Intermediates for the preparation of omeprazole

DESCRIPTION · !.

SCOPE OF VVBTRVSVOS.

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

HISTORY OF VVVTRVSVOS.

• 1 2 Compounds of the general formula (s) wherein B and B are the same or several are each selected from each of the hydrogen, alkyl, halogen, carboxymethoxy, alkanoyl alkyl groups. * e.g. You are in the Bearded Bachelor's degree. 0005129 as useful therapeutic compounds. Hia of these compounds, known by the generic name omecrazole (B^{1 =} 5-0CB;² = H)

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(i) • 4. - was not developed as a drug to inhibit gastric acid secretion. It may also be used to provide gastrointestinal acid-protective effects in mammals and humans.

It is important to obtain effective intermediates and routes of synthesis for sucrose, more generally, for therapeutically active compounds as pyridine-containing enzymidazole:

OCH3

-., hu (h)

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The present invention provides "compounds which are useful in the preparation of therapeutically active compounds as derivatives containing a pyridylmethyl radical of formula (iii), and a process for the preparation of such compounds.

• L.

Predictors TBJHIH.

Benzimidazole containing pyridine radicals of formula (iii) are eliminated inter alia by European patent 000512; The problem with these compounds is their hardness characteristics. When storing without taking any special precautions, either the Ratio or the higher is desirable. E.g. By storage of demeprazole, or any substituted benzimidazole Decomposed in the above-mentioned patent under accelerated conditions, at + 37 ° C with a relative humidity of about 6 ° C.

ABSTRACT DESCRIPTION OF THE INVENTOR.

It has been found in accordance with the present invention that compounds of the formula

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Where 1 is I or Oly is a novel intermediate useful in the preparation of pharmaceutically useful compounds, e.g., substituted benzimidazoles of general formula (i). Compounds of formula I are the products obtained from the previous nitration reaction (not incorporated below), for which any form of oxide may be considered Necessary, whether or not Substitution reaction in any form whatsoever of Odds.

In addition, the H-oxide disorder of the compounds of formula I is highly favorable for conversion to 2-hydroxymethylpyridine (Methods A and B). Direct hydrosymethylation of the Corresponding Unsaturated Pyridines

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gives only low yields (/ 2 &lt;#).

7.

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-,

- 4 Compounds of formula I can advantageously be provided by conducting both of the (Nitro-Substituted Nitro-Pyridine Intermediate) Nitrogen-Pyridine intermediates. Formula I inventions are useful as intermediates in the delivery of the corresponding 2-hydroxymethylpyridine having active derivatives thereof:

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(Iii) or a salt thereof, in any of which Z is a hydroxy or active esterified hydroxy, e.g. halogen to cis-p-toluenesulfonyl used for the preparation of e.g. of omeprazole. The Active Intermediate of the Type I React Hereinafter is known in a t-type enzymidazole derivative

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where subsequently or ozidation is known in a manner known as the reaction product of the type ocH,

L (»)

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gives omeprazole. A preferred method of preparing omeprazole is to use a compound of general formula I, wherein R is *. The intermediate; The most preferred method of preparing omeprazole is to use a compound, wherein CH is as an intermediate.

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- 5 * This invention also relates to a method for the preparation of the compounds of formula I.

The compounds of the formula I invention are prepared according to the invention by a) reacting a compound of the formula I

II *

wherein R is I or Cly with nitrate as the nitrate

00} to form a compound of formula i

HOx t '₃

III Where S has the following significance given above. B) or a compound of formula IV Reacts directly with methoxide to give the desired end product of formula t

OCH3

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wherein S is H or OH ^.

The reaction conditions for step a) and b) are preferably the following.

For reaction a) at the usual conditions of nitration, i.e., a mixture of concentrated sulfuric acid and nitric acid of varying concentrations, it is possible to use mixtures containing both organic sulfuric acid.

Preferably Z / anion solution is used for reaction P)

- 6 methoxide. It is also possible to use methoxide salts in inert solvents such as toluene. A solution of methoxide in methanol can be prepared by adding 1 ml of sodium hydrogen oxide to methanol.

* 1 using compounds I in the preparation of active derivatives of the corresponding 2-hydroxy-methylpyridine may be administered as shown below.

A. Method useful for the preparation of a compound of the compound of formula I wherein S is CIII using

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. -SKS ** - # '(wv)

B. Method useful for preparing a compound of formula (iii) using a compound of formula I wherein R is H '.

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the presence of a free radical source

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Suitable free radical sources are e.g. (DD) d_L.0_The or other salts 2 2 2 of the acid sulfate.

The so-called Compound of interest (iii), or Sv thereof, is an antihydrate well known in the art as described in the art of producing the desired enzyme imidazole (iv) as described.

The invention is illustrated by peculiar examples i

EXAMPLE 1. Provision of 2,3,5-trimester; yl-4-methoxypyridine-i-oxide.

Dissolve 2,3,5-trimethylpyridine-1-oxide (1457 g, 10 moles) in a reflux (1200 ml, 22.08 moles) in a 5 liter reaction vessel. Nitrate solution (ΐ75 mg, 32.2 moles of pyridoxine 2065 mg, 25.84 moles of 65% 65%) was added at 50 ° C for 1 hour.

The solution is stirred at 50 ° for 1.5 h and cooled to 30 ° C. The pH of the reaction mixture is then adjusted by adding 10 M NaOH (11.65 liters, 116.5 moles) during cooling with water so that the temperature is maintained below 40 ° C. LaClI is added gently for about 2 hours. Then CH2Ci (25 liters) is added and the mixture is stirred vigorously for 30 minutes. The phases formed are separated by chi or phase I1_?The bag is packed with 100 liters of reaction buffer. * 1 phase water is discarded. Methylene chloride is removed by distillation. 15 liters of toluene are added to the precipitate which is then distilled off under reduced pressure under pressure. A portion of 15 liters of toluene which is also distilled off is added. Add 8 liters of methanol when the step is heated to boiling temperature. Add a solution of NaOH (555 TP; 14.5 moles) in CH OH (16 liters) at about 1.5 hours. The reaction mixture obtained was cooled to pH 8 adjusted using ref. H ^ SO ^ ^²^ 0 ml,

4.6 mol). The residual methanol is removed by distillation with the OH added.₂ (20 liters). The mixture is stirred for about 30 minutes when the inorganic salts are filtered off with CH2 Cl2. The obtained filtrates are evaporated to yield 1287 g of 2,3,5-trimethyl-4-methoxy-pyridine-H-85% pure. The identity of the reaction product was verified by MSc. ^ Eh ^ C. s'¹E-MSc. : δ (CDC | p 2.22 (d, 3H), 2.27 (d, 3H), 2.51 (d, 3H), 3, d (d, 3H), 8.18 ( (W, HH).

The number of reactions is ·. Y \

HU

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It was used for the first time in the production of 2,3,5-p-dimethylpyridine-1-oxide by the addition of 2,3,5-p-methyl-pyridine-1-oxide.

2,3,5-Frimethylpyridine (10.9 kg, 89.2 mol) was added in a 100 liter reaction vial with acid acid (30 liters). * 1 temperature goes to JO ° C. The mixture was stirred for 3 hours, then cooled to 60 ° C, then added (35% solution, 3122 ml, 35.67 mol) for 1 hour. Then the temperature rises to 90 ° C. The reaction mixture is stirred gently overnight. After cooling to 40 ° C, an additional amount of IgO solution (10.7 mol) was added over an hour. The temperature is usually set at 90 ° C. The reaction mixture was stirred for 3 hr and allowed to stand unheated until overnight. The acetic acid candle is removed by vacuum distillation. . ChiCl (10 M) to PI 10. Add CHτόC; (λί liters) and the batch mix is ​​vigorously stirred. The CHgCtf phase is separated by aqueous or aqueous water followed by CH 2 CC; (10 liters). The following phases CH ^ Ci_g They are dried over Kgl2O3 and filtered. The filtrate was evaporated to yield 2,3,5- * Pimethyl-pyridine-I-oxide (11920 g, 94% purity). '^THE product ID was authenticated by ^ 0 PM

EXAMPLE 2. Preparation of 3,5-6-dimethyl-4-methoxy-pyridine-1'-oxide.

Dissolve 3&gt; 5^-imidyl-pyridine-1-oxide (3500 YP; 28.5 mol) in a concentration of S2 SO4 (3500 mL, 64.4 mol). The solution was cooled to 90 ° C and nitrate solution (5 liters, 91.5 moles, concentrated SO2 and 5.9 liters, 1.85 moles HNO2 65%) was added over 4 hours at 90 ° C. The filtrate is stirred at 90 ° C overnight. The solution is cooled to 30 ° C and neutralized with 10 M 10 OH (36 liters, 360 mol) for 4 hours and maintained below 30 ° C. Add acetonitrile (35 liters) to the mixture / stir vigorously for 30 minutes, remove acetonitrile layer. The extraction process is repeated - 15 liters V · / · J

- 9 acetonitrile, the combined acetonitrile is extracted with water (10 liters at 6 ° C). Harvest or top layer is extracted under reduced pressure (bp 30-55 ° C / 34 mm Hg). Toluene (1 L) is added to the extruded water gently removed by aqueous distillation at reduced pressure (bp 55-65 ° C / l3Om). Methyl alcohol was added (7 liters, 173 mol) and the mixture was heated to reflux. A solution of LacB (1138 TP · 28.45 mol) was added within 30 liters of methyl alcohol for 15 h. The reaction mixture was cooled to PI adjusted to 9 using aqueous IC / (1200 mL, 14 mol). The methanol solution is evaporated.

The chill is cooled and added to CK ^ O? (^ ° liters) of activated carbon (50 g). The mixture was stirred for 30 min, filtered and the residue was washed with Cl2C2. The filtrates were evaporated. * 6 solid product is washed with petroleum ether, (5 liters bp 6O-8O ° C) at 50 ° C and 30 min filtered. * This process is repeated only once. The dye is dried in a reduced humidity. Ahodosi 2400 g of 3,5-dimethyl-4-methoxypyridine-1 L-oxide with a purity of JOfi. The identity of the product was minimized ¹1 hay ^ O-MS.

i-PCS » δ (CDCX2) 2.23 (d, 61), 3 D 81 (2.3), 8.03 (d, 2H).

The 3,5-dimethyl-nidro-n-oxide grafting compound used as the starting material 6

Dissolve 3,5-butidine (15 kg, 1 &lt;0.2 mol) in dioxic acid (4 L) at 60 ° C. Hydrogen peroxide (8430 mmol, molar) is added over a period of 3 hours. The solution is heated to JO ° C and kept at this temperature for 3 hours. The reaction mixture was cooled to 60 ° C with hydrogen hydroxide (3500 mL, 41 mol) added at about 1 ° C. The temperature rises to 90 ° C and is maintained for 16 hours. The reaction mixture was evaporated to a reduced volume (70 ° C, 300 mmH). The pellet (about 25 liters) was cooled to pH 10 with a solution of Halogen (23 liters 10 M). Add acetonitrile (30 liters) and the mixture is stirred for 30 min. The sodium acetate is separated and washed with 10 liters of acetonitrile. The liquid phase was evaporated to a reduced volume (55 ° C, 200 mmH). The aqueous solution (about 25 liters) is mixed with CH ^ C;

(20 liters and 3 x 5 liters). The attached organic layers are dried overnight

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M-SO, filtered and evaporated to reduced elution (50 C 200 V 4

When all the CIgC? _g untreated or unreacted 3.5-^&amp;uthidine with 8 mmHg. . Emission of 14940 g of 3,5-dimethylchiridine-H-diazide.

· / · I have been infected with PMS.

Conversion of the compounds of formula I to 2,5-dimethyl-4-methoxy-2-hydroxymethylpyridine may be administered in accordance with Method A and Method B as described above and are discussed below.

METHOD A.

Grade 1:

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2,3,5-Dimethyl-4-methoxypyridine-1-di-azide (1268 g, 6.75 mol) obtained from Example 1, dissolved in acetic acid (740 mL), dropwise (Cl2 CO) is added.₂0 (2140 ml) heated to JO ° C. * 1 heating vary depending on the duration of the addition. The temperature has risen to 130 ° C. Then the reaction solution is stirred at 1 ° C for 1 hour then cooled to 80 * 0 ° C. Then C1 Cl (2 &lt;0 mL) is added. The reaction is evaporated at 2 ° C using 2 minutes directly .

Step 2 t

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To the residue of step 1 was added KOH (33 mL of 10 M), the mixture was refluxed for 5 h, cooled and extracted with CH 2 O 2. ₉ (8 liters). The phases of hai or water phases are extracted with C ^ Ci_g (2 liters 4 liters).

The combined phases of CH 2 C 2 are dried over SO 2, refluxed with a few grams of decolorization carbon and filtered, yielding 3/5 "dimethyl-4-methoxy-2-hydroxy-methylpyridine (J41 g). The identity of the product is confirmed by H. Yes

C MSc

METHOD B:

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7.

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3,5-Dimenyl-4-methoxypyridine-H-oxide (61.2 g) obtained from Example 2 is dissolved in CH2 OH (45® mL). Dimethyl sulfide (38 mL 0.4 mol) was added dropwise over 15 minutes at pH adjusted to 5.0 using 10 M NaOH. The mixture was stirred for 15 min at reflux for 1 hour. An additional amount of dimethyl sulfide (3.8 mL, 0.04 mol) was added dropwise over the mixture, refluxed at 1.5 g, or stirred overnight at room temperature. Then the mixture is heated to reflux with HP® added *¹⁰Molecules} dissolved in water, xxxml) for 1.75 hours, then Reflux at 1.5 hours. Stir at room temperature overnight. Cl2 OH (452 ​​mL) is then added. Salted Salts Removed by Filtration Reject. After evaporation of CH2 OH, or Residual aqueous phase (pH 0.6), adjust to a pH of 10.0 using 1CM lacl (145 mL). The aqueous phase is extracted with Cl2Cl3. The accompanying phases are dried over Ha 2 SO 2, evaporated and dried, yielding 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine (44.2 g). * The product identity was confirmed by 2 hrs. chai or purity was checked by gas chromatography.