CN1014885B - Asymmetric synthesis of optically active alpha substituted benzylamine - Google Patents

Asymmetric synthesis of optically active alpha substituted benzylamine

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CN1014885B
CN1014885B CN 88105925 CN88105925A CN1014885B CN 1014885 B CN1014885 B CN 1014885B CN 88105925 CN88105925 CN 88105925 CN 88105925 A CN88105925 A CN 88105925A CN 1014885 B CN1014885 B CN 1014885B
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pinanone
hydroxyl
imines
benzyl
solution
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CN1039582A (en
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陈元伟
密爱巧
肖
蒋跃忠
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Chengdu Institute of Organic Chemistry of CAS
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Chengdu Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to an alpha-substituted benzylamine asymmetric synthesis method which uses 2-hydroxy-pinanone-3 as a chiral source to be condensed with benzylamine to obtain hydroxy pinanone imine as a chiral template which then reacts with hydroxylamine after deprotonation and asymmetric alkylation to obtain optically active alpha-substituted benzylamine. The product has the optical yield of 93.9 to 99.9% and the chemical yield of 31.1 to 54.6%. Simultaneously, the 2-hydroxy-pinanone-3 can be obtained in the form of oxime and can be recovered by the prior art for repeated use.

Description

Asymmetric synthesis of optically active alpha substituted benzylamine
The present invention relates to the method for asymmetric synthesis of optical activity α-Qu Daibianan, belong to technical field of organic synthesis.
The optically active amines compounds is the important compound of a class in the organic chemistry, and it is widely used as the chiral separation agent, splits organic acid.And it is the important intermediate of organic synthesis industry, medicine industry, perfume industry etc.
In the past, people generally obtain optically active amines (5783 pages of " JACS " nineteen fifty-ones) by resolving racemic, but Split Method is time-consuming, trivial operations, and yield is low, will cause the cost height with a large amount of chiral separation agent simultaneously.Closely during the last ten years, people seek the optically active amines compounds that a kind of method of asymmetric synthesis synthesizes a kind of single configuration in attempt.1977 Germany scientist Huo Na (Horner) etc. reported with a series of chiral quaternary ammonium salts in " Libiee's tin chemistry annual report " 1365 pages and induce the electrochemical reduction schiff alkali to prepare optically active amines, its optical yields 0～12.8%.Another is that Ha Qilisi (Hutchins) etc. has reported employing chiral hydride reagent reduction diphenylphosphine imide [R at the U.S.'s " organic chemistry magazine " 702 pages in 1987 than successful method 1R 2C=N-OP(C 6H 5) 2], obtaining optical yields through acid hydrolysis again is 1～100% optically active amines.Though the reduction method of Ha Qilisi has all obtained the higher product of some optical purities, prepares different amine, will be with different substrates (diphenylphosphine imide).They prepare complicated; Simultaneously, the stereoselectivity difference of different substrates is also bigger.1987, Jiang Yuezhong etc. are chiral template with (+)-camphor and benzylamine condensation product camphorphorone imines for 1545 pages at " synthesising communication " (Synth Commu), have synthesized the optical activity α-Qu Daibianan of 0～90% optical yields.This method is simple to operate than reduction method, utilize same chiral template (reaction substrate just),, just can obtain different α-Qu Daibianan by the different alkylating reagent of conversion, but this chiral template is along with the difference of alkylating reagent, and stereoselective difference is also bigger.Some group, as cyclohexyl, optical yields only is 29%, methyl then optical yields is almost nil.Optical purity (-)-camphor is difficult to obtain simultaneously, just is difficult to synthesize (S)-α-Qu Daibianan.
Synthetic optical activity α-Qu Daibianan of the present invention, optical yields are up to 93.9～99.9%, and optical yields is not different and different with alkylating reagent.Save time than traditional Split Method, simple to operate.
The objective of the invention is to adopt (+)-or (-)-2-hydroxyl pinanone-3(be designated hereinafter simply as the hydroxyl pinanone) with the condensation product of benzylamine, N-benzyl-2-hydroxyl pinanone-3-imines (hereinafter to be referred as hydroxyl pinanone imines) is a chiral template, by asymmetric alkylation reaction, highly selective synthesis of optically active α-Qu Daibianan.
The object of the present invention is achieved like this: the condensation product hydroxyl pinanone imines with hydroxyl pinanone and benzylamine is a chiral template, again through deprotonation, asymmetric alkylation, gets the optical activity α-Qu Daibianan with azanol reaction, and its reaction formula is:
(seeing page 5 figure below)
Wherein: X=chlorine, bromine, iodine;
The aliphatic alkyl of R '=1～6 carbon, methoxyl group, chlorine, bromine, iodine, hydroxyl, nitro;
The aliphatic alkyl of R=1～6 carbon, cyclohexyl, cyclopentyl, benzyl, the meta-methoxy benzyl, to methoxy-benzyl, 3,4-dimethoxy-benzyl etc.
More than Fan Ying concrete implementation step was made up of following three steps:
(1) in reaction flask, add (+) or (-)-hydroxyl pinanone, benzylamine, its mol ratio is 1: 1～3, add boron trifluoride ether solution (1～5ml/mol hydroxyl pinanone) and solution (benzene or toluene again, 3A or 5A molecular sieve drying, 1500～3000ml/mol hydroxyl pinanone).Load onto the Cope water trap, use nitrogen protection, temperature rising reflux 7～16 hours, rotary evaporation desolvates, and underpressure distillation gets little yellow liquid hydroxyl pinanone imines.
(2) tetrahydrofuran solution of adding hydroxyl pinanone imines in the long-neck reaction flask; the dry ice bath is cooled to-78 ℃; nitrogen protection; stir and add butyllithium hexane solution (2-4mol/mol hydroxyl pinanone imines) down; stirred 0.5～6 hour down at-78 ℃; the tetrahydrofuran solution (1-4mol/mol hydroxyl pinanone imines) that adds haloalkane then; stirred 10～100 hours at-78 ℃ then, reaction is controlled (developping agent: vinyl acetic monomer and sherwood oil volume ratio are 1: 2～10) with thin-layer chromatography.After finishing, reaction adds saturated aqueous ammonium chloride, rise to room temperature, reaction solution benzene extraction 4 times, extracting solution washs anhydrous magnesium sulfate drying, filtration, pressure reducing and steaming solvent three times through saturated and salt solution, get light yellow oil, separate the alkylate that (silica gel H, 10～40 μ are sorbent material, developping agent: vinyl acetic monomer and sherwood oil volume ratio are 1: 2～10) obtains hydroxyl pinanone imines through column chromatography again.
(3) alkylate and acetic acid azanol ethanol solution (mol ratio 1: 1～4) are mixed, after stirring 3～15 hours under 10～40 ℃, rotary evaporation desolventize light yellow mixture, be dissolved in benzene again, use saturated sodium bicarbonate aqueous solution, saturated aqueous common salt respectively washs three times, with anhydrous magnesium sulfate drying, refilter, pressure reducing and steaming benzene gets light yellow oily liquid.Add 5% hydrochloric acid, stir 0.5～5 hour salify after, with ether extraction 3～5 times, the ether layer is through the saturated common salt water washing, ether is removed in anhydrous magnesium sulfate drying, filtration, the white solid oxime.Water layer is with 5～20%.Wet chemical is neutralized to pH=8～11, and with ether extraction repeatedly, solvent is filtered, boiled off to the saturated common salt water washing of ether layer, at anhydrous magnesium sulfate drying, faint yellow residual being coated with, through underpressure distillation, optical activity α-Qu Daibianan colourless liquid.
Compare with existing method, the present invention has following characteristics:
1. the optical yields of synthetic optical activity α-Qu Daibianan is up to 93.9～99.9%, and optical yields is different and different along with alkylating reagent.Total chemical yield 31.1～54.6%.Save time than traditional Split Method, simple to operate, cost is low.
2. adopt same chiral template (substrate), select different alkylating reagents for use, just can get different α-Qu Daibianan.
3. chiral source-hydroxyl the pinanone of this invention employing is to be got by the α-Pai Xi oxidation.And α-Pai Xi has abundant natural resource in China.Simultaneously, the hydroxyl pinanone can also obtain with the form of oxime after using, and adopts prior art to reclaim through the titanous chloride effect.And adopt the not chiral source of isomorphism type, just can obtain the not α-Qu Daibianan of isomorphism type.
The present invention is further described below in conjunction with embodiment.
1.(+)-N-benzyl-2-hydroxyl pinanone-3-imines and (-)-N-benzyl-2-hydroxyl pinanone-3-imines is synthetic:
In the 250ml reaction flask, add 17.1g benzylamine (0.16mol), 13.4g(-)-and hydroxyl pinanone (0.08mol), 170ml benzene and 0.3ml boron trifluoride ether solution are loaded onto the Cope water trap and the spherical condensation tube that are placed with a little molecular sieve, with N 2Protection is backflow 12hr down, boils off benzene solvent, and underpressure distillation gets 15.2g(+)-hydroxyl pinanone imines, be light yellow oil, productive rate 74%, b.p134～136 ℃/0.15mmHg.[α] 25 D=+1.4(C, 2,0, ETOH) V Max1650,695,730,3430,3560Cm -1; δ H: 0.85(3H, S), 1.33,1.52(6H, 2S), 1.6～2.55(7H, m) 4.47(2H, S) 7.20～7.35(5H, m) ppm; M/z:258(M ++ 1)
(-)-N-benzyl-2-hydroxyl pinanone-3-imines can obtain with (+)-hydroxyl pinanone such as above-mentioned working method.Productive rate 77%, b.p134～136 ℃/0.15mmHg[α] 25 D=-1.7(C, 1.8, EtOH), v Max695,730,1650,3430,3560m -1δ H: 0.85(3H, S), 1.35,1.62(6H, 2S), 165～2.65(7H, m) 4.25(2H, S) 7.20～7.35(5H, m) ppm; M/z:258(M ++ 1)
2.(R)-(+)-α)-methylbenzylamine synthetic:
In 50 milliliters dry round-bottomed flask; add 1.54g(+)-hydroxyl pinanone imines (6mmol) and 10ml tetrahydrofuran (THF); under nitrogen protection, be cooled to-78 ℃; dripping 9ml butyllithium hexane solution (12mmol) then stirred after 4 hours; the solution that adds 2ml methyl iodide and 5ml tetrahydrofuran (THF); stir 10 hours (with thin-layer chromatography detection reaction terminal point, developping agent: the volume ratio of sherwood oil and vinyl acetic monomer is 8: 1) down at-78 ℃.Question response finishes, and adding 10ml saturated aqueous ammonium chloride allows it rise to room temperature, and (4 * 10ml) extract, and (4 * 20ml) washings, anhydrous magnesium sulfate drying filters the extracting solution of merging, boils off benzene, gets light yellow oil through saturated aqueous common salt with benzene.Separate (eluent: the volume ratio of sherwood oil and vinyl acetic monomer is 8: 1) with column chromatography, get the 0.92g alkylate, productive rate 56.5%.v max700，760，1650，3450，3560cm -1，δ H：0.97（3H，S），1.38，1.60（6H，2S），1.45，1.52（3H，d，I＝6H z，2.00～2.65（7H，m），4.46，4.55，4.64，4.80（1H，q，J 1＝J 2＝7H 2）7.25～7.40（5H，m）ppm;m/z;271;
In the 50ml round-bottomed flask, add alkylate (3.4mmol) the 20ml0.5M acetic acid azanol ethanol solution of 0.92g gained, stirring at room 4.5hr.The pressure reducing and steaming solvent adds 50ml benzene and makes the raffinate dissolving, respectively washs three times with saturated sodium bicarbonate, saturated aqueous common salt successively, anhydrous magnesium sulfate drying, filters, boils off benzene, must light yellow oil.
15ml5% hydrochloric acid is added in the oily matter obtain, stirs 2hr, allow its salify, with ether (20 * 6ml) extract, and the ether extracting solution of merging boils off ether through saturated common salt water washing, drying, can reclaim oxime.
Water layer is neutralized to the pH value with 10% solution of potassium carbonate and reaches 8～9, uses ether extraction 8 times.Ether extracted liquid through saturated common salt water washing, drying, boil off ether, weak yellow liquid.50～60 ℃/0.5mmHg fraction is collected in underpressure distillation, gets the 0.2g colourless liquid, is (R)-(+)-Alpha-Methyl benzylamine.Productive rate 48.6%[α] D=28.7(C, 0.5, absolute ethanol), with " JACS " nineteen sixty-five 1757 pages of reports: [α] D=30 ° (C, 2.0, absolute ethanol) relatively gets optical yields is 95.7%.
v max700，765，3300，3370cm -1;δ H：1.42，1.50（3H，d，J＝6H z），4.00，4.08，4.16，4.25（1H，q.J 1＝J 2＝7H z），4.80（2H，S）7.15-7.35（5H，m）ppm;m/z：121。
3.(R)-(-)-α-benzyl benzylamine synthetic:
In the 50ml round-bottomed flask; add 1.03g(+)-hydroxyl pinanone imines (4mm-ol) and 10ml tetrahydrofuran (THF); under the nitrogen protection; stir; be cooled to-78 ℃; drip 9ml butyllithium hexane solution (12mmol), stir the solution that adds 1.4ml benzyl chlorine (12mmol) and 4ml tetrahydrofuran (THF) after 5 hours.React 46 hours (control reaction end with thin-layer chromatography, developping agent: the volume ratio of sherwood oil and vinyl acetic monomer is 7: 1) down at-78 ℃.Reaction finishes, and as above method is handled the back) through column chromatography (eluent: the volume ratio of sherwood oil, vinyl acetic monomer is 8: 1), get the 0.71g alkylate, productive rate 50.8%, v Max695,710,750,755,1635,3350,3400cm -1; δ H; 0.32,1.18(6H, 2S, 1.42(3H, S), 1.70～2.55(7H, m) 3.08,3.17(2H, d, J=6H z), 4.65,4.74,4.83(1H, 1, J=7H z), 7.0～7.40(10H, m) ppm; M/z; 348(M ++ 1).
0.71g alkylate and 20ml0.5M acetic acid azanol ethanol solution, stirring at room 10 hours, as above method is handled.100～110 ℃/0.05mmHg fraction is collected in underpressure distillation, gets the 0.25g colourless liquid, is (R)-(-)-α-benzyl benzylamine, productive rate 60.5%.[α] D=-45.6(C, 1.1, dehydrated alcohol), with " JACS " 2282 pages of reports in 1971: [α] D=-45(C, 2.0, ethanol) compare optical yields＞99.9%.v max＝700，755，3300，3370cm -1;δ H：2.87，2.98（2H，d，J＝8H z），3.40（2H，S），4.05，4.14，4.23（1H，t，J＝7H z）;7.00～7.40（10H，m）ppm;m/z;198（M ++1）。
4.(R)-(+)-α-cyclohexyl benzylamine synthetic:
In the 50ml round-bottomed flask, add 1.03g(+)-hydroxyl pinanone imines (4mmol) and 10ml tetrahydrofuran (THF), nitrogen protection is stirred, and is cooled to-78 ℃, drips 9ml butyllithium hexane solution (12mmol).Stirred 6 hours, and dripped 1.5ml bromocyclohexane (12mmol) and 5ml tetrahydrofuran solution, react 46 hours, get 0.87g alkylate productive rate 64.1%, v through aftertreatment Max: 700,760,1650,3450,3570cm -1, δ H: 0.92(3H, S), 1.0～2.6(24H, m) 4.05,4.15(1H, d, J=8H z) 7.15～7.33(5H, m) ppm; M/z, 340(M ++ 1).
0.71g alkylate and 25ml0.5M acetic acid azanol ethanol solution, stirring at room 6 hours.After aftertreatment, 60～65 °/0.1mmHg fraction is collected in underpressure distillation, gets 0.27g(R)-(+)-cyclohexyl benzylamine, productive rate 60.5%, [α] D=+10.7(C, 1.0, benzene).[α] with U.S.'s " organic chemistry magazine " 2309 pages of reports in 1974 D=+9.8 ° (C, 2.0, benzene) compare optical yields＞99.9%, v Max, 700,765,3300,3375cm -1; δ N: 0.70～2.00(13H, m), 3.46,3.55(1H, d, J=7H z) 7.10～7.25(5H, m) ppm; M/:189.
5.(S)-(+)-α-benzyl benzylamine synthetic:
In the 50ml round-bottomed flask, add 1.03g(-)-hydroxyl pinanone imines (4mmol) and 10ml tetrahydrofuran (THF), nitrogen protection is stirred and is cooled to-78 ℃, drips 9ml butyllithium hexane solution (12mmol).Stirred 5 hours, and added 1.4ml benzyl chlorine (12mmol) and 4ml tetrahydrofuran solution, reacted 60 hours down,, get the 0.6g alkylate, productive rate 43% through aftertreatment at-78 ℃.v max：695，705，750，760，1635，3350，3410cm -1，δ H：0.32，1.15（6H，2S），1.47（3H，S），1.65～2.55（7H，m）3.00，3.10（2H，d，J＝6H z）4.63，4.72，4.08（1H，t，J＝7H z）7.02～7.32（10H，m）ppm;m/z，348（M ++1）。
0.5g alkylate and 25ml0.5M acetic acid azanol ethanol solution, stirring at room 9 hours is through aftertreatment.120～125 °/0.07mmHg fraction is collected in underpressure distillation, gets 0.2g(S)-(+)-α-benzyl benzylamine, productive rate 70.4%.[α] D=+46.4 ° (C, 1.2, dehydrated alcohol), with " JACS " 2282 pages of reports in 1971: [α] D=+45(C, 2.1, ethanol) compare optical yields＞99.9%.v max700，765，3300，3370cm -1;δ H;2.90，3.04（2H，d，J＝8H z），4.02，4.12，4.22（1H，t，J＝7H z），5.04（2H，S），7.00～7.30（10H，m）ppm，m/z：198（M+1）。
6.(S)-(-)-α-cyclohexyl benzylamine synthetic:
In the 50ml round-bottomed flask, add 1.03g(-)-hydroxyl pinanone imines (4mmol) and 10ml tetrahydrofuran (THF), nitrogen protection is stirred, and is cooled to-78 ℃, drips 9ml butyllithium hexane solution (12mmol).Stir after 5 hours, drip the 5ml tetrahydrofuran solution of 1.5ml bromocyclohexane (12mmol), reacted 72 hours, get the 0.95g alkylate through aftertreatment, productive rate 69.9%, v Max700,760,1652,3450,3570cm -1; δ H: 0.92(3H, S) 1.0～2.60(24H, m) 4.05,4.15(1H, d, J=8H z), 7.15～7.33(5H, m) ppm; M/z:340(M ++ 1).
0.85g alkylate and 25ml0.5M acetic acid azanol ethanol solution, stirring at room 10 hours.Through aftertreatment, 60～65/0.1mmHg fraction is collected in underpressure distillation, gets 0.37g(S)-(-)-α-cyclohexyl benzylamine, productive rate 78.1%, [α] D=-9.2 ° (C, 2.0, benzene).[α] with U.S.'s " organic chemistry magazine " 2309 pages of reports in 1974 D=-9.8 ° (C, 2.0, benzene) compares to such an extent that optical yields is 93.9%.v max700，765，3310，3380cm -1，δ H：0.70～2.10（13H，m），3.55，3.64（1H，d，J＝7H z），7.20～7.35（5H，m）ppm;m/z：189。
Figure 88105925_IMG3

Claims (3)

1, a kind of method of asymmetric synthesis of the optical activity α-Qu Daibianan to following structural formula,
Figure 88105925_IMG1
The aliphatic alkyl of R=1-6 carbon wherein; cyclohexyl; cyclopentyl; benzyl; the meta-methoxy benzyl; to methoxy-benzyl; 3; 4-dimethoxy-benzyl etc. is characterized in that: (1) adds (+) or (-)-2-hydroxyl pinanone-3 (hereinafter to be referred as the hydroxyl pinanone); benzylamine; mol ratio 1: 1-3; add boron trifluoride ether solution (1～5ml/mol hydroxyl pinanone) and solvent (benzene or toluene again; 1500～3000ml/mol hydroxyl pinanone) loads onto the Cope water trap, under nitrogen protection, refluxed 7～16 hours; boil off solvent; underpressure distillation gets N-benzyl-2-hydroxyl pinanone-3-imines (hereinafter to be referred as hydroxyl pinanone imines), is a kind of little yellow liquid that is, and its structural formula is:
Figure 88105925_IMG2
2, under nitrogen protection, the tetrahydrofuran solution that adds above-mentioned product, be cooled to-78 ℃, add butyllithium hexane solution (2～4mol/mol hydroxyl pinanone imines), stirred 0.5～6 hour, the tetrahydrofuran solution (1～4mol/mol hydroxyl pinanone imines) that adds haloalkane then, stirred 10～100 hours, reaction finishes and rises to room temperature, add saturated aqueous ammonium chloride, use the organic solvent extraction reaction solution, through washing after drying, filtering and boil off solvent, get light yellow oil, after separating, get the alkylate of hydroxyl pinanone imines;
3, (mol ratio is 1: 1-4) mix with alkylate and acetic acid azanol ethanol solution, get light yellow mixture after after stirring 3～15 hours under 10～40 ℃, boiling off solvent, be dissolved in organic solvent after washing, dry, filter, the pressure reducing and steaming solvent gets light yellow oily liquid, add after dilute hydrochloric acid stirs 0.5～5 hour salify, use ether extraction, the ether layer is through washing, dry, filter, remove ether, get the white solid oxime, water layer is neutralized to pH=8～11, uses ether extraction, and the ether layer is through washing, dry, filter, remove desolvate faint yellow raffinate, through distill α-Qu Daibianan.
CN 88105925 1988-07-26 1988-07-26 Asymmetric synthesis of optically active alpha substituted benzylamine Expired CN1014885B (en)

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