CN107963989A - A kind of preparation method of Mitiglinide Calcium - Google Patents
A kind of preparation method of Mitiglinide Calcium Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of Mitiglinide Calcium, the described method comprises the following steps:The synthesis of step 1, benzylidene succinic acid:The synthesis of step 2, benzyl butanedioic acid:The synthesis of step 3, (S) benzyl butanedioic acid (R) α phenyl ethylamine salt:The synthesis of step 4, (S) benzyl butanedioic acid:The synthesis of step 5,2S xylylenimine butyric acid:The synthesis of step 6, Mitiglinide Calcium crude product:Step 7:Mitiglinide Calcium refines.
Description
Technical field
The invention belongs to pharmaceutical field, and the present invention relates to a kind of preparation method of Mitiglinide Calcium.
Background technology
Mitiglinide calcium salt dihydrate, chemical name are:Double ((2s) -2- benzyls -3- (cis- hexahydro iso-indoles -2- carbonyls)
Propionic acid) single calcium dihydrate, structural formula is as follows:
Molecular formula:C38H48CaN2O6·2H2O
Molecular weight:704.91
Mitiglinide Calcium is the antidiabetic drug that Japanese tachibana life company develops, and is a kind of novel benzyl succinic acids insulin secretion
Accelerating agent.Mitiglinide causes stream in Ca2+, makes intracellular by closing the ATP dependence K+ passages on pancreatic beta cell film
Ca2+ concentration increases and makes the vesica threshing of extracellular insulin-containing, so as to stimulate the secretion of insulin.Mitiglinide calcium tablet is (former
Grind Kissei Pharmaceutical Co., Ltd. of company) listed in April, 2004 in Japan, trade nameFor dietotherapy and fortune
Dynamic therapy cannot obtain the diabetes B Patients' rights postprandial blood sugar of promising result.Cannot effectively it be controlled through diet and kinesiatrics
The Patients with NIDDM of hyperglycaemia processed.Mitiglinide is the 3rd mage row carbamide type medicine after Repaglinide, Nateglinide,
It is the derivative of phenylalanine.According to the literature, Mitiglinide and Repaglinide, Na Gelie a kind of apples and traditional sulfonylureas
Compare, have the advantage that:1. mechanism of action is novel, work faster, acting duration is shorter;2. curative effect is stronger;3. it is administered
Flexibly;4. there is the laudatory title of " external pancreas ";5. early stage and the first-line treatment medicine of mild diabetes patient;6. it is safe, it is resistance to
It is good by property.
Japanese tachibana give birth to company in 1991 the Mitiglinide pharmaceutical compound in national applications such as the U.S., Japan, Europe respectively
Thing and its for treating the use patent of diabetes, and disclose the method for synthesizing the compound and its commonly making as medicine
Agent prescription.Due to China before 1993《Patent Law》Do not give medical compounds patent protection, therefore the patent is not in China
Application.
Have been disclosed for the preparation method of a variety of Mitiglinide Calciums:
Such as the method for following Chinese patent:
Common process route is as follows:Using dimethyl succinate and benzaldehyde as raw material, it is condensed, hydrolyzes, takes off through Stobble
Water contracts with cis- hexahydroisoindoline into acid anhydrides, is reduced after conjunction and obtain racemization acid, reacted with cylite, into salt, what be presently, there are asks
Topic:The step of having, is short, does not reach purity, some technique reaches purity, but step is grown, and has 10 steps to complete to react.
The content of the invention
Present invention aims at provide a kind of preparation method of Mitiglinide Calcium.The Mitiglinide Calcium technique letter of the present invention
It is single, it is environmentally protective.
Preparation method of the present invention, comprises the following steps:
The synthesis of step 1, benzylidene succinic acid:
Absolute methanol, sodium methoxide are added in retort after stirring and dissolving, diethyl succinate is added, is heated to back
Stream, is added dropwise benzaldehyde, then steams methanol, be slowly added into sodium hydroxide solution, adds drinking water, dichloromethane, and stirring 30~
60 minutes, concentrated hydrochloric acid is added dropwise, precipitates, to obtain the final product;
The synthesis of step 2, benzyl butanedioic acid:
Benzylidene succinic acid is dissolved with absolute ethyl alcohol, adds activated carbon decolorizing, filters out activated carbon, adds in retort and stirs
Mix, be passed through nitrogen, drain air, add 10% palladium carbon, be passed through hydrogen and carry out hydrogenation, until reaction terminates, will with nitrogen
Hydrogen drains in retort, filters out palladium carbon;
The synthesis of step 3, (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt:
Benzyl butanedioic acid, absolute ethyl alcohol are added in retort and stirred, is heated to flowing back, is slowly added into (R)-α-benzene second
Amine, slightly cold addition crystal seed slowly with absolute ethyl alcohol washed, dried by cooling crystallization, centrifuge separation, filter cake, with absolute ethyl alcohol essence
System, drying, 50~60 DEG C of drying, obtain (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt;
The synthesis of step 4, (S)-benzyl butanedioic acid:
(S)-benzyl butanedioic acid (R)-α-phenylethylamine salt, sodium hydroxide solution, dichloromethane are added in retort and stirred
Dissolving, separates organic phase, and water is mutually washed with dichloromethane, divides and goes organic phase;Water phase transfer to retort stirs, and concentrated hydrochloric acid tune is added dropwise
PH value, separates out mass crystallization, continues to stir, centrifuge, washing, dries, obtains (S)-benzyl butanedioic acid;
The synthesis of step 5,2S- xylylenimine butyric acid:
(S)-benzyl butanedioic acid is taken, is dissolved, is cooled down, thionyl chloride is slowly added dropwise below 0 DEG C of temperature control, then below 0 DEG C
After cis hexahydro iso-indoles is added dropwise, slowly heating, stirring, refines reaction solution, obtains 2S- xylylenimine butyric acid;
The synthesis of step 6, Mitiglinide Calcium crude product:
2S- xylylenimines butyric acid, absolute ethyl alcohol are added into retort, stirring and dissolving, adds 4% sodium hydroxide solution,
After adding, calcium chloride solution is slowly added into, during dropwise addition, adds ethanol solution, continues to stir after dripping off, centrifuge separation,
Ethanol elution, drying, obtain Mitiglinide Calcium crude product;
Step 7:Mitiglinide Calcium refines:
Mitiglinide Calcium crude product, absolute ethyl alcohol are added in retort, stirring and dissolving, add activated carbon decolorizing, filtering, obtains
Filtrate, is slowly added dropwise purified water under stirring, stirring, centrifuge separation, vacuum drying, to obtain the final product.
Wherein, in step 1, the mole ratio 4.0~5.5 of diethyl succinate and benzaldehyde.
Wherein, in step 3, the mole ratio 1.0~1.3 of (R)-α-phenylethylamine and benzyl butanedioic acid.Wherein, in step 5,
The mole ratio 0.3~0.8 of cis hexahydro iso-indoles and (S)-benzyl butanedioic acid.
The preparation method is that obtained after many experiments screen,
Different temperature and PH are optimized, and xylylenimine butyric acid purity is index, optimizes experiment, obtains
Result to optimization is as follows:
Thionyl chloride is slowly added dropwise in -15 DEG C~-12 DEG C or so of temperature control, and after dripping off, -15 DEG C to 0 DEG C reactions 4~6 are small
When.Then cis hexahydro iso-indoles is added dropwise at -15 DEG C~-12 DEG C or so, its rear process optimization is as follows:Acid solution is added, with having
Machine reagent is extracted, and PH is adjusted with alkali again in extracting solution, is washed with organic reagent, then carries out tune PH with acid, and use is organic
Reagent extracts, and recycles organic reagent.
Acid in the above process includes but not limited to hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid;Alkali used includes but is not limited to
Sodium hydroxide, sodium carbonate, sodium acid carbonate.Above-mentioned organic reagent used includes but is not limited to dichloromethane, ethyl acetate.
Its optimization process is as follows:Calculated with the ratio of A and B substance, design different elution program and PH gradients.To examine
A/B ratios are examined, technique is optimized.A is (3a, 7a- are suitable)-a- benzyls hexahydro-gamma-carbonyl group -2- xylylenimines
Butyric acid (alias is mitiglinide acid), to synthesize Mitiglinide Calcium raw material;B is Mitiglinide acid isomer, to belong to impurity.
Step 5 of the present invention:The purpose of the synthesis optimizing of xylylenimine butyric acid is, reduces the generation of this impurity of B, carries
The purity of high product.
3%HCl stirrings are added preferably in reaction solution, if insoluble matter should filter out insoluble matter, separate lower aqueous layer, second
Ethyl acetate layer is washed with salt, is then adjusted with saturated sodium carbonate solution.To aqueous ph value to 7~8, extracting solution is merged, is used
Ethyl acetate washs.Concentrated hydrochloric acid is added dropwise to alkali layer and adjusts pH value to 1~2, is extracted with ethyl acetate, merges extracting solution, filtrate subtracts
Pressure concentration carries out the next step without ethyl acetate.
The refined of xylylenimine butyric acid can also carry out in the following way.
The synthesis of xylylenimine butyric acid:Will ethyl acetate, triethylamine add retort in stir, sequentially add imidazoles,
(S)-benzyl butanedioic acid, is partly dissolved.Cooling, thionyl chloride is slowly added dropwise in -15 DEG C or so of temperature control, after dripping off, -15 DEG C to 0
DEG C reaction 4 it is small when.Then after -15 DEG C or so are added dropwise cis hexahydro iso-indoles, slowly heating, stirring reacts small not less than 15
When.3%HCl stirrings are added into reaction solution, if insoluble matter should filter out insoluble matter, separate lower aqueous layer, ethyl acetate layer
Add in pillar and eluted.
Above-mentioned pillar includes but is not limited to silicagel column, acid amides column.
It turns out that many organic reagents can be saved, and it is more environmentally friendly, calculated, expected not with the ratio of A and B substance
99.8% can be obtained to Mitiglinide Calcium purity, therefore is also a kind of to the effective process for purification of xylylenimine butyric acid.
Preferably, the synthesis of step 5,2S- xylylenimine butyric acid:
Ethyl acetate, triethylamine are added in retort and stirred, sequentially adds imidazoles, the dissolving of (S)-benzyl butanedioic acid, it is cold
But, thionyl chloride is slowly added dropwise in -15 DEG C~-12 DEG C of temperature control, after dripping off, -15 DEG C to 0 DEG C reaction 4~6 it is small when, then -
After 15 DEG C~-12 DEG C are added dropwise cis hexahydro iso-indoles, slowly heating, when stirring reaction is small not less than 15;Added in reaction solution
3%HCl is stirred, and if insoluble matter should filter out insoluble matter, separates lower aqueous layer, and ethyl acetate layer is washed with salt, then with full
Adjusted with sodium carbonate liquor to aqueous ph value to 7~8, extracting solution is merged, is washed with ethyl acetate, dense salt is added dropwise to alkali layer
Acid adjusts pH value to 1~2, is extracted with ethyl acetate, merges extracting solution, filtrate decompression concentration without ethyl acetate, to obtain the final product.It is preferred that
, the synthesis of step 5,2S- xylylenimine butyric acid:
Ethyl acetate, triethylamine are added in retort and stirred, sequentially adds imidazoles, (S)-benzyl butanedioic acid, part is molten
Solution, cooling, is slowly added dropwise thionyl chloride below -10 DEG C of temperature control, after dripping off, less than -10 DEG C react 4~6 it is small when, then -
After cis hexahydro iso-indoles is added dropwise in less than 8 DEG C DEG C left and right, slowly heating, when stirring reaction is small not less than 15;Added in reaction solution
3%HCl is stirred, and if insoluble matter should filter out insoluble matter, separates lower aqueous layer, and ethyl acetate layer is washed with salt, then with full
Extracted with sodium carbonate liquor to aqueous ph value to 7~8, extracting solution is merged, is washed with ethyl acetate, dense salt is added dropwise to alkali layer
Acid adjusts pH value to 1~2, is extracted with ethyl acetate, merges extracting solution, filtrate decompression concentration without ethyl acetate, to obtain the final product.
Preferably, the synthesis of step 5,2S- xylylenimine butyric acid:
Ethyl acetate, triethylamine are added in retort and stirred, sequentially adds imidazoles, (S)-benzyl butanedioic acid, part is molten
Solution, cooling, is slowly added dropwise thionyl chloride below -10 DEG C of temperature control, after dripping off, less than -10 DEG C react 4~6 it is small when, then -
After cis hexahydro iso-indoles is added dropwise in less than 8 DEG C DEG C left and right, slowly heating, when stirring reaction is small not less than 15;Added in reaction solution
3%HCl is stirred, and if insoluble matter should filter out insoluble matter, separates lower aqueous layer, ethyl acetate layer is small not less than 15 with reaction is mixed
When, 3%HCl stirrings are added into reaction solution, if insoluble matter should filter out insoluble matter, separate lower aqueous layer, ethyl acetate layer
Add in pillar and eluted, collect ethyl acetate layer, filtrate decompression concentration is without ethyl acetate, to obtain the final product.
Filler in pillar can be one of silica gel, polyamide granules, ion exchange resin or both combination.
The present invention is improved as follows relative to existing preparation method:
The present invention shortens reactions steps, is refined in 2S- xylylenimine butyric acid and column chromatography and PH are used in purge process
Gradient is adjusted, and can save substantial amounts of reagent, environmentally protective, the purity of Mitiglinide Calcium can reach 99.6%, and single impurity is small
In 0.03%, always miscellaneous to be less than 0.1%, related material significantly reduces, and the side effect of human body is reduced, and reaches preferable clinical effectiveness.
Embodiment:
By following embodiments, the present invention is further illustrated, but not as the limitation of the present invention.
Step 1:The synthesis of benzylidene succinic acid:It is molten by being stirred in 480 grams of absolute methanols, 65 grams of sodium methoxides addition retort
Xie Hou, adds 450 grams of diethyl succinates, is heated to reflux, 100 grams of benzaldehydes is added dropwise, when reflux is small not less than 1, so
After steam methanol, be slowly added into 480 gram of 40% sodium hydroxide solution, add drinking water, dichloromethane, stir 30~60 minutes,
Concentrated hydrochloric acid is added dropwise and adjusts pH value to 2~3, is settled out product, drying.
Above-mentioned reaction diethyl succinate and benzaldehyde and mole ratio 5.0.
Step 2:The synthesis of benzyl butanedioic acid:Benzylidene succinic acid is molten with the absolute ethyl alcohol of 4.8 times of benzylidene succinic acids
Solution, add 3% activated carbon decolorizing 2 it is small when, filter out activated carbon, add in retort and stir, be passed through nitrogen, drain air, add
25 gram of 10% palladium carbon, is passed through hydrogen and carries out hydrogenation, until reaction terminates, drain hydrogen in retort with nitrogen, filter out
Palladium carbon.
Step 3:(S) synthesis of-benzyl butanedioic acid (R)-α-phenylethylamine salt:By upper step benzyl butanedioic acid ethanol, anhydrous
Ethanol is added in retort and stirred, and is heated to flowing back, is slowly added into 146ml (R)-α-phenylethylamine, and slightly cold addition crystal seed is slowly cold
But crystallization.Centrifuge separates, and filter cake is washed with absolute ethyl alcohol, dried, refined, dried with absolute ethyl alcohol, 50~60 DEG C of drying,
Obtain (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt.
Above-mentioned reaction (R)-α-phenylethylamine and the mole ratio 1.1 with benzyl butanedioic acid.
Step 4:(S) synthesis of-benzyl butanedioic acid:By (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt, 1100 gram of 4% hydrogen
Sodium hydroxide solution, 600ml dichloromethane add stirring and dissolving in retort, separate organic phase, and water is mutually washed with dichloromethane, divide and go
Organic phase;Water phase transfer to retort stirs, and concentrated hydrochloric acid tune pH value is added dropwise to 1~3, separates out mass crystallization, continues 30 points of stirring
Clock, centrifuge, washing, 50~60 DEG C of drying, obtain (S)-benzyl butanedioic acid.
Step 5:The synthesis of xylylenimine butyric acid:455 grams of ethyl acetate, 120 grams of triethylamines are added in retort and stirred
Mix, sequentially add 28 grams of imidazoles, 38 grams of (S)-benzyl butanedioic acids, be partly dissolved.Cool down, chlorine is slowly added dropwise below -10 DEG C of temperature control
Change sulfoxide, after dripping off, when less than -10 DEG C reactions 4~6 are small.Then cis hexahydro iso-indoles is added dropwise in left and right below -8 DEG C DEG C
Afterwards, slowly heating, when stirring reaction is small not less than 15;3%HCl stirrings are added in reaction solution, if insoluble matter should filter out not
Molten thing, separates lower aqueous layer, and ethyl acetate layer is washed with salt, is then extracted with saturated sodium carbonate solution to aqueous ph value to 7
~8, extracting solution is merged, is washed with ethyl acetate.Concentrated hydrochloric acid is added dropwise to alkali layer and adjusts pH value to 1~2, is carried with ethyl acetate
Take, merge extracting solution, filtrate decompression concentration without ethyl acetate, carry out the next step.
Above-mentioned reaction (S)-benzyl butanedioic acid and cis hexahydro iso-indoles and mole ratio 0.7.
Step 6:The synthesis of Mitiglinide Calcium crude product:2S- xylylenimines butyric acid, 250 grams of absolute ethyl alcohols are added into reaction
Tank, stirring and dissolving, is slowly added into 52 gram of 4% sodium hydroxide solution at 10~15 DEG C, after adding, is slowly added at 10-15 DEG C
100 grams of 1N calcium chloride solutions, continue stirring and are not less than 30 minutes after dripping off, centrifuge separation, 90% ethanol are washed, 50~60 DEG C of bakings
It is dry, obtain Mitiglinide Calcium crude product.
Above-mentioned reaction 2S- xylylenimines butyric acid and calcium chloride and mole ratio 0.45.
Step 7:Mitiglinide Calcium refines:Mitiglinide Calcium crude product, 180 grams of absolute ethyl alcohols are added in retort, stirring
Dissolving, add about 5% activated carbon decolorizing 1 it is small when more than, filtering, obtains filtrate, purified water is slowly added dropwise under stirring.Stirring 30 minutes
More than, centrifuge separation, 50-60 DEG C of vacuum drying.Total moles yield is between 15.6%, mitiglinide calcium
99.8%, single impurity 0.02%, always miscellaneous is 0.05%.
Embodiment 2
Step 1:The synthesis of benzylidene succinic acid:It is molten by being stirred in 480 grams of absolute methanols, 65 grams of sodium methoxides addition retort
Xie Hou, adds 450 grams of diethyl succinates, is heated to reflux, 100 grams of benzaldehydes is added dropwise, when reflux is small not less than 1, so
After steam methanol, be slowly added into 480 gram of 40% sodium hydroxide solution, add drinking water, dichloromethane, stir 30~60 minutes,
Concentrated hydrochloric acid is added dropwise and adjusts pH value to 2~3, is settled out product, drying.
Above-mentioned reaction diethyl succinate and benzaldehyde and mole ratio 5.0.
Step 2:The synthesis of benzyl butanedioic acid:Benzylidene succinic acid is molten with the absolute ethyl alcohol of 4.8 times of benzylidene succinic acids
Solution, add 3% activated carbon decolorizing 2 it is small when, filter out activated carbon, add in retort and stir, be passed through nitrogen, drain air, add
25 gram of 10% palladium carbon, is passed through hydrogen and carries out hydrogenation, until reaction terminates, drain hydrogen in retort with nitrogen, filter out
Palladium carbon.
Step 3:(S) synthesis of-benzyl butanedioic acid (R)-α-phenylethylamine salt:By upper step benzyl butanedioic acid ethanol, anhydrous
Ethanol is added in retort and stirred, and is heated to flowing back, is slowly added into 146ml (R)-α-phenylethylamine, and slightly cold addition crystal seed is slowly cold
But crystallization.Centrifuge separates, and filter cake is washed with absolute ethyl alcohol, dried, refined, dried with absolute ethyl alcohol, 50~60 DEG C of drying,
Obtain (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt.
Above-mentioned reaction (R)-α-phenylethylamine and the mole ratio 1.1 with benzyl butanedioic acid.
Step 4:(S) synthesis of-benzyl butanedioic acid:By (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt, 1100 gram of 4% hydrogen
Sodium hydroxide solution, 600ml dichloromethane add stirring and dissolving in retort, separate organic phase, and water is mutually washed with dichloromethane, divide and go
Organic phase;Water phase transfer to retort stirs, and concentrated hydrochloric acid tune pH value is added dropwise to 1~3, separates out mass crystallization, continues 30 points of stirring
Clock, centrifuge, washing, 50~60 DEG C of drying, obtain (S)-benzyl butanedioic acid.
Step 5:The synthesis of xylylenimine butyric acid:470 grams of ethyl acetate, 130 grams of diethylamine are added in retort and stirred
Mix, sequentially add 21 grams of pyridines, 38 grams of (S)-benzyl butanedioic acids.Cool down, thionyl chloride is slowly added dropwise below -10 DEG C of temperature control, drip
After complete, when less than -10 DEG C reactions 4~6 are small.Then after cis hexahydro iso-indoles is added dropwise in left and right below -8 DEG C DEG C, slowly rise
Temperature, when stirring reaction is small not less than 15;3%HCl stirrings are added in reaction solution, if insoluble matter should filter out insoluble matter, are separated
Lower aqueous layer, ethyl acetate layer with mix reaction not less than 15 it is small when.3%HCl stirrings are added into reaction solution, if insoluble matter
Insoluble matter should be filtered out, separates lower aqueous layer, ethyl acetate layer is added to be filled with the pillar of silica gel and eluted, and collects ethyl acetate
Layer, filtrate decompression concentration carry out the next step without ethyl acetate.
Above-mentioned reaction (S)-benzyl butanedioic acid and cis hexahydro iso-indoles and mole ratio 0.7.
Step 6:The synthesis of Mitiglinide Calcium crude product:30 grams of 2S- xylylenimines butyric acid, 250 grams of absolute ethyl alcohols are added
Retort, stirring and dissolving, is slowly added into 21 grams of saturated sodium carbonate solutions at 10-15 DEG C, after adding, at 10-15 DEG C slowly plus
Enter 105 grams of 1N calcium chloride solutions, continue stirring after dripping off and be not less than 30 minutes, centrifuge separation, 90% ethanol are washed, 50~60 DEG C
Drying, obtains Mitiglinide Calcium crude product.
Above-mentioned reaction 2S- xylylenimines butyric acid and calcium chloride and mole ratio 0.45.
Step 7:Mitiglinide Calcium refines:12 grams of Mitiglinide Calcium crude products, 170 grams of absolute ethyl alcohols are added in retort,
Stirring and dissolving, add about 5% activated carbon decolorizing 1 it is small when more than, filtering, obtains filtrate, purified water is slowly added dropwise under stirring.Stirring 30
More than minute, centrifuge separation, 50-60 DEG C of vacuum drying.Total moles yield is 16.7%, mitiglinide calcium
99.9%, single impurity 0.01%, always miscellaneous is 0.03%.
Claims (8)
1. a kind of preparation method of Mitiglinide Calcium, it is characterised in that comprise the following steps:
The synthesis of step 1, benzylidene succinic acid:
Absolute methanol, sodium methoxide are added in retort after stirring and dissolving, diethyl succinate is added, is heated to reflux,
Benzaldehyde is added dropwise, then steams methanol, is slowly added into sodium hydroxide solution, adds drinking water, dichloromethane, stirs 30~60 points
Clock, is added dropwise concentrated hydrochloric acid, precipitates, to obtain the final product;
The synthesis of step 2, benzyl butanedioic acid:
Benzylidene succinic acid is dissolved with absolute ethyl alcohol, adds activated carbon decolorizing, filters out activated carbon, adds in retort and stirs,
Nitrogen is passed through, drains air, adds 10% palladium carbon, hydrogen is passed through and carries out hydrogenation, until reaction terminates, will be reacted with nitrogen
Hydrogen drains in tank, filters out palladium carbon;
The synthesis of step 3, (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt:
Benzyl butanedioic acid, absolute ethyl alcohol are added in retort and stirred, is heated to flowing back, is slowly added into (R)-α-phenylethylamine, slightly
Cold addition crystal seed slowly with absolute ethyl alcohol washed, dried, refined, got rid of with absolute ethyl alcohol by cooling crystallization, centrifuge separation, filter cake
Dry, 50~60 DEG C of drying, obtain (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt;
The synthesis of step 4, (S)-benzyl butanedioic acid:
(S)-benzyl butanedioic acid (R)-α-phenylethylamine salt, sodium hydroxide solution, dichloromethane are added into stirring and dissolving in retort,
Organic phase is separated, water is mutually washed with dichloromethane, is divided and is gone organic phase;Water phase transfer to retort stirs, and concentrated hydrochloric acid tune pH value is added dropwise,
Mass crystallization is separated out, continues to stir, centrifuge, washing, dries, obtains (S)-benzyl butanedioic acid;
The synthesis of step 5,2S- xylylenimine butyric acid:
(S)-benzyl butanedioic acid is taken, is dissolved, is cooled down, thionyl chloride is slowly added dropwise below 0 DEG C of temperature control, is then added dropwise below 0 DEG C
After cis hexahydro iso-indoles, slowly heating, stirring, refines reaction solution, obtains 2S- xylylenimine butyric acid;
The synthesis of step 6, Mitiglinide Calcium crude product:
2S- xylylenimines butyric acid, absolute ethyl alcohol are added into retort, stirring and dissolving, adds 4% sodium hydroxide solution, add
Afterwards, calcium chloride solution is slowly added into, during dropwise addition, adds ethanol solution, continues to stir after dripping off, centrifuge separation, ethanol
Elution, drying, obtain Mitiglinide Calcium crude product;
Step 7:Mitiglinide Calcium refines:
Mitiglinide Calcium crude product, absolute ethyl alcohol are added in retort, stirring and dissolving, add activated carbon decolorizing, filtering, must filter
Liquid, is slowly added dropwise purified water under stirring, stirring, centrifuge separation, vacuum drying, to obtain the final product.
2. preparation method according to claim 1, it is characterised in that in step 1, diethyl succinate and benzaldehyde rub
You measure ratio 4.0~5.5.
3. preparation method according to claim 1, it is characterised in that in step 3, (R)-α-phenylethylamine and benzyl butanedioic acid
Mole ratio 1.0~1.3.
4. preparation method according to claim 1, it is characterised in that in step 5, cis hexahydro iso-indoles and (S)-benzyl
The mole ratio 0.3~0.8 of butanedioic acid.
5. preparation method according to claim 1, it is characterised in that the synthesis of step 5,2S- xylylenimine butyric acid:Will
Ethyl acetate, triethylamine add stirring in retort, sequentially add imidazoles, the dissolving of (S)-benzyl butanedioic acid, cooling, temperature control -15
DEG C~-12 DEG C thionyl chloride is slowly added dropwise, after dripping off, -15 DEG C to 0 DEG C reaction 4~6 it is small when, then -15 DEG C~-12
After DEG C cis hexahydro iso-indoles being added dropwise, slowly heating, when stirring reaction is small not less than 15;3%HCl stirrings are added in reaction solution,
If insoluble matter should filter out insoluble matter, lower aqueous layer is separated, ethyl acetate layer is washed with salt, then uses saturated sodium carbonate solution
Adjust to aqueous ph value to 7~8, extracting solution merged, is washed with ethyl acetate, to alkali layer be added dropwise concentrated hydrochloric acid adjust pH value to
1~2, extracted with ethyl acetate, merge extracting solution, filtrate decompression concentration without ethyl acetate, to obtain the final product.
6. preparation method according to claim 1, it is characterised in that the synthesis of step 5,2S- xylylenimine butyric acid:Will
Ethyl acetate, triethylamine add stirring in retort, sequentially add imidazoles, (S)-benzyl butanedioic acid, are partly dissolved, and cool down, control
Thionyl chloride is slowly added dropwise in less than -10 DEG C of temperature, after dripping off, when less than -10 DEG C reactions 4~6 are small, then below -8 DEG C DEG C
After cis hexahydro iso-indoles is added dropwise in left and right, slowly heating, when stirring reaction is small not less than 15;3%HCl is added in reaction solution to stir
Mix, if insoluble matter should filter out insoluble matter, separate lower aqueous layer, ethyl acetate layer is washed with salt, then uses saturated sodium carbonate
Solution is extracted to aqueous ph value to 7~8, and extracting solution is merged, is washed with ethyl acetate, concentrated hydrochloric acid, which is added dropwise, to alkali layer adjusts PH
Value is extracted with ethyl acetate to 1~2, merges extracting solution, filtrate decompression concentration without ethyl acetate, to obtain the final product.
7. preparation method according to claim 1, it is characterised in that the synthesis of step 5,2S- xylylenimine butyric acid:Will
Ethyl acetate, triethylamine add stirring in retort, sequentially add imidazoles, (S)-benzyl butanedioic acid, are partly dissolved, and cool down, control
Thionyl chloride is slowly added dropwise in less than -10 DEG C of temperature, after dripping off, when less than -10 DEG C reactions 4~6 are small, then below -8 DEG C DEG C
After cis hexahydro iso-indoles is added dropwise in left and right, slowly heating, when stirring reaction is small not less than 15;3%HCl is added in reaction solution to stir
Mix, if insoluble matter should filter out insoluble matter, separate lower aqueous layer, ethyl acetate layer with mix reaction it is small not less than 15 when, to anti-
Answer and 3%HCl stirrings are added in liquid, if insoluble matter should filter out insoluble matter, separate lower aqueous layer, ethyl acetate layer adds pillar
In eluted, collect ethyl acetate layer, filtrate decompression concentration is without ethyl acetate, to obtain the final product, the filler in pillar can be silica gel,
One of polyamide granules, ion exchange resin or both combine.
8. preparation method according to claim 1, it is characterised in that comprise the following steps:
Step 1:Step 1:The synthesis of benzylidene succinic acid:480 grams of absolute methanols, 65 grams of sodium methoxides are added in retort and stirred
After dissolving, 450 grams of diethyl succinates are added, are heated to reflux, 100 grams of benzaldehydes are added dropwise, when reflux is small not less than 1,
Then methanol is steamed, is slowly added into 480 gram of 40% sodium hydroxide solution, adds drinking water, dichloromethane, stirs 30~60 points
Clock, dropwise addition concentrated hydrochloric acid adjusting pH value to 2~3, is settled out product, dry,
Above-mentioned reaction diethyl succinate and benzaldehyde and mole ratio 5.0,
Step 2:The synthesis of benzyl butanedioic acid:The benzylidene succinic acid absolute ethyl alcohol of 4.8 times of benzylidene succinic acids is dissolved, is added
Enter 3% activated carbon decolorizing 2 it is small when, filter out activated carbon, add in retort and stir, be passed through nitrogen, drain air, add 25 grams
10% palladium carbon, is passed through hydrogen and carries out hydrogenation, until reaction terminates, drain hydrogen in retort with nitrogen, filter out palladium carbon,
Step 3:(S) synthesis of-benzyl butanedioic acid (R)-α-phenylethylamine salt:By upper step benzyl butanedioic acid ethanol, absolute ethyl alcohol
Add in retort and stir, be heated to flowing back, be slowly added into 146ml (R)-α-phenylethylamine, slightly cold addition crystal seed slowly cools down analysis
Crystalline substance, centrifuge separation, filter cake are washed with absolute ethyl alcohol, dried, refined, dried with absolute ethyl alcohol, and 50~60 DEG C of drying, obtain
(S)-benzyl butanedioic acid (R)-α-phenylethylamine salt,
Above-mentioned reaction (R)-α-phenylethylamine and the mole ratio 1.1 with benzyl butanedioic acid,
Step 4:(S) synthesis of-benzyl butanedioic acid:By (S)-benzyl butanedioic acid (R)-α-phenylethylamine salt, 1100 gram of 4% hydroxide
Sodium solution, 600ml dichloromethane add stirring and dissolving in retort, separate organic phase, and water is mutually washed with dichloromethane, point go organic
Phase;Water phase transfer to retort stirs, and dropwise addition concentrated hydrochloric acid tune pH value to 1~3, separates out mass crystallization, continues stirring 30 minutes, from
Scheming centrifugation, washing, 50~60 DEG C of drying, obtain (S)-benzyl butanedioic acid,
Step 5:The synthesis of xylylenimine butyric acid:470 grams of ethyl acetate, 130 grams of diethylamine are added in retort and stirred, according to
21 grams of pyridines of secondary addition, 38 grams of (S)-benzyl butanedioic acids, cool down, and thionyl chloride is slowly added dropwise below -10 DEG C of temperature control, drips off
Afterwards, when less than -10 DEG C reactions 4~6 are small, after then cis hexahydro iso-indoles is added dropwise in left and right below -8 DEG C DEG C, slowly heating,
When stirring reaction is small not less than 15;3%HCl stirrings are added in reaction solution, if insoluble matter should filter out insoluble matter, separate lower floor
Water layer, ethyl acetate layer with mix reaction not less than 15 it is small when, into reaction solution add 3%HCl stirring, if insoluble matter should be filtered
Except insoluble matter, lower aqueous layer is separated, ethyl acetate layer is added to be filled with the pillar of silica gel and eluted, and collects ethyl acetate layer,
Filtrate decompression is concentrated without ethyl acetate, carries out the next step,
Above-mentioned reaction (S)-benzyl butanedioic acid and cis hexahydro iso-indoles and mole ratio 0.7,
Step 6:The synthesis of Mitiglinide Calcium crude product:30 grams of 2S- xylylenimines butyric acid, 250 grams of absolute ethyl alcohols are added into reaction
Tank, stirring and dissolving, is slowly added into 21 grams of saturated sodium carbonate solutions at 10~15 DEG C, after adding, is slowly added at 10-15 DEG C
105 grams of 1N calcium chloride solutions, continue stirring and are not less than 30 minutes after dripping off, centrifuge separation, 90% ethanol are washed, 50~60 DEG C of bakings
It is dry, Mitiglinide Calcium crude product is obtained,
Above-mentioned reaction 2S- xylylenimines butyric acid and calcium chloride and mole ratio 0.45,
Step 7:Mitiglinide Calcium refines:12 grams of Mitiglinide Calcium crude products, 170 grams of absolute ethyl alcohols are added in retort, stirring
Dissolving, add about 5% activated carbon decolorizing 1 it is small when more than, filtering, obtains filtrate, and purified water is slowly added dropwise under stirring, stirs 30 minutes
More than, centrifuge separation, 50-60 DEG C of vacuum drying, to obtain the final product.
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