DK157486B - ANALOGY PROCEDURE FOR PREPARING POLYPRENYL DERIVATIVES - Google Patents

Description

DK 157486 B

The invention relates to an analogous process for the preparation of novel polypreneyl derivatives of the general formula (I) set forth in the preamble of the invention which are useful as medicaments for the treatment of peptic ulcers.

It has been reported that gefarnatum (international pharmaceutical name for geranyl farnesyl acetate), a polyprinyl compound, is active against ulcers [E. Adami et al., Arch. Int. Pharmacodyn., 147, no. 1-2, 113 (1964)]; but there is a growing need for new and improved drugs to treat a wide variety of ulcers, especially peptic ulcers such as gastric ulcers or duodenal ulcers.

It has now surprisingly been found that a diterpendiol compound which can be isolated from plants of the genus Croton [especially Plau-noi (Croton Sublyratus Kurz, Croton Columnaris Airy Shans), Plau-luat (Croton Hutchinsonianus Hosseus) and Plau-noi. yai (Croton oblongifolius Roxb., which grows in Thailand) has a low toxicity and is highly effective in the treatment of peptic ulcers. The isolated compound is (E, Z, E) - 7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol. According to the invention, methods have been found for the synthesis of this diterpendiol compound as well as its homologues and derivatives thereof, which have also been found to be useful in the treatment of peptic ulcers. These compounds have several double bonds and thus may exist in the form of various geometric isomers; these isomers are named according to the E, Z convention proposed by the International Union of Pure and Applied Chemistry in J.

Org. Chem. 3, 2849 (1970). The compounds prepared by the process according to the invention have shown in the test systems used a greater activity than gefarnatum.

Thus, by the process of the invention, polyprenyl derivatives of the general formula (I) are prepared:

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2 C 1 -R 1 CH 2 R 2 CH 3 CH 3 -C = CH-CH 2 - (CH 2 -C = CH-CH 2 -) nCH 2 -C = CH-CH 2 -O R 3 (I) wherein n is 1, 2 or 3.

1 2 R and each R are the same or different and mean H or 3 2 3 in OR, with at least one R being OR and at least one of R and the 2 optional other R groups being H and the R 3 groups being the same or different and means H, alkyl of 1-8 carbon atoms, aliphatic acyl of 2-18 carbon atoms, benzoyl or phenyl-slifatic-acyl of 2 or 3 carbon atoms in the aliphatic acyl moiety.

When R 3 represents an alkyl group, it may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl or octyl. When R 3 represents an aliphatic acyl group, it may be an alkanoyl group, e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl, 2-methyl-n-valeryl, heptanoyl, octanoyl, 2-ethylhexanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, myristoyl, pentadecanoyl, palmitoyl stearoyl; or an alkenoyl group, e.g. acryloyl, methacryloyl, crotonoyl, 3-butenoyl, tigloyl, sorboyl, 10-undecenoyl or oleoyl. When R 3 represents a phenylaliphatic-acyl group, it may e.g. be phenylacetyl, phenylpropionyl or cinnamoyl.

A preferred subclass of polyprenyl derivatives of formula (I) are those compounds wherein R and R are the same or different and represent H or OR 3 with the above restrictions and R 3 represents hydrogen, alkyl of 1-4 carbon atoms, aliphatic acyl with 2-12 carbon atoms, benzoyl or cinnamoyl.

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3

A more preferred subclass of polyprenyl derivatives of formula (I) are those compounds wherein R is H, R is H or OR, wherein at least one R R is OR OR, and R ^ is H, alkyl of 1-4 carbon atoms. , aliphatic acyl of 2-12 carbon atoms, benzoyl or cinnamoyl.

The most preferred subclass of polyprenyl derivatives of the general formula (I) are those compounds wherein R R is H, and R R is H or OR ^, where R ^ in the side chain at the 7-position is DR and R is hydrogen. , methyl, ethyl, aliphatic acyl of 2-12 carbon atoms, benzoyl or cinnamoyl.

Because the various double bonds in the polyprenyl derivatives of general formula (I) can take on different configurations, the compounds of the invention may exist as a number of geometric isomers, and the invention comprises the preparation of both the individual isomers and mixtures. of two or more isomers. Thus, the compounds of the invention may exist as the following isomers:

A compound wherein n is 1; (E, Z) and (E, E) isomers;

Compounds wherein n is 2: (Ε, Ζ, Ε), (Ε, Ε, Ε), (Ζ, Ε, Ε), (Ζ, Ζ, Ε), (Ζ, Ζ, Ζ), (Ζ, Ε, Ζ), (Έ, Ζ, Ζ) and (Ε, Ε, Ζ) isomers;

Compounds wherein η is 3: (Ε, Ζ, Ε, Ε), (Ζ, Ε, Ε, Ε), (Ζ, Ζ, Ε, Ε), (Ε, Ζ, Ζ, Ε), (Ε, Ε, Ζ, Ε), (Ζ, Ζ, Ζ, Ε), (Ζ, Ε, Ζ, Ε) and (Ε, Ε, Ε, Ε) isomers;

These individual isomers can be prepared separately as described below, or mixtures of the isomers can be prepared, and the individual isomers can then iso

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4 are taught by methods known per se. Alternatively, if desired, mixtures of isomers may be used to treat peptic ulcers.

The present compounds of the general formula (I) are prepared by the process according to the invention, which is characterized by the characterizing part of the claim. The process comprises the following variants.

PROCESS (a)

Compounds of general formula (I) which have the Z-configuration at the 6-position and have a 7-hydroxymethyl group, namely those compounds of formula (II) CH 2 R 1 CH 2 R 2 'CH 2 OH CH 3 CH, -C = CH -CH - (- CH.-C = CH-CH2 - rCH2 -C = C-CH2 -CH2 -C = CH-CH2OR3 'J LLZ ni Z 7 f 2 2 2 H (II 11 o 1 wherein n is 1, 2 or 3, R and R are the same or different 3 '] root and means H or OR, at least one of R and R being H and the 3' R groups being the same or different and means H or alkyl of 1-8 carbon atoms may be prepared by a modified Wittig reaction, whereby a compound of formula (III):

1 I »I O Η I

CH2RX CH2R ^ CH3-C = CH-CH2-eCH2-C = CH-CH2 ^ -j-CH2-CH2-P® (R4) 3X9 (III) wherein n has the above meaning, R and each R are the same or different and means H or OR, at least

Tf I I 2 '1 * 3 I I I

one of R and R is H and the R groups are the same or different and represent a hydroxy protecting group selected from 5 or 6 membered heterocyclic groups containing an oxygen and / or sulfur atom in the ring and may have one or more methoxy substituents, alkoxyalkyl groups having 1-4 carbon atoms in the alkoxy moiety and alkylene moiety and trialkylsilyl groups having 1-4 carbon atoms in each alkyl moiety, or an alkyl group having 1-8 carbon atoms, R4 means a

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5 is hydrocarbon residue (e.g., phenyl or n-butyl), and X is halogen (e.g., bromine or solute) and a compound of formula (IV): ch3 OHC - CH2 - CH2 - C = CH - CH2 - OR 3 '' (IV) 3 '' wherein R is as defined above is reacted with formaldehyde, preferably in the form of paraformaldehyde, in the presence of a base to form a compound of formula (V): CH 2 R 1 'CH 2 R 2' 'CH 2 OH CH 3 CH , -C = CH-CH, - (- CH "-C = CM-rCH" -C = C-CH9-CH "-C = CH-CH" -OR3 "'(\ l]

3 ILL · n-1 Z 7, Z Z Z

L H

In which n, R, R and R are as defined above and any hydroxy protecting groups are removed by hydrolysis in a manner known per se.

The hydroxy protecting groups are: 3- or 6-membered heterocyclic groups containing an oxygen and / or sulfur atom in the ring and may have one or more methoxy substituents, e.g. 2-tetrahydrofuranyl, 2-tetrahydropyranyl, 2-tetrahydrothienyl, 2-tetrahydrothiopyranyl or 4-methoxy-tetrahydropyran-4-yl; alkoxyalkyl groups having 1-4 carbon atoms in the alkoxy moiety and the alkyl moiety, e.g. methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butixymethyl, isobutoxymethyl, 1-ethoxyethyl-1-ethoxypropyl or 1-methoxy-1-methylethyl; or trialkyl silyl groups having 1-4 carbon atoms in each alkyl moiety, e.g. trimethylsilyl, triethylsilyl, tri-n-propylsilyl, triisopropylsilyl, tri-n-butylsilyl or triisobutylsilyl. Particularly preferred protecting groups are 2-tetrahydropyranyl, methoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl or trimethylsilyl, but other of the protecting groups mentioned may also be used.

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6

Process (a) involves reacting compound (III), compound (IV) and formaldehyde, preferably in the form of para-formaldehyde, in the presence of a base and preferably also a solvent, to form the desired compound of formula (V). There is no particular limitation on the nature of the base used and any base commonly used for normal Wittig reactions can be used. Particularly preferred are alkyl lithium such as n-butyllithium, s-s-butyllithium or t-butyllithium. Also, there is no particular restriction on the nature of the solvent which can be used, except that it has no detrimental effect on the reaction. It is particularly preferred to use ethers (such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane) or aliphatic hydrocarbons (such as n-pentane or n-hexane). The reaction is preferably conducted at a relatively low temperature, more preferably between -80 ° C and room temperature. It is also preferred that the reaction be conducted under a stream of an inert gas such as nitrogen, helium or argon.

The reaction is preferably carried out as follows. First, the compound (III) is dissolved in an organic solvent such as tetrahydrofuran and while the temperature is maintained between -5 and 0 ° C, a base such as n-butyllithium is added under a stream of inert gas such as argon. Then, while maintaining the temperature between -50 and -80 ° C, preferably about -78 ° C, compound (IV) is added to the mixture; and after the temperature has been allowed to rise to between -30 and -60 ° C, preferably about -50 ° C, s-butyllithium or t-butyllithium is added, and finally paraformaldehyde is added at a temperature between -10 ° C and room temperature. . The time required for the reaction will vary, depending mainly on the type of base used and the reaction temperature; but the reaction is usually completed within 2-6 hours. Upon completion of the reaction, the desired compound (V) is recovered from the reaction mixture by conventional means. For example, the reaction mixture

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7 is added to ice water and then extracted with an organic solvent such as n-hexane. The organic solution is then washed and dried, and the desired compound is obtained after evaporation of the solvent. If necessary, this compound can be further purified by conventional means such as column chromatography or thin layer chromatography.

If the compound of formula (V) contains hydroxy protecting groups, these must be removed to form compound (II); and the reaction in question will depend on the nature of the protecting group. For example, if the protecting group is a heterocyclic group (such as 2-tetrahydropyranyl) or an alkoxyalkyl group (such as methoxymethyl), it can be easily removed simply by contacting the compound (V) with an acid. Preferred acids are organic acids such as formic acid, acetic acid, propionic acid or p-toluenesulfonic acid. The reaction can be carried out in the presence or absence of a solvent, but the presence of a solvent allows the reaction to proceed more smoothly and is therefore preferred. Preferred solvents are water, alcohols such as methanol or ethanol, and mixtures of water with one or more of these alcohols. There is no particular restriction on the reaction temperature, but room temperature is appropriate and therefore preferred.

On the other hand, if the hydroxy protecting group is a trialkylsilyl group (such as trimethylsilyl), it can be easily removed by contacting the compound (V) with water or an aqueous solution of an acid or a base. Suitable acids are organic acids such as formic acid, acetic acid or propionic acid, and inorganic acids such as hydrochloric acid or sulfuric acid; suitable bases are hydroxides of alkali metals (such as potassium hydroxide), hydroxides of alkaline earth metals (such as potassium carbonate), and carbonates of alkaline earth metals (such as calcium carbonate). There is no particular restriction on the reaction temperature, but room temperature is appropriate and therefore preferred.

8 DK 1574868

The time required for the reaction to remove the protecting group will largely depend on the nature of the protecting group used.

Upon completion of the reaction, the desired compound (II) is obtained from the reaction mixture by conventional means. For example, upon completion of the reaction, the reaction mixture can be neutralized and then extracted with an organic solvent such as diethyl ether. The organic extract is then washed and dried and the solvent is evaporated to give the desired compound. If desired, this compound can be further purified by conventional methods such as column chromatography or thin layer chromatography.

Process (b)

A compound of formula (I) in the form of a mixture of isomers with the Z and E configurations in the 6-position, i.e. a compound of formula- (VI-):] ii o il 9 il ch2r ch2 ft ch2rz ch3 CH3-C = CH-CH2- (• CH2C = CH-CH2 -) - ^ 3j'CH2-C2 ^ C-Cl -12-CH2-C = CH-CH2-OR ^ "^ (VI) 1 η 2" wherein n has the above meaning, R and each R are 3 "the same or different and mean H or OR, wherein at least

2 "3" i ii 2K

one R is OR and at least one of R and any other R - 3 "groups is H and the R groups are the same or different and mean H, alkyl of 1-8 carbon atoms, aliphatic acyl of 2-4 carbon atoms or benzoyl may be prepared by a modified Wittig reaction, whereby a compound of formula (VII):

C 2 R 1 CH 2 R A

CH3-C = CH-CH2 - (- CH2-C = CH-CH2) n ~ jj CH2-CO (VII) 2rl !!

wherein n is as defined above, A is CH 2 R

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Or acetal-protected formyl, R and each R are the same or different and mean H or OR, with at least one 2II II 2 II 1 1 "" 2 "" R being OR and at least one of R and the other R groups are 3 π rf per H and the R groups are the same or different and represent a hydroxy protecting group selected from 5- or 6-membered heterocyclic groups containing an oxygen and / or sulfur atom in the ring and may have one or more methoxy substituents, alkoxyalkyl groups having 1-4 carbon atoms in the alkoxy moiety and alkylene moiety respectively, trialkyl silyl groups having 1-4 carbon atoms in each alkyl moiety, aliphatic acyl groups having 2-4 carbon atoms and benzoyl, or ... - * an alkyl group having 1 '"= 8' carbon atoms ^ is redefined with a compound of formula (VIII): S Ch3 XO (R4); 3P-CH2-CH2-CH2-C = CH-CH2-OR3" "( VIII) 3 "" 4 wherein R, R and X have the above meaning in the presence of a base to form a compound of formula (IX): i ii ii 7 ii ii CH2RJ 'CH2R ^ A CH3 CH, -C = CH -CH 9 - (- CHO-C = CH-CH2 -) - rCH-C = C-CH9 -CH2 -C = CH-CH2 -OR3 "3 2 2 2 Π" 1-j / r ~ $ 2 2 2 ”(ix) 2 I! II 2, f 11 3 »II o wherein n, A, R, R and R have the above meaning and then any hydroxy protecting groups and / or formyl protecting groups are removed by hydrolysis in a manner known per se, but only if desired , if the hydroxy protecting groups are aliphatic acyl or benzoyl and any aldehyde formed is reduced.

The hydroxy protecting groups may be any of those listed under process (a). Further, they may be aliphatic acyl groups having 2-4 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl, or benzoyl. It is particularly preferred to use 2-tetrahydropyranyl, methoxymethyl, trimethylsilyl, acetyl or benzoyl.

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The formyl protecting group is a group capable of forming an acetal group of the formyl group. Preferred are groups which form dimethoxymethyl, diethoxymethyl or ethylenedioxymethyl.

The reaction of the compound (Wil) with the compound (VIII) to form the compound (IX) is carried out in the presence of a base and preferably a solvent. There is no particular restriction on the nature of the base used, and any base commonly used for a Wittig reaction can be used; especially preferred are alkyl lithium (such as n-butyllithium, s-butyllithium or t-butyllithium), lithium dialkylamides (such as lithium diethylamide or lithium diisopropylamide), alkali metal hydrides (such as sodium hydride), alkali metal amides (such as sodium amide or potassium amide) and butoxide). Also, there is no particular restriction on the nature of the solvent used, unless it has a detrimental effect on the reaction. Preferred solvents are: ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; aliphatic hydrocarbons such as n-pentane or n-hexane; aromatic hydrocarbons such as benzene or toluene; dialkyl aliphatic acid amides such as dimethylformamide or dimethylacetamide; and dimethyl sulfoxide. Also, there is no particular restriction on the reaction temperature, although it is preferable to use relatively low temperatures to avoid side reactions. Most preferably, the reaction is carried out at a temperature between -20 ° C and room temperature and under a stream of inert gas such as nitrogen, helium or argon.

The reaction is preferably carried out as follows. First, the compound (VIII) is dissolved in an organic solvent (such as tetrahydrofuran) and while maintaining the temperature between -20 and 0 ° C, a base (such as n-butyllithium or sodium hydride) is added to the solution under a stream of an inert DK 157486 B. ·; 11 gas (such as argon). While keeping the reaction mixture temperature below room temperature, the compound of formula (VII) is then added. The time required for the reaction will depend mainly on the nature of the base used and the reaction temperature, but the reaction will generally require 2 to 8 hours. Upon completion of the reaction, the desired compound (IX) is recovered from the reaction mixture by conventional means; eg. ice water is added to the reaction mixture and the mixture is then extracted with an organic solvent such as n-hexane. The organic extract is washed and dried and, after evaporation of the solvent, the desired compound is obtained. If necessary, this compound can be further purified by conventional means such as column chromatography or thin layer chromatography.

before or after the recovery and purification of compound (IX), any hydroxy protecting and / or formyl protecting groups must be removed, however only if desired if the hydroxy protecting groups are aliphatic acyl or benzoyl.

The reaction used to remove the hydroxy protecting group will depend on the nature of the protecting group.

For example, if the protecting group is an acyl group (e.g., acetyl or benzoyl), this reaction can be carried out by a conventional hydrolysis or alcoholysis using a base or an acid, preferably a base. Preferred bases are alkali metal and alkaline earth metal hydroxides (such as sodium hydroxide, potassium hydroxide or barium hydroxide) and alkali and alkaline earth metal carbonates (such as sodium carbonate, potassium carbonate or calcium carbonate). the reaction is preferably carried out in water, in an organic solvent (such as an alcohol, e.g., methanol, ethanol or n-propanol, or an ether, e.g. tetrahydrofuran or dioxane) or in a mixture of water and one or more of these organic solvents. There is no particular restriction on the reaction temperature, but in general it is preferred to use a temperature around room temperature. Hydroxy-protected groups other than acyl groups can be removed as described for the corresponding groups under Process (a).

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A formyl protecting group can be removed by conventional acetal hydrolysis. This involves reacting the compound (IX) with an acid. Preferred acids are organic acids such as formic acid, acetic acid or propionic acid, and inorganic acids such as hydrochloric acid or sulfuric acid. The reaction can be carried out in water or in an aqueous organic solvent. Preferred aqueous organic solvents are alcohols (such as methanol or ethanol) and ethers (such as tetrahydrofuran or dioxane). There is no particular restriction on the reaction temperature, but it is generally preferred to use a temperature around room temperature.

After removal of the formyl protecting group, the resulting compound is recovered from the reaction mixture by conventional means; eg. the reaction mixture is first extracted with an organic solvent such as n-hexane, then the organic extract is washed and dried and the solvent is evaporated to give the desired compound. The formyl group in this connection is then reduced by contacting the compound with a reducing agent, preferably in the presence of a solvent, to convert it into a hydroxymethyl group. Ser is no particular limitation on the nature of the reducing agent used, merely being able to convert a formyl group to a hydroxymethyl group without affecting other parts of the compound. Preferred reducing agents are alkali metal hydride complex salts (such as sodium borohydride, lithium aluminum hydride or potassium borohydride) and aluminum triisopropoxide. Also, there is no particular restriction on the nature of the solvent used, provided it does not damage the reaction. If the reducing agent used is an alkali metal hydride complex salt, the solvent is preferably an alcohol (such as methanol or ethanol) or an ether (such as diethyl ether, tetrahydrofuran or dioxane). If the reducing agent is aluminum triisopropoxide, isopropanol is the preferred solvent. There is no particular restriction on the reaction temperature, but it is generally preferred to use a temperature between GDC and room temperature.

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13

Upon completion of the reaction, the desired compound is recovered from the reaction mixture by conventional means. For example, excess reagent is first degraded and then the mixture is extracted with an organic solvent such as n-hexane. The extract is washed and dried, then the solvent is evaporated to give the desired compound. If the compound obtained by reduction carries a residual protecting group for the hydroxy group, the desired compound is obtained by removal of the protecting group in the manner described above. The desired compound can then be further purified, if necessary, by conventional means such as column chromatography or thin layer chromatography.

Process (c)

A compound of formula (I) in the form of a mixture of isomers with the Z and E configurations at the 6-position and with a hydroxymethyl group at the 7-position, i.e. a compound of formula (X): ch 1 "ch 2 r 2" ch 2 and ch 3 CH 3 -C = CH-CH 2 -FCH 2 -C = CH-CH 24 ^ jCH 2 -C = C-CH 2 -CH 2 -C = CH-CH 2 -OR 3 Z / E "(X) 1" 2 "3" wherein n, R, R and R have the meaning given in Process (b) can be prepared by reacting a compound of formula (XI):

1 Ml! O II II

CH 2 CH 2 R 2

CH3-C = CH-CH2 - (- Ch'2-C = CH-CH2 ^ riCH2X (XI) 1 hu 2 π n wherein n, R, R and X have the meaning given in Process (b) and a compound of formula (XII): (r6o) 2poch2coor5 (XII) wherein R3 and R4 are the same or different and each independently means alkyl of 1-4 carbon atoms, with a compound of formula (XIII): 14

DK 157486B

(XIII) 311 wherein R is as defined in Process (b), in the presence of a base to form a compound of formula (XIV): ch3 ohc-ch2-ch2-c = ch-ch2or3

i vs ti 9 it it Q

CH2R CH2R COGR- ^ CH3 CH, -C = CH-CHO - (- CH2 -C = CH-CH9i fCH7-C = C-CH7-CH -C = CK-CH -OR "3 ZZ z nl z Z / E ^ zzl '··' Η (XIV> j »i il o11” 3 »ii * 5 wherein n, R, R, R and R have the meaning given above, reducing this compound (XIV) and removing any hydroxy protecting agents groups by hydrolysis in a manner known per se, but only if desired, if the hydroxy-protecting groups are aliphatic acyl or benzoyl.

Condensate! The reaction of the orb-in de Is [Xh'r, the compound (XII) and the compound (XIII) is a modified reactive reaction, carried out in the presence of a base and preferably an enlightenment. There is no particular restriction on the nature of the base used, even though one of them is preferred, but is proposed for the modified Wi-tier action of 11.3. Wsdworth and W.D. Emmons [J. Amer. Chem. Sao., 8_3, 33733 (1961)]. Preferred reducing agents are alkali metal such as n-butyllithium or t-butyllithium; alkali metal hydrides (such as sodium hydride), alkaline earth metal hydrides (such as calcium hydride), alkali metal amides (such as sodium amide, They also do not limit the nature of the solvent used, unless they do not damage the reaction. Preferred solvents are: ethers such as diethyl ether, tetrahydrofuran or 1, 2-dimethoxyethar <i el: · fatic ear hydride der, r. As em n-pen *? R or r, -he> an i * - «·. · In generated hydrocarbons such as me il · - hl or id .. : hlo: oF · “

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Or ethylene dichloride; aromatic hydrocarbons such as benzene or toluene; aliphatic alcohols such as nethanol, ethanol, n-propanol, isopropanol or t-butanol; dialkyl aliphatic acid amides such as dimethylformamide or diethylformamide; and dimethyl sulfoxide. The solvent will generally be selected taking into account the base used. Also, there is no particular restriction on the reaction temperature, although it is preferred that the reaction be carried out at a temperature of 0 - 70 ° C and in a stream of an inert gas such as nitrogen, helium or argon.

The most preferred procedure is as follows: First, the compound (XII) is dissolved in an organic solvent (such as 1,2-dimethoxyethane) and then while the solution is kept under a stream of an inert gas (such as argon) and the temperature is maintained between 0 ° C and room temperature, a base (such as sodium hydride) is added followed by the compound (XI) at a temperature between room temperature and 50 ° C. An additional amount of the base is then added at about 0 ° C, followed by the compound (XIII) at between room temperature and 50 ° C.

The time required for the reaction will depend on the base used and the reaction temperature, although it is usually 2 - 5 hours.

Upon completion of the reaction, the desired compound (XII /) is recovered from the reaction mixture by conventional means. For example, ice water is first added to the reaction mixture and then extracted with an organic solvent such as n-hexane. The organic extract is washed and dried, then the solvent is evaporated to give the desired compound. If necessary, this compound can be further purified by conventional means such as column chromatography or thin layer chromatography.

The ester group at the 7-position of the compound (XIV) is reduced by contacting the compound with a reducing agent, preferably in the presence of a solvent. There is no particular restriction on the nature of the option used

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16, but it is capable of reducing an ester group to a hydroxymethyl group without affecting other parts of the compound. It is preferred to use an aluminum hydride compound such as aluminum hydride itself, lithium aluminum monoethoxy hydride, diisobutyl aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride. Preferred solvents are ethers such as diethyl ether or tetrahydrofuran aliphatic hydrocarbons such as n-pentane or n-hexane; and aromatic hydrocarbons such as benzene or toluene. There is no particular restriction on the reaction temperature, although it is preferred to use a temperature between -10 ° C and room temperature.

The removal of any hydroxy protecting groups may be carried out as previously described under Process A and B: but if the protecting group is an acyl group (e.g., acetyl or benzoyl), the deed may conveniently be removed during the reduction.

Upon completion of the reaction, the desired compound of formula (X) is recovered from the reaction mixture by conventional means. For example, ethyl acetate is first added to the reaction medium and none to decompose any excess nests. -tion agent, and then the resulting precipitate is filtered off. The solvent is evaporated from the filtrate to give the desired compound. This compound can be further purified, if necessary, by conventional means, such as silica gel chromatography or thin 1 chromatogr.

Process (d;

A compound of formula (I) having E-configuration ions at the 6-position ag a hydroxymethyl group at the 7-position, namely a compound of formula 'XV;

CH? 0H

CH2R Ch ^ FT i H CH? CH3-C = CH-CH2 - (- CH? -C = CH-CH? D ^ 7jCH? -L = C-CH2-CH9-C = CH-Ci -: - 17

nod 1Π / i c · /: □. Ui \ i O / * t O O D

1 π 2 "3" in which n, R, R and R have the meaning given in Process (b) can be prepared by isomerizing a compound of formula (XVI): Ί ti MO II MCH 0 CI- ^ R1 CH2 Rz IH CH3 CH, -C = CH-CH9-fCH9-C = CH-CH9 ^ -rCH9-C = C-CH9-CH9-C = CH-CH9-OR3

j L L Z Π „1 Z Z / E ^ Z Z Z

H (XVI) 2 It II 2 n 11 Η Π wherein n, R, R and R have the meaning given in Process (b) to form a compound of formula (XVII): 1 π ti 7 Π II nun CH 2 R 2 j H CHl5 CH, -C = CH-CH9-fCH "-CzCH-CH" - - RCH9-C = C-CH "-CH" -C = CH-CH9-OR3 "" 3 2 2 2 n-1 2 ^ .22 2 (XVII) wherein n, R, R and R have the meaning given in Process (b), removing any hydroxy protecting groups by hydrolysis in a manner known per se, but only if desired if the hydroxy protecting groups are aliphatic acyl or benzoyl, and subsequent reduction of the compound.

The isomerization of compound (XVI) to compound (XVII) is carried out using a catalyst in the presence or absence of a solvent. Any catalyst commonly used for the isomerization of double bonds can be used and there is no particular limitation on its nature. Preferred catalysts are: bases, e.g. alkali metal hydroxides (such as sodium hydroxide or potassium hydroxide) and alkali metal alkoxides (such as sodium methoxide, sodium ethoxide or potassium t-butoxide); inorganic acids such as hydrochloric acid, sulfuric acid or perchloric acid; organic acids such as benzenesulphonic acid or p-toluenesulphonic acid; Leic acid, such as boron trifluoride and aluminum chloride; iodine; metallic palladium; and free radical forming agents such as 2,2'-azobisisobutyronitrile or benzoyl peroxide. Also, there is no particular restriction on the nature of the solvent that can

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18 is used, provided it does not damage the reaction. Preferred solvents are: water; organic solvents such as alcohols (eg methanol, ethanol or n-propanol), ethers (such as diethyl ether, teterahydrofuran or dioxane) and aromatic hydrocarbons (such as benzene or toluene); and mixtures of water with one or more of these organic solvents. There is also no particular restriction on the reaction temperature, but it is preferable to use a temperature between room temperature and the reflux temperature of the solvent, if such is used. The tic. required for the reaction will depend mainly on the nature of the catalyst and on the reaction temperature, but is usually between 2 and 12 hours.

Upon completion of the reaction, desired compound of formula (XVII) is recovered from the reaction mixture by conventional means. For example, the compound can be obtained by the following procedure, if necessary after neutralizing the reaction mixture: first the solvent is evaporated and then the reaction mixture is extracted with an organic solvent (such as diethyl ether). The organic extract is washed and dried and the solvent evaporated to give the desired compound.

Any hydroxy protecting groups are removed and the compound is reduced by the procedures previously described. However, the hydroxy protecting groups can be removed during isomerization or during reduction.

The compound of formula (XV) thus obtained can be further purified by conventional methods, such as column chromatography or thin layer chromatography.

Acyler inq

A compound of formula (I) wherein R 1 is acyl may be free;

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19 is positioned by acylating the hydroxy groups in compounds prepared by the foregoing processes (a) - (d).

This acylation can be accomplished simply by contacting the compound containing the hydroxy groups with a corresponding acylating agent in the presence or absence of a solvent. There is no particular restriction on the nature of the acylating agent used, and any type of acylating agent commonly used for the acylation of hydroxy groups can be used. Especially preferred are: acid anhydrides such as acetic anhydride, propionic anhydride or capric anhydride; or acid chlorides such as acetyl chloride, acetyl bromide, butyryl chloride, isobutyryl chloride, octanoyl chloride, lauroyl chloride, palmitoyl chloride, crotonoyl chloride, benzoyl chloride, phenacetyl chloride or cinnamoyl chloride. The reaction is preferably carried out in the presence of a base, e.g. an organic base such as triethylamine, pyridine, picoline or lutidine; an inorganic base, e.g. an alkali metal hydroxide (such as sodium hydroxide or potassium hydroxide) or an alkali metal carbonate (such as sodium carbonate or potassium carbonate); or an alkali metal salt of an organic acid such as sodium acetate or potassium acetate. If a solvent is used, there is no particular limitation on its nature, provided it does not damage the reaction; preferred solvents are: water; ethers such as diethyl ether, tetrahydrofuran or dioxane; halogenated hydrocarbons such as methylene chloride or chloroform; aromatic hydrocarbons such as benzene or toluene; and heterocyclic bases such as pyridine or picoline. There is also no particular restriction on the reaction temperature, although it is preferred to use a temperature between 0 ° C and room temperature. The time required for the reaction will depend mainly on the nature of the acylating agent and the reaction temperature, but it is usually between 2 and 10 hours.

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20

Upon completion of the reaction, the desired compound is recovered from the reaction mixture by conventional means.

For example, the reaction mixture is added to ice water and extracted with an organic solvent such as diethyl ether. The organic extract is washed and dried, then the solvent is evaporated to give the desired compound. If necessary, this compound can be further purified by conventional means such as column chromatography or thin layer chromatography.

Alkylation

A compound of formula (Γ) wherein is alkyl may be prepared by alkylating the hydroxy groups of the compounds prepared by the foregoing processes (a) - (d). This alkylation reaction can be carried out by contacting the hydroxy group-containing compound with a corresponding alkylating agent in the presence or absence of a solvent. There is no particular restriction on the nature of the alkylating agent used, and any type of alkylating agent commonly used for the alkylation of hydroxy groups. can be used. It is particularly preferred to use an alkyl halide in conjunction with a dehydrohalogenating agent. Examples of alkyl halides which can be used are methyl chloride, methyl bromide, methyl iodide, ethyl iodide, n-propyl iodide, isopropyl iodide, n-butyl iodide, isobutyl iodide, hexyl iodide and octyl iodide. Examples of dehydrohalogenating agents are metal oxides such as silver oxide, calcium oxide or barium oxide; metal hydrides such as sodium hydride or calcium hydride; and metal amides such as sodium amide or potassium amide. If a solvent is used, there is no particular restriction on its nature, unless it damages the reaction. Preferred solvents are: ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene or toluene; dialkyl aliphatic acid amides such as dimethylformamide or dimethylacetamide; and dimethyl sulfoxide. There is

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Also, no particular restriction on the reaction temperature is preferred, but it is preferred to use a temperature around room temperature. The time required for the reaction will vary mainly depending on the nature of the alkylating agent and the temperature, but will generally be between 5 and 20 hours.

Upon completion of the reaction, the desired compound is recovered from the reaction mixture by conventional means.

For example, any excess alkyl halide is first removed from the reaction mixture by evaporation. Water is then added to the residue and the resulting mixture is extracted with an organic solvent (such as n-hexane). The organic extract is washed and dried, then the solvent is evaporated to give the desired compound.

If desired, this compound can be further purified by conventional means such as column chromatography or thin layer chromatography.

Most of the starting materials used in the above processes are known compounds or can be prepared by methods well known in the preparation of analogous compounds. However, the compounds of formula (VII) used as starting materials in Process (b), with the exception of geranyl acetone, are novel compounds which can be prepared by the preparations A or B described below.

PREPARATION A

Compounds of formula (VII) wherein A is alkoxymethyl or protected formyl may be prepared by reacting a compound of the general formula (XVIII):

111 II O ft II

ch2rx ch2r ^ CH3-C = CH-CH2 ~ - ^ 0Η2-0 = 0Η-0Η2 -> ^ ΓγΧ (XVIII)

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zz 2 n to 2 "n wherein n, R, R and X have the meaning given in Process (b), with a compound having the formula (XIX): A'COCH2C00R7 (XIX) wherein A 'means alkoxymethyl having 1-8 carbon atoms or acetal-protected formyl, for example, dimethoxymethyl, diethoxymethyl or phethylenedioxymethyl, and R7 is alkyl of 1-4 carbon atoms, in the presence of a base and hydrolyzers and decarboxylates the resulting compound.

This reaction is carried out in the presence of a base and preferably a solvent. There is no particular restriction on the nature of the base used and any base commonly used for alkylation of active methylene groups can be used. It is preferred to use alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium p-butoxide; alkali metal hydrides such as sodium hydride; alkaline earth metal hydrides such as calcium hydride; or alkyl lithium such as n-butyllithium, s-butyllithium or t-butyllithium.

Hydrolysis and decarboxylation of the compounds thus obtained can be carried out under the conditions commonly used for ketonic hydrolysis of a β-keto ester; preferably, the reaction is carried out by heating the compound under reflux with an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in an aqueous alcohol (e.g., aqueous methanol or aqueous ethanol).

PREPARATION B

Compounds of formula (VII) wherein A is acyloxymethyl (i.e., one of the possible protected hydroxymethyl groups;) can be prepared by the processes summarized in the following reaction scheme:

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23 j ft π 9 f f

CH2ir CH2R

CH3-C = CH-CH2-fCH2-C = CH-CH2 -) - ^ CH2C00H (XX) Ί II tt 9 II ft cH2ir ch2it (l ^ -> CH3-C = CH-CH2 - (- CH -CzCH- CH ^^ jCHgCOX (XXI) i π π 9 ti ti

CH2fr CH2fT

- (il) -> CH3-C = CH-CH2 - (- CH2-C = CH-CH2 -> ^ rjCH2COCHN2 (XXII)

Ί ft f 9 II II

cH2ir ch2r a "(-2l) aCH, -C = CH-CH9 - (- CH9-C = CH-CH9 -) - t-CH9CO (XXIII) 3 2 2 L n-1 2 2 rr ii 2" "I the above formulas n, R, R and X have the meaning given in Process (b) and A "means aliphatic acyl oxymethyl having 2-4 carbon atoms in the acyl group, e.g. acetoxymethyl or propionyloxymethyl, or benzoyloxymethyl.

In this reaction scheme, step (i) consists of the preparation of a carboxylic acid halide derivative of formula (XXI) by halogenating a carboxylic acid derivative of formula (XX) in the presence or absence of a solvent. There is no particular limitation on the nature of a halogenating agent used in this halogenation step, and any halogenating agent commonly used in the preparation of acid halides can be used. Preferred halogenating agents are thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide and oxalyl chloride.

In step (ii), the acid halide (XXI) is reacted with diazomethane in the presence of a solvent to prepare a diazocetone of formula (XXII).

In step (iii), the diazoketone (XXII) is heated with a corresponding carboxylic acid (e.g. acetic or propionic acid) to give the desired compound of formula (XXIII) wherein A "means aliphatic acyloxymethyl having 2-4 carbon atoms in the acyl group or benzoyloxymethyl .

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24

The polyprenyl derivatives of general formula (I) have ulcer suppressive activity as demonstrated by the following pharmacological test data.

(1) Inhibition of reserpine-induced ulceration in mice

The method used to produce and assess reserpine-induced ulcers was essentially that described by C. Blackmann, D.S. Campion and F. K. Fastier in the British Journal of Pharmacology and Chemotherapy, 14, 11Σ (1959). The experiment was conducted on male mice of the ddY strain with a body weight of 28 - 33 g. The mice were injected intraperitoneally with the test compound at the dosage given in Table lj 30 minutes later, reserpine was administered subcutaneously at a dose of 10 mg. / 'kg. 18 hours after administration of the reserpine, the animals were sacrificed and the stomach removed. The stomach was inflated with 2 ml of 0.5¾ formalin and fixed. It was then opened by a section along the largest curve, and the total ulcerated area was measured by a stereoscopic microscope. The total ulcerated area (mm) was the sum of the areas (length x width) of the ulcer. The ulcerated areas for the treated group and for a control group were similar-n-similar and the inhibition ratios were calculated. The results are listed in Table 1.

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TABLE 1

Sample Number Inhibition Compound_Dose (mq / kq) Mouse_ Ratio (¾) A 100 5 68.4 B 100 5 65.0 C 100 5 59.0 D 127 5 54.2 E 171 5 64.5 F 220 5 63.3 G 109 5 45.0 H 100 5 57.0 I 127 5 64.5 J 100 5 49.4 K 100 5 58.7 L 100 5 55.3 M 77.8 5 60.1 N 105 5 64.5 0 122 5 74.2 P 150 5 45.7 Q 193 5 56.2

The test compounds used in this experiment and listed in Table 1 are identified as follows:

Compound A: (E, Z, E) -7-hydroxymethyl ~ 3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol

Compound B = (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol

Compound C: (Ε, Ζ, Ε), (E, E, E), (Z, Z, Ej & (Z, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2, 6,10,14-hexadecatetraen-l-ol

Compound D: (E, Z, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol diacetate

Compound E: (E, Z, E) -7-Hydroxymethyl-3,11,15-trimethyl-2,6.10.14-hexadecatetraene-1-ol-dibenzoate

Compound F: (E, Z, E) -7-Hydroxymethyl-3,11,15-trimethyl-2,6.10.14-hexadecatetraene-1-ol dilaurate

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26

Compound G: (E, Z, E) -1-Methoxy-7-methoxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene

Compound H: (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6.10.14-hexadecatetraene-1-o1

Compound I: (E, E, E) -7-hydroxymethyl-3,11,15-triethyl-2,6,10,14-hexadecatetraene-1-ol diacetate

Compound J: (Z, E, E) -7-hydroxymethyl 1-3. li, 15-irinet h> I- 2.6.10.14- hexadecatetraen-1-ol

Compound K: (Ε, Ζ, Ζ) & (E, E, Z) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol

Compound Li (Ε, Ε, Ε, (Ε, Ζ, Ε), (Ε, Ε, Ζ)) (E, Z, Z> -11-hydro-y-methyl-3,7,15-trimethyl-2 , 6,10,14-hexadeca-tetraen-l-ol

Compound Μ: (Ε, Ζ) & (E, E) -7-hydroxymethyl-3,11-dimethyl-2,6,10-dodecatrien-1-ol

Compound N: (Ε, Ζ, Ε, Ε) & (E, E, E, E) -7,15-Dihydraxymethyl-3,11-dimethyl-2,6,6,10,14-hexadecatetraene-1-el

Compound 0: (E, Ε, Ε, Ε), (Ε, Ζ, Ε, Ε), (E, Ε, Ζ, Ε) & (Ε, Ζ, Ζ, .Ε) - 7-hydroxymethyl-3, 11,15,19-tetramethyl-2,6, 10,14,18-eicosapentaen-1-ol

Compound P: (E, Ε, Ε, Ε), (Ε, Ζ, Ε, Ε), (E, Ε, Ζ, Ε) & (Ε, Ζ, Ζ, Ε · - 7-hydroxymethyl-3, 11) , 15,19-tetramethyl-2,6, 10,14,18-eicosaperrtaene-1-ol diacetate

Compound Q: (E, Ε, Ε, Ε), (Ε, Ζ, Ε, Ε), (E, Ε, Ζ, Ε) & (Ε, Ζ, Ζ, Ε; - 7-hydroxymethyl-3, 11) , 15,19-Tetramethyl-2,6, 10,14,18-eicosapentaen-1-ol-dibenzoate (2) Inhibition of stress-induced ulceration in rats

The method used to produce and assess stress-induced ulcers was essentially that described by K. Takagi and S. Okabe in The Japanese Journal of Pharmacology, J 8, 9 (1967), which uses male rats of the Donryu strain with a body weight of 200 - 220 g. The animals were placed strapped in a stress cage and immersed vertically up to the level of their xiphisternum in a water bath maintained at 23-1 ° C for 8 hours. After this stress period, the animals were sacrificed. Their stomachs were removed and fixed with 27 formalin. The gastric sacs were then opened and examined for lesions. The "ulcer index" was calculated as the sum of the length of the lesions found. The ulcer-inhibiting effect of the agents listed in Table 2 was assessed by administering them orally to the test animals at the dosages listed in Table 2, three days before and immediately before the animals were subjected to stress. As a control, similar experiments were performed without administration of any ulcer-inhibiting agent and using the known agent gefarnatum.

TABLE 2

Sample Dose Number of Ulcer Inhibitory Failure (mq / kq / daq x, 4) rat index ratio_

Control - 16 22.3

Compound A 10 5 18.3 17 30 6 13.8 37 * 100 11 12.7 43 *

Hazard date 100 5 25.3 -13 300 11 35.0 -57 x · p Significant inhibition at a probability of less than 0.05 (3) Inhibition of cysteamine-induced duodenal ulceration in rats

The method used to produce and assess cysteamine-induced duodenal ulcers was essentially that described by H. Selye and S. Szabo in Nature, 244, 458 (1973). The experiment was conducted on male rats of the Donryu strain with a body weight of 200 - 220 g, which had been fasted overnight before the start of the experiment. 300 mg / kg of cysteamine was administered orally to the rats to induce duodenal ulceration. Each test compound was administered to the rats orally four times 2 days and the day before, immediately before and the day after cysteamine treatment. Two days after cysteamine administration, the animals were sacrificed and the duodenal

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28 ulcer indices were determined. A similar experiment was performed on a control group which had not been administered any ulcer inhibitor and groups treated with known ulcer inhibitor agents.

The duodenal ulcer index for each animal was evaluated according to the following criteria, and the results were calculated as the mean for each group (S is the product of length and cross diameter for each ulcer): 0 = no lesions 1 - bleeding spots 2. = S < 16 mm2 3 = 16 C 5 ^ 25 4 = S> 25 mm2 5 = perforated ulcer

The results obtained are listed in Table 3.

TABLE 3

Dosage

Sample (mg / kg / day Number of Duodenal Inhibition Compound_x 4) _ Rat Ulcer Index Ratio_

Control - 20 2.45

Compound A 100 10 2.00 18

Compound A 300 18 1.56 34 *

Hazard date 300 10 2.20 10 L-glutamine 1,000 10 1.70 31 * "Significant inhibition at a probability of less than 0.05

The acute toxicity of compound A is as listed in Table 4.

TABLE 4

Tried animals_ Oral dose_Die / survivor

Male mice of ddY strain 5,000 mg / kg 0/5 strain ^ "6 ^ 1,000" 9 / kg 0/5

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29

As can be seen from the tables, the compounds prepared by the process of the invention are better at treating peptic ulcers than the known compound gefarnatum.

Pharmaceutical compositions containing these active compounds may be formulated in the conventional manner using solid or liquid pharmaceutical carriers or diluents and optionally also pharmaceutical additives of a type suitable for the intended mode of administration. The compounds may be administered parenterally (by subcutaneous or intramuscular injection) or orally in the form of, for example, tablets, capsules, granules or powders. The dose to be administered will depend on the patient's condition, age and weight and the mode of administration, but the dosage for adults is preferably 10-1,000 mg per day. per day, administered in divided doses 2-4 times per day. day.

The process of the invention is illustrated in more detail by the following examples and the preparation of starting materials is illustrated in Preparations 1-7.

EXAMPLE 1 (E, Z, E) -7-Hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecetetra-1-ol 9.0 g (E) -5,9-dimethyl -4,8-decadien-1-yl-triphenylphosphonium iodide [RM Coates and W, H. Robinson, J. Arner. Chem.

Soc., 9J, 1785 (1971)] was suspended, in 60 ml of anhydrous tetrahydrofuran. An equimolar amount of a solution of n-butyllithium in n-hexane was added dropwise to this suspension at a temperature of from -5 to 0 ° C under a stream of argon. After stirring the mixture for 30 minutes at room temperature, it was cooled to -78 ° C; and to this mixture was added dropwise 3.3 g of (E) -4-methyl-6- (2-tetrahydropyranyloxy) -4-hexenal in 20 ml of anhydrous tetrahydrofuran. The mixture became

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The mixture was stirred for 30 minutes and cooled to -50 ° C, then an equimolar amount of a solution of s-butyl lithium in pentane was added. The temperature of the mixture was slowly boiled to -10 ° C and then 1.5 g of dry para-formaldehyde was added at one time. The reaction mixture was then stirred for 2 hours at room temperature and after addition of ice water extracted with n-hexane. The solvent was evaporated from the n-hexane extract to give 7.2 g of an oil which was chromatographed in a column containing 20 g of silica gel. The resulting 5.8 g of oil was dissolved in 50 ml of methanol solution containing 100 mg of p-toluenesulfonic acid and the mixture was allowed to stand overnight. Then, an aqueous sodium hydrogen carbonate solution was added to the mixture, which was extracted with diethyl ether. The crude product obtained by evaporation of the solvent from the ether extract was further purified by chromatography through a column containing 30 g of silica gel. 1.8 g of the desired product were obtained. NMR Spectrum S ppm (CCl +): 1.58 (6H, singlet) 1.66 (6H, singlet) 1.9 - 2.3. (12H, multiplet) 3.94 (2H, singlet) 3.97 (2H, doublet) 5.0 - 5.3 (4H, multiplet) IR spectrum V cm 2 (liquid): 3,300, 1,665, EXAMPLE 2 (Ε, Ζ, Ε) & (E, E, E) -7-Hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1 ol 58.6 g (E) -4-methyl-6- (2-tetrahydropyranyloxy) -4-hexen-1-yl triphenylphosphonium iodide [R. Czech and 3rd Reason,

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31

Ann., 853 (1974)] was suspended in 300 ml of anhydrous tetrahydrafurani. An equimolar amount of a solution of n-butyl lithium in n-hexane was then added dropwise to the mixture at -20 ° C under a stream of nitrogen. The mixture was stirred and then 25.4 g of (E) -1,1-dimethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared as described in Preparation 1) was added for 50 minutes. ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours and, after the addition of ice water, was extracted with n-hexane. The crude oil obtained after evaporation of the n-hexane was suspended in 300 ml of 50% acetic acid and the mixture was stirred at room temperature for 2 hours. After this time, the mixture was extracted with n-hexane to give, after evaporation of the solvent from the extract, 28.0 g of 7-formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1 -ol-tetra-hydropyranylether.

This compound was dissolved in 200 ml of ethanol and after addition of 1.5 g of sodium hydride the mixture was stirred for 2 hours under ice-cooling. The mixture was then treated with dilute acetic acid and after addition of water extracted with n-hexane. The solvent was evaporated and the residue dissolved in 200 ml of methanol. To the resulting solution was added 200 mg of p-toluenesulfonic acid, and the resulting mixture was allowed to stand overnight, after which it was neutralized with an aqueous solution of sodium hydrogen carbonate. After evaporation of the methanol, the residue was extracted with ether and the solvent was evaporated from the ether extract to give an oil. This oil was chromatographed on silica gel to give 18.2 g of a mixture of the (Ε, Ζ, Ε) and (E, E, E) isomers of 7-hydroxymethyl-3, 11, 15-trimethyl-2,6,10,14-hexadecatetraen-l-ol.

NMR Spectrum $ ppm (CCll): 1.58 (6H, singlet) 1.66 (6H, singlet)

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32 1.9 - 2.3 (12H, multiplet) 3.94 (2H, singlet) 3.97 (2H, doublet) 5.0 - 5.3 (4H, multiplet) IR spectrum "V cm ): 3,300, 1,665, 1,440, 1,380, 1,000, 840 EXAMPLE 3 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3, 11, 15-trimethyl-2, 6,10,14-Hexadecatetraen-1-ol 5.4 g (E) -6-acetoxy-4-methyl-4-hexen-1-yltriphenylphosphonium iodide was suspended in 30 ml of anhydrous tetrahydrofuran and then 2-molar was added. equivalents of a "solution of n-butyllithium in n-hexane dropwise to this suspension at -20 ° C under a stream of nitrogen. The mixture was stirred at -20 ° C for 2 hours, then 2.5 g of (E) -6,10-dimethyl-2-oxo-5,9-undecadien-1-ol acetate (prepared as described in Preparation) was added. 2) in 10 ml of anhydrous tetrahydrofuran.

The resulting mixture was again stirred at room temperature for 3 hours and after addition of ice water extracted with diethyl ether. The ether was evaporated from the ether extract to give a crude oil which was dissolved in 25 ml of a 5% solution of potassium hydroxide in ethanol under ice-cooling and allowed to stand for 2 hours. After adding water to the mixture, it was extracted with diethyl ether and then treated in the same manner as described in Example 2. The resulting product was chromatographed on silica gel to give 0.95 g of the desired product. The NMR spectrum and the IR spectrum of this product were identical to the spectra of the product prepared in Example 2.

EXAMPLE 4 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol 0.75 g 5025 sodium hydride was suspended in 10 ml of 1,2-dimethoxyethane and after addition of 4.5 g of triethylphosphonoacetate this suspension was stirred for 30 minutes. To the resulting mixture was added 5.6 g of homogeranyl iodide and the reaction allowed to continue at 50 ° C for 2 hours. The reaction mixture was then cooled to 0 - 5 ° C and after addition of 0.75 g of 50 µl in sodium hydride the mixture was stirred at room temperature for 1 hour. Then 3.4 g of (E) -6-acetoxy-4-methyl-4-hexenal was added and the mixture was allowed to react at 50 ° C for 1 hour. After this time, water was added to the reaction mixture and then extracted with n-hexane. The solvent was evaporated from the extract which was then purified by silica gel column chromatography to give 4.7 g of 7-carboethoxy-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol acetate.

This ester was then further reduced with aluminum hydride (prepared from 760 mg of lithium aluminum hydride and 800 mg of aluminum chloride) in 7 ml of diethyl ether. After completion of this reaction, ethyl acetate was added to the reaction mixture and the resulting precipitate was filtered off. The solvent was evaporated from the filtrate to give 3.5 g of the desired product. The NMR and IR spectra of this product were identical to the spectra of the product prepared in Example 2.

EXAMPLE 5 (Ε, Ζ, Ε), (Ζ, Ζ, Ε), (Ζ, Ε, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6, 10,14-hexadecatetraen-1-ol 10.78 g of a mixture of the (E) and (Z) isomers of 4-methyl

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6- (2-Tetrahydropyranyloxy) -4-hexen-1-yl-triphenylphosphonium bromide (E / Z ratio 7: 3) was suspended in 50 ml of anhydrous tetrahydrofuran, and an equimolar amount of a solution of n-butyllithium in n-hexane was then added dropwise to this suspension at -20 ° C under a stream of nitrogen. The mixture was stirred at 20 ° C for 1 hour, then 5.0 g of (E) -1,1-dimethoxy-6,10-dimethyl-5,9-undecadien-2-one was added in 15 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature and then treated as described in Example 2 to give 3.0 g of the desired product.

NMR Spectrum S ppm (CDCl3): 1.58, 1.64 (12H) 1.9 - 2.3 (12H) 3.95, 4.02, 4.08 (4H, multiplet) 5.9 - 6.6 ( 4H, multiplet) IR spectrum Ycm (liquid): 3 325, 1 665, 1 440, 1 380, 1 000.

EXAMPLE 6 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol diacetate 1.0 g -hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadeca-tetraen-1-ol was dissolved in 5 ml of anhydrous pyridine and then 2 ml of acetic anhydride was added. The mixture was then allowed to stand overnight at room temperature, after which it was poured into ice water and extracted with diethyl ether. The ether layer was washed successively with aqueous sodium hydrogen carbonate solution, dilute hydrochloric acid and water; After evaporation of the solvent, 1.1 g of the desired diacetate was obtained.

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NMR Spectrum δ ppm (CDCl 3): 1.58 (3H, singlet) 1.62 (3H, singlet) 1.70 (6H, singlet) 2.07 (6H, singlet) 1.8 - 2.4 (12H, multiplet) ) 4.60 (2H, doublet) 4.67 (2H, singlet 4.9 - 5.6 (4H, multiplet) IR spectrum V cm 2 (liquid): 1 740, 1 445, 1 370, 1 235, 1 02960).

EXAMPLE 7 (E, Z, E) & (E, E, E) -7-Hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol-dibenzoate 1.0 g of 7-hydroxymethyl -3,11,15-trimethyl-2,6,10,14-hexadeca-tetraen-1-ol was dissolved in 5 ml of tetrahydrofuran and then 1.0 ml of benzoyl chloride was added to this solution. After allowing the solution to stand overnight at room temperature, it was treated as described in Example 6 to give 1.5 g of the dibenzoate.

NMR Spectrum δ ppm (CCl ^): 1.53 (6H, singlet) 1.60 (3H, singlet) 1.80 (3H, singlet) 1.8 - 2.4 (12H, multiplet) 4.69 (2H, doublet) 4.76 (2H, singlet) 5.0 - 5.4 (4H, multiplet) 7.2 - 7.4 (6H, multiplet) 8.0 (4H, multiplet)

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36 IR spectrum Y'cnT '* (liquid): 1 720, 1 603, 1 590, 1 450, 1 380, 1 315, 1 270, 1 175, 1 105, 1 070, 1 030, 940, 710 , 685.

EXAMPLE 8 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol dilaurate 1.0 g Hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadeca-tetraen-1-ol was dissolved in 5 ml of anhydrous pyridine and then 2 ml of lauroyl chloride was added to this solution. After allowing the mixture to stand at room temperature overnight, it was treated as described in Example 6 to give 1.8 g of the desired dilaurate.

NMR Spectrum $ ppm (CCl ^): 0.85 (6H, multiplet) 1.2 (40H, multiplet) 1.55 (12H, singlet) 1.8 - 2.4 (12H, multiplet) 4.35 (2H , doublet) 4.42 (2H, singlet) 4.9 - 5.4 (4H, multiplet) IR spectrum 'Vom -' * (liquid): 1 738, 1 670, 1 460, 1 380, 1 160, 1 108, 960 EXAMPLE 9 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol-di-n -eaproate 1 mg of 7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadeca- 37

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tetraen-1-ol was dissolved in 5 ml of anhydrous pyridine, after which 0.5 ml of n-capric anhydride was added to this solution. After allowing the mixture to stand overnight at room temperature, it was poured into ice water and extracted with n-hexane. The extract was treated as described in Example 6 to obtain 300 mg of the desired di-n-caproate.

NMR Spectrum S ppm (CCll): 0.86 (6H, triplet) 1.3 (8H, multiplet) 1.48 (6H, singlet) 1.55 (3H, singlet) 1.60 (3H, singlet) 4.35 (2H, doublet) 4.40 (2H, singlet) 4.8 - 5.3 (4H, multiplet) IR spectrum V cm 2 (liquid): 1 740, 1 670, 1 450, 1 380, 1 310, 1 270, 1 240, 1 170, 1 105, 1 090.

980, 840.

EXAMPLE 10 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol dicrotonate 1 mg 7-hydroxymethyl -3,11,15-trimethyl-2,6,10,14-hexadeca-tetraen-1-ol was dissolved in 2 ml of pyridine, then 0.5 ml of crotonic anhydride was added. After allowing the mixture to stand overnight at room temperature, it was poured into ice water and then extracted with n-hexane. The extract was then treated as described in Example 6 to give 100 mg of the desired diorotonate.

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38 NMR spectrum ppm (CCll): 1.59 (6H, singlet) 1.65 (3H, singlet) 1.71 (3H, singlet) 1.89 (6H, singlet) 4.0 (2H, singlet) 4, 53 (2H, doublet) 5.0 (4H, multiplet) 5.73 (2H, doublet) 6.85 (2H, multiplet) IR spectrum V cm 2 (liquid): 1 720, 1 700, 1 660, 1 440, 1 380, 1 310, 1 295, 1 260, 1 100, 1 005, 970, 840, 785, 760.

EXAMPLE 11 (Ε, Ζ, Ε) & (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene-1-ol dicinnamate 1 mg 7-hydroxymethyl -3,11,15-trimethyl-2,6,10,14-hexadeca-tetraen-1-ol was dissolved in 2 ml of pyridine and 0.5 ml of cinnamoyl chloride was added to the solution. After allowing the mixture to stand overnight at room temperature, it was poured into ice water and extracted with n-hexane. The extract was then treated as described in Example 6 to obtain 300 mg of the desired dicinnamate.

NMR Spectrum t ppm (CCl ^): 1.49 (6H, singlet) 1.55 (3H, singlet) 1.67 (3H, singlet) 4.55 (2H, doublet) 4.6 (2H, singlet)

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39 5.0 (2H, multiplet) 5.3 (2H, multiplet) 6.25 (2H, doublet) 7.2 (10H, multiplet) 7.5 (2H, doublet) IR spectrum V cm (liquid): 1,710 , 1 640, 1 580, 1 500, 1 450, 1 380, 1 325, 1 305, 1 280, 1 250, 1 200, 1 160, 1 100, 1 070, 1 000, 980, 860, 765, 708 , 680.

EXAMPLE 12 (E, Z, E) -1-Methoxy-7-methoxymethyl-3,11,15-trimethyl-2,6,6,10,14-hexadecatetraene 1 g of 7-hydroxymethyl-3,11,15-trimethyl-2 , 6,10,14-Hexadecate-Tren-1-ol was dissolved in 10 ml of IM, N-dimethylformamide. To the solution was added 2 ml of methyl iodide and 3 g of silver oxide, and the resulting mixture was stirred vigorously at room temperature for 16 hours. After this time, the excess methyl iodide was distilled off and after addition of water the residue was extracted with n-hexane. The extract was washed with water and dried, then the solvent was distilled off and the resulting oil was chromatographed through silica gel to give 900 mg of the desired compound.

NMR Spectrum S ppm (CDCl3): 1.56 (6H, singlet) 1.64 (6H, singlet) 1.8 - 2.3 (12H, multiplet) 3.26 (6H, singlet) 3.85 (2H, singlet) 3.86 ( 2H, doublet) 4.8 - 5.4 (4H, multiplet)

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IR spectrum Vcm 2 (liquid): 1 680, 1 455, 1 390, 1 100, 960, 920.

EXAMPLE 13 (E, E, E) -7-hydroxymethyl-1,3,11,15-trimethyl-2,6,10,14-hexadecetetra-1-ol 10.0 g of 7-formyl-3,11,15-trimethyl -2,6,10,14 rhexadecatetraene-1-ol-tetrahydropyran ether (prepared as described in Example 2) was dissolved in 100 ml of methanol. To the solution was added 100 mg of p-toluenesulfonic acid and the mixture was allowed to stand overnight at room temperature. The mixture was then neutralized with an aqueous solution of sodium hydrogen carbonate, then the methanol was distilled off and the residue extracted with diethyl ether. After evaporation of the solvent from the ether extract (E, E, E) -7-formyl-3,11,15-trimethyl-2,6,10,14-hexedecatetraen-1-ol was dissolved in 60 ml of ethanol. After adding 5.5 g of sodium borohydride under ice-cooling of the solution, the mixture was stirred vigorously for 2 hours. The mixture was then treated with dilute acetic acid and after addition of water extracted with diethyl ether. The oil obtained after evaporation of the solvent from the ether layer was purified by silica gel column chromatography to give 6.6 g of the desired compound.

NMR Spectrum § ppm (CDCl3): 1.51 (6H, singlet) 1.58 (6H, singlet) 1.8 - 2.2 (12H, multiplet) 3.95 (2H, singlet) 4.05 ( 2H, doublet) 5.0 - 5.3 (4H, multiplet)

DK 157486B

41 IR spectrum V cm 2 (liquid): 3,300, 1,670, 1,440, 1,380, 1,000, 840.

Example 14 (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecetraene-1-ol diacetate

Acetylation was performed as described in Example 6 except 1 g of (E, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol was used. , whereby 1.0 g of the desired diacetate was obtained.

NMR Spectrum S ppm (CCl ^) in 1.60 (6H, singlet) 1.66 (3H, singlet) 1.71 (3H, singlet) 1.97 (3H, singlet) 2.00 (3H, singlet) 1.9 - 2.2 (12H, multiplet) 4.45 (2H, singlet) 4.50 (2H, doublet) 4.9 - 5.5 (4H, multiplet) IR spectrum V cm 2 (liquid): 1 750, 1 680, 1 445, 1 285, 1 375, 1 240, 1 030, 960.

EXAMPLE 15 (Z, E, E) -7-hydroxymethyl-3,11,15-trimethyl-2,6,10, 14-hexadecetetra-1-ol 37.2 g (Z) -6-acetoxy-4 -Methyl-4-hexen-1-yl-triphenylphosphonium iodide was suspended in 250 ml of anhydrous tetrahydrofuran and two molar equivalents of a solution of n-butyllithium

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42 n-hexane was added dropwise to this solution at -20 ° C under a stream of nitrogen. The resulting one! mixture was then stirred for 1 hour at -20 ° C, then 19.0 g of (E) -1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one dissolved in 50 ml of anhydrous tetrahydrofuran was added. The mixture was then stirred at room temperature for 3 hours and after addition of ice water extracted with n-hexane. The solvent was evaporated to give a crude oil which was hydrolyzed with a 5¾ alcoholic solution of sodium hydroxide and then reacted with 50% acetic acid at room temperature for 2 hours. The product thus obtained was dissolved in 100 ml of n-hexane and after addition of 100 g of calcium chloride the mixture was shaken vigorously at room temperature. The resulting calcium chloride addition product was digested with water and then extracted with n-hexane to give (Z, E, E) -7-formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraene -laugh out loud. This compound was dissolved in 200 ml of ethanol, and after the addition of 1 g of sodium borohydride under ice-cooling, the mixture was stirred for 2 hours. The mixture was then treated with dilute acetic acid, water added and then extracted with diethyl ether. The extract was purified by column chromatography using 120 g of alumina to give 5.8 g of the desired product.

NMR Spectrum S ppm (CDCl3): 1.50 (6H, singlet) 1.57 (3H, singlet) 1.61 (3H, singlet 1.8 - 2.2 (12H, multiplet) 3.85 (2H , singlet) 3.91 (2H, doublet) 5.0 - 5.3 (4H, multiplet) IR spectrum V cm 2 (liquid): 3,300, 1,665, 1,440, 1,380, 1,000, 840.

EXAMPLE 16 (Ε, Ζ, Ζ) & (E, E, Z) -7-hydroxymethyl-3,11,15-trimethyl-2,6r, 10,14-hsxadecatetraen-1-ol 18 g (E ) -6-acetoxy-4-methyl-4-hexen-1-yl-triphenylphosphonium iodide was suspended in 125 ml of anhydrous tetrahydrofuran, and 2 molar equivalents of a solution of n-butylli th iun: in n-hexane was added dropwise to the suspension at -20 ° C under a stream of nitrogen. After stirring the resulting mixture at -20 ° C for 1 hour, 8.4 g of (Z) -1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared as described in Preparation) were added. 3} in 25 ml of anhydrous tetrahydrofuran, The mixture was then stirred at room temperature for 3 hours, ice-water was added and the mixture was extracted with * -hexane. After evaporation of the n-hexane from the extract D1: - When an oil was obtained, this oil was treated with a natural clay-n, -droxide solution and with acetic acid, and then reduced using 150 mg of sodium borohydride in the manner described in Example 15. 3.0 was obtained. g of a television rch: of the (.Ε, Ζ, Ζ) - and (E, E, Z) isomers of the desired link j ....

NHR Spectrum S ppm (CDCl3): 1.73 (3H, singlet) 1.78 (9H, singlet) 1.8 - 2.4 (12H, multiplet) 4.18 (2H, singlet) 4.25 ( 2H, doublet) 5.2 - 5.5 (4H, multiplet) IR spectrum / ³Wcm ^ (liquid):

3 350, 1 670, 1 450, 1 385, 1 005, in J

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EXAMPLE 17 11-Hydroxymethyl-3,7,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol 23.1 g (E) -4-ethyl-6- (2-tetrahydropyranyloxy) -4- hexen-1-yl triphenylphosphonium iodide was suspended in 120 ml of anhydrous tetrahydrofuran. According to the procedure described in Example 2, an equimolar amount of n-butyllithium and 7.2 g of 6-acetoxymethyl-10-methyl-5,9-undecadien-2-one was added (prepared as described in Preparations 4 and 5). , and the mixture was allowed to react. The product was then hydrolyzed with 70 ml of 5¾ alcoholic solution of sodium hydroxide and then treated overnight at room temperature with methanol containing 10 mg of p-toluenesulfonic acid. The product was purified by column chromatography through 100 g of silica gel to give 3.7 g of the desired product in the form of a mixture of (Ε, Ε, Ε) -, (Ε, Ζ,,) -, (Ε, Ζ , Ε) and (E, E, Z) isomers.

NMR Spectrum S ppm (CDCl3): 1.60 (6H, singlet) 1.70 (6H, singlet).

1.8 - 2.4 (12H, multiplet) 4.13 (2H, singlet) 4.13 (2H, doublet) 5.0 - 5.4 (4H, multiplet) IR spectrum V cm 2 (liquid): 3 350, 1 670, 1 440, 1 380, 1 010, 840.

EXAMPLE 18 (E, Z) & (E, E) -7-hydroxymethyl-3,11-dimethyl-2,6,10-dodecatrien-1-ol 1.5 g of 50¾ sodium hydride was suspended in 20 ml of anhydrous 45

DK 15748.6 B

1,2-dimethoxyethane, and after adding 8.9 g of triethyl phosphonoacetate to the suspension, the resulting mixture was stirred at room temperature for 1 hour. Then 6.5 g of 4-methyl-3-pentenyl bromide was added and the mixture was allowed to react at 50 ° C for 3 hours. The reaction mixture was then cooled to a temperature of 0-5 ° C and after addition of 1.5 g of 50% sodium hydride the mixture was stirred at room temperature for 1 hour. Then 6.8 g (E) -6-acetoxy-4-methyl-4-hexenal was added to the reaction mixture which was allowed to react for 1 hour. After this time, water was added and the mixture was then extracted with n-hexane. The extract was chromatographed through silica gel to give 2.2 g of 7-ethoxycarbonyl-3,11-dimethyl-2,6,10-dodecatriene-i-ol acetate.

This acetate was reduced with aluminum hydride (prepared from 380 mg of lithium aluminum hydride and 440 mg of aluminum chloride) in diethyl ether to give 7 8G mg of the desired product.

NMR Spectrum δ ppm (CDCl 3): 1.60 (3H, singlet) 1.68 (6H, singlet) 2.1 (8H, multiplet) 4.08 (2H, singlet) 4.10 (2H, doublet) 5.2 - 5.4 (3H, multiplet; IR spectrum γ cm 2 (liquid): 3 350, 1 670, 1 375, 1 240, in 0 ϋ Li, t -> D.

EXAMPLE 19 (Ε, Ζ, Ε, Ε) & (E, E, E, E) - 7.15 - d i h y d r o x y m e t h y 1 - 5,11 - d i m e i t '2,6,10,14-hexadecatetraene-1-ol

DK 157486 B

46 II, II diethoxy-2,6-dimethyl-10-oxo-2,6-undecandien-1-ol, prepared as described in Preparation 6, was acetylated by a conventional process. 9 g of the resulting acetate was treated with 16.3 g of (E) -4-methyl-6- (2-tetrahydropyryloxy) -4-hexen-1-yltriphenylphosphonium iodide, which had already been mixed with an equimolar amount of n. -butyllithium in 100 ml of anhydrous tetrahydrofuran. The product was then hydrolyzed with 1 g of sodium carbonate in methanol and stirred in 80 ml of 50% acetic acid at room temperature for 3 hours to hydrolyze the acetal. The formyl group of the resulting compound was reduced by 200 mg of sodium borohydride in 30 ml of ethanol and then the "protective tetrahydropyranyl group of the product was removed by treatment with p-toluene sulfonic acid in methanol in the same manner as described in Example 2. 4 g of an oil and this was purified by silica gel column chromatography to give 1.0 g of the desired compound.

NMR Spectrum S ppm (CDCl3): 1.65 (3H, singlet) 1.68 (6H, singlet) 2.1 (8H, multiplet) 4.08 (2H, singlet) 4.10 (2H, doublet) 5.2 - 5.4 (3H, multiplet) IR spectrum Vcm 3 (liquid): 3 350, 1 670, 1 375, 1 240, 1 000, 830.

EXAMPLE 20 7-Hydroxymethyl-3,11,15,19-tetramethyl-2,6,10,14,18-eicosa-pentaen-1-ol

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47

According to the procedure described in Example 2, 5.8 g of (E) -4-methyl-6- (2-tetrahydropyranyloxy) -4-hexen-1-yl-triphenylphosphonium iodide was treated with n-butyllithium in 30 ml of anhydrous tetrahydrofuran. The resulting product was then treated with 3.2 g of 1,1-dimethoxy-6,10,14-trimethyl-5,9,13-pentadecatrien-2-one (prepared as described in Preparation 7) * The resulting oil was then reacted with 40 ml of 50% acetic acid to give 4.2 g of 1-tetrahydropyranyloxy-7-formyl-3,11,15,19-tetramethyl-2,6,10,14,18-eicosapentaene. This product was reduced with 150 mg of ns-tri-borohydride and treated with p-toluenesulfonic acid in methanol as described in Example 2, and the product was purified by silica gel column chromatography to give 1.6 g of the desired product. This was a mixture of (Ε, Ε, Ε, Ε) -, (Ε, Ζ, Ζ, Ε) -, (Ε, Ζ, Ε, Ε) - and the E, E, Z, E) isomers, NMR Spectrum £ ppm (CDCl3): 1.50 (9H, singlet; 1.58 (6H, singlet) 1.8 - 2.7 (16H, multiplet) 3.96 (2H, singlet) 4.00 (2H, doublet) 4.9-5.4 (5H, multiplet) IR spectrum V cm 2 (liquid; 3,350, 1,670, 1,445, 1,380, 1,000, 1,000) - EXAMPLE 21 7-Hydroxymethyl-3 , 11,15,19-Tetramethyl-2,6,10 <14, Jd. »·: pentaen-1-ol diacetate 1 mg 7-hydroxymethyl-3,11,15,19-tetramethyl-1 2.6, in G: '4 1-' ·· eicosapentaen-1-ol was acetylated in 5 ml of anhydrous pyridi. * With 0.5 ml of vinegar sy reanhyd dr. The resulting product *:

DK 157486 B

48 treated as described in Example 6 to obtain 300 mg of the desired diacetate, NMR spectrum pp ppm (CCl ^): 1.30 - 1.61 (15H, singlet) 1.90 (3H, singlet) 1 , 92 (3H, singlet) 1.8 - 2.4 (16H, multiplet) 4.34 (2H, singlet) 4.41 (2H, doublet) 4.8 - 5.4 (5H, multiplet) IR spectrum Vcm 2 (liquid ): 1 750, 1 690, 1 390, 1 385, 1 238, 1 025, 960, 840.

EXAMPLE 22 7-hydroxymethyl-3,11,15,19-tetramethyl-2,6,10,14,18-eicosa-pentaen-1-ol-dibenzoate 1 mg 7-hydroxymethyl-3,11,15,19-tetramethyl -2,6,10,14,18-eicosapentaen-1-ol was benzoylated in 5 ml of anhydrous pyridine with 0.5 ml of benzoyl chloride. The resulting product was then treated as described in Example 7 to give 280 mg of the desired dibenzoate.

NMR Spectrum g ppm (CCl ^): 1.55 (9H, singlet) 1.62 (3H, singlet) 1.75 (3H, singlet) 1.9 - 2.2 (16H, multiplet) 4.70 (2H, doublet) 4.77 (2H, singlet) 5.0 - 5.4 (5H, multiplet)

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49 7.3 (6H, multiplet) 7.90 (4H, multiplet) IR spectrum Vcm 2 (liquid): 1 725, 1 680, 1 610, 1 590, 1 455, 1 390, 1 320, 1 275, 1 180, 1 110, 1 075, 1 030, 950, 940, 840, 710, 690.

Some of the starting materials used in the foregoing examples were prepared as described in the following preparations.

PREPARATION 1 (E) -1,1-dimethoxy-6,10-dimethyl-5,9-undecadien-2-one 17.4 g of metallic sodium was dissolved in 350 ml of anhydrous ethanol, and 160 g of methyl-4.4. dimethoxyacetoacetate was added dropwise to the resulting solution with stirring at room temperature. After 1 hour, geranyl bromide (prepared from 130 g of geraniol) was added dropwise to the resulting mixture under ice-cooling. The mixture was then allowed to etch overnight at room temperature, after which it became up to <g; n: v under reflux for 1 hour. Then 42 g of sodium hydroxide in a mixture of 1.4 liters of ethanol and 1.18 liters of water were added to the reaction mixture and heated under reflux for 6 hours. After this time, the mixture was extracted with n-hexane and the solvent was distilled off from the extract under reduced pressure to give 134 g of the desired product, bp: 92-95 ° C / 0.05 mmHg.

NMR Spectrum S ppm (CDCl3): 1.58 (6H, singlet) 1.62 (3H, singlet) 1.8 - 2.7 (8H, multiplet) δ

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3.35 (6H, singlet) 4.39 (1H, singlet) 5.05 (2H, multiplet) IR spectrum Vcm 2 (liquid): 1 735, 1.075, 1000.

PREPARATION 2 (E) -6,10-dimethyl-2-oxo-5,9-undecadien-1-ol acetate 32 g of oxalyl chloride was added to 19.6 g of geranyl acetic acid and the mixture was allowed to stand overnight at room temperature. The mixture was then evaporated under reduced pressure to remove excess reagents and the resulting acid chloride was dissolved in 100 ml of diethyl ether and added dropwise under ice-cooling to an ether solution containing 0.2 mole of diazomethane. After completion of the reaction, the diethyl ether was removed by evaporation and the resulting diazo ketone was dissolved in 100 ml of acetic acid and heated to 90 ° C for 5 hours. The reaction mixture was then diluted with water and extracted with diethyl ether. The ether extract was washed successively with an aqueous solution of sodium hydrogen carbonate and with water, then dried and the solvent evaporated. The residual oil was distilled under reduced pressure to give 15.0 g of the desired product, bp: 132 ° C / 0.02 mmHg.

NMR Spectrum S ppm (CDCl3): 1.56 (9H, singlet) 2.05 (3H, singlet) 4.45 (2H, singlet) 4.8 - 5.3 (2H, singlet) IR spectrum cm liquid): 1 755, 1 740, 1 375, 1 230, 1 060.

51

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PREPARATION 5 (Z) -1,1-Diethoxy-6,10-dimethyl-5,9-undecadien-2-one

According to the procedure described in Preparation 1, neryl bromide (prepared from 31 g of nerol) was reacted with 41.5 g of ethyl 4,4-diethoxyacetoacetate to give 20 g of the desired product, bp: 122 ° C / 0.02 mmHg.

NMR Spectrum δ ppm (CDCl 3): 1.32 (6H, triplet) 1.65 (3H, singlet) 1.74 (6H, singlet) 1.8 - 2.7 (8H, multiplet) 3.71 ( 4H, multiplet) 4.61 (1H, single) 5.19 (2H, multiplet) IR spectrum Y cm (liquid): 1 735, 1.075, 1000.

PREPARATION 4 1,1-Diethoxy-6-methyl-5-hepten-2-one

According to the procedure described in Preparation 1, 7.3 g of ethyl 4,4-diethoxyacetoacetate was reacted with 4.0 g of 3-methyl-2-butenyl chloride in the presence of sodium ethoxide. The resulting product was decarboxylated with alcoholic sodium hydroxide to give 4.1 g of the desired product, bp: 102 - 103 ° C / 1 mmHg.

NMR Spectrum <pp ppm (CCl ^): 1.19 (3H, triplet) 1.60 (3H, singlet)

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52 1.63 (3H, singlet) 2.42 (4H, singlet) 3.55 (4H, multiplet) 4.31 (1H, singlet) 5.02 (1H, triplet) IR spectra V cm 2 (liquid) : 1 730, 1 445, 1 400, 1 380, 1 315, 1 150, 1 100, 1 060, 900, 830, 745.

PREPARATION 5 (E) & (Z) -6-acetoxymethyl-10-methyl-5,9-undecadien-2-one 38.5 g of 4,4-ethylenedioxypentan-1-yl-triphenylphosphonium bromide were suspended in 160 ml of anhydrous tetrahydrofuran, and an equimolar amount of a solution of n-butyllithium in n-hexane was added to the suspension at -20 ° C under a stream of nitrogen. The reaction mixture was stirred for 1 hour and then cooled to -60 ° C. Then, 14.5 g of 1,1-diethoxy-6-methyl-5-hepten-2-one was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was added to ice water and then extracted with n-hexane. An extract was obtained from the extract which was suspended in 250 ml of 50¾ acetic acid and stirred at room temperature for 1 hour. The 2,2-ethylenedioxy-6-formyl-5-methyl-5,9-undecadiene obtained by extracting this mixture with n-hexane was reduced without purification in 100 ml of ethanol by means of 500 mg of sodium borohydride. The resulting product was chromatographed on a column containing 100 g of silica gel to give 7.3 g of 2,2-ethylenedioxy-6-hydroxymethyl-10-methyl-5,9-undecadiene.

NMR Spectrum δ ppm (CDCl 3): 1.19 (3H, singlet) 1.47 (3H, singlet)

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1.58 (3H, singlet) 3.75 (4H, singlet) 3.91 (2H, singlet) 5.0 - 5.3 (2H, multiplet) IR spectrum Vcm-1 (unwanted): 3 450, 1 680.

7.2 g of the 2,2-ethylenedioxy-6-hydroxymethyl-10-methyl-5,9-undecadiene prepared above was acetylated with acetic acid in anhydrous pyridine at room temperature and the product was dissolved in 70 ml of methanol. To the resulting solution was added 70 mg of p-toluenesulfonic acid and the mixture was allowed to stand overnight at room temperature. The product was then neutralized with an aqueous solution of sodium bicarbonate and extracted with n-hexane. After evaporation of the solvent, 7.2 g of the desired product were obtained.

NMR Spectrum δ ppm (CDCl 3): 1.50 (3H, singlet) 1.58 (3H, singlet) 1.91 (3H, singlet) 1.99 (3H, singlet) 4.32 and 4.47 (EogZ) (2 H, singlet) 5.0 - 5.3 (2H, multiplet) IR spectrum Vcm -1 (liquid): 1 740, 1 720, 1 440, 1 370, 1 230, 1 160, 1 050, 1 025, 960, 830.

PREPARATION 6 (E, E) -11,11-diethoxy-2,6-dimethyl-10-oxo-2,6-undecadien-1-ol 7.4 g of 1,1-diethoxy-6,10-dimethyl-2 -oxo-5,9-undecadiene was

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54 dissolved in 70 ml of 95 ° ethanol, 1.7 g of selenium oxide was added to the resulting solution and the mixture was heated under reflux for 15 minutes. After this time, the ethanol was removed by evaporation, water was added to the residue and the mixture was extracted with diethyl ether. The ether extract was washed with an aqueous solution of sodium hydrogen carbonate and dried. The solvent was then removed by evaporation leaving an oil which was purified by silica gel column chromatography to give 3.0 g of the desired product.

NMR Spectrum δ ppm (CCl ^): 1.20 (6H, triplet) 1.50 (6H, singlet) 3.5 (4H, multiplet) 3.80 (2H, broad singlet) 4.32 (1H, singlet) ) 5.0 - 5.3 (2H, multiplet) IR spectrum Vcm 2 (liquid): 3,500, 1,740, 1,450, 1,380, 1,325, 1,250, 1,160, 1,105, 1,070, 1 020, 900.

PREPARATION 7 (E, E) & (Z, E) -1,1-Dimethoxy-6,10,14-trimethyl-5,9,13-penta-decatrien-2-one

According to the procedure described in Preparation 1, farnesyl bromide (prepared from 22 g of nerolidol) was reacted with 19 g of methyl 4,4-dimethoxyacetoacetate and the reaction mixture was purified by column chromatography using 200 g of silica gel. 12.8 g of the desired product were obtained.

55

...... DK i57486B

NMR Spectrum S ppm (CDCl3): 1.47 (9H, singlet) 1.54 (3H, singlet) 1.8 - 2.7 (12H, multiplet) 3.28 (6H, singlet) 4.30 ( 1H, singlet) 4.98 (3H, multiplet) 1R spectrum "Vom ^ (liquid): 1 742, 1 460, 1 390, 1 230, 1 200, 1 118, 1 080, 1 000, 960, 845.

Claims (2)

3. L ln 2 2 wherein n is 1, 2 or 3, 1 2 R and each R is the same or different and means H or 3 2 3 in OR, with at least one R being OR and at least one of R and the 2 any other R groups are H and the R 3 groups are the same or different and means H, alkyl of 1-8 carbon atoms, aliphatic acyl of 2-18 carbon atoms, benzoyl or phenyl aliphatic acyl of 2 or 3 carbon atoms in the aliphatic acyl moiety, characterized in that (a) a compound of formula (III): 1. in 9 ni ch2r1 ch2r- 'g CH_-C = CH-CH, - (- CH, -C = CH-CH, ·) - rCH, -CH, -P (R4), X (III) 3 Z 2 2 n-1 Z 2 3 ii '2 "1 wherein n has the above meaning, R and each R are 2 ~ t II I the same or different and represents H or OR, wherein at least one of R and R is H and the R groups are the same or different 3 and means a hydroxy protecting group selected from 5 or 6 membered heterocyclic groups containing an oxygen and / or sulfur atom ring and may have one or more methoxy substituents, alkoxyalkyl groups of 1-4 carbonato more in the alkoxy moiety and alkylene moiety and trialkylsilyl groups having 1-4 carbon atoms in each alkyl moiety, or an alkyl group having 1-8 carbon atoms, R means a hydrocarbon residue, and X means halogen, and a compound of formula (IV): ch3 OKMUBSQ (IV) 3n 1 wherein R is as defined above is reacted with formaldehyde in the presence of a base to form a compound of formula (V): ch2r1u 'ch2r2' "ch2oh ch3 CH3-C = CH-CH2 - (- CH2-C = CH-CH2 ^ rYCH2-C = C-CH2-CH2-C = CH-GH2-0R3" 'Z' (V) 2. r 211 1 3111 wherein n, R, R and R are as defined above, and any hydroxy protecting groups are removed by hydrolysis in a manner known per se to form a compound of formula (II): c1R1 'ch2r2' dh2oh ch3 CH3- C = CH-CH2-eCH2-C = CH-CH2 ^ :: ^ CK2-C = C-CH2-CH2 - (> CH-CH2-OR3 'Z "(II) 11' 2 'wherein n has the above meaning , R and each R are the same 3 '1 or different and mean H or OR, with at least one of R 2 in 3 i and R being H and R group r is the same or different and means H or alkyl of 1-8 carbon atoms, or (b) a compound of formula (VII): I Π II ΟΗ / ΙΤ CH 2 R 1 CH 2 R 2 A CH 3 -C = CH-CH 2 fCH 2 -C = CH EH 2 - ^^ CH 2 -CO (VII) 21111 wherein n is as defined above, A means CH? R or acetal protected formyl, R and each R are one or three ITs different and mean H or OR, with at least one 2 "i" i 3 "ii * ^ η ii R is OR, and at least one of R and any other 2" II 3 II II R groups is H and the R groups are the same or different and represent a hydroxy protecting agent group selected from 5- or 6-membered heterocyclic groups containing an oxygen and / or sulfur atom in the ring and may have one or more methoxy substituents, alkoxyalkyl groups of 1-4 carbon atoms in the alkoxy moiety and alkylene moiety respectively, DK 157486 B trialkylsilyl -4 carbon atoms in each alkyl moiety, aliphatic acyl groups of 2-4 carbon atoms and benzoyl, or an alkyl group of 1-8 carbon atoms are reacted with a compound of formula (VIII): m CH, η λ ® I 3 -zii ii X (R) 3P-CH 2 -CH 2 -CH 2 -C = CH-CH 2 -OR 2 (VIII) 3 "" 4 wherein R, R and X has the above meaning, in the presence of a base to form a compound of formula (IX): 1 It If O II II CH 2 R CH 2 R 2 a ch 3 CH, -C = CH-CHO - (- CHO-C = CH- CH 2 -) - z-CH 2 -C = C-CH 2 -CH 2 -C = CH-CH 2 -OR 3 "3 2 2 2 n-1 2 z / E? 2 (2) "(IX) wherein n, A, R, R and R are as defined above and any hydroxy protecting and / or formyl protecting groups are removed by hydrolysis in a manner known per se, but only if desired, if the hydroxy protecting groups is aliphatic apyl or benzoyl, and any aldehyde formed is reduced, or (c) a compound of formula (XI): in it CH9 - (- CH2 -C = CH-CH9 ·) -rCH2 X (XI) 3 2 2 2 n-1 2 2 ti ti 2ff π 0 wherein n, R, R and X have the above meaning and a compound of formula (XII): (r6o) 2poch2coor5 (XII) wherein R3 and R4 are the same or different and each independently means alkyl of 1-4 carbon atoms, reacted with a compound of formula (XIII): ch2-c = ch-ch2-or3 "" (XIII) 3. in which R has the above meaning, in the presence of a base to form a compound of formula (XIV) s CH2R CH2Rz coor ^ CH3 CH3- C = CH-CH2 - (- CH2-C = CH-CH2 -> ^ 3yCH2-C = C-CH2-CH2-C = CH-CH2-OR3 ^ (XIV) wherein n , R 1, R, R and R have the above meaning and this compound is reduced, whereby any hydroxy protecting groups, if aliphatic acyl or benzoyl, if desired only, are removed by hydrolysis in a manner known per se to form of a compound of formula vX;: CH? R1 "CH2R2" CH2QH CK.3 CH3-C = CH-CH2 - (- CH2-C = CH-CH2> ^ rYCH2-C = C-CH2-CH2-C = CH -CH2 ~ OP3 "2 / Ei (X) 1. ii 2" wherein n has the above meaning, R and each R are 3 "the same or different and means H or OR, with at least 0. II one R being OR and at least one of R and any of the other 311 3 'R groups is H and R is the same as R above or aliphatic acyl of 2-4 carbon atoms or benzoyl, or (d) a compound of formula (XVI) ); i ii ii 9 π π CHZRX CH2RZ cho ch3 CH3-C = CH-CH2-fCH2-C = CH-CH2 ^ rYCH2-C = C-CH2-CH2-C = CH-CH2-OR3 "'/ Η (XVI) IH II 2 tr 3 3 II II wherein n, R, R and R have the above meaning are catalytically isomerized to a compound of formula (XVII): 1 tf II 7 II II CHO CH "R1 CH" RZ IH CH 1. I * l | 1 J 7 II II CH3-C = CH-CH2 - (- CH2-C = CH-CH2- ^ rjCH2-C = C ~ CH2-CH2 ~ C = CH-CH2-OR ^ E (XVII) 1. ii 1.1 2 "" 3 "11 0 wherein n, RR and R. are as defined above, whereby any hydroxy protecting groups, if aliphatic acyl or benzoyl, if desired only, are removed from the compound (XVII) without hydrolysis on and off is known, and the compound is reduced to form a compound of formula (XV): in π 2 "CH 2 R CH 2 R 2 H ch 3 CH, -C = CH-CH" - (- CH "-C = CH-CHO -) - i-CH" -C = C-CHo-CHo-C = CH-CH "-0R3 "!> il in η-li £ Li L (XV) 1. ii 2" 3 »wherein n, R, R and R have the above meaning, wherein one under (a), (b), (c) or ( d) forming a hydroxy compound, if desired, acylated or alkylated to form an ester or ether thereof, of the general formula (I) wherein R 3 has one of the above values different from H.