DE839496B - Process for the preparation of pentaenes (vitamin A or -ethers and -esters) - Google Patents

Description

(WiGBl. P. 175)

ISSUED MAY 19, 1952

H 625 IV c 1 12th

Several syntheses of vitamin A and its ethers have already been published. The known processes break up the carbon structure of vitamin A from 20 carbon atoms as follows: 5 - [2 ', 6', o'-trimethylcyclohexen- (i ') - yl] 3-methyli> entadiie.n- (2, 4) -al- (i) is condensed with 3-methyll> uiten- (2) -al- (i) (C ₁₅ + C ₅ = C ₂₀ ; reports of the German Chemical Society, Rd. 70 1193d], p. 853) . The same aldehyde C ₁₅ or the chloride of the corresponding acid are added to malonic acid esters with methyl vinyl ketone and the carboxyl groups are subsequently split off (C ₁₅ -f C ₄ + C ₃ = C ₂₂ - C ₂ = C ₂₀ ; American patent specification -'369 15S). 6- | /, 6 ', (S'-trimethylcyclohexen- (i') - yl] -4-methyllhexadien- (3, 5) -in- (i) and 6- [2 ', 6', o'- Trimethylcyclohexen- (1 ') -ylj 3-oxy-4-methyl ^l hexen- (4) -in- (1) are condensed with methyl vinyl ketone or with esters or ethers of i-oxybutanone- (3) (C ₁₆ + C ₄ = C ₂₀ ; American patents 2369156, 2369160 and 2382085) 4- [2 ', 6', o'-trimethylcyclohiexen- (1 ') -yl | -2-methyibutene- (2) -al- (1) is with ι-methoxy-3-methylpeniten- (2) -in- (4) or with ethers of 1, 3-dioxy-3-methylpentin- (4) implemented (C ₁₄ + C ₆ = C ₂₀ ; Experientia, Vol. 2 [1946], p. 31; American patent specification 2369157) Finally, syntheses of vitamin A methyl ether were published from 5- [2 ', 6', 6'-tri

methylcyc lohexen- (i ') - yl ¹ ] - 3-oxy - 3 - methylpentene (4) - in - (ι) and 1 - methoxy - 3 - methyl - 4 - chilor-, buten- (2), ( Journal of the American Chemical Society, vol. 67 [1945], p. 1627), and from 4- (V ₁ O ', 5 o'-trimethylcyclohexen - (ι') - yl] - buten - (3) -one - (2) (/ 3-ionone) and 1 - methoxy - 3 - methyl - 6 - bromo hexadiene (2,4) (Chemistry and Industry, Vol. 58 [1939], p. 802) These last two syntheses were not supported by any biological test results, and a published ultraviolet absorption spectrum shows no absorption maximum at 325 to 328 νημ, which is characteristic of vitamin A and its derivatives (Journal of the American Chemical Society, Vol. 67 [1945],

S. T627).

CH ₃ CH ₃

As has now been found, vitamin A active compounds are obtained in that one by means of a Grignard reaction / J-ionon with ι -Oxy-3-methylhexen- (2) 4n- (5) or its ether or esters condensed, to the three-fold division of the condensation product obtained 1 mol Hydrogen attaches, the 1, 7-dioxy-3 thus formed, 7-di.methyl-9- [2 ', 6', 6'itrimethylcyclohiexen- (i ') - yl] -nonatnien- (2,5,8) or its ether by the action of an acylating agent, expedient in the presence of a diluent, rearranged in a manner known per se and then splitting off acid.

The synthesis should proceed according to the following equation:

, -CH = CH-CO + CH = C-CH ₂ -C = CH-CH ₂ OR

CH ₃ (I)

CH3 CH3

CH ₃

OH CH,

(Π)

i-CH = CH-C-CsC-CH ₂ -C = CH-CH ₂ OR

CH,

(III)

CH ₃
CH ₃ CH ₃ OH

-CH = CH-C-CH = CH-CHo-C = CH-CHoOR

- CH = CH-C = CH-CH-CH "- C = CH - CH" OR

CH

CH ₃ CH ₃

CH = CH-C = CH-CH = CH-C = CH-CH, OR

CH,

CH ₃

(VI)

X = hydroxyl, acyloxy or halogen.

R = hydrocarbon residue, acyl or hydrogen.

The synthesis of vitamin A or its ethers and esters ge.li.ngit according to the invention Assembling of / 3-ion (I) with 13 carbon atoms with an ether side chain (II) with 7 carbon atoms to a condensation product (III) with 20 carbon atoms. This conidensation product contains a triple bond and three double bonds, of which nmr two are conjugated to each other. This becomes the sensitive system of five contiguous

jugated double bonds of vitamin A only in the triple bond through the last reaction stage after previous partial hydrogenation Esterification proceeding with allyl rearrangement of the 7-position hydroxyl group and subsequent acid elimination.

That used for condensation with / i-ionone i-Üxy-3-methylhexen- (2) -in- (5) or its ethers and esters were not yet known. your

ίο The representation succeeds · for example from propargyl chromium and methyl vinyl ketone in the following way: ι moles of propargyl bromide and 2 to 4 moles of dry methyl vinyl ketone are condensed in benzene solution under the usual conditions of the Reformatsky reaction at the boiling point with 1 to 3 moles of zinc shavings. The resulting zinc salt of this condensation product is decomposed with acids and the solvent is evaporated. The 3-oxy-3-methylhexen- (i) -in- (5) with bp ₁₂ = 44 to 47 ⁰ can be distilled out in good yield from the viscous residue;

n ² » ⁰ = 1.460; d ' ^s , ⁰ = 0.916.

»5 ι -Methoxy-3-methylhexen- (2) -in- (5) is formed from 3-0xy-3-methylhexen- (i) -in- (5) by halogenation z. B. with phosphorus halidiums, where the halogen occurs with allyl rearrangement in the 1-S division, and implementation of the i-halogen-3-methylhexene (2) yne- (5) formed with 1 equivalent of sodium methylate in methyl alcohol. The i-methoxy-3-methylhexen- (2) -in- (5) sieidet l> ei 47 to 49 ^0/1 5 mm;

= 1.455; d'f = 0.913.

i-Acetoxy-3-methylhexen- (2) -in- (5) is formed when 3-Oxy-3-mathylhexen- (i) -m- (5) is boiled with acetic anhydride. After evaporation of the excess acetic anhydride, the residue is fractionated in vacuo. i-Acetoxy-3-mathylhexen- (2) -in- (5) boils at 56 to 57 ° / i2mm; n ¹⁰ ° = 1.450; d'f = 0.968.

i-Oxy-3-methylhexeti- (2) -in- (5) is used in the saponification of i-Acetoxy ^ rnethylh, exen- (2) -iin- (5) under gentle soil conditions as when reacting with 3 equivalents of Grignard- Reagent (ethylmagnesium bromide) obtained with subsequent mild hydrolysis. It boils 1> about 68 to 70 ^0/15 mm;

η'S "= 1.448; d'J ⁰ = 0.874.

The first stage of the present process is a Grignard reaction, in which i-Oxy-3-methylhexen- (2) -in- (5) or its ether or lister with an alkylmagnesium halide (e.g. Ethylmagnesiium bromide) is used. Using of L-oxy-3-methylhexen- (2) -in- (5) one needs 2 equivalents, l> for its ether 1 and for the ester 3 equivalents of Grignard reagent. From the ethers a monomagnesium halogen compound arises and from the i-Qxy-3-methylhexen- (2) -in- (5) a disubstituted halogen atom which is also substituted on the hydroxyl group, The ester group becomes the ester group with saponification the same dimagnesium halide compound formed as from the free alcohol. This Magnesium halide compounds are now used in usually condensed with / 3-ionone, the implementation succeeds in common solvents such as ethyl ether. The reaction product is hydrolyzed under mild conditions, e.g. B. with an ammonium salt solution in the cold. The reaction conditions are to be chosen so that no undesired elimination of water he follows. The raw condensation product can be used directly. To the distance from small amounts of starting materials unchanged 1 - oxy - 3 - methylhexene - (2) - in - (5) or its ether evaporated in vacuo and unreacted / 3-ionone in the form of a crystallizing Derivatives (e.g. as semicarbazone) are separated. The purification of this formed i, 7 "Dioxy-3, 7-dimethyl-9- [2 ', 6', 6'-trimethylcyclohexene- (Y) -yl] -nonaidiene- (2, 8) -in- (5) or its Ätlier can also be achieved by means of a continuous chromatogram, z. B. by a deactivated alumina column or burn through between Solvents such as low-boiling petroleum ether and aqueous methyl alcohol.

The purified conidensation product easily splits off water when heated. It shows im Ultravioletite absorption spectrum none or only; low absorption over 260 m /, ί. At you Zerewitinoff determination of the product of i-oxy-3-methylhexen- (2) -in- (5) or its ester The result is values for 2, from whose ether values for ι active hydrogen atom. :

The condensation product (ΠΙ) is now subjected to the partial hydrogenation of the triple bond. In this stage too, care must be taken that no undesired elimination of water occurs. For the selective uptake of 1 mole of hydrogen, the catalytic hydrogenation! »Has particularly proven itself. Suitable catalysts are, for example, palladium-calcium carbonate, palladium-barium sulfate and palladium-carbon, onto which quinoline is adsorbed before use. If a crude condensation product is subjected to the partial hydrogenation, from which only the unchanged i-oxy-3-methylhexene (2) -in- (5) or its ether has been separated off, a corresponding to the / 3-ionone content is left lower amount of hydrogen \ act. After the calculated amount of hydrogen has been taken up, the hydrogen supply is interrupted. The hydrogenated product can be purified in the same way as the product (HI) of the 1st reaction stage. The separation between solvents such as light petroleum ether and aqueous, generally speaking, methyl alcohol is particularly advantageous. The purified product 1, 7-dioxy-3, 7-idimethyl-9- [2 ', 6', o'-trimethylcyclohexein- (Y) -yl] -nonatriene- (2, 5, 8) or its ether shows in the ultraviolet absorption spectrum no or almost no absorption above 260 πΐμ. Desired case can be the unsathered connection by mild

496

Action of ι moles of an acylating agent the terminal hydroxyl group are esterified.

The component obtained by partial hydrogenation

Densation product is now dehydrated with rearrangement; this is done by treating with an esterifying agent which causes a so-called AlIy! rearrangement (Hüekel, Theoretical Fundamentals of Organic Chemistry, Leipzig ^. Edition, Vol. I [1943], pp. 297 and 298fr ".) and subsequent elimination of acid During the allyl rearrangement, the permanent hydroxyl group moves with esterification into the 5-position and the double bond from the 5- to the 6-position. In this reaction stage, 1,7-D10XV-3, /-di.methyl-9-[2 ' , 6 ', 6'-trimethylcyclohexen - (V) - yl] - nonatriene - (2, 5,8) or its ether rearranged in a manner known per se by acylation and heating ^1. A method is chosen in which as little as possible unwanted side reactions (elimination of water prior to rearrangement, polymerization, cyclization, etc.) occur. The condensation product (IV) can be esterified by the action of organic acylating agents; for example, the lower fatty acid anhydrides in the presence of basec are suitable for this reaction hen means. The presence of wasiser-releasing agents can be disadvantageous because they can intensify the undesired elimination prior to the rearrangement. (Thus, for example, forms from i-methoxy-3,7-d ^imethyl-l 7-oxy- 9 '[2', 6 ', o'-trimethyl-ii ^ -ylj-nonatrien- (2, 5, 8) When p-toluenesulfonic acid acts in glacial acetic acid at room temperature, a compound isomeric to vitamin A methyl ether, which has a lower absorption intensity in the ultraviolet spectrum; the absorption maximum is 310 to 315 iTU /. The same compound is formed in small amounts of vitamin A Methyl ether oil when boiling with toluene in the presence of small amounts of iodine.) Even strong acids and acidic agents can cause premature dehydration. The same risk of premature cleavage exists when using halogenating agents (e.g. phosphorus halides)

♦ 5 which, depending on the method of application, the desired Reaction occurs only in small endings. The intermediates obtained by the allyl rearrangement correspond to formula (V). It is not necessary to isolate them.

A further double bond is introduced by splitting off acid, namely in the Way that the one that had migrated to the fifth was esterified Hydroxyl group with one hydrogen T atom of the neighboring 4-permanent carbon atom Splits off acid. Depending on the choice of relocation conditions the cleavage can take place in the same reaction stage as the Rearrangement (e.g. when heated with acetic anhydride in the presence of basic agents such as quinoline), or the cleavage can be a separate 'Represent the traversing step. The elimination of acid from the rearranged ester (V) can be done, for example, by heating with quinoline to 180 ° or by boiling with tertiary potassium amylate take place in tertiary amyl alcohol.

These rearrangements and cleavages give rise to pentaenes which correspond to formula (VI), wherein the terminal functional group is a free, esterified or etherified one Can be hydroxyl group; desired case the esters obtained can be saponified to form free vitamin A.

According to the invention, the representation of pentaenes can be done as follows:

/ 3-ionone is condensed with i-methoxy-3-methyl (hexen- (i) -in- (5) using 1 mol of ethylinagnesium bromide in ethereal solution. After hydrolysis with ammonium salt solution, the triple bond of the condensation product obtained is deposited using palladium -Baniium sulfate catalyst 1 mol of hydrogen. The i-methoxy-3, 7-dimethyl-7-oxy-9 "[2 ', 6', 6'-trimethiykyclohexen- (i ') - yl] -nonatrien- ( 2, 5, 8) is boiled with acetic anhydride in the presence of potassium acetate and then heated with tertiary amyl alcohol in Kaliumiamylat ¹ A modification of this method testeht that the obtained by partial hydrogenation i-methoxy-3 / man - dimethyl ^ oxy. -9- [2 ', 6', 6'-trimethylcyclohexen- (i ') - yl] -nonatriene (2, 5, 8) gradually heated ^{to 160 to 180 01 with acetic anhydride and quinoline.}

According to the embodiments explained above the invention, you get vitamin A, vitamin Α ester or vitamin Α ether, which in their physical, chemical and biological properties to vitamin A and its esters from natural sources. You are! particularly characterized by those in the ultraviolet spectrum Pentaene absorption occurring at 325 to 330 m «.

Process products can be cleaned using the same methods as from natural ones Sources (obtained high concentrations of vitamin A and vitamin Α-esters (separate between Solvents, fractional precipitation from alcoholic solution, gentle distillation, chromatagraphic Adsorption and crystallization of the free alcohol or suitable derivatives). To the Separation of the by-products caused by undesired The elimination of water before the allyl release occurs, is the chromatographic adsorption particularly useful.

The products are like vitamin Α preparations from natural sources against the destructive influence to protect from light, air and heat. It is recommended to add antioxidants, which can also be present during the entire course of the synthesis; Tocopherols are included in this l> especially suitable.

example 1

5.2 parts by weight of 1-methoxy-3-methylhexen- (2) -in- (5) in 10 parts by volume of ether are added in the course of ι hour in a nitrogen atmosphere with stirring

added to an ethylmagnesium bromide solution, which was prepared from ι part by weight of aluminum shavings and 4.5 parts by weight of Ä thy! bromide in 20 space parts of ether. The mixture is then refluxed for 4 hours, during which the magnesium compound formed precipitates as a resinous mass. It is allowed to cool and a solution of 7 parts by weight /? - ionone in 10 parts by volume of ether is added over the course of ^{1 hour and the solution is completed} Condensation by stirring for 4 hours at 1κ · ί room temperature. The clear reaction solution is decomposed by pouring it onto 50 parts by weight of ice and 10 parts by weight of ammonium nitrate. The ether solution is washed with ammonium salt solution and water, dried with sodium sulfate and the solvent is evaporated off in vacuo, avoiding any overheating to prevent undesired elimination of water. For the purification of this crude condensation product, unreacted / S-ionone is precipitated as semicarbazone by means of a solution of 2 parts by weight of semicarbazide in 20 parts by volume of methyl alcohol. In the case of urgency, double the amount of water is added and shaken out with petroleum ether. When the petroleum ether is washed with water, a further amount of I-ionone semicarbazone precipitates and is filtered off. The ficrate is dried and adsorbed onto the 20% of weakly activated aluminum oxide, while unreacted 1-methoxy-3-methyrhexcnine and dehydration products can be washed out with petroleum ether. The purified i-meth ^ox y ~ 3> 7-dimethyl-7-oxy-o, - [2 ', 6', 6'-trimethylcvclohexen- (i ') -vl | -tu> nadiene- (2, 8) -in- (5) is eluted with ether. Evaporation of the solvent gives 5 to 7 parts by weight of pure conidus product as a thick, clear oil.

The constitution of the compound is demonstrated by the Zerewitinoff Bastimniung, the values for 1 active hydrogen atom results and that Ultraviolettabsorptionsspektruin showing only below 270 with significant absorption and therefore only allows conjugation.

10 parts by weight of pure i-Alethoxy-3, 7-diimethyl-7-oxy-C) - [2 ', 6', 6'-trimethylcyclohexen- (i ') - yl] -nonadiene- (2, S) -in- (5) are dissolved in 100 parts by volume of methyl alcohol and hydrogenated using 1.5 parts by weight of i% palladium barium sulfate catalyst l> at room temperature, 0.05 parts by weight of tocopherol being added to the hydrogenation solution as an antioxidant. Xach uptake of 1 mol and 770 parts by volume of hydrogen (740 mm, 20 ⁰⁾ is stopped and the hydrogenation catalyst abgenuitscht. The filtrate is added to water for the removal of some water elimination product with 4 parts and shaken with a little petroleum ether of boiling point 30 to 6o ^c. The methyl alcohol solution is then diluted with 200 parts of water, extracted with ether and the ether extracts are dried and concentrated. This gives about q parts by weight of i-methoxy-3, 7-dimethyl-7-oxy-9-I 2 ', 6', (/ -triniethylcyclohexen- (V) -yl] -nonatriene- (2, 5, 8) as a yellowish, viscous oil with η ² o = 1.513. The Zerewitir.off determination shows ι active hydrogen content. The ultraviolet ^{absorption measurement 1} gives no or only little absorption over 260 m / <. ■

4 parts by weight of this product; the partial hydrogenation are dissolved in 20 parts by weight of acetic anhydriide, 4 parts by weight of dry potassium acetate are added and the mixture is refluxed for 2 hours under Lichitauissohhiß. The excess acetic acid anhydride is then evaporated and the glacial acetic acid formed is evaporated in vacuo and the residue is taken up in petroleum ether with a boiling point of 30 ° to 60 ° and water. The petroleum ether solution is washed with sodium bicarbonate and water, dried with sodium sulphate and evaporated. The remaining brown oil ¹ is fractionated in a molecular vacuum. In addition to a small forerun, 3 parts by weight of a yellowish oil with a boiling point of 80 to 90 ° / ¹⁰ ~ 5 mm are obtained, which in the ultraviolet spectrum shows pronounced absorption in the pentaene region (315 to 335 m / i) and in the growth rate is the most common in the vitamin A-deficient rat is highly effective.

The amount of final product showing the specific absorption in ultraviolet light can be can be increased by boiling with tertiary potassium amylate in amylene hydrate.

Example 2

to parts by weight of the crude condensation product the Grignard reaction (shown according to Example 1) are in methyl alcoholic at room temperature Solution with precise control of the hydrogen uptake hydrogenated with 1 part by weight 4% palladium-barium sulfate catalyst, the was activated beforehand by heating to 6oo ° des. After taking in anything less than ι mol of hydrogen, the catalyst is filtered off, unreacted /? - ionone precipitated as semikaribazoni, The hydrogenated compound worked up as in Example 1 and with acetic anhydride in the presence one! «Asian means implemented. Receives one in good distribution the same product as in example 1.

110 B eis ρ ie 1 '3

3 parts by weight of i-methoxy-3, 7-dimethyl-7-oxy-9 - [2 ', 6', 6'-trimethylcyck> hexen- (i ') - yl-] -nonatriene- (2, 5, 8) (shown according to Example 1) are dissolved in 30 parts by weight of quinoline and 6 parts by weight of acetic anhydride and first heated to 80 to 100 ° for 2 hours and then to 160 to 180 ° for 1 hour. After cooling, it is taken up in low-boiling petroleum ether and then washed out several times with 95% methyl alcohol and water. The residue of the petroleum ether solution is fractionated in a molecular vacuum. This gives about 2 parts by weight of a yellow, viscous oil of boiling point 80 'to 90 ⁰ ZiO ^-5 mm, which in a pronounced ultraviolet spectrum

Shows absorption in the pentaene region. The product also contains a maximum in the tetraene region l> ei 310 to 315 mm, which probably originates from an isomeric compound lx? I which an undesired elimination of water occurred before the esterification. The separation of this compound succeeds, for. B. through a flow chromatogram by means of petroleum ether 'through little activated aluminum oxide.

Example 4

2 parts by weight of i-methoxy-3, 7-methyl-7-oxy-9- [2 ', 6', 6'-trimethylcyclohexen- (i ') - yl] nonate ^: rien- (2, 5, 8 ), shown according to Example 1, are left with 4 parts by volume of acetic anhydride and 8 parts by volume of pyridine for 70 hours at room temperature. The reaction solution is then poured onto ice and extracted with petroleum ether at a boiling point of 30 ° to 60 °. The extracts are washed with τ n-sulfuric acid, bicarbonate solution and water, dried with sodium sulfate and evaporated. The residue, 1.5 parts by weight, gives an intense blue coloration with amimony trichloride in chloroform solution (main absorption maximum l> ei 620 mt <, secondary maximum at 580 χημ).

2 parts by weight of this reaction product are dissolved in 4 parts by volume of tertiary amyl alcohol and added over 15 minutes with stirring and introduction of nitrogen to a boiling solution of 1 part by weight of ¹ potassium in 20 parts by volume of tertiary amyl alcohol. After ι hour, the reaction solution is cooled, diluted with petroleum ether of boiling point 30 to 6o ^Q diluted and washed with 95 ° / pc alcohol, methyl alcohol and water. Dry and evaporate the solvent. The petroleum ether residue, a yellow-brown oil, contains about 10% vitamin A methyl ether according to the ultraviolet absorption measurement and the Carr Price determination.

For purification, this crude product is chromatographed with petroleum ether on a column with weakly activated aluminum oxide. After the addition of alcohol, a vitamin A methyl ether preparation is obtained as the eluate of the main zone, which is greenish, fluorescent in the light of the quartz lamp, of the chromatogram, which is ^{distilled from 80 to 90 0} ZiO ^-4 mm and is highly biologically effective.

Example 5

3.2 parts by weight of 1-methoxy-3, 7-dimethyl-7-oxy - 9 - [2 ', 6', 6'-trimethylcyclohexen - (1 ') - yl] nonatriene- (2 ,, 5, 8) are dissolved in 20 parts by volume of pyridine and 10 parts by volume of chloroform and with stirring and ice-cooling in the course of an hour with a solution of 1.5 parts by weight Benzoyl chloride added in 10 parts by volume of chloroform. The temperature of the yellow solution is left rise to room temperature over the course of 12 hours, then dilute with petroleum ether from the boiling point 30 to -6o °, cools with ice, washes with bicarbonate solution; dilute sulfuric acid and water, dries and evaporates the solvent. The yellow-brown residue is according to the information in example 4 with potassium tert-amylate in tertiary amyl alcohol! ». A crude product with a content of 5 to 10% is obtained Vitamin A methyl ether, which can be cleaned according to the information in Example 4. Instead of Benzoylchlofild can in this example have the equi- 7 » the equivalent amount of acetyl chloride used. The vitamin A methyl ether is obtained in this way same yield.

Claims (2)

PATENT CLAIMS: 1. A method for the preparation of pentaenes (vitamin A or ethers and esters), characterized in that by means of a Grignard reaction /? - ionone with i-oxy-3-methyüiexen- (2) - ^j in ( 5) or its ethers condensed esters, to the Dreifachibrfung of the KonidensiatiionsprodukteiS ι mol of hydrogen added, the so formed i, 7 "Dioxy-3, 7-dimethyl-9- [2 ', C /, 6'-trimethylcyclohexen- (i ') - yl] - nonatriene- (2, 5, 8) or its ether by the action of an acylation agent, expediently in the presence of a diluent, is removed in a manner known per se and then acid is split off. 2. The method according to claim 1, characterized in that that antioxidants are added to the reaction mixtures. 5020 5.52