CH659650A5 - OXIMINOVERBINDUNGEN AND IMIDAZOLE N-OXIDE FOR PRODUCING cimetidine and PROCESS FOR PRODUCING. - Google Patents

Description

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PATENT CLAIMS 6. Method according to spoke 5, characterized in that

1. Oximino compounds of the formula one the compound of formula III with N-benzylmethyleneimine

NqN implements.

ch_ccch_sch ch nhc ^^. (III) 5

31H 2 2 2 on nhch

3 The invention relates to oximino compounds and imidazole N-oxides for use as intermediates for the manufacture of

wherein one of the substituents A and B is NOH and the other oil of cimetidine and processes for their preparation. 10 A method is described in GB-PS1533 380 according to

2. Imidazole-N-oxides of the formula cimetidine, namely N-cyano-N'-methyl-N "- [2 - [(5-methyl-

sf '4-imidazolyl) methylthio] ethyl] guanidine of the following formula ch3Ç = Çch2SCH2CH2NHCN: (IV'V) CH_ CH0SCH_CH NHC = NCN

w ■ NHCH i5 3 \ y 2 2 2 i

3rd f NHCH.

where T is a group of the formula j | 3rd

~ 0-n + = ch-ny

I I 20 is prepared by meaning a compound of the formula wherein Y is hydrogen or a benzyl group. CH CH Z

3. Process for the preparation of oximino compounds of - I 2

formula

NCN

>

ch3ccch2sch2ch2nhc ^ (iii) 25 hn \ ^ n

FROM NHCH

3 where Z is a cleavable group, with a mercap

wherein one of the substituents A and B NOH and the other O ton of the formula _

means, characterized in that a connection -jNCN

of the formula CIT CCCH x HSCH CH NHC (^

m ®

wherein X is a cleavable group, with a compound that allows 35 to react.

Formula In the Spanish PS 463 839 is the production of cimetidine

- "^ NCN by treating 4-methyl-5-hydroxy-methylimidazole with

HSCH CH NHC CID thiourea and subsequent reaction with N-cyano-N'-

2 2 methyl-N "- (2-hydroxyethyl) guanidine.

NHCH3 4 () DE-OS 2211454 describes the preparation of a compound of the class containing cimetidine by reacting one. ... , Compound Het-CH2Q, wherein Q is a removable group

4. The method according to claim 3, characterized in that Het can represent, inter alia, a 4-methyl-5-imidazolyl-X-halogen or an acyloxy, tosyloxy or tnalkylammo group, with cysteaninHSCH2CH2NH2reagie-

is nio group. and formation of Het-CH2SCH2-CH2NH2, which

5. Process for the preparation of imidazole-N-oxides which send inter alia with a compound

Formula - .NCN JJCN

CH3C = CCH2sch2CH2NHC ^ '(IV, V)

l J ^ -NHCH, \

T 3 so NHCH.,

wherein T is a group of the formula

+ _ is treated in which formula alkyl-aryl or aryl-alkyl

O-N = CH-NY and Z represent oxygen or sulfur.

'1 It is known that the starting materials, i.e. This means, where Y is hydrogen or a benzyl group, 55 tuid imidazoles, for this and other known processes characterized in that an oximino compound is not easy to prepare, and the formula according to the invention therefore uses a completely different procedure, both

^ with respect to the starting materials as well as with respect to the ch-ccch sch ch nhc ^ (III) pathway.

•> 11 II 1 \ This consists in the first method according to the invention

AB nhch ^ Starting material from a compound of the formula

CH_CCCH "X

wherein one of the substituents A and B NOH and the other O

means with a compound of the formula

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YN = CH2 m in which one of the substituents A and B is NOH and the other O in which Y is hydrogen or the benzyl group. means. X stands for a suitable cleavable group, such as

(I)

3rd

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e.g. B. OH and preferably halogen or an acrylic, tosyloxy YN = CH2 ortrialkylammonio group. The preferred starting materials are the readily available halogen compounds-N-benzylmethyleneimine.

conditions such. B. l-Bromo-3-oximino-2-butanone and 4-chloro-3- The compounds of formulas III, IV and V are new and they oximino-2-butanone. In the first process 5, the compound I and also the processes described above for its preparation with a compound of the formula represent aspects of the present invention.

jNCN Since the compounds of formula III not yet

HSCH_CH "NHC ^ (H)

were known and since they have a variety of reactive centers

2 2, it is unexpected and surprising that they are in good

NHCH 10 yields can be converted to imidazole N-oxides.

3 It is particularly surprising that the N-cyanoguanidine

implemented, preferably under cold conditions in contrast to the rest of the treatment with the necessary for the ring closure were a strong base, such as. B. sodium ethylate, with formation of reagents and can also after the «time

of oximino compounds of the formula III writing for chemistry », 10 (1970), 211 to 215,2-unsubstituted ncn imidazole-N-oxides under reaction conditions which are analogous to

“_H rH / jrn those used according to the invention cannot be isolated.

3 | U 2 2 2 The compound of the formula IV or V can then be hydrogenolized starting from when Y is a benzyl group, um

3rd

Cleave benzyl, and finally it can be deoxygenated wherein A and B are as defined above. 20, the oxygen is removed, whereby cimetidine

In the second method according to the invention, is formed in the. Deoxygenation can also be carried out before

Compound of formula III a ring closure can be carried out by implementation. If in the ring closure product Y

tion with a compound of the formula hydrogen, the deoxygenation is directly

25 feasible. The benzyl group can be split off with sodium in

YN = CH2 liquid ammonia can be carried out. The deoxygenation of the compounds of formula IV and V can be carried out under where Y is hydrogen or a benzyl group, using trialkylamine-sulfur oxide complexes such as an imidazole-N-oxide of formula IV and V z. B. (CH3) 3N + -S02- or formamidinosulfinic acid,

, ncn leads.

ch_c = cch0sch ch_nhc ^ (iv, v)

The invention is illustrated by the following examples

3j ~ I 2 2 2 X. 'explained, but is not limited to this.

w nhch in which T is a group of the formula "Example 1 (first reaction stage)

_ + 35 N-cyano-N'-methyl-N "- [[2- (3-oximino-2-oxobutyl) thio] -

o-n = ch-ny ethyl] -guanidine (purple)

«| 11.0 g (0.48 mol) of sodium were added to 250 ml of ethanol.

and where Y has the meaning given above. give.

When A, 0 and B are NOH, a 3-oxido-4-methylimi- is added to the above mixture at 20-25 ° C, a solution of dazol-5-yl compound of formula IV. The formulas of io of 86.0 g (0.524 mol) of l-bromo-3-oximino-2-butanone in 250 ml of imidazolyl group in these compounds are as follows: anhydrous ethanol was added dropwise. The reaction mixture was left at 5 ° C overnight, the precipitated sodium bromide was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 45,800 ml of acetonitrile and stirred with silica for 30 minutes, the silica was then removed by filtration, and the filtrate was evaporated in vacuo. After trituration with ether, the title compound could be isolated (99.0 g, 80%). Stirring with water and filtering (Vai 50 gave an analytically pure sample, F.lllbisll2 ° C.

Analysis for C9H15N502S:

found (calc.): C41.97 (42.00), H5.90 (5.88), N27.08 (27.22), S 12.66 (12.46).

The IR and 'H NMR spectra were consistent with the

If Y is hydrogen, these compounds can have a 55 structure.

Example 2 (first reaction stage) N- (cyano-N'-methyl-N "- [[2- (2-oximino-3-oxobutyl) thio-the intermediate compound of the formula] ethyl] guanidine (Illb)

60 5.75 g (0.250 mol) of sodium were dissolved in 100 ml of ethanol YN = CH2 and 39.6 g (0.250 mol) of N-cyano-N'-methyl-N "- (2-mercapto-

ethyl) guanidine (II) in 60 ml of ethanol was added. The resultant can (a) formaldehyde or a formaldehyde donor, such as solution was stirred under nitrogen for 1 hour and z. B. paraformaldehyde, or mixtures of formaldehyde and / then to a solution of 33.9 g (0.250 mol) of 4-chloro-3 or formaldehyde donors and 65 oximino-2-butanone in 80 ml of ethanol within a period

(b) from ammonia or ammonia donors, such as. B. of 40 min at 25 ° C. The resulting solution was

Ammonium acetate, or benzylamine. Preferably left to stand at 5 ° C. overnight, and the precipitate became wise. The compound of the formula iso- by filtering and then washing with ethanol.

consist of a mixture of two tautomers, e.g. an N-oxide and the corresponding N-hydroxy tautomer.

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4th

liert. This product was stirred with water for 30 min and isolated again to give the title compound in the form of beige crystals (36.8 g, 57%), mp 133-134 ° C (dec.).

Analysis for C9H15N502S:

found (calc.): C42.15 (42.00), H6.00 (5.88), N 26.96 (27.22), S 12.20 (12.46).

The IR and "tì-NMR spectra were consistent with the structure given.

Example 3 (second reaction stage) N-cyano-N'-methyl-N "- [2 - [[(l-benzyl-3-oxido-4-methylimid-azol-5-yl) methyl] thio] ethyl] guanidine ( IVa)

67.5 g (0.262 mol) of the compound Illa in 1.01 methanol were mixed with 62.0 g (0.521 mol) N-benzylmethyleneimine in 1.01 petroleum ether and the mixture was heated under reflux for 72 hours. The methanol phase was isolated, extracted with petroleum ether and the solvent was evaporated in vacuo at 40 ° C. The semi-crystalline residue was stirred with ether, which led to further crystallization, and the crystals were filtered off. The mother liquor was again concentrated and treated again with ether to give a new batch of crystalline material. The combined product was dissolved in a 1: 4 mixture of methanol and chloroform, the solution was stirred with silica and the silica was filtered off. The filtrate was concentrated in vacuo, the residue was stirred with acetonitrile and the resulting crystals were filtered off and washed with ether to give the title compound (66.0 g, 70%), mp 186-187 ° C (dec).

Analysis for CnH22N6OS:

found (calc.): C56.56 (56.95), H6.17 (6.19), N23.23 (23.45), S 8.78 (8.95).

The IR, 'H NMR and 13C NMR spectra were consistent with the structure given.

Example 4 (second reaction stage) N-cyano-N'-methyl-N "- [2 - [[(l-benzyl-3-oxido-4-methylimid-azol-5-yl) methyl] thio] ethyl] guanidine ( IVa)

12.9 g (50 mmol) of N-cyano-N'-methyl-N "- [[2- (3-oximino-2-oxobutyl) thio] ethyl] guanidine (purple) in 60 ml of methanol were mixed with 9, 0 g (75 mmol) of N-benzyl-methyleneimine and 0.6 g (10 mmol) of acetic acid were mixed and stirred for 18 hours at 25 ° C. The solvent was evaporated in vacuo at 60 ° C. The resulting residue was washed with 100 ml Acetone was heated to reflux for 30 min, with crystallization occurring, and after cooling to 10 ° C, the crystals were filtered off and dried to give the title compound (15.2 g, 85%), mp 183 to 184 ° C ( Dec.).

Example 5 (second reaction stage) N-cyano-N'-methyl-N "- [2 - [[(1-benzyl-3-oxido-5-methyl-imi-dazol-4-yl) methyl] thio] ethyl ] guanidin (Va)

2.57 g (0.010 mol) of compound Illb in 25 ml of methanol were mixed with 2.38 g (0.020 mol) of N-benzylmethyleneimine and heated under nitrogen and under reflux for 17 hours. The resulting solution was evaporated to dryness in vacuo and the residue was crystallized in acetonitrile to give the title compound (2.87 g, 80%), mp 178-180 ° C (dec.).

Analysis for C17H22N6OS

found (calc.): C56.77 (56.96), H6.20 (6.19), N23.61 (23.45), S9.03 (8.95).

The IR and 'H NMR spectra matched the structure given.

Example 6 (removal step) N-cyano-N'-methyl-N "- [2 - [[(3-oxido-4-methylimidazol-4-yl) methyl] thio] ethyl] guanidine (IVb) 5 35.0 g (0.0976 mol) of Compound IVa was suspended in 700 ml of liquid ammonia and 7.2 g (0.31 mol) of sodium was added, followed by 16.7 g (0.31 mol) of ammonium chloride was then removed by heating to room temperature, 200 ml of 10% anhydrous alcohol was added, the reaction mixture was stirred and filtered for 30 min, the filtrate was concentrated in vacuo, the residue was washed with ethyl acetate, the ethyl acetate phase was decanted off and the resulting residue became crystallized in methanol to give the title compound (15.3 g, 58%), mp 161-162 ° C.

Analysis for C10H16N6OS:

found (calc.): C 43.65 (44.75), H 6.00 (6.01), N 30.86 (31.32), S 12.02 (11.95).

The IR, 'H NMR and 13C NMR spectra were consistent with the structure given.

Example 7 (Removal Step) N-Cyano-N'-methyl-N "- [2 - [[(3-oxido-5-methylimidazol-5-25 yl) methyl] thio] ethyl] guanidine (Vb)

3.59 g (10.0 mmol) of compound IVb was dissolved in 100 ml of liquid ammonia, and 0.53 g (23 mmol) of sodium was added in small portions, followed by 1.23 g (23 mmol) of ammonium chloride . The Ammo-30 niak was removed by heating to room temperature, propanol was added, the suspension formed was stirred for 30 minutes and filtered. The filtrate was seeded with compound Vb crystals and cooled. The precipitated crystalline material was filtered off and dried to give the title compound (2.0 g, 75%), mp 176 to 178 ° C (dec.). After recrystallization from dry methanol, the F. rose to 180 to 183 ° C (dec.).

Analysis for C10H16N6OS:

found (calc.): C44.62 (44.75), H5.96 (6.01), N31.24 (31.32), S 11.98, (11.95).

The IR and 'H NMR spectra were consistent with the structure given.

40

45 Example 8 (second reaction stage - Illb - »Vb direct) Compound Vb 2.57 g (10.0 mmol) of compound Illb, 1.15 g (15.0 mmol) ammonium acetate and 0.33 g (11.0 mmol) ) Paraformaldehyde in 50 20 ml of 2N acetic acid were stirred at 65 ° C for 2 hours. HPLC showed a yield of 72% of the title compound. The solvent was removed in vacuo and the residue was adjusted to pH 8 with 3N potassium hydroxide. The solvent was removed in vacuo and the residue 55 was dissolved in chloroform: methanol (4: 1), then stirred with silica and filtered. The filtrate was evaporated in vacuo and the residue was crystallized in methanol, giving 1.20 g of compound Vb. H20 received. The mother liquor gave another batch of compound Vb. H20 60 (0.51 g) by chromatography on silica gel. The overall yield of crystalline compound Vb. H20 was 60%.

Analysis for C10H16N6OS.H-> O:

found (calc.): C41.70 (41.94), H 6.19 (6.34), N29.42 (29.35), S 11.25 (11.20), H20 6.33 (6, 29)

65 After recrystallization from dry ethanol, the F. rose to 181 to 183 ° C (dec.).

The compound was identical to an authentic sample (IR and 'H NMR spectroscopy).

Example 9 (second reaction stage - Illb - »Vb direct) Compound Vb 5.15 g (20.0 mmol) of compound Illb, 2.30 g (20.0 mmol) ammonium dihydrogen phosphate, 1.32 g (10.0 mmol) Ammonium hydrogen phosphate and 0.72 g (24 mmol) of paraformaldehyde in 40 ml of water were stirred at 65 ° C. for 2 hours, after which HPLC analysis showed a compound Vb content of 57%. The reaction mixture was adjusted to pH 8 with aqueous ammonia and the solvent was removed in vacuo. The residue was chromatographed on silica gel using chloroform: methanol (3: 1) as the eluent. The main fraction was crystallized in methanol, giving 2.73 g (48%) of compound Vb. H20 received.

Example 10 (second reaction stage - Illb -> Vb direct)

Compound Vb 3.86 g (15.0 mmol) of compound Illb, 1.61 g (21.0 mmol) ammonium acetate and 0.63 g (21.0 mmol) paraformaldehyde in 40 ml acetic acid were stirred at room temperature for 10 hours . The solvent was removed in vacuo and the residue was chromatographed on silica gel with chloroform: methanol (3: 1) as the eluent. The main fraction was crystallized in methanol, whereby the compound Vb. H20 was obtained (1.71 g, 41%), which was identical to an authentic sample by IR and XH-NMR.

Example 11 (second reaction stage - purple- »IVb direct)

Compound IVb 2.57 g (10.0 mmol) of compound Illa, 1.15 g (11.0 mmol) of ammonium acetate and 0.33 g (11.0 mmol) of paraformaldehyde in 20 ml of 2N acetic acid were added for 2 hours Stirred 65 ° C, then the HPLC analysis showed a content of a compound IVb of 40%. The solvent was removed in vacuo and the residue was adjusted to pH 8 with 3N potassium hydroxide, after which it was again evaporated in vacuo. The residue was chromatographed on silica gel with chloroform: methanol (3: 1) as the eluent. The main fraction was crystallized in methanol to give 0.68 g (25%) of Compound IVb.

Application examples for the production of cimetidine:

Example A (deoxidation stage)

3.00 g (11.2 mmol) of compound IVb and 2.7 g (22 mmol) of trimethylamine sulfur dioxide ((CH3) 3N + -S02 ") in 60 ml of methanol were heated at 130 ° C. in an autoclave for 5 hours After cooling, the reaction mixture was concentrated in vacuo, 6 ml of water and 2.0 g (14.5 mmol) of potassium carbonate were added, so that an almost quantitative yield of crude cimetidine could be isolated (2.83 g, F. 136 to 138 ° C.) After recrystallization, the F. rose to 142 to 143 ° C.

Analysis for C10H16N6S:

found (calc.): C47.60 (47.60), H6.42 (6.39), N32.94 (33.31), S 12.81 (12.71).

The IR and 'HNMR spectra were identical to those of an authentic sample.

Example B (deoxidation stage)

121 mg (0.45 mmol) of compound IVb was dissolved in 4.8 ml of dimethylformamide, 49 mg (0.45 mmol) of formamidinosulfonic acid ((H2N) 2 + C-SO2 ~) was added, and the mixture was Heated to 100 ° C for 1 hour, then HPLC showed that it contained 48% cimetidine.

Example C (deoxidation stage)

2.00 g (7.5 mmol) of compound IVb were dissolved in 40 ml of

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Ethoxyethanol dissolved and 2.70 g (21.9 mmol) of trimethylammonium sulfinate were added and the mixture was heated under reflux for 15 minutes. Subsequently, the HPLC analysis indicated the presence of 72% cimetidine, from which 1.30 g (69%) could be isolated.

Example D (Deoxidation Step) Compound Vb was deoxygenated analogously to the procedure described in Example 11, giving cimetidine.

Example E (Deoxidation of compound Va before removal of the benzyl group) N-cyano-N'-methyl-N "- [2 - [[(1-benzyl-5-methyl-imidazol-4-yl) methyl] thio] ethyl ] guanidine

7.2 g (20 mmol) of the compound of formula Va were refluxed with 1.7 M trimethylamine sulfur dioxide in 24 ml of ethanol for 16 hours. After cooling to 0 ° C., the crystals were filtered off and dried, giving N-cyano-N'-methyl-N "- [2 - [[(l-benzyl-5-methyl-imidazol-4-yl) methyl] thio] ethyl] guanidine (6.2g91%), m.p. 178-179 ° C.

Analysis for CnH22N6S:

found (calc.): C59.53 (59.62), H6.55 (6.48), N24.43 (24.54), S 9.41 (9.36).

The 'H NMR and 13C NMR spectra were consistent with the structure given. Cimetidine can be prepared from this compound as described in Example G below.

Example F (Deoxidation of compound IVa before removal of the benzyl group) N-cyano-N'-methyl-N "- [2 - [[(1-benzyl-4-methyl-imidazol-5-yl) methyl] thio] ethyl ] guanidine

(a) 17.9 g (50 mmol) of the compound of formula IVa were refluxed with 1.7 M trimethylamine sulfur dioxide in 60 ml of ethanol for 5 hours. After cooling to 0 ° C., the crystals were filtered off and dried, giving N-cyano-N'-methyl-N "- [2 - [[(l-benzyl-4-methyl-imidazol-5-yl) methyl] thio] ethyl] guanidine (14.9 g, 87%), mp 173-175 ° C.

Analysis for C17H22N6S:

found (calc.): C 59.81 (59.62), H 6.44 (6.48), N 24.83 (24.54), S9.42 (9.36).

The 'H NMR and 13C NMR spectra were consistent with the structure given.

(b) 3.58 g (10 mmol) of compound IVa was dissolved in 50 ml of methanol and 0.36 g of 5% palladium on carbon was added. The mixture was stirred in a hydrogen atmosphere (1 atm) for 3 days at room temperature. The catalyst was filtered off. The filtrate was evaporated to dryness, 60 ml of acetone was added to the residue and the mixture was heated to reflux. After cooling to room temperature, the crystals were filtered off and dried,

giving the deoxygenated compound (3.05 g, 89%), mp 172-175 ° C.

Example G

274 g (0.80 mol) of the compound from Example F were suspended in 1200 ml of liquid ammonia. 40.0 g (1.74 mol) of sodium were added, followed by 93.1 g (1.74 mol) of ammonium chloride, dissolved in 400 ml of water. The excess ammonia was allowed to evaporate. The resulting suspension was filtered. The precipitate was dried to give cimetidine; (185 g, 92%), mp 138-141 ° C. HPLC indicated 97% purity.

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