CN101486691B - Method for synthesizing N-(benzyloxycarbonyl)-amino-epoxy-phenyl butane - Google Patents
Method for synthesizing N-(benzyloxycarbonyl)-amino-epoxy-phenyl butane Download PDFInfo
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- CN101486691B CN101486691B CN2009100252270A CN200910025227A CN101486691B CN 101486691 B CN101486691 B CN 101486691B CN 2009100252270 A CN2009100252270 A CN 2009100252270A CN 200910025227 A CN200910025227 A CN 200910025227A CN 101486691 B CN101486691 B CN 101486691B
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Abstract
The invention relates to a synthetic method of N-(carbobenzoxyl)-amino-epoxy-phenyl butane, which adopts L-phenylalanine as a starting raw material and carries out diazotization, selective reduction and hydrolysis for preparation. The method includes the following technological steps: pyridine and an acid activator are added into an organic solvent I containing the L-phenylalanine for reaction and added into the ether solution of diazomethane for reaction to obtain an intermediate compound I; the ethyl acetate solution of chlorine hydride is added into an organic solvent II of the intermediate compound I in a dropwise manner for reacting at -20 DEG C to -40 DEG C for 1h to 2h in a heat preservation way to obtain a crude product of a compound II; the crude product of the compound II is added into an organic solvent III containing a catalyst for reaction, and the pH value is adjusted by a product of an inorganic acid acidification reaction to 2 to 4, then a crude product of a compound III is obtained; and an inorganic base is dissolved in the water and an organic solvent IV and the crude product of the compound III are added in sequence for reaction to obtain the compound, namely the N-(carbobenzoxyl)-amino-epoxy-phenyl butane. The method has high reaction safety, comparatively good selectivity, comparatively high product yield, high product purity and low cost.
Description
(1) technical field
The present invention relates to the synthetic method of key intermediate N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane of AIDS drug Saquinavir (SAQUINAVIR).Belong to organic chemical industry's synthesis technical field.
(2) background technology
{ N-benzyloxycarbonyl-3 (S)-amino-l, 2 (S)-epoxy-4-phenylbutane} are key intermediates of AIDS drug viracept see nelfinaivr (Nelfinavir) to N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane.Saquinavir is that first is by the hiv protease inhibitor of FDA approval listing.Because this product processes complexity, the production process safety control is had relatively high expectations, and production firm seldom in the world.Numerous documents and patent report preparation method separately.
Its preparation method that at present reported in literature arranged, specific as follows:
The synthetic method of EP604185A1 report need be carried out flash chromatography three times, uses CH then under-78 ℃ low temperature
2Cl
2Recrystallization purifying, yield only are 26.2%.
Method or operational path that WO2002064553A1, EP0774453 and WO9845271A1 disclose are long, or use inflammable and explosive chemical in a large number, so people are still not stopping to explore new synthesis technique, to satisfy the needs of medical field.
(3) summary of the invention
The objective of the invention is to overcome above-mentioned deficiency, the method for a kind of reaction safety height, product purity height, good optical rotation of melting point, product yield height, synthetic N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane that production cost is low is provided.
The object of the present invention is achieved like this: a kind of N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane synthetic method, it is characterized in that described method is is starting raw material with the L-phenylalanine, make through diazotization, selective reduction and hydrolysis, described method comprises following processing step:
Step 1, diazotization
Pyridine and acid activators adding are contained in the organic solvent I of L-phenylalanine, in temperature is-60～-20 ℃ of reaction 0.5～2h down, the diethyl ether solution that adds diazomethane, reaction 1～4h after reaction is carried out fully, adds saturated sodium bicarbonate solution and destroys unnecessary diazomethane, reaction system is warming up to room temperature naturally, with the washing of equal-volume saturated sodium-chloride, underpressure distillation is removed unnecessary solvent I and is promptly obtained intermediate compound I
Described organic solvent I is a kind of of toluene, tetrahydrofuran (THF), vinyl acetic monomer, ether and N-BUTYL ACETATE; The weight percent concentration of L-phenylalanine is 8%～12% in this organic solvent;
The weight percent concentration of diazomethane is 5～15% in the diethyl ether solution of described diazomethane;
The molar ratio of described L-phenylalanine, diazomethane, pyridine and acid activators is the L-phenylalanine: diazomethane: pyridine: acid activators=1: 1～2: 1～2: 1～2,
Described acid activators is chloro-formic ester, Vinyl chloroformate, isobutyl-, PCl
3, PCl
5And SO
2Cl
2In a kind of,
Step 2, selective reduction
The hydrogenchloride vinyl acetic monomer solution of Dropwise 5～15% weight percent concentration is to the organic solvent II of intermediate compound I, at-5～-40 ℃ of following insulation reaction 1-2h, after reaction is finished, wash with saturated sodium-chloride, underpressure distillation is removed excessive organic solvent II and is promptly got Compound I I crude product
The molar ratio of described intermediate compound I and hydrogenchloride is intermediate compound I: hydrogenchloride=1: 1～2;
Described organic solvent II is a kind of in tetrahydrofuran (THF), toluene, vinyl acetic monomer, ether and the N-BUTYL ACETATE, and the weight percent concentration of intermediate compound I is 1～5% in this organic solvent II,
Step 3, hydrolysis
Compound I I crude product is poured among the organic solvent II I that contains catalyzer,-10～-30 ℃ of following insulation reaction 1-4h, use mineral acid acidification reaction product to PH=2～4 then, add and the isopyknic hexanaphthene of reaction soln, leave standstill 3-4h, centrifugal then, rinsing, drying promptly obtain the compound III crude product.
The molar ratio of described Compound I I crude product and catalyzer is a Compound I I crude product: catalyzer=1: 1～2;
Described catalyzer is a kind of among aluminum isopropylate, NaBH4 and the KBH4,
Described mineral acid is HCl, HSO
4With rare H
3PO
4In a kind of;
Described organic solvent II I is a kind of in toluene, vinyl acetic monomer, acetone, methyl alcohol and the ethanol, and the weight percent concentration of catalyzer is 5～10% among this organic solvent II I.
Step 4, secondary hydrolysis
Mineral alkali is dissolved in the water, add organic solvent I V, add the compound III crude product again, reacted 2 hours down at 20～40 ℃, add water then, the product of collecting with the mode of crystallization is N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane again.
Production method of the present invention, technology is easy, raw material is easy to get, production cost is low, is suitable for industrialized production, and the total molar yield of product reaches 75%, optical purity of products reaches more than 99%, can be used for synthetic Saquinavir medicine, process of producing product does not use deleterious raw material and solvent, so production process is safe and reliable.
(4) embodiment
The N-that the present invention relates to (carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane synthetic method, described method is to be starting raw material with the L-phenylalanine, makes through diazotization, selective reduction, hydrolysis and secondary hydrolysis, described method comprises following processing step:
Step 1, diazotization
Pyridine and acid activators adding are contained in the organic solvent I of L-phenylalanine, in temperature is-60～-20 ℃ of reaction 0.5～2h down, the diethyl ether solution that adds diazomethane, reaction 1～4h after reaction is carried out fully, adds saturated sodium bicarbonate solution and destroys unnecessary diazomethane, reaction system is warming up to room temperature naturally, with the washing of equal-volume saturated sodium-chloride once, underpressure distillation is removed unnecessary solvent I and is promptly obtained intermediate compound I
Described organic solvent I is a kind of of toluene, tetrahydrofuran (THF), vinyl acetic monomer and ether and N-BUTYL ACETATE; The weight percent concentration of L-phenylalanine is 8%～12% in this organic solvent I;
The weight percent concentration of diazomethane is 5～15% in the diethyl ether solution of described diazomethane;
The molar ratio of described L-phenylalanine, diazomethane, pyridine and acid activators is the L-phenylalanine: diazomethane: pyridine: acid activators=1: 1～2: 1～2: 1～2.
Described acid activators is chloro-formic ester, Vinyl chloroformate, isobutyl-, PCl
3, PCl
5And SO
2Cl
2In a kind of,
Its reaction expression is:
Step 2, selective reduction
The hydrogenchloride vinyl acetic monomer solution of Dropwise 5～15% weight percent concentration is to the organic solvent II of intermediate compound I, at-5～-40 ℃ of following insulation reaction 1-2h, after reaction is finished, use the saturated sodium-chloride washed twice, underpressure distillation is removed excessive organic solvent II and is promptly got Compound I I crude product
The molar ratio of described intermediate compound I and hydrogenchloride is intermediate compound I: hydrogenchloride=1: 1～2;
Described organic solvent II is a kind of in tetrahydrofuran (THF), toluene, vinyl acetic monomer, ether and the N-BUTYL ACETATE, and the weight percent concentration of intermediate compound I is 1～5% in this organic solvent II, and its reaction expression is:
Step 3, hydrolysis
Compound I I crude product is poured among the organic solvent II I that contains catalyzer,-10～-30 ℃ of following insulation reaction 1-4h, use mineral acid acidification reaction product to PH=2～4 then, add and the isopyknic hexanaphthene of reaction soln, leave standstill 3-4h, centrifugal then, rinsing, drying promptly obtain the compound III crude product.
The molar ratio of described Compound I I crude product and catalyzer is a Compound I I crude product: catalyzer=1: 1～2;
Described catalyzer is aluminum isopropylate, NaBH
4And KBH
4In a kind of,
Described mineral acid is HCl, HSO
4With rare H
3PO
4In a kind of;
Described organic solvent II I is a kind of in toluene, vinyl acetic monomer, acetone, methyl alcohol and the ethanol, and the weight percent concentration of catalyzer is 5～10% among this organic solvent II I; Its reaction expression is:
Step 4, secondary hydrolysis
Mineral alkali is dissolved in the water, add organic solvent I V, add the compound III crude product again, reacted 2 hours down at 20～40 ℃, add water then, the product of collecting with the mode of crystallization is N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane again.
Described mineral alkali is a kind of among NaOH and the KOH; Described organic solvent I V is a kind of in toluene, vinyl acetic monomer, acetone, methyl alcohol and the ethanol; Its reaction expression is:
The molar ratio of described mineral alkali and organic solvent I V and compound III crude product is: compound III crude product: mineral alkali: organic solvent I V=1: 1～2: 26～28.
According to optimized technical scheme of the present invention, preceding three-step reaction must carry out under anhydrous condition, and therefore solvent that is adopted and the material that is reacted all carry out processed earlier.
According to optimized technical scheme of the present invention, step 4 adds entry after reaction finishes, left standstill 30 minutes, and centrifugal then, rinsing, drying promptly obtain N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane.
Embodiment:
Step 1, the 8kgL-phenylalanine is dissolved in the 100L vinyl acetic monomer, it is cooled to-50 ℃, remain on this below temperature, add 4.3L pyridine and 3L Vinyl chloroformate, add the diethyl ether solution (weight percent concentration of diazomethane is 10%) of diazomethane behind the 0.5h.TLC adds the 3L saturated sodium bicarbonate solution and destroys unnecessary diazomethane after showing that reaction has been carried out fully, and reaction system is warming up to room temperature naturally, and with the washing of equal-volume saturated sodium-chloride once, underpressure distillation is removed unnecessary vinyl acetic monomer and got intermediate compound I.
Step 2,15kg intermediate compound I is dissolved in the 300L Glacial acetic acid ethyl ester, it is cooled to-10 ℃, keep under the situation of this temperature, drip 10% hydrogenchloride vinyl acetic monomer solution 60Kg.TLC uses the saturated sodium-chloride washed twice after showing that reaction is finished, and underpressure distillation is removed unnecessary Glacial acetic acid ethyl ester and got Compound I I crude product.
Step 3,20kg catalyzer aluminum isopropylate is dissolved in the 300L toluene, be cooled to-20 ℃, add 20kg Compound I I crude product, after TLC showed that reaction is finished, the hydrochloric acid soln with 10% was transferred pH value to 3, adds the 200L hexanaphthene then, leave standstill 4h after stirring 5min, then feed liquid is filtered, filter cake obtains the compound III crude product with hexanaphthene washing back oven dry.
Step 4,3.4Kg sodium hydroxide is dissolved in the 30Kg water, add 95Kg acetone, add 20Kg compound III crude product again, be warming up to 30 ℃, be incubated 2 hours, after TLC shows that reaction is finished, drip water 250Kg, temperature is controlled less than 30 ℃, drips off to stir 30 minutes, be cooled to 0 ℃, be incubated 1 hour, feed liquid is filtered, filter cake washes the back oven dry with water, obtain optical purity and be target product N-(carbobenzoxy-(Cbz))-amino-epoxy group(ing)-phenyl butane of 99%, four step mole total recoverys are 75%.
Claims (1)
1. (3S)-3-(N-carbobenzoxy-(Cbz)) amino-1,2-epoxy group(ing)-4-phenyl butane synthetic method, it is characterized in that described method is is starting raw material with N-carbobenzoxy-(Cbz)-L-phenylalanine, make that described method comprises following processing step through diazotization, selective reduction and hydrolysis:
Step 1,8kg N-carbobenzoxy-(Cbz)-L-phenylalanine is dissolved in the 100L vinyl acetic monomer, it is cooled to-50 ℃, remain on this below temperature, add 4.3L pyridine and 3L Vinyl chloroformate, 0.5h the back adds the diethyl ether solution of diazomethane, the weight percent concentration of diazomethane is 10%, after TLC shows that reaction has been carried out fully, add the 3L saturated sodium bicarbonate solution and destroy unnecessary diazomethane, reaction system is warming up to room temperature naturally, with the washing of equal-volume saturated sodium-chloride once, underpressure distillation is removed unnecessary vinyl acetic monomer and is got intermediate compound I;
Step 2,15kg intermediate compound I is dissolved in the 300L Glacial acetic acid ethyl ester, it is cooled to-10 ℃, keep under the situation of this temperature, drip 10% hydrogenchloride vinyl acetic monomer solution 60kg, after TLC shows that reaction is finished, use the saturated sodium-chloride washed twice, underpressure distillation is removed unnecessary Glacial acetic acid ethyl ester and is got Compound I I crude product;
Step 3,20kg catalyzer aluminum isopropylate is dissolved in the 300L toluene, be cooled to-20 ℃, add 20kg Compound I I crude product, after TLC showed that reaction is finished, the hydrochloric acid soln adjust pH to 3 with 10% added the 200L hexanaphthene then, leave standstill 4h after stirring 5min, then feed liquid is filtered, filter cake obtains the compound III crude product with hexanaphthene washing back oven dry;
Step 4,3.4kg sodium hydroxide is dissolved in the 30kg water, add 95kg acetone, add 20kg compound III crude product again, be warming up to 30 ℃, be incubated 2 hours, after TLC shows that reaction is finished, drip water 250kg, temperature control drips off and stirred 30 minutes less than 30 ℃, is cooled to 0 ℃, be incubated 1 hour, feed liquid is filtered, and filter cake washes the back oven dry with water, obtains finished product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860903B (en) * | 2015-04-30 | 2017-05-24 | 上海应用技术学院 | Preparation method of saquinavir intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860903B (en) * | 2015-04-30 | 2017-05-24 | 上海应用技术学院 | Preparation method of saquinavir intermediate |
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