CN103694230B - A kind of High-purity canagliflozin compound and preparation method thereof - Google Patents

A kind of High-purity canagliflozin compound and preparation method thereof Download PDF

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CN103694230B
CN103694230B CN201310656792.3A CN201310656792A CN103694230B CN 103694230 B CN103694230 B CN 103694230B CN 201310656792 A CN201310656792 A CN 201310656792A CN 103694230 B CN103694230 B CN 103694230B
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gelie
clean
amino acid
solid
mixture
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CN103694230A (en
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赵俊
宗在伟
杜有国
刘子宁
于春江
刘同根
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Jiangsu Aosaikang Pharmaceutical Co Ltd
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Jiangsu Aosaikang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The invention belongs to pharmaceutical synthesis field, relate to Ka Gelie shown in a kind of high purity formula I and purify compound and preparation method thereof.The content that Ka Gelie provided by the present invention purifies the α-configuration impurity of compound Chinese style II is less than 1%, further, be less than 0.5%, its preparation method comprises: by Ka Gelie, clean and amino acid forms eutectic thing in a solvent, be separated this eutectic thing, and then eutectic thing is decomposed, obtain Ka Gelie and purify compound.？

Description

A kind of High-purity canagliflozin compound and preparation method thereof
Technical field
The invention belongs to pharmaceutical synthesis field, relate to and a kind ofly prepare the clean method of high purity Ka Gelie, particularly relate to and a kind ofly use amino acid and Ka Gelie only to form mixture to carry out the clean method of purifying Ka Gelie.
Background technology
Ka Gelie is a kind of sodium-glucose cotransporter 2 (SGLT-2) inhibitor only, and be used for the treatment of diabetes, it has as shown in the formula the structural formula shown in I:
Its conventional synthetic route is:
Wherein M is lithium or zinc, and Z is protecting group, commonly uses as TMS.
In above-mentioned preparation process, the glycosidic link of formation has α and β two kinds of configurations, and Ka Gelie is β type only.Although advantage is in formation beta comfiguration in preparation process, unavoidably still there is the generation of α-configuration impurity.
In patent application CN101801371, (embodiment 7-9) discloses ethanoyl protection Ka Gelie being carried out only hydroxyl, then deprotection, then obtains the clean method of Ka Gelie through recrystallization, and route is as follows:
But, this method increase two-step reaction, reduce yield, and and fail effectively to reduce Ka Gelie clean in the content of α-configuration impurity.
In order to ensure validity and the security of prepared medicine, in the clean bulk drug of Ka Gelie, need the foreign matter content of control α configuration, and have not yet to see and need effective means to reduce α-configuration impurity.
WO2013064909(publication date on May 10th, 2013) in disclose the crystalline composites of 1:1 of the clean and L-PROLINE of Ka Gelie, D-PROLINE, L-Phe.WO2012154812(publication date on November 15th, 2012) in disclose the crystalline composites that the clean and citric acid of Ka Gelie or L-PROLINE formed.In these two parts of patents, do not relate to the clean α configuration impurity of Ka Gelie and Ka Gelie to cleanse problem.
Summary of the invention
The Ka Gelie that the object of the present invention is to provide a kind of α-configuration foreign matter content low purifies compound and preparation method thereof.
An aspect of of the present present invention, provides the Ka Gelie shown in a kind of formula I and purifies compound,
The content of the α shown in its Chinese style II-configuration impurity is less than 1%, and preferably content is less than 0.5%,
In the research process improving the clean compound purity of Ka Gelie, contriver finds that Ka Gelie is clean and amino acid forms eutectic thing in a solvent, is separated this eutectic thing, and then is decomposed by eutectic thing, the Ka Gelie obtained purifies compound, and wherein α-configuration impurity can effectively reduce.
Another aspect of the present invention, provide the preparation method that a kind of above-mentioned Ka Gelie purifies compound, it comprises the following steps:
Steps A: dissolve clean for Ka Gelie in a solvent with amino acid, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: the clean and separation for amino acids by Ka Gelie in clean for Ka Gelie amino acid complex, obtains Ka Gelie and purify compound.
Solvent selected from methanol in described steps A, ethanol, Virahol, water, methylene dichloride, acetonitrile, acetone, methyl tertiary butyl ether, ether, isopropyl ether, ethyl acetate, isopropyl acetate, or the mixed solvent of water and ethanol, methyl alcohol, Virahol, acetone or acetonitrile.
Amino acid used in described steps A can be hydrophobic amino acid or hydrophilic amino acid; Described hydrophobic amino acid is preferably L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, proline(Pro), phenylalanine, tryptophane or methionine(Met); Described hydrophilic amino acid is preferably glycine, Serine, Threonine, halfcystine, tyrosine, l-asparagine, glutamine, Methionin, arginine, Histidine, aspartic acid or L-glutamic acid.
Preferably, described amino acid is proline(Pro) or phenylalanine.
Amino acid described above can select the L-type or D type amino acid with optical purity, is preferably L-type amino acid.
Described amino acid whose consumption, in mole dosage, is preferably the clean 0.8-5 of Ka Gelie doubly.
The Crystallization method of described steps A can adopt the method for cooling crystallization, also can adopt the method for steaming except partial solvent crystallization, or add the method for anti-solvent crystallization.
In the method for described anti-solvent crystallization, anti-solvent used is selected from non-polar hydrocarbon kind solvent, is preferably hexane or heptane.
Filtration in described steps A can be filtered by suction filtration or centrifugal method, obtains the clean amino acid complex of Ka Gelie.At the crystal adopting anti-solvent Crystallization method to obtain, can also preferably clean for the Ka Gelie obtained amino acid complex crystallization solvent be washed.
In stepb, a kind of preferably method that the is Ka Gelie in amino acid complex clean for Ka Gelie is clean and separation for amino acids comprises: dissolved by clean for Ka Gelie amino acid complex or be suspended in water, regulate pH to acid or alkaline with acid or alkali, then organic solvent is used, extraction, by the organic phase of extraction through concentrated or cooling, precipitation obtains Ka Gelie and purifies compound.
Described organic solvent can be ethers, ester class or dichloromethane solvent, is preferably ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate, isopropyl acetate or methylene dichloride.
When using acid for adjusting pH, pH value is preferably adjusted to 1 ~ 2; When using alkali to regulate pH, pH value is preferably adjusted to 12 ~ 13.
The Ka Gelie that described precipitation obtains purifies compound and preferably through filtration, washing, drying, can obtain Ka Gelie and purify compound finished product.
Purify in the preparation method of compound at a kind of preferred above-mentioned Ka Gelie provided by the invention, comprise the steps:
Steps A: dissolve clean for Ka Gelie in a solvent with hydrophobic amino acid, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: suspended by clean for Ka Gelie amino acid complex or be dissolved in water, regulates pH with acid or alkali, then uses organic solvent extraction, is separated and obtains Ka Gelie purification compound from organic phase.
Wherein, solvent selected from methanol used in steps A, ethanol, Virahol, water, acetonitrile, acetone, ethyl acetate, isopropyl acetate, or the mixed solvent of water and ethanol, methyl alcohol, Virahol, acetone or acetonitrile.
Hydrophobic amino acid used in steps A is selected from L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, proline(Pro), phenylalanine, tryptophane or methionine(Met); Described hydrophobic amino acid can select the L-type or D type amino acid with optical purity.
Described amino acid whose consumption, in mole dosage, is preferably the clean 0.8-5 of Ka Gelie doubly.
The method of crystallization described in steps A is preferably the method for cooling crystallization, or steams the method except partial solvent crystallization.
Filtration described in steps A can be filtered by suction filtration or centrifugal method.
In stepb, described organic solvent can be ethers or esters solvent, is preferably ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate or isopropyl acetate.
Be separated from organic phase described in step B and obtain Ka Gelie and purify compound and can be undertaken by method that is concentrated or cooling crystallization.Preferably, can further include filtration, drying, obtain finished product.
Purify in the preparation method of compound at the preferred above-mentioned Ka Gelie of another kind provided by the invention, comprise the steps:
Steps A: dissolves clean for Ka Gelie in a solvent with proline(Pro) or phenylalanine, crystallization of lowering the temperature, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: clean for Ka Gelie amino acid complex suspended or be dissolved in water, regulates pH with acid or alkali, then uses organic solvent extraction, is separated that to obtain high purity Ka Gelie clean from organic phase.
Solvent selected from methanol used in steps A, ethanol, Virahol, water, acetonitrile, acetone, ethyl acetate, isopropyl acetate, or the mixed solvent of water and ethanol, methyl alcohol, Virahol, acetone or acetonitrile.
Proline(Pro) used in steps A or phenylalanine preferably have optically active amino acid, such as L-PROLINE, D-PROLINE, L-Phe, D-phenylalanine.
Described amino acid whose consumption, in mole dosage, is preferably the clean 1-3 of Ka Gelie doubly.
Filtration described in steps A can be filtered by suction filtration or centrifugal method.
In stepb, described organic solvent can be ethers or esters solvent, is preferably ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate or isopropyl acetate.
Described in step B, from organic phase, separation obtains Ka Gelie purification compound and can use method that is concentrated or cooling crystallization.Preferably, can further include filtration, drying, obtain finished product.
The above-mentioned various Ka Gelie provided purify the preparation method of compounds, in step, clean and amino acid can be dissolved in identical or different solvents respectively by Ka Gelie, then be mixed by two solution, the clean amino acid complex of precipitation Ka Gelie; Also Ka Gelie can be dissolved in a solvent only, then amino acid solid be added, separate out the clean amino acid complex of Ka Gelie.
If Ka Gelie is clean or amino acid can not all dissolve in a solvent, solubleness can be improved by the method for heating, after solid all dissolves, reduce temperature, the clean amino acid complex of Ka Gelie is separated out.
If the clean amino acid complex of Ka Gelie solubleness is in a solvent comparatively large, the solid of precipitation is less, can be increased the precipitation quantity of solid by the method reducing temperature.
Ka Gelie provided by the present invention is clean, and the content of wherein α-configuration impurity is less than 1%, is preferably less than 0.5%.The preparation method that Ka Gelie provided by the invention is clean, simple and easy to operate, obtained Ka Gelie clean α-configuration foreign matter content is low, can be less than 0.5%, is suitable for applying in industrial production.
Embodiment
Below in conjunction with specific embodiment, the present invention is conducted further description.It will be appreciated that the detailed description of following embodiment just to part embodiment of the present invention, is not limitation of the scope of the invention.
In following each embodiment, Ka Gelie uses HPLC to analyze only, and HPLC condition is as follows:
Determined wavelength 254nm
Moving phase is: component A: the trifluoroacetic acid aqueous solution of 0.1%
B component: acetonitrile, A:B is 30:70
Chromatographic column is: C18 chromatographic column
Flow velocity: 1ml/min.
Preparation example 1
According to JournalofMedicinalChemistry2010; 53; method in 6355-60 obtains the Ka Gelie clean (formula 1) of trimethyl silicon based protection, then trimethyl silicon based and methoxyl group is removed according to the method announced in the document, obtains Ka Gelie clean (formula 2).Concrete method is as follows:
By compound 1(6.3kg, 13.2mol) join in 60L methylene dichloride, add triethyl silicane (4.6kg, 39.9mol) with dry ice acetone cooling, boron trifluoride ether solution (5L, 39.5mmol) is dripped and enters, then reaction mixture is warming up to 0 DEG C, stir 2 hours, saturated sodium bicarbonate aqueous solution (80L) is slowly joined in reactor, will cancellation be reacted.Layering, organic phase is evaporated to dry, add water 100L and ethyl acetate 70L, after stirring extraction, aqueous phase is used 70L extraction into ethyl acetate again, merge organic phase, use 50L water washing, then with the washing of 50L saturated nacl aqueous solution, add anhydrous magnesium sulfate drying, by siccative filtering, add gac, stir after 30 minutes, by activated carbon filtration, filtrate reduced in volume is to dry, residue with ethyl acetate (30L) is dissolved, ether (60L) is slowly added, has solid to separate out, for Ka Gelie is clean, 3.98kg altogether.
HPLC detects α-configuration impurity: 4.35%.
Reference examples 1
Prepare Ka Gelie according to the method for the embodiment 7-9 in patent application CN101801371 clean, concrete grammar is as follows:
By clean for Ka Gelie (11.9g, 26.8mmol), 4-methylmorpholine (14.5ml, 130.0mmol), N, N-Dimethylamino pyridine (325mg, 2.6mmol) join in 100ml tetrahydrofuran (THF), in ice bath, while stirring the light green mixture of gained is cooled to-10 DEG C, then aceticanhydride (12.5ml, 130mmol) is dripped and enter, control rate of addition, make temperature not higher than 0 DEG C.After dropwising, stirring 15 minutes is continued below 0 DEG C, then slowly room temperature is risen to, stir 1 hour at 20 DEG C, then be evaporated to dry at 32 DEG C, the phosphoric acid 30ml of 10% is added in resistates, define cream-colored throw out, ethyl acetate 80ml is added in mixture, tetrahydrofuran (THF) 30ml, toluene 30ml, under stirring, solid is all dissolved, layering, organic phase saturated sodium bicarbonate solution and saturated nacl aqueous solution are washed successively, with anhydrous sodium sulfate drying, by siccative filtering, concentrating under reduced pressure, obtain syrup, methyl alcohol 30ml is added, separate out off-white color solid, stir 30 minutes, filter, 45 DEG C of vacuum-dryings, obtain the clean 12.9g of four acetylizad Ka Gelie, yield 78%.
By the clean (12g of four acetylizad Ka Gelie obtained, 19.6mmol) join in the mixed solvent of tetrahydrofuran (THF) (53ml) and methyl alcohol (80ml), obtain suspension, by a hydronium(ion) Lithium Oxide 98min (410mg, 9.5mmol) be dissolved in 26ml water, join in above-mentioned mixture, stirred at ambient temperature 12 hours, reaction solution is evaporated to tetrahydrofuran (THF) and methyl alcohol is closely dry, ethyl acetate 39ml is added in resistates, stir separatory, aqueous phase is with 10ml extraction into ethyl acetate 3 times, merge organic phase, wash with saturated nacl aqueous solution 20ml, add anhydrous magnesium sulfate drying, be evaporated to dry, obtain foaming solid,
0.6ml water and 27.5ml ethyl acetate is added in this foaming solid, solid is entirely molten, is heated to 35 DEG C under stirring, is dripped by 15.5ml normal heptane and enters, gradually reaction solution becomes muddy and stops dropping normal heptane, stir 2 hours at such a temperature, remaining normal heptane is dripped and enters, then add 3ml normal heptane, reaction solution is stirred after 30 minutes and filter, the filter cake mixed solvent of 2.5ml ethyl acetate and 2.5ml normal heptane washs, and vacuum-drying, obtains off-white color solid 4.5g.
HPLC detects α-configuration impurity: 1.35%.
Reference examples 2
By clean for Ka Gelie (10.0g, 22.5mmol) join in Iso Butyl Acetate (100ml), add monohydrate potassium (5.2g, 24.8mmol, 1.1eq), mixture is heated to backflow, gradually solid all dissolves, then room temperature is cooled to, by the solid filtering of separating out, wash with a small amount of Iso Butyl Acetate, the solid obtained is added in purified water (200ml), pH to 13 is regulated with sodium hydroxide, extract with methyl tertiary butyl ether (100ml × 3), merge organic phase, concentrating under reduced pressure, a large amount of solid is had to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.8g of Ka Gelie, yield 78%
HPLC detects α-configuration impurity: 1.25%
Embodiment 1:
By clean for Ka Gelie (10.0g, 22.5mmol) be dissolved in dehydrated alcohol (200ml), add L-PROLINE (7.8g, 67.7mmol, 3eq), be heated to backflow, solid is whole clearly molten, is then slowly cooled to room temperature, by the solid filtering of separating out, filter cake absolute ethanol washing, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (200ml), with salt acid for adjusting pH to 2, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, filter cake methyl tertiary butyl ether cold on a small quantity washing, 50 DEG C of vacuum-dryings, obtain the clean finished product 8.9g of Ka Gelie, yield 89%.
HPLC detects α-configuration impurity: 0.017%.
Embodiment 2:
Joined in 95% ethanol (250ml) by Ka Gelie clean (17.2g, 38.7mmol), add L-PROLINE (11.1g, 96.4mmol, 2.5eq), be heated to backflow, solid is whole clearly molten, is then slowly cooled to 10 DEG C, gradually has solid to separate out.By the solid filtering of separating out, filter cake absolute ethanol washing, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (200ml), with salt acid for adjusting pH to 1, with ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, filter cake washed with diethylether cold on a small quantity, 55 DEG C of vacuum-dryings, obtain the clean finished product 15.4g of Ka Gelie, yield 90%.
HPLC detects α-configuration impurity: 0.026%.
Embodiment 3:
Joined in 95% ethanol (180ml) by Ka Gelie clean (10.5g, 23.5mmol), add L-PROLINE (2.2g, 19.2mmol, 0.8eq), be heated to backflow, solid is whole clearly molten, is then slowly cooled to 10 DEG C, gradually has solid to separate out.By the solid filtering of separating out, filter cake 95% washing with alcohol, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), with salt acid for adjusting pH to 2, with ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, filter cake washed with diethylether cold on a small quantity, 55 DEG C of vacuum-dryings, obtain the clean finished product 8.4g of Ka Gelie, yield 80%.
HPLC detects α-configuration impurity: 0.019%.
Embodiment 4:
Joined in 95% ethanol (220ml) by Ka Gelie clean (13.0g, 29.2mmol), add L-PROLINE (5.0g, 43.5mmol, 1.5eq), be heated to backflow, solid is whole clearly molten, is then slowly cooled to room temperature, gradually has solid to separate out.By the solid filtering of separating out, filter cake 95% washing with alcohol, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), with salt acid for adjusting pH to 2, with ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, filter cake washed with diethylether cold on a small quantity, 55 DEG C of vacuum-dryings, obtain the clean finished product 10.9g of Ka Gelie, yield 84%.
HPLC detects α-configuration impurity: 0.015%.
Embodiment 5:
By clean for Ka Gelie (10.0g, 22.5mmol) be dissolved in acetone (200ml), add L-PROLINE (12.9g, 112.1mmol, 5eq), be warming up to 40 DEG C, solid is whole clearly molten, is then slowly cooled to 0 DEG C, by the solid filtering of separating out, filter cake washing with acetone, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (200ml), regulate pH to 12 with 10%NaOH solution, with methylene dichloride (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of washed with dichloromethane of filter cake, 50 DEG C of vacuum-dryings, obtain the clean finished product 8.7g of Ka Gelie, yield 87%.
HPLC detects α-configuration impurity: 0.037%.
Embodiment 6:
By clean for Ka Gelie (20.0g, 45.0mmol) be dissolved in methyl alcohol (200ml), add L-PROLINE (18.1g, 157.3mmol, 3.5eq), be warming up to 50 DEG C, solid is whole clearly molten, is then slowly cooled to 0 DEG C, by the solid filtering of separating out, filter cake washing with acetone, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (300ml), regulate pH to 1 with hydrochloric acid soln, with ethyl acetate (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of ethyl acetate of filter cake is washed, 50 DEG C of vacuum-dryings, obtain the clean finished product 16.8g of Ka Gelie, yield 84%.
HPLC detects α-configuration impurity: 0.041%.
Embodiment 7:
By clean for Ka Gelie (14.2g, 31.9mmol) be dissolved in acetonitrile (250ml), add L-PROLINE (15.8g, 137.2mmol, 4.3eq), be warming up to 60 DEG C, solid is whole clearly molten, is then slowly cooled to 10 DEG C, by the solid filtering of separating out, filter cake washing with acetone, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (300ml), regulate pH to 1 with hydrochloric acid soln, with isopropyl acetate (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of isopropyl acetate of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 11.1g of Ka Gelie, yield 78%.
HPLC detects α-configuration impurity: 0.027%.
Embodiment 8:
By clean for Ka Gelie (8.7g, 19.6mmol) be dissolved in in the mixed solvent of methyl alcohol (250ml) and water (30ml), add L-PROLINE (6.7g, 58.9mmol, 3eq), be warming up to 60 DEG C, solid is whole clearly molten, is then slowly cooled to 10 DEG C, by the solid filtering of separating out, filter cake absolute ethanol washing, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methylene dichloride (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of washed with dichloromethane of filter cake, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.1g of Ka Gelie, yield 82%.
HPLC detects α-configuration impurity: 0.025%.
Embodiment 9:
By clean for Ka Gelie (9.0g, 20.2mmol) be dissolved in ethyl acetate (250ml), add L-PROLINE (11.7,101.5mmol, 5eq), be warming up to 60 DEG C, solid is whole clearly molten, is then slowly cooled to 10 DEG C, by the solid filtering of separating out, filter cake ethyl acetate cold on a small quantity washing, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with isopropyl ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of isopropyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.0g of Ka Gelie, yield 78%.
HPLC detects α-configuration impurity: 0.057%.
Embodiment 10:
By clean for Ka Gelie (12.5g, 28.1mmol) be dissolved in ethyl acetate (250ml), add L-PROLINE (8.8g, 76.4mmol, 2.7eq), be warming up to 60 DEG C, solid is whole clearly molten, is then slowly cooled to 10 DEG C, by the solid filtering of separating out, filter cake ethyl acetate cold on a small quantity washing, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 9.9g of Ka Gelie, yield 79%.
HPLC detects α-configuration impurity: 0.087%.
Embodiment 11:
By clean for Ka Gelie (17.0g, 38.2mmol) be dissolved in ethanol (250ml), L-PROLINE (11.0g, 95.5mmol, 2.5eq) is dissolved in ethanol (50ml), by two solution mixing, be cooled to 0 DEG C, gradually have solid to separate out, by the solid filtering of separating out, filter cake washing with alcohol cold on a small quantity, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 12 with 10% sodium hydroxide solution, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 13.3g of Ka Gelie, yield 78%.
HPLC detects α-configuration impurity: 0.12%.
Embodiment 12:
By clean for Ka Gelie (17.0g, 38.2mmol) be dissolved in ethanol (250ml), by L-PROLINE (8.8,76.4mmol, 2eq) be dissolved in water (10ml), by two solution mixing, gradually solid is had to separate out, by the solid filtering of separating out, filter cake washing with alcohol cold on a small quantity, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 14.3g of Ka Gelie, yield 84%.
HPLC detects α-configuration impurity: 0.059%.
Embodiment 13:
By clean for Ka Gelie (13.2g, 29.7mmol) add in Virahol in (250ml), by L-PROLINE (10.3g, 89.4mmol, 3eq) be dissolved in water (50ml), after mixing, be warming up to 60 DEG C, solid is whole clearly molten, then 10 DEG C are slowly cooled to, by the solid filtering of separating out, filter cake washed with isopropyl alcohol cold on a small quantity, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 11.1g of Ka Gelie, yield 84%.
HPLC detects α-configuration impurity: 0.145%.
Embodiment 14:
By clean for Ka Gelie (13.0g, 29.2mmol) add in acetone in (180ml), by L-PROLINE (10.1g, 87.7mmol, 3eq) be dissolved in water (50ml), after mixing, be warming up to 60 DEG C, solid is whole clearly molten, then 10 DEG C are slowly cooled to, by the solid filtering of separating out, the filter cake mixed solvent of acetone cold on a small quantity and water washs, and obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (120ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 11.3g of Ka Gelie, yield 87%.
HPLC detects α-configuration impurity: 0.204%.
Embodiment 15:
By clean for Ka Gelie (13.5g, 30.4mmol) add in acetonitrile in (250ml), by L-PROLINE (12.2g, 106.0mmol, 3.5eq) be dissolved in water (50ml), after mixing, be warming up to 60 DEG C, solid is whole clearly molten, then 20 DEG C are slowly cooled to, by the solid filtering of separating out, filter cake water washing cold on a small quantity, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added purified water (120ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 11.3g of Ka Gelie, yield 84%.
HPLC detects α-configuration impurity: 0.204%.
Embodiment 16:
By clean for Ka Gelie (13.0g, 29.2mmol) add in water (250ml), by D-PROLINE (10.1g, 87.7mmol, 3eq) be dissolved in water (10ml), by two solution mixing, gradually solid is had to separate out, by the solid filtering of separating out, filter cake water washing cold on a small quantity, obtains the clean D-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 6.8g of Ka Gelie, yield 52%.
HPLC detects α-configuration impurity: 0.251%.
Embodiment 17:
By clean for Ka Gelie (12.0g, 27.0mmol) add in Virahol (250ml), by D-PROLINE (9.3g, 80.8mmol, 3eq) add, be heated to 60 DEG C, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake washed with isopropyl alcohol cold on a small quantity, obtains the clean D-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 6.5g of Ka Gelie, yield 54%.
HPLC detects α-configuration impurity: 0.330%.
Embodiment 18:
By clean for Ka Gelie (12.0g, 27.0mmol) add in methyl tertiary butyl ether (400ml), by D-PROLINE (6.5g, 56.5mmol, 2.1eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake methyl tertiary butyl ether cold on a small quantity washing, obtains the clean D-PROLINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.1g of Ka Gelie, yield 59%.
HPLC detects α-configuration impurity: 0.464%.
Embodiment 19:
By clean for Ka Gelie (13.5g, 30.4mmol) add in 95% ethanol (300ml), by L-Phe (15.1g, 91.4mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake absolute ethanol washing cold on a small quantity, obtains the clean L-Phe mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 11.8g of Ka Gelie, yield 87%.
HPLC detects α-configuration impurity: 0.102%.
Embodiment 20:
By clean for Ka Gelie (13.3g, 29.9mmol) add in ethanol (300ml), by L-Phe (17.2,104.1mmol, 3.5eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake absolute ethanol washing cold on a small quantity, obtains the clean L-Phe mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 10.8 of Ka Gelie, yield 81%.
HPLC detects α-configuration impurity: 0.274%.
Embodiment 21:
By clean for Ka Gelie (12.0g, 27.0mmol) add in acetonitrile (250ml), by L-Phe (15.6g, 94.4mmol, 3.5eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake absolute ethanol washing cold on a small quantity, obtains the clean L-Phe mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 9.4g of Ka Gelie, yield 78%.
HPLC detects α-configuration impurity: 0.226%.
Embodiment 22:
By clean for Ka Gelie (10.0g, 22.5mmol) add in acetonitrile (250ml), by D-phenylalanine (11.2g, 67.8mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake absolute ethanol washing cold on a small quantity, obtains the clean D-phenylalanine mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.6g of Ka Gelie, yield 76%.
HPLC detects α-configuration impurity: 0.216%.
Embodiment 23:
By clean for Ka Gelie (11.0g, 24.7mmol) add in 95% ethanol (250ml), by ALANINE (5.5g, 61.8mmol, 2.5eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake absolute ethanol washing cold on a small quantity, obtains the clean ALANINE mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.9g of Ka Gelie, yield 72%.
HPLC detects α-configuration impurity: 0.198%.
Embodiment 24:
By clean for Ka Gelie (10.0g, 22.5mmol) add in 95% ethanol (250ml), by Valine (6.6g, 56.2mmol, 2.5eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, filter cake absolute ethanol washing cold on a small quantity, obtains the clean Valine mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 5.1g of Ka Gelie, yield 51%.
HPLC detects α-configuration impurity: 0.198%.
Embodiment 25:
By clean for Ka Gelie (12.0g, 27.0mmol) add in 95% ethanol (250ml), by L-Leu (10.6,80.8mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-Leu mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (120ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.4 of Ka Gelie, yield 62%.
HPLC detects α-configuration impurity: 0.165%.
Embodiment 26:
By clean for Ka Gelie (13.0g, 29.2mmol) add in 95% ethanol (250ml), by ILE (11.5g, 87.6mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean ILE mixture of Ka Gelie.
This mixture is added purified water (200ml), regulate pH to 2 with hydrochloric acid soln, with methyl tertiary butyl ether (130ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.7g of Ka Gelie, yield 59%.
HPLC detects α-configuration impurity: 0.168%.
Embodiment 27:
By clean for Ka Gelie (13.2g, 29.7mmol) add in 95% ethanol (200ml), by L-Trp (18.2g, 89.1mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-Trp mixture of Ka Gelie.
This mixture is added purified water (200ml), regulate pH to 2 with hydrochloric acid soln, with methyl tertiary butyl ether (130ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.6 of Ka Gelie, yield 58%.
HPLC detects α-configuration impurity: 0.237%.
Embodiment 28:
By clean for Ka Gelie (14.6g, 32.8mmol) add in 95% ethanol (350ml), by L-Methionine (14.7,98.5mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-Methionine mixture of Ka Gelie.
This mixture is added purified water (250ml), regulate pH to 2 with hydrochloric acid soln, with methyl tertiary butyl ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 9.5g of Ka Gelie, yield 65%.
HPLC detects α-configuration impurity: 0.233%.
Embodiment 29:
By clean for Ka Gelie (12.0g, 27.0mmol) add in 95% ethanol (250ml), by L-glycine (6.1g, 81.2mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains Ka Gelie clean L-glycine mixture.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 6.5g of Ka Gelie, yield 54%.
HPLC detects α-configuration impurity: 0.134%.
Embodiment 30:
By clean for Ka Gelie (13.0g, 29.2mmol) add in 95% ethanol (250ml), by Serine (12.3g, 117.0mmol, 4eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean Serine mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 8.7g of Ka Gelie, yield 67%.
HPLC detects α-configuration impurity: 0.189%.
Embodiment 31:
By clean for Ka Gelie (12.5g, 28.1mmol) add in 95% ethanol (250ml), by L-threonine (10.0,84.0mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-threonine mixture of Ka Gelie.
This mixture is added purified water (150ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (150ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 5.9g of Ka Gelie, yield 47%.
HPLC detects α-configuration impurity: 0.164%.
Embodiment 32:
By clean for Ka Gelie (10.0g, 22.5mmol) add in 95% ethanol (250ml), by Cys (11.0g, 90.7mmol, 4eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean Cys mixture of Ka Gelie.
This mixture is added purified water (130ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 5.6g of Ka Gelie, yield 56%.
HPLC detects α-configuration impurity: 0.166%.
Embodiment 33:
By clean for Ka Gelie (10.8g, 24.3mmol) add in 95% ethanol (250ml), by TYR (15.4g, 85.0mmol, 3.5eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean TYR mixture of Ka Gelie.
This mixture is added purified water (130ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 4.9g of Ka Gelie, yield 45%.
HPLC detects α-configuration impurity: 0.154%.
Embodiment 34:
By clean for Ka Gelie (8.9g, 20.0mmol) add in 95% ethanol (150ml), by altheine (7.9g, 60.1mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean altheine mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (80ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 4.8g of Ka Gelie, yield 54%.
HPLC detects α-configuration impurity: 0.369%.
Embodiment 35:
By clean for Ka Gelie (8.0g, 18.0mmol) add in 95% ethanol (150ml), by L-glutaminate (7.9g, 54.1mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-glutaminate mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 1 with hydrochloric acid soln, with methyl tertiary butyl ether (80ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 3.9g of Ka Gelie, yield 49%.
HPLC detects α-configuration impurity: 0.189%.
Embodiment 36:
By clean for Ka Gelie (12.0g, 27.0mmol) add in 95% ethanol (200ml), by 1B (11.8g, 81.0mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean 1B mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 13 with 10% sodium hydroxide solution, with methyl tertiary butyl ether (80ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.7g of Ka Gelie, yield 64%.
HPLC detects α-configuration impurity: 0.189%.
Embodiment 37:
By clean for Ka Gelie (12.0g, 27.0mmol) add in 95% ethanol (200ml), by L-arginine (14.1g, 81.0mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-arginine mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 13 with 10% sodium hydroxide solution, with methyl tertiary butyl ether (80ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 7.6g of Ka Gelie, yield 63%.
HPLC detects α-configuration impurity: 0.220%.
Embodiment 38:
By clean for Ka Gelie (13.0g, 29.2mmol) add in 95% ethanol (200ml), by L-Histidine (15.9g, 102.4mmol, 3.5eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-Histidine mixture of Ka Gelie.
This mixture is added purified water (120ml), regulate pH to 13 with 10% sodium hydroxide solution, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 9.1g of Ka Gelie, yield 70%.
HPLC detects α-configuration impurity: 0.320%.
Embodiment 39:
By clean for Ka Gelie (10.0g, 22.5mmol) add in 95% ethanol (200ml), by L-Aspartic acid (9.0g, 67.5mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean L-Aspartic acid mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 13 with 10% sodium hydroxide solution, with methyl tertiary butyl ether (100mlL × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 5.6g of Ka Gelie, yield 56%.
HPLC detects α-configuration impurity: 0.180%.
Embodiment 40:
By clean for Ka Gelie (10.0g, 22.5mmol) add in 95% ethanol (200ml), by Pidolidone (9.9g, 67.4mmol, 3eq) add, be heated to backflow, after solid is entirely molten, be cooled to room temperature, gradually solid is had to separate out, by the solid filtering of separating out, 95% cold on a small quantity washing with alcohol of filter cake, obtains the clean Pidolidone mixture of Ka Gelie.
This mixture is added purified water (100ml), regulate pH to 13 with 10% sodium hydroxide solution, with methyl tertiary butyl ether (100ml × 3) extraction, merge organic phase, wash with saturated nacl aqueous solution, concentrated, there is a large amount of solids to separate out, filter, the a small amount of methyl tertiary butyl ether of filter cake washs, 50 DEG C of vacuum-dryings, obtain the clean finished product 6.4g of Ka Gelie, yield 64%.
HPLC detects α-configuration impurity: 0.336%.

Claims (1)

1. the Ka Gelie shown in formula I purifies a preparation method for compound,
Comprise the following steps:
Steps A: dissolve clean for Ka Gelie in a solvent with amino acid, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: the clean and separation for amino acids by Ka Gelie in clean for Ka Gelie amino acid complex, obtains Ka Gelie and purify compound;
In steps A, described solvent selected from methanol, ethanol, Virahol, water, acetonitrile, acetone, ethyl acetate, or the mixed solvent of water and ethanol, methyl alcohol, Virahol, acetone or acetonitrile; Amino acid used is selected from proline(Pro), phenylalanine; Described amino acid is the L-type amino acid with optical purity; Described amino acid whose consumption in mole dosage, for the clean 0.8-5 of Ka Gelie doubly;
In step B, method that is Ka Gelie in amino acid complex clean for Ka Gelie is clean and separation for amino acids comprises: dissolved by clean for Ka Gelie amino acid complex or be suspended in water, pH is regulated with acid or alkali, then organic solvent extraction is used, by the organic phase of extraction through concentrated or cooling, precipitation obtains Ka Gelie and purifies compound; Described organic solvent is ether, isopropyl ether, methyl tertiary butyl ether or methylene dichloride; When using acid for adjusting pH, pH value is adjusted to 1 ~ 2; When using alkali to regulate pH, pH value is adjusted to 12 ~ 13.
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