DE2351729B2 - PROCESS FOR MANUFACTURING BIFUNCTIONAL ASYMMETRIC CYCLOPROPANES - Google Patents

Description

(D

Usually esterified with an alkanol or converted into salts.

wherein R ₁ , R ₂ and R _{3 are} short-chain alkyl radicals, X fine —CH ₂ OR or —COORj group, in which | l is hydrogen, an alkyl, acyl or optionally N-phenyl-substituted carbamoyl _{radical and R 1 is} hydrogen or an alkyl radical and R ₁ ', R ₂ and R ₃ , which can be identical or different, denote hydrogen atoms or short-chain alkyl radicals, of their esters, salts or oximes, characterized in that a ketone is represented by the general formula

R ₂ -CC-CH ₂ R ₂
R ₃ O

in which R ₁ , R ₂ , R ₃ and R _{2 have} the above meaning, treated with sodium amide, sodium hydride or tertiary sodium butoxide in hexamethylphosphotriamine, dimethyl sulfoxide, tetrahydrofuran or an aromatic hydrocarbon, the carbanion formed of the general formula II

R,

-CCC ⁰

O R, '

(ID

The chemistry of cyclopropanes was predominantly in the field of monofunctional derivatives developed. In contrast, there are comparatively few processes for the production of bifunctional Derivatives, and far fewer processes, are known for the production of bifunctional enable asymmetric derivatives, d. H. so of derivatives that have two different on the cyclopropane ring carry functional substituents.

The best-known works in the field of bifunctional cyclopropanes concern chrysanthemic acids, however, this work is directed exclusively to compounds in which one of the both functional groups no heteroatoms, but unsaturated carbon-carbon bonds having.·

As far as asymmetric bifunctional cyclopropanes are known, they are either unsatisfactory Yields or obtained in a cumbersome manner.

The present invention now relates to a simple process for the preparation of bifunctional asymmetric Cyclopropanes of the general formula

with an epichlorohydrin derivative of the general formula III

R ₃ " K

Cl-CH

i
R,

(111)

reacted, where R ₁ 'and R _{3 have} the above meaning and R ^ is a hydrogen atom or an alkyl radical, and finally the alcohol function of the resulting keto alcohol, optionally in a manner known per se either

a) with chromosulfuric acid at 20 ⁰ C.

b) with an alkyl halide,

c) with an acid chloride in the presence of anhydrous pyridine,

d) with phenyl isocyanate in ligroin at reflux temperature ¹ -.

wherein R ₁ , R-. and R ₃ short-chain alkyl radicals. X is a -CH ₂ OR or COOR _r group in which R is hydrogen, an alkyl, acyl or optionally N-phenyl-substituted carbamoyl _{radical and R 1 is} hydrogen or an alkyl radical and R ₁ ', R ₂ ' and R ₃ '. which can be identical or different, denote hydrogen atoms or short-chain alkyl radicals, of which esters, salts or oximes, which is characterized in that one has a ketone of the general formula

R ₂ CC-CH ₂ R ₂

/ Ii

Il

R.1 O

in which R ,, R ₂ , R ₃ and R _{2 have} the above meaning, with sodium amide, sodium hydride or tertiary sodium butoxide in hexamethylphosphotriamiri. Dimethyl sulfoxide, tetrahydrofuran or a

Ll

aromatic hydrocarbon treated, the formed carbanion of the general formula II

^R v ^c ~ n

R ₃ OR

(H)

with an epichlorohydrin derivative of the general ones Formula III

Cl-CH

!
R /

reacted, where R ₁ 'and R ₃ ' have the above meaning and R ₄ 'is a hydrogen atom or alkylresl, and finally the alcohol function of the resulting keto alcohol, optionally in a manner known per se either

a) with chromosulfuric acid at 2O ⁰ C, bi with an alkyl halide.

c) with an acid chloride in the presence of anhydrous Pyridine,

d) with phenyl isocyanate in ligroin at reflux temperature,

e) with phosgene and ammonia or

f) with excess hydroxylamine hydrochloride reacts in the presence of pyridine and

optionally the product obtained according to a) in Usually esterified with an alkanol or converted into salts.

It has proven particularly advantageous to produce esters by reacting the acids with branched or straight-chain aliphatic or subsiluted or unsubstituted aromatic alcohols can be obtained.

Typical cyclopropar.compounds which can be prepared according to the invention are z. B. tertiary butylcarbonyl-2 - cyclopropylcarbinol, tertiary butylcarbony! 2-cyclopropanoic acid, tertiary butylcarbonyl-2-cyclopropy! - trimethoxybenzoate, the phenyl urethane of • tertiary butyl carbonyl - 2 - cyclopropylcarbinol. the carbamate of tertiary butylcarbonyl-2-cyclopropylcarbinol and the oxime of tertiary butylcarbonyl-2-cyclopropyIcarbinoI.

Are cycloprcpane derivatives according to the process according to the invention by allowing epichlorohydrin to act or its derivatives are prepared on a carbanion of a suitable ketone, so first obtain a cyclopropane alcohol according to the following reaction equation:

R ₁ -CCC + Cl-CH

O R, '

R4

\ 7

R ₁ -CCC

Il i

R ₃ OR ₂

CHOH -

wherein ', R _3' and R ^ are as defined in the general formulas R _1, R _2, R _3, R /, _R.sub.2.

According to the method of the invention, the carbanion is in the α-position of the ketone by the action of Sodium amide, sodium hydride or tertiary sodium butoxide in the form of a suspension in hexamethylphosphotriamine, dimethyl sulfoxide, tetrahydrofuran or an aromatic hydrocarbon.

Then epichlorohydrin or a derivative thereof of the given general formula III, preferably at room temperature, directly with that obtained in the previous process step Mixture implemented.

After the reaction has ended, the remaining sodium-containing agent is removed using the usual methods, in particular by hydrolysis with ice water, destroyed. The organic phase obtained is in the usual manner separated and worked up, e.g. B. by concentration or distillation.

The yields obtained are good.

The cyclopropanes which can be prepared according to the invention can be used as intermediates, e.g. B. for production of pharmaceuticals.

The following examples are intended to explain the invention in more detail.

example 1

Tertiary butylcarbonyl-2-cyclopropylcarbinol

One mole of pinacolone was added dropwise to a solution of sodium amide in hexamethylphosphotriamine. The reaction mixture obtained was heated to 100 ° C. for 2 hours and then cooled to room temperature. Thereafter dropwise 1 mole of epichlorohydrin was added, the rate of addition of the epichlorohydrin was controlled in such a manner that the temperature of the reaction mixture did not exceed 20 ⁰ C. The reaction mixture was then allowed to stand for a few hours at room temperature, after which the remaining sodium-containing agent was destroyed by hydrolysis by pouring the mixture into ice water. The organic phase obtained was concentrated and then distilled.

The tertiary butylcarbonyI-2-cyclopropylcarbinol formed was at 135-138 ° C under a pressure of 15 mm Hg in a yield of 60 to 70%. It had the following formula:

CH ₂ OH

and was identified by the following analytical characteristics:

23

Gross formula QH ₁₆ O,

Molecular weight 156.2

Refractive index η'- = 1.460

Infrared spectrum, absorption bands (rcm ~ ') ^: 3450 (OH), 3010 (cyclopropane — CH), 2880 to 3000 (aliphatic CH), 1680 to 1690 (CO group). 1030 pulsation band).

Nuclear Magnetic Resonance Spectrum (nuclear magnetic resonance spectrum) in CCl ₄ (Λ in ppm, based on tetramethylsilane): 1 (multiple of cyclopropane — CH ₂ ), 1.2 (singlet of methyl groups), 1.5 (signal of cyclopropane — CH in / i position to the CO group). 2.15 (signal of the cyclopropane — CH in position to the CO group), 3.5 and 3.6 (signal of the CH ₂ group [alcohol]), 3.95 (singlet of the alcohol proton).

Example 2
Tertiary butylcarbonyl-2-cyclopropanecarboxylic acid

To prepare this compound, 1 mol of the KctoalkohoN obtained in Example 1 was used in Ether solution allowed to act on a chromosulfuric acid mixture, the oxidizing agent in light Excess was used. During the additions, the temperature of the mixture was about 20 "C. The resulting reaction mixture was left to stand for 6 hours at room temperature. The organic phase was then separated off, whereupon this with an aqueous sodium bicarbonate solution was treated. After acidification of the aqueous phase, the process product was in the form of crystals obtained in a yield of 85%. The product of the process had the formula

35 CH ₃ . O

729

CH ₃ -CC

CH ₃ O OH

and had the following analytical characteristics:

Gross formula C ₉ H ₁₄ O,

Molecular weight 170.2

F 90 ⁰ C

Elemental analysis consistent with gross formula.

Infrared spectrum in accordance with the structure.

Nuclear Magnetic Resonance Spectrum (Λ in ppm): 1.2 (singlet of the methyl groups), 1.4 and 1.5 (signal of the cyclopropane methylene protons), 2 (signal of the methine proton in the α-position to the carboxyl group), 2.6 (signal of the methine proton in -position to the carbonyl group), the singlet of the acid proton from 8 disappeared at Addition of deuterium water, extinction through isotope exchange.

Example 3

Tertiary butyl carbonyl 2-cyclopropyl trimethoxybenzoate

To prepare this compound, 1 mole of trimethoxybenzoic acid chloride was dissolved in a chloroform solution with 1 mol of the obtained according to Example 1, dissolved in chloroform keto alcohol in the presence of 1 mol anhydrous pyridine implemented. After completion

After the addition, the resulting reaction mixture was heated to the reflux temperature of the solvent for 2 hours heated. After water treatment, the obtained organic phase was washed with an aqueous solution of sodium bicarbonate, and then washed with water until neutral. After distillation the oily residue was crystallized from the solvent. After recrystallization from hexane became a compound of the following formula

CH ₃

\
CH ₃ -CC-

/ ii
CH ₃ O

OCH ₁
> —OCH,

OCH,

obtained in a yield of 90%, their analytical Characteristics were as follows:

Gross Formula C ₁₉ H ₂₆ O ₆

Molecular weight 350.4

F 80 to 81 C

Elementary analysis in accordance with the Bruito formula.

Thin layer chromatography

Carrier silica

Solvent ethyl acetate

Pctrolether 25 75

Development of UV light and iodine

Rf value 0.7

Infrared spectrum: KBr - pastilles, absorption;, - bands (rcm " ¹ ): 3050 (CH aromatic), 2800 to 3000 (CH aliphatic), 1730 (C = O ester). IoVÜ (C = O ketone), 1590 (C ■ = - C aromatic).

B c i s ρ i e 1 4

Phylurethane of tertiary butylcarbyl-2-cyclopropylcarbinol

1 mol of the keto alcohol obtained in Example 1 and 1 mol of Phcnylisocyanat were in a Solution of ligroin (100 to 140 ° C) heated to reflux temperature for 1 hour. The crystals formed were collected by filtration and recrystallized from benzene. The yield was quantitative. The process product obtained had the formula

^CH \

CH ₃ -CC-

-CH ₁ -OC-NH-

CH,

and had the following analytical characteristics:

Gross Formula C ₁₆ H ₂₁ O ₁ N

Molecular weight 275.34

F 108 "C

Elemental analysis in accordance with gross formula.

Infrared spectrum (.cm " ¹ ): 3320 (NH), 1730 (C- = O urethane), 1685 (C = O ketone).

7 J8

Nuclear Magnetic Resonance Spectrum (Λ in ppm): 1 (cyclopropane gross form C ₁₀ H ₁₇ NU,

Methylene), 1.2 (singlet of methyl groups), 1.6 molecular weight 199.2

(Signal of the cyclopropane —CH), 2.2 (Signal of the CH F ". 88 C

in «position to the CO group), 4 and 4.15 (doublet

of exocyclic methylene), 7 to 7.4 (aromatic 5 infrared spectrum and NMR spectrum in over-

Protons and those of NH). agreement with the structure.

Example

Carbamate of tertiary butylcarbonyl-2-cyclopropylcarbinol

A solution was added dropwise to a toluene solution containing slightly excess phosgene of 1 mol of the keto alcohol obtained in Example 1 and 1 mole of dimethylaniline in anhydrous benzene was added. After standing for an hour Ammonia was bubbled into the reaction mixture for 30 minutes at room temperature. The formed dimethylaniline hydrochloride was removed by filtration and after usual treatment the desired product was obtained in a yield of 90% in the organic phase lanasam crystallized. The compound obtained had the formula

CH ₃

\
CH ₃ - CC

- CH ₂ -OC-NH ₂

Examples

Oxime of tertiary butylcarbonyl-2-cyclopropylcarbinol

The keto alcohol obtained according to Example 1 was in alcoholic solution with an excess of Treated hydroxylamine hydrochloride in the presence of pyridine. That obtained in a yield of 85% Product had the following formula

- ¹ _x

ru —r r

CH ₃ L L

rn mi LH ₂ UH

and had the following analytical characteristics: and had the following analytical characteristics:

Gross formula C ₉ H ₁₇ NO,

Molecular weight 171.2

_F "105 = C

Elemental analysis in accordance with gross lormel.

Infrared spectrum in accordance with the structure.

Claims (1)

Claim: e) with phosgene and ammonia or f) reacts with excess hydroxylamine hydrochloride in the presence of pyridine and Process for the preparation of bifunctional asymmetric cyclopropanes of the general 5, if appropriate, the product obtained according to a) in Formula I.