CN106632288A - Method for preparing empagliflozin - Google Patents
Method for preparing empagliflozin Download PDFInfo
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- CN106632288A CN106632288A CN201610975986.3A CN201610975986A CN106632288A CN 106632288 A CN106632288 A CN 106632288A CN 201610975986 A CN201610975986 A CN 201610975986A CN 106632288 A CN106632288 A CN 106632288A
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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
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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
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Abstract
The invention provides a method for preparing empagliflozin. The method comprises the following steps: by taking (S)-3-(4-(5-bromine-2-chlorobenzyl) phenoxyl) tetrahydrofuran and glucolactone as initial raw materials, performing coupling so as to obtain an intermediate compound 3, performing etherification so as to obtain an intermediate compound 4, performing reduction so as to obtain a crude empagliflozin compound 5, and performing refining, thereby obtaining a qualified empagliflozin finished product.
Description
Technical field
The invention belongs to technical field of medicine synthesis, more particularly to the preparation method that a kind of En Gelie is net.
Background technology
Diabetes are one group of metabolic diseases being characterized with hyperglycaemia.Hyperglycaemia be then due to defect of insulin secretion or
Its biological agent is damaged, or both have concurrently and cause.Long-standing hyperglycaemia during diabetes, cause various tissues, particularly eye,
Kidney, heart, blood vessel, chronic lesion, the dysfunction of nerve.
En Gelie is the selective 2 type sodium glucose collaboration of one kind of German Boehringer Ingelheim companies research and development only
Transport protein (SGLT2) inhibitor, obtains FDA and ratifies for treating diabetes B in August, 2014.SGLT2 inhibitor is mainly led to
The SGLT2 for suppressing to be expressed in kidney is crossed, reabsorption of the kidney to glucose is reduced, increases the excretion of glucose in urine, so as to
Plasma glucose levels are reduced, and the hypoglycemic effect does not rely on β cell functions and insulin resistance.
At present, the net methods of En Gelie are prepared, because synthesis route is relatively complicated, severe reaction conditions are difficult to reach
Arrive, the reason such as starting material is difficult to obtain causes the En Gelie net products yield that obtains not high and quality is unstable.
The content of the invention
It is an object of the invention to provide a kind of En Gelie net preparation method, it is intended to solve prior art and prepare En Gelie
Net method synthesis route is loaded down with trivial details, severe reaction conditions, starting material are difficult to obtain, and causes the En Gelie net products for obtaining
The problem that yield is not high and quality is unstable.
The present invention is achieved in that a kind of net preparation methods of En Gelie, comprises the following steps：
The THF solution of compound 1 is provided, under an inert atmosphere, the THF that temperature control -90～-85 DEG C are added dropwise n-BuLi is molten
Liquid, 30～60min of stir process；Continue temperature control -90～-85 DEG C, the THF solution of compound 2, stirring reaction 1～3 hour is added dropwise
After be quenched, prepare compound 3, reaction equation is as follows：
The compound 3 is dissolved in methyl alcohol and obtains the solution of compound 3, add stirring after Loprazolam to be warming up to 40～43
DEG C, it is quenched after reaction 3-5 hours, compound 4 is prepared, reaction equation is as follows：
The compound 4 is dissolved in dichloromethane and obtains the solution of compound 4, stir process after acetonitrile is added, in inertia
Under atmosphere, temperature control -20～-10 DEG C are added dropwise triethyl silicane, after 30～60min of stirring reaction, boron chloride ether are added dropwise, and stir
It is quenched after mixing reaction 2～5 hours, prepares compound 5, reaction equation is as follows：
The compound 5, ethanol is placed in reactor, temperature rising reflux is molten obtains the solution of compound 5 clearly for stirring；Described
After activated carbon backflow 30～60min of decolouring is added in the solution of compound 5, heat filtering process is carried out, collect filtrate；By the filtrate
55～60 DEG C are warming up to, crystal seed is added, 45～50 DEG C are cooled to, after separating out white solid, stirring and crystallizing 1～2 hour；It is cooled to
10～15 DEG C, stirring and crystallizing 1～2 hour is collected by filtration filter cake, En Gelie is obtained after cleaned, dried process net (EMPA).
The En Gelie for providing of the invention net preparation method, with (S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) tetrahydrochysene
Furans and glucolactone are coupled for initiation material Jing and the prepared midbody compound 4 of midbody compound 3, etherificate are obtained, go back
The original net crude Compounds 5 of prepared En Gelie, are refining to obtain the net finished products of qualified En Gelie.The En Gelie for providing of the invention net system
Preparation Method, not only preparation process is simple, convenient, and preparation efficiency is high, can obtain steady quality, controllable En Gelie and produce only
Product.Specifically, in the En Gelie net products of the different batches for preparing according to the inventive method, compound 4, the chemical combination of following structures
Thing 6, compound 7, compound 8, compound 9 are not detected, content≤0.058% of isomeric compound 10 of following structures；
And in the En Gelie net products of the different batches for obtaining, maximum unknown list is miscellaneous≤0.040%, total impurities≤
0.066%, residue on ignition≤0.11%, the standard of heavy metal satisfaction≤20ppm, chloride meet≤0.01% standard, grace
Lattice row net products purity >=99.39%；Molar yield >=84.15%.
Specific embodiment
In order that the technical problem to be solved in the present invention, technical scheme and beneficial effect become more apparent, below in conjunction with
Embodiment, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only to explain
The present invention, is not intended to limit the present invention.
A kind of net preparation methods of En Gelie are embodiments provided, is comprised the following steps：
S01. the THF solution of compound 1 is provided, under an inert atmosphere, temperature control -90～-85 DEG C are added dropwise the THF of n-BuLi
Solution, 30～60min of stir process；Continue temperature control -90～-85 DEG C, the THF solution of compound 2 is added dropwise, stirring reaction 1～3 is little
When after be quenched, prepare compound 3, reaction equation is as follows：
S02. the compound 3 is dissolved in methyl alcohol and obtains the solution of compound 3, add stirring after Loprazolam to be warming up to 40
～43 DEG C, it is quenched after reaction 3-5 hours, prepares compound 4, reaction equation is as follows：
S03. the compound 4 is dissolved in dichloromethane and obtains the solution of compound 4, add stir process after acetonitrile,
Under inert atmosphere, temperature control -20～-10 DEG C are added dropwise triethyl silicane, after 30～60min of stirring reaction, boron chloride second are added dropwise
Ether, stirring reaction is quenched after 2～5 hours, prepares compound 5, and reaction equation is as follows：
S04. the compound 5, ethanol is placed in reactor, temperature rising reflux is molten obtains the solution of compound 5 clearly for stirring；
After activated carbon backflow 30～60min of decolouring is added in the solution of the compound 5, heat filtering process is carried out, collect filtrate；Will be described
Filtrate is warming up to 55～60 DEG C, adds crystal seed, is cooled to 45～50 DEG C, after separating out white solid, stirring and crystallizing 1～2 hour；Drop
To 10～15 DEG C, stirring and crystallizing 1～2 hour is collected by filtration filter cake to temperature, obtains En Gelie after cleaned, dried process net
(EMPA)。
In above-mentioned steps S01, the compound 1, the compound 2 and n-BuLi form in organic solvent reactant
System, by coupling reaction compound 3 is prepared.
Wherein, the compound 2 can commercially buy acquisition, it is also possible to voluntarily prepare.When voluntarily preparing institute
When stating compound 2, the preparation method of the compound 2 is as follows：
In a kettle. add glucolactone, N- methyl woodss, THF, stir process, under an inert atmosphere, temperature control-
5～0 DEG C, trim,ethylchlorosilane is added dropwise, is warming up to 20～25 DEG C, stirring reaction 15-20 hour prepares compound 2.This
Bright embodiment, by the effect of alkaline matter N- methyl woodss, using the trim,ethylchlorosilane as protection reagent, described
Trimethyl silyl protecting group is introduced on the hydroxyl of glucolactone.
Specifically, above-mentioned preparation reaction is carried out in an inert atmosphere, it is to avoid the oxidation of product.The inert atmosphere include but
It is not limited to nitrogen atmosphere.Because heat release is more acute when the trim,ethylchlorosilane and the N- methyl woods reacting generating complex
It is strong, therefore, the trim,ethylchlorosilane is added dropwise, temperature control -5～0 DEG C is needed, to avoid reaction excessively violent.Further, it is being added dropwise
After the trim,ethylchlorosilane, be warming up to 20～25 DEG C, stirring reaction 15-20 hour, concretely 15 hours, 16 hours, 17
Hour, 18 hours, 19 hours, 20 hours, to promote the reaction of complex compound and the glucolactone, prepare compound
2。
Preferably, after completion of the reaction, can add quencher that reaction is quenched.The embodiment of the present invention is due to the polarity of compound 2
It is less, normal heptane is preferably added in reaction system, it is cooled to -5 DEG C.Temperature control -5～5 DEG C, are slowly added dropwise purified water and are quenched, can
To avoid exothermic reaction excessively violent.5～10 DEG C of stir process of Bi Shengzhi are added dropwise, reaction is quenched, the time is 20-40 point
Clock, concretely 30 minutes.
It is further preferred that being quenched after reaction, below 10 DEG C of temperature control, organic phase is collected in reaction system layering, and water is mutually used again
Normal heptane is extracted once, merges organic phase.Below 10 DEG C of embodiment of the present invention temperature control, reaction system layered effect is more good,
And beneficial to the extraction of the reactant 2, improve yield.After collecting organic phase, successively with saturation biphosphate sodium water solution, purifying
Water, saturated nacl aqueous solution respectively washed once, the preferred washing system, can comprehensively reduce what is may introduced in reaction system
Various impurity.Continue (beneficial to extraction, to improve yield) below 10 DEG C of temperature control, organic phase is collected and combined after layering, use anhydrous slufuric acid
Sodium is dried.Dried organic phase is carried out into filtration treatment, solid material has been incorporated into normal heptane phase is collected after normal heptane drip washing
In machine phase.Below 40 DEG C of temperature control, organic filtrate is decompressed to dry, is steamed once with normal heptane band, obtain highly purified compound 2.
Coupling reaction described in the embodiment of the present invention between compound 1, the compound 2 is carried out under an inert atmosphere, can
To avoid reactant from aoxidizing, and then improve the purity and yield of product.The inert atmosphere includes but is not limited to nitrogen gas
Atmosphere.Specifically, after the compound 1 is added in reactor, inert atmosphere protection is filled with, sequentially adds other raw materials.
In the embodiment of the present invention, first the solution of the compound 1 is added in reactor, n-BuLi is then added dropwise
Solution, Jing after being sufficiently stirred for processing, is added dropwise the solution of the compound 2.Specifically, the solution of the compound 1, the positive fourth
The solution of the solution of base lithium, the compound 2, it is preferred to use same organic solvent dissolves to be formed respectively.Specifically, adopt
Used as solubilising reagent, each material can obtain preferable solute effect to THF.The embodiment of the present invention respectively by the compound 1,
Compound 2, n-BuLi is dissolved in TFA, obtains THF solution, the THF solution of compound 2, the normal-butyl of corresponding compound 1
The THF solution of lithium.Preferably, in the step of preparing the compound 3, the compound 1, the mass ratio of compound 2 are (3.0
～3.5):(5.5～6.0), be particularly preferred as the compound 1, compound 2 mass ratio be 3.2：5.9.By above-mentioned quality
The regulation and control of ratio, on the premise of reaction efficiency is ensured, can as far as possible improve the yield and purity of compound 3, additionally, may be used also
To avoid the waste of material.
Because the n-BuLi chemical reactivity is very high, in order to avoid excessively acute reaction, rate of addition is unsuitable too fast, should
It is slowly added dropwise as far as possible.When the THF solution of the n-BuLi is added dropwise, temperature fluctuation is unsuitable excessive, needs temperature control -90～-85 DEG C, and one
Aspect can avoid reaction excessively acutely, on the other hand, it is often more important that, this temperature can be excellent with formation condition, non-caking
Reaction system so that reaction is fully, completely, and then purity it is high, substantially without the product of miscellaneous point generation.When temperature is reaction temperature
Spend for -80～-70 DEG C when, though can react complete, the impurities phase of reaction system is to more, and product purity and income are low；When
When reaction temperature is less than the temperature range, reactant liquor solidification caking causes reaction incomplete.After completion of dropping, stir process 30
～60min, makes the compound 1 fully react with the n-BuLi, specifically, mixing time can for 30min, 45min,
60min.Based on the reason for same, when being slowly added dropwise the THF solution of the compound 2, temperature control -90～-85 DEG C, it is to avoid reacted
In violent.Further, for reactant substantially efficiently reacting generating compound 3, stirring reaction 1～3 hour, concretely
1 hour, 2 hours, 3 hours etc..During stirring reaction, reaction monitoring detection reaction end can be carried out.Specifically, after sampling,
The point sample on TCL, with volume ratio as 5：1 EA：PE when raw material point disappears on TCL, is then considered as and has reacted as mobile phase
Entirely.
After the completion of reaction, add quencher that reaction is quenched in reaction system.Preferably, it is described that being quenched for employing is quenched
Agent is the aqueous ammonium chloride solution that mass percentage concentration is 20～28%, is particularly preferred as the ammonium chloride that mass percentage concentration is 25%
The aqueous solution.Specifically, when adding quencher, below 10 DEG C of temperature control, finish, be warmed to room temperature (15-30 DEG C) stirring 10-20min, tool
Body can be 10min, 15min, 20min.The embodiment of the present invention reduces the absorption of solid, together in the process that is quenched of solutions of weak acidity
When two-phase is clear when making extraction point liquid, because the acidity of the ammonium chloride is suitable, will not have too strong to other sensitive groups
Effect, relatively safety.
In the embodiment of the present invention, it is preferred that after being quenched, also include that the product to obtaining is layered successively, extract, wash
And concentration, concrete grammar is：
After product system layering, collected organic layer after water ethyl acetate is carried, collects ethyl acetate phase, is associated with
After machine phase, washed with saturated nacl aqueous solution, by washing after the organic phase carry out drying under reduced pressure process, the drying under reduced pressure
40 DEG C of temperature ＜ of process.
The preferred post-processing approach, using ethyl acetate as extractant, not only can be by describedization in reaction system
Compound 3 is fully extracted, and the other impurities that can avoid being produced in the coupling reaction process in processing procedure
Introduce；Using saturated nacl aqueous solution as cleaning solution, the impurity introduced in the step reaction system can be effectively removed, enter one
Walk the purity of the compound 3；Preferred drying mode and baking temperature, not only can avoid the loss of the compound 3 (such as
Pyrolytic), and the introducing of other impurities is avoided that, and then improve the yield and purity of the compound 3.
In above-mentioned steps S02, the compound 3 forms in organic solvent reaction system, Jing ethers with the Loprazolam
Change reaction and prepare compound 4.Preferably, the mass ratio of the compound 3 and the Loprazolam is (6.0～7.0):
(0.1～0.2), the mass ratio for being particularly preferred as the compound 3 and the Loprazolam is 6.57：0.167.By above-mentioned matter
The regulation and control of amount ratio, can react complete within the relatively short time, and substantially free of impurities is produced, such that it is able to ensure reaction effect
On the premise of rate, the yield and purity of compound 4 is improved as far as possible.
, using methyl alcohol as reaction dissolvent, not only effect is good for the embodiment of the present invention, and subsequently easily removes in the product.This
In bright embodiment, 40～43 DEG C of the etherificate countercharge temperature.Impact of the reaction temperature to the etherification reaction is larger, specifically, its
In the case of its parameter constant, if the temperature of the etherification reaction is too high, reaction speed is fast, but easily produces more impurity；
If the temperature of the etherification reaction is too low, reaction speed is slow, and reaction is difficult fully.
Preferably, after completion of the reaction, can add quencher that reaction is quenched.With preferred, matter is added in reaction system
Amount percentage concentration is the sodium bicarbonate solution of 8-12%, is particularly preferred as adding mass percentage concentration to be 10% in reaction system
Sodium bicarbonate solution.Specifically, after etherification reaction terminates, 5 DEG C are cooled to, sodium bicarbonate solution is added dropwise, it is to avoid reaction is excessively
Acutely.After dripping, 20～25 DEG C of temperature control, stirring reaction 10-20min, concretely 10min, 15min, 20min, are quenched
Go out reaction.The embodiment of the present invention using the sodium bicarbonate solution of 8-12% as quencher, not only can effectively in neutralization reaction
The acid of generation or alkali；And be conducive to improving aqueous ion intensity, it is that separation condition has been created in next step extraction.
It is further preferred that being quenched after reaction, also include that the product to obtaining is layered successively, extract, wash and dense
Contracting is processed, and concrete grammar is：
Vacuum distillation removes the methyl alcohol in reaction system, adds ethyl acetate and purified water to be extracted in residue, receives
Collection organic phase, water mutually again with organic phase is collected after ethyl acetate extraction, merges organic phase, after being washed with saturated nacl aqueous solution again
Secondary collection organic phase, is processed with anhydrous sodium sulfate drying.Dried organic phase is carried out into filtration treatment, solid material acetic acid second
Ethyl acetate phase is collected after ester drip washing, in being incorporated into organic phase.Below 40 DEG C of temperature control, organic filtrate is decompressed to dry, obtains light
The compound 4 of yellow.
The preferred post-processing approach, using ethyl acetate as extractant and solvent, not only can be by reaction system
The compound 4 is fully extracted, and can avoid in processing procedure during the etherification reaction produce other
The introducing of impurity；Using saturated nacl aqueous solution as cleaning solution, introduce in the step reaction system miscellaneous can be effectively removed
Matter, the purity of compound described further 4；Preferred drying mode and baking temperature, not only can avoid the compound 4
Loss is avoided that the introducing of other impurities (such as pyrolytic), and then improves the yield and purity of the compound 4.
In above-mentioned steps S03, the Jing reduction reactions of the compound 4 prepare compound 5.Described in the embodiment of the present invention also
Original reaction is carried out under an inert atmosphere, can avoid oxidation introducing side reaction, and then improves the purity and yield of product.Institute
State inert atmosphere and include but is not limited to nitrogen atmosphere.Specifically, after the solution of the compound 4 is added in reactor, fill
Enter inert atmosphere protection, add other raw materials.
Specifically, the solution of compound 4 is obtained during the compound 4 is dissolved in organic solvent, wherein, it is described for dissolving
The organic solvent of compound 4 has various, including but not limited to acetone, dichloromethane, ethyl acetate, isopropyl acetate.The present invention
Embodiment selects dichloromethane as organic solvent, can effectively dissolve the compound 4, has excellent impurity-eliminating effect concurrently again.
Further, stirring reaction after acetonitrile is added, under an inert atmosphere, temperature control -20～-10 DEG C obtain reaction efficiency height, reaction and fill
Divide and the few product system of impurity.Further, triethyl silicane is added dropwise as reaction reducing agent, 30～60min of stirring reaction
Afterwards, boron chloride ether stirring reaction is added dropwise 2～5 hours, prepare compound 5.
Preferably, the compound 4, triethyl silicane, the mass ratio of boron chloride ether are (4.0-4.5):(2.3-
2.8):(2.4-2.8), completely reaction system can be reacted so as to be formed, is particularly preferred as the compound 4, triethyl group silicon
Alkane, the mass ratio of boron chloride ether are 4.18：2.53：2.63.
Preferably, after completion of the reaction, can add quencher that reaction is quenched.With preferred, matter is added in reaction system
Amount percentage concentration is the sodium bicarbonate solution of 8-12%, is particularly preferred as adding mass percentage concentration to be 10% in reaction system
Sodium bicarbonate solution.Specifically, after reduction reaction terminates, 0 DEG C is cooled to, sodium bicarbonate solution is added dropwise, it is to avoid reaction is excessively
Acutely.After dripping, room temperature (15-30 DEG C) stirring reaction 10-20min, concretely 10min, 15min, 20min, are quenched
Go out reaction.The embodiment of the present invention using the sodium bicarbonate solution of 8-12% as quencher, not only can effectively in neutralization reaction
The acid of generation or alkali；And be conducive to improving aqueous ion intensity, it is that separation condition has been created in next step extraction.
It is further preferred that being quenched after reaction, also include that the product to obtaining is layered successively, extract, wash and dense
Contracting is processed, and concrete grammar is：
Vacuum distillation removes dichloromethane and acetonitrile, until flowing out without cut goes out, collects a large amount of off-white powders (product), plus
Enter isopropyl acetate and water, be cooled to 15～20 DEG C, stirring and crystallizing more than 12 hours.Then filtered, with purifying water wash,
It is filtered dry collection filter cake.It is vacuum dried at 55～60 DEG C, obtains the crude product of compound 5.
Further, dichloromethane, backflow is added to be beaten 20-40 minutes in the crude product of the compound 5, concretely
30 minutes；It is cooled to 10～15 DEG C, stirring and crystallizing 2-4 hour, concretely 3 hours.Then filtration treatment is carried out, filter cake uses two
Chloromethanes drip washing, is filtered dry, and 8-10 hours are vacuum dried at 55～60 DEG C, concretely 9 hours, obtains final product high-purity compound 5.Send out
The sample that the reduction reaction is obtained is sampled detection, HPLC >=97.0% by bright embodiment.
The preferred post-processing approach (including Extraction solvent, crystallization system include temperature and processing mode, drying mode and
The comprehensive selection of baking temperature), the compound 5 in reduction reaction system not only can fully be extracted, Er Qieke
To avoid the loss (such as pyrolytic) of the compound 5 and the introducing of impurity in processing procedure, and then improve finished product
Yield and purity.The sample that the reduction reaction is obtained is sampled detection by the embodiment of the present invention, and the yield of compound 5 is
55-65%.
In above-mentioned steps S04, the compound 5 for obtaining is carried out into refinement treatment, obtain En Gelie net (EMPA).It is refined
Process is one of committed step of the embodiment of the present invention.Specifically, first the compound 5 is dissolved in ethanol, stirring is warming up to
75-85 DEG C, more preferably 80 DEG C, backflow molten clear (i.e. backflow dissolving) obtains the solution of compound 5.
Activated carbon is added in the solution of the compound 5, the sample after desolventing technology is carried out into heat filtering process, collect high
The filtrate of purity, removes foreign pigment.
The filtrate is warming up to into 55～60 DEG C, crystal seed is added, 45～50 DEG C are cooled to, after separating out white solid, stirring
Crystallization 1～2 hour；Slow cooling to 10～15 DEG C, stirring and crystallizing 1～2 hour.Embodiment of the present invention temperature hierarchy is to crystallization
Purity and efficiency affect larger, and first by temperature control at 55～60 DEG C, En Gelie net energy is enough dissolved completely in the embodiment of the present invention
In ethanol；Further recrystallization temperature is controlled between 45～50 DEG C, crystallization yield can be made to reach 80%, purity is more than
99.5%；Again by slow cooling, with further crystallization yield.
Sample yield after the embodiment of the present invention is refined is 80-90%.Decolouring, hot filter through step S04, crystallization, mistake
Filter is processed, and can effectively be removed in above-mentioned steps S01-03 and be produced or the various impurity that introduce step by step, and obtains high-purity qualified
Net (EMPA) products of En Gelie.
En Gelie provided in an embodiment of the present invention net preparation method, not only preparation process is simple, convenient, and prepares effect
Rate is high, can obtain steady quality, controllable En Gelie net products.Specifically, the difference for preparing according to present invention method
In the En Gelie net products of batch, compound 4, the compound 6 of following structures, compound 7, compound 8, compound 9 are not examined
Go out, content≤0.058% of isomeric compound 10 of following structures；
And maximum unknown list it is miscellaneous≤0.040%, total impurities≤0.066%, residue on ignition≤0.11%, heavy metal meets≤
The standard of 20ppm, chloride meet≤0.01% standard, En Gelie net products purity >=99.39%；Molar yield >=
84.15%.
It should be noted that the preparation method of En Gelie described in the embodiment of the present invention net (EMPA) can obtain in high yield and
Net (EMPA) products of highly purified En Gelie, not a step both can achieve the effect that, but each step forms an entirety
Comprehensive realization.
Illustrate with reference to specific embodiment.
The preparation of the compound 2 of embodiment 1
Compound 1 (2.25kg), N-methylmorpholine (8.17kg), THF (15.0kg), stirring are added in 100L reactors
And nitrogen charging gas shielded, it is cooled to -5 DEG C.Temperature control -5～0 DEG C, is slowly added dropwise TMSCl (7.00kg), and system is produced during dropwise addition
A large amount of smog.It is added dropwise and finishes, rises to 20～25 DEG C and stir 16 hours.
Normal heptane (30kg) is added in reaction system, -5 DEG C are cooled to.Temperature control -5～5 DEG C, are slowly added dropwise purified water
(34kg) it is quenched.Bi Shengzhi 5～10 DEG C of stirrings, 30 minutes (reaction is quenched) is added dropwise.
Below 10 DEG C of reaction system temperature control after being quenched, layering, water mutually uses again normal heptane (16.5kg) to extract once；Control
Less than 10 DEG C of temperature, layering, organic phase uses successively saturation biphosphate sodium water solution (23kg), purified water (23kg), saturation chlorination
Sodium solution (23kg) respectively washed once；Below 10 DEG C of temperature control, layering, it is little that merging organic phase anhydrous sodium sulfate (3.0kg) is dried 1
When.
Dried organic phase is filtered, solid material normal heptane (1.5kg) drip washing；Below 40 DEG C of temperature control, filtrate is subtracted
Be depressed into it is dry, with normal heptane (5kg) band steam once, obtain the grease about 5.9kg of compound 2.The compound 2 can be used THF
(12.68kg) dissolve, it is standby.
The preparation of the compound 3 of embodiment 2
Load weighted compound 1 (3.2kg), THF (30kg), stirring and nitrogen charging gas shielded are added in 100L reactors.
Less than -85 DEG C of cooling.- 90 DEG C～-85 DEG C of temperature control, is slowly added dropwise the THF solution (4.18L) of n-BuLi.It is added dropwise and finishes, temperature control-
90 DEG C～-85 DEG C, stir 30 minutes.- 90 DEG C～-85 DEG C of temperature control, is slowly added dropwise the THF (12.68kg) of compound 1 (5.9kg)
Solution.It is added dropwise and finishes, -90 DEG C～-85 DEG C of temperature control is stirred 1 hour.
Below 10 DEG C of temperature control, 25% aqueous ammonium chloride solution (12kg) is added to be quenched in reaction system.Finish, be warmed to room temperature
10 minutes (reaction is quenched) of stirring.
After reaction system layering after being quenched, water mutually uses again ethyl acetate (15kg) to extract once.Merge organic phase to satisfy
Washed once with sodium chloride solution (10kg)；Below 40 DEG C of temperature control, organic phase is decompressed to dry.Obtain oily compounds 3 about
6.57Kg.The compound 3 can be dissolved with methyl alcohol (25.34kg), as the raw material for standby of following etherification reactions.
The preparation of the compound 4 of embodiment 3
Addition compound 3 (6.57kg) and methyl alcohol (25.34kg) in 100L reactors, Loprazolam (0.167kg), and
Stirring heats up.40～43 DEG C of temperature control, reacts 3 hours.Sampling, TLC detections, raw material point disappears and is considered as reaction (dichloromethane completely：
MeOH=20：1).
Reaction is finished, and is cooled to 5 DEG C, 10% sodium bicarbonate solution (10kg) is added dropwise reaction is quenched.It is added dropwise and finishes, temperature control 20～25
DEG C, stir 10 minutes (reaction is quenched).
Reaction system vacuum distillation after being quenched removes methyl alcohol, and ethyl acetate (30kg) and purified water are added in residue
(13kg) extract, water is mutually again with ethyl acetate (10kg) extraction.Merge organic phase saturated aqueous common salt (10kg) washed once；Have
Machine phase anhydrous sodium sulfate drying 1 hour.
Organic phase is filtered, with a small amount of ethyl acetate (2kg) drip washing, is filtered dry；Merging filtrate, the reduced pressure concentration at 40 DEG C
It is extremely dry.Obtain the grease about 4.18kg of faint yellow compound 4.
The preparation of the compound 5 of embodiment 4
Compound 4 (4.18kg) dichloromethane (22.2kg) is dissolved, to adding in 100L reactors, acetonitrile is added
(26.3kg), stirring and nitrogen charging gas shielded.Less than -20 DEG C of cooling.- 20 DEG C～-10 DEG C of temperature control, is added dropwise triethyl silicane
(2.53kg).It is added dropwise and finishes, -20 DEG C～-10 DEG C of temperature control is stirred 30 minutes.- 20 DEG C～-10 DEG C of temperature control, is slowly added dropwise boron trifluoride
Ether (2.63kg).It is added dropwise and finishes, -20 DEG C～-10 DEG C of temperature control is stirred 2 hours.Sampling, HPLC detections.When compound 4≤1.0%
When, that is, it is considered as reaction complete.
Reaction is finished, and below 0 DEG C of temperature control, 10% sodium bicarbonate solution (20kg) is added dropwise.Finish, be warmed to room temperature 15 points of stirring
Clock.Vacuum distillation removes dichloromethane and acetonitrile.Flowing out without cut goes out, and stops distillation, separates out a large amount of off-white powders (product), plus
Enter isopropyl acetate (18.2kg) and water (18.2kg) (crystallization).15～20 DEG C are cooled to, stirring and crystallizing more than 12 hours.
Reaction system after being quenched is filtered, and with purified water (20kg) drip washing, is filtered dry.Filter cake is collected, at 55～60 DEG C
Vacuum drying 8 hours, obtains final product the crude product about 3.28Kg of compound 5.The crude product of above-claimed cpd 5 is added in 100L reactors, then is added
Enter dichloromethane (62.2kg) backflow beating 30 minutes.10～15 DEG C are cooled to, stirring and crystallizing 2 hours.Filter, use dichloromethane
(5kg) drip washing, is filtered dry.
It is vacuum dried 8 hours at 55～60 DEG C, obtains final product the about 2.36kg of compound 5, sampling detection, HPLC >=97.0%.
The product yield of the embodiment is 55～65%.
The preparation of the compound 6 of embodiment 5
First by compound 5 (2.36kg), ethanol (18.62kg) input 50L reactors, stirring temperature rising reflux is molten clear.It is molten
After clear, activated carbon (0.24kg), backflow is added to decolourize 30 minutes.Heat filtering, a small amount of ethanol rinse collects filtrate.Filtrate is turned
In entering the 50L reactors of another cleaning, 55-60 DEG C of intensification adds a small amount of crystal seed, lowers the temperature 45-50 DEG C.Separate out a large amount of white solids
Afterwards, stirring and crystallizing 1 hour.10-15 DEG C of slow cooling, stirring and crystallizing 1 hour.
Filter, filter cake ethanol (5kg) drip washing for having cooled down.It is filtered dry, obtains white solid.Filter cake in 55～60 DEG C, vacuum
It is dried 8 hours.Obtain finished product EMPA about 2kg.The full review of sampling.
The product yield of the embodiment is 80～90%.
Embodiment 6
En Gelie net preparation method, prepares according to the method for embodiment 1-5, the net lot number difference of the En Gelie for obtaining
For EMPA-2014001F, the performance test results of En Gelie net products are as shown in table 1 below embodiment 6.
Embodiment 7
En Gelie net preparation method, prepares according to the method for embodiment 1-5, the net lot number difference of the En Gelie for obtaining
For EMPA-2014002F, the performance test results of En Gelie net products are as shown in table 1 below embodiment 7.
Embodiment 8
En Gelie net preparation method, prepares according to the method for embodiment 1-5, the net lot number difference of the En Gelie for obtaining
For EMPA-2014003F, the performance test results of En Gelie net products are as shown in table 1 below embodiment 8.
Table 1
From table 1, the net preparation method of embodiment of the present invention En Gelie has good reappearance and controllability, exploitation
Technique can meet the demand of the big production of commercialization.
Presently preferred embodiments of the present invention is the foregoing is only, not to limit the present invention, all essences in the present invention
Any modification, equivalent and improvement made within god and principle etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of En Gelie net preparation method, comprises the following steps：
The THF solution of compound 1 is provided, under an inert atmosphere, temperature control -90～-85 DEG C are added dropwise the THF solution of n-BuLi, stir
Mix 30～60min of process；Continue temperature control -90～-85 DEG C, the THF solution of compound 2 is added dropwise, stirring reaction is quenched after 1～3 hour
Go out, prepare compound 3, reaction equation is as follows：
The compound 3 is dissolved in methyl alcohol and obtains the solution of compound 3, add stirring after Loprazolam to be warming up to 40～43 DEG C,
It is quenched after reaction 3-5 hours, prepares compound 4, reaction equation is as follows：
The compound 4 is dissolved in dichloromethane and obtains the solution of compound 4, stir process after acetonitrile is added, in inert atmosphere
Under, temperature control -20～-10 DEG C are added dropwise triethyl silicane, after 30～60min of stirring reaction, boron chloride ether are added dropwise, and stirring is anti-
It is quenched after answering 2～5 hours, prepares compound 5, reaction equation is as follows：
The compound 5, ethanol is placed in reactor, temperature rising reflux is molten obtains the solution of compound 5 clearly for stirring；In the chemical combination
After activated carbon backflow 30～60min of decolouring is added in the solution of thing 5, heat filtering process is carried out, collect filtrate；The filtrate is heated up
To 55～60 DEG C, crystal seed is added, be cooled to 45～50 DEG C, after separating out white solid, stirring and crystallizing 1～2 hour；It is cooled to 10～
15 DEG C, stirring and crystallizing 1～2 hour is collected by filtration filter cake, obtains En Gelie after cleaned, dried process net.
2. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 3,
The compound 1, the mass ratio of compound 2 are (3.0～3.5):(5.5～6.0).
3. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 3,
It is described that the quencher that adopts is quenched for aqueous ammonium chloride solution that mass percentage concentration is 20～28%.
4. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 3,
After being quenched, also include that the product to obtaining is layered successively, extract, wash and concentration, concrete grammar is：
After product system layering, collected organic layer after water ethyl acetate is carried, collects ethyl acetate phase, merges organic phase
Afterwards, washed with saturated nacl aqueous solution, by washing after the organic phase carry out drying under reduced pressure process, the drying under reduced pressure is processed
40 DEG C of temperature ＜.
5. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 4,
The mass ratio of the compound 3 and the Loprazolam is (6.0～7.0):(0.1～0.2).
6. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 4,
It is described the quencher that adopts is quenched for mass percentage concentration for 8-12% sodium bicarbonate solution.
7. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 4,
After being quenched, also include that the product to obtaining is layered successively, extract, wash and concentration, concrete grammar is：
Vacuum distillation removes the methyl alcohol in reaction system, adds ethyl acetate and purified water to be extracted in residue, and collection has
Machine phase, water mutually again with organic phase is collected after ethyl acetate extraction, merges organic phase, receives again after being washed with saturated nacl aqueous solution
Collection organic phase, is processed with anhydrous sodium sulfate drying.
8. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 5,
The compound 4, triethyl silicane, the mass ratio of boron chloride ether are (4.0-4.5):(2.3-2.8):(2.4-2.8).
9. En Gelie as claimed in claim 1 net preparation method, it is characterised in that in the step of preparing the compound 5,
It is described the quencher that adopts is quenched for mass percentage concentration for 8-12% sodium bicarbonate solution.
10. En Gelie as claimed in claim 1 net preparation method, it is characterised in that the step of preparing the compound 5
In, after being quenched, also including that the product to obtaining is layered successively, extract, wash and concentration, concrete grammar is：
Below 10 DEG C of temperature control, after product system layering, organic phase is collected, water normal heptane collects organic phase after extracting, and closes
And after organic phase, collect organic phase after being washed with saturated nacl aqueous solution again, carry out drying under reduced pressure process, the drying under reduced pressure
40 DEG C of temperature ＜ of process.
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| 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 |
| CN109988161A (en) * | 2017-12-29 | 2019-07-09 | 徐州万邦金桥制药有限公司 | A kind of preparation method that suitable industrialized production En Gelie is net |
| CN112574186A (en) * | 2020-12-22 | 2021-03-30 | 山东永丞制药有限公司 | Refining method of engagliflozin |
| CN114380775A (en) * | 2021-12-22 | 2022-04-22 | 江苏德源药业股份有限公司 | A kind of empagliflozin intermediate and preparation method thereof |
| 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 |
| CN116462670A (en) * | 2023-04-26 | 2023-07-21 | 福安药业集团重庆博圣制药有限公司 | Method for preparing empagliflozin in one pot |
| WO2023217058A1 (en) * | 2022-05-12 | 2023-11-16 | 浙江华海药业股份有限公司 | Method for preparing glucopyranosyl-containing compound |
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| CN116462670A (en) * | 2023-04-26 | 2023-07-21 | 福安药业集团重庆博圣制药有限公司 | Method for preparing empagliflozin in one pot |
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