WO2020237836A1

WO2020237836A1 - Preparation method for 4-idarubicin hydrochloride

Info

Publication number: WO2020237836A1
Application number: PCT/CN2019/100198
Authority: WO
Inventors: 苏进财; 代清宇; 吴舰; 王华萍; 柴雨柱; 徐丹; 朱春霞; 田舟山
Original assignee: 南京正大天晴制药有限公司
Priority date: 2019-05-31
Filing date: 2019-08-12
Publication date: 2020-12-03
Also published as: CN112010913A; CN112010913B

Abstract

Provided is a method for preparing 4-idarubicin hydrochloride. The method comprises the step of preparing compound B into compound C in the presence of tetrabutyl ammonium halide, and the 4-idarubicin hydrochloride can be further obtained. The preparation method can reduce the usage amount of a salt in a reaction system, and also reduce the effect of yield reduction due to reaction amplification, inhibit the increase of impurity I and impurity II during the reaction process, and has great advantages in production practice.

Description

Preparation method of 4-demethoxydaunorubicin hydrochloride

This application claims the priority of the Chinese patent application whose application number is 201910466305.4 and the application date is 2019.5.31.

Technical field

The invention relates to the field of medicinal chemistry, in particular to a preparation method of 4-demethoxydaunorubicin hydrochloride.

Background technique

Anthracycline compounds are a class of substances widely used in the treatment of hematological malignancies and solid tumors, among which (7S,9S)-9-acetyl-7,8,9,10-tetrahydro-6,7,9, 11-tetrahydroxy-7-O-(2,3,6-tideoxy-3-amino-α-L-lyxo-hex-pyranose)-5,12-tetraphenyl hydrochloride, namely 4 -Demethoxydaunorubicin is a first-line drug for the treatment of relapsed and refractory adult acute myeloid leukemia (AML). It was developed and produced by Pharmacia Pretron and was approved by the FDA on September 27, 1990. Approved by CFDA in 2004 for listing. Compared with daunorubicin hydrochloride, 4-demethoxydaunorubicin has the advantages of less side effects, better curative effect, and lower drug resistance.

Summary of the invention

The present invention aims to provide an improved (7S,9S)-9-acetyl-7,8,9,10-tetrahydro-6,7,9,11-tetrahydroxy-7-O suitable for scale-up production -(2,3,6-Tideoxy-3-amino-α-L-lyxo-hex-pyranose)-5,12-Phenyltetraphenyl hydrochloride synthesis method.

In one aspect, the present invention provides a method for preparing a compound of formula C, the route is as follows:

Compound B is reacted in the presence of anhydrous MgX ₂ , YI and tetrabutylammonium halide to obtain compound C, wherein R _{1 is} selected from C1-C3 alkyl, X is halogen, and Y is alkali metal.

In some embodiments, the compound B: MgX ₂ : YI: tetrabutylammonium halide = 1:1~3:0.5~2:0.1~2 is charged in a molar ratio for reaction; preferably, it is in molar ratio The ratio is calculated according to the compound B: MgX ₂ : YI: tetrabutylammonium halide=1:1.5～2:1～2:0.3～1 or 1:1.5～2:1～2:0.1～2 for reaction ; More preferably, based on the molar ratio, the compound B: MgX ₂ : YI: tetrabutylammonium halide=1:1.7:1.6:0.5 is charged for the reaction.

In some embodiments, X is selected from Cl, Br, or I; preferably Cl.

In some embodiments, Y is selected from Na or K; preferably K.

In some embodiments, the tetrabutylammonium halide is selected from one or a mixture of two or more of tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; preferably tetrabutylammonium iodide Ammonium.

In some embodiments, R ₁ is methyl, ethyl, n-propyl or isopropyl; preferably methyl.

In some embodiments, the reaction solvent is tetrahydrofuran, dioxane or ethylene glycol dimethyl ether; preferably tetrahydrofuran.

In some embodiments, the above reaction temperature is 35-75°C; preferably 50-75°C; more preferably 50-60°C.

In some embodiments, the reaction time of the above reaction is 6 to 48 hours; preferably 10 to 36 hours, more preferably 12 to 24 hours.

In some embodiments, the above reaction process is carried out under water-controlled conditions; preferably, the water content of the reaction system is controlled within 3%; more preferably, the water content of the reaction system is controlled within 1%.

In some embodiments, nitrogen gas and/or molecular sieves are added to control moisture.

In some embodiments, the molecular screen is selected from

or

Molecular sieve; preferably

Molecular sieve.

In some embodiments, the amount of molecular sieve added is 0.2 to 1 times that of Compound B by mass; preferably 0.3 to 0.8 times; more preferably 0.4 to 0.6 times; most preferably 0.5 times.

In some embodiments, the MgX ₂ , YI and tetrabutylammonium halide are added to the reaction vessel by batch feeding.

In some embodiments, the solvent, compound B, and optional molecular sieve are added to the reaction vessel in the first batch of the above reaction; the second to the last batch is put into the pre-packed mixture of MgX ₂ , YI and tetrabutylammonium halide Preferably, the batches are fed in batches of 3-10 batches; more preferably, the batches are fed in 4-8 batches; more preferably, the batches are fed in 4-7 batches; most preferably, the batches are fed in 6 batches.

In some embodiments, the present invention provides a method for preparing compound C, the route is as follows:

Wherein, compound B is heated and reacted in the presence of MgCl ₂ , KI, TBAI and molecular sieves to obtain compound C, wherein, in molar ratio, according to compound B: MgCl ₂ : KI: TBAI=1:1.7:1.6:0.5 The reaction is carried out in the amount of feeding; in terms of mass ratio, the molecular sieve is 0.5 times that of compound B; the reaction temperature is 50-60°C; the reaction time is 11-15h; the reaction is carried out by batch feeding.

On the other hand, the present invention provides a method for preparing compound D according to the following reaction route:

On the other hand, the present invention provides a preparation method of compound E, which is carried out according to the following reaction route:

On the other hand, the present invention provides a method for preparing compound F, which is carried out according to the following reaction route:

On the other hand, the present invention provides a method for preparing compound B, wherein R ₁ is a methyl group, and proceed according to the following reaction route:

The new preparation method provided by the present invention can reduce the amount of salt used in the reaction system, reduce the impact of reduced yield due to reaction amplification, and inhibit the increase of impurity I and impurity II during the reaction process, and has great advantages in production practice .

The terms or symbols in the present invention are defined as follows:

The term "C1-C3 alkyl" includes C1 alkyl, C2 alkyl, and C3 alkyl. Examples include but are not limited to methyl, ethyl, n-propyl, and isopropyl.

TBAI refers to tetrabutylammonium iodide.

K refers to potassium.

I means iodine.

h means hour.

eq means equivalent.

Me refers to methyl.

Compound C refers to a compound with a molecular structure of Formula C, rather than elemental carbon.

The structural formula of impurity I is:

The structural formula of impurity II is:

Specific implementation plan

In order to facilitate those skilled in the art to understand the present invention, the following specific examples illustrate the synthetic route of the present invention:

Analytical method: According to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512), use octadecyl silane bonded silica as filler [Welch Ultimate AQ-C18 (4.6mm×250mm, 5μm) or equivalent chromatogram Column]; Using 0.1% phosphoric acid solution as mobile phase A and methanol as mobile phase B, perform linear gradient elution according to the following table; flow rate is 1.0 ml per minute; column temperature is 35°C; detection wavelength is 254 nm. Accurately measure 20μl of the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the content of compound B, compound C, impurity I and impurity II by area normalization.

Example 1 The influence of MgCl ₂ , KI and TBAI on the reaction

According to the following reaction formula, add tetrahydrofuran and 2.2 kg of compound B (R ¹ =Me, about 3.53 mol, counted as 1 eq) into the reactor, stir (150r/min～250r/min), according to the charging shown in Table 1. Add anhydrous magnesium chloride, potassium iodide and tetrabutylammonium iodide at one time, vacuum and nitrogen replacement, stir at room temperature for 0.5h, turn on the heating circulation system, control the reaction temperature to 40±3℃, react for 7h, then get compound C and impurities I and impurities II.

The reaction results were detected by HPLC, and the area normalization method was used to calculate the content of products and impurities. The results are shown in Table 1.

Table 1

Note: Unknown impurities are not listed.

Compound ^{C: [M + Na] +} 632.0; [MH] - 608.1;

Compound C ¹ H-NMR (500MHz, DMSO-d ₆ ) ppmδ: 1.152～1.165 (3H, d), 1.509～1.541 (1H, m), 2.053～2.119 (2H, m), 2.215～2.243 (1H, d) ), 2.293(3H,s), 2.920(2H,s), 3.535(1H,s), 4.052～4.078(1H,m), 4.230～4.268(1H,m), 4.878(1H,s), 4.960( 1H, s), 5.237 (1H, s), 5.492 (1H, s), 7.300 ~ 7.316 (1H, d), 7.655 ~ 7.670 (1H, d), 7.746 ~ 7.778 (1H, t), 9.005 ~ 9.019 ( 1H, d), 11.869 (1H, s), 12.717 (1H, s), 13.313 (1H, s).

Example 2 The influence of temperature on the reaction

According to the method described in Example 1, tetrahydrofuran and 2.2 kg of compound B (R ₁ =Me, about 3.53 mol, calculated as 1 eq) were added to the reaction kettle, stirred (150r/min～250r/min), according to Table 2 Add anhydrous magnesium chloride, potassium iodide and tetrabutylammonium iodide at one time to the feeding ratio shown, vacuum nitrogen replacement, stir at room temperature for 0.5h, turn on the heating circulation system, control the reaction temperature according to Table 2, and react for 7h. At the end, the reaction result was detected by HPLC, and the area normalization method was used to calculate the content of the product and impurities.

Table 2

Note: Unknown impurities are not listed.

Example 3 The influence of molecular sieve on the reaction

will

After the molecular sieve is crushed, it is put into a crucible, placed in a muffle furnace and heated to 400℃±10℃ for 2 hours, cooled to 100℃±10℃ for 1 hour, then transferred to a large airtight dry container filled with nitrogen for storage, and cooled More than 3h.

According to the method described in Example 1, tetrahydrofuran and 2.2 kg of compound B (R ₁ =Me, about 3.53 mol, calculated as 1 eq) were added to the reaction kettle, stirred (150r/min～250r/min), according to Table 3 The charging ratio shown is one-time addition of activated molecular sieve, anhydrous magnesium chloride, potassium iodide, and tetrabutylammonium iodide, vacuum nitrogen replacement, stirring at room temperature for 0.5h, turning on the heating circulation system, and controlling the reaction temperature to 50-60°C. After 7h, the reaction is over, HPLC detects the reaction result, and the area normalization method calculates the content of product and impurities. The results are shown in Table 3.

table 3

Note: W/W is expressed as the mass ratio of molecular sieve to compound B; unknown impurities are not listed.

In the reactions No. 3-1 to No. 3-4, the inventors observed that when the amount of molecular sieve input was increased, the amount of compound C produced could not be significantly improved, but the entire reaction system would change with the increase of the amount of molecular sieve input. Make it more viscous, affecting subsequent operations.

Example 4 The effect of batch feeding method on the reaction

According to the method described in Example 1, add tetrahydrofuran and 2.2 kg of compound B (R ₁ =Me, about 3.53 mol, calculated as 1 eq) into the reaction kettle, stir (150r/min～250r/min), add 1.1kg to activate After the molecular sieve, add the pre-selected mixture of anhydrous magnesium chloride, potassium iodide and tetrabutylammonium iodide according to the feeding ratio shown in Table 4. After each feeding, vacuum nitrogen replacement, open the heating circulation system, and control the reaction temperature The reaction time is 50-60°C, and the reaction time is as shown in Table 4. After the reaction is completed, HPLC detects the reaction result, and the area normalization method calculates the content of each product and impurities.

Table 4

Note: "+" means supplement; unknown impurities are not listed.

Example 5 Preparation of Compound D

According to the following reaction formula, compound C (2.5mol, counted as 1eq), trifluoromethanesulfonic anhydride (1eq), N,N-diisopropylethylamine (3eq) and 4-dimethylaminopyridine (0.5eq) Put into the pyridine solution, carry out the reaction, after the reaction is finished, separate and purify by the silica gel column, obtain compound D.

Example 6 Preparation of Compound E

According to the following reaction formula, compound D (2.5mol, calculated as 1eq), palladium acetate (0.1eq), 1,1'-bis(diphenylphosphine)ferrocene (0.1eq), N-ethyl diiso Propylamine (2eq) and formic acid (2eq) were added to the solvent dioxane and reacted at 40-60°C. After the reaction was completed, compound E was obtained.

Example 7 Preparation of Compound F

According to the following reaction formula, add 1.0M sodium hydroxide aqueous solution, stir at room temperature for 1 h, adjust the pH of the hydrochloric acid aqueous solution to 3-4, perform salting and crystallization, and then suction filtration and drying to obtain compound F with a purity of >98%.

Example 8 Preparation of Compound B (R ₁ =Me)

According to the following reaction formula, using dichloromethane/methanol and a mixed solution as the reaction solvent, compound A (3.5mol, recorded as 1eq), N-ethyldiisopropylamine (5eq) and CF ₃ COOEt (4eq), 30～ Stir at 40°C for 5 hours to obtain compound B (R ₁ =Me).

Comparative example 1

2.2 kg of compound B (R ₁ =Me) was dissolved in 4.95 L of tetrahydrofuran. Add 2.75 kg of anhydrous magnesium chloride and 2.2 kg of anhydrous potassium iodide to an environment that is not in contact with atmospheric moisture. The mixture is reacted at 40°C for 7 hours to obtain compound C, impurity I and impurity II.

The reaction results were detected by HPLC, and the area normalization method was used to calculate the content of products and impurities. The results are shown in the following table.

化合物BCompound B	化合物CCompound C	杂质IImpurity I	杂质IIImpurity II
13.92％13.92%	17.71％17.71%	16.43％16.43%	44.35％44.35%

Note: Unknown impurities are not listed.

Claims

A method for preparing a compound of formula C, the route is as follows:

Wherein, compound B is reacted in the presence of anhydrous MgX 2 , YI and tetrabutylammonium halide to obtain compound C, wherein R 1 is selected from C1-C3 alkyl, X is halogen, and Y is alkali metal.
The preparation method according to claim 1, wherein X is selected from Cl, Br or I.
The preparation method according to claim 2, wherein X is Cl.
The preparation method according to claim 1, wherein Y is selected from Na or K.
The preparation method according to claim 4, Y is K.
The preparation method according to claim 1, wherein the tetrabutylammonium halide is selected from one or a mixture of two or more of tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide.
The preparation method according to claim 6, wherein the tetrabutylammonium halide is tetrabutylammonium iodide.
The preparation method according to claim 1, wherein R 1 is methyl, ethyl, n-propyl or isopropyl.
The preparation method according to claim 8, wherein R 1 is a methyl group.
The preparation method according to claim 1, wherein the compound B: MgX 2 : YI: tetrabutylammonium halide=1:1～3:0.5～2:0.1～2 are charged and reacted in molar ratio.
The preparation method according to claim 10, based on the molar ratio, the compound B: MgX 2 : YI: tetrabutylammonium halide=1:1.5-2:1-2:0.3-1 is charged and reacted.
The preparation method according to claim 11, based on the molar ratio, the compound B: MgX 2 : YI: tetrabutylammonium halide=1:1.7:1.6:0.5 is charged and reacted.
The preparation method according to claim 1, wherein the reaction solvent is tetrahydrofuran, dioxane or ethylene glycol dimethyl ether.
The preparation method according to claim 13, wherein the reaction solvent is tetrahydrofuran.
The preparation method according to claim 1, wherein the reaction temperature is 35-75°C.
The preparation method according to claim 15, wherein the reaction temperature is 50-75°C.
The preparation method according to claim 16, wherein the reaction temperature is 50-60°C.
The preparation method according to claim 1, wherein the reaction time is 6 to 48 hours.
The preparation method according to claim 18, the reaction time is 10 to 36 hours.
The preparation method according to claim 19, the reaction time is 12-24h.
The preparation method according to claim 1, wherein the reaction process is carried out under controlled water conditions.
The preparation method according to claim 21, wherein the water content of the reaction system is controlled within 3%.
The preparation method according to claim 22, wherein the water content of the reaction system is controlled within 1%.
According to the preparation method according to any one of claims 21-23, nitrogen is introduced and/or molecular sieve is added to control moisture.
The preparation method of claim 24, the molecular screening is from
or
Molecular sieve.
The preparation method of claim 25, wherein the molecular sieve is
Molecular sieve.
The preparation method according to claim 24, wherein the amount of molecular sieve added is 0.2 to 1 times that of compound B by mass.
The preparation method according to claim 27, wherein the amount of molecular sieve added is 0.4 to 0.6 times that of compound B by mass.
The preparation method according to claim 28, wherein the amount of molecular sieve added is 0.5 times that of compound B by mass.
The preparation method according to claim 1, wherein the MgX 2 , YI and tetrabutylammonium halide are fed into the reaction vessel in batches.
The preparation method according to claim 30, the solvent, compound B and optional molecular sieve are added into the reaction vessel in the first batch; the pre-packed MgX 2 , YI and tetrabutylammonium halide are put into the second to the last batch mixture.
The preparation method according to claim 30 or 31, wherein the batches of batch feeding are 3-10 batches.
The preparation method according to claim 30 or 31, wherein the batches of batch feeding are 4-8 batches.
The preparation method according to claim 30 or 31, the batches of batch feeding are 4-7 batches.
The preparation method according to claim 30 or 31, wherein the batch of batch feeding is 6 batches.
A preparation method of compound C, the route is as follows:

Wherein, compound B is heated and reacted in the presence of MgCl 2 , KI, TBAI and molecular sieves to obtain compound C, wherein, in molar ratio, according to compound B: MgCl 2 : KI: TBAI=1:1.7:1.6:0.5 The reaction is carried out in the amount of feeding; in terms of mass ratio, the molecular sieve is 0.5 times that of compound B; the reaction temperature is 50-60°C; the reaction time is 11-15h; the reaction is carried out by batch feeding.
A method for preparing a compound of formula D, firstly using the preparation method of any one of claims 1-35 or the preparation method of claim 36 to obtain compound C, and then further obtain compound D according to the following reaction route:
A method for preparing a compound of formula E, firstly using the preparation method of claim 37 to obtain compound D, and then further obtaining compound E according to the following reaction route:
A method for preparing a compound of formula F, firstly adopting the preparation method of claim 38 to obtain compound E, and then further obtaining compound F according to the following reaction route:
According to the preparation method of any one of claims 1-35 or the preparation method of claim 36, compound B can be prepared according to the following reaction route: