DE1200288B - Process for the preparation of farnesyl compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07c

German class: 12 ο -19/03

Number: 1200 288

File number: H 45605IV b / 12 ο

Filing date: April 27, 1962

Opening day: September 9, 1965

The invention relates to a process for the preparation of farnesyl compounds in general formula

CH ₃ R ₂ CH ₃

ι. i

CC CH ₂ CH ₂ C 1-4 η;

Process for the preparation of farnesyl compounds

CH ₃

-CH- CH ₂ - CH ₂ - C = CH - CH ₂ - R ₃

(D

where R ₁ and R _{2 are} hydrogen or a lower alkyl group and R _{3 is} a mercapto group, an etherified hydroxyl or mercapto group or an amino group and the bonds shown in dashed lines can be hydrogenated, as well as salts of these compounds.

The amino group in the molecule can be primary, secondary or tertiary, and basic derivatives can be in In the form of acid addition salts or quaternary compounds. The substituents of the amino group can for their part also be basic.

Applicant:

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr. G. Schmitt, lawyer, Lörrach (Bad.), Friedrichstr. 3

Named as inventor:

Dr. Rudolf Rüegg, Bottmingen (Switzerland); Dr. Peter Schmialek, Berlin-Dahlem

Claimed priority:

Switzerland of May 24, 1961 (6019)

The process for the preparation of farnesyl compounds is characterized in that one Halide of the general formula

CH ₃ R ₂ CH ₃ CH ₃

[ 1

R ₁ -CH ₂ -C - C - CH ₂ -CH ₂ -C-CH-CH ₂ -CH ₂ -C = CH -CH ₂ -X (II)

where X is a halogen atom, R ₁ and R _{2 are} hydrogen or lower alkyl and the bonds shown in dashed lines can be hydrogenated in a manner known per se with a compound of the general formula

AR ₃

(III)

where R ₃ denotes a mercapto group, an etherified hydroxyl or mercapto group or an amino group and A denotes hydrogen or an alkali or alkaline earth metal and, if R _{3 is} a disubstituted amino group, also denotes a lower alkyl radical, and converts any basic compounds obtained into salts.

The corresponding bromides, such as farnesyl bromide and 1 - bromide - 3,7,11 - trimethyltridecatriene - (2,6,10), are expediently used as halides. Hydrogen sulfide, lower alkanols such as methanol, ethanol, dimethylaminoethanol, phenol and benzyl alcohol, and lower thioalcohols such as methyl mercaptan and ethyl mercaptan can be used as the second reaction component. In all these cases, ie when the symbol A in the above general formula denotes hydrogen and the symbol R ₃ denotes the mercapto group or an etherified hydroxy or mercapto group, the reaction must be carried out in the presence of an acid binder, such as sodium carbonate, potassium carbonate and sodium bicarbonate. It is therefore advisable to use the corresponding metal compounds, such as sodium methylate, in order to avoid this measure. Further examples of compounds according to general formula III are ammonia, primary or secondary amines, such as methylamine, dimethylamine and diethylaminoethylamine.

The basic compounds obtained can be converted into the acid addition salts or quaternary compounds be converted by treating them with the appropriate acids, e.g. B. hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or with alkyl halides, such as methyl

509 660/505

bromide, ethyl bromide. Quaternary connections can also be obtained directly through this by reacting the halide with a tertiary amine.

The new process products are insecticidal. In contrast to most of the previously known Pesticides which, as contact or food poisons, kill, paralyze or drive away the animals, the compounds which can be prepared according to the invention intervene in the hormonal system of the animal organism a. They are able to inhibit the transformation of insects into imago, i. H. the generational sequence to interrupt and thus indirectly destroy the animals. The process products can therefore be used Control of insects can be used. The new connections are useful for * 5 warm-blooded animals non-toxic. DDT is fatal in rats at a concentration of 175 mg / kg in 50% of the animals. In comparison for this, the corresponding lethal dose is z. B. with farnesyl diethylamine 560 mg / kg, with farnesyl mercap a ° tan more than 5000 mg / kg. The isoprenoids are also easily broken down in the organism. The danger an accumulation is therefore excluded. In addition, the compounds can be used in the fragrance industry Find use.

example 1

6 g of sodium are dissolved in 120 ml of anhydrous methanol and this solution is cooled to 0 ° C. 64 g of farnesyl bromide are added dropwise to this solution in the course of 30 minutes and the mixture is stirred overnight at about 25 ° C. The precipitated sodium bromide is then filtered off, the filtrate is diluted with 200 ml of water, the precipitated oil is taken up in petroleum ether and the washes Petroleum ether solution with water neutral. The solution is dried over sodium sulfate and filtered through a chromatography tube with 500 g of aluminum oxide (activity II). The solvent is evaporated off in vacuo and the residue is distilled in a high vacuum. Farnesyl methyl ether is obtained as a colorless, slightly viscous oil; B.p. 0 ₀₅ 72 ° C; nt = 1.4750.

The farnesyl bromide used as starting material can in a manner not claimed here as can be obtained as follows:

An initially on - cooled 10 ⁰ C solution of 50 g of trans-Nerolidol and 1 g of pyridine in 150 ml of petroleum ether are added dropwise over 20 minutes a mixture of 10 ml of phosphorus tribromide and 50 ml of petroleum ether so to that the temperature did not exceed -5 ° C increases. The mixture is then stirred for a further 1 hour at about -5 ° C., the solution is poured onto ice water, the aqueous layer is separated off and the petroleum ether solution is washed neutral with water. It is dried over sodium sulfate and the solvent is evaporated off in vacuo at 30.degree. The farnesyl bromide obtained has a refractive index of nl ⁴ = 1.5040.

Example 2

60

64 g of farnesyl bromide are added to a boiling suspension of 100 g of potassium carbonate in 300 ml anhydrous methanol was added dropwise. The mixture is stirred under reflux for 20 hours, then cooled, the salt was filtered off and the solvent was evaporated off in vacuo. The residue is in 200 ml Petroleum ether dissolved and filtered through 500 g of aluminum oxide (activity II). After removing the Solvent, the residue is distilled in a high vacuum, farnesyl methyl ether being obtained.

According to the information above, the following can be produced:

Farnesyl n-butyl ether, boiling point ₀₁ 85 to 87 ° C; n% = 1.4699;

l-methoxy-3,7, ll-trimethyltridecatriene- (2,6,10), boiling point 65 ° C .; nf = 1.4750 (colorless, slightly viscous oil).

Example 3

64 g of farnesyl bromide are mixed with 50 ml of diethylamine and refluxed for 3 hours. The excess diethylamine is distilled off, the residue is taken up in petroleum ether and the reaction product is isolated by extraction with 1η hydrochloric acid. The acidic solution is made alkaline with sodium hydroxide solution, the free base is taken up in petroleum ether, washed with 50 ml of water and dried over sodium sulfate. The solvent is distilled off and the residue is distilled in a high vacuum. Farnesyl diethylamine is obtained as a colorless, slightly viscous oil of boiling point ₀₀₁ 97 to 98 ° C .; nf = 1.4771.

According to the information above, the following can be produced:

Tetrahydrofarnesyl diethylamine,
H ² S = 1.4562;

Kp.o.0! 96 ⁰ C;

3,7,10,11 - tetramethyldodecatriene - (2,6,10) - yldiethylamine, boiling point _{0> 01} 104 to 106 ⁰ C; n% ° = 1.4820.

Example 4

64 g of farnesyl bromide are added dropwise at 5 to 10 ° C to a saturated hydrogen sulfide solution of 10 g of sodium hydroxide in 150 ml of anhydrous alcohol. The solution is stirred for 5 hours at 25 ^° C. while passing in hydrogen sulfide and then admixed with 300 ml of water. The separated oil is taken up in petroleum ether and the petroleum ether solution is washed neutral with water. After drying over sodium sulfate, the solvent is distilled off and the residue is fractionated in a high vacuum. Farnesyl mercaptan is obtained as a colorless, easily mobile oil with a boiling point of ₀₁ 76 ° C .; nt = 1.5030.

Example 5

64 g of farnesyl bromide are mixed with 25 ml of benzene and 25 ml of triethylamine. The mixture is during Heated to 30 ° C for 2 hours, cooled, some precipitated salt filtered off and in vacuo to Evaporated to dryness. The solid residue is with 200 ml of petroleum ether (40 to 45 ° C) for 2 hours shaken, whereby the solid cake disintegrates. It is quickly filtered through a suction filter and washed with Petroleum ether and dries over calcium chloride in the desiccator. Farnesyltriethylammonium bromide is obtained as a light gray, very hygroscopic powder.

Example 6

7 g of sodium are dissolved in 400 ml of ammonia. After the solution has decolored, 64 g of farnesyl

5 6

bromide was added dropwise in 150 ml of absolute ether. The 1-bromine used as the starting compound

The solution is stirred for 5 hours, then 3,7,1-trimethyldodecadiene- (2,6) cannot be added to 25 g of ammonium chloride and the ammonia can be prepared as follows, as is claimed: evaporated. The remaining slurry is with petroleum To a cooled to 0 ⁰ C solution of 100 g

diluted ether, washed neutral with water and evaporated the 5 3,7,11 - trimethyldodecadiene - (1,6) - oil - (3) in 200 ml of petroleum ether solution after drying. absolute ethyl ether is adsorbed after adding 2 g of the crude farnesylamine to 500 g of aluminum oxide pyridine, a mixture of 50 g of phosphorus tribromide and (activity II), the secondary per- 100 ml of absolute ethyl ether formed are added dropwise. The interior products washed through with petroleum ether, the pure temperature should not exceed ^{0 to 5 0 C.} The product is eluted with ether and, after evaporation, the reaction mixture is then distilled for 2 hours with the solvent in a high vacuum. The mixture is stirred from 0 to 5 ^° C. and poured onto ice. The ether contains farnesylamine of bp _0f02 HO ⁰ C; n% ° = 1.4887. phase is washed neutral with water, over

Sodium sulphate and dried under reduced pressure at a bath temperature of a maximum of 30 ^° C

B eis ρ ie 1 7 i ₅ evaporated. The l-bromo-3,7, ll-tri-

methyldodecadiene- (2,6) («I ³ = 1.4760) can be used without

6 g of sodium are dissolved in 150 ml of methanol and 13 g of methyl mercaptan are added dropwise for further purification for the synthesis of the dihydro at 0 ° C. Farnesylmethyläthers can now be used, the mixture is left to stand for 30 minutes and 64 g of farnesyl-. -I ₁₁

bromide and then boils for 2 hours on 20 B e 1 s ρ 1 e 1 11

Reflux. The solvent is then distilled off, In a cooled to 0 ° C solution of 60 g of diethyl

the residue is taken up in petroleum ether, 130 g of water are washed neutral with amine in 200 ml of absolute ethyl ether, dried and evaporated crude 1 -Bromo-3,7,11 -trimethyldodecaen- (2). The above residue is added dropwise in a high vacuum. The internal temperature should be 0 to 10 ° C distilled. One receives methyl farnesyl sulfide of 25 not exceeding. The reaction temperature is then 0.02 85 ⁰ C; «O ⁰ = 1.5044. mixture stirred overnight at room temperature and

a further 2 hours under reflux conditions

Example 8 Boiling heated. Then the cooled mixture

made Congo acidic by adding 3η hydrochloric acid

53 g of farnesyl bromide in 40 ml of ether are extracted into 60 g and extracted with ether. The eluate is separated Ν, Ν-diethylaminoethylamine added dropwise to 60 ml of ether. and discarded. The hydrochloric acid aqueous phase is made alkaline by adding sodium hydroxide solution to the mixture under reflux for a further 4 hours. The boils and then diluted sodium hydroxide solution and the amine that is separated out is absorbed in ether. The water poured. It is extracted with ether and the ether phase is dried over sodium sulfate and the ether solution is washed three times with water, dried and evaporated. Spread the remaining tetrahydrofuran over sodium sulfate and evaporate the solvent. syldiäthylamin is by fractional distillation. The residue is distilled in a high vacuum. It is cleaned in a fine vacuum. _{B.p. OiO1} 96 ° C; r? § = 1.4542. receives Ν, Ν-diethylamino-N'-farnesylamine of b.p. _{0> 05} The 1-bromine used as the starting compound

119 to 122 ° C. 3,7, ll-trimethyldodecaen- (2) cannot be considered here

40 claimed way can be produced as follows:

Example 9 13 g of sodium are dissolved in 500 g of liquid ammonia

solved. Acetylene is added to this solution for as long

53 g of farnesia bromide in 40 ml of benzene are added until the blue color has disappeared. Then a solution of 4.3 g of sodium in 22 g of dimethyl, a solution of 100 g of aminoethanol in 60 ml of benzene at 0 to 10 ° C is added dropwise in the course of one hour. 45 Hexahydropseudojonon in 300 ml absolute ether Then, the mixture is added dropwise for 5 hours at 2O ⁰ C. The reaction mixture is stirred overnight and then, as indicated in Example 8, stirred up, added dropwise with 200 ml of water and worked. ^{The crude product is heated to 20 °} C. in a high vacuum to remove the ammonia and distilled. This gives N-dimethylaminoethyl farnesyl The upper layer is taken up in ether with ether, bp. _OiO1 105 ⁰ C. 50 water until neutral, dried over sodium sulfate and evaporated. The 3,7,11 - trimethyldodecene - (1) - oil - (3) that remains is purified by fractional distillation in a fine vacuum in Example 10.

Kp _{0, 01} 80 ° C. β »= 1.4480.

In a chilled to 0 ⁰ C solution of 12 g sodium 55105 g of 3,7, ll-Trimethyldodecaen- (l) -OL- (3) in 300 ml of methyl alcohol, 125 g of crude 1-bromo-in 400 ml of petroleum ether ( Boiling range 60 to 90 ° C) dissolved 3,7, II-trimethyldodecadiene- (2,6) was added dropwise in the course of one and after addition of 5 g Lindlar catalyst and 2 g hour. The internal temperature should not exceed quinoline below 0 to 5 ^{° C. in a hydrogen atmosphere.} The pressure is then shaken from about a column of water until the reaction mixture has taken up 1 mol of hydrogen for 2 hours without cooling. The is then stirred and the catalyst is filtered off under reflux for a further hour and the reaction solution is heated to boiling with some conditions. The cooled reduced pressure is then concentrated. The remaining mixture is shaken with 300 ml of ice water and extracted with crude 3,7,1-trimethyldodecaen- (1) -ol- (3) like petroleum ether (boiling range 40 to 45 ⁰ C). This follows further processed:

Eluate washed neutral with water is dried over 65 g to a solution of 105 g of sodium sulfate cooled ^{to 0 ° C. and evaporated.} The 3,7,1-trimethyldodecaen- (l) -ol- (3) remaining in 200 ml of ether dihydrofarnesylmethyl ether can be purified by fractional distillation after adding 2 g of pyridine. 50 g phosphorus tribromide in 100 ml absolute ether

dripped in. The internal temperature should not exceed 0 to 5 ° C. The reaction mixture is then stirred for 2 hours at 0 to 5 ° C. and poured onto ice. The ether phase is washed neutral with water, dried over sodium sulfate and evaporated. The l-bromo-3,7, ll-trimethyldodecaen- (2) (nff = 1.4742) which separates out can be used for the synthesis of tetrahydrofarnesyl diethylamine without further purification.

Claims (1)

Claim: Process for the preparation of farnesyl compounds, characterized in that one is a halide of the general formula CH3 CH _S CH2 - C "^ C - CH ₂ - CHg - C" »CH - CH ₂ CH ₃ - C - CH - (Π) wherein X is a halogen atom, R ₁ and R _{2 are} hydrogen or lower alkyl groups and the bonds shown in dashed lines can be hydrogenated in a manner known per se with a compound of the general formula AR ₃ (III) where R _{3 is} a mercapto group, an etherified hydroxyl or mercapto group or an amino group and A is hydrogen or an alkali or alkaline earth metal and, if R _{3 is} a disubstituted amino group, also a lower alkyl radical, is reacted and any basic compounds obtained are converted into salts . 509 660/508 8.65 © Bundesdruckerei Berlin