CS209056B1 - Process for preparing a novel compound 2- (3-chloropropyl) -4-pentenal - Google Patents

Abstract

2-Allyl-5-chloropentanal of formula I is an important intermediate in the synthesis of some drugs. It is prepared from 4-pentenal imines of general formula II, in which Rj1 and R2 denote alkyl with 1 or 2 carbon atoms, or R1 and R2 together denote a tetramethylene or pentamethylene chain, by alkylation with 1-bromo-3-chloropropane of formula III in tetrahydrofuran at temperatures below -50 °C in the presence of strong bases such as lithium diethylamide, lithium diisopropylamide, lithium isopropylcyclohexylamide or lithium dicyclohexylamide.

Description

2-Allyl-5-chloropentanal of formula I

CHO

C1-CH ₂ -CH ₂ -CH ₂ -CH-CH ₂ -CH = CH ₂ (I), is an important intermediate in the synthesis of some drugs.

Prepared from 4-pentenal imines of formula II, R ¹

CH ₂ = CH-CH ₂ -CH ₂ -CH = N-CH <), (II) _______________________________- - - ------------------ R @ ^2!

-. J in which R ¹¹ (R ² denotes alkyl having 1 or 2 carbon atoms, or R ¹ and R ² together denote a tetramethylene or pentamethylene chain, by alkylation 1) with bromo-3-chloropropane of formula III

Br-CH ₂ -CH ₂ -CH ₂ -C 1 (clay) in tetrahydrofuran at temperatures lower than -50 ° C in the presence of strong bases such as lithium diethylamidp, tithium-dusopropylamidu, lithium isopropyl209056

The present invention relates to a process for the preparation of the novel 2- (3-chloropropyl) -4-pentenal compound of formula I

CHO

AND

Cl-CH ₂ -CH ₂ -CH ₂ -CH-CH ₂ -CH = CH ₂ (I),

This compound is an important intermediate in the manufacture of some drugs. It is produced by the process according to the invention, which is characterized in that the imines of the 4-pentenal of the general formula II / ^R1

CH ₂ = CH-CH ₂ -CH ₂ -CH-N-CH <(II), ^X R ² wherein R ¹ and R ² denote alkyl I -or 2 carbon atoms, or R ¹ and R ² together denote tetramethylene or pentamethylene chain, alkylated with 1-bromo-3-chloropropane of formula III

Br - CH _{2 -} CH _{2 -} CH _{2 -} Cl (III), used in stoichiometric amounts or in excess of 5 to 10% by weight, in the presence of strong bases, in particular lithium dialkylamides, for example lithium diethylamide, rithium diisopropylamide, lithium dicyclohexylamide or lithium isopropylcyclohexylamide, in anhydrous tetrahydrofuran, at temperatures below -50 ° C, preferably at a temperature of a cooling mixture of acetone or methanol and solid carbon dioxide, in an atmosphere of an inert gas such as nitrogen.

Alternatively, the aldehyde of formula (I) may be prepared by alkylation in the presence of lithium diethylamide in a mixture of tris (dimethylamide) phosphoric acid (HMPA), benzene and tetrahydrofuran. The disadvantage of this procedure is the need to use expensive HMPA.

Further details of the process according to the invention can be seen from the following examples.

Example 1

A solution of lithium diisopropylamide (0.644 mol), prepared from diisopropylamide (65.17 g, 0.644 mol), n-butyllithium (2.65 M) in hexane (2.65 M) and literature (600 ml) of absolute tetrahydrofuran in a known manner, is cooled under nitrogen to - 78 ° C. With stirring, then a solution W4,0 g (0.629 mol) of N- (4-pentenyliden) cyclohexylamine [II, R ¹ + R ² = CH ₂ (CH _{2) 3} CH _2] in 100 ml of absolute tetrahydrofuran within 30 minutes . After stirring for 30 minutes, 107.06 g (0.680 mol) of 1-bromo-3-chloropropane (III) was added dropwise over 35 minutes, and the mixture was further stirred

2.5 h at -78 ° C. The reaction mixture is allowed to warm to room temperature over 4.5 h with stirring, and is stirred for 3 h, then poured into a mixture of 111 ml of concentrated hydrochloric acid and 850 ml of water over 10 minutes with stirring. After stirring for 15 h, the organic phase was separated and the aqueous phase was extracted with ether (2 x 200 mL). The combined organic phases are washed with 250 ml of a 3% hydrochloric acid solution, 250 ml of water and 250 ml of brine and, after drying over anhydrous sodium sulfate, are evaporated on a rotary evaporator. The residue was distilled in an oil pump vacuum. 78.8 g (78.0%) of 2- (3-chloropropyl) -4-pentenal (I) are obtained. The heat (boiling) lies in the range of 67 to 69 ° C / 130 Pa.

To a solution of lithium isopropylcyclohexylamide (0.31 mol) in absolute tetrahydrofuran (300 ml) was added _; at -75 ° C under nitrogen was added dropwise over 30 minutes a solution of I, 37.56 g (0.3 mol) of N- (4-pentenyl ylidene) -2-propylamine hydrochloride (II, R = R ² = CH ₃₎ 35 ml of absolute tetrahydrofuran. After stirring for 45 minutes, 51.95 g (0.33 mol) of 1-bromo-3-chloropropane (ΠΙ) was added dropwise over 25 minutes. The reaction mixture j is stirred under cooling for 2 h, allowed to warm to rt; at room temperature over 3.5 h, stirred for an additional 4 h and then poured into 410 ml of a 5% hydrochloric acid solution with stirring. After stirring for 13 h, the organic phase is separated and the aqueous phase is extracted with 150 ml of ether. The combined organic phases were washed with 150 ml of 3% hydrochloric acid, 2 X 100 ml of water and dried over anhydrous magnesium sulfate. After evaporation in a water pump vacuum, the residue is distilled under reduced pressure. 32.9 g (68.3%) of 2- (3-chloropropyl) -4-pentenal (I) are obtained, b.p.

i Example 3

Using the procedure described in Example 2, from 0.5 mol of lithium dicyclohexylamide, 75.1 g (0.49 mol) of N - (4-pentenylidene) -3-pentylamine (ΙΪ, R ^{1 =} R ² = = CH ₂₎ . CH ₃ ) and 81.9 g (0.52 mol) of 1-bromo-3-chloropropane (ΙΠ) gave 48.4 g (61.5%) of 2- (3-chloropropyl) -4-pentenal (I) with boiling point 64-65 ° C at 93 Pa.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of the novel 2- (3-chloropropyl) -4-pentenal of formula (I), characterized in that the imines of the 4-pentenal of formula (II) CHO C1-CH ₂ -CH ₂ -CH ₂ -CH = CH ₂ -CH = CH ₂ CH = CH-CH ₂ -CH ₂ -CH-N-CH? R ¹ (I) AR2 (Π), j wherein R ¹ and R ² denote alkyl having 1 or 2 carbon atoms, or R ¹ and R ² together denote a tetramethylene or pentamethylene chain, alkylate with 1-bromo-3-chloipropane of formula III Br-CH ₂ -CH ₂ -CH ₂ -Cl (III) and i; used in a stoichiometric amount or in an excess of 5-10% by weight, in the presence of strong bases, in particular lithium dialkylamides, for example lithium diethylamide, lithium diisopropylamide, lithium dicyclahexylamide or lithium isopropylcyclohexylamide, in anhydrous tetrahydrofuran, at temperatures below -50 ° C preferably at the temperature of the cooling mixture of acetone or methanol and solid carbon dioxide, in an atmosphere of an inert gas such as nitrogen.