CN101219963B - Phenylcarbinol kearny ester compounds - Google Patents

Phenylcarbinol kearny ester compounds Download PDF

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CN101219963B
CN101219963B CN 200810014212 CN200810014212A CN101219963B CN 101219963 B CN101219963 B CN 101219963B CN 200810014212 CN200810014212 CN 200810014212 CN 200810014212 A CN200810014212 A CN 200810014212A CN 101219963 B CN101219963 B CN 101219963B
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benzyloxycarbonyl
trimethylammonium
chlorination
ammonium
acyloxy
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CN101219963A (en
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徐文方
贡肖巍
冯波
翟海民
崔美兰
王丽
徐桂英
张志华
赵雪坤
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Shandong University
Shandong Qidu Pharmaceutical Co Ltd
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Shandong Qidu Pharmaceutical Co Ltd
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Abstract

The invention discloses a group of benzyl alcohol Kearny ester compounds, which have low moisture and good stability and are the pro-drug of a carnitine with a completely new structure.

Description

Phenylcarbinol kearny ester compounds
Technical field
The present invention relates to the pharmaceutical chemistry field, more specifically, relate to Phenylcarbinol kearny ester compounds.
Background technology
The research of levocarnitine derivative is carried out in the fifties in last century, mainly is the biological activity around vitamin BT, and the imitation coenzyme A prepares various acidylate vitamin BTs.Since 1980, further investigation along with vitamin BT mechanism of action in human body, a series of vitamin BT transhipment enzymes are found, the research of vitamin BT and derivative thereof thereupon deeply, its effect field is constantly expanded, the pharmaceutical use of vitamin BT derivative becomes increasingly conspicuous, and that has used clinically at present comprises: acetylcarnitine, propionyl vitamin BT, lemon acyl vitamin BT etc., wherein acetylcarnitine, propionyl vitamin BT go on the market in Europe.Acetyl-L-carnitine is better than levocarnitine aspect neuroprotective activity, be used for the treatment of the cholinomimetic insufficiency of function relevant with the age at present, for example neurofibril disease (dementia) and peripheral neuropathy.Chronic nephropathy, diabetics also there is certain curative effect.The propionyl levocarnitine is mainly used in chronic heart failure and peripheral vascular disease.Its curative effect all is better than levocarnitine.But these vitamin BT derivatives are because special chemical structure, have extremely strong draw moist, and also there is very strong hydrolysis tendency in they in the aqueous solution, brought great inconvenience for the research and development of preparation, the kind of listing only limits to minority formulations such as tablet, capsule, freeze-dried powder at present, and the preparation difficulty is bigger.The present invention has synthesized the ester class of a series of acyl group vitamin BTs, i.e. the prodrug of acyl group vitamin BT has improved it to a great extent and drawn moistly, and corresponding its stability that increased, and can prolong in vivo action time has the excellent research prospect.
Summary of the invention
The invention provides the following formula I compound:
Figure S200810014212XD00011
Formula I
Wherein, R is the C1-20 alkyl, and the one or more carbon atoms in this alkyl can be substituted by nitrogen, oxygen or sulphur atom, and R is optional by one or more halogens, hydroxyl, amino, sulfydryl, nitro, oxygen base, carboxyl or cyano group replacement; X -Be pharmaceutically acceptable counter ion, this ion can be monovalence, divalence or trivalent ion, the known X that works as of chemical field technician -During the expression divalent ion, the mol ratio of these counter ion and Ligusticum wallichii alcohol card Buddhist nun ester parent compound is 1: 2, works as X -During the expression trivalent ion, the mol ratio of these counter ion and Ligusticum wallichii alcohol card Buddhist nun ester parent compound is 1: 3, exemplary counter ion are such as mineral ion such as chlorion, bromide anion, iodide ion, bisulfate ion, sulfate radical, phosphate radical etc., such as organic ion such as aspartate, citrate, tartrate anion, fumaric acid radical, Phosphoric acid glycerol esters root, lactate, glactaric acid root, maleate, whey acid group, oxalate, nicotinic acid root, trichoroacetic acid(TCA) root, trifluoroacetic acid root, methanesulfonate, palmoxiric acid root etc.
In a preferred embodiment of the invention, carbon atom shown in the * is the R configuration in the formula I compound.
In a preferred embodiment of the invention, the X in the formula I compound -The expression chlorion.
Particular compound below the present invention also provides:
Chlorination 3-benzyloxycarbonyl-2-(R)-acetoxyl group-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-propionyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-butyryl acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-isobutyl acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-penta acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-isoamyl acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-hexylyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-Xin acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-oily acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-cinnamoyloxy group-N, N, N-trimethylammonium-1-third ammonium.
The present invention provides the preparation method of above-claimed cpd on the other hand, with the levocarnitine is raw material, and its hydroxyl and acyl chlorides (RCOCl) reaction forms ester, thereby products therefrom and oxalyl chloride reaction make the carboxyl of vitamin BT be converted into acyl chlorides, be reacted into ester with phenylcarbinol again, thereby obtain end product.Reaction process is as follows:
Figure S200810014212XD00031
The mode of the change acid group by routine such as products therefrom is mixed with alkali, is removed and is desalted, and then with sour blended mode, can obtain X -Compound for other counter ion.
According to the general theory of synthetic chemistry as can be known, in above-mentioned preparation flow, racemization can not take place in chiral centre, that is, adopt R configuration raw material (levocarnitine) will obtain the end product of R configuration, has proved this result by circular dichroism spectrum and/or CD spectrum yet.
" alkyl " described herein has the general implication on the chemical field,, by the group that carbon atom and hydrogen atom are formed, comprises alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl etc. that is.
Embodiment
Embodiment 1
The preparation of cinnamyl chloride
Get styracin 29.6g (0.2mol) and add sulfur oxychloride 100ml (0.84mol), stirring and dissolving, reflux 4h steams and removes excessive sulfur oxychloride, gets yellow solid, is cinnamyl chloride, is directly used in next step reaction.
The preparation of chlorination of hydrochloric acid cinnyl levocarnitine
Get hydrochloric acid levocarnitine 30.06g (0.125mol) and add CF 3COOH 100ml, stirring and dissolving, 0 ℃ of gradation adds top gained cinnamyl chloride, drips to finish to be warming up to 45～50 ℃, insulation reaction 20 hours.Reaction finishes to take out and is cooled to room temperature, adds acetone 800ml, stirs 2 hours, filters, and adds ether 1000ml in the filtrate, is stirred to the adularescent precipitation and separates out, and puts into refrigerator cold-storage 12 hours.After the taking-up, stirred 1 hour, filter, drying, white solid 36.30g, i.e. chlorination of hydrochloric acid cinnyl levocarnitine, yield: 76%
The preparation of chlorination of hydrochloric acid cinnyl levocarnitine acyl chlorides
Get chlorination of hydrochloric acid cinnyl levocarnitine 26.4g (0.09mol) and add methylene dichloride 100ml, stirring and dissolving, 0 ℃ of gradation 15ml (0.12mol) oxalyl chloride drips to finish and is warming up to 45～50 ℃, insulation reaction 4 hours.Steaming desolventizes, and gets white solid, and promptly chlorination of hydrochloric acid cinnyl levocarnitine acyl chlorides is directly used in the next step.
The preparation of chlorination of hydrochloric acid cinnyl levocarnitine benzene methyl
Gained chlorination of hydrochloric acid cinnyl levocarnitine is dissolved among the anhydrous DMSO of 100ml, adds 20ml (0.18mol) phenylcarbinol, heat up straight 50 ℃ gradually, the TLC monitoring reaction is complete, be cooled to room temperature, add ether 80ml, stirred 2 hours, the adularescent precipitation is separated out, filter, drying gets white solid 21.80g, be chlorination of hydrochloric acid cinnyl levocarnitine benzene methyl, yield: 58%.
Refining: get chlorination of hydrochloric acid cinnyl levocarnitine benzene methyl 8.36g (0.02mol) and be dissolved in the 25ml95% ethanol, add the 25ml ethyl acetate, the 50ml ether refrigerates 24 hours, gets colourless crystallization.
M.p：90～92℃
1HNMR(300Hz，D 2O)：2.71-2.76(2H，m，-CH 2COO-)；2.98(9H，S，(CH 3) 3N-)；3.58(2H，d，d，-NCH 2-)；4.79(2H，s，-CH 2C 6H 5)；5.60(1H，m，-NCH 2 CH-)；6.05(1H，d，- CH＝CHCOO-)；6.05(1H，d，-CH＝ CHCOO-)；6.84-7.00(5H，d，-CH 2C 6H 5)；7.10-7.4(5H，d，-CH＝CHC 6H 5)
IR(KBr?plate)：3067，3027(γ CH)，1729，1695(γ C＝O)，1669，1628(γ C＝C)，1504，1588(γ Ar-C)，1486，1431(δ CH2，CH3)，1208(v C-N)，681，695，723，758，917(aromatic?ring).ESI-MS(m/z)：436.2[M+H] +.
Embodiment 2
According to embodiment 1 similar methods, replace cinnamyl chloride with Acetyl Chloride 98Min., preparing R is CH 3Formula I compound.
1H?NMR(300Hz，D 2O)：2.01(3H，s，CH 3COO-)；2.62-2.65(2H，m，-CH 2COO-)；3.12(9H，S，(CH 3) 3N-)；3.58(2H，d，d，-NCH 2-)；4.56(2H，s，-CH 2C 6H 5)；5.53(1H，m，-NCH 2 CH-)；7.35-7.39(5H，d，-CH2C 6H 5)
IR(KBr?plate)：3013(γ CH)，1733(γ C＝O)1478，1411(δ CH2，CH3)，1215(v C-N)，709，726，768，934(aromatic?ring).ESI-MS(m/z)：294.4[M+H] +.
Embodiment 3
According to embodiment 1 similar methods, replace cinnamyl chloride with propionyl chloride, preparing R is CH 2CH 3Formula I compound.
1H?NMR(300Hz，D 2O)：1.00-1.05(3H，t，CH 3CH 2COO-)；2.51-2.58(2H，m，-CH 3CH 2COO-)；3.03-3.08(2H，m，-CH 2COO-)；3.19(9H，S，(CH 3) 3N-)；3.58(2H，d，d，-NCH 2-)；4.49(2H，s，-CH 2C 6H 5)；5.01(1H，m，-NCH2 CH-)；7.25-7.30(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3061，2926(γ CH)，1725(γ C＝O)，1479，1403(δ CH2，CH3)，1177(v C-N)，727，768，876，933(aromatic?ring).ESI-MS(m/z)：308.7[M+H] +.
Embodiment 4
According to embodiment 1 similar methods, replace cinnamyl chloride with butyryl chloride, preparing R is CH 2CH 2CH 3Formula I compound.
1H?NMR(300Hz，D 2O)：0.75-0.81(3H，t，CH 3CH 2-)；1.40-1.47(2H，m，-CH 3CH 2-)；2.18-2.22(2H，m，-CH 2CH 2COO-)；3.14-3.27(2H，m，-CHCH 2COO-)；3.05(9H，S，(CH 3) 3N-)；3.58(2H，d，d，-N CH2-)；5.10(2H，s，-CH 2C 6H 5)；5.57(1H，m，-NCH 2 CH-)；7.31-7.37(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：2966(γ CH)，1739(γ C＝O)，1690(γ C＝C)，1504，1588(γ Ar-C)，1483，1456(δ CH2，CH3)，1173(v C-N)，681，699，752，968(aromatic?ring).ESI-MS(m/z)：322.4[M+H] +.
Embodiment 5
According to embodiment 1 similar methods, replace cinnamyl chloride with isobutyryl chloride, preparing R is CH (CH 3) 2Formula I compound.
1H?NMR(300Hz，D 2O)：0.97-1.09(6H，m，(CH 3) 2CH-)；2.46-2.51(1H，m，(CH 3) 2 CH-)；2.75-2.78(2H，m，-CH 2COO-)；2.83(9H，S，(CH 3) 3N-)；3.56(2H，d，d，-NCH 2-)；5.12(2H，s，-CH 2C 6H 5)；5.59(1H，m，-NCH 2 CH-)；7.32-7.38(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3229，2971(γ CH)，1732(γ C＝O)，1480，1391(δ CH2，CH3)，1179(v C-N)，700，718，755，799，935(aromatic?ring).ESI-MS(m/z)：422.6[M+H] +.
Embodiment 6
According to embodiment 1 similar methods, replace cinnamyl chloride with valeryl chloride, preparing R is CH 2CH 2CH 2CH 3Formula I compound.
1H?NMR(300Hz，D 2O)：0.77-0.80(3H，t，CH 3CH 2-)；0.88-0.93(2H，m，-CH 3CH 2-)；1.45-1.47(2H，m，-CH 2CH 2CH 2-)；2.54-2.62(2H，m，-CH 2CH 2COO-)；3.04-3.07(2H，m，-CHCH 2COO-)；3.13(9H，S，(CH 3) 3N-)；3.58(2H，d，d，-NCH 2-)；5.08(2H，s，-CH 2C 6H 5)；5.55(1H，m，-NCH 2 CH-)；7.34(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3020，2959(γ CH)，1732(γ C＝O)，1480，1455(δ CH2，CH3)，1173(v C-N)，616，700，753，936(aromatic?ring).ESI-MS(m/z)：337.4[M+H] +.
Embodiment 7
According to embodiment 1 similar methods, replace cinnamyl chloride with isoveryl chloride, preparing R is CH 2CH (CH 3) 2Formula I compound.
1H?NMR(300Hz，D 2O)：0.78-0.87(6H，m，(CH 3) 2CH-)；2.15-2.19(1H，m，(CH 3) 2 CH-)；2.77-2.84(2H，m，-CH 2COOCH-)；3.10-3.15(2H，m，-CH 2COOCH 2-)；3.07(9H，S，(CH 3) 3N-)；3.56-3.76(2H，d，d，-NCH 2-)；5.11(2H，s，- CH2C 6H 5)；5.59(1H，m，-NCH 2 CH-)；7.34-7.38(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3020，2957(γ CH)，1736，1704(γ C＝O)，1488，1412(δ CH2，CH3)，1181(v C-N)，665，699，752，880，938(aromatic?ring).ESI-MS(m/z)：336.5[M+H] +.
Embodiment 8
According to embodiment 1 similar methods, replace cinnamyl chloride with caproyl chloride, preparing R is CH 2CH 2CH 2CH 2CH 3Formula I compound.
1H?NMR(300Hz，D 2O)：0.62-0.64(3H，t，CH 3CH 2-)；0.96-1.02(4H，m，-CH 3CH 2CH 2-)；1.98-2.07(2H，m，-CH 2CH 2COO-)；2.53-2.62(2H，m，-CH 2CH 2COO-)；3.07-3.12(2H，m，-CHCH 2COO-)；3.04(9H，S，(CH 3) 3N-)；3.56(2H，d，d，-NCH 2-)；4.90(2H，s，-CH 2C 6H 5)；5.50-5.57(1H，m，-NCH 2 CH-)；7.29-7.31(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3014，2957(γ CH)，1734(γ C＝O)，1480，1413(δ CH2，CH3)，1174(v C-N)，700，727，768，935(aromatic?ring).ESI-MS(m/z)：350.4[M+H] +.
Embodiment 9
According to embodiment 1 similar methods, replace cinnamyl chloride with capryl(yl)chloride, preparing R is CH 2(CH 2) 5CH 3Formula I compound.
M.p：122-125℃
1H?NMR(300Hz，D 2O)：0.76-0.78(3H，t，CH 3CH 2-)；1.08-1.24(8H，m，-CH 3(CH 2) 2-)；2.35-2.40(2H，m，-CH 2CH 2COO-)；2.75-2.78(2H，m，-CH 2CH 2COO-)；3.10-3.16(2H，m，-CHCH 2COO-)；3.13(9H，S，(CH 3) 3N-)；3.60(2H，d，d，-NCH 2-)；5.08(2H，s，-CH 2C 6H 5)；5.57-5.63(1H，m，-NCH 2 CH-)；7.33-7.39(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3017，2927(γ CH)，1735，1698(γ C＝O)，1646(γ C＝C)，1482，1416(δ CH2，CH3)，1174(v C-N)，666，726，880，938(aromatic?ring).ESI-MS(m/z)：378.6[M+H] +.
Embodiment 10
According to embodiment 1 similar methods, replace cinnamyl chloride with oleoyl chloride, preparing R is (CH 2) 7CH=CH (CH 2) 7CH 3Formula I compound.
1H?NMR(300Hz，D 2O)：0.86-0.90(3H，t，CH 3CH 2-)；1.18-1.42(20H，m，-(CH 2) 6CH 2CHCHCH 2(CH 2) 4；1.68(4H，m，-CH 2CHCHCH 2-)；2.22-2.29(2H，m，-CH 2CH 2COO-)；2.75-2.80(2H，m，-CH2CH 2COO-)；3.03-3.10(2H，m，-CHCH 2COO-)；3.24(9H，s，(CH 3) 3N-)；3.87(2H，d，d，-NCH 2-)；5.10(2H，s，-CH 2C 6H 5)；5.51-5.62(1H，m，-NCH 2 CH-)；6.43(1H，d，- CH＝CH-)；6.87(1H，d，-CH＝ CH-)；7.27-7.36(5H，d，-CH 2C 6H 5)
IR(KBr?plate)：3034，3028(γ CH)，1735，1688(γ C＝O)，1479，1468(δ CH2，CH3)，1184(v C-N)，705，712，753，799，914(aromatic?ring).ESI-MS(m/z)：552.7[M+H] +.
The experiment of embodiment 11 accelerated stabilities
Precision is measured each three parts of propionyl vitamin BT and the about 50mg of example 3 compounds, put in the measuring bottle of 2ml, add the injection water respectively to scale, under 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition, placed 3 months, respectively at 0,1,2, the sampling in March measures every index with high performance liquid phase.
Propionyl vitamin BT and example 3 compound accelerated test results (RH75%, 40 ℃)
Lot number Time (moon) Proterties Clarity Related substance Content (%)
Propionyl vitamin BT example 3 compounds 0 does not have 1 nothing, 2 nothings, 3 nothings, 0 nothing 1 does not have 2 nothings, 3 nothings Look clear and bright solution look clear and bright solution look clear and bright solution look clear and bright solution look clear and bright solution look clear and bright solution look clear and bright solution look clear and bright solution Qualified 1.18 4.51 5.75 7.15 1.41 1.67 1.53 1.95 98.82 95.45 94.25 92.85 98.59 98.33 98.47 98.15
The stability of example 3 compounds in the aqueous solution is apparently higher than the propionyl vitamin BT.
Embodiment 12 draws moist experiment
Precision is measured each three parts of propionyl vitamin BT and the about 50mg of example 3 compounds, puts in the measuring bottle of 2ml, places under 25 ℃ ± 2 ℃ of temperature, relative humidity 35% ± 5% condition, after 24 hours, observe, the propionyl vitamin BT has become clear aqueous solution, and example 3 compounds only have moisture absorption phenomenon slightly.
Relatively example 3 compounds of the present invention and propionyl vitamin BT are relatively: draw the moist propionyl vitamin BT that is starkly lower than
The experiment of embodiment 12 neurocyte protections
Damage model: CoCl 2The anoxia-induced apoptosis that causes
Cell viability measuring method: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) method
Testing sequence:
1, the PC12 that takes the logarithm vegetative period (pheochromocytoma) cell is inoculated into after the trysinization in 6 orifice plates, and cell density is about 5 * 10 5Individual/ml, culture condition is that DMEM adds 10% horse serum and 5% foetal calf serum;
Treat after the cell attachment that 2, add the sample that 2 μ l hepatomicrosome enzymes and final concentration are 10mg/l (compound among the embodiment), sample solvent is DMSO, storing solution concentration is 10g/l;
3, add after 4 hours, final concentration is 500,300, or the CoCl of 200 μ M 2, continued to hatch 12-16 hour.
Adopt mtt assay to measure the Ligustrazine series derivates to CoCl 2The provide protection of the PC12 cell hypoxia damage that causes.In the PC12 of various processing cell, add solution, its final concentration is reached under 37 ℃ of the 0.5mg/mL hatched 2-4 hour.After termination is hatched, inhale and remove supernatant, add DMSO (pH 4.7), De Jia Za particle in the dissolving viable cell.Under the 570nm wavelength, measure optical density value OD with microplate reader 570, reference wavelength is that (light absorption value is expressed as OD to 630nm 630).
Activity test the results are shown in following table:
Sample Average (OD 630) SD
Blank 1 0
CoCl 2(alone) 0.539831 0.075356
Embodiment 2 0.592519 0.08673
Acetylcarnitine 0.596925 0.06745
Vitamin BT 0.591801 0.09853
The result shows: The compounds of this invention can be brought into play the effect of vitamin BT, acetylcarnitine under the hepatomicrosome enzyme effect.

Claims (6)

1. following formula: compound:
Figure FSB00000244419300011
Wherein, R is alkyl or the alkenyl of C1-20, and the one or more carbon atoms in this group can be substituted by nitrogen, oxygen or sulphur atom, and R is optional by one or more halogens, hydroxyl, amino, sulfydryl, nitro, oxygen base, carboxyl or cyano group replacement; X -Be chlorion, bromide anion, iodide ion, bisulfate ion, lactate, whey acid group, nicotinic acid root, trichoroacetic acid(TCA) root, trifluoroacetic acid root, methanesulfonate.
2. compound according to claim 1, wherein carbon atom shown in the * is the R configuration.
3. compound according to claim 1, wherein X -Be chlorion.
4. compound according to claim 1, it is:
Chlorination 3-benzyloxycarbonyl-2-(R)-acetoxyl group-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-propionyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-butyryl acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-isobutyl acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-penta acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-isoamyl acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-hexylyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-Xin acyloxy-N, N, N-trimethylammonium-1-third ammonium
Chlorination 3-benzyloxycarbonyl-2-(R)-oily acyloxy-N, N, N-trimethylammonium-1-third ammonium.
5. the preparation method of the described compound of claim 1, it is characterized in that, with the vitamin BT is raw material, the acyl chloride reaction of its hydroxyl and formula RCOCl forms ester, thereby products therefrom and oxalyl chloride reaction make the carboxyl of vitamin BT be converted into acyl chlorides, be reacted into ester with phenylcarbinol again, thereby obtain required product, wherein the implication of R according to claim 1.
6. compound according to claim 1 is used for the purposes of neurocyte protection and treatment cardiovascular and cerebrovascular diseases medicament in preparation.
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* Cited by examiner, † Cited by third party
Title
Xun Li, et al..(R,E)-[4-(Benzyloxy)-2-(cinnamoyloxy)-4-oxobutyl]trimethylammonium chloride hydrochloride.Acta Crystallographica Section E63 Part 11.2007,63(Part 11),o4239-o4240. *
XunLi et al..(R

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