HU176607B - Process for producing compounds of optical activity - Google Patents

Abstract

1460781 Reduction SNAMPROGETTI SpA 9 April 1974 [13 April 1973] 15781/74 Headings C2C and C2P The invention comprises a process for converting by hydrogen transfer a prochiral or racemic starting material to an optically active product, which process comprises reacting the starting material with an alane selected from (a) optically active aminoalanes having the two following general formulae and and (b) optically active polyiminoalanes having in their molecule a group having the general formula wherein X is a hydrogen, chlorine or bromine atom or a group of the formula -NR<SP>3</SP> 2 or -OR<SP>3</SP>, n is an integer having a value greater than 4, each of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP>, which can be the same or different, is an alkyl, aryl, alkaryl, aralkyl or cycloalkyl radical, or R<SP>1</SP> and R<SP>2</SP> together represent a divalent alkylene radical and with the nitrogen atom to which they are attached form a hetero ring; with the proviso that in the alane at least one radical attached to the nitrogen atom(s) contains at least one asymmetric centre, and with the proviso that in the polyiminoalane there is for each aluminium atom, at least one direct Al-N bond and in the polyiminoalane there is at least one Al-H bond. Examples describe the preparation of α- methyl benzyl alcohol; but-2-yl-n-butylamine; 3 - methyl - 1 - phenyl - 1 - phosphacyclopent- 3-ene and 1,2-dimethyl-n-butylamine.

Description

The present invention relates to a process for the preparation of optically active compounds, namely alcohols, N-substituted amines, amines and trialkylphosphine compounds, by reduction of the corresponding prochiral or racemic compounds using monomeric aminoalanes or polymeric iminoalanes. These compounds are useful in the synthesis of various organic compounds.

Optically active compounds, for example in the synthesis of alcohols, amines, are of increasing technological and economic importance in the preparation of the final product in high sterile purity. In recent years, the synthesis of optically active compounds by direct synthesis has become more and more important than the partial or total synthesis of natural materials, so that the separation of the optical antipode is no longer necessary.

Until now, the optically pure product has been obtained by enzymatic or microbiological asymmetric synthesis, but the use of this technology in many processes, especially in continuous processes, is very problematic.

Thus, prochiral compounds such as ketones, imines, or racemic compounds, e.g. epoxides, trialkylphosphinoxides, asymmetric hydrogenation with optically active complex metal hydrides - for the preparation of optically active alcohols, amines.

To date, the direct or indirect reduction of the above compounds with hydrides has been restricted to the III of the periodic table. is carried out in the presence of optically active alcohol in the hydrogen transfer reaction of aluminum and lithium hydride.

In general, the reaction proceeds with the formation of alkoxide hydrides of the above metals.

The optical efficiency of the reaction is very low and due to the poor solubility of the reagents, it can only be carried out under very stringent reaction conditions.

According to the literature, the highest level of optical activity is 45-50%.

The degree of optical activity was calculated from the following ratio:

[a] measured --100 15 [a] max

It has been found that the asymmetric hydrogen transfer reaction from aluminum hydride can be carried out with greater optical efficiency by employing the following optically active aminoalanes and polyiminoalanes instead of optically active aluminum alkoxy hydrides containing an asymmetric alkoxy group: (HAlNR) _n and HjAlNRjRj.

In the general formula R, R 1 and R _{2 are C} 1-4 alkyl, phenyl or phenyl (C 1-4) alkyl, n is an integer greater than 4, the compound has at least one direct P 1 -N and It contains an Al-H bond per aluminum atom and the third substituent attached to the aluminum may be hydrogen or -N (R ₂ ) ₂ ; the asymmetry center is represented by a primary or secondary amino group having at least one optically active alkyl group.

In the presence of the above compounds, asymmetric hydrogenation, the prochiral ketones, imines, N-substituted imines, oximes or racemic trialkylphosphine oxides can be converted very effectively to the corresponding reduced and optically active product.

The degree of optical activity reaches 85%.

The good solubility of the aluminum compounds used in the present invention in many solvents, even at low temperatures, allows them to be used under conditions where AlH ₃ and LiAlH ₄ or other hydrides no longer yield good results.

Amino- and iminoalanes are prepared from an optically active primary or secondary amine by reaction with -AlH ₃ D or LiAlH ₄ .

The reaction proceeds as follows:

'H R *'

I I

.D @ 1 H 1 + R * ₃ NH ₂ - * S-Al-N-J-2 D _p + ₂ h

2. LiAlH ₄ + RR * NH.HCl - * RR * N-AlH ₂ -f-LiCl | -H ₂

3. A1H ₃ .D + RR * NH -r * rn — Aih ₂ + d + h ₂

4. A1H ₂ XD | RR * NH-R * RN — Aihx + d + h ₂ (X = C1, Br)

5. AlH ₃ .Df-2 RR * NH - * RR * N-A1H-NRR * 4-D-

-2H ₂ (D = Lewis base: (CH ₃ ) ₃ N, (C ₂ H ₅ ) ₃ N, etc.)

Examples of the amine include: bomylamine, sec.butylamine, phenethylamine, menthylamine and any primary amine having an optically active substituent; or any secondary amine having at least one optically active substituent such as N-methylphenethylamine, pipecoline, deoxyephedrine, O-methylephedrine and the other substituent being chiral or acrylic. Exemplary alanes prepared as above are compounds of formulas I, II, III, IV, V, VI, VII.

These chemical compounds can be used in the reduction of prochiral substances such as ketones, imines and oximes in various solvents at temperatures ranging from 4 to 50 ° C to -100 ° C. The temperature used is chosen depending on the nature of the solvent and the starting compound. Depending on the above factors, the asymmetric induction value can reach 85%.

The reaction scheme is illustrated in Schemes 1, 2, 3 and 4.

In the reaction scheme (Al-H *) = optically active diacylaminoalane or polyiminoalane.

After the reaction, the asymmetric amine can be almost completely recovered without significant racemization. This fact excludes the possibility of hydrogen transfer from the asymmetric carbon atom if the amine has the following structure:

C * / X H R '

Through the use of amino-alans, it is possible to use wide temperature ranges and different solvents - for asymmetric hydrogenation. In addition, the optical activity of the resulting product is much higher than that of the prior art metal hydrides. In addition, it is possible to recover the optical induction compound almost completely.

Example 1

A solution of 0.215 mol of acetophenone in 100 ml of ether was slowly added dropwise to a solution of 0.11 mol of N-methylphenethylaminoalane in 600 ml of ether, which was previously cooled to 0 ° C. After 4 hours, the solution was hydrolyzed with water and ice with a pH of 4. The pH was adjusted with HCl.

The aqueous phase was extracted with ether (3 x 100 mL) to remove the organic phase. The extracts were combined and concentrated to a small volume.

The residual oil was treated with semicarbazide, HCl and sodium acetate in a 1: 4 mixture of water and ethanol at 60 ° C.

The mixture was diluted with a large amount of water and cooled to 0 ° C. Unreacted acetophenone as a semicarbazone was removed by filtration.

The clear solution is extracted with 100 ml of ether in four flavors. The combined extracts were dried over Na 2 SO 4 and the solvent was evaporated.

The residue was evaporated in vacuo (0.1-0.15 mm Hg) to afford 23.6 g of phenylmethylcarbinol.

Yield: 90% [j _Roerig ²³ D = -5.5 °.

Optical activity: 12.5%.

The aqueous hydrolysis mother liquor was made basic, extracted with ether and treated with HCl gas. 19.1 g of N-methylphenethylamine hydrochloride are obtained.

Yield: 93%; [ _.alpha. ] D @ ₂₀ = -29.9 DEG (EtOH, C-5).

The amine hydrochloride was used in the synthesis of dialkylaminoalane with a specific rotation: species -30.0 ° (EtOH, C-5).

Example 2

The procedure of Example 1 is followed. Acetophenone and N-methylphenethylaminoalane are reacted in a 2: 1 ratio at -73 ° C in ethyl ether.

Phenylmethylcarbinol is thus obtained in a yield of 57.5%. Specific rotation.

[ «^ -37.2 °.

Optical activity: 85%.

Example 3

The procedure of Example 1 is followed. Acetophenone and N-methylphenyl ethyl amide are reacted 2; 1 ratio at 0 ° C in toluene medium.

. Phenyl-m-tSrcarbinol was prepared in 88% yield. Specific optical rotation image; Merafct® “12.04 °; optical activity was 27.4%.

Example 4

Example 1 was followed. Acetophenone and N-methylphenethylamine are reacted in a 2: 1 ratio at -70 ° C in toluene medium.

Phenylmethylcarbinol was prepared in 63.5% yield. Specific optical rotation: [litter ⁼ = -32.6 °; optical activity: 74%.

Example 5 At -70 DEG C., 11.4 g of N- (n-butyl) imino-2-butanol are added to a solution of 16.3 g of N-methylphenethylaminoalane in ethyl ether.

After the reaction was complete, the mixture was hydrolyzed with ice-cooled alkali. The ether fraction was separated and the aqueous phase was extracted three times with ether. The ether extracts were combined and dried over Na ₂ SO ₄ and evaporated in vacuo.

Secondary butylamine is recovered from the residual oil by fractionation at 12 mm Hg. Yield 40-45%. Specific rotation: [litter + 2.9 °; optical activity: 22.5%.

Example 6

The procedure of Example 1 is followed. Acetophenone and (+) pipecolinoalane were reacted in a 2: 1 ratio at -70 ° C in tetrahydrofuran.

Following a phenylmethyl carbinol in 60% yield: [a] D -9.8 ° _measured; optical activity: 22.5%.

methylmethylphenethylamine was recovered (boiling point 0.1 = 48 ° C; yield 70-75%, optical purity = 98%).

The product is obtained as 3-methyl-1-phenyl-1-phospho-3-cyclopentene (Formula IX). Yield: 55-60%; [a] ohm ⁼ 5 = + 6.78 °.

The maximum specific rotation of the phosphine compound is unknown.

Example 9

13.2 g (0.115 mol) of i-butylmethyl ketoxime are added very slowly (1 hour 30 minutes) to a solution of 20.8 g (0.13 ml) of N-methylphenethylamine alanine in 250 ml of ether. DEG.

The solution is then refluxed for three hours. It is then hydrolysed with ice and the solution is made alkaline.

It is then extracted three times with 100 ml of ether.

The extracts were combined, dried over KOH and evaporated.

The residue was distilled at 15 mm Hg. The different fractions were analyzed by GLC.

Iso-butyl-methyl-amine in 50% yield nyer25 needles, [ag> ³ _meter -θ = 63 °.

(Theoretical: -10.7 °, optical activity = = 5.9%.) N-methylphenethylamine as chlorohydrate was recovered from the distillation residue in 90% yield.

The recovered amine had an optical purity of 98% relative to the starting material.

All optical rotations were measured on undiluted, clean specimens.

Example 7

The procedure described in Example 1 was followed. Acetophenone and poly [(-) phenethyl] iminoalane are reacted at 0 ° C in ethyl ether. Phenylmethylcarbinol was prepared in 80% yield, [alpha] + 4.42 °; optical activity: 14.4%.

Example 8

A solution of 0.31 mol of N-methylphenethylaminoalane in benzene is stirred at 25 ° C in a benzene solution of 3-methyl-1-phenyl-1-phospho-3-cyclopentene-1-oxide (Formula VIII).

After the addition was complete, the mixture was stirred at room temperature for three hours. It is then hydrolysed with ice and alkali. The benzene phase was extracted and dried over KOH and evaporated under reduced pressure.

Claims (1)

A method of optically active compounds selected from alcohols, substituted amines, amines and trialkilfoszfinok preparing hydrogen transfer asymmetric reaction, characterized in that the corresponding prochiral or racemic ketones, N-substituted imines, imines or tríalkilfoszfinoxidokat optically active, _H2 AINRjR _2; HAI (NR J R K _{2) 2} H (AlNR) n or aminoalánnal poliiminoalánnal formula - R, wherein R and _R2 are C1-4 alkyl, phenyl or phenyl (Cl-C4) alkyl, n is an integer greater than 4, the compound contains at least one direct bond A1-N and A1-H per aluminum atom, and the third substituent attached to aluminum is hydrogen or N (R2) _2, and the asymmetric center is the primary or secondary amine. a group having at least one optically active alkyl group at a temperature of -100 to +50 ° C.