CN105367470A - Method for preparing vildagliptin - Google Patents
Method for preparing vildagliptin Download PDFInfo
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- CN105367470A CN105367470A CN201510953331.1A CN201510953331A CN105367470A CN 105367470 A CN105367470 A CN 105367470A CN 201510953331 A CN201510953331 A CN 201510953331A CN 105367470 A CN105367470 A CN 105367470A
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- vildagliptin
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- acetonitrile
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- oily matter
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention discloses a method for preparing vildagliptin. A heterogeneous system which adopts cetonitrile a main solvent and based on potassium carbonate and iodate is adopted, two key fragments, namely, (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine and 3-amidogen-1-adamantanol are coupled, the vildagliptin is prepared, and the intermediate conversion rate and yield are both superior to those of the prior art. According to the method for preparing the vildagliptin, salt of iodide ions is adopted for activating chlorine in a reactant structure, and a phase transfer catalyst is selectively added to promote the effect of a heterogeneous reaction.
Description
Technical field
The present invention relates to pharmaceutical technology sectors, particularly relate to a kind of preparation method of Vildagliptin.
Background technology
Diabetes are the metabolic syndromes caused by the acting in conjunction of h and E factor, can cause the absolute and relative hyposecretion of human insulin, and cause sugar in body, protein, the metabolism disorders such as fat are a kind of chronic diseases very large to human health risk.
Vildagliptin (English: Vildagliptin), commodity are called Jia Weile, are a kind ofly to have selectivity, competitiveness, reversible DPP-4 (dipeptidyl peptidase-4) inhibitor class oral antidiabetic, are used for treating type ii diabetes.Be uniquely a kind of no matter can the material of glucagon suppression when hyperglycemia or hypoglycemia.
On September 28th, 2007, the Vildagliptin (vildagliptin, trade(brand)name: Galvus) of Novartis Co., Ltd obtains EU Committee's approval, goes on the market with Ireland in 27 European Union member countries and Norway.
Within 2011, ratify the compound preparation at Chinese import Vildagliptin tablet and Vildagliptin and N1,N1-Dimethylbiguanide.Galvus be in medicine of the same type unique one can with N1,N1-Dimethylbiguanide, the medicine of the antidiabetic drug conbined usage such as thiazole dioxane ketone.
Vildagliptin is that the researcher DdwinB.Villhauer of Novartis finds when research adamantane derivative in 1998.Chemistry (S)-1-by name [[(3-hydroxyl-1-amantadine) the is amino] ethanoyl] tetrahydro pyrrolidine-2-formonitrile HCN of Vildagliptin, molecular formula C17H25N3O2, relative molecular mass is 303.4.
Containing a hand-type carbon atom, the structure focusing on skeleton of its study on the synthesis work and the introducing of hand-type carbon atom in the chemical structure of Vildagliptin.Theoretical according to reverse reaction, Vildagliptin can be divided into two fragments to synthesize: (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine (compound 1) and 3-amino-1-adamantane alcohol (compound 2), reaction formula is as follows:
Summary of the invention
The object of the invention is the technological deficiency for existing in prior art, and a kind of preparation method of Vildagliptin of high yield is provided.
The technical scheme adopted for realizing object of the present invention is: a kind of preparation method of Vildagliptin, is characterized in that, comprises the following steps:
(1) 3-amino-1-adamantane alcohol, acid binding agent, phase-transfer catalyst are joined in acetonitrile, at 60 DEG C, slowly drip the solution of (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine to acetonitrile;
(2) react 6 hours under remaining on the temperature of 60 DEG C, filter, filtrate is spin-dried for, and obtains oily matter A;
(3) the oily matter A that step (2) obtains is added 300mL methylene dichloride, 100mL water, extracting and washing, organic phase is with after saturated common salt water washing, dry, filters, is spin-dried for, obtains oily matter B;
(4) obtain light yellow product after the oily matter B that step (3) obtains being carried out vacuum-drying, to obtain final product.
Preferably, described acid binding agent is salt of wormwood.
The cesium carbonate of 10% mol ratio is added, to improve the activity of acid binding agent in described salt of wormwood.
Preferably, described phase-transfer catalyst is tetrabutylammonium chloride, Tetrabutyl amonium bromide or tetrabutylammonium iodide.
Preferably, described acetonitrile solution also adds toluene, tetrahydrofuran (THF) (THF), dimethyl formamide (DMF) or methyl alcohol.
The feature of the preparation method of above-mentioned Vildagliptin is: use acetonitrile as primary solvent, salt of wormwood and salt compounded of iodine are main nonhomogeneous system, by (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine and two the critical segment couplings of 3-amino-1-adamantane alcohol, prepare Vildagliptin, converted rate and yield are all better than prior art; The preparation method of above-mentioned Vildagliptin uses the salt of iodide ion, the chlorine in activated reactant structure, and choosing promotes the effect of inhomogeneous reaction with phase-transfer catalyst.
The inventive principle of above-mentioned Vildagliptin preparation method uses salt of wormwood as acid binding agent (the optional cesium carbonate adding 0.1 mol ratio, to improve acid binding agent activity); Use KI or NaI as activator; Choosing adds tetrabutylammonium chloride/Tetrabutyl amonium bromide/tetrabutylammonium iodide as phase-transfer catalyst.Optimum condition uses salt of wormwood+tetrabutylammonium iodide system, and now tetrabutylammonium iodide is not only as phase-transfer catalyst, also provides iodide ion as activator.The solvent system of above-mentioned Vildagliptin preparation method, through screening, can be selected acetonitrile system, acetonitrile+toluene system, acetonitrile+THF system, acetonitrile+DMF system or acetonitrile+methanol system, preferably use acetonitrile system.
Present invention also offers a kind of technique preparing Vildagliptin intermediate 3-amino-1-adamantane alcohol, it is characterized in that comprising the following steps:
(1) sour A is poured in there-necked flask, drip water, under magnetic agitation, add amantadine hydrochloride in batches; Then reducing reacting liquid temperature is 0-5 DEG C;
(2) slowly drip sour B, dropping process keeps reacting liquid temperature to be 0-5 DEG C; Dropwise, keep thermotonus 2h, then raised temperature to 20 DEG C, continue reaction 12h;
(3) react complete, under ice-water bath, add alkali lye and regulate pH >=12; Filtering insolubles, filtrate concentrates;
(4) filtrate after step (3) is concentrated is placed in reflux in toluene 1.5h, gets supernatant liquor crystallization, suction filtration, after filtration cakes torrefaction and get final product.
Described sour A and sour B is combined as: the vitriol oil and nitrosonitric acid, concentrated nitric acid and oleum, sulfuric acid and nitric acid, oleum and nitrosonitric acid.
Preferably, being combined as of described sour A and sour B: the vitriol oil and nitrosonitric acid.
The alkali lye added in described step (3) is potassium hydroxide solution, sodium hydroxide solution, solution of potassium carbonate or sodium carbonate solution.
Preferably, the alkali lye added in described step (3) is potassium hydroxide solution.
This feature preparing the technique of 3-amino-1-adamantane alcohol is: pass through amantadine hydrochloride, use the sulfonitric system (vitriol oil-nitrosonitric acid, concentrated nitric acid-oleum, sulfonitric, oleum-nitrosonitric acid, preferred: the vitriol oil-nitrosonitric acid system), use lye pH adjustment controlled oxidization, oxidation step obtains 3-amino-1-adamantane alcohol; This preparation technology reacts fast, yield is high.
Present invention also offers the technique that one prepares Vildagliptin intermediate (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine, it is characterized in that comprising the following steps:
(1) by L-prolineamide, acid binding agent, join in solvent system, control temperature is at 0-15 DEG C and stir, and slowly drips chloroacetyl chloride;
(2), after dropwising, room temperature is returned to, and Keep agitation; After TLC point plate reacts completely, suction filtration, obtains filtrate;
(3) filtrate is stirred under the temperature condition of 0-15 DEG C, drips dewatering agent simultaneously; After dropwising at 25 DEG C Keep agitation;
(4) after TLC point plate reacts completely, be spin-dried for, then add ethyl acetate, continue to revolve to steam and take unnecessary dewatering agent out of; So repeated multiple times, residue is dissolved in ethyl acetate, is 8 by sodium carbonate solution adjust ph, organic phase saturated common salt water washing, with anhydrous sodium sulfate drying, filters, is spin-dried for, obtains oily matter;
(5) oily matter hold over night, obtains brown solid after solidification, is (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine crude product.
Solvent system in described step (1) be acetonitrile, acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and THF combination;
Preferably, described solvent system is acetonitrile.
Described acid binding agent is salt of wormwood, sodium carbonate or cesium carbonate.
Preferably, described acid binding agent is salt of wormwood.
Described dewatering agent is trifluoroacetic anhydride (TFAA) or phosphorus oxychloride.
Preferably, described dewatering agent is trifluoroacetic anhydride (TFAA).
Use acetonitrile as primary solvent system in the technique of preparation provided by the invention (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine, or use acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and THF combination solvent system; Carbonate is as acid binding agent; Trifluoroacetic anhydride (TFAA) or phosphorus oxychloride are as dewatering agent; With L-prolineamide for raw material sets out, through two-step reaction, (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine intermediate is somebody's turn to do in one kettle way preparation, and technique is convenient, and yield is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Embodiment 1:
A kind of preparation method of Vildagliptin, comprise the following steps: 3-amino-1-adamantane alcohol (20g, 0.120mol), salt of wormwood (20g, 0.464mol), tetrabutylammonium iodide (2g, cat) join in 150mL acetonitrile, (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine (20g is slowly dripped at 60 DEG C, 0.116mol) be dissolved in the solution (time for adding 2 ~ 3 hours) of 150mL acetonitrile, after dropwising, 60 DEG C are kept to react 6 hours, filter, filtrate is spin-dried for, obtain oily matter, add 300mL methylene dichloride, 100mL water, extracting and washing, organic phase is with after saturated common salt water washing, dry, filter, be spin-dried for, obtain oily matter, light yellow product 28g is obtained after vacuum-drying, purity 96%, yield: 80.2%.
Embodiment 2:
A kind of preparation method of Vildagliptin, comprise the following steps: 3-amino-1-adamantane alcohol (20g, 0.120mol), salt of wormwood (20g, 0.464mol), potassiumiodide (2g, cat) join in 150mLDMF, (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine (20g is slowly dripped at 60 DEG C, 0.116mol) be dissolved in the solution (time for adding 2 ~ 3 hours) of 150mL acetonitrile, after dropwising, 60 DEG C are kept to react 6 hours, filter, filtrate is spin-dried for, obtain oily matter, add 300mL methylene dichloride, 100mL water, extracting and washing, organic phase is with after saturated common salt water washing, dry, filter, be spin-dried for, obtain oily matter, light yellow product 25g is obtained after vacuum-drying, purity 98%, yield: 71.6%.
Present invention also offers a kind of process example preparing Vildagliptin intermediate 3-amino-1-adamantane alcohol:
The step of preparation 3-amino-1-adamantane alcohol is: pour in there-necked flask by the 46.94g vitriol oil, drip 0.7g water, adds amantadine hydrochloride 10g altogether under magnetic agitation in batches.Then reduce reacting liquid temperature to 0-5 DEG C, start slowly to drip 7.75g nitrosonitric acid, drip process heat release comparatively obvious, keep reacting liquid temperature 0-5 DEG C; Dropwise, after reaction solution reacts 2h at this temperature, then raised temperature to 20 DEG C, continue reaction 12h.
Reaction formula is:
React complete, under ice-water bath, 50%KOH solution adjust pH >=12, filtering insolubles, filtrate concentrate, a small amount of toluene band water, then by it in reflux in toluene 1.5h, get supernatant liquor crystallization, suction filtration, filtration cakes torrefaction obtains 8.2g crude product, and yield is 85%, and purity is 97.5%.
Present invention also offers the process example that one prepares Vildagliptin intermediate (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine:
By L-prolineamide (20g, 0.175mol), salt of wormwood (48g, 0.348mol) join in 400mL acetonitrile, 16mL (0.21mol) chloroacetyl chloride (time for adding 2-3 hour) is slowly dripped under 0-15 DEG C of stirring, after dropwising, recover stirred overnight at room temperature, after TLC point plate reacts completely, suction filtration, 13.4mL (0.094mol) TFAA is dripped under filtrate 0-15 DEG C of stirring, after dropwising, stir at 25 DEG C and spend the night, after TLC point plate reacts completely, be spin-dried for, then add 20mL ethyl acetate to continue to revolve to steam and take unnecessary TFAA out of, so 3 times repeatedly, residue is dissolved in 150mL ethyl acetate, be 8 by sodium carbonate solution adjust ph, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain oily matter, hold over night, solidification is not (if solidified, crystal seed slightly can be added) before leaving standstill, brown solid (compound 2) 12.2g, yield 92%.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a preparation method for Vildagliptin, is characterized in that, comprises the following steps:
(1) 3-amino-1-adamantane alcohol, acid binding agent, phase-transfer catalyst are joined in acetonitrile, at 60 DEG C, slowly drip the solution of (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine to acetonitrile;
(2) react 6 hours under remaining on the temperature of 60 DEG C, filter, filtrate is spin-dried for, and obtains oily matter A;
(3) the oily matter A that step (2) obtains is added 300mL methylene dichloride, 100mL water, extracting and washing, organic phase is with after saturated common salt water washing, dry, filters, is spin-dried for, obtains oily matter B;
(4) obtain light yellow product after the oily matter B that step (3) obtains being carried out vacuum-drying, to obtain final product.
2. the preparation method of a kind of Vildagliptin according to claim 1, is characterized in that described acid binding agent is salt of wormwood; The cesium carbonate of 10% mol ratio is added in described salt of wormwood.
3. the preparation method of a kind of Vildagliptin according to claim 1, is characterized in that described phase-transfer catalyst is tetrabutylammonium chloride, Tetrabutyl amonium bromide or tetrabutylammonium iodide.
4. the preparation method of a kind of Vildagliptin according to claim 1, is characterized in that described acetonitrile solution also adds and has toluene, tetrahydrofuran (THF), dimethyl formamide or methyl alcohol.
5. the preparation method of a kind of Vildagliptin according to claim 1, is characterized in that the technique preparing described 3-amino-1-adamantane alcohol, comprises the following steps:
(1) sour A is poured in there-necked flask, drip water, under magnetic agitation, add amantadine hydrochloride in batches; Then reducing reacting liquid temperature is 0-5 DEG C;
(2) slowly drip sour B, dropping process keeps reacting liquid temperature to be 0-5 DEG C; Dropwise, keep thermotonus 2h, then raised temperature to 20 DEG C, continue reaction 12h;
(3) react complete, under ice-water bath, add alkali lye and regulate pH >=12; Filtering insolubles, filtrate concentrates;
(4) filtrate after step (3) is concentrated is placed in reflux in toluene 1.5h, gets supernatant liquor crystallization, suction filtration, after filtration cakes torrefaction and get final product.
6. the preparation method of a kind of Vildagliptin according to claim 5, is characterized in that being combined as of described sour A and sour B: the vitriol oil and nitrosonitric acid, concentrated nitric acid and oleum, sulfuric acid and nitric acid, oleum and nitrosonitric acid.
7. the preparation method of a kind of Vildagliptin according to claim 5, is characterized in that the alkali lye added in described step (3) is potassium hydroxide solution, sodium hydroxide solution, solution of potassium carbonate or sodium carbonate solution.
8. the preparation method of a kind of Vildagliptin according to claim 1, it is characterized in that the technique preparing Vildagliptin intermediate (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine, comprise the following steps: (1) by L-prolineamide, acid binding agent, join in solvent system, control temperature is at 0-15 DEG C and stir, and slowly drips chloroacetyl chloride;
(2), after dropwising, room temperature is returned to, and Keep agitation; After TLC point plate reacts completely, suction filtration, obtains filtrate;
(3) filtrate is stirred under the temperature condition of 0-15 DEG C, drips dewatering agent simultaneously; After dropwising at 25 DEG C Keep agitation;
(4) after TLC point plate reacts completely, be spin-dried for, then add ethyl acetate, continue to revolve to steam and take unnecessary dewatering agent out of; So repeated multiple times, residue is dissolved in ethyl acetate, is 8 by sodium carbonate solution adjust ph, organic phase saturated common salt water washing, with anhydrous sodium sulfate drying, filters, is spin-dried for, obtains oily matter;
(5) oily matter hold over night, obtains brown solid after solidification, is (S)-1-(2-chloroacetyl chloride)-2-itrile group tetramethyleneimine crude product.
9. the preparation method of a kind of Vildagliptin according to claim 8, the solvent system that it is characterized in that in described step (1) is the combination of acetonitrile, acetonitrile and toluene, acetonitrile and DMF combination or acetonitrile and THF combination.
10. the preparation method of a kind of Vildagliptin according to claim 8, is characterized in that described acid binding agent is salt of wormwood, sodium carbonate or cesium carbonate.
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| CN201510953331.1A CN105367470A (en) | 2015-12-15 | 2015-12-15 | Method for preparing vildagliptin |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045891A (en) * | 2016-07-05 | 2016-10-26 | 天津民祥生物医药股份有限公司 | Process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine |
| CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
| CN112250594A (en) * | 2020-10-19 | 2021-01-22 | 浙江荣耀生物科技股份有限公司 | Method for preparing 3-acetamido-1-adamantanol |
| CN112939837A (en) * | 2021-02-03 | 2021-06-11 | 海南通用三洋药业有限公司 | Method for preparing vildagliptin through multiphase compound continuous production |
-
2015
- 2015-12-15 CN CN201510953331.1A patent/CN105367470A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045891A (en) * | 2016-07-05 | 2016-10-26 | 天津民祥生物医药股份有限公司 | Process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine |
| CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
| CN112250594A (en) * | 2020-10-19 | 2021-01-22 | 浙江荣耀生物科技股份有限公司 | Method for preparing 3-acetamido-1-adamantanol |
| CN112250594B (en) * | 2020-10-19 | 2023-09-12 | 浙江荣耀生物科技股份有限公司 | Method for preparing 3-acetamido-1-adamantanol |
| CN112939837A (en) * | 2021-02-03 | 2021-06-11 | 海南通用三洋药业有限公司 | Method for preparing vildagliptin through multiphase compound continuous production |
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