CN103694230A - High-purity canagliflozin compound and preparation method thereof - Google Patents
High-purity canagliflozin compound and preparation method thereof Download PDFInfo
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- CN103694230A CN103694230A CN201310656792.3A CN201310656792A CN103694230A CN 103694230 A CN103694230 A CN 103694230A CN 201310656792 A CN201310656792 A CN 201310656792A CN 103694230 A CN103694230 A CN 103694230A
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- C07—ORGANIC CHEMISTRY
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- 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 the field of drug synthesis and relates to a high-purity canagliflozin compound represented by a formula I shown in a drawing and a preparation method thereof. According to the canagliflozin compound provided by the invention, the content of an alpha-configuration impurity represented by a formula II shown in a drawing is lower than 1% and is further lower than 0.5%. The preparation method comprises the steps of preparing a eutectic substance from canagliflozin and amino acid in a solvent, separating the eutectic substance, and then, decomposing the eutectic substance, thereby obtaining the canagliflozin compound.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to a kind of clean method of high purity Ka Gelie of preparing, particularly relate to and a kind ofly with amino acid and Ka Gelie, only form mixture and 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, is used for the treatment of diabetes, and 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 two kinds of configurations of β, and Ka Gelie is β type only.Although advantage, in forming beta comfiguration, unavoidably still has the generation of α-configuration impurity in preparation process.
In patent application CN101801371, (embodiment 7-9) discloses the ethanoyl protection of Ka Gelie being carried out only to hydroxyl, deprotection then, then obtain the clean method of Ka Gelie through recrystallization, route is as follows:
But the method has increased two-step reaction, reduced yield, and and fail effectively to reduce Ka Gelie clean in the content of α-configuration impurity.
In order to guarantee validity and the security of prepared medicine, in the clean bulk drug of Ka Gelie, need to control the foreign matter content of α configuration, and have not yet to see, need effective means to reduce α-configuration impurity.
The crystalline composites of the 1:1 of the clean and L-PROLINE of Ka Gelie, D-PROLINE, L-Phe is disclosed open day on May 10th, 2013 of WO2013064909().The clean crystalline composites with citric acid or L-PROLINE formation of Ka Gelie is disclosed open day on November 15th, 2012 of WO2012154812().In these two parts of patents, do not relate to the clean α configuration impurity of Ka Gelie and the Ka Gelie problem of cleansing.
Summary of the invention
The object of the present invention is to provide the Ka Gelie that a kind of α-configuration foreign matter content is low to purify compound and preparation method thereof.
An aspect of of the present present invention, provides the Ka Gelie shown in a kind of formula I to purify compound,
The content of the α-configuration impurity shown in its Chinese style II is less than 1%, and preferably content is less than 0.5%,
In improving the research process of the clean compound purity of Ka Gelie, contriver finds that Ka Gelie is clean and amino acid forms eutectic thing in solvent, separated this eutectic thing, and then eutectic thing is decomposed, the Ka Gelie obtaining purifies compound, and wherein α-configuration impurity can effectively reduce.
Another aspect of the present invention, provides a kind of above-mentioned Ka Gelie to purify the preparation method of compound, and it comprises the following steps:
Steps A: be dissolved in solvent with amino acid Ka Gelie is clean, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: Ka Gelie in the clean amino acid complex of Ka Gelie is only separated with amino acid, obtain Ka Gelie and purify compound.
Solvent in described steps A is selected from methyl alcohol, 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.
In described steps A, amino acid used 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 be selected L-type or the 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 adds the method for anti-solvent crystallization.
Anti-solvent used in the method for described anti-solvent crystallization 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.Crystal adopting anti-solvent crystallization method to obtain, can also preferably wash the clean amino acid complex of the Ka Gelie obtaining with crystallization solvent.
In step B, a kind of preferably by the Ka Gelie in the clean amino acid complex of Ka Gelie only the method separated with amino acid comprise: the clean amino acid complex of Ka Gelie is dissolved or is suspended in water, with acid or alkali, regulate pH to acid or alkaline, then use organic solvent, extraction, the organic phase of extraction, through concentrated or cooling, separated out and obtained Ka Gelie purification 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 regulating pH with alkali, pH value is preferably adjusted to 12～13.
The described Ka Gelie purification compound obtaining of separating out preferably can, through filtering, wash, being dried, obtain Ka Gelie purification compound finished product.
At a kind of preferred above-mentioned Ka Gelie provided by the invention, purify in the preparation method of compound, comprise the steps:
Steps A: be dissolved in solvent with hydrophobic amino acid Ka Gelie is clean, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: the clean amino acid complex of Ka Gelie suspended or is dissolved in water, regulate pH with acid or alkali, then using organic solvent extraction, separation obtains Ka Gelie and purifies compound from organic phase.
Wherein, in steps A, solvent used is selected from methyl alcohol, ethanol, Virahol, water, acetonitrile, acetone, ethyl acetate, isopropyl acetate, or the mixed solvent of water and ethanol, methyl alcohol, Virahol, acetone or acetonitrile.
In steps A, hydrophobic amino acid used is selected from L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, proline(Pro), phenylalanine, tryptophane or methionine(Met); Described hydrophobic amino acid can be selected L-type or the 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 step B, 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, the separated Ka Gelie purification compound that obtains can be undertaken by the method for concentrated or cooling crystallization.Preferably, can further include filtration, dry, obtain finished product.
At another kind provided by the invention, preferred above-mentioned Ka Gelie purifies in the preparation method of compound, comprises the steps:
Steps A: be dissolved in solvent with proline(Pro) or phenylalanine Ka Gelie is clean, cooling crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: the clean amino acid complex of Ka Gelie suspended or is dissolved in water, regulate pH with acid or alkali, then using organic solvent extraction, it is clean that separation obtains high purity Ka Gelie from organic phase.
In steps A, solvent used is selected from methyl alcohol, ethanol, Virahol, water, acetonitrile, acetone, ethyl acetate, isopropyl acetate, or the mixed solvent of water and ethanol, methyl alcohol, Virahol, acetone or acetonitrile.
In steps A, proline(Pro) used or phenylalanine are preferably and have optically active amino acid, for example 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 step B, 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, the separated Ka Gelie that obtains purifies the method that compound can be used concentrated or cooling crystallization.Preferably, can further include filtration, dry, obtain finished product.
The above-mentioned various Ka Gelie that provide purify the preparation method of compounds, in steps A, can be by Ka Gelie clean and amino acid be dissolved in respectively in identical or different solvents, then two solution are mixed, separate out the clean amino acid complex of Ka Gelie; Also Ka Gelie can be dissolved in 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 solvent, can improve solubleness by the method for heating, after solid all dissolves, reduce temperature, the clean amino acid complex of Ka Gelie is separated out.
If the solubleness of the clean amino acid complex of Ka Gelie in solvent is larger, the solid of separating out is less, can increase by reducing the method for temperature the quantity of separating out of solid.
Ka Gelie provided by the present invention is clean, and wherein the content of 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, the clean α-configuration of prepared Ka Gelie foreign matter content is low, can be less than 0.5%, suitablely in industrial production, applies.
Embodiment
Below in conjunction with specific embodiment, the present invention is conducted further description.It will be appreciated that the just detailed description to part embodiment of the present invention of following embodiment, is not limitation of the scope of the invention.
In following each embodiment, Ka Gelie is used HPLC to analyze only, and HPLC condition is as follows:
Detect wavelength 254nm
Moving phase is: A component: 0.1% trifluoroacetic acid aqueous solution
B component: acetonitrile, A:B is 30:70
Chromatographic column is: C18 chromatographic column
Flow velocity: 1ml/min.
Preparation example 1
According to Journal of Medicinal Chemistry2010; 53; the Ka Gelie clean (formula 1) that method in 6355-60 obtains trimethyl silicon based protection, then removes trimethyl silicon based and methoxyl group according to the method for announcing 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) cooling by dry ice acetone, boron trifluoride ether solution (5L, 39.5mmol) is dripped and entered, then reaction mixture is warming up to 0 ℃, stir 2 hours, saturated sodium bicarbonate aqueous solution (80L) is slowly joined in reactor, will react cancellation.Layering, organic phase is evaporated to dry, add water 100L and ethyl acetate 70L, stir after extraction, water is extracted by 70L 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 decompression is concentrated into dry, ethyl acetate for resistates (30L) is dissolved, ether (60L) is slowly added, have solid to separate out, clean for Ka Gelie, be total to 3.98kg.
HPLC detects α-configuration impurity: 4.35%.
Reference examples 1
According to the method for the embodiment 7-9 in patent application CN101801371, prepare Ka Gelie clean, concrete grammar is as follows:
By the clean (11.9g of Ka Gelie, 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 ℃, then aceticanhydride (12.5ml, 130mmol) is dripped and entered, control rate of addition, make temperature not higher than 0 ℃.After dropwising, 0 ℃ of following continuation, stir 15 minutes, then slowly rise to room temperature, at 20 ℃, stir 1 hour, then at 32 ℃, be evaporated to dry, to the phosphoric acid 30ml that adds 10% in resistates, formed cream-colored throw out, in mixture, add ethyl acetate 80ml, tetrahydrofuran (THF) 30ml, toluene 30ml, under stirring, solid is all dissolved, layering, organic phase is washed successively with saturated sodium bicarbonate solution and saturated nacl aqueous solution, 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 ℃ of vacuum-dryings, obtain the clean 12.9g of four acetylizad Ka Gelie, yield 78%.
By the clean (12g of the four acetylizad Ka Gelie that obtain, 19.6mmol) join in the mixed solvent of tetrahydrofuran (THF) (53ml) and methyl alcohol (80ml), obtain suspension, by a hydronium(ion) oxidation lithium (410mg, 9.5mmol) be dissolved in 26ml water, join in above-mentioned mixture, under room temperature, stir 12 hours, reaction solution is evaporated to tetrahydrofuran (THF) and methyl alcohol is closely dry, in resistates, add ethyl acetate 39ml, stir separatory, water is extracting 3 times by 10ml ethyl acetate, merge organic phase, with saturated nacl aqueous solution 20ml, wash, add anhydrous magnesium sulfate drying, be evaporated to dry, obtain spumescence solid,
In this spumescence solid, add 0.6ml water and 27.5ml ethyl acetate, solid is entirely molten, is heated to 35 ℃ under stirring, and 15.5ml normal heptane is dripped and entered, gradually reaction solution becomes muddiness and stops dripping normal heptane, at this temperature, stir 2 hours, remaining normal heptane is dripped and entered, then add 3ml normal heptane, reaction solution stirring was filtered after 30 minutes, the mixed solvent washing of 2.5ml ethyl acetate and 2.5ml normal heptane for filter cake, vacuum-drying, obtains off-white color solid 4.5g.
HPLC detects α-configuration impurity: 1.35%.
Reference examples 2
By the clean (10.0g of Ka Gelie, 22.5mmol) join in Iso Butyl Acetate (100ml), add monohydrate potassium (5.2g, 24.8mmol, 1.1eq), mixture is heated to reflux, gradually solid all dissolves, then be cooled to room temperature, by the solid filtering of separating out, with a small amount of Iso Butyl Acetate washing, the solid obtaining is added in purified water (200ml), with sodium hydroxide, regulate pH to 13, with methyl tertiary butyl ether (100ml * 3), extract, merge organic phase, concentrating under reduced pressure, there are a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) be dissolved in dehydrated alcohol (200ml), add L-PROLINE (7.8g, 67.7mmol, 3eq), be heated to reflux, solid is all molten clear, 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 to purified water (200ml), with salt acid for adjusting pH to 2, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, a small amount of cold methyl tertiary butyl ether washing for filter cake, 50 ℃ of vacuum-dryings, obtain the clean finished product 8.9g of Ka Gelie, yield 89%.
HPLC detects α-configuration impurity: 0.017%.
Embodiment 2:
Ka Gelie clean (17.2g, 38.7mmol) is joined in 95% ethanol (250ml), add L-PROLINE (11.1g, 96.4mmol, 2.5eq), be heated to reflux, solid is all molten clear, is then slowly cooled to 10 ℃, 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 to purified water (200ml), with salt acid for adjusting pH to 1, with ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, a small amount of cold ether washing for filter cake, 55 ℃ of vacuum-dryings, obtain the clean finished product 15.4g of Ka Gelie, yield 90%.
HPLC detects α-configuration impurity: 0.026%.
Embodiment 3:
Ka Gelie clean (10.5g, 23.5mmol) is joined in 95% ethanol (180ml), add L-PROLINE (2.2g, 19.2mmol, 0.8eq), be heated to reflux, solid is all molten clear, is then slowly cooled to 10 ℃, 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 to purified water (150ml), with salt acid for adjusting pH to 2, with ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, a small amount of cold ether washing for filter cake, 55 ℃ of vacuum-dryings, obtain the clean finished product 8.4g of Ka Gelie, yield 80%.
HPLC detects α-configuration impurity: 0.019%.
Embodiment 4:
Ka Gelie clean (13.0g, 29.2mmol) is joined in 95% ethanol (220ml), add L-PROLINE (5.0g, 43.5mmol, 1.5eq), be heated to reflux, solid is all molten clear, 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 to purified water (150ml), with salt acid for adjusting pH to 2, with ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, a small amount of cold ether washing for filter cake, 55 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) be dissolved in acetone (200ml), add L-PROLINE (12.9g, 112.1mmol, 5eq), be warming up to 40 ℃, solid is all molten clear, is then slowly cooled to 0 ℃, 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 to purified water (200ml), with 10%NaOH solution, regulate pH to 12, with methylene dichloride (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, the a small amount of washed with dichloromethane of filter cake, 50 ℃ 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 the clean (20.0g of Ka Gelie, 45.0mmol) be dissolved in methyl alcohol (200ml), add L-PROLINE (18.1g, 157.3mmol, 3.5eq), be warming up to 50 ℃, solid is all molten clear, is then slowly cooled to 0 ℃, 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 to purified water (300ml), with hydrochloric acid soln, regulate pH to 1, with ethyl acetate (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs by a small amount of ethyl acetate, 50 ℃ 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 the clean (14.2g of Ka Gelie, 31.9mmol) be dissolved in acetonitrile (250ml), add L-PROLINE (15.8g, 137.2mmol, 4.3eq), be warming up to 60 ℃, solid is all molten clear, is then slowly cooled to 10 ℃, 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 to purified water (300ml), with hydrochloric acid soln, regulate pH to 1, with isopropyl acetate (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of isopropyl acetate, 50 ℃ 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 the clean (8.7g of Ka Gelie, 19.6mmol) in being dissolved in the mixed solvent of methyl alcohol (250ml) and water (30ml), add L-PROLINE (6.7g, 58.9mmol, 3eq), be warming up to 60 ℃, solid is all molten clear, is then slowly cooled to 10 ℃, 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 to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methylene dichloride (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, the a small amount of washed with dichloromethane of filter cake, 50 ℃ 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 the clean (9.0g of Ka Gelie, 20.2mmol) be dissolved in ethyl acetate (250ml), add L-PROLINE (11.7,101.5mmol, 5eq), be warming up to 60 ℃, solid is all molten clear, is then slowly cooled to 10 ℃, by the solid filtering of separating out, a small amount of cold ethyl acetate washing for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with isopropyl ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of isopropyl ether, 50 ℃ 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 the clean (12.5g of Ka Gelie, 28.1mmol) be dissolved in ethyl acetate (250ml), add L-PROLINE (8.8g, 76.4mmol, 2.7eq), be warming up to 60 ℃, solid is all molten clear, is then slowly cooled to 10 ℃, by the solid filtering of separating out, a small amount of cold ethyl acetate washing for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (17.0g of Ka Gelie, 38.2mmol) be dissolved in ethanol (250ml), L-PROLINE (11.0g, 95.5mmol, 2.5eq) is dissolved in ethanol (50ml), two solution are mixed, be cooled to 0 ℃, gradually have solid to separate out, by the solid filtering of separating out, a small amount of cold washing with alcohol for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with 10% sodium hydroxide solution, regulate pH to 12, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (17.0g of Ka Gelie, 38.2mmol) be dissolved in ethanol (250ml), by L-PROLINE (8.8,76.4mmol, 2eq) be dissolved in water (10ml), two solution are mixed, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold washing with alcohol for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.2g of Ka Gelie, 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 ℃, solid is all molten clear, then be slowly cooled to 10 ℃, by the solid filtering of separating out, a small amount of cold washed with isopropyl alcohol for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.0g of Ka Gelie, 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 ℃, solid is all molten clear, then be slowly cooled to 10 ℃, by the solid filtering of separating out, the mixed solvent washing of a small amount of cold acetone and water for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (120ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.5g of Ka Gelie, 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 ℃, solid is all molten clear, then be slowly cooled to 20 ℃, by the solid filtering of separating out, a small amount of cold water washing for filter cake, obtains the clean L-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (120ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.0g of Ka Gelie, 29.2mmol) add in water (250ml), by D-PROLINE (10.1g, 87.7mmol, 3eq) be dissolved in water (10ml), two solution are mixed, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold water washing for filter cake, obtains the clean D-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in Virahol (250ml), by D-PROLINE (9.3g, 80.8mmol, 3eq) add, be heated to 60 ℃, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold washed with isopropyl alcohol for filter cake, obtains the clean D-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in methyl tertiary butyl ether (400ml), by D-PROLINE (6.5g, 56.5mmol, 2.1eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold methyl tertiary butyl ether washing for filter cake, obtains the clean D-PROLINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.5g of Ka Gelie, 30.4mmol) add in 95% ethanol (300ml), by L-Phe (15.1g, 91.4mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold absolute ethanol washing for filter cake, obtains the clean L-Phe mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.3g of Ka Gelie, 29.9mmol) add in ethanol (300ml), by L-Phe (17.2,104.1mmol, 3.5eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold absolute ethanol washing for filter cake, obtains the clean L-Phe mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in acetonitrile (250ml), by L-Phe (15.6g, 94.4mmol, 3.5eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold absolute ethanol washing for filter cake, obtains the clean L-Phe mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) add in acetonitrile (250ml), by D-phenylalanine (11.2g, 67.8mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold absolute ethanol washing for filter cake, obtains the clean D-phenylalanine mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (11.0g of Ka Gelie, 24.7mmol) add in 95% ethanol (250ml), by ALANINE (5.5g, 61.8mmol, 2.5eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold absolute ethanol washing for filter cake, obtains the clean ALANINE mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) add in 95% ethanol (250ml), by Valine (6.6g, 56.2mmol, 2.5eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of cold absolute ethanol washing for filter cake, obtains the clean Valine mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in 95% ethanol (250ml), by L-Leu (10.6,80.8mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-Leu mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (120ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.0g of Ka Gelie, 29.2mmol) add in 95% ethanol (250ml), by ILE (11.5g, 87.6mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean ILE mixture of Ka Gelie.
This mixture is added to purified water (200ml), with hydrochloric acid soln, regulate pH to 2, with methyl tertiary butyl ether (130ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.2g of Ka Gelie, 29.7mmol) add in 95% ethanol (200ml), by L-Trp (18.2g, 89.1mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-Trp mixture of Ka Gelie.
This mixture is added to purified water (200ml), with hydrochloric acid soln, regulate pH to 2, with methyl tertiary butyl ether (130ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (14.6g of Ka Gelie, 32.8mmol) add in 95% ethanol (350ml), by L-Methionine (14.7,98.5mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-Methionine mixture of Ka Gelie.
This mixture is added to purified water (250ml), with hydrochloric acid soln, regulate pH to 2, with methyl tertiary butyl ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in 95% ethanol (250ml), by L-glycine (6.1g, 81.2mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-glycine of Ka Gelie mixture.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.0g of Ka Gelie, 29.2mmol) add in 95% ethanol (250ml), by Serine (12.3g, 117.0mmol, 4eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean Serine mixture of Ka Gelie.
This mixture is added to purified water (100ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.5g of Ka Gelie, 28.1mmol) add in 95% ethanol (250ml), by L-threonine (10.0,84.0mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-threonine mixture of Ka Gelie.
This mixture is added to purified water (150ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (150ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) add in 95% ethanol (250ml), by Cys (11.0g, 90.7mmol, 4eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean Cys mixture of Ka Gelie.
This mixture is added to purified water (130ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.8g of Ka Gelie, 24.3mmol) add in 95% ethanol (250ml), by TYR (15.4g, 85.0mmol, 3.5eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean TYR mixture of Ka Gelie.
This mixture is added to purified water (130ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (8.9g of Ka Gelie, 20.0mmol) add in 95% ethanol (150ml), by altheine (7.9g, 60.1mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean altheine mixture of Ka Gelie.
This mixture is added to purified water (100ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (80ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (8.0g of Ka Gelie, 18.0mmol) add in 95% ethanol (150ml), by L-glutaminate (7.9g, 54.1mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-glutaminate mixture of Ka Gelie.
This mixture is added to purified water (100ml), with hydrochloric acid soln, regulate pH to 1, with methyl tertiary butyl ether (80ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in 95% ethanol (200ml), by 1B (11.8g, 81.0mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean 1B mixture of Ka Gelie.
This mixture is added to purified water (100ml), with 10% sodium hydroxide solution, regulate pH to 13, with methyl tertiary butyl ether (80ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (12.0g of Ka Gelie, 27.0mmol) add in 95% ethanol (200ml), by L-arginine (14.1g, 81.0mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-arginine mixture of Ka Gelie.
This mixture is added to purified water (100ml), with 10% sodium hydroxide solution, regulate pH to 13, with methyl tertiary butyl ether (80ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (13.0g of Ka Gelie, 29.2mmol) add in 95% ethanol (200ml), by L-Histidine (15.9g, 102.4mmol, 3.5eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-Histidine mixture of Ka Gelie.
This mixture is added to purified water (120ml), with 10% sodium hydroxide solution, regulate pH to 13, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) add in 95% ethanol (200ml), by L-Aspartic acid (9.0g, 67.5mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean L-Aspartic acid mixture of Ka Gelie.
This mixture is added to purified water (100ml), with 10% sodium hydroxide solution, regulate pH to 13, with methyl tertiary butyl ether (100mlL * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ 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 the clean (10.0g of Ka Gelie, 22.5mmol) add in 95% ethanol (200ml), by Pidolidone (9.9g, 67.4mmol, 3eq) add, be heated to reflux, solid complete molten after, be cooled to room temperature, gradually there is solid to separate out, by the solid filtering of separating out, a small amount of 95% cold washing with alcohol for filter cake, obtains the clean Pidolidone mixture of Ka Gelie.
This mixture is added to purified water (100ml), with 10% sodium hydroxide solution, regulate pH to 13, with methyl tertiary butyl ether (100ml * 3) extraction, merge organic phase, with saturated nacl aqueous solution, wash, concentrated, there is a large amount of solids to separate out, filter, filter cake washs with a small amount of methyl tertiary butyl ether, 50 ℃ of vacuum-dryings, obtain the clean finished product 6.4g of Ka Gelie, yield 64%.
HPLC detects α-configuration impurity: 0.336%.
Claims (10)
1. the Ka Gelie shown in formula I purifies a compound,
It is characterized in that, the content of the α-configuration impurity shown in its Chinese style II is less than 1%, and preferably content is less than 0.5%,
2. Ka Gelie according to claim 1 purifies compound, it is characterized in that, the preparation method that described Ka Gelie purifies compound comprises the following steps:
Steps A: be dissolved in solvent with amino acid Ka Gelie is clean, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: Ka Gelie in the clean amino acid complex of Ka Gelie is only separated with amino acid, obtain Ka Gelie and purify compound.
3. Ka Gelie claimed in claim 1 purifies the preparation method of compound, comprises the following steps:
Steps A: be dissolved in solvent with amino acid Ka Gelie is clean, crystallization, filtration obtain the clean amino acid complex of Ka Gelie;
Step B: Ka Gelie in the clean amino acid complex of Ka Gelie is only separated with amino acid, obtain Ka Gelie and purify compound.
4. preparation method according to claim 3, it is characterized in that, solvent described in steps A is selected from methyl alcohol, 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.
5. preparation method according to claim 3, is characterized in that, in steps A, amino acid used is hydrophobic amino acid or hydrophilic amino acid; Described hydrophobic amino acid is preferably and is selected from L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, proline(Pro), phenylalanine, tryptophane or methionine(Met); Described hydrophilic amino acid is preferably and is selected from glycine, Serine, Threonine, halfcystine, tyrosine, l-asparagine, glutamine, Methionin, arginine, Histidine, aspartic acid or L-glutamic acid.
6. preparation method according to claim 3, is characterized in that, amino acid is L-type or the D type amino acid with optical purity described in steps A.
7. preparation method according to claim 3, is characterized in that, described amino acid whose consumption is in mole dosage, for the clean 0.8-5 of Ka Gelie doubly.
8. preparation method according to claim 3, it is characterized in that, in step B, by the Ka Gelie in the clean amino acid complex of Ka Gelie only the method separated with amino acid comprise: the clean amino acid complex of Ka Gelie is dissolved or is suspended in water, with acid or alkali, regulate pH, then use organic solvent extraction, the organic phase of extraction, through concentrated or cooling, separated out and obtained Ka Gelie purification compound.
9. preparation method according to claim 8, is characterized in that, described organic solvent is ethers, ester class or dichloromethane solvent, is preferably ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate, isopropyl acetate or methylene dichloride.
10. preparation method according to claim 8, is characterized in that, when using acid for adjusting pH, pH value is adjusted to 1～2; When regulating pH with alkali, pH value is adjusted to 12～13.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102167715A (en) * | 2011-03-07 | 2011-08-31 | 上海惠斯生物科技有限公司 | Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals |
| CN102177147A (en) * | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | Processes for the preparation of SGLT2 inhibitors |
| WO2012154812A1 (en) * | 2011-05-09 | 2012-11-15 | Janssen Pharmaceutica Nv | L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r )- 2- (3- ((5- (4-fluorophenyl)thiophen-2-yl) methyl) -4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol |
| TW201328698A (en) * | 2011-10-31 | 2013-07-16 | Scinopharm Taiwan Ltd | Crystalline and non-crystalline forms of SGLT2 inhibitors |
-
2013
- 2013-12-06 CN CN201310656792.3A patent/CN103694230B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102177147A (en) * | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | Processes for the preparation of SGLT2 inhibitors |
| CN102167715A (en) * | 2011-03-07 | 2011-08-31 | 上海惠斯生物科技有限公司 | Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals |
| WO2012154812A1 (en) * | 2011-05-09 | 2012-11-15 | Janssen Pharmaceutica Nv | L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r )- 2- (3- ((5- (4-fluorophenyl)thiophen-2-yl) methyl) -4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol |
| TW201328698A (en) * | 2011-10-31 | 2013-07-16 | Scinopharm Taiwan Ltd | Crystalline and non-crystalline forms of SGLT2 inhibitors |
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