CN102126979A - Preparation method of optically pure 3-(carbamoylmethyl)-5-methyl-hexanoic acid - Google Patents
Preparation method of optically pure 3-(carbamoylmethyl)-5-methyl-hexanoic acid Download PDFInfo
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Abstract
The invention discloses a resolution preparation method of optically pure 3-(carbamoylmethyl)-5-methyl-hexanoic acid. The method is as follows: 3-(carbamoylmethyl)-5-methyl-hexanoic acid racemate is used as a raw material, alkamine derivative used as resolving agent is added to react and generate a salt which is not diastereoisomer, the optically pure salt which is not diastereoisomer is obtained through recrystallization, and optically pure R-(-)-3-(carbamoylmethyl)-5-methyl-hexanoic acid can be obtained. The enantioselectivity is more than 99%ee, the yield is stabilized to about 37% by regarding racemate as 100%. The method is characterized in that the solvent used in the resolution process is water, alcohol or ketone which is environmentally friendly.
Description
Technical field:
The present invention relates to the preparation method of key intermediate optical purity (R)-(-)-3-(carboxamide the methyl)-5-methylhexanoic acid of a kind of novel γ-An Jidingsuan (GABA) receptor agonism medicine.
Technical background:
Many compounds with inhibition type neurotransmitter γ-An Jidingsuan (GABA) structure, the pharmacological action that all has analgesia and auxiliary therapy epilepsy, gabapentin 1-(amino methyl)-Cyclohexaneacetic acid for example, particularly its follow-up medicine lyrica (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid is a kind of novel γ-An Jidingsuan (GABA) receptor stimulant, energy blocking voltage dependent calcium channel, reduce the release of neurotransmitter, clinical being mainly used in treated peripheral neuralgia and the epileptic seizures of auxiliary therapy limitation part.So the synthesising process research to lyrica is with a wide range of applications.
Optical purity (R)-(-) 3-(carboxamide methyl)-5-methylhexanoic acid is the key intermediate of synthetic lyrica (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, its structure such as figure one:
General optical purity (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid methods of synthesizing and splitting that adopt that prepare more.
3-(carboxamide the methyl)-5-methylhexanoic acid that discloses use chiral selectors (R)-(+)-α-Ben Yian and racemization in the U.S. Pat 5616793 generates salt, yield 42%, can obtain optically pure (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid through recrystallization, resolving agent dissociation process again, enantioselectivity is greater than 99%.But this method for splitting solvent for use is chloroform and alcoholic acid mixed system, splits 1 kilogram of raceme and needs 11.5 liters of chloroforms, and the volatility of solvent is big, fluctuation of service, and big to human toxicity, environmental pollution is big, and uses the mixed solvent operation also more loaded down with trivial details.
Disclose use 1R among the world patent WO2006122259,2S-(-) ephedrine (salt), norephedrine (salt) generate salt, structure such as figure two with 3-(carboxamide the methyl)-5-methylhexanoic acid of racemization:
The salt of gained passes through recrystallization again, and the resolving agent dissociation process can obtain optically pure (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid, yield 45%-48%, and enantioselectivity is greater than 90%.The toxicity of the used chiral separation agent of this method for splitting ephedrine, norephedrine is big, costs an arm and a leg and is difficult for buying.
The fractionation preparation method of above-mentioned 3-(carboxamide methyl)-5-methylhexanoic acid exists toxicity big, and environmental pollution is big, or resolving agent is not easy to obtain and problems such as valency height.
Summary of the invention
Purpose of the present invention just provides the new preparation process of a kind of optical purity 3-(carboxamide methyl)-5-methylhexanoic acid.3-(carboxamide the methyl)-5-methylhexanoic acid of racemization can be split into individual isomer or high optically pure (R)-(-)-or (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid by this method of racemization.
Technical scheme provided by the invention is: adopt the resolving agent of optically pure structural formula shown in figure three, 3-(carboxamide methyl)-5-methylhexanoic acid with racemization in solvent forms diastereoisomeric salt, the salt that obtains in the salt of directly separating out or the mother liquor is separated and dissociate, obtain individual isomer or high optically pure (R)-or (S) 3-(carboxamide methyl)-5-methylhexanoic acid
R=H wherein, NO
2, CN, X,
R
1, R
2The alkyl of=C1-C4, or H, or the arbitrary combination of the two,
R
3The alkyl alcohol of=C1-C4, or Ar,
X=F, Cl, Br, or 1.
Figure three
The aminoalcohol derivative of chemical resolving agent shown in figure three that the present invention is used, its configuration can be optically active (S, R), (R, S), (R, R) or (S, S) configuration.Can be optically active (1S, 2R) or (1R, 2S) 1-p-nitrophenyl-2-amino-1, ammediol (D or the mould amine of L-chlorine), N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (the two mould amine of chlorine that methylate of D or L-), 2-amino-1,2-phenylbenzene alcoholic acid derivative.Be preferably optically pure ((1S, 2R) or (1R, 2S) 1-p-nitrophenyl-2-amino-1, ammediol (D or the mould amine of L-chlorine), N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (the two mould amine of chlorine that methylate of D or L-), 2-amino-1,2-phenylbenzene ethanol.Be preferably especially optically pure (1S, 2R) or (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol, (1S, 2R) or (1R, 2S)-1-p-nitrophenyl-2-amino-1, ammediol.
The mol ratio of aminoalcohol derivative resolving agent and racemic 3-(carboxamide methyl)-5-methylhexanoic acid can be 0.6～1.2: 1, is preferably 1: 1.Form diastereoisomeric salt under the solvent refluxing temperature, separate out diastereoisomeric salt under 0～70 ℃, have different the bests to separate out temperature to different solvents, to separate out temperature be 58 ℃ to the best when solvent is water, and to separate out temperature be 65 ℃ to the best when solvent is Virahol.Isolated salt is used acid dissociation in organic solvent or water, can prepare individual isomer or high optically pure (R)-(-) or (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid.
The diastereomeric salt of 3-(carboxamide methyl)-5-methylhexanoic acid and aminoalcohol derivative can improve optical purity by recrystallization method.
We screen multiple solvent, alcohols such as methyl alcohol, ethanol, Virahol etc., and ketone such as acetone, 2-butanone, pimelinketone etc., and tetrahydrofuran (THF), ethyl acetate, acetonitrile, toluene, normal hexane, and water etc.
Fractionation described in the present invention and recrystallization solvent can be water, can be alcohols, include but not limited to methyl alcohol, ethanol, Virahol etc.; Can also be ketone, include but not limited to acetone, 2-butanone etc.; Be preferably water, Virahol, ethanol, be preferably water, Virahol especially.
The used acid of dissociating can be organic acid and mineral acid, includes but not limited to hydrochloric acid, acetic acid, sulfuric acid etc., preferred hydrochloric acid.
Among the preparation method of the present invention, with (1S, 2R) or (1R, 2S)-1-p-nitrophenyl-2-amino-1, when ammediol was resolving agent, described organic solvent was preferably Virahol, ethanol, 2-butanone etc., especially preferably uses Virahol.Single splits and is dissociated by the diastereomeric salt that obtains in the mother liquor, can obtain individual isomer or high optically pure 3-(carboxamide methyl)-5-methylhexanoic acid.
Among the preparation method of the present invention, with (1R, 2S) or (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol are as resolving agent, described solvent is a water.Be preferably water especially.Single splits and is dissociated by the solid diastereomeric salt of separating out, and can obtain individual isomer or high optically pure 3-(carboxamide methyl)-5-methylhexanoic acid.
Among the preparation method of the present invention, with (1S, 2R) or (1R, 2S)-2-amino-1,2-phenylbenzene ethanol splits, described solvent is a Virahol.Be preferably Virahol.Single splits and is dissociated by the diastereomeric salt that obtains in the mother liquor, can obtain individual isomer or high optically pure 3-(carboxamide methyl)-5-methylhexanoic acid.
Above-described method for splitting diastereomeric salt is without recrystallization, 3-(carboxamide the methyl)-5-methylhexanoic acid that just can directly dissociate and obtain individual isomer or high-optical-purity.
Preparation method of the present invention can prepare the optically pure R-of key intermediate (-)-3-(carboxamide the methyl)-5-methylhexanoic acid of medicine lyrica (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
Preparation method of the present invention, different resolving agents and consumption thereof, solvent types and consumption in the split process, and recrystallization temperature all have a significant impact split result.
It is resolution solvent that preparation method of the present invention adopts water, alcohol or ketone, helps environment protection.
Advantages such as preparation method of the present invention has environmental protection, resolving agent is cheap and easy to get, method is easy, high yield and highly selective are a kind of methods that is suitable for suitability for industrialized production.
Embodiment
To help by the following example and to understand the present invention, but be not limited to content of the present invention.
Resolution yield is 100% calculating with raceme among the embodiment.
The foundation of 3-(carboxamide methyl)-5-methylhexanoic acid enantioselectivity measuring method
With 3-(carboxamide methyl)-5-methylhexanoic acid 197 milligrams (1.05 mmole) and benzyl bromine 171 milligrams (1 mmoles) in the presence of triethylamine, 160 ℃ were reacted ten minutes in dimethylbenzene, generate 3-(carboxamide methyl)-5-methylhexanoic acid benzene methyl, survey the enantioselectivity of product then with HPLC.
HPLC chromatographic column: OD-H,
Detect wavelength: 220nm,
Moving phase: 15% Virahol: 85% normal hexane
Flow velocity: 1.0 ml/min,
Instrument: GILSON,
3-(carboxamide methyl)-5-methylhexanoic acid enantiomer detection time: t
R=10.5 minutes, t
S=13.5 minutes with (1R, 2S)-N, N-dimethyl 1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of L-chlorine that methylates) splits 3-(carboxamide the methyl)-5-methylhexanoic acid of racemization
Embodiment one
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 12 gram (50 mmole) (1R, 2S)-and N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of L-chlorine that methylates), 50 ml waters add 100 milliliters of three-necked bottles, reflux, solid all dissolves, and stirs 5 minutes, slowly be cooled to 50 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine diastereomeric salt 9.8 grams, yield 46%.
Diastereomeric salt
1H-NMR (DMSO-d6,300MHz): δ 0.81-0.83 (d, 6H, J=6.4), δ 1.08-1.12 (m, 2H), 1.60 (m, 1H), δ 1.99-2.22 (m, 5H), δ 2.39 (s, 6H), and δ 2.59-2.61 (m, 1H), δ 3.36-3.45 (m, 2H), δ 4.68-4.70 (d, 1H, J=7.47), 5.2 (s, (broad), 3H) δ 6.75 (s, 1H), δ 7.30 (s, 1H), 7.62-7.64 (d, 2H, J=7.44), 8.16-8.19 (d, 2H, J=8.54).
This salt adds 18 ml waters, 25 milliliters of concentrated hydrochloric acids dissociate, and the clarification back is muddy earlier for solution, stirring at normal temperature 2 hours, be cooled to 3 ℃ afterwards, continue to stir 1 hour, filter, with the washing of a small amount of ice dilute hydrochloric acid, drain, wherein the 3-of (R)-(-) (carboxamide methyl)-5-methylhexanoic acid occupies the majority, and enantioselectivity is 98.9%ee, [α]
20 D=-1.2 (C=2, MeOH), yield 36%.
Embodiment two
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 12 gram (50 mmole) (1R, 2S)-and N, N-dimethyl 1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of L-chlorine that methylates), 50 ml waters add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 60 ℃, be incubated 1.5 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 10.2 grams, yield 47.8%.Behind the salt acid dissociation, wherein (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and enantioselectivity is 79.0%ee.
Get 5 gram (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, the ammediol amine salt adds the water recrystallization and gets 4.1 grams, yield 82%, behind the salt acid dissociation, wherein (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and enantioselectivity is 97.3%ee, [α]
20D=-0.8 (C=2, MeOH).
Embodiment three
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 9.6 gram (40 mmole) (1R, 2S)-and N, N-dimethyl 1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of L-chlorine that methylates), 50 ml waters add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 60 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 10.5 grams, yield 55%.Behind the salt acid dissociation, wherein (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and enantioselectivity is 65.3%ee.
With (1S, 2R)-N, N-dimethyl 1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates) splits 3-(carboxamide the methyl)-5-methylhexanoic acid of racemization
Embodiment four
11.22 gram (60 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 14.4 gram (60 mmole) (1S, 2R)-and N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 100 ml waters add 250 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 34 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 10 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 8.92 grams, yield 29%.
Diastereomeric salt
1H-NMR (DMSO-d6,300MHz): δ 0.81-0.83 (d, 6H, J=6.4), δ 1.08-1.12 (m, 2H), δ 1.60 (m, 1H), δ 1.99-2.22 (m, 5H), δ 2.39 (s, 6H), and δ 2.59-2.61 (m, 1H), δ 3.36-3.45 (m, 2H), δ 3.5 (broad, 3H), δ 4.68-4.70 (d, 1H, J=7.47), δ 6.75 (s, 1H), δ 7.30 (s, 1H), δ 7.62-7.64 (d, 2H, J=7.44), δ 8.16-8.19 (d, 2H, J=8.54).(S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and enantioselectivity is 95.6%ee.
Mother liquor concentrates, adding water stirs evenly, transfer pH=1.5 with concentrated hydrochloric acid, the clarification back is muddy earlier for solution, reduces to 0 ℃ and stirs 1 hour, filters, the washing of a small amount of ice dilute hydrochloric acid, obtain (R)-(-)-3-solid that (carboxamide methyl)-the 5-methylhexanoic acid occupies the majority 4.995 grams, yield 44.5%, its enantioselectivity are 48.7%ee.
Embodiment five
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 12 gram (50 mmole) (1S, 2R)-and N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 50 ml waters add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 55 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 10 grams, yield 46.5%.(S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 95.6%ee.
Mother liquor concentrates, adding water stirs evenly, transfer pH=1.5 with concentrated hydrochloric acid, the clarification back is muddy earlier for solution, reduces to 0 ℃ and stirs 1 hour, filters, the small amount of acid washing, obtain (R)-(-)-3-solid that (carboxamide methyl)-the 5-methylhexanoic acid occupies the majority 4.49 grams, its enantioselectivity is 75.8%ee, yield 47.5%.
Embodiment six
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 14.4 gram (60 mmole) (1S, 2R)-and N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 50 ml waters add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 50 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 8.3 grams, yield 35%.(S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 92.4%ee.
Mother liquor concentrates, and adds water and stirs evenly, and transfers pH=1.5 with concentrated hydrochloric acid, and the clarification back is muddy earlier for solution, reduce to 0 ℃ and stirred 1 hour, filter, the small amount of acid washing, obtain (R)-(-)-3-solid that (carboxamide methyl)-the 5-methylhexanoic acid occupies the majority 4.88 grams, yield 52.3%, enantioselectivity are 60.4%ee.
Embodiment seven
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 14.4 gram (60 mmole) (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 45 ml waters add 100 milliliters three-necked bottle, are heated to backflow, and solid all dissolves, stirred 5 minutes, slowly be cooled to 55 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 8.45 grams, (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid occupied the majority after this salt of yield: 35.6%. dissociated, and its enantioselectivity is 97.0%ee.
Mother liquor concentrates, and adds 30 milliliters in water, recrystallization, and 30 ℃ of filtrations obtain 6.56 gram solids, yield 27.6%, dissociating obtains (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and occupies the majority, and its enantioselectivity is 57.0%ee.
Embodiment eight
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 13.2 gram (55 mmole) (1S, 2R)-and N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 50 ml waters add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 55 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 9.15 grams, yield 40.6%.(S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 94.7%ee.
Mother liquor concentrates, and adds 20 milliliters in water, recrystallization, and 30 ℃ of filtrations obtain 8.69 gram solids, yield 38.5%, dissociating obtains (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and occupies the majority, and its enantioselectivity is 70.3%ee.
Embodiment nine
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 13.2 gram (55 mmole) (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 45 ml waters add 100 milliliters three-necked bottle, are heated to backflow, solid all dissolves, stirred 5 minutes, and slowly be cooled to 55 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 8.79 grams, yield 39%, (S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 97.9%ee.
Mother liquor concentrates, and adds 20 milliliters in water, recrystallization, and 30 ℃ of filtrations obtain 5.75 gram solids, yield 25.5%, dissociating obtains (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and occupies the majority, and its enantioselectivity is 85.3%ee.
Embodiment ten
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 12.6 gram (52.5 mmole) (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 48 ml waters add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly is cooled to 55C, be incubated 3 hours, reduce to 30 ℃ again, filter 5 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-and N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 8.92 grams, yield 40.6%, (S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 99.3%ee, [α]
20 D=+1.8 (C=2, MeOH).
Mother liquor concentrates, and adds 20 milliliters in water, recrystallization, and 30 ℃ of filtrations obtain 7.24 gram solids, yield 33%, dissociating obtains (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and occupies the majority, and its enantioselectivity is 79.5%ee.
Embodiment 11
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 12 gram (50 mmole) (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 80 ml waters add 250 milliliters three-necked bottle, are heated to backflow, solid all dissolves, stirred 5 minutes, and slowly be cooled to 55C, be incubated 3 hours, reduce to 30 ℃ again. filter, 5 milliliters of washings, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 7.36 grams, (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid occupied the majority after yield 34.5%, this salt dissociated, its enantioselectivity is 98.0%ee, [α]
20 D=+1.3 (C=2, MeOH).
Mother liquor concentrates, and adds 20 milliliters in water, recrystallization, and 20 ℃ of filtrations obtain 9.735 gram solids, yield 45.7%, dissociating obtains (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and occupies the majority, and its enantioselectivity is 40.0%ee.
Embodiment 12
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 12 gram (50 mmole) (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 30 ml waters add 100 milliliters three-necked bottle, are heated to backflow, solid all dissolves, stirred 5 minutes, and slowly be cooled to 60 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 5 milliliters of washings obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 11.10 grams, yield 52%, (S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 79.9%ee.
Mother liquor concentrates, adding water stirs evenly, transfer pH=1.5 with concentrated hydrochloric acid, the clarification back is muddy earlier for solution, reduces to 0 ℃ and stirs 1 hour, filters, the washing of a small amount of ice dilute hydrochloric acid, obtain (R)-(-)-3-solid that (carboxamide methyl)-the 5-methylhexanoic acid occupies the majority 3.89 grams, yield 41.6%, its enantioselectivity are 25.2%ee.
Embodiment 13
18.7 gram (0.1 mole) 3-(carboxamide methyl)-5-methylhexanoic acid, 24 gram (0.1 mole) (1S, 2R)-and N, N dimethyl-1-p-nitrophenyl-2-amino-1, ammediol (two mould amine of D-chlorine that methylates), 100 ml waters add 250 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 10 minutes, slowly be cooled to 55 ℃, be incubated 3 hours, reduce to 30 ℃ again, filter, 10 milliliters of washings, obtain S-(+)-3-(carbamyl methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, ammediol amine salt 18.6 grams, yield 43.6%.This salt adds 36 ml waters, and 6 milliliters of concentrated hydrochloric acids dissociate, and the clarification back is muddy earlier for solution, stirring at normal temperature 2 hours, be cooled to 3 ℃ afterwards, continue to stir 1 hour, filter, with a small amount of ice dilute hydrochloric acid washing, drain, obtain solid 7.43g, wherein (S)-(+)-3-(carbamyl methyl)-5-methylhexanoic acid occupies the majority, its enantioselectivity is 94.4%ee, yield 91.2%.
Mother liquor concentrates, and adds water and stirs evenly, and transfers pH=1.5 with concentrated hydrochloric acid, the clarification back is muddy earlier for solution, reduces to 0 ℃ and stirs 1 hour, filters, the small amount of acid washing obtains R-(-)-3-solid that (carbamyl methyl)-the 5-methylhexanoic acid occupies the majority 10 grams, and its enantioselectivity is 70.1%ee.
Split 3-(carboxamide the methyl)-5-methylhexanoic acid of racemization with the mould amine of D-chlorine
Embodiment 14
1.87 gram (10 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 2.12 gram (10 mmole) (1S, 2R)-1-p-nitrophenyl-2-amino 1, ammediol (the mould amine of D-chlorine), 22.5 milliliters of Virahols add 100 milliliters three-necked bottle, are heated to backflow, solid all dissolves, stirred 5 minutes, and slowly be cooled to 65 ℃, be incubated 2 hours, reduce to 30 ℃ again, be incubated 0.5 hour, filter, 5 milliliters of Virahols are washed, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-and 1-p-nitrophenyl-2-amino-1, ammediol amine salt 2.01 grams, yield 50.5%.
Diastereomeric salt
1H-NMR (DMSO-d6,300MHz): δ 0.81-0.83 (d, 6H, J=6.4), δ 1.07-1.11 (m, 2H), δ 1.58-1.60 (m, 1H), δ 2.00-2.17 (m, 5H), δ 2.78-2.80 (m, 1H), and δ 3.15-3.21 (m, 1H), δ 3.34-3.40 (m, 1H), δ 4.70-4.72 (d, 1H, J=4.98), δ 4.8 (broad, 3H), δ 6.74 (s, 1H), δ 7.33 (s, 1H), 7.59-7.62 (d, 2H, J=8.62), 8.18-8.21 (d, 2H, J=8.62).(S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 59.8%ee.
Mother liquor concentrates, add 5 milliliters in water, concentrated hydrochloric acid is transferred pH=1.5, and the rising temperature for dissolving clarification is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 0.58 gram (R)-(-)-3-solid that (carboxamide methyl)-the 5-methylhexanoic acid occupies the majority, yield 31%, its enantioselectivity are 93.0%ee.
Embodiment 15
3.74 gram (20 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 4.24 gram (20 mmole) (1S, 2R)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of D-chlorine), 45 milliliters of Virahols add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 65 ℃, be incubated 2 hours, reduce to 30 ℃ again, be incubated 0.5 hour, filter, 6 milliliters of Virahols are washed, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-1-p-nitrophenyl-2-amino-1, salt 4.01 grams of ammediol amine, (S)-(+) after yield 50.3%, this salt dissociate-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 76.8%ee.
Mother liquor concentrates, and adds 10 milliliters in water, and concentrated hydrochloric acid is transferred pH=1.5, the rising temperature for dissolving clarification, be cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing, obtain 1.17 gram (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acids, enantioselectivity is 100%ee, yield 31.4%.
Embodiment 16
37.4 gram (0.2 mole) 3-(carboxamide methyl)-5-methylhexanoic acid, 43 gram (0.2 mole) (1S, 2R)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of D-chlorine), 450 milliliters of Virahols add 1000 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly be cooled to 65 ℃, be incubated 2 hours, reduce to 30 ℃ again, be incubated 1 hour, filter, 60 milliliters of Virahols are washed, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-1-p-nitrophenyl-2-amino-1, salt 43.2 grams of ammediol amine, yield 53.7%, this salt dissociate and obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid solid that occupies the majority, and its enantioselectivity is 56.3%ee.
Mother liquor concentrates, add 80 milliliters in water, concentrated hydrochloric acid is transferred pH=1.5, and the rising temperature for dissolving clarification is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 12.9 gram (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acids solid that occupies the majority, its enantioselectivity is 99.2%ee, yield 34.5%.
Embodiment 17
3.74 gram (20 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 4.24 gram (20 mmole) (1S, 2R)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of D-chlorine), 40 milliliters of dehydrated alcohols add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, and stirs 5 minutes, slowly is cooled to 50 ℃, be incubated 2 hours, reduce to 30 ℃ again, be incubated 30 minutes, filter, 4 milliliters of dehydrated alcohols are washed, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-1-p-nitrophenyl-2-amino-1, salt 3.05 grams of ammediol amine, (S)-(+) after yield 38%. these salt dissociate-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 85.7%ee.
Mother liquor concentrates, add 8 milliliters in water, concentrated hydrochloric acid is transferred pH=1.5, and the rising temperature for dissolving clarification is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 2.6 gram (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acids solid that occupies the majority, yield 34.5%, its enantioselectivity are 64.3%ee.
Embodiment 18
9.35 gram (50 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 10.6 gram (50 mmole) (1S, 2R)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of D-chlorine), 50 milliliters of 2-butanone add 100 milliliters three-necked bottle, be heated to backflow, solid all dissolves, stirred 5 minutes, slowly be cooled to 30 ℃, be incubated 2 hours, filter, 5 milliliters of 2-butanone are washed, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-1-p-nitrophenyl-2-amino-1, salt 7.994 grams of ammediol amine, (S)-(+) after yield 36%. these salt dissociate-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 80.0%ee.
Mother liquor concentrates, add 20 milliliters in water, concentrated hydrochloric acid is transferred pH=1.5, and the rising temperature for dissolving clarification is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 4.27 gram (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acids and occupies the majority, its enantioselectivity is 38.7%ee, yield 45.7%.
Embodiment 19
3.74 gram (20 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 2.544 gram (12 mmole) (1S, 2R)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of D-chlorine), 45 milliliters of Virahols add 100 milliliters three-necked bottle, are heated to backflow, and solid all dissolves, stirred 5 minutes, slowly be cooled to 48 ℃, be incubated 2 hours, reduce to 30 ℃, filter, 5 milliliters of Virahols are washed, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-1-p-nitrophenyl-2-amino-1, ammediol amine salt 3.716 grams, yield 59%.(S)-(+) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 53.2%ee.
Mother liquor concentrates, and adds 8 milliliters in water, and concentrated hydrochloric acid is transferred pH=1.5, the rising temperature for dissolving clarification, be cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing, obtain 1.094 gram (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acids and occupy the majority, its enantioselectivity is 57.3%ee, yield 29%.
Split 3-(carboxamide the methyl)-5-methylhexanoic acid of racemization with the mould amine of L-chlorine
Embodiment 20
1.87 gram (10 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 2.12 gram (10 mmole) (1R, 2S)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of L-chlorine), 22.5 the milliliter Virahol adds 100 milliliters three-necked bottle, is heated to backflow, solid all dissolves, stirred 5 minutes, slowly be cooled to 65 ℃, be incubated 2 hours, reduce to 30 ℃, filter, 5 milliliters of Virahols are washed, obtain (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-1-p-nitrophenyl-2-amino-1, ammediol amine salt 2.014 grams, yield 50.5%.
Diastereomeric salt
1H-NMR (DMSO-d
6, 300MHz): δ 0.81-0.83 (d, 6H, J=6.4), δ 1.07-1.11 (m, 2H), δ 1.58-1.60 (m, 1H), δ 2.00-2.17 (m, 5H), δ 2.78-2.80 (m, 1H), and 3.15-3.21 (m, 1H), δ 3.34-3.40 (m, 1H), δ 4.70-4.72 (d, 1H, J=4.98), δ 4.8 (broad, 3H), δ 6.74 (s, 1H), δ 7.33 (s, 1H), δ 7.59-7.62 (d, 2H, J=8.62), δ 8.18-8.21 (d, 2H, J=8.62).(R)-(-) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 65.2%ee.
Mother liquor concentrates, add 4 milliliters in water, concentrated hydrochloric acid is transferred pH=1.5, and the rising temperature for dissolving clarification is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 0.58 gram (S)-(+)-3-solid that (carboxamide methyl)-the 5-methylhexanoic acid occupies the majority, yield 31%, its enantioselectivity are 96.8%ee.
Embodiment 21
1.87 gram (10 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 2.12 gram (10 mmole) (1R, 2S)-1-p-nitrophenyl-2-amino-1, ammediol (the mould amine of L-chlorine), 20 milliliters of dehydrated alcohols add 100 milliliters three-necked bottle, are heated to backflow, solid all dissolves, stirred 5 minutes, and slowly be cooled to 50 ℃, be incubated 2 hours, reduce to 30 ℃ again, be incubated 30 minutes, filter, 2 milliliters of dehydrated alcohols are washed, obtain (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-and 1-p-nitrophenyl-2-amino-1, ammediol amine salt 1.55 grams, yield 38.9%.(R)-(-) after this salt dissociates-3-(carboxamide methyl)-5-methylhexanoic acid occupies the majority, and its enantioselectivity is 69.3%ee.
Mother liquor concentrates, add 4 milliliters in water, concentrated hydrochloric acid is transferred pH=1.5, and the rising temperature for dissolving clarification is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 939 milligrams of (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid solid that occupies the majority, its enantioselectivity is 55.0%ee, yield 50.2%.
With (1S, 2R)-(+)-2-amino-1,2-phenylbenzene ethanol splits
Embodiment 22
935 milligrams of (5 mmole) 3-(carboxamide methyl)-5-methylhexanoic acid, 1.065 gram (5 mmole) (1S, 2R)-(+)-2-amino-1,2-phenylbenzene ethanol, 25 milliliters of Virahols add 50 milliliters of round-bottomed flasks, are heated to backflow, and solid all dissolves, stirred 5 minutes, slowly be cooled to 63 ℃, be incubated 2 hours, reduce to 30 ℃ again, filter, 2 milliliters of Virahols are washed, oven dry obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-(+)-2-amino-1,2-phenylbenzene alcoholic acid diastereomeric salt 1.3 grams, yield 65%.
1H-NMR (the D of diastereomeric salt
2O, 300MHz): δ 0.84-0.87 (d, 6H, J=6.5), δ 1.14-1.17 (m, 2H), δ 1.58-1.65 (m, 1H), δ 2.08-2.25 (m, 5H), δ 4.63-4.65 (d, 1H, J=6.2), δ 5.22-5.24 (d, 1H, J=6.2), δ 7.27-7.73 (m, 4H), and δ 7.39-7.45 (m, 6H).Fusing point: 135.7-137.2 °
This salt adds 10 milliliters in water, strong caustic is transferred pH＞10, add dichloromethane extraction twice, water is transferred pH=1.5 with concentrated hydrochloric acid, and solid is separated out, be cooled to 0 ℃, stirred 30 minutes, and filtered, a little ice dilute hydrochloric acid washing, obtain (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and occupy the majority, its enantioselectivity is 58.6%ee.
Mother liquor concentrates, and adds 5 milliliters in water, and strong caustic is transferred pH＞10, add dichloromethane extraction twice, water is transferred pH=1.5 with concentrated hydrochloric acid, and solid is separated out, and is cooled to 0 ℃, stirred 30 minutes, filter, a little ice dilute hydrochloric acid washing obtains 190 milligrams of (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid solid that occupies the majority, its enantioselectivity is 97.2%ee, yield 20%.
Claims (5)
1. compound, its be (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, the diastereomeric salt of ammediol amine.
2. compound, its be (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-N, N-dimethyl-1-p-nitrophenyl-2-amino-1, the diastereomeric salt of ammediol amine.
3. compound, its be (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-1-p-nitrophenyl-2-amino-1, the diastereomeric salt of ammediol amine.
4.-the kind compound, its be (R)-(-)-3-(carboxamide methyl)-5-methylhexanoic acid and (1R, 2S)-1-p-nitrophenyl-2-amino-1, ammediol amine diastereomeric salt.
5. compound, its be (S)-(+)-3-(carboxamide methyl)-5-methylhexanoic acid and (1S, 2R)-(+)-2-amino-1,2-phenylbenzene alcoholic acid diastereomeric salt.
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