CN107698634B

CN107698634B - Preparation method of idarubicin hydrochloride

Info

Publication number: CN107698634B
Application number: CN201710864446.2A
Authority: CN
Inventors: 刘丹; 苏进财; 代清宇; 吴舰; 王华萍; 柴雨柱; 徐丹; 朱春霞; 田舟山
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2017-09-22
Filing date: 2017-09-22
Publication date: 2020-03-10
Anticipated expiration: 2037-09-22
Also published as: CN107698634A

Abstract

The invention belongs to the field of drug synthesis, and discloses a preparation method of idarubicin hydrochloride, wherein a metal nickel catalyst/organic phosphine ligand/silane reducing agent is adopted to remove 4-methoxy group of an anthracycline compound in one step so as to prepare the idarubicin hydrochloride. The method has the advantages of short steps and low synthesis cost, can reduce the generation of impurities A and B, and improves the quality of the final product idarubicin hydrochloride.

Description

Preparation method of idarubicin hydrochloride

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of idarubicin.

Background

Idarubicin, 4-demethoxydaunorubicin, is a semi-synthetic anthracycline antineoplastic drug used clinically in the treatment of Acute Myeloid Leukemia (AML) and was marketed in the united states in 1990. The mechanism of action is that idarubicin with a rigid structure is inserted into DNA to interfere nucleic acid synthesis, and can also interact with topoisomerase II to further interfere with nucleic acid synthesis. Idarubicin is currently the first choice for treating AML in combination with cytarabine.

The synthesis of idarubicin reported in the literature mainly comprises the following two methods:

the method comprises the following steps:

document "journal of chinese antibiotics, 2006, 31 (3): 181-183' reports a semisynthetic route of idarubicin hydrochloride, acid hydrolysis of daunorubicin hydrochloride is carried out to obtain 2,3, 6-trideoxy-3-hexosamine (1) and tetracyclic anthrone structure (2), and glycosyl donor 2,3, 6-deoxy-3-hexosamine chloride (4) can be obtained from compound 1 through two-step reaction; the compound 2 can obtain a tetracyclic anthrone structure compound 8 with 4-methoxy removed through four-step reaction; the compound 3 and the compound 8 are subjected to glycosylation under the action of silver salt to obtain a compound 10, and the idarubicin hydrochloride is obtained after the protective group is removed and salified.

This route has the following disadvantages: the ethylene glycol is used for protecting C-13 ketonic carbonyl and needs a solvent benzene; the glycosidation reaction has the problems of stereoselectivity and harsh reaction conditions; the reaction steps are long.

The second method comprises the following steps:

CN102757470B discloses the above synthetic route, which comprises protecting 3' -amino of daunorubicin with trifluoroacetyl group to obtain compound 15, and passing through anhydrous MgCl₂Removing 4-methyl to obtain a compound 16, then removing 4-phenolic hydroxyl and 3' -amino protecting groups through three-step reaction to obtain idarubicin, and further salifying to obtain idarubicin hydrochloride. The route has the advantages of avoiding cutting off the glycosidic bond at the 7-position, shortening the reaction route and simultaneously improving the reaction yield.

In the process of researching the reported idarubicin synthesis method, the inventor finds that the final product contains a certain amount of impurity A and impurity B, and the polarity of the impurity A and the impurity B is very similar to that of the idarubicin hydrochloride, so that the separation and purification are very difficult.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for preparing high-purity idarubicin hydrochloride so as to reduce the generation of impurities A and B.

The invention is realized by the following scheme:

a preparation method of idarubicin hydrochloride comprises the following steps:

(a) the protecting group on the 3' -amino group of the daunorubicin hydrochloride is used for preparing a compound 15 shown in the following formula,

wherein R is selected from trifluoroacetyl, benzyloxycarbonyl, fluorenyl methoxycarbonyl, trimethylsiloxyethoxycarbonyl, fluorenyl,

Trityl, p-methoxybenzyl and benzyl;

(b) removing 4-methoxy group from the compound 15 in an organic solvent containing a metallic nickel catalyst and an organophosphorus ligand by using a silane reducing agent to generate a compound 10 shown in the following formula,

(c) and (3) removing a protecting group on the 3' -amino of the compound 10, and further performing salt forming reaction to prepare the idarubicin hydrochloride.

The metallic nickel catalyst is preferably Ni (COD)₂(ii) a The amount of the catalyst is 0.01 to 0.4mol, preferably 0.05 to 0.15mol, per 1mol of the compound 15.

The organophosphine ligand is selected from tricyclohexylphosphine, bis (dicyclohexylphosphine) methane, 1, 3-bis (dicyclohexylphosphine) propane, 1, 4-bis (dicyclohexylphosphine) butane, 1, 3-bis (diphenylphosphino) propane, 1' -bis (diphenylphosphino) ferrocene, preferably tricyclohexylphosphine; the molar weight of the organic phosphine ligand is 0.5 to 3 times of that of the metal catalyst, preferably 2 to 3 times.

The silane reducing agent is selected from 1,1,3, 3-tetramethyl disiloxane and methyl dimethoxysilane; the amount of the silane reducing agent is 1 to 10mol, preferably 1 to 2mol, per 1mol of the compound 15.

Preferably, the organic solvent of step (b) is selected from toluene, o-xylene, trimethylbenzene, methylcyclohexane, dioxane, ethylene glycol dimethyl ether.

Preferably, the reaction temperature in the step (b) is 60-140 ℃, preferably 80-110 ℃.

In a preferred embodiment, R is trifluoroacetyl, and the metallic nickel catalyst is Ni (COD)₂The organophosphorus ligand is tricyclohexylphosphine, and the silane reducing agent is 1,1,3, 3-tetramethyldisiloxane.

The beneficial effects of the invention are shown as follows:

1. the method for preparing the idarubicin hydrochloride can obviously reduce the contents of the impurity A and the impurity B in a final product and improve the quality of the idarubicin hydrochloride;

2. the 4-methoxy of the anthracycline compound is removed in one step by adopting a metallic nickel catalyst/an organic phosphine ligand/a silane reducing agent, compared with the prior art, the reaction steps are greatly shortened, the synthesis cost is reduced, and no literature reports exist at present about a method for removing the 4-methoxy of the anthracycline compound in one step;

3. compared with the prior art which needs pyridine as a trifluoromethanesulfonylation solvent, the method disclosed by the invention does not need to carry out trifluoromethanesulfonylation, does not need a pyridine solvent which is malodorous, high in toxicity and difficult to treat, and is environment-friendly.

Detailed Description

The present invention is described more specifically below, but the following examples are not to be construed as limiting the scope of the present invention in any way. Further, the reaction conditions such as solvent, reaction temperature, reaction time and the like are not limited to the following examples. The reference substances of the impurities A and B are self-made by the company and can be prepared by the methods of the documents CN101331147B, chem.pharm.Bull.1988,36(10) 3897-.

Abbreviations:

TMDSO: 1,1,3, 3-tetramethylsiloxane

PCy 3: tricyclohexylphosphine

EXAMPLE 1 preparation of idarubicin hydrochloride

(1) Preparation of Compound 15 (R is trifluoroacetyl)

Dissolving 10g of daunorubicin hydrochloride in 100ml of dichloromethane, adding 10g of triethylamine and 7.5g of ethyl trifluoroacetate, and stirring at room temperature for 4 hours; the reaction mixture was diluted with 100ml of dichloromethane, washed twice with water and the organic phase was spin-dried to give 10.5g of a solid (yield 95%, HPLC purity 97%).

(2) Preparation of Compound 10 (R is trifluoroacetyl)

Under anhydrous and oxygen-free conditions, 8g of compound 15 is dissolved in anhydrous toluene (80ml), Ni (COD)2(0.15eq) and PCy3(0.075eq) and TMDSO (1eq) are added, after stirring for 2h at 80 ℃, the temperature is increased to 110 ℃ for reaction for 10h, 100ml of ethyl acetate is added to dilute the reaction solution, the reaction solution is washed twice, and the organic phase is dried by spinning to obtain 5.7g of solid (yield 75%).

(3) Preparation of idarubicin hydrochloride

5g of compound 10 are dissolved in 50ml of 0.3N aqueous sodium hydroxide solution and stirred for 1h at room temperature, and the pH is adjusted to 8 by 10% dilute hydrochloric acid; the aqueous layer was extracted three times with dichloromethane, the organic phases were combined, until about 60ml of the organic phase remained, the pH was adjusted to 3 with 10% HCl-methanol solution, 3.6g of yellow solid was precipitated (yield 80%), melting point 183-,¹H NMR(DMSO-d6):δ1.19(3H,d,J＝6.4),1.75(1H,dd,J＝11.9,3.7),1.93(1H,dt,J＝12.8,3.7),2.10(1H,dd,J＝14.3,4.9),2.22(1H,d,J＝12.8),2.32(3H,s),2.96(2H,m),3.40(1H,d,J＝12.3),3.67(1H,d,J＝4.1),4.25(1H,q,J＝12.9,6.3),4.91(1H,s),5.30(1H,d,J＝2.5),5.46(1H,d,J＝6.0),5.6(1H,s),7.95-7.97(2H,m),8.21-8.24(2H,m)。

example 2 preparation of idarubicin hydrochloride

(1) Preparation of Compound 15 (R is benzyloxycarbonyl)

Dissolving 10g of daunorubicin hydrochloride in 100ml of anhydrous dichloromethane, adding 2.3g N, N' -diisopropylethylamine and 4.5g of benzyl chloroformate, and stirring at room temperature for 10 hours; the reaction mixture was diluted with 100ml of dichloromethane, washed twice with water and the organic phase was spin-dried to give 10.6g of a solid (yield 92%, HPLC purity 96%).

(2) Preparation of Compound 10 (R is benzyloxycarbonyl)

Under anhydrous and oxygen-free conditions, 8g of compound 15 is dissolved in anhydrous toluene (80ml), Ni (COD)2(0.15eq) and PCy3(0.075eq) and TMDSO (1eq) are added, after stirring for 2h at 80 ℃, the temperature is increased to 110 ℃ for reaction for 10h, 100ml of ethyl acetate is added to dilute the reaction solution, the reaction solution is washed twice, and the organic phase is dried by spinning to obtain 5.9g of solid (yield 77%).

(3) Preparation of idarubicin hydrochloride

5g of Compound 10, 0.5g of palladium hydroxide (10%) are dissolved in 50ml of tetrahydrofuran, stirred for 4h at 40 ℃, insoluble matter is filtered off, the filtrate is dried by spinning, dissolved in 60ml of dichloromethane, the pH is adjusted to 3 with 10% hydrogen chloride-methanol solution, 3.2g of a yellow solid is precipitated (yield 74%), and the melting point and hydrogen spectrum data correspond to those of example 1.

EXAMPLE 3 preparation of idarubicin hydrochloride

(1) Preparation of Compound 15 (R is p-methoxybenzyl)

Dissolving 10g of daunorubicin hydrochloride in 100ml of acetonitrile, adding 4.9g of potassium carbonate and 4.2g of p-methoxybenzyl chloride, and stirring at room temperature for 10 hours; the reaction mixture was diluted with 100ml of dichloromethane, washed twice with water, and the organic phase was spin-dried to obtain 9.6g of a solid (yield 88%, HPLC purity 96%).

(2) Preparation of Compound 10 (R is p-methoxybenzyl)

Under anhydrous and oxygen-free conditions, 8g of compound 15 is dissolved in anhydrous toluene (80ml), Ni (COD)2(0.15eq) and PCy3(0.075eq) and TMDSO (1eq) are added, after stirring for 2h at 80 ℃, the temperature is increased to 110 ℃ for reaction for 10h, 100ml of ethyl acetate is added to dilute the reaction solution, the reaction solution is washed twice, and the organic phase is dried by spinning to obtain 5.6g of solid (yield 73%).

(3) Preparation of idarubicin hydrochloride

5g of Compound 10, 0.5g of palladium hydroxide (10%) was dissolved in 50ml of tetrahydrofuran, and the mixture was stirred at 40 ℃ for 4 hours, insoluble matter was filtered off, the filtrate was dried by evaporation, dissolved in 60ml of diethyl ether, and the pH was adjusted to 3 with 10% hydrogen chloride-methanol solution, whereby 3.5g of a yellow solid was precipitated (yield 77%)

Reference example 1 reference is made to the method of patent CN102757470B (application No. 201210074569.3)

Idarubicin is prepared according to the method of patent CN102757470B in examples 2,3, 4, 5 and 7. Dissolving 5g of idarubicin crude product in 70mL of anhydrous dichloromethane, adjusting the pH value to 3 by using 10% hydrogen chloride-methanol solution, separating out orange red solid, and performing suction filtration to obtain 4.2g of idarubicin hydrochloride.

Reference example 2 reference document "method of China antibiotic journal 2006, 3.3.31, 3 rd stage

The idarubicin hydrochloride orange solid is prepared by a method of reference to the literature 'semi-synthesis research of idarubicin hydrochloride at 3 rd volume 31, 3 rd phase 2006 in Chinese antibiotic journal'.

Example 4 detection of impurity A, B

And detecting the content of the impurity A, B in the final product of the idarubicin hydrochloride by using a high performance liquid chromatography.

Chromatographic conditions are as follows:

the instrument comprises the following steps: agilent type 1260

A chromatographic column: c18 column

Detection wavelength: 254nm

Flow rate: 1.0ml/min

Column temperature: 30 deg.C

Sample introduction amount: 10uL

Mobile phase: methanol-Water-30% phosphoric acid solution (790:210:1) containing 4.0g of sodium dodecyl sulfate per 1000mL

Preparing a blank solution: the mobile phase was taken as a blank solution.

Preparing a positioning solution: precisely weighing appropriate amount of reference substances of impurity A and impurity B, respectively, adding mobile phase for dissolving, and diluting to obtain solution containing 0.2mg per 1ml as positioning solution of impurity A and impurity B.

Preparing a system applicability solution: precisely weighing appropriate amount of impurity A reference substance and impurity B reference substance, adding mobile phase for dissolving, and diluting to obtain solutions each containing 0.02mg per 1ml as system applicability solutions.

Preparing a test solution: taking the product, precisely weighing, adding mobile phase for dissolving, and quantitatively diluting to obtain solution containing about 0.2mg per 1ml as test solution.

And (3) determination: 10. mu.L of each of the above solutions was taken and injected into a liquid chromatograph, and a chromatogram was recorded. And calculating the impurity content of each sample according to a self-comparison method.

The results of the measurement were as follows:

the experimental results show that the idarubicin hydrochloride prepared by the method of the invention in the embodiments 1, 2 and 3 can obviously reduce the content of the impurity A, B and improve the purity of the idarubicin hydrochloride product.

Example 5 stability test

The samples of examples 1 to 3 and the samples of reference examples 1 and 2 were subjected to accelerated test investigation at a temperature of 40. + -.2 ℃ and a relative humidity of 75. + -. 5%, left for 30 days, sampled on days 0, 10 and 30, and examined for changes in appearance and purity, and the results are shown in the following table:

the results show that the appearance of the product is almost unchanged in color under the accelerated test condition of the sample prepared by the method, and the HPLC detection of chemical purity also shows that the product is very stable, so that the storage of the raw material medicine is facilitated.

Claims

1. A preparation method of idarubicin hydrochloride comprises the following steps:

wherein R is selected from trifluoroacetyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, trimethylsilyloxycarbonyl, trityl, p-methoxybenzyl and benzyl;

(b) removing 4-methoxy group from the compound 15 in an organic solvent containing a metallic nickel catalyst and an organic phosphine ligand by using a silane reducing agent to generate a compound 10 shown in the following formula,

(c) removing a protecting group on the 3' -amino of the compound 10, and further performing salt-forming reaction to prepare idarubicin hydrochloride;

wherein the organic solvent of step (b) is selected from toluene, o-xylene, trimethylbenzene, methylcyclohexane, dioxane or ethylene glycol dimethyl ether.

2. The method of claim 1, wherein the metallic nickel catalyst is Ni (COD)₂。

3. The process for the preparation of idarubicin hydrochloride according to claim 1 wherein the organic phosphine ligand is selected from tricyclohexylphosphine, bis (dicyclohexylphosphine) methane, 1, 3-bis (dicyclohexylphosphine) propane, 1, 4-bis (dicyclohexylphosphine) butane, 1, 3-bis (diphenylphosphino) propane or 1, 1' -bis (diphenylphosphino) ferrocene.

4. The process for the preparation of idarubicin hydrochloride according to claim 1 wherein the silane reducing agent is selected from 1,1,3, 3-tetramethyldisiloxane or methyldimethoxysilane.

5. The method of preparing idarubicin hydrochloride according to claim 1 wherein the amount of metallic nickel catalyst used is 0.01 to 0.4mol per 1mol of compound 15.

6. The method of claim 5, wherein the amount of the metallic nickel catalyst is 0.05 to 0.15mol per 1mol of the compound 15.

7. The method of preparing idarubicin hydrochloride according to claim 1, wherein the molar amount of the organophosphine ligand is 0.5 to 3 times that of the metal catalyst.

8. The method of preparing idarubicin hydrochloride according to claim 7, wherein the molar amount of the organophosphine ligand is 2 to 3 times that of the metal catalyst.

9. The method of preparing idarubicin hydrochloride according to claim 1 wherein the amount of silane reducing agent used is 1-10 mol per 1mol of compound 15.

10. The method of claim 9, wherein the silane reducing agent is used in an amount of 1 to 2 moles per 1 mole of compound 15.

11. The method for preparing idarubicin hydrochloride according to claim 1, wherein the reaction temperature in step (b) is 60-140 ℃.

12. The method for preparing idarubicin hydrochloride according to claim 1, wherein the reaction temperature in step (b) is 80-110 ℃.

13. The method of claim 1, wherein R is trifluoroacetyl, the metallic nickel catalyst is Ni (COD)₂The organophosphorus ligand is tricyclohexylphosphine, and the silane reducing agent is 1,1,3, 3-tetramethyldisiloxane.