FR2534256A1 - - Google Patents

Abstract

A NEW PROCESS IS DESCRIBED FOR THE PRODUCTION OF 4-METHYL-5-ALKYL-THIOMETHYL-IMIDAZOLES, IN PARTICULAR CIMETIDINE OF FORMULA: (CF DRAWING IN BOPI) OR ALK IS PREFERRED -CH-CH AND ALK PREFERREDLY CH. UNEXPECTEDLY, THE PROCESS IS CARRIED OUT WITH EXTREMELY GOOD PERFORMANCE.

Description

-1 -

  Process for producing imidazoles and novel processes

  mediates for use in the process.

  The invention relates to a novel method for

  the manufacture of 4-methyl-5-alkylthiomethylimidazoles.

  In British Patent No. 1,533,380 there is disclosed a process according to which compounds, for example of the following formula: Het-CH 2 -S-CH 2 CH 2 NH-C ENHR 1

  are produced, in which Het is a heterocyclic group

  for example, an imidazole group, E is S or NCN-and R 1 is H or lower alkyl, leaving a compound of the formula: Het-CH 2 Z wherein Het is defined as above and Z is a mobile group or interchangeable (leaving) react with a mercaptan of formula:

HS-CH 2 CH 2 -NH-C NHNR 1

1 "NHR

  wherein R is defined as above.

  Spanish Patent No. 463,839 describes the preparation of

  Cimetidine, N-cyano-N-methyl-N "-L 2-1 (4-methyl-5-

  imidazolyl) methylthiol-ethyl-guanidine by treating 4-methyl-

  -hydrozymethylimidazole with thiourea followed by the reaction

  with N-cyano-N'-methyl-N "- (2-hydroxyethyl) guanidine.

  German Patent No. 2,211,454 describes the preparation of, for example, cimetidine, leaving: Het-CH 2 -Q wherein Q is a mobile group and Het is a 4-methyl-5-imidazolyl group, reacting with

HSCH 2 CH 2 NH 2

  to form Het-CH 2 SCH 2 CH 2 NH 2 which is subsequently treated with:

3 2 NR 2

R 3 Z-C NHRR 1

  to give, for example, Cimetidine or R is CH 3, R 2 is CN, R is alkyl or aryl and Z is S. It is known that the starting materials, i.e. substituted imidazoles, for these methods, and others

  known methods are not easy to obtain and the pre-

  this method, therefore, employs a total approach

  different, both from the starting material and from the reactions,

  In the process according to the present invention, the material

  The starting material consists of a compound:

CH 3 C-CCH 2 X

lil (1)

AB

  Wherein one of the substituents A and B is NQH and the other is O or NOH X is a suitable leaving group, for example a halogen or OZ, wherein Z is a hydrogen atom or an acyl group or an tosyl group, or X is NR 3-wherein R is alkyl; the preferred starting material being the readily available halogen compounds, for example: 1-bromo-3-oximino-2-butanone 4-chloro-3-oximino-2-butanone compound (I) is treated in a first step with: NCN HS Alk NH-C 2 Alk NH (I) preferably cold, in the presence of a strong base, such as Na ethoxide, to give: NCN CH 3 C-CCH 2 S Alk NH -C 2 NNH Alk 2 (III) in which Alk is an alkylene group and Alk 2 is a

  alkyl group having 1 to 4 carbon atoms.

  3 - Compounds (III) are new and constitute another

aspect of the invention.

  In a second step, the compound III is closed in a ring by treatment with formaldehyde or a donor of (body

  yielding formaldehyde, for example paraformaldehyde or

  Formaldehyde and / or formaldehyde donors and ammonia or ammonia donors, eg ammonium acetate or reagents of the formula YN = CH 2 wherein Y is HO or preferably aralkyl, although other groups may also be appropriate, to give an imidazole N-oxide IV or V.

+ N CH 3,

1 a NCN

1 N CH 2 SCH 2 CH 2 NH-C (IV)

1 2 y _-NHCH 3 Y Y

N CH 3

i j s ,, NCN

+ N CH 2 SCH 2 CH 2 NH-C (V)

NNHCH 3

  Where Y is defined as above, or -H when Y is H, the

  compound may consist of a mixture of two tauto-

  mothers, for example an N-oxide and the corresponding N-hydroxy tautomer. Compound IV or V is then selectively reduced, if Y is other than H or OH, to reduce the group Y to H and finally deoxygenated to give the desired product: N

<N 'CH 3

  <N CH 2 S Alk 1 -NH-C / NCN \ NH Alk 2H 4 - which, in the preferred use of Alk 1 = CH 4 and Alk 2 = CH :, is Cimetidine Deoxygenation can

  also take place before the reduction.

  Compounds III were previously unknown, and since they contain a multitude of reactive sites, it is both unexpected and surprising that they can

  be transformed into imidazole N-oxides with good yields

  It is particularly surprising that the part

  N-cyanoguanidine may be treated with the

  necessary for ring looping, and in addition,

  according to the "Zeitschrift fur Chemie" 10 (1970), 211-

  215, the 2-unsubstituted imidazole N-oxides can not be isolated under reaction conditions analogous to

  those used in the present invention.

  The selective reduction of IV and V was unpredictable and quite surprising; a priori we would expect the benzyl C-S bond to be the most easily

reduced by known methods.

  Nor was it foreseeable that the deoxygenation of compounds IV and V could be undertaken because of

  number of other reactive sites that are open for

  by the known deoxygenation reagents, and the

  use of these also leads to unsatisfactory results.

  In a surprising way, it has been found that

  sulfur dioxide-trialkylamine plexes, for example (CH 3) 3 N -SO 2, or formamidinosulfinic acid gave the desired product in good yield. The resulting sulfur trioxide would have been expected to

  sulphonic acid gives unreliable lateral reactions.

some (see Synthesis, 1979, 36).

  The following examples illustrate the present invention.

  Example 1 (first step of the reaction) N-Cyano-N'-methyl-N "- {{2- (3-oximino-2-oxobutyl) thio} ethyl}

guanidine (II Ia).

  Sodium (11.0 g, 0.48 mol) was added to ethanol (250 mL) followed by N-cyano-N-methyl-N "- (2-mercaptoethyl)

guanidine (11.73 g, 0.48 mol).

  To the above mixture, a solution of 1-bromo-3-oximino-2-butanone (86.0 g, 0.524 mol) in anhydrous ethanol (250 ml) was added dropwise at 20-25 ° C. The reaction mixture was left at 5 ° C overnight, the sodium bromide precipitate was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in acetonitrile (800.degree. ml) and stirred with

  silica for 30 minutes, the silica was then

  Filtered, and the filtrate was evaporated in vacuo.

  After trituration with ether, the title compound was able to

  isolated (99.0 g, 80%) by shaking with water and

  trage, an analytically pure sample was obtained.

  M.p. 111-112 C C 9 H 15 N 502 S; Found (Calc): C 41.97

  (42.00), H 5.90 (5.88), N 27.08 (27.22), S 12.66 (12.46).

  The IR and H-NMR spectra are in agreement with the structure

indicated.

  Example 2 (first step of the reaction) N-Cyano-N'-methyl-N "-f- (2- (2-oxo-3-oxobutyl) -thio} ethyl}

guanidine (II Ib).

  Sodium (5.75 g, 0.250 mol) was dissolved in ethanol

  (100 ml) and added to N-cyano-N'-methyl-N "- (2-mercapto)

  ethyl) guanidine (II, 39.6 g, 0.250 mol) in ethanol (60 ml) The resulting solution was added under nitrogen

  for 1 hour, and then added to a solution of 4-chloro

  3-oximino-2-butanone (33.9 g, 0.250 mol) in ethanol (80 ml) for a period of 40 min at 250 ° C. The resulting solution was kept overnight at 5 ° C., and the precipitate isolated by followed by washing with ethanol This product was stirred in water for 30 min, and reisolated to give the title compound (36.8 g, 57%) as

  of beige colored crystals P F 133-134 QC (dec).

  C 9 H 15 N 502 S, found (Calc) C 42.15 (42.00), H 6.00 (5.88)

915 5 2

  N 26.96 (27.22), S 12.20 (12.46) The IR and H-NMR spectra are in agreement with the indicated structure. Example 3 (second stage of the reaction)

  N-Cyano-N-methyl-N "- {2 - {{(1-benzyl-3-oxido-methylimidazole)

  -yl) methyl} thio} ethyl} guanidine (I Va). Compound II Ia (67.5 g, 0.262 mol) in methanol (1.0 L) was mixed with N-benzylmethyleneimine (62.0 g, 0.521 mol) in petroleum ether (1.0 g). 1) and the mixture has been

  reflux for 72 h The methanol phase was isolated, ex-

  treated with petroleum ether and the solvent was evaporated, in vacuo, at 40 ° C. The semicrystalline residue was

  agitated with ether, which caused another crystal

  and the crystals were separated by filtration.

  The mother liquor was concentrated again and again treated with ether, allowing a new crystal crop. 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,

  stirred with acetonitrile, and the resulting crystals

  both were filtered off and washed with ether

  to give the title compound (66.0 g, 70%) P F 186-

  187 C (dec) C 17 H 22 N 60 S; found (Calc) C 56.56 (56.95), H 6.17 (6, 19), N 23.23 (23.45) S 8.78 (8.95) Spectra

1 13

  IR, 1 H-NMR and 1 C-NMR are in agreement with the structure

indicated.

  Example 4 (second stage of the reaction) N-Cyano-N'-methyl-N "- {2 - {{(Ibenzyl-3-oxo-4-methyl)

  imidazol-5-yl) methyl} thio} ethyl} guanidine (I Va).

  N-Cyano-N-methyl-N "- {{2- (3-oxymino-2-oxobutyl) -

  thio} ethyl guanidine (II Ia) (12.9 g, 50 mmol) in methanol (60 ml) was mixed with N-benzylmethyleneimine (9.0 g, 75 mmol) and Acetic acid (0.6 g, 10 mmol) then stirred at 25 ° C. for 18 h. The solvent was evaporated in vacuo at 5.degree. C. The resulting residue was refluxed with acetone (100 ml) for 30 minutes. After which crystallization occurred. After cooling to 10 ° C the crystals were filtered off and dried to give the title compound (15.2 g 85%) mp 183-184 ° C (dec).

  Example 5 (Second step of the reaction).

  N-Cyano-N-methyl-N "- {2 {(1-benzyl-3-oxo-5-methylimidazole)

  zol-4-yl) methyl} thio} ethyl} guanidine (Va).

  Compound II Ib (2.57 g, 0.010 mol) in methanol (25 ml) was mixed with N-benzylmethyleneimine (2.38 g, 0.020 mol) and heated under nitrogen at reflux for 17 h. evaporated to dryness in vacuo and the residue crystallized from acetonitrile to give

  the title compound (2.87 g, 80%, mp 178-180 ° C dec).

  C 17 H 22 N 6 OS; found (Calc) C 56.77 (56.96), H 6.20 (6.19), N 23.61 (23.45), S 9.03 (8.95) IR and H-NMR spectra

  are in accordance with the indicated structure.

  Example 6 (extraction step) N-Cyano-N'-methyl-N "- {2 {{(1-oxo-5-methylimidazol-4-yl)

  methyl} thio} ethyl} guanidine (I Vb).

  Compound I Va (35.0 g, 0.0976 mol) was suspended in liquid ammonia (700 mL) and sodium (7.2 g, 0-, 31 mol) was added followed ammonium chloride (16.7 g, 0.31 mol). The ammonia was then removed by heating at room temperature, anhydrous alcohol (200 ml) was added, and the reaction mixture was stirred. stirred for 30 min and then filtered. The filtrate was concentrated,

  in vacuo the residue was washed with ethyl acetate.

  The ethyl acetate phase was separated by decantation, and the resulting residue crystallized from methanol to give

  give the title compound (15.3 g, 58%) mp 161-162 ° C.

  8 - C 10 H 16 N 6 OS; found (Calc) C 43.65 (44.75), H 6.00 (6.01), N 30.86 (31.32), S 12.02 (11.95) IR spectra 1 H-NMR and 13 C-NMR are in agreement with the indicated structure. EXAMPLE 7 (Extraction Step) NCyano-N'-methyl-N "- {2 - {{(1-oxo-4-methylimidazol-5-yl)

  methyl} thio} ethyl} guanidine (Vb).

  Compound I Vb (3.59, 10.0 mmol) was dissolved in liquid ammonia (100 ml) and sodium (0.53 g, 23 mmol) was added in small proportions, followed by chloride ammonium (1.23 g 23 mmol) The ammonia was removed by heating at room temperature; propanol has been added,

  the suspension formed was stirred for 30 minutes and filtered.

  The filtrate was inoculated with Vb crystals and cooled

  The precipitated crystalline product was separated by filtration.

  The residue was dried and dried to give the title compound (2.0 g, 75%) mp 176 ° -178 ° C. (dec) Recrystallization from dry methanol raised the mp to 180 ° -183 ° C. (dec) C 10 H 16 N 60 S; found (Calc) C 44.62 (44.75), H 5.96 (6.01), N 31.24 (31.32), S 11.98 (11.95) IR and 1H-spectra NMR are in agreement

with the indicated structure.

  Example 8 (Second step of the IIIB Vb reaction directly)

Compound Vb.

  Compound II Ib (2.57 g, 10.0 mmol), ammonium acetate,

  ium (1.15 g, 15.0 mmol) and paraformaldehyde (0.33 g, 11.0

  mmol) in 2 N acetic acid (20 ml) were stirred

  2 hours at 65 ° C HPLC indicates a 72% yield of

  The solvent was removed in vacuo, and the residue adjusted to pH 8 with 3 N potassium hydroxide. The solvent was removed in vacuo and the residue was dissolved in chloroform-methanol (4: 1), followed by stirring with silica and filtering. The filtrate was evaporated in vacuo and the residue was crystallized from methanol to give 1.20 g of Vb, H. The mother liquor provided another crop of Vb, H. (0.51 g) by silica gel chromatography The total yield of crystals Vb, H was 60% C 10 H 16 N 6 OS, H 20; found (Calc) C 41.70

  (41.94), H 6.19 (6.34), N 29.42 (29.35), S 11.25 (11.20),

  6.33 (6.29) Recrystallization from dry ethanol raised the pH to 181 ° -183 ° C. (dec) The compound is identical to an authentic sample (IR spectrometer and

1 H-NMR).

  Example 9 (Second stage of reaction II Ib) Vb directly)

Compound Vb.

  Compound II Ib (5.15 g, 20.0 mmol) of ammonium dihydrogenphosphate (2.30 g, 20.0 mmol), ammonium hydrogenphosphate (1.32 g, 10.0 mmol) and paraformaldehyde (0.72 g, 24 mmol) in water (40 ml) were stirred for 2 h at 65 ° C; after which the HPLC analysis showed 57% of compound Vb. 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. silica with chloroformemethanol (3: 1) as the eluent The main fraction of this was crystallized with

  methanol to give 2.73 g (48%) of Vb; H 20.

  Example 10 (Second step of the reaction -III b Vb directly)

Compound Vb.

  Compound II Ib (3.86 g, 15.0 mmol) of ammonium acetate (1.61 g, 21.0 mmol) and paraformaldehyde (0.63 g, 21.0 mmol) in Acetic acid (40 ml) was stirred for h at room temperature, the solvent was removed in vacuo and the residue was chromatographed on silica with chloroform-methanol (3: 1) as eluent. methanol to give

  Vb, H (1.71 g, 41%), identical with IR and 1 H-NMR at

  authentic sample, - Example 11 (Second stage of the reaction II Ia I Vb)

Compound I Vb.

  Compound II Ia (2.57 g, 10.0 mmol) of ammonium acetate (1.15 g, 11.0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2 N acetic acid (20 ml) was stirred for 2 hours at 65 ° C; after which HPLC analysis showed 40% by weight of the solvent was removed in vacuo, and the residue was adjusted to pH 8 with 3N potassium hydroxide, followed by further evaporation, in vacuo. The residue of this

  was chromatographed on silica gel with chlorine

  form-methanol (3: 1) as eluent The main fraction was crystallized from methanol to give 0.68 g

(25%) I Vb.

  Example 12 (Deoxidation step) N-Cyano-N'-methyl-N "- {2- {4-methylimidazol-5-yl) methyl}

  thiolethyl guanidine (Cimetidine).

  Compound I Vb (3.00 g, 11.2 mmol) trimethylamine sulfur dioxide ((CH 3) 3 N -SO 2, 2.7 g, 22 mmol) in methanol

  (60 ml) were heated at 130 ° C. for 5 hours in an autoclave

  After cooling, the reaction mixture was concentrated in vacuo. Water (6 ml) and potassium carbonate (2.0 g, 14.5 mmol) were added, which allowed the isolation of the reaction mixture. almost quantitative yield of crude Cimetidine (2.83 g, mp 136-138 O) After recrystallization, the mp was raised to 142-143 ° C 10 H 16 N 6 S; found (Calc)

  C-47.60 (47.60), H 6.42 (6.39), N 32.94 (33.31), S 12.81

  (12,71) The IR and HNMR spectra are identical to those

an authentic sample.

  Example 13 (Deoxidation step) Cimetidine Compound I Vb (121 mg, 0.45 mmol) was dissolved in

  dimethylformamide (4.8 ml), formamidinosulfide

  (H 2 N) 2 C-202, 49 mg, 0.45 mmol) was added and the mixture was heated at 100 ° C for 1 h; after which we 11 -

  found that it contained 48% of Cimetidine by HPLC.

  Example 14 (Deoxidation step)

  Cimetidine. Compound I Vb (2.00 g, 7.5 mmol) was dissolved in 2-ethoxyethanol (40 ml), trimethylammonium sulfinate (2.70 g, 21.9 mmol) was added and the mixture was heated. at reflux for 15 minutes. Then, analysis by HPLC showed the presence of 72% of Cimetidine, of which 1.30 g, 69%

could be isolated.

  Example 15 (Deoxidation step) Cimetidine. Compound Vb was deoxygenated analogously to

  the method described in Example 11 to give Cime-

  tidine. Example 16 (Deoxidation of V before removal of the benzyl group) N-Cyano-N'-methyl-N "- {2 - {{(1-benzyl) -5-methyl imidazol

  4-yl) methyl} thio} ethyl} guanidine (A).

  N-Cyano-N'-methyl-N "- {2 {{(1-benzyl-3-oxo-5-methyl)

  imidazol-4-yl) methyl} thio} ethyl} guanidine (V) (7.2 g,

  mmol) was refluxed with 1.7 M trimethylamine.

  Sulfur dioxide in ethanol (24 ml) for 6 h After cooling to OC, the crystals were filtered off and dried to give the title compound (6.2 g, 91%) mp 178-179 ° C 17 H 22 N 6 S; found (Calc)

  C 59.53 (59.62), H 6.55 (6.48), N 24.43 (24.54), S 9.41

  (9,36) The H-NMR and 13 C-NMR spectra are consistent with

the indicated structure.

  Example 17 (Deoxidation of I Va before removal of the benzyl group)

  N-Cyano-N'-methyl-N "- {2 - {{(1-benzyl-4-methyl) imidazole

  -yl) methyl} thiolethyl} guanidine (B) Method I. 12 -

  N-Cyano-N'-methyl-N "- {2 - {(1-benzyl-3-oxo-4-

  methyl-imidazol-5-yl) methyl} thio} ethyl} guanidine (IVa)

  (17.9 g, 50 mmol) was refluxed with 1.7 M trimethyl-

  amine sulfur dioxide in ethanol (60 ml) for 5 hours. After cooling to 0 ° C, the crystals were filtered off and dried to give the title compound (14.9 g, 87%) mp 173-175 ° C; found (calc)

17 22 6

  C 59.81 (59.62), H 6.44 (6.48), N 24.83 (24.54), 59.42

  (9,36) The spectra H-NMR and T 3 C-NMR are in agreement

with the indicated structure.

Example 18

(B) Method II.

  Compound IVa (3.58 g, 10 mmol) was dissolved in methanol (50 mL) and 5% palladium on carbon (0.36 g) was added. The mixture was stirred in an atmosphere. Hydrogen (1 atm) for 3 days at room temperature Catalyst was filtered. The filtrate was evaporated to dryness; To the residue was added acetone (60 ml) and heated to reflux. After cooling to room temperature, the crystals were filtered off and dried to give the title compound

(3.05 g, 89%) mp 172-175C.

  Example 19 (Removal of benzyl group) N-Cyano-N-methyl-N "- {2 - {{(4-methylimidazol-5-yl) methyl}

  thiolethyl guanidine (Cimetidine).

  Compound B (274 g, 0.80 mol) was suspended in liquid ammonia (1200 U ml). Sodium (40.0 g, 1.74 mol) was added followed by sodium chloride. ammonium (93.1 g, 1.74 mol) dissolved in water (400 ml) Oh evaporated

  the excess of ammonia The suspension obtained was filtered.

  The precipitate was dried to give the title compound (185 g, 92%) 138-141 ° C HPLC indicates purity of

97%.

Claims (4)

claims   4 Process for the manufacture of 4-methyl-5-alkylthio- imidazoles, of general formula: N CH   Embedded image Alk 1 is an alkylene group and Alk is an alkyl group having 1-4 carbon atoms, comprising reacting the compounds of formula: ## STR2 ## CH C-CCH X   X is a mobile group and one of the substituents A and B is NO Hr, the other being O or NOH, with a compound of the formula: NCN HS Alk NH C Hk C 2 NH Alk o Alk and Alk are defined as above to give: - NCN CH 3 C-CCH 2 S Alk NH-C 2 I II NH Alk 2 AB 2 NH Alk B which is then looped in a ring by treatment with formaldehyde or a formaldehyde ring, or mixtures   formaldehyde or formaldehyde and ammonia   nium or an ammonia donor, or reagents of the formula: YN = CH 2   o Y is H or a removable group to form: -0 + 1 C NCN   ## STR5 ## ÈNH Alk-   14 - o, if Y is H or OH is deoxygenated to give the desired product, and if Y is other than H or OH is subjected to a separate reduction and deoxygenation reactions   to reduce the group Y to H and remove the oxygen, respec-   to give the desired product. The process according to claim 1, wherein X is a halogen,   acyloxy or tosyloxy, or NR 3 o R is alkyl.   3. Process according to claim 1, wherein Alk 1 is CH 2 CH 2 and Alk is CH 3.   As a novel product for use in the process of claim 1, the compounds having the formula: 4 NCN CH 3 C-C-CH 2 SCH 2 CH 2 NH-C 3, A B 2 22 NHCH 3   one of the substituents A and B is NOH and the other is O or NOH.