sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate, magnesiumcarbonate, tri-n-butylamine or triethylamine; Described organic solvent is selected from sulfone, sulfoxide, alcohols, amides, ethers and nitrile solvents.
5. preparation technology according to claim 1, is characterized in that, described step 2) described in acid be selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, Phenylsulfonic acid, tosic acid, toxilic acid, succsinic acid, phenylformic acid; Organic solvent is selected from sulfone, sulfoxide, alcohols, amides and ether solvent.
6. preparation technology according to claim 5, is characterized in that, described step 2) described in acid be selected from hydrochloric acid or tosic acid; Organic solvent is selected from ethanol, Virahol or tetrahydrofuran (THF).
7. preparation technology according to claim 1, it is characterized in that, described step 2) described in alkali neutralizing treatment and purification operations be by step 2) the bent Ge Lieting .HA salt that obtains is placed in water and organic solvent, adds alkali, stirrings, separatory, extraction, concentrate and obtain bent Ge Lieting.
8. by claim 1 ?preparation technology described in 7 any one, the compound 6 prepared, structural formula is shown in following:
CN201410462005.6A 2014-09-11 2014-09-11 New trelagliptin preparation process Pending CN105418580A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008459A (en) * 2016-08-05 2016-10-12 平原县四环药业有限公司 Trelagliptin preparation method
CN107778281A (en) * 2016-08-26 2018-03-09 扬子江药业集团江苏紫龙药业有限公司 One koji Ge Lieting process for purification

Citations (2)

* Cited by examiner, † Cited by third party
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
CN103819450A (en) * 2014-01-25 2014-05-28 浙江永宁药业股份有限公司 Novel method for preparing alogliptin benzoate

Patent Citations (2)

* Cited by examiner, † Cited by third party
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
CN103819450A (en) * 2014-01-25 2014-05-28 浙江永宁药业股份有限公司 Novel method for preparing alogliptin benzoate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008459A (en) * 2016-08-05 2016-10-12 平原县四环药业有限公司 Trelagliptin preparation method
CN106008459B (en) * 2016-08-05 2018-07-13 山东四环药业股份有限公司 The preparation method of one koji Ge Lieting
CN107778281A (en) * 2016-08-26 2018-03-09 扬子江药业集团江苏紫龙药业有限公司 One koji Ge Lieting process for purification
CN107778281B (en) * 2016-08-26 2020-06-30 扬子江药业集团江苏紫龙药业有限公司 Refining method of trelagliptin

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