DE1092003B - Stereospecific process for the preparation of 1,3-dihydroxy-2-amino-alkenene-4 - Google Patents

Description

GERMAN

The invention relates to an improvement of the method of manufacture described in patent 1,070,168 of 1,3-dihydroxy-2-amino-alken-4 of the formula

R-CH = CH-CHOH-CHNh ₂ -CH ₂ OH

where R is an alkyl, in particular a higher alkyl radical, and its acyl compounds in Form of their various geometric and optical isomers. This procedure is characterized by that alkyne-2-ale-1 is condensed with / 3-nitroethanol, the l, 3-dihydroxy-2-nitro-alkynes-4 obtained are reacted with an aldehyde, in the obtained nitro-m-dioxanes, optionally after isomerization by heating or by treatment with alkaline agents, the nitro group reduced, optionally acylated the amino group obtained, the dioxane ring with acidic agents splits and at any stage before or after the splitting of the dioxane ring, but after the reduction of the nitro group converts the triple bond into a double bond and, if appropriate, the obtained Aminodiols converted into the acyl derivatives or the acyl derivatives obtained into the aminodiols and / or the racemates obtained are broken down into their optical antipodes and / or the bases obtained are broken down into their salts or converting the salts obtained into the free bases.

It has now been found that this process can be simplified considerably if the 1,3-dihydroxy-2-nitro-alkynes-4 reduced directly to the 1,3-dihydroxy-2-amino-alkynes-4 and the latter then according to Main patent for the 1,3-dihydroxy-2-amino-alkenes-4 partially hydrogenated or if the 1,3-dihydroxy-2-nitro-alkynes-4 reduced in one process step to the 1,3-dihydroxy-2-amino-alkenes-4. It is accordingly it is not necessary to prepare the nitro-m-dioxane compounds before the reduction of the nitro group.

Before the reduction mentioned, the 1,3-dihydroxy-2-nitro-alkynes-4 are broken down into their diastereoisomers, preferably by crystallization. the Reduction of the nitrodiols is preferably done with acidic agents, primarily with zinc and hydrochloric acid or with Iron and glacial acetic acid. But you can also use them in any other acidic media, such as B. by means of Make aluminum amalgam in ether and a little glacial acetic acid. The corresponding 1,3-dihydroxy-2-amino-alkynes-4 are obtained in this way. In the aminodiols obtained, the triple bond can be found in accordance with the main patent Convert 1 070168 into a double bond. For this purpose, hydrogen is preferably used in the presence a Lindlar catalyst or a palladium catalyst poisoned with quinoline, thus obtaining cis compounds. To prepare the trans isomers, it is preferred to reduce with an alkali metal, especially Sodium or potassium, in the presence of an alcohol or stereospecific method

for the production of 1,3-dihydroxy

2-amino-alkenes-4

Addendum to patent 1,070,168

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney,
Hamburg 36, Neuer Wall 10

Claimed priority:
Switzerland from April 9, 1957

Dr. Cyril Grob and Dr. Erwin Jenny,

Basel, Switzerland),
have been named as inventors

with a dimetal hydride such as lithium aluminum hydride, preferably in tetrahydrofuran.

But you can also reduce the nitro group and the triple bond in the same step. Treated to do so one the nitro-alkynes-4 preferably with a dimetal hydride, such as lithium aluminum hydride, whereby one trans-amino-alkenes-4 is obtained. Corresponding cis compounds are obtained by treating with catalytically excited hydrogen, such as hydrogen in the presence of a Lindlar catalyst, the first stage being the Reduction of the triple bond to the double bond, 'rapidly, while the second stage, the reduction of the nitro group, going slowly. The reduction in the presence of Lindlar catalyst is preferably carried out in alcohol, wherein, after taking up 1 molar equivalent of hydrogen, cis-1,3-dihydroxy-2-nitro-alkenes-4 which can be isolated if desired. Working with hydrogen in the presence a platinum catalyst, the reduction is broken after taking up what is necessary for the reduction Hydrogen. In these reactions, mixtures of different reaction products are often obtained can be separated in the usual way. The reductions mentioned are preferably carried out in the presence of absolute alcohol. Aminodiols obtained in this way can, if desired, be in a manner known per se

009 630/416

Way to convert into acyl derivatives. One can also obtain racemates, e.g. B. by treatment with optically active glutamic acid or by microbiological means into their optical antipodes.

Depending on the reaction conditions, the aminodiols are obtained as free bases or in the form of their salts, preferably as salts with acids such as hydrohalic acids, e.g. B. hydrochloric acid, sulfuric acid, phosphoric acids, Perchloric acid, acetic acid, citric acid, oxalic acid, tartaric acid, ascorbic acid, methanesulfonic acid, Oxyethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid or acetylsalicylic acid. The bases can be converted into their salts in a manner known per se, and the salts obtained can be converted into their bases as usual convert.

The starting material used for the present process is known or can be per se known methods.

The products of the process can be used as medicaments or as intermediate products for their production ao Find.

In the examples below, the temperatures are given in degrees Celsius.

Example 1 ₃ _

47 g of hexadecyne-2-al-1 and 20 g of nitroethanol are precooled to 0 ° and a cooled suspension of 2 g of potassium carbonate in 90 cm ^{3 of} methanol is added. After 15 minutes standing at 0 °, the potassium carbonate is filtered off with suction and ^{acidified at 0 ° with 3 cm 3 of} concentrated hydrochloric acid in 5 cm ^{3 of} methanol, the solution is extracted with ether, the ether extracts are washed with plenty of water and dried with sodium sulfate. After evaporation, a yellow syrup is obtained which is dissolved in 40 cm ^{3 of} ether, whereupon the solution is ^{diluted with 400 cm 3 of} pentane. The resulting solution is left to stand at 22 ° for 16 hours, the precipitated threo-IS-dihydroxy ^ -nitro-octadecin ^ with a temperature of 74 to 75 ° and of the formula

H NO ₂

CH ₃ (CH _{2) m} - C = C - C C - CH ₂ OH

! I.

OH H

off, the mother liquors are evaporated and 250 cm ^{3 of} pentane are added to them. Further crystals with a melting point of 69 to 72 ° precipitate, which are combined with the first obtained and, after recrystallization from ether-pentane, melt at 74 to 75 °. The filtrate is left to stand at 0 ° for 48 hours. The precipitated crystals of the erythro-lS-dihydroxy ^ -nitro-octadecin ^ of the formula

H H

CH ₃ (CH ₂ J ₁₂ -C = CCC-CH ₂ OH

OH NO «

55

60

melt after recrystallization at 43 to 45 °.

4.0 g of erythro-1,3-dihydroxy-2-nitro-octadecin-4 are dissolved in 30 cm ^{3 of} ethanol and slowly added dropwise, while cooling with ice and stirring, to a mixture of 10 cm ^{8 of} concentrated hydrochloric acid and 10 cm ^{3 of} ethanol. At the same time, 8.0 g of zinc dust are introduced in small portions and, in the course of the reduction, four times 5 cm ^{3 of} concentrated hydrochloric acid are added at intervals of about 5 to 10 minutes. The mixture is then stirred for a further 20 to 30 minutes. Any foaming can be controlled by injecting small amounts of alcohol. The reaction mixture is then filtered off with suction, the excess zinc dust is washed with aqueous ethanol and the filtrate is made alkaline with 10 N sodium hydroxide solution. It is extracted with ether, the ether components are washed neutral with water, dried over sodium sulfate, filtered and evaporated. The crystalline residue, the erythro-1,3-dihydroxy-2-amino-octadecin-4 of the formula

H H

40

45 OH NH ₂

can be recrystallized from chloroform-pentane and then melts at 74 to 77 °.

2.0 g of crude erythro-IS-dihydroxy ^ -amino-octadecin ^ are heated in 50 cm ^{3 of} absolute tetrahydrofuran with 1.5 g of lithium aluminum hydride for 4 hours on the steam bath. 4N hydrochloric acid is then added while cooling with ice, the mixture is concentrated somewhat in vacuo, ether is added and the mixture is extracted. The ether extracts are washed with 4N hydrochloric acid, 2N soda solution and with water, dried over sodium sulfate and evaporated in vacuo. The erythro-trans-DL-!, S-dihydroxy-amino-octadecene-which has the configuration of the natural erythro-trans-sphingosine is obtained from ether-pentane. It melts at 64 to 68 °.

The lithium aluminum hydride ^{solution can also be mixed with about 10 cm 3 of} water, filtered and evaporated. After recrystallization from chloroform-pentane, the residue gives the same product.

Example 2

If 10 g of threo-l.S-dihydroxy ^ -nitro-octadecin-4 are reduced analogously to the manner described in Example 1, dasthreo-l.S-dihydroxy ^ -amino-octadecin ^ is obtained the formula

H NH ₂

CH ₃ (CH _{2) 12} -C = C CC-CH ₂ OH

OH H

after recrystallization from chloroform-pentane Melts from 83 to 84 °.

Instead of zinc and hydrochloric acid, iron and glacial acetic acid or aluminum amalgam can also be used in little Use glacial acetic acid for reduction.

Example 3

2 g of threo-lS-dihydroxy ^ -nitro-octadecyne ^, obtained according to Example 1, are slurried in 50 cm ³ 60 ° / ₀ aqueous acetic acid and 13 g of iron powder added. The reaction temperature rises slowly to 30 °. The mixture is then stirred for a further 1 hour at 40 °. The reaction product is diluted with methanol, filtered and the filtrate is poured into a mixture of 24 g of powdered potassium sulfide in 160 cm ^{3 of} methanol. The precipitated iron sulfide is filtered off with suction, the filtrate is acidified with concentrated hydrochloric acid, the crystallized potassium chloride is separated off, the filtrate is evaporated in vacuo at 40 °, the residue is made alkaline with 10N sodium hydroxide solution and extracted with ether. The ether extract, washed neutral with water and dried over sodium sulfate, is evaporated to dryness in vacuo, and the residue is recrystallized from chloroform-pentane. That's how you get it

threc-l.S-Dihydroxy ^ -amino-octadecin ^ from F. 82 to 84 °, which does not result in a melting point depression with material obtained in another way.

Example 4

Dissolve 0.5 gthreo-IS-dihydroxy ^ -nitro-octadecin ^, obtained according to Example 1, in 20 cm ^{3 of} ether, mixed with 2 cm ^{3 of} water, 4 cm ^{3 of} glacial acetic acid and with aluminum amalgam made from 0.5 g of aluminum was obtained and stirred for 8 hours at room temperature. The aluminum sludge is filtered off, extracted twice with boiling ether, the ether extracts are shaken with 2N hydrochloric acid and washed with water. The aqueous, hydrochloric acid solution, which contains the resulting amino diol as hydrochloride, is made alkaline with 2η sodium hydroxide solution, and the mixture is extracted with ether. The ether extracts are washed with water, dried over sodium sulfate, and the ether is evaporated in vacuo. The remaining oil is dissolved in a little benzene, mixed with pentane, and threo-1,3-dihydroxy-2-amino-octadecyne with a melting point of 83 ° to 84 ° is obtained.

Example 5

5 g of pure threo-1,3-dihydroxy-2-nitro-octadecyne-4, obtained according to Example 1, are dissolved in 40 cm ^{3 of} absolute tetrahydrofuran and a solution of 5.4 g of lithium aluminum hydride in 90 cm is slowly added with stirring ^{3 to} absolute tetrahydrofuran. The reaction temperature rises to 65 °. The mixture is then refluxed for a further 5 hours. The excess lithium aluminum hydride is decomposed with 35 cm ^{3 of} water, the precipitated sludge is filtered off with suction and the filtrate is evaporated at 40 ° in a water jet vacuum. The residue is sublimed in a high vacuum at a bath temperature of 120 ° and the sublimate is recrystallized from chloroform-pentane. A product with a melting point of 95 ° to 97 ° is thus obtained which, with threo-trans-1,3-dihydro-2-amino-octadecene-4 having a melting point of 95 ° to 97 °, which is obtained in another way, does not result in a depression of the melting point.

40 Example 6

10 g of pure threo-1,3-dihydroxy-2-nitrooctadecin-4, obtained according to Example 1, are dissolved in 250 cm ^{3 of} absolute ethyl acetate and hydrogenated with hydrogen at room temperature and under normal pressure in the presence of 1 g of Lindlar catalyst. After 1 equivalent of hydrogen has been taken up, the reaction comes to a standstill, whereupon the solution is freed from the catalyst and evaporated in vacuo at 40 °. The residue, after recrystallization from chloroform-pentane, gives shiny flakes with a melting point of 79 to 80 °, which have the formula

CH ₃ (CHg) ₁₂ . ,H

^X C
NO, Il

CH, -CH-CH '

OH

comes to.

OH

Example 7

55

60

1 g of pure threo-1,3-dihydroxy-2-nitro-octadecyne-4 obtained according to Example 1 is dissolved in 25 cm ^{3 of} absolute alcohol and shaken at room temperature and normal pressure with 50 mg of platinum oxide in the presence of hydrogen. After consumption of about 3.8 molar equivalents of hydrogen, the hydrogen uptake slows down noticeably. The hydrogenation is interrupted, the product which has crystallized out is brought back into solution by heating, this is filtered warm and the filtrate is evaporated. The residue is recrystallized from chloroform-pentane. This gives a mixture mainly consisting of threo-1,3-dihydroxy-2-amino-octadecane and the unsaturated cisthreo-1,3-dihydroxy-2-amino-octadecene-4 with a melting point of 75 ° to 85 °.

Example 8

1 g of pure threo-1,3-dihydroxy-2-nitro-octadecin-4, obtained according to Example 1, is dissolved in 25 cm ^{3 of} absolute alcohol and shaken in the presence of 100 mg of Lindlar catalyst under hydrogen at room temperature and normal pressure. 1 equivalent of hydrogen is absorbed very quickly. To. If a further 2.6 molar equivalents of hydrogen are taken up, the hydrogenation comes to a standstill. The reaction solution worked up by customary methods gives, after crystallization from chloroform-pentane, a mixture with a melting point of 65 ° to 70 ° which contains threo-cis-1,3-dihydroxy-2-amino-octadecene-4.

Claims (8)

Patent claims: 1. Stereospecific process for the preparation of 1,3-dihydroxy-2-amino-alkenes-4 of the formula R - CH = CH - CHOH - CHNH ₂ - CH ₂ OH where R is an alkyl radical, and its acyl compounds in the form of their various geometric and optical isomers according to the main patent 1070168 by condensation of alkyne-2-alen-l with / 3-nitroethanol, characterized in that the obtained l.S-dihydroxy ^ -nitro-alkynes ^, optionally after decomposition into their diastereoisomers, preferably by crystallization, directly to the 1,3-dihydroxy-2-amino-alkynes-4 reduced and the latter then according to the main patent to the 1,3-dihydroxy-2-amino-alkenes-4 partially hydrogenated or that the l, 3-dihydroxy-2-nitro-alkynes-4 in one Process step reduced to the 1,3-dihydroxy-2-aminoalkenes-4. 2. The method according to claim 1, characterized in that the reduction with acidic agents performs. 3. Process according to Claims 1 and 2, characterized in that the reduction is carried out with Zinc and hydrochloric acid. 4. The method according to claim 1, characterized in that the reduction with lithium aluminum hydride performs. 5. The method according to claim 1, characterized in that the reduction with catalytic excited hydrogen. 6. The method according to claim 5, characterized in that there is hydrogen for the partial hydrogenation used in the presence of Lindlar catalyst. 7. The method according to claim 5, characterized in that there is hydrogen for the partial hydrogenation used in the presence of a platinum catalyst. 8. The method according to claim 7, characterized in that the reduction is terminated after taking up about 3.5 to 4 molar equivalents of hydrogen. © 009 630/416 10.60