CN104387299B - The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide - Google Patents
The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide Download PDFInfo
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Abstract
The invention discloses a kind of 4 amino N [(2R, 3S) 3 amino 2 hydroxyl 4 benzene butyl] preparation method of N isobutyl-benzene sulfonamide, comprising: S1, L phenylalanine and Azimethylene. are carried out reaction and obtains dizaomethyl ketone intermediate product, dizaomethyl ketone intermediate product is reacted with halogen acids, obtains compound A；S2, to the carbonyl reduction in compound A, obtains compound B；S3, in the presence of isobutyl amine, makes compound B carry out successively being cyclized, ring-opening reaction, obtains compound C；S4, makes compound C react with 4-Nitrobenzenesulfonyl chloride, obtains compound D；S5, reduces to the nitro in compound D, obtains 4 amino N [(2R, 3S) 3 amino 2 hydroxyl 4 benzene butyl] N isobutyl-benzene sulfonamide.The method route is simple, low cost, mild condition, intermediate product stability are higher, beneficially industrial applications.
Description
Technical field
The present invention relates to technical field of medicine synthesis, in particular to a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-
Benzene butyl] preparation method of-N-isobutyl-benzene sulfonamide.
Background technology
4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide is very important in medicine synthesis
A kind of intermediate, it has a following structure:
Amprenavir (Amprenavir), DRV (Darunavir), Fosamprenavir (Fosamprenavir) etc. are a series of anti-
HIV medicine all can be prepared by above-mentioned intermediate.In the 5th generation that wherein amprenavir is developed by Glaxo-Simth company of Britain, is degeneration-resistant
Turn virus protein inhibitor, in May, 1999 in the U.S. and Japan's listing；DRV is that branch company of Iceland of the Johson & Johnson base of a fruit is won
The one non-peptides HIV-1 protein inhibitor of Tyke research and development, lists in the U.S. in June, 2006；The calcium salt of Fosamprenavir, by
The prodrug of a kind of protease inhibitor Amprenavir of Britain GSK and Vertex company of U.S. joint development, 2003 first
List in the U.S..
At present, the synthesis of key intermediate 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide
Side has a variety of, it has been reported that have the synthetic route of industrial application value mainly to have the most several:
Patent (CN101037403A) is catalyzed bromine from L-phenylalanine through N protection, esterification, Claisen condensation, copper
Generation, decarboxylation, carbonyl reduction and epoxidation, obtain epoxy intermediate through 7 step reactions.Further with in epoxy intermediate synthesis
State key intermediate.This route is tediously long, use the CuBr2 of big excess and formic acid, low-temp reaction etc. be all amplification industrialized production and
Equipment is made troubles, and increases energy consumption and the discharge of the three wastes.
Document (Angew.Chem.Int.Ed.1999,38,1931-1934) report chiral quaternary ammonium salt asymmetry catalysis Henry reaction
Highly-solid selectively builds amino alcohol intermediate 18, after the reduction of further nitro, through reduction amination, sulfonylation, the de-benzyl of hydrogenation
Base protection group obtains key intermediate, and synthetic route is as follows:
In process above route, complex synthetic route, cost are high, are unfavorable for industrial mass production.Therefore, existing for solving
A difficult problem present in technology, captures the technology barriers of external drugmaker, suddenly waits to find a technique simple, with low cost, suitable
Close the synthetic route of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide of large-scale production.
Summary of the invention
It is desirable to provide the system of a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide
Preparation Method, to solve to prepare in prior art 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonyl
The problem that amine route is complicated, cost is high.
To achieve these goals, according to an aspect of the invention, it is provided a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl
Base-4-benzene butyl] preparation method of-N-isobutyl-benzene sulfonamide, comprise the following steps: S1, by L-phenylalanine and Azimethylene.
Carry out reaction and obtain dizaomethyl ketone intermediate product, dizaomethyl ketone intermediate product is reacted with halogen acids, obtains compound A；
S2, reduces to the carbonyl in compound A, obtains compound B；S3, in the presence of isobutyl amine, makes compound B depend on
Secondary carry out being cyclized, ring-opening reaction, obtain compound C；S4, makes compound C react with 4-Nitrobenzenesulfonyl chloride, obtains chemical combination
Thing 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 sulfonamide.
Further, above-mentioned steps S1 includes: S11, in the presence of the first alkali, is entered with carbonochloridic acid ester by L-phenylalanine
Row reaction, generates activated intermediate；S12, reacts activated intermediate with Azimethylene., generates and produces in the middle of dizaomethyl ketone
Thing；And S13, dizaomethyl ketone intermediate product is reacted with halogen acids, obtains compound A.
Further, above-mentioned first alkali one in N-methylmorpholine, triethylamine, diisopropyl ethyl amine and tri-n-butylamine
Or multiple, preferably triethylamine；Carbonochloridic acid ester is selected from methyl chlorocarbonate, chloro ethyl formate, carbonochloridic acid propyl ester, chlorine
One or more in acute pyogenic infection of nails isopropyl propionate, carbonochloridic acid butyl ester and carbonochloridic acid isobutyl ester, preferably chloro ethyl formate；Hydrogen
Hydracid is selected from hydrogen bromide or hydrogen chloride.
Further, above-mentioned first alkali is 1～1.5:1 with the mol ratio of L-phenylalanine；Carbonochloridic acid ester rubs with L-phenylalanine
Your ratio is 1～1.5:1；Halogen acids is 1～2:1 with the mol ratio of L-phenylalanine.
Further, above-mentioned steps S2 includes: S21, is mixed with reducing agent, alcohol and the first organic solvent by compound A,
Obtain the first question response system；S22, makes the first question response system reaction, obtains the first product system；And S23, purify the
One product system, obtains compound B.
Further, above-mentioned reducing agent is in isobutanol aluminum, aluminum isopropylate., tert-butyl alcohol aluminum and three tertiary butyoxy aluminum lithiums
One or more, preferably isobutanol aluminum；Alcohol one in isopropanol, ethanol, isobutanol, Hexalin and cyclopentanol or
Multiple, preferably isopropanol；First organic solvent is selected from toluene, dimethylbenzene, chlorobenzene, benzene, oxolane or dioxane,
It is preferably toluene.
Further, above-mentioned reducing agent is 0.5～1.5:1 with the mol ratio of compound A；Alcohol is 4～15:1 with the mol ratio of compound A；
First organic solvent is 2.5～10:1 with the weight ratio of compound A.
Further, the step purifying the first product system in above-mentioned steps S23 includes: cancellation the first product system, is quenched
Go out thing；Adding the first crystallize agent in quencher, separated out by the compound B in quencher, solid-liquid separation obtains compound B.
Further, above-mentioned steps S3 includes: S31, is mixed with isobutyl amine, the second alkali and the second organic solvent by compound B,
Obtain the second question response system；S32, makes the second question response system reaction, forms the second product system；And S33, remove the
The solvent of two product system, obtains compound C.
Further, above-mentioned second alkali is selected from KOH, NaOH, NaH, double (trimethyl is silica-based) Sodamide., double (trimethyl is silica-based)
One or more in potassamide and double (trimethyl is silica-based) Lithamide., preferably KOH；Second organic solvent is selected from ethanol, first
Alcohol, propanol, isopropanol or n-butyl alcohol, preferably ethanol.
Further, above-mentioned isobutyl amine is 5.0～20:1 with the mol ratio of compound B；Second alkali with the mol ratio of compound B is
1～2:1；Second organic solvent is 3～15:1 with the weight ratio of compound B.
Further, above-mentioned steps S4 includes: S41, by organic with 4-Nitrobenzenesulfonyl chloride, the 3rd alkali and the 3rd for compound C
Solvent mixes, and obtains the 3rd question response system；S42, makes the 3rd question response system reaction, forms third product system；And S43,
Purify third product system, obtain compound D.
Further, above-mentioned 3rd alkali is selected from triethylamine, diisopropyl ethyl amine, sodium carbonate, potassium carbonate, sodium bicarbonate, carbon
Potassium hydrogen phthalate, pyridine, DMAP, 2,6-lutidines and 2, one or more in 6-dichloride base pyridine, be preferably
Triethylamine；3rd organic solvent selected from isopropanol, dichloromethane, oxolane, glycol dimethyl ether, ethanol, methanol, third
Alcohol, butanol or toluene, preferably isopropanol.
Further, above-mentioned 4-Nitrobenzenesulfonyl chloride is 1.1～1.5:1 with the mol ratio of compound C；3rd alkali is with compound C's
Mol ratio is 1.1～1.5:1；3rd organic solvent is 2～10:1 with the weight ratio of compound C.
Further, the step purifying third product system in above-mentioned steps S43 includes:
In third product system, add the second crystallize agent, carry out solid-liquid separation after crystallize, obtain solids；
Solids is carried out recrystallization, obtains compound D.
Further, above-mentioned steps S5 includes: S51, by organic molten with catalyst, hydrogen source, organic acid and the 4th for compound D
Agent mixes, and obtains the 4th question response system；S52, makes formation the 4th question response system react, obtains the 4th product system；And
S53, purifies the 4th product system, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulphonyl
Amine；Wherein, in step S51, hydrogen source is ammonium formate or formic acid.
Further, above-mentioned catalyst is selected from Pd/C or Pd (OH) 2；Organic acid is selected from acetic acid, formic acid, propanoic acid or pivalic acid；
One or more in oxolane, methanol, ethanol, ethyl acetate and isopropyl acetate of 4th organic solvent；It is preferably
Oxolane.
Further, above-mentioned catalyst is 0.05～0.3:1 with the mass ratio of compound D；Ammonium formate and the mol ratio of compound D
It is 4.0～10.0:1；Organic acid is 2～10:1 with the mol ratio of compound D；4th organic solvent with the weight ratio of compound D is
3～10:1.
Further, above-mentioned it is characterized in that, the step purifying the 4th product system in step S53 includes: by the 4th product body
System carries out solid-liquid separation, obtains filtrate；Filtrate is carried out crystallize, and solid-liquid separation obtains crude product；And crude product is carried out weight
Crystallization, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide.
Further, in the step of above-mentioned recrystallization, the recrystallization solvent of employing is selected from isopropanol, ethanol, methanol, acetic acid second
Ester, isopropyl acetate or methyl tertiary butyl ether(MTBE)..
The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide of the present invention, closes
Becoming route relatively simple, cost of material is relatively low.It addition, the process conditions of each step are the gentleest, the stability of each intermediate product
Higher, and the separation for each intermediate is relatively easy to.The factor of each side is all conducive to industrialization large-scale application.
Accompanying drawing explanation
The Figure of description of the part constituting the application is used for providing a further understanding of the present invention, and the present invention's is schematic real
Execute example and illustrate for explaining the present invention, being not intended that inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 shows the compound B of preparation in the embodiment of the present invention 11HNMR spectrogram；
Fig. 2 shows the compound C of preparation in the embodiment of the present invention 11HNMR spectrogram；
Fig. 3 shows the compound D of preparation in the embodiment of the present invention 11HNMR spectrogram；And
Fig. 4 shows 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl of preparation in the embodiment of the present invention 1
Base benzsulfamide1HNMR spectrogram.
Detailed description of the invention
It should be noted that in the case of not conflicting, the embodiment in the application and the feature in embodiment can be mutually combined.
Describe the present invention below with reference to the accompanying drawings and in conjunction with the embodiments in detail.
As background section is introduced, prior art is prepared 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene fourth
Base]-N-isobutyl-benzene sulfonamide time, there is the problem that route is complicated, cost is high.In order to solve this problem, inventor
Provide the preparation method of a kind of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, its bag
Include following steps: S1, carry out reacting the dizaomethyl ketone intermediate product obtained, by diazonium first by L-phenylalanine and Azimethylene.
Base ketone intermediate product reacts with halogen acids, obtains compound A；S2, reduces to the carbonyl in compound A, obtains
Compound B；S3, in the presence of isobutyl amine, makes compound B carry out successively being cyclized, ring-opening reaction, obtains compound C；
S4, makes compound C react with 4-Nitrobenzenesulfonyl chloride, obtains compound D；And S5, the nitro in compound D is carried out
Reduction, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide.
In above-mentioned preparation method provided by the present invention, L-phenylalanine is reacted with Azimethylene., carboxylic in L-phenylalanine
Hydroxyl on base can be replaced by dizaomethyl, forms dizaomethyl ketone intermediate product.Dizaomethyl ketone intermediate product and halogen acids
During reaction, halogen atom replaces dizaomethyl and forms compound A.After reducing the carbonyl in compound A, carbonyl is changed into
Hydroxyl forms corresponding compound B.In the presence of isobutyl amine, compound B can occur cyclization and ring-opening reaction successively,
Obtain compound C.After being reacted with 4-Nitrobenzenesulfonyl chloride by compound C, then carry out nitro reduction, it becomes possible to obtain target and produce
Thing 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide.
Preparation method provided by the present invention, synthetic route is relatively simple, and cost of material is relatively low.Additionally, the technique bar of each step
Part is the gentleest, and the stability of each intermediate product is higher, and the separation for each intermediate is relatively easy to.The factor of each side is equal
Be conducive to industrialization large-scale application.
In actual mechanical process, after preferably the amino in raw material L-phenylalanine being carried out Boc protection, the L-that Boc is protected
Phenylalanine (shown in formula G) puts into next step reaction.
It is below the concrete synthetic route of the above-mentioned preparation method of the present invention:
Corresponding halogen atom during wherein X is halogen acids.
In a preferred embodiment, above-mentioned steps S1 includes: S11, in the presence of the first alkali, by L-phenylalanine
React with carbonochloridic acid ester, generate activated intermediate；S12, reacts activated intermediate with Azimethylene., generates weight
N-methyl ketone intermediate product；And S13, dizaomethyl ketone intermediate product is reacted with halogen acids, obtains compound A.
In the basic conditions, the carboxyl in L-phenylalanine can be activated by carbonochloridic acid ester, makes formic acid ester group replace carboxyl
In hydrogen atom formed activated intermediate.This is conducive to promoting the double bond oxygen in dizaomethyl attack L-phenylalanine, and then generates
Dizaomethyl ketone intermediate product.Again dizaomethyl ketone intermediate product is reacted with halogen acids, just can obtain compound A.
The compound A prepared according to the method has higher productivity.
In the above-mentioned step preparing compound A of the present invention, it is preferred to use the mode of seriality flowing phase reaction is prepared.This has
It is beneficial to improve the stability of reaction, is allowed to be more suitable for commercial Application.
The first alkali, the raw material such as carbonochloridic acid ester that use in above-mentioned steps S1 may each be the conventional raw material in pharmaceutical synthesis field.
In a preferred embodiment, above-mentioned first alkali includes but not limited to N-methylmorpholine, triethylamine, diisopropyl ethyl amine
And one or more in tri-n-butylamine, preferably triethylamine；Carbonochloridic acid ester includes but not limited to methyl chlorocarbonate, chloro
One or many in Ethyl formate, carbonochloridic acid propyl ester, isopropyl chloroformate, carbonochloridic acid butyl ester and carbonochloridic acid isobutyl ester
Kind, preferably chloro ethyl formate；Halogen acids is selected from hydrogen bromide or hydrogen chloride.Mentioned reagent is more easy to get, and cost is relatively low.Make
For preparing the raw material of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, it is possible to drop further
Low production cost so that it is be more suitable for commercial Application.In actual operating process, it is directly added into hydrogen bromide or hydrogen chloride just can
React.In addition it is also possible to the solution containing halogen acids is added, the methanol solution of such as hydrogen chloride, the ethanol of hydrogen chloride
Solution, the methanol solution of hydrogen bromide, the ethanol solution of hydrogen bromide, the THF solution of hydrogen chloride, the THF solution of hydrogen bromide, bromine
Change the acetic acid solution of hydrogen, the acetic acid solution etc. of hydrogen chloride.The most above-mentioned halogen acids adds with the form of the THF solution of hydrogen chloride.
Above-mentioned preparation method provided by the present invention, when carrying out the preparation of compound A, those skilled in the art can select each former
Concrete between material use magnitude relation.In a preferred embodiment, the first alkali is 1～1.5:1 with the mol ratio of L-phenylalanine；
Carbonochloridic acid ester is 1～1.5:1 with the mol ratio of L-phenylalanine；Halogen acids is 1～2:1 with the mol ratio of L-phenylalanine.Will be each
The consumption of raw material controls in above-mentioned scope, it is possible on the basis of reducing production cost, makes the productivity that compound A holding is higher.
In above-mentioned steps S2, the carbonyl in reducing compound A uses carbonyl reduction commonly used in the art with the method preparing compound B
Method.In a preferred embodiment, above-mentioned steps S2 includes: S21, by compound A and reducing agent, alcohol and
First organic solvent mixes, and obtains the first question response system；S22, makes the first question response system reaction, obtains the first product
System；And S23, purify the first product system, obtain compound B.After compound A is reduced under the effect of reducing agent,
The product obtained is purified, obtains the purest compound B.This desirably prevents impurity and impacts subsequent reactions,
Ensure productivity and the purity of target product.
The above-mentioned reducing agent that uses when preparing compound B, solvent etc. can be the reagent that those skilled in the art commonly use.In one
In preferred embodiment, above-mentioned reducing agent includes but not limited to isobutanol aluminum, aluminum isopropylate., tert-butyl alcohol aluminum and three tert-butoxies
One or more in lithium aluminium hydride reduction；One or more in isopropanol, ethanol, isobutanol, Hexalin and cyclopentanol of alcohol,；
First organic solvent is selected from toluene, dimethylbenzene, chlorobenzene, benzene, oxolane or dioxane.Use above-mentioned several reducing agent and
When carbonyl in compound A is reduced by alcohol, there is higher reduction selectivity.And these reagent are relatively inexpensive, it is possible to enter
One step reduces production cost.Preferably, above-mentioned reducing agent is isobutanol aluminum, and alcohol is isopropanol, and the first organic solvent is toluene.
Isobutanol aluminum has higher selectivity when reducing carbonyl becomes hydroxyl, by its with isopropanol with the use of, it is possible to carry further
The productivity of high compound B.
Those skilled in the art can make the usage ratio of each raw material of employing be adjusted to preparing compound B.Preferred in one
Embodiment in, the mol ratio of above-mentioned reducing agent and compound A is 0.5～1.5:1；Alcohol is 4～15:1 with the mol ratio of compound A；
First organic solvent is 2.5～10:1 with the weight ratio of compound A.The amount ratio of each raw material is controlled in above-mentioned scope, it is possible to
Reduce significant loss, while reducing production cost, make reaction have higher conversion ratio.Furthermore it is preferred that above-mentioned steps
Reaction temperature in S22 is room temperature.
The purifying technique that the step of above-mentioned purification the first product system can use those skilled in the art to commonly use.Preferred in one
In embodiment, the step purifying the first product system in above-mentioned steps S23 includes: cancellation the first product system, obtains cancellation
Thing；Adding the first crystallize agent in quencher, separated out by the compound B in quencher, solid-liquid separation obtains compound B.Quench
Go out the first product system, it is possible to prevents system from the reaction of further impurity occurring, to improve product purity.Cancellation process uses
Quencher can be hydrochloric acid, and its concentration can be the hydrochloric acid of any concentration, preferably 1mol/L.Further, in quencher
Target product compound B carry out crystallize, the compound B of isolated has higher purity.The used in Crystallization Process
One crystallize agent can be the crystallize agent that those skilled in the art commonly use, it is preferable that this first crystallize agent is normal heptane or normal hexane.
In above-mentioned preparation method provided by the present invention, the step preparing compound C for raw material with compound B in step S3 is permissible
Use those skilled in the art to carry out cyclization and close processing step conventional during ring-opening reaction.In a preferred embodiment,
Above-mentioned steps S3 includes: S31, is mixed with isobutyl amine, the second alkali and the second organic solvent by compound B, obtains second and treats instead
Answer system；S32, makes the second question response system reaction, forms the second product system；And S33, remove the second product system
Solvent, obtains compound C.
Carry out compound B and isobutyl amine, the second alkali and the mixing of the second organic solvent being cyclized, open loop " one kettle way " reaction.Instead
Answer process as follows:
This " one kettle way " reaction can reduce the remaining time of the unstable epoxy intermediate because of cyclization formation.Make shakiness
There is ring-opening reaction in fixed epoxy intermediate under the effect of isobutyl amine, forms stable compound C in time.Additionally, " one kettle way "
Reaction can also Simplified flowsheet, it is to avoid separate unstable epoxy intermediate.
In the above-mentioned step preparing compound C, the second alkali of employing, the second organic solvent etc. can be reagent customary in the art.
In a preferred embodiment, above-mentioned second alkali includes but not limited to KOH, NaOH, NaH, double (trimethyl is silica-based) ammonia
One or more in base sodium, double (trimethyl is silica-based) potassamide and double (trimethyl is silica-based) Lithamide., preferably KOH；Second has
Machine solvent includes but not limited to ethanol, methanol, propanol, isopropanol or n-butyl alcohol, preferably ethanol.These reagent are relatively inexpensive,
While can improving reaction stability, also help reduction production cost.
In above-mentioned steps S3, each raw material is that those skilled in the art can be adjusted with magnitude relation.The most real in one
Executing in mode, above-mentioned isobutyl amine is 5.0～20:1 with the mol ratio of compound B；Second alkali is 1～2:1 with the mol ratio of compound B；
Second organic solvent is 3～15:1 with the weight ratio of compound B.Raw material controlled in above-mentioned scope with magnitude relation, it is possible to increase
Reaction stability, the productivity of increase compound C.Meanwhile, reduction production cost is also helped so that it is be more suitable for industrial applications.
The method of the solvent removing the second product system in above-mentioned steps S33 uses the method that those skilled in the art commonly use.
Preferably, the mode of concentrating under reduced pressure is used to remove solvent.
In above-mentioned preparation method, the method preparing compound D with compound C for raw material in step S4 can use commonly used in the art
Method.In a preferred embodiment, above-mentioned steps S4 includes: S41, by compound C and 4-Nitrobenzenesulfonyl chloride,
3rd alkali and the mixing of the 3rd organic solvent, obtain the 3rd question response system；S42, makes the 3rd question response system reaction, forms the 3rd
Product system；And S43, purify third product system, obtain compound D.By compound C with 4-Nitrobenzenesulfonyl chloride at alkali
React under the conditions of property, it is possible to increase the productivity of target product compound D.The reaction preferably preparing compound D is at room temperature carried out.
In the above-mentioned step preparing compound D, the 3rd alkali of employing, 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, carbon
In acid potassium, sodium bicarbonate, potassium bicarbonate, pyridine, DMAP, 2,6-lutidines and 2,6-dichloride base pyridine
One or more, preferably triethylamine；3rd organic solvent includes but not limited to isopropanol, dichloromethane, oxolane, second
Glycol dimethyl ether, ethanol, methanol, propanol, butanol or toluene, preferably isopropanol.Using above-mentioned alkaline reagent as the 3rd alkali,
The productivity of compound D can be improved further.It addition, above-mentioned alkaline reagent and organic solvent are relatively inexpensive, it is more suitable for extensive
Application.
Usage ratio between each raw material used in above-mentioned steps S4 can be adjusted.In a preferred embodiment,
Above-mentioned 4-Nitrobenzenesulfonyl chloride is 1.1～1.5:1 with the mol ratio of compound C；3rd alkali with the mol ratio of compound C is
1.1～1.5:1；3rd organic solvent is 2～10:1 with the weight ratio of compound C.The consumption preparing each raw material of compound D is closed
System controls within the above range, is conducive to improving reaction stability and conversion ratio.Meanwhile, advantageously reduce the wasting of resources, reduce
Production cost.
In above-mentioned steps S4, the purification process of third product system can be used purifying technique commonly used in the art.Excellent in one
In the embodiment of choosing, the step purifying third product system in above-mentioned steps S43 includes: add the in third product system
Two crystallize agent, carry out solid-liquid separation, obtain solids after crystallize；Solids is carried out recrystallization, obtains compound D.This mistake
The the second crystallize agent used in journey is preferably water.After crystallize, the solids obtained is carried out recrystallization, it is possible to remove in product
A small amount of chiral isomer, the recrystallization solvent this time used in recrystallization process include but not limited to isopropanol, ethanol, methanol,
Ethyl acetate, isopropyl acetate or methyl tertiary butyl ether(MTBE).Preferably, recrystallization solvent is ethanol.It is highly preferred that recrystallization is molten
Agent is 1～5:1 with the mass ratio of compound C.
In above-mentioned preparation method, step S5 is prepared 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene fourth of target product
Base]-N-isobutyl-benzene sulfonamide time, as long as nitro can be reduced to amino.In a preferred embodiment, above-mentioned
Step S5 includes: S5a, is mixed with catalyst, ammonium formate, organic acid and the 4th organic solvent by compound D, obtains the 4th
Question response system；S5b, makes formation the 4th question response system react, obtains the 4th product system；And S5c, purify the 4th product
Objects system, obtains 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide.
Above-mentioned prepare target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl with compound D for raw material
During base benzsulfamide, have employed ammonium formate as hydrogen source, the nitre in reducing compound D by the way of ortho-hydrogens shifts
Base.This can improve the productivity of target product, can reduce the consumption of catalyst so that it is be more suitable for industrial applications simultaneously.
The reagent that the reagent such as the catalyst used in above-mentioned steps and organic acid are conventional when can be this area reduction nitro.In one
In preferred embodiment, above-mentioned catalyst includes but not limited to Pd/C or Pd (OH) 2；Organic acid include but not limited to acetic acid,
Formic acid, propanoic acid or pivalic acid；4th solvent includes but not limited to oxolane, methanol, ethanol, ethyl acetate and isopropyl acetate
One or more in ester；It is preferably oxolane.
In above-mentioned steps S5, each raw material can be adjusted with magnitude relation.In a preferred embodiment, above-mentioned catalyst
It is 0.05～0.3:1 with the mass ratio of compound D；Ammonium formate is 4.0～10.0:1 with the mol ratio of compound D；Organic acid and chemical combination
The mol ratio of thing D is 2～10:1；4th organic solvent is 3～10:1 with the weight ratio of compound D.The consumption of each raw material is controlled
In above-mentioned scope, be conducive to improving stability and the conversion ratio of reaction.In a preferred embodiment, above-mentioned catalyst with
The mass ratio of compound D is 0.1:1.Just because of have employed ammonium formate during the present invention above-mentioned reduction nitro as hydrogen source,
The percent reduction of nitro can be improved, the consumption of above-mentioned noble metal catalyst can be reduced, reduce reaction cost further.
The method in above-mentioned steps S5c reduced the 4th product system uses method of purification commonly used in the art.One
In planting preferred embodiment, the step purifying the 4th product system in above-mentioned steps S5c includes: carried out by the 4th product system
Solid-liquid separation, obtains filtrate；Filtrate is carried out crystallize, and solid-liquid separation obtains crude product；Crude product is carried out recrystallization, obtains
4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide.
4th product system is carried out solid-liquid separation, it is possible to remove the catalyst in the 4th product system.Filtrate is carried out crystallize,
The target product being dissolved in system can be separated and separate out.The crude product separated out is carried out recrystallization, it is possible to purify mesh further
Mark product.
Preferably, above-mentioned Devitrification step includes: add hydrochloric acid in filtrate, after being heated to 35～45 DEG C of stirrings 3～5h, is cooled to
Pretreatment filtrates is obtained after 15～25 DEG C；After removing the solvent in pretreatment filtrates, add water, and regulate pH after 14, at frozen water
It is intended to lower crystallize, obtains crude product.In filtrate, add hydrochloric acid can slough the Boc blocking group on amino.
Preferably, in the above-mentioned step that crude product carries out recrystallization, the recrystallization solvent of employing is selected from isopropanol, ethanol, first
Alcohol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether(MTBE).Preferably recrystallization solvent is isopropanol.
Being described in further detail the present invention below in conjunction with specific embodiment, these embodiments are it is not intended that limit institute of the present invention
Claimed scope.
Embodiment 1
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, concrete preparation process is as follows:
Step S1, prepares compound A
Equipped with the methanol/H of KOH (33.6g, 0.6mol) in container A2O (1:1 volume ratio) solution, altogether 0.5L；Container
B is equipped with the methanol solution of diazonium raw material 1-methyl isophthalic acid-nitroso ureas (3.30g, 32mmol), 54mL；In container C equipped with
The L-phenylalanine (6.4mmol) of Boc protection and the THF solution of triethylamine (6.72mmol) 20mL altogether；In container D
Equipped with the THF solution of chloro ethyl formate (6.4mmol), 20mL altogether.By the thing in reaction vessel C and reaction vessel D
Material is pumped in reaction center II by tetrafluoro pipeline；By the solution in reaction vessel A and reaction vessel B by tetrafluoro pipeline pump
Entering in reaction center I (wherein KOH and diazonium material molar ratio are 2:1), the Azimethylene. that heart I produces in the reaction passes through
The overfall of reaction center enters reaction center III, and the activated intermediate that reaction center II produces is pumped in reaction center III and weight
Nitrogen methane reaction, its product is pumped in reaction center IV；Simultaneously pump into the HCl/THF of 2M to reaction center IV molten
Liquid 40mL, pumps into post processing center after 0 DEG C of stirring 10min, obtains the compound A of 1.8g.Yield 95%, purity
HPLC > 98%.
Step S2, prepares compound B
In 20L four-hole bottle, it is sequentially added into toluene 3.41Kg, compound A (1Kg, 3.36mol) stir afterwards, will be dissolved with different
After isopropanol (1.2Kg) solution of aluminium butoxide (0.413kg, 1.68mol, 0.50equiv.) joins reaction system, 15～
Stir 15～20 hours at a temperature of 20 DEG C.After dripping hydrochloric acid (5.4Kg) the cancellation system of 1M after completion of the reaction in system,
Add the normal heptane stirring of 12L, crystallize of lowering the temperature, after a large amount of white solids separate out, filter, after the water washing of filter cake 1L × 6
After vacuum drying, obtain 0.95Kg compound B (compound B's1HNMR spectrogram is as it is shown in figure 1, add during Ce Lianging
Adding equal trimethoxy-benzene is internal standard, and test condition is: 400MHz, DMSO).Yield 92%, HPLC purity 92%.
Step S3, prepares compound C
In 20L four-hole bottle, be sequentially added into ethanol 6.5Kg, water 1Kg and compound B (1Kg, 3.36mol), under stirring to
System drips isobutyl amine (2.46Kg, 33.6mol, 10equiv.), is then slowly added dropwise in system containing KOH (0.207
Kg, 2.69mol, 1equiv) water (1Kg) solution.Stir 15～20 hours at a temperature of 15～20 DEG C after dropping.
Then, after decompression distills out ethanol, in system, the water of 4Kg, and crystallize in ice-water bath are added.Filter, filter cake water 1L
× 3 washing after, filter cake vacuum drying after, obtain 1.1Kg compound C (compound C's1HNMR spectrogram as in figure 2 it is shown,
Adding equal trimethoxy-benzene during measurement is internal standard, and test condition is: compound C 50.8mg, equal trimethoxy-benzene 28.9 ×
97%mg, 400MHz, chloroform).Yield 97.3%, HPLC purity 96%.
Step S4, prepares compound D
In 20L four-hole bottle, it is sequentially added into isopropanol 9.4Kg, triethylamine (0.18Kg, 1.78mol, 1.20equiv) and changes
Compound C (0.512Kg, 1.52mol, 1equiv.) stirs, and is heated at 40～60 DEG C, is dividedly in some parts 4-Nitrobenzenesulfonyl chloride
(0.388Kg, 1.75mol, 1.15equiv.).After charging, stirring 2～3 hours at such a temperature, add water to system
1Kg, drips complete, stirs 0.5 hour, cools to room temperature, and a large amount of solids separate out.Sucking filtration, filter cake is successively with water 1.5L × 3
Washing, 3.6L water/isopropanol (1/1 volume ratio) washs, after the washing of 1L isopropanol, after Vacuum dry filter cake, filter cake 6 bodies
Long-pending ethyl alcohol recrystallization, obtain 730g compound D (compound D's1HNMR spectrogram is as it is shown on figure 3, add during Ce Lianging
Adding equal trimethoxy-benzene is internal standard, and test condition is: 500MHz, the chloroform 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 sulfonamide
Be sequentially added in 20L four-hole bottle THF 6.35Kg, compound D (1.44Kg, 2.77mol), relative to compound
The Pd/C (0.144Kg) of D mass 10% and acetic acid (0.66Kg, 11.08mol, 4equiv.), be dividedly in some parts first under stirring
Acid ammonium (0.69Kg, 11.08mol, 4equiv.).After charging, the system heat release for the treatment of is the most gentle, 15～20 DEG C of temperature
Lower stirring 15～20 hours.Then system is filtered and remove after Pd/C, at temperature control 15～25 DEG C, in filtrate, add concentrated hydrochloric acid
(mass concentration is 36%) 2.6Kg.It is then heated to 35～45 DEG C stir 3～5 hours, after system cools to 15～25 DEG C,
Concentrate and remove after THF, in system, add 10Kg water, cool to 15～25 DEG C, regulate PH with NaOH after 14, ice
Crystallize under water-bath.Filter after crystallize, after filter cake washes with water, after vacuum drying, obtain 1Kg 4-amino with recrystallisation from isopropanol
-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide be (target product1HNMR spectrogram as shown in Figure 4,
Test condition is: 400MHz, DMSO).Yield 93%, HPLC purity>=99.4%, single miscellaneous<0.1%.
Embodiment 2
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, concrete preparation process is as follows:
Step S1, prepares compound A
Equipped with the methanol/H of NaOH (112g, 2.8mol) in container A2O (1:1 volume ratio) solution, altogether 3L；Container B
Equipped with the methanol solution of diazonium raw material 1-methyl isophthalic acid-nitroso ureas (131.9g, 1.28mol), 0.54L；Equipped with Boc in container C
The L-phenylalanine (640mmol) of protection and the 1L THF of tri-n-butylamine (672mmol)；Equipped with chloro first in container D
The THF solution of acetoacetic ester (640mmol), altogether 0.5L.Material in reaction vessel C and reaction vessel D is passed through tetrafluoro
Pipeline is pumped in reaction center II；Solution in reaction vessel A and reaction vessel B is pumped in reaction by tetrafluoro pipeline
In heart I, 0 DEG C of reaction (wherein KOH and diazonium material molar ratio are 2:1), the Azimethylene. that heart I produces in the reaction passes through
The overfall of reaction center enters reaction center III, and the activated intermediate that reaction center II produces is pumped in reaction center III and weight
Nitrogen methane reaction, its product is pumped in reaction center IV, simultaneously pumps into the HCl/THF of 2M to reaction center IV molten
Liquid 1.6L, pumps into post processing center after 0 DEG C of stirring 10min, obtains 178g compound A.Yield 94%, purity HPLC > 98%.
Step S2, prepares compound B
In 10L four-hole bottle, it is sequentially added into toluene 1.7Kg, compound A (0.5Kg, 1.68mol) stir afterwards, will be dissolved with different
After isopropanol (the 0.6Kg) solution of aluminium butoxide (0.246kg, 1.0mol, 0.6equiv.) joins reaction system, at 15～20 DEG C
The lower stirring of stirring 15～20 hours.After dripping hydrochloric acid (1.3Kg) the cancellation system of 2M after completion of the reaction in system, add
The normal hexane stirring of 5L, crystallize of lowering the temperature, after a large amount of white solids separate out, filters, the water washing final vacuum of filter cake 0.5L × 6
After drying, 0.46Kg compound B is obtained.Yield 95%, HPLC purity 95%.
Step S3, prepares compound C
Ethanol 3Kg, water 0.5Kg and compound B (0.5Kg, 1.68mol) it is sequentially added into, under stirring in 10L four-hole bottle
In system, drip isobutyl amine (1.23Kg, 16.8mol, 10equiv.), be then slowly added dropwise in system containing NaOH (0.207
Kg, 2.69mol, 1equiv) water (0.5Kg) solution.Stir 15～20 hours at 15～20 DEG C after dropping.So
After rear decompression is completely distilled off out ethanol, in system, add the water of 2Kg, and crystallize in ice-water bath.Filter, filter cake use water 0.5
After the washing of L × 3, after filter cake vacuum drying, obtain 0.5Kg compound C.Yield 95%, HPLC purity 95%.
Step S4, prepares compound D
Isopropanol 9.4Kg, diisopropyl ethyl amine (0.23Kg, 1.78mol, 1.20equiv.) it is sequentially added in 20L four-hole bottle
And compound C (0.512Kg, 1.52mol, 1equiv.) stirring, it is heated at 40～50 DEG C, is dividedly in some parts p-nitrophenyl sulphur
Acyl chlorides (0.388Kg, 1.75mol, 1.15equiv.), after charging, stirring 2～3 hours, add to system at such a temperature
Entering water 1Kg, drip complete, stir 0.5 hour, cool to 10～15 DEG C, a large amount of solids separate out.Sucking filtration, filter cake is used successively
Water 1.5L × 3 are washed, and 3.6L water/isopropanol (1/1 volume ratio) washs, after the washing of 1L isopropanol, 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%, isomer
Content < 0.1%.
Step S5, prepares target product 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide
Be sequentially added in 20L four-hole bottle THF 6.35Kg, compound D (1.44Kg, 2.77mol), relative to compound
The Pd/C (0.144Kg) of D mass 10% and acetic acid (0.66Kg, 11.08mol, 4equiv.), be dividedly in some parts first under stirring
Acid ammonium (0.69Kg, 11.08mol, 4equiv.).After charging, the system heat release for the treatment of is the most gentle, 15～20 DEG C of temperature
Lower stirring 15～20 hours.Then system is filtered and remove after Pd/C, at temperature control 15～25 DEG C, in filtrate, add concentrated hydrochloric acid
(mass concentration is 36%) 2.6Kg.It is then heated to 35～45 DEG C stir 3～5 hours, after system cools to 15～25 DEG C,
Concentrate and remove after THF, in system, add 10Kg water, cool to 15～25 DEG C, regulate PH with NaOH after 14, ice
Crystallize under water-bath.Filter after crystallize, after filter cake washes with water, after vacuum drying, obtain 1Kg 4-amino with recrystallisation from isopropanol
-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide.Yield 93%, HPLC purity >=99.4%, single
Miscellaneous < 0.1%.
Embodiment 3
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, concrete preparation process is as follows:
Step S1, prepares compound A
Equipped with the methanol/H of KOH (33.6g, 0.6mol) in container A2O (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；Hold
Device C is total to equipped with the L-phenylalanine (6.4mmol) of Boc protection and the THF solution of N-methylmorpholine (6.4mmol)
20mL；Equipped with the THF solution of carbonochloridic acid propyl ester (9.6mmol) in container D, 20mL altogether.By reaction vessel C and
Material in reaction vessel D is pumped in reaction center II by tetrafluoro pipeline；Molten by reaction vessel A and reaction vessel B
Liquid is pumped in reaction center I (wherein KOH and diazonium material molar ratio are 2:1) by tetrafluoro pipeline, and heart I produces in the reaction
Raw Azimethylene. enters reaction center III by the overfall of reaction center, and the activated intermediate that reaction center II produces is pumped into
With diazomethane reaction in reaction center III, its product is pumped in reaction center IV；Pump into reaction center IV simultaneously
The HCl/ ethanol solution 30ml of 2M, pumps into post processing center after 0 DEG C of stirring 10min, obtains the compound A of 1.5g.Yield
79%, purity HPLC > 97%.
Step S2, prepares compound B
In 20L four-hole bottle, it is sequentially added into oxolane 3.41Kg, compound A (1Kg, 3.36mol) stir afterwards, by molten
After Hexalin (1.2Kg) solution having tert-butyl alcohol aluminum (5.04mol) joins reaction system, stir at a temperature of 15～20 DEG C
15～20 hours.After dripping hydrochloric acid (5.4Kg) the cancellation system of 1M after completion of the reaction in system, add the positive heptan of 12L
Alkane stirs, crystallize of lowering the temperature, and after a large amount of white solids separate out, filters, and the water washing final vacuum of filter cake 1L × 6 is dried,
Compound B to 0.91Kg.Yield 88%, HPLC purity 95%.
Step S3, prepares compound C
Propanol 3Kg, water 1Kg and compound B (1Kg, 3.36mol) it is sequentially added into, to body under stirring in 20L four-hole bottle
System drips isobutyl amine (67.2mol), is then slowly added dropwise in system containing double (trimethyl is silica-based) Sodamide .s (3.36mol)
Water (1Kg) solution.Stir 15～20 hours at a temperature of 15～20 DEG C after dropping.Then after decompression distills out ethanol,
The water of 4Kg, and crystallize in ice-water bath is added in system.Filtering, after the washing of filter cake use water 1L × 3, filter cake is vacuum dried
After, obtain 473Kg compound C.Yield 90%, HPLC purity 94%.
Step S4, prepares compound D
Be sequentially added in 20L four-hole bottle ethanol 9.4Kg, sodium carbonate (1.672mol) and compound C (0.512Kg, 1.52
Mol, 1equiv.) stirring, it is heated at 40～60 DEG C, is dividedly in some parts 4-Nitrobenzenesulfonyl chloride (1.672mol).Feed complete
After, stirring 2～3 hours at such a temperature, add water 1Kg to system, drip complete, stir 0.5 hour, cool to room temperature,
A large amount of solids separate out.Sucking filtration, filter cake washs with water 1.5L × 3 successively, and 3.6L water/isopropanol (1/1 volume ratio) washs, 1L
After isopropanol washing, after Vacuum dry filter cake, the filter cake ethyl alcohol recrystallization of 6 volumes, obtain 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 sulfonamide
Be sequentially added in 20L four-hole bottle methanol 6.35Kg, compound D (1.44Kg, 2.77mol), relative to compound
The Pd/C (0.144Kg) of D mass 30% and pivalic acid (5.54mol), be dividedly in some parts ammonium formate (27.7mol) under stirring.
After charging, the system heat release for the treatment of is the most gentle, stirs 15～20 hours at a temperature of 15～20 DEG C.Then system is crossed elimination
After Pd/C, at temperature control 15～25 DEG C, in filtrate, add concentrated hydrochloric acid (mass concentration is 36%) 2.6Kg.It is then heated to
35～45 DEG C are stirred 3～5 hours, after system cools to 15～25 DEG C, concentrate after removing THF, add 10Kg in system
Water, cools to 15～25 DEG C, regulates PH with NaOH > after 14, crystallize under ice-water bath.Filtering after crystallize, filter cake washes with water
After, obtain 1Kg 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl with recrystallisation from isopropanol after vacuum drying
Base benzsulfamide.Yield 88.7%, HPLC purity>=99.2%, single miscellaneous<0.1%.
Embodiment 4
Preparation 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, concrete preparation process is as follows:
Step S1, prepares compound A
Equipped with the methanol/H of KOH (33.6g, 0.6mol) in container A2O (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；In container C
L-phenylalanine (6.4mmol) and the THF solution 20mL altogether of N-methylmorpholine (9.6mmol) equipped with Boc protection；
Equipped with the THF solution of carbonochloridic acid butyl ester (5.12mmol) in container D, 20mL altogether.Reaction vessel C and reaction are held
Material in device D is pumped in reaction center II by tetrafluoro pipeline；Solution in reaction vessel A and reaction vessel B is passed through
Tetrafluoro pipeline is pumped in reaction center I (wherein KOH and diazonium material molar ratio are 2:1), the weight that heart I produces in the reaction
Formylmerphalan alkane enters reaction center III by the overfall of reaction center, and the activated intermediate that reaction center II produces is pumped in reaction
With diazomethane reaction in heart III, its product is pumped in reaction center IV；Pump into 2M's to reaction center IV simultaneously
HBr/ ethanol solution 60ml, pumps into post processing center after 0 DEG C of stirring 10min, obtains the compound A of 1.53g.Yield 70%,
Purity HPLC > 95%.
Step S2, prepares compound B
In 20L four-hole bottle, it is sequentially added into chlorobenzene 3.41Kg, compound A (1Kg, 3.36mol) stir afterwards, will be dissolved with three
After Hexalin (1.2Kg) solution of tertiary butyoxy aluminum lithium (1mol) joins reaction system, at a temperature of 15～20 DEG C
Stir 15～20 hours.After dripping hydrochloric acid (5.4Kg) the cancellation system of 1M after completion of the reaction in system, add 12L's
Normal heptane stirs, crystallize of lowering the temperature, and after a large amount of white solids separate out, filters, and the water washing final vacuum of filter cake 1L × 6 is dried,
Obtain the compound B of 0.775Kg.Yield 75%, HPLC purity 95%.
Step S3, prepares compound C
In 20L four-hole bottle, be sequentially added into propanol 15Kg, water 1Kg and compound B (1Kg, 3.36mol), under stirring to
System drips isobutyl amine (16.8mol), is then slowly added dropwise in system containing double (trimethyl is silica-based) Sodamide .s (6.72mol)
Water (1Kg) solution.Stir 15～20 hours at a temperature of 15～20 DEG C after dropping.Then after decompression distills out ethanol,
The water of 4Kg, and crystallize in ice-water bath is added in system.Filtering, after the washing of filter cake use water 1L × 3, filter cake is vacuum dried
After, obtain 427Kg compound C.Yield 88%, HPLC purity 94%.
Step S4, prepares compound D
Be sequentially added in 20L four-hole bottle ethanol 9.4Kg, pyridine (2.28mol) and compound C (0.512Kg, 1.52mol,
1equiv.) stirring, is heated at 40～60 DEG C, is dividedly in some parts 4-Nitrobenzenesulfonyl chloride (2.28mol).After charging,
Stir 2～3 hours at a temperature of Gai, add water 1Kg to system, drip complete, stir 0.5 hour, cool to room temperature, in a large number
Solid separates out.Sucking filtration, filter cake washs with water 1.5L × 3 successively, and 3.6L water/isopropanol (1/1 volume ratio) washs, 1L isopropyl
After alcohol washing, after Vacuum dry filter cake, the filter cake ethyl alcohol recrystallization of 6 volumes, obtain 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 sulfonamide
Be sequentially added in 20L four-hole bottle methanol 6.35Kg, compound D (1.44Kg, 2.77mol), relative to compound
The Pd/C (0.144Kg) of D mass 5% and propanoic acid (27.7mol), be dividedly in some parts ammonium formate (11.8mol) under stirring.Add
After material, the system heat release for the treatment of is the most gentle, stirs 15～20 hours at a temperature of 15～20 DEG C.Then system is filtered and remove
After Pd (OH) 2, at temperature control 15～25 DEG C, in filtrate, add concentrated hydrochloric acid (mass concentration is 36%) 2.6Kg.It is then heated to
35～45 DEG C are stirred 3～5 hours, after system cools to 15～25 DEG C, concentrate after removing THF, add 10Kg in system
Water, cools to 15～25 DEG C, regulates PH with NaOH > after 14, crystallize under ice-water bath.Filtering after crystallize, filter cake washes with water
After, obtain 0.91Kg 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-with recrystallisation from isopropanol after vacuum drying different
Butyl benzene sulfonamide.Yield 85%, HPLC purity>=99.2%, single miscellaneous<0.1%.
From above description and data, it can be seen that the above embodiments of the present invention achieve following technique effect:
Preparation method provided by the present invention is used to prepare 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl group
Benzsulfamide, route is relatively simple.Each step is respectively provided with higher productivity, and the purity of the product of each step is higher.Same with this
Time, in each step, the separating-purifying for intermediate product is relatively simple.It addition, in the preparation method of present invention employing, each raw material
Being the reagent that this area is common, raw material is relatively inexpensive.Comprehensive above each factor, the preparation method that the present invention uses is more suitable for work
Industry large-scale application.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for those skilled in the art
For, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, any amendment of being made, etc.
With replacement, improvement etc., should be included within the scope of the present invention.
Claims (22)
1. the preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide, its feature
It is, comprises the following steps:
S1, after the amino in L-phenylalanine is carried out Boc protection, the L-phenylalanine that described Boc is protected and chloro
Formic acid esters carries out reaction and generates activated intermediate, then described activated intermediate and Azimethylene. is carried out reaction and obtains diazonium
Methyl ketone intermediate product, reacts described dizaomethyl ketone intermediate product with halogen acids, obtains compound A；
S2, reduces to the carbonyl in compound A, obtains compound B；
S3, in the presence of isobutyl amine, makes described compound B carry out successively being cyclized, ring-opening reaction, obtains compound C；
S4, makes described compound C react with 4-Nitrobenzenesulfonyl chloride, 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 sulfonamide；
The structural formula of described compound A, described compound B, described compound C and described compound D is as follows:
Wherein, corresponding halogen atom during X is described halogen acids；
Described step S2 includes:
S21, mixes described compound A with reducing 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, purifies described first product system, obtains described compound B；
Described reducing agent is isobutanol aluminum；Described alcohol is isopropanol；Described first organic solvent is toluene；Described reduction
Agent is 0.5～1.5:1 with the mol ratio of described compound A；Described alcohol is 4～15:1 with the mol ratio of described compound A；
Described first organic solvent is 2.5～10:1 with the weight ratio of described compound A.
Preparation method the most according to claim 1, it is characterised in that described step S1 includes:
S11, in the presence of the first alkali, after the amino in described L-phenylalanine is carried out Boc protection, by described Boc
The L-phenylalanine of protection reacts with described carbonochloridic acid ester, generates described activated intermediate；
S12, reacts described activated intermediate with described Azimethylene., generates described dizaomethyl ketone intermediate product；
And
S13, reacts described dizaomethyl ketone intermediate product with described halogen acids, obtains described compound A.
Preparation method the most according to claim 2, it is characterised in that described first alkali selected from N-methylmorpholine, triethylamine,
One or more in diisopropyl ethyl amine and tri-n-butylamine；Described carbonochloridic acid ester is selected from methyl chlorocarbonate, chloro
One in Ethyl formate, carbonochloridic acid propyl ester, isopropyl chloroformate, carbonochloridic acid butyl ester and carbonochloridic acid isobutyl ester
Or it is multiple；Described halogen acids is selected from hydrogen bromide or hydrogen chloride.
Preparation method the most according to claim 3, it is characterised in that described first alkali is triethylamine；Described carbonochloridic acid ester
For chloro ethyl formate.
5. according to the preparation method according to any one of claim 2 to 4, it is characterised in that described first alkali and described L-phenylpropyl alcohol
The mol ratio of propylhomoserin is 1～1.5:1；Described carbonochloridic acid ester is 1～1.5:1 with the mol ratio of described L-phenylalanine；Described hydrogen
Hydracid is 1～2:1 with the mol ratio of described L-phenylalanine.
Preparation method the most according to claim 1, it is characterised in that purify described first product system in described step S23
Step include:
First product system described in cancellation, obtains quencher；And
In described quencher, add the first crystallize agent, the described compound B in described quencher is separated out, solid-liquid separation
Obtain described compound B.
Preparation method the most according to claim 1, it is characterised in that described step S3 includes:
S31, mixes described compound B with described isobutyl amine, 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.
Preparation method the most according to claim 7, it is characterised in that described second alkali is selected from KOH, NaOH, NaH, double
One or more in (trimethyl is silica-based) Sodamide., double (trimethyl is silica-based) potassamide and double (trimethyl is silica-based) Lithamide.；
Described second organic solvent is selected from ethanol, methanol, propanol, isopropanol or n-butyl alcohol.
Preparation method the most according to claim 8, it is characterised in that described second alkali is KOH；Described second organic solvent
For ethanol.
Preparation method the most according to claim 8 or claim 9, it is characterised in that described isobutyl amine and described compound B mole
Ratio is 5.0～20:1；Described second alkali is 1～2:1 with the mol ratio of described compound B；Described second organic solvent is with described
The weight ratio of compound B is 3～15:1.
11. preparation methoies according to claim 1, it is characterised in that described step S4 includes:
S41, mixes described compound C with described 4-Nitrobenzenesulfonyl chloride, the 3rd alkali and the 3rd organic solvent, obtains
Three question response systems；
S42, makes described 3rd question response system reaction, forms third product system；And
S43, purifies described third product system, obtains described compound D.
12. preparation methoies according to claim 11, it is characterised in that described 3rd alkali is selected from triethylamine, diisopropyl ethyl
Amine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, DMAP, 2,6-lutidines and
One or more in 2,6-dichloride base pyridine；Described 3rd organic solvent selected from isopropanol, dichloromethane, oxolane,
Glycol dimethyl ether, ethanol, methanol, propanol, butanol or toluene.
13. preparation methoies according to claim 12, it is characterised in that described 3rd alkali is triethylamine；Described 3rd organic molten
Agent is isopropanol.
14. preparation methoies according to claim 12, it is characterised in that described 4-Nitrobenzenesulfonyl chloride is with described compound C's
Mol ratio is 1.1～1.5:1；Described 3rd alkali is 1.1～1.5:1 with the mol ratio of described compound C；Described 3rd organic molten
Agent is 2～10:1 with the weight ratio of described compound C.
15. according to the preparation method according to any one of claim 11 to 14, it is characterised in that purify institute in described step S43
The step stating third product system includes:
In described third product system, add the second crystallize agent, carry out solid-liquid separation after crystallize, obtain solids；
Described solids is carried out recrystallization, obtains described compound D.
16. preparation methoies according to claim 1, it is characterised in that described step S5 includes:
S51, mixes described compound D with catalyst, hydrogen source, organic acid and the 4th organic solvent, obtains the 4th and treats instead
Answer system；
S52, makes described formation the 4th question response system react, obtains the 4th product system；And
S53, purifies described 4th product system, obtains described 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene fourth
Base]-N-isobutyl-benzene sulfonamide；
Wherein, hydrogen source described in described step S51 is ammonium formate or formic acid.
17. preparation methoies according to claim 16, it is characterised in that described catalyst is selected from Pd/C or Pd (OH)2；Described
Organic acid is selected from acetic acid, formic acid, propanoic acid or pivalic acid；Described 4th organic solvent selected from oxolane, methanol, ethanol,
One or more in ethyl acetate and isopropyl acetate.
18. preparation methoies according to claim 17, it is characterised in that described 4th organic solvent is oxolane.
19. preparation methoies according to claim 17, it is characterised in that described catalyst with the mass ratio of described compound D is
0.05～0.3:1；Described ammonium formate is 4.0～10.0:1 with the mol ratio of described compound D；Described organic acid and described chemical combination
The mol ratio of thing D is 2～10:1；Described 4th organic solvent is 3～10:1 with the weight ratio of described compound D.
20. according to the preparation method according to any one of claim 16 to 19, it is characterised in that purify institute in described step S53
The step stating the 4th product system includes:
Described 4th product system is carried out solid-liquid separation, obtains filtrate；
Described filtrate is carried out crystallize, and solid-liquid separation obtains crude product；And
Described crude product is carried out recrystallization, obtains described 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-
Isobutyl-benzene sulfonamide.
21. preparation methoies according to claim 15, it is characterised in that in the step of described recrystallization, the recrystallization of employing is molten
Agent is selected from isopropanol, ethanol, methanol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether(MTBE).
22. preparation methoies according to claim 20, it is characterised in that in the step of described recrystallization, the recrystallization of employing is molten
Agent is selected from isopropanol, ethanol, methanol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether(MTBE).
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| CN109824756B (en) * | 2019-03-19 | 2022-03-22 | 山东大学 | Phenylalanine derivative containing 4- (benzenesulfonyl) piperazine-2-ketone and preparation method and application thereof |
| CN117142989A (en) * | 2020-12-30 | 2023-12-01 | 上海飞腾医药科技有限公司 | Growth method of anti-HIV drug intermediate crystal A and crystal obtained by same |
| CN113896658A (en) * | 2021-09-24 | 2022-01-07 | 上药康丽（常州）药业有限公司 | Method for synthesizing darunavir intermediate by using microchannel reactor |
| CN114276280B (en) * | 2021-10-30 | 2023-10-31 | 苏州汉酶生物技术有限公司 | Preparation method of chiral phenterminol sulfonamide compound, intermediate for preparing chiral phenterminol sulfonamide compound and preparation method of chiral phenterminol sulfonamide compound |
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