CN101289387A - 6-chlor-2,3-dihydro- indene-3-ketone-1-carboxyl acid optical isomer and method for preparing same - Google Patents
6-chlor-2,3-dihydro- indene-3-ketone-1-carboxyl acid optical isomer and method for preparing same Download PDFInfo
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- CN101289387A CN101289387A CNA200810123964XA CN200810123964A CN101289387A CN 101289387 A CN101289387 A CN 101289387A CN A200810123964X A CNA200810123964X A CN A200810123964XA CN 200810123964 A CN200810123964 A CN 200810123964A CN 101289387 A CN101289387 A CN 101289387A
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Abstract
The invention relates to the field of pharmacochemistry, in particular to two optical isomers of 6-chlorine-2, 3-dihydro-indene-3-ketone-1-carboxylic acid (1), the optical isomers are (S)-(+)-1 and (R)-(-)-1 respectively, the preparation method is also disclosed by the invention.
Description
Technical field
The present invention relates to chemical field, be specifically related to 6-chloro-2, two optical isomers and their preparation method of 3-dihydro-indenes-3-ketone-1-carboxylic acid.
Background technology
The Yin ketone compounds is important medicine of a class and chemical intermediate, has a wide range of applications in the exploitation of antitumor, anti-degenerative brain disorder and analgesic.6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid (1) is the important intermediate of synthetic analgesic, but compound 1 contains a chiral centre, there are two optical isomers, target compound by different optical siomerism precursor reactant generations, its biological activity and/or toxic side effect are different often, therefore, prepare two optical isomers (S)-(+)-1 of this compound and (R)-(-)-1, for 6-chloro-2, the preparation and the bioactivity research of the derivative of 3-dihydro-indenes-3-ketone-1-carboxylic acid have great importance.
Summary of the invention
The purpose of this invention is to provide (S)-(+) of high-optical-purity-or (R)-(-)-6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid;
Another object of the present invention provides the 6-chloro-2 of preparation high-optical-purity, a kind of method of 3-dihydro-indenes-3-ketone-1-carboxyl acid optical isomer.
Structural formula of compound of the present invention is as follows:
Wherein (S)-(+)-1 is S-(+)-6-chloro-2, and 3-dihydro-indenes-3-ketone-1-carboxylic acid (R)-(-)-1 is R-(-)-6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid.
The preparation method of compound of the present invention is as follows: with chloro-phenyl-succsinic acid (2) between racemization is raw material; with the α-Ben Yian of chirality as the chiral separation agent; with two optical isomers of chloro-phenyl-succsinic acid between the chemical resolution method preparation, the chloro-phenyl-succsinic acid obtains the purpose product through Fu-Ke acylation reaction cyclization again between chirality.
Preparation process provided by the present invention is as follows:
The preparation method of compound (S)-(+)-1 comprises:
Chloro-phenyl-succsinic acid between racemization and (S)-(-)-α-Ben Yian is dissolved in ethanol, salify, cooling, filter (S)-(+)-chloro-phenyl-succsinic acid (S)-(-)-α-Ben Yian salt crude product, ethyl alcohol recrystallization gets elaboration, and elaboration is dissolved in the NaOH solution, adds methylene dichloride, mix, the water intaking layer is used the concentrated hydrochloric acid acidifying, separates out solid, filter (S)-(+)-2, make acyl chlorides with refluxing in (S)-(+)-2 adding sulfur oxychloride, the cooling back adds oil of mirbane and aluminum trichloride (anhydrous) reacts, and reaction solution is poured in the frozen water, component distillation, cooling obtains (S)-(-)-1.
Wherein the chloro-phenyl-succsinic acid with (S)-(-)-preferred 1: 1～1: 2.5 of the mol ratio of α-Ben Yian, compound (S)-(+)-2 is 1: 1～1: 4 with the mol ratio of aluminum chloride.Between the chloro-phenyl-succsinic acid with (S)-(-)-mol ratio of α-Ben Yian further preferred 1: 2～1: 2.2, the mol ratio of compound (S)-(+)-2 and aluminum chloride further preferred 1: 2～1: 3.
Wherein add preferred 30～100 ℃ of temperature of reaction behind the aluminum trichloride (anhydrous), preferred 0.5～5 hour of reaction times.Further preferred 60～90 ℃ of temperature of reaction behind the adding aluminum chloride, further 1～2 hour of reaction times.
Preferred 0.1～the 10mol/L of the concentration of NaOH solution wherein.
The preparation method of compound (R)-(-)-1 comprises:
Chloro-phenyl-succsinic acid between racemization and (R)-(+)-α-Ben Yian is dissolved in ethanol, salify, cooling, filter (R)-(-)-chloro-phenyl-succsinic acid (R)-(+)-α-Ben Yian salt crude product, ethyl alcohol recrystallization gets elaboration, and elaboration is dissolved in the NaOH solution, adds methylene dichloride, mix, the water intaking layer is used the concentrated hydrochloric acid acidifying, separates out solid, filter (R)-(-)-2, make acyl chlorides with refluxing in (R)-(-)-2 adding sulfur oxychloride, the cooling back adds oil of mirbane and aluminum trichloride (anhydrous) reacts, and reaction solution is poured in the frozen water, component distillation, cooling obtains (R)-(-)-1.
Wherein the chloro-phenyl-succsinic acid with (R)-(+)-preferred 1: 1～1: 2.5 of the mol ratio of α-Ben Yian, preferred 1: 1～1: 4 of the mol ratio of compound (R)-(-)-2 and aluminum chloride.
Between the chloro-phenyl-succsinic acid with (R)-(+)-mol ratio of α-Ben Yian further preferred 1: 2～1: 2.2, the mol ratio of compound (R)-(-)-2 and aluminum chloride further preferred 1: 2～1: 3.
Wherein add preferred 30～100 ℃ of temperature of reaction behind the aluminum trichloride (anhydrous), preferred 0.5～5 hour of reaction times.
Further preferred 60～90 ℃ of temperature of reaction behind the adding aluminum chloride, preferred 1～2 hour of reaction times.
Preferred 0.1～the 10mol/L of the concentration of NaOH solution wherein.
Embodiment
The present invention is described further below by embodiment, but embodiment does not limit protection scope of the present invention.The preparation method of object is as follows:
Fusing point RY-1 type fusing point instrument, thermometer is not proofreaied and correct; Ultimate analysis is measured with Carlo Erba 1106 type elemental analysers; IR spectrum Nicolet Impact 410 type determination of infrared spectroscopy, the KBr compressing tablet;
1HNMR finishes (mark in the TMS) with JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser; MS measures with Agilent 1100 type Fourier transform mass spectrometer.The capillary electrophoresis measuring method: be not coated with stain quartz capillary column 45.0/53.5 (I/L) cm * 50mm, back-ground electolyte is 100mmol/L Tris, regulates pH to 5.5 with phosphoric acid, chiral additives is 50g/L HP-β-CD, running voltage+25kV, 25 ℃ of capillary temperatures detect wavelength 200nm.
Embodiment 1
(S)-(+)-a chloro-phenyl-succsinic acid (S)-(-)-α-Ben Yian salt (3)
Between chloro-phenyl-succsinic acid 5.0g (0.022mol) and (S)-(-)-α-Ben Yian 5.42g (0.047mol) heating for dissolving in 70ml ethanol, standing over night, crystallization filters and obtains white crystal 5.2g, this crystal 5 .2g is dissolved among the hot ethanol 45ml, standing over night, crystallization obtains white crystal 3.0g, continue to use twice of ethyl alcohol recrystallization, get white crystal 2.4g, m.p.180-183 ℃, yield 23.3%.
(S)-(+)-a chloro-phenyl-succsinic acid ((S)-(+)-2)
Get the NaOH solution 15ml that this crystal 1.0g places 2.5M, add methylene dichloride 50ml, stir 30min, divide water-yielding stratum, with washed with dichloromethane once, water layer concentrated hydrochloric acid acidifying, washing, dry white solid (S)-(+)-20.4g that gets, yield 82.1%, m.p.174-175 ℃, [α]
D 20=+114.4 (c=1, MeOH), chirality capillary electrophoresis mensuration ee%=94.3%.
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：12.44(2H，bs，COOH)，7.35～7.38(3H，m，ArH
4，ArH
5，ArH
6)，7.26～7.27(1H，m，ArH
7)，3.91～3.95(1H，dd，J
1＝5.4Hz，J
2＝9.8Hz，H
2)，2.92～2.98(1H，dd，J
1＝9.8Hz，J
2＝16.9Hz，H
3a)2.56～2.60(1H，dd，J
1＝5.4Hz，J
2＝16.9Hz，H
3b)
MS(ESI(-)70V，m/z)：226.8([M-H]
-，base?peak)
Anal.Calcd.For?C
10H
9ClO
4:C?52.53，H?3.97；Found：C?52.19，H?4.13
(S)-(+)-and 6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid ((S)-(+)-1)
In the 25ml three-necked bottle, add (S)-(+)-23g (0.013mol), SOCl
23ml stirs, temperature rising reflux 0.5h, and cold slightly back adds anhydrous oil of mirbane 6ml, anhydrous AlCl
33.4g (0.026mol), 80 ℃ of reaction 1.5h.Pour in the 75ml frozen water, component distillation is removed oil of mirbane, and final volume is 55ml, adds gac 0.5g and decolours, and heat filter, and jolting cooling rapidly get yellowish pink solid.Column chromatography for separation, white solid (S)-(+)-1 1.4g, yield 50.6%, m.p.144～146 ℃, [α]
D 20=+34.7 (c=1, MeOH).
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：13.06(1H，bs，COOH)，7.76(1H，s，ArH)，7.64～7.67(1H，d，J＝8.1Hz，ArH)，7.54～7.57(1H，d，J＝8.1Hz，ArH)，4.31～4.34(1H，m，H
1)，2.88～2.90(2H，m，H
2).MS(ESI(-)70V，m/z)：208.7([M-H]
-).
Anal.Calcd.For?C
10H
7ClO
3:C?57.03，H?3.35；Found：C?57.25，H?3.29
Embodiment 2
(R)-(-)-a chloro-phenyl-succsinic acid (R)-(+)-α-Ben Yian salt (4)
With 2 and (R)-(+)-and α-Ben Yian is a raw material, the relevant operation with reference to compound 3 among the embodiment 1 obtains white crystal, yield 23.1%, m.p.180-183 ℃.
(R)-(-)-a chloro-phenyl-succsinic acid ((R)-(-)-2)
The operation of same compound (S)-(+)-2 gets (R)-(-)-2, yield 82.1%, white solid, m.p.174-175 ℃, [α]
D 20=-110.1 (c=1, MeOH), chirality capillary electrophoresis mensuration ee%=96.3%.
1H-NMR(500MHz，DMSO-d6)，δ(ppm)：12.50(2H，bs，COOH)，7.32～7.38(3H，m，ArH
4，ArH
5，ArH
6)，7.26～7.27(1H，m，ArH
7)，3.91～3.95(1H，dd，J
1＝5.4Hz，J
2＝9.8Hz，dd，H
2)，2.92～2.98(1H，dd，J
1＝9.8Hz，J
2＝16.9Hz，H
3a)，2.56～2.60(1H，dd，J
1＝5.4Hz，J
2＝16.9Hz，H
3b)
MS(ESI(-)70V，m/z)：226.8([M-H]
-，base?peak)Anal.Calcd.For?C
10H
9ClO
4:C?52.53，H?3.97；Found：C?52.22，H?4.33
(R)-(-)-and 6-chloro-2,3-dihydro-indenes-3-ketone-1-carboxylic acid ((R)-(-)-1)
Operation with preparing compound (S)-(+)-1 among the embodiment 1 obtains (R)-(-)-1, white solid, yield 53%, m.p.144～146 ℃, [α]
D 20=-32.9 (c=1, MeOH).
1H-NMR(300MHz，DMSO-d6)，δ(ppm)：13.05(1H，bs，COOH)，7.76(1H，s，ArH)，7.64～7.67(1H，d，J＝8.1Hz，ArH)，7.54～7.57(1H，d，J＝8.1Hz，ArH)，4.31～4.34(1H，m，H
1)，2.88～2.90(2H，m，H
2)MS(ESI(-)70V，m/z)：208.7([M-H]
-)
Anal.Calcd.For?C
10H
7ClO
3:C?57.03，H?3.35；Found：C?57.34，H?3.32
Claims (8)
1. descend the compound of array structure:
2. the preparation method of (S)-(+)-1 compound of claim 1 comprises:
Chloro-phenyl-succsinic acid between racemization and S-(-)-α-Ben Yian are dissolved in ethanol, salify, cooling, filter (S)-(+)-chloro-phenyl-succsinic acid (S)-(-)-α-Ben Yian salt crude product, ethyl alcohol recrystallization gets elaboration, and elaboration is dissolved in the NaOH solution, adds methylene dichloride, mix, the water intaking layer is used the concentrated hydrochloric acid acidifying, separates out solid, filter (S)-(+)-2, make acyl chlorides with refluxing in (S)-(+)-2 adding sulfur oxychloride, the cooling back adds oil of mirbane and aluminum trichloride (anhydrous) reacts, and reaction solution is poured in the frozen water, component distillation, cooling obtains (S)-(+)-1.
3. the preparation method of (R)-(-)-1 compound of claim 1 comprises:
Chloro-phenyl-succsinic acid between racemization and (R)-(+)-α-Ben Yian is dissolved in ethanol, salify, cooling, filter (R)-(-)-chloro-phenyl-succsinic acid (R)-(+)-α-Ben Yian salt crude product, ethyl alcohol recrystallization gets elaboration, and elaboration is dissolved in the NaOH solution, adds methylene dichloride, mix, the water intaking layer is used the concentrated hydrochloric acid acidifying, separates out solid, filter (R)-(-)-2, make acyl chlorides with refluxing in (R)-(-)-2 adding sulfur oxychloride, the cooling back adds oil of mirbane and aluminum trichloride (anhydrous) reacts, and reaction solution is poured in the frozen water, component distillation, cooling obtains (R)-(-)-1.
4. claim 2 or 3 preparation method, wherein the chloro-phenyl-succsinic acid with (S)-(-)-mol ratio of α-Ben Yian or (R)-(+)-α-Ben Yian is 1: 1～1: 2.5, compound (S)-(+)-2 or be 1: 1～1: 4 with the mol ratio of aluminum chloride (R)-(-)-2.
5. the preparation method of claim 4, wherein the chloro-phenyl-succsinic acid with (S)-(-)-mol ratio of α-Ben Yian or (R)-(+)-α-Ben Yian is 1: 2～1: 2.2, compound (S)-(+)-2 or be 1: 2～1: 3 with the mol ratio of aluminum chloride (R)-(-)-2.
6. claim 2 or 3 preparation method, the temperature of reaction that wherein adds behind the aluminum trichloride (anhydrous) is 30～100 ℃, the reaction times is 0.5～5 hour.
7. the preparation method of claim 6, the temperature of reaction that wherein adds behind the aluminum chloride is 60～90 ℃, the reaction times is 1～2 hour.
8. claim 2 or 3 preparation method, wherein the concentration of NaOH solution is 0.1～10mol/L.
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|---|---|---|---|
| CNA200810123964XA CN101289387A (en) | 2008-05-30 | 2008-05-30 | 6-chlor-2,3-dihydro- indene-3-ketone-1-carboxyl acid optical isomer and method for preparing same |
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|---|---|---|---|
| CNA200810123964XA CN101289387A (en) | 2008-05-30 | 2008-05-30 | 6-chlor-2,3-dihydro- indene-3-ketone-1-carboxyl acid optical isomer and method for preparing same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130794A (en) * | 2015-09-02 | 2015-12-09 | 彭静 | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine |
| CN111620777A (en) * | 2020-06-10 | 2020-09-04 | 成都蓝蜻蜓生物技术有限公司 | Resolution method of (S) -1,2,3, 4-tetrahydro-1-naphthoic acid |
-
2008
- 2008-05-30 CN CNA200810123964XA patent/CN101289387A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130794A (en) * | 2015-09-02 | 2015-12-09 | 彭静 | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine |
| CN111620777A (en) * | 2020-06-10 | 2020-09-04 | 成都蓝蜻蜓生物技术有限公司 | Resolution method of (S) -1,2,3, 4-tetrahydro-1-naphthoic acid |
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Open date: 20081022 |