DE2101998A1 - Tetrahydropyridines prepn - from 1-benzyl-tetrahydropyridines - Google Patents

Abstract

Tetrahydropyridines of formula (I) (where R1 and R2 are H, alkyl, phenyl opt. substd by lower alkyl NO2, or halogen, or aralkyl or aralkenyl opt substd in aryl gp. by lower alkyl, NO2 or halogen), which are of use as intermediates for pharmaceuticals (e.g. the choleretic 2-hydroxyphenylacetic acid 4-methyl-1,3,5,6-tetrahydropyridide), are prepared by reacting a 1-benzyl-tetrahydro pyridine of formula (II): with a phenyl chlorocarbonate of formula (III) (where R3 and R4 are H, lower alkyl or halogen) at ca 20-140 degrees C, and saponifying the resulting phenoxycarbonyl-tetrahydropyridine (IV) in alkaline soln at ca 60-140 degrees C.

Description

Process for the preparation of tetrahydropyridines the subject of Invention is a new chemically peculiar process for the production of partial known and unknown 1,2,5,6-tetrahydropyridines, which are important intermediates can be used for the synthesis of drugs.

It has already become known that 4-methyl-1,2,5,6-tetrahydropyridine obtained by reducing 4-methylpyridine with the aid of sodium in butanol (Coll. czechoslov. Chem. 24: 1029 (1959). However, the yield is below 50%. About that In addition, a large excess of metallic sodium must be used to prevent the Makes the process uneconomical.

It is also known to use 4-methylpyridine by electrolytic reduction to convert into the corresponding tetrahydropyridine (Chem. Listy 52 (1958), 668). However, the yields are too poor for industrial use of the process. In addition, unreacted starting product must be separated off, which is on The reason for the boiling points of the starting and end product is only due to a complex distillation can be achieved.

In addition, the production of tetrahydropyridine from the Tosylhydrazone of N-acetylpiperidone- (4) by saponification described (Ann. Chim. (Rome) 54 (1964), 1291). The process has due to its many stages no technical significance.

It has now been found that the 1,2,5,6-tetrahydropyridines of the formula (I) in which R1 and R represent hydrogen, a straight-chain or branched alkyl radical, a phenyl radical which is optionally substituted by lower alkyl, nitro groups or halogen, or an aralkyl or aralkenyl radical which is optionally substituted in the aromatic part by lower alkyl, nitro groups or halogen is substituted, are obtained in a simple manner and in good yields if 1-benzyl-1,2,5,6-tetrahydropyridines of the formula (II) in which and R2 have the abovementioned meaning and represents hydrogen, a lower alkyl radical or halogen, with phenyl chloroformates of the formula (III) in which fi stands for hydrogen, a lower alkyl radical or halogen, at temperatures between about 20 and 140? C with elimination of the corresponding benzyl chlorides to form carbamic acid phenyl esters of the formula (IV) in which R1, R2 and R4 have the meaning given above, and the compounds of the formula IV thus obtained are saponified in alkaline solution at temperatures between about 60 and 1400.degree.

It can be described as extremely surprising that with the reaction according to the invention, the unsaturated piperidines with phenyl chloroformates in such high yields with short reaction times and without formation actually to expecting numerous byproducts to debenzylate smoothly. The after Prior art known carbamic acid ethyl ester, which is composed of 1-benzylpyridine by boiling for 18 hours in benzene with ethyl chloroformate (; r, org. Chem. 26 (1961), 4057), are because of their severe saponifiability (Angew. Chem. 74 (1962), 866) hardly suitable as intermediate products. The use of Chloroformic phenyl ester avoids these disadvantages.

If, for example, 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridine is used as the starting material and phenyl chloroformate is used as the reactant, the reaction b) can be represented by the following equation: The 1-benzyl-1,2,5,6-tetrahydropyridines used for the process are known or can be prepared by known processes, for example by NaBH4 reduction of the corresponding 1-benzylpyridinium salts (J. org.

Chem. 34: 3672 (1969)).

Particularly suitable starting materials are 1-benzyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridine, 1-benzyl-5-methyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-p-chlorophenyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-ethyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-n-propyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-n-butyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-n-pentyl-1,2,526-tetrahydropyridine, 1-benzyl-4-n-nonyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-n-nonadecyl-1w2,5,6-tetrahydropyridine, 1-Benzyl-4- (2-methyl) -n-propyl 2,4 $ 6-tetrahydropyridines 1-Benzyl-4- (1 ', 1'-diispropyl) -methyl-1,2,5,6-tetrahydropyridine, 1-renzyl-4- (1t-n-propyl) -n-butyS 2s5s6-tetrahydropyridineS 1-renzyl-4- (3'-methyl) -n-butyl-1§2,5,6-tetrahydropyridine, 1-benzyl-4-n-hexyl-1,2,5,6-tetrahydropyridine, 1 ~ renzyl-4- (2'-ethyl) -n-propyl-12,5,6-tetrahydropyridine, 1-benzyl-4-n-heptyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4-styryl-1,2,5,6-tetrahydropyridine, 1-Benzyl-4- (p-chlorostyryl) -1? 2,5,6-tetrahydropyridine, 1-benzyl-4- (m-nitrostyryl) -1,2,5,6-tetrahydropyridine, 1-benzyl-4- (2t-phenyl) -§thyl-12,5s6-tetrahydropyridine, 1-benzyl-4- (2'-p-chlorophenyl) -ethyl-1,2,5,6-tetrahydropyridine, 1-benzyl-4- (2'-p-nitrophenyl) ethyl-1,2,5,6-tetrahydropyridine, 1-benzyl-3-n-pentyl-1,2,5,6-tetrahydropyridine.

In addition, the corresponding tetrahydropyridines can also be used For example, use the following benzyl radicals: 1-p-chlorobenzyl-1-p-methylbenzyl-1 m-Chlorobenzyl-The aryl chloroformate obtained in the first stage of the reaction can be used in pure form as well as in the technically occurring raw form will. For example, phenyl chloroformate, p-chlorophenyl chloroformate, Chloroformic acid m-tolyl ester * The reaction can be carried out in one for both components inert solvents are carried out. Aromatic solvents are suitable Hydrocarbons such as benzene, toluene or xylene, nitriles such as aoetonitrile or propionitrile or also ethers such as diethylene glycol dimethyl ether or ethylene glycol diethyl ether. But you can also carry out the conversion without a diluent.

Expediently, 1 mol of the corresponding 1-benzyl-tetra hydriopoyridine is used with 1 to 1.1 moles of the selected chloroformic acid acrylate. The reaction temperature is between 20 and 1400 ° C., in particular between 80 and 1200 ° C. The reaction time depends on the reaction temperature and is between 4 and 12 hours. the Reaction can, depending on the choice of solvent, at normal pressure or in one Pressure vessel to be guided.

To isolate the phenyl carbamic acid formed in the first stage the solvent is removed in vacuo and the benzyl chloride formed is distilled completely, which can be used again for a further implementation.

You can purify the reaction product by distillation, it In most cases, however, the crude product obtained in this way is sufficient without a reduction in yield to saponify.

The phenyl carbamate used in the second stage can saponified in pure form or in the raw form obtained from the first stage will.

Aqueous, aqueous-alcoholic or alcoholic are suitable for the saponification Alkaline solutions such as sodium hydroxide solution or potassium hydroxide solution, whereby the alcohols in particular are ethanol, Propanol or n-butanol are suitable. The concentrations of alkali hydroxide can vary between 8 and 20%. It is advisable to choose the concentration and the water-alcohol ratio so that the reaction mixture at least at the beginning the saponification is homogeneous. You can also use a solid, preferably without a solvent powdery alkali hydroxide e.g. B. sodium or potassium hydroxide, saponify.

Expediently, 1 mole of phenyl carbamic acid is used with at least 3 moles of alkali metal hydroxide, preferably with 4 to 6 moles of alkali metal hydroxide. The response time depends on the temperature and is e.g. 3. at 800 C for 4 to 5 hours, at 130 up to 140 ° r for 30 to 60 minutes.

To isolate the compound obtainable according to the invention, acidify rnn with solvent saponification with excess mineral acid, e.g. B. hydrochloric acid, on, the Tetrahydro pyridine wins in the form of their hydrochloride by evaporation in the vacuum and sets them from the residue with strong alkaline solutions, preferably Soda or potassium hydroxide, in freedom. You can by extraction with a solvent, z. B. ether, can be isolated from the aqueous-alkaline suspensions. After a They are obtained in pure form by distillation.

But you can also with a saponification without a solvent, the amines distill off directly from the reaction mixture, preferably under reduced pressure Pressure. They then fall together with some water that z. B. with potassium hydroxide or Potassium carbonate can be removed directly in pure form.

The products of the process according to the invention are valuable intermediate products. So z. B. from 2-hydroxyphenylacetic acid lactone and 4-methyl-1,2,5,6-tetrahydropyridine 2-hydroxyphenylacetic acid (4-methyl-1,2,5,6-tetrahydropyidide) that is considered choleretic effective drug can be used (British Patent 1,154,189).

The implementation of the method according to the invention should be based on the following examples.

Example 1 187 parts by weight of 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridine are in 500 parts by volume of toluene at 20-300 C with 172 parts by weight of phenyl chloroformate added and stirred at 100 to 1100 C for 10 hours. The reaction mixture is left cool, removed the solvent in vacuo and then distilled the benzyl chloride formed through a small column at 0.1 Torr. In arrears what remains is the 1-phenoxycarbonyl-4-methyl-1,2,5,6-tetrahydropyridine, which is produced by distillation can be cleaned.

Yield 216 parts by weight KP0.1 138 - 1420 C.

216 parts by weight of the phenyl carbamic acid obtained are heated to 1250 C, slowly mixed with 224 parts by weight of solid potassium hydroxide while cooling, stirred for 1 hour at 1300 ° C., the reaction mixture was cooled to 800 ° C. and distilled the amine formed at 20 torr. The distillate is dried over potassium carbonate and rectified. Yield 78 g of 4-methyl-boiling point 760 137-138 ° C., nD: 1.4772, suspicious 79% 1.4770.

The following are behaved in the same way: 1,2,5,6-tetrahydropyridine Kp760 116-117Q r, nD20: 1.4802 yield 80 k.

3-methyl-1,2,5,6-tetrahydropyridine, boiling point 760 138-1390 C, nD °: 1.4772, Yield 79% 4-ethyl-1,2,5,6-tetrahydropyridine, boiling point 760 162-1630 C, nD20: 1.4790, Yield 88%.

Example 2 346 parts by weight of 1-benzyl-4- (2'-methyl) propyl-1,2,5,6-tetrahydropyridine are with 261 parts by weight of phenyl chloroformate and 750 parts by volume of xylene Stirred at 1200 ° C. for 9 hours. The reaction mixture is allowed to cool, the removed Solvent in vacuo, then the resulting benzyl chloride at 0.1 Torr and a bath temperature of 100-1200 C. Yield 408.6 parts by weight of 1-phenoxycarbonyl 4- (2'-methyl) -propyl-1,2,5,6-tetrahydropyridine, which can be further processed for purification will.

A solution of 408.6 parts by weight of the phenyl carbamic acid obtained is heated in 2250 parts by volume of alcoholic aqueous 4N potassium hydroxide solution (alcohol-rasser ratio (80:20) 5 hours under reflux, allowed to cool, mixed with 1250 parts by volume concentrated hydrochloric acid at 5 to 100 C and then heated for 15 minutes Reflux. After cooling, the precipitated potassium chloride is filtered off with suction and evaporated the solution, distributed the residue in 100 parts by volume of water and continues Amine with excess 50% potassium hydroxide solution in freedom. It is extracted with ether. After evaporation of the solvent and distillation, 145.6 parts by weight are obtained (69%) 4- (2'-methyl) -propyl-1,2,5,6-tetrahydropyridine: bp1376-770 C, n20. 1 4724.

The following are obtained in the same way: Tetrahydropyridine yield. nD20 Kp in ° C / Torr in% 4-pentyl-1,2,5,6-tetrahydropyridine 71 1.4770 100-102 / 12 4-nonyl-1,2,5,6-tetrahydropyridine 69 1.4740 102-103 / 0.03 4-butyl-1,2,5,6-tetrahydropyridine 75 1.4756 87-89 / 13-14 4- (3'-methyl) -butyl-1,2, 5,6-tetrahydropyridine 65 1.4735 99-101 / 13-14 4-propyl-1,2,5,6-tetrahydropyridine 64 1.4762 68-71 / 12-13 4- (2'-methyl) -butyl-1,2,5,6-tetrahydropyridine 66 1,4755 95-96 / 14 - (2'-phenyl) -ethyl-1,2,5,6-tetrahydropyridine 74 1.5519 100-103 / 0.01 Example 3 A mixture of 262 is stirred Parts by weight of 1-benzyl-4-hexyl-1,2,5,6-tetrahydropyridine, 173 parts by weight of phenyl chloroformate and 200 parts by volume of toluene for 10 hours at 1000 C, allowed to cool, removed the solvent in vacuo and then distilled the benzyne chloride formed at 0.1 torr away. There are 305 parts by weight of 1-phenoxycarbonyl-4-hexyl-1,2,5,6-tetrahydropyridine obtained, which can be further processed without cleaning.

305 parts by weight of 1-phenoxycarbonyl-4-hexyl-1,2,5,6-tetranydropyridine are mixed with 250 parts by weight of potassium hydroxide at 130 - 1400 C. After this After the vigorous reaction has subsided, the mixture is stirred for 1 hour at 1400 ° C. and diluted at about 70 - 800 C with 500 parts by volume of water, separates the resulting reaction product and extracted the aqueous alkaline phase with ether. One gets in this way after removal of the solvent and completed distillation 124 parts by weight (73 5 ') 4-Hexyl-1,2,5,6-tetrahydropyridine, nD20: 1.4744, bp13: 116-1180 C.

The following are obtained in an analogous manner: 4-heptyl-1,2,5,6-tetrahydropyridine. Yield 85% KP 0.03: 70-72 ° C, nD20: 1.4746.

Example 4 A mixture of 75 parts by weight of 1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine is stirred, 61 parts by weight of phenyl chloroformate and 150 parts by volume of xylene for 9 hours at 1200 C, allowed to cool and removed the solvent as well the benzyl chloride formed in vacuo.

88 parts by weight of 1-phenoxycarbonyl-4-phenyl-1,2,5,6-tetrahydropyridine are obtained.

88 parts by weight of the phenyl carbamic acid obtained are combined with 900 parts by volume of butanol and 72 parts by weight of sodium hydroxide for 4 hours Reflux heated; the reaction mixture obtained is acidified at 5 to 100.degree concentrated hydrochloric acid, heated to 80 ° for 15 minutes and removed after suction of the sodium hydroxide the solvent in vacuo. The residue is 50 parts by volume Stirred water and mixed with excess 50 pointer potassium hydroxide solution. That so in Freed amine is taken up with ether and after removal of the solvent distilled. Yield 32 parts by weight of h-phenyl-1,2,5,6-tetrahydropyridine, nD20: 1.5962, KP0.05: 94 - 97 ° C.

Example 5 82.5 parts by weight of 1-benzyl-4- (2'-phenyl) -ethenyl-1,2,5,6-tetrahydropyridine are together with 61 parts by weight of phenyl chloroformate and 140 parts by volume Toluene stirred at 1000 ° C. for 12 hours. The reaction product crystallizes on cooling largely off. It is filtered off with suction and the mother liquor is completely evaporated in vacuo and rub the residue with toluene, whereby the remaining reaction product separates. In this way, 78.2 parts by weight of 1-phenoxycarbonyl-4- (2'-phenyl) ethyl-1,2,5,6-tetrahydropyridine are obtained.

Mp. 133-1350 C.

61 parts by weight of the phenyl carbamic acid obtained are heated in 600 ml of 2N ethanolic sodium hydroxide solution for 7 hours in a nitrogen atmosphere under reflux, allowed to cool, acidified at 10 to 150 C with excess concentrated Hydrochloric acid, then heated to 80 ° C for a further 15 minutes, then filtered off with suction and evaporated the filtrate in vacuo, one sets the amine from the residue with excess 4 N sodium hydroxide solution in freedom, extracted it with chloroform and dried the solution Via Na2SO4 The crude product remaining after evaporation can dirch crystallization can be purified from ether / petroleum ether. Yield 17.3 parts by weight, m.p. 71-730 C. 4- (2'-Phenyl) -ethenyl-1,2,5,6-tetrahydropyridine.

Claims (1)

Claim Process for the preparation of tetrahydropyridines of the formula (1), in which and R2 stands for hydrogen, a straight-chain or branched alkyl radical, for a phenyl radical which is optionally substituted by lower alkyl, nitro groups or halogen, or for an alkyl or aralkenyl radical which is optionally substituted in the aromatic part by lower alkyl, nitro groups or halogen , are, characterized in that 1-benzyl-1,2,5,6-tetrahydropyridines of the formula (IJ) in which R1 and R2 have the abovementioned meaning and R3 is hydrogen, a lower alkyl radical or halogen, with phenyl chloroformates of the formula (III) in which R4 is hydrogen, a lower alkyl radical or halogen, at temperatures between about 20 and 1400 C with elimination of the corresponding benzyl chlorides to form carbamic acid phenyl esters of the formula (IV) in which R1, R2 and R4 have the meaning given above, is reacted and the compounds of the formula (IV) thus obtained are saponified in alkaline solution at temperatures between about 60 and 1400.degree.