KR100573705B1 - Method of preparing sulfide derivatives - Google Patents

Abstract

Provided are methods for preparing sulfide derivatives. In this manufacturing method, borohydride exchange resin, or ^{_{(R 11) 4 N + BH}} 4 - and by using the using the sulfide derivative simple manufacturing process can be produced in a high yield.

Sulfide, borohydride

Description

Method for producing a sulfide derivative {METHOD OF PREPARING SULFIDE DERIVATIVES}

The present invention relates to a process for the preparation of sulfide derivatives and, more particularly, to a process for the preparation of high yield sulfide derivatives.

Sulphide derivatives include omeprazole, lanprprazole, lansoprazole, pantoprazole, and labe, which have gastric acid secretion inhibition, gastric mucosa protection and antiulcer activity. Precursors of rabeprazole and reminoprazole.

Methods for preparing the sulfide derivatives are described in British Patent Nos. 1,525,958, 2,134,523 and 2,163,747, US Patents 4,255,431, 4,182,766, 4,472,409, 4,808,596 and 5,374,730, and Japanese Patent Publication Nos. 83-39,622 European Patent Nos. 166,287 and 268,956 and Korean Patent Publication Nos. 88-1714 and 92-2128.

The sulfide manufacturing method is classified into three types as follows.

1) Manufacturing Method Ⅰ

In Scheme 1, R ₁ is hydrogen; Linear or branched alkyl having 1 to 6 carbons; OR ₆ ; -O- (CH ₂ ) _m -OR ₇ ; And -NR ₈ R ₉ , m is an integer from 1 to 6, R ₆ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And straight or branched chain alkyl having 1 to 6 carbons substituted with 1 to 5 halogen atoms, R ₇ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And ordinary alcohol protecting groups, R ₈ and R ₉ are the same or different and each is hydrogen; And straight or branched chain alkyl having 1 to 6 carbons,

R ₂ and R ₃ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And OR ₆ ,

R ₄ and R ₅ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; -OR ₁₀ ; And -COOR _{6 It} is selected from the group consisting of, R ₁₀ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And a methyl group substituted with 1 to 3 halogen atoms.

The preparation method I has the disadvantage that the compound of formula 4 is unstable, the preparation method is very complicated, and the yield of the compound of formula 1 is very low.

2) Preparation II

In Scheme 2, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as defined above, and X is a common leaving group.

The preparation II is generally used, but has a relatively low yield (65 to 85%) and has a disadvantage in that a purification process must be performed to obtain a pure compound of formula (I).

3) Preparation III

In Scheme 3, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as defined above, M represents lithium, sodium and potassium, Y represents chlorine, bromine, iodine, methanesulfonyloxy and Paratoluenesulfonyloxy is represented and n is an integer of 0-1.

The preparation II has a disadvantage in that it is difficult to prepare a compound of formula 7 and the yield of the product is low.

It is an object of the present invention to provide a process for the preparation of high yields of sulfide derivatives.

Another object of the invention relates to a process for the preparation of sulfide derivatives using a simple preparation process.

In order to achieve the above object, the present invention provides a compound, a compound or its hydrochloride salt of formula (6) of formula (5), and the solvent from the borohydride exchange resin (borohydride exchange resin) and ^{_{(R 11) 4 N + BH}} 4 - ( where In which R ₁₁ is a straight or branched chain lower alkyl having 1 to 6 carbons), and a process for preparing a sulfide derivative of formula 1 comprising the step of reacting in the presence of a borohydride-based compound.

The present invention is a compound of formula (V), in a solvent of the compound or its hydrochloride salt of formula (10), borohydride exchange resin, and ^{_{(R 11) 4 N + BH}} 4 - ( where R ₁₁ is from 1 to 6 carbon It provides a process for producing a sulfide derivative of formula (2) comprising the step of reacting in the presence of a borohydride-based compound selected from the group consisting of linear or branched lower alkyl having a.

Wherein R ₁ is hydrogen; linear or branched alkyl having 1 to 6 carbons; OR ₆ ; —O— (CH ₂ ) _m —OR ₇ ; and —NR ₈ R ₉ M is an integer of 1 to 6, R ₆ is hydrogen; straight or branched chain alkyl having 1 to 6 carbons; and straight chain having 1 to 6 carbons substituted with 1 to 5 halogen atoms, or Is selected from the group consisting of branched alkyl, R ₇ is hydrogen; straight or branched chain alkyl having from 1 to 6 carbons; and common alcohol protecting groups, and R ₈ and R ₉ are the same or different, respectively Hydrogen and straight or branched chain alkyl having 1 to 6 carbons,

R ₂ and R ₃ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And OR ₆ ,

R ₄ and R ₅ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; -OR ₁₀ ; And -COOR _{6 It} is selected from the group consisting of, R ₁₀ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And it is selected from the group consisting of methyl group substituted with 1 to 3 halogen atoms,

X represents a normal leaving group.)

The present invention provides a process for preparing sulfide derivatives in the presence of borohydride-based compounds.

In this method, compound and, borohydride exchange resin, or ^{_{(R 11) 4 N + BH}} 4 of the compound or its hydrochloride salt of formula (VI) in a suitable solvent of the general formula (V) ^from (here, R ₁₁ is one to six linear Or branched chain lower alkyl, for example tetrabutylammonium borohydride).

Alternatively, the sulfide derivative of Formula 2 may be prepared using the compound of Formula 10 instead of the compound of Formula 6.

[Formula 1]

[Formula 2]

[Formula 5]

[Formula 6]

[Formula 10]

In the above formula, R ₁ is hydrogen; Linear or branched alkyl having 1 to 6 carbons; OR ₆ ; -O- (CH ₂ ) _m -OR ₇ ; And -NR ₈ R ₉ , m is an integer from 1 to 6, R ₆ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And straight or branched chain alkyl having 1 to 6 carbons substituted with 1 to 5 halogen atoms, for example 2,2,2-trifluoroethyl, wherein R ₇ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And conventional alcohol protecting groups such as trialkylsilyl, benzyl, methoxyethyl, acetyl and benzyloxycarbonyl, R ₈ and R ₉ are the same or different and each is hydrogen; And straight or branched chain alkyl having 1 to 6 carbons,

R ₂ and R ₃ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And OR ₆ ,

R ₄ and R ₅ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; -OR ₁₀ ; And -COOR _{6 It} is selected from the group consisting of, R ₁₀ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And it is selected from the group consisting of methyl group substituted with 1 to 3 halogen atoms,

X represents common leaving groups such as halogen, for example bromine, chlorine, iodine, lower alkylsulfonyloxy and arylsulfonyloxy.

By using borohydride-based compounds, pure sulfide derivatives can be prepared without further purification. In particular, when the borohydride exchange resin is used as the borohydride-based compound, a very pure compound is produced. In addition, the use of borohydride exchange resins is preferred because it can greatly increase the yield of the product.

The borohydride exchange resin is prepared by reacting an amberite IRA 400-X type resin with sodium borohydride (NaBH ₄ ) in an aqueous solution according to a conventional method (J. Chem. Soc. Chem. Comm. 1997, 915, US Pat. No. 4,107,099). For the production of borohydride exchange resins, the Ambition IRA 400-X type resin, the Ambition IRA 416-X type resin, the Ambition IRA 420-X type resin, the Ambition IRA 900-X type resin, and the Amberberry IRA 904-X type resin, Amberlyte IRA 910-X type resin, Amberlyte CG 400-X type resin, Amberlyte CG400-II-X type resin, Amberlyte IRA 743-X type resin, Amber Amberlyst A-26-X type resins and Amberlyst A-27-X type resins may be used. At this time, X is Cl ^- is selected from the group consisting of acetate and SCN ^{-, Br -, F -,} I -, CN -, HO -, NO 2 -, NaCO 3 -,.

The solvent comprises a straight or branched chain lower alcohol having 1 to 6 carbons, and methanol is preferably used as the solvent. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent.

In the present invention, the yields of the formulas (1) and (2) are very high and there is no need to carry out separate processes such as extraction and purification after the reaction is completed. In addition, after the reaction is completed, the used resin can be washed with dilute hydrochloric acid and used again, thereby lowering the production cost.

Molecular structure is measured by infrared spectrometry, ultraviolet-visible spectrometry, nuclear resonance spectrometry or mass spectrometry to compare elemental analysis and actual measurements Confirmed.

The following examples illustrate the invention in more detail, but the invention is not limited thereto.                 

(Example 1)

Preparation of 5-methoxy-2- [3,5-dimethyl-4-methoxy-2-pyridyl] methylthio-1H-benzimidazole

3,5-dimethyl and borohydride exchange resin (BER) made from 5-methoxy-2-mercaptobenzimidazole (20.28 g, 112.56 mmol), IRA400-Cl ^- type resin (46.58 g, 135.07 mmol) 4-methoxypyridyl-2-methylchloride (20.86 g, 112,56 mmol) was added to methanol (550 ml) and reflux-stirred for 1 hour. In this process, instead of 3,5-dimethyl-4-methoxypyridyl-2-methylchloride, its hydrochloride salt may be used.

The obtained product was cooled to room temperature and filtered to remove the resin. The filtrate was concentrated in vacuo. The concentrated product was dissolved in acetone (50 ml) and crystallized by slowly adding petroleum ether (350 ml). The crystals were filtered to give white crystals (35.61 g, yield: 96%).

mp: 118-120 degreeC

NMR (CDCl ₃ , δ)

: 2.26 (s, 2H), 2.30 (s, 3H), 23.76 (s, 3H), 3.82 (s, 3H), 4.32 (s, 2H),

5.77-6.82 (m, 1H), 6.89-7.07 (m, 1H), 7.29-7.45 (m, 1H), 8.24 (s, 1H)

Elemental analysis

Calculated (%): C; 61.99, H; 5.81, N; 12.76, S; 9.73

Found (%): C; 61.91, H; 5.72, N; 12.85. S; 9.53                 

(Examples 2 to 11)

Preparation of 5-methoxy-2- [3,5-dimethyl-4-methoxy-2-pyridyl] methylthio-1H-benzimidazole

A sulfide derivative was prepared in the same manner as in Example 1 except that the resin type was changed as shown in Table 1 in the borohydride exchange resin (BER). The reaction temperature, time and yield are shown in Table 1.

(Example 12)

A sulfide derivative was prepared in the same manner as in Example 1 except that (n-Bu) ₄ N ⁺ Cl ^- was used. The reaction temperature, time and yield are shown in Table 1.

Borohydride-based compounds Reaction temperature [℃] Reaction time [h] yield[%] Example 2 Amberlyst A-27-Cl ^- Room temperature One 95 Example 3 Discard cancer agent CG-400-Cl ^- reflux One 92 Example 4 Discard cancer agent CG-400II-Cl ^- reflux One 96 Example 5 Cancer discard bit IRA-416-Cl ^- reflux One 95 Example 6 Cancer discard bit IRA-420-Cl ^- reflux One 93 Example 7 Cancer discard bit IRA-900-Cl ^- reflux One 95 Example 8 Cancer discard bit IRA-904-Cl ^- reflux One 93 Example 9 Cancer discard bit IRA-910-Cl ^- reflux One 94 Example 10 Cancer discard bit IRA-743-Cl ^- reflux One - Example 11 Amberlyst A-26-Cl ^- reflux One 95 Example 12 ^{_{(n-Bu) 4 N +}} Cl - reflux One 69

Example 13

Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyltyro-1H-benzimidazole                 

2-mercaptobenzimidazole (3.42 g, 22.76 mmol), BER (15.75 g, 45.52 mmol) made from IRA 400-Cl ^- type resin, 3-methyl-4- (2,2,2-trifluoro Ethoxy) pyridyl-2-methylchloride (6.0 g, 25.04 mmol) was added to methanol (200 ml) and reflux-stirred for 50 minutes. In this process, hydrochlorides thereof can be used in place of 3-methyl-4- (2,2,2-trifluoroethoxy) pyridyl-2-methylchloride.

The obtained product was cooled to room temperature, filtered to remove the resin, and concentrated in vacuo. The concentrated product was crystallized using ethyl acetate and n-hexane and filtered to give a white product (7.8 g, yield: 97%).

mp: 148-150 degreeC

NMR (δ, CDCl ₃ ): 2.31 (s, 3H), 4.36 to 4.47 (q, 2H), 4.40 (s, 2H),

6.71-6.73 (d, 1H), 7.14-7.19 (m, 2H),

7.42 to 7.53 (b, 2H), 8.39 to 8.42 (d, 1H)

(Examples 14 to 23)

Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-vanzimidazole

A sulfide derivative was prepared in the same manner as in Example 13 except that the resin type in BER was changed as shown in Table 2.

(Example 24)                 

A sulfide derivative was prepared in the same manner as in Example 13 except that (n-Bu) ₄ N ⁺ Cl ^- was used.

Borohydride-based compounds Reaction temperature Reaction time [h] yield[%] Example 14 Cancer discard bit IRA-416-Cl ^- reflux One 93 Example 15 Cancer discard bit IRA-420-Cl ^- reflux One 94 Example 16 Cancer discard bit IRA-900-Cl ^- reflux One 96 Example 17 Cancer discard bit IRA-904-Cl ^- reflux One 95 Example 18 Cancer discard bit IRA-910-Cl ^- reflux One 95 Example 19 Cancer discard bit IRA-743-Cl ^- reflux One - Example 20 Discard cancer agent CG-400-Cl ^- reflux One 90 Example 21 Discard cancer agent CG-400-II-Cl ^- reflux One 95 Example 22 Amberlyst A-26-Cl ^- reflux One 92 Example 23 Amberlyst A-27-Cl ^- reflux One 93 Example 24 ^{_{(n-Bu) 4 N +}} Cl - reflux One 60

(Example 25)

Preparation of 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole

The product was prepared in the same manner as in Example 1 except that 5- (difluoromethoxy) 2-mercaptobenzimidazole and 3,4-dimethoxypyridyl-2-methylchloride were used. In this example, instead of 3,4-dimethoxypyridyl-2-methylchloride, its hydrochloride may be used.                 

mp: 117-119 deg.

NMR (CDCl ₃ , δ): 3.92 (s, 3H), 3.94 (s, 3H), 4.40 (s, 2H), 6.51 (t, 1H),

6.86 (d, 1H J = 5.7 Hz), 6.98 (dd, 1H), 7.32 (d, 1H),

7.63 (d, 1 H), 8.26 (d, 1 H), 12.5 (br, 1 H)

(Example 26)

Preparation of 2- [4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methylthio-1H-benzimidazole

The product was prepared in the same manner as in Example 1 except that 4- (3-methoxypropoxy) -3-methylpyridyl-2-methylchloride and 2-mercaptobenzimidazole were used. In this example, hydrochlorides thereof can be used in place of 4- (3-methoxypropoxy) -3-methylpyridyl-2-methylchloride.

NMR (CDCl3, δ): 2.09 (t, 2H), 2.26 (s, 3H), 3.35 (s, 3H), 3.56 (t, 2H),

4.13 (t, 2H), 4.37 (s, 2H), 6.76 (d, J = 6.1 Hz, 1H),

7.1 to 7.25 (m, 2H), 7.5 (br, s, 2H),

8.33 (d, J = 6.1 Hz, 1H)

(Example 27)

Preparation of 2- [4- (3-hydroxypropoxy) -3-methyl-2-pyridyl] methylthio-1H-benzimidazole

The product was prepared in the same manner as in Example 1 except that 4- (3-hydroxypropoxy) -3-methylpyridyl-2-methylchloride and 2-mertoptobenzimidazole were used. In this example, hydrochloride may be used instead of 4- (3-hydroxypropoxy) -3-methylpyridyl-2-methylchloride.

NMR (CDCl ₃ , δ): 1.8 to 2.1 (m, 2H), 2.24 (s, 3H), 3.6 (t,, 2H),

4.2 (t, 2H), 4.7 (s, 2H), 7.0 to 7.38 (m, 3H),

7.38 to 7.6 (m, 2H), 8.35 (d, J = 6.1 Hz, 1H)

(Example 28)

Preparation of 2- [2- (N-isobutyl-N-methylamino) benzyl] thio-1H-benzimidazole

A product was prepared in the same manner as in Example 1 except for using 2- (N-isobutyl-N-methylamino) benzylchloride and 2-mercaptobenzimidazole. In this example, instead of 2- (N-isobutyl-N-methylamino) benzylchloride, its hydrochloride may be used.

NMR (CDCl ₃ , δ): 0.6 to 2.0 (m, 7H), 2.7 to 3.1 (m, 2H), 2.88 (s, 3H),

4.42 (s, 2H), 6.8-7.7 (m, 8H)

As described above, the present invention can produce sulfide derivatives in high yield, and the production method is very simple.

While the invention has been described in detail with reference to preferred embodiments, those skilled in the art can make various modifications and substitutions without departing from the spirit and scope of the invention as set forth in the appended claims.

Claims (13)

The compound of formula (5), and the compound of formula (6) or a hydrochloride salt thereof are selected from (R ₁₁ ) ₄ N ⁺ BH ₄ ^- under a solvent selected from the group consisting of straight or branched chain lower alcohols having 1 to 6 carbons. Reacting in the presence of a borohydride-based compound selected from the group consisting of R ₁₁ is straight or branched chain lower alkyl having 1 to 6 carbons A method for producing a sulfide derivative of formula (I) comprising the step. [Formula 1]

[Formula 5]

[Formula 6]

In the above formula, R ₁ is hydrogen; Linear or branched alkyl having 1 to 6 carbons; OR ₆ ; -O- (CH ₂ ) _m -OR ₇ ; And -NR ₈ R ₉ , m is an integer from 1 to 6, R ₆ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And straight or branched chain alkyl having 1 to 6 carbons substituted with 1 to 5 halogen atoms, R ₇ is hydrogen; And straight or branched chain alkyl having 1 to 6 carbons, R ₈ and R ₉ are the same or different and each is hydrogen; And straight or branched chain alkyl having 1 to 6 carbons, R ₂ and R ₃ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And OR ₆ , R ₄ and R ₅ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And -OR _{10 It} is selected from the group consisting of, R ₁₀ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And it is selected from the group consisting of methyl group substituted with 1 to 3 halogen atoms, X represents a leaving group selected from the group consisting of halogen atoms. The method of claim 1, wherein the borohydride exchange resin is prepared by reacting a resin with sodium borohydride (NaBH ₄ ), the resin is Ambition IRA 400-X type, Ambbert IRA 416-X type, AMBERT IRA 420-X, AMB divert IRA 900-X, AMB divert IRA 904-X, AMB divert IRA 910-X, AMB divert CG 400-X, AMB divert CG400- II- X-type, rock discard bit IRA 743-X type, and selected from the Amberlyst a-26-X-type and the group consisting of Amberlyst a-27-X-type, X is Cl ^-, Br ^-, F ^-, I ^{-, CN -, HO -,} NO 2 -, NaCO 3 -, - method of is selected from the group consisting of SCN and acetate. The process of claim 1, wherein the solvent comprises a straight or branched chain lower alcohol having 1 to 6 carbons. The method of claim 1, wherein the reaction step is carried out at room temperature to the reflux temperature of the solvent. The borohydride exchange resin and (R ₁₁ ) ₄ N ⁺ BH ₄ under the solvent selected from the group consisting of a compound of the formula (5) and a compound of the formula (10), or a hydrochloride salt thereof, of a straight or branched chain lower alcohol having 1 to 6 carbons ^- reacting in the presence of a series compound borohydride is selected from the group consisting of (wherein R ₁₁ is is 1 to 6 carbon straight or branched chain lower alkyl having) Method for producing a sulfide derivative of formula (2) comprising the step. [Formula 1]

[Formula 2]

[Formula 5]

[Formula 6]

[Formula 10]

In the above formula, R ₁ is hydrogen; Linear or branched alkyl having 1 to 6 carbons; OR ₆ ; -O- (CH ₂ ) _m -OR ₇ ; And -NR ₈ R ₉ , m is an integer from 1 to 6, R ₆ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And straight or branched chain alkyl having 1 to 6 carbons substituted with 1 to 5 halogen atoms, R ₇ is hydrogen; And straight or branched chain alkyl having 1 to 6 carbons, R ₈ and R ₉ are the same or different and each is hydrogen; And straight or branched chain alkyl having 1 to 6 carbons, R ₂ and R ₃ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And OR ₆ , R ₄ and R ₅ are the same or different and each is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And -OR _{10 It} is selected from the group consisting of, R ₁₀ is hydrogen; Straight or branched chain alkyl having 1 to 6 carbons; And it is selected from the group consisting of methyl group substituted with 1 to 3 halogen atoms, X represents a leaving group selected from the group consisting of halogen atoms. The method of claim 5, wherein the borohydride exchange resin is prepared by reacting a resin with sodium borohydride (NaBH ₄ ), the resin is Ambolite IRA 400-X type, Ambbert IRA-416-X type , Amberlyte IRA 420-X, Amberlyte IRA 900-X, Amberlyte IRA 904-X, Amberlyte 910-X, Amberlyte CG 400-X, Amberlyte CG 400 -II X-type, rock discard bit IRA 743-X type, and selected from the Amberlyst a-26-X-type and the group consisting of Amberlyst a-27-X-type, X is X is Cl ^-, Br ^-, F ^{-, I -, CN -,} HO -, NO 2 -, NaCO 3 -, - method of is selected from the group consisting of SCN and acetate. 6. A process according to claim 5 wherein the solvent comprises a straight or branched chain lower alcohol having 1 to 6 carbons. The method of claim 5, wherein the reaction step is carried out at room temperature to the reflux temperature of the solvent. Reacting 5-methoxy-2-mertoptobenzimidazole with 3,5-dimethyl-4-methoxypyridine-2-methylchloride or a hydrochloride thereof in the presence of a borohydride exchange resin A process for producing 5-methoxy-2- [3,5-dimethyl-4-methoxy-2-pyridyl] methylthio-1H-benzimidazole comprising a step. Reacting 2-mercaptobenzimidazole with 3-methyl-4- (2,2,2-trifluoroethoxy) pyridyl-2-methylchloride or a hydrochloride thereof in the presence of a borohydride exchange resin A process for producing 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole comprising the step.  Reacting 2-mercaptobenzimidazole with 4- (3-methoxypropoxy) -3-methylpyridyl-2-methylchloride or its hydrochloride in the presence of a borohydride exchange resin A process for producing 2- [4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methylthio-1H-benzimidazole comprising a step.  Reacting 2-mercaptobenzimidazole with 4- (3-hydroxypropoxy) -3-methylpyridyl-2-methylchloride or a hydrochloride thereof in the presence of borohydride exchange resin A process for producing 2- [4- (3-hydroxypropoxy) -3-methyl-2-pyridyl] methylthio-1H-benzimidazole comprising a step. Reacting 2-mercaptobenzimidazole with 2- (N-isobutyl-N-methylamino) benzylchloride or its hydrochloride in the presence of a borohydride exchange resin A process for producing 2- [2- (N-isobutyl-N-methylamino) benzyl] thio-1H-benzimidazole comprising the process.