Process for the preparation of intermediates namely 3,5-dimethyl-4-methoxypyridine-n-oxide and 2,3,5-trimethyl-4-methoxypyridine-n-oxide useful for the preparation of omeprazole

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in which the representation of a hydrogen atom in the Style group is a novel and useful intermediate in the preparation of useful and pharmaceutical compounds, for example generally substituted benzyridazoles (i). The compounds of this invention will generate the following products: (i) will result in a subsequent reaction (see ε: ρ: tr will bring up), for which ε forxi '' -oxide may be consi3u; uds 2.j055õeriú and e. south following substitution re erection. whereas pyridine pyridine is not the same as regards yields.

;.home. In addition, the oxide from the genera of E. coli eplesters is the first version of the subsequent version of the hydroxyethyl pyridine (therapeutics). 1 kiâror.insectile d:.: Riridir.ef · uõc oxi matching fingers of ic-rrulg gerei 1

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be isolation of the intermediate i.itrc-pyrldi:. ^r? est · ve ·. ' can be a bulk senate weapon. fo? According to the present invention, general compounds are useful as compounds thereof, in the price of the corresponding 1-hydroxymethylpyridine and its derivatives. reactive derivatives of formula ge&gt;.

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wherein Z is a ester or reactive hydroxy group, for example one. halogen, such as chlorine, or a p-toluenesnflenyl group,

ç. Its utility prepares, for example, creprasole.

The general pour-off reset compound (iii) is then reacted in a known manner as a derivative of ceridic acid simidazole.

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hello / rr.ec cmeprazcle. A preferable method of pricing of a homeprascle is en. Use of a compound of formula 21 wherein R is represented by hydrogen, the intermediate compound. The most advantageous process for preparing omeprazole is to use, as an intermediate compound, a compound in which K is methyl.

J. The present invention also relates to a process ie preparation of compounds of formula I.

The compounds according to the present invention of general formula I are prepared as follows: a) By reacting a compound of general formula. ...

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wherein R represents a hydrogen atom or one. group m-tik oom a nitrating agent with nitric acid

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fc) Referring directly to the compound of formula I will have IV;

uromethoxide for the intended final product of formula ί, - 'ΐ'ί.Ι,

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I na. what ?. represents an atom of hydrogen or a C-? methyl,: 3 reaction conditions of the phases ε) and thi are, preferably, es.

^rreaction a) nitre conditions are used_sIn addition, a mixture of concentrated sulfuric acid nearic acid of different concentrations. Ib-can anyone use mix?

It contains organic solids such as. c acetic acid and n er tr nc.

^rand rsfc ^ oo l_? it is better ”£ .l to use a sclu₄oc · de ar.iãc tc: .i ir in metonol. Inert 2-methoxide salts may also be used, such as tolane. A solution of rotexide in methanol can be prepared from sodium hydroxide and methanol.

use of formula compounds. I in the preparation of reocctive derivatives of the corresponding Z-hydroxymethylmiridine may

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Α Appropriate technique for preparing the compound of formula (iii) using a compound of formula I, wherein R is a methyl group:

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ch₃ (ch₃co)₂O

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Ξ Appropriate key to stop the preparation of a southern flue gate?_çer: 1 (iii), using one. compound of general formula 1, re -μ ·, c mmbclc r. represents one. hydrogen atom:

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CH₂0H

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Suitable sources of free radicals are, for example, (Π ^) ^ 0_no or other salts of persulfuric acid.

The compound of formula (iii) was then reacted in this manner, or a salt thereof, in a known manner with the extended benzimidazole derivative of light (iv) form. .tes .. · ·

The following examples illustrate the present invention.

example 1 note, εο io 1,2, β-trimethyl --- methoxypyridine -''-oxide; t

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1457 g (1C moles) of 2,3,5-trimethyl-pyridyr-1'-oxide ex 1200 ml (22.03 moles) of concentrated sulfuric acid are added to a 50 ml reaction vessel. liters. At 1 ° C for 1 hour, a concentrated nitric solution / 1750 sl (32.2 moles) 5e concentrated sulfuric acid and 2 CO5 irl (29.34 moles) of erotic acid are added; Stir the solution at 9 ° C for one hour and then cool to 30 ° C.^çC. The reaction mixture is adjusted to pH by the addition of 11.1 liters (11.5 moles) of sodium hydroxide, which is cooled with water. keep the temperature at 4p^çC. Sodium hydroxide is added over about 2 hours. Lm. Then 25 liters of methylene chloride are added and the mixture is stirred vigorously for 30 minutes. The lyses had been sapped; irregular and transfer to the methylene chloride phase. - &lt;·? Í '\ λ ·'

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to a 10C liter reaction vessel. One thinks of this aquosq. Methylene chloride is removed by distillation. To residue 1? liters of toluene which is then distilled off under reduced pressure; postpone another 1? liters of toluene ns is also removed by distillation. Do you join? liters of methanol and the mixture is heated to boiling temperature. Over an hour and a half, a reduction of&gt; 95 t (1.9.9 moles) of silicon hydroxide in 1 liter of methanol is added. The reaction mixture obtained is cooled and adjusted to pH 1. 3 using 2 ° C ml (* T, mole) of concentrated sulfuric acid. The remaining methanol is distilled off and to the residue is added 20 liters of methylene chloride. The mixture is stirred for about 30 minutes and filtered to separate the six inorganics which are washed with methylene chloride. The obtained filtrates are combined and evaporated to 123 ° C. g of 2,3;^l-i-methoxypyridine oxide of a purity of SÇ7. The predicted identity of the reaction is stated by R1? and^1SCH! ·? '. ³E-RX ': S (δ), 2.22 (s, 3H), 2.27 (s, 3H), 2.51 (e, 5H), 3.81 (s, 3H), 8.18 ( e.H).

The sequence is as follows:

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In the following manner the 2,3,5-trimethylpyridine-oxide used as the starting compound is separated;

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Frequency of 2,1,5-trlmetll-plridInc.-^r-6&gt; .Mo · '···.' . i • · - · ?;

· - tv: ·¹ 10.9 kg (29.2 moles) of 2,3,5-trimethylpyridine and C liters of acetic solids are added to a 100 liter reaction vessel. The temperature is raised to 90 ° C. The mixture is stirred for 3 hours and then cooled to 60Â ° C, after which it is added over 1 hour 3-122 ml (35.7 mmol) and a peroxide solution of the mixture. hydrogen at 35 ° C and then temperature to-° C. The reaction mixture is stirred for overnight. After cooling to 40 ° C, an additional 93 ml (10.7 mol) of hydrogen peroxide solution is added over 1 hour. The temperature is then raised to 90 ° C. The reaction mixture is stirred for 3 hours and left to reoccur without heating overnight. It is distilled in a vacuum to eliminate excess acetic acid. To the residue, a solution of sodium hydroxide (1CX) to pE10 is added. 1 liter of methylene chloride is added and the resulting mixture is stirred vigorously. The methylene chloride phase is separated and the aqueous phase is extracted twice with 10 liters of methylene chloride. The combined phases are dried over methylene chloride over magnesium sulfate and filtered. The filtrate is screened, giving 11,920 g of 2,3,5-triethylethyl pyridine-exide (purity d = 94). The identity of the product is obtained. upon¹H F.fe ¹²C RK '.

Example 2

Rrc-para, 3's₎5-dim5-11-4-methoxy-plridine - '' - oxide · · '' '.' · I.

25CC g (29.5 moles) of 2,5-dimethyl-pyrldinyl is dissolved.

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The oxide was 3500 ral (64.4 moles) of concentrated sulfuric acid. The solution is cooled to 90 ° C and added at this temperature to 0 DEG. In the 4 hour course, the 5 liter (91.5 raole) nitration solution of

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tonitrile and extract the solutions with 1 liter of water at 0 ° C. acetonitrile combined. Step 3: Remove the upper whitewash under reduced pressure (FE 30-55 ° C / 13C ee Eg). 10 liters of toluene are added and the remaining water eluted out by azeotropic distillation under reduced pressure (1.55-65 ° C / 130 mm

Eg). Methanol (7 liters) is added and the mixture is heated to reflux temperature. In the course of 1? hours, the solution of 13.3 g (23.45 aoles) of sodium hydroxide in 30 liters of methanol. The reaction mixture is cooled and adjusted to pH? using 120 ml (14 moles) of concentrated hydrochloric acid. The remaining netanol is evaporated, the residue is cooled and the residue is cooled.^Ç liters of methylene chloride and 5f ε of charcoal. The mixture is stirred at room temperature for minutes. The residue is filtered off and chlorinated. of methylene. AND^vafter filtering. It is the solid product with 100 liters of petroleum (·. L. 1: -50¾) at 0 ° C for 3 minutes and filtered. A '·: ε this technique. The product is dried under reduced pressure ds. 240C g of 3,5-diethyl-4-ylmethoxypyrrole with one. 50 g purity. Check product identity by ^ Ε-ήϊί¹' and ¹²ç-?.:?·. -bi-Rí ·? ': k (coci. 2.23 (5.61 :), 3.31 (1.3%), S, δ 3 (0.2: - :).

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In the following manner the 3, dimerstyr-pyrldlr.s-¹-oxide, using as the starting compound!

15 Rg (14c, 2 moles) of 3,5-lutidine is dissolved in 4 liters of acetic acid at 0 ° C. In the course of 3 harca is added, •• v

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8430 ml (98 mol) of hydrogen peroxide. The solution is heated to 90 ° C and held at this temperature for 3 hours. The reaction mixture is cooled to 60 ° C and 3,500 nil (41 moles) of hydrogen peroxide is added over 1 hour. Rise to

Temperatura Λ * temperature up to 90 ° C and held at this temperature for 16 hours. Evaporate the reaction mixture under reduced pressure (70 ° C / 300 mm Hg). Cool the residue (about 25 liters) and adjust zz

-Be to pH 10 with 23 liters of a sodium hydroxide solution (leu). 30 liters of acetonitrile are added and the mixture is stirred for 30 minutes. The sodium acetate is isolated and washed with 10 liters of acetonitrile. The liquid phase is evaporated under reduced pressure (55 ° C / 200 mm Hg). The remaining solution (about 25 liters) is extracted with methylene chloride (20 liters and 3 x 5 liters). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure (50 ° C / 200 mm Hg). Once all methylene chloride is distilled off, unreacted 3,5-lutidine is evaporated at 75 ° C / 8 mm Hg. Thus, 14940 g of 3,5-dimethyl pyridine-N-oxide are obtained. Identity is confirmed by 'K R1ÍK and pj' K, 'w *

The compounds of formula I may be converted to 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine according to technique A and technique E described above and exemplified below.

Technique A .: '

Stage 1:

OCH,

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• H · (ch₅co)₂O

-T *

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1268 g (6.75 moles) of 2,3,5-dimethyl-4-methoxypyridine-N-oxide obtained in Example 1 dissolved in 740 ml of acetic acid are added dropwise to 214θ ml of acetic anhydride heated to 90 ° C. Heating is discontinued during the addition. The temperature rises to 130 ° C. The reaction solution is then stirred for 1 hour, then cooled to 80 ° C and 2460 ml of methanol added. The reaction solution and residue are evaporated and used directly in Stage 2.

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3500 ml of sodium hydroxide (10M) is added to the residue from Stage 1. The mixture is heated at reflux for 5 hours, cooled and extracted with 8 liters of methylene chloride. The phases are dried and the aqueous phase is extracted into methylene chloride (2x4 liters). The combined methylene chloride phases are dried over magnesium sulfate and refluxed with a few grams of decolorizing charcoal and filtered to give 941 g of 3,5-methyl-4-methoxy. -2-hydroxymethylpyridine.

1?

The identity of the product is confirmed by 1 H NMR and 0 RMK.

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61.2 g of 3.5 'dimethyl-4-methoxypyridine-1 is dissolved.^M-oxide, acid in Example 2, in 453 ml of methanol. 33 ml (0.4 mole) of dimethyl sulphate are added dropwise over 15 minutes. It is adjusted to pH 5.0 using 1CM sodium hydroxide. I did The mixture is stirred for 15 minutes and then heated to reflux. xc for 1 hour. Add, by dropwise addition, an additional amount of dimethyl sulfide (3.0 mL, 0.4 mol) and the mixture is refluxed for half an hour. After stirring at room temperature overnight, the mixture is heated to reflux and a solution of ≤ 1 min. 2 g (C, 4 mole) of (HCl-ECEC) in 15 ml of water is heated under reflux for one and a half hours and stirred rapidly at room temperature. At room temperature, 452 ml of methanol are then added The precipitated salts are separated by filtration to a crude station. After evaporation of methanol, add the remaining aqueous phase (pE 0.6) to pH1.0 using 145 sl of 10K sodium hydroxide. Extract -εε three times the aqueous phase with. methylene chloride. The combined methylene chloride phases are dried over sodium sulfate, evaporated. 4

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This is dried and dried to give 44.2 g of 3.5 g of 3'-dimethyl-4-methoxy-2-hydroxymethylpyridine. Product identity is confirmed by 3KK and RM *^? and the degree of purity is avalig. by gas chromatography.

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