JPH1171371A - Production of pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely obtain a sulfoxide compound useful as a medicine in a high yield without by-producing a sulfone compound and without using a halogenated hydrocarbon solvent by oxidizing a thioether compound with a specific compound in the presence of a base. SOLUTION: A thioether compound of formula I (R<1> is H, methoxy or the like; R<2> is methyl, methoxy; R<3> is 3-methoxypropoxy, methoxy or the like; R<4> is H, methyl) is oxidized with an N-halosuccinic acid, 1,3-dihalo-5,5- dimethylhydantoin or a dichloroisocyanuric acid salt in the presence of a base (preferably an inorganic base such as sodium hydroxide) to produce the objective compound of formula II. The N-halosuccinic acid imide is preferably N-chloro or N-bromosuccinic acid imide. The N-halosuccinic acid imide is preferably used in an amount of 0.9-1.5 equivalents based on the compound of formula I. The reaction is preferably carried out in the presence of water in a solvent selected from acetonitrile, toluene and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to Japanese Patent Application Laid-Open No. 1-6270.
(Example 32), JP-A-61-50978 (Example 2), JP-A-5
No. 4-141783 (Example 21) or described in JP-A-61-22079, etc., a high yield of sulfoxides useful as pharmaceuticals or intermediates in the production of drugs such as gastric acid secretion inhibitors and anti-ulcer agents. It relates to a production method with high efficiency, high purity and high safety.

[0002]

2. Description of the Related Art Conventional sulfoxides are disclosed in
(EP-268956, US-5045552), JP-A-61-50978 (EP-17
4726, US-4628098), JP-A-54-141783 (EP-5129, US
-4255431), JP-A-61-22079 (EP-166287, US-47585)
79), thioether is converted to hydrogen peroxide, m-chloroperbenzoic acid, sodium dichlorite,
It has been produced by oxidation with an oxidizing agent such as sodium bromite. (See the following reaction formula, wherein R ^{1 to} R ⁴ have the same meaning as described above.)

[0003]

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Among the above-mentioned oxidizing agents, m-chloroperbenzoic acid is frequently used from the viewpoints of easy weighing, storage stability, reaction activity and the like.

[0005]

[Problems to be solved by the present invention] For example, JP-A-1-62
In Example 32 of Publication No. 70, the thioether is oxidized using 0.96 equivalents (purity conversion) of m-chloroperbenzoic acid, but the yield of sulfoxide is 80%, which is sufficient for industrial production. It was not a rate. Further, depending on the reaction conditions, there is also a problem that the reaction does not stop at the sulfoxide, and a side reaction occurs in which a part of the generated sulfoxide is further oxidized to sulfone as shown in the following reaction formula. In addition, when sulfone is formed, not only the problem that the yield of the target sulfoxide decreases, but also the problem that separation and purification are difficult because the physicochemical properties of the two are extremely similar. (In the formula, R ^{1 to} R ⁴ have the same meaning as described above.)

[0006]

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In Japanese Patent Application Laid-Open No. 1-6270, etc., the oxidation reaction is carried out in dichloromethane (methylene chloride), but there is a problem that halogenated hydrocarbon solvents cannot be used industrially due to environmental measures. . In addition, m-chloroperbenzoic acid is expensive and extremely disadvantageous in production cost. further,
m-Chloroperbenzoic acid is also designated as a dangerous substance, and requires extra care in use and storage, and has a problem that it is difficult to handle in large quantities.

Thus, industrially superior sulfoxides
At present, the production method of (II) has not been established yet, and a new excellent method for producing sulfoxide (II) has been demanded.

[0009]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
By the following method, it was found that the desired sulfoxide (II) can be produced in high yield, without forming a sulfone, and safely, and without using a halogenated hydrocarbon solvent. Reached.

Hereinafter, the present invention will be described in detail. First,
The thioether (I) according to the present invention is represented by the following general formula.

[0011]

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(Wherein R ¹ is a hydrogen atom, a methoxy group or a difluoromethoxy group, R ² is a methyl group or a methoxy group, R ³ is a 3-methoxypropoxy group, a methoxy group or a 2,2
R ² represents a hydrogen atom or a methyl group, and R ² represents a 2,2-trifluoroethoxy group. This compound is more specifically described in 2-([4- (3-methoxypropoxy)-) described in JP-A-1-6270 (Example 31).
3-methylpyridin-2-yl] methylthio} -1H-benzimidazole, a compound described in JP-A-61-50978 (Example 1) (R ¹ = H, R ² = CH ₃ , R ³ = H, R ⁴ = CH ₂ CF ₃ , n = 0, chemical name; 2-{[4-
(2,2,2-trifluoroethoxy) -3-methylpyridin-2-yl] methylthio} -1H-benzimidazole, JP-A-54-14
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio] -1H-benzimidazole which is a precursor of the compound described in No. 1783 (Example 21) or JP-A-61-61 -22079
And the same compound as 5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl) methylthio] -1H-benzimidazole which is a precursor of the compound described in is there. Any of the compounds can be produced by the methods described in the respective publications.

Next, the sulfoxide (II) according to the present invention is represented by the following general formula.

[0014]

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(Where R¹~ R^FourHas the same meaning as above
You. This compound is more specifically described in JP-A No. 1-6270 (
2-{[4- (3-methoxypropoxy)-described in Example 32)
3-methylpyridin-2-yl] methylsulfinyl} -1H-be
Nsimidazole: Generic name: Rabeprazole educt (Rab
eprazole free base), JP-A-61-50978 (Example 2)
Described compound (R¹= H, R^Two= CH_Three, R^Three= H, R^Four= CH_TwoCF _Three, N = 1): General
Name; Lansoprazole: Chemical name; 2-{[4-
(2,2,2-trifluoroethoxy) -3-methylpyridine-2-i
[Methylsulfinyl] -1H-benzimidazole, JP
5-methoxy-2-[(4-) described in JP-A-54-141783 (Example 21)
(Methoxy-3,5-dimethyl-2-pyridyl) methylsulfini
Ru] -1H-benzimidazole: Generic name: omeprazole
(Omeprazole), or 5-diene described in JP-A-61-22079.
Fluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl) meth
Tylsulfinyl] -1H-benzimidazole: Generic name;
It is the same compound as Pantoprazole etc.
Thus, it is an object compound of the present invention.

More specifically, examples of the sulfoxide (II) include the following compounds.

[0017]

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Next, the production method of the present invention will be described in detail. The present invention specifically relates to a method of converting a thioether (I) into an N-halosuccinimide, 1,3-dihalo-5,5-
A process for producing sulfoxide (II), which comprises oxidizing with dimethylhydantoin or dichloroisocyanurate.

The type of the oxidizing agent N-halosuccinimide used here is not limited, but is usually N-chlorosuccinimide [NCS, CAS registration No.:128-09-6] or N-chlorosuccinimide. Bromosuccinimide [NBS, CAS Registry No.:128-08-5] is preferred. N-halosuccinimides are generally commercially available as reagents, industrial raw materials, and the like.

The amount of the N-halosuccinimide to be used is not limited, but usually 0.8 to 1.7 equivalents, more preferably 0.85 to 1.6 equivalents, and still more preferably 0.9 to 1.5 equivalents to thioether (I). .

Next, the type of 1,3-dihalo-5,5-dimethylhydantoin is not limited.
5,5-Dimethylhydantoin [CAS registration No .: 118-52-5] or 1,3-dibromo-5,5-dimethylhydantoin [CAS registration N
o.:77-48-5]. In addition, 1,3-dihalo-5,5-dimethylhydantoin is also generally commercially available as a reagent or industrial raw material.

The amount of 1,3-dihalo-5,5-dimethylhydantoin to be used is not limited, but is usually 0.3 to 1.0 equivalent, more preferably 0.35 to 0.9 equivalent, and still more preferably 0.3 to 1.0 equivalent to thioether (I). Use 0.4-0.8 equivalents.

The type of the dichloroisocyanurate according to the present invention is not limited, but is usually sodium dichloroisocyanurate (CA).
S registration No.:2893-78-9] or potassium dichloroisocyanurate [Potassium Dichloroisocyanurate, CAS registration No .:
2244-21-5] is preferred. Note that dichloroisocyanurate is also generally commercially available as a reagent, industrial raw material, or the like.

Although the amount of the dichloroisocyanurate used is not limited, it is usually 0.3 to 1.0 with respect to the thioether (I).
The equivalent is used, more preferably 0.35 to 0.9 equivalent, even more preferably 0.4 to 0.8 equivalent.

Next, in the present invention, the reaction is carried out in the presence of a base. Here, the base in the present invention is not limited as long as it is inert to thioether (I), sulfoxide (II) or an oxidizing agent.In general, an inorganic base is preferable, and more specifically, for example, water Sodium oxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, sodium formate, potassium formate, sodium acetate, potassium acetate, etc. And a mixture of two or more kinds. Although the amount of the base used is not limited, it is usually 0.8 to 4.0 with respect to N-halosuccinimide.
The equivalent is used, more preferably 0.85 to 3.5 equivalents, even more preferably 0.9 to 3.0 equivalents. Also, for 1,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate, usually 0.4 to 2.0 equivalents, more preferably 0.4 to 2.0 equivalents.
1.71.75 eq, more preferably 0.4-1.5 eq.

In this reaction, a solvent is used. The solvent is not limited as long as it is inert to thioether (I), sulfoxide (II), an oxidizing agent or a base, and it may be used alone or as a mixture. But usually N, N-dimethylformamide,
The use of one or more of acetonitrile, toluene, tetrahydrofuran, lower fatty acid esters or water gives favorable results. The solvent may be a mixture.

More preferably, the use of one or more solvents selected from N, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran or lower fatty acid esters in the presence of water as the solvent is more preferable. give. Here, the amount of water used is not limited,
Usually, 0.1 to 50 ml, more preferably 0.25 to 20 ml, even more preferably 0.5 to 10 m, per 1 g of thioether (I).
Use l.

The lower fatty acid ester according to the present invention is not limited as long as it is formed by dehydrating lower fatty acids having 6 or less carbon atoms and lower alcohols having 6 or less carbon atoms. For example, methyl formate, ethyl formate, propyl formate, butyl formate, amyl formate, methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate,
N-butyl acetate, i-butyl acetate, t-butyl acetate, n-amyl acetate, i-amyl acetate, sec-amyl acetate, t-amyl acetate,
N-butyl propionate, ethyl butyrate, i-propyl butyrate,
Methyl isobutyrate, ethyl isobutyrate, methyl valerate, ethyl isovalerate, ethyl pivalate and the like,
Ethyl acetate is more preferred.

In the case of a mixed solvent, the mixing ratio is not limited, and the mixing can be carried out at an arbitrary ratio. The amount of the solvent used is not limited, but is usually thioether (I)
1 to 100 ml, more preferably 5 to 50 ml, even more preferably 10 to 30 ml per 1 g is used.

Although the reaction temperature is not limited, it is usually -50 ° C.
To room temperature, more preferably at -30 ° C to 20 ° C, even more preferably at -20 ° C to 10 ° C.

Next, the order of adding each reagent (raw material) in the present reaction is not limited, but a better result can be obtained, for example, by carrying out in the following order. (1) A base is added to a solution or suspension of thioether (I), and N-halosuccinimide is added thereto at low temperature and stirred. (2) In a solution of N-halosuccinimide, a solution of thioether (I) and a base is added at low temperature and stirred. (3) A base solution is dropped into a solution of thioether (I) and N-halosuccinimide and stirred. (4) A base is added to the solution or suspension of thioether (I), and 1,3-dihalo-5,5-dimethylhydantoin is added thereto at low temperature and stirred. (5) A solution of thioether (I) and a base is added to a solution of 1,3-dihalo-5,5-dimethylhydantoin at a low temperature and stirred. (6) A solution of a base is dropped into a solution of thioether (I) and 1,3-dihalo-5,5-dimethylhydantoin and stirred. (7) A base is added to the solution or suspension of thioether (I), and dichloroisocyanurate is added thereto at low temperature and stirred. (8) A solution of thioether (I) and a base is added to the solution of dichloroisocyanurate at a low temperature and stirred. (9) A solution of a base is dropped into a solution of thioether (I) and dichloroisocyanurate and stirred. In carrying out the above (1) to (9), even better results can be obtained by monitoring that the pH of the reaction solution is always basic, more preferably pH ≧ 12.

The reaction time depends on the type and amount of the oxidizing agent,
The reaction is usually completed in about 30 minutes to 6 hours, depending on the amount of the solvent used or the reaction temperature.

The treatment after the completion of the reaction is not limited. For example, a reducing agent such as sodium hydrosulfite, sodium sulfite, sodium thiosulfate or the like is added to decompose excess reagents. If necessary, the pH of the aqueous phase is adjusted. , And concentrated under reduced pressure, or the precipitated crystals are collected by filtration. The obtained sulfoxide (II) can be purified by a conventional method such as crystallization, recrystallization, and column chromatography. If necessary, the salt can be converted into a salt according to a known method.

Incidentally, Japanese Patent Application Laid-Open No. 54-141783 (EP-5129, US
-4255431) include nitric acid, hydrogen peroxide, peracid, perester, ozone, nitrogen tetroxide, iodosobenzene, 1-chlorobenzotriazole, and tertiary oxidants that can be used to oxidize thioether to sulfoxide. Butyl hypochloride, diazobicyclo [2,2,2] octane complex with bromine, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerica ammonium nitrate, bromine, chlorine and sulfuryl chloride, Halosuccinimide has been described. However, specifically disclosed in the examples of the publication is peracid m-
It is only chloroperbenzoic acid, and anywhere in the full specification,
Among the vast oxidizing agents described above, there is no description that only N-halosuccinimide is specifically superior, or no description that analogizes it. Furthermore, there is no description that the presence of a base is essential or that a combination is preferred. Therefore, the description of the oxidizing agent in this publication merely lists examples of general oxidizing agents and does not affect the novelty of the present invention.

Next, JOC, 33 (10), 3976-7, 1968.
-Sulfides (thioethers) with halosuccinimides
Reactions relating to the oxidation of are described. However, the sulfides specifically disclosed in this document include dimethyl sulfide, diethyl sulfide, di-n-propyl sulfide,
There are only a total of six compounds of dibenzyl sulfide, benzyl phenyl sulfide and diphenyl sulfide, and the structure is completely different from the thioether (I) according to the present invention.

Next, the present invention will be described in more detail with reference to the following examples. However, it goes without saying that the present invention is not limited to these examples.

[0037]

【Example】

Examples 1 to 9; oxidation with N-halosuccinimide Examples 10 to 13; oxidation with 1,3-dihalo-5,5-dimethylhydantoin Example 14; oxidation with dichloroisocyanurate

HPLC analysis conditions 固定 Stationary phase: NUCLEOSIL ₅ C ₁₈ (4.6 mm ID × 150 mm, 5 μm) Mobile phase : MeOH / 0.05M-phosphate buffer (pH7) = 3: 2 Flow rate: 1.0ml / min Temperature; 25 ℃ Detector: UV 290nm ────────────────── ──────

Example 1 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
Synthesis of Nsimidazole (Rabeprazole free base)

[0040]

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2-{[4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methylthio} -1H-benzimidazole
5.0 g (14.6 mmol) of (Compound 1) was dissolved in 20 ml of N, N-dimethylformamide, and 18 ml of a 2N aqueous solution of sodium hydroxide was added thereto. To this solution was added dropwise a solution of N-chlorosuccinimide (2.71 g, 20.3 mmol) / N, N-dimethylformamide (10 ml) at -20 to -10 ° C. The reaction mixture is -15 to -7
Reaction was performed at 1.5 ° C. for 1.5 hours. 5 ml of a 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 2 minutes, and then a solution of ammonium acetate (23.1 g) / water (60 ml) was added. Ethyl acetate
60 ml and 10 g of common salt were added for extraction, and the aqueous layer was further extracted with 40 ml of ethyl acetate. Combine the organic layers and add 15% saline 8
After washing three times with 0 ml, the solvent was distilled off under reduced pressure. Ethyl acetate 12 ml, hexane 28 ml, toluene 10 m
l was added and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed twice with 10 ml of a 30% ethyl acetate / hexane mixed solvent, and dried under reduced pressure to obtain 4.7 g of the title compound as off-white crystals. (Yield; 90.6%, HPLC purity; 99.3%)

¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 1.10
(t, J = 7.2Hz, 3H), 2.13 (s, 3H), 3.50 (q, J = 7.2Hz, 2H), 3.71
(m, 2H), 4.16 (m, 2H), 4.70 (d, J = 13.6Hz, 1H), 4.78 (d, J = 13.
6Hz, 1H), 6.96 (d, J = 5.6Hz, 1H), 7.28 (m, 2H), 7.62 (m, 2H),
8.20 (d, J = 5.6Hz, 1H).

Example 2 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (14.6 mmol) of a synthetic compound of n-simidazole (Rabeprazole free base) was suspended in 20 ml of acetonitrile, and 14.5 ml of a 2N aqueous solution of sodium hydroxide was added thereto. Add this solution to N-chlorosuccinimide at -18 to -8 ° C.
(2.13 g, 16.0 mmol) / N, N-dimethylformamide (8 ml) solution was added dropwise. The reaction mixture was reacted at -15 to 0 C for 1.5 hours. 5 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
And stirred for 2 minutes, then ammonium acetate (10 g) / water
(60 ml) solution was added. 60 ml of ethyl acetate and 10 g of common salt were added for extraction, and the aqueous layer was further extracted with 40 ml of ethyl acetate. The organic layers were combined, washed three times with 80 ml of 15% saline, and the solvent was distilled off under reduced pressure. Ethyl acetate is added to the obtained oil.
Add 12 ml, hexane 28 ml, toluene 12 ml, and add
Stirred for hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of a 30% ethyl acetate / hexane mixed solvent, and dried under reduced pressure.
4.68 g of the title compound was obtained as off-white crystals. (Yield: 90.0
%)

Example 3 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (14.6 mmol) of a synthetic compound of benzoimidazole (Rabeprazole free base) was suspended in a mixed solvent of 20 ml of toluene and 10 ml of acetonitrile, and 14.5 ml of a 2N aqueous solution of sodium hydroxide was added thereto. At 0-9 ° C, add N-
A solution of chlorosuccinimide (2.13 g, 16.0 mmol) / N, N-dimethylformamide (8 ml) was added dropwise. The reaction mixture is
Reaction was performed at 1.5 ° C. for 1.5 hours. After adding 5 ml of 10% aqueous sodium thiosulfate solution to the reaction mixture and stirring for 2 minutes, 14.5 ml of 2N aqueous sodium hydroxide solution was added. After adding 10 ml of toluene and separating the organic layer, 2.2 ml of acetic acid was added to the aqueous layer to adjust the pH.
Was adjusted to 8.5. 60 ml of ethyl acetate and 5 g of common salt were added for extraction, and the aqueous layer was further extracted with 40 ml of ethyl acetate.
After combining the organic layers and washing three times with 80 ml of 15% saline,
The solvent was distilled off under reduced pressure. Ethyl acetate 10m to the obtained oil
1, 10 ml of toluene and 20 ml of t-butyl methyl ether were added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals are collected by filtration and t
After washing twice with 10 ml of -butyl methyl ether and drying under reduced pressure, 3.9 g of the title compound was obtained as off-white crystals. (Yield; 74.
8%)

Example 4 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (14.6 mmol) of a synthetic compound of benzoimidazole (Rabeprazole free base) was suspended in 20 ml of tetrahydrofuran, and 14.5 ml of a 2N aqueous solution of sodium hydroxide was added thereto. At 0-9 ° C, add N-chlorosuccinimide
(2.13 g, 16.0 mmol) / N, N-dimethylformamide (8 ml) solution was added dropwise. The reaction mixture was reacted at 5-0 ° C for 1 hour. 5 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 2 minutes.
4.5 ml was added. After adding 40 ml of toluene and separating the organic layer, 2.2 ml of acetic acid was added to the aqueous layer to adjust the pH to 8.5.
60 ml of ethyl acetate and 4 g of common salt were added for extraction, and the aqueous layer was further extracted with 40 ml of ethyl acetate. Combine the organic layers, 1
After washing three times with 80 ml of 5% saline, the solvent was distilled off under reduced pressure.
Ethyl acetate 10 ml, toluene 10 ml, t-
20 ml of butyl methyl ether was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and t-butyl methyl ether 1
After washing twice with 0 ml, drying under reduced pressure gave 3.9 g of the title compound as off-white crystals. (Yield; 74.8%)

Example 5 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (14.6 mmol) of a synthetic compound of n-simidazole (Rabeprazole free base) was suspended in 20 ml of acetonitrile, and 14.5 ml of a 2N aqueous solution of sodium hydroxide was added thereto. To this solution at -5 to 5 ° C, N-chlorosuccinimide (2.
32 g, 17.4 mmol) / N, N-dimethylformamide (8.5 ml) solution was added dropwise. During this time, monitor the pH of the reaction solution and
10 ml of a 2N aqueous solution of sodium hydroxide was simultaneously added dropwise so that the pH did not fall below 12. After completion of the dropwise addition, the reaction was further performed at -3 to 0 ° C for 45 minutes. 10 ml of a 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 2 minutes, and then 60 ml of water was added. After adding about 2.5 ml of acetic acid to adjust the pH to 9.2, 60 ml of ethyl acetate and 12 g of sodium chloride were added for extraction, and the aqueous layer was further extracted with 40 ml of ethyl acetate. The organic layers were combined, washed three times with 80 ml of 15% saline, and the solvent was distilled off under reduced pressure. 12 ml of ethyl acetate and hexane were added to the obtained oil.
28 ml and toluene 10 ml were added, and the mixture was stirred at room temperature for 1 hour.
The precipitated crystals were collected by filtration, washed twice with 10 ml of a 30% ethyl acetate / hexane mixed solvent, and dried under reduced pressure to obtain 4.76 g of the title compound as off-white crystals. (Yield; 91.3%)

Example 6 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (14.6 mmol) of a synthetic compound of n-simidazole (Rabeprazole free base) was suspended in 20 ml of acetonitrile, and 14.5 ml of a 2N aqueous solution of sodium hydroxide was added thereto. To this solution at -5 to 5 ° C, N-chlorosuccinimide (2.
32 g, 17.4 mmol) / N, N-dimethylformamide (8.5 ml) solution was added dropwise. During this time, monitor the pH of the reaction solution and
10 ml of a 2N aqueous solution of sodium hydroxide was simultaneously added dropwise so that the pH did not fall below 12. After completion of the dropwise addition, the reaction was further performed at -3 to 0 ° C for 45 minutes. After adding 10 ml of a 10% aqueous sodium thiosulfate solution to the reaction mixture and stirring for 2 minutes, acetonitrile was distilled off under reduced pressure. 85 ml of water and about 1.2 ml of acetic acid
After adjusting H to 9.1, the mixture was stirred at 4 ° C for 12 hours. The precipitated crystals were collected by filtration, washed three times with 20 ml of water, and dried under reduced pressure to give 3.97 g of the title compound as off-white crystals. (Yield; 76.2%)

Example 7 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (14.6 mmol) of a synthetic compound of n-simidazole (Rabeprazole free base) was suspended in 20 ml of acetonitrile, and 14.5 ml of a 2N aqueous solution of sodium hydroxide was added thereto. To this solution at -5 to 5 ° C, N-chlorosuccinimide (2.
32 g, 17.4 mmol) / N, N-dimethylformamide (8.5 ml) solution was added dropwise. During this time, monitor the pH of the reaction solution and
10 ml of a 2N aqueous solution of sodium hydroxide was simultaneously added dropwise so that the pH did not fall below 12. After completion of the dropwise addition, the reaction was further performed at -3 to 0 ° C for 45 minutes. 10 ml of a 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 2 minutes, and then 60 ml of water was added. After adjusting the pH to 9.2 by adding about 1.3 ml of acetic acid,
Add 50 ml of isopropyl acetate and 50 ml of hexane, and add
Stir for 2 hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of a 30% isopropyl acetate / hexane mixed solvent, and dried under reduced pressure to obtain 3.47 g of the title compound as off-white crystals. (Yield; 66.6%)

Example 8 2-{[4- (3-methoxypropoxy)
-3-methylpyridin-2-yl] methylsulfinyl} -1H-be
15.0 g (43.7 mmol) of a synthetic compound 1 of nuzuimidazole (Rabeprazole free base) was suspended in 75 ml of acetonitrile, and 75 ml of a 2N aqueous sodium hydroxide solution was added. To this solution at -5 ° C, 6.42 g (48 mmol) of N-chlorosuccinimide
Was added little by little. The reaction mixture was reacted at -5 ° C for 1.5 hours. 5 ml of a 1M aqueous solution of sodium thiosulfate in the reaction mixture
Was added and stirred for 2 minutes, followed by washing twice with 100 ml of toluene. Thereafter, 4.2 g of formic acid was added to the aqueous layer at 5 ° C. to adjust the pH to 9.0.
Was adjusted. The mixture was stirred at the same temperature for about 15 hours, and the precipitated slurry was separated by filtration. The obtained solid was dried to obtain 14.00 g of the title compound as white crystals. (Yield: 89.2%, Purity: 99.8%)

Example 9 2-{[3-methyl-4- (2,2,2-trif
Fluoroethoxy) pyridin-2-yl] methylsulfinyl}
Synthesis of -1H-benzimidazole (Lansoprazole)

[0051]

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1.0 g (2.83 mmol) of 2-{[3-methyl-4- (2,2,2-trifluoroethoxy) pyridin-2-yl] methylthio} -1H-benzimidazole was suspended in 8 ml of acetonitrile,
To this, 3.5 ml of 2N-sodium hydroxide aqueous solution was added. To this solution was added N-chlorosuccinimide (453 mg, 3.
40 mmol) / N, N-dimethylformamide (2 ml) solution was added dropwise. Thereafter, the reaction was further performed at −3 to 0 ° C. for 1.5 hours. After adding 2 ml of 10% aqueous sodium thiosulfate solution to the reaction mixture and stirring for 2 minutes, 20 ml of water and 0.4 ml of acetic acid were added to adjust the pH to about
Adjusted to 8.5. 20 ml of ethyl acetate and 3 g of sodium chloride were added for extraction, and the aqueous layer was further extracted with 10 ml of ethyl acetate. The organic layers were combined, washed three times with 10 ml of 15% saline, and the solvent was distilled off under reduced pressure. 3 ml of ethyl acetate was added to the obtained oil,
Hexane (7 ml) and toluene (2.5 ml) were added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed twice with 3 ml of a 30% ethyl acetate / hexane mixed solvent, and dried under reduced pressure to obtain 0.88 g of the title compound as off-white crystals. (Yield; 84.1%)

¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 2.16
(s, 3H), 4.74 (d, J = 13.7Hz, 1H), 4.87 (d, J = 13.7Hz, 1H), 4.8
8 (d, J = 8.8Hz, 1H), 4.91 (d, J = 8.8Hz, 1H), 7.08 (d, J = 5.9Hz,
1H), 7.29 (m, 2H), 7.56 (m, 1H), 7.70 (m, 1H), 8.27 (d, J = 5.9H
(z, 1H), 13.55 (s, 1H).

Example 10 2-{[4- (2-methoxypropoxy)
B) -3-Methylpyridin-2-yl] methylsulfinyl} -1H
-Synthetic compound 1 of benzimidazole (Rabeprazole free base) 10.0 g (29.1 mmol) in dimethylformamide 80m
l, and potassium hydrogen carbonate 2.91 g (29.1 mmol)
/ Water (20 ml) solution was added, and the mixture was stirred under ice cooling. At the same temperature, 4.01 g (20.37 mmol) of 1,3-dichloro-5,5-dimethylhydantoin / dimethylformamide (15
ml) solution was added dropwise over 3 minutes, and the mixture was stirred at the same temperature for 70 minutes. Further, 0.34 g (8.73 mmol) of 1,3-dichloro-5,5-dimethylhydantoin was added, and the mixture was stirred for 40 minutes. Add 103 ml of an aqueous solution of 5.13 g (40.74 mmol) of sodium sulfite
After stirring for 5 minutes, add 6 ml of 2M aqueous sodium hydroxide solution and add p.
Adjusted to H8. 80 ml of water is added and the aqueous phase is
The mixture was extracted twice with 0 ml and once with 100 ml. The organic phase was washed twice with 150 ml of 10% saline. The organic phase was concentrated under reduced pressure, and the residue was ethyl acetate 30 ml, toluene 30 ml, n-hexane 30 ml
Was added and stirred at -15 ° C for 11 hours. The precipitated crystals were filtered under reduced pressure, washed twice with 25 ml of t-butyl methyl ether, and dried to obtain 7.33 g of the title compound as a white solid. (yield;
70.0%, HPLC purity; 98.9%)

Example 11 2-{[4- (2-methoxypropoxy)
B) -3-Methylpyridin-2-yl] methylsulfinyl} -1H
-Synthetic compound 1 of benzimidazole (Rabeprazole free base) 10.0 g (29.1 mmol) in dimethylformamide 80m
l, and add sodium hydrogen carbonate 2.46g (29.2mmo
l) / water (20 ml) solution was added, and the mixture was stirred under ice cooling. At the same temperature, 4.01 g (20.37 mmol) of 1,3-dichloro-5,5-dimethylhydantoin / dimethylformamide (20
ml) solution was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 80 minutes. Further, 115 mg (0.58 mmol) of 1,3-dichloro-5,5-dimethylhydantoin was added, and the mixture was stirred for 20 minutes. 1.0M
An aqueous sodium thiosulfate solution (30 ml) was added, and the mixture was stirred for 5 minutes. Then, 30 ml of saturated saline was added, and the mixture was extracted with 100 ml of ethyl acetate × 2. The organic phase was washed with 15% saline (100 ml, 50 ml) and concentrated under reduced pressure. Toluene 15ml, ethyl acetate
15 ml, add 15 ml of t-butyl methyl ether and add 13 ml at -10 ° C.
Stirred for hours. The precipitated crystals were filtered under reduced pressure, washed twice with t-butyl methyl ether (50 ml × 2), and dried to obtain 7.05 g of the title compound as a white solid. (Yield; 67.0%)

Example 12 2-{[4- (2-methoxypropoxy)
B) -3-Methylpyridin-2-yl] methylsulfinyl} -1H
-Dissolve 5.0 g (14.5 mmol) of synthetic compound 1 of benzimidazole (Rabeprazole free base) in 25 ml of ethyl acetate,
Here, sodium hydrogen carbonate 3.21 g (32.1 mmol) / water (25 ml)
The solution was added, and the mixed solution was stirred under ice cooling. Here, at the same temperature, 1,3-dichloro-5,5-dimethylhydantoin 2.
87 g (14.6 mmol) was added and the mixture was stirred for 2 hours. 3 at -10 ° C
Stirred for 0 minutes. The precipitated crystals were filtered under reduced pressure, and water 10 ml ×
2. Washed with t-butyl methyl ether (10 ml × 2) and dried to obtain 2.79 g of the title compound as white crystals. (Yield; 5
3.3%, HPLC purity; 98.8%)

Example 13 2-{[4- (2-methoxypropoxy)
B) -3-Methylpyridin-2-yl] methylsulfinyl} -1H
-Synthesis compound 1 10.0 g (29.1 mmol) of benzimidazole (Rabeprazole free base) is dissolved in 40 ml of ethyl acetate, and 13.9 g (140 mmol) of sodium hydrogen carbonate / water (55
ml) solution was added and the mixed solution was stirred at -5 ° C. Here, at the same temperature, 1,3-dichloro-5,5-dimethylhydantoin
A solution of 6.88 g (34.92 mmol) / ethyl acetate (60 ml) was added. Two
After stirring for an hour, 50 ml of a 10% aqueous sodium hydrosulfite solution was added, and the mixture was stirred for 10 minutes. A (1: 1) n-hexane / toluene mixture (110 ml) was added thereto, and the mixture was stirred at -20 ° C for 1.5 hours. The precipitated crystals were collected by filtration, washed with 50 ml of water x 4 and 25 ml of t-butyl methyl ether and dried to obtain 7.09 g of the title compound as white crystals. (Yield; 68%, HPLC purity; 9
8.2%)

Example 14 2-{[4- (2-methoxypropoxy)
B) -3-Methylpyridin-2-yl] methylsulfinyl} -1H
Dissolve 5.0 g (14.5 mmol ) of synthetic compound 1 of benzimidazole (Rabeprazole free base) in 20 ml of acetonitrile, add 2M aqueous sodium hydroxide solution (21.9 ml) and add -15 ° C
With stirring. At the same temperature, a solution of 2.24 g (10.2 mmol) of sodium dichloroisocyanurate / 15 ml of water was added dropwise over 10 minutes. During this time, the temperature of the reaction solution was -15 ° C to -5.6 ° C
Up. After stirring at the same temperature for 15 minutes, a solution of sodium hydrosulfite (0.50 g / water (5 ml)) was added, and the mixture was stirred for 30 minutes, and insoluble materials were removed by filtration. The filtrate was adjusted to pH 7 by adding about 3 ml of formic acid, and the aqueous phase was extracted once with 25 ml of ethyl acetate and once more.
Extracted once with 0 ml. The organic phase was washed with 10 ml of saturated saline and concentrated under reduced pressure.
ml and 20 ml of n-hexane were added and stirred at -15 ° C for 11 hours.
After filtering the precipitated crystals under reduced pressure, t-butyl methyl ether 2
The residue was washed twice with 0 ml and dried to obtain 3.71 g of the title compound as pale yellowish white crystals. (Yield; 70.8%, HPLC purity: 97.3%)

From the above results, it is apparent that the desired sulfoxide (II) can be obtained in a high yield and safely according to the present invention. Furthermore, N-halosuccinimide, 1,3-dihalo
-5,5-Dimethylhydantoin and dichloroisocyanurate are not dangerous substances, and can be easily handled in large quantities. It is clear that the present invention is an industrially excellent method for producing sulfoxide (II).

[Brief description of the drawings]

FIG. 1 shows the high purity of 2-{[4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methylsulfinyl} -1H-benzimidazole (Rabeprazole free base) obtained in Example 1. It is a HPLC chart (unit: minute) which shows that there is.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hirofumi Kuroda 2-27-7 Onohara, Kamisu-cho, Kashima-gun, Ibaraki Prefecture

Claims (12)

[Claims] 1. A thioether (I) represented by the following general formula: (Wherein, R ¹ represents a hydrogen atom, a methoxy group or a difluoromethoxy group, R ² represents a methyl group or a methoxy group, and R ³ represents 3-
A methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy group, and R ⁴ represents a hydrogen atom or a methyl group, respectively. ) Is oxidized with N-halosuccinimide, 1,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate in the presence of a base, wherein the sulfoxide (II) represented by the following general formula: ) Manufacturing method. Embedded image (In the formula, R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above.) 2. The N-halosuccinimide according to claim 1, wherein the N-halosuccinimide is N-chlorosuccinimide or N-bromosuccinimide.
The method for producing the sulfoxide (II) described above. 3. The process for producing a sulfoxide (II) according to claim 1, wherein the amount of the N-halosuccinimide used is 0.9 to 1.5 equivalents based on the thioether (I). 4. The method of claim 1, wherein the 1,3-dihalo-5,5-dimethylhydantoin is 1,3-dichloro-5,5-dimethylhydantoin or 1,3-dichloro-5,5-dimethylhydantoin.
The method for producing sulfoxide (II) according to claim 1, which is dibromo-5,5-dimethylhydantoin. 5. The sulfoxide (II) according to claim 1 or 4, wherein the amount of 1,3-dihalo-5,5-dimethylhydantoin used is 0.4 to 0.8 equivalent relative to thioether (I). ) Manufacturing method. 6. The process for producing sulfoxide (II) according to claim 1, wherein the dichloroisocyanurate is sodium dichloroisocyanurate or potassium dichloroisocyanurate. 7. The amount of dichloroisocyanurate used is:
The method for producing sulfoxide (II) according to claim 1 or 6, wherein the amount is 0.4 to 0.8 equivalent relative to thioether (I). 8. The method according to claim 1, wherein the base is an inorganic base.
The method for producing the sulfoxide (II) described above. 9. The base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate,
9. The sulfoxide according to claim 1, which is at least one selected from sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, sodium formate, potassium formate, sodium acetate and potassium acetate. II) Manufacturing method. 10. The base is used in an amount of 0.9 to 3.0 equivalents with respect to N-halosuccinimide and 0.4 with respect to 1,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate. 2. The composition according to claim 1, wherein the amount is from 1.5 to 1.5 equivalents.
10. The method for producing sulfoxide (II) according to any one of claims 9 to 9. 11. The oxidation reaction is carried out by N, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran,
The method for producing sulfoxide (II) according to any one of claims 1 to 10, wherein the method is carried out in one or more solvents selected from lower fatty acid esters and water. 12. The method according to claim 1, wherein the oxidation reaction is carried out in the presence of water in one or more solvents selected from N, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran and lower fatty acid esters. 11
The method for producing the sulfoxide (II) described above.