CN1517335A - Improved preparation method of Nagelinei - Google Patents
Improved preparation method of Nagelinei Download PDFInfo
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- CN1517335A CN1517335A CNA031005594A CN03100559A CN1517335A CN 1517335 A CN1517335 A CN 1517335A CN A031005594 A CNA031005594 A CN A031005594A CN 03100559 A CN03100559 A CN 03100559A CN 1517335 A CN1517335 A CN 1517335A
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Abstract
An improved process for preparing 'Nagelienai' features that the p-isopropylbenzoic acid is reduced by the reducer chosen from active Ni and active Pd or Pd-C to become 4-isopropylcyclohexaformic acid, or the mixture of cis-and anti-4-isopropylcyclohexaformic acids are converted to anti-isopropylcyclohexaformic acid under the action of hydroxide of alkali metal, or the anti-4-isopropylcyclohexacyl chloride reacts on D-phenylpropanoic acid in a mixed solvent system, or the Nagelienai from previous step is recrystallized prification in the mixed organic solvent, and the any two, three, or four of above-said steps are combined.
Description
Technical field
The present invention relates to the improved preparation method of nateglinide.
Technical background
Following formula nateglinide (Nateglinide, chemical name N-(trans-4-isopropylcyclohexyl-
Nateglinide structural formula-1-formyl radical)-and the D-phenylalanine) be the hypoglycemic drug of meals conditioning agent class, it is by optionally controlling level of postprandial blood sugar, for the treatment of type ii diabetes provides important means.It has the short characteristics of rapid-action, drug effect, and is more responsive to the response of glucose concn in the recycle system, thereby the glucose level can make meals the time obtains more physiological control, and the incidence of hypoglycin is lower, demonstrates application promise in clinical practice.
In view of the nateglinide dosage is bigger, must set up the synthesis technique that is fit to suitability for industrialized production.But known each row preparation method how exists following deficiency:
The committed step of nateglinide preparation is trans-promptly form tremelloid precipitation in 4-sec.-propyl cyclohexanecarbonyl chloride and the reinforced process of being reflected at of D-phenylalanine condensation, be difficult to finish or fully thereby make to react;
The reaction product of nateglinide preparation adopts methanol-water mixed solvent recrystallization to carry out purifying, and condition is wayward, and the gained solid is a jelly, filtration difficulty, and its purification efficiency is low, and one time recrystallization purity can only reach 93-94%;
The key intermediate of nateglinide preparation is trans-and the preparation of 4-heptanaphthenic acid need use expensive platinum oxide as the hydro-reduction catalyst for reaction, need adopt protection and deprotection during configuration conversion, uses sodium hydride.
Further, European patent EP 196222 discloses a kind of synthesis technique of nateglinide: with right-isopropyl acid is raw material, get the mixture of 4-isopropyl hexahydrobenzoic acid cis-trans-isomer through hydrogenation, its methyl ester derivation carries out configuration conversion, hydrolysis under the sodium hydride effect, get trans-4-isopropylcyclohexyl-formic acid, then the active ester of its N-hydroxy-succinamide again with the condensation of D-phenylalanine methyl ester, hydrolysis, the preparation nateglinide:
The master that this synthesis technique exists is if it were not for being: 1, in the large-scale industrial production, the by-product of dicyclohexylurea in the active ester preparation process is difficult to separate removes; 2, it is more expensive to prepare the hydrogenation catalyst system therefor platinum oxide of 4-isopropyl hexahydrobenzoic acid by right-isopropyl acid; 3, condensation product methanol-water mixed solvent recrystallization purifying, condition is wayward, and the gained solid is a jelly, filtration difficulty, its purification efficiency is low, and one time recrystallization purity can only reach 93-94%; 4, configuration conversion need be used sodium hydride, and reaction conditions requires harsh, operation inconvenience; 5, repeatedly esterification/saponification of intermediate, reactions steps is longer.
Japanese Patent JP 07/17899 discloses the method with trans-4-isopropylcyclohexyl-formyl chloride and the direct condensation prepared target compound of D-phenylalanine:
The committed step of this technology is trans-and the condensation of 4-sec.-propyl-cyclohexyl formyl chloride and D-phenylalanine carries out in the reaction system of acetone-water, promptly forms the pasty colloid thing in reinforced process, is difficult to abundant stirring, causes reaction not exclusively.
Above technology is not suitable for need of industrial production.
Summary of the invention
The inventor has now found that after deliberation by or bonded independent to differential responses step in the nateglinide preparation process and improves, and can improve the productive rate of final product nateglinide, purity and preparation cost, thus the industrially scalable of realizing nateglinide prepares.
Therefore, the present invention relates to prepare improving one's methods of nateglinide, it is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; Or
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; Or
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; Or
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture;
E. above-mentioned a, b, the arbitrarily combination of two or three or four features among c and the d.
According to the present invention, the condensation reaction of trans-4-sec.-propyl cyclohexanecarbonyl chloride and D-phenylalanine is carried out in the homogeneous reaction system of tetrahydrofuran (THF)-water among the preferred C.This feature forms the paste jelly when having solved in the prior art reaction of trans 4-sec.-propyl cyclohexanecarbonyl chloride and D-phenylalanine, thereby causes reacting incomplete problem.
According to the present invention, recrystallization carries out with the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture among the preferred d.Feature d has solved the purity problem of nateglinide.
According to the present invention, preferred a) middle palladium-carbon replaces platinum oxide as the hydro-reduction catalyst for reaction, prepares 4-sec.-propyl heptanaphthenic acid by right-isopropyl acid;
According to the present invention; preferred a) in the preparation of trans-4-sec.-propyl heptanaphthenic acid directly under the potassium hydroxide effect, carry out configuration conversion with the mixture of 4-sec.-propyl-heptanaphthenic acid cis-trans-isomer; omit protection and two reactions steps of deprotection among the patent documentation EP814073, avoided use hazardous chemical sodium hydride simultaneously.
According to the present invention, nateglinide is the preparation method be characterised in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect.
According to the present invention, nateglinide is the preparation method be characterised in that:
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water.
According to the present invention, nateglinide is the preparation method be characterised in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water.
According to the present invention, nateglinide is the preparation method be characterised in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
According to the present invention, nateglinide is the preparation method be characterised in that:
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
According to the present invention, nateglinide is the preparation method be characterised in that:
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
According to the present invention, nateglinide is the preparation method be characterised in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water.
According to the present invention, nateglinide is the preparation method be characterised in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
According to the present invention, nateglinide is the preparation method be characterised in that:
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
According to the present invention, nateglinide is the preparation method be characterised in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
According to the present invention, wherein reductive agent is 10% palladium charcoal among a.
According to the present invention, wherein alkali metal hydroxide is a potassium hydroxide among the b.
According to the present invention, wherein mixed solvent is the mixed solvent of tetrahydrofuran (THF) and water among the c.
According to the present invention, wherein organic solvent is a sherwood oil among the d.
According to the present invention, wherein said basic metal is meant lithium, sodium or potassium.
According to the present invention, explanation as an example, the present invention prepares nateglinide and improves one's methods shown in the available following reaction scheme:
In the reaction scheme, be that raw material prepares right-isopropyl acid (I) through the Cobaltous diacetate catalyzed oxidation in the above, carry out catalytic hydrogenation with 10% palladium-carbon then and generate 4-sec.-propyl-heptanaphthenic acid (II) with the P-Cymene; Generate trans-4-sec.-propyl heptanaphthenic acid (III) through configuration conversion again, react transly with phosphorus pentachloride-4-sec.-propyl cyclohexanecarbonyl chloride (IV), last and D-phenylalanine condensation makes nateglinide (V).
More specifically say, in conjunction with top reaction scheme, the catalyzer described in the reaction of method catalytic hydrogenation generation 4-sec.-propyl heptanaphthenic acid of the present invention (II) is active nickel, active palladium or palladium carbon, is preferably palladium carbon, its usage quantity is the 1-200% of (I), is preferably 20%; Hydrogen pressure is 10-120kg/cm
2, be preferably 55kg/cm
2Temperature of reaction is 50-250 ℃, is preferably 150 ℃; Reaction times is 2-20 hour, is preferably 4-10 hour; Acid solvent is organic acid and mineral acid such as formic acid, acetate, propionic acid, butyric acid and hydrochloric acid, is preferably glacial acetic acid, and its usage quantity is (I) 2-100 a times, is preferably 4-20 doubly; The reaction products therefrom is through the underpressure distillation purifying;
Cis-trans-isomer (II) with 4-sec.-propyl-heptanaphthenic acid described in the method for the present invention carries out the trans-4-sec.-propyl heptanaphthenic acid (III) of configuration conversion generation under alkali metal hydroxide such as potassium hydroxide effect.Usage quantity is preferably 1-5 doubly for the 0.5-10 of (II) doubly measures; Temperature of reaction is 50-250 ℃, preferred 120-180 ℃; Reaction times is 2-15 hour, is preferably 3-8 hour; Extraction solution is the mixing solutions of organic alcohol or organic alcohol and water, and organic alcohol is methyl alcohol, ethanol, Virahol, is preferably methyl alcohol, and alcohol is 10-1: 0.1-1 with the ratio of the aqueous solution, is preferably 1: 1; The pH value of acidification reaction is 0.1-6, is preferably 1-4; The low temperature churning time is 0.5-5 hour, is preferably 0.8-3 hour; Recrystallization solvent is organic acid solvent formic acid, acetate, propionic acid and butyric acid, is formic acid, and the content of formic acid is 50-100%, be preferably 〉=85%; The recrystallization number of times is 1-5 time, is preferably 2 times;
Of the present invention trans-4-sec.-propyl cyclohexanecarbonyl chloride (IV) and the condensation reaction of D-phenylalanine in, trans-4-sec.-propyl cyclohexanecarbonyl chloride (IV) is 1 with the ratio of D-phenylalanine usage quantity: 0.5-10 is preferably 1: 1.2; Reaction solvent is dioxane, tetrahydrofuran (THF), is preferably tetrahydrofuran (THF); The ratio of D-phenylalanine and tetrahydrofuran (THF) is 1: 1-10 is preferably 1: 2-6; Trans-4-sec.-propyl cyclohexanecarbonyl chloride (IV) is 1 with the ratio of tetrahydrofuran (THF): 1-10 is preferably 1: 2-6; The concentration of aqueous sodium hydroxide solution is 2-40%, is preferably 10%; The ratio of aqueous sodium hydroxide solution and tetrahydrofuran (THF) is 1: 1-10 is preferably 1: 1; Temperature of reaction is-20-10 ℃, be preferably-5 ℃; Reaction times is 1-20 hour, is preferably 7 hours.
The finished product extract with alkane solvents such as sherwood oil, normal hexane, hexanaphthenes in the method for the present invention, remove 4-sec.-propyl heptanaphthenic acid, and preferred solvent is a sherwood oil; The specification of sherwood oil is 30-60 ℃, 60-90 ℃, 90-120 ℃, is preferably 60-90 ℃; Service temperature is-10-100 ℃, be preferably room temperature; Extraction time is 1-30 hour, is preferably 12 hours.
The following examples are to the describing in further detail of the inventive method, but do not mean that any restriction to the present invention.
Reference example (JP07/17899)
One, the preparation of trans-4-sec.-propyl cyclohexanecarbonyl chloride (IV)
With the trans-4-sec.-propyl heptanaphthenic acid (III) of 13.2 grams, 17 gram phosphorus pentachlorides, 80 milliliters of exsiccant
1, the 2-ethylene dichloride adds in the reaction flask successively, and stirring reaction is 3 hours under 40 ℃ of oil baths, and exothermic heat of reaction is obvious.Then, remove solvent under reduced pressure, get colourless transparent liquid 14.1 grams, stand-by.
Two, the preparation of N-(trans-4-isopropylcyclohexyl--1-formyl radical)-D-phenylalanine (V)
Getting 10 gram D-phenylalanines is dissolved in 52 milliliter of 10% aqueous sodium hydroxide solution, add 52 milliliters of acetone again, bathe cooling down in cryosel behind the stirring and evenly mixing, be added dropwise to the solution of the 14.1 trans-4-sec.-propyl cyclohexanecarbonyl chlorides (IV) of gram and 30 milliliters of acetone, temperature in keeping＜0 ℃.Drip and finish, separate out a large amount of white solids in the reaction mixture, in stirring at room reaction 3 hours, solids faded away again, and reaction solution is yellow-green colour.Stir down, with the dilute hydrochloric acid acidification reaction liquid of ice-cold 1.0N, the leaching white precipitate, abundant washing gets 19.3 gram product V after the drying, with the crystallization of methanol-water solution weight, dry that white solid 9 restrains.Dissolve with 120 ml methanol, 45 ℃ of water bath heat preservations are added dropwise to about 70 ml water solution under stirring, and to muddiness is arranged, promptly nature standing over night under room temperature gets white pasty colloid thing, filter (difficulty), and washing gets product 5 grams, fusing point 130-2 ℃ behind the filtration cakes torrefaction; It is 94% that HPLC analyzes content.
The HPLC analysis condition:
The single pump (U.S.) of instrument: HP1100, SP UV2000 detector, SP ISM100 totalizing instrument (U.S.);
Chromatographic column: Hypersil ODS 5 μ; 250 * 4.6mmid; Moving phase: 0.01M potassium primary phosphate (contain 0.2% triethylamine, transfer to pH3.0): methyl alcohol: acetonitrile=30: 30: 40 with phosphoric acid;
The preparation of embodiment one, right-isopropyl acid (I)
The P-Cymene raw material is put in the 1.0L autoclave aerating oxygen to interior pressure 22kg/cm
2, be heated to 105 ℃ under stirring, kept stress reaction 2.5 hours.With reaction solution filtering solid, decompression and solvent recovery; In resistates impouring 500ml frozen water, the deep green precipitation appears in stirring; Solid filter collection is washed to such an extent that crude product 65.0 restrains.With Glacial acetic acid-water recrystallization, get white crystals I 50.5 grams, fusing point 118-119 ℃, yield 86%.Ultimate analysis (C
10H
12O
2=164.20): calculated value C 73.15 H 7.37; Measured value C73.08 H 7.37.
The preparation of embodiment two, 4-sec.-propyl-heptanaphthenic acid (II)
In 1.0 liters of autoclaves, right-isopropyl acid 50.0 grams are dissolved in 500 milliliters of Glacial acetic acid, add 10.0 gram 10%Pd-C again, feed hydrogen to 55.0kg/cm
2, be heated to 150 ℃ of reactions 8 hours under stirring.After the cooling,, reclaim catalyzer with reacting liquid filtering; Filtrate decompression is steamed and is slipped, and reclaims acetic acid.Remaining oily matter gets water white transparency thick liquid 46.1 grams in 126 ℃/0.7mmHg distillation, is 4-different third
The mixtures II of the own formic acid cis-trans-isomer of basic ring, yield 89%.
The preparation of embodiment three, trans-4-sec.-propyl heptanaphthenic acid (III)
Get said mixture II 46.0 grams, be dissolved in 150 milliliters of cymenes, add 37.0 gram solid potassium hydroxide (content is no less than 82%), under nitrogen protection, be heated to 145 ℃, stirring reaction 6 hours.Cooling is finished in reaction; The mixing solutions that adds 60 ml waters and 60 ml methanol extracts, and behind the standing demix lower floor's (water/pure phase) is separated, and is acidified to pH2 with concentrated hydrochloric acid under the ice bath; Low temperature stirred 1 hour, and the leaching precipitation with formic acid (content is not less than 85%) recrystallization twice, gets white crystal III37.0 gram, and fusing point: 94-95 ℃, yield 80%.HPLC analyzes content greater than 99%, does not detect cis-isomeride.Ultimate analysis (C
10H
18O
2=170.25): calculated value (%) C 70.55 H 10.66; Measured value (%) C 70.57 H10.84.
HPLC instrument: Waters Delta 600 HPLC, 7125 sampling valves, SP1000 UV-detector, TSP DataJet totalizing instrument;
Chromatographic column: Polaris C
18-A, 5 μ, 250 * 4.6mm id;
Moving phase: A liquid: 0.01mol/L potassium dihydrogen phosphate (contain 0.2% triethylamine, be adjusted to pH3.0): methyl alcohol=5: 5 with phosphoric acid
B liquid: 0.01 mol/L potassium dihydrogen phosphate (contain 0.2% triethylamine, be adjusted to pH3.0): methyl alcohol=1: 9 with phosphoric acid
Measuring method: in 30min, gradient elution becomes B by A, keeps 6min, becomes A again by B in 4 minutes.Flow velocity 1.0ml/min; Detect wavelength: 220nm.
The preparation of embodiment four, trans-4-sec.-propyl cyclohexanecarbonyl chloride (IV)
Get the trans-4-sec.-propyl heptanaphthenic acid (III) of 37.0 grams and be dissolved in 320 milliliters of exsiccant 1, in the 2-ethylene dichloride, added behind the 46.0 gram phosphorus pentachlorides in 40 ℃ of oil baths stirring reaction 3 hours.Reaction is finished, and removes solvent under reduced pressure, gets colourless transparent liquid; Add 200 milliliter 1, the dissolving of 2-ethylene dichloride with after frozen water (200 milliliters * 1), 5% sodium hydrogen carbonate solution (200 milliliters * 3), frozen water (200 milliliters * 3) washing, is collected organic phase successively, spends the night with anhydrous sodium sulfate drying.Behind the filtering siccative, remove solvent under reduced pressure, get water white acyl chlorides liquid IV38.0 gram, yield 93%.
The preparation of embodiment five, N-(trans-4-isopropylcyclohexyl--1-formyl radical)-D-phenylalanine (V)
Getting 40.0 D-phenylalanines is dissolved in 180 milliliter of 10% aqueous sodium hydroxide solution, add 180 milliliters of tetrahydrofuran (THF)s again, bathe cooling down in cryosel behind the stirring and evenly mixing, drip 38.0 trans-4-sec.-propyl cyclohexanecarbonyl chlorides (IV), keep Nei Wen-10--5 ℃ in the solution of 180 milliliters of tetrahydrofuran (THF)s.Drip and finish, ice bath stirs anti-down
Answered 5 hours, and be placed to room temperature, continue reaction 2 hours, the most of tetrahydrofuran (THF) of pressure reducing and steaming under room temperature adds reaction solution in the hydrochloric acid of 1000 milliliters of ice-cold 1.0N in stirring down, separates out a large amount of white precipitates, leaching throw out, fully washing.Filtration cakes torrefaction is placed in 2000 milliliters of triangular flasks, adds 1000 milliliters of sherwood oils (60-90 ℃), stirs under room temperature and spends the night, filter, filter cake with petroleum ether after, dry 41.0 gram product V.Acid solution neutralization, reclaim the D-phenylalanine; Steaming petroleum ether reclaims transly-4-sec.-propyl heptanaphthenic acid.The fusing point 128-129 of product V ℃, [α]
D 20-10.1 ° of (CH
3OH, c=1), yield 64%.HPLC analyzes content＞99.0%; Ultimate analysis (C
19H
27NO
3=317.43): calculated value (%) C71.89 H 8.57 N 4.41; Measured value (%) C 7 1.92 H 8.87 N4.26.
Claims (11)
1, the preparation method of nateglinide is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; Or
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; Or
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; Or
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture;
E. above-mentioned a, b, the arbitrarily combination of two or three or four features among c and the d.
2, according to the method for claim 1, it is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect.
3, according to the method for claim 1, it is characterized in that:
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water.
4, according to the method for claim 1, it is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water.
5, according to the method for claim 1, it is characterized in that
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
6, according to the method for claim 1, it is characterized in that:
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
7, according to the method for claim 1, it is characterized in that:
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
8, according to the method for claim 1, it is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water.
9, according to the method for claim 1, it is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
10, according to the method for claim 1, it is characterized in that:
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
11, according to the method for claim 1, it is characterized in that:
A. with being selected from active nickel, the reductive agent of active palladium or palladium charcoal is reduced to 4-sec.-propyl heptanaphthenic acid with right-isopropyl acid; With
B. the cis-trans mixture with 4-sec.-propyl heptanaphthenic acid is converted into trans 4-sec.-propyl heptanaphthenic acid under the alkali metal hydroxide effect; With
C. trans 4-sec.-propyl hexamethylene acyl chlorides and D-phenylalanine are reacted in the mixed solvent system of organic solvent that is selected from dioxolane or tetrahydrofuran (THF) and water; With
D. product nateglinide among the c is carried out recrystallization purifying in the organic solvent that is selected from sherwood oil, normal hexane or hexanaphthene or their mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104513170A (en) * | 2013-09-29 | 2015-04-15 | 天津瑞安医药科技发展有限公司 | Production technology of trans-4-aminocyclohexaneformic acid |
| CN109651129A (en) * | 2018-12-28 | 2019-04-19 | 浙江清和新材料科技有限公司 | A kind of 4- isopropyl cyclohexanecarboxylic acid turns structure and separation method along anti-mixture |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1334963E (en) * | 2000-10-18 | 2007-09-20 | Ajinomoto Kk | Process for producing nateglinide crystal |
| CN1517334A (en) * | 2003-01-17 | 2004-08-04 | 上海华拓医药科技发展有限公司 | Improvement of synthesis process ofhypoglycemic medicine Nagelinei |
-
2003
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104513170A (en) * | 2013-09-29 | 2015-04-15 | 天津瑞安医药科技发展有限公司 | Production technology of trans-4-aminocyclohexaneformic acid |
| CN104513170B (en) * | 2013-09-29 | 2018-02-27 | 天津瑞安医药科技发展有限公司 | A kind of trans production technology to cyclohexane-carboxylic acid |
| CN109651129A (en) * | 2018-12-28 | 2019-04-19 | 浙江清和新材料科技有限公司 | A kind of 4- isopropyl cyclohexanecarboxylic acid turns structure and separation method along anti-mixture |
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| CN1318392C (en) | 2007-05-30 |
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