CN107652278A - A kind of synthesis technique net Yi Palie - Google Patents

A kind of synthesis technique net Yi Palie Download PDF

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Publication number
CN107652278A
CN107652278A CN201710674023.4A CN201710674023A CN107652278A CN 107652278 A CN107652278 A CN 107652278A CN 201710674023 A CN201710674023 A CN 201710674023A CN 107652278 A CN107652278 A CN 107652278A
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bromo
palie
explanation
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net
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冯成亮
严宾
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Nantong Textile Vocational Technology College
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Nantong Textile Vocational Technology College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 present invention relates to the synthesis technique that a kind of Yi Palie is net, using 4 toluene fluorides as initiation material, through free radical bromo-reaction; pay gram alkylated reaction; deprotection, diazotising chlorination, alkylated reaction obtain intermediate (S) 3 (4 (chlorobenzyl of 5 bromine 2) phenoxy group) tetrahydrofuran; then with 2; 3,4,6 four O trimethyls silicon substrate D glucolactones are through condensation; etherificate, it is net that demethoxylation obtains antidiabetic drug Yi Palie.The advantage of the invention is that：Synthesis technique net Yi Palie of the present invention, compared with existing synthetic method, using 4 toluene fluorides as initiation material, cost of material is cheap and easily-available, and technique easily realizes industrialization, and synthetic route is short, easy to operate；And in preparation process, each temperature conditionss are easy to control, and reaction conversion rate is higher, total recovery can be made up to more than 70%；In addition, by the synthesis technique of the present invention, product is not easy isomerization, and impurity is less, it is possible to increase the purity of product, purity can be made to reach more than 99%.

Description

A kind of synthesis technique net Yi Palie
Technical field
The invention belongs to medicinal chemistry arts, more particularly to a kind of Yi Palie be only (2S, 3R, 4R, 5S, 6R)- 2- ［ 3- ［ 4- ［ (3S)-tetrahydrofuran ］ -3- hydroxyphenyls ］ methyl ］ -4- chlorphenyl -6- methylol oxepane -3,4,5- triols Synthesis technique.
Background technology
Yi Palie is net (Empagliflozin), chemical name：(2S, 3R, 4R, 5S, 6R) -2- ［ 3- ［ 4- ［ (3S) - tetrahydrofuran ］ -3- hydroxyphenyls ］ methyl ］ -4- chlorphenyl -6- methylol oxepanes -3,4,5- triols, by Boehringer Ingelheim Company and the type sodium glucose cotransporter inhibitor of one kind 2 of Li Lai companies joint development.SGLT-2 inhibitor is a kind of New antidiabetic drug, the SGLT-2 of kidney is mainly expressed in by suppression, reduces kidney to glucose reabsorption, increase Portugal in urine Grape sugar excretion, so as to reduce plasma glucose levels, its hypoglycemic effect independent ofβCell function and insulin resistance.This Product ratify listing first in May, 2014 Europe drug administration (EMA), and in August, 2014, U.S. FDA approval listed, For treating 2 patients with type Ⅰ DM.Its Empagliflozin/linagliptin combined tablet-preparation, suppress for first SGLT-2 Agent and the compound hypoglycemic agent of dipeptidyl peptidase-4 inhibitors.
Synthetic method net Yi Palie mainly includes following three kinds：Scheme 1：Using the bromo- 2- chlorobenzoic acids of 5- as raw material, through acyl Chlorination, occur friedel-crafts acylation, reduction, hydrolysis with methyl phenyl ethers anisole, obtained phenolic hydroxyl group product, hydroxyl protection, and 2,3,4, - O- trimethylsilyl-D- glucopyras the saccharic acids 1 of 6- tetra-, ester condensation in 5-, methyl-etherified, reduce de-methoxy, then with (S) It is net that alkylated reaction get Yi Palie occurs for -3- tolysulfonyl epoxide-tetrahydrofuran；Such as patent：US 20100099641, PCT Int. Appl., 2007128749, PCT Int. Appl., 2007093610, PCT Int. Appl., 2006117359, specific synthetic route is as follows：
The route shares ten single step reactions, and phenolic hydroxyl group need to be protected, and yield is relatively low, and cost is higher, tetrahydrochysene in final step Furans epoxide, the easy isomerization of product, impurity is more, and purity is not high, and total recovery is 11. 9%.
Scheme two：Phenol reacts with (S) -3- dihydroxy-tetrahydros furans, and the chloro- 5- bromo-benzoyl chlorides of 2- occur Fu Ke and are acylated instead Deserved (the chloro- phenyl of the bromo- 2- of 5-)-(4- (S)-tetrahydrofuran -3- bases epoxide-phenyl)-ketones, through reduction reaction obtain (S) - The chloro- 2- of the bromo- 1- of 4- (4- tetrahydrofuran -3- bases epoxide-benzyl) benzene, and 2,3,4,6- tetra--O- trimethylsilyl-D- pyrans Gluconic acid 1, ester condensation in 5-, methyl-etherified, reduction de-methoxy get Yi Palie are net；Such as patent：PCT Int. Appl., 2006120208, US:2005020916, US:20100099641, specific synthetic route is as follows：
This route first connects tetrahydrofuran epoxide on phenyl ring, then carries out Fu Ke acylation reactions, reduces reactions steps, yield ratio Route one slightly improves, and total recovery is 13. 6%.
Scheme three：Using the iodo- 2- chlorobenzoic acids of 5- as initiation material, Fu Ke acylation reactions occur with fluorobenzene after chloride, Then with (S) -3- hydroxyl tetrahydrofurans reaction, reducing carbonyl obtain the chloro- 2- of the iodo- 1- of (S) -4- (4- tetrahydrofuran -3- bases epoxide - Benzyl) benzene, then with Turbogrignard solution (isopropylmagnesium chloride/lithium chloride iPrMgCl/LiCl RMgBrs) Carry out after Mg/I is exchanged with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyras saccharic acids 1, ester condensation in 5-, then first Be etherified, reduce product Yi Palie is net；Such as：US:20107772191, Org Lett, 2014,16:4 090-4 093, US: 2011237789, specific synthetic route is as follows：
This route carries out reaction temperature when Mg/I is exchanged and preferably controlled, and reaction conversion rate is higher, and total recovery is but former up to 54. 6% Costly, cost is higher for material.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of cost it is cheap, it is easy to operate, synthesis
Route is short and can improve the net synthesis techniques of the Yi Palie of product yield and purity.
In order to solve the above technical problems, the technical scheme is that：Synthesis technique net a kind of Yi Palie, its innovative point It is：Using 4- toluene fluorides as initiation material, through free radical bromo-reaction, gram alkylated reaction is paid, is deprotected, diazotising chloro is anti- Should, alkylated reaction obtains intermediate (S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran, then with 2,3,4,6- Four-O- trimethyls silicon substrates-D-Glucose acid lactone is through condensation, and etherificate, it is net that demethoxylation obtains antidiabetic drug Yi Palie；Specifically include Following steps：
（1）The preparation (I) of antisepsin：Para-bromoaniline is soluble in water, under ice bath, the methanol solution of acetic anhydride is added dropwise, After being added dropwise, 3-5h is reacted at room temperature, prepares antisepsin（I）；Specific reaction is as follows：
（2）Preparation to fluorobenzyl bromide（II）：4- toluene fluorides and NBS are dissolved in solvent, prepared in the presence of initiator to fluorine benzyl Bromine（II）；Specific reaction is as follows：
II
（3）The bromo- 2- of 4-（4- luorobenzyls）The preparation of antifebrin（III）：Fluorobenzyl bromide and antisepsin are dissolved in solvent, The bromo- 2- of synthesis 4- are reacted by Louis acid catalysis（4- luorobenzyls）Antifebrin（III）；Specific reaction is as follows：
III
（4）The bromo- 2- of 4-（4- luorobenzyls）The preparation of aniline（IV）：By the bromo- 2- of 4-（4- luorobenzyls）Antifebrin is dissolved in water solubility In solvent, the watery hydrochloric acid that molar concentration is 2-3mol/L is added, deacetylation protection prepares the bromo- 2- of 4-（4- luorobenzyls）Aniline （IV）；Specific reaction is as follows：
IV
（5）The bromo- 2- of 4-（4- luorobenzyls）The preparation of chlorobenzene（V）：By the bromo- 2- of 4-（4- luorobenzyls）Aniline is dissolved in molar concentration In 12mol/L concentrated hydrochloric acid, diazotising is reacted with natrium nitrosum, after reaction completely, it is bromo- to synthesize 4- with stannous chloride reaction chloro 2-（4- luorobenzyls）Chlorobenzene（V）；Specific reaction is as follows：
V
（6）(S) preparation (VI) of -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran：By the bromo- 2- of 4-（4- luorobenzyls） Chlorobenzene with（S）- 3- hydroxyl tetrahydrofurans, which are dissolved in polar solvent, to react, in the presence of highly basic, alkylated reaction synthesis (S)- 3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran (VI)；Specific reaction is as follows：
（7）The chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrofuran -3- bases epoxide-benzyl Base)-benzene preparation（VII）：(S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran is dissolved in solvent, and 2,3, 4,6- tetra--O- trimethyls silicon substrates-maltonic acid lactone reaction, are condensed under the catalysis of n-BuLi, then in methanesulfonic acid bar Under part, reacted with methanol, etherificate prepares 1- chloro- 4- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrochysene furan Mutter -3- bases epoxide-benzyl)-benzene（VII）；Specific reaction is as follows：
VII
（8）Preparation net Yi Palie（VIII）：The chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S) - tetrahydrofuran -3- bases epoxide-benzyl)-benzene is dissolved in dichloromethane/acetonitrile, and under Louis acid catalysis, silicon hydrogen reduction agent is also It is net that former demethoxylation prepares Yi Palie（VIII）；Specific reaction is as follows：
Further, the step（2）In, any of carbon tetrachloride or chloroform may be selected in solvent, and BPO may be selected in initiator Or any of AIBN.
Further, the step（3）In, any of ethyl acetate, carbon disulfide or nitrobenzene may be selected in solvent, Any of alchlor or alchlor may be selected in lewis acid.
Further, the step（4）In, any of tetrahydrofuran, methanol, ethanol or acetonitrile may be selected in solvent.
Further, the step（6）In, any of methanol, ethanol, THF or acetonitrile may be selected in polar solvent, by force Any of potassium tert-butoxide or sodium tert-butoxide may be selected in alkali.
Further, the step（7）In, solvent may be selected in ether/toluene or tetrahydrofuran/toluene solvant system It is any.
Further, the step（8）In, appointing in zinc chloride, anhydrous Aluminum chloride or lithium chloride may be selected in lewis acid Any of trimethyl silicane hydrogen or triethyl group silicon hydrogen may be selected in one kind, silicon hydrogen reduction agent.
The advantage of the invention is that：Synthesis technique net Yi Palie of the present invention, compared with existing synthetic method, with 4- fluorine first Benzene is initiation material, and cost of material is cheap and easily-available, and technique easily realizes industrialization, and synthetic route is short, easy to operate；And preparation technology During, each temperature conditionss are easy to control, and reaction conversion rate is higher, can make total recovery up to more than 70%；In addition, pass through the present invention's Synthesis technique, product are not easy isomerization, and impurity is less, it is possible to increase the purity of product, purity can be made to reach more than 99%.
Embodiment
The following examples can make professional and technical personnel that the present invention be more fully understood, but therefore not send out this It is bright to be limited among described scope of embodiments.
Synthesis technique net Yi Palie of the present invention, using 4- toluene fluorides as initiation material, through free radical bromo-reaction, pay gram alkane Glycosylation reaction, deprotection, diazotising chlorination, alkylated reaction obtain intermediate (S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) benzene oxygen Base) tetrahydrofuran, then with 2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone is through condensation, etherificate, demethoxylation It is net to obtain antidiabetic drug Yi Palie；Specifically comprise the following steps：
（1）The preparation (I) of antisepsin：Para-bromoaniline is soluble in water, under ice bath, the methanol solution of acetic anhydride is added dropwise, After being added dropwise, 3-5h is reacted at room temperature, prepares antisepsin（I）；Specific reaction is as follows：
（2）Preparation to fluorobenzyl bromide（II）：4- toluene fluorides and NBS are dissolved in solvent, prepared in the presence of initiator to fluorine benzyl Bromine（II）；Wherein, any of carbon tetrachloride or chloroform may be selected in solvent, and the preferably weaker chloroform of toxicity is as solvent；Trigger Any of BPO or AIBN, the preferably weaker BPO of toxicity may be selected in agent；Specific reaction is as follows：
（3）The bromo- 2- of 4-（4- luorobenzyls）The preparation of antifebrin（III）：Fluorobenzyl bromide and antisepsin are dissolved in solvent, By Louis acid catalysis, 70~80 ° of bromo- 2- of reaction synthesis 4-（4- luorobenzyls）Antifebrin（III）；Wherein, solvent is optional Any of ethyl acetate, carbon disulfide or nitrobenzene are selected, preferably toxicity is weak, and low boiling point ethyl acetate is as solvent；Louis This acid optional any of alchlor or alchlor, preferably cheap alchlor；Specific reaction is as follows：
（4）The bromo- 2- of 4-（4- luorobenzyls）The preparation of aniline（IV）：By the bromo- 2- of 4-（4- luorobenzyls）It is molten that antifebrin is dissolved in polarity In agent, the watery hydrochloric acid that molar concentration is 2-3mol/L is added, deacetylation protection prepares the bromo- 2- of 4-（4- luorobenzyls）Aniline （IV）；Wherein, any of tetrahydrofuran, methanol, ethanol or acetonitrile may be selected in solvent, and the preferably weak ethanol of toxicity is as molten Agent；Specific reaction is as follows：
（5）The bromo- 2- of 4-（4- luorobenzyls）The preparation of chlorobenzene（V）：By the bromo- 2- of 4-（4- luorobenzyls）It is 12mol/ that aniline, which is dissolved in concentration, L concentrated hydrochloric acid, mass ratio 1:2~4, diazotising is reacted with natrium nitrosum, after reaction completely, is closed with stannous chloride reaction chloro Into the bromo- 2- of 4-（4- luorobenzyls）Chlorobenzene（V）；Specific reaction is as follows：
（6）(S) preparation (VI) of -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran：By the bromo- 2- of 4-（4- luorobenzyls） Chlorobenzene with（S）- 3- hydroxyl tetrahydrofurans react in polar solvent, in the presence of highly basic, alkylated reaction synthesis (S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran (VI)；Wherein, methanol, ethanol, THF or acetonitrile may be selected in polar solvent Any of, preferably THF；Any of potassium tert-butoxide or sodium tert-butoxide, preferably potassium tert-butoxide may be selected in highly basic；It is specific anti- Should be as follows：
（7）The chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrofuran -3- bases epoxide-benzyl) The preparation of-benzene（VII）：(S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran is dissolved in solvent, with 2,3,4,6- Four-O- trimethyls silicon substrates-maltonic acid lactone reaction, are condensed under the catalysis of n-BuLi, then under the conditions of methanesulfonic acid, 1- chloro- 4- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrofuran -3- bases are prepared with methanol etherification Epoxide-benzyl)-benzene（VII）；Wherein, ether/toluene or tetrahydrofuran/toluene, preferably tetrahydrofuran/first may be selected in solvent Benzene；Specific reaction is as follows：
（8）Preparation net Yi Palie（VIII）：The chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S) - tetrahydrofuran -3- bases epoxide-benzyl)-benzene is dissolved in dichloromethane/acetonitrile system, and under Louis acid catalysis, silicon hydrogen is also It is net that former agent reduction demethoxylation prepares Yi Palie（VIII）；Wherein, zinc chloride, anhydrous Aluminum chloride or chlorination may be selected in lewis acid Any of lithium, preferably anhydrous Aluminum chloride；Any of trimethyl silicane hydrogen or triethyl group silicon hydrogen may be selected in silicon hydrogen reduction agent, It is preferred that triethyl group silicon hydrogen；Specific reaction is as follows：
Below by the synthesis technique that specific embodiment is net to Yi Palie of the present invention, it is described in detail：
The preparation (I) of the antisepsin of embodiment 1
Para-bromoaniline 171kg is taken, is dissolved in 300kg water, 30min is stirred under ice bath, the methanol solution of acetic anhydride is added dropwise（Acetic acid Acid anhydride 102kg+ methanol 200kg）, 30min is dripped off, and after dripping, 1h is stirred under ice bath, is then heated to room temperature and is continued to react 2h, After reaction terminates, filtering, filter cake is washed to neutrality, dry light yellow solid 210kg, yield 99%.
Preparation (II) of the embodiment 2 to fluorobenzyl bromide
4- toluene fluoride 110kg are taken, are dissolved in 500kg chloroforms, add 180kg NBS, BPO12kg is added, is warming up to 70 DEG C of backflows Reaction, 6h is reacted, after reaction terminates, is cooled to room temperature, is filtered, filtrate decompression recovery chloroform, Liquid Residue is evaporated under reduced pressure to pale yellow Color liquid 177kg, yield 95%.
The bromo- 2- of the 4- of embodiment 3（4- luorobenzyls）The preparation of antifebrin（III）
Take to fluorobenzyl bromide 94kg, antisepsin 110kg, be dissolved in 400kg ethyl acetate, stirred 30 minutes under ice bath, point Criticize and add aluminum trichloride (anhydrous) 70kg, continue to stir 30min under ice bath, then heat to room temperature and continue to react 2h, system liter Temperature continues to react 4h to 75 DEG C, and after reaction terminates, system is cooled to room temperature, and the dilute of frozen water 300kg, 3mol/L is added in system Salt acid for adjusting pH to 2-3, filtering, filtrate liquid separation, organic layer is washed to neutrality, anhydrous sodium sulfate drying, filtered, add in filtrate Enter 16kg activated carbon decolorizings, flow back 3h, filters while hot, and filtrate is cooled to room temperature, adds 300kg petroleum ethers, is crystallized under ice bath Light yellow solid 146kg, yield 91%.
The bromo- 2- of the 4- of embodiment 4（4- luorobenzyls）The preparation of aniline（IV）
Take the bromo- 2- of 4-（4- luorobenzyls）Antifebrin 146kg, the dissolving of 300kg ethanol is added, addition molar concentration is 2mol/L Watery hydrochloric acid 300kg, heating reflux reaction 8h, reaction terminate after, most of ethanol is removed under reduced pressure, with 1mol/L hydroxide Sodium solution adjusts Liquid Residue to pH to 8-9, separates out a large amount of yellow solids, filters, and filter cake is washed to neutrality, dry yellow solid 123kg, yield 97%.
The bromo- 2- of the 4- of embodiment 5（4- luorobenzyls）The preparation of chlorobenzene（V）
Take the bromo- 2- of 4-（4- luorobenzyls）Aniline 140kg, it is dissolved in 400kg concentrated hydrochloric acids, is cooled under ice bath<- 5 DEG C, nitrous is added dropwise The ice water solution of sour sodium（Natrium nitrosum 34kg+ frozen water 200kg）, 1h drips off, and controls temperature to be no more than 0 DEG C during dropwise addition, drop After adding, less than 0 DEG C reaction 2h, after completion of the reaction, stannous chloride 60kg is added in system, system is to slowly warm up to 60 DEG C 3h is reacted, separates out a large amount of solids after completion of the reaction, in system, is filtered, filter cake is washed to neutrality, solid ethyl acetate：Oil Ether（1:1）Recrystallize to obtain white crystals 132kg, yield 89%.
The preparation (VI) of embodiment 6 (S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran
Take the bromo- 2- of 4-（4- luorobenzyls）Chlorobenzene 148kg,（S）- 3- hydroxyl tetrahydrofuran 45kg, are dissolved in 300kg tetrahydrofurans, Ice bath is cooled to 0 DEG C, under nitrogen protection, and the tetrahydrofuran solution of potassium tert-butoxide is added dropwise（Potassium tert-butoxide 56kg, tetrahydrofuran 150kg）30min is dripped off, and is added dropwise, and 5-10 DEG C of reaction 1h, after reaction terminates, is added 300kg Shui temper and is gone out reaction, distillation recovery Tetrahydrofuran, Liquid Residue add the extraction of 300kg ethyl acetate, anhydrous sodium sulfate drying, filtering, filtrate recycling design, 70% ethanol Recrystallize to obtain white solid 161kg, yield 88%.
The chloro- 4- of the 1- of embodiment 7 (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrofuran -3- Base epoxide-benzyl)-benzene preparation (VII)
Take (S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran 183kg, anhydrous tetrahydro furan/toluene 400kg (1 ：4) mixed solvent is added in the 3000 liters of reactors dried through nitrogen, and liquid nitrogen is cooled to -78 °, and 1. 6 mol L are slowly added dropwise-1Just The hexane solution 345L of butyl lithium, maintain to stir 1h at a temperature of this；By be cooled to -78 DEG C the-O- trimethyls silicon substrates of 2,3,4,6- tetra- - The toluene solution 600kg of D-Glucose acid lactone (256kg) is slowly added dropwise into above-mentioned reaction solution, -78 ° of reactions 3 h, TLC After detecting fundamental reaction, methanol solution (the methanesulfonic acid 225kg+ methanol of 500kg Loprazolams is added at such a temperature 275kg)；In 0 DEG C of stirring reaction 4h, 40 DEG C of stirring reaction 6h are then heated to；5 mol•L-1Sodium hydrate aqueous solution add In reaction solution, pH is adjusted to 7-8；30min is stirred, is extracted with ethyl acetate (300kg × 2), organic phase saturated sodium-chloride The aqueous solution is washed to neutrality, then adds anhydrous sodium sulfate drying, and filtering, filtrate is concentrated to dryness, and obtains faint yellow sticky oil thing 208kg, yield 87%.
The preparation net Yi Palie of embodiment 8（VIII）
Take the chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrofuran -3- bases epoxide-benzyl Base)-benzene 208kg, dichloromethane 150kg and acetonitrile 450kg add in 3000L reactors, stir；Reaction solution cools down To -5 DEG C, 15kg aluminum trichloride (anhydrous)s are added, stir 30min, keep the temperature that 125kg Et are added dropwise3SiH, drop finish, and slowly rise Temperature reacts 2h to 10 DEG C.Reaction finishes, and is cooled to -5 DEG C, and saturated sodium bicarbonate solution is added dropwise, and adjusts pH to 6~7.Use acetic acid Ethyl ester (300kg × 2) is extracted, and organic phase washed with water, saturated nacl aqueous solution are washed to neutrality, then add anhydrous slufuric acid Sodium is dried, and filtering, filtrate decompression concentration and recovery ethyl acetate, adds 400kg methanol and dichloromethane (1:1) mixed solution, Stirring, a large amount of solids separate out, cooling and stirring 1h.Filtering, cold ethanol wash solid, and 30 DEG C are dried in vacuum overnight, and obtain white solid 138kg, yield 71%.Purity 99.32%.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The skill of the industry For art personnel it should be appreciated that the present invention is not limited to the above embodiments, described in above-described embodiment and specification is explanation The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and Its equivalent thereof.

Claims (7)

  1. A kind of 1. synthesis technique net Yi Palie, it is characterised in that：It is anti-through free radical bromo using 4- toluene fluorides as initiation material Should, gram alkylated reaction, deprotection are paid, diazotising chlorination, alkylated reaction obtains intermediate (S) -3- (4- (bromo- 2- chlorine of 5- Benzyl) phenoxy group) tetrahydrofuran, then with 2,3,4,6- tetra--O- trimethyls silicon substrates-D-Glucose acid lactone is through condensation, ether Change, it is net that demethoxylation obtains antidiabetic drug Yi Palie；Specifically comprise the following steps：
    （1）The preparation (I) of antisepsin：Para-bromoaniline is soluble in water, under ice bath, the methanol solution of acetic anhydride is added dropwise, After being added dropwise, 3-5h is reacted at room temperature, prepares antisepsin（I）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image002.jpg
    （2）Preparation to fluorobenzyl bromide（II）：4- toluene fluorides and NBS are dissolved in solvent, prepared in the presence of initiator to fluorine benzyl Bromine（II）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image004.jpg
    II
    （3）The bromo- 2- of 4-（4- luorobenzyls）The preparation of antifebrin（III）：Fluorobenzyl bromide and antisepsin are dissolved in solvent, The bromo- 2- of synthesis 4- are reacted by Louis acid catalysis（4- luorobenzyls）Antifebrin（III）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image006.jpg
    III
    （4）The bromo- 2- of 4-（4- luorobenzyls）The preparation of aniline（IV）：By the bromo- 2- of 4-（4- luorobenzyls）Antifebrin is dissolved in water solubility In solvent, the watery hydrochloric acid that molar concentration is 2-3mol/L is added, deacetylation protection prepares the bromo- 2- of 4-（4- luorobenzyls）Aniline （IV）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image008.jpg
    IV
    （5）The bromo- 2- of 4-（4- luorobenzyls）The preparation of chlorobenzene（V）：By the bromo- 2- of 4-（4- luorobenzyls）Aniline is dissolved in molar concentration In 12mol/L concentrated hydrochloric acid, diazotising is reacted with natrium nitrosum, after reaction completely, it is bromo- to synthesize 4- with stannous chloride reaction chloro 2-（4- luorobenzyls）Chlorobenzene（V）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image010.jpg
    V
    （6）(S) preparation (VI) of -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran：By the bromo- 2- of 4-（4- luorobenzyls） Chlorobenzene with（S）- 3- hydroxyl tetrahydrofurans, which are dissolved in polar solvent, to react, in the presence of highly basic, alkylated reaction synthesis (S)- 3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran (VI)；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image012.jpg
    （7）The chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrofuran -3- bases epoxide-benzyl Base)-benzene preparation（VII）：(S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrofuran is dissolved in solvent, and 2,3, 4,6- tetra--O- trimethyls silicon substrates-maltonic acid lactone reaction, are condensed under the catalysis of n-BuLi, then in methanesulfonic acid bar Under part, reacted with methanol, etherificate prepares 1- chloro- 4- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S)-tetrahydrochysene furan Mutter -3- bases epoxide-benzyl)-benzene（VII）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image014.jpg
    VII
    （8）Preparation net Yi Palie（VIII）：The chloro- 4- of 1- (1- methoxy-D-glucopyranos -1- bases) -2- (4- (S) - tetrahydrofuran -3- bases epoxide-benzyl)-benzene is dissolved in dichloromethane/acetonitrile, and under Louis acid catalysis, silicon hydrogen reduction agent is also It is net that former demethoxylation prepares Yi Palie（VIII）；Specific reaction is as follows：
    Explanation:Explanation: D:Software cpc cases inventions e8aecd91-e536-4ad5-8f9c-aaabed5899ca new 100001 dest_path_image016.jpg。
  2. 2. synthesis technique net Yi Palie according to claim 1, it is characterised in that：The step（2）In, solvent is optional Any of carbon tetrachloride or chloroform are selected, any of BPO or AIBN may be selected in initiator.
  3. 3. synthesis technique net Yi Palie according to claim 1, it is characterised in that：The step（3）In, solvent is optional Any of ethyl acetate, carbon disulfide or nitrobenzene are selected, times in alchlor or alchlor may be selected in lewis acid It is a kind of.
  4. 4. synthesis technique net Yi Palie according to claim 1, it is characterised in that：The step（4）In, solvent is optional Select any of tetrahydrofuran, methanol, ethanol or acetonitrile.
  5. 5. synthesis technique net Yi Palie according to claim 1, it is characterised in that：The step（6）In, polar solvent Any of methanol, ethanol, THF or acetonitrile may be selected, any of potassium tert-butoxide or sodium tert-butoxide may be selected in highly basic.
  6. 6. synthesis technique net Yi Palie according to claim 1, it is characterised in that：The step（7）In, solvent is optional Select any of ether/toluene or tetrahydrofuran/toluene solvant system.
  7. 7. synthesis technique net Yi Palie according to claim 1, it is characterised in that：The step（8）In, lewis acid Any of zinc chloride, anhydrous Aluminum chloride or lithium chloride may be selected, trimethyl silicane hydrogen or triethyl group may be selected in silicon hydrogen reduction agent Any of silicon hydrogen.
CN201710674023.4A 2017-08-09 2017-08-09 A kind of synthesis technique net Yi Palie Pending CN107652278A (en)

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CN109053400A (en) * 2018-08-24 2018-12-21 江苏工程职业技术学院 A kind of preparation method of Lei Dipawei key intermediate
CN109374782A (en) * 2018-12-21 2019-02-22 安徽联创生物医药股份有限公司 A method of with the related substance of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie
CN109456314A (en) * 2018-10-19 2019-03-12 威海迪素制药有限公司 A kind of preparation method that En Gelie is net
CN110683998A (en) * 2019-11-20 2020-01-14 杭州华东医药集团浙江华义制药有限公司 Preparation method of empagliflozin intermediate

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
CN109053400A (en) * 2018-08-24 2018-12-21 江苏工程职业技术学院 A kind of preparation method of Lei Dipawei key intermediate
CN109456314A (en) * 2018-10-19 2019-03-12 威海迪素制药有限公司 A kind of preparation method that En Gelie is net
CN109374782A (en) * 2018-12-21 2019-02-22 安徽联创生物医药股份有限公司 A method of with the related substance of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie
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CN110683998A (en) * 2019-11-20 2020-01-14 杭州华东医药集团浙江华义制药有限公司 Preparation method of empagliflozin intermediate

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