CN107382903B

CN107382903B - Preparation method of anticancer drug intermediate

Info

Publication number: CN107382903B
Application number: CN201710365496.6A
Authority: CN
Inventors: 刘登贵; 杨坤于; 周伟; 陈浩; 曾庆东
Original assignee: Chongqing Nansongkai Biological Pharmaceutical Co ltd
Current assignee: Chongqing Nansongkai Biological Pharmaceutical Co ltd
Priority date: 2017-05-22
Filing date: 2017-05-22
Publication date: 2021-02-26
Anticipated expiration: 2037-05-22
Also published as: CN107382903A

Abstract

The invention discloses a preparation method of an anticancer drug intermediate, which takes glyceraldehyde acetonide and L-cysteine hydrochloride as raw materials, and obtains a compound shown in a formula VI by the steps of ring closing, oxidation, propylidene removal, reoxidation, halogenation and the like, and further obtains a compound shown in a formula I by the Wittig reaction of the compound shown in the formula VI and isobutyraldehyde.

Description

Preparation method of anticancer drug intermediate

Technical Field

The invention belongs to the field of pharmaceutical chemicals.

Background

Tubulysins is a medicine with important curative effect on prostate cancer, and key intermediates and process research thereof are particularly important. Currently, the ketene intermediate 2-acetyl-4-formate thiazole is obtained by using L-cysteine ethyl ester hydrochloride as a raw material through ring closing and oxidation. The intermediate ketene is subjected to a series of reactions to prepare the Tubulysins.

The ketene intermediate was prepared as follows:

the route involves ring closure of L-cysteine hydrochloride and methylglyoxal followed by oxidation with manganese dioxide. According to literature reports, the yield of the two steps is only 52%. Then titanium tetrachloride is used for catalyzing the condensation reaction in the next step to generate ketene, and the ketene is dehydrated to generate the target compound. The conditions of the step are very harsh, and require-78 ℃ and anhydrous and anaerobic conditions. The last step has many reaction sites, self-condensation is easy to occur, reaction impurities are very many, post-treatment and purification are difficult, the yield of the reaction is greatly influenced, and the separation difficulty is increased. Although the yield is reported in the literature to be 77%, the post-treatment is realized by passing through a column, which is extremely limited industrially. The total yield of the whole route is 40%.

Disclosure of Invention

In order to overcome the existing difficulties, the invention discloses a preparation method of an anticancer drug intermediate.

In the first step, glyceraldehyde acetonide RM1 and L-cysteine hydrochloride (RM 2) are subjected to ring closing to obtain a thiazole ring compound (formula II), wherein R is C1-C6 alkyl. The reaction temperature is within the range of 0-80 ℃, and the effect is better at 25-35 ℃. The reaction solvent is water/ethanol, water/acetonitrile or water/tetrahydrofuran, more preferably water/ethanol, the proportion of the mixed solvent is 1.0-5.0: 1.0, and the experimental result shows that the effect is best when the proportion is 1.5: 1.0.

In a second step, the compound II is oxidized and depropylidene is removed to obtain a compound III, the definition of R is consistent with that of the compound III,

oxidizing the compound II with an oxidant, and then removing propylidene under an acidic condition to obtain a compound III. The reaction solvent is acetonitrile, ethanol, chloroform and DMF, wherein the acetonitrile has the best solubility to the compound II. The oxidant is manganese dioxide, and the weight ratio of the substrate to the manganese dioxide is 1.0: 20.0. The oxidation temperature is 35-80 deg.C, more preferably 60-65 deg.C. The acidic condition required by the depropylene is usually hydrochloric acid, acetic acid and sulfuric acid, and the hydrochloric acid has the best effect. The molar ratio of the substrate to the concentrated hydrochloric acid is 1.0: 3.0-10.0, and more preferably 1.0: 5.0.

In the third step, the compound III is oxidized to obtain a compound IV, the definition of R is consistent with that of the compound IV,

and oxidizing the compound III with manganese dioxide to obtain a compound IV, wherein the reaction solvent is acetonitrile, ethanol, chloroform and DMF, and acetonitrile is preferred. The temperature is 35-80 deg.C, more preferably 60-65 deg.C. The weight ratio of the substrate to the manganese dioxide is 1: 10 to 40. More preferably 1.0: 10.0.

fourthly, the compound IV is halogenated to obtain a compound V, R is consistent with the definition, X is a halogen atom,

the halogenating agent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, preferably thionyl chloride. The reaction temperature is 40-80 ℃, preferably 60-70 ℃. The molar ratio of the halogenated reagent to the substrate is 1.0-5.0: 1.0, more preferably 1.2: 1.0.

the fifth step, the preparation of compound VI,

reacting the compound V with triphenylphosphine to obtain an intermediate compound VI';

the reaction solvent is toluene, ethanol, chloroform, isopropyl ether, DMF, and more preferably toluene. The temperature is 60 to 100 deg.C, more preferably 80 to 85 deg.C. And VI' is dissociated under an alkaline condition, wherein the alkali is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, and the dissociation temperature is 0-50 ℃, more preferably 15-25 ℃, so as to obtain the compound VI.

Sixthly, performing witting reaction on the compound VI and aldehyde to obtain a ketene compound I,

the reaction solvent is chloroform, ethanol, isopropyl ether, preferably chloroform. The temperature is 30-100 deg.C, preferably 60-70 deg.C.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 1

Synthesis of Compound II (R = Et)

1.1L-cysteine ethyl ester hydrochloride (10 g, 0.054 mol) was dissolved in 100ml of water, and sodium hydrogencarbonate (4.5 g) was added. After stirring and dissolving, the mixture was dropped into a solution of 10.5g (0.081 mol) of D-glyceraldehyde acetonide in ethanol (65 ml). After the dripping is finished, heating to 25-35 ℃ and reacting for 1 h. After completion of the reaction, the mixture was extracted twice with 100ml of methylene chloride. The combined organic layers were washed with 50ml of water. Dried over anhydrous magnesium sulfate and concentrated to obtain 12.1 g.

1.2L-cysteine ethyl ester hydrochloride (10 g, 0.054 mol) was dissolved in 100ml of water, and sodium hydrogencarbonate (4.5 g) was added thereto. After stirring and dissolving, the mixture was dropped into a solution of 10.5g (0.081 mol) of D-glyceraldehyde acetonide in ethanol (65 ml). After the dripping is finished, the temperature is raised to 40-50 ℃ for reaction for 0.5 h. After completion of the reaction, the mixture was extracted twice with 100ml of methylene chloride. The combined organic layers were washed with 50ml of water. Dried over anhydrous magnesium sulfate and concentrated to obtain 10.8 g.

Example 2

Synthesis of Compound III (R = Et)

2.1 dissolving 10g of compound II (R = Et, 0.038 mol) in 100ml of acetonitrile, adding 80g of manganese dioxide, stirring and heating to 60-65 ℃ for reaction for 2h, performing suction filtration, adding 17ml of concentrated hydrochloric acid into the filtrate, and stirring at 30-40 ℃ for 1 h. Concentrating under reduced pressure at 30-40 ℃, adding 50ml of dichloromethane and 20ml of water for dissolving, and adjusting the alkali to be neutral by using a saturated sodium bicarbonate solution. The aqueous layer was extracted with 25ml of dichloromethane, the organic layers were combined, washed with 50ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 7.4g of a solid was obtained.

2.2 dissolve 10g of Compound II (R = Et, 0.038 mol) in 100ml of acetonitrile, add 80g of manganese dioxide, stir and heat to 50-55 ℃ for reaction for 3 h. And (5) suction filtration. Adding 17ml of concentrated hydrochloric acid into the filtrate, and stirring for 1 hour at the temperature of 30-40 ℃. Concentrating under reduced pressure at 30-40 ℃, adding 50ml of dichloromethane and 20ml of water for dissolving, and adjusting the alkali to be neutral by using a saturated sodium bicarbonate solution. The aqueous layer was extracted with 25ml of dichloromethane, the organic layers were combined, washed with 50ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 6.1g of solid was obtained.

Example 3

Synthesis of Compound IV (R = Et)

3.1 dissolve 10g of Compound III (R = Et, 0.046 mol) in 100ml of acetonitrile, add 40g of manganese dioxide, stir and heat to 60-65 ℃ for reaction for 2 h. And (5) suction filtration. Concentrating under reduced pressure. 8.9g of a solid was obtained.

3.2 dissolve 10g of compound III (R = Et, 0.046 mol) in 100ml of chloroform, add 40g of manganese dioxide, stir and heat to 60-65 ℃ for reflux reaction for 4 h. And (5) suction filtration. Concentration under reduced pressure gave 8.2g of a solid.

Example 4

Synthesis of Compound V (R = Et, X = Cl)

4.1 dissolve 5g of compound IV (R = Et, 0.023 mol) in 30ml of chloroform, cool to 0-5 ℃, add 2.8g of triethylamine, drop by drop 3.3g of thionyl chloride, and after dropping, heat up and reflux react for 1.5 h. Concentrating under reduced pressure. The residue was dissolved in 10ml of chloroform, 10ml of aqueous solution was added and extracted once with 5ml of chloroform, and the combined organic phases were washed once with 10ml of water, dried over anhydrous sodium sulfate and concentrated. 4.5g of a solid are obtained.

4.2 dissolving 5g of compound IV (R = Et, 0.023 mol) in 8ml of phosphorus oxychloride, heating to 30-35 ℃, dropwise adding 1.7g of N, N-dimethylformamide, and heating to 45-50 ℃ after dropwise adding to react for 1 h. Cooling to room temperature, slowly adding the reaction solution into crushed ice, adding 25ml of X2 dichloromethane for extraction, washing the extract with water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. Drying sodium salt, and concentrating. 4.2g of a solid are obtained.

Example 5

Synthesis of Compound VI (R = Et)

5.1 20g of Compound V (R = Et, X = Cl, 0.086 mol) are added to 100ml of toluene, and 24.6g of triphenylphosphine are added with stirring, and the mixture is heated to 80-85 ℃ and reacted for 10 h. Filtering, washing a filter cake with 50ml of toluene, drying, adding the obtained solid into 350ml of water, stirring, adjusting the pH value to 8-9 by using 1N sodium hydroxide solution, stirring for 30 minutes, and performing suction filtration. The filter cake was washed to neutrality with 100ml water. Drying to obtain 35.4g with purity of 98.9%.

5.2 20g of Compound V (R = Et, X = Cl, 0.086 mol) are introduced into 150ml of isopropyl ether, and 24.6g of triphenylphosphine are added with stirring and the reaction is carried out at elevated temperature and reflux for 12 h. Filtering, washing a filter cake with 50ml of isopropyl ether, drying, adding the obtained solid into 300ml of water, stirring, adjusting the pH value to 8-9 by using 1N sodium hydroxide solution, stirring for 30 minutes, and performing suction filtration. The filter cake was washed to neutrality with 100ml water. 34.9g of the dried product is obtained, and the purity is 98.0%.

Example 6

Synthesis of Compound I

6.1 dissolve 5.0g of Compound VI (R = Et, 0.011 mol) in 25ml of chloroform, add 3.92g of isobutyraldehyde, stir and raise the temperature to 60-70 ℃ for 45 h. After desolventizing under reduced pressure, 2.5g of white solid with a purity of 99.0% was obtained by refining with n-heptane.

6.2 dissolve 5.0g of Compound VI (R = Et, 0.011 mol) in 25ml of chloroform, add 3.92g of isobutyraldehyde, stir and raise the temperature to 50-60 ℃ for 50 h. After desolventizing under reduced pressure, 2.46g of white solid with a purity of 99.2% was obtained by refining with n-heptane.

6.3 dissolve 5.0g of Compound VI (R = Et, 0.011 mol) in 25ml of isopropyl ether, add 3.92g of isobutyraldehyde, stir and raise the temperature to 50-60 ℃ for reaction for 52 h. After desolventizing under reduced pressure, 2.49g of a white solid was obtained by refining with n-heptane, the purity was 99.0%.

Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.

Claims

1. A preparation method of a compound of a formula VI is characterized in that the compound of the formula V is prepared, the compound V reacts with triphenylphosphine to obtain an intermediate VI ', and then the VI' is dissociated under an alkaline condition to obtain a compound VI,

wherein R is C1-C6 alkyl, and X is halogen atom; the compound V is prepared from a compound IV through halogenation, and the compound IV is prepared from a compound III through oxidation.

2. The process of claim 1, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

3. The process according to claim 2, wherein the reaction solvent is toluene, ethanol, chloroform, isopropyl ether, or DMF.

4. The process according to claim 2, wherein the reaction temperature is preferably between 80 and 85 ℃; the dissociation temperature is preferably 15 to 25 ℃.

5. The process of claim 1, wherein the halogenation conditions are: the halogenated reagent is thionyl chloride, phosphorus oxychloride and phosphorus trichloride; the reaction temperature is preferably 60-70 ℃.

6. The process of claim 1, wherein the oxidation reaction conditions are: the oxidant is manganese dioxide; the reaction solvent is acetonitrile, ethanol, chloroform and DMF, and the temperature is preferably 60-65 ℃.

7. A process according to claim 1, comprising preparing the compound of formula III from the compound of formula II by oxidation and depropylidene under acidic conditions,

wherein R is C1-C6 alkyl.

8. The method of claim 7, wherein the oxidizing agent is manganese dioxide; the reaction solvent is acetonitrile, ethanol, chloroform and DMF, and the reaction temperature is preferably 60-65 ℃; the reaction is carried out under the condition of hydrochloric acid, acetic acid or sulfuric acid to remove propylidene.

9. The process of claim 7, wherein the compound of formula III is prepared from RM1 and RM2,

wherein R is C1-C6 alkyl.

10. The process according to claim 9, wherein the solvent is selected from the group consisting of water/ethanol, water/acetonitrile, water/tetrahydrofuran, and the reaction temperature is preferably in the range of 25 to 35 ℃.

11. A process for the preparation of a compound of formula I, wherein R is C1-C6 alkyl, by reacting a compound of formula VI with isobutyraldehyde, using a process of claim 1 for the preparation of a compound of formula VI

。

12. The method according to claim 11, wherein the reaction solvent is chloroform, ethanol or isopropyl ether, and the reaction temperature is 60 to 70 ℃.