DE2348802C3 - Process for the production of pure tetrazole-1-acetic acid - Google Patents

Description

Several methods are known to make tetrazole-1-acetic acid to produce, which in most cases run through the corresponding alkyl esters:

1. Addition of HN ₃ to ethyl isonitriloacetate (Zimmermann & Olofson in Tetrahedron Letters 58 (1969), pp. 5081-84).

2. Addition of HN ₃ to ethyl N-formimidate, e.g. B. from glycine (Hagedorn & Winkelmann in Chemischeberichte 99 [1966], p. 853).

3. After an analogous reaction as in 2), but worked out as a one-pot process, the N-formimidic acid ethyl ester from glycine ethyl ester hydrochloride or glycine and trialkyl orthoformate is formed in a manner known per se in the presence of HN ₃ and immediately cyclized to the tetrazole ring (Fujisawa Pharmaceutical Co. Ltd., Osaka in DT-OS 2147023).

4. Tetrazole is used as the triethylamine salt with ethyl chloroacetate implemented in acetone. This produces a mixture of isomers of tetrazole-1-es ethyl acetate and the corresponding ester substituted in the 2-position (Raap & Howard in Can. J. Chem. 47 11969], pp. 813-19).

A more or less heavily contaminated crude ester is formed in all reaction paths. This is how z. B. after the method described in DT-OS 2147023 a black-brown crude ester from which After inoculation with crystals of the ester, after 48 hours of storage at + 4 ° C., a maximum of 9% by weight crystalline Share is to be isolated. Raap describes that the tetrazole-2-acetic acid ester in Allow vacuum to separate from the corresponding 1-esters by distillation; the remaining ester residues are saponified, and it is then the tetrazole-1-acetic acid awkwardly cleaned. Raap expressly points out that the Can not distill ethyl ester of tetrazole-1-acetic acid.

If you try the tetrazole-1-acetic acid starting directly from glycine to produce yourself, you also get a deep brown product.

Surprisingly, it has now been found that a completely pure tetrazole-1-acetic acid can be obtained can, if one of their alkyl esters with 1 to 4 carbon atoms in the alkyltcil according to the principle of falling film molecular distillation at temperatures below 130 ° C under a vacuum of < K) 'Torr matured by distillation ι> _ !, i and a lisch nc ßc ι i (J uhiic wciicic RciiiigüngSüpera-

tion is hydrolyzed.

If the corresponding 2-ester is not an impurity is contained, even pure tetrazole-1-acetic acid ester is produced by only one-time molecular distillation

tion received. This result is completely unexpected because Raap once described that a lower alkyl ester of tetrazole-1-acetic acid cannot be distilled without decomposition, which is confirmed by this is that z. B. their ethyl esters already at

ίο 130 ° C to decompose during a distillation attempt begins. Furthermore, it was by no means foreseeable that according to the principle of molecular distillation, which does not cause any separation effect, as it is known from normal distillation columns,

a pure melting point ester is obtained immediately which even after the analysis method of thin-layer chromatography only hints of contamination shows well below one percent. The principle of molecular distillation differs

ao detach itself from normal bubble distillation by that the evaporation takes place from a product film, and the distillation path to the condenser lies in the range of the mean free path of the gas molecules. The evaporation must take place at vacuums of The process of molecular distillation is described in detail, e.g. in Ulmann's Encyklopadie der technischen Chemie (1969), Volume 2/1, pp. 72-76, or in Houben-Weyl, Methods of organic chemistry (1958), volume I / l, p.

916-926.

Appropriate ready-made distillation units are offered.

With the option of purifying an alkyl ester with 1 to 4 carbon atoms in the alkyl part by distillation The tetrazole-1-acetic acid as a precursor of the acid is a way found after a technically very simple one Process the tetrazole-1-acetic acid, which is of great interest for pharmaceutical products, with the required Degree of purity (m.p. 128-131 ° C) to be obtained.

With this acid in particular, purification by known processes of recrystallization and treatment with bleaching agents such as activated charcoal or fuller's earth is very lossy and not very effective.
Not only the separation of more or less unknown impurities, as they arise by the methods of HN, addition to isonitrile or the formimidoester, is possible with the help of molecular distillation, but also the isomer mixture of tetrazole-1- and -2-acetic acid ester can are separated by distillation. Here, however, work must be carried out at least twice under different vacuums.

The pressure to be maintained during the distillation must be less than K) " ¹ Torr; a lower limit cannot be specified theoretically and is only limited by current technology. In practice, however, minimum pressures of around 10" Torr can be achieved on technically available systems. In general, between 5 XK) " ² and 10"'Torr is used.

The distillation temperature depends on the pressure. The outlet temperature of the still residue should not be over 130 ° C, the optimal temperature of the evaporator surface for a technical Distillation is between 95 and 120 ° C, with a very high vacuum also lower Temperatures before. z. B. 70 to 95 ° C can be used be able.

For the implementation of ucf rallfilm-rvjOl

All known apparatuses are suitable for the stillation, taking into account the pressure and temperature ranges mentioned, where the creation of a thin film of the product to be distilled is crucial on a heated surface and, if necessary, a cooled condensation surface at a short distance of which are to be provided. Various systems are suitable with z. B. heated finger-like hanging Evaporator, which is charged from above, and with a device for spreading out the material to be distilled Product such as stirring spirals, rollers, wiper blades o. The like. Is provided, and a pipe jacket as a capacitor. Systems with a jacket-type evaporator that is charged from above and heated from the outside are also suitable, run along the corresponding, possibly rotatable, spreading devices on the inside, and in its interior e> n capacitor z. B. is arranged in the form of a cold finger. the The space between the evaporator and condenser is z. B. one Mercury condensation pump can be evacuated.

In an upstream vacuum zone with a slightly lower vacuum of about 10 "'to 5 X 10" ² Torr, the removal of lower-boiling substances from the thin layer over z. B. a heating jacket or a spiral running product to be distilled.

There are drainage devices for the pure product under the condenser and under the evaporator a drain to be heated for the impurities that have not evaporated.

The preparation of the crude tetrazole-1-acetic acid ester can be done in a number of known ways. It is Z. B. also possible, first a corresponding To produce crude acid and to esterify it before distillation.

The saponification of the resulting alkyl tetrazole-1-acetic acid ester takes place by known methods in water, optionally neutral or basic, preferably im acidic environment, with the resulting acid catalyzing the hydrolytic saponification process itself. It is advantageous for the saponification time at temperatures above 100 ° C at normal pressure or to work at the overpressure given by the intrinsic pressure at the respective temperature, but not above 130 ° C.

It is also possible, in the pressure vessel at up to 10 at and z. B. 50 to 120 ° C to work.

No further impurities are formed during the saponification process, so that after crystallization the tetrazole-1-acetic acid from the supersaturated solution by cooling the aqueous filtrate for one next saponification can be reused. Accordingly, the yield from this operation is almost 100%.

The only possible alkyl esters of tetrazole-1-acetic acid are those with 1 to 4 carbon atoms in the alkyl radical, although only the physical property of the boiling point, but not chemical reasons, have a limiting effect. A C ₅ ester distills at the achievable vacuum of 10 ^-3 Torr only above 130 ° C and thus with decomposition, so that the essential criterion of complete purity of the ester no longer applies solely by distillation.

Tetrazole-1-acetic acid is not used as a pharmaceutical itself active intermediate product for the production of PiCuarti "sr antibiotics like 7-'2 '! H-Tetrazo! -! - yl) acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yI) -thiomethyl-S-cephem ^ -carboxylic acid.

example 1

Obtaining tetrazole-1-acetic acid ethyl ester

According to the working instructions of DOS 2147023, Example 5, an experiment was carried out with 10 times the amount carried out on chemicals.

A mixture of 140 g (1 mol) of glycine ethyl ester hydrochloride + 72 g of sodium azide + 160 g of methyl orthoformate + 200 ml of glacial acetic acid is heated to 70 ° C. for two hours. In the gas space, HN ₃ concentrations of starting 16% by volume down to

»5 falling ~ 4 vol.% Measured with the help of a calibrated colorimetric method in which the dark red-colored azide-iron complex [Fe (N ₃ ) ₆ ] serves as the color carrier.

All volatile constituents are then distilled off at 20 torr up to a bath temperature of 100.degree. The residue is mixed with 2 liters of cold water and the oil-water emulsion that forms with 2 liters Added chloroform. After thorough mixing, the layers are separated, the aqueous layer

»5 discarded and the chloroform solution dried _{with Na 2} SO _4. After the chloroform has been separated off by distillation, the residue remains a deep dark brown oil of 145 g.

After cooling to 0 ° C. and inoculating with pure ester, 14 g of crystals can be filtered off with suction after 48 hours will; these crystals are still brownish in color due to adhering impurities and melt completely at 23 ° C. This corresponds to 14 g of Kiristallisat 9% of the theoretical yield. The extraction of sufficiently pure ethyl ester cannot therefore be obtained by crystallization.

Purification of the ester

The oil obtained, together with the 14 g of crystals, is via a laboratory molecular distillation plant distilled.

The product first runs in a thin layer over a coil heated to 90 ° C; the vacuum applied is approximately 10 ^-2 Torr. This pretreatment is important to guarantee complete pre-degassing of the product in order to maintain the vacuum required in the subsequent molecular distillation. For the distillation, the pre-degassed product is dripped onto the heated evaporator and spread onto the evaporator as a thin film with the help of a spiral. The temperature of the distillation residue, measured under the evaporator, is 100 ° C. This spiral is rotated via a magnetic coupling. Directly opposite the evaporator is the jacket condenser. The vacuum achieved is 5 X 10 ^-3 Torr.

A virtually colorless oil is collected as the distillate, which after cooling to 0 ° C. overnight has completely crystallized (melting point 32-34 ° C.).
The distillation residue is a tarry product which solidifies very quickly, so that it is heated with infrared lamps to keep it flowing. It will echo:

112 g of distillate = 72% of the theoretical amount, based on the glycine ester used;
33 g residue.
After thin-layer chromatographic analysis

M / trH QiiRpr f \ (* rv \

wr *! _

> cctoc'Jurp_utK \ fl *> ct ^ r only

an impurity of <0.1% found at the start point. In the NMR spectrum there are no signals from Isomers or impurities detectable. The found melting point of 32-34 ° C corresponds to References for the pure ester.

hydrolysis

156 g (1 mol) of tetrazole-1-acetic acid ethyl ester distillate with a melting point of 32-34 ° C. are refluxed for 1 hour with 300 ml of approx. 10% strength hydrochloric acid. At the same time, alcohol is distilled overhead. By cooling to room temperature with stirring the tetrazole-1-acetic acid crystallizes out. After sharp suction through a suction filter and Drying the filter cake at 100 ° C in a circulating air cabinet, 102 g of tetrazole-1-acetic acid (79.5%

d. Th.) With an mp = 128-13 Γ C. In order to obtain a completely HCl-free product, the acid can again; recrystallized from H _{2 O.}

The aqueous hydrochloric acid filtrate can be used for another Approach to be reused.

The total yield including the amount recovered from the filtrate is 122 g of tetrazole-1-acetic acid = 95.5% d. Th.

Example 2

In a manner similar to that in Example 1, a) the methyl ester b) the n-butyl ester of tetrazole-1-acetic acid Purified by molecular distillation and then the acid obtained by hydrolysis.

¹ S with good yields and equally good purity being found.

Claims (1)

Claim: Process for the production of pure tetrazole-1-acetic acid, characterized in that an alkyl tetrazole-1-acetic acid ester with 1 to 4 carbon atoms prepared by known methods in the alkyl radical by molecular distillation at temperatures below 130 ° C under vacuum of <10 "'Torr obtained in pure form and then is gently hydrolyzed by known methods.