JPH0579061B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an imidazole N-oxide compound used in the production of cimetidine and a method for producing the same. British Patent No. 1533380 describes the formula:

【formula】 [In the formula, Z means a leaving group] A compound represented by the formula:

Cimetidine, i.e., the formula:

N-cyano-N′-methyl-N″-[2-
[(5-methyl-4-imidazolyl)methylthio]
A method for producing ethyl]guanidine is described. DE 2211454 describes compounds of the formula: Het-CH ₂ Q in which Q is a leaving group and Het means, inter alia, a 4-methyl-5-imidazolyl group. , and cysteamine represented by the formula: HSCH ₂ CH ₂ NH ₂ to form the formula: Het−
An amine of the form CH ₂ SCH ₂ CH ₂ NH ₂ is formed, which is then treated with, for example, the formula:

A method is described for producing a group of compounds containing cimetidine by reacting compounds of the formula: [wherein R is alkyl, aryl or arylalkyl, and Z means oxygen or sulfur] . It is known that the starting materials, i.e. substituted imidazoles, are not easy to obtain by these known methods, and therefore the method of the present invention requires a completely different approach, both with regard to the starting materials and the reaction route. Adopt. The imidazole N-oxide of the present invention is a key intermediate in a novel reaction route to synthesize cimetidine, with the formula:

[ka] or

3-oxide-4-methylimidazol-5-yl compound () or 3-oxide-5-methylimidazol-4-yl represented by [Formula, Y means hydrogen or a leaving group] Any of the compounds (). When Y is hydrogen, the compound may consist of two tautomers, namely the N-oxide and the corresponding N-hydroxy tautomer. The leaving group represented by Y is OH, or aralkyl, for example benzyl. In the method of the invention, these imidazole N-oxides () and () have the formula:

[Formula] [In the formula, one of substituents A and B is NOH
and the other is oxygen] or a mixture of formaldehyde and/or a formaldehyde donor, e.g.
It is produced by reacting with a compound represented by =CH ₂ (Y is the same as above). The starting material () has the formula:

[Formula] [In the formula, one of substituents A and B is NOH
and the other is oxygen, and X means a leaving group, such as hydroxy, chlorine, bromine, acyloxy, tosyloxy or trialkylammonio group] and a compound of the formula:

It is produced by reacting a compound represented by the formula under cooling conditions, preferably in the presence of a strong alkali such as sodium ethoxide. Preferably, the starting material for compound () is a readily available halogen compound, 1-bromo-3-
Oximino-2-butanone and 4-chloro-
3-oximino-2-butanone. Preferably, YN= _CH2 is N-benzylmethyleneimine. Since compound () is hitherto unknown and has many reactive sites, it is unexpected and surprising that it can be transferred to imidazole N-oxide in good yield. It is the right thing to do. What is particularly surprising is that N-cyano-
The guanidine moiety is resistant to treatment with the reagents necessary for ring closure and further
Chemie) 10 (1970), 211-215, 2-unsubstituted imidazole N-oxides cannot be isolated under reaction conditions similar to those used in the present invention. In the case of a compound () or () in which Y is hydrogen, it is produced by reduction of a compound () or () in which Y is a leaving group. Reduction can be carried out using, for example, sodium in liquid ammonia. Compound () or (), where Y is hydrogen, is finally deoxygenated to obtain cimetidine. Deoxygenation can also be carried out before reduction. In the product of the ring-closing reaction when Y is hydrogen, deoxygenation can be carried out directly. Deoxygenation of compounds () and () can be achieved using trialkylamine-sulfur dioxide complexes, e.g. ( _CH3 ) ₃
This can be carried out using N ⁺ -SO ₂ ^- or formamidinosulfinic acid. Deoxygenation can also be carried out by catalytic hydrogenation using a palladium-carbon catalyst. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 11.0g (0.48mol) of sodium in ethanol
250 ml and then 76.0 g (0.48 mol) of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (). To this mixture, 1-
Bromo-3-oximino-2-butanone 86.0g
(0.524 mol) dropwise at 20-25°C. After the reaction mixture is left at 5° C. overnight, the precipitated sodium bromide is filtered off and the filtrate is evaporated to dryness under vacuum. After the residue is dissolved in 800 ml of acetonitrile and stirred with silica for 30 minutes, the silica is filtered off and the filtrate is evaporated under vacuum. After trituration with ether, N-cyano-N′-methyl-N″-[2
-(3-oxyimino-2-oxobutylthio)
ethyl]guanidine (a) 99.0g (yield 80%)
isolate. Stir with water and filter to obtain an analytically pure sample. Melting point 111-112℃. Elemental analysis: As C ₉ H ₁₅ N ₅ O ₂ S, actual measured values (calculated values): C41.97 (42.00), H5.90 (5.88), N27.08
(27.22), S12.66 (12.46). IR and ¹ H-NMR spectra are consistent with the structural formula. Reference example 2 5.75g (0.250mol) of sodium in ethanol
100 ml and added to 39.6 g (0.250 mol) of N-cyano-N'-methyl-N''-(2-mercaptoethyl)guanidine () in 60 ml of ethanol.
After stirring the obtained solution for 1 hour under nitrogen atmosphere,
-Chloro-3-oximino-2-butanone
33.9 g (0.250 mol) in a solution in 80 ml of ethanol
Add over 40 minutes at 25°C. The obtained solution is
After standing overnight at 0.degree. C., the precipitate is isolated by filtration and then washed with ethanol. The product was stirred with water for 30 minutes, isolated again and N-cyano-
N′-methyl-N″-[2-(2-oximino-3
-oxobutylthio)ethyl]guanidine (
36.8 g (yield 57%) of beige crystals of b) are obtained. Melting point 133-134°C (decomposition). Elemental analysis: As C ₉ H ₁₅ N ₅ O ₂ S, actual measured values (calculated values): C42.15 (42.00), H6.00 (5.88), N26.96
(27.22), S12.20 (12.46). IR and ¹ H-NMR spectra are consistent with the structural formula. Example 1 (ring closure) Compound (a) 67.5 g in methanol 1.0
(0.262 mol) is mixed with 62.0 g (0.521 mol) of N-benzylmethyleneimine in 1.0 petroleum ether and the mixture is refluxed for 72 hours. The methanol phase was isolated and extracted with petroleum ether, leaving the solvent at 40 °C.
Evaporate under vacuum. The semi-crystalline residue is further crystallized by stirring with ether and the crystals are filtered off. The mother liquor is concentrated again and treated once more with ether to obtain more crystals. The products were combined and dissolved in a 1:4 mixture of methanol and chloroform;
The solution is stirred with silica and the silica is filtered off. Concentrate the filtrate in vacuo and stir the residue with acetonitrile. The obtained crystals were collected by filtration and washed with ether to give N-cyano-N'-methyl-N''-
66.0 g (yield 70%) of [2-[(1-benzyl-3-oxide-4-methylimidazol-5-yl)methylthio]ethyl]guanidine (a) is obtained. Melting point 186-187°C (decomposition). Elemental analysis C ₁₇ H ₂₂ N ₆ As OS, measured value (calculated value): C56.56 (56.95), H6.17 (6.19), N23.23
(23.45), S8.78 (8.95). IR, ¹ H-NMR and ¹³ C-NMR spectra are consistent with the structural formula. Example 2 (ring closure) Compound (a) 12.9 g (50
mmol) to 9.0 g of N-benzylmethyleneimine
(75 mmol) and 0.6 g (10 mmol) of acetic acid and stirred at 25° C. for 18 hours. Solvent at 60℃
Evaporate under vacuum. The resulting residue was dissolved in acetone.
Heat to reflux with 100 ml for 20 minutes. This causes crystallization. After cooling to 10℃, the crystals were collected by filtration.
Dry to give N-cyano-N′-methyl-N″-[2-
15.2 g (yield: 85%) of [(1-benzyl-3-oxide-4-methylimidazol-5-yl)methylthio]ethyl]guanidine (a) are obtained. Melting point 183-184°C (decomposition). Example 3 (ring closure) 2.57 g of compound (b) in 25 ml of methanol
(0.010 mol), N-benzylmethyleneimine
Mixed with 2.38g (0.020mol) under nitrogen atmosphere,
Heat to reflux for 17 hours. The resulting solution was evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give N-cyano-N'-methyl-N''-[2-[(1-
2.87 g (yield: 80%) of benzyl-3-oxide-5-methylimidazol-4-yl)methylthio]ethyl]guanidine (a) is obtained. Melting point 178
~180℃ (decomposition). Elemental analysis value, C ₁₇ H ₂₂ N ₆ OS, actual measured value (calculated value): C56.77 (56.96), H6.20 (6.19), N23.61
(23.45), S9.03 (8.95). IR and ¹ H-NMR spectra are consistent with the structural formula. Reference example 3 (reduction) 35.0 g of compound (a) in 700 ml of liquid ammonia
(0.0976 mol) and 7.2 g (0.31 mol) of sodium
mol), then 16.7 g (0.31 mol) of ammonium chloride
mol). Next, heat to room temperature to remove ammonia, add 200 ml of absolute alcohol,
The reaction mixture is stirred for 30 minutes and filtered. The filtrate is concentrated under vacuum, the residue is washed with ethyl acetate and the ethyl acetate phase is decanted off. The resulting residue was crystallized from methanol to give N-cyano-N'-methyl-N''-[2-[(3-oxide-4
-methylimidazol-5-yl)methylthio]
ethyl]guanidine (b) 15.3g (yield 58%)
get. Melting point 161-162℃. Elemental analysis value, C ₁₀ H ₁₆ N ₆ OS, actual measured value (calculated value): C43.65 (44.75), H6.00 (6.01), N30.86
(31.32), S12.02 (11.95). IR, ¹ H-NMR and ¹³ C-NMR spectra are consistent with the structural formula. Reference example 4 (reduction) 3.59 g of compound (a) in 100 ml of liquid ammonia
(10.0 mmol) dissolved, 0.53 g of sodium
(23 mmol) is added little by little, followed by 1.23 g (23 mmol) of ammonium chloride. Heat to room temperature to remove ammonia and add propanol. The resulting suspension is stirred for 30 minutes and filtered. The filtrate is seeded with crystals of compound (b) and cooled. The precipitated crystalline material was filtered, dried, and
-Cyano-N'-methyl-N''-[2-[(3-oxide-5-methylimidazol-4-yl)methylthio]ethyl]guanidine (b) 2.0 g (yield 75%) is obtained. Melting point 180 ~183℃ (decomposed). Elemental analysis value, C ₁₀ H ₁₆ N ₆ OS, actual measured value (calculated value): C44.62 (44.75), H5.96 (6.01), N31.24
(31.32), S11.98 (11.95). IR and ¹ H-NMR spectra are consistent with the structural formula. Example 4 (Direct ring closure from compound (b) to (b)) In 20 ml of 2N acetic acid, 2.57 g (10.0 mmol) of compound (b), 1.15 g (15.0 mmol) ammonium acetate and 0.33 g (11.0 mmol) paraformaldehyde. Stir at 65°C for 2 hours. HPLC analysis shows the formation of the desired compound in 72% yield. The solvent is removed in vacuo and the residue is adjusted to pH 8 with 3N potassium hydroxide. Remove the solvent under vacuum;
The residue is dissolved in chloroform-methanol (4:1), stirred with silica and filtered. The filtrate is evaporated in vacuo and the residue is crystallized from methanol to yield 1.20 g of compound (b) monohydrate. A further 0.51 g of compound (Vb) monohydrate is obtained from the mother liquor by chromatography on silica gel. The total yield of crystal (b) monohydrate is 60%. Elemental analysis value, C ₁₀ H ₁₆ N ₆ OS・H ₂ O, actual measured value (calculated value): C41.70 (41.94), H6.19 (6.34),
N29.42 (29.35), S11.25 (11.20), _H2O6.33 (6.29)
. When recrystallized from dry ethanol, the melting point is 181 ~
The temperature rises to 183℃ (decomposition). Compounds were immobilized with standard standards (IR and ¹ H-NMR spectroscopy). Example 5 (Direct ring closure from compound (b) to (b)) In 40 ml of water, 5.15 g (20.0 mmol) of compound (b), 2.30 g (20.0 mmol) of ammonium dihydrogen phosphate, 1.32 g of ammonium hydrogen phosphate (10.0
mmol) and paraformaldehyde 0.72g
(24 mmol) was stirred at 65°C for 2 hours. After that time, HPLC analysis showed that the yield of compound (b) was 57
% is shown. PH the reaction mixture with aqueous ammonia
8 and remove the solvent in vacuo. The residue is chromatographed on silica gel, eluting with chloroform-methanol (3:1). The main fraction was crystallized from methanol to form the compound (
b) 2.73 g (48% yield) of monohydrate are obtained. Example 6 (Direct ring closure from compound (b) to (b)) In 40 ml of acetic acid, 3.86 g (15.0 mmol) of compound (b), 1.61 g (21.0 mmol) of ammonium acetate
and 0.63 g (21.0 mmol) of paraformaldehyde are stirred at room temperature for 10 hours. After removing the solvent under vacuum, the residue was chromatographed on silica gel with chloroform-methanol (3:
Elute with 1). The main fraction is crystallized from methanol to obtain 1.71 g (41% yield) of compound (b) monohydrate. Identification was performed using standard specimens by IR and ¹ H-NMR. Example 7 (Direct ring closure from compound (a) to (b)) In 20 ml of 2N acetic acid, 2.57 g (10.0 mmol) of compound (a), 1.15 g (11.0 mmol) ammonium acetate and 0.33 g (11.0 mmol) paraformaldehyde. Stir at 65°C for 2 hours. After that time, HPLC analysis shows a content of compound (b) of 40%. The solvent is removed under vacuum and the residue is adjusted to pH 8 with 3N potassium hydroxide and then evaporated again under vacuum. The residue was chromatographed on silica gel using chloroform-methanol (3:
Elute with 1). The main fraction was crystallized from methanol to yield 0.68 g of compound (b) (yield 25%).
get. Reference Example 5 (Deoxygenation) 3.00 g of compound (b) in 60 ml of methanol
(11.2 mmol) and 2.7 g (22 ^mmol ) of trimethylamine-sulfur dioxide (( _CH3 ) _3N ⁺ _-SO2- )
is heated to 130°C for 5 hours in an autoclave.
After cooling, the reaction mixture is concentrated under vacuum. 6ml water
and 2.0 g (14.5 mmol) of potassium carbonate almost quantitatively produced crude cimetidine.
2.83 g (melting point 136-138°C) are isolated. After recrystallization, the melting point increases to 142-143 °C. Reference Example 6 (Deoxygenation) 121 ml (0.45 mmol) of compound (b) was dissolved in 4.8 ml of dimethylformamide, and 49 mg (0.45 mmol) of formamidinosulfonic acid ((H ₂ N) ₂ ⁺ C-SO ₂ ^- )
mmol) and heat the mixture at 100°C for 1 hour. After that time, HPLC analysis shows it contains 48% cimetidine. Reference Example 7 (Deoxygenation) 2.00 g (7.5 mmol) of compound (b) was
2.70 g (21.9 mmol) of trimethylammonium sulfonate dissolved in 40 ml of ethoxyethanol
is added and the mixture is heated to reflux for 15 minutes. HPLC analysis showed the presence of 72% cimetidine, its 1.30
g (69% yield) can be isolated. Reference Example 8 (Deoxygenation) Compound (b) is deoxidized by the same method as described in Reference Example 5 to obtain cimetidine. Reference Example 9 (Deoxygenation of compound (a) before reduction) 7.2 g (20 mmol) of compound (a) is heated under reflux in 24 ml of ethanol with 1.7 M trimethylamine-sulfur dioxide for 16 hours. After cooling to 0°C, the crystals were collected by filtration and dried to give N-cyano-N'-
Methyl-N″-[2-(1-benzyl-5-methylimidazol-4-yl)methylthio]ethyl]
6.2 g (91%) of guanidine (a) are obtained. melting point
178-179℃. Elemental analysis value, C ₁₇ H ₂₂ N ₆ S, actual measured value (calculated value): C59.53 (59.62), H6.55 (6.48), N24.43
(24.54), S9.41 (9.36). ¹ H-NMR and ¹³ C-NMR spectra are
Matches the structural formula. Reference example 10 (Deoxygenation of compound (a) before reduction) 17.9g (50 mmol) of compound (a) was added to 1.7M
of trimethylamine-sulfur dioxide in 60 ml of ethanol and heated under reflux for 5 hours. After cooling to 0°C, the crystals were collected by filtration and dried to give N-cyano-N'-
Methyl-N″-[2-(1-benzyl-4-methylimidazol-5-yl)methylthio]ethyl]
14.9 g (yield 87%) of guanidine (b) is obtained.
Melting point 173-175℃. Elemental analysis value, C ₁₇ H ₂₂ N ₆ S, actual measured value (calculated value): C59.81 (59.62), H6.44 (6.48), N24.83
(24.54), S9.42 (9.36). ¹ H-NMR and ¹³ C-NMR spectra are
Matches the structural formula. Reference Example 11 (Deoxygenation) Dissolve 3.58 g (10 mmol) of compound (a) in methanol (50 ml) and add 0.36 g of 5% palladium-carbon.
Add g. The mixture is stirred at room temperature for 3 days under a hydrogen atmosphere (1 atm). The catalyst is filtered off, the filtrate is evaporated to dryness, and 60 ml of acetone is added to the residue, which is heated to reflux. After cooling to room temperature, the crystals are collected by filtration and dried to obtain 3.05 g of compound (b) (yield: 89%). Melting point 172-175℃. Reference Example 12 (Reduction) 274 g (0.80 mol) of compound (b) is suspended in 1200 ml of liquid ammonia. Sodium 40.0g
(1.74 mol) is added followed by 93.1 g (1.74 mol) of ammonium chloride dissolved in 400 ml of water. Evaporate excess ammonia. The resulting suspension is filtered. Dry the precipitate and add cimetidine 185
g (yield 92%). Melting point 138-141℃. HPLC
indicates a purity of 97%.

Claims (1)

[Scope of Claims] 1 An imidazole N-oxide represented by the formula: [Image Omitted] or [Imidazole N-oxide] [In the formula, Y means hydrogen, OH or aralkyl]. 2 Formula: [In the formula, one of substituents A and B means NOH and the other means oxygen] An oximino compound represented by the formula: [formula] is combined with formaldehyde or a formaldehyde donor and ammonia or an ammonia donor. or a mixture with a compound of the formula: YN=CH ₂ [Y means hydrogen, OH or aralkyl]. is the same as above] A method for producing imidazole N-oxide.