CN109456314A - A kind of preparation method that En Gelie is net - Google Patents
A kind of preparation method that En Gelie is net Download PDFInfo
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- CN109456314A CN109456314A CN201811218393.8A CN201811218393A CN109456314A CN 109456314 A CN109456314 A CN 109456314A CN 201811218393 A CN201811218393 A CN 201811218393A CN 109456314 A CN109456314 A CN 109456314A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 11
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 9
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims abstract description 5
- VOLMSPGWNYJHQQ-UHFFFAOYSA-N Pyranone Natural products CC1=C(O)C(=O)C(O)CO1 VOLMSPGWNYJHQQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000009754 Vitis X bourquina Nutrition 0.000 claims abstract description 5
- 235000012333 Vitis X labruscana Nutrition 0.000 claims abstract description 5
- 235000014787 Vitis vinifera Nutrition 0.000 claims abstract description 5
- 125000004803 chlorobenzyl group Chemical group 0.000 claims abstract description 5
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 4
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 240000006365 Vitis vinifera Species 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 42
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000011347 resin Substances 0.000 claims description 5
- 229920005989 resin Polymers 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- JBQLQIMCKFDOHK-UHFFFAOYSA-N Stephanol Natural products CC(O)C1(O)CCC2(O)C3(O)CC=C4CC(O)CCC4(C)C3C(O)C(O)C12C JBQLQIMCKFDOHK-UHFFFAOYSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims 1
- 229910000077 silane Inorganic materials 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- -1 then Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical class CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000004519 grease Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005352 clarification Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 238000010583 slow cooling Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 241000219095 Vitis Species 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 2
- 229960003345 empagliflozin Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 1
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical class C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The present invention relates to a kind of preparation methods that En Gelie is net, belong to bulk pharmaceutical chemicals preparation technical field.Preparation method of the present invention, first by 2,3,4,6- tetra--O- (trimethylsilyl)-D- grape pyranone is reacted with Grignard Reagent prepared by (S) -3- [4- (the chloro- benzyl of the iodo- 2- of 5-)-phenoxy group]-tetrahydrofuran, then, methanol is added and acid cation exchange resin is converted into formula II；Formula II obtains chemical compounds I through reduction.Preparation method of the present invention reduces the waste water in technical process, is good for the environment；Easy operation, it is easily operated in industrialized production；Furthermore the yield of product and purity have a distinct increment.
Description
Technical field
The present invention relates to a kind of preparation methods that En Gelie is net, belong to bulk pharmaceutical chemicals preparation technical field.
Background technique
En Gelie net (empagliflozin) also known as Empagliflozin, Ai Gelie be net, Yi Palie is net, in May, 2014 takes the lead in
It is listed in Europe, later in Augusts, 2014 and December respectively in the U.S. and Japan's listing, and in September, 2017 in Discussion on Chinese Listed.
The medicine be by German Boehringer Ingelheim company and Lilly Co., Eli.'s R & D Cooperation sodium glucose cotransporter 2 (
SGLT-2) inhibitor is a kind of novel oral hypoglycemic agents.
Patent WO 2006/120208 (CN103524468A) discloses a kind of net preparation method of En Gelie, referring to implementation
Example XVIII scheme E, detailed process is as follows: in low temperature by (S) -3- [4- (the chloro- benzyl of the iodo- 2- of 5-)-phenoxy group]-tetrahydro furan
Mutter andi- PrMgCl/LiCl carries out halogen-metal exchange in THF, and 2,3,4,6- tetra--O- (trimethyl silanes are then added
Base) the progress addition reaction of-D- grape pyranone, end of reaction, addition NH4Cl aqueous solution (mass fraction 25%) terminates anti-
It answers, then adds methyl t-butyl ether liquid separation, isolate the organic layer containing intermediate product, intermediate product regenerates ketal, finally
It is net that En Gelie is obtained through reduction.
Patent CN201080042705 points out that above-mentioned patent (CN103524468A) method is in addition methyl t-butyl ether
Later, it is intended to observe that the separation of aqueous layer and organic layer causes difficulty when amplifying the scale of this method, such as will form three
Phase.Based on problem above, patent CN201080042705 replaces ammonium chloride with organic acid in quenching reaction, is easy to after being quenched point
Liquid, and it is net to finally obtain En Gelie.But this method is quenched liquid separation process and can generate a large amount of acid waste waters, is unfavorable for environmental protection, and
And must liquid separation just can be carried out subsequent step, operate relatively cumbersome.
Summary of the invention
Goal of the invention: for technical problem present in the net bulk pharmaceutical chemicals synthesis process of existing En Gelie, a kind of be suitble to is provided
The En Gelie net system Preparation Method of industrialized production.
Technical solution of the present invention relates generally to the preparation method of En Gelie net (chemical compounds I) a kind of, first compound III
Compound ii is generated with IV reaction, II obtains chemical compounds I using reduction, and reaction equation is as follows:
。
Specific reaction step are as follows:
(S) -3- shown in tetra--O- of 2,3,4,6- shown in first step formula III (trimethylsilyl)-D- grape pyranone and formula IV
The Grignard Reagent reaction of [4- (the chloro- benzyl of the iodo- 2- of 5-)-phenoxy group]-tetrahydrofuran preparation, reaction temperature are -30 ~ -20 DEG C；
Second step reacts in gained mixture to the first step, and methanol is added and acid cation exchange resin is converted into the change of formula II
Object is closed, the acid cation exchange resin is selected from Dowex50WX8-400-H+；
Third step II obtains chemical compounds I by reduction, and reducing agent is triethylsilane.
Preferably, at the first step -30 ~ -20 DEG C, into IV compound of formula, compound III is slowly added dropwise, after being added dropwise,
- 10 ~ -5 DEG C are warming up to, the reaction was continued.
Preferably, second step methanol usage is 0.5 ~ 5.0 times of compounds Ⅳ quality.
Preferably, second step is added acid cation and exchanges resin Dowex50WX8-400-H+Afterwards, reaction temperature be 25 ~
65℃.More preferable 60 ~ 65 DEG C.
Preferably, second step is added acid cation and exchanges resin Dowex50WX8-400-H+Amount be compounds Ⅳ matter
0.15 ~ 0.40 times of amount.
Preferably, the dosage of third step reducing agent triethylsilane is 1.0 ~ 3.5 times of compounds Ⅳ quality.
The utility model has the advantages that
The characteristics of technical solution of the present invention, is: tetra--O- of 2,3,4,6- shown in formula III (trimethylsilyl)-D- grape pyranone and
After the Grignard Reagent reaction of [4- (the chloro- benzyl of the iodo- 2- of 5-)-the phenoxy group]-tetrahydrofuran of (S) -3- shown in formula IV preparation, first is used
Pure and mild acid cation exchange resin quenching reaction, is converted into key intermediate compound II without isolation, beneficial to effect
Fruit is as follows: using non-aqueous system quenching reaction, reduces the generation of waste water, be good for the environment, reduce the net manufacturing cost of En Gelie；
Subsequent operation is directly carried out without liquid separation after being quenched, easy operation；And the net purity and yield of En Gelie of this method preparation
It is good.
Preparation method of the present invention reduces the waste water in technical process, is good for the environment；Easy operation, industrialization
It is easily operated in production；Furthermore the yield of product and purity have a distinct increment.
Specific embodiment:
For a better understanding of the present invention, it is described further combined with specific embodiments below, but the present invention is not limited to this.
Test example 1: the preparation of compounds Ⅳ
130 Kg tetrahydrofurans and 52 Kg (3S) -3- [4- [(the chloro- 5- iodo of 2-) methyl] phenoxy group] are added into reaction kettle
Tetrahydrofuran stirs dissolved clarification, is cooled to -25 DEG C, isopropylmagnesium chloride/lithium chloride solution that concentration is about 1mol/L is slowly added dropwise
125 temperature control≤- 20 DEG C Kg().Drop finishes, and insulation reaction 0.5 hour.After reactant is directly used in without processing according to the rate of producing at full capacity
Continuous reaction.
Test example 2: the preparation of compound III
32 Kg D-Glucose acid lactones, 360 Kg tetrahydrofurans, 149 Kg N- methylmorphines are sequentially added into reaction kettle
Quinoline, stirring are cooled to -5 DEG C, and 118 Kg trim,ethylchlorosilanes (temperature control≤5 DEG C) are added dropwise.Drop, which finishes, to be warming up to 35 DEG C and is stirred to react 5
Hour, it is cooled to 25 DEG C and reacts 12 hours.After completion of the reaction, the stirring of 360 Kg toluene, and fast cooling are added into reaction solution
To -5 DEG C.1300 Kg water (temperature control≤10 DEG C) are added dropwise, drips and finishes stirring 0.5 hour, stand liquid separation.Separate organic phase, lower layer's water phase
It is primary with the extraction of 120 Kg toluene.Merge organic phase and successively with 160 Kg, 8% sodium bicarbonate solution, 160 Kg water and 160 Kg
25% sodium chloride solution washed once.Organic phase obtains light yellow liquid after being concentrated under reduced pressure, and is not required to purify, directly use according to the rate of producing at full capacity
In in next step.
Embodiment 1: the preparation of compound ii
1 gained compounds Ⅳ of test example is down to -25 DEG C, compound III (preparing according to test example 2) is slowly added dropwise, drop finishes, and rises
Temperature continues stirring 1 hour to -5 DEG C at this temperature.After completion of the reaction, 22 Kg of methanol is added dropwise, stirs 0.5 hour, is added
17 Kg of cation exchange resin (Dowex50WX8-400-H+), is warming up to 25 DEG C, filters after being stirred to react 12 hours, filtrate
It is concentrated under reduced pressure, obtains thick pale yellow grease, be not required to purifying and directly throw into reaction in next step.
Embodiment 2: the preparation of chemical compounds I
205 Kg anhydrous acetonitriles, 36 Kg anhydrous AlCl3s are added into reaction kettle, the stirring of 45Kg triethylsilane is cooled to -10
℃.1 gained grease of embodiment is dissolved in 140 Kg methylene chloride, is instilled in said mixture, drop finishes, and is warming up to 20 DEG C, protects
Temperature reaction 1 hour.After completion of the reaction, it is cooled to 0 DEG C, 230 Kg water (temperature control≤10 DEG C) are slowly added into reaction solution, is depressurized
275 Kg isopropyl acetates are added in concentration, are concentrated under reduced pressure.275 Kg isopropyl acetates are added into above-mentioned concentrate, are warming up to
45 DEG C, insulated and stirred 0.5 hour.Slow cooling continues stirring 4 hours to 10 DEG C in 3 hours.Filtering, a small amount of acetic acid of filter cake
After isopropyl ester (20 Kg) elution, baking material 4 hours (loss on drying≤1%) in 65 DEG C of air dry ovens, off-white powder is obtained.
150 Kg, 80% ethyl alcohol is added in above-mentioned solid, is heated to 75 DEG C of stirring dissolved clarifications.It filters while hot, slow cooling is to 0 in 8 hours
℃.Filtering, filter cake is eluted with dehydrated alcohol (20 Kg), baking material 4 hours (loss on drying≤1%) in 65 DEG C of air dry ovens,
46.4 Kg whites are obtained to the net crude product of off-white color En Gelie, purity > 99.5%, yield 82%(is in terms of compounds Ⅳ).
Embodiment 3: the preparation of compound ii
1 gained compounds Ⅳ of test example is down to -20 DEG C, compound III (preparing according to test example 2) is slowly added dropwise, drop finishes, and rises
Temperature continues stirring 1 hour to -5 DEG C at this temperature.After completion of the reaction, methanol 218Kg is added dropwise, stirs 0.5 hour, is added
Cation exchange resin (Dowex50WX8-400-H+) 6.5 Kg, 60 DEG C are warming up to, is reacted 0.5 hour.Filtering, filtrate subtract
Pressure concentration, obtains thick pale yellow grease, is not required to purifying and directly throws into reaction in next step.
Embodiment 4: the preparation of chemical compounds I
200 Kg anhydrous acetonitriles, the anhydrous AlCl of 90 Kg are added into reaction kettle3, 153 Kg triethylsilanes stirring be cooled to-
10℃.140 Kg methylene chloride will be dissolved according to grease obtained by 1 method of embodiment, instilled in said mixture, drop finishes, heating
To 25 DEG C, insulation reaction 1 hour.After completion of the reaction, 5 DEG C are cooled to, 230 Kg water (temperature control≤10 are slowly added into reaction solution
DEG C), it is concentrated under reduced pressure, 300 Kg isopropyl acetates is added, be concentrated under reduced pressure.300 Kg isopropyl acetates are added into above-mentioned concentrate
Ester is warming up to 50 DEG C, insulated and stirred 0.5 hour.Slow cooling continues stirring 4 hours to 10 DEG C in 3 hours.Filtering, filter cake are used
After a small amount of isopropyl acetate (20 Kg) elution, baking material 4 hours (loss on drying≤1%) in 65 DEG C of air dry ovens, it is white to obtain class
Color solid.200 Kg, 70% ethyl alcohol is added in above-mentioned solid, is heated to 75 DEG C of stirring dissolved clarifications.It filters while hot, in 8 hours slowly
It is cooled to 5 DEG C.Filtering, filter cake are eluted with dehydrated alcohol (10 Kg), 4 hours (losss on drying of baking material in 65 DEG C of air dry ovens
≤ 1%) 24.9 Kg whites, are obtained to the net crude product of off-white color En Gelie, purity > 99.9%, yield 78%(is in terms of compounds Ⅳ).
Embodiment 5: the preparation of compound ii
1 gained compounds Ⅳ of test example is down to -30 DEG C, compound III (preparing according to test example 2) is slowly added dropwise, drop finishes, and rises
Temperature continues stirring 1 hour to -10 DEG C at this temperature.After completion of the reaction, methanol 152Kg is added dropwise, stirs 0.5 hour, is added
Cation exchange resin (Dowex50WX8-400-H+) 11 Kg, 65 DEG C are warming up to, is reacted 0.5 hour.Filtering, filtrate decompression
Concentration, obtains thick pale yellow grease, is not required to purifying and directly throws into reaction in next step.
Embodiment 6: the preparation of chemical compounds I
240 Kg anhydrous acetonitriles, the anhydrous AlCl of 60 Kg are added into reaction kettle3, 96 Kg triethylsilanes stirring be cooled to-
10℃.180 Kg methylene chloride will be dissolved according to grease obtained by 1 method of embodiment, instilled in said mixture, drop finishes, heating
To 25 DEG C, insulation reaction 1 hour.After completion of the reaction, it is cooled to 0 DEG C, 230 Kg water (temperature control≤10 are slowly added into reaction solution
DEG C), it is concentrated under reduced pressure, 300 Kg isopropyl acetates is added, be concentrated under reduced pressure.300 Kg isopropyl acetates are added into above-mentioned concentrate
Ester is warming up to 50 DEG C, insulated and stirred 0.5 hour.Slow cooling continues stirring 4 hours to 5 DEG C in 3 hours.Filtering, filter cake are used
After a small amount of isopropyl acetate (20 Kg) elution, baking material 4 hours (loss on drying≤1%) in 65 DEG C of air dry ovens, it is white to obtain class
Color solid.220 Kg, 90% ethyl alcohol is added in above-mentioned solid, is heated to 75 DEG C of stirring dissolved clarifications.It filters while hot, in 8 hours slowly
It is cooled to 5 DEG C.Filtering, filter cake are eluted with dehydrated alcohol (15 Kg), 4 hours (losss on drying of baking material in 65 DEG C of air dry ovens
≤ 1%) 48.1 Kg whites, are obtained to the net crude product of off-white color En Gelie, purity > 99.0%, yield 88%(is in terms of compounds Ⅳ).
Claims (7)
1. a kind of preparation method of the net bulk pharmaceutical chemicals of En Gelie, which comprises the following steps:
(S) -3- shown in tetra--O- of 2,3,4,6- shown in first step formula III (trimethylsilyl)-D- grape pyranone and formula IV
The Grignard Reagent reaction of [4- (the chloro- benzyl of the iodo- 2- of 5-)-phenoxy group]-tetrahydrofuran preparation, reaction temperature are -30 ~ -20 DEG C；
Second step reacts in gained mixture to the first step, and methanol is added and acid cation exchange resin is converted into II chemical combination of formula
Object, the acid cation exchange resin are selected from Dowex50WX8-400-H+；
Third step II obtains chemical compounds I by reduction, and reducing agent is triethylsilane, and reaction equation is as follows:
。
2. the preparation method of the net bulk pharmaceutical chemicals of En Gelie according to claim 1, which is characterized in that at the first step -30 ~ -20 DEG C,
Into IV compound of formula, compound III is slowly added dropwise, after being added dropwise, is warming up to -10 ~ -5 DEG C, the reaction was continued.
3. the preparation method of the net bulk pharmaceutical chemicals of En Gelie according to claim 1, which is characterized in that second step methanol usage is to change
0.5 ~ 5.0 times for closing IV mass of object.
4. the preparation method of the net bulk pharmaceutical chemicals of En Gelie according to claim 1, which is characterized in that second step be added acid sun from
Son exchange resin Dowex50WX8-400-H+Afterwards, reaction temperature is 25 ~ 65 DEG C.
5. the preparation method of the net bulk pharmaceutical chemicals of En Gelie according to claim 1, which is characterized in that second step be added acid sun from
Son exchange resin Dowex50WX8-400-H+Afterwards, reaction temperature is 60 ~ 65 DEG C.
6. the preparation method of the net bulk pharmaceutical chemicals of En Gelie according to claim 1, which is characterized in that second step be added acid sun from
Son exchange resin Dowex50WX8-400-H+Amount be 0.15 ~ 0.40 times of compounds Ⅳ quality.
7. the preparation method of the net bulk pharmaceutical chemicals of En Gelie according to claim 1, which is characterized in that third step reducing agent triethyl group
The dosage of silane is 1.0 ~ 3.5 times of compounds Ⅳ quality.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112574186A (en) * | 2020-12-22 | 2021-03-30 | 山东永丞制药有限公司 | Refining method of engagliflozin |
| CN116063294A (en) * | 2022-12-13 | 2023-05-05 | 山东能源集团新材料有限公司 | A kind of preparation method and process system of empagliflozin bulk drug |
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| CN112574186A (en) * | 2020-12-22 | 2021-03-30 | 山东永丞制药有限公司 | Refining method of engagliflozin |
| CN116063294A (en) * | 2022-12-13 | 2023-05-05 | 山东能源集团新材料有限公司 | A kind of preparation method and process system of empagliflozin bulk drug |
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