CN108178761A - A kind of synthetic method of Xi Gelieting - Google Patents
A kind of synthetic method of Xi Gelieting Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of Xi Gelieting, including formula IV compound, (R) (+) t-butyl sulfonamide, hydrogen are carried out that Formula V compound is obtained by the reaction under catalyst；Then Formula V compound is obtained into Formula IV compound, i.e. Xi Gelieting by hydrolysis.Method raw material provided by the invention is easy to get, and step is simple, and yield is higher, and reaction condition is mild, suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of synthetic method of Xi Gelieting.
Background technology
The chemical name of Xi Gelieting is 7- [(3R) -3 amino -1- oxos -4- (2,4,5- trifluorophenyl) butyl] -5,6,
7,8- tetrahydrochysene -3- Trifluoromethyl-1s, 2,4- triazols [4,3-a] pyrazine, is a kind of oral DPP-IV inhibitor, for treating
Type-2 diabetes mellitus.Xi Gelieting is best-selling kind, 2015, Januvia and Janumet were total in granted listing in 2006
Sales volume is the first big kind in DPP-IV inhibitor up to 62.9 hundred million dollars.
Initial Merck ＆ Co., Inc. has just applied for the preparation method patent CN1761642 of the compound, which disclose with 2,
4,5- trifluorophenyl acetic acid are starting material, react to form corresponding enol class chemical combination with malonic acid ring (Asia) isopropyl ester first
And then object carries out substitution with corresponding Pyrazine intermediate and prepares 1,3- diones intermediates with decarboxylic reaction, passes through later
The enamine of carbonyl obtains, and obtains product Xi Gelieting finally by asymmetric reduction, sees route one.This method is in enamine chemical combination
It needs to use complicated and expensive rhodium complex and ligand compound, while the starting that this method uses in the asymmetric reduction of object
Raw material 2,4,5- trifluorophenyl acetic acid are also more expensive, these limit the industrial prospect of this method.
In many years later, the foundation of the chiral centre of Xi Gelieting is all the key point of research, has developed packet
Include chiral induction, asymmetry catalysis and many methods split.In comparison, asymmetry catalysis is typically all to need costliness
Metal and ligand are unfavorable for industrializing；The method of fractionation can slattern the isomers of half, increase production cost.Meanwhile recently
Also disclose that the new method of much structures for Xi Gelieting mother nucleus structures.
CN106146514 discloses one kind using itaconic acid as raw material, and by condensation, coupling, asymmetric reduction is halogenated, ammonia
Base (sodium azide is raw material), de- Boc protect to obtain corresponding Xi Gelieting compounds (see route two).This method is not right
Claim to use complicated iron complex in reduction, increase the cost of reaction.Meanwhile it is used in the synthesis of compound 2-6 folded
Nitrogen compound so that the technics comparing is dangerous, is not suitable for industrialized production.
In addition to this, CN 105017099 and Tetrahedron, 28 (1), 34-40,2017 disclose with 2,4,5- trifluoros
Ethylalbenzene is starting material, first with (R)-(+)-t-butyl sulfonamide condensation corresponding imine compound of synthesis, is connect
Get off through asymmetric addition, decarboxylation, hydrolyze, condensation, hydrolysis obtains corresponding Xi Gelieting compounds (see route three).The party
Method is there are step is longer, yield is relatively low, raw material is more expensive, the defects of preparing more complicated and yield bottom again, limits to a certain extent
The industrial applications of this method.
WO2011142825 disclose it is a kind of through formula IV compound and (R)-(+)-t-butyl sulfonamide by enamine, also
Original, splits, and the process of hydrolysis prepares corresponding Xi Gelieting compounds, sees route four.But this method is needed through fractionation
Method obtains the intermediate of single chiral, this is a greatly waste, and right for resource for industrial production
In formula IV compound synthesis there is also expensive starting materials, the problem of step is more.
Invention content
Goal of the invention：In order to solve the above-mentioned problems in the prior art, the present invention provides a kind of Xi Gelieting's
Synthetic method, this method can be avoided using expensive raw material, be avoided using toxic hazardous chemical, and reaction is mild, economy
Environmentally friendly, simple for process and yield is higher, suitable for industrialized production.
Technical solution：The synthetic method of Xi Gelieting of the present invention, includes the following steps：
(1) formula IV compound, (R)-(+)-t-butyl sulfonamide, hydrogen are obtained by the reaction under catalyst
Formula V compound；
(2) Formula V compound is obtained into Formula IV compound, i.e. Xi Gelieting by hydrolysis,
In step (1), which is the reductive amination process that compound IV is carried out with (R)-(+)-t-butyl sulfonamide.
Formula IV compound and the molar ratio of (R)-(+)-t-butyl sulfonamide are 1.0: (1.0-2.5), preferably 1: 1.05；The catalysis
Agent is platinum dioxide, and the dosage of the platinum dioxide is the 1%-10% of formula IV compound by weight, preferably 2%；The reaction is hydrogen
Change reaction, the pressure of hydrogen in reaction is 3-8bar, preferably 6bar.
In step (1), reaction dissolvent is tetrahydrofuran, ether, dioxane, one kind in glycol dimethyl ether or several
Kind, preferably tetrahydrofuran；Reaction temperature is -5 DEG C -5 DEG C, preferably 0 DEG C；Reaction time is 4-6h.
Step (2) carries out in acid condition, and the acid is hydrochloric acid, hydrobromic acid, one or more of sulfuric acid, preferably
Hydrochloric acid, i.e., using aqueous hydrochloric acid solution as reaction dissolvent.A concentration of 3-7M, preferably 5M of acid；Reaction temperature is 50 DEG C -90 DEG C, excellent
Select 70 DEG C；Reaction time is 1-3h.
In step (1), the formula IV compound is prepared by following methods：
(1-1) by 2,4,5- trifluorobromobenzene of compound of formula I and diethyl malonate be obtained by the reaction Formula II compound 4- (2,4,
5- trifluorophenyls) ethyl butyrate -3- ketone；
(1-2) is by Formula II compound 4- (2,4, the 5- trifluorophenyl) ethyl butyrate -3- ketone and the formula III compound
3- (trifluoromethyl) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazol [4,3-a] pyrazine occur substitution reaction and obtain formula IV compound,
In step (1-1), Liv Ullmann coupling reaction of the reaction between halogenated aryl hydrocarbon and active methylene group uses catalysis
Agent, ligand, alkali participate in reaction.It is reacted using catalyst, the catalyst is cuprous iodide.Using ligand assisted reaction,
The ligand is one or more of L-PROLINE, 2- pyridine carboxylic acids, 2-piperidinecarboxylic acid, preferably L-PROLINE；Addition alkali pushes away
The progress of dynamic reaction, the alkali are one or more of cesium carbonate, potassium phosphate, sodium methoxide, sodium hydride, preferably potassium phosphate；Formulas I
Compound and the molar ratio of diethyl malonate are 1.0: (2.1-5.0), preferably 1.0: 3.0；Compound of formula I and catalyst rub
You are than being 1.0: (0.05-0.3), preferably 1.0: 0.10；Compound of formula I and the molar ratio of ligand are 1.0: (0.05-0.6), it is excellent
Select 1.0: 0.2；Compound of formula I and the molar ratio of alkali are 1.0: (2.5-5.0), preferably 1.0: 3.5.
In step (1-1), one or more of reaction dissolvent DMSO, DMF, NMP, reaction temperature are 60 DEG C -110
DEG C, preferably 85 DEG C -100 DEG C；Reaction time is 18-36h.
Step (1-2) carries out under alkaline condition, and the alkali is potassium tert-butoxide, in sodium tert-butoxide, sodium methoxide, sodium ethoxide
One or more, preferably potassium tert-butoxide；The molar ratio of Formula II compound, formula III compound and alkali is 1.0: (0.9-1.1)
: (1.5-3.0), preferably 1.0: 1.0: 2.0.
In step (1-2), reaction dissolvent is tetrahydrofuran, in dioxane, ether, dichloromethane, 1,2- dichloroethanes
One or more, preferred tetrahydrofuran；Reaction temperature is 20 DEG C -40 DEG C, preferably 25 DEG C；Reaction time is 30-90min.
In step (1-2), the formula III compound is passed through by trifluoroacetic anhydride, 1- tert-butoxycarbonyl-piperazines, hydrazine hydrate
The reaction of oxidative coupling cyclization one-step method is prepared.
The oxidative coupling cyclization one-step method reaction participates in reaction using oxidant, catalyst, secondary amine.The reaction is oxygen
Change coupling reaction, oxidant is hydrogen peroxide, the mixture of tert-butyl hydroperoxide or both, when making oxidant with hydrogen peroxide
When, because hydrogen peroxide easily decomposes on this condition, the mode it is advantageous to be slowly added dropwise adds in hydrogen peroxide, and with tertiary fourth
There is no need to be slowly added dropwise when base hydrogen peroxide makees oxidant, because tert-butyl hydroperoxide is more stable on this condition；It urges
Agent is one or more of potassium iodide, sodium iodide, tetrabutylammonium iodide, iodine, preferably tetrabutylammonium iodide；Because hydrazine hydrate
Smaller nucleophilie nucleus ability, so needing to add in secondary amine as activator, secondary amine is morpholine, one kind in piperidines, nafoxidine
Or several, preferred morpholine；The molar ratio of 1- tert-butoxycarbonyl-piperazines, trifluoroacetic anhydride and hydrazine hydrate is 1.0: (1.1-3.0):
(1.5-3.0), preferably 1.0: 1.5: 2.0；The molar ratio of 1- tert-butoxycarbonyl-piperazines and oxidant is 1.0: (3.0-5.0), it is excellent
Select 1.0: 4.0；The molar ratio of 1- tert-butoxycarbonyl-piperazines and catalyst is 1.0: (0.02-0.3), preferably 1.0: 0.1；The tertiary fourths of 1-
The molar ratio of oxygen carbonyl piperazine and secondary amine is 1.0: (0.05-0.3), preferably 1.0: 0.2.
The reaction dissolvent of the oxidative coupling cyclization one-step method reaction is dioxane, n,N-Dimethylformamide, second
One or more of glycol dimethyl ether, preferably dioxane；Reaction temperature is 50 DEG C -90 DEG C, preferably 65 DEG C -80 DEG C；Instead
It is 5-12h between seasonable.
The synthetic route of the present invention is as follows：
Advantageous effect：Method provided by the invention can avoid using expensive raw material, avoid using toxic hazardous chemical
Reagent, raw material are easy to get, and reaction condition is mild, economic and environment-friendly, simple for process and yield is higher, suitable for industrialized production.
Specific embodiment
The preparation of embodiment 1, Formula II compound
In the single port bottle of 50mL, 2,4,5- trifluorobromobenzenes (I) (2.10g, 10mmol), diethyl malonate are sequentially added
(4.80g, 30mmol), cuprous iodide (0.19g, 1mmol), L-PROLINE (0.23g, 2mmol), potassium phosphate (7.43g,
35mmol) replaced three times with nitrogen with the anhydrous DMSO of 20mL, reaction system.90 DEG C are warming up to, reaction is for 24 hours.Later, on filter paper
One layer of diatomite, filtering are spread, 10mL ethyl acetate washing filter cake obtains mother liquor.70mL ethyl acetate dilution mother liquor is added, with saturation
Aqueous ammonium chloride solution washs three times, washed once with saturated sodium-chloride water solution, finally washes again once, vacuum rotary steam falls acetic acid
Ethyl ester obtains crude product.Crude product with methanol is recrystallized to give faint yellow solid 2.28g, as compound II, yield at 0 DEG C
88%, purity 99%.
The preparation of embodiment 2, formula III compound
In the single port bottle of 50mL, 1- tert-butoxycarbonyl-piperazines (1.87g, 10mmol), trifluoroacetic anhydride are sequentially added
A hour is stirred at room temperature in the anhydrous dioxane of (3.15g, 15mmol) and 15mL.Hydrazine hydrate is sequentially added later
(80%, 1.25g, 20mmol), tetrabutylammonium iodide (0.37g, 1mmol), morpholine (0.17g, 2mmol) then increase temperature
To 70 DEG C.Hydrogen peroxide (30%, 4.53g, 40mmol) is dissolved in the dioxane of 5mL, this hydrogenperoxide steam generator is delayed
Slowly it is added drop-wise in above-mentioned reaction solution, control 4h is dripped, and then proceedes to reaction 2h.Later, it is dilute to add in 80mL ethyl acetate
Mother liquor is released, with saturated aqueous sodium sulfite washing three times, washed once with saturated sodium-chloride water solution, finally wash one again
Secondary, vacuum rotary steam falls ethyl acetate and obtains crude product.12h is dried under reduced pressure at 45 DEG C, obtains the crude product 1.75g of compound III, is received
Rate 92%.
The preparation of embodiment 3, formula IV compound
In the single port bottle of 100mL, potassium tert-butoxide (2.24g, 20mmol) is dissolved in the tetrahydrofuran of 40mL, room temperature
Stirring one minute.Then sequentially add compound III (1.91g, 10mmol), compound II (2.60g, 10mmol), room temperature after
Continuous stirring 60min.Reaction dissolvent tetrahydrofuran is fallen in vacuum distillation later, adds the water of 50mL and the dichloromethane of 50mL, extracts
Organic phase is obtained, organic phase is dried with anhydrous sodium sulfate, is then evaporated under reduced pressure to the crude solid of yellow.Crude product dichloro
Methane is recrystallized with hexamethylene, obtains 3.33g compound IV, yield 82%, purity 99%.
The preparation of embodiment 4, Formula V compound
In the pressure pipe of 50mL, compound IV (4.06g, 10mmol), (R)-(+)-tertiary butyl sulfenyl are sequentially added
Amine (1.27g, 10.5mmol), platinum dioxide (0.08g), the tetrahydrofuran of 20mL, hydrogen are replaced three times.Then 0 DEG C is cooled to,
Hydrogen Vapor Pressure is improved to 6bar, reacts 5h.Later, pressure is slowly removed, in one layer of filter paper upper berth diatomite, filtering, 10mL bis-
Chloromethanes washs filter cake, obtains filtrate.The crude solid of brown is evaporated under reduced pressure to, with ethyl acetate, hexamethylene recrystallizes
To compound IV4.75g, yield 93%, purity 98%.
The preparation of embodiment 5, Formula IV compound
In the single port bottle of 50mL, compound V (5.11g, 10mmol) is sequentially added, the hydrochloric acid (20mL) of 5M is warming up to
70 DEG C, stir 2h.Later, 50mL water dilute reaction solutions are added in, are then 8-9 with the Ph of sodium carbonate adjusting water phase.With 50mL second
Acetoacetic ester extracts product, then washes primary.Then vacuum distillation obtains the crude solid of yellow, is tied again with methyl tertiary butyl ether(MTBE)
Crystalline substance obtains the solid 3.62g of white, as Xi Gelieting products.Yield 89%, purity 99%.
MS：[M+H]+：408.1276
1H-NMR (400MHz, CDCl3) δ 2.72 (m, 2H), 2.88 (m, 2H), 3.66 (m, 1H), 3.82 (m, 1H), 4.15
(m, 3H), 4.92 (m, 2H), 4.93 (m, 1H), 7.16 (m, 1H)
The preparation of embodiment 6, Formula II compound
It is same as Example 1, it differs only in：
Ligand is 2- pyridine carboxylic acids, and alkali is sodium methoxide；Compound of formula I and the molar ratio of diethyl malonate are 1.0: 2.1；
Compound of formula I and the molar ratio of cuprous iodide are 1.0: 0.05；Compound of formula I and the molar ratio of 2- pyridine carboxylic acids are 1.0:
0.05；Compound of formula I and the molar ratio of sodium methoxide are 1.0: 2.5.Reaction dissolvent is DMF, and reaction temperature is 110 DEG C.
The preparation of embodiment 7, Formula II compound
It is same as Example 1, it differs only in：
Ligand is 2-piperidinecarboxylic acid, and alkali is cesium carbonate；Compound of formula I and the molar ratio of diethyl malonate are 1.0: 5.0；
Compound of formula I and the molar ratio of cuprous iodide are 1.0: 0.3；Compound of formula I and the molar ratio of 2-piperidinecarboxylic acid are 1.0：0.6；
Compound of formula I and the molar ratio of cesium carbonate are 1.0：5.0.Reaction dissolvent is NMP, and reaction temperature is 60 DEG C.
The preparation of embodiment 8, formula III compound
In the single port bottle of 50mL, 1- tert-butoxycarbonyl-piperazines (1.87g, 10mmol), trifluoroacetic anhydride are sequentially added
A hour is stirred at room temperature in the anhydrous dioxane of (3.15g, 15mmol) and 15mL.Hydrazine hydrate is sequentially added later
(80%, 1.25g, 20mmol), tetrabutylammonium iodide (0.37g, 1mmol), morpholine (0.17g, 2mmol), tert-butyl hydroperoxide
Hydrogen (70%, 5.15g, 40mmol) then increases temperature to 70 DEG C, reacts 7h.Later, it is female to add in the dilution of 80mL ethyl acetate
Liquid with saturated aqueous sodium sulfite washing three times, washed once with saturated sodium-chloride water solution, finally wash once, subtract again
Pressure rotates ethyl acetate and obtains crude product.12h is dried under reduced pressure at 45 DEG C, obtains the crude product 1.77g of compound III, yield
93%.
The preparation of embodiment 9, formula III compound
It is same as Example 2, it differs only in：
Catalyst is potassium iodide；Secondary amine is piperidines；The molar ratio of 1- tert-butoxycarbonyl-piperazines, trifluoroacetic anhydride and hydrazine hydrate
It is 1.0: 1.1: 1.5；The molar ratio of 1- tert-butoxycarbonyl-piperazines and hydrogen peroxide is 1.0: 3.0；1- tert-butoxycarbonyl-piperazines with
The molar ratio of potassium iodide is 1.0: 0.02；The molar ratio of 1- tert-butoxycarbonyl-piperazines and piperidines is 1.0: 0.05.
Reaction dissolvent is n,N-Dimethylformamide；Reaction temperature is 90 DEG C.
The preparation of embodiment 10, formula III compound
It is same as Example 2, it differs only in：
Catalyst is iodine；Secondary amine is nafoxidine；The molar ratio of 1- tert-butoxycarbonyl-piperazines, trifluoroacetic anhydride and hydrazine hydrate
It is 1.0: 3.0: 3.0；The molar ratio of 1- tert-butoxycarbonyl-piperazines and hydrogen peroxide is 1.0: 5.0；1- tert-butoxycarbonyl-piperazines with
The molar ratio of iodine is 1.0: 0.3；The molar ratio of 1- tert-butoxycarbonyl-piperazines and nafoxidine is 1.0: 0.3.Reaction dissolvent is second
Glycol dimethyl ether；Reaction temperature is 50 DEG C.
The preparation of embodiment 11, formula IV compound
It is same as Example 3, it differs only in：
Alkali is sodium methoxide；The molar ratio of Formula II compound, formula III compound and sodium methoxide is 1.0: 0.9: 1.5.React molten
Agent is ether；Reaction temperature is 20 DEG C.
The preparation of embodiment 12, formula IV compound
It is same as Example 3, it differs only in：
Alkali is sodium tert-butoxide；The molar ratio of Formula II compound, formula III compound and sodium tert-butoxide is 1.0: 1.1: 3.0.Instead
It is dichloromethane to answer solvent；Reaction temperature is 40 DEG C.
The preparation of embodiment 13, Formula V compound
It is same as Example 4, it differs only in：
Formula IV compound and the molar ratio of (R)-(+)-t-butyl sulfonamide are 1.0: 1.0；The dosage of platinum dioxide is
The 1% of formula IV compound by weight；The pressure of hydrogen in reaction is 3bar.Reaction dissolvent is ether；Reaction temperature is 5 DEG C.
The preparation of embodiment 14, Formula V compound
It is same as Example 4, it differs only in：
Formula IV compound and the molar ratio of (R)-(+)-t-butyl sulfonamide are 1.0: 2.5；The dosage of platinum dioxide is
The 10% of formula IV compound by weight；The pressure of hydrogen in reaction is 8bar.Reaction dissolvent be glycol dimethyl ether in one kind or
It is several；Reaction temperature is -5 DEG C.
Claims (10)
1. a kind of synthetic method of Xi Gelieting, which is characterized in that include the following steps：
(1) formula IV compound, (R)-(+)-t-butyl sulfonamide, hydrogen are carried out that Formula V is obtained by the reaction under catalyst
Compound；
(2) Formula V compound is obtained into Formula IV compound, i.e. Xi Gelieting by hydrolysis,
2. the synthetic method of Xi Gelieting according to claim 1, which is characterized in that in step (1), formula IV compound with
(R) molar ratio of-(+)-t-butyl sulfonamide is 1.0: (1.0-2.5)；The catalyst be platinum dioxide, the titanium dioxide
The dosage of platinum is the 1%-10% of formula IV compound by weight；The pressure of hydrogen in reaction is 3-8bar.
3. the synthetic method of Xi Gelieting according to claim 1, which is characterized in that in step (1), reaction dissolvent four
One or more of hydrogen furans, ether, dioxane, glycol dimethyl ether；Reaction temperature is -5 DEG C -5 DEG C.
4. the synthetic method of Xi Gelieting according to claim 1, which is characterized in that in step (1), the formula IV
Object is closed to be prepared by following methods：
Formula II compound is obtained by the reaction in compound of formula I and diethyl malonate by (1-1)；
The Formula II compound and the formula III compound substitution reaction and obtain formula IV compound by (1-2) occurs,
5. the synthetic method of Xi Gelieting according to claim 4, which is characterized in that in step (1-1), use catalysis
Agent, ligand, alkali participate in reaction, and the catalyst is cuprous iodide, and the ligand is L-PROLINE, 2- pyridine carboxylic acids, 2- piperidines
One or more of formic acid, the alkali are one or more of cesium carbonate, potassium phosphate, sodium methoxide, sodium hydride；Formulas I chemical combination
The molar ratio of object and diethyl malonate is 1.0: (2.1-5.0)；Compound of formula I and the molar ratio of catalyst are 1.0: (0.05-
0.3)；Compound of formula I and the molar ratio of ligand are 1.0: (0.05-0.6)；Compound of formula I and the molar ratio of alkali are 1.0: (2.5-
5.0)。
6. the synthetic method of Xi Gelieting according to claim 4, which is characterized in that in step (1-1), reaction dissolvent is
One or more of DMSO, DMF, NMP, reaction temperature are 60 DEG C -110 DEG C.
7. the synthetic method of Xi Gelieting according to claim 4, which is characterized in that step (1-2) is under alkaline condition
It carries out, the alkali is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide；Formula II compound, formula III
Compound and the molar ratio of alkali are 1.0: (0.9-1.1): (1.5-3.0).
8. the synthetic method of Xi Gelieting according to claim 4, which is characterized in that in step (1-2), reaction dissolvent is
One or more of tetrahydrofuran, dioxane, ether, dichloromethane, 1,2- dichloroethanes；Reaction temperature is 20 DEG C -40
℃。
9. the synthetic method of Xi Gelieting according to claim 4, which is characterized in that in step (1-2), the formula
III compounds are prepared by trifluoroacetic anhydride, 1- tert-butoxycarbonyl-piperazines, hydrazine hydrate by the reaction of oxidative coupling cyclization one-step method
It arrives.
10. the synthetic method of Xi Gelieting according to claim 9, which is characterized in that the oxidative coupling cyclization one
Footwork reaction participates in reaction using oxidant, catalyst, secondary amine, and oxidant is hydrogen peroxide, tert-butyl hydroperoxide or both
Mixture；Catalyst is one or more of potassium iodide, sodium iodide, tetrabutylammonium iodide, iodine；Secondary amine for morpholine, piperidines,
One or more of nafoxidine；The molar ratio of 1- tert-butoxycarbonyl-piperazines, trifluoroacetic anhydride and hydrazine hydrate is 1.0: (1.1-
3.0)∶(1.5-3.0)；The molar ratio of 1- tert-butoxycarbonyl-piperazines and oxidant is 1.0: (3.0-5.0)；1- tertbutyloxycarbonyl piperazines
The molar ratio of piperazine and catalyst is 1.0: (0.02-0.3)；The molar ratio of 1- tert-butoxycarbonyl-piperazines and secondary amine is 1.0: (0.05-
0.3)。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108675962A (en) * | 2018-07-04 | 2018-10-19 | 中昊(大连)化工研究设计院有限公司 | One-step method green syt phthalylhydrazine |
| CN109682921A (en) * | 2019-01-15 | 2019-04-26 | 通化东宝药业股份有限公司 | A kind of detection method of free hydrazine and its application in phosphoric acid Xi Gelieting bulk pharmaceutical chemicals defects inspecting |
| CN116102556A (en) * | 2022-09-14 | 2023-05-12 | 重庆普佑生物医药有限公司 | Preparation method of sitagliptin intermediate |
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| 朱怡君等: "叔丁基亚磺酰胺在手性胺类药物合成中的应用", 《中国医药工业杂志》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675962A (en) * | 2018-07-04 | 2018-10-19 | 中昊(大连)化工研究设计院有限公司 | One-step method green syt phthalylhydrazine |
| CN109682921A (en) * | 2019-01-15 | 2019-04-26 | 通化东宝药业股份有限公司 | A kind of detection method of free hydrazine and its application in phosphoric acid Xi Gelieting bulk pharmaceutical chemicals defects inspecting |
| CN116102556A (en) * | 2022-09-14 | 2023-05-12 | 重庆普佑生物医药有限公司 | Preparation method of sitagliptin intermediate |
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