Synthesis method of 3-(5-bromopyrimidinyl) benzyl alcohol

Abstract

The invention discloses a synthesis method of 3-(5-bromopyrimidinyl) benzyl alcohol, and relates to the technical field of medicine preparation. Compared with a method for synthesizing 3-(5-bromopyrimidyl) benzyl alcohol by taking 3-(hydroxymethyl) phenylboronic acid as a raw material, the synthesis method disclosed by the invention has the advantages that the raw materials are cheap and easy to obtain, and the reaction yield is high.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol. Background Technology

[0002] Terportinib is an oral MET inhibitor with the structure shown below, intended for the treatment of non-small cell lung cancer (NSCLC) patients with MET exon 14 (METex14) skipping mutations. NSCLC is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases. MET is one of the driver genes for cancer, and approximately 3%-4% of NSCLC patients have MET mutations. These patients are generally older and often have a poorer prognosis. Furthermore, the MET signaling pathway plays a crucial role in driving resistance to other targeted therapies in lung cancer. Terportinib is designed to inhibit oncogenic MET receptor signaling caused by MET gene mutations, including METex14 skipping alterations, MET amplification, or MET protein overexpression. It is designed to improve the prognosis of aggressive tumors with these specific mutations and is intended for development in indications including NSCLC, hepatocellular carcinoma, colorectal cancer, and other solid tumors with MET mutations.

[0003]

[0004] 3-(5-bromopyrimidinyl)benzyl alcohol is a key building block in the synthesis of terpotentiol. Reference 1 (Dorsch D, Schadt O, Stieber F, et al. Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors[J]. Bioorganic & Medicinal Chemistry Letters, 2015, 25(7):1597-1602. DOI:10.1016 / j.bmcl.2015.02.002.) discloses a method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol: Under nitrogen atmosphere, an aqueous solution of sodium carbonate is added to a solution of 5-bromo-2-iodopyrimidine in toluene and heated to 80°C. Palladium di(triphenylphosphine) chloride is added, followed by dropwise addition of an ethanolic solution of 3-(hydroxymethyl)phenylboronic acid. The reaction mixture is stirred at 89°C for 18 hours. The reaction mixture was cooled to room temperature and filtered. Ethyl acetate and water were added to the filtrate, and the organic phase was separated. This phase was dried over sodium sulfate and evaporated. The residue was recrystallized from 2-propanol to give pale yellow crystals of [3-(5-bromopyrimidin-2-yl)-phenyl]-methanol in 72% yield. The reaction process is shown in the following formula. This synthesis process suffers from poor selectivity of the Suzuki coupling reaction and cumbersome post-processing, resulting in a low yield of 3-(5-bromopyrimidinyl)benzyl alcohol. Furthermore, the palladium catalyst is relatively expensive.

[0005]

[0006] The raw material for the above synthesis method is 3-(hydroxymethyl)phenylboronic acid. Foreign patent WO2014201073A1 discloses the reaction of 3-bromobenzyl alcohol with triisopropyl borate and butyllithium to obtain 3-(hydroxymethyl)phenylboronic acid. Triisopropyl borate is expensive and difficult to obtain.

[0007] In view of this, and to address the shortcomings of existing technologies, this invention provides a novel method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol. The 3-(5-bromopyrimidinyl)benzyl alcohol prepared using this invention can be used to prepare terpoxtinib, and has excellent research and development prospects. Summary of the Invention

[0008] The purpose of this invention is to provide a method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol, which uses inexpensive and readily available raw materials, has a high reaction yield, and is suitable for large-scale industrial production.

[0009] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0010] This invention provides a method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol, wherein the 3-(5-bromopyrimidinyl)benzyl alcohol is synthesized using m-methylbenzonitrile as a raw material through the following method:

[0011]

[0012] Preferably, step 1 further includes a post-processing operation after the reaction to obtain compound II or its salt;

[0013] The post-processing operation is selected from one of the following three operations:

[0014] Operation a: Routine post-processing;

[0015] Operation b: Add NaOH to the reaction solution and perform routine post-treatment;

[0016] Operation c: Add acid to the reaction solution to form salt crystals.

[0017] More preferably, the compound II or its salt is selected from at least one of 3-methylbenzamidin free base, 3-methylbenzamidin hydrochloride, 3-methylbenzamidin sulfate, 3-methylbenzamidin carboxylate, 3-methylbenzamidin acetate, and 3-methylbenzamidin trifluoroacetate.

[0018] More preferably, the method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol includes the following steps:

[0019] Step 1: Mix the alcohol reagent and acetyl chloride, control the temperature of the mixture to below 5°C, and keep it at this temperature for 1-4 hours. Then mix the mixture with m-methylbenzonitrile, control the temperature of the mixture to 5-25°C, and keep it at this temperature for 17-23 hours. Concentrate the reaction system and cool it to below 0°C. Then add NH3 to carry out the reaction. Control the system temperature at 15-35°C during the reaction. After the reaction is completed, perform post-processing to obtain compound II or its salt.

[0020] Step 2: Mix the acid reagent with compound II or its salt, purge with nitrogen, and maintain the temperature of the mixture at 80-100℃. Mix the mixture with malondialdehyde bromo, and maintain the temperature of the mixture at 80-100℃. Continue the reaction at this temperature until compound III is obtained.

[0021] Step 3: Mix solvent 1, compound III, brominating agent and free radical initiator, replace with nitrogen, heat to 65-85℃, maintain the temperature for reaction, and obtain compound IV after the reaction is completed;

[0022] Step 4: Mix solvent 2, compound IV, alkaline reagent, and water. Keep the temperature of the mixture at 70-90℃ and continue the reaction at this temperature. Slowly cool the mixture to 15-35℃ to quench the reaction and obtain compound V.

[0023] Preferably, in step 1, the alcohol reagent is selected from at least one of methanol, ethanol, and isopropanol.

[0024] More preferably, in step 1, the alcohol reagent is methanol.

[0025] Preferably, in step 1, the acid in operation c is selected from at least one of sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid.

[0026] More preferably, in step 1, the acid in operation c is acetic acid.

[0027] Preferably, in step 2, the acid reagent is selected from at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid.

[0028] More preferably, in step 2, the acid reagent is selected from at least one of acetic acid and trifluoroacetic acid.

[0029] More preferably, in step 2, the acid reagent is acetic acid.

[0030] Preferably, in step 3, the solvent 1 is selected from at least one of acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamine, tetrahydrofuran, isopropyl acetate, propylene glycol, and pyridine.

[0031] More preferably, in step 3, the solvent 1 is selected from at least one of acetonitrile and tetrahydrofuran.

[0032] More preferably, in step 3, solvent 1 is acetonitrile.

[0033] Preferably, in step 3, the brominating agent is selected from at least one of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBH), 1,3-dibromo-1,3,5-triazine-2,4,6-trione (DBI), N-bromo-o-sulfonylbenzeneimide (NBSac), and ethyl 2-(dimethylamino)acrylate (NBP).

[0034] More preferably, in step 3, the brominating reagent is selected from at least one of NBS and DBH.

[0035] More preferably, in step 3, the brominating agent is NBS.

[0036] Preferably, in step 3, the free radical initiator is selected from at least one of azobisisobutyronitrile (AIBN) and benzoyl peroxide (BPO).

[0037] More preferably, in step 3, the free radical initiator is AIBN.

[0038] Preferably, in step 4, the solvent 2 is selected from at least one of acetone, dioxane, n-butanol, n-pentanol, isopropanol, and ethyl acetate.

[0039] More preferably, in step 4, the solvent 2 is selected from at least one of dioxane and n-butanol.

[0040] More preferably, in step 4, the solvent 2 is dioxane.

[0041] Preferably, in step 4, the alkaline reagent is selected from at least one of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, and triethylamine.

[0042] More preferably, in step 4, the alkaline reagent is selected from at least one of sodium carbonate and potassium carbonate.

[0043] More preferably, in step 4, the alkaline reagent is sodium carbonate.

[0044] The beneficial effects of this invention are as follows:

[0045] Compared with the method of synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol from 3-(hydroxymethyl)phenylboronic acid, the present invention uses m-methylbenzonitrile as a raw material to synthesize 3-(5-bromopyrimidinyl)benzyl alcohol, which not only uses inexpensive and readily available raw materials, but also has a high reaction yield. Attached Figure Description

[0046] Figure 1 The mass spectrum of 3-(5-bromopyrimidinyl)benzyl alcohol synthesized in Example 1 is shown.

[0047] Figure 2 The hydrogen spectrum of 3-(5-bromopyrimidinyl)benzyl alcohol synthesized in Example 1 is shown. Detailed Implementation

[0048] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0049] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention were obtained through conventional commercial means. Unless otherwise specified, all contents mentioned below are mass contents. Unless otherwise specified, it is understood that the process was carried out at room temperature.

[0050] Example 1

[0051] 1. Synthesis of 3-methylbenzoamidine hydrochloride (compound II hydrochloride)

[0052] 3-Methylbenzoamidine hydrochloride was prepared according to the following procedure:

[0053]

[0054] Methanol (24 g) was added to the reaction flask, and the temperature was maintained at 0°C. Acetyl chloride (40 g) was added dropwise, and the mixture was kept at 0°C for 1-2 hours. Then, m-methylbenzonitrile (10 g) was added, and the mixture was kept at 15°C for 20 hours. The reaction system was concentrated to 2 vol., cooled to below 0°C, and ammonia-methanol solution (7 N, 40 g) was added. The mixture was kept at 25°C for 3 hours. After post-treatment, crystallization yielded 13 g of 3-methylbenzoamide hydrochloride, with a purity of 95% and a yield of 89%. LC-MS: [M+H] + =135.

[0055] 2. Synthesis of 5-bromo-2-(3-tolyl)pyrimidine (compound III)

[0056] 5-Bromo-2-(3-Tolyl)pyrimidine was prepared according to the following procedure:

[0057]

[0058] Acetic acid (50 g) and 3-methylbenzamide hydrochloride (10 g) were added to the reaction flask at a controlled temperature of 25 °C. The mixture was purged with nitrogen and maintained at 90 °C. Bromomalondialdehyde (10 g) was then slowly added dropwise to the reaction flask, and the mixture was maintained at 90 °C for 20 h. After post-treatment, crystallization yielded 8.6 g of 5-bromo-2-(3-tolyl)pyrimidine, with a purity of 95% and a yield of 59%. LC-MS: [M+H] + =349.

[0059] 3. Synthesis of 5-bromo-2-[3-(bromomethyl)phenyl]pyrimidine (compound IV)

[0060] 5-Bromo-2-[3-(bromomethyl)phenyl]-pyrimidine was prepared according to the following procedure:

[0061]

[0062] Acetonitrile (86 g), 5-bromo-2-(3-tolyl)pyrimidine (10 g), and NBS (9 g) were added to the reaction flask. Azobisisobutyl nitrile (0.1 eq) was then added, followed by nitrogen purging. The mixture was heated to 75 °C and held at this temperature for 4 h. After further processing, crystallization yielded 13 g of 5-bromo-2-[3-(bromomethyl)phenyl]pyrimidine, with a purity of 97% and a yield of 99%. LC-MS: [M+H] + =328.

[0063] 4. Synthesis of 3-(5-bromopyrimidinyl)benzyl alcohol (compound V)

[0064] 3-(5-bromopyrimidinyl)benzyl alcohol was prepared according to the following procedure:

[0065]

[0066] 1,4-Dioxane (55 g), 5-bromo-2-[3-(bromomethyl)phenyl]pyrimidine (10 g), sodium carbonate (10 g), and water (50 g) were added to the reaction flask, and the mixture was kept at 80 °C for 30 h. The reaction was quenched by slowly cooling to 25 °C. After post-treatment, crystallization yielded 5.9 g of 3-(5-bromopyrimidinyl)benzyl alcohol with a purity of 98% and a yield of 73%. LC-MS: [M+H] + =265.0.

[0067] 1 H NMR (DMSO-d6) δ: 9.08 (s, 2H), 8.36 (s, 1H), 8.22 (s, 1H), 7.51 (s, 1H), 7.47 (s, 1H), 5.35 (s, 1H), 4.60 (s, 2H).

[0068] Example 2

[0069] Synthesis of 1,3-methylbenzamidin acetate (compound II acetate)

[0070] 3-Methylbenzoamidine acetate was prepared according to the following procedure:

[0071]

[0072] Methanol (24 g) was added to the reaction flask, and the temperature was maintained at 0°C. Acetyl chloride (40 g) was added dropwise, and the mixture was kept at 0°C for 1-2 hours. Then, m-methylbenzonitrile (10 g) was added, and the mixture was kept at 15°C for 20 hours. The reaction system was concentrated to 2 vol., cooled to below 0°C, and ammonia-methanol solution (7 N, 40 g) was added. The mixture was kept at 25°C for 3 hours. After the reaction was complete, acetic acid (6 g) was added to form a salt. Crystallization yielded 14.9 g of 3-methylbenzoamide acetate, with a purity of 94% and a yield of 90%. LC-MS: [M+H] + =135.

[0073] 2. Synthesis of 5-bromo-2-(3-tolyl)pyrimidine (compound III)

[0074] 5-Bromo-2-(3-Tolyl)pyrimidine was prepared according to the following procedure:

[0075]

[0076] Trifluoroacetic acid (100 g) and 3-methylbenzamide acetate (12.7 g) were added to the reaction flask at a controlled temperature of 25 °C. The mixture was purged with nitrogen and maintained at 90 °C. Bromomalondialdehyde (11 g) was then slowly added dropwise to the reaction flask, and the mixture was maintained at 90 °C for 20 h. After post-treatment, crystallization yielded 11.4 g of 5-bromo-2-(3-tolyl)pyrimidine, with a purity of 94% and a yield of 70%. LC-MS: [M+H] + =349.

[0077] 3. Synthesis of 5-bromo-2-[3-(bromomethyl)phenyl]pyrimidine (compound IV)

[0078] 5-Bromo-2-[3-(bromomethyl)phenyl]-pyrimidine was prepared according to the following procedure:

[0079]

[0080] Tetrahydrofuran (86 g), 5-bromo-2-(3-tolyl)pyrimidine (10 g), and DBH (7 g) were added to the reaction flask, followed by the addition of azobisisobutyl nitrile (0.1 eq). The mixture was purged with nitrogen and heated to 75 °C for 4 h. After post-treatment, crystallization yielded 13 g of 5-bromo-2-[3-(bromomethyl)phenyl]pyrimidine, with a purity of 96% and a yield of 99%. LC-MS: [M+H] + =328.

[0081] 4. Synthesis of 3-(5-bromopyrimidinyl)benzyl alcohol (compound V)

[0082] 3-(5-bromopyrimidinyl)benzyl alcohol was prepared according to the following procedure:

[0083]

[0084] To a reaction flask, add n-butanol (54 g), 5-bromo-2-[3-(bromomethyl)phenyl]pyrimidine (10 g), potassium carbonate (9.8 g), and water (50 g), and maintain the temperature at 80 °C for 30 h. Slowly cool to 25 °C to quench the reaction. After post-treatment, crystallization yielded 5.8 g of 3-(5-bromopyrimidinyl)benzyl alcohol, with a purity of 98% and a yield of 71%. LC-MS: [M+H] + =265.0.

[0085] 1 H NMR (DMSO-d6) δ: 9.08 (s, 2H)), (s, 1H), 8.22 (s, 1H), 7.51 (s, 1H), 7.47 (s, 1H), 5.35 (s, 1H), 4.60 (s, 2H).

[0086] Comparative Example 1

[0087] 3-(5-bromopyrimidinyl)benzyl alcohol was prepared according to the following procedure:

[0088]

[0089] A solution of 7.0 g sodium carbonate in 32.5 mL of water was added to a solution of 9.5 g 5-bromo-2-iodopyrimidine in 32.5 mL of toluene, maintained under nitrogen atmosphere, and the mixture was heated to 80 °C. 0.23 g of bis(triphenylphosphine)palladium chloride was added, followed by dropwise addition of a solution of 5 g 3-(hydroxymethyl)phenylboronic acid dissolved in 65 mL of ethanol. The reaction mixture was stirred at 80 °C for 18 hours. 100 mL of ethyl acetate and 100 mL of water were added to the filtrate. The organic phase was separated, dried over sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography yielded 6.01 g of 3-(5-bromopyrimidinyl)benzyl alcohol, in 68% yield.

[0090] Comparative Example 2

[0091] 3-(5-bromopyrimidinyl)benzyl alcohol was prepared according to the following procedure:

[0092]

[0093] A solution of 9.1 g potassium carbonate in 32.5 mL of water was added to a solution of 9.5 g 5-bromo-2-iodopyrimidine in 32.5 mL of toluene, maintained under nitrogen atmosphere. The mixture was then heated to 80 °C. 0.23 g of bis(triphenylphosphine)palladium chloride was added, followed by dropwise addition of a solution of 5 g 3-(hydroxymethyl)phenylboronic acid dissolved in 65 mL of ethanol. The reaction mixture was stirred at 80 °C for 18 hours. 100 mL of ethyl acetate and 100 mL of water were added to the filtrate. The organic phase was separated, dried over sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography yielded 3.05 g of 3-(5-bromopyrimidinyl)benzyl alcohol, in 34.5% yield.

[0094] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol, characterized in that, The 3-(5-bromopyrimidinyl)benzyl alcohol was synthesized from m-methylbenzonitrile using the following method:

2. The synthesis method according to claim 1, characterized in that, Step 1 further includes performing a post-processing operation after the reaction to obtain compound II or its salt; The post-processing operation is selected from one of the following three operations: Operation a: Routine post-processing; Operation b: Add NaOH to the reaction solution and perform routine post-treatment; Operation c: Add acid to the reaction solution to form salt crystals.

3. The synthesis method according to claim 2, characterized in that, The compound II or its salt is selected from at least one of 3-methylbenzoamidine free base, 3-methylbenzoamidine hydrochloride, 3-methylbenzoamidine sulfate, 3-methylbenzoamidine carboxylate, 3-methylbenzoamidine acetate, and 3-methylbenzoamidine trifluoroacetate.

4. The synthesis method according to claim 2, characterized in that, The method for synthesizing 3-(5-bromopyrimidinyl)benzyl alcohol includes the following steps: Step 1: Mix the alcohol reagent and acetyl chloride, control the temperature of the mixture to below 5°C, and keep it at this temperature for 1-4 hours. Then mix the mixture with m-methylbenzonitrile, control the temperature of the mixture to 5-25°C, and keep it at this temperature for 17-23 hours. Concentrate the reaction system and cool it to below 0°C. Then add NH3 to carry out the reaction. Control the system temperature at 15-35°C during the reaction. After the reaction is completed, perform post-processing to obtain compound II or its salt. Step 2: Mix the acid reagent with compound II or its salt, purge with nitrogen, and maintain the temperature of the mixture at 80-100℃. Mix the mixture with malondialdehyde bromo, and maintain the temperature of the mixture at 80-100℃. Continue the reaction at this temperature until compound III is obtained. Step 3: Mix solvent 1, compound III, brominating agent and free radical initiator, replace with nitrogen, heat to 65-85℃, maintain the temperature for reaction, and obtain compound IV after the reaction is completed; Step 4: Mix solvent 2, compound IV, alkaline reagent, and water, keep the temperature of the mixture at 70-90℃, maintain the temperature for the reaction, cool down to 15-35℃, and quench the reaction to obtain compound V.

5. The synthesis method according to claim 4, characterized in that, In step 1, the alcohol reagent is selected from at least one of methanol, ethanol, and isopropanol.

6. The synthesis method according to claim 4, characterized in that, In step 1, the acid in operation c is selected from at least one of sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid.

7. The synthesis method according to claim 4, characterized in that, In step 2, the acid reagent is selected from at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid.

8. The synthesis method according to claim 4, characterized in that, In step 3, Solvent 1 is selected from at least one of acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamine, tetrahydrofuran, isopropyl acetate, propylene glycol, and pyridine; The free radical initiator is selected from at least one of AIBN and BPO.

9. The synthesis method according to claim 4, characterized in that, In step 3, the brominating reagent is selected from at least one of NBS, DBH, DBI, NBSac, and NBP.

10. The synthesis method according to claim 4, characterized in that, In step 4, The solvent 2 is selected from at least one of acetone, dioxane, n-butanol, n-pentanol, isopropanol, and ethyl acetate; The alkaline reagent is selected from at least one of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, and triethylamine.

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