CN111233915B - Preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone - Google Patents
Preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone Download PDFInfo
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- CN111233915B CN111233915B CN201811430125.2A CN201811430125A CN111233915B CN 111233915 B CN111233915 B CN 111233915B CN 201811430125 A CN201811430125 A CN 201811430125A CN 111233915 B CN111233915 B CN 111233915B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone, which comprises the steps of dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, after dropwise adding, adding glucolactone in batches, and then adding 4-dimethylpyridine for reaction to obtain 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone; the reaction formula is as follows:
Description
Technical Field
The invention relates to a preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone, belonging to the technical field of organic chemistry.
Technical Field
The compound I related by the invention is 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone, the CAS number of the compound is 32384-65-9, and the specific structural formula is shown as follows:
the compound I is a key starting material for preparing a drug SGLT-2 inhibitor for treating type II diabetes of adult patients, such as canagliflozin, dapagliflozin, enggliflozin and the like, and has very wide application.
The preparation reaction formula of canagliflozin is as follows:
the preparation reaction formula of dapagliflozin is shown as follows:
the preparation reaction formula of the englitjing is shown as follows:
for the preparation of compound I, there are several patents and literature reports on the synthetic route of the compound I by using gluconolactone as a starting material and reacting with trimethylchlorosilane (TMSCl) under different conditions.
PCT patent WO2016142950A1 discloses that glucolactone is taken as a starting material, trimethylchlorosilane (TMSCl) -5-0 ℃ is dropwise added into a reaction system in a 4-methylmorpholine (NMM) and Tetrahydrofuran (THF) system, and the mixture is reacted for 18-20 hours at 25-30 ℃ after the dropwise addition is finished; after the reaction is finished, toluene/n-heptane is used as an extractant, and the organic phase is extracted by the extractant through water washing, sodium bicarbonate water solution washing or saturated saline water washing after the pH is adjusted to 7-8, and the oily product is obtained after the organic phase is concentrated and combined.
The specification of Chinese patent CN106632288A discloses a preparation method of the compound I as follows: adding glucolactone, N-methylmorpholine and THF into a reaction kettle, stirring, controlling the temperature to-5-0 ℃ in an inert atmosphere, dropwise adding trimethylchlorosilane, heating to 20-25 ℃, and stirring for reacting for 15-20 hours to obtain the compound I. Specifically, the preparation reaction is carried out in an inert atmosphere, so that oxidation of a product is avoided; in addition, as the heat release is relatively intense when the trimethylchlorosilane and the N-methylmorpholine react to generate a complex, the trimethylchlorosilane is dropwise added, and the temperature is required to be controlled to be between-5 and 0 ℃ so as to avoid the excessive intense reaction.
CN102574829 example 4 discloses that in the preparation of compound I, 130.8kg of trimethylchlorosilane is added at 13-19 ℃ over 50 minutes to treat 42.0kg of a suspension of gluconolactone, 277.2kg of tetrahydrofuran, 4-methylmorpholine (152.4 kg) and 4-dimethylpyridine (1.44 kg), after the addition is completed, stirring is continued at 20-22 ℃ for 1.5 hours, then 216.4kg of n-heptane is added and the mixture is cooled to 5 ℃, 143kg of water is added at 3-5 ℃ over 15 minutes, stirring, separating the phases, distilling and 130kg of n-heptane is added to the residue, filtering, washing, and distilling to obtain oily compound I containing residual n-heptane. The TMSCl must be added dropwise within 50 minutes, and the heat release is serious in the dropping process, so that the method has potential safety hazard in industrial mass production and is not suitable for industrial mass production.
Step 3 in CN102656177a example 1: to a solution of gluconolactone (7.88 kg,44.23 mol) and N-methylmorpholine (3.58 kg,353.9 mol) in tetrahydrofuran (70 kg) was added trimethylchlorosilane (29.1 kg,267.9 mol) at 40℃or lower, and the resulting mixture was stirred at 30-40℃for 2 hours. The reaction mixture was cooled to 0℃and toluene (34 kg) and water (39 kg) were added, and an organic layer was separated, washed 2 times with a 5% aqueous solution of sodium dihydrogen phosphate (39.56 kg), 1 time with water (39 kg) and distilled under reduced pressure to give compound I.
CN107286143A example 1 was prepared by adding 8.0kg of tetrahydrofuran, 1.0kg of gluconolactone and 4.54kg of N-methylmorpholine to a reaction vessel at room temperature, dropwise adding 3.66kg of trimethylchlorosilane under the protection of nitrogen, reacting completely, and adding ice water to quench. 26kg of purified water and 5.0kg of n-heptane were added to the reaction mixture, followed by stirring and delamination by standing. The organic layer was washed with 15kg of 5% aqueous sodium dihydrogen phosphate solution, 15kg of purified water and 15kg of aqueous sodium chloride solution, anhydrous magnesium sulfate was added, and the mixture was concentrated under reduced pressure to give 2.41kg of a colorless oily compound I in 92% yield and 95.8% in gas phase purity.
In the preparation methods disclosed in the publications, glucolactone is used as a starting material, then is mixed with N-methylmorpholine and tetrahydrofuran, TMSCl is added dropwise, inert gas is needed to protect products from oxidation in the reaction process, and the dripping temperature and the dripping time are harsh; if the dropping temperature and dropping time are relaxed, the yield and purity may be lowered.
The feeding mode has strict requirements on the cooling efficiency of production equipment, limits the industrialized mass production of products, and easily causes unstable production of product quality, so that a preparation method with good safety, convenient and controllable operation, low requirements on site equipment and easy realization of large-scale mass production is urgently needed.
Disclosure of Invention
The invention aims to solve the problems that the cooling efficiency of production equipment is strictly required, the production quality of products is unstable and the like in the large-scale production of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone, and particularly provides a preparation method of the 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone, which adopts the following steps:
dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, after dropwise adding, adding glucolactone in batches, and then adding 4-lutidine for reaction to obtain 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone; the reaction formula is as follows:
preferably, the temperature of the trimethylchlorosilane is controlled between-5 and 40 ℃ in the feeding process.
Preferably, the temperature of the gluconolactone is controlled to be-5-40 ℃ during the feeding process.
Preferably, the gluconolactone addition time is 1 to 18 hours.
Preferably, the molar ratio of the glucolactone to the trimethylchlorosilane, the N-methylmorpholine and the 4-dimethylaminopyridine is 1:5.0-6.0:6.0-7.0:0.02-0.05.
Preferably, the molar volume ratio of the glucose lactone to the tetrahydrofuran is 1:5-10.
The invention provides a preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone, which adopts the following preferable technical scheme:
dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, controlling the feeding temperature to be between-5 and 40 ℃, after the dropwise adding, adding glucolactone in batches, controlling the feeding temperature to be between-5 and 40 ℃, and then adding 4-lutidine for reaction; after the reaction is finished, toluene is added, the temperature is reduced to 0 to 10 ℃, and water is added for quenching; then adding water, layering, extracting the water phase with toluene, washing the organic phase with a sodium dihydrogen phosphate aqueous solution and saturated saline respectively, and concentrating under reduced pressure after over-alkaline aluminum oxide to obtain the high-purity 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone.
The more preferable technical scheme is that the preparation method adopts the following steps:
400L tetrahydrofuran and 290kg (2.86 kmol,6.4 eq) N-methylmorpholine are added into a reaction bottle, the temperature is reduced to-5-15 ℃, 250kg (2.3 mol,5.1 eq) trimethylchlorosilane is slowly added dropwise, the temperature of the system is controlled to-5-15 ℃, 80kg (449.4 mol,1.0 eq) gluconolactone is added in batches after the dropwise addition, and the temperature is controlled to-5-20 ℃; 1.4kg (23 mol,0.05 eq) DMAP is added after the addition, and then the temperature is raised to 30-35 ℃ for reaction for 3-5 h; 400kg of toluene is added, the temperature is reduced to 0-10 ℃, 100L of aqueous solution is dripped to quench the mixture to 0-10 ℃, 250L of water is added to dissolve the system, the aqueous phase is separated, 100L of toluene is used for extraction and combination of organic phases, 540kg of 7% sodium dihydrogen phosphate aqueous solution is used for washing the organic phases respectively, 520kg of saturated saline water is used for washing the organic phases, the organic phases are subjected to over-alkaline aluminum trioxide and then are decompressed and concentrated to obtain colorless to light yellow oily matter of 207.6kg, the yield is 99.1%, the GC purity is 98.7%, and the impurity compound IV purity is 0.11%.
The present inventors found through studies that:
the gluconolactone can easily form five-membered ring impurities (compound III) under alkaline conditions, TMSCl can be further reacted to become five-membered ring impurities (compound IV) after being added dropwise, and the following graph is shown:
in addition, in the reaction, the dosage of TMSCl is at least more than 5.0 equivalents, the dosage of NMM is more than 6.0, the heat release amount is quite large in the process of dropwise adding TMSCl, the neutralization heat of acid and alkali and the reaction heat are released together, once the cooling effect of equipment is poor, or the large-scale dosage in production is large, the cooling effect is poor easily, and the dropwise adding time is prolonged.
The inventor researches find that according to the prior art method, when TMSCI is dripped into an alkaline system of gluconolactone at the temperature of-10-0 ℃ for more than 6 hours, the compound IV can be obviously increased by more than 1%; when the temperature of the dripping is higher than 0 ℃, the dripping time is longer than 2 hours, the compound IV is increased to 2% -3%, the impurities are not easy to remove, the quality specification is influenced, and the pressure is caused to the purification of the subsequent process.
In the preparation method of the compound I, TMSCl is firstly dripped into a system of THF and NMM, and then raw material gluconolactone is added in batches; on the one hand, TMSCl is firstly added to weaken the alkalinity of the whole system, so that the time of raw materials in an alkaline environment can be reduced to the greatest extent, and the generation of impurity compounds IV can be effectively reduced;
on the other hand, the acid and alkali neutralization heat in the earlier stage releases most of the reaction heat, only part of the reaction heat in the later stage is consumed by TMSCl, so that the risk is greatly reduced, the system is not sensitive to temperature and time, the generation of impurity compounds IV can be better controlled, the controllable range of the product quality is wider, the process repeatability is better, the product quality is better, and the product purity can reach more than 98%.
In the third aspect, as the late heat release is less, the requirements on the feeding temperature and the feeding time are wider during the reaction, and the requirements on the cooling efficiency of production equipment are reduced, so that the whole synthesis process is simpler and more convenient to operate, and the mass production reproducibility is more stable.
Detailed Description
In order that the manner in which the invention can be understood more readily, a more particular description of the invention will be rendered by reference to specific embodiments thereof. The examples illustrate the invention but do not limit it.
Example 1
400L tetrahydrofuran and 290kg (2.86 kmol,6.4 eq) N-methylmorpholine are added into a reaction bottle, the temperature is reduced to-5-15 ℃, 250kg (2.3 mol,5.1 eq) trimethylchlorosilane is slowly added dropwise, the temperature of the system is controlled to-5-15 ℃, 80kg (449.4 mol,1.0 eq) gluconolactone is added in batches after the dropwise addition, and the temperature is controlled to-5-20 ℃; 1.4kg (23 mol,0.05 eq) DMAP is added after the addition, and then the temperature is raised to 30-35 ℃ for reaction for 3-5 h; 400kg of toluene is added, the temperature is reduced to 0-10 ℃, 100L of aqueous solution is dripped to quench the mixture to 0-10 ℃, 250L of water is added to dissolve the system, the aqueous phase is separated, 100L of toluene is used for extraction and combination of organic phases, 540kg of 7% sodium dihydrogen phosphate aqueous solution is used for washing the organic phases respectively, 520kg of saturated saline water is used for washing the organic phases, the organic phases are subjected to over-alkaline aluminum trioxide and then are decompressed and concentrated to obtain colorless to light yellow oily matter of 207.6kg, the yield is 99.1%, the GC purity is 98.7%, and the impurity compound IV purity is 0.11%.
Example 2
200ml of tetrahydrofuran and 79.7g (787.5 mmol,7.0 eq) of N-methylmorpholine are added into a reaction bottle, the temperature is reduced to 15-30 ℃, 73.3g (675 mmol,6.0 eq) of trimethylchlorosilane is slowly added dropwise, the temperature of the system is controlled to 15-30 ℃,20g (112.5 mmol,1.0 eq) of gluconolactone is added in batches after the dropwise addition, and the temperature is controlled to 20-40 ℃; after the addition, 0.27g (2.25 mmol,0.02 eq) DMAP is added, and then the temperature is raised to 30-35 ℃ for reaction for 3-5 h; 100g of toluene is added, the temperature is reduced to 5-15 ℃,25 ml of aqueous solution is dripped to quench the mixture to 5-15 ℃, 62.5ml of water is added to dissolve the system, the aqueous phase is separated, 25ml of toluene is used for extraction and combination of organic phases, 135g of 7% sodium dihydrogen phosphate aqueous solution is used for washing the aqueous phase, 130g of saturated saline water is used for washing the organic phase, the organic phase is subjected to over-alkaline aluminum trioxide and then is decompressed and concentrated to obtain a colorless to pale yellow oily substance 52.15g, the yield is 99.5%, the GC purity is 98.3%, and the impurity compound IV purity is 0.16%.
Example 3
200ml of tetrahydrofuran and 145g (1.43 mol,6.4 eq) of N-methylmorpholine are added into a reaction bottle, the temperature is reduced to 20-30 ℃, 125g (1.15 mol,5.1 eq) of trimethylchlorosilane is slowly added dropwise, the temperature of the system is controlled to 25-40 ℃, after the addition of the trimethylchlorosilane is completed, half of 20g (112.6 mmol,0.5 eq) of gluconolactone is added in batches, the temperature is controlled to 25-40 ℃ and the mixture is stirred overnight, and then the other half of 10g (112.6 mmol,0.5 eq) of gluconolactone is added; after the addition, 1.4g (11.5 mmol,0.05 eq) DMAP is added, and then the temperature is raised to 30-35 ℃ for reaction for 3-5 h; 200g of toluene is added, the temperature is reduced to 5-15 ℃, 50ml of aqueous solution is dripped to quench the mixture to 5-15 ℃, 125ml of water is added to dissolve the system, the water phase is separated, 50ml of toluene is used for extraction and combination of organic phases, 270g of 7% sodium dihydrogen phosphate aqueous solution is used for washing the organic phases respectively, 260g of saturated saline water is used for washing the organic phases, the organic phases are subjected to over-alkaline aluminum trioxide and then are decompressed and concentrated to obtain colorless to light yellow oily matter 104.3g, the yield is 99.5%, the GC purity is 98.1%, and the impurity compound IV purity is 0.13%.
Comparative example 1: (according to WO2016142950A1 example 1)
100ml of tetrahydrofuran, 72.5g (716.8 mmol,6.4 eq) of N-methylmorpholine, 20g (112.5 mmol,0.5 eq) of gluconolactone and 62.5g (575.5 mmol,5.1 eq) of trimethylchlorosilane are slowly added dropwise, the system is controlled to be-5-0 ℃, and after the dropwise addition, the temperature is controlled to be 25-35 ℃ for reaction for 18-20 hours; after the reaction, 100g of toluene was added, the mixture was washed with water and sodium bicarbonate until the pH was 7 to 8, and after washing with saturated brine, the organic phase was concentrated to give 51.63g of an oil with a yield of 98.5% and a GC purity of 97.3%.
Comparative example 2: (according to procedure 3 in example 1 of CN 102656177A:)
To a solution of gluconolactone (7.88 kg,44.23 mol) and N-methylmorpholine (3.58 kg,353.9 mol) in tetrahydrofuran (70 kg) was added trimethylchlorosilane (29.1 kg,267.9 mol) at 40℃or lower, and the resulting mixture was stirred at 30-40℃for 2 hours. The reaction mixture was cooled to 0℃and toluene (34 kg) and water (39 kg) were added, and an organic layer was separated, washed 2 times with a 5% aqueous solution of sodium dihydrogen phosphate (39.56 kg), 1 time with water (39 kg) and distilled under reduced pressure to give compound I.
Table 1 shows a comparison of the preparation of the compounds I according to the invention with the prior art
According to the analysis of the results in table 1, the compound I obtained by the method of CN102574829a, although having good purity and yield, must have a dropping temperature controlled between 13 and 19 ℃ and should have tmcl dropped within 50 minutes, and because the dropping process has serious heat release, the requirement on cooling production equipment is very high and the dropping time is short, which has potential safety hazard in industrial mass production and is not suitable for industrial mass production; according to the method of CN102656177A, when the dripping temperature exceeds 0 ℃, the dripping time exceeds 2 hours, the compound IV is increased to 2% -3%, the impurities are not easy to remove, the quality specification is influenced, and the pressure is caused to the purification of the subsequent process. Compared with the prior art, the preparation method has the advantages of wider requirements on the feeding temperature and the feeding time, wider range of controllable quality, good process repeatability, reduced cooling requirement on production equipment, and larger advantages in the aspects of product purity and impurity compound IV control.
The preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone provided by the invention has been described by examples, and the related technicians can obviously modify or appropriately modify and combine the preparation method of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone disclosed herein without departing from the content, spirit and scope of the invention, so as to realize the technology of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the spirit, scope and content of the invention.
Claims (2)
1. The preparation method of the 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone is characterized by comprising the following steps of:
dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, adding glucolactone after dropwise adding, and then adding 4-dimethylaminopyridine for reaction to obtain 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone; the reaction formula is as follows:
wherein the temperature of the trimethylchlorosilane is controlled at-5-40 ℃ in the feeding process; the temperature of the gluconolactone is controlled to be between-5 and 40 ℃ in the feeding process; the molar ratio of the dosage of the gluconolactone to the trimethylchlorosilane, the N-methylmorpholine and the 4-dimethylaminopyridine is 1:5.0-6.0:6.0-7.0:0.02-0.05; the molar volume ratio of the dosage of the glucolactone to the tetrahydrofuran is 1:5-10; the charging time of the gluconolactone is 1-18 hours.
2. The preparation method of the 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone is characterized by comprising the following steps of:
dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, controlling the feeding temperature to be between-5 and 40 ℃, after the dropwise adding, adding glucolactone in batches, controlling the feeding temperature to be between-5 and 40 ℃, and then adding 4-lutidine for reaction; after the reaction is finished, toluene is added, the temperature is reduced to 0 to 10 ℃, and water is added for quenching; then adding water, layering, extracting the water phase with toluene, washing the organic phase with a sodium dihydrogen phosphate aqueous solution and saturated saline respectively, and concentrating under reduced pressure after over-alkaline aluminum oxide to obtain the 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6069238A (en) * | 1998-09-30 | 2000-05-30 | Eli Lilly And Company | Spirocyclic C-glycosides |
| CN101065391A (en) * | 2004-09-23 | 2007-10-31 | 布里斯托尔-迈尔斯斯奎布公司 | C-aryl glucoside sglt2 inhibitors and method |
| CN102574829A (en) * | 2009-09-30 | 2012-07-11 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6069238A (en) * | 1998-09-30 | 2000-05-30 | Eli Lilly And Company | Spirocyclic C-glycosides |
| CN101065391A (en) * | 2004-09-23 | 2007-10-31 | 布里斯托尔-迈尔斯斯奎布公司 | C-aryl glucoside sglt2 inhibitors and method |
| CN102574829A (en) * | 2009-09-30 | 2012-07-11 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
Non-Patent Citations (2)
| Title |
|---|
| Development of a Scalable Synthesis of Tofogliflozin;Yoshihito Ohtake等;《J. Org. Chem.》;第81卷;第2148-2153页 * |
| SGLT2抑制剂Dapagliflozin的全合成;邵华等;《合成化学》;第18卷(第3期);第389-392页 * |
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