SA96170440B1 - benzimidazole A process that synthesizes a benzimidazole compound - Google Patents

Abstract

Abstract: The invention relates to a process for the manufacture of omeprazole from pyrmethyl alcohol via pyrmethyl chloride and pyrmetazole characterized by the fact that the entire reaction chain is carried out without any isolation or purification of intermediates. Further, the reaction is performed in a master solvent system that circulates throughout the reaction series and is inert to the reactants formed during the process as well as those used in the process. The process according to the present invention may also include an additional purification step.

Description

XY - 2 Process for the synthesis of benzimidazoles Full Description BACKGROUND The present invention relates to a new process for the synthesis of: 5-methoxy-2-»(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl! sulphinyl!-1H-be nzimidazole gle oo is known by the common name omeprazole .omeprazole Further to “dd the invention also relates to omeprazole being an inhibitor of gastric acid secretion and this makes it a useful Jel aS anti-ulcer. US Patent No. 4,255,431 (corresponding to EP No. 0005129 (EP) discloses a process for the preparation of this type of 0-substituted benzimidazoles. The said process includes a set of reaction steps. In the last three steps of The process uses more than one solvent and it is required to isolate the intermediates to obtain the omeprazole product (sled) and the resulting product is contaminated with starting materials and by-products.

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International Application No. 18895/91 WO discloses an improved process for the synthesis of omeprazole.

0 This process describes the oxidation step and procedure to obtain omeprazole. And in

The oxidation step is to use m-chloroperoxybenzoic acid.

In a system containing methylene chloride | Water having a pH constant to 0 greatly ranges from AV MA and includes ol ja) obtaining omeprazole

On the crystallization of omeprazole by adding alkyl formate

Another process for making omeprazole is described in a US patent

JUS No. 5391752 This process also describes the oxidazing step and in the oxidation step

The aforementioned uses monoperoxy phthalate (magnesium onoperoxyphtalate).

0 as an oxidizing agent. The resulting product is filled with the starting material and by-products.

‎5 cls omeprazole dye 1 4535 A Sha) gins 58] Be dl

In US Patent No. 4,619,997 intermediates have been isolated; But it was not met

Different solvent systems were used in the chemical steps throughout the process. In light of the foregoing, there is still a need for a new, acceptable or more efficient process for the manufacture of omeprazole

1 . omeprazole 00

General description of the invention

In the following developed process, Scheme #1 is revealed below, which describes three reactions

A major sequence used in the manufacture of Omeprazole 006. In the above diagram it was mentioned

The full chemical names as well as the abbreviated names of the different starting materials and intermediates. Subject

yy

A can easily be used using the J 1 intermediate procedures as well as the reaction materials used

Re and mo 2 yeah inadvertently dda wrote about it. Leg described 1 Scheme No. 1: Step No. p. © Lz OH > (4-Methoxy-3,5 - dimethyl-2 -pyridinyl) methyl ) pyrmethyl alcohol) +

SOCI2 ( or another suitable chlorinating agent) - continued o

JAN x HCI oFCl

N

(4-Methoxy-3.5 - dimethyl-2-pyridinyl) methyl chloride- 2 -pyridinyl chloride( pyrmethyl 110 chloride) yy

: a : for step 3 number 1 p. | TR x HCl 2 Cl

N

(4-Methoxy-3.5 - dimethyl-2-pyridinyl) methyl chloride- 2 -pyridinyl chloride( pyrmethyl chloride) . - + °

N On Return to mm A H . 2-Mercapto-5-methoxybenzimidazole ( Metmercazole) { N Ne x

IT

—N 5-Methoxy-2 ((( 4- methoxy 3.5 - dimethyl-2-pyridinyl)- methyl)- thio)- 1H- benzimidazole ( pyrmetazole) Va yy

M 1 to step 3 number: Q N Ne N II ' —N 5-Methoxy-2 ((( 4- methoxy 3.5 - dimethyl-2-pyridinyl)- methyl)- thio)- 1H- benzimidazole ( pyrmetazole) 0 + 0 : C1 m - Chloroperoxybenzoic acid continued - Q N Oe 0 \ 8 7 H e: N 5-Methoxy-2 (( ( 4- methoxy 3.5 - dimethyl-2-pyridinyl)- methyl)- sulfinyl)- 1H- Ce benzimidazole ( pyrmetazole) A

Z: “0 Scheme No. 1: The improved process advantages of the present invention will be described in the following paragraphs: One of the objectives of the present invention is to present a process for the manufacture of omeprazole using all three reaction steps previously described and which are performed without isolation or 0 feedstock purification; it is performed in a single master solvent system generalized in all successive steps.This CA Lee eliminates the time consuming steps of isolating and purifying intermediates or changing the modifier used in the process and this makes the process more efficient and results in an intensity High throughput.Another important benefit of such a process is that the circulation of toxic intermediates suspected of causing transduction (Jia pyrmethyl chloride) is eliminated; Another feature of the present invention is to provide a process that uses an environmentally friendly solvent system: in order to avoid the egress of harmful solvents.There is a general interest from the Ally interested group within and outside the pharmaceutical industry pertaining to the imperative for the industry to use and develop environmentally friendly processes.In some countries, the relevant authorities have established restrictions harmful chlorine-containing solvents into the air. to and surprisingly; The new process of the present invention yields omeprazole of Ale purity without any separation or purification of the intermediates. The omeprazole obtained in the purification step may optionally be further dalled ge 0 and/or optionally processed to obtain its pharmaceutically acceptable salts. yy

Z A - . A DAT objective of the present invention is to provide a process for selectively prophylactic step for omeprazole. Further, the sequence of the present invention starts from pyrmethyl alcohol through pyrmethyl chloride and pyrmetazole to obtain omeprazole. © and can be performed in a single master solvent system used throughout the entire reaction sequence. The solvent system is preferably inert to all reactants and suitable for all three steps of the process. In step 1, the pyrmethyl alcohol reacts with an ample amount of 0-thionyl chloride, i.e. pyrmethyl chloride. It is preferable to conduct the reaction at air temperature for approximately 71 minutes. The reaction can also be carried out at a temperature ranging from -# C to Yo C. The reaction is performed in a solvent system; It is used throughout the entire reaction sequence described in Scheme 1, i.e. from pyrmethyl alcohol to omeprazole Ve. Such a solvent system suitable for the present process includes a primary solvent and optionally one or more co-solvents. It is preferable that the main solvent is immiscible with water. Such as carbon tetrachloride, 01 7- trichloroethane 2, chlorofim, methylene chloride, or toluene. Toluene is preferred in particular from the point of view of preserving the environment. z yy

M: In addition, the solvent system may optionally include co-solvent(s) to further improve/enhance the solubility of the reactants or products during the entire reaction sequence. The solvent system will function without any addition of a co-solvent; but the addition of such a solvent The adsorbents will enhance the amplitude of the process i.e. the yield of the process per unit volume The preferred auxiliary solvents © are alcohols, especially small alcohols containing from 1 to 4 carbon atoms, where the carbon chain is branched or straight Examples of solvent systems contain, but are not limited to, 71 to 80 percent (by volume) of methylene chloride or Je toluene as small as ethanol (. by volume) from alcohol / 1 to 1 0 which is formed in step number pyrmethyl chloride pyrmethyl chloride oF in step number 0 metmercazole reacts metmercazole solution Jie under alkaline conditions metmercazole with metmercazole In the presence of an alkaline aqueous pyrmethyl chloride catalyst, it is prepared and mixed with pyrmethyl chloride.

Lil m01 to shift the phase. It may be preferable to carry out the reaction at a temperature of 0 to Z for an extended period of time. 10 Methmercazole is supplied in an amount approximately equivalent to pyrmethyl chloride. A chlorination catalyst such as a tertiary amine may be used; Tetrabutylammonium bromide is preferred. The two phases formed are separated; The aqueous phase may be extracted using the organic solvent other than | miscible with water; Such as methylene chloride or toluene. And furthermore any

“0 0 Moreover, an aqueous alcohol may be added to the pyrmetazole solution to improve the solubility of the intermediate, pyrmetazole. In step oF, m-chloroperoxybenzoic acid was dissolved In a water immiscible organic solvent, Jia methylene chloride or 0 toluene, JH. toluene, add m (aes - chloroperoxybenzoic 0e) to pyrmetazole which Obtained in a two-phase buffer system consisting of the water-immiscible solvent Jie methylene chloride or toluene 6 » and a methyl base such as sodium or potassium bicarbonate and the solvent may optionally be diluted organic alcohol with alcohol in order to enhance the solubility of =m aes m-chloroperoxybenzoic acid.It is preferable to perform oxidation using =m aes m-chloroperoxybenzoic acid at a temperature ranging from zero to Yo M. The product thus obtained is extracted to an alkaline aqueous phase; The product formed from the Sl phase is precipitated by lowering the pH of the solution to approximately 9 at ambient temperature. Omeprazole is isolated .alué omeprazole 0 and the total yield from the process is usually greater than #0 . Additional purification may be performed by crystallization from a single organic solvent or multiple organic solvents; Or by precipitation from alkaline water by lowering the pH by adding acid or alkyl formate: yy

on - Examples of manic acids include; But not limited to; Carboxylic acids such as formic acid, acetic acid, or saan citric acid ¢ and mineral acids JA « mineral acids hydrogen chloride or hydrogen bromide bromide or hydrogen fluoride © or hydrogen iodide or hydrogen iodide or sulfuric acid or nitric acid or phosphoric acid preferred acids are carboxylic acids and include Suitable alkyl formats. but not limited to; Methyl formate and ethyl formate The preferred alkyl formate is 0.methyl formate The present invention will be described in more detail in the following non-specific examples of the scope of the invention. Manufacture of omeprazole: Example No.: 1: 117.8 g (io mol) of thionyl chloride was added in VY ml of methylene chloride » to A solution of methylene chloride in which 1.8 0 g (10© mol) of pyrmethyl alcohol is dissolved at ambient temperature. The solution was stirred for approximately 0 minutes. Then he mixed YA g (AN mol) of metmercazole and £V,Y g (A) m mol) of aqueous sodium hydroxide (© 7 w/w) and tetrabutylammonium Tetrabutylammonium bromide (+ 9 g) at ambient temperature. Chloride solution was added: NHNH

11 - 50 m WYO was returned at a temperature ranging from pyrmethyl chloride to ? hour. The two phases were separated from each other, and the mixed phase 1 was washed for a period ranging from, and the organic phases were collected. methylene chloride aqueous with dissolved methylene chloride potassium bicarbonate mol) of potassium bicarbonate 0) 001.40 g .pyrmetazole in water was added to a solution of © g (1.04 mol) of « -chloropyroxybenzoic acid YYW added ml of methylene chloride £Y wt. | weight) dissolved in 7 Ye) m-chloroperoxybenzoic acid to the mixture that was prepared, which is 10% ethanol, methylene chloride and potassium bicarbonate, methylene chloride in pyrmetazole for methylene chloride. in water. The oxidation was carried out at a temperature ranging from zero to potassium bicarbonate | 0 alkali by adding pH m. The product was extracted to the aqueous phase at a pH No. The two phases were separated and the organic phase was washed using sodium hydroxide: an alkaline aqueous solution, and the aqueous phases were collected. The aqueous phase was added by adding ? ml methyl formate 5a omeprazole Omeprazole was precipitated and dried. done | hassoul methanol; It was filtered and washed with water [methyl formate Ve 0 1 16] with omeprazole products on omeprazole.

YY

1 - - M “Example No. ?: VY, g (+1 mol) of chloride (lionyl chloride) was added to dnt; to a solution of toluene 166 in which VY g (0 mol) of pyrmethyl alcohol is dissolved at ambient temperature. The reaction lasted approximately 0 © minutes. 0 The pyrmethyl chloride was mixed in the toluene formed with an alkaline aqueous solution containing VA g (0001 mol) of metmercazole. Jeli was performed in the presence of 0.5 g of eae tetrabutylammonium bromide 2 over 2 hours. The two phases were separated from each other and the aqueous phase was extracted using toluene. Ethanol was added to improve the solubility of the resulting product before the solution was cooled to 0 °C. 4,4 has been added? g (10, mol) of m-chloroperoxybenzoic acid dissolved in 57 ml toluene 0 1 ml ethanol to a two-phase system prepared from a solution of pyrmetazole in toluene toluene obtained and potassium bicarbonate (a> 0", 8) potassium bicarbonate in 1" (mL) water. 0 The oxidation was carried out at a temperature ranging from zero to room temperature. The Extraction of the product to an alkaline aqueous phase by adding sodium hydroxide The two phases were separated and the organic phase was washed with water Omeprazole was precipitated by reducing the pH of the solution to approximately 4 at ambient temperature The omeprazole was Omeprazole was washed and dried, the total yield was 77: approx.

Additional Remediation of Omeprazole: Cumulative Example: 0.00 g (.059979 mol) of omeprazole prepared according to example 1, 81 ml methanol and 0 ¢ ml water were mixed At da jo is the air temperature.

0 The product was dissolved at an alkaline pH by adding sodium hydroxide. The solution was filtered and cooled to almost zero degrees Celsius. The product was precipitated by adding dilute acetic acid, filtering, washing with water/cmethanol, and then dried. Omeprazole was obtained with a yield of qv 7

12 Example No. 0 for Example Ek that omeprazole was prepared from omeprazole (Joo vio 4) g 1111 g 1 ml methylene chloride and 4 7 ml methylene chloride methanol were mixed 0 1.19 ml methanol No. 08 ammonia at the atmosphere temperature and the solution was filtered and then obtained under reduced pressure. methylene chloride The product was deposited by evaporating methylene chloride and the slurry was cooled to zero celsius ammonia 1.3 ml ammonia added approx 1 vol/v/ 1 containing methanol product filtered and washed with 1 60 methanol by omeprazole; And it was dried. Omeprazole ammonia was obtained from ammonia and from an environmental point of view, the best way to implement one of the features of the present invention is according to the process described in Example No. ?.

Claims (1)

- \o — Claims: Process for manufacturing 1 - 1 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulphinyl}- 7 1H-be nzimidazole And, where it includes “(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl alcohol from 1: M: the following reaction steps C: 1: Step number >: Sun > 7 _z OH N : (4-Methoxy-3.5 - dimethyl-2-pyridinyl) methyl ( pyrmethyl alcohol) A | : ¥ q SOCI2 ( or another suitable chlorinating agent) - continued 0 4 a x HCL 11 Cz Cl N (4-Methoxy-3.5 - dimethyl-2-pyridinyl) methyl chloride- 2 -pyridinyl 1 chloride( pyrmethyl chloride) yy yy : step number Y¢ p | = x HCI re Cl Yo N (4-Methoxy-3.5 - dimethyl-2-pyridinyl) methyl chloride- 2 -pyridinyl a chloride( pyrmethyl chloride) VY + base a mm YA N H 2 - Mercapto - 5 - methoxybenzimidazole ( Metmercazole) 14 Q N A sd a and hy 7 0 11 —N © 5-Methoxy-2 ((( 4- methoxy 3,5 - dimethyl-2-pyridinyl)- methyl)- thio)- ¥ 1H- benzimidazole ( pyrmetazole) YY Step number?: yy 4 x SN ye N 11 —N yy 117 - | - 5-Methoxy-2 ((( 4- methoxy 3.5 - dimethyl-2-pyridinyl)- methyl)- thio)- Yo 1H- benzimidazole ( pyrmetazole) 7 PAL * 0 A > OH Cl m - Chloroperoxybenzoic acid Yq m continued - / Q N 0 0 > 1 L J \ 1 N H —N 5-Methoxy-2 ((( 4- methoxy 3.5 - dimethyl-2-pyridinyl)- methyl)- vy sulfinyl)- 1H- benzimidazole ( pyrmetazole ) vy ve where the reaction steps are performed in sequential order without isolating the intermediates Yo formed during the process; Whereas, a single principal solvent system is used that is generalized throughout each YO reaction sequence. 1 ?- The process of claim 0; wherein the solvent system comprises a Y|principal and optionally one or more co-solvents. yy A= : - 1 ©#- The process according to claim number oY where the main solvent is VY methylene chloride. 1;- The process according to Claim No. oY where the main solvent is toluene .toluene Y : 100 #- process according to claim of where the co-solvent is ¥ alcohol .alcohol : 1 +- process according to claim 1a where step 1 is performed at a temperature of -59 °C to Yo °C 1 #7- Process according to claim #1; where step is performed? using a YO phase-shifting catalyst. 1 +- Process according to of claim No. wherein the phase shift catalyst is Y tetrabutylammonium bromide: 1 +- the process according to claim No. 0) where step ? is performed at a temperature ranging from Y to Ta m YY -\a- ,-01 1 | |Process according to any of the foregoing claims where further purification of 5-methoxy-2-[[(4-methoxy-3,5 -dimethyl-2-pyridinyl)-methyl]sulphinyl]- Y 1H-be occurs nzimidazole ¥ 3 in the purification step. 1-11-1 The process according to claim No. Clem 01, where the purification step includes crystallization “from the single organic solvent used or multiple organic solvents. of alkaline water by reducing the pH to 11oC by adding ¥ acid or any alkyl formate. 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl}- vo 1H-be nzimidazole ¢ yy