CN101967130B - Synthesis method of ritonavir midbody - Google Patents
Synthesis method of ritonavir midbody Download PDFInfo
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- CN101967130B CN101967130B CN 201010216337 CN201010216337A CN101967130B CN 101967130 B CN101967130 B CN 101967130B CN 201010216337 CN201010216337 CN 201010216337 CN 201010216337 A CN201010216337 A CN 201010216337A CN 101967130 B CN101967130 B CN 101967130B
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Abstract
The invention discloses a synthesis method of (2S,3S,5C)-5-(Butyloxycarbonylamino)-2-(N-5- thiazolyl-carbomethoxy) amino-1,6-diphenyl-3-hydroxyhexane which is prepared from (2S,3S,5C)-2-amino-3-hydroxy-5-(Butyloxycarbonylamino)-1,6-diphenylhexane and 5-thiazolylmethyl-4-nitrobenzophenone carbonic ester through the nucleophilic substitution reaction, wherein the (2S,3S,5C)-2-amino-3-hydroxy-5-(Butyloxycarbonylamino)-1,6-diphenylhexane is prepared through the reducing step, the amino protection step and the catalytic reduction step on (S,Z)-5-amino-2-(dibenzylamino)-1,6-diphenylhexane-4-alkene-3-ketone. The synthesis method is an in situ synthesis method, not only reduces the reaction steps but also reduce the time consumption brought by intermediate product separation, improves the yield and does not influence the purity and the quality of the product.
Description
Technical field
The present invention relates to a kind of improved compound method, relate to a kind of ritonavir midbody particularly---(2S, 3S, 5S)-and 5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1, the compound method of 6-phenylbenzene-3-hydroxyl hexane.
Background technology
Ritonavir can be treated late period or non-progressive AIDS patient separately or with the other medicines coupling, and has following structure:
When synthesizing ritonavir, need make the midbody of ritonavir in advance---(2S, 3S, 5S)-and 5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1,6-phenylbenzene-3-hydroxyl hexane (compound VI), structure is following:
The method for preparing compound VI relate to (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1,6-phenylbenzene hexane (compound IV) and 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V).
In above-mentioned reaction, for reducing (2S, 3S; 5S)-and 2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1, by product quantity and by product kind that 6-phenylbenzene hexane (compound IV) produces when reacting with 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) guarantee the compound VI yield; Can obtain highly purified (2S; 3S, 5S)-amino-3 hydroxyls-5 of 2-(tert.-butoxy formamido group)-1, the core place of 6-phenylbenzene hexane (compound IV).In existing disclosed method; Compound IV is through (S; Z)-and 5-amino-2-(dibenzyl amino)-1,6-phenylbenzene hexane-4-alkene-3-ketone (compound I) obtains compound I I, t-butoxycarbonyl amino protection through reduction and obtains that compound III and catalytic reduction debenzylation step obtain.In order to improve the purity of compound IV, after the debenzylation step, compound IV earlier with succsinic acid react (2S; 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1,6-phenylbenzene hexane SUMATRIPTAN SUCCINATE (compound VI I); Again by (2S; 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1, after desalting, 6-phenylbenzene hexane SUMATRIPTAN SUCCINATE (compound VI I) further obtains compound VI with 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) reaction.This compound method (2S, 3S, 5S)-and 5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1,6-phenylbenzene hexane (compound IV) needs to use earlier the method into SUMATRIPTAN SUCCINATE refining; Obtain purity reach more than 99% (2S, 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1; The pure article of 6-phenylbenzene hexane SUMATRIPTAN SUCCINATE, SUMATRIPTAN SUCCINATE, this salify purified method are removed in alkali cleaning then; Complex steps, length consuming time need to consume a large amount of organic solvents, intermediate product (2S; 3S, 5S)-5-tert.-butoxy formamido group-2-amino-3-hydroxyl-1, the separation of 6-phenylbenzene hexane SUMATRIPTAN SUCCINATE has also improved cost.Therefore, need a kind of more economical compound method.
The route of synthesis of existing open compound IV is as follows:
Summary of the invention
The invention provides the compound method of a kind of ritonavir midbody " (2S, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1; 6-phenylbenzene-3-hydroxyl hexane (compound VI) "; This compound method is an in-situ synthetic method, and it has not only reduced reactions step, has also reduced intermediate product and has separated the time loss that is brought; Improve yield, and do not influenced degree of purity of production and quality.
The technical scheme that the present invention adopts is following:
The compound method of compound shown in the formula VI (ritonavir midbody) is characterized in that, comprises the steps:
A, (S, Z)-5-amino-2-(dibenzyl amino)-1,6-phenylbenzene hexane-4-alkene-3-ketone (compound I) through carbonyl reduction, C=C reduce (2S; 3S; 5S)-and 5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane (compound I I);
B, (2S, 3S, 5S)-5-amino-2-(N; The N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane (compound I I), adopt tertbutyloxycarbonyl BOC protect (2S; 3S; 5S)-and 2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound III);
C, (2S, 3S, 5S)-2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane (compound III) is taken off benzyl through catalysis, obtain (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane (compound IV) bullion, through alkali cleaning, sodium-chlor is washed; Use the normal heptane crystallization again, cross and filter wet article, obtain pure article after the oven dry;
D, (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; The pure article of 6-phenylbenzene hexane (compound IV) and 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) are through nucleophilic substitution, and crystallization filters; After the oven dry (2S, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1; 6-phenylbenzene-3-hydroxyl hexane (compound VI)
In the preferred embodiment of the present invention, (2S, the 3S that obtain among the step C; 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane bullion is used the ETHYLE ACETATE stirring and dissolving, successively with 5%～10% sodium carbonate solution and the washing of 8%～10% sodium chloride solution, concentrates again; The normal heptane crystallization is crossed the wet article that filter.Through above-mentioned mode, not only reduced reactions step, also reduce intermediate product and separated the time loss that is brought.
In the preferred embodiment of the present invention, (S, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reductive agent that uses in 4-alkene-3-ketone (compound I) reduction process can be one or more in Peng Qinghuana or the POTASSIUM BOROHYDRIDE 97MIN.
In the preferred embodiment of the present invention; (S; Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reduction of 4-alkene-3-ketone (compound I) carries out under acidic conditions, used acid can be one or more in hydrochloric acid, sulfuric acid, sulfonic acid, acetic acid or the methylsulfonic acid.
In the preferred embodiment of the present invention; (2S; 3S; 5S)-and 2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1, the debenzylation of 6-phenylbenzene hexane (compound III) is realized through one or more the catalyzed reaction in the palladium catalyst charcoal, Palladous chloride, rhodium carbon, platinum oxide.
In the preferred embodiment of the present invention, the temperature of reaction of nucleophilic substitution is 25 ℃～100 ℃ in the steps d, and optimum temps is 60 ℃～80 ℃.
Ritonavir midbody provided by the invention " (2S; 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) is amino-1,6-phenylbenzene-3-hydroxyl hexane (compound VI) " compound method be in-situ synthetic method; It has not only reduced reactions step; Also reduced intermediate product and separated the time loss that is brought, improved yield, and do not influenced degree of purity of production and quality.
Embodiment
Below in conjunction with embodiment the present invention is done further description, but do not constitute any restriction of the present invention.
Embodiment 1
1, (2S, 3S, 5S)-5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane (compound I I) synthetic
In the 1000ml four-hole boiling flask that TM, mechanical stirring and tap funnel are housed, add Peng Qinghuana 3.8g and glycol dimethyl ether 154.7m1, stir and be cooled to-10 ℃.Dropping contains the ethylene glycol dimethyl ether solution (methylsulfonic acid: glycol dimethyl ether=15.5ml:24ml), control interior temperature and be no more than 5 ℃ of methylsulfonic acid.After drip finishing, drip again Virahol (19m1), ethylene glycol bisthioglycolate methyl alcohol 35.7m1 and (S, Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-mixed solution of 4-alkene-3-ketone (compound I) 14.6g, temperature is no more than 0 ℃ in the control.After dripping end, after reacting completely, drip the ethylene glycol dimethyl ether solution (containing trolamine 14.3g) of trolamine again in reaction below 0 ℃ more than 12 hours, temperature is no more than 5 ℃ in the control, stirs 30 minutes.Slowly drip the dimethylacetamide solution (containing Peng Qinghuana 3.1g) of Peng Qinghuana again, slowly be warming up to room temperature, insulated and stirred 2 hours.After reacting completely, in reaction solution, slowly add entry, add MTBE under the room temperature, standing demix.Organic layer is successively with 10% aqueous sodium hydroxide solution 476m1 washing, and aqueous ammonium chloride solution 476m1 washing and sodium chloride solution 593ml wash.With anhydrous magnesium sulfate drying 2 hours, solvent evaporated obtained lurid oily product under 30 ℃ of water-baths with the organic layer that obtains.
2, (2S, 3S, 5S)-2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound III) synthetic
Upwards the step concentrates oily matter adding methyl alcohol 15ml, and stirring and dissolving adds triethylamine 6.47g, water 79ml; Tert-Butyl dicarbonate 7g stirs 2h, after reacting completely; Standing demix, organic layer water 86ml washing, organic layer concentrating under reduced pressure solvent obtains light yellow oil.
3, (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane (compound IV) synthetic
Upwards the step concentrates oily matter and adds ethanol 190ml, and 40 ℃ of stirring and dissolving add ammonium formiate 10.4g, Pd/C 7g, and back flow reaction 4 hours is until the raw material complete reaction.Filter, get the compound IV bullion.The compound IV bullion is with going into ETHYLE ACETATE 170ml dissolving; Slowly add 10% sodium carbonate solution 100ml washing, 10% sodium-chlor 100ml washing, organic layer is evaporated to dried for 50 ℃; Add normal heptane 110ml; Stir, cross the wet article that filter, dry to such an extent that purity is 99.5% pure article of compound IV for 50 ℃.
4, (2S, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) is amino-1,6-phenylbenzene-3-hydroxyl hexane (compound VI) synthetic
1000ml four-hole boiling flask to TM, mechanical stirring and tap funnel are housed add (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane (compound IV) 20g and 5-thiazolyl methyl-4-nitrophenyl carbonate (compound V) 14.5g, ETHYLE ACETATE 300ml, heating in water bath is to refluxing; 60 ℃ of insulation reaction 12～14 hours, be cooled to room temperature, add ammoniacal liquor 3g; Stirred 1 hour, and added 4% sodium hydroxide solution 100ml * 3 again, sodium chloride solution 100ml * 2; It is dried that 50 ℃ of organic layers are evaporated to, golden yellow oily matter, add ETHYLE ACETATE/normal heptane crystallization.
Embodiment 2
What embodiment 2 and embodiment 1 were different is, (2S, 3S, 5S)-2-(N; The N-dibenzyl amino)-and 3-hydroxyl-5-(tert.-butoxy formamido group)-1, the mode below 6-phenylbenzene hexane (compound III) adopts is synthetic: the step that makes progress concentrates oily matter and adds MTBE 40ml, and stirring and dissolving adds salt of wormwood 8.77g; Water 79ml, tert-Butyl dicarbonate 7g stirs 2h, after reacting completely; Standing demix, organic layer water 86ml washing, organic layer concentrating under reduced pressure solvent obtains light yellow oil.
Embodiment 3
What embodiment 3 and embodiment 1 were different is (2S, 3S; 5S)-and 2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1, the mode below 6-phenylbenzene hexane (compound IV) adopts is synthetic: upward the step concentrates and adds methyl alcohol 190ml, 40 ℃ of stirring and dissolving in the oily matter; Add Pd/C 7g; Feed the air in the hydrogen exchange autoclave, hydrogen pressure reaches 0.5Mpa in still, reacts 4 hours until the raw material complete reaction.Filter, concentrate, get the compound IV bullion.Add ETHYLE ACETATE 170ml, stirring and dissolving slowly adds 5% sodium carbonate solution 100ml washing; 8% sodium-chlor 100ml washing, 60 ℃ of organic layers are evaporated to dried, add normal heptane 110ml; Stir, cross the wet article that filter, dry to such an extent that purity is 99.6% pure article of compound IV for 50 ℃.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (7)
1. the compound method of compound shown in the formula VI is characterized in that, comprises the steps:
Shown in a, the formula I (S, Z)-5-amino-2-(dibenzyl amino)-1,6-phenylbenzene hexane-4-alkene-3-ketone through carbonyl reduction, C=C reduce shown in the formula II (2S, 3S, 5S)-5-amino-2-(N, N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane;
Shown in b, the formula II (2S, 3S, 5S)-5-amino-2-(N; The N-dibenzyl amino)-3-hydroxyl-1,6-phenylbenzene hexane, adopt tertbutyloxycarbonyl BOC protect (the 2S shown in the formula III; 3S; 5S)-and 2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1,6-phenylbenzene hexane;
Shown in c, the formula III (2S, 3S, 5S)-2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane is taken off benzyl through catalysis, obtain shown in the formula IV (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane bullion, through alkali cleaning, sodium-chlor is washed; Use the normal heptane crystallization again, cross and filter wet article, obtain pure article after the oven dry;
Shown in d, the formula IV (2S, 3S, 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; Pure article of 6-phenylbenzene hexane and 5-thiazolyl methyl-4-nitrophenyl carbonate is through nucleophilic substitution, and crystallization filters; After the oven dry shown in the formula VI (2S, 3S, 5S)-5-(tert.-butoxy formamido group)-2-(N-5-thiazolyl-methoxycarbonyl) amino-1; 6-phenylbenzene-3-hydroxyl hexane
2. according to the compound method of compound shown in the formula VI described in the claim 1, it is characterized in that: (2S, the 3S shown in the formula IV that obtains among the step c; 5S)-2-amino-3-hydroxyl-5-(tert.-butoxy formamido group)-1; 6-phenylbenzene hexane bullion is used the ETHYLE ACETATE stirring and dissolving, successively with 5%～10% sodium carbonate solution and the washing of 8%～10% sodium chloride solution, concentrates again; The normal heptane crystallization is crossed the wet article that filter.
3. according to the compound method of compound shown in the formula VI described in the claim 1; It is characterized in that: (the S shown in the step a Chinese style I; Z)-5-amino-2-(dibenzyl amino)-1, the 6-phenylbenzene oneself-reductive agent that uses in 4-alkene-3-ketone reduction process is one or more in Peng Qinghuana or the POTASSIUM BOROHYDRIDE 97MIN.
4. according to the compound method of compound shown in the formula VI described in the claim 3; It is characterized in that: (the S shown in the step a Chinese style I; Z)-5-amino-2-(dibenzyl amino)-1; The 6-phenylbenzene oneself-reduction of 4-alkene-3-ketone carries out under acidic conditions, used acid is one or more in hydrochloric acid, sulfuric acid, hydrofluoric acid, sulfonic acid or the acetic acid.
5. according to the compound method of compound shown in the formula VI described in the claim 1; It is characterized in that: (the 2S among the step c shown in the formula III; 3S; 5S)-and 2-(N, N-dibenzyl amino)-3-hydroxyl-5-(tert.-butoxy formamido group)-1, the debenzylation of 6-phenylbenzene hexane is realized through one or more the catalyzed reaction in the palladium catalyst charcoal, Palladous chloride, rhodium carbon, platinum oxide.
6. according to the compound method of compound shown in the formula VI described in the claim 1, it is characterized in that: the temperature of reaction of nucleophilic substitution is 25 ℃～100 ℃ in the steps d.
7. according to the compound method of compound shown in the formula VI described in the claim 5, it is characterized in that: the temperature of reaction of nucleophilic substitution is 60 ℃～80 ℃ in the steps d.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102180812B (en) * | 2011-03-16 | 2013-06-19 | 济南爱思化工有限公司 | New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane |
| CN104093702A (en) * | 2012-02-03 | 2014-10-08 | 吉里德科学公司 | Methods and intermediates for preparing pharmaceutical agents |
| CN102786494B (en) * | 2012-07-26 | 2016-01-06 | 合肥华方医药科技有限公司 | The study on the synthesis of ritonavir isomer impurities and control method |
| CN107602454B (en) * | 2017-09-19 | 2020-12-01 | 佛山科学技术学院 | Sulfonamide compound and preparation method and application thereof |
| CN111454168B (en) * | 2020-04-14 | 2022-04-05 | 南通森萱药业有限公司 | Synthesis method of ritonavir intermediate BDH |
| CN112500367A (en) * | 2020-12-16 | 2021-03-16 | 盐城迪赛诺制药有限公司 | Refining method of ritonavir intermediate |
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| US5508409A (en) * | 1993-10-22 | 1996-04-16 | Abbott Laboratories | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane |
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