CN118652277A - A method for preparing a compound for treating cancer - Google Patents

Abstract

The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a compound for treating cancer diseases. The method comprises the following steps: S1: 6-chloroguanine (intermediate 4) and bromoethanol are subjected to a hydroxyethylation reaction under a strong base condition to generate an intermediate 2-(2-amino-6-chloro-9H-purine-9-yl)ethanol (intermediate 9); S2: intermediate 9 is subjected to a condensation reaction with diethyl p-toluenesulfonyloxymethylphosphonate under a strong base condition to generate an intermediate 11; S3: intermediate 11 is subjected to amination reaction with cyclopropylamine to obtain a phosphonate (intermediate 12); S4: the phosphonate (intermediate 12) is subjected to hydrolysis with trimethylsilyl bromide (TMSBr) to obtain a corresponding phosphonic acid (intermediate 7); S5: intermediate 7 is subjected to a mixed reaction with L-alanine ethyl ester hydrochloride, a base, triphenylphosphine and 2,2'-dithiodipyridine to generate GS9219. The preparation process is simpler, the raw materials are cheap and readily available, the product yield is higher, and the method is suitable for large-scale industrial production.

Description

A method for preparing a compound for treating cancer

Technical Field

The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing a compound for treating cancer.

Background Art

Rabacfosadine (GS-9219, CAS: 859209-74-8) is a novel prodrug of the nucleoside analog PMEG, used as a cytotoxic agent that preferentially targets lymphocytes. GS-9219 is a novel pharmaceutical compound with potential anticancer activity. It belongs to a class of compounds known as small molecule targeted drugs that are able to inhibit tumor growth and spread by interfering with the growth signaling pathways of cancer cells. The mechanism of action of GS-9219 is mainly through inhibiting DNA synthesis and repair of tumor cells, thereby leading to the death of tumor cells. It can also interfere with the metabolic pathways of tumor cells, blocking the growth and proliferation of tumor cells.

GS-9219 can be used to treat many types of cancer, such as leukemia, lymphoma, etc. On July 16, 2021, the U.S. Food and Drug Administration (FDA) approved Rabacfosadine injection for the first time to treat lymphoma (B cell, T cell, skin, newly diagnosed or recurrent cases) in dogs. The drug can be used alone or in combination with doxorubicin, and only 5 to 6 treatments are required, depending on the treatment regimen used. Although Rabacfosadine is more expensive than some conventional chemotherapy drugs, the total cost tends to be lower due to the reduction in the number of follow-up visits. In general, GS-9219 is a drug compound with potential anti-cancer activity and is expected to become one of the new options for the treatment of cancer in the future.

At present, regarding the preparation of GS9219, the invention patent with publication number CN101816664A in the prior art discloses a phosphonate, a monophosphonic acid amide, and a bisphosphonic acid amide for treating viral diseases, which are mainly prepared by the following method:

In the preparation method, 1,3-dioxolane is mainly used as a starting material, which reacts with acetyl chloride and zinc chloride to prepare acetoxyethoxymethyl chloride, which then reacts with triisopropyl phosphate to obtain diisopropyl phosphate, which is hydrolyzed to obtain the corresponding alcohol. The alcohol reacts with 6-chloroguanine to obtain the phosphonate of purine, which is then aminated with cyclopropylamine and hydrolyzed with trimethylsilyl bromide to obtain the corresponding phosphonic acid; the phosphonic acid reacts with L-alanine ethyl ester hydrochloride under the action of triethylamine, triphenylphosphine and 2,2'-dithiodipyridine to produce GS9219.

This process has seven steps of reaction, and the reaction is carried out under harsh conditions (such as low temperature reaction at -15°C). The reaction conditions are strict and difficult to control, and the yield of intermediate 3 is only 40%; the yield of intermediate 4 based on GS9219 is only 20%; the total yield is 8%. Therefore, the overall preparation process reaction yield is relatively low. In addition, a large amount of expensive reagent intermediate 8 is used, the production cost is high, and it is not suitable for industrial scale-up production.

Summary of the invention

Based on the above problems, the purpose of the present invention is to provide a method for preparing a compound for treating cancer diseases, that is, to provide a method for preparing GS9219, which has a simpler preparation process, low-cost and easily available raw materials, a higher product yield, and is suitable for large-scale industrial production.

The embodiments of the present invention are implemented by the following technical solutions:

A preparation method of GS9219, the reaction formula of which is as follows:

.

Specifically, a method for preparing GS9219 comprises the following steps:

Step 1: 6-chloroguanine (intermediate 4) and bromoethanol are subjected to hydroxyethylation reaction under strong alkaline conditions to generate the intermediate 2-(2-amino-6-chloro-9H-purine-9-yl)ethanol (intermediate 9);

Step 2: Intermediate 9 is condensed with diethyl p-toluenesulfonyloxymethylphosphonate under strong alkaline conditions to generate intermediate 11;

Step 3: Intermediate 11 is reacted with cyclopropylamine to obtain phosphonate (intermediate 12);

Step 4: The phosphonate (intermediate 12) is hydrolyzed with trimethylsilyl bromide (TMSBr) to give the corresponding phosphonic acid (intermediate 7);

Step 5: The intermediate 7 is mixed with L-alanine ethyl ester hydrochloride, and reacted in the presence of a base (such as triethylamine), triphenylphosphine and 2,2'-dithiodipyridine to generate GS9219, which is the compound for treating cancer diseases of the present invention.

More specifically:

In the first step, the molar ratio of 6-chloroguanine to 2-bromoethanol is 1:1-1.5; the molar ratio of the strong base to 2-bromoethanol is 1.1-1.4:1; and the strong base is one or more of potassium carbonate, cesium carbonate, and sodium hydride.

In the second step, the molar ratio of intermediate 9 to a strong base and diethyl p-toluenesulfonyloxymethylphosphonate is 1:(1.2-1.7):(2.0-3.0); the strong base is one or more of magnesium tert-butoxide, magnesium ethoxide, sodium tert-butoxide, and sodium methoxide.

In the third step, the molar ratio of the intermediate 11 to cyclopropylamine is 1:(2.0-4.0); the reaction temperature is 90-120° C.; and the reaction solvent is one or more of acetonitrile, tetrahydrofuran, and N,N-dimethylformamide.

In the fourth step, the molar ratio of the intermediate 12 to trimethylsilyl bromide is 1:(2.5-3.5); the reaction temperature is 10-30° C.; and the reaction solvent is one or more of acetonitrile, tetrahydrofuran, and N,N-dimethylformamide.

In the fifth step, the reaction temperature is 60-80°C; when the intermediate 7 reacts with L-alanine ethyl ester hydrochloride, a base, triphenylphosphine and 2,2'-dithiodipyridine are added; wherein the molar ratio of the intermediate 7, L-alanine ethyl ester hydrochloride, the base, 2,2'-dithiodipyridine and triphenylphosphine is 1:(3-5):(3-5):(3-5):(3-5).

The technical solution of the embodiment of the present invention has at least the following advantages and beneficial effects:

The invention uses 6-chloropurine as a starting material, and prepares the target product GS-9291 through a five-step reaction, and the obtained yield is relatively high; the raw materials used are inexpensive and easy to obtain, and the reaction conditions are mild; the entire synthetic route is short, the preparation process is stable and reliable, the operation is simple, the production cost is low, the generation of by-products can be significantly suppressed, and excessive pollution to the environment will not be caused, and the invention is suitable for large-scale industrial production.

DETAILED DESCRIPTION

In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

The following is a detailed description of the preparation method of a compound (GS9219) for treating cancer provided in an embodiment of the present invention.

Example 1: Preparation of Intermediate 2-(2-amino-6-chloro-9H-purin-9-yl)ethanol

Add 350ml of solvent N,N-dimethylformamide and raw material 2-amino-6-chloropurine (50g, 294.9mmol) to a 500ml three-necked flask. Stir until turbid. Cool to 0-5℃ and add solid cesium carbonate (114.4g, 353mmol). After the addition is complete, add 2-bromoethanol (55.26g, 442mmol) dropwise and stir for 24 hours. Filter the solution and spin dry. The product was then washed with water, slurried, filtered, and dried in a forced air drying oven at 65°C to obtain the intermediate 2-(2-amino-6-chloro-9H-purine-9-yl)ethanol (53.9 g, 252.3 mmol) with a yield of 85.6%; HNMR (DMSO) 8.05 (s, 1H), 6.33 (s, 2H), 4.96 (s, 1H), 4.05(m, 2H), 3.86 (m, 2H).

Example 2: Preparation of intermediate diethyl ((2-(2-amino-6-chloro-9H-purin-9-yl)ethoxy)methyl)phosphonate

In a 500ml three-necked flask, add N,N-dimethylformamide (250ml), intermediate 2-(2-amino-6-chloro-9H-purin-9-yl)ethanol (50g, 234.1mmol), and then add solid magnesium tert-butoxide (64g, 370mmol) and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) (96.4g, 600mmol) under stirring, and stir the reaction overnight. After the reaction of intermediate 1 was completed, the solvent was removed by concentration under reduced pressure, and no liquid dripped from the condenser to obtain intermediate ((2-(2-amino-6-chloro-9H-purin-9-yl)ethoxy)methyl)phosphonic acid diethyl ester (63.9 g, 175.7 mmol) with a yield of 75.1%; HNMR (DMSO) 8.05 (s, 1H), 4.96 (s, 2H), 4.25 (m, 4H), 4.00 (m, 2H), 3. 86 (m, 2H), 1.36 (m, 6H).

Example 3: Preparation of intermediate diethyl ((2-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)ethoxy)methyl)phosphonate

In a 500 ml high pressure container, add the intermediate ((2-(2-amino-6-chloro-9H-purin-9-yl)ethoxy)methyl)phosphonic acid diethyl ester (36.0 g, 99 mmol), cyclopropylamine (17.1 g, 270 mmol) and acetonitrile solution (300 mL), heat to 100 ° C and stir overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The intermediate diethyl ((2-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)ethoxy)methyl)phosphonate (31.2 g, 81.2 mmol) was obtained in a yield of 82.0%; HNMR (DMSO) 7.64 (s, 1H), 4.99 (s, 2H), 4.25 (m, 4H), 4.00 (m, 2H), 3.86 (m, 2H),3.01 (s, 1H), 1.36 (m, 6H), 0.87 (m, 2H), 0.62 (m, 2H).

Example 4: Preparation of intermediate ((2-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)ethoxy)methyl)phosphonic acid

In a 500 ml reaction bottle, add the intermediate ((2-(2-amino-6-(cyclopropylamino)-9H-purine-9-yl)ethoxy)methyl)phosphonic acid diethyl ester (30 g, 78 mmol), acetonitrile solution 200 ml, trimethylsilyl bromide (30 mL, 210 mmol). The reaction mixture was stirred at room temperature overnight. The reactants were concentrated under reduced pressure until no liquid dripped. The residue was dissolved in H2O (250 mL), and the pH was adjusted to 12 with ammonium hydroxide. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in H2O (30 mL), and the pH was adjusted to 2 with concentrated hydrochloric acid. The fine solid was collected and dried in vacuo to give the intermediate ((2-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)ethoxy)methyl)phosphonic acid (20 g, 60.9 mmol) in a yield of 78.1%; HNMR (D2O) 7.65 (s, 1H), 4.98 (s, 2H), 4.33 (m, 2H), 4.01 (m, 2H), 3.85 (m, 2H), 2.55 (s, 1H), 0.88 (m, 2H), 0.63 (m, 2H).

Implementation Case 5: Preparation of Products

A mixture of intermediate ((2-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)ethoxy)methyl)phosphonic acid (5 g, 9.5 mmol), L-alanine ethyl ester hydrochloride (8.0 g, 52.1 mmol) and triethylamine (15 ml) in pyridine (50 ml) was heated to 60°C for 30 minutes;

Then a freshly prepared bright yellow solution of 2,2'-dithiodipyridine (11 g, 49.9 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) in pyridine (50 mL) was added to the above reaction mixture. The reaction was stirred at 60 °C overnight. The reaction solution was cooled to room temperature and concentrated. The product obtained after the above reaction was partitioned between ethyl acetate and saturated NaHCO _3. The organic phase was washed with brine, Na ₂ SO ₄ , dried, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the product (2.3 g, 4.4 mmol) in a yield of 46.2%; HNMR (CDCl3) δ 7.68 (s, 1H), 5.89 (s, 1H), 5.01 (s, 2H), 4.26 (m, 6H), 4.03 (m, 2H), 3.86 (m, 2H), 3.75 (m, 2H), 3.05 (s, 1H),1.32 (m, 6H), 1.28 (m, 6H), 0.82 (m, 2H), 0.64 (m, 2H).

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A process for the preparation of a compound for the treatment of cancer diseases, characterized by the following reaction formula:

。

2. A method of preparing a compound for use in the treatment of cancer diseases according to claim 1, comprising the steps of:

s1, carrying out hydroxyethylation reaction on 6-chloroguanine serving as a starting material and 2-bromoethanol under a strong alkali condition to obtain an intermediate 9;

S2, condensing the intermediate 9 and diethyl p-toluenesulfonyloxy methylphosphonate under the condition of strong alkali to generate an intermediate 11;

s3, ammoniating the intermediate 11 with cyclopropylamine to obtain an intermediate 12;

s4, hydrolyzing the intermediate 12 through trimethyl bromosilane to obtain an intermediate 7;

s5, reacting the intermediate 7 with L-alanine ethyl ester hydrochloride to generate GS9219.

3. The method of preparing a compound for use in treating cancer according to claim 2, wherein in S1, the molar ratio of 6-chloroguanine to 2-bromoethanol is 1:1-1.5; the molar ratio of the strong base to the 2-bromoethanol is 1.1-1.4:1.

4. The method for preparing a compound for treating cancer diseases according to claim 2, wherein in S2, the molar ratio of intermediate 9 to strong base and diethyl p-toluenesulfonyloxy methylphosphonate is 1: (1.2-1.7): (2.0-3.0).

5. The method for preparing a compound for treating cancer diseases according to claim 2, wherein in S1, the strong base is one or more of potassium carbonate, cesium carbonate, sodium hydride; in S2, the strong base is one or more of magnesium tert-butoxide, magnesium ethoxide, sodium tert-butoxide and sodium methoxide.

6. The method of preparing a compound for use in treating cancer according to claim 2, wherein in S3, the molar ratio of intermediate 11 to cyclopropylamine is 1: (2.0-4.0).

7. The method for preparing a compound for treating cancer according to claim 2, wherein in S3, the reaction temperature is 90 to 120 ℃; the reaction solvent is one or more of acetonitrile, tetrahydrofuran and N, N-dimethylformamide.

8. The method of preparing a compound for use in treating cancer according to claim 2, wherein in S4, the molar ratio of intermediate 12 to trimethylbromosilane is 1: (2.5-3.5).

9. The method for preparing a compound for treating cancer diseases according to claim 2, wherein in S4, the reaction temperature is 10 to 30 ℃; the reaction solvent is one or more of acetonitrile, tetrahydrofuran and N, N-dimethylformamide.

10. The method for preparing a compound for treating cancer according to claim 2, wherein in S5, a base, triphenylphosphine and 2,2' -dithiodipyridine are added when intermediate 7 is reacted with L-alanine ethyl ester hydrochloride; wherein, the mol ratio of the intermediate 7 to the L-alanine ethyl ester hydrochloride to the alkali to the 2,2' -dithiodipyridine to the triphenylphosphine is 1: (3-5): (3-5): (3-5): (3-5).