Method for preparing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile

Abstract

The present invention relates to a method for preparing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile, which comprises reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, 3-formyl-4-methoxybenzonitrile, and sodium ethoxide solution.

Description

[Technical Field]

[0001] The present invention relates to the field of synthesis in organic and medicinal chemistry. More particularly, the present invention provides an improved method for preparing the anticancer drug, (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile. [Background technology]

[0002] Kinesins are a superfamily of motor proteins with ATPase activity. They are involved in various normal cellular biological activities, including mitosis, mitosis, and intracellular vesicle transport. Kinesin family member 20A (KIF20A, also known as MKlp2), located on chromosome 5q31.2, plays an important role in tumor initiation and development. In recent years, several studies have demonstrated that KIF20A may also play an important role in the development and progression of many different types of cancer, such as melanoma, breast cancer, nasopharyngeal carcinoma, pancreatic cancer, hepatocellular carcinoma, lung cancer, and colorectal cancer.

[0003] Over the past few years, a class of indole derivatives has been developed as compounds that target KIF20A (MKlp2), such as the compounds described in International Patent Application WO 2014 / 086964.

[0004] More specifically, WO 2014 / 086964 focuses on (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (Example 38 of WO 2014 / 086964), which has been evaluated for its efficient antitumor activity at nanomolar efficiency against various human cancer cells, thereby generating strong interest in using this lead compound for the treatment of a large group of cancers, including, for example, acute myeloid leukemia, lymphoma, breast cancer, pancreatic cancer, lung cancer, and colon cancer. (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile can be obtained by reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate with sodium hydride dispersion (NaH), followed by the addition of 3-formyl-4-methoxybenzonitrile. However, this synthesis using NaH does not meet the requirements for industrial scale and safety. In fact, (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile was obtained in only 30% yield, and the use of NaH is accompanied by delayed reaction initiation, exothermic heat, hydrogen gas evolution, and potential contamination of the final product with mineral oil. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Patent Application WO 2014 / 086964 Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there is a need to develop and provide a process for synthesizing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile that is suitable for industrial scale, including economic and safety goals. [Means for solving the problem]

[0007] In this regard, we have developed new reactive conditions for the preparation of (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile starting from tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile. Unexpectedly, we have shown that replacing the sodium hydride dispersion with a more process-friendly reagent, i.e., sodium ethoxide solution, affords (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile in an improved yield of 74% and a high LCMS purity of 99.1%.

[0008] The present invention therefore provides a method for preparing Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile, which comprises: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile with sodium ethoxide solution; and b) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile The present invention relates to a method, including:

[0009] In particular, the sodium ethoxide solution is preferably a sodium ethoxide / ethanol solution with a concentration of 21 w / w%.

[0010] In a particular embodiment, step a) is reacted at a temperature in the range of 25 to 60°C, preferably 40 to 45°C.

[0011] In a more particular embodiment, step a) is reacted for a period of 1 to 3 hours, preferably about 2 hours.

[0012] In a preferred embodiment, step a) is reacted at a temperature in the range of 40-45° C. for about 2 hours.

[0013] In a further preferred embodiment, sodium ethoxide solution, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile are used in stoichiometric amounts in step a).

[0014] In certain embodiments, step b) comprises: b1) adding water to the mixture of step a); b2) filtering the mixture and then washing and drying the crude material; b3) optionally purifying the crude material with MEK solution; and b4) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile Includes. DETAILED DESCRIPTION OF THE INVENTION

[0015] The following formula:

[0016] [ka]

[0017] (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (compound (6)), having the formula:

[0018] The present invention provides a simple and safe method for preparing this compound in high yield and purity starting from tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile using sodium ethoxide solution.

[0019] The present invention provides a method for preparing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile, comprising: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile with sodium ethoxide solution; and b) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile The present invention relates to a method, including:

[0020] Sodium ethoxide (CAS number: 141-52-6), also known as sodium ethylate or sodium ethanolate and having the formula CHONa, is a strong base and can be dissolved in polar solvents such as methanol or ethanol. In a preferred embodiment, sodium ethoxide is dissolved in ethanol to form a sodium ethoxide / ethanol solution, preferably at a concentration of 21 w / w%. It is understood that the sodium ethoxide / ethanol solution can be easily prepared by one skilled in the art or purchased commercially.

[0021] In certain embodiments, step a) is reacted at a temperature in the range of 25 to 60°C, 30 to 55°C, 35 to 50°C, preferably 40 to 45°C.

[0022] In a more particular embodiment, step a) is reacted for 1 to 3 hours, 1.5 to 2.5 hours, preferably for about 2 hours.

[0023] As used herein, the term "about" is understood by those of ordinary skill in the art and can vary to some extent depending on the context in which it is used. Where some uses of the term are not clear to those of ordinary skill in the art depending on the context, "about" will mean plus or minus 30%, 20%, preferably plus or minus 10%, and more preferably plus or minus 5% of the particular term.

[0024] In a preferred embodiment, the present invention provides a method for preparing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile, comprising: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile with sodium ethoxide / ethanol solution at a temperature in the range of 40-45° C. for about 2 hours; and b) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile The present invention relates to a method, including:

[0025] In a more particular embodiment, sodium ethoxide solution, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, and 3-formyl-4-methoxybenzonitrile are used in stoichiometric amounts in step a).

[0026] Those skilled in the art, such as organic chemists, are familiar with the concept of stoichiometry. For example, sodium ethoxide solution or sodium ethoxide / ethanol solution, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, and 3-formyl-4-methoxybenzonitrile are reacted in approximately equal molar amounts or in a molar ratio equal to about 1. For example, sodium ethoxide / ethanol solution, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, and 3-formyl-4-methoxybenzonitrile are each used in an amount of 1.00 to 1.05 equivalents relative to the others. Preferably, as defined herein, 1.00 equivalents of tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, 1.00 equivalents of sodium ethoxide / ethanol solution, and 1.02 equivalents of 3-formyl-4-methoxybenzonitrile are used in step a).

[0027] Step b) of the process of the present invention, which involves the recovery of (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile, including the non-exhaustive steps of quenching, filtration, washing, purification and drying, can be easily carried out by one skilled in the art.

[0028] For example, step b) of the method of the present invention may be as follows: b1) adding water to the mixture of step a); b2) filtering the mixture and then washing and drying the crude material; b3) optionally purifying the crude material with MEK solution; and b4) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile It may further include.

[0029] In a preferred embodiment, the method of the present invention comprises: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile with sodium ethoxide / ethanol solution; and b1) adding water to the mixture of step a); b2) filtering the mixture and then washing and drying the crude material; b3) optionally purifying the crude material with MEK solution; and b4) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile Includes.

[0030] In a more preferred embodiment, the method of the present invention comprises: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile with sodium ethoxide / ethanol solution at a temperature in the range of 40-45° C. for about 2 hours; and b1) adding water to the mixture of step a); b2) filtering the mixture and then washing and drying the crude material; b3) optionally purifying the crude material with MEK solution; and b4) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile Includes.

[0031] The starting materials tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile can be prepared by any known synthetic method, including any chemical synthesis currently used in organic chemistry. These starting materials can also be purchased commercially (tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, CAS number: 1419874-03-5; and 3-formyl-4-methoxybenzonitrile, CAS number: 21962-53-8).

[0032] For example, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile can be prepared by the synthetic procedures disclosed by WO 2014 / 086964.

[0033] In certain embodiments, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate is selected from the group consisting of: - reacting 5-bromo-1H-indole-3-carbaldehyde with formamide, methanol, and sodium borohydride, then adding potassium cyanide, and stirring the resulting mixture at a temperature in the range of 40-45°C to obtain 2-(5-bromo-1H-indol-3-yl)acetonitrile; and - reacting 2-(5-bromo-1H-indol-3-yl)acetonitrile with di-tert-butyl-dicarbonate and 4-dimethylaminopyridine with acetonitrile at room temperature; and - recovering tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate. It is prepared by a method comprising:

[0034] In certain embodiments, 3-formyl-4-methoxybenzonitrile is: - reacting 4-fluoro-3-formylbenzonitrile with methanol and sodium methoxide at room temperature to obtain 3-formyl-4-methoxybenzonitrile; and - recovering 3-formyl-4-methoxybenzonitrile. It is prepared by a method comprising:

[0035] Further aspects and advantages of the present invention are illustrated in the following examples, which should be considered as illustrative and not limiting. [Example]

[0036] The method for preparing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile is reproduced by the following Scheme 1.

[0037] Scheme 1 [ka]

[0038] 1. Synthesis of tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate (3) 1.1. Synthesis of 2-(5-bromo-1H-indol-3-yl)acetonitrile (2) To a solution of 5-bromo-1H-indole-3-carbaldehyde (1 equiv.) (1) in methanol:formamide (7:1) was added sodium borohydride at 0-10 °C. The reaction mixture was then stirred at room temperature for 30 min, and potassium cyanide (2.5 equiv.) was added. The mixture was stirred at 40-45 °C for 12 h and then quenched with water. The crude residue was filtered, washed with EtOH:HO (1:1), and dried to afford 2-(5-bromo-1H-indol-3-yl)acetonitrile (2) in 57% yield.

[0039] 1.2. Synthesis of tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate (3) To a solution of di-tert-butyl dicarbonate (1.1 equivalents) and dimethylaminopyridine (0.05 equivalents) in acetonitrile was added 2-(5-bromo-1H-indol-3-yl)acetonitrile (2) (1 equivalent) at room temperature. The reaction mixture was then stirred at room temperature for 1 hour and then quenched with water. The crude residue was filtered, washed with heptane, and dried to give tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate (3) in 93% yield.

[0040] 2. Synthesis of 3-formyl-4-methoxybenzonitrile (5) To a solution of 4-fluoro-3-formylbenzonitrile (4) (1 equivalent) in methanol was added 5.4 M sodium methoxide / methanol solution (1.05 equivalents) at 0-10 °C. The reaction mixture was then stirred at room temperature for 1.5 h and quenched with water. The crude residue was filtered, washed with heptane, and dried to give 3-formyl-4-methoxybenzonitrile (5) in 69% yield.

[0041] 3. Synthesis of (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (6) (Method according to the invention) To a solution of tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate (3) (1 equivalent) and formyl-4-methoxybenzonitrile (5) (1.02 equivalents) in ethanol was added sodium ethoxide / ethanol solution (1.00 equivalents) at room temperature. The reaction mixture was then stirred at 40-45 °C for 2 hours and quenched with water. The crude residue was filtered, washed with ethanol, and dried. The material was added to a methyl ethyl ketone (MEK) solution, and the temperature was adjusted to 70-75 °C. The MEK solution was then clarified by filtration. The filtrate was concentrated, and the solid was then dried to afford (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile in 74% yield. APCI-MS: (M−H) = 376 1 H NMR (300 MHz, DMSO-d6) δ ppm: 11.99 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.91 (s, 2H), 7.70 (s, 1H), 7.60 - 7.15 (m, 3H), 3.97 (s, 3H). LCMS purity: 99.1%

[0042] 4. Synthesis of (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (Comparative Method) To a solution of tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate (3) (1 equivalent) in THF was added sodium hydride (1.5 equivalents) under an argon atmosphere at 0-5°C. Then, 3-formyl-4-methoxybenzonitrile (5) (1.2 equivalents) was added in small portions, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water. The resulting solid was filtered, washed successively with water, CHCl, DIPE, and acetonitrile, and dried under vacuum to afford (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile in 30% yield.

Claims

1. 1. A process for preparing (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile, comprising the steps of: a) reacting tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate and 3-formyl-4-methoxybenzonitrile with sodium ethoxide solution; and b) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile A method comprising:

2. 2. The method according to claim 1, wherein the sodium ethoxide solution is preferably a sodium ethoxide / ethanol solution at a concentration of 21 w / w%.

3. 3. The method according to claim 1, wherein step a) is reacted at a temperature in the range of 25 to 60°C.

4. 4. The method according to claim 1, wherein step a) is reacted at a temperature in the range of 40 to 45°C.

5. 5. The method according to claim 1, wherein step a) is reacted for a period of 1 to 3 hours.

6. 6. The method according to claim 1, wherein step a) is reacted for about 2 hours.

7. 7. The method according to any one of claims 1 to 6, wherein step a) is reacted at a temperature in the range of 40 to 45°C for a period of about 2 hours.

8. 8. The method according to claim 1, wherein sodium ethoxide solution, tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate, and 3-formyl-4-methoxybenzonitrile are used in stoichiometric amounts in step a).

9. Step b) is as follows: b1) adding water to the mixture of step a); b2) filtering the mixture and then washing and drying the crude material; b3) optionally purifying the crude material with MEK solution; and b4) recovering (Z)-3-(2-(5-bromo-1H-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 9. The method of any one of claims 1 to 8, comprising:

10. tert-Butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate can be prepared as follows: - reacting 5-bromo-1H-indole-3-carbaldehyde with formamide, methanol, and sodium borohydride, then adding potassium cyanide and stirring the resulting mixture at a temperature in the range of 40 to 45°C to obtain 2-(5-bromo-1H-indol-3-yl)acetonitrile; and - reacting 2-(5-bromo-1H-indol-3-yl)acetonitrile with di-tert-butyl-dicarbonate and 4-dimethylaminopyridine with acetonitrile at room temperature; and - recovering tert-butyl 5-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate.

10. The method of any one of claims 1 to 9, wherein the compound is prepared by a method comprising:

11. 3-Formyl-4-methoxybenzonitrile is: - reacting 4-fluoro-3-formylbenzonitrile with methanol and sodium methoxide at room temperature to obtain 3-formyl-4-methoxybenzonitrile; and - recovering 3-formyl-4-methoxybenzonitrile.

10. The method of any one of claims 1 to 9, wherein the compound is prepared by a method comprising:

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