DE2351729A1 - BIFUNCTIONAL ASYMMETRIC CYCLOPROPANES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Bifunctional Asymmetric Cyclopropanes and Processes too

their manufacture

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

The most famous work in the field of bifunctional Cyclopropanes affect the chrysanthemum acids, and this works however, they are aimed exclusively at compounds in which one of the two functional groups does not have any heteroatoms, but unsaturated carbon-carbon bonds exhibit··

The present invention relates to bifunctional asymmetric cyclopropanes having at least one heteroatom in the functional Substituents corresponding to the general formula

R ₂ CC

0 H

₃ 2

9817/1139

correspond, where mean:

a carboxy or unsubstituted carbamoyl radical, or a carbamoyl radical which is N-mono- or disubstituted with an alkyl or carbamide _{radical f} or a gyano, formyl, hydroxymethyl, alkyl-substituted hydroxymethyl or aminomethyl radical »or a carbamoyloxymethyl radicalV of the N- is mono- or disubstituted with a radical R or a carbamoyl radical, or an R-oxymethyl or acyloxymethyl radical , - ..- ".:" - "■" · ■ '■■■'"- - ■ '■ - ""

^{f ß} l ^ ¹¹ ^ · ^{Rf d} * ^{e can be} equal ^ or different, hydrogen atoms, short-chain alkyl radicals, short-chain alkenyl radicals, short-chain alkynyl radicals, phenyl radicals or mono-, di- or tricyclic aromatic radicals with 5 or 6 chain links and 0 to 4 heteroatoms , and

v can be identical or different, hydrogen atoms or short-chain alkyl radicals,

as well as the esters and salts of the specified acids and alcohols and the oximes of the ketones.

Ssters which have been found to be particularly preferred are those obtained by reaction with acids or branched or straight-chain ones aliphatic or substituted or unsubstituted aromatic alcohols.

With short-chain alkyl, alkenyl or alkynyl radicals such «it denotes 1 to 6 carbon atoms, these Residues can be straight or branched.

409817/1139

Typical cyclopropane compounds according to the invention are, for. B .;

tert-butyl carbonyl-2-cyclopropylcarbinol, tert-butylcarbonyl-T-2-cyclopropanoic acid, tert-ButylcarbonylT ^ cyclopropyl-trimethoxybenzoate, the phenyl urethane of tert-I ^ tylcarbony-L-i ^ cyelOpropylcarbinol, the carbamate of tert ^ butylcarbonyl-2-cyclopropylcarliinol and the oil of tert ^ butylcarbonyl ^ -eyclopropylcarbinol

To prepare the cyclopropane derivatives according to the invention, epichlorohydrin or its derivatives are allowed to act on a carbanion of a suitable ketone. In this way, a cyclopropane keto alcohol is obtained according to the following reaction equation: .- ': ..' ■

^C 1 _X H. 'R'

L - G - C - C ^e + Cl - CH-

3 ·

M /

^l 1 CH
-CCC

^ 5 " ^ - CHOH

R ₃ 2. , -. ^ v ₁

where in the formulas R ₁ , R ₂ , R ,, R ^, R | _t and Rl have the meaning given and R! can be a hydrogen atom or an alkyl radical. . .

A09817 / 1139

-4- 2351723

The keto alcohol obtained can be due to the known: reactions the alcohol function in compounds according to the invention be transferred, e.g. B. in an acid, in an aldehyde, a Ether, an ester, a urethane or a csrbamate.

According to the method of the invention, the carbanion in ot. ~ Position of the ketone produced by the action of a na- trium containing agent, preferably sodium amide, sodium hydride or sodium tert-butoxide, in the form of a suspension in a solvent such as. B. hexamethylphosphotriamine, Dimethyl sulfoxide, tetrahydrofuran or an aromatic hydrocarbon, on the ketone.

Thereafter, epichlorohydrin or a derivative thereof is preferred at room temperature, reacted directly with the mixture obtained in the preceding process step.

When the reaction is complete, the remaining sodium becomes Means destroyed using customary known methods, in particular by hydrolysis in ice water. The obtained organic Phase is isolated and purified in a conventional manner (e.g. by concentration or distillation).

The resulting keto alcohol then becomes other according to the invention Get connections, in particular:

a keto acid by oxidation,

a ketoaldehyde by mild oxidation, a ketoether by treatment with an alkyl halide, a ketoester due to the action of an acid chloride, a urethane by the action of an isocyanate and a carbamate by the action of phosgene and ammonia.

The cyclopropanes according to the invention can be used as synthesis intermediates, z. B. for the pharmaceutical industry;

. 4098 17/1139

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

example 1

1 mole of pinacolone was added facing © au a solution of Katriumamid in Hexamethylphosphotriamin added "The obtained reaction mixture was 2 hours erh.itat to 100 ⁰ C, after which it was allowed to cool to room temperature" was added dropwise 1 mole of epichlorohydrin is added Thereafter ^ wherein di @ rate of addition of Ipichlorhydrins was controlled in such a manner that the .Temperature of .Reaktionsgemisches 20 ⁰ G not stiege the reaction mixture was sodasia. Left to stand for a few hours at room temperature, whereupon 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 tert-butylcarbonyl-2-cyclopropylcarbinol formed was obtained at 135 to 138 ^° C. under a pressure of 15 mm Hg. It had the following formula

C - C - ^ -: - ^ - CH ₀ OH

II - 2

0 - ·

and was ficated by the following analyticals

409817/1 139

Gross formula:

Molecular weight: 156.2

Refractive index: n | j = 1 460

Infrared spectrum, absorption bands (ν · cm ") s 3,450 (OH), 3,010 (cyclopropane-CH), 2,880 to 3000 (aliphatic CH) _t 1,680 to 1,690 (ketone), 1,030 (" respiratory ^ band ),

NMR spectrum (nuclear magnetic resonance spectrum) in CCl * (S in ppm, based on TMS) s 1 (multiplet of the cyclopropane CHg), 1.2 (singlet of the methyl groups), 1.5 (signal of the 8-position cyclopropanine sur CO group), 2.15 (signal of the cyclopropanine attitude to the CO group), 3.5 and 3 _S 6 (signal of the CH «(AIkOiIOl)), 3.95 (singlet of the alcohol proton)» ■

Example 2

tert B u "fcylcarb on _f yl-2 ~ cj ^ lopropansäure

To prepare this compound, 1 mol of the keto alcohol obtained in accordance with Example 1 was allowed to act in an ether solution on a suIfoehroin mixture (the oxidizing agent being used in a slight excess). Driving the addition, the temperature of the mixture was maintained at about 20 ⁰ G. The reaction mixture obtained was left to stand for 6 hours at room temperature. The organic phase was then separated off, whereupon it was treated with an aqueous sodium bicarbonate solution. To. Acidification of the aqueous phase gave the process product in the form of crystals »The process product had the formula:

4098 1 7/11 39

CH - C - C

⁵ ^ il

and indicated the following analytical characteristics on the gross formula:

Molecular weight: 170.2

p: 90 ^° C

Centesimal Analysis Consistent
Infrared spectrum consistent with the structure

Nuclear Magnetic Resonance Spectrum (& in ppm): 1.2 (singlet of the methyl groups), 1.4 and 1.5 (signal of the cyclopropane methylene _{protons) t} 2 (signal of the methine proton in cc position to the carboxyl), 2.6 ( Signal of the methine proton in cc position to the carbonyl), the singlet of the acid proton from 8 onwards disappeared when deuterium water was added, extinction due to isotope exchange

Example 3 ,

tert-butylcarbonyl-2-c-cyclopropyl-trimethoxybenzoate

To prepare this compound, 1 mol of zo e acid chi or id in chloroform solution to 1 mol of the according to Example 1 obtained keto alcohol dissolved in chloroform is allowed to act in the presence of 1 mol of anhydrous pyridine,

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7351729

After the addition, the reaction rate was - .. heated to reflux temperature of the solvent mixture for 2 hours. After treatment with water, the organic phase obtained was washed with an aqueous solution of sodium bicarbonate and then with water until it was neutral. After the solvent had been distilled off, the oily residue was crystallized. After recrystallization from
Hexane became a compound of the following formula

_CH σ _ c— ^ ^ _{--- CH n} O -C-

³ - Il " ² Il

CH ₃ ^ 0 0

whose analytical characteristics were as followsί

Gross formula: ^C 19 ^H 26 ° 6

Molecular weight 350.4

Τ £: 80 to 81 ⁰ C

Elemental analysis: in agreement

Thin-layer chromatography:

! Embossers! Silica

Solvent: ethyl acetate / petroleum ether 25/75

Development: UV and iodine

Rf value: 0.7

Infrared spectrum: KBr lozenges, absorption bands (y cm "): 3 O5O (Cl ^ aromatic), 2,800 to 3,000 (Cl ^ iliphatic), 1,720

409817/1139

(C = O ester), 1,690 (G = O ketone), 1,590 (C = C aromatic).

Example 4 Phenyl urethane of tert-butyl carbonyl-g-cyclopropyloarbinol

1 mol of the keto alcohol obtained according to Example 1 and 1 mole of phenyl isocyanate were heated in a solution of ligroin (100 to 140 ⁰ C) for 1 hour at reflux temperature. The crystals formed were collected by filtration and recrystallized from benzene. The yield was quantitative. The process product obtained had the formula

CH ₀ - 0 - C- - NH- <P \

² I.

and had the following analytical characteristics on the gross formula: C ₁₆ H ₂₁ O ^ N ■.

Molecular weight: 275 _f 34:

Tp: 108 ^° C
Elemental analysis in accordance

Infrared spectrum (v cm " ¹ ): 3,320 (NH), 1,730 (C = O urethane), 1,685 (C = O ketone).

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Nuclear Magnetic Resonance Spectrum (S in ppm): 1 (cyclopropane-methylene), 1.2 (singlet of the methyl groups), 1.6 (signal of the cyclopropane-CH), 2.2 (signal of the CH in oc-position to CO) , 4 and 4.15 (doublet of extracyclic methylene), 7 to 7.4 (aromatic protons and those of NH) *

Example 5 Carbamate of tert-butylcarbonyl-2-cyclopropylcarbinol

To a toluene solution containing a slight excess of phosgene, was dropwise a solution of 1 mol of the keto alcohol obtained in Example 1 and 1 mol of dimethylaniline in added to anhydrous benzene. After standing at room temperature for 1 hour, the reaction mixture was poured into the reaction mixture for 30 minutes long introduced ammonia. The dimethylaniline hydrochloride formed was removed by filtration and after customary treatment of the organic phase, the sought product was obtained, that slowly crystallized. The compound obtained had the formula

CH _n - 0 - C - NH ₀

ei It d

and had the following analytical characteristics: Gross formula C ₁₀ H ₁₇ NO,

Molecular weight: 199.2.

409817/1139

T °; 88 ⁰ O -. · = ■■

Infrared spectrum and NMR spectrum: in accordance with, the Structure.

Example 6 Oxime of tert-butylcarbonyl ^ -cyclopropyl-carbinol

The keto alcohol obtained according to Example 1 was in alcoholic Solution with an excess of hydroxylamine hydrochloride treated in the presence of pyridine. The product obtained had the following formula

CH ₃ - C - C - t - - ^ CH ₂ OH

OH S ^N

^GH 3 I -OH

and had the following analytical characteristics: Gross formula: C ₀ H ₄

Molecular Weight: 171.2 Tp: 105 ^° C

Elemental analysis in accordance with the infrared spectrum in accordance with the structure «

4 0 9 8 17/1139

Claims (9)

Claims where mean: X is a carboxy or unsubstituted carbamoyl radical, or a carbamoyl radical which is N-mono- or disubstituted is with an alkyl or carbamide radical, or a cyano, formyl, hydroxymethyl, alkyl-substituted hydroxymethyl or aminomethyl radical, or a carbamoyloxymethyl radical which is N-mono- or disubstituted is with a radical R or a carbamoyl radical, or an R-oxymethyl or acyloxymethyl radical, R ₁ , R ₂ , R, and R, which can be the same or different. Hydrogen atoms, short-chain alkyl radicals, short-chain alkenyl radicals, short-chain alkynyl radicals, phenyl radicals or mono-, di- or tricyclic aromatic radicals with 5 or 6 chain links and 0 to 4 heteroatoms, and 409817/1139 R !, RX and Ri, which can be the same or different, Hydrogen atoms or short-chain alkyl radicals, as well as the esters and salts of the specified acids and alcohols and the oximes of the ketones. 2. Cyclopropanes according to claim 1, characterized in that the esters of the acids and alcohols of the formula I are formed by the action of an alcohol or an acid, which have a branched or straight-chain aliphatic structure. 3. Cyclopropanes according to Claim 1, characterized in that the esters of the acids and alcohols of the formula I are acted upon of an alcohol or an acid which have a substituted or unsubstituted aromatic structure exhibit. 4. Cyclopropanes according to claim 1, characterized in that they consist of tert-butylcarbonyl-2-cyclopropylcarbinol, tert-butylcarbonyl-2-cyclopropyltrimethoxybenzoate, the phenyl urethane of tert-butylcarbonyl-2-cyclopropylcarbinol, - ■ '■ - "> * ■■ the carbamate of tert-butylcarbonyl-2-cyclopropylcarbinol or -.-. ■■
the oxime of tert-butylcarbonyl-2-cyclopropylearbinol 5. A process for the preparation of cyclopropanes ^ according to claims 1 to 4, of the formula I " 817/11 39 7351729 C - σ / T J ¹ Η ₂ Λ H _n . χ] ⁵ (ι) where mean: X is a carboxy or unsubstituted carbamoyl radical, or a carbamoyl radical which is N-mono- or disubstituted with an alkyl or carbamide radical, or a cyano, formyl, hydroxymethyl, alkyl substituted one Hydroxymethyl or aminomethyl radical, or a carbamoyloxymethyl radical which is N-mono- or disubstituted is with a radical R or a carbamoyl radical, or an R-oxymethyl or acyloxymethyl radical, R .., R_, R ^ and R, which can be the same or different, Hydrogen atoms, short-chain alkyl groups, short-chain alkenyl groups, short-chain alkynyl groups, phenyl groups or mono-, di- or tricyclic aromatic radicals with 5 or 6 chain links and 0 bis 4 heteroatoms, and Ri, RI and Ri, which can be the same or different, Hydrogen atoms or short-chain alkyl radicals, as well as the esters and salts of the specified acids and alcohols and the oximes of ketonesj characterized in that a ketone under conditions such that it is a carb 409817/1139 anion of formula II forms -C-C * (II) I I O R with an epichlorohydrin derivative of the formula III ^H 3? 4 Cl - GH -? (III) R ' reacted, where R ₁ , Rp »R ^ f RIf RA u ^ d ^ o in the formulas II and III have the same meaning as in. Formula I and R ^ is a hydrogen atom or an alkyl radical, and then the alcohol function of the keto alcohol obtained in in a conventional manner to give further compounds of the formula I. . 6. The method according to claim 5, characterized in that one the carbon atom in OL position to the ketone into a carbanion converted with the help of a sodium-containing agent from sodium amide, sodium hydride or sodium tert-^ butoxide in one suitable solvent. 7. The method according to claim 6, characterized in that one as solvent hexamethylphosphotriamine, dimethylsulf- " oxide, tetrahydrofuran or an aromatic hydrocarbon is used. -4098 17/1139 8. The method according to claims 5 to 7, characterized in that pinacolone in the presence of sodium amide in Hexamethylphosphotriamine with epichlorohydrin to give tert-butylcarbonyl-2-cyclopropylcarbinol the formula CH, C - C £ - ^ CH ₀ OH ³ / Il ² implements. 9. The method according to claims 5 to 7, characterized in that one tert-butylcarbonyl-2-cyclopropanoic acid, tert-butylcarbonyl-2-cyclopropyl-trimethoxybenzoate, the phenyl urethane of tert-butylcarbonyl-2-cyclopropylcarbinol, the Carbamate of tert-butylcarbonyl-2-cyclopropylcarbinol or produces the oxime of tert-butylcarbonyl-2-cyclopropylcarbinol. 4098 17/1 139