DK159309B - METHOD FOR PREPARING 4-METHYL-5-ALKYLTHIOMETHYL-IMIDAZOLES - Google Patents

Description

DK 159309 B

The invention relates to a particular process for the preparation of 4-methyl-5-alkylthiomethylimidazoles of the general formula A shown in claim 1, wherein Alk and Alk have the same meanings stated. The process according to the invention is characterized by the characterizing part of claim 1.

British Patent No. 1,533,380 discloses a process for the preparation of compounds of, for example, the following formula 10

Het-CH 2 -S-CH 2 CH 2 -NH-C 1 NHR 1 wherein Het is a heterocyclic group, e.g., an imidazole group, E is S or NCN and R is H or lower alkyl, by leaving a compound of the formula

Het-CH 2 Z

Wherein Het is as defined above and Z is an interchangeable group, reacting with a mercaptan of the formula

.NCN

p

HS-CH ~ CH "-NH-C

22 x 1

XNHR

Wherein R1 is as defined above.

Spanish Patent No. 463,839 discloses the preparation of cimetidine, N-cyano-N'-methyl-N "- (2 - [(4-methyl-5-imidazolyl) methylthio] -ethyl) -guanidine of the formula

30 H

N CH, JTT p N-Xh2SCH2CH2NHCNHCH3, by treatment of 4-methyl-5-hydroxymethylimidazole with thiourea, followed by reaction with N-cyano-N'-methyl-N "- (2-hydroxyethyl) guanidine.

2

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German Patent Publication No. 2211454 discloses the manufacture of i.a. cimetidine by reaction of a compound of the formula

Het-CH2-Q

wherein Q is a replaceable group and Het is a 4-methyl-5-imidazolyl group, having a compound of formula io hsch2ch2-nh2 to form a compound of formula

Het-CH2SCH2CH2NH2 which is then treated with a compound of formula NR2 3

R Z

20 to form Cimetidine if R is CH 2, R is CN, R is alkyl or aryl and Z is S.

German Patent Laid-Open No. 29 28 857 discloses a process for the preparation of cimetidine, in which first it is known in the known manner to convert chlorodiacetyl with ethylene glycol to a corresponding ethylene ketal hemiketal, which is then reacted with N-cyano-N'-methyl-N - (2-Mercapto-ethyl) -guanidine is converted to N-cyano-N'-methyl-N "- [2- (butane-2,3-dionyl) -thioethyl] -guanidine-ethylene ketal hemiketal of the formula

OH NCN

CHj - ^> {x— c-ch2sch2ch2nh - (! - nhch3 B

IN_! OCH0CH0OH

35 * Å

DK 159309 B

3, and by acid hydrolysis the corresponding o-diketone which is condensed with formaldehyde and ammonia is converted to cimetidine.

The chloro diacetyl used in this process as starting material 5 is completely different from the 1 (4) -halo-3-oxyimino-2-butanone used in the present process (see Example 1 below). Furthermore, chlorodiacetyl is an unstable and difficult-to-handle substance that is allergic and tear-inducing; it cannot be regarded as usable on an industrial scale. The examples of the script also concern the use of only a few grams of material. It is necessary to protect the chlorodiacetyl before reacting with the mercaptan, and although the description states that good yield is obtained, there is no evidence for this since the examples are without yield indications.

After removal of the ketal protection groups, the substituted diacetyl compound formed with formaldehyde / ammonia is cyclized to cimetidine. The only similarity between the cyclization step of the German disclosure and the cyclization step of the process of the present invention is that the latter may be among several other possibilities by means of formaldehyde or a formaldehyde donor and ammonia or an ammonia donor.

25 Both formaldehyde and ammonia are involved in countless chemical reactions with or without ring closure. The two relevant ring closures can be summarized as follows: 30 German submission 2928847:

N

N C / C

C ++ -> C I

»C Vc 35 4

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The invention:

ISLAND

C + i -> C f

N ί V

5 u

Thus, there are two chemically quite different reactions, in which case new types of compound are cyclized. According to German writing, three reactants are used so that it is a C + N + C9 condensation.

10 ^ 6

According to the invention, two reactants are used so that it is a C-N + ONCC condensation. The result of the two condensations are also different products. In the reaction according to the invention, the novel cimetidine N-oxides are formed as reaction products, while the known cimetidine is formed according to the German patent.

No expert could foresee from the German script that cimetidine N-oxides could be prepared in the manner proposed by the invention. The reaction conditions are quite different, and the reaction mechanisms, ie. the fundamental nature of the reactions is fundamentally different.

As mentioned, according to both prior art and the invention, one of the starting materials may have one in common, namely formaldehyde (donor) plus ammonia (donor). However, the common starting material is applied to two essentially different reactants, under different circumstances and with different reaction products.

Thus, in the process of the invention, a compound of formula 30 CH3-C-C-CH2-X (X) is used as starting material

II II

A B

5

DK 159309 B

wherein one of the substituents A and B is NOH and the other is O or NOH. X is a leaving group, for example a halogen atom or a group OZ where Z is a hydrogen atom or, for example, an acyl or tosyl group, or X is NR 1 where R is an alkyl group. Preferred starting materials are the readily available halogen compounds such as, for example, 1-bromo-3-oximino-2-butanone and 4-chloro-3-oximino-2-butanone.

In the first reaction step, compound I is reacted with a compound of formula 10

. NCN

1 S

HSAlk NH-C (II) V 2 x NHAlk 1 2 15 where Alk is a C 1-4 alkylene group and Alk a C 1-4 alkyl group; the reaction preferably takes place in the cold in the presence of sodium ethoxide (or another strong base) to form

20 .NCN

1 ^ CH -C-C-CH 2 -S-Alk -NH-C (III) II II ^ v. N AB ^ NHAlk 6

DK 159309 B

or

Y

Jvch3 <+ lf i ^ NCN (V) 'N ^ CH ^ SAlk NH-C -I 2 V 2 0 x NHAlk 5 1 2 where Alk, Alk and Y have the above meanings.

If Y is different from OH, the compound IV or V is selectively reduced with sodium in ammonia to convert the Y group to hydrogen and before or after the reduction 10 deoxygenates with formamidine sulfinic acid or a complex compound of a trialkylamine and sulfur dioxide to form the final product / S / CH3

A j | NCN

Preferably, cimetidine, where Alk = ^ 2 ^ 4 ° 9 = CH3 * The oxygenation can also occur before the reduction.

20

The compounds of formula III are, as previously mentioned, novel and since they contain numerous reactive positions, it is both unexpected and surprising that they can be converted to imidazole N-oxides in good yields. It is especially surprising that the N-cyanoguanide group 25 can withstand the treatment with the reagents required for the cyclization, and furthermore that according to Zeitschrift fur Chemie, 1J) (1970), 211-215, 2-unsubstituted imidazole N-oxides cannot isolated under reaction conditions analogous to those used in the present process.

Furthermore, the selective reduction of a compound of formula IV or V is unpredictable and quite surprising. A priori, it would be expected that the benzyl C-S bond would be easiest to reduce by known methods and it is surprising that the reducing agent used leaves it intact.

DK 159309B

7

Also, it could not be foreseen that the deoxygenation of compounds IV and V could occur as set forth in claim 1, since there are several other reactive positions open to attack by known deoxygenating agents; the use of these then also leads to unsatisfactory results. It was therefore surprising that it was found that complexes of trialkylamine and sulfur dioxide, e.g. (CH3) 3N + -SO4 FF. Synthesis (1979), 36.

The following examples illustrate the process according to the invention, the individual examples each illustrating a process step in the overall process.

15

Example 1 N-Cyano-N'-methyl-N "- ([2- (3-oxymino-2-oxobutyl) -thio] -tyl) -guanidine (IIla)

Sodium (11.0 g, 0.48 mol) was added to ethanol (250 ml) followed by N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine (II, 76.0 g, Then, 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. ° C until the next day when the precipitated sodium bromide was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in acetonitrile (800 ml) and stirred with silica gel for 30 minutes.

DK 159309 B

after which the silica gel was filtered off and the filtrate was evaporated in vacuo. After trituration with ether, the title compound could be isolated (99.0 g, 80%). Stirring in water followed by filtration gave an analytical product, mp 111-112 ° C.

Calculated for C 9 H 15 N 5 ° 2S: C 42.00; H, 5.88; N, 27.22; S, 12.46 Found: C, 41.97; H, 5.90; N, 27.08; S 12.66 in IR and H NMR spectra were consistent with the structure indicated.

10

Example 2 N-Cyano-N'-methyl-N "- ([2- (2-oxymino-3-oxobutyl) -1io] xyl] guanidine (IIIb)

Sodium (5.75 g, 0.250 mol) was dissolved in ethanol (100 ml) and N-cyano-N'-methyl-N "- (2-mercapto-ethyl) -guanidine (II, 39.6 g, 0.250 mole) in ethanol (60 ml).

The resulting solution was stirred under nitrogen for one hour, then, over 40 minutes at 25 ° C, was added to a solution of 4-chloro-3-oximino-2-butanone (33.9 2Q 9 0.250 mol) in ethanol (80 mL). The resulting solution was left at 5 ° C until the next day, when the precipitate was filtered off and washed with ethanol. The product was stirred with water for 30 minutes and the title compound was isolated as beige crystals (36.8 g, 57%) with melting point 22-133 ° C under decomposition.

Calculated for C CH ^ CC ^S: C, 42.00; H, 5.88; N, 27.22; S, 12.46

Found: C, 42.15; H, 6.00; N, 26.96; S 12.20 IR and H NMR spectra were in accordance with -------------- the structure indicated.

30

Example 3 N-Cyano-N, -methyl-N "- [2 - [[(1-benzyl-3-oxido-4-methylimidazol-5-yl) -methyl] -thio] -ethyl] -guanidine (IVa)

Compound IIa (67.5 g, 0.262 mol) dissolved in meth-22 anol (1000 ml) was mixed with N-benzylmethylenimine (62.0 g, 0.521 mol) in petroleum ether (1000 ml) and the mixture was refluxed for 72 hours . The methanol phase is isolated

DK 159309B

9 was extracted and extracted with petroleum ether and the solvent was evaporated in vacuo at 40 ° C. The semi-crystalline residue was stirred with ether which induced further crystallization and the crystals were filtered off. The mother liquor was again concentrated and treated with ether to give a new harvest of crystalline material. The combined product was dissolved in a 1: 4 mixture of methanol and chloroform, the solution was stirred with silica gel and filtered off. The filtrate was evaporated 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 under decomposition.

Calculated for C C HH ^NgOS: C, 56.95; N, 6.19; N, 23.45; S 8.95

Found: C, 56.56; H, 6.17; N, 23.23; S 8.78 15 1 13 The IR, H-NMR and C-NMR spectra were consistent with the structure indicated.

Example 4 N-Cyano-N'-methyl-N "- (2- [T / 1-benzyl-3-oxido-4-methylimidazol-5-ylmethyl) -thio] ethyl] -guanidine (IVa)

Compound IIa (12.9 g, 50 mmol) in methanol (60 ml) was mixed with N-benzylmethylenimine (9.0 g, 75 mmol) and acetic acid (0.6 g, 10 mmol) and stirred at 25 ° C for 18 hours. hours.

The solvent was evaporated in vacuo at 60 ° C. The residue was boiled under reflux with acetone (100 ml) for 30 minutes to give crystallization.

After cooling to 10 ° C, the crystals were filtered off and dried to give the title compound in a yield of 15.2 g (85%). Mp. 183-184 ° C (dec.).

Example 5 N-Cyano-N1-methyl-N "- (2- [beta-benzyl-3-oxido-5-methylimide-azol-4-yl) -thioethyl] -guanidine (Va)

Compound Hib (2.57 g, 0.010 mol) in methanol (25 ml) was mixed with N-benzylmethylene (2.38 g, 0.020 mol) and heated under nitrogen to reflux for 17 hours. The resulting solution evaporates

DK 159309 B

to dryness in vacuo and the residue crystallized from acetonitrile to give the title compound (2.87 g, 80%), mp 178-180 ° C under decomposition.

Calculated for C H, 6.19; N, 23.45; S 8.95 c Found; C, 56.77; H, 6.20; N, 23.61; S 9.03 in the IR and H-NMR spectra were consistent with the structure indicated.

Example 6 N-Cyano-N1-methyl-N "- [2- (711-oxido-5-methylimidazol-4-yl) -methyl7-thio] ethyl7-guanidine (IVb)

Compound IVa (35.0 g, 0.0976 mole) was suspended in liquid ammonia (700 mL) and sodium (7.2 g, 0.31 mole) was added followed by ammonium chloride (16.7 g, 0.31 mole). ). The ammonia was removed by heating to room temperature, anhydrous ethanol (200 ml) was added, and the reaction mixture was stirred for 30 minutes and then filtered. The filtrate was evaporated in vacuo and the residue was washed with ethyl acetate. The ethyl acetate phase was quenched and the residue crystallized from methanol to give the title compound (15.3 g, 58%), mp 161-162 ° C.

Calculated for C C ^H NNgOS: C, 44.74; H, 6.01; N, 31.32; S 11.95

Found: C, 43.65; H, 6.00; N, 30.86; S 12.02 1 13 1 IR, H-NMR and C-NMR spectra were consistent with the structure indicated.

Example 7 N-Cyano-N1-methyl-N "- 2 - ([(1-oxido-4-methylimidazol-5-yl) -methyl7-thio) ethyl] -guanidine (Vb)

Compound IVb (3.59 g, 10.0 mmol) was dissolved in liquid ammonia (100 ml) and sodium (0.53 g, 23 mmol) was added in small portions followed by ammonium chloride (1.23 g, 23 mmol). The ammonia was removed by heating to room temperature with propanol added and the resulting suspension was stirred for 30 minutes and filtered. The filtrate was seeded with Vb crystals and cooled. The separated crystalline material was filtered off and dried

DK 159309 B

to give the title compound (2.0 g, 75%), mp 176-178 ° C under decomposition. Recrystallization from dry methanol raised the melting point to 180-183 ° C under decomposition.

Calculated for C C ^H NNgOS: C, 44.75; H, 6.01; N, 31.32; S 11.95 5 Found ·. C, 44.62; H, 5.96; N, 31.24; S 11.98 IR and 1 H NMR spectra were consistent with the structure indicated.

Example 8 Direct conversion of Hib to Vb

Compound Hib (2.57 g, 10.0 mmol), ammonium acetate (1.15 g, 15.0 mmol) and paraformaldehyde (0.33 g, 11.0 mmol) in 2N acetic acid (20 ml) hours at 65 ° C. HPIiC (high pressure liquid chromatography) indicated a yield of 72% Vb. 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 dissolved in a mixture of chloroform and methanol (4: 1) followed by stirring with silica gel and filtration.

The filtrate was evaporated in vacuo and the residue crystallized from methanol to give 1.20 g of the monohydrate of Vb. The mother liquor gave a further harvest of Vb, H 2 O (0.51 g) by chromatography on silica gel. The total yield of Vb, H 2 O was 60%.

Calcd for Cl () H 16 N 60 S, H 2 O: C 41.94; H 6.34; N, 29.35; S, 11.20; H20 6.29

Found: C, 41.70; H, 6.19; N, 29.42; S, 11.25; H20 6.33

Recrystallization from dry ethanol increased the melting point to 181-183 ° C during decomposition.

The compound was identical to an authentic sample 1 (IR and H-NMR spectroscopy).

Example 9 35 Direct conversion of Hib to Vb

Compound Hib (5.15 g, 20.0 mmol), ammonium dihydrogen phosphate (2.30 g, 20.0 mmol), ammonium hydrogen phosphate

DK 159309 B

12 (1.32 g, 10.0 mmol) and paraformaldehyde (0.72 g, 24 mmol) in water (40 ml) were stirred for 2 hours at 65 ° C, after which an HPLC analysis showed a 57% content of the compound Vb. The reaction mixture was adjusted to pH 8 with ammonia water and the solvent removed in vacuo. The residue was chromatographed on silica gel with chloroform methanol (3: 1) as eluent. The major fraction thereof was crystallized from methanol to give 2.73 g (48%) of V

Example 10 1 0 Direct conversion of Hib to Vb

Compound Hib (3.86 g, 15.0 mmol), ammonium acetate (1.61 g, 21.0 mmol) and paraformaldehyde (0.63 g, 21.0 mmol) in acetic acid (40 ml) was stirred for 10 h. room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel with chloroform methanol (3: 1) as eluent. The major fraction was crystallized from methanol to give Vb, H ~ 0 (1.71 g, 41%) obtained by IR and H-NMR spectroscope! could appear to be identical to an authentic sample.

20

Example 11

Direct conversion of Illa to IVb

Compound IIa (2.57 g, 10 mmol), ammonium acetate (1.15 g, 11.0 mmol) and paraformaldehyde (0.33 g, 11 mmol) in 2N acetic acid (20 ml) was stirred for 2 hours at 65 ° C. ° C, after which an HPLC analysis showed a content of 40% IVb. The solvent was removed in vacuo and the residue was adjusted to pH 8 with 3N potassium hydroxide and then evaporated in vacuo. The residue was chromatographed on silica gel with chloroform-methanol (3: 1) as eluent. The main fraction was crystallized from methanol to give 0.68 g (25%) of IVb.

35

DK 159309 B

13

Example 12 N-Cyano-N'-methyl-N "- (2- [T4-methylimidazol-5-yl) methyl) -thio7-yl] -guanidine (cimetidine)

Compound IVb (3.00 g, 11.2 mmol) and trimethylamine sulfur dioxide ((CH 3) 3 N + -SO ~ 2.7 g, 22 mmol) in methanol (6 mL) was heated in an autoclave to 130 ° C for 5 minutes. hours. After cooling, the reaction mixture was concentrated in vacuo.

Water (6 ml) and potassium carbonate (2.0 g, 14.5 mmol) were added to allow a near-isolation. quantitative yield of crude cimetidine (2.83 g, mp 136-138 ° C).

10 o'clock

Upon recrystallization, the melting point was raised to 142-143 ° C.

Calculated for C10H16N6S: C, 47.60? H, 6.39; N, 33.31; S, 12.71

Found: C 47.60? H 6.42; N, 32.94; S, 12.81

The IR and NMR spectra are identical to those for an authentic sample.

15

Example 13 Cimetidine

Compound IVb (121 mg, 0.45 mmol) was dissolved in dimethylformamide (4.8 ml) added to formamidine sulfinic acid ((1N) 2 -C.SO 4, 49 mg, 0.45 mmol), and the mixture was heated to 100 ° C for one hour, after which it could be shown by HPLC to contain 48% cimetidine.

Example 14 Cimetidine

Compound IVb (2.00 g, 7.5 mmol) was dissolved in 2-ethyl-oxyethanol (40 ml), added with trimethylammonium sulfinate (2.70 g-21.9 mmol), and the mixture was heated under reflux for 15 minutes. . Analysis by HPLC then showed the presence of 72% cimetidine from which 1.30 g (69%) could be isolated.

Example 15

cimetidine

By analogy to the method described in Example 12, compound Vb was deoxygenated to cimetidine.

35 14

DK 159309B

Example 16

Deoxygenation of Compound V before Removal of the Benzyl Group N-Cyano-N'-Methyl-N "- (2- [7- (Benzyl-5-methylimidazol-4-yl7-methyl) -thioethyl) -guanidine (A)"

Compound Va (7.2 g, 20 mmol) was refluxed for 16 hours with 1.7M trimethylamine sulfur dioxide in ethanol (24 ml). After cooling to 0 ° C, separated crystals were filtered off and dried to give the title compound (6.2 g, 91%), m.p. 178-179 ° C.

10

Calculated for C C HH NNgS: C, 59.62; H 6.48; N, 24.54; S, 9.36

Found: C, 59.53; H, 6.55; N, 24.43; S 9.41 1 13 The H-NMR and C-NMR spectra correspond to the structure indicated.

15,

Example 17

Deoxygenation of Compound IVa before removal of the benzyl group N-Cyano-N * -methyl-N "- [2 - ([U-benzyl-4-methylimidazol-5-yl) methyl] thio] ethyl7-guanidine (B). Method I.

20

Compound IVa (17.9 g, 50 mmol) was refluxed for 5 hours with 1.7M trimethylamine sulfur dioxide in ethanol (60 ml). After cooling to 0 ° C, separated crystals were filtered off and dried to give the title compound (14.9 g, 87%) with m.p. 173-175 ° C.

25

Calculated for C C HH NNgS: C, 59.62; H 6.48; N, 24.54; S, 9.36

Found: C, 59.81; H 6.44; N, 24.83; S 9.42 1 13 The H-NMR and C-NMR spectra correspond to the structure indicated.

30 35

DK 159309 B

15

Example 18 N-Cyano-N'-methyl-N "- [2 ([74-methylimidazol-5-yl) -methyl] -thio) -ethyl] -guanidine (cimetidine)

Compound B (274 g, 0.80 mol) was suspended in liquid ammonia (1200 ml). Sodium (40.0 g, 1.74 mol) was added followed by ammonium chloride (93.1 g, 1.74 mol) dissolved in water (400 ml). Excess ammonia is allowed to evaporate. The resulting suspension was filtered. The precipitate was dried to give the title compound (185 g, 92%) at 10 m.p. 138-141 ° C. HPLC showed a purity of 97%.

. · ..% * 15 20 25 30 35

Claims (4)

A process for the preparation of 4-methyl-5-alkyl-thioimidazoles of the general formula 5> NVCH3 · in NCN λ CH9S Alk '-NH-C ^ H \ 2 NHAlk 10 1 wherein Alk is an alkylene group of 1-4 carbon atoms and 2 Alk an alkyl group having 1-4 carbon atoms characterized by reacting a compound of formula 15 ch, -cc-ch9x IAB where X is a leaving group and one of the substituents 2q is A and B is NOH and the other O or NOH, with a compound of the formula NOT HS-Alk1-NH-CT II 25. NHAlk2 1 2 wherein Alk and Alk have the above meanings to form a compound of the formula .NCN 30. S H-2C-C-C-CH0-S-Alk -NH-C III 3 || The compound is then cyclized to a compound of formula IV B or VB by treatment with formaldehyde or a formaldehyde donor, or mixtures of formaldehyde and / or formaldehyde donors and ammonia or an ammonia donor, DK 159309 B or a compound having Formula IVA or VA having a reagent of formula YN = CH2 wherein Y is OH or a protecting group of the aralkyl type which is removed by reduction to form an imidazole N-oxide of formula 5 ° o / SrCH3 'ηΛ CH.SAlkWc ^ 1 * ™, A in 2 ^ NHAlk2 or Y in N s-, CH- (li v A CH.SAlk1NH-C ^ NCN, _ '^ NHAlk2 Wherein Y, Alk and Alk have the meanings set forth above, which N-oxide is selectively reduced by Na in ammonia to the mono-N-oxide 20 "o CH3 N ^ ch-saiAh-c ^ 0 ** 9 IV B i ^ NHAlk H or H New CH3 \ JL 1 ncn vb + N CH-SAlk NH-C JW -30-0 "NHAlk2 if Y is different from OH and partly before or after the reduction is deoxygenated with formamidine sulfinic acid or a complex compound of a trialkylamine and sulfur dioxide 35 DK 159309 B Process according to Claim 1, characterized in that X is halogen, acyloxy or tosyloxy, or NR 2, wherein R 1 is alkyl. Process according to claim 1 or 2, characterized in that Alk 2 is C 1 -C 2 and Alk 2 is CH 2. 4. A process according to claim 1, 2 or 3, characterized in that the first reaction step is carried out in the cold in the presence of sodium ethoxide. 10 15 20 25 30 35