TW202114994A - Preparation method of 1,6-dihydropyridine-3-formamide derivative - Google Patents

Abstract

The disclosure relates to a preparation method of 1,6-dihydropyridine-3-formamide derivative. In particular, a method for preparing 4-(6-methylpyridine-3-methoxy)-2-(2-fluoro-4-iodophenylamino)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-formamide is provided.

Description

A kind of preparation method of 1,6-dihydropyridine-3-carboxamide derivative

The present disclosure belongs to the field of medicine, and specifically relates to a preparation method of 1,6-dihydropyridine-3-carboxamide derivatives.

MEKs, also known as MAP kinases (MAPKK or Erk kinase), are dual-specific kinases that can phosphorylate silk/threonine residues and tyrosine residues (Erk1 phosphorylation) of MAPK (p44MAPK(Erk1) and p42MAPK(Erk2) The sites are T202 and Y204, and the phosphorylation sites of Erk2 are T183 and Y185). The MEK family contains five genes: MEK1, MEK2, MEK3, MEK4 and MEK5.

Currently, a series of MEK inhibitors have been published, such as PD98059, PD184352, AZD8330 (sumetinib), TAK-733, Trametinib, Vemurafenib, etc. that inhibit Mek activity by Raf kinase. AZD8330 is an orally active, selective MEK inhibitor with IC50 of 7nM. It has potential anti-tumor activity, especially inhibits mitogen-activated protein kinase kinase 1 (MEK or MAP/ERK kinase 1), thereby inhibiting growth factor-regulated Cell signaling and tumor cell proliferation. Trametinib is an effective and selective allosteric inhibitor of MEK1 and MEK2 (MEK1/2) enzymes. It has shown anti-tumor activity in a phase I clinical trial (ASCO2010). TAK-733 is a potent and selective ATP-noncompetitive MEK allosteric site inhibitor with IC50 of 3.2nM.

WO2015058589 discloses a new generation of high-efficiency and low-toxicity inhibitors for MAPKs signaling pathway, 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodoanilino)-1 -Methyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide, the structural formula is as follows:

WO2016155473 reports the mesylate form of the aforementioned MEK kinase inhibitor, providing 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodoanilino)-1-methyl- 6-Carbonyl-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate, the drug salt has good crystal stability and chemical stability, and has low toxicity and low solvent residues, which is better for Clinical application.

On the other hand, 3-methyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H, 3H,8H)-trione is a key intermediate for the preparation of the aforementioned MEK kinase inhibitors. WO2015058589 reports a conventional preparation method, that is, under high temperature conditions, a compound of formula a reacts with diethyl malonate to form a compound of formula b . The reaction conditions of the process are harsh, and high temperature conditions are required to cause the condensation reaction. The side reactions of the process are serious.

In view of the consideration of simplifying the preparation process and reducing the production cost, the present disclosure provides a new 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodoanilino)-1- Methyl-6-carbonyl-1,6-dihydropyridine-3-methyl The preparation method of amide has mild process conditions and is suitable for large-scale industrial production.

The disclosure provides a method for preparing a compound of formula b or a pharmaceutically acceptable salt thereof, including the step of reacting a compound of formula a with malonic acid to form a compound of formula b,

In some embodiments, the molar ratio of the compound of formula a to malonic acid is 1:1 to 1:10, including but not limited to 1:2, 1:3, 1:4, 1:5, 1:6, 1 ：7, 1:8, 1:9, 1:10 or any value between any two numbers, preferably 1:2~1:6.

In other embodiments, the solvent used in the reaction of the compound of formula a with malonic acid is selected from aprotic solvents, including but not selected from acetonitrile, THF, dioxane, ethylene glycol dimethyl ether and toluene, preferably toluene.

In some preferred embodiments, the method for preparing the compound of formula b or its pharmaceutically acceptable salt further contains C ₁ -C ₆ alkyl acid anhydride or C ₁ -C ₆ alkyl acid chloride, including but not limited to trifluoroacetic anhydride, Trifluoroacetyl chloride, acetic anhydride, acetyl chloride, preferably acetyl chloride or acetic anhydride.

In an embodiment, acetic anhydride or acetyl chloride is selected to promote the condensation reaction. On the other hand, C ₁ -C ₆ alkyl acid anhydride or C ₁ -C ₆ alkyl chloride can effectively reduce the reaction temperature, making the condensation reaction conditions more gentle, suitable for industrial scale-up production, and at the same time, the mild reaction is also reduced by temperature. The occurrence rate of side reactions can effectively improve the product yield and quality. In some embodiments, the aforementioned condensation reaction temperature is 40~150°C, including 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C ℃ or any value between any two numbers, preferably 60~90℃.

In other embodiments, the molar ratio of acetic anhydride or acetyl chloride to the compound of formula a is 2:1-20:1, including but not limited to 2:1, 3:1, 4:1, 5 :1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1 , 18:1, 19:1, 20:1 or any value between any two numbers, preferably 4:1~12:1.

Further, the method for preparing a compound of formula b or a pharmaceutically acceptable salt thereof includes the step of reacting a compound of formula a with malonic acid to form a compound of formula b, wherein the molar ratio of the compound of formula a to malonic acid is 1:2~ 1:6, the molar ratio of the compound of formula a to acetyl chloride or acetic anhydride is 1:4~1:12, the solvent used in the reaction is an aprotic solvent, and the reaction temperature is 40~150℃, including but not limited to 40℃, 50 ℃, 60℃, 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, 130℃, 140℃, 150℃ or any value between any two numbers.

Further, the method for preparing the compound of formula b or a pharmaceutically acceptable salt thereof in the present disclosure further includes the steps of filtration, washing or drying.

On the other hand, the present disclosure also provides a method for preparing a compound of formula I or a usable salt thereof, including the steps of the method for preparing a compound of formula b or a pharmaceutically acceptable salt thereof, and the conversion of a compound of formula b into a compound of formula I or a usable salt thereof A step of,

Further, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof includes the step of reacting a compound of formula c with 6-methyl-3-hydroxypyridine under alkaline conditions to form a compound of formula d,

In some embodiments, the agent that provides alkalinity is selected from (trimethylsilyl) amide lithium, n-butyl lithium, or tertiary butyl lithium.

In other embodiments, the ratio of the used amount of the alkaline reagent to the molar amount of the compound of formula c is 1:1~1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or any value between any two numbers.

In some embodiments, the molar ratio of the compound of formula c to 6-methyl-3-hydroxypyridine is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1 : 1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or any value between any two numbers.

Furthermore, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof further comprises the step of converting a compound of formula e into a compound of formula I,

In some embodiments, the compound of formula e is under trifluoroacetic acid conditions to form the compound of formula I.

In some embodiments, the method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof includes:

Step 1) A compound of formula a reacts with malonic acid to form a compound of formula b; Step 2) A compound of formula b is converted to a compound of formula c; Step 3) A compound of formula c is combined with 6-methyl-3-hydroxypyridine under basic conditions React with A compound of formula d is formed; step 4) a compound of formula d is converted into a compound of formula e; step 5) a compound of formula e is converted into a compound of formula I,

In some embodiments, the reaction of the compound of formula b with trifluoromethanesulfonic anhydride to form the compound of formula c can be carried out with reference to the reaction conditions in WO2015058589, and the relevant content is incorporated into the present disclosure for illustration.

In other embodiments, the compound of formula d is converted into the compound of formula e under the condition of lithium hydroxide, which can be carried out with reference to the reaction conditions in WO2015058589, and the relevant content is incorporated into the present disclosure for illustration.

The preparation of the compound formed by the compound of formula I and inorganic acid or organic acid of the present disclosure to obtain a pharmaceutically acceptable salt of the compound of formula I can be carried out with reference to the reaction conditions in WO2016155473, and the relevant content is incorporated into the present disclosure for illustration.

Further, the method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof in the present disclosure further includes the steps of filtration, washing or drying.

The present disclosure also provides another method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, including the step of converting a compound of formula e into a compound of formula I,

In some embodiments, the compound of formula e is under trifluoroacetic acid conditions to form the compound of formula I. Compared with aluminum trichloride, trifluoroacetic acid is more conducive to the removal of amine protecting groups, and at the same time, it avoids the occurrence of side reactions in the process.

Further, the compound of formula e can be prepared according to the aforementioned scheme.

The present disclosure also provides a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof prepared by the foregoing method, and one or more pharmaceutically acceptable carriers, diluents or excipients .

The present disclosure also provides a use of the compound of formula I prepared by the foregoing method or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating diseases related to MEK kinase inhibitors. The diseases are preferably tumors, and more preferably melanomas.

The “pharmaceutically acceptable salts” mentioned in the present disclosure refer to the salts of the compounds of the present disclosure. Such salts are safe and effective when used in mammals, and have due biological activity, specifically the compounds of the present disclosure and inorganic Compounds formed by acids or organic acids, including but not limited to: hydrohalides, carbonates, sulfates, hydrogen sulfates, phosphates, acetates, oxalates, tartrates, maleates, and fumarates , Sulfonate, amino acid salt, etc., preferably p-toluenesulfonate.

The "alkyl" mentioned in the present disclosure refers to a saturated aliphatic hydrocarbon group, preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl Group, 1,2-dimethylpropyl, 2,2-dimethylpropyl Group, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from aryl, heteroaryl Group, halogen substituted.

The “medical composition” in the present disclosure means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmacological Medicinal carriers and excipients. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The purity or content of the present disclosure is determined by HPLC detection, and the compound characterization data is obtained by analyzing the nuclear magnetic resonance spectrum; the reagents used in the present disclosure can be purchased through commercial channels.

The present disclosure will be explained in more detail below in conjunction with embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and the essence and scope of the present disclosure are not limited thereto.

Example 1:

Toluene (160ml), malonic acid (8.65g, 4.0eq) and acetyl chloride (9.79g, 6.0eq) were added to a 250ml three-necked flask, heated to 70~80℃ and stirred for reaction, then added the compound of formula a (10.0 g, 1.0 eq), continue to stir the reaction, cool, add water to quench the reaction, extract with dichloromethane, dry, and concentrate to obtain 12.3 g of yellow solid.

Take 9.1g of yellow solid and add 18.4ml of tetrahydrofuran and 92ml of tertiary butyl methyl ether, heating under reflux and stirring to react for 2h, and then falling to room temperature to filter to obtain 6.12g of solid, HPLC: 98.23%, yield: 72.58%.

Example 2:

Add diethyl malonate (4.99g, 3.0eq), compound of formula a (5g) and dimethyl ether (50ml) to a 100ml reaction flask, heat to 240℃ and stir to react, cool and concentrate the reaction solution The crude product was obtained, HPLC: 75.88%.

Example 3

Add formula e (6.15 g, 10.01 mmol) and trifluoroacetic acid (56.8 g) into a 100 mL reaction flask and stir. The reaction was heated to reflux, followed by TLC (DCM: MeOH=20:1) until the raw material disappeared, and the reaction was stopped. Concentrate under reduced pressure to remove trifluoroacetic acid, add acetone (25mL) to the residue, adjust the pH to 8-9 with 0.5M sodium hydroxide solution, filter, wash the filter cake with purified water, and dry to obtain a solid 4.61g, yield 93.2%, purity 98.14%.

Example 4:

step 1:

Add the raw materials 3-hydroxy-6-methylpyridine (51.6g, 472.59mmol) and tetrahydrofuran (1.5kg) into a 5L three-necked reaction flask, dropwise add 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (LiHMDS) (452mL, 452.04mmol), the tetrahydrofuran solution of the compound of formula c (280.0g, 1.5kg tetrahydrofuran) was added dropwise, and the reaction was stirred at 50-55°C. TLC (DCM:MeOH=20:1) was followed until the raw material disappeared, and the reaction was stopped. Concentrate, add acetone (440g) to the residue, stir, filter, and dry to obtain a solid 184.1g with a yield of 69.9% and a purity of 98.77%.

Step 2:

Put the compound of formula d (195.7g, 305.59mmol) into a 3L reaction flask, add tetrahydrofuran (1100g), add lithium hydroxide monohydrate (29.5g, 916.76mmol) to purified water (400g), stir to dissolve, add the above In the reaction solution, the reaction was stirred at 50-55°C, followed by TLC (MeOH:DCM=20:1) until the raw materials disappeared, and the reaction was stopped. The insoluble matter was removed by filtration, concentrated, the residue was washed with dichloromethane solvent, brine, dried and concentrated. The residue was added with acetone (630g) and stirred at room temperature, filtered and dried to obtain a solid 151.5g, yield 86.8%, purity 99.28% .

Step 3:

Formula e (154.5 g, 251.46 mmol) and trifluoroacetic acid (1500 g) were added to a 2L three-necked reaction flask, and the stirring was turned on. The reaction was heated to reflux, followed by TLC (DCM: MeOH=20:1) until the raw material disappeared, and the reaction was stopped. Concentrate under reduced pressure to remove trifluoroacetic acid, add acetone (440g) to the residue, adjust pH to 8-9 with 0.5M sodium hydroxide solution, filter, wash the filter cake with purified water, and dry to obtain a solid 110.3g, yield 91.7%, purity 98.78%.

Claims (15)

A method for preparing a compound of formula b or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula a with malonic acid to form a compound of formula b,

The method according to claim 1, which further contains C ₁ -C ₆ alkyl acid anhydride or C ₁ -C ₆ alkyl acid chloride, preferably trifluoroacetic anhydride, trifluoroacetyl chloride, acetic anhydride, acetyl chloride , More preferably acetyl chloride or acetic anhydride. The method according to claim 1 or 2, wherein the molar ratio of the compound of formula a to malonic acid is 1:1 to 1:10, preferably 1:2 to 1:6. The method according to claim 2, wherein the molar ratio of acetic anhydride or acetyl chloride to the compound of formula a is 2:1-20:1, preferably 4:1-12:1. The method according to any one of claims 1 to 4, wherein the solvent used in the reaction is selected from aprotic solvents, preferably acetonitrile, THF, dioxane, ethylene glycol dimethyl ether and toluene, more preferably toluene. The method according to any one of claims 1 to 5, wherein the reaction temperature is 40 to 150°C, preferably 60 to 90°C. A method for preparing a compound of formula I or a usable salt thereof, comprising the method steps described in any one of claims 1 to 6, and the step of converting a compound of formula b into a compound of formula I or a pharmaceutically acceptable salt thereof,

The method according to claim 7, which includes the step of reacting the compound of formula c with 6-methyl-3-hydroxypyridine under alkaline conditions to form the compound of formula d,

The method according to claim 8, wherein the reagent for providing alkalinity is selected from (trimethylsilyl) amide lithium, n-butyl lithium or tertiary butyl lithium. The method according to claim 8 or 9, which further comprises the step of converting the compound of formula e into the compound of formula I,

The method according to claim 10, wherein the compound of formula e is subjected to trifluoroacetic acid conditions to form the compound of formula I. The method according to any one of claims 7 to 11, comprising: step 1) reacting a compound of formula a with malonic acid to form a compound of formula b; step 2) converting a compound of formula b into a compound of formula c; step 3) base Under natural conditions, a compound of formula c reacts with 6-methyl-3-hydroxypyridine to form a compound of formula d; step 4) a compound of formula d is converted into a compound of formula e; step 5) a compound of formula e is converted into a compound of formula I,

The method according to any one of claims 7 to 12, wherein the pharmaceutically acceptable salt of the compound of formula I is selected from p-toluenesulfonate. A pharmaceutical composition containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof prepared by the method described in any one of claims 7 to 13, and one or more pharmaceutically acceptable carriers, Diluent or excipient. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for use in the preparation of a medicine for treating diseases related to MEK kinase inhibitors. The disease is better than tumor and better melanin tumor.