TWI274749B - Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone - Google Patents

Abstract

A four-step process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl)-ethanone of the formula, starting from 2-methyl-5-ethylpyridine is described. 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)-phenyl]ethanone is an intermediate for preparing COX-2 inhibitors.

Description

1274749

V. DESCRIPTION OF THE INVENTION (丨) Description The present invention includes a novel process for the preparation of 1-(6-methylcyclopyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone,

(Please read the notes on the back and fill out this page.) S〇2CH3 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone is prepared An intermediate product of the so-called COX-2 inhibitor, which has an analgesic and anti-inflammatory pharmaceutically active compound (RS Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998) 2777, 2782; WO98/03484) 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of formula I is an unknown novel compound in the literature It is an object of the present invention to provide a novel intermediate product for the manufacture of a COX-2-inhibitor and to provide an industrially practicable process for the preparation of an intermediate of the formula I. This object is achieved by a novel method according to the first aspect of the patent application. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printing The method according to the invention is characterized by four steps, wherein in the first step a), 2-methylethylpyridine is converted to 2 in the presence of a catalyst at 50 CTC to 700 °C. -methyl-5-vinylpyridine, in the second step b), 2-methylco-vinylpyridine uses ozone and then The original treatment is converted to 2-methylpyridinaldehyde. In the third step c), 2-methylpyridine-5-formaldehyde is dialkylamine and 3 paper scales are applicable to the Chinese National Standard (CNS) A4 specification (2i0X29). ??) 1274749 A7 B7 V. Description of the invention (less) Conversion of the CN compound to the equivalent N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and in the last step d), N,N-Dialkylamino-(6-methyl-3-acridinyl)acetonitrile is reacted with 4-(methylsulfonyl)benzyl halide in the presence of a base to give 1-(6-methyl) Pyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone to give the final product. Significant advantages of the process according to the invention include the industrially available 2-methyl-5- The fact that ethylpyridine can be used as a starting material. Step a: From the literature (for example, A. Nenz et al., Hydrocarbon Processing, 47 (11), 1968, 139-144; US-A 2,769,773) Dehydration of 2-methyl-ethylpyridine results in 2-methyl-5-vinylpyridine. The reaction is carried out in the presence of many different catalysts at 50 (TC to 700 ° C. In general, based on vermiculite, 矽Gel, iron oxide, oxidation Zinc, chromium oxide 'copper chromite, magnesium oxide, potassium oxide, aluminum oxide or boron phosphate catalysts', either alone or as a mixture, if appropriate applied to the support. In particular, zinc oxide applied to the pumice as a support is used. The catalyst gives good results. Diluting 2-methylpyridine with steam or an inert gas is advantageous for the reaction, but it is preferred to use a vapor. 2-Methyl-vinylpyridine can be purified in a simple process, for example by removing the aqueous phase and later by steam distillation or vacuum distillation to make it suitable for subsequent steps b) 〇Step b: ______ 4 Paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 麓) (Please read the note on the back and fill out this page), τ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1274749 7 A7 B7 V. Invention Description (4) The reaction with ozone is advantageously carried out at a temperature of from -20 ° C to 〇 ° C in the presence of a mineral acid, preferably at a temperature of from -15 ° C to -5 ° C. Suitable mineral acids are sulfuric acid or phosphoric acid, and especially sulfuric acid. Suitable reaction media are water and polar solvents. As the polar solvent, an alcohol such as methanol, ethanol, propanol, butanol, pentanol or hexanol can be used. Mixtures of lower alcohols such as methanol or ethanol with water have been found to be useful. The ozone complex formed by the intermediate product is reductively treated, preferably with an alkali metal hydrogensulfite, to obtain 2-methyl-5-formaldehyde. A suitable alkali metal bisulfite is sodium or potassium hydrogen sulfite. However, it is also possible to select other known reducing agents, such as dimethyl sulfide, thiourea or trimethyl phosphite or hydrogen, in the presence of a suitable catalyst. In the case of a preferred reduction treatment with an alkali metal hydrogensulfite, the reaction is carried out in a medium substantially the same as the medium used for ozonation, usually at a temperature of -2 (TC to 20 ° C, preferably From 0 to C. Depending on the further processing step, 2-methylpyridine-5-formaldehyde, or an adduct of an alkali metal hydrogensulfite and 2-methylpyridine-5-formaldehyde can be formed. Isolation of 2-methyl-5-formaldehyde, which may be selective extraction of the reaction mixture with a suitable organic solvent at a pH of about 4 to 5, for example, extraction with ethyl acetate. Preferably, alternatively, the alkali metal bisulfite An adduct with 2-methylpyridine-5-formaldehyde can be formed first, which is then cleaved to 2-methyl-5-formaldehyde at a pH of about 10. However, it is particularly preferred to be an alkali metal bisulfite and 2- The adduct of methyl-pyridine-5-formic acid is used immediately in the further reaction of step c). Therefore, it is possible to separate the less stable 2-methylpyridine-5-formaldehyde in a preferred manner. 5 The paper size applies to the Chinese National Standard (CNS) A4 specification (210'乂297 public^"5 (please read the note on the back and fill out this page). The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print A7 B7 1274749 V. INSTRUCTION DESCRIPTION (IV) Adducts of alkali metal hydrogensulfite and 2-methylpyridin-5-formaldehyde are novel and unknown in the literature and are therefore part of the subject matter of the invention. Has a general formula

0H

Among them, hydrazine is an alkali metal and is called 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate. The metal ruthenium is advantageously Na or ruthenium. Step c: The reaction of 2-methylpyridin-5-formaldehyde or an alkali metal bisulfite with an adduct of 2-dimethylpyridin-5-formaldehyde according to the principle of Strecker synthesis, using a CN compound and a dioxane The amine is carried out to give the equivalent N,N-dialkylamino-(6-methylpyridyl)acetonitrile. An aqueous solution of HCN or an aqueous solution of an alkali metal cyanide can be used herein as a CN compound. A suitable dialkylamine is a Cw dialkylamine ', especially dimethylamine or diethylamine. The reaction temperature is advantageously in the range of up to 30 t. It is advantageous to add a water-incompatible solvent such as 'toluene or tertiary-butyl methyl ether. The treatment and sterolization of N,N-dialkylamino-(1-methylpyridinyl)acetonitrile can then be carried out by simple phase separation. N,N-Dialkylamino-(1-methylpyridyl)acetonitrile of the general formula 111, (please read the note on the back and then fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 1 ___ -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1274749 A7 B7 V. Invention Description (< )

(Please read the note on the back and then fill out this page.) Aik is an alkyl group of 1 to 4 carbon atoms, which is an unknown novel compound in the literature, and therefore it also forms part of the subject matter of the present invention. The alkyl group is determined to be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. A preferred definition of alkyl is methyl or ethyl. Step d: conversion of N,N-dialkylamino-(6-methylpyridyl)acetonitrile to a final product of formula I by reaction with 4-(methylsulfonyl)benzyl halide It is carried out in the presence of a base. A suitable heart (methylsulfonyl) benzyl halide is the heart (methylsulfonyl) benzyl chloride. The base used for printing by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs may be an aqueous solution of an alkali metal hydroxide, preferably an aqueous solution of sodium hydroxide, in which case a conventional phase transfer catalyst is used. A suitable phase transfer catalyst is, for example, a tetraalkylammonium halide such as tetra-n-butylammonium chloride or tetra-n-butylammonium bromide. The reaction temperature is in the range of 40 ° C to 70 ° C. It is advantageous to add a solvent which is not miscible with water, for example, toluene, methylene chloride or tertiary-butyl methyl ether. Alternatively and preferably, the base used is an alkali metal alkoxide. Suitable alkali metal alkoxides are, for example, tertiary sodium butoxide, tertiary butanol or tertiary sodium pentoxide, and preferably tertiary sodium butoxide. The recommended solvent is an ether such as tetrahydrofuran. The reaction temperature in this variation method is usually from 15 ° C to 25 ° C. 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone oxime Ί This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) PCT 1: '- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1274749 A7 B7 V. Description of Invention (V) In a manner known to those skilled in the art, for example by acidifying the reaction mixture, followed by: For example, toluene extraction. Further purification can be carried out, for example, by recrystallization in acetonitrile.Example 1 Preparation of 2-methyl-5-vinylpyridine. Pumice having a particle size of 6 to 8 mm is wetted with water and Mix with 25% dry weight powder form zinc oxide, fill the reactor with water vapor (tube length 750 mm, tube diameter 60 mm) and leave at 650 ° C to 700 ° C for 24 hours under nitrogen flow. 680C and 665 pens; under the bar, 76 ml / h of 2-methyl-5-ethylpyridine was passed through the above catalyst together with 87 ml / h of vapor. At the reactor end, 40.6 wt% of 2-methyl was taken out. a product stream consisting of -5-vinylpyridine and 56.3% methylethylpyridine. Based on pyridine, a yield of 93.0% is achieved. To prepare pure 2-methyl-5-vinyl Dttidine, the product mixture is then subjected to steam distillation (266 mbar, overhead temperature 59 ° C-6 CTC) or vacuum distillation ( 2 mbar, temperature 9 〇 ° C). Example 2 Preparation of 2-methylpyridine-5-carbaldehyde Initially charged 11.92 g of methyl vinyl pyridine (content 85%, 85 mmol), 5 g ml Methanol and 10 ml of water. Measured concentrated sulfuric acid ___ 8 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the note on the back and fill out this page) Clothing Order 1274749 A7 B7 V. Description of the invention (q) (9.81 g, 98 mmol) such that the temperature does not exceed 2 ° C. The solution is cooled from -12 ° C and an ozone/oxygen mixture is introduced (about 5% 02 3 ' in 02) Liters/hour) until 2-methyl-5-vinylpyridine was completely reacted. Carefully metered water (50 ml) and 40% aqueous NaHS03 solution (22.7 g, 85 mmol). Warm the reaction mixture to 20 °C and neutralized with 30% NaOH (approx. 32 g, 0.24 mol). Distill off methanol at 30-40 ° C, then form bisulfite To the mixture, an additional 22.7 g of a 4 〇妒 NaHS 〇3 solution was added. The mixture was stirred for 30 minutes, after which the pH was readjusted to neutral' and then 35 ml of tertiary butyl methyl ether was used to extract neutral impurities. %Na〇H was adjusted to pH 10, and 26.5 g of _2 [〇3 (〇·25 旲 ear) was added. The released aldehyde was extracted with 280 ml of tri-butyl-methyl acid to concentrate the solvent to give 9 g of 2-carboindole as a slightly yellow oil. 〇W-NMR CCD Ch: 2.66 (s, 3H) 7.35 (d, J = 8 Hz, 1H); 8.07 (dd, 8 Hz and 2·1 Hz ' 1H) ' 8.96 (d, J = 2.1 Hz, 1H); 10.08 (s, 1H). 13C-NMR (CDC13): 24.98(CH3); 123.72(05); 129.32(03); 135.88(04); 151.87(02); ____ 9____- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back and fill out this page.) Order Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1274749 A7 ______B7 _ ______ V. Invention Description (A) (6-methylindole ratio steep) acetonitrile, 30 ml of toluene and 10.0 g of diatomaceous earth. Then, 72 g (5 equivalents) of a 50% aqueous NaOH solution was added over a period of 15 minutes to maintain the temperature at 20 ° C. The reaction mixture was heated to 45 °C. Stir vigorously while adding 0.32 g of the first portion of tetra-n-butylammonium bromide. Immediately thereafter, 0.32 g of tetra-n-butylammonium bromide and 44,52 g (1.2 equivalents) of 4-(methylsulfonyl)benzyl chloride in 200 ml of toluene were added over a period of 1.5 hours. Solution. After half of the addition, 32 g of the third portion of tetra-n-butylammonium bromide was added and stirring was continued at 45 ° C for 6 hours. The reaction mixture was then warmed to room temperature and then 100 ml of water and 100 ml of toluene were added. The mixture was filtered, and the residue was washed with 25 ml of toluene, and then the phases were separated. The aqueous phase was extracted with 2 x 50 mL of toluene. The combined organic phase was then stroked with 3 80 liters of IN HC1. The title product was crystallized by neutralization with 2.9 g of a 29% aqueous NaOH solution. The suspension was filtered and the product was washed with 2 x 100 ml of water and 2 x 80 ml of isopropanol / water 1:1 and then dried at 20 ° C / 20 mbar. This gave 4 〇.19 g (76. 4%) of the title compound with a 99.0% content. Μ·ρ· 182 ° C, 183 ° C. lH-NMR (CDCl3): 9.15 (lH, s); 8.18 (1 Η, d); 7.92 (2H, d); 7.47 (2H, d); 7·30 (1Η, d); 4.39 (2H, s); ___ 13____ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 read 1 ' ' : '^^ (please read the back note first and then fill out this page) Book 1274749 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperative Printed 5, Invention Description ((>) 3·04(3Η, s); 2·63(3Η,s) 〇Example 4b. 1-(6-Methylpyridin-3-yl)- Preparation of 2-[(4-(methyl-sulfonyl)phenyl]ethanone (alkoxide, anhydrous) at 20 ° C over 48 ml of 20 ml of tetrahydrofuran over 30 min (84.5%, 1.00 eq. N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile is added to a suspension of 38.58 g (1.7 equivalents) of potassium tert-butoxide in 60 ml of tetrahydrofuran. 42.59 g (1.03 equivalents) of 4-(methylsulfonyl)benzyl chloride in 60 ml of tetrahydrofuran was added during 20 hours from 20 ° C to 25 ° C. The reaction mixture was stirred at 20 ° C for 0.5 h, then Dilute with 100 ml of water and adjust to pH by adding 180 ml of 2N HC1 over 1 hour. 2. After another 0.5 hour at 20 ° C, the mixture was adjusted to pH 3 with 10 g of 30% aqueous NaOH solution. The suspension was stirred at 20 ° C for one hour and then filtered, and the product was 2 x 150 ml water and 2 x 100 ml water. /Isopropanol 1: 1 wash. Drying at 2 (TC/20 mbar yields 53.72 g (92%) of the title compound with 99.1% content. Mp 182 〇C-183 〇C lH-NMR (CDCl3) · 9· 15 (1H, s); 8.18 (1H, d); 7.92 (2H, d); 7.47 (2H, d); 14 This paper scale applies to the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) (please Read the notes on the back and fill out this page.) 1274749 A7 B7 V. INSTRUCTIONS (U) 7·30 (1H, d); 4.39 (2H, s); 3·04 (3H, s); 2.63 (3Η, s). (Please read the notes on the back and fill out this page.) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2!0' canine 297 mm) 1

Claims (1)

A8B8C8D8 III 1274749 Patent Application ι· a method for preparing a formula II: u(6•methylpyridinyl) winter [(4-(methylsulfonyl)phenyl]ethanone, It is characterized in that 'I methyl-5-vinylpyridinyl is first reacted with ozone, and is reduced with an alkali metal hydrogensulfite to produce a hydroxy group (6-methyl Dtt pyridine)-based methane. Sulfonate II, wherein hydrazine is an alkali metal, which is then reacted with a monoalkylamine and a cyano compound to give a formula of ν, ν__ aristyl-(6-methyl_3_1) than hydrazine) R2 XN >τ where R1 and R2 are the same or different and are Cm-hospital, and finally reacted with 4-(methylsulfonyl)benzyl halide in the presence of a base to give 1- (6-Methylpyridin-3-yl)_2-[(4-(methylsulfonyl)phenyl]ethanone 2. The method according to the application of the patent, which is characterized by 2-A ( Please read the notes on the back and write this page. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1274749 C8 D8 VI. Patent Range The reaction of the base-5-vinylpyridine with ozone is carried out in the presence of a mineral acid. 3. The method according to claim 2, characterized in that the reaction of 2-methyl-5-vinylpyridin with ozone is carried out at a temperature of from -20 ° C to Ot. 4. The method of claim 1, wherein the reduction reaction is carried out at a temperature of from -20 ° C to 20 ° C. 5. The method according to claim 1 or 4, characterized in that N,NZ of the formula III is prepared using an unisolated 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate: Alkylamino-(6-methylbutyryl)acetonitrile. The method according to any one of claims 1 to 4, characterized in that it is used in the reaction of 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of the formula II. The cyano compound is an aqueous solution of HCN or an aqueous solution of an alkali metal cyanide. 7. The method according to any one of claims 1 to 4, characterized in that the 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of the formula II is dialkylamine and cyanide The temperature of the compound reaction is from 0 ° C to 30 ° C. The method according to any one of claims 1 to 4, characterized in that it is used in the reaction of hydrazine, hydrazine-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of formula III The base is an aqueous alkali metal hydroxide solution together with a phase transfer catalyst or an alkali metal alkoxide. The method according to any one of claims 1 to 4, wherein the 2-methylvinylpyridine is prepared by using 2-methyl-5-ethylpyridine as a starting material. 10. The method according to claim 9 of the patent application, characterized in that 2-methyl-5-ethylpyridinium is used in the presence of a catalyst at a temperature of 5 ° C to 700 ° C for 2 degrees for the Chinese country Standard (CNS) A4 size (210 X 297 mm) _ ' ......................... (Please read the notes on the back and then 塡Write this page) - έ Line I 1274749 . I D8 VI. The scope of the patent application is changed to 2 - methyl-5' B. 11. The method according to claim 10, characterized in that the catalyst used is vermiculite, bismuth gel, iron oxide, zinc oxide, chromium oxide, copper chromite, magnesium oxide, potassium oxide, aluminum oxide. Or boron phosphate, either alone or as a mixture. 12. The method according to claim 11, characterized in that the catalyst used is applied to the support. The method according to claim 11, wherein the reaction is carried out at a temperature of from 600 ° C to 700 ° C. I4· A 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of formula II S〇3OM0 « Where Μ is an alkali metal. I5·—Preparation as required in the 14th item of the patent application 彳 彳 彳 _ 6_ methyl coffee! After the completion of the two __, Pucheng in ^ methyl _5_ 乙基基' 疋 brain by 顚 New Zealand, and then reduced with _ _ _ bis bisulphite 'converted into the final product of Formula II. !6·-N of formula III, Nq-substituted amine ♦ methylindole ratio steep) acetonitrile, 乂 N (Please read the notes on the back and fill out this page) Line I 1274749 A8 B8 C8 D8 One by one Patent Application Range wherein R and R2 are the same or different and are alkyl groups. 17. A method for preparing N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula πι, as described in claim 16 of the patent application, characterized in that it is characterized by 2_methyl' η 丨 经 经 经 经 经 经 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 18. A process for the preparation of iota (i-methylpyridyl)-methylsulfonyl) phenyl]ethanone of formula I, so2ch3 in a first step a), 2-methyl-5-ethylpyridinium at 50 (TC to 700 ° (: converted to 2-methyl-5-vinylpyridin in the presence of a catalyst, in the second step b), 2-methyl-5-vinyl is determined by reaction with ozone And the reduction reaction with an alkali metal bisulfite to produce a 1-carbyl-(6-methylpyridin-3-yl)-carboxate of the formula II. The paper scale is applicable to the Chinese national standard ( CNS)A4 specification (210 X 297 么' PCT) ...............ώτ,..............订.........— Line · (Please read the note on the back and fill out this page) 098 8 99 ABCD 1274749 VI. Patent application scope 0H Wherein, in the third step c), the 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of the formula π is converted into a dialkylamine and a cyanide compound. Corresponding oxime, Ν-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and finally, in the last step d), N,N-dialkylamino-(6-methyl-3 -pyridyl)acetonitrile is reacted with 4-(methylsulfonyl)benzyl halide in the presence of a base to give 1-(6-methyl-pyridin-3-yl)-2-[(4-(A Alkylsulfonyl)phenyl]ethanone. 5 .................>0^-..........,玎·!-. ...........t· (Please read the notes on the back and write this page first.) This paper size applies to National Standard (CNS) A4 (210 X 297 mm).