CN105753827A - Method for preparing compound - Google Patents
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- CN105753827A CN105753827A CN201410788642.2A CN201410788642A CN105753827A CN 105753827 A CN105753827 A CN 105753827A CN 201410788642 A CN201410788642 A CN 201410788642A CN 105753827 A CN105753827 A CN 105753827A
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Abstract
The present invention provides a method for preparing a compound, the method comprises of contacting of a formula 1 compound with a Grignard reagent to obtain a formula 2 compound; contacting of the formula 2 compound with a formula 3 compound to obtain a formula 4 compound, and reduction reaction of the formula 4 compound to obtain a compound represented by formula I. By use of the method, the compound represented by formula I can be effectively shown.
Description
Technical field
The present invention relates to the field of chemical synthesis, specifically, the present invention relates to a kind of method preparing compound shown in Formulas I.
Background technology
Compound shown in Formulas I is the important intermediate that Da Gelie is clean.Da Gelie is a kind of selective reversible sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor only, can independent of glucose unnecessary in the outer purged body of insulin.It is ratified SGLT2 inhibitor for treating type 2 diabetes mellitus first by Drug Administration mechanism.
Bristol-Myers Squibb Co discloses following synthetic route in Chinese patent CN1756759:
Coupling reaction in this route employs butyl lithium, and reaction condition requires low temperature less than-70 DEG C, and reaction condition is harsher, and operation requires height, control complexity in reaction, by-product is more, and intermediate is not readily separated, processing step is many, and production cost is high, is not easy to industrialized production.
Therefore, shown in current Formulas I, the preparation method of compound, still haves much room for improvement.
Summary of the invention
It is contemplated that solve one of above-mentioned technical problem at least to a certain extent or provide at a kind of useful business selection.For this, it is an object of the present invention to propose the preparation method of compound shown in a kind of Formulas I.
According to embodiments of the invention, the preparation method of compound shown in Formulas I includes: (1) makes compound shown in formula 1 contact with Grignard reagent, compound shown in production 2；(2) compound shown in formula 2 is made to contact with compound shown in formula 3, compound shown in production 4；(3) compound shown in formula 4 is made to carry out reduction reaction, compound shown in production I；
Wherein, the R in compound shown in formula 2 is magnesium chloride and/or lithium chloride.
Inventor have found that, the method utilizing the above embodiment of the present invention can fast and effeciently prepare compound shown in Formulas I, and synthetic route is short, the yield of environmental friendliness, target product and purity higher, raw material is easy to get, operate and post processing is simple, be suitable for industrialized production.In one embodiment of the invention, the synthetic route of compound shown in Formulas I is:
According to embodiments of the invention, the initiation material (compound shown in formula 1 is commercially available) cheap and easy to get that the present invention adopts, and step is few, and synthesis technique is succinct.According to embodiments of the invention, it is possible to three-step reaction is arranged in same reaction vessel and is operated.Greatly simplify technological operation, reduce device requirement, improve production efficiency, cost is low.It addition, according to embodiments of the invention, product yield, purity are high, and by-product is few, and three industrial wastes are easily processed, safety and environmental protection, is conducive to the industrialized production of this compound.
The term " contact " used in this article should be interpreted broadly, and it can be any mode that can make at least two reactant generation chemical reaction, for instance can be mixed under suitable condition by two kinds of reactants.In this article, " compound N " in this article otherwise referred to as " shown in formula N compound ", N is the arbitrary integer of 1-4 in this article, for instance " compound 2 " can also be called " shown in formula 2 compound " in this article.
In describing the invention, it is to be understood that term " first ", " second " only for descriptive purposes, and it is not intended that instruction or hint relative importance or the implicit quantity indicating indicated technical characteristic.Thus, define " first ", the feature of " second " can express or implicitly include one or more these features.In describing the invention, " multiple " are meant that two or more, unless otherwise expressly limited specifically.
Below the conventional method of compound shown in the preparation Formulas I adopted in an embodiment of the present invention is described:
Step (1): make compound shown in formula 1 contact with Grignard reagent, compound shown in production 2；
Concrete reaction equation is:
Wherein, the R in compound shown in formula 2 is magnesium chloride and/or lithium chloride, and R represents from the magnesium chloride in Grignard reagent or lithium chloride, or magnesium chloride and lithium chloride.R ' represents the organic group in Grignard reagent.
According to a particular embodiment of the invention, at least one in the Grignard reagent (R '-MgCl/LiCl) of magnesium chloride and/or lithium chloride is selected.Inventor have found that, use Grignard reagent to can be good at replacing reagent n-butyllithium, thus avoid use ultralow temperature reaction condition, substantially increase production efficiency, decrease production cost.
According to a particular embodiment of the invention, in described Grignard reagent, organic group R ' is ethyl, isopropyl, propyl group, sec-butyl, butyl, the tert-butyl group or n-pentyl, it is preferred to isopropyl or sec-butyl.Inventor have found that, the Grignard reagent activity of isopropyl or sec-butyl is significantly better than the grignard reagent of other substituent group.
According to embodiments of the invention, in step (1), compound shown in described formula 1 contacts in the first organic solvent with Grignard reagent, and described first organic solvent is absolute ether or oxolane.
According to embodiments of the invention, in step (1), the mol ratio of compound shown in described formula 1 and described Grignard reagent is 1:(1-6).Inventor have found that, when the amount of Grignard reagent is excessive, it is possible to improve the formation efficiency of compound shown in formula 2, but when the amount of alkali is too high, cost can be caused to improve, the defect such as by-product increase.When the amount of alkali is too low, raw material reaction can be directly resulted in not complete, reduce product yield, add cost of material.Through a large amount of screening operations, inventor is found surprisingly that, and the mol ratio of compound shown in described formula 1 and described Grignard reagent is 1:(1.1-3) time, it is ensured that under an economical condition, efficiently compound shown in preparation formula 2.
According to embodiments of the invention, compound shown in described formula 1 and described formula 3, the mol ratio of compound is 1:(1-3), it is preferred to 1:(1.2-3).Inventor have found that, when shown in described formula 3, the amount of compound is excessive, the growing amount of compound shown in formula 4 can be improved, but when the amount of compound shown in described formula 3 too high to certain procedures time, the growing amount of compound shown in formula 4 will not be improved, cause cost to improve, increase the defects such as post-processing difficulty.When the amount of the growing amount of compound is too low shown in formula 4, compound shown in formula 2 can be directly resulted in and cannot react completely, reduce product yield, cost can be caused to improve, the defect such as by-product increase.Through a large amount of screening operations, inventor is found surprisingly that, and the mol ratio of compound shown in formula 1 and compound shown in described formula 3 is 1:(1.2-3) time, it is ensured that under an economical condition, efficiently compound shown in preparation formula 4.
Reaction temperature according to embodiments of the invention, compound shown in formula 1 described in step (1) and described Grignard reagent is at-30～5 DEG C, it is preferred to-20～-5 DEG C.Inventor have found that, when reaction temperature is low, it is possible to improve the growing amount of compound shown in formula 2, but when the reaction temperature is excessively low, the response time can be greatly prolonged, cause cost to improve.When temperature is too high, response speed is too fast, and by-product rolls up, and reduces product yield, adds cost of material.Through a large amount of screening operations, inventor is found surprisingly that, described in, the reaction temperature of compound shown in formula 1 described in step (1) and described Grignard reagent is when-20～-5 DEG C, it is ensured that under an economical condition, efficiently compound shown in preparation formula 2.
Step (2): make compound shown in formula 2 contact with compound shown in formula 3, compound shown in production 4.
According to embodiments of the invention, in step (2), compound shown in described formula 3 is obtained by reacting by gluconic acid lactone and acetic anhydride.Acetyl acid anhydride not only does reactant but also make solvent, is greatly saved cost, and post processing is simple, and man-hour is shorter, greatly reduces production cost, the gluconic acid lactone good stability of acetyl group protection, is not easily decomposed.
According to embodiments of the invention, in step (2), the temperature that compound shown in described formula 2 contacts with compound shown in described formula 3 is-70～0 DEG C, it is preferred to-40～-20 DEG C.Inventor have found that, when reaction temperature is low, it is possible to improve the growing amount of compound shown in formula 4, but when the reaction temperature is excessively low, the response time can be greatly prolonged, cause cost to improve.When temperature is too high, response speed is too fast, and by-product rolls up, and reduces product yield, adds cost of material.Through a large amount of screening operations, inventor is found surprisingly that, in step (2), when the temperature that compound shown in described formula 2 contacts with compound shown in described formula 3 is for-40～-20 DEG C, can ensure that under an economical condition, efficiently compound shown in preparation formula 4.
Step (3): make compound shown in formula 4 carry out reduction reaction, compound shown in production I.
According to embodiments of the invention, compound shown in described formula 4 is carried out reduction reaction by step (3) and farther includes: in a second organic solvent, under the lewis acid effect with silane reagent, carry out reduction reaction；Inventor have found that, under the lewis acid effect with silane reagent, carry out reduction reaction, it is possible to increase the selectivity of reaction, reduce the generation amount of isomer.
According to a particular embodiment of the invention, described second organic solvent is at least one in dichloromethane, acetonitrile, toluene, oxolane and ether.
According to a particular embodiment of the invention, described lewis acid is at least one in boron trifluoride-oxolane, Eorontrifluoride etherate and aluminum chloride.Inventor have found that, when lewis acid is boron trifluoride-oxolane, Eorontrifluoride etherate or aluminum chloride, the selectivity of reaction is all fine.
According to a particular embodiment of the invention, described silane reagent is at least one in triethyl silicane and trimethyl silane.Inventor have found that, when silane reagent is triethyl silicane or trimethyl silane, reduction reaction effect is all fine.
The preparation method of compound shown in Formulas I according to embodiments of the present invention, it is possible to achieve following advantages at least one:
1, in the preparation method of compound shown in Formulas I according to embodiments of the present invention, coupling reaction condition requires low.
2, the preparation method of compound shown in Formulas I according to embodiments of the present invention can be avoided using trim,ethylchlorosilane (being called for short TMSCl); TMSCl shifts inconvenience in process of production; see that the water in air can produce a large amount of hydrochloric acid smog; need to use massive laundering in reaction treatment to wash; with the hydrochloric acid produced in removing process, therefore avoid using TMSCl to be conducive to environmental conservation.The gluconic acid lactone of TMSCl protection simultaneously is unstable in reaction system, it is easy to Deprotection, produces multiple intermediate state, is unfavorable for the monitoring of reaction and the setting of intermediate quality.
3, in the preparation method of compound shown in Formulas I according to embodiments of the present invention, the gluconic acid lactone of acetyl group protection is raw material; this protection base is stable in system; be conducive to the monitoring of reaction and the setting of intermediate quality, make production stage short simultaneously, substantially increase production efficiency.
4, in the preparation method technique of compound shown in Formulas I according to embodiments of the present invention, dopant species and quantity significantly reduce, and produce yield high, and product purity is high.For it as medicine and materials industry intermediate, when producing new drug especially as medicine intermediate, reduce product impurity, control drug quality and provide safeguard.
5, the preparation method of compound shown in Formulas I according to embodiments of the present invention be more suitable on a large scale, industrialized production, it is to avoid produce Artificial Control bad and produce a large amount of impurity or need a large amount of solvent, it is to avoid human and material resources consumption, save cost.
6, the preparation method reaction condition of compound shown in Formulas I according to embodiments of the present invention is gentle, it is not necessary to specific response equipment, be not difficult to the compound that separates in preparation process, and technological operation is easy, and production efficiency is high, is suitable for industrialized large-scaled production.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become apparent from the description below, or is recognized by the practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or the additional aspect of the present invention and advantage are from conjunction with will be apparent from easy to understand the accompanying drawings below description to embodiment, wherein:
Fig. 1 be 2 gained according to embodiments of the present invention product Formulas I shown in the HPLC collection of illustrative plates of compound；
Fig. 2 is the HPLC collection of illustrative plates clean for product Da Gelie of 5 gained according to embodiments of the present invention；
Fig. 3 be 2 gained according to embodiments of the present invention product Formulas I shown in compound1H-NMR collection of illustrative plates；
The product Da Gelie that Fig. 4 is 5 gained according to embodiments of the present invention is clean1H-NMR collection of illustrative plates；
The product Da Gelie that Fig. 5 is 5 gained according to embodiments of the present invention is clean13C-NMR collection of illustrative plates.
Detailed description of the invention
Embodiments of the invention are described below in detail, it is necessary to explanation is that the embodiments described below is illustrative of, and is only used for explaining the present invention, and is not considered as limiting the invention.Additionally, without clearly stating, it is commercially available that all reagent adopted in the following embodiments are on market, or can synthesize according to text or known method, for the reaction condition do not listed, also it is what those skilled in the art were readily available.
Conventional method
Adopt following process route:
The method preparing the clean intermediate of Da Gelie (shown in Formulas I compound) comprises the following steps:
(1), grignard reaction: compound shown in formula 1 and Grignard reagent are reacted compound shown in production 2 in organic solvent.
(2), coupling reaction: in step (one) system, adding compound shown in formula 3, reaction prepares compound shown in formula 4.
(3), reduction reaction: compound shown in the formula 4 obtained in step (two) is added organic solvent, uses compound shown in reducing agent reduction production I.
The preparation method of compound shown in Formulas I provided by the invention, employs the gluconic acid lactone of acetyl group protection, it is to avoid goes up acetyl group protection in step below again, directly shortens production technology, make production efficiency substantially increase.
Specific embodiments of the invention are as follows:
Embodiment 1
The preparation of 2,3,4,6-tetra--0-acetyl group-β-D-Glucose acid lactone (shown in formula 3 compound):
Acetic anhydride (1710g is added in 3L reaction bulb, 16.75mol), 192g trifluoroacetic acid (192g, 1.68mol), lower addition 300g gluconic acid lactone (300g is stirred at room temperature, 1.68mol), keep temperature 20～30 DEG C reaction, gluconic acid lactone solids disappeared after reacting 14 hours, mixture is concentrated under vacuo removing acetic anhydride again, again with 1L toluene dissolved sugar pulpous state product, it is washed till neutrality with 3 times of volume saturated sodium bicarbonate waters under condition of ice bath, after saturated NaCl washing once, by dry for organic facies concentration, prepare compound 583g (purity 97.8%) shown in formula 3, molar yield: 100%.
Embodiment 2
The preparation of compound shown in Formulas I:
By compound (300g shown in formula 1,0.81mol) stir in 300ml oxolane under room temperature, in a nitrogen atmosphere, it is cooled to-20～-10 DEG C, dropping isopropylmagnesium chloride-lithium chloride (685ml, 0.89mol), dropwises for about 30 minutes, and by-20～10 DEG C of stir abouts of solution 1 hour of gained, then cool down and control system temperature-30～-20 DEG C.
The oxolane of the weight such as the use of compound (336g, 0.97mol) shown in the formula 3 of embodiment 1 is dissolved, is added drop-wise in a reaction system, about 1 hour dropping finish ,-30～-20 DEG C stirring 30 minutes after, add 500ml6% aqueous hydrochloric acid solution, it is warming up to 20 DEG C, dilute with water.System stands separatory, separates organic layer, by organic layer concentrating under reduced pressure, is dissolved by the grease 1.8L acetonitrile obtained and is directly used in next step.
The solution of previous step is cooled to-5 DEG C, it is subsequently adding 374g triethyl silicane (374g, 3.22mol), drip Eorontrifluoride etherate (227g again, 1.61mol),-5～10 DEG C of stirrings are complete to raw material reaction, after adding the aqueous solution cancellation reaction of 1L saturated sodium bicarbonate, stirring mixture 30 minutes, stand, separate organic layer, then water layer 1L extraction into ethyl acetate, merges organic layer 1L saturated sodium bicarbonate and washs, then concentrated by organic layer, adding the making beating of 1L dehydrated alcohol, sucking filtration obtains solid.The ethyl acetate/hexane recrystallization of solid 800ml25%, filters, and compound 220g shown in dry Formulas I, purity 99.6%, yield is 47.4%.
Embodiment 3
The preparation of compound shown in Formulas I:
By compound (300g shown in formula 1,0.81mol) stir in 300ml oxolane under room temperature, in a nitrogen atmosphere, it is cooled to-15～-5 DEG C, dropping isopropylmagnesium chloride. lithium chloride (1062ml, 1.38mol), dropping in about 30 minutes is finished, and the solution-15～-5 DEG C of gained is stirred 1 hour, then cool down and control system temperature-40～-30 DEG C.
The oxolane of the weight such as the use of compound (561g, 1.62mol) shown in formula 3 is dissolved, is added drop-wise in a reaction system, about 1 hour dropping finish ,-40～-30 DEG C stirring 30 minutes after, add 500ml6% aqueous hydrochloric acid solution, it is warming up to 20 DEG C, dilute with water.System stands separatory, separates organic layer, by organic layer concentrating under reduced pressure, is dissolved by the grease 1.8L acetonitrile obtained and is directly used in next step.
The solution of previous step is cooled to-5 DEG C, it is subsequently adding triethyl silicane (374g, 3.22mol), add aluminum chloride (201g again, 1.5mol), after adding, 10～20 DEG C of stirrings that heat up are complete to raw material reaction, after adding the aqueous solution cancellation reaction of 1L saturated sodium bicarbonate, stirring mixture 30 minutes, stand, separate organic layer, then water layer 1L extraction into ethyl acetate, merge organic layer 1L saturated sodium bicarbonate to wash, then being concentrated by organic layer, add the making beating of 1L dehydrated alcohol, sucking filtration obtains solid.The ethyl acetate/hexane recrystallization of solid 1L25%, filters, and compound 172g shown in dry Formulas I, purity is 99.5%, and yield is 37.0%.
Embodiment 4
The preparation of compound shown in Formulas I:
By compound (300g shown in formula 1,0.81mol) stir in 300ml oxolane under room temperature, in a nitrogen atmosphere, it is cooled to-5～5 DEG C, dropping isopropylmagnesium chloride. lithium chloride (1870ml, 2.43mol), dropping in about 30 minutes is finished, and the solution-5～5 DEG C of gained is stirred 1 hour, then cool down and control system temperature-30～-20 DEG C.
The oxolane of the weight such as the use of compound (841g, 2.43mol) shown in formula 3 is dissolved, is added drop-wise in a reaction system, about 1 hour dropping finish ,-30～-20 DEG C stirring 30 minutes after, add 500ml6% aqueous hydrochloric acid solution, it is warming up to 20 DEG C, dilute with water.System stands separatory, separates organic layer, by organic layer concentrating under reduced pressure, is dissolved by the grease 1.8L acetonitrile obtained and is directly used in next step.
The solution of previous step is cooled to-5 DEG C, it is subsequently adding trimethyl silane (240g, 3.24mol), drip boron trifluoride-oxolane (200g again, 1.62mol), 15～20 DEG C of stirrings are complete to raw material reaction, after adding the aqueous solution cancellation reaction of 1L saturated sodium bicarbonate, stirring mixture 30 minutes, stand, separate organic layer, then water layer 1L extraction into ethyl acetate, merges organic layer 1L saturated sodium bicarbonate and washs, then concentrated by organic layer, adding the making beating of 1L dehydrated alcohol, sucking filtration obtains solid.The ethyl acetate/hexane recrystallization of solid 800ml25%, filters, compound 163g shown in dry Formulas I.Purity is 99.8%, and yield is 35.1%.
Embodiment 5
The preparation that Da Gelie is clean
By compound (100g shown in formula 4 prepared in embodiment 2 at 0 DEG C, 0.173mol) join in 500ml oxolane/methanol/water (2:3:1), lithium hydroxide monohydrate (8g is added under stirring, 0.19mol), keeping reacting under 5～10 DEG C of conditions, reaction is finished, and system is extracted with ethyl acetate, separating organic layer, grease is done to obtain in concentration.
The grease 400ml acetic acid ethyl dissolution obtained, the S-propylene glycol of 13g is added under 20 DEG C of conditions of room temperature, add crystal seed crystallize, the stirring of 200ml normal hexane is added after stirring 1 hour, filtration drying obtains the clean 78.5g of white solid Da Gelie, purity: 99.67% (see Fig. 2), yield is 90.0%, Structural Identification collection of illustrative plates: accompanying drawing 4 is1H-NMR collection of illustrative plates and accompanying drawing 5 are13C-NMR collection of illustrative plates.
Comparative example 1
Prepared by 2,3,4,6-tetra--0-TMS-β-D-Glucose acid lactone (gluconic acid lactone of TMS protection)
Adding oxolane 87g, gluconic acid lactone 9.8g (9.8g, 0.06mol), N-methylmorpholine (44.3g, 0.44mol) in room temperature downhill reaction bottle, then nitrogen is replaced twice, and solution temperature is dropped to less than-10 DEG C.Start to drip trim,ethylchlorosilane (35.6g, 0.33mol) temperature control≤5 DEG C.After dropwising, temperature of reaction system is risen to 20～30 DEG C, react 12 ± 2 hours.After reacting completely, it is cooled to less than-10 DEG C, starts to drip about 30.0g shrend and go out, temperature control≤-5 DEG C.After dropwising, add 253.5g water and 106.5g normal heptane.Stirring, stratification, separate water layer.
5% biphosphate sodium water solution 150.0g is added to upper organic phase, stirring, stratification, separate not layer；Add 150.0g water, stirring, stratification to upper organic phase, separate organic layer.Add saturated nacl aqueous solution 150.0g washing, stirring, stratification to upper organic phase, abandon lower floor's aqueous phase barrelling and post label.To organic addition anhydrous magnesium sulfate, stirring is dry, dry complete, filters, filtrate reduced in volume, obtains the gluconic acid lactone 22.6g of TMS protection, yield 88.0%.
Comparative example 2
The preparation of compound shown in Formulas I:
In dry reaction bottle, add compound (13.7g, 0.04mol) shown in 105g oxolane and formula 1, nitrogen protection, solution temperature is dropped to-70～-75 DEG C.Start to drip 2.5M n-BuLi hexane solution (24ml, 0.06mol), and control system temperature-70～-80 DEG C.After dropwising, temperature control reacts 1 hour at-70～-80 DEG C.
Then previous step controls system temperature less than-70 DEG C, starts to drip the gluconic acid lactone (oxolane of the weight such as use dissolves) of the TMS protection of comparative example 1 preparation.Dropwise, insulation reaction 2 hours.Control system temperature less than-60 DEG C, be slowly added dropwise methanesulfonic acid methanol solution (15.0g methanesulfonic acid).Dropwise, reaction system is warmed up to 20～30 DEG C react completely after, stratification, separate lower floor, it is cooled to less than-10 DEG C, adding 62.5g ethyl acetate, then temperature control is less than-5 DEG C, is slowly added dropwise about 120g saturated sodium bicarbonate solution, stirring, stratification, separates organic facies concentrating under reduced pressure, obtains grease.
By molten clearly for gained grease 75.0g toluene in upper step, then it is added dropwise in 300g normal heptane.After dropwising, being stirred at room temperature 2 hours, filtration drying obtains solid (shown in formula A compound).
Adding 97.5g dichloromethane and previous step gained solid 10.5g (shown in formula A compound) in reaction bulb, stirring is down to-5～0 DEG C.Control temperature at-5～0 DEG C, add N-methylmorpholine (22.4g, 0.22mol), stir, add dimethylamino naphthyridine 0.14g.Control temperature below 0 DEG C, add acetic anhydride (22.6g, 0.22mol).Control temperature 10～20 DEG C of reactions, after reacting completely, cool the temperature to-5～0 DEG C, be slowly added to 115.5g water, stirring, stratification, lower floor's organic facies is washed with 10% aqueous hydrochloric acid solution, then with anhydrous sodium sulfate, filters after stirring 1～1.5 hour, concentrate filtrate to without fraction, obtain yellow oil.Adding 105g acetonitrile, stirring makes it dissolve, and is subsequently adding 0.4g water, stirs, is cooled to-5～0 DEG C.
Temperature control, below 0 DEG C, adds triethyl silicane (18.6g, 0.16mol), after stirring 5 minutes, and dropping boron trifluoride diethyl etherate (11.3g, 0.08mol).Dropwise, control temperature at-5～0 DEG C, reaction, after reacting completely, add 34g dehydrated alcohol, concentrating under reduced pressure, now add 99.2g dehydrated alcohol, temperature control 30～40 DEG C, stir 1 hour, filtration drying obtains compound 8.1g shown in Formulas I, yield 38.1%.
The contrast of 1 two kinds of system preparation method evaluation results of table
Contrast, it can be seen that the technique of the present invention is substantially better than existing technique from the viewpoint of production operation and yield, thus can affirm fully the superiority of the present invention.
In the description of this specification, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means in conjunction with this embodiment or example describe are contained at least one embodiment or the example of the present invention.In this manual, the schematic representation of above-mentioned term is not necessarily referring to identical embodiment or example.And, the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiments or example.
Although above it has been shown and described that embodiments of the invention, it is understandable that, above-described embodiment is illustrative of, being not considered as limiting the invention, above-described embodiment can be changed when without departing from principles of the invention and objective, revises, replace and modification by those of ordinary skill in the art within the scope of the invention.
Claims (10)
1. the method preparing compound shown in Formulas I, it is characterised in that including:
(1) compound shown in formula 1 is made to contact with Grignard reagent, compound shown in production 2；
(2) compound shown in formula 2 is made to contact with compound shown in formula 3, compound shown in production 4；
(3) make compound shown in formula 4 carry out reduction reaction, generate containing compound shown in Formulas I,
Wherein, the R in compound shown in formula 2 is magnesium chloride and/or lithium chloride.
2. method according to claim 1, it is characterised in that the organic group in described Grignard reagent is ethyl, isopropyl, propyl group, sec-butyl, butyl, the tert-butyl group or n-pentyl, it is preferred to isopropyl or sec-butyl.
3. method according to claim 1 and 2, it is characterised in that in step (1), compound shown in described formula 1 contacts in the first organic solvent with Grignard reagent, and described first organic solvent is absolute ether or oxolane.
4. the method according to any one of claim 1-3, it is characterised in that in step (1), compound shown in described formula 1 is contact at the temperature of-30～5 degrees Celsius with described Grignard reagent, it is preferable that-20～-5 degrees Celsius.
5. the mol ratio of the method according to any one of claim 1-4, it is characterised in that in step (1), compound shown in described formula 1 and described Grignard reagent is 1:(1-6), it is preferred to 1:(1.1-3).
6. the method according to any one of claim 1-5, it is characterised in that the mol ratio of compound shown in described formula 1 and compound shown in described formula 3 is 1:(1-3), it is preferred to 1:(1.2-3).
7. method according to claim 1, it is characterised in that compound shown in described formula 3 is obtained by reacting by gluconic acid lactone and acetic anhydride.
8. the method according to any one of claim 1-6, it is characterised in that in step (2), compound shown in described formula 2 is contact at the temperature of-70～0 degree Celsius with compound shown in described formula 3, it is preferable that-40～-20 degrees Celsius.
9. the method according to any one of claim 1-7, it is characterised in that in step (3), in a second organic solvent, makes compound shown in described formula 4 carry out described reduction reaction under the lewis acid effect with silane reagent,
Optionally, described lewis acid is at least one in boron trifluoride-oxolane, Eorontrifluoride etherate and aluminum chloride,
Optionally, described silane reagent is triethyl silicane and/or trimethyl silane,
Optionally, described second organic solvent is at least one in dichloromethane, acetonitrile, toluene, oxolane and ether.
10. the method according to any one of claim 1-9, it is characterised in that in step (3), makes compound shown in described formula 4 carry out described reduction reaction at the temperature of-10～40 degrees Celsius, it is preferable that-5～20 degrees Celsius.
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Cited By (2)
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| CN106279072A (en) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技（武汉）有限公司 | Compound as well as preparation method and application thereof |
| CN109705075A (en) * | 2018-12-13 | 2019-05-03 | 江苏苏中药业集团股份有限公司 | Purification method of dapagliflozin |
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