HU187792B - Process for producing 1-alkyl-5-mercapto-1h-tetrazoles of high purity - Google Patents

Abstract

The procedure is of high purity general formula 1 - where R is straight or C 1 -C 4 branched alkyl Compound II. general image - where R is the same as above compound and sodium azide in an aqueous alcoholic medium in the form of sodium azide in aqueous or aqueous and methanolic solutions stirring and heating at a steady pace 2.5 to 10 hours, preferably 6 hours, is added to General 11 a methanolic solution of the compound of Formula I and then at the end of dosing for 0.5 to 5 hours, preferably 2 hours stirring the reaction mixture at the source temperature, the methanol is then evaporated, the residue remaining pH at 0 ° C with mineral acid, preferably HCl to pH 1.0, then a) the crystals are filtered off, washed and dried and treating the mother liquor according to method b), or b) reacting the reaction mixture with a water immiscible organic compound. extracted with a solvent, preferably chloroform, to extract crystallization after drying evaporate and then boil after boiling solution is liquid, straight or branched with a mixture of hydrocarbons, preferably petroleum ether saturated, the crystals formed are filtered, washed dried. The product is for the production of semi-synthetic antibiotics used as an intermediate.

Description

The present invention relates to a process for the preparation of high purity 1-alkyl-5-mercapto-1H-tetrazoles.

The main applications of 1-alkyl-5-mercapto-1H-tetrazoles are in the photographic and pharmaceutical industries. While 1-alkyl-5-mercapto-1H-tetrazoles of various chain lengths have been used in photography to stabilize silver halides of photographic emulsions, U.S. Patent No. 2,403,927 has been used in the pharmaceutical industry for the past five years in the field of cephalosporin chemistry. -mercapto-1H-tetrazole has gained large-scale use. This compound is a constituent of many modern cephalosporin antibiotic formulations (Cefamandol, Cefazaflor, Cefaperazonc, Cefmetazole, Moxalactam, etc.) [O'Callaghau C .: .1. Antimicrob. Chemoth. 5, 635 (1979)]. Synthesis of these cephalosporin antibiotics generally requires highly purified 1-methyl-5-mercapto-1H-tetrazole.

1-Methyl-5-mercapto-1H-tetrazole was first reported by Stolle et al. Berichte, 55, 1291 (1922), J. Prakt. Chem. 124, 261 (1930), J. Pract. Chem. 133, 60 (1932)] from methyl isothiocyanate and sodium azide in a 95% ethyl alcohol medium with the introduction of carbon dioxide at reflux for 8 hours, yielding 88%.

In 1959, Licber et al. [Can. J. Chem 37, 101 (1959) 1 -. Same ^Ίζ foregoing starting products, also an aqueous medium, the target compound was isolated in 52% yield after 8 hours of reflux.

1963 n Orth et al. [J. Pharm. Sci. 52, 909 (1963)] prepared the desired final product in the same manner as in the prior art, in 52% yield.

According to other methods, U.S. Patent No. 2,386,869 to Orth, R.E., J. Pharrn. Sci. 51, 862 (1962), 2,465.149. U.S. Pat. No. 5,194] at various temperatures, prepared N-methyldithiocarbamic acid derivatives and sodium azide in aqueous alcohol to produce 1-methyl-α-α-β-captapto-1 H-tetrazole. However, the authors did not report any returns or only reported extremely low (7%) production.

One of the recent syntheses by Raap et al. published [Raap, R .; Can. J. Chem. 49, 2139 (1971)]. According to this, l-melyltetrazole was reacted with elemental sulfur in a tetrahydrofuran medium at low temperature (-65 ° C) under nitrogen atmosphere to give the target compound in 67% yield.

In 1958, Lieber et al. [Chem. Ind. 461 (1958)] also replicated the production of 1-phenyl-5-mercapto-1H-tetrazole by Stolle and isolated the product in only 47% yield. The pure mix. preparation required an additional three recrystallizations. Similarly, the Stolee synthesis of 1-methyl-5-mercapto-1H-tetrazole by us has shown that the final product obtained is not uniform and therefore the yield of the target product is not relevant (see Example 1).

Stolle et al. they stress the need to introduce carbon dioxide, according to carbon dioxide, sodium azide produces azoimidic acid (N ₃ H) which reacts with methyl isothiocyanate to give the desired product.

In our experiments it was clearly proved that the introduction of the reaction does not require the introduction of carbon dioxide gas or other gas, moreover, the introduction of carbon dioxide gas leads to a deterioration of the yield and to the formation of a unitary product by layer chromatography. During the reproduction of the Stolle description (see Fig

EXAMPLE I) The product obtained contains only 75% of 1-methyl-5-mcaptoct-11-tetrazole and two significant amounts of the product were isolated as the main impurity. The formation of these by-products is not mentioned in the Stolle paper because the authors did not yet have the methods known today to verify the uniformity of the end product obtained. The test methods described herein are not sufficient to characterize the product. In our investigations, we verified the chemical structure of the main product contaminants. 1-Methyl-5-mercapto-1H-tetrazolyl, prepared according to the Stolle specification, was found to be contaminated with about 10% N, N'-dimethyltloxybromide. For the formation of other N, N-substituted thioureas, Lieber et al. reported in [Can. J. Chem. 35, 832 (1975)].

However, during the reproduction of the Stolle process, the formation of another by-product was also observed. The compound was chromatographically similar to Ν, Ν'-dimethylthiourea but with a different melting point. Based on elemental analysis, mixture melting point, and infra- and ¹ HNMR spectra, the substance was undoubtedly found to be identical to N-methylthiourea and its structure was confirmed by synthesis (see Example 1).

These by-products have a chemical behavior similar to l-nethyl-5-mercapto-llltetrazole and are therefore difficult to distinguish from the target compound.

It is an object of the present invention to provide a process which is commercially applicable and which produces high purity 1-alkyl-5-mercapto-1H-tetrazole free of the above by-products in higher yields than described previously.

In our experiments to develop the process, it has been found that by using a water-methanol mixture of water-methanol mixtures commonly used as the reaction medium, the reaction conditions (temperature, reaction time) are optimized and the order of addition of the reactants appropriately selected. can be obtained in higher yields than previously known processes.

The preparation of the compounds of formula I of high purity according to the invention is carried out by adding to the solution of sodium azide in aqueous or aqueous methanol under constant stirring and heating over a period of 2.5 to 10 hours, preferably six hours. The reaction mixture is stirred at reflux for 0.5 to 5 hours, preferably for 2 hours, and then the methanol is evaporated to dryness and the pH of the residue is 0 ° C.

187,792 acids, preferably hydrochloric acid, are adjusted to pH 1.0 and then

(a) the precipitated crystals are filtered off, washed, dried and the mother liquor processed in accordance with method (b), or |

b) reacting the reaction mixture with a water immiscible agent.

extraction is carried out with a solvent, preferably chloroform. The resulting solution is saturated with a mixture of liquid, straight or branched hydrocarbons, preferably petroleum ether, and the resulting crystals are filtered, washed, dried. 1

In our experiments, in order to avoid unwanted degradation products, it is advisable to maintain the temperature during the addition of the methyl isocyanate at 70-80 ° C and to select a methanol-water system having a boiling point not exceeding 80 ° C as the reaction medium. A water: methanol 2: 1 mixture was found to be most suitable for this purpose.

In our experience, the order and method of addition of the reactants are crucial for the yield of the main product and especially for the impurities involved. When slowly and steadily stirring, while stirring and heating, a methanolic solution of methyl isocyanate is added to the sodium azide solution, it is continuously reacted out of the solution to avoid unwanted side reactions in the reaction mixture, resulting in an excess of methylisocyanate. degradation products with a chemical behavior similar to that of the target compound and difficult to separate.

It has also been found in our experiments that, when the reaction mixture is stirred for a few hours after addition, the methyl isocyanate disappears completely from the solution.

After evaporation of the methanol from the reaction mixture, 1-methyl-5-mercapto-1H-tetrazole was isolated from the evaporation residue with concentrated mineral acid, preferably hydrochloric acid. It has been found that the solution is acidified at 0 ° C.

According to our experiments, the crystalline final product can be filtered directly after acidification of the solution (method a) or extracted with a water immiscible solvent, preferably chloroform, and after concentration of the extract, it can be separated with a suitable liquid hydrocarbon, preferably petroleum ether (method b). Additional material can be recovered from the mother liquor of the product filtered by method (a) by method (b).

The process of the present invention provides high purity 1-alkyl-5-mercapto-1H-tetrazole without by-products in 90-96% yield. The following examples further illustrate the process of the invention.

Melting point determinations were performed on a Thiele melting point apparatus, thin layer chromatography on DC-Alufolien Kieselgel 60F ₂₅₄ adsorbent, benzene: methanol = 6: 4, benzene: acetone = 1: 1, carbon tetrachloride: ethyl acetate = 1: 2 .

IR spectra were performed on a Perkin-Elmer 283B infrared spectrophotometer in a KBr pastille, and NMR spectra were performed on a Bruker WP 200 SY pulsed-FT NMR spectrometer in CDCl ₃ . Video densitometry was performed on a Shimadzu High-Sped Thin-Layer Chromato Scanner (Model CS-920).

Example 1

Preparation of -methyl-5-ηιεrkapto-1H-tetrazole (reproduction of the description of olle Stolle Half) An alcoholic solution of methyl isothiocyanate (0.2 mol) in carbon dioxide gas and stirring 19.5 g (0.3 mol) of sodium azide 250 ml 95 dropwise, and the reaction mixture was heated for 8 hours. The solution, filtered hot from unreacted sodium azide, was evaporated in a water bath. A small amount of unreacted methyl isothiocyanate was extracted with ether from the aqueous solution of the evaporation residue and, after acidification with hydrochloric acid, concentrated under reduced pressure. The dry residue was triturated several times with ether to give a yellow crystalline solid which was recrystallized from chloroform.

Product: 19 g (Theoretical 23.8 g)

Melting point: 113-120 ° C

TLC showed no uniform product. Benzokmctanol = 6: 4 mixture by chromatography solvent mixture contains three major components, _Rf values are respectively: 0.5, 0.63 and 0.72.

By video densitometry, the relative proportions of the components having the above Rf values were 75% to 15% and 10% respectively.

Preparative layer chromatography separated the three main components and identified their structure by melting point, elemental analysis, IR and NMR spectra.

The Rf 0.5 component is 1-methyl-5-mercapto-

1H-tetrazole. op: 125-126 ° C Analysis: C ₂ H ₄ N ₄ S, Ms: 116.145: calculated: C = 20.67 11 = 3.47 N = 48.25 S, 27.61 Found: C, 20.82; H, 3.55; N, 48.35 S, 27.52 IR: 1510 cm (N-C = S), 1350 cm ^-1 (C = S),

1305 cm ^-1 (-NN = N-)

187,792

The Rf 0.63 component was found to be N-methylthiourea.

op: 121-122 ° C Analysis: C ₂ II ₆ N ₂ S, Ms: 90.14: calculated: C = 26.64 H = 6.70 N = 31.07 S = 35.56 Found: C, 26.68; H, 6.72; N, 31.11; S, 35.62 IR: 3330, 3250 cm ^-1 (-NH ₂ ); 3170 cm ^-1 (-NH)

. I

1630 cm ^-1 (-Nil ₂ -C = S);

. , ¹ H NMR (6 ppm); 1555 ^cm-1 / CH ₃ -NH-C = S;

1300 cm ^-1 (C = S) 1 The Rf 0.72 component was found to be N, N'-dimethylthio-urea. op: 61-62 ° C Analysis: C ₃ H ₈ N ₂ S, Ms: 104.18: calculated: C = 34.58; H = 7.74; N = 26.89 S, 30.78 Found: C, 34.42; H, 7.50; N, 27.10 S, 30.92

¹ H, 3300 cm ^-1 (NH); 1550 cm ¹ (-N_C = S)

N-methylthiourea is described in Org. Synth. 21, 83 (1941). The product thus obtained proved to be identical to the material separated by chromatography.

EXAMPLE 2 A solution of methyl isothiocyanate (g, 0.04 mol) in methanol (20 ml) was added over a period of 6 hours, with stirring and reflux, to a solution of sodium azide (2.9 g, 0.044 mol) in water (15 ml) and methanol (10 ml). After the addition, it was stirred for one hour under reflux. The reaction mixture was evaporated to dryness under methanol and acidified to pH 1.0 with concentrated hydrochloric acid. The acidified solution was extracted five times with an equal volume of chloroform. The combined chloroform solutions were dried over magnesium sulfate, evaporated under reduced pressure to an initial crystallization and then heated to reflux and saturated with petroleum ether. It was allowed to crystallize at room temperature and then refrigerated. The precipitated crystals were filtered, washed with chloroform-petroleum ether, and dried under infrared light.

Product: 4.3 g (90% yield) m.p. 125-126 ° C Example 3 A solution of methyl isothiocyanate (g, 0.04 mol) in ethyl alcohol (20 ml) was added over a period of 2.5 hours with constant stirring at 2.9. g (0.044 mol) of sodium azide in 15 ml of water at 80 ° C. After the addition, it was stirred under reflux for 5.5 hours. The reaction mixture was evaporated under reduced pressure to ethyl alcohol-free, acidified to pH 1.0 with 50% sulfuric acid with cooling and stirring. The acidified solution was extracted with an equal volume of ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to remove ethyl acetate in chloroform. Concentrated idoroform solution until crystallization began was saturated with hot petroleum ether. It was allowed to crystallize at room temperature and then refrigerated. The precipitated crystals were filtered, washed with chloroform-petroleum ether, and dried under infrared light.

Product: 4.1 g (84% yield) m.p. 125-126 ° C

Example 4 A solution of methyl isothiocyanate (30 g) (0.04 mol) in methanol (30 ml) was added in a uniform manner to a solution of sodium azide (2.9 g, 0.044 mol) in water (15 ml) at 60-65 ° C. After the addition, the reaction mixture was stirred at 60-65 ° C for an additional hour, then evaporated to methanol-free under reduced pressure and acidified to pH 1.0 with concentrated hydrochloric acid at 0 ° C with constant stirring. The acidified solution started to precipitate at 0 ° C. The crystalline mixture was allowed to stand overnight in a refrigerator, cold filtered, washed with ice water, dried over phosphorus pentoxide in vacuo at 60 ° C.

Product: 3.8 g (80% yield) m.p. 124-126 ° C

Additional product was obtained by chloroform extraction of the aqueous mother liquor and crystallization as described in the examples below.

Generation 11: 0.5 g (10.4% yield) mp 125-126 ° C

EXAMPLE 5 A solution of methyl isothiocyanate (g, 0.04 mol) in ethanol (20 ml) was added to a suspension of sodium azide (2.9 g, 0.044 mol) in 95 ml of ethyl alcohol (95 ml) at constant stirring over a period of 8 hours. you. After the addition, the reaction mixture was stirred at 60-65 ° C for an additional two hours. In the following, the same procedure as described in Pl. 2 was followed.

187,792

Product: 4.2 g (88% yield) mp 125-126 ° C

Example 6 A solution of methyl isothiocyanate (150 g) (0.4 mol) in methanol (150 ml) was added to a solution of sodium azide (29 g, 0.44 mol) in water (70-80 ° C) under constant stirring over 6 hours. After the addition, the reaction mixture was further mixed. and stirred for 1 hour at 70-80 ° C. Hereinafter referred to as'

Example 2 was followed. .

Product: 45.8 g (96% yield) m.p. 125-126 ° C

Example 7 A solution of g (0.4 mol) of methyl isothiocyanate in 150 ml of methanol was added over 5 hours to a solution of 29 g (0.44 mol) of sodium azide in 75 ml of water at 70-80 ° C. After the addition, the reaction mixture was heated for a further 3 hours with constant stirring. In the following, the procedure of Example 4 was followed.

Water precipitated: 43.2 g (88.6% yield), mp 125-126 ° C

Generation 11: 3.1 g (6.4% yield) m.p. 125-126 ° C

Example 8

A solution of 1500 g (20 mol) of methyl isothiocyanate in 5000 ml of methanol was added to a stirred solution of 1450 g (22 mol) of sodium azide in 3750 ml of water and 2500 ml of methanol under constant stirring over 6 hours. After addition, the reaction mixture was stirred for a further two hours under reflux. In the following, the procedure of Example 4 was followed.

Water precipitated: 2150 g (90% yield) mp 124-126 ° C

II. generation: 119 g (5% yield) mp 124-126 ° C

Example 9

A solution of 3.48 g (0.04 mol) of ethyl isothiocyanate in 30 ml of methanol was added over a period of 6 hours under constant stirring to a solution of 2.9 g (0.044 mol) of sodium azide in 70 ml of 15 ml of water. After the addition, the reaction mixture was refluxed for a further two hours with constant stirring. In the following, the procedure of Example 2 was followed.

Product: 4.68 g (90% yield) mp 49-50'C

Claims (6)

Patent claims A process for the preparation of a highly purified compound of formula I wherein R is a C 1 -C 4 linear or branched alkyl group of formula 11 - where 1 R is as defined above, for the preparation of a compound and sodium azide in an aqueous alcoholic medium, characterized in that a solution of sodium azide in aqueous or aqueous and methanolic With stirring and heating, 1E is added at a constant rate over a period of 2.5 to 10 hours, preferably 6 hours. methanolic solution of the compound of formula (I), and after the addition is complete, the reaction mixture is stirred for 0.5 to 5 hours, preferably 2 hours. At a temperature of 20 ° C, the methanol is evaporated and the residue is adjusted to pH 1.0 with mineral acid, preferably concentrated hydrochloric acid, at 0 ° C. A) filtering, washing, drying and crystallizing the precipitated crystals according to method b), or b) extracting the reaction mixture with a water-immiscible seraphic solvent, preferably chloroform, evaporating the extract to a crystallization that begins after drying, and heating the resulting solution to a boiling point with a mixture of liquid, straight or branched hydrocarbons, filtered, washed, dried. The process according to claim 1, wherein the concentration of methyl isothiocyanate in the methanolic solution is 5-50% w / v, preferably 20-30% w / v. 3. A process according to any one of claims 1 to 4, characterized in that the initial concentration of sodium azide in the aqueous or aqueous-nanomolar solution is 5-50% w / v, preferably 20-35% w / v. 4. Process according to claims 1 to 4, characterized in that the reaction mixture has a methanol: water volume ratio of 19: 1 to 1: 4, preferably 2: 1. 55 5. Process according to claims 1 to 3, characterized in that dichloroethane, carbon tetrachloride, diethyl ether, ethyl or butyl acetate, methyl ethyl ketone, methyl butyl ketone, benzene or toluene, preferably chloroform, are used for the extraction. 6. Process according to claims 1 to 5, characterized in that the reaction temperature is from + 50 to + 100 ° C, preferably from 60 to 80 ° C. We keep it between 65.