CN104387299A - Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide - Google Patents
Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide Download PDFInfo
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Abstract
The invention discloses a method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide. The method comprises the following steps: S1: enabling L-phenylalanine and diazomethane to react to obtain a diazo methyl ketone intermediate product, and enabling the diazo methyl ketone intermediate product and haloid acid to react to obtain a compound A; S2, conducting carbonyl deoxidation on the compound A to obtain a compound B; S3, under the existence of iso-butylamine, conducting cyclization reaction and ring-opening reaction on the compound B in sequence to obtain a compound C; S4, enabling the compound C and nitrobenzenesulfonyl chloride to react to obtain a compound D; S5, conducting nitro reduction on the compound D to obtain the 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide. The method is simple in course, low in cost, mild in condition, and higher in intermediate product stability, and is beneficial for industrial application.
Description
Technical field
The present invention relates to technical field of medicine synthesis, in particular to the preparation method of a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
Background technology
4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide is very important a kind of intermediate in medicine synthesis, and it has following structure:
A series of inverases such as amprenavir (Amprenavir), DRV (Darunavir), Fosamprenavir (Fosamprenavir) all can be obtained by above-mentioned intermediate.Wherein in amprenavir the 5th generation of being developed by Glaxo-Simth company of Britain, degeneration-resistantly turns viral protein inhibitor, in May, 1999 in the U.S. and Japan's listing; DRV is the non-peptides HIV-1 protein inhibitor of one that branch office of Iceland of the Johson & Johnson base of a fruit wins Tyke research and development, goes on the market in June, 2006 in the U.S.; The calcium salt of Fosamprenavir, by the prodrug of a kind of proteinase inhibitor Amprenavir of Britain GSK and Vertex company of U.S. joint development, goes on the market in the U.S. for 2003 first.
At present, the synthesis side of key intermediate 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide has a variety of, has reported that the synthetic route of industrial application value mainly contains several as follows:
Patent (CN101037403A) through N protection, esterification, Claisen condensation, copper catalysis bromo, decarboxylation, carbonyl reduction and epoxidation, is obtained by reacting epoxy intermediate through 7 steps from L-Phe.Above-mentioned key intermediate is synthesized further with epoxy intermediate.This route is tediously long, use CuBr2 excessive greatly and formic acid, low-temp reaction etc. be all amplify suitability for industrialized production and equipment is made troubles, the discharge of increase energy consumption and the three wastes.
Document (Angew.Chem.Int.Ed.1999; 38; 1931-1934) report that chiral quaternary ammonium salt asymmetry catalysis Henry reacts highly-solid selectively and builds amino alcohol intermediate 18; after further nitroreduction; through reduction amination; sulfonylation, hydrogenation debenzylation protecting group obtains key intermediate, and synthetic route is as follows:
In above operational path, complex synthetic route, cost are high, are unfavorable for industrial mass production.Therefore; for solving the difficult problem existed in prior art; capture the technology barriers of external drugmaker; suddenly wait to find a technique simple, with low cost; be applicable to the synthetic route of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide of large-scale production.
Summary of the invention
The present invention aims to provide a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl] preparation method of-N-isobutyl-benzene sulphonamide, the problem that 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide route is complicated, cost is high is prepared to solve in prior art.
To achieve these goals, according to an aspect of the present invention, provide a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl] preparation method of-N-isobutyl-benzene sulphonamide, comprise the following steps: S1, L-Phe and diazomethane are carried out being obtained by reacting dizaomethyl ketone intermediate product, dizaomethyl ketone intermediate product and haloid acid is reacted, obtains compd A; S2, reduces to the carbonyl in compd A, obtains compd B; S3, under the existence of isobutylamine, makes compd B carry out cyclisation, ring-opening reaction successively, obtains Compound C; S4, makes Compound C and 4-Nitrobenzenesulfonyl chloride react, obtains Compound D; And S5, the nitro in Compound D is reduced, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
Further, above-mentioned steps S1 comprises: S11, under the existence of the first alkali, L-Phe and carbonochloridic acid ester is reacted, and generates activated intermediate; S12, reacts activated intermediate and diazomethane, generates dizaomethyl ketone intermediate product; And S13, dizaomethyl ketone intermediate product and haloid acid are reacted, obtains compd A.
Further, above-mentioned first alkali be selected from N-methylmorpholine, triethylamine, diisopropyl ethyl amine and tri-n-butylamine one or more, be preferably triethylamine; Carbonochloridic acid ester be selected from methyl chlorocarbonate, chloro ethyl formate, carbonochloridic acid propyl ester, isopropyl chloroformate, carbonochloridic acid butyl ester and carbonochloridic acid isobutyl ester one or more, be preferably chloro ethyl formate; Haloid acid is selected from hydrogen bromide or hydrogenchloride.
Further, the mol ratio of above-mentioned first alkali and L-Phe is 1 ~ 1.5:1; The mol ratio of carbonochloridic acid ester and L-Phe is 1 ~ 1.5:1; The mol ratio of haloid acid and L-Phe is 1 ~ 2:1.
Further, above-mentioned steps S2 comprises: S21, is mixed by compd A with reductive agent, alcohol and the first organic solvent, obtains the first question response system; S22, makes the first question response system reaction, obtains the first product system; And S23, the first product system of purifying, obtains compd B.
Further, above-mentioned reductive agent be selected from isobutanol aluminum, aluminum isopropylate, trimethyl carbinol aluminium and three tertiary butyoxy aluminium lithiums one or more, be preferably isobutanol aluminum; Alcohol be selected from Virahol, ethanol, isopropylcarbinol, hexalin and cyclopentanol one or more, be preferably Virahol; First organic solvent is selected from toluene, dimethylbenzene, chlorobenzene, benzene, tetrahydrofuran (THF) or dioxane, is preferably toluene.
Further, the mol ratio of above-mentioned reductive agent and compd A is 0.5 ~ 1.5:1; The mol ratio of alcohol and compd A is 4 ~ 15:1; The weight ratio of the first organic solvent and compd A is 2.5 ~ 10:1.
Further, the step of the first product system of purifying in above-mentioned steps S23 comprises: cancellation first product system, obtains quencher; In quencher, add the first crystallization agent, separated out by the compd B in quencher, solid-liquid separation obtains compd B.
Further, above-mentioned steps S3 comprises: S31, is mixed by compd B with isobutylamine, the second alkali and the second organic solvent, obtains the second question response system; S32, makes the second question response system reaction, forms the second product system; And S33, remove the solvent of the second product system, obtain Compound C.
Further, above-mentioned second alkali be selected from KOH, NaOH, NaH, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide and two (trimethyl silicon based) Lithamide one or more, be preferably KOH; Second organic solvent is selected from ethanol, methyl alcohol, propyl alcohol, Virahol or propyl carbinol, is preferably ethanol.
Further, the mol ratio of above-mentioned isobutylamine and compd B is 5.0 ~ 20:1; The mol ratio of the second alkali and compd B is 1 ~ 2:1; The weight ratio of the second organic solvent and compd B is 3 ~ 15:1.
Further, above-mentioned steps S4 comprises: S41, Compound C is mixed with 4-Nitrobenzenesulfonyl chloride, the 3rd alkali and the 3rd organic solvent, obtains the 3rd question response system; S42, makes the 3rd question response system reaction, forms third product system; And S43, purification third product system, obtains Compound D.
Further, above-mentioned 3rd alkali is selected from triethylamine, diisopropyl ethyl amine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, pyridine, DMAP, 2, one or more in 6-lutidine and 2,6-dichloride base pyridine, are preferably triethylamine; 3rd organic solvent is selected from Virahol, methylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether, ethanol, methyl alcohol, propyl alcohol, butanols or toluene, is preferably Virahol.
Further, the mol ratio of above-mentioned 4-Nitrobenzenesulfonyl chloride and Compound C is 1.1 ~ 1.5:1; The mol ratio of the 3rd alkali and Compound C is 1.1 ~ 1.5:1; The weight ratio of the 3rd organic solvent and Compound C is 2 ~ 10:1.
Further, the step of third product system of purifying in above-mentioned steps S43 comprises:
In third product system, add the second crystallization agent, carry out solid-liquid separation after crystallization, obtain solids;
Solids is carried out recrystallization, obtains Compound D.
Further, above-mentioned steps S5 comprises: S51, Compound D is mixed with catalyzer, hydrogen source, organic acid and the 4th organic solvent, obtains the 4th question response system; S52, makes formation the 4th question response system react, obtains the 4th product system; And S53, the 4th product system of purifying, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide; Wherein, in step S51, hydrogen source is ammonium formiate or formic acid.
Further, above-mentioned catalyzer is selected from Pd/C or Pd (OH) 2; Organic acid is selected from acetic acid, formic acid, propionic acid or trimethylacetic acid; 4th organic solvent be selected from tetrahydrofuran (THF), methyl alcohol, ethanol, ethyl acetate and isopropyl acetate one or more; Be preferably tetrahydrofuran (THF).
Further, the mass ratio of above-mentioned catalyzer and Compound D is 0.05 ~ 0.3:1; The mol ratio of ammonium formiate and Compound D is 4.0 ~ 10.0:1; The mol ratio of organic acid and Compound D is 2 ~ 10:1; The weight ratio of the 4th organic solvent and Compound D is 3 ~ 10:1.
Further, above-mentionedly to it is characterized in that, the step of the 4th product system of purifying in step S53 comprises: the 4th product system is carried out solid-liquid separation, obtains filtrate; Carry out crystallization to filtrate, solid-liquid separation obtains crude product; And recrystallization is carried out to crude product, obtain 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
Further, in the step of above-mentioned recrystallization, the recrystallization solvent of employing is selected from Virahol, ethanol, methyl alcohol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether.。
The preparation method of 4-amino-N-of the present invention [(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, synthetic route is comparatively simple, and raw materials cost is lower.In addition, the processing condition of each step are comparatively gentle, and the stability of each intermediate product is higher, and comparatively easy for the separation of each intermediate.The factor of each side is all conducive to industrialization large-scale application.
Accompanying drawing explanation
The Figure of description forming a application's part is used to provide a further understanding of the present invention, and schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 shows the compd B of preparation in the embodiment of the present invention 1
1hNMR spectrogram;
Fig. 2 shows the Compound C of preparation in the embodiment of the present invention 1
1hNMR spectrogram;
Fig. 3 shows the Compound D of preparation in the embodiment of the present invention 1
1hNMR spectrogram; And
Fig. 4 shows 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide of preparation in the embodiment of the present invention 1
1hNMR spectrogram.
Embodiment
It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.Below with reference to the accompanying drawings and describe the present invention in detail in conjunction with the embodiments.
Introduce as background technology part, when preparing 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide in prior art, there is route complexity, problem that cost is high.In order to address this problem, inventor provides a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl] preparation method of-N-isobutyl-benzene sulphonamide, it comprises the following steps: S1, L-Phe and diazomethane are carried out the dizaomethyl ketone intermediate product be obtained by reacting, dizaomethyl ketone intermediate product and haloid acid are reacted, obtains compd A; S2, reduces to the carbonyl in compd A, obtains compd B; S3, under the existence of isobutylamine, makes compd B carry out cyclisation, ring-opening reaction successively, obtains Compound C; S4, makes Compound C and 4-Nitrobenzenesulfonyl chloride react, obtains Compound D; And S5, the nitro in Compound D is reduced, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
In above-mentioned preparation method provided by the present invention, L-Phe and diazomethane are reacted, the hydroxyl in L-Phe on carboxyl can be replaced by dizaomethyl, forms dizaomethyl ketone intermediate product.When dizaomethyl ketone intermediate product and haloid acid react, halogen atom replaces dizaomethyl and forms compd A.After reducing to the carbonyl in compd A, carbonyl changes hydroxyl into and forms corresponding compd B.Under the existence of isobutylamine, can there is cyclization and ring-opening reaction in compd B, obtain Compound C successively.After Compound C and 4-Nitrobenzenesulfonyl chloride being reacted, then carry out nitroreduction, just can obtain target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
Preparation method provided by the present invention, synthetic route is comparatively simple, and raw materials cost is lower.In addition, the processing condition of each step are comparatively gentle, and the stability of each intermediate product is higher, and comparatively easy for the separation of each intermediate.The factor of each side is all conducive to industrialization large-scale application.
In actual mechanical process, after preferably the amino in raw material L-Phe being carried out Boc protection, the L-Phe (shown in formula G) protected by Boc drops into next step reaction.
Be below the concrete synthetic route of the above-mentioned preparation method of the present invention:
Wherein X is corresponding halogen atom in haloid acid.
In a preferred embodiment, above-mentioned steps S1 comprises: S11, under the existence of the first alkali, L-Phe and carbonochloridic acid ester is reacted, and generates activated intermediate; S12, reacts activated intermediate and diazomethane, generates dizaomethyl ketone intermediate product; And S13, dizaomethyl ketone intermediate product and haloid acid are reacted, obtains compd A.
In the basic conditions, carbonochloridic acid ester can activate the carboxyl in L-Phe, and the hydrogen atom that formic acid ester group is replaced in carboxyl forms activated intermediate.This is conducive to impelling the double bond oxygen in dizaomethyl attack L-Phe, and then generates dizaomethyl ketone intermediate product.Again dizaomethyl ketone intermediate product and haloid acid are reacted, just can obtain compd A.The compd A prepared according to the method has higher productive rate.
The present invention is above-mentioned to be prepared in the step of compd A, preferably adopts the mode of continuity moving phase reaction to be prepared.This is conducive to the stability improving reaction, makes it to be more suitable for industrial application.
The raw materials such as the first alkali adopted in above-mentioned steps S1, carbonochloridic acid ester can be all the conventional raw materials in pharmaceutical synthesis field.In a preferred embodiment, above-mentioned first alkali include but not limited in N-methylmorpholine, triethylamine, diisopropyl ethyl amine and tri-n-butylamine one or more, be preferably triethylamine; Carbonochloridic acid ester include but not limited in methyl chlorocarbonate, chloro ethyl formate, carbonochloridic acid propyl ester, isopropyl chloroformate, carbonochloridic acid butyl ester and carbonochloridic acid isobutyl ester one or more, be preferably chloro ethyl formate; Haloid acid is selected from hydrogen bromide or hydrogenchloride.Mentioned reagent is comparatively easy to get, and cost is lower.As the raw material of preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, production cost can be reduced further, make it be more suitable for industrial application.In the operating process of reality, directly add hydrogen bromide or hydrogenchloride just can react.In addition, also the solution containing haloid acid can be added, the THF solution of the methanol solution of the methanol solution of such as hydrogenchloride, the ethanolic soln of hydrogenchloride, hydrogen bromide, the ethanolic soln of hydrogen bromide, hydrogenchloride, the THF solution of hydrogen bromide, the acetic acid solution of hydrogen bromide, the acetic acid solution etc. of hydrogenchloride.Preferred above-mentioned haloid acid adds with the form of the THF solution of hydrogenchloride.
Above-mentioned preparation method provided by the present invention, when carrying out the preparation of compd A, those skilled in the art can select specifically between each raw material to use magnitude relation.In a preferred embodiment, the mol ratio of the first alkali and L-Phe is 1 ~ 1.5:1; The mol ratio of carbonochloridic acid ester and L-Phe is 1 ~ 1.5:1; The mol ratio of haloid acid and L-Phe is 1 ~ 2:1.The consumption of each raw material is controlled in above-mentioned scope, on the basis of reducing production cost, the productive rate that compd A keeps higher can be made.
The carbonyl reduction method that carbonyl in above-mentioned steps S2 in reducing compound A adopts this area conventional with the method preparing compd B.In a preferred embodiment, above-mentioned steps S2 comprises: S21, is mixed by compd A with reductive agent, alcohol and the first organic solvent, obtains the first question response system; S22, makes the first question response system reaction, obtains the first product system; And S23, the first product system of purifying, obtains compd B.After by reduction under the effect of compd A at reductive agent, the product obtained is purified, obtains comparatively pure compd B.This is conducive to preventing impurity from impacting subsequent reactions, ensures productive rate and the purity of target product.
The above-mentioned reductive agent, solvent etc. adopted when preparing compd B can be the reagent that those skilled in the art commonly use.In a preferred embodiment, above-mentioned reductive agent includes but not limited to one or more in isobutanol aluminum, aluminum isopropylate, trimethyl carbinol aluminium and three tertiary butyoxy aluminium lithiums; Alcohol be selected from Virahol, ethanol, isopropylcarbinol, hexalin and cyclopentanol one or more; First organic solvent is selected from toluene, dimethylbenzene, chlorobenzene, benzene, tetrahydrofuran (THF) or dioxane.When adopting above-mentioned several reductive agent and alcohol to reduce to the carbonyl in compd A, there is higher reduction selectivity.And these reagent are comparatively cheap, production cost can be reduced further.Preferably, above-mentioned reductive agent is isobutanol aluminum, and alcohol is Virahol, and the first organic solvent is toluene.Isobutanol aluminum has higher selectivity when reducing carbonyl becomes hydroxyl, by itself and Virahol with the use of, the productive rate of compd B can be improved further.
Those skilled in the art can make the usage ratio of each raw material of employing adjust to preparing compd B.In a preferred embodiment, the mol ratio of above-mentioned reductive agent and compd A is 0.5 ~ 1.5:1; The mol ratio of alcohol and compd A is 4 ~ 15:1; The weight ratio of the first organic solvent and compd A is 2.5 ~ 10:1.The amount ratio of each raw material is controlled in above-mentioned scope, can, in minimizing significant loss, while reducing production cost, make reaction have higher transformation efficiency.In addition, preferably, the temperature of reaction in above-mentioned steps S22 is room temperature.
The purifying technique that the step of above-mentioned purification first product system can adopt those skilled in the art to commonly use.In a preferred embodiment, the step of the first product system of purifying in above-mentioned steps S23 comprises: cancellation first product system, obtains quencher; In quencher, add the first crystallization agent, separated out by the compd B in quencher, solid-liquid separation obtains compd B.Cancellation first product system, can prevent system from the reaction of further impurity occurring, to improve product purity.The quencher that cancellation process adopts can be hydrochloric acid, and its concentration can be any concentration, is preferably the hydrochloric acid of 1mol/L.Further, crystallization is carried out to the target product compd B in quencher, be separated the compd B obtained and there is higher purity.The the first crystallization agent adopted in Crystallization Process can be the crystallization agent that those skilled in the art commonly use, and preferably, this first crystallization agent is normal heptane or normal hexane.
In above-mentioned preparation method provided by the present invention, be that the step that Compound C prepared by raw material can adopt those skilled in the art to carry out processing step conventional when cyclization closes ring-opening reaction with compd B in step S3.In a preferred embodiment, above-mentioned steps S3 comprises: S31, is mixed by compd B with isobutylamine, the second alkali and the second organic solvent, obtains the second question response system; S32, makes the second question response system reaction, forms the second product system; And S33, remove the solvent of the second product system, obtain Compound C.
Compd B and the mixing of isobutylamine, the second alkali and the second organic solvent are carried out cyclisation, open loop " one kettle way " reaction.Reaction process is as follows:
This " one kettle way " reaction can reduce the remaining time of the unstable epoxy intermediate because of cyclization formation.Make unstable epoxy intermediate in time ring-opening reaction occur under the effect of isobutylamine, form stable Compound C.In addition, " one kettle way " reaction can also Simplified flowsheet, avoids being separated the epoxy intermediate of instability.
In the step of above-mentioned preparation Compound C, second alkali, the second organic solvent etc. of employing can be the usual reagent in this area.In a preferred embodiment, above-mentioned second alkali include but not limited in KOH, NaOH, NaH, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide and two (trimethyl silicon based) Lithamide one or more, be preferably KOH; Second organic solvent includes but not limited to ethanol, methyl alcohol, propyl alcohol, Virahol or propyl carbinol, is preferably ethanol.These reagent are comparatively cheap, while can improving reaction stability, also help reduction production cost.
In above-mentioned steps S3, each raw material be that those skilled in the art can adjust with magnitude relation.In a preferred embodiment, the mol ratio of above-mentioned isobutylamine and compd B is 5.0 ~ 20:1; The mol ratio of the second alkali and compd B is 1 ~ 2:1; The weight ratio of the second organic solvent and compd B is 3 ~ 15:1.Raw material controlled in above-mentioned scope with magnitude relation, reaction stability can be improved, increase the productive rate of Compound C.Meanwhile, also help reduction production cost, make it be more suitable for industrial applications.
The method that the method removing the solvent of the second product system in above-mentioned steps S33 adopts those skilled in the art to commonly use.Preferably, the mode of concentrating under reduced pressure is adopted to remove solvent.
In above-mentioned preparation method, be the method that the method that Compound D prepared by raw material can adopt this area conventional with Compound C in step S4.In a preferred embodiment, above-mentioned steps S4 comprises: S41, Compound C is mixed with 4-Nitrobenzenesulfonyl chloride, the 3rd alkali and the 3rd organic solvent, obtains the 3rd question response system; S42, makes the 3rd question response system reaction, forms third product system; And S43, purification third product system, obtains Compound D.Compound C and 4-Nitrobenzenesulfonyl chloride are reacted in the basic conditions, the productive rate of target product Compound D can be improved.The reaction of preferred preparation Compound D is at room temperature carried out.
The 3rd alkali adopted in the step of above-mentioned preparation Compound D, the 3rd organic solvent etc. can be the conventional reagent of this area.In a preferred embodiment, above-mentioned 3rd alkali includes but not limited to triethylamine, diisopropyl ethyl amine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, pyridine, DMAP, 2,6-lutidine and 2, one or more in 6-dichloride base pyridine, are preferably triethylamine; 3rd organic solvent includes but not limited to Virahol, methylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether, ethanol, methyl alcohol, propyl alcohol, butanols or toluene, is preferably Virahol.Using above-mentioned alkaline reagents as the 3rd alkali, the productive rate of Compound D can be improved further.In addition, above-mentioned alkaline reagents and organic solvent are comparatively cheap, are more suitable for large-scale application.
Usage ratio between each raw material used in above-mentioned steps S4 can adjust.In a preferred embodiment, the mol ratio of above-mentioned 4-Nitrobenzenesulfonyl chloride and Compound C is 1.1 ~ 1.5:1; The mol ratio of the 3rd alkali and Compound C is 1.1 ~ 1.5:1; The weight ratio of the 3rd organic solvent and Compound C is 2 ~ 10:1.Each raw material of preparation Compound D controlled in above-mentioned scope with magnitude relation, is conducive to improving reaction stability and transformation efficiency.Meanwhile, be conducive to reducing the wasting of resources, reduce production cost.
In above-mentioned steps S4, to the purifying technique that the purification process of third product system can adopt this area conventional.In a preferred embodiment, the step of third product system of purifying in above-mentioned steps S43 comprises: in third product system, add the second crystallization agent, carry out solid-liquid separation, obtain solids after crystallization; Solids is carried out recrystallization, obtains Compound D.The the second crystallization agent adopted in this process is preferably water.After crystallization, the solids obtained is carried out recrystallization, can remove chiral isomer a small amount of in product, the recrystallization solvent this time adopted in recrystallization process includes but not limited to Virahol, ethanol, methyl alcohol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether.Preferably, recrystallization solvent is ethanol.More preferably, the mass ratio of recrystallization solvent and Compound C is 1 ~ 5:1.
In above-mentioned preparation method, when preparing 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide of target product in step S5, as long as can be amino by nitroreduction.In a preferred embodiment, above-mentioned steps S5 comprises: S5a, Compound D is mixed with catalyzer, ammonium formiate, organic acid and the 4th organic solvent, obtains the 4th question response system; S5b, makes formation the 4th question response system react, obtains the 4th product system; And S5c, the 4th product system of purifying, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
Above-mentioned is that target product 4-amino-N-[(2R prepared by raw material with Compound D, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide process in, have employed ammonium formiate as hydrogen source, the nitro in the mode reducing compound D shifted by ortho-hydrogens.This can improve the productive rate of target product, can reduce the consumption of catalyzer simultaneously, make it be more suitable for industrial applications.
The reagent that the reagent such as the catalyzer adopted in above-mentioned steps and organic acid are conventional when can be this area reduction nitro.In a preferred embodiment, above-mentioned catalyzer includes but not limited to Pd/C or Pd (OH) 2; Organic acid includes but not limited to acetic acid, formic acid, propionic acid or trimethylacetic acid; 4th solvent include but not limited in tetrahydrofuran (THF), methyl alcohol, ethanol, ethyl acetate and isopropyl acetate one or more; Be preferably tetrahydrofuran (THF).
In above-mentioned steps S5, each raw material can adjust with magnitude relation.In a preferred embodiment, the mass ratio of above-mentioned catalyzer and Compound D is 0.05 ~ 0.3:1; The mol ratio of ammonium formiate and Compound D is 4.0 ~ 10.0:1; The mol ratio of organic acid and Compound D is 2 ~ 10:1; The weight ratio of the 4th organic solvent and Compound D is 3 ~ 10:1.The consumption of each raw material is controlled in above-mentioned scope, be conducive to the stability and the transformation efficiency that improve reaction.In a preferred embodiment, the mass ratio of above-mentioned catalyzer and Compound D is 0.1:1.Have employed ammonium formiate as hydrogen source in process just because of the above-mentioned reduction nitro of the present invention, the reduction ratio of nitro can be improved, the consumption of above-mentioned noble metal catalyst can be reduced, reduce reaction cost further.
The method of purification that the method for reducing to the 4th product system in above-mentioned steps S5c adopts this area conventional.In a preferred embodiment, in above-mentioned steps S5c, the step of purification the 4th product system comprises: the 4th product system is carried out solid-liquid separation, obtains filtrate; Carry out crystallization to filtrate, solid-liquid separation obtains crude product; Recrystallization is carried out to crude product, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
Solid-liquid separation is carried out to the 4th product system, the catalyzer in the 4th product system can be removed.Crystallization is carried out to filtrate, the target product be dissolved in system can be divided and isolate.Recrystallization is carried out, target product of can purifying further to the crude product of separating out.
Preferably, above-mentioned Devitrification step comprises: in filtrate, add hydrochloric acid, after being heated to 35 ~ 45 DEG C of stirring 3 ~ 5h, obtains pretreatment filtrates after being cooled to 15 ~ 25 DEG C; After removing the solvent in pretreatment filtrates, add water, and after regulating pH>14, at frozen water for lower crystallization, obtain crude product.In filtrate, add hydrochloric acid can Boc blocking group on deaminize.
Preferably, above-mentionedly carry out in the step of recrystallization to crude product, the recrystallization solvent of employing is selected from Virahol, ethanol, methyl alcohol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether.Preferred recrystallization solvent is Virahol.
Be described in further detail the present invention below in conjunction with specific embodiment, these embodiments can not be interpreted as restriction the present invention scope required for protection.
Embodiment 1
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, concrete preparation process is as follows:
Step S1, prepares compd A
Methyl alcohol/the H of KOH (33.6g, 0.6mol) is housed in container A
2o (1:1 volume ratio) solution, altogether 0.5L; Container B is equipped with the methanol solution of diazonium raw material 1-methyl isophthalic acid-nitrosourea (3.30g, 32mmol), 54mL; The L-Phe (6.4mmol) of Boc protection and the THF solution 20mL altogether of triethylamine (6.72mmol) are housed in container C; The THF solution of chloro ethyl formate (6.4mmol) is housed, altogether 20mL in container D.Material in reaction vessel C and reaction vessel D is pumped in reactive center II by tetrafluoro pipeline; Solution in reaction vessel A and reaction vessel B is pumped into (wherein KOH and diazonium material molar ratio are 2:1) in reactive center I by tetrafluoro pipeline, the diazomethane that heart I produces in the reaction enters reactive center III by the spillway of reactive center, reactive center II produce activated intermediate be pumped in reactive center III with diazomethane reaction, its reaction product is pumped in reactive center IV; Pump into the HCl/THF solution 40mL of 2M simultaneously to reactive center IV, pump into aftertreatment center after 0 DEG C of stirring 10min, obtain the compd A of 1.8g.Yield 95%, purity HPLC>98%.
Step S2, prepares compd B
Toluene 3.41Kg is added successively in 20L four-hole bottle, compd A (1Kg, stir 3.36mol), isobutanol aluminum (0.413kg will be dissolved with, 1.68mol, after Virahol (1.2Kg) solution 0.50equiv.) joins reaction system, stir 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Drip hydrochloric acid (5.4Kg) the cancellation system of 1M after completion of the reaction in system after, the normal heptane adding 12L stirs, cooling crystallization, after a large amount of white solid is separated out, filter, after the water washing final vacuum drying of filter cake 1L × 6, obtain 0.95Kg compd B (compd B
1as shown in Figure 1, add equal trimethoxy-benzene in measuring process is interior mark to HNMR spectrogram, and test condition is: 400MHz, DMSO).Yield 92%, HPLC purity 92%.
Step S3, preparation Compound C
Ethanol 6.5Kg is added successively in 20L four-hole bottle, water 1Kg and compd B (1Kg, 3.36mol), in system, isobutylamine (2.46Kg is dripped under stirring, 33.6mol, 10equiv.), then slowly drip containing KOH (0.207Kg in system, 2.69mol, 1equiv) water (1Kg) solution.Stir 15 ~ 20 hours at 15 ~ 20 DEG C of temperature after dropwising.Then, after underpressure distillation goes out ethanol, in system, add the water of 4Kg, and in ice-water bath crystallization.Filter, filter cake use water 1L × 3 washing after, after filter cake vacuum-drying, obtain 1.1Kg Compound C (Compound C
1as shown in Figure 2, add equal trimethoxy-benzene in measuring process is interior mark to HNMR spectrogram, and test condition is: Compound C 50.8mg, all trimethoxy-benzene 28.9 × 97%mg, 400MHz, trichloromethane).Yield 97.3%, HPLC purity 96%.
Step S4, preparation Compound D
Virahol 9.4Kg, triethylamine (0.18Kg is added successively in 20L four-hole bottle, 1.78mol, 1.20equiv) and Compound C (0.512Kg, 1.52mol, 1equiv.) stir, at being heated to 40 ~ 60 DEG C, add 4-Nitrobenzenesulfonyl chloride (0.388Kg in batches, 1.75mol, 1.15equiv.).After reinforced, stir 2 ~ 3 hours at such a temperature, add water 1Kg, dropwise to system, stir 0.5 hour, cool to room temperature, a large amount of solid is separated out.Suction filtration, filter cake uses water 1.5L × 3 to wash successively, 3.6L water/Virahol (1/1 volume ratio) wash, after 1L washed with isopropyl alcohol, after Vacuum dry filter cake, the filter cake ethyl alcohol recrystallization of 6 volumes, obtain 730g Compound D (Compound D
1as shown in Figure 3, add equal trimethoxy-benzene in measuring process is interior mark to HNMR spectrogram, and test condition is: 500MHz, the trichloromethane containing ethanol).Yield 92%, HPLC purity >=99.4%, content of isomer <0.1% (direct liquid phase figure ratio, molar fraction).
Step S5, prepares target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide
THF 6.35Kg, Compound D (1.44Kg is added successively in 20L four-hole bottle, 2.77mol), relative to Pd/C (0.144Kg) and the acetic acid (0.66Kg of Compound D quality 10%, 11.08mol, 4equiv.), add ammonium formiate (0.69Kg under stirring in batches, 11.08mol, 4equiv.).After reinforced, the system heat release for the treatment of is gentle gradually, stirs 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Then system is filtered after removing Pd/C, at temperature control 15 ~ 25 DEG C, in filtrate, add concentrated hydrochloric acid (mass concentration is 36%) 2.6Kg.Then be heated to 35 ~ 45 DEG C to stir 3 ~ 5 hours, after system cools to 15 ~ 25 DEG C, after concentrated removal THF, in system, add 10Kg water, cool to 15 ~ 25 DEG C, after regulating PH>14 with NaOH, crystallization under ice-water bath.Filter after crystallization, after filter cake washes with water, after vacuum-drying with recrystallisation from isopropanol obtain 1Kg 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide (target product
1as shown in Figure 4, test condition is HNMR spectrogram: 400MHz, DMSO).Yield 93%, HPLC purity >=99.4%, single assorted <0.1%.
Embodiment 2
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, concrete preparation process is as follows:
Step S1, prepares compd A
Methyl alcohol/the H of NaOH (112g, 2.8mol) is housed in container A
2o (1:1 volume ratio) solution, altogether 3L; Container B is equipped with the methanol solution of diazonium raw material 1-methyl isophthalic acid-nitrosourea (131.9g, 1.28mol), 0.54L; The L-Phe (640mmol) of Boc protection and the 1L THF of tri-n-butylamine (672mmol) are housed in container C; The THF solution of chloro ethyl formate (640mmol) is housed, altogether 0.5L in container D.Material in reaction vessel C and reaction vessel D is pumped in reactive center II by tetrafluoro pipeline; Solution in reaction vessel A and reaction vessel B is pumped in reactive center I by tetrafluoro pipeline, 0 DEG C of reaction (wherein KOH and diazonium material molar ratio are 2:1), the diazomethane that heart I produces in the reaction enters reactive center III by the spillway of reactive center, reactive center II produce activated intermediate be pumped in reactive center III with diazomethane reaction, its reaction product is pumped in reactive center IV, pump into the HCl/THF solution 1.6L of 2M to reactive center IV simultaneously, pump into aftertreatment center after 0 DEG C of stirring 10min, obtain 178g compd A.Yield 94%, purity HPLC>98%.
Step S2, prepares compd B
Toluene 1.7Kg is added successively in 10L four-hole bottle, compd A (0.5Kg, stir 1.68mol), isobutanol aluminum (0.246kg will be dissolved with, 1.0mol, after Virahol (0.6Kg) solution 0.6equiv.) joins reaction system, stir 15 ~ 20 hours under stirring at 15 ~ 20 DEG C.Drip hydrochloric acid (1.3Kg) the cancellation system of 2M after completion of the reaction in system after, the normal hexane adding 5L stirs, cooling crystallization, after a large amount of white solid is separated out, filter, after the water washing final vacuum drying of filter cake 0.5L × 6, obtain 0.46Kg compd B.Yield 95%, HPLC purity 95%.
Step S3, preparation Compound C
Ethanol 3Kg is added successively in 10L four-hole bottle, water 0.5Kg and compd B (0.5Kg, 1.68mol), in system, isobutylamine (1.23Kg is dripped under stirring, 16.8mol, 10equiv.), then slowly drip containing NaOH (0.207Kg in system, 2.69mol, 1equiv) water (0.5Kg) solution.Stir 15 ~ 20 hours at 15 ~ 20 DEG C after dropwising.Then reduce pressure after distilling out ethanol completely, in system, add the water of 2Kg, and in ice-water bath crystallization.Filter, after the washing of filter cake use water 0.5L × 3, after filter cake vacuum-drying, obtain 0.5Kg Compound C.Yield 95%, HPLC purity 95%.
Step S4, preparation Compound D
Virahol 9.4Kg, diisopropyl ethyl amine (0.23Kg is added successively in 20L four-hole bottle, 1.78mol, 1.20equiv.) and Compound C (0.512Kg, 1.52mol, 1equiv.) stir, at being heated to 40 ~ 50 DEG C, add 4-Nitrobenzenesulfonyl chloride (0.388Kg, 1.75mol in batches, 1.15equiv.), after reinforced, stir 2 ~ 3 hours at such a temperature, add water 1Kg to system, dropwise, stir 0.5 hour, cool to 10 ~ 15 DEG C, a large amount of solid is separated out.Suction filtration, filter cake uses water 1.5L × 3 to wash successively, and 3.6L water/Virahol (1/1 volume ratio) washs, and after 1L washed with isopropyl alcohol, after Vacuum dry filter cake, the filter cake ethyl alcohol recrystallization of 6 volumes, obtains 700g Compound D.Yield 88.2%, HPLC purity >=99.4%, content of isomer <0.1%.
Step S5, prepares target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide
THF 6.35Kg, Compound D (1.44Kg is added successively in 20L four-hole bottle, 2.77mol), relative to Pd/C (0.144Kg) and the acetic acid (0.66Kg of Compound D quality 10%, 11.08mol, 4equiv.), add ammonium formiate (0.69Kg under stirring in batches, 11.08mol, 4equiv.).After reinforced, the system heat release for the treatment of is gentle gradually, stirs 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Then system is filtered after removing Pd/C, at temperature control 15 ~ 25 DEG C, in filtrate, add concentrated hydrochloric acid (mass concentration is 36%) 2.6Kg.Then be heated to 35 ~ 45 DEG C to stir 3 ~ 5 hours, after system cools to 15 ~ 25 DEG C, after concentrated removal THF, in system, add 10Kg water, cool to 15 ~ 25 DEG C, after regulating PH>14 with NaOH, crystallization under ice-water bath.Filter after crystallization, after filter cake washes with water, after vacuum-drying, obtain 1Kg 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide with recrystallisation from isopropanol.Yield 93%, HPLC purity >=99.4%, single assorted <0.1%.
Embodiment 3
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, concrete preparation process is as follows:
Step S1, prepares compd A
Methyl alcohol/the H of KOH (33.6g, 0.6mol) is housed in container A
2o (1:1 volume ratio) solution, altogether 0.5L; Container B is equipped with the methanol solution of diazonium raw material N-methyl-N-nitro-p-toluenesulfonamide (6.86g, 32mmol), 54mL; The L-Phe (6.4mmol) of Boc protection and the THF solution 20mL altogether of N-methylmorpholine (6.4mmol) are housed in container C; The THF solution of carbonochloridic acid propyl ester (9.6mmol) is housed, altogether 20mL in container D.Material in reaction vessel C and reaction vessel D is pumped in reactive center II by tetrafluoro pipeline; Solution in reaction vessel A and reaction vessel B is pumped into (wherein KOH and diazonium material molar ratio are 2:1) in reactive center I by tetrafluoro pipeline, the diazomethane that heart I produces in the reaction enters reactive center III by the spillway of reactive center, reactive center II produce activated intermediate be pumped in reactive center III with diazomethane reaction, its reaction product is pumped in reactive center IV; Pump into the HCl/ ethanolic soln 30ml of 2M simultaneously to reactive center IV, pump into aftertreatment center after 0 DEG C of stirring 10min, obtain the compd A of 1.5g.Yield 79%, purity HPLC>97%.
Step S2, prepares compd B
Tetrahydrofuran (THF) 3.41Kg is added successively in 20L four-hole bottle, compd A (1Kg, stir 3.36mol), after hexalin (1.2Kg) solution being dissolved with trimethyl carbinol aluminium (5.04mol) is joined reaction system, stir 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Drip hydrochloric acid (5.4Kg) the cancellation system of 1M after completion of the reaction in system after, the normal heptane adding 12L stirs, cooling crystallization, after a large amount of white solid is separated out, filter, after the water washing final vacuum drying of filter cake 1L × 6, obtain the compd B of 0.91Kg.Yield 88%, HPLC purity 95%.
Step S3, preparation Compound C
Propyl alcohol 3Kg is added successively in 20L four-hole bottle, water 1Kg and compd B (1Kg, 3.36mol), in system, drip isobutylamine (67.2mol) under stirring, in system, then slowly drip water (1Kg) solution containing two (trimethyl silicon based) sodium amide (3.36mol).Stir 15 ~ 20 hours at 15 ~ 20 DEG C of temperature after dropwising.Then, after underpressure distillation goes out ethanol, in system, add the water of 4Kg, and in ice-water bath crystallization.Filter, after the washing of filter cake use water 1L × 3, after filter cake vacuum-drying, obtain 473Kg Compound C.Yield 90%, HPLC purity 94%.
Step S4, preparation Compound D
Ethanol 9.4Kg, sodium carbonate (1.672mol) and Compound C (0.512Kg is added successively in 20L four-hole bottle, 1.52mol, 1equiv.) stir, at being heated to 40 ~ 60 DEG C, add 4-Nitrobenzenesulfonyl chloride (1.672mol) in batches.After reinforced, stir 2 ~ 3 hours at such a temperature, add water 1Kg, dropwise to system, stir 0.5 hour, cool to room temperature, a large amount of solid is separated out.Suction filtration, filter cake uses water 1.5L × 3 to wash successively, and 3.6L water/Virahol (1/1 volume ratio) washs, and after 1L washed with isopropyl alcohol, after Vacuum dry filter cake, the filter cake ethyl alcohol recrystallization of 6 volumes, obtains 658g Compound D.Yield 83%, HPLC purity >=99.2%, content of isomer <0.1%.
Step S5, prepares target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide
Methyl alcohol 6.35Kg, Compound D (1.44Kg is added successively in 20L four-hole bottle, 2.77mol), relative to the Pd/C (0.144Kg) of Compound D quality 30% and trimethylacetic acid (5.54mol), under stirring, add ammonium formiate (27.7mol) in batches.After reinforced, the system heat release for the treatment of is gentle gradually, stirs 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Then system is filtered after removing Pd/C, at temperature control 15 ~ 25 DEG C, in filtrate, add concentrated hydrochloric acid (mass concentration is 36%) 2.6Kg.Then be heated to 35 ~ 45 DEG C to stir 3 ~ 5 hours, after system cools to 15 ~ 25 DEG C, after concentrated removal THF, in system, add 10Kg water, cool to 15 ~ 25 DEG C, after regulating PH>14 with NaOH, crystallization under ice-water bath.Filter after crystallization, after filter cake washes with water, after vacuum-drying, obtain 1Kg 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide with recrystallisation from isopropanol.Yield 88.7%, HPLC purity >=99.2%, single assorted <0.1%.
Embodiment 4
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, concrete preparation process is as follows:
Step S1, prepares compd A
Methyl alcohol/the H of KOH (33.6g, 0.6mol) is housed in container A
2o (1:1 volume ratio) solution, altogether 0.5L; Container B is equipped with the methanol solution of diazonium raw material N-methyl-N-nitro-p-toluenesulfonamide (32mmol), 54mL; The L-Phe (6.4mmol) of Boc protection and the THF solution 20mL altogether of N-methylmorpholine (9.6mmol) are housed in container C; The THF solution of carbonochloridic acid butyl ester (5.12mmol) is housed, altogether 20mL in container D.Material in reaction vessel C and reaction vessel D is pumped in reactive center II by tetrafluoro pipeline; Solution in reaction vessel A and reaction vessel B is pumped into (wherein KOH and diazonium material molar ratio are 2:1) in reactive center I by tetrafluoro pipeline, the diazomethane that heart I produces in the reaction enters reactive center III by the spillway of reactive center, reactive center II produce activated intermediate be pumped in reactive center III with diazomethane reaction, its reaction product is pumped in reactive center IV; Pump into the HBr/ ethanolic soln 60ml of 2M simultaneously to reactive center IV, pump into aftertreatment center after 0 DEG C of stirring 10min, obtain the compd A of 1.53g.Yield 70%, purity HPLC>95%.
Step S2, prepares compd B
Chlorobenzene 3.41Kg is added successively in 20L four-hole bottle, compd A (1Kg, stir 3.36mol), after hexalin (1.2Kg) solution being dissolved with three tertiary butyoxy aluminium lithiums (1mol) is joined reaction system, stir 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Drip hydrochloric acid (5.4Kg) the cancellation system of 1M after completion of the reaction in system after, the normal heptane adding 12L stirs, cooling crystallization, after a large amount of white solid is separated out, filter, after the water washing final vacuum drying of filter cake 1L × 6, obtain the compd B of 0.775Kg.Yield 75%, HPLC purity 95%.
Step S3, preparation Compound C
Propyl alcohol 15Kg is added successively in 20L four-hole bottle, water 1Kg and compd B (1Kg, 3.36mol), in system, drip isobutylamine (16.8mol) under stirring, in system, then slowly drip water (1Kg) solution containing two (trimethyl silicon based) sodium amide (6.72mol).Stir 15 ~ 20 hours at 15 ~ 20 DEG C of temperature after dropwising.Then, after underpressure distillation goes out ethanol, in system, add the water of 4Kg, and in ice-water bath crystallization.Filter, after the washing of filter cake use water 1L × 3, after filter cake vacuum-drying, obtain 427Kg Compound C.Yield 88%, HPLC purity 94%.
Step S4, preparation Compound D
Ethanol 9.4Kg, pyridine (2.28mol) and Compound C (0.512Kg is added successively in 20L four-hole bottle, 1.52mol, 1equiv.) stir, at being heated to 40 ~ 60 DEG C, add 4-Nitrobenzenesulfonyl chloride (2.28mol) in batches.After reinforced, stir 2 ~ 3 hours at such a temperature, add water 1Kg, dropwise to system, stir 0.5 hour, cool to room temperature, a large amount of solid is separated out.Suction filtration, filter cake uses water 1.5L × 3 to wash successively, and 3.6L water/Virahol (1/1 volume ratio) washs, and after 1L washed with isopropyl alcohol, after Vacuum dry filter cake, the filter cake ethyl alcohol recrystallization of 6 volumes, obtains 676g Compound D.Yield 82%, HPLC purity >=99.2%, content of isomer <0.1%.
Step S5, prepares target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide
Methyl alcohol 6.35Kg, Compound D (1.44Kg is added successively in 20L four-hole bottle, 2.77mol), relative to the Pd/C (0.144Kg) of Compound D quality 5% and propionic acid (27.7mol), under stirring, add ammonium formiate (11.8mol) in batches.After reinforced, the system heat release for the treatment of is gentle gradually, stirs 15 ~ 20 hours at 15 ~ 20 DEG C of temperature.Then system is filtered after removing Pd (OH) 2, at temperature control 15 ~ 25 DEG C, in filtrate, add concentrated hydrochloric acid (mass concentration is 36%) 2.6Kg.Then be heated to 35 ~ 45 DEG C to stir 3 ~ 5 hours, after system cools to 15 ~ 25 DEG C, after concentrated removal THF, in system, add 10Kg water, cool to 15 ~ 25 DEG C, after regulating PH>14 with NaOH, crystallization under ice-water bath.Filter after crystallization, after filter cake washes with water, after vacuum-drying, obtain 0.91Kg 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide with recrystallisation from isopropanol.Yield 85%, HPLC purity >=99.2%, single assorted <0.1%.
From above description and data, can find out, the above embodiments of the present invention achieve following technique effect:
Adopt preparation method provided by the present invention to prepare 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, route is comparatively simple.Each step all has higher productive rate, and the purity of the product of each step is higher.Meanwhile, the separating-purifying for intermediate product in each step is comparatively easy.In addition, in the preparation method that the present invention adopts, each raw material is the common reagent in this area, and raw material is comparatively cheap.Comprehensive above each factor, the preparation method that the present invention adopts is more suitable for industrialization large-scale application.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (20)
1. a preparation method for 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide, is characterized in that, comprise the following steps:
S1, is undertaken being obtained by reacting dizaomethyl ketone intermediate product by L-Phe and diazomethane, described dizaomethyl ketone intermediate product and haloid acid is reacted, obtain compd A;
S2, reduces to the carbonyl in compd A, obtains compd B;
S3, under the existence of isobutylamine, makes described compd B carry out cyclisation, ring-opening reaction successively, obtains Compound C;
S4, makes described Compound C and 4-Nitrobenzenesulfonyl chloride react, obtains Compound D; And
S5, reduces to the nitro in described Compound D, obtains described 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
2. preparation method according to claim 1, is characterized in that, described step S1 comprises:
S11, under the existence of the first alkali, reacts described L-Phe and carbonochloridic acid ester, generates activated intermediate;
S12, reacts described activated intermediate and described diazomethane, generates described dizaomethyl ketone intermediate product; And
S13, reacts described dizaomethyl ketone intermediate product and described haloid acid, obtains described compd A.
3. preparation method according to claim 2, is characterized in that, described first alkali be selected from N-methylmorpholine, triethylamine, diisopropyl ethyl amine and tri-n-butylamine one or more, be preferably triethylamine; Described carbonochloridic acid ester be selected from methyl chlorocarbonate, chloro ethyl formate, carbonochloridic acid propyl ester, isopropyl chloroformate, carbonochloridic acid butyl ester and carbonochloridic acid isobutyl ester one or more, be preferably chloro ethyl formate; Described haloid acid is selected from hydrogen bromide or hydrogenchloride.
4. the preparation method according to Claims 2 or 3, is characterized in that, the mol ratio of described first alkali and described L-Phe is 1 ~ 1.5:1; The mol ratio of described carbonochloridic acid ester and described L-Phe is 1 ~ 1.5:1; The mol ratio of described haloid acid and described L-Phe is 1 ~ 2:1.
5. preparation method according to claim 1, is characterized in that, described step S2 comprises:
S21, mixes described compd A with reductive agent, alcohol and the first organic solvent, obtains the first question response system;
S22, makes described first question response system reaction, obtains the first product system; And
S23, described first product system of purifying, obtains described compd B.
6. preparation method according to claim 5, is characterized in that, described reductive agent be selected from isobutanol aluminum, aluminum isopropylate, trimethyl carbinol aluminium and three tertiary butyoxy aluminium lithiums one or more, be preferably isobutanol aluminum; Described alcohol be selected from Virahol, ethanol, isopropylcarbinol, hexalin and cyclopentanol one or more, be preferably Virahol; Described first organic solvent is selected from toluene, dimethylbenzene, chlorobenzene, benzene, tetrahydrofuran (THF) or dioxane, is preferably toluene.
7. preparation method according to claim 6, is characterized in that, the mol ratio of described reductive agent and described compd A is 0.5 ~ 1.5:1; The mol ratio of described alcohol and described compd A is 4 ~ 15:1; The weight ratio of described first organic solvent and described compd A is 2.5 ~ 10:1.
8. the preparation method according to any one of claim 5 to 7, is characterized in that, the step of described first product system of purifying in described step S23 comprises:
Described in cancellation, the first product system, obtains quencher; And
In described quencher, add the first crystallization agent, separated out by the described compd B in described quencher, solid-liquid separation obtains described compd B.
9. preparation method according to claim 1, is characterized in that, described step S3 comprises:
S31, mixes described compd B with described isobutylamine, the second alkali and the second organic solvent, obtains the second question response system;
S32, makes described second question response system reaction, forms the second product system;
S33, removes the solvent of described second product system, obtains described Compound C.
10. preparation method according to claim 9, it is characterized in that, described second alkali be selected from KOH, NaOH, NaH, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide and two (trimethyl silicon based) Lithamide one or more, be preferably KOH; Described second organic solvent is selected from ethanol, methyl alcohol, propyl alcohol, Virahol or propyl carbinol, is preferably ethanol.
11. preparation methods according to claim 10, is characterized in that, the mol ratio of described isobutylamine and described compd B is 5.0 ~ 20:1; The mol ratio of described second alkali and described compd B is 1 ~ 2:1; The weight ratio of described second organic solvent and described compd B is 3 ~ 15:1.
12. preparation methods according to claim 1, is characterized in that, described step S4 comprises:
S41, mixes described Compound C with described 4-Nitrobenzenesulfonyl chloride, the 3rd alkali and the 3rd organic solvent, obtains the 3rd question response system;
S42, makes described 3rd question response system reaction, forms third product system; And
S43, described third product system of purifying, obtains described Compound D.
13. preparation methods according to claim 12, it is characterized in that, described 3rd alkali is selected from triethylamine, diisopropyl ethyl amine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, pyridine, DMAP, 2,6-lutidine and 2, one or more in 6-dichloride base pyridine, are preferably triethylamine; Described 3rd organic solvent is selected from Virahol, methylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether, ethanol, methyl alcohol, propyl alcohol, butanols or toluene, is preferably Virahol.
14. preparation methods according to claim 13, is characterized in that, the mol ratio of described 4-Nitrobenzenesulfonyl chloride and described Compound C is 1.1 ~ 1.5:1; The mol ratio of described 3rd alkali and described Compound C is 1.1 ~ 1.5:1; The weight ratio of described 3rd organic solvent and described Compound C is 2 ~ 10:1.
15., according to claim 12 to the preparation method according to any one of 14, is characterized in that, the step of described third product system of purifying in described step S43 comprises:
In described third product system, add the second crystallization agent, carry out solid-liquid separation after crystallization, obtain solids;
Described solids is carried out recrystallization, obtains described Compound D.
16. preparation methods according to claim 1, is characterized in that, described step S5 comprises:
S51, mixes described Compound D with catalyzer, hydrogen source, organic acid and the 4th organic solvent, obtains the 4th question response system;
S52, makes described formation the 4th question response system react, obtains the 4th product system; And
S53, described 4th product system of purifying, obtains described 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide;
Wherein, hydrogen source described in described step S51 is ammonium formiate or formic acid.
17. preparation methods according to claim 16, is characterized in that, described catalyzer is selected from Pd/C or Pd (OH)
2; Described organic acid is selected from acetic acid, formic acid, propionic acid or trimethylacetic acid; Described 4th organic solvent be selected from tetrahydrofuran (THF), methyl alcohol, ethanol, ethyl acetate and isopropyl acetate one or more; Be preferably tetrahydrofuran (THF).
18. preparation methods according to claim 17, is characterized in that, the mass ratio of described catalyzer and described Compound D is 0.05 ~ 0.3:1; The mol ratio of described ammonium formiate and described Compound D is 4.0 ~ 10.0:1; The mol ratio of described organic acid and described Compound D is 2 ~ 10:1; The weight ratio of described 4th organic solvent and described Compound D is 3 ~ 10:1.
19., according to claim 16 to the preparation method according to any one of 18, is characterized in that, the step of described 4th product system of purifying in described step S53 comprises:
Described 4th product system is carried out solid-liquid separation, obtains filtrate;
Carry out crystallization to described filtrate, solid-liquid separation obtains crude product; And
Recrystallization is carried out to described crude product, obtains described 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonamide.
20. preparation methods according to claim 15 or 19, it is characterized in that, in the step of described recrystallization, the recrystallization solvent of employing is selected from Virahol, ethanol, methyl alcohol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether.
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