CA2485739C - Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone - Google Patents
Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
1- (6-Methylpyridin-3-yl) -2- [ (4- (methylsulfonyl)phenyl] ethanone of the formula <See formula I> and a process for preparing such is disclosed. 1-(6-Methylpyridin-3-yl) -2- [(4-(methylsulfonyl)phenyl] ethanone is an important intermediate for preparing so-called COX-2 inhibitors, which are pharmaceutically active compounds having analgesic and anti-inflammatory action.
Description
Process for Preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl~ Ethanone This application is a division of Canadian Patent Application Serial No. 2,359,958. The claims of the present application are directed to a process for the production of 1-(6-methylpyridin-3-yl)-2-((4-(methylsulfonyl)phenyl]ethanone, as well as to an N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, in which the alkyl radicals are C1-C4 and are identical or different. However, for a ready understanding of the overall invention, including all features which are inextricably bound up in one and the same inventive concept, the teachings of those features claimed in Canadian Patent Application Serial No. 2,359,958 are all retained herein.
Description The invention comprises a novel process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(rnethylsulfonyl)phenyl]-ethanone of the formula (I) 1- (6-Methylpyridin-3-yl) -2- [ (4- (methylsulfonyl) phenyl] -ethanone is an important intermediate for preparing so-called COX-2 inhibitors, which are 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). 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of the formula (I) is a novel compound which is not known from the literature.
-la-It is an object of the invention to provide a novel intermediate for the production of COX-2 inhibitors and to provide an industrially feasible process for preparing the intermediate of the formula (I).
As an aspect of the invention which is claimed in Canadian Patent Application Serial No. 2,359,958, there is provided a process for preparing 1-(6-methylpyridin-3-yl)-2- [ (4- (methylsulfonyl)phenyl] ethanone of the formula SOiCH3 (I) wherein 2-methyl-5-vinylpyridine is initially converted, by reaction with ozone and subsequent reduction, into 2-methylpyridine-5-carbaldehyde or into 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid or acid salt of the formula / SOC M~
(II) in which M is an alkali metal, which is then reacted with a dialkylamine and a cyano compound to give a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula -lb-R~
~T
jV~~,R2 ~~ (III) in which R1 and Rz are identical or different and are each C1_4-alkyl, and the acetonitrile (III) is finally reacted, in the presence of a base, with a 4-(methylsulfonyl)benzyl halide to give 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]-ethanone of the formula (I).
As another aspect of the invention, which is claimed in Canadian Patent Application Serial No. 2,359,958, there is provided a 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt of the formula SOGM~~~
Description The invention comprises a novel process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(rnethylsulfonyl)phenyl]-ethanone of the formula (I) 1- (6-Methylpyridin-3-yl) -2- [ (4- (methylsulfonyl) phenyl] -ethanone is an important intermediate for preparing so-called COX-2 inhibitors, which are 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). 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of the formula (I) is a novel compound which is not known from the literature.
-la-It is an object of the invention to provide a novel intermediate for the production of COX-2 inhibitors and to provide an industrially feasible process for preparing the intermediate of the formula (I).
As an aspect of the invention which is claimed in Canadian Patent Application Serial No. 2,359,958, there is provided a process for preparing 1-(6-methylpyridin-3-yl)-2- [ (4- (methylsulfonyl)phenyl] ethanone of the formula SOiCH3 (I) wherein 2-methyl-5-vinylpyridine is initially converted, by reaction with ozone and subsequent reduction, into 2-methylpyridine-5-carbaldehyde or into 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid or acid salt of the formula / SOC M~
(II) in which M is an alkali metal, which is then reacted with a dialkylamine and a cyano compound to give a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula -lb-R~
~T
jV~~,R2 ~~ (III) in which R1 and Rz are identical or different and are each C1_4-alkyl, and the acetonitrile (III) is finally reacted, in the presence of a base, with a 4-(methylsulfonyl)benzyl halide to give 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]-ethanone of the formula (I).
As another aspect of the invention, which is claimed in Canadian Patent Application Serial No. 2,359,958, there is provided a 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt of the formula SOGM~~~
(II) in which M is an alkali metal.
A further aspect of the invention claimed in Canadian Patent Application Serial No. 2,359,958, provides a process for preparing a 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt as defined herein, wherein 2-methyl-5-vinylpyridine is converted, by reaction with ozone and subsequent reduction with an alkali metal hydrogen sulfite, into the end product of the formula (II) .
Yet another aspect of the invention claimed in Canadian Patent Application Serial No. 2,359,958, provides a process for preparing a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula (III) T
r'yRz C1j (III) in which R1 and RZ are identical or different and are each C1_4-alkyl, wherein 2-methylpyridine-5-carbaldehyde or 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt of the formula (II) so~ M°
(II) is reacted with a dialkylamine and a e:yano compound to give the end product of the formula (III).
The invention also provides, as claimed in Canadian Patent Application Serial No. 2,359,958, a process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of the formula S 42C~-i3 (I) -1d-wherein in a first step a), 2-methyl-5-ethylpyridine is converted at a temperature of 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-vi.nylpyrdine is converted by reaction with ozone and subsequent reduction into 2-methylpyridine-5-carbaldehyde, in a third step c), 2-methylpyridine-S-carbaldehyde is converted, using a dialkylamine and a cyano compound, into the corresponding N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and finally, 35 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 halide to give 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone.
As a further aspect, the invention provides a process for preparing 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]-ethanone of the formula (I) wherein N,N-Dialkylamina-(6-methyl-3-pyridyl)acetonitrile in which the alkyl radicals are Cl_C4 alkyl and are identical or different, is reacted in the presence of a base with a 4-(Methylsulfonyl)benzyl halogenide to give 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]--le-ethanone, wherein the base is an alkali alkoholate and is used in the presence of an organic solvent at a temperature of 15°C to 25°C.
Finally, the invention provides a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of formula ~f 1 '1 (III) wherein R1 and R2 are the same or different and represent Cl_4-alkyl .
The process according to the invEntion comprises four steps, where in the first step a) 2-methyl-5-ethylpyridine is converted at from 500°C to 700°C ire the presence of a catalyst into 2-methyl-5-vinylpyridine, in the second step b) the 2-methyl-5-vinylpyridine is converted with ozone and subsequent reductive work-up into 2-methylpyridin-5-carbaldehyde, .in the third step c) the 2-methylpyridin-5-carbaldehyde is converted with a dialkylamine and a CN
compound into the corresponding N,N-dialkylamino-~6-methyl-3-pyridyl)acetonitrile and f finally in the 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 halide to give 1-(6-methylpyridin-3-yl)-2-j(4-(methylsulfonyl)phenyl]ethanone to give the end product.
A considerable advantage 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), 1958, 139-144; lJS-A 2,769,773) .
The reaction proceeds at from 500°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 chroriite, 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 vakuum distillation, such that it is suitable for the 3S 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°G, preferably at a temperature of from -1S°C to -5°C. Suitable mineral acids are sulfuric acid or phosphoric acid, and in particular sulfuric acid. Suitable reaction media are water and/or a polar solvent. As a polar solvent C1_6 alcohols can be used such as methanol, ethanol, propanol, butanol, pentanol or hexanol. Mixtures of a lower alcohol, such as methanol or ethanol, with water have been found to be 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 15. 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 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-S-carbaldehyde is employed immediately for further reaction 'in step c) . Thus, it is possible to circumvent isolation of the relatively unstable 2-methylpyridine-5-carbaidehyde in an elegant manner.
The adduct of alkali metal hydrogen sulphite with the 2-methyipyridine-5-carbaldehyde is novel and not known from the literature and accordingly also part of the subject-matter of the invention. The adducts have the general formula O~I
.''~ $ ~°SUUM~? ( s in which M is an alkali metal, and are referred to as 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salts. The alkali metal M, is advantageously Na or K.
Step c:
The reaction .of the 2-rnethylpyridine-5-carbaldehyde or the adduct of alkali metal hydrogen sulphite with the 2-methylpyridi,ne-5-carbaldehyde is 2o carried out accordirAg to the principle of the Strecker synthesis using a CN compound and a dialkylamine to give the corresponding' N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitriie.
An aqueous HCN solution or an aqueous solution of an alkali metal cyanide may serve as CN compound here. A
suitable dialkylamine is a C~_4-dialkylamine, in particular 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 N(Alk)i (III) i N
in which Alk is an al kyl group of from 1 to 4 carbon atoms are novel compounds which are not known from the literature, and they therefore also form part of the subject-matter of the invention.
Alkyl is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tent-butyl. The preferred meaning of Alk is methyl or ethyl.
Step d: .
The conversion of the N,N-dialkyla~ino-(5 methyl-3-pyridyl) acetonitrile by reaction with the 4 (methylsulfonyl)benzyl halide to give the end product of the formula I is carried out in the presence of a base. A suitable 4-(methylsulfonyl)benzyl halide is 4-(a~ethylsulfonyl)benzyi 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 ~0°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 is an alkali metal ~alkoxide. Suitable alkali metal alkoxides are, for example, sodium tart-butoxide, potassium tart-butoxide or sodium tart-pentoxide, and preferably potassium tart-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 sulfonyl)phenyl]ethanone can be isolated in a manner known to the person skilled in the art, for example by acidifying the reaction mixture, followed b_y extraction with, for example, toluene. Further purification can be carried out by recrystallization, for example in acetonitrile.
Example 1 Preparation of 2-methyl-5-vinylpyriciine Pumice having a particle size of from 6 to 8 mrn 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 togethe r with 87 m1/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-vinyipyridine, the product mixture was subsequently su'.bjected to steam distillation (266 mbar, overhead temperature 59°C-60°C) or to vacuum distillatian (20 mbar, temperature 90 °C) .
Example 2 Preparation of 2-methylpyridine-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 19.81 g, 98 mmol) was metered in such that the temperature did not exceed 20°C;. The solution was _ 7 _ cooled from -12°C and an ozone/oxygen mixture (about 50 03 in OZ, SO 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 mrnol) 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 bisulphate adduct, another 22.7 g of 40% NaH503 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 (CDC13) : 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);
10.08 (s, 1H).
;3C-NMR (CDC13) : 24.98 (CH3) ;
123.72 (C-5);
129.32 (C-3);
135.88 (C-4);
151.8? (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-S-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 (90.10).
1H-NMR (CDC13) : 8.65 (1H, s) ;
7.?5 (1H, d) ;
7 . 20 ( d) 1H, ;
A further aspect of the invention claimed in Canadian Patent Application Serial No. 2,359,958, provides a process for preparing a 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt as defined herein, wherein 2-methyl-5-vinylpyridine is converted, by reaction with ozone and subsequent reduction with an alkali metal hydrogen sulfite, into the end product of the formula (II) .
Yet another aspect of the invention claimed in Canadian Patent Application Serial No. 2,359,958, provides a process for preparing a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula (III) T
r'yRz C1j (III) in which R1 and RZ are identical or different and are each C1_4-alkyl, wherein 2-methylpyridine-5-carbaldehyde or 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salt of the formula (II) so~ M°
(II) is reacted with a dialkylamine and a e:yano compound to give the end product of the formula (III).
The invention also provides, as claimed in Canadian Patent Application Serial No. 2,359,958, a process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of the formula S 42C~-i3 (I) -1d-wherein in a first step a), 2-methyl-5-ethylpyridine is converted at a temperature of 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-vi.nylpyrdine is converted by reaction with ozone and subsequent reduction into 2-methylpyridine-5-carbaldehyde, in a third step c), 2-methylpyridine-S-carbaldehyde is converted, using a dialkylamine and a cyano compound, into the corresponding N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and finally, 35 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 halide to give 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone.
As a further aspect, the invention provides a process for preparing 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]-ethanone of the formula (I) wherein N,N-Dialkylamina-(6-methyl-3-pyridyl)acetonitrile in which the alkyl radicals are Cl_C4 alkyl and are identical or different, is reacted in the presence of a base with a 4-(Methylsulfonyl)benzyl halogenide to give 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]--le-ethanone, wherein the base is an alkali alkoholate and is used in the presence of an organic solvent at a temperature of 15°C to 25°C.
Finally, the invention provides a N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of formula ~f 1 '1 (III) wherein R1 and R2 are the same or different and represent Cl_4-alkyl .
The process according to the invEntion comprises four steps, where in the first step a) 2-methyl-5-ethylpyridine is converted at from 500°C to 700°C ire the presence of a catalyst into 2-methyl-5-vinylpyridine, in the second step b) the 2-methyl-5-vinylpyridine is converted with ozone and subsequent reductive work-up into 2-methylpyridin-5-carbaldehyde, .in the third step c) the 2-methylpyridin-5-carbaldehyde is converted with a dialkylamine and a CN
compound into the corresponding N,N-dialkylamino-~6-methyl-3-pyridyl)acetonitrile and f finally in the 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 halide to give 1-(6-methylpyridin-3-yl)-2-j(4-(methylsulfonyl)phenyl]ethanone to give the end product.
A considerable advantage 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), 1958, 139-144; lJS-A 2,769,773) .
The reaction proceeds at from 500°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 chroriite, 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 vakuum distillation, such that it is suitable for the 3S 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°G, preferably at a temperature of from -1S°C to -5°C. Suitable mineral acids are sulfuric acid or phosphoric acid, and in particular sulfuric acid. Suitable reaction media are water and/or a polar solvent. As a polar solvent C1_6 alcohols can be used such as methanol, ethanol, propanol, butanol, pentanol or hexanol. Mixtures of a lower alcohol, such as methanol or ethanol, with water have been found to be 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 15. 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 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-S-carbaldehyde is employed immediately for further reaction 'in step c) . Thus, it is possible to circumvent isolation of the relatively unstable 2-methylpyridine-5-carbaidehyde in an elegant manner.
The adduct of alkali metal hydrogen sulphite with the 2-methyipyridine-5-carbaldehyde is novel and not known from the literature and accordingly also part of the subject-matter of the invention. The adducts have the general formula O~I
.''~ $ ~°SUUM~? ( s in which M is an alkali metal, and are referred to as 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonic acid salts. The alkali metal M, is advantageously Na or K.
Step c:
The reaction .of the 2-rnethylpyridine-5-carbaldehyde or the adduct of alkali metal hydrogen sulphite with the 2-methylpyridi,ne-5-carbaldehyde is 2o carried out accordirAg to the principle of the Strecker synthesis using a CN compound and a dialkylamine to give the corresponding' N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitriie.
An aqueous HCN solution or an aqueous solution of an alkali metal cyanide may serve as CN compound here. A
suitable dialkylamine is a C~_4-dialkylamine, in particular 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 N(Alk)i (III) i N
in which Alk is an al kyl group of from 1 to 4 carbon atoms are novel compounds which are not known from the literature, and they therefore also form part of the subject-matter of the invention.
Alkyl is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tent-butyl. The preferred meaning of Alk is methyl or ethyl.
Step d: .
The conversion of the N,N-dialkyla~ino-(5 methyl-3-pyridyl) acetonitrile by reaction with the 4 (methylsulfonyl)benzyl halide to give the end product of the formula I is carried out in the presence of a base. A suitable 4-(methylsulfonyl)benzyl halide is 4-(a~ethylsulfonyl)benzyi 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 ~0°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 is an alkali metal ~alkoxide. Suitable alkali metal alkoxides are, for example, sodium tart-butoxide, potassium tart-butoxide or sodium tart-pentoxide, and preferably potassium tart-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 sulfonyl)phenyl]ethanone can be isolated in a manner known to the person skilled in the art, for example by acidifying the reaction mixture, followed b_y extraction with, for example, toluene. Further purification can be carried out by recrystallization, for example in acetonitrile.
Example 1 Preparation of 2-methyl-5-vinylpyriciine Pumice having a particle size of from 6 to 8 mrn 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 togethe r with 87 m1/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-vinyipyridine, the product mixture was subsequently su'.bjected to steam distillation (266 mbar, overhead temperature 59°C-60°C) or to vacuum distillatian (20 mbar, temperature 90 °C) .
Example 2 Preparation of 2-methylpyridine-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 19.81 g, 98 mmol) was metered in such that the temperature did not exceed 20°C;. The solution was _ 7 _ cooled from -12°C and an ozone/oxygen mixture (about 50 03 in OZ, SO 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 mrnol) 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 bisulphate adduct, another 22.7 g of 40% NaH503 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 (CDC13) : 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);
10.08 (s, 1H).
;3C-NMR (CDC13) : 24.98 (CH3) ;
123.72 (C-5);
129.32 (C-3);
135.88 (C-4);
151.8? (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-S-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 (90.10).
1H-NMR (CDC13) : 8.65 (1H, s) ;
7.?5 (1H, d) ;
7 . 20 ( d) 1H, ;
5.00 (1H, S) i 2. 68 (2H, m) ;
2.59 (13H;s);
2.50 (2H, m);
1. 10 ( t 6H, ) .
1H-NMR ( D6-DMSO) : 8 . ( s ) ;
5 d 1H, 7.70 (1H, d);
7.32 (1H, d) ;
5.45 (1H, s);
2.58 (2H, m);
2.50 (3H, S);
2.40 (2H, m);
1.02 (6H, t).
Example 3b.
Preparation of N,N-diethylaminc~-(6--methylpyridin-3 yl)acetonitrile (via the adduct of 2-methylpyridine-5 carbaldehyde ~rith sodium hydrogen sulphite) The ozonolysis was carried out as in Example 2, starting from 23.84 g of 2-methyl-5-vinylpyridine (83.10 GC, 106.2 mmol). After the impurities had been extracted at neutral pH, the aqueous phase was cooled to 15°C and diethylamine (21.94 g, 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 _ g _ 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 S as an orange oil. Content: 83.7% {GC, % by weight), 0.34% of aldehyde). Yield: 92.?% based on 2-methyl-5-vinylpyridine.
1H-NMR (CDC13) : 1.08 (t, 6H) ;
2:50 (m, 2H);
2. 58 (s~,3H) ;
2. 65 (m, 2H) ;
5.00 (s, 1H);
? . 18 (d, J = 8 Hz, 1H) ;
7.74 (dd,J = 8 Hz, 2 Hz, 1H) ;
8. 66 (d, J = 2 Hz, 2H) .
Example 3c.
Preparation and characterization of the adduct of 2-methylpyridine-5-carbaldehyde tait:h sodium hydrogen sulphite After the addition of bisulphite, the 1H- 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-ds): 1.96 (s, 3H);
5.01 (s, 1H};
2.59 (13H;s);
2.50 (2H, m);
1. 10 ( t 6H, ) .
1H-NMR ( D6-DMSO) : 8 . ( s ) ;
5 d 1H, 7.70 (1H, d);
7.32 (1H, d) ;
5.45 (1H, s);
2.58 (2H, m);
2.50 (3H, S);
2.40 (2H, m);
1.02 (6H, t).
Example 3b.
Preparation of N,N-diethylaminc~-(6--methylpyridin-3 yl)acetonitrile (via the adduct of 2-methylpyridine-5 carbaldehyde ~rith sodium hydrogen sulphite) The ozonolysis was carried out as in Example 2, starting from 23.84 g of 2-methyl-5-vinylpyridine (83.10 GC, 106.2 mmol). After the impurities had been extracted at neutral pH, the aqueous phase was cooled to 15°C and diethylamine (21.94 g, 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 _ g _ 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 S as an orange oil. Content: 83.7% {GC, % by weight), 0.34% of aldehyde). Yield: 92.?% based on 2-methyl-5-vinylpyridine.
1H-NMR (CDC13) : 1.08 (t, 6H) ;
2:50 (m, 2H);
2. 58 (s~,3H) ;
2. 65 (m, 2H) ;
5.00 (s, 1H);
? . 18 (d, J = 8 Hz, 1H) ;
7.74 (dd,J = 8 Hz, 2 Hz, 1H) ;
8. 66 (d, J = 2 Hz, 2H) .
Example 3c.
Preparation and characterization of the adduct of 2-methylpyridine-5-carbaldehyde tait:h sodium hydrogen sulphite After the addition of bisulphite, the 1H- 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-ds): 1.96 (s, 3H);
5.01 (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) .
isC-NMR {DMSO-d6): 20.23 (GH3};
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-j(4-(methyl-aultonpl)pbsayl,ethanons (aqueous ~ao$ as baae) 41.07 g (89.1, 1.00 eq.) of N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile, 30 ml of toluene and 10.0 g of Celite were initially charged. ?2 g (5 eq.) of a 50o 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 1N HCl. 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 mi of isopropanol/water 1:1 and subsequently dried at 20°C/20 mbar.
This gave 40.19 g (?6.4%) of~the title product having a content of 99 . 0 0 .
M.p. 182°C-183°C
1H-NMR (CDCi~) : 9.15 (1H, s) ;
7. 93 (d, J = 2 Hz, 1H) .
isC-NMR {DMSO-d6): 20.23 (GH3};
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-j(4-(methyl-aultonpl)pbsayl,ethanons (aqueous ~ao$ as baae) 41.07 g (89.1, 1.00 eq.) of N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile, 30 ml of toluene and 10.0 g of Celite were initially charged. ?2 g (5 eq.) of a 50o 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 1N HCl. 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 mi of isopropanol/water 1:1 and subsequently dried at 20°C/20 mbar.
This gave 40.19 g (?6.4%) of~the title product having a content of 99 . 0 0 .
M.p. 182°C-183°C
1H-NMR (CDCi~) : 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. (3H,s) 63 .
_...-.. ..._ ._.. .......... , _._ ......_ _...~.-._ .....-.,."",.. . .. . .~x . > .~:..r.:aa , s"..anv.,~.....".~".r,.... ..."....,.w-......., ..-..........,__.....~_~..._...._.. .._._.._...__.. ....._.~._...
........____.__.,.."""..
,. s°r~m-r.;.w. n:~~,::..,.-°-.-.: 'crrr"~.aac.. ~n=:..
. CA 02485739 2000-O1-13 Example 4b.
Preparation of 1-(6-methylpyridin-3-yl)-2-j(4-(methyl-suifonyl)phenyl]ethanone ~alkouide, 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 HCl 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
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°x.
M.p. 182°C-183°C
1H-NMR (CDC13) : 9.15 (1H,s) ;
8.18 (1H,d) ?.92 (2H,d);
7 . 47 (2H;d) 7.30 (1H,d);
4. 39 (2H,s) ;
3.04 (3H,s) ;
2.63 (3H,s) .
7. 92 (2H, d) ;
7.47 (2H,d);
7.30 (1H,d);
4.39 (2H,s);
3.04 (3H,s);
2. (3H,s) 63 .
_...-.. ..._ ._.. .......... , _._ ......_ _...~.-._ .....-.,."",.. . .. . .~x . > .~:..r.:aa , s"..anv.,~.....".~".r,.... ..."....,.w-......., ..-..........,__.....~_~..._...._.. .._._.._...__.. ....._.~._...
........____.__.,.."""..
,. s°r~m-r.;.w. n:~~,::..,.-°-.-.: 'crrr"~.aac.. ~n=:..
. CA 02485739 2000-O1-13 Example 4b.
Preparation of 1-(6-methylpyridin-3-yl)-2-j(4-(methyl-suifonyl)phenyl]ethanone ~alkouide, 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 HCl 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
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°x.
M.p. 182°C-183°C
1H-NMR (CDC13) : 9.15 (1H,s) ;
8.18 (1H,d) ?.92 (2H,d);
7 . 47 (2H;d) 7.30 (1H,d);
4. 39 (2H,s) ;
3.04 (3H,s) ;
2.63 (3H,s) .
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]-ethanone of the formula wherein N,N-Dialkylamino-(6-methyl-3-pyridyl)acetonitrile in which the alkyl radicals are C1-C4 alkyl and are identical or different, is reacted in the presence of a base with a 4-(Methylsulfonyl)benzyl halogenide to give 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]-ethanone, wherein the base is an alkali alkoholate and is used in the presence of an organic solvent at a temperature of 15°C to 25°C.
2. The process according to claim 1, wherein the 4-(methylsulfonyl)benzyl halogenide is 4-(methylsulfonyl)benzyl-chloride.
3. The process according to claim 1 or 2, wherein the acetonitrile is added to a water-free suspension of the alkali alkoholate.
4. The process according to any one of claims 1 to 3, wherein the alkali alkoholate is selected from a group comprising sodium tert-butanolate, potassium tert-butanolate and sodium tert-pentanolate.
5. The process according to claim 4, wherein the alkali alkoholate is potassium tert-butanolate.
6. The process according to any one of claims 1 to 5, wherein the organic solvent is an ether.
7. The process according to claim 6, wherein the ether is tetrahydrofuran.
8. A N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of formula wherein R1 and R2 are the same or different and represent C1-4-alkyl.
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| US60/145,996 | 1999-07-29 | ||
| CA002359958A CA2359958C (en) | 1999-01-14 | 2000-01-13 | Process for preparing 1-(6-methylpyridin-3yl)-2-[(4-methylsulfonyl)phenyl]ethanone |
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| IL127441A (en) * | 1996-07-18 | 2003-02-12 | Merck Frosst Canada Inc | Substituted pyridines, pharmaceutical compositions comprising them and their use in the preparation of anti-inflammatory medicaments or as selective cyclooxygenase-2 inhibitors |
| TW492959B (en) * | 1997-04-18 | 2002-07-01 | Merck & Co Inc | Process for making 2-aryl-3-aryl-5-halo pyridines useful as cox-2 inhibitors |
| AR015938A1 (en) * | 1997-09-25 | 2001-05-30 | Merck Sharp & Dohme | PROCEDURE TO PREPARE DIARIL PIRIDINES USEFUL AS COX-2 INHIBITORS AND INTERMEDIATE COMPOUND |
| SK284805B6 (en) * | 1998-04-24 | 2005-11-03 | Merck & Co., Inc. | Process for synthesizing 3,5-disubstituted-2-(phenyl or pyridyl)-pyridines |
-
2000
- 2000-01-13 PT PT03024787T patent/PT1394149E/en unknown
- 2000-01-13 ES ES03024787T patent/ES2235138T3/en not_active Expired - Lifetime
- 2000-01-13 EP EP03024787A patent/EP1394149B1/en not_active Expired - Lifetime
- 2000-01-13 AT AT00901555T patent/ATE253559T1/en active
- 2000-01-13 DE DE50009312T patent/DE50009312D1/en not_active Expired - Lifetime
- 2000-01-13 ES ES00901555T patent/ES2209807T3/en not_active Expired - Lifetime
- 2000-01-13 CA CA002359958A patent/CA2359958C/en not_active Expired - Fee Related
- 2000-01-13 CA CA002485739A patent/CA2485739C/en not_active Expired - Fee Related
- 2000-01-13 SK SK972-2001A patent/SK284903B6/en not_active IP Right Cessation
- 2000-01-13 PT PT00901555T patent/PT1159270E/en unknown
- 2000-01-13 DE DE50004327T patent/DE50004327D1/en not_active Expired - Lifetime
- 2000-01-13 AU AU22908/00A patent/AU2290800A/en not_active Abandoned
- 2000-01-13 DK DK00901555T patent/DK1159270T3/en active
- 2000-01-13 HU HU0105124A patent/HUP0105124A3/en unknown
- 2000-01-13 CN CNB008027218A patent/CN1170820C/en not_active Expired - Fee Related
- 2000-01-13 CZ CZ20012457A patent/CZ302270B6/en not_active IP Right Cessation
- 2000-01-13 JP JP2000593582A patent/JP4765167B2/en not_active Expired - Fee Related
- 2000-01-13 CN CNB200410069946XA patent/CN1281589C/en not_active Expired - Fee Related
- 2000-01-13 IL IL14398100A patent/IL143981A0/en active IP Right Grant
- 2000-01-13 DK DK03024787T patent/DK1394149T3/en active
- 2000-01-13 AT AT03024787T patent/ATE287396T1/en active
- 2000-01-13 EP EP00901555A patent/EP1159270B1/en not_active Expired - Lifetime
- 2000-01-13 WO PCT/EP2000/000240 patent/WO2000042014A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| CA2485739A1 (en) | 2000-07-20 |
| CZ20012457A3 (en) | 2002-01-16 |
| JP2003518002A (en) | 2003-06-03 |
| ES2209807T3 (en) | 2004-07-01 |
| DK1394149T3 (en) | 2005-04-04 |
| CA2359958A1 (en) | 2000-07-20 |
| WO2000042014A3 (en) | 2000-12-07 |
| EP1159270A2 (en) | 2001-12-05 |
| EP1394149A1 (en) | 2004-03-03 |
| PT1394149E (en) | 2005-05-31 |
| AU2290800A (en) | 2000-08-01 |
| ATE253559T1 (en) | 2003-11-15 |
| HUP0105124A2 (en) | 2002-04-29 |
| DE50009312D1 (en) | 2005-02-24 |
| DK1159270T3 (en) | 2004-02-23 |
| PT1159270E (en) | 2004-03-31 |
| ATE287396T1 (en) | 2005-02-15 |
| EP1394149B1 (en) | 2005-01-19 |
| IL143981A0 (en) | 2002-04-21 |
| WO2000042014A2 (en) | 2000-07-20 |
| CA2359958C (en) | 2006-04-04 |
| SK9722001A3 (en) | 2001-12-03 |
| CN1359374A (en) | 2002-07-17 |
| JP4765167B2 (en) | 2011-09-07 |
| CN1170820C (en) | 2004-10-13 |
| CN1281589C (en) | 2006-10-25 |
| HUP0105124A3 (en) | 2002-05-28 |
| ES2235138T3 (en) | 2005-07-01 |
| DE50004327D1 (en) | 2003-12-11 |
| SK284903B6 (en) | 2006-02-02 |
| EP1159270B1 (en) | 2003-11-05 |
| CN1583723A (en) | 2005-02-23 |
| CZ302270B6 (en) | 2011-01-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDC | Discontinued application reinstated | ||
| MKLA | Lapsed |
Effective date: 20130114 |