CN102584749A - Synthesizing method of antiviral drug amprenavir intermediate - Google Patents
Synthesizing method of antiviral drug amprenavir intermediate Download PDFInfo
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Abstract
The invention discloses a synthesizing method of an antiviral drug amprenavir intermediate. The synthesizing method is implemented according to the following steps: dissolving (2S, 3R)-3-hydroxy-4-( isobutyric amino)-1-phenyl-2-butyle amino tert-butyl carbamate shown in formula (I) and organic base into an organic solvent, dropping organic solution of 4-nitrobenzenesulfonyl chloride, stirring for reaction, introducing hydrogen chloride gas for reaction, alkali washing inorganic base, drying inorganic salt, dropping organic solution of (S)-3-tetrahydrofuran epoxide-disuccinimidyl carbonate, reacting completely, then reducing pressure to remove the solvent, washing by water, and drying to obtain amprenavir intermediate shown as formula (II). According to the method, the use of the organic solvent and the separation and purification step are reduced, and the product yield is high.
Description
(1) technical field
The present invention relates to a kind of compound method of antiviral VX-478 midbody.
(2) background technology
VX-478 (Amprenavir); Systematic naming method is (3S)-3-tetrahydrofuran oxygen base N-[(1S; 2R)-and 3-(N-isobutyl-N-4-aminobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate; Be degeneration-resistant commentaries on classics hiv protease inhibitor of the 5th generation, go on the market in the U.S. and Japan in May, 1999 by the exploitation of Britain Glaxo-Smith company.It has stronger antiviral activity and good resistance, therefore has the good clinical using value.The synthetic route of existing industrial prospect is with L-phenylalanine(Phe) deutero-(2R; 3S)-2-epoxy group(ing)-4-phenyl-3-butyl carbamic acid tert-butyl ester is a raw material; Warp carries out the amino-alkylation reaction with isobutylamine and obtains midbody (I), carries out sulfonylation, deprotection with the 4-nitrobenzene sulfonyl chloride again; Carry out condensation reaction with (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate and obtain midbody (II), last hydrogenation obtains the bulk drug VX-478.In synthetic, need to use a large amount of different organic solvent and organic acids and base reagent,, cause environmental pollution easily owing to reclaim difficulty.Need carry out the separating for several times purification step in the synthesis technique simultaneously, labour intensity is big, and yield is lower.
(3) summary of the invention
For solve the consumption of organic solvent that exists in the preparation VX-478 bulk drug prior art big, be difficult to a series of problems such as repeated use, complex operation; Follow a kind of green more and synthetic efficiently theory simultaneously; The invention provides a kind of compound method of new antiviral VX-478 midbody; Reduce the use of solvent, and operation is easy, solvent is prone to reclaim and the product yield height.
The technical scheme that the present invention adopts is:
A kind of compound method of antiviral VX-478 midbody, described compound method is carried out according to following steps:
A kind of compound method of antiviral VX-478 midbody; Described compound method is carried out according to following steps: (1) will be suc as formula (the 2S shown in (I); 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester is dissolved in the organic solvent A with organic bases ,-10 ℃～30 ℃ down dropping being dissolved with solution suc as formula the organic solvent B of the 4-nitrobenzene sulfonyl chloride shown in (III), after dropwising; At 0 ℃～45 ℃ following stirring reactions; When the ultraviolet absorption peak of liquid-phase chromatographic analysis detection reaction system Chinese style (I) compound disappears (≤0.5%), finish reaction, feed the hydrogen chloride gas precursor reactant down at-10 ℃～45 ℃ again, compound has almost reacted shown in the midbody formula V that generates up to the amidation of liquid chromatographic detection formula (I) and formula (III); Promptly the peak of this midbody no longer reduces (its ultraviolet absorption peak≤1%) for reacting completely; Add the inorganic base aqueous solution washing, leave standstill the branch water-yielding stratum, add the dry reaction solution A of getting of inorganic salt; Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester, be 1: 1～1.5: 1.1～3: 2～20 suc as formula the amount of substance ratio of 4-nitrobenzene sulfonyl chloride, organic bases and the hydrogenchloride shown in (III); Described organic bases is triethylamine, pyridine, imidazoles, Tributylamine or triethylene diamine; Said mineral alkali is sodium hydroxide, Pottasium Hydroxide, yellow soda ash or salt of wormwood; Said inorganic salt are anhydrous magnesium sulfate, SODIUM SULPHATE ANHYDROUS 99PCT or Calcium Chloride Powder Anhydrous; (2) said reaction solution A drips down at 0～50 ℃ and is dissolved with the solution suc as formula the organic solvent C of (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV); Dropwise the back stirring reaction; Decompression desolventizing after reacting completely, washing and drying promptly gets suc as formula the VX-478 midbody shown in (II); Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester is 1: 0.7～2 with amount of substance ratio suc as formula (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV).
Reaction formula of the present invention is as follows:
Reacting completely in the step of the present invention (1) is to be standard with the ultraviolet absorption peak of liquid-phase chromatographic analysis reaction system Chinese style (I) compound≤0.5%; Feed the hydrogen chloride gas precursor reactant down at-10 ℃～45 ℃, finish for reaction when the ultraviolet absorption peak of compound no longer reduces (its ultraviolet absorption peak≤1%) shown in the midbody formula V that after the amidation of liquid-phase chromatographic analysis formula (I) and formula (III), generates; The ultraviolet absorption peak that reaction in the step (2) ends up being suc as formula VX-478 midbody shown in (II) no longer increases.
Organic solvent A of the present invention, organic solvent B or organic solvent C; The A here, B, C do not have specific implication; Different steps just for the ease of describing, is distinguished the organic solvent that the differential responses step is used, with organic solvent A, organic solvent B or organic solvent C on chemical substance; Organic solvent A, organic solvent B or organic solvent C do not have the difference on the certain sense, all are organic appearance agent that representative participates in a certain step chemical reaction.
Further, organic solvent A of the present invention, organic solvent B or organic solvent C independently are separately: the arbitrary combination of one or more in methylene dichloride, toluene, ETHYLE ACETATE, ethylene dichloride or the chloroform.
The dropping temperature that the middle dropping of the preferred step of the present invention (1) is dissolved with suc as formula the solution of the organic solvent B of the 4-nitrobenzene sulfonyl chloride shown in (III) is 0 ℃.
Stirring reaction temperature in the preferred step of the present invention (1) is 25 ℃.
Organic solvent A in the preferred step of the present invention (1), organic solvent B or organic solvent C are methylene dichloride.
Organic bases in the preferred step of the present invention (1) is a triethylamine.
Inorganic base aqueous solution is that concentration is the sodium hydroxide solution of 1～20mol/L in the preferred step of the present invention (1).
Preferred organic A of the present invention,, organic solvent B or organic solvent C be identical organic solvent.
Particularly; The method that the present invention recommends is carried out as follows: (1) will be suc as formula (the 2S shown in (I); 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester is dissolved in the methylene dichloride with triethylamine, 0 ℃ down dropping suc as formula the dichloromethane solution of the 4-nitrobenzene sulfonyl chloride shown in (III), after dropwising; Finish reaction at 25 ℃ of following stirring reactions up to ultraviolet absorption peak≤0.5% of formula (I) compound; Be generally 20h, ultraviolet absorption peak≤1% that feeds compound shown in the midbody formula V that the hydrogen chloride gas precursor reactant generates after the amidation of liquid-phase chromatographic analysis formula (I) and formula (III) is generally 10h o'clock for reacting completely; The sodium hydroxide solution thorough washing that adds 5mol/L no longer changes to organic phase pH, adds anhydrous sodium sulfate drying and gets reaction solution A; Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester, be 1: 1.1: 1.5: 15 suc as formula the amount of substance ratio of 4-nitrobenzene sulfonyl chloride, triethylamine and the hydrogenchloride shown in (III); (2) said reaction solution A drips down at 10 ℃ and is dissolved with the solution suc as formula the methylene dichloride of (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV); Dropwise back stirring reaction 20h; Reaction to the ultraviolet absorption peak suc as formula VX-478 midbody shown in (II) no longer increases; Decompression desolventizing after promptly reacting completely, washing and drying promptly gets suc as formula the VX-478 midbody shown in (II); Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester is 1: 0.9 with amount of substance ratio suc as formula (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV).
The present invention compares suc as formula the VX-478 midbody method shown in (II) with existing preparation, and beneficial effect of the present invention is: reduce the use of organic solvent, reduce post-processing operation, product yield is high.
(4) embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited in this.
The liquid-phase chromatographic analysis condition: C18 post, moving phase are methyl alcohol and water (7: 3), 1mL/min, and UV-detector, wavelength are 254nm.
Embodiment 1:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (20.5g; 0.2mol) be dissolved in methylene dichloride (150mL), drip 4-nitrobenzene sulfonyl chloride (27.0g, dichloromethane solution 0.12mol) (150mL) down at-10 ℃; Behind 30 ℃ of following stirring reaction 20h, liquid-phase chromatographic analysis formula (I) peak disappears, and is cooled to 10 ℃; Feed hydrogen chloride gas (1mol) reaction in the 6h, add the aqueous sodium hydroxide solution 300mL alkali cleaning three times of 2mol/L, standing demix; Get organic layer; With SODIUM SULPHATE ANHYDROUS 99PCT (30g) drying, drip (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (23.0g, dichloromethane solution 0.1mol) (100mL) down at 20 ℃; Decompression removes methylene dichloride behind the reaction 20h; Washing and drying promptly obtain described VX-478 midbody (II) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (38.9g, 72% yield).(m.p.：152～154℃；1HNMR(500MHz，DMSO-d6)：0.84(d，6H)，1.75-1.80(m，1H)，1.95-1.99(m，1H)，2.02-2.08(m，1H)，2.45-2.47(m，1H)，2.92-2.98(m，2H)，3.06-3.09(m，1H)，3.14-3.18(m，1H)，3.34-3.40(m，3H)，3.50-3.51(m，2H)，3.58-3.62(m，1H)，3.65-3.72(m，2H)，4.94-4.96(m，1H)，5.04(dr，1H)，7.16-7.45(m，5H)，8.06(d，2H)，8.38(d，2H)；MS(+ESI)：536(M+H)
+，558(M+Na
+)。The product structure characterization result that following examples obtain is identical.
Embodiment 2:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (30.8g; 0.3mol) be dissolved in toluene (150mL), 10 ℃ drip 4-nitrobenzene sulfonyl chloride (33.8g, toluene solution 0.15mol) (150mL) down; At 45 ℃ of following stirring reaction 30h, liquid-phase chromatographic analysis formula (I) peak disappears, under this temperature; Flow velocity feeds hydrogen chloride gas (2mol) reaction in the 20h, and the gained reaction solution adds the potassium hydroxide aqueous solution 300mL alkali cleaning three times of 2mol/L, leaves standstill branchs except that water layer; Organic layer drips (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (16.1g, toluene solution 0.7mol) (100mL) with anhydrous magnesium sulfate (35g) drying down at 50 ℃; Decompression removes toluene behind the reaction 20h; Washing and drying promptly obtain described VX-478 midbody (5) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (32.4g, 60% yield).
Embodiment 3:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and pyridine (24g; 0.3mol) be dissolved in ethylene dichloride (150mL) ,-10 ℃ drip 4-nitrobenzene sulfonyl chloride (27.0g, dichloroethane solution 0.12mol) (150mL); At 40 ℃ of following stirring reaction 20h, liquid-phase chromatographic analysis formula (I) peak disappears, and is cooled to-10 ℃; Feed hydrogen chloride gas (1.2mol) reaction in the 6h, add the aqueous sodium carbonate 1000mL alkali cleaning three times of 0.5mol/L, leave standstill branchs except that water layer; Organic layer drips (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (46.0g, dichloroethane solution 0.2mol) (100mL) with Calcium Chloride Powder Anhydrous (26g) drying down at 10 ℃; Decompression removes ethylene dichloride behind the reaction 40h; Washing and drying promptly obtain described VX-478 midbody (5) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (40.5g, 75% yield).
Embodiment 4:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and imidazoles (7.5g; 0.11mol) be dissolved in ETHYLE ACETATE (150mL), 30 ℃ drip 4-nitrobenzene sulfonyl chloride (22.5g, ethyl acetate solution 0.1mol) (150mL); At 20 ℃ of following stirring reaction 40h, liquid-phase chromatographic analysis formula (I) peak disappears, and feeds hydrogen chloride gas (0.2mol) reaction in the 3h; Add the wet chemical 300mL alkali cleaning three times of 2mol/L, leave standstill branch and remove water layer, organic layer is with SODIUM SULPHATE ANHYDROUS 99PCT (30g) drying; Drip (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (20.7g down at 20 ℃; 0.7mol) ethyl acetate solution (100mL), decompression removes ETHYLE ACETATE behind the reaction 20h, washing and drying promptly obtain described VX-478 midbody (5) (3S)-3-tetrahydrofuran oxygen base N-[(1S; 2R)-and 3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (24.3g, 45% yield).
Embodiment 5:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and Tributylamine (37.1g; 0.2mol) be dissolved in chloroform (150mL), 0 ℃ drips 4-nitrobenzene sulfonyl chloride (27.0g, chloroformic solution 0.12mol) (150mL); At 30 ℃ of following stirring reaction 40h, liquid-phase chromatographic analysis formula (I) peak disappears, and is cooled to 10 ℃; Feed hydrogen chloride gas (1.5mol) reaction in the 6h, add the potassium hydroxide aqueous solution 300mL alkali cleaning of 2mol/L, leave standstill branch and remove water layer; Organic layer drips (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (20.7g, chloroformic solution 0.9mol) (100mL) with SODIUM SULPHATE ANHYDROUS 99PCT (30g) drying down at 0 ℃; Decompression removes chloroform behind the reaction 5h; Washing and drying promptly obtain described VX-478 midbody (5) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (40.0g, 74% yield).
Embodiment 6:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and triethylene diamine (22.5g; 0.2mol) (volume ratio is 1: 1, and 150mL), 0 ℃ drips 4-nitrobenzene sulfonyl chloride (27.0g to be dissolved in the mixing solutions of toluene and methylene dichloride; 0.12mol) toluene and methylene dichloride mixing solutions (150mL), at 30 ℃ of following stirring reaction 40h, liquid-phase chromatographic analysis formula (I) peak disappears; Under this temperature, feed hydrogen chloride gas (0.8mol) reaction in the 6h, add the aqueous sodium hydroxide solution 300mL alkali cleaning three times of 2mol/L; Leave standstill branch and remove water layer; Organic layer drips (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (20.7g, identical mixing solutions (100mL) 0.9mol) with SODIUM SULPHATE ANHYDROUS 99PCT (30g) drying down at 0 ℃; Decompression removes organic solvent behind the reaction 5h; Washing and drying promptly obtain described VX-478 midbody (5) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (38.9g, 72% yield).
Embodiment 7:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (15.4g; 0.15mol) be dissolved in methylene dichloride (50mL), drip 4-nitrobenzene sulfonyl chloride (24.8g, toluene solution 0.11mol) (300mL) down at 25 ℃; Behind 25 ℃ of following stirring reaction 5h, liquid-phase chromatographic analysis formula (I) peak disappears, and feeds hydrogen chloride gas (0.5mol) reaction in the 3h; Add the aqueous sodium hydroxide solution 300mL alkali cleaning three times of 2mol/L, standing demix is got organic layer; With SODIUM SULPHATE ANHYDROUS 99PCT (50g) drying, drip (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (23.0g, toluene solution 0.1mol) (100mL) down at 20 ℃; Decompression removes organic solvent behind the reaction 10h; Washing and drying promptly obtain described VX-478 midbody (II) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (37.8g, 70% yield).
Embodiment 8:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (25.7g; 0.25mol) be dissolved in ethylene dichloride (50mL), drip 4-nitrobenzene sulfonyl chloride (27.0g, ethyl acetate solution 0.11mol) (150mL) down at 10 ℃; Behind 25 ℃ of following stirring reaction 10h, liquid-phase chromatographic analysis formula (I) peak disappears, and feeds hydrogen chloride gas (0.8mol) reaction in the 5h; Add the aqueous sodium hydroxide solution 300mL alkali cleaning three times of 2mol/L, standing demix is got organic layer; With SODIUM SULPHATE ANHYDROUS 99PCT (30g) drying, drip (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (23.0g, ethyl acetate solution 0.1mol) (100mL) down at 20 ℃; Decompression removes organic solvent behind the reaction 10h; Washing and drying promptly obtain described VX-478 midbody (II) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (35.6g, 66% yield).
Embodiment 9:
With raw material (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester (I) (34.0g, 0.1mol) and triethylamine (25.7g; 0.25mol) be dissolved in methylene dichloride (200mL), drip 4-nitrobenzene sulfonyl chloride (27.0g, dichloromethane solution 0.12mol) (100mL) down at 0 ℃; Behind 25 ℃ of following stirring reaction 10h, liquid-phase chromatographic analysis formula (I) peak disappears, and feeds hydrogen chloride gas (1.5mol) reaction in the 10h; Add the aqueous sodium hydroxide solution 300mL alkali cleaning three times of 2mol/L, standing demix is got organic layer; With anhydrous magnesium sulfate (45g) drying, drip (S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate (23.0g, dichloromethane solution 0.1mol) (100mL) down at 30 ℃; Decompression removes methylene dichloride behind the reaction 30h; Washing and drying promptly obtain described VX-478 midbody (II) (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl--N-4-nitrobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate (50.0g, 76% yield).
Claims (10)
1. the compound method of an antiviral VX-478 midbody, described compound method is carried out according to following steps: (1) will suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl is amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester and organic bases be dissolved in the organic solvent A; Under-10 ℃～30 ℃, drip and be dissolved with solution, after dropwising, at 0 ℃～45 ℃ following stirring reactions suc as formula the organic solvent B of the 4-nitrobenzene sulfonyl chloride shown in (III); React completely; Feed the hydrogen chloride gas precursor reactant down at-10 ℃～45 ℃, reaction finishes, and adds the solution washing of mineral alkali; Leave standstill the branch water-yielding stratum, add the dry reaction solution A of getting of inorganic salt; Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester, be 1: 1～1.5: 1.1～3: 2～20 suc as formula the amount of substance ratio of 4-nitrobenzene sulfonyl chloride, organic bases and the hydrogenchloride shown in (III); Described organic bases is triethylamine, pyridine, imidazoles, Tributylamine or triethylene diamine; Described mineral alkali is sodium hydroxide, Pottasium Hydroxide, yellow soda ash or salt of wormwood; Said inorganic salt are anhydrous magnesium sulfate, SODIUM SULPHATE ANHYDROUS 99PCT or Calcium Chloride Powder Anhydrous; (2) get said reaction solution A dropping under 0～50 ℃ and be dissolved with solution suc as formula the organic solvent C of (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV); Dropwise the back stirring reaction; Reaction finishes back decompression desolventizing, and washing and drying promptly gets suc as formula the VX-478 midbody shown in (II); Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester is 1: 0.7～2 with amount of substance ratio suc as formula (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV);
2. compound method as claimed in claim 1; It is characterized in that reacting completely in the step (1) is that ultraviolet absorption peak≤0.5% with liquid-phase chromatographic analysis reaction system Chinese style (I) compound is a standard; Feed the hydrogen chloride gas precursor reactant down at-10 ℃～45 ℃, the ultraviolet absorption peak of the compound shown in the midbody formula V that after the amidation of liquid-phase chromatographic analysis formula (I) and formula (III), generates no longer is reduced to reaction to be finished; The ultraviolet absorption peak that reaction in the step (2) ends up being suc as formula VX-478 midbody shown in (II) no longer increases;
3. compound method as claimed in claim 1 is characterized in that described organic solvent A, organic solvent B or organic solvent C independently are separately: the arbitrary combination of one or more in methylene dichloride, toluene, ETHYLE ACETATE, ethylene dichloride or the chloroform.
4. compound method as claimed in claim 1, it is characterized in that dripping in the described step (1) dropping temperature that is dissolved with suc as formula the solution of the organic solvent B of the 4-nitrobenzene sulfonyl chloride shown in (III) is 0 ℃.
5. compound method as claimed in claim 1 is characterized in that the stirring reaction temperature in the described step (1) is 25 ℃.
6. compound method as claimed in claim 1 is characterized in that organic solvent A, organic solvent B or the organic solvent C in the described step (1) is methylene dichloride.
7. compound method as claimed in claim 1 is characterized in that the organic bases in the described step (1) is a triethylamine.
8. compound method as claimed in claim 1 is characterized in that the aqueous solution of mineral alkali in the described step (1) is that concentration is the sodium hydroxide solution of 1～20mol/L.
9. compound method as claimed in claim 1 is characterized in that described organic solvent A, organic solvent B or organic solvent C are identical organic solvent.
10. compound method as claimed in claim 1; It is characterized in that described method carries out as follows: (1) will be suc as formula (the 2S shown in (I); 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester and triethylamine be dissolved in the methylene dichloride; At 0 ℃ of dichloromethane solution that drips down suc as formula the 4-nitrobenzene sulfonyl chloride shown in (III), after dropwising, finish reaction up to ultraviolet absorption peak≤0.5% of formula (I) compound at 25 ℃ of following stirring reactions; The ultraviolet absorption peak of compound no longer is reduced to and reacts completely shown in the midbody formula V that the gas reaction of feeding excessive hydrogen chloride generates after the amidation of liquid-phase chromatographic analysis formula (I) and formula (III); The aqueous sodium hydroxide solution thorough washing that adds 5mol/L no longer changes to organic phase pH, leaves standstill the branch water-yielding stratum, adds anhydrous sodium sulfate drying and gets reaction solution A; Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester, be 1: 1.1: 1.5: 15 suc as formula the amount of substance ratio of 4-nitrobenzene sulfonyl chloride, triethylamine and the hydrogenchloride shown in (III); (2) said reaction solution A drips down at 10 ℃ and is dissolved with the solution suc as formula the methylene dichloride of (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV); Dropwise back stirring reaction 20h; Ultraviolet absorption peak suc as formula VX-478 midbody shown in (II) in the reaction system no longer increases; Decompression desolventizing after promptly reacting completely, washing and drying promptly gets suc as formula the VX-478 midbody shown in (II); Said suc as formula shown in (I) (2S, 3R)-3-hydroxyl-4-(isobutyl amino)-1-phenyl-2-butyl carbamic acid tert-butyl ester is 1: 0.9 with amount of substance ratio suc as formula (the S)-3-tetrahydrofuran oxygen base-succinimidyl carbonate shown in (IV).
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| US5783701A (en) * | 1992-09-08 | 1998-07-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
-
2011
- 2011-12-16 CN CN2011104223109A patent/CN102584749A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5783701A (en) * | 1992-09-08 | 1998-07-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
Non-Patent Citations (1)
| Title |
|---|
| B. MOON KIM,SUNG JIN BAE,SOON MOG SO,ET AL: "Synthesis of a Chiral Aziridine Derivative as a Versatile Intermediate for HIV Protease Inhibitors", 《ORGANIC LETTERS》, vol. 3, no. 15, 29 June 2001 (2001-06-29), pages 2349 - 2351 * |
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