NL8403481A - 2,6-Dihydroxycineole and inters - as choleretic agents prepd. in pure form from pure pinol - Google Patents

Abstract

Title cpds. are prepd. from sobrerol by (a) hydrogenated to form pinol (II) which can be either treated with a peracid to an epoxy pinol and hydrolysed to the 2,6-dihydroxycineol (I) prod. or (II) can be brominated and the obtd. 2,6-di-bromopineole (III) treated with sodium acetate to form the 2,6-diacetoxycineole and then with sulphuric acid to form (I). Medicaments contain (I), (II) or (III) in unit doses contg. 100-200mg. active ingredient. The reaction gives a high yield of prods. in a pure form.

Description

% VO 6638

Title i Process for the preparation of high-purity pinole compounds with a choleretic effect.

The invention relates to a process for the preparation of pineapple compounds with a choleretic action, starting from very pure sobrerol.

In particular, the invention relates to a process for the preparation of 2,6-dihydroxycinole starting from high purity sobreroL formation of pinoy as an intermediate.

The compound 2,6-dihydroxycinole has recently been the subject of some publications regarding structural studies (J. Wolinski et al. Tetrahedron, vol. 27 753/65 1971, 1579/87, 10 · Cocker and coll- 1. Chenr Soc Perkins-Trans 1972, 15/1, Bist 1971/80).

It has been found in these investigations that this? compound was previously referred to as cis-pinole glycol and therefore corresponds to the industrially prepared product using the methods described in Italian Application 25127 A / 73.

This product, which is not commercially available, has hitherto never been prepared on an industrial scale; nor was its use known as a compound with choleretic activity in the pharmaceutical field.

The aforementioned publications relate to some small scale laboratory preparation methods which do not take into account the yields and purity of the finished product which is therefore unsuitable for use in pharmaceuticals.

According to the process of the present invention, 2,6-dihydroxycinole of formula 1 of the formula sheet is obtained starting from sobrerol of formula 2 of the formula sheet, forming pinoi of formula 3 of the formula sheet as intermediate, by hydrolysis of an acetoxy compound of 2 6-dihydroxycinol, slide is obtained from the compound obtained by pinot bromination 84 03 4 8 1 _____'____________ * / 4 -2-2 2,6-dibromocineole of formula 4 of the formula sheet, previously referred to as pinooldibromida ..

The preparation of pinoi. starting from sobrerol, it has been mentioned by "various authors, starting with Sobrero (comp. 1851, 5 33 ', 67), who, however, did not foresee that it could be obtained with very high purity, which is only checked. can be achieved by highly sensitive analytical methods such as gas chromatographic analysis, which was not available at the time.

Investigations made up to. The present invention has aimed, in the first place, at obtaining a very pure pinball.

An important condition for this is that one starts from. very pure sobrerol, such as. industrial scale can only be obtained using da in. British Patent Specification No. 15: 1.29-5.580.-.

Also? it is noted that when studying the om. • - Settling Skeleton of Sobrerol in Pinooi, among the ones used in previous investigations. has found that. ; is always in equilibrium with a certain percentage of cis-sobrerol; it can therefore easily happen that the latter compound is extracted together with the pinion, thus forming an impurity which, even after many washes with water, in which cis-sobrerol is soluble, and, by stretching in a distillation stage, which is difficult to perform, difficult to separate.

This cis-sobrerol, which is present as an impurity, gives rise during the bromination of pinot to the formation of reaction products which form impurities which are very difficult to separate from., 2,6-dihydroxycinole.

If also, like- generally it. In this case, the starting sobrerol contains impurities of a terpenic nature (carveols, campfolene aldehyde, etc.), as in the. sobrerol, which is prepared by various methods, such as, for example, described in U.S. Pat. Nos. 2,949,489 and 2,8X5,378, the system to be purified is even more complex and the purification of pineapple becomes depleted. industrial: 35 scale very difficult.

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It is therefore out. the literature (Cocker, Crowley, biz. 1972) discloses that the pinoi obtained invariably has a purity of at most 95%.

In contrast, kinetic studies now have the 5 optimal conditions. determine, so that the balance is almost completely shifted to the formation of pinoi.

Such conditions are more accurately reported in the following examples. The ability to obtain pure pinpoint greatly facilitates subsequent operations.

Set 2,6-dihydroxycinole according to the method of the invention is obtained by bromination of pinoi, whereby 2,6-dibromocineole is obtained and the subsequent conversion into the di-acetory compound of 2,6-dihydroxycinole, followed by hydrolysis of these link.

15 It should be noted that the direct bromination of. pinooi can also be made in acetic acid, chloroform, carbon tetrachloride, in which the pinooi is dissolved. Brominated is the same solvent.

solved: in which the reaction. is carried out and added dropwise: at 10 DEG-10 DEG C. After removal; 2.6 to 20 · dihydroxycinole of the solvents are recirstallized.

In this case, however, fairly low yields (60-70%) are obtained. On the other hand, the bromination can be according to; another embodiment of the process of the invention may be carried out, i.e. by indirect bromination of pinot with organic brominating agents such as pyridine bromohydrate, N-bromosuccinimide, N-bromoacetamide, to form 2,6-dihydroxycinole.

In this case, very pure products are obtained with yields of 80-90%, i.e. much higher than obtained by direct bromination.

In practice, pinoi is dissolved in chloroform, or carbon tetrachloride. it is reacted with the organic brominating agent in an amount such that 2 bromine atoms are supplied per molecule of pinole. The reaction proceeds by refluxing until the bromine reaction ceases. The reaction times are from 3 to 24 hours. The product is filtered hot to remove the insoluble bromine-liberated amides, which are allowed to crystallize.

The product thus obtained has a melting point of 94 ° C and a purity of more than 98%.

Then, 2, S-dibromocinole is melted with sodium acetate and the presence of acetic acid, to form 2,6-diacetoxycinole, which is diluted by hydrolysis with. H ^ SQ ^ leads to the formation of 2,6-dihydroxycinole.

Wolinski has proposed a preparation starting from 10 - the dibromide using lead hydroxide; it is- however clear: that. such a reaction is unsuitable in view of the pharmaceutical application, owing to the possibility of impurities. Establishing the end product with lead salts. For similar reasons and due to high cost, di-acetylation with silver acetate events should be discarded once.

: Identity of the process according to the invention:

* f · obtained »dihydroxycinole was it the first ?, place? confirmed by in-i · 'i. infrared spectrometry - "I

The infrared spectrum. of 2, S-dihydroxycinole,. Obtained -20 in a 10% CHCX2 solution? showed the following absorption maxima: 3360 cm ”1 (» 2-, 97 μ) 1453 cm. ”1 (= 6.88 μ> 1370 cm” 1 (-: 7.30 μ) 1107 cm7 (= 9, 03 μ) 1075 graft "1 C- 9> 30 μ) 1010 cm" 1 9.90 μ)

According to the method using KB ^ plates, the values were confirmed by the following data: 3340 cmT1 C-2.99 'μ) 1456 cm ”1 (- 6.87 μ) 136S cm” 1 (- 7.31 μ) 1116Γ cm ”1 (= 8.96 μ) 1080 cm” 1 (· 9.26 μ) 1017 cm ”1 (= 9.83 μ)

Then it was. the dihydroxycinole examined by nuclear magnetic resonance. The nuclear magnetic resonance data were obtained using "according to". samples of the method of the invention prepared and analyzed for. the Institute of Chemistry of the Polytechnic School in Milan and. are shown in the attached figure 1 (dissolution of the samples in CDCl 3).

35 With regard to the application of the method according to the method 84 03 4 8 1_______? Compounds obtained according to the invention are noted that in toxicological studies these products showed a very low toxicity, while pharmacological tests showed a choleretic action which is particularly evident in the case of 2,6-dihydroxycinole.

The invention will now be elucidated on the basis of the following examples r which, however, do not limit the invention.

Example Γ.

Preparation of pinole starting from sobrerol with a purity of. 99%.

10l Men. 1.020 kg of sobrerol mat dissolves a purity of at least 99% in SO liters of distilled water at 50 ° C. 0.050 kg of 27% SCI is then added, which is made up to .2000 ml with distilled water. to. Men. completes the reaction with stirring in 24 hours.

The reaction product is allowed to cool to room temperature, extracted with ethyl acetate and the extract separated.

Men. the organic solution evaporates it. is appropriately dehydrated. with salts such as, sodium sulfate ,. magnesium sulfate ,.

. potassium carbonate in an anhydrous state, in vacuo to remove the volatile solvent. The resulting mixture is stretched.

20; crude oil with a Todd type column, with a. height of- 80 cm. and two packed elements. The product containing pinole was collected with a boiling point of 183-184 ° C. Yield; 75-80%. of the theoretical value.

Example Ib; Preparation of pinole starting from crude sobrerol.

The procedure is as in Example 1, but the high-purity sobrerol is replaced by crude sobrerol, whereby a crude oil is obtained which, by stretching, produces a pinole which is impure due to the presence of about 4-5% impurities, the separation 30 cannot be performed by a standard distillation method, even when the relative reflux amounts change. In any case, such a process would not be acceptable from an economic point of view since the preparation times would be considerably extended.

Example II.

84 0 3 4 8 T _'_____ 1 i s -6-

Preparation of. pinooi starting from pure sobrerol (99%) op. industrial scale

It is dissolved. 20 kg. sobrerol with a purity of 99% in a suitable glass reaction vessel in 1200 l of distilled water, and then S adds about 20 kg of 96% H 2 SO 2 diluted with distilled water to a total amount. , from 100. 1.

The reaction mass is kept. 8 hours at 60 ° C. The mass is then stirred at room temperature for 12 hours. The aqueous mass is extracted with 300 l of chloroform, the separated organic solution is evaporated and evaporated in vacuo. to remove. the organic solvent. The crude oil obtained is reacted to form a pinion with the following properties! ! .

Yield compared to the theoretical value. 95%? ά ~ η = 0.942.

1.4714., "15 Example III.

Preparation of a gas chromatographically pure pinoi. outbound ; ; of 99% sobrerol ,, under water on an industrial scale- 'r · 4' ·. ·· Γ • · -! ·· -

20 kg of sobrerol are suspended. with a purity of. 99% in *. k-. · * A stove-enamelled autoclave in 1200: I distilled water, containing 0.2. kg 20 · oxalic acid is dissolved. Men. close the autoclave and keep it at 120-125 ° C for 45 minutes. Then the aqueous mass is extracted with 50 l of methylene chloride. The organic solution is thoroughly washed, and dried over anhydrous RT-CO 2 evaporated. Men. stretches. the crude oil to form a gas chromatographically pure pinot in a yield of 95% of the theoretical value.

• Example Illbr

Preparation vair pinooi. starting from raw sobrerol. in a reaction vessel under pressure.

In a 5 l stainless steel autoclave, 0.2 kg of crude sobrerol is suspended in 2 l of distilled water, in which 2 g of oxalic acid is dissolved. The treatment is carried out as in Example II.

The resulting pinole has a purity of 95% and cannot be economically purified by fractional distillation due to the impurities that are difficult to remove and losses in yield.

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Example IV.

Preparation of 2,6-dibromocneol. mixed bromine of pinole.

31.3 g of pinole with a purity of 98%, obtained by the method described in Examples 1 and IX, are dissolved in 200 g of chloroform. The bromination is carried out by adding a solution of dropwise. 15 g of bromine in 100 g of chloroform, at 5 ° C and separates the brominated product in the form of crystals by partial evaporation of the solvent. The yield of the product thus obtained was about 70% of the theoretical value.

Example V-.

Preparation of 2, β-dibromocineole by bromination with N-bromo-succinimide.

31.3 g of pinole, the same amount as in Example 15 Wr, is dissolved in 400. g of anhydrous carbon tetrachloride and then, with good stirring, 35 g of it-bromosuceinimide are added, and the mixture is refluxed until the bromine reaction ends. The mass is separated, filtered hot, the succinimidate is precipitated and the brominated product is obtained by crystallization after partial evaporation. The product is obtained in almost theoretical yield.

Example Ex?

Preparation of Z, 5-dibromocinole by bromination. with N-bromo-acetamide-

31.3 g of pinole in 400 g of carbon tetrachloride are reacted with 28 g of N-bromoacetamide -

The reaction is carried out in the same way as in Example IV, except that after cooling, it is diluted with 500 ml of ether to separate acetamide. After filtration, the dibromo compound is obtained by evaporation of solvent. the organic filtrate.

30 The yield is more than 90% of the theoretical value.

Example VI,

Preparation of 2,6-dibromocineole using N-bromosuccinimide on an industrial scale.

In a 1000 L stove, equipped with stirrer, reflux condenser and condenser, 50.1 kg of pinole with a purity 8403481 -8- of 99% is introduced and dissolved in 300 L of carbon tetrachloride.

Then 50 kg are added. Add N-bromosuccinimide with good stirring and reflux the mass for about 1 hour.

The bromine reaction stops after about 8 hours.

The hot mass is transferred by suction from the reaction vessel to one. press filter to remove the succinimide ..

The liquid is returned. same bromination vessel and evaporates. under vacuum, up to 1/3 of: the volume »

Men. transfers the concentrated product externally.

10. -cooled, reaction vessel with an inhouti. from. 500 l and let it crystallize therein. Thus, 100 kg of an almost pure 2-6 dibromocinole with a melting point of 940 ° C. are obtained.

Example: VII.

Preparation of 2,6-dihydroxycinole starting from 2,6-dibromo-15.. cineoL on industrial: scale - m a closed stove: cooking vessel, »with a. a "condenser" is introduced into a condenser, 313 kg 2r6-dihromocinole 25Q kg is introduced. ...; glacial acetic acid and 20 kg anhydrous sodium acetate. The mass is heated at 80 ° C for 2 hours and maintained at temperature for 36 hours to complete the.

20 * conversion of the product to 2 ', 6-dihydraxycinole diacetate. The whole is then placed under reduced pressure. of 50 mm at a temperature of 60 ° C, whereby acetic acid is distilled in a yield of 90%.

The residual mass is diluted with 100 l of water, dissolving the bromide and acetic acid, the crude 2,6-dihydroxycinole diacetate is filtered and crystallized, if purification is desired. In this case, 35 kg of product are obtained with a Melting point of 97-98 ° C »

However, this purification is not necessary for the preparation of 2, S-dihydroxycinole. The resulting paste-like product (about 40 kg) is left in a stove-lined reaction vessel. equipped with a reflux condenser, react with 200 l of a 5% H 2 SO 2 solution, and reflux for 10-12 hours. Finally, one adds. after evaporation add up to half the volume to the cooled mass of salt, and extract with chloroform.

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The 2,6-dihydroxycinole is separated off by crystallization after the partially evaporated chloroform solution. 15 kg of 2,6-dihydroxycinole with a melting point of 125 ° C are obtained.

S4 05 4 8 1 ______

Claims (4)

4. Process according to claim 2 or 3, characterized in that the reaction is carried out in an autoclave using oxalic acid. 5. Process according to one or more of claims 2-4, characterized in that 2,6-dibromocineole is prepared by dissolving the 8403481 -11-pineapple. in an organic solvent, in particular chloroform or carbon tetrachloride, using an organic brominating agent such as pyridine bromohydrate, N-bromosuccinimide and N-bromoacetamide, in an amount such that 5 bromine atoms are present per molecule of the treated pineapple. are, taking 3-24 hours. refluxes to the bromine reaction. stops and then filters hot to remove the insoluble bromine-free amines and crystallizes. 6. Process according to claim 5, characterized in that 2, β-dihydroxycinole diacetate is prepared from the 2,6-dibromocineole formed by means of anhydrous sodium acetate and acetic acid, the crude diacetate is filtered and purified by crystallization in a boiling aqueous solution-. 7 ,. Process according to one or more of Claims 1 to 6, characterized in that the preparation is carried out on an industrial scale. r '-'. * i 84 05 4 8 1______ S 'V y 1. CH3 CH3 HO ^ S-OH "IV VAC-OH / \ / \ CH3 CH3 CH3 CH3 3 4 p CH3 Br-x'vV'8r ° I ^ J. -CI / \ A-1 CH3 ( J CHj 8403481 Camillo Corvi SpA