CN104130301A - Preparation method of gemcitabine hydrochloride intermediate - Google Patents

Abstract

The present invention relates to a method for preparing a gemcitabine hydrochloride intermediate. Cytosine is used as a raw material and reacted with hexamethyldisilazane to form a silyl ether protecting group. The product is then docked with 2-deoxy-2,2-difluoro-D-erythro-pentafuranosyl-3,5-diphenylmethyl-1-methanesulfonate and then post-treated with hydrochloric acid to obtain the final product. The method is simple in process, has more convenient operating conditions, produces a high ratio of the desired isomer, uses a green solvent, does not require harsh reaction conditions, and is suitable for industrial production.

Description

A kind of preparation method of gemcitabine hydrochloride intermediate

technical field

The invention belongs to the field of pharmacy, and in particular relates to a preparation method of a gemcitabine hydrochloride intermediate.

Background technique

Gemcitabine is a difluoronucleoside anticancer drug that destroys cell replication. It mainly acts on tumor cells in the DNA synthesis phase, that is, cells in the S phase. Under certain conditions, it can prevent the progression from the G1 phase to the S phase. Its chemical name It is 2'-deoxy-2', 2'-difluorocytidine, and its chemical structure is as follows:

There are many synthetic methods of gemcitabine hydrochloride reported so far, and most of the synthetic routes go through an important intermediate β-1-(2'-deoxy-2', 2'-difluoro-3', 5'-di-O -Benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride, the structural formula is as formula (I). It is deprotected and salified, and the final product is in the form of hydrochloride.

the

The Chinese patent 200580049120.X of Dabur Pharmaceutical Company of India discloses that substituted cytosine is used as a raw material and hexamethyldisilazane is used to form a cytosine protecting group, which is then catalyzed by trimethylsilyl trifluoromethanesulfonate and sugar Base docking generates an analog of the gemcitabine hydrochloride intermediate (I). Chinese patent 201210040408.2 also uses cytosine as a raw material and hexamethyldisilazane to generate a cytosine protecting group, and then docks with a sugar group under the catalysis of trimethylsilyl triflate to generate a gemcitabine hydrochloride intermediate (I ) This process, and the amount of trimethylsilicone trifluoromethanesulfonate is equivalent to cytosine, which is three times the amount of glycosyl compounds. Moreover, the by-product trifluoromethanesulfonic acid generated after the reaction is the strongest organic acid, and sulfuric acid with an acidity of more than 100% is a super acid. Not only there are certain safety hazards in operation, but also there is serious corrosion to the equipment. Although Chinese patent 201110334019.6 uses a tetrahydropyran ring to protect the two hydroxyl groups on the glycosyl of the gemcitabine intermediate, p-toluenesulfonic acid is used as a catalyst for the docking reaction between the glycosyl and cytosine, and the residue of p-toluenesulfonic acid can lead to Later alcohol reagents react to generate tosylate, and p-toluenesulfonate is a genotoxic impurity that is potentially destructive to DNA, so try to avoid using such substances in the process.

Therefore, it is of great significance to find a safe and environmentally friendly process to prepare the gemcitabine hydrochloride formula (I) intermediate.

Contents of the invention

The present invention aims to provide a safe and environment-friendly process for preparing gemcitabine hydrochloride formula (I) intermediate.

The present invention is achieved through the following technical solutions:

A preparation method of a compound of formula (I), comprising the following steps:

a) Take cytosine as the raw material and hexamethyldisilazane under the catalysis of ammonium sulfate to reflux reaction. After the solution is dissolved, the excess hexamethyldisilazane is evaporated to obtain the cytosine protecting group, and then the solvent is added and the temperature is raised to 70-80°C to obtain a solution of cytosine silyl ether protecting group;

b) Dissolve 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate in the solvent and stir, then add the catalyst and heat to the boiling point of the solvent 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate solution at the following temperature of 10°C to 5°C;

Also includes the following step c)

Drop the silyl ether protecting group solution in a) into the 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonic acid in step b) Ester solution, 2-3 hours dropwise, then continue to keep warm for 2-2.5 hours, then drop to 40-50°C and filter through diatomaceous earth, add hydrochloric acid dropwise to the filtrate, precipitate solid and dry to obtain the compound of formula (I) .

The reaction equation is as follows:

The step a), step b) solvent is isoamyl alcohol or n-amyl alcohol.

In the preparation method of the compound of formula (I), the catalyst in step b) is phosphotungstic acid or phosphomolybdic acid.

In the preparation method of the compound of formula (I), the silicon ether protecting group solution in step a) is dripped into the 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5 - During the dropwise addition of the diphenylmethyl ester-1-methanesulfonate solution, keep the temperature of the solution in step b) from the boiling point to 5°C below the boiling point.

In the present invention, phosphotungstic acid or phosphomolybdic acid are used to replace the toxic trimethylsilicon trifluoromethanesulfonate or p-toluenesulfonic acid, which avoids the generation of trifluoromethanesulfonic acid and is more friendly to the environment; and the solid acid (phosphorus Tungstic acid or phosphomolybdic acid) instead of liquid trimethylsilicone trifluoromethanesulfonate avoids the situation that the liquid acid decomposes and generates smoke when it encounters moisture in the air during operation, and it is more convenient in the feeding process.

Low-toxic isoamyl alcohol or n-amyl alcohol is used to make the process more green and safe. The docking of cytosine and glycosyl compounds is an SN2 reaction. Experiments have proved that adding cytosine protecting group solution to glycosyl compound solution under high temperature conditions is beneficial Choice of intermediate (I) configuration.

The preparation process of the present invention has the following advantages:

1. Using solid acid phosphotungstic acid or phosphomolybdic acid to replace trimethylsilicone trifluoromethanesulfonate or p-toluenesulfonic acid makes the operation more convenient, the process is safer and greener; and avoids sulfonate or salt by-products generate.

2. Using low-toxic solvent isoamyl alcohol or n-amyl alcohol to make the process more in line with the concept of green chemistry.

3. Dropping the cytosine protecting group solution into the glycosyl compound solution under high temperature conditions ensures the selection of the configuration of the intermediate (I).

The glycosyl compound in the present invention refers to 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only, and are not intended to limit the scope of the present invention. In addition, in the following description, descriptions of known technologies are omitted to avoid unnecessarily confusing the concept of the present invention.

The percentage content of 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate used in the following examples is above 95%.

Example 1

Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of isoamyl alcohol to a 500mL reaction flask, stir, heat to 70-80°C to dissolve the white solid, and transfer it to an insulated dropping funnel.

Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 0.5g to a 1L three-necked flask Phosphotungstic acid and 100mL isoamyl alcohol were stirred and heated to 128-132°C, and then the cytosine silyl ether protecting group was added dropwise. After 2.5 hours of dropwise addition, the temperature was raised to reflux for 2 hours, and TLC was detected until 2-deoxy-2,2- Difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate stopped the reaction after the raw material point disappeared, lowered the temperature to 40-50°C, filtered through diatomaceous earth, and poured into the filtrate Hydrochloric acid solution (200mL, 6M) was added dropwise and stirred for 2h to crystallize, resulting in a large amount of white solid. After filtering the filter cake and drying, 45.6g of white solid was obtained, with a yield of 90%.

Example 2

Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. The temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of isoamyl alcohol to a 500mL reaction flask, stir, heat to 70-80°C to dissolve the white solid, and transfer it to an insulated dropping funnel.

Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-benzhydryl-1-methanesulfonate (45g, 0.1mol) and 0.8g to a 1L three-necked flask Phosphomolybdic acid and 100mL isoamyl alcohol were stirred and heated to 128-132°C, then the cytosine silyl ether protecting group was added dropwise, after 3 hours of dropping, the temperature was raised to reflux for 2 hours, and TLC was detected until 2-deoxy-2,2-di Fluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate stop the reaction after the raw material point disappears, cool down to 40-50°C, filter with diatomaceous earth, drop into the filtrate Add hydrochloric acid solution (200mL, 6M) and stir for crystallization for 2.5h, producing a large amount of white solid. After filtering the filter cake and drying, 47.0g of white solid is obtained, with a yield of 93%.

Example 3

Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of n-pentanol to a 500mL reaction flask and stir, heat to 70-80°C to dissolve the white solid and transfer it to an insulated dropping funnel.

Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 1.0g to a 1L three-necked flask Phosphomolybdic acid and 100mL of n-amyl alcohol were stirred and heated to 128-137°C, then the cytosine silyl ether protecting group was added dropwise, after 2 hours of dropping, the temperature was raised to reflux for 3 hours, and TLC was detected until 2-deoxy-2,2-di Fluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate stop the reaction after the raw material point disappears, cool down to 40-50°C, filter with diatomaceous earth, drop into the filtrate Add hydrochloric acid solution (200mL, 6M) and stir for crystallization for 2.5h, producing a large amount of white solid. After filtering the filter cake and drying, 48.2g of white solid is obtained, with a yield of 95%.

Example 4

Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of pentanol to a 500mL reaction flask and stir, heat to 70-80°C to dissolve the white solid and transfer it to an insulated dropping funnel.

Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 1.2g to a 1L three-necked flask Phosphotungstic acid and 100mL amyl alcohol were stirred and heated to 132-137°C, then the cytosine silyl ether protecting group was added dropwise, after 3 hours of dropping, the temperature was raised to reflux for 2.5 hours, and TLC was detected until 2-deoxy-2,2-di Fluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate stop the reaction after the raw material point disappears, cool down to 40-50°C, filter with diatomaceous earth, drop into the filtrate Add hydrochloric acid solution (200mL, 6M) and stir for crystallization for 2.5h, producing a large amount of white solid. After filtering the filter cake and drying, 47.5g of white solid is obtained, with a yield of 94%.

Referring to the detection method of gemcitabine hydrochloride finished product on page 2230-2231 of European Pharmacopoeia 8.0, the samples in Examples 1-4 were detected by HPLC. The results are shown in the table below:

 

Remarks: The above data are calculated by the area percentage method, and the largest single impurity is cytosine.

The statistics of HPLC results show that the gemcitabine hydrochloride intermediate prepared by the process of the present invention has a high purity of more than 99%, and the maximum monocytosine is less than 0.15%, which can be removed after deprotection and salt formation in the later stage.

Although the embodiments of the present invention have been described in detail, it should be understood that the various changes, substitutions and alterations could be made hereto without departing from the spirit and scope of the invention.

Claims (4)

1. A preparation method of a compound of formula (I), comprising the following steps: Using cytosine as a raw material and hexamethyldisilazane under the catalysis of ammonium sulfate to reflux reaction until the solution is dissolved, then distill off excess hexamethyldisilazane to obtain cytosine protecting group, then add solvent and heat up to 70- 80°C to obtain a solution of cytosine silyl ether protecting group; 2-Deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate is dissolved in the solvent and stirred, then the catalyst is added and heated to the boiling point of the solvent to the boiling point 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate solution at the following 10°C; It is characterized in that: it also includes the following steps c) Drop the silyl ether protecting group solution in a) into the 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonic acid in step b) In the ester solution, the dropwise addition is completed in 2-3 hours, the temperature is raised to reflux for 2-2.5 hours, and then the temperature is lowered to 40-50°C, filtered through diatomaceous earth, hydrochloric acid is added dropwise to the filtrate, stirred, and the solid is precipitated and dried to obtain the formula (I ) compound. 2. The preparation method according to claim 1, characterized in that: the solvent in step a) and step b) is isoamyl alcohol or n-amyl alcohol. 3. The preparation method according to claim 1, characterized in that: the catalyst described in step b) is phosphotungstic acid or phosphomolybdic acid. 4. The preparation method of the compound of formula (I) according to claim 1, characterized in that: the silicon ether protecting group solution of step a) is dripped into the 2-deoxy-2,2-difluoro-D- During the dropwise addition of the erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate solution, keep the temperature of the solution in step b) from the boiling point to 5°C below the boiling point.