IL143981A

IL143981A - 1 - (6 - methylpyridine - 3 - yl) - 2 -

Info

Publication number: IL143981A
Application number: IL143981A
Authority: IL
Original assignee: Merck & Co Inc; Lonza Ag
Priority date: 1999-01-14
Filing date: 2001-06-25
Publication date: 2006-12-31
Also published as: KR100446324B1; MXPA01007169A; NO319822B1; US20050159458A1; NO20013498D0; IL176734A; IL176734A0; US7141673B1; KR20010089587A; US7355048B2; NO20013498L

Description

13258/01 1Π] Π"7 nVTU ΠΙΠΝ ['7Ί9('7Ί1-3'710'71Π?]) - 4] - 2 - - 3 - Ι^Τα^ΠΤ] - 6) - 1 -(6-METHYLPYRIDINE-3-YL)-2-[4-(METHYLSULFONYL)PHENYL]ETHANONE AND METHOD FOR ITS PREPARATION WO 00/42014 - 1 PCT/EPOO/00240 Description The invention relates to the compound l-(6-methylpyridin-3-yl) -2- [ (4- (methylsulphonyl) phenyl] -ethanone of the formula and a process for the preparation thereof. 1- (6-methylpyridin-3-yl) -2- [ (4- (methylsulphonyl) phenyl] ethanone is a novel starting material for preparing so-called COX-2 inhibitors, pharmaceutically active compounds having analgesic and anti-inflammatory action (R.S. Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998) 2777-2782; WO 98/03484) .

It was the object of the present invention to provide a novel starting material for pharmaceutically active compounds. Another object was to provide an industrially feasible process for preparing the said starting material.

The object was achieved by the compound according to Claim 1 and the novel process according to Claim 2.

The process according to the invention represents, in a particularly advantageous embodiment, the last step in a four-step process, where in a first step a) 2-methyl-5-ethylpyridine is converted at from 500°C to 700°C in the presence of a catalyst into 2-methyl-5-vinylpyridine, in a second step b) the 2-methyl-5-vinylpyridine is converted with ozone and subsequently by reduction into 2 -methylpyridine-5-carbaldehyde , in a third step c) the 2-methylpyridine-5-carbaldehyde is converted with a dialkylamine and a cyano compound into the corresponding N, -dialkylamino- ( 6-methyl-3-pyridyl) acetonitrile and finally in a last step d) the N,N, -dialkylamino- ( 6-methyl-3-pyridyl) acetonitrile is reacted in the presence of a base with a 4- (methylsulphonyl) benzyl halide to give 1- (6-methylpyridin-3-yl) -2- [ (4- (methylsulphonyl) phenyl] -ethanone as the end product.

A considerable advantage of this embodiment of the process according to the invention consists in the fact that industrially available 2-methyl-5-ethylpyridine can be used as starting material .

Step a) : The dehydration of 2-methyl-5-ethylpyridine to give 2-methyl-5-vinylpyridine is known from the literature (for example A. Nenz et al., Hydrocarbon Processing, 47(11), 1968, 139-144; US-A 2 , 769 , 773 ) .

The reaction proceeds at from 500°C to 700°C, preferably at from 600°C to 700°C, in the presence of a large number of different catalysts. In general, catalysts based on silica, silica gel, iron oxide, zinc oxide, chromium oxide, copper chromite, magnesium oxide, potassium oxide, alumina or boron phosphate, alone or as a mixture, if appropriate applied to a support, are employed. Good results can be obtained inter alia with a zinc oxide catalyst applied to pumice as support. It is furthermore advantageous for the reaction to dilute the 2-methylpyridine with steam or an inert gas, but preferably with steam.

The 2-methyl-5-vinylpyridine can be purified in a simple manner, for example by removal of the aqueous phase, and subsequent_ steam distillation or by vacuum distillation, such that it is suitable for the subsequent step b) .

Step b) : The reaction with ozone is advantageously carried out in the presence of a mineral acid at a temperature of from -20°C to 0°C, preferably at a temperature of from -15°C to -5°C. Suitable mineral acids are sulphuric acid or phosphoric acid, and in particular sulphuric acid. Suitable reaction media are water and/or a polar solvent. The. polar solvent employed may be a Ci-6-alcohol such as methanol, ethanol, propanol, butanol, pentanol or hexanol . Mixtures of a Ci-6-alcohol, such as methanol or ethanol, with water have been found to be particularly useful. The ozone complex which is formed as an intermediate is worked up reductively, preferably with an alkali metal hydrogen sulphite, to obtain the 2-methyl-5-carbaldehyde .

Suitable alkali metal hydrogen sulphites are sodium or potassium hydrogen sulphite. However, it is also possible to choose other known reducing agents, such as, for example, dimethyl sulphide, thiourea or trimethyl phosphite, or hydrogen in the presence of a suitable catalyst.

In the case of the preferred reductive work-up with alkali metal hydrogen sulphite, the reaction is carried out in essentially the same medium as used for the ozonization, generally at a temperature of from -20°C to 20°C, preferably from -10°C to 0°C.

Depending on the further work-up steps, the 2-methylpyridine-5-carbaldehyde or an adduct of alkali metal hydrogen sulphite with the 2-methylpyridine-5-carbaldehyde, specifically a 1-hydroxy- ( 6-methylpyridin-3-yl) methanesulphonic acid salt, can be formed.

If it is desired to isolate the 2-methyl-5-carbaldehyde, it is possible to selectively extract the reaction mixture at a pH of about 4 to 5 with a suitable organic solvent, such as, for example, with ethyl acetate. Alternatively, but preferred, an adduct of alkali metal hydrogen sulphite with the 2-methylpyridine-5-carbaldehyde may be formed initially, which is then cleaved at a pH of about 10 into the 2-methyl-5-carbaldehyde .

Particularly preferably, however, the adduct of alkali metal hydrogen sulphite with the 2-methyl-pyridine-5-carbaldehyde is employed immediately for further reaction in step c) . Thus, it is possible to circumvent isolation of the relatively unstable 2-methylpyridine-5-carbaldehyde in an elegant manner.

The adducts of alkali metal hydrogen sulphite with the 2-methylpyridine-5-carbaldehyde are novel and not known from the literature and accordingly, like the process for the preparation thereof, also part of the subject-matter of the invention. The adducts have the general formula in which M is an alkali metal, and are referred to as 1-hydroxy- (6-methylpyridin-3-yl)methanesulphonic acid salts. Preferred alkali metals are Na or K.

Step c) : The reaction of the 2-methylpyridine-5-carbaldehyde or the adduct of alkali metal hydrogen sulphite with the 2-methylpyridine-5-carbaldehyde is carried out according to the principle of the Strecker synthesis using a cyano compound and a dialkylamine to give the corresponding N, N-dialkylamino- ( 6-methyl-3-pyridyl ) acetonitrile .

An aqueous HCN solution or an aqueous solution of an alkali metal cyanide may serve as cyano compound here. Particularly suitable dialkylamines are C1-4-dialk^lamihe', in which Ci-4-alkyl is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl . Preferred dialkylamines are dimethylamine or diethylamine .

The reaction temperature is advantageously in the range of from 0°C to 30°C.

It may be advantageous to add a water-immiscible solvent, such as, for example, toluene or t-butyl methyl ether. Work-up and isolation of the corresponding N, N-dialkylamino- (6-methyl-3-pyridyl) -acetonitrile can then be carried out by simple phase separation. The N, N-dialkylamino- (6-methyl-3-pyridyl) -acetonitriles of the general formula in which R1 and R2 are identical or different and are Ci-4-alkyl, are novel compounds which are not known from the literature, and they therefore, like the process for the preparation thereof, also form part of the subject-matter of the invention.

Ci-4-Alkyl is, as above, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

The preferred meaning of alkyl is methyl or ethyl.

Step d) : The conversion of the N, N-dialkylamino- ( 6-methyl-3-pyridyl) acetonitrile by reaction with the 4- (methylsulphonyl) benzyl halide to give the end product of the formula I is carried out in the presence of a base. A preferred 4- (methylsulphonyl) benzyl halide is 4- (methylsulphonyl) benzyl chloride.

The base used can be an aqueous alkali metal hydroxide solution, preferably an aqueous sodium hydroxide solution, where in this case the presence of a customary phase-transfer catalyst is useful. Suitable phase-transfer catalysts are, for example, tetraalkylammonium halides, such as, for example, tetra-n-butylammonium chloride or tetra-n-butylammonium bromide. The reaction temperature is in the range of from 40°C to 70°C. It may be advantageous to add a water-immiscible solvent, such as, for example, toluene, methylene chloride or t-butyl methyl ether.

Alternatively and preferably, the base used may also be an alkali metal alkoxide. Suitable alkali metal alkoxides are, for example, sodium tert-butoxide, potassium tert-butoxide or sodium tert-pentoxide, and preferably potassium tert-butoxide. Recommended solvents are ethers, such as, for example, tetrahydrofuran. The reaction temperature in this variant is generally from 15°C to 25°C.

The 1- (6-methylpyridin-3-yl) -2- [ (4- (methyl-sulphonyl ) phenyl ] ethanone can be isolated in a manner known to the person skilled in the art, for example by acidifying the reaction mixture, followed by extraction with, for example, toluene. Further purification can be carried out by recrystallization, for example in acetonitrile.

Example 1 Preparation of 2-methyl-5-vinylpyridine Pumice having a particle size of from 6 to 8 mm is moistened with water and mixed with 25% of its dry weight of zinc oxide in powder form, filled moist into the reactor (length of the tube 750 mm, diameter of the tube 60 mm) and left in a stream of nitrogen at from 650°C to 700°C for 24 h. 76 ml/h of 2-methyl-5-ethylpyridine together with 87 ml/h of steam were passed over the abovementioned catalyst at from 670°C to 680°C and 665 mbar. At the end of the reactor, a product stream consisting of 40.6% by weight of 2-methyl-5-vinylpyridine and 56.3% of 2-methyl-5-ethylpyridine was taken off. Based on reacted 2-methyl-5-ethylpyridine, a yield of 93.0% was achieved.

To prepare pure 2-methyl-5-vinylpyridine, the product mixture was subsequently subjected to steam distillation (266 mbar, overhead temperature 59°C-60°C) .

The purification of 2-methyl-5-vinylpyridine can also be carried out by means of vacuum distillation (20 mbar, temperature about 90°C) .

Example 2 Preparation of 2-met ylpyridine-5-carbaldehyde 11.92 g of 2-methyl-5-vinylpyridine (content 85%, 85 mmol), 50 ml of methanol and 10 ml of water were initially charged. Concentrated sulphuric acid (9.81 g, 98 mmol) was metered in such that the temperature did not exceed 20°C. The solution was cooled from -12°C and an ozone/oxygen mixture (about 5% 03 in 02, 50 1/h) was introduced until the 2-methyl-5-vinylpyridine had reacted completely. Water (50 ml) and 40% aqueous NaHS03 solution (22.7 g, 85 mmol) were carefully metered in. The reaction mixture was warmed to 20°C and neutralized using 30% NaOH (about 32 g, 0.24 mol) . Methanol was distilled off at 30-40°C, and then, to form the bisulphite adduct, another 22.7 g of 40% NaHS03 solution were added. The mixture was stirred for 30 min, after which the pH was readjusted to neutral, and the neutral impurities were subsequently extracted using 35 ml of t-butyl methyl ether. The aqueous phase was adjusted to pH 10 using 30% NaOH, and 26.5 g of Na2C03 (0.25 mol) were added. The liberated aldehyde was extracted using 2 x 80 ml of t-butyl methyl ether. Concentration of the solvent gave 9 g of 2-methylpyridine-5-carbaldehyde as a slightly yellowish oil . 1H-NMR (CDCI3) : 2.66 (s, 3H) ; 7.35 (d, J = 8 Hz, 1H) ; 8.07 (dd, J = 8 Hz and 2.1 Hz, 1H) ; 8.96 (d, J = 2.1 Hz, 1H) ; .08 (s, 1H) .

C-NMR (CDCI3) : 24.98 (CH3); 123.72 (C-5) 129.32 (C-3) 135.88 (C-4) 151.87 (C-2) 164.87 (C-6) 190.51 (C=0) Example 3a.

Preparation of N,N-diethylamino- (6-methylpyridin-3-yl)acetonitrile (from 2-methylpyridine-5-carbaldehyde) At from 10°C to 15°C, 73.2 g (1.25 eq. ) of diethylamine and 100.3 g (1.15 eq.) of a 25% HCN solution were added simultaneously over a period of one hour to a mixture of 98.3 g (1.0 eq. ) of 2-methylpyridine-5-carbaldehyde in 200 ml of water and 200 ml of toluene which was stirred efficiently. The reaction mixture was stirred at 30°C for 3 h.

The phases were then separated and the aqueous phase was extracted with 2 x 100 ml of toluene. The organic phases were combined and the toluene was then removed, giving the title product in the form of a yellowish oil and in a yield of 172.3 g (90.1%).

(CDCI3) : 8.65 (1H, s) 7.75 (1H, d) 7.20 (1H, d) .00 (1H, s) 2.68 (2H, m) 2.59 (13H, s) 2.50 (2H, m) ; 1.10 (6H, t) . 1H-NMR (D6-DMS0) : 8.50 (1H, s) 7.70 (1H, d) 7.32 (1H, d) .45 (1H, s) 2.58 (2H, m) 2.50 (3H, s) ; 2.40 (2H, m) ; 1.02 (6H, t) .

Example 3b.

Preparation of N,N-diethylamino- ( 6-methylpyridin-3-yl) acetonitrile (via the adduct of 2-methylpyridine-5-carbaldehyde with sodium hydrogen sulphite) The ozonolysis was carried out as in Example 2, starting from 23.84 g of 2-methyl-5-vinylpyridine (83.1% GC, 166.2 mmol) . After the impurities have been extracted at neutral pH, the aqueous phase was cooled to 15°C and 21.94 g of diethylamine (0.3 mol) and then 9.8 g of NaCN (0.2 mol) were added (in each case addition over a period of 10 min) . The solution was stirred at 15°C for 4.5 h, and the product was subsequently extracted with 3 x 85 ml of toluene. The combined extracts were concentrated. Obtained: 37.4 g of N, N-diethylamino- ( 6-methylpyridin-3-yl) acetonitrile as an orange oil. Content: 83.7% (GC, % by weight), 0.34% of aldehyde). Yield: 92.7% based on 2-methyl-5-vinylpyridine .

NMR (CDCla) 1.08 (t, 6H) 2.50 (m, 2H) 2.58 (s, 3H) 2.65 (m, 2H) .00 (s, 1H) 7.18 (d, J = 8 Hz, 1H) ; 7.74 (dd, J --= 8 Hz, 2 Hz, 1H) ; 8.66 (d, J = 2 Hz, 1H) .

Example 3c.

Preparation and characterization of the adduct of 2-methylpyridine-5-carbaldehyde with sodium hydrogen sulphite After the addition of bisulphite, the H- and 13C-NMR of a sample were measured. The NMR signals of the aldehyde had disappeared completely, and the following signals were observed instead: 1H-NMR (DMSO-de) : 1.96 (s, 3H) ; .01 (s, 1H) ; 6.85 (d, J = 8 Hz, 1H) ; 7.45 (dd, J = 8 and 2 Hz, 1H) ; 7.93 (d, J = 2 Hz, 1H) . 13C-NMR (DMSO-de): 20.23 (CH3); 81.78 (CH) ; 124.14 (C-5); 130.02 (C-3); 138.76 (C-4); 143.08 (C-2) ; 156.04 (C-6) .

Example 4a.

Preparation of 1- ( 6-methylpyridin-3-yl) -2- [ (4- (methylsulphonyl)phenyl] ethanone (aqueous NaOH as base) 41.07 g (89.1%, 1.00 eq. ) of N, -diethy1amino- ( 6-methylpyridin-3-yl) acetonitrile, 30 ml of toluene and 10.0 g of Celite were initially charged. 72 g (5 eq. ) of a 50% aqueous NaOH solution were then added over a period of 15 minutes such that the temperature could be maintained at 20°C. The reaction mixture was heated to 45°C. With vigorous stirring, a first portion of 0.32 g of tetra-n-butylammonium bromide was added.

Immediately after that, a solution of 0.32 g of tetra-n-butylammonium bromide and 44.52 g (1.2 eq.) of 4- (methylsulphonyl) benzyl chloride in 200 ml of toluene was added over a period of 1.5 h. After half had been added, a third portion of 0.32 g of tetra-n-butylammonium bromide was added, and stirring was continued at 45°C for 6 h.

The reaction mixture was then warmed to room temperature, and 100 ml of water and 100 ml of toluene were then added. The mixture was filtered, the residue was washed with 25 ml of toluene and the phases were then separated. The aqueous phase was extracted with 2 x 50 ml of toluene. The combined organic phases were then extracted with 380 ml of IN HC1. Neutralization with 29.6 g of 50% aqueous NaOH solution to pH 4.5 resulted in the title product crystallizing out. 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 subsequently dried at 20°C/20 mbar.

This gave 40.19 g (76.4%) of the title product having a content of 99.0%.

M.p. 182°C-183°C 1H-NMR (CDC13) 9.15 (1H, s) 8.18 (1H, d) 7.92 (2H, d) 7.47 (2H, d) 7.30 (1H, d) 4.39 (2H, s) 3.04 (3H, s) 2.63 (3H, s) Example 4b.

Preparation of 1- ( 6-methylpyridin-3-yl) -2- [ (4- (methyl-sulphonyl) henyl] ethanone (alkoxide, anhydrous) At 20°C, 48.16 g (84.5%, 1.00 eq. ) of N, N-diethylamino- (6-methylpyridin-3-yl)acetonitrile in 20 ml of tetrahydrofuran were added over a period of 30 minutes to a suspension of 38.58 g (1.7 eq.) of potassium t-butoxide in 60 ml of tetrahydrofuran. Immediately afterwards, 42.59 g (1.03 eq.) of 4-(methylsulphonyl) benzyl chloride in 60 ml of tetrahydrofuran were added at from 20°C to 25°C over a period of 1.5 h.

The reaction mixture was stirred at 20°C for 0.5 h and then diluted with 100 ml of water, and adjusted to pH 2 by addition of 180 ml of 2N HC1 over a period of one hour. After a further 0.5 h at 20°C, the mixture was adjusted to pH 3 using 10 g of a 30% aqueous NaOH 143981/2 - 12 - solution. The suspension was stirred at 20°C for one hour and then filtered, and the product was washed with 2 x 150 ml of water and 2 x 100 ml of water/isopropanol 1:1. Drying at 20°C/20 mbar gave 53.72 g (92%) of the title product having a content of 99.1%. 182°C-183°C 1H-NMR ( CDC13 ) : 9 15 (1H, s) ; 8 18 <1H, d) ; 7 92 (2H, d) ; 7 47 (2H, d) ; 7 30 (1H, d) ; 4 39 (2H, s) ; 3 04 (3H, s) ; 2 63 (3H, s) .

Material which is outside the scope of the claims does not constitute part of the claimed invention. 13 143981/3

Claims

1. Process for preparing l-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of the formula wherein 2-methyl-5-vinylpyridine is first converted, by reaction with ozone and subsequent reduction, to 2-methylpyridine-5-carbaldehyde, which is then reacted with a dialkylamine and a cyano compound to give a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the general formula wherein R1 and R2 are the same or different and represent Ci-4-alkyl, which finally is reacted, in the presence of a base, with a 4-(methylsulfonyl)benzyl halide to give l-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]-ethanone of formula I.

2. Process according to claim 1, wherein the reaction of 2-methyl-5-vinylpyridine with ozone is carried out in the presence of a mineral acid, preferably at a temperature of from -20°C to 0°C. 14 143981/2

3. Process according to claim 1 or 2, wherein the reduction is carried out using an alkali hydrogen sulfite, with formation of a l-hydroxy-(6-methylpyridin-3-yl)methane-sulfonic acid salt of the general formula II wherein M is an alkali metal.

4. Process according to claim 3, wherein the reduction is carried out at a temperature of from -20°C to 20°C.

5. Process according to claim 3 or 4, wherein the 1 -hydroxy- (6-methylpyridin-3-yl)methanesulfonic acid salt is used without isolation for preparing the N,N-dialkylamino-(6-methyl-3pyridyl)acetonitrile of the general formula III.

6. Process according to any one of claims 1 to 5, wherein the cyano compound used in the reaction of the 2-methylpyridine-5-carbaldehyde is an aqueous HCN solution or an aqueous solution of alkali cyanide.

7. Process according to any one of claims 1 to 6, wherein the temperature for the reaction of the 2-methylpyridine-5-carbaldehyde with the dialkylamine and the cyano compound is from 0°C to 30°C.

8. Process according to any one of claims 1 to 7, wherein the base used in the reaction of the N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula III is either an aqueous alkali hydroxide solution together with a phase-transfer catalyst or an alkali alkoxide in the presence of an 15 143981/2 organic solvent.

9. Process according to any one of claims 1 to 8, wherein the 2-methyl-5-vinylpyridine is obtained starting from 2-methyl-5-ethylpyridine.

10. Process according to claim 9, wherein 2-methyl-5-ethylpyridine is converted at from 500°C to 700°C in the presence of a catalyst to 2-methyl-5-vinylpyridine.

11. Process according to claim 10, wherein the catalyst used is silica, silica gel, iron oxide, zinc oxide, chromium oxide, copper chromite, magnesium oxide, potassium oxide, aluminium oxide or borophosphate, on its own or as a mixture, optionally applied to a support.

12. Process according to claim 10 or 11, wherein the reaction is carried out at a temperature of from 600°C to 700°C.

13. A 1-hydroxy- (6-methylpyridin-3-yl)methanesulfonic acid salt of the formula wherein M is an alkali metal.

14. Process for preparing l-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salts according to claim 13, wherein 2-methyl-5-vinylpyridine is converted, by reaction with ozone and subsequent reduction with an alkali hydrogen sulfite, to the end product of formula II.

15. A N,N-dialkylamino-(6-metriyl-3-pyridyl)acetoriitrile of formula wherein R1 and R2 are the same or different and represent Ci-4-alkyl.

16. Process for preparing a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the general formula III according to claim 15, wherein 2-methylpyridine-5-carbaldehyde or a l-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt of formula II is reacted with a dialkylamine and a cyano compound to give the end product of the formula III.

17. Process for preparing l-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of formula 17 143981/2 characterized in that in a first step a), 2-methyl-5-ethylpyridine is converted at from 500°C to 700°C in the presence of a catalyst into 2-methyl-5-vinylpyridine, in a second step b), the 2-methyl-5-vinylpyridine is converted, by reaction with ozone and subsequent reduction, to 2-methylpyridine-5-carbaldehyde, in a third step c), 2-methylpyridine-5-carbaldehyde is converted, using a dialkylamine and a cyano compound, to the corresponding N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and finally, in a last step d), the N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile is reacted in the presence of a base with a 4-(methylsulfonyl)benzyl hahde to give l-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]-ethanone.

18. l-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of the formula #596103 LliZZATTO 4 LU2ZATTO