CN103980263A - New synthesis process of canagliflozin - Google Patents
New synthesis process of canagliflozin Download PDFInfo
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Abstract
The present invention discloses a new synthesis process of canagliflozin. The new synthesis process comprises: adopting 2-methyl benzoic acid as a starting raw material, and adopting a self-made catalyst, iodic acid and iodine to carry out a reaction to produce an intermediate 1, or adopting 2-methyl benzoic acid as a starting raw material, and adding liquid bromine under effects of a metal reagent and a catalyst to synthesize an intermediate 2; optionally selecting the intermediate 1 or 2 to carry out an acylation reaction with thionyl chloride, and then carrying out a Friedel-Crafts reaction to produce an intermediate 3; adopting ALPHA-D-glucose as a raw material, carrying out a reaction with pivaloyl chloride to protect all hydroxyl, and carrying out a reaction with zinc bromide and bromotrimethylsilane to produce an intermediate 4; linking the intermediate 3 and the intermediate 4 to produce an intermediate 5; and finally under an acid condition, removing the pivaloyl to produce the target compound. The new synthesis process has characteristics of high yield, mild condition, safety, reliability, cheap and easily available raw material, and easy production cost control, and is suitable for industrial production.
Description
Technical field
The present invention relates to the clean new synthetic process of a kind of Ka Gelie.
Background technology
The clean Canagliflozin of Kan Gelie is first SGLT2 inhibitor medicaments of being ratified by FDA, can be used for the treatment of adult's diabetes B by the mode excreting by kidney after breakdown of glucose is reduced to blood sugar, has broad prospects.Except good glycemic control, the antiobesity action of Canagliflozin is more remarkable, and compares with glimepiride, and hypoglycemia event that canagliflozin causes is far away few many.
The existing synthetic route processing condition of reported in literature are harsh, as adopt high warm filter, and high to production unit requirement, industrialized cost is higher; Because syntheti c route is longer, the yield of each step is lower, causes total recovery low, and environmental pollution is large, is unfavorable for suitability for industrialized production.Therefore, need to provide a kind of new technical scheme to solve the problems referred to above.
Summary of the invention
For addressing the above problem, the invention provides the clean new synthetic process of a kind of Ka Gelie.
The technical solution used in the present invention:
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.5 ~ 1.0 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, and aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle;
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent and super acidic catalyst, adding mole multiple is 1.05 ~ 1.5 bromine, and adopts molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, then at-10 ~ 25 ℃, react generation intermediate four with zinc bromide, bromotrimethylsilane;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 76-80 degree Celsius connects and generates intermediate five under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with different solvents is more progressively removed various impurity, obtains purity higher than 98% target product.
In b step, metal reagent is Fe powder or iron bromide, and super acidic catalyst is trifluoromethanesulfonic acid or tosic acid.
In d step, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride, in the technique of upper protecting group, add a small amount of sulfur oxychloride.
In f step, solvent is the mixed solvent of methyl alcohol, acetic acid or methyl alcohol, acetic acid and water.
For the generation of above-mentioned each intermediate, then explain by following chemical equation, chemical equation is:
Intermediate one
Intermediate two
Intermediate three
Intermediate four
Intermediate five
Product
Advantage of the present invention is: yield is high, and mild condition is safe and reliable, is applicable to suitability for industrialized production, and raw material is cheaply easy to get, and is conducive to production control cost.
Embodiment
Following embodiment is only for the present invention is described, but can not limit protection scope of the present invention.
Embodiment 1
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.5 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle, specific as follows: temperature of reaction is down to 20 degrees Celsius, a large amount of solids are separated out, at this temperature, the product that is mixed with catalyzer is filtered, mother liquor is applied mechanically next time, can connected set 5 times, after filter cake dissolves with ethyl propenoate, normal temperature filters, catalyzer is leached and applied mechanically next time, can apply mechanically 5 times, after filtrate precipitation, the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtain white products and obtain product, yield is more than 88%,
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid, adding mole multiple is 1.05 bromine, and adopt molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-, yield is more than 85%;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three, yield 78%;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, react and generate intermediate four at-10 ℃ with zinc bromide, bromotrimethylsilane again, in the technique of upper protecting group, add a small amount of sulfur oxychloride, make pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is greater than 67%;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 76 degrees Celsius, under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution, connect and generate intermediate five, yield is more than 71%;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with methyl alcohol is more progressively removed various impurity, obtains purity higher than 98% target product, and yield is more than 85%.
Embodiment 2
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.7 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle, specific as follows: temperature of reaction is down to 18 degrees Celsius, a large amount of solids are separated out, at this temperature, the product that is mixed with catalyzer is filtered, mother liquor is applied mechanically next time, can connected set 3 times, after filter cake dissolves with ethyl propenoate, normal temperature filters, catalyzer is leached and applied mechanically next time, can apply mechanically 3 times, after filtrate precipitation, the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtain white products and obtain product, yield is more than 88%,
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent iron bromide and super acidic catalyst tosic acid, adding mole multiple is 1.25 bromine, and adopt molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-, yield is more than 85%;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three, yield 78-80%;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, react and generate intermediate four at 10 ℃ with zinc bromide, bromotrimethylsilane again, in the technique of upper protecting group, adopt the way that adds a small amount of sulfur oxychloride, make pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is greater than 67%;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 78 degrees Celsius, under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution, connect and generate intermediate five, yield is more than 71%;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with acetic acid is more progressively removed various impurity, obtains purity higher than 98% target product, and yield is more than 85%.
Embodiment 3
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 1.0 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle, specific as follows: temperature of reaction is down to 22 degrees Celsius, a large amount of solids are separated out, at this temperature, the product that is mixed with catalyzer is filtered, mother liquor is applied mechanically next time, can connected set 4 times, after filter cake dissolves with ethyl propenoate, normal temperature filters, catalyzer is leached and applied mechanically next time, can apply mechanically 4 times, after filtrate precipitation, the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtain white products and obtain product, yield is more than 88%,
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid, adding mole multiple is 1.5 bromine, and adopt molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-, yield is more than 85%;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three, yield 80%;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, react and generate intermediate four at 25 ℃ with zinc bromide, bromotrimethylsilane again, in the technique of upper protecting group, adopt the way that adds a small amount of sulfur oxychloride, make pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is greater than 67%;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 80 degrees Celsius, under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution, connect and generate intermediate five, yield is more than 71%;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with methyl alcohol and water mixed solvent is more progressively removed various impurity, obtains purity higher than 98% target product, and yield is more than 85%.
In f step, mixed solvent can also be the mixed solvent of acetic acid and water.
Be below the preparation process of each intermediate:
Prepare intermediate one: in 500ml reaction flask, add, 2-methyl-phenylformic acid 40g, 0.113mol iodine, the 70% acid iodide aqueous solution, catalyst molecule sieve load ferric oxide, acetic acid, acetic anhydride, is warming up to backflow, in LC, controls, and cooling crystallization, filters mother liquid recycle.Crude product adds ethyl propenoate entirely molten to product, removes by filter zeolite, is spin-dried for, and the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtains white products 67.76g, yield 88%, purity 94%(LC).
Prepare intermediate and in ml reaction flask add 2-methyl-phenylformic acid 40g at two: 250, iron powder, trifluoromethanesulfonic acid, bromine/methylene dichloride (through molecular sieve pre-treatment), be warming up to backflow, drip 0.388mol bromine/dichloromethane solution, drip and finish, backflow is spent the night, in TLC, control to reaction finishes, cooling, drips saturated sodium bisulfite to redness and takes off, separatory, water layer 30ml dichloromethane extraction, merge organic layer, washing, is spin-dried for to obtain crude product 53g, ethyl alcohol recrystallization, obtain product 54.09g, yield 85%, purity 95%(LC).
Prepare intermediate three: in 250ml four-hole boiling flask, add the iodo-2-tolyl acid of 5-20g, methylene dichloride, dimethyl fumarate, be warming up to 20 ℃, drip sulfur oxychloride.Drip and finish, be warming up to backflow, after 1.5h, sampling LC monitoring is without raw material.Be cooled to 2 ℃, add aluminum chloride, stir 15min, drip 13.6g2-(to fluorophenyl) the DCM solution of-thiophene.Drip to finish, react 3h at 20 ℃, in LC, control is without raw material.Be cooled to 2 ℃, add aluminum chloride, stir 15min, drip the acetonitrile solution of TMDSO, be warming up to back flow reaction 5h, in LC, control to reaction finishes.Reaction solution is poured in 5% hydrochloric acid soln, stirred, dichloromethane extraction twice water layer for, merges organic layer, washing, and anhydrous sodium sulfate drying, is spin-dried for, use ethyl acetate and Virahol recrystallization, obtain product 21.75g, yield 70%, purity 98%(LC).
Prepare intermediate three: in 10L four-hole boiling flask, add the bromo-2-tolyl acid of 5-800g, methylene dichloride, dimethyl fumarate, is warming up to backflow, drips sulfur oxychloride, and in sampling LC, control to reaction finishes.Be cooled to 2 ℃, add aluminum chloride, drip equimolar 2-(to fluorophenyl) the DCM solution of-thiophene.Drip to finish, react 3 hours at 20 ℃, LC monitors without raw material.Be cooled to 2 ℃, add aluminum chloride.Drip acetonitrile, drip and finish, drip fast the acetonitrile solution of TMDSO, be warming up to back flow reaction 5h, in LC, control to reaction finishes.Reaction solution is poured in 10% hydrochloric acid soln, stirred 15min, water layer 3L dichloromethane extraction, merges organic layer, and washing, is spin-dried for, and use ethyl acetate and Virahol recrystallization, obtain product 1009.6g, yield 75%, purity 96%(LC).
Prepare intermediate four: in 10L four-hole reaction flask, add 384g alpha-D-glucose, pyridine, methylene dichloride, DMAP, mechanical stirring, is heated to 48 ℃.Close heating, add 10ml sulfur oxychloride.Start to drip pivaloyl chloride 1412g, 2h dropwises, and temperature maintains 50 ℃ of back flow reaction.Control during HPLC detects.Reaction finishes rear negative pressure and is concentrated into dryly, adds methylene dichloride and dilute hydrochloric acid stirring and dissolving, stratification, separatory.After organic phase washing, use anhydrous Na
2sO
4dry, filtration.Organic phase negative pressure is concentrated into dry, obtains light yellow solid 1830g.Crude product dehydrated alcohol recrystallization, obtains white solid 1096g, purity 98%, and yield 82%, standby.
In 20L four-hole reaction flask, pass into N
2, add 750g Calcium Chel 330, methylene dichloride, zinc bromide, stirs.Reaction solution is cooled to 10 ℃, starts to drip the mixture of bromotrimethylsilane and methylene dichloride, and 1.5h dropwises.Control temperature 20-25 ℃, stirring reaction 1.5h.HPLC detects to reaction end.Suction filtration goes out zinc bromide, obtains yellow clarified liq.Be cooled to 0 ℃, drip sodium bicarbonate aqueous solution, monitoring pH value is at 7-8.Separatory obtains organic layer and adds anhydrous Na
2sO
4dry, filter.Organic layer negative pressure concentrates to obtain lurid solid 700g, crude product purity 88%.Virahol is washed and starched, and obtains product 599.7g, yield 83%, purity 97.5%.Total recovery 68.06%.
Prepare intermediate five: anhydrous and oxygen-free device, in 500ml reaction flask, add intermediate three 40.8g, n-butyl ether, toluene, logical nitrogen, cools to-40 ℃, drips butyllithium, drips Bi Baowen 2h.Drip zinc bromide lithiumbromide butyl ether solution, drip and finish, 30 ℃ of insulation 2h.The toluene solution that drips intermediate four, is warming up to 90 ℃ of insulations after dripping, in sampling LC, control to reaction finishes.After cooling, reaction solution is poured in the hydrochloric acid that 500ml is rare, separatory, 120ml*3 ethyl acetate extraction for water layer, merges organic layer, and washing, separatory, the concentrated brown oil of doing to obtain, add ethyl alcohol recrystallization to obtain product 55.5g.Purity 95%, yield 71%.
In the four-hole boiling flask of the preparation that Ka Gelie is clean: 2L, add 150g intermediate five, methyl alcohol, stirring at room 15min.Drip the methanol solution of 30% sodium methylate, dropwise and be warming up to backflow.In LC, control is to reacting complete.Normal pressure steams after the feature impurity that is difficult for removing, and concentrated to obtain crude product, then adds the method that methyl alcohol, Acetic Acid-Water, water, methanol-water equal solvent repeatedly pulls an oar and progressively remove various impurity, filter, recrystallizing methanol obtains solid 72.6g, yield 85%, purity 98%(LC) more than.
The clean new synthetic process of Ka Gelie of the present invention advantage specific as follows:
1) intermediate one is synthetic, adopts catalytic synthetic techniques, uses the molecular sieve carried ferric oxide catalyst of self-control to participate in reaction, and the selectivity of 5 upper iodine is increased to almost absolutely from 60%.This step yield is brought up to more than 88%, greatly improved yield, reduced impurity.In this external aftertreatment, evaded the comparatively step of complicated fine particle high temperature heat filtering, because this step is high to equipment requirements, temperature is slightly low, and product is just separated out from filtrate, stops up filter cloth.Present method changes it, adopts the rear cold filtration of cooling, the way of mother liquid recycle.Filter cake adopts the stripping of lower step solvent, after filtration catalizer, containing product filtrate, participates in the next step directly.Technique is simple to operation, greatly reduces treatment time and difficulty, and producing feasibility obviously improves, and also can improve yield, and has reduced the pollution to environment.
2) intermediate two is synthetic by the groping of reaction conditions and synthesis mechanism, and makes 3 special adaptations.The one, molecular sieve to carry out pre-treatment to reaction solvent, make it definitely anhydrous; The metal reagents such as the two Fe powder that will add catalytic amount, iron bromide; The super acids such as three trifluoromethanesulfonic acids that will add wherein catalytic amount, tosic acid, can will originally almost accomplish high yield without the reaction of product.
3) upper pivaloyl group one step during synthetic intermediate four, adds a small amount of sulfur oxychloride, in the situation that yield does not fall, the consumption of pivaloyl chloride can be reduced to 50%, reduce the pollution to environment.
4), during synthetic intermediate five, evaded traditional TMS protection glucose and dock the method for dehydroxylation of reducing afterwards with intermediate three, with 2; 3,4,6-O-, tetra-pivaloyl groups-ALPHA-D-bromo Glucopyranose docks with intermediate three; can avoid dehydroxylation, improve total recovery, greatly cost-saving.And adopting homemade bridge joint catalyzer to connecting, make yield improve 20% than original.
Claims (4)
1. the clean new synthetic process of Ka Gelie, is characterized in that, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.5 ~ 1.0 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, and aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle;
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent and super acidic catalyst, adding mole multiple is 1.05 ~ 1.5 bromine, and adopts molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, then at-10 ~ 25 ℃, react generation intermediate four with zinc bromide, bromotrimethylsilane;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 76-80 degree Celsius connects and generates intermediate five under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with different solvents is more progressively removed various impurity, obtains purity higher than 98% target product.
2. the clean new synthetic process of Ka Gelie according to claim 1, is characterized in that: in b step, metal reagent is Fe powder or iron bromide, and super acidic catalyst is trifluoromethanesulfonic acid or tosic acid.
3. the clean new synthetic process of Ka Gelie according to claim 1, is characterized in that: in d step, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride, add a small amount of sulfur oxychloride in the technique of upper protecting group.
4. the clean new synthetic process of Ka Gelie according to claim 1, is characterized in that: in f step, solvent is the mixed solvent of methyl alcohol, acetic acid or methyl alcohol, acetic acid and water.
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| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN105399735A (en) * | 2015-12-29 | 2016-03-16 | 上海应用技术学院 | Empagliflozin intermediate, and preparation method and application thereof |
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