CN102491915B

CN102491915B - Method for preparing ubenimex hydrolysis intermediates

Info

Publication number: CN102491915B
Application number: CN 201110397388
Authority: CN
Inventors: 陈轶之; 张广明; 钱建彬; 钱怀伟
Original assignee: WANLE PHARMACEUTICAL CO Ltd SHENZHEN
Current assignee: WANLE PHARMACEUTICAL CO Ltd SHENZHEN
Priority date: 2011-12-02
Filing date: 2011-12-02
Publication date: 2013-08-28
Anticipated expiration: 2031-12-02
Also published as: CN102491915A

Abstract

The invention provides a method for preparing ubenimex hydrolysis intermediates (2S and 3R)-3-amino-2-hydroxyl-4-phenylbutyric acid. A method that a potential of hydrogen (pH) value is adjusted after hydrolysis is directly utilized to dissociate a resolving agent, hydrochloric acid solution with proper concentration and volume is selected to perform the hydrolysis, thereby enabling operation to be suitable for industrialization production and achieving ideal yield and purity. By utilizing dimethyl formamide (DMF) solvent crystallization, product quality is further improved and white crystals with high purity and optical activity are produced. The method is simple and convenient to operate, saved in solvents and energy sources, high in yield and suitable for the industrialization production.

Description

A kind of ubenimex hydrolysis intermediates preparation

Technical field

The present invention relates to organic chemistry filed, further relate to ubenimex hydrolysis intermediates preparation.

Background technology

Ubenimex (outer literary fame Ubenimex, Bestalin) be separating obtained dipeptide compound from the nutrient solution of streptomyces (Streptomyces ofivorecticuli), can suppress aminopeptidase B (aminopeptidase B) and leucine peptase (Leucineamino Peptidase) and caspase (Caspase) competitively, strengthen the function of T cell, the vigor that kills and wounds of NK cell is strengthened, and can make synthetic the increasing of G CFS and regeneration and the differentiation of stimulation medullary cell.Can disturb the metabolism of tumour cell, suppress tumor cell proliferation, make apoptosis of tumor cells, and the human activin cellular immune function, the generation of stimulating cytokine and secretion, generation and the propagation of promotion anti-tumour effect cell.But the treatment after leukemia, multiple myeloma, myelodysplastic syndrome and hematopoietic stem cell transplantation of combined with chemotherapy, radiotherapy and combined utilization, and other patients with solid tumor.Ubenimex chemistry N-[(2S by name, 3R)-4-phenyl-3-amino-2-maloyl group]-the L-leucine, its structural formula is as follows:

From the structural formula of ubenimex as can be seen, exist three chiral centres in the molecule, the report of synthetic ubenimex is to cultivate by biochemical fermentation using bacteria the earliest.Along with the continuous development of asymmetric synthesis, increasing chemical synthesis process is in the news out.The intermediate that contains two chiral centres is that the synthetic of 4-phenyl-3-amino-2-hydroxybutyric acid is the emphasis of research, the method of existing synthetic this intermediate exists synthesis step long, the very low temperature reaction, use various shortcomings such as hazardous agents, and synthetic is raceme, need have optically active ubenimex through could further synthesizing after the complicated fractured operation.J.Antib.1983 wherein, 36 (6), 695-9 reported method raw materials cost is low, do not use hazardous agents, and what obtain is that (2S 3R)-4-phenyl-3-amino-2-hydroxybutyric acid, early splits and can improve yield the synthetic needed optical isomer of ubenimex, simplify subsequent step, be fit to industrial production and use.Document reported method reaction scheme is as follows:

Wherein intermediate 4a is (2S, 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt can prepare 5a earlier but not separate purifying, continue to add concentrated hydrochloric acid be hydrolyzed reaction obtain intermediate 6 namely (2S, 3R)-3-amino-2-hydroxyl-4-benzenebutanoic acid.This method utilizes sodium bicarbonate will go up step resolved product dissolving, resolving agent is free, remove S (-)-α-Ben Yian three times with ethyl acetate extraction, water concentrated hydrochloric acid acidifying, be evaporated to about certain volume, add concentrated hydrochloric acid again and refluxed 2 hours, reaction solution continues to be evaporated to dried, be dissolved in water, under ice bath, regulate pH=5-6 with aqueous sodium hydroxide solution, separate out solid, filter, washing, drying obtain the hydrolysis intermediate (2S, 3R)-3-amino-2-hydroxyl-4-benzenebutanoic acid, yield 63.8%, optically-active+32.5 ° (C=0.76,1N HCl).The technology of this method will be used ethyl acetate extraction three times except resolving agent and hydrolysis proceed step by step, the twice concentrating under reduced pressure aqueous solution, and waste solvent and big energy-consuming are not suitable for scale operation.

Summary of the invention

The invention provides a kind of ubenimex hydrolysis intermediate (2S, 3R)-preparation method of 3-amino-2-hydroxyl-4-benzenebutanoic acid, this preparation method is with (2S, 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian is hydrolyzed and obtains, remove resolving agent simultaneously, this method is easy and simple to handle, save energy, the yield height is fit to suitability for industrialized production.

A kind of ubenimex hydrolysis intermediates preparation provided by the invention is characterized in that, comprises following steps:

1) hydrolysis: will (2S, 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt adds in the hydrochloric acid soln of 4-6N 40～85 ℃ of reactions 3～5 hours;

2) crystallization: with sodium hydroxide solution adjust pH to 4.5～9.5, separate out solid, suction filtration, dry (2S, 3R)-3-amino-2-hydroxyl-4-benzenebutanoic acid crude product;

3) recrystallization: crude product carries out recrystallization purifying with DMF-water as recrystallization solvent.

The raw material of technology of the present invention (2S, 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt is according to J.Antib.1983, and 36 (6), the preparation of 695-9 reported method.

(2S, 3R)-mass ratio of 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt and hydrolysis used salt acid solution is 1: 3～6, with (2S, 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt adds in the hydrochloric acid soln of different concns, react in 50～60 ℃, utilize high performance liquid chromatography to carry out reaction monitoring, product and raw material HPLC area percentage result such as following table under the differential responses condition:

As seen selecting concentration for use is that the efficient of hydrochloric acid soln hydrolysis reaction of 4～6N is higher, and adopt serious hysteresis of hydrochloric acid soln reaction times of the concentration of 1～3N consequently to react at short notice not exclusively, and when adopting concentration greater than the hydrochloric acid soln of 6N, because the hydrochloric acid soln volume is very few, the stirring when being not easy to crystallization.In addition, (2S, 3R)-mass ratio of 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt and hydrolysis used salt acid solution is to be more suitable for stirring and crystallization in 1: 3～6 o'clock.

Step 2) utilizes 3～8N concentration hydrogen sodium hydroxide solution conditioned reaction system pH, reach the purpose of free resolving agent and crystallization simultaneously.The contriver with 100g (2S 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt hydrolysis in the 4N hydrochloric acid soln, after reaction is finished, utilizes the 4N sodium hydroxide solution to be adjusted to different pH values, separate out crude product suction filtration drying after the result as follows:

The pH value	3.5	4.5	5.5	6.5	7.5	8.5	9.5	10.5
									Crude product is heavy	21.2g	48.6g	52.3g	52.2g	54.9g	55.0g	49.7g	18.3g

By last table result as can be known, at pH value peracid or cross alkali, for example under the condition of pH3.5 and pH10.5, the product major part remains in the solvent system, and that crude product is separated out in pH7.5～8.5 is maximum, preferably transfers pH to 7.5～8.5, and most preferably 8.2.

Recrystallization solvent of the present invention is 50～70% the DMF-aqueous solution, preferred 60% the DMF-aqueous solution is removed impurity in resolving agent residual in the crude product and the reaction to reach, and improves the purpose of product quality, the mass ratio of crude product and recrystallization solvent is 1: 6～12, preferred 1: 9.The contriver once attempted the DMF aqueous solution of other concentration, find to cause the crystallization difficulty under the too much situation of DMF, and the situation of water excess caused the dissolving crude product difficulty.The contriver is that 1: 9 60% the DMF aqueous solution carries out recrystallization with product crude product mass volume ratio, and crystallization after product and crude product contrast with optically-active through HPLC, and the result is as follows:

	HPLC purity	Specific rotation
			The product crude product	95.4％	+28.6
Recrystallized product	98.6％	+31.7

By the result as can be known, DMF-aqueous solution recrystallization can effectively be removed resolving agent residual in the crude product and impurity, improves product quality.

A kind of ubenimex hydrolysis intermediate (2S provided by the invention, 3R)-preparation method of 3-amino-2-hydroxyl-4-benzenebutanoic acid, with document J.Antibiotics, 36 (1983), the method of 695～699 records is compared, the present invention directly utilizes the free resolving agent of the method for regulating pH after the hydrolysis, saves the sodium bicarbonate aqueous solution dissolving and then with the step of ethyl acetate washing three times, saves a large amount of solvents; Save twice simultaneously for the distillation of the used aqueous solution, save energy; Select the hydrochloric acid soln of proper concn and volume, make operation be more suitable for suitability for industrialized production, reach desirable yield and purity; Utilize the DMF solvent crystallization, further improve the quality of products, it is higher to obtain purity, the white crystal that specific rotation is higher.Therefore method of the present invention is easy and simple to handle, saves solvent and the energy, and the yield height is fit to suitability for industrialized production.

The present invention of embodiment below in conjunction with embodiment is described in further detail.

Embodiment

Embodiment 1

With 200g (2S, 3R)-and 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt puts into reactor, adds the aqueous hydrochloric acid of 640g 4N, stirred 3 hours down in 50 ℃, the sodium hydroxide solution that adds 4N is regulated pH=8.2, and suction filtration gets crude product 109.6g.Utilize the DMF-aqueous solution of 986.4g 60% to be heated to 90 ℃ of dissolvings crude product, stirring and crystallizing at room temperature, suction filtration, drying gets white crystal 103.63g, purity 98.6%, optically-active+31.7 ° (C=1,1N HCl), yield 93.27%.

Embodiment 2

With 200g (2S, 3R)-and 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt puts into reactor, adds the aqueous hydrochloric acid of 640g 4N, stirred 3 hours down in 70 ℃, the sodium hydroxide solution that adds 6N is regulated pH=8.2, and suction filtration gets crude product 110.1g.Utilize the DMF-aqueous solution of 990.9g 60% to be heated to 90 ℃ of dissolvings crude product, stirring and crystallizing at room temperature, suction filtration, drying gets white crystal 102.98g, purity 98.5%, optically-active+31.5 ° (C=1,1N HCl), yield 92.87%.

Embodiment 3

With 200g (2S, 3R)-and 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt puts into reactor, adds the aqueous hydrochloric acid of 1000g 4N, stirred 3 hours down in 60 ℃, the sodium hydroxide solution that adds 6N is regulated pH=8.2, and suction filtration gets crude product 105.4g.Utilize the DMF-aqueous solution of 700g 70% to be heated to 90 ℃ of dissolvings crude product, stirring and crystallizing at room temperature, suction filtration, drying gets white crystal 103.50g, purity 98.2%, optically-active+31.4 ° (C=1,1N HCl), yield 93.21%.

Comparative example 1:

With 200g (2S, 3R)-and 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt puts into reactor, adds the aqueous hydrochloric acid of 640g 3N, stirred 12 hours down in 50 ℃, the sodium hydroxide solution that adds 6N is regulated pH=8.2, and suction filtration gets crude product 101.5g.Utilize the DMF-aqueous solution of 913.5g 60% to be heated to 90 ℃ of dissolvings crude product, violent crystallization at room temperature, suction filtration, drying gets white crystal 92.43g, purity 98.7%, optically-active+31.5 ° (C=1,1N HCl), yield 83.19%.

Claims

1. a ubenimex hydrolysis intermediates preparation is characterized in that, comprises following steps:

1) hydrolysis: will (2S, 3R)-3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt adds in the hydrochloric acid soln of 4～6N 40～85 ℃ of reactions 3～5 hours;

2. method according to claim 1 is characterized in that, the described temperature of reaction of step 1) is 50～60 ℃.

3. method according to claim 1 is characterized in that, and step 1) (2S, 3R)-mass ratio of 3-acetylaminohydroxyphenylarsonic acid 2-hydroxyl-4-benzenebutanoic acid S (-)-α-Ben Yian salt and hydrochloric acid soln is 1: 3～6.

4. method according to claim 1 is characterized in that step 2) described concentration sodium hydroxide is 3～8N.

5. method according to claim 1 is characterized in that step 2) described pH value is 7.5～8.5.

6. method according to claim 1 is characterized in that step 2) described pH value is 8.2.

7. method according to claim 1 is characterized in that, the described recrystallization solvent of step 3) is the DMF-aqueous solution of 50-70%.

8. method according to claim 7 is characterized in that, the described recrystallization solvent of step 3) is 60% the DMF-aqueous solution.

9. method according to claim 1 is characterized in that, the mass ratio of the described crude product of step 3) and recrystallization solvent is 1: 6～12.

10. method according to claim 9 is characterized in that, the mass ratio of the described crude product of step 3) and recrystallization solvent is 1: 9.