3,5-dimethyl-4-methoxy pyridyl-n-oxides,their preparation and their use as intermediates for the preparation of omeprazole derivatives

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3,5-DIMETHYL-4-METH0XY PYRIDYL-N-OXIDES, THEIR PREPARATION AND THEIR USE AS INTERMEDIATES FOR THE PREPARATION OF OMEPRAZOLE DERIVATIVES ,י דים op א ו -N -5,3-דימתיל-4-מתאוקםיפירידיל הכנתם,והמימוש בהם כחומרי ביניים להכנת תולדות של אומפראזול«

Novel compounds of the formula

ABSTRACT

<img file="IL69175A_D0001.tif" />

wherein R is H or CH^, a process for their preparation, and their use as intermediates in the preparation of pharmaceutically useful compounds, e.g. substituted benzimidazoles containing a pyridine radical,

i.a. omeprazole.

Η 703-1

27־06־83

Intermediates for the Preparation of Omeprazole

DESCRIPTION

Field of the invention /

The present invention relates to novel chemical intermediates, a process for their preparation, and their use in the preparation of pharmacologically active substances.

Background of the invention

2

Compounds of the general formula (i) wherein R and R are the same or different and are each selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, alkoxy and alkanoyl have been disclosed in e.g. European patent No. 0005 129 as useful. therapeutical compounds.

One of these compounds, known under the generic name omeprazole (R¹ = = ⁵⁰־^CH3 ^12־ = ^H> OCH.

is being developed as a.gastric acid secretion inhibiting drug. It can also be used for providing gastrointestinal cytoprotective effects in mammals and man.

It is important to obtain simple and efficient intermediates and routes of synthesis for omeprazole and, in a more general sense, for thera3q peutically active compounds such as benzimidazole derivatives containing the pyridyl methyl moiety

OCH, I

The present invention provides novel compounds which are useful as intermediates in the preparation of therapeutically active comounds such as benzimidazole derivatives which contain a pyridylmethyl radical of the formula (ii), and methods for the preparation of such compounds.

Prior art :

Substituted benzimidazoles containing a pyridine radical of the formula (ii) are disclosed i.a. in European patent 0005 129. A problem with these compounds is their stability characteristics. Upon storage without any special precautions being t;aken, they are degraded at a rate which is higher than desired. E.g. by storage of omeprazole, which is a.substituted benzimidazole disclosed in the patent cited above, at accelerated conditions, that is at +37°C and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradetion products.

Detailed description of the invention

It has been found according to the present invention that the compounds of the formula

<img file="IL69175A_D0002.tif" />

wherein R is H or CH^, are novel and useful intermediates in the pre30 paration of pharmaceutically useful compounds, e.g. substituted benzimidazoles of the general formula (i). The compounds of the formula

I are the products obtained from the preceding nitration reaction (see preparation below), for which the N-oxide form may be considered necessary, and the following substitution reaction in which the pyridine

N-oxide form is very advantageous considering the yields.

In addition, the N-oxide state of the compounds of the formula I is very advantageous for the subsequent conversion to the 2-hydroxymethylpyridine (procedures A and B). Direct hydroxymethylation of the correspending non-oxidized pyridines

<img file="IL69175A_D0003.tif" />

¹⁰ * only gives low yields (&lt;20%).

The compounds of the formula I may advantageoulsly be prepared by pro15 cessing both the nitration step and the substitution step without isolation of the intermediate nitro-pyridine. Furthermore they are stable and can be stored in bulk form. For example, the compounds according to the invention of the formula I are useful as intermediates in the preparation of the corresponding 2-hydroxymethylpyridine and reactive 20 derivatives thereof of the formula

<img file="IL69175A_D0004.tif" />

or a salt thereof, in which formula Z is a hydroxy group or reactive esterified hydroxy group, e.g. halogen such as Cl and p-toluenesulfonyl used for the preparation of e.g. omeprazole. The reactive intermediate of the formula (iii) is then reacted in known manner with a benzimid azole derivative of the formula

<img file="IL69175A_D0005.tif" />

whereafter oxidation in known manner of the reaction product of the formula

OCH, , 0 yields omeprazole. A preferable method of preparing omeprazole is to use a compound with the general formula I, wherein R is H as an intermediate. The most preferable method of preparing omeprazole is to use a compound, wherein R is CH^ as an intermediate.

The present invention also relates to a process for the preparation of the compounds of the formula I.

The compounds of. the invention of the formula I are prepared according 20 to the invention by

a) reacting a compound of the formula wherein R is H or CH^, with a nitrating agent such as nitric acid

HNO,

III to the formation of a compound of the formula

<img file="IL69175A_D0006.tif" />

wherein R has the meaning given above whereafter

b) the compound of the formula IV is directly reacted with methoxide to give the desired end product of the formula

<img file="IL69175A_D0007.tif" />

wherein R is H or CH^.

The reaction conditions for the steps a) and b) are suitably the following.

For reaction a), ordinary nitration conditions, i.e., a mixture of 25 cone, sulfuric acid and nitric acid of different concentrations are used. Mixtures containing organic solvents such as acetic acid and nitromethane may also be used.

For reaction b) a solution of methoxide anion in methanol is preferably 30 used. Methoxide salts in inert solvents such as toluene may also be used. A solution of methoxide in methanol can be prepared from sodium hydroxide and methanol.

The utilization of the compounds I in the preparation of reactive de35 rivatives of corresponding 2-hydroxymethylpyridine can be carried out as illustrated, below; .

A. Procedure useful, for the preparation of a compound of the formula (iii) utilizing a compound of the formula I wherein R is CH_q:

<img file="IL69175A_D0008.tif" />

(ווו)

B. Procedure useful for the preparation of a compound of the formula (iii) utilizing a compound of the formula I wherein R is H:

<img file="IL69175A_D0009.tif" />

<img file="IL69175A_D0010.tif" />

COH

י. 0 presence of a source of free radicals

<img file="IL69175A_D0011.tif" />

(ווו)

Suitable sources of free radicals are e.g. or other salts of persulfuric acid.

The compound of the formula (iii) thus obtained, or a salt thereof, is thereafter in known manner as described in the prior art reacted with the desired benzimidazole derivative (iv) as described above.

The invention is illustrated by the following examples.

Example 1. Preparation of 2,3,5-trimethyl-4-methoxypyridine-N-oxide

2,3,5-trimethyl-pyridine-N-oxide (1457 g, 10 moles) was dissolved in cone. H^SO^ (1200 ml, 22.08 moles) in a 50 litres reaction vessel. A nitration solution (1750 ml, 32.2 moles cone. and 2065 ml, 29.84 moles 65% HNO^) was added at 90°C during 1 hour. The solution was stirred at 90° for 1.5 hours and thereafter cooled to 30°C. The pH of the reaction mixture was then adjusted by adding 1OM NaOH (11.65 litres, 116.5 moles). during cooling with water so that the temperature was kept below 40°C. The NaOH was added during about 2 hours. Thereafter CH2C12 (25 litres) was.added and the mixture stirred vigorously for 30 minutes. The phases formed were separated and the CH₂C!₂־phase was transferred to a 100 litres reaction vessel. The water phase was discarded. The methylenechloride was distilled off. To the remainder was added 15 1 of toluene which was then distilled off under reduced pressure, followed by another 15 1 portion of toluene which was also removed by distillation. 8 litres of methanol was added and the mixture heated to boiling temperature. A solution of NaOH (595 g, .14.9 moles) in CH₇0H (16 litres) was added during about 1.5 hours. The reaction mixture obtained was cooled and its pH adjusted to 8 using cone. H^SO^ (250 ml, 4.6 moles). Remaining methanol was distilled off and CH₂C1₂ (20 litres) was added to the remainder. The mixture was stirred for about 30 minutes . and inorganic .salts were filtered off and washed with CH₂c!₂. The fil8 trates obtained were pooled and evaporated, yielding 1287 g of 2,3,5־ trimethyl-4-methoxy-pyridine-N-oxide with a purity of 89%. The identity

13 1 of the reaction product was confirmed with H and C NMR. H-NMR:

cT(COClo) 2.22(s,3H),2.27(s,3H),2.51(s,3H),3.81(s,3H),8.18(s,lH).

The reaction sequence is:

<img file="IL69175A_D0012.tif" />

5ן The 2,3,5-trimethylpyridine-N-oxide used as starting material was prepared as follows.

Preparation of 2.,3,5-trimethyl-pyridine-N-oxide.

To a 100 litres reaction vessel was added 2,3,5-trimethyl-pyridine (10.9 kg, 89.2 moles) and acetic acid (30 litres). The temperature was raised to 90°C. The mixture was stirred for 3 hours and thereafter cooled to 60°C, whereafter H₂0₂ (35% solution, 3122 ml, 35,67 moles) was added ׳during 1 hour. The temperature was then raised to 90°C. The • 25 reaction mixture was stirred overnight. After cooling to 40°C an addi. tional amount of T^O^, solution (936 ml, 10.7 moles) was added during 1 hour. The temperature was then raised to 90°C. The reaction mixture was stirred for 3 hours and was allowed to stand without heating overnight.Excess of acetic acid was distilled off under vaccum. To the remainder was added NaOH (10M) until pH 10. CH₂C1₂ (10 litres) was added and the resulting mixture was stirred vigorously. The CH^Cl₂phase was separated and the water phase was extracted twice with CH^CI^ (10 litres). The combined Ch^C^ ־ phases were dried over MgSO^ and filtrated. The filtrate was evaporated yielding 2,3,5-trimethyl-pyri35 dine-N-oxide (11920 g, 94% purity). The identity of the product was confirmed with ^H and NMR.

Example 2. Preparation of 3,5-dimethyl-4-methoxy-pyridine-N-oxide.

3.5- dimethyl-pyridine-N-oxide (3500 g, 28.5 moles) was dissolved in cone. H^SO^ (3500 ml, 64.4 moles). The solution was cooled to 90°C and nitration solution (5 1, 91.5 moles, cone. and 5.9 1, 85 moles

65% HNO-j) was added during 4 hours at 90°C. The solution was stirred at . 90°C over night. The solution was cooled to 30°C and neutralized with

10M NaOH (36 1, 360 moles) during 4 hours and the temperature kept below 30°C. Acetonitrile (35 litres) was added and the mixture stirred vigorously for 30 minutes. The acetonitrile layer was separated. The extraction procedure was repeated with 15 1 of acetonitrile, and the combined acetonitrile were extracted with water (10 1 at 60°C). The upper layer was collected and evaporated at reduced pressure (bp 30־ 55°C/130 mm Hg). Toluene (10 1) was added and remaining water was thoroughly removed by azeotropic distillation at reduced pressure (bp

55-65°C/130 mm Hg). Methyl alcohol (7 1, 173 moles) was added and the mixture was heated to reflux temperature. A solution of NaOH (1138 g, 28.45 moles) in 30 litres methylalcohol was added over a period of 15 hours. The reaction mixture was cooled and pH adjusted to 9 using cone. HCl (1200 ml, 14 moles). Remaining methanol was evaporated. The residue was cooled and CH^C^ (30 1) and activated carbon (50 g)were added. The mixture was stirred for 30 minutes, filtered and the residue washed with CH^C^. The filtrates were evaporated. The solid product was washed with petroleum ether, (5 litres bp 60-80°C) at 50°C for minutes and filtered. This procedure was repeated once. The product was dried at reduced pressure. Yield 2400 g 3,5-dimethyl־4־methoxypyridine-N-oxide with a purity of 90%. The identity of the product was confirmed with ¹H- and ¹³C-NMR. ¹H-NMR: J(COC1₃) 2.23(s,6H),3.81(2,3H), 8.03(s,2H).

The 3,5-dimethyl-pyridine-N-oxide used as starting material was prepared as follows.

3.5- lutidine (15 kg, 140.2 moles), was dissolved in acetic acid (48 1) at 60°C. Hydrogen peroxide (8430 ml,. 98 moles) was added during 3 hours.

The solution was heated to 90°C and kept at this temperature for 3 hours. The reaction mixture was cooled to 60°C and hydrogen peroxide (3500. ml, 41 moles) was added during 1 hour. The temperature was raised סו to 90°C and kept there for 16 hours. The reaction mixture was evaporated at reduced pressure (70°C 300 mm Hg). The residue (approx 25 litres) was cooled and pH adjusted to 10 with NaOH-solution (23 litres 1ΌΜ). Acetonitrile (30 litres) was added and the mixture was stirred for 30 minutes.

The sodiumacetate was separated off and washed with 10 1 acetonitrile. The liquid phase was evaporated at reduced pressure (55°C, 200 mm Hg). The remaining solution (approx 25 litres) was extracted with CH^Cl^ (20 litres and 3x5 litres). The combined organic layers were dried over MgSO^, filtrated and evaporated at reduced pressure (50°C 200 mm

Hg). When all CHgCl^ had distilled off unreacted 3,5-lutidine was evaporated at 75°C, 8 mm Hg. Yield 14940 g of 3,5-dimethylpyridine-N-oxide.

13

The identity was confirmed with Hand C NMR.

The conversion of the compounds of the formula I to 3,5-dimethyl4־15 methoxy-2-hydroxymethylpyridine can be carried out according to Proce. dure A and Procedure B as described above and exemplified below.

Procedure A:

step 1:

<img file="IL69175A_D0013.tif" />

2,3,5~dimethyl־4־methoxypyridine־N-oxide (1268 g, 6.75 moles) obtained in Example 1, dissolved in acetic acid (740 ml), was added dropwise to (CH,C0)2140) 0״ ml) heated to 90°C. The heating was discontinued during the addition. The temperature rose to 130°C. Thereafter the reaction solution was stirred for 1 hour and then cooled to 80°C whereafter CH-OH (2460 ml) was added. The reaction solution was evaporated

O and the remainder used directly in step 2.

וו

<img file="IL69175A_D0014.tif" />

<img file="IL69175A_D0015.tif" />

To the remainder from step ו was added NaOH (3300 ml, 10M). The mixture was refluxed for 5 hours, cooled and extracted with CHgCl^ (8 litres). The phases were separated and the water phase extracted with CH^Cl% (2x4 litres). The combined CHgClg - phases were dried over MgSO^, refluxed with a few grams of decolorizing carbon and filtrated, yielding

3,5-dimethyl4־-methoxy2־-hydroxy־methylpyridine (941 g). The identity

13 of the product was confirmed with H and C NMR.

Procedure B:

<img file="IL69175A_D0016.tif" />

3.5-Dimethyl-4-methoxypyridine-N-oxide (61.2 g) obtained in Example 2 was dissolved in CH^OH (458 ml). Dimethyl sulfate (38 ml 0.4 moles) was added dropwise during 15 minutes and pH adjusted to 5.0 using 10M NaOH. The mixture was stirred for 15 minutes and thereafter refluxed for 1 hour. An additional amount of dimethylsulfate (3.8 ml, 0.04 moles) was added dropwise and the mixture was refluxed for 1.5 hours. Stirring was continued overnight at room temperature. Thereafter the mixture was heated to reflux and (NH^J^S^Og (91.2 g, 0.4 moles) dissolved in water (169ml) was added during 1.75 hours, followed by refluxing for 1.5 hours and stirring at room temperature overnight. Thereafter CH^OH (452 ml) was added. Precipitated salts were filtered off and discarded.

After evaporation of CHgOHj.the remaining water phase (pH 0.6) was adjusted to pH 10.0 using 1OM NaOH (145 ml). The water phase was extracted three times with CH₂C1₂- The combined CH₂C1₂ phases were dried over Na₂S0₄, evaporated and dried, yielding 3,5-dimethyl-4-methoxy-210 -hydroxymethylpyridine (44.2 g). The identity of the product was con113 firmed with H and C NMR and the purity checked with gas chromatography.