CH619211A5 - Process for the preparation of 11-cis-13-desmethyl vitamin A acid and all-trans-13-desmethyl vitamin A acid and their derivatives - Google Patents

Description

The invention relates to a process for the preparation of ll-cis-13-desmethyl-vitamin-A-acid and all-trans-13-des-methyl-vitamin-A-acid as defined in claim 1.

The compounds prepared in this way can be converted into their derivatives according to patent claims 3, 4 and 5.

Tetrahedron 22 (1966) page 293 describes the preparation of all-trans-13-desmethyl-vitamin-A acid methyl ester from trans - /? - ionylidene acetaldehyde and crotonic acid methyl ester-y-diethylphosphonate as an intermediate for the biologically completely inactive all-trans-13 -Desmethyl-vitamin-A-acetate described.

A 220 MHz HNMR spectrum of all-trans-13-des-methyl-vitamin-A-acid without further details on the properties of the substance mentioned is in O. Isler, Caro-tenoids, page 241, Birkhäuser Verlag, Basel , 1974. The ll-cis-13-desmethyl-vitamin-A-acid has not yet been described.

The compounds of formulas I and II are prepared using the method defined in claim 1.

Examples of X © in the starting compound of the formula III are: halides, in particular the chloride and the bromide, hydrogen sulfate or tosylate.

If R3 in the formulas IV, V and VI is an alkyl radical having 1 to 4 carbon atoms, z. As methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl into consideration. Sodium or potassium ions are particularly suitable as alkali metal ions.

The starting compounds of formula III are known and their preparation can be readily found in the literature, e.g. B. DE-PS 1 060 386.

The fumaraldehyde acid or its derivatives and salts required for the preparation of the starting compounds can be prepared as described in Annalen der Chemie 697 (1966) pages 52, 53 and 56 to 59. Starting compounds of the formula IV in which R3 is hydrogen, methyl, ethyl, sodium, potassium or ammonium are preferably used.

Suitable inert solvents for the reaction of the compounds of the formulas III and IV in the specified temperature range are, for. B. dialkyl ethers and saturated cyclic ethers, such as diethyl ether, dioxane, tetrahydrofuran, cyclic hydrocarbons, such as cyclohexane, aromatic hydrocarbons, such as benzene, toluene, xylene, nitrobenzene, nitriles and esters of lower aliphatic carboxylic acids, such as acetonitrile and ethyl acetate, acid amides, lower carbohydrates, such as dimethylformamide, and lower aliphatic alcohols, such as methanol, ethanol, isopropanol.

Alkali, alkaline earth metal hydroxides, alcohol latexes, amines or nitrogen bases, such as ammonia or sodium methylate, can be used as bases. The amount of base expediently used is calculated from the stoichiometry in order to convert the compound of the formula III into the corresponding ylide.

The reaction conditions mentioned correspond to those of the known Wittig reaction. The mixture of isomers obtained in this reaction can be separated by recrystallization or by chromatographic separation on a column. A heptane-isopropanol mixture or methanol can be used for recrystallization. A silica gel column with the solvent petroleum ether or petroleum ether ether is suitable for column-chromatographic separation.

It is also possible to saponify the esters of the formulas V and VI obtained first and to carry out the separation of the isomer mixture at the carboxylic acid stage.

The esters of the formulas V and VI can be saponified as follows:

The esters are heated with 1 to 3 moles of a strong base, e.g. B. sodium hydroxide or potassium hydroxide, in a suitable alcohol, e.g. B. ethanol, until quantitative saponification. The carboxylic acids can be separated by recrystallization from methanol or by column chromatography, as in the separation of the acids.

The corresponding derivatives of the formulas I 'and II' are obtained from the acids of the formulas I and II thus obtained using the process defined in claim 3. Examples of the radical R in these formulas are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, with ethoxy and in particular isopropoxy being preferred, and Phenoxy and 2-carboxylphenoxy, the latter being particularly preferred.

With the help of the method defined in claim 4, one arrives from the acids of the formulas I and II to the derivatives of the formulas I "and II".

Examples of the R1 radical in these formulas are: amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec.-butylamino, tert.-butylamino, isobutylamino, phenylamino, 2,4-dimethylamino , 4-carboxylphenylamino, 4-carboxymethylphenylamino, 4-carboxyethylphenylamino, dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino and diphenylamino, with the 3,4-dimethylamino group and the 4-carboxyethylphenylamino group being particularly preferred; furthermore the aziridino, piperidino or morpholino radical, of which the latter two are particularly preferred; and the hydrazino, methylhydrazino and phenylhydrazino radical.

Derivatives of the formulas I '"and II'" are finally obtained with the aid of the method defined in claim 5. Examples of R2 include: acetoxy, propionyloxy

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619 211

4th

and butyryloxy and the remainder Ci8H25C0-0— in the configuration of the ll-cis-13-desmethyl-vitamin-A-acid or the all-trans-13-desmethyl-vitamin-A-acid.

The compounds of the formulas I and II are first converted into their acid chlorides in the case of their further treatment in accordance with patent claims 3 to 5. This can be done in the usual way and without difficulty with the aid of inorganic acid chlorides, such as thionyl chloride. The acid chloride is conveniently in the form of a solution in an anhydrous organic solvent, e.g. B. diethyl ether, tetrahydrofuran, benzene or toluene. The acid chlorides obtained from the acids of the formulas I and II are expediently used for the further reactions immediately after preparation.

To prepare the compounds of the formulas I 'or II', alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, or phenols, such as phenol or salicylic acid, are used as the compounds which donate the radical R.

For the preparation of the compounds of the formulas I 'and II ", the following compounds, for example the following compounds, are suitable:

Amines, such as methylamine, ethylamine, .propylamine, dimethylamine, diethylamine, piperidine, morpholine, furthermore sodium azide, hydrazine or phenylhydrazine, as well as aniline, 4-carb-ethoxyaniline and 3,4-dimethylanioline.

For the preparation of the compounds of the formulas I '"and II'", the corresponding acids are recommended as the compounds which give off the rest R2.

The reactions are expediently carried out at temperatures in the range from -20 to + 50 ° C. It is advantageous to exclude the reaction in an inert gas atmosphere, for. B. under nitrogen, and avoiding exposure to strong light.

It is expedient to trap the hydrogen chloride formed in the reaction with a stoichiometrically equivalent amount of an HCl acceptor. For this purpose, tertiary amines, such as triethylamine or pyridine, or, in the case of the reaction with the amines releasing R1, a corresponding excess of the amine used can be used.

Of the compounds obtainable according to the invention, in addition to those mentioned in the examples, special mention should be made of:

ll-cis-13-desmethyl-vitamin A acid methyl ester, 11-cis-13-desmethyl-vitamin A acid ethyl ester and ll * -cis-13-des-methyl vitamin A acid acid isopropyl ester.

The compounds obtainable according to the invention, in particular the all-trans-13-desmethyl-vitamin-A-acid and its methyl ester, surprisingly show effects on cell regeneration. They activate cell metabolism and promote granulation so that they can be used as therapeutic agents for topical and systemic use.

Compared to the well-known vitamin A acid, for example, ll-cis-13-desmethyl vitamin A acid has a much stronger effect.

For example, if a culture of epidermal cells obtained by trypsin treatment (0.25%) of guinea pig skin in vitro vitamin A acid or II-cis-13-des-methyl vitamin A acid or their derivatives, e.g. B. 11-cis-13-desmethyl-vitamin A acid salicylic acid ester, or all-trans-13-desmethyl vitamin A acid, each dissolved in dimethyl sulfoxide, and incubated for 1 hour with 2 / i Ci 3H-Thymidinmethyl-3H, the stimulating effect on cell growth in DNA synthesis, measured by thymidine incorporation by means of liquid scintillation counting, is clearly recognizable [methodology see E. Christophers, The Journal of Investigative Dermatology 63 (1974) No. 6]. Outstanding effectiveness is found with ll-cis-13-desmethylvita-min-A-acid. Compared to vitamin A acid, the stimulating effect when adding 10 / tg / ml cell culture is more than one and a half times greater with ll-cis-13-desmethyl-vitamin A acid. Based on the growth of control cell cultures, vitamin A acid increases growth by about three times, but that of ll-cis-13-desmethyl-vitamin A acid increases by about five times. The all-trans-13-desmethyl-vitamin-A-acid and the 11-cis-13-desmethyl-vitamin-A-acidic salicylate are effective to a lesser extent.

The following table shows the influence of all-trans-13-desmethyl-vitamin-A-acid, ll-cis-13-desmethyl-vitamin-A-acid and ll-cis-13-desmethyl-vitamin-A acid acid -cylic acid ester compared to vitamin A acid on the DNA synthesis of in vitro grown epidermal cells.

incubated substance

Number of the middle

(10 µg / ml)

Try 1

DNA synthesis

in percent

of control2

control

3rd

100

all-trans-13-desmethyl

vitamin A acid

1

130.2

1 l-cis-13-desmethyl

vitamin A acid

3rd

552.3

ll-cis-13-desmethyl

vitamin A acid

salicylic acid ester 1 169.2

Vitamin A acid 3,391.7

1 Each test result is an average of 3 results.

2 Measured as cpm / culture 3H-TdR incorporation with 1 to 2 hour incubation (1 fiCi 3H-T dR).

The outstanding effect of ll-cis-13-desmethyI-vitamin-A-acid on the growth of epithelial cells can also be demonstrated in vivo. If, according to the method of Heite [Arzneimittel-Forschung 23 (1973) 1342], a tissue defect is placed on both sides of rabbit ears by punching out a circular piece with a diameter of 6 mm through all tissue layers of the ear under anesthesia and additionally the defect area with X-rays (500 R, 55 KV, tube 1.5 cm, skin distance 10 cm) damages, furthermore the spontaneous wound healing by daily application of prednisolone (1 to 2 mg / kg sc) inhibits, so the daily local treatment leads to a side with a gel preparation, containing 0.05% ll-cis-13-desmethyl-vitamin-A-acid or all-trans-13-desmethyl-vitamin-A-acid or vitamin-A-acid, in the course of 4 to 7 weeks into one defect healing significantly faster than treatment with an empty gel on the contralateral side.

Here, too, ll-cis-13-desmethyl-vitamin-A-acid shows the strongest wound-regenerating activity. Within 6 weeks, the wound diameter was reduced by 54% due to ll-cis-13-desmethyl-vitamin-A-acid compared to the defect size at the start of the experiment, by 43% due to vitamin A-acid and by 17.2 to due to an empty gel 19.9%.

The compounds obtainable according to the invention can be used to treat diseases which are associated with a cell regeneration disorder, such as, for example, burns, impaired wound healing, acne, cornification disorders, such as ichthyosis, psoriasis, pityriasis, rosacea or dandruff.

The compounds obtainable according to the invention can be processed into the corresponding pharmaceutical preparations by the methods customary in galenics. The choice of the forms of preparation as well as the ones to be used

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Auxiliaries depend on the intended type of application. Forms of preparation for external applications on the skin are, for example, solutions, gel forms, creams, ointments or powder; those for systemic use, for example tablets, capsules, dragées or solutions.

The most preferred preparations for local use are solutions, creams and gels, for systemic use drops and capsules.

The preferred preparation forms contain the 11-cis-13-desmethyl-vitamin-A-acid or its derivatives. Of these, the ll-cis-13-desmethyl-vitamin-A acid itself and the 1 l-cis-13-desmethyl-vitamin A acid salicylic acid ester are particularly noteworthy.

Active ingredient concentrations of 0.01 to 1.0%, preferably 0.05 to 0.1%, are suitable for local application. For systemic use, a single dose of 1 to 5 mg is preferred, and the daily dose can be up to 100 mg.

Alcohols such as isopropanol, oxyethylated castor oil or oxyethylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, polyethyleneglycol 400, polyethyleneglycol 400 stearate and ethoxylated fatty alcohols and for the systemic application of lactose, lactose, propellant are, for example, auxiliary substances for local use used.

Example 1 ,

all-trans-13-desmethyl-vitamin-A acid ethyl ester

C00CnHc 2 5

Analysis: C21H30O2 found: C 80.2 calc .: C 80.21

UV: / imax = 360 nm Ej1 = 14 100

MW = 314.45 H 9.6 O 9.6% H 9.62 O 10.18%

in ethanol

Example 2

all-trans-13-desmethyl-vitamin-A-acid

COOK

11.4 g (0.036 mol) of all-trans-13-desmethyl-vitamin-A acid ethyl ester are mixed with 62 ml (0.062 mol) of i-N-ethanol

sheared caustic potash boiled under reflux for 2 hours. The reaction mixture is cooled to room temperature and poured into 40 ml of 20% sulfuric acid. It is diluted with 200 ml of water and extracted three times with 60 ml of methylene chloride. The 5 methylene chloride phase is washed with 60 ml of water, dried and concentrated. 11.1 g of yellow crystals are obtained as a crude product. After recrystallization three times from methanol, the all-trans-13-desmethyl-vitamin-A-acid is clean by thin layer chromatography.

io Orange-yellow crystals m.p .: 130 to 136 ° C.

= Analysis: C19H2602 MG = 286.40

found: C 79.4 H 9.0 O 1-1.4%

calc .: C 79.68 H 9.15 O 11.17%

UV in isopropanol: Ämax = 355 nm 15 0 1 = 1704

egg

13 C-NMR (CDC13; TMS standard)

17 IS

00 h

The changed numbering according to the above formula was only made for the purpose of NMR assignment (see figure in Isler, Carotenoids, Basel, 1974).

Carbon atom

To 800 ml of a dimethylformamide solution containing 0.435 mol / 3-ionylidenethyl-triphenylphosphonium chloride, 55.7 g (0.435 mol) of ethyl fumaraldehyde are added, the mixture is cooled to -20.degree. C. and 1.7 mol of sodium ethylate is added within 30 minutes. At room temperature, stirring is continued for 2 hours. The reaction mixture is poured into excess 20% sulfuric acid and extracted five times with 250 ml each of n-heptane. The heptane phase is washed three times with 600 ml of methanol: water = 60:40 and then with 11 water, dried and concentrated. This gives 113.9 g of oil = 83% of crude product which, according to the 220 MHz NMR spectrum, contains about 20% of all-trans-13-desmethyl-vitamin-A acid ethyl ester and about 45% of 11-cis-13-desmethyl contains vitamin A acid ethyl ester. The oil can be crystallized with 110 ml of n-heptane and 110 ml of isopropanol. The product is recrystallized twice from heptane-isopropanol: yellow crystals mp 95 to 98 ° C.

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65

Chemical shift (ppm)

1 34.4

2 39.8

3 19.3

4 33.2-

5 130.5

6 137.8

7 129.9

8 137.1

9 141.6

10 129.2

11 129.9

12 129.1

13 138.4

14 118.9

15 172.5

16 29.0

17 29.0

18 21.7

19 12.9

Example 3 11-Eis-13-Desmethyl-vitamin-A-acid

COOK

192 g (1.5 mol) of ethyl fumaraldehyde ester are added to a solution of 1.5 mol / 3-ionylidenethyl-triphenyl-phosphonium chloride in dimethylformamide, the mixture is cooled to −20 ° C. and 3 mol of sodium ethylate is added. After stirring for 3 hours

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6

at room temperature, the reaction mixture is poured into excess 20% sulfuric acid. It is extracted five times with 800 ml of n-heptane and the collected heptane extracts are washed three times with 11 60% aqueous methanol and once with 2 l of water. After drying and concentrating, 405 g of crude oil are obtained. The crude oil is heated with 1.85 l of a solution of potassium hydroxide in ethanol under reflux for 2 hours. It is acidified with 600 ml of 20% sulfuric acid, extracted with ether, the ether phase is washed with water and concentrated after drying. 362 g of crude product are obtained, which is dissolved in 41 warm petroleum ether. By cooling to -20 ° C., 154 g of a crystalline mixture can be isolated, which according to the 220 MHz NMR spectrum consists of all-trans-des-methyl-vitamin-A-acid and ll-cis-13-desmethyl-vitamin -A-acid exists.

By repeated recrystallization from methanol, 50 g of pure ll-cis-13-desmethyl-vitamin-A-acid can be isolated.

Yellow crystals mp: 151 to 156 ° C.

Analysis: Ci9H2602 MG = 286.40

found: C 79.5 H 8.8 O 11.2%

calc .: C 79.68 H 9.15 O 11.17% 220 MHZ-HNMR: ll-cis-13-desmethyl-vitamin-A-acid

UV: E7 = Ï2004nm

13 C-NMR (CDC13; TMS standard)

19th

11

12

10th

13

18th

15

COOH

The changed numbering according to the above formula was only made for the purpose of NMR assignment in accordance with O. Isler, Carotenoids, Basel, 1974.

Carbon atom chemical shift (ppm)

1

34.3

2nd

39.7

3rd

19.3

4th

33.2

5

130.4

6

137.5

7

129.8

8th

137.2

9

141.4

10th

124.1

11

134.1

12

125.1

13

141.0

14

120.0

15

172.8

16

29.0

17th

29.0

18th

21.7

19th

12.5

Example 4 11-cis-l 3-desmethyl vitamin A acid

COOH

68 g (3.78 mol) of ammonia are introduced into a solution of 0.652 g mol of β-ionylidenethyl-triphenylphosphonium chloride and 66 g (0.66 mol) of fumaraldehyde acid in 1600 ml of methanol at −20 to −25 ° C. . 100 ml of a 30% sodium methylate solution in methanol are added. The mixture is stirred at room temperature for 1 1/2 hours and then for 2 hours at 40 ° C. The mixture is concentrated on a rotary evaporator, acidified with 10% sulfuric acid and extracted with ether. The ether phase is washed with water, dried and concentrated. The residue is purified by column chromatography on silica gel (mobile phase petroleum ether, petroleum ether: ether = 10: 1) and recrystallized from methanol.

Yield: 30.3%.

Analysis: Ci9H2602 MG = 286.40

found: C 79.5 H 9.0 O 11.6%

calc .: C 79.68 H 9.15 O 11.17%

UV: Amax = 355nm. ,

Ei1 = 1180 m ethanol

Example 5

ll-cis-13-desmethyl-vitamin-A acid chloride

C-Cl

II

0

20 g (0.07 mol) of 11-ice-13-desmethyl-vitamin-A-acid are dissolved in 300 ml of dry ether and 5.7 ml of dry pyridine. With nitrogen protection and moisture exclusion, 5.5 ml of distilled thionyl chloride in 20 ml of dry ether are added dropwise at -10 ° C within 45 minutes. The mixture is stirred for a further V2 hour at −10 ° C. and 2 hours at room temperature and the pyridine hydrochloride which has precipitated is filtered off with suction. The solution of ll-cis-13-desmethyl-vitamin-A-acid chloride is immediately implemented further.

The all-trans-13-desmethyl-vitamin-A acid chloride is prepared in the same way.

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Example 6

II-cis-13-desmethyl-vitamin-A-acid-aniIid-4'-carbon-acidic acid ethyl ester

To a suspension of 11.6 g (0.07 mol) of ethyl p-aminobenzoate in 50 ml of dry ether is added a freshly prepared solution of 0.035 mol of II-cis-13-desme-thyl-vitamin-A-acid chloride in 150 ml of dry ether and heated under reflux for 4 hours. After suction, the ethereal filtrate is washed with water, dried and concentrated. The remaining oil is stirred with methanol and recrystallized several times from methanol.

Yield: 39%

Yellow Crystals Mp .: 107 to 112; thin-layer chromatographic-graphic uniform.

Analysis: MG = 433.57

found: C 77.0 H 7.8 N 3.7 O 11.2% calc .: C 77.56 H 8.14 N 3.23 O 11.07% The 220 MHz HNMR spectrum proves this Structure of the ll-cis-13-desmethyl-vitamin-A-anilide-4'-carboxylic acid ethyl ester.

Example 7

ll-cis-13-desmethyl-vitamin-A-acid salicylic acid ester

0.035 mol of pyridine is added to a freshly prepared solution of 10 g (0.035 mol) of 11-cis-13-desmethyl-vitamin A acid chloride in 150 ml of dry ether, and a solution of 4.84 g (0.035 mol) is added dropwise Salicylic acid in 20 ml dry ether. After 3 hours of stirring at room temperature, the product is filtered off; the filtrate is washed with dilute hydrochloric acid and with water, dried and concentrated. The crude product is purified by column chromatography (silica gel, eluent, petroleum ether + ether). It is recrystallized from petroleum ether: ether = 10: 1 at -30 ° C.

Yellow crystals: 130 to 138 ° C.

Analysis:

found: C 76.3 H 7.6 O 15.8%

calc .: C 76.82 H 7.44 O 15.74%

UV: Amax = 368 nm En1 = 836

HNMR and IR spectra match the structure.

in ethanol

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Example 8

ll-cis-13-desmethyl-vitamin-A-acid-3 ', 4'-dimethylanilide

0 N-

30th

To a solution of 24.2 g (0.2 mol) of 3,4-dimethylaniline in 100 ml of dry ether is added a freshly prepared solution of 0.1 mol of II-cis-13-desmethyl-vitamin-A-acid chloride and heated under reflux for 6 hours. It is suctioned off, the ethereal filtrate is washed with dilute hydrochloric acid and with water, dried and concentrated. The oily crude product is recrystallized from petroleum ether in the cold and further purified by recrystallization from aqueous ethanol.

Yellow crystals mp: 156 to 161 ° C.

Analysis: C27H3sNO MG = 389.56 found: C 83.2 H 8.4 N 4.0 calc .: C 83.24 H 9.06 N 3.60 UV in ethanol: A max = 367 nm Et1 = 1236

O O

4.4% 4.11%

50

HNMR spectrum and IR spectrum match the structure.

Example 9

ll-cis-13-desmethyl-vitamin-A acid piperidide

55

60

65 To a solution of 6.93 ml (0.07 mol) of piperidine in 100 ml of dry ether, a freshly prepared solution of 0.035 mol of II-cis-13-methylamine-A-acid chloride in dry ether is left at room temperature drop.

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After stirring for 4 hours, the product is filtered off with suction. The filtrate is washed with dilute hydrochloric acid and with water, dried and concentrated. The crude product is recrystallized once from petroleum ether and twice from aqueous ethanol.

Yellow crystals mp: 114 to 116 ° C.

Analysis: C24H3SNO MG = 1258

found: C 81.8 H 9.8 O 4; 7 N 4.3% calc .: C 81.53 H 9.98 O 4.52 N 3.96% UV (ethanol)

/ max = 356 nm Ej1 = 1258

HNMR spectrum and IR spectrum match the structure.

Example 10

ll-cis-13-desmethyI-vitamin-A-acid morpholide

Preparation analogous to Example 6. After column chromatography purification on neutral aluminum oxide (mobile solvent hexane: ether: methanol = 50: 10: 2), the product is recrystallized from petroleum ether.

5 yellow crystals mp: 90 to 93.5 ° C.

Analysis:

found: C 76.90 H 9.5 O 9.5 N 3.6% calc .: C 77.70 H 9.35 O 9.0 N 3.94% UV (ethanol)

io max = 358 nm Ex1 = 1132

IR and HNMR spectrum match the structure.

Claims (5)

619 211 2. The method according to claim 1, characterized in that ll-cis-13-desmethyl-vitamin-A-acid of the formula I is prepared. 2nd PATENT CLAIMS 1. Process for the preparation of ll-cis-13-desmethyl-vitamin-A-acid of formula I. and all-trans-13-desmethyl-vitamin-A-acid of formula II 0 P (CgH5) 3X0 (III), wherein X® is an organic or inorganic acid residue, with a compound of formula IV 0. / c H , 0 (IV), (V) (VI) separates and the esters obtained saponified before or after the separation. 3rd 619 211 Acid chloride is transferred and the latter is reacted with a compound which gives off the radical R1. 3. Process for the preparation of compounds of the formulas I 'or II' io 15 or 20th characterized in that a compound of the form 25 mei III 30th 35 / '\ r3 wherein R3 is hydrogen, alkyl having 1 to 4 carbon atoms, ammonium or an alkali metal ion, in an inert solvent at temperatures from -20 to + 30 ° C in the presence of a base, the mixture of isomers obtained from compounds of the formulas V and VI 60 65 wherein R is an alkoxy group with a maximum of 4 carbon atoms or an unsubstituted or substituted by hydroxyl or carboxy-substituted phenoxy group, characterized in that a compound of the formula I or II is prepared by the process according to claim 1, this is converted into the corresponding acid chloride and the latter is reacted with a compound donating the radical R. 4. Process for the preparation of compounds of the formulas I "or II" 40 (I ") or 50 55 di "), in which R1 is a mono- or disubstituted amino group, optionally substituted by alkyl having 1 to 4 carbon atoms or phenyl, which in turn can be substituted by hydroxyl, alkyl having 1 to 4 carbon atoms, carboxy, carboxymethyl or carboxyethyl, a 3-bonded via the nitrogen atom to 6-membered saturated nitrogen-containing heterocyclic ring, the azido group or an unsubstituted or substituted by methyl or phenyl hydrazine radical, characterized in that a compound of the formula I or II is prepared by the process according to claim 1, this into the corresponding 5. Process for the preparation of compounds of the formulas V "or II '" or 0 wherein R2 is an acyloxy group with 2 to 4 carbon atoms or the radical C18H2sCO-Ò- with the configuration of ll-cis-13-desmethyl-vitamin-A-acid in the case of the formula I '"and the configuration of the all-trans-13- Desmethyl-vitamin-A-acid in the case of the formula II '"means, characterized in that a compound of the formula I or II is prepared by the process according to claim 1, this is converted into the corresponding acid chloride and the latter with one the rest R2 releasing connection implements.