CN1837203A - Chiral 4,4'-dimethoxy-5,6,5',6'-bis methylene dioxy -2,2'-phthalic acid derivatives and process for preparing same - Google Patents
Chiral 4,4'-dimethoxy-5,6,5',6'-bis methylene dioxy -2,2'-phthalic acid derivatives and process for preparing same Download PDFInfo
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- CN1837203A CN1837203A CN 200610017503 CN200610017503A CN1837203A CN 1837203 A CN1837203 A CN 1837203A CN 200610017503 CN200610017503 CN 200610017503 CN 200610017503 A CN200610017503 A CN 200610017503A CN 1837203 A CN1837203 A CN 1837203A
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Abstract
The invention relates to chiral 4,4'-dimethoxy-5,6,5',6'-bis methylene dioxy -2,2'-phthalic acid derivatives represented by formula I and II, as well as its preparing process, wherein R1 is CH3, CH3CH2, n-Pro, i-Pr, n-Bu-, i-Bu, R2 is selected from three compounds disclosed in the specification, R and S represent corresponding chirality centered formation, R3 is CH3 or CH2Ph, the compound can be used for treating viral hepatitis and liver functional disturbance.
Description
Technical field
The present invention relates to a class organic compound, referred more particularly to alkoxyl group biphenyl compound and synthetic method thereof.
Background technology
The alkoxyl group biphenyl compound is a class bioactive ingredients that is present in the Schisandraceae plant.So far, people's separation and Extraction goes out more than 100 kind of alkoxyl group biphenyl compound, and they show and protect the liver, protect multiple biological activitys such as central nervous system, anticancer, hepatitis B virus resisting, anti AIDS virus
[1-3]Wuweizisu C (schisndrinC) has hepatitis virus resisting activity
[5], steganacin (steganacin) has notable antitumor activity
[6]
Wuweizisu C Steganacin Gomisin G
The biphenyl structural unit of natural alkoxyl group couplet benzene ring octadiene compounds all has specific configuration.The biphenyl structural unit of alkoxyl group biphenol compounds such as Wuweizisu C, steganacin, Gomisin G is the S configuration.(Tomioka, K such as Tomioka; Ishiguro, T.; Mizuguchi, H.et al.Absolutestructure-cytotixic activity relationships of steganacin congeners and analogues.J.Med.Chem.1991,34,54) discover by the cytotoxic activity of and analogue of the same clan that the unitary absolute configuration of biphenyl is all very crucial to its antitumour activity to steganacin.
The related compound 4 of the natural alkoxyl group biphenyl of synthetic such as Xie Jingxi lignin, 4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid esters are simple for structure than the cyclooctadiene class biphenol compound of natural extract, but still have the close biological activity of relevant native annulus octadiene class biphenol compound.4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid esters have the activity of inhibition hepatitis B virus (HBV), hiv virus (HIV).Become at present the marketed drug of treatment hepatitis.
4,4 '-dimethoxy-5,6, in 5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid ester molecules, the existence of two the inferior methoxyl groups in biphenyl singly-bound ortho position and two ester groups, the rotation of biphenyl singly-bound is obstructed, produce two axle chiral isomers that configuration is different, studies show that there is difference (" herbal medicine Study on Modernization " in the biological activity of two chiral isomer, in the institute of Materia Medica,Chinese Academy of Medical Sciences, the first roll, 1995, p385).But the marketed drug Biphenylylmethylcarbinol is a R/S DL body.
It is generally acknowledged that the use of optical homochiral medicine can change drug effect, less toxic side effect.Obviously, development particular configuration optical purity 4,4 '-dimethoxy-5,6, the preparation method of 5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid esters is very necessary.
In order to obtain 4 of particular configuration, 4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid esters, document is taked indirect method for splitting, with 4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid esters are hydrolyzed to carboxylic acid, with the brucine is the repeatedly fractionation of resolving agent, and methylating with diazomethane then obtains the product of two kinds of configurations respectively; Or, non-mapping ester is separated, reduces the product that obtains two kinds of configurations after taking off benzyl, catalytic esterification respectively through silica gel column chromatography with dicarboxylic acid and chirality octyl group benzyl alcohol reaction esterification (US Pat.5,504,221,1997.).
Yet the inevitable result of above-mentioned method for splitting is no matter target product is S type or R type, at most also can only obtain 50%.Reason is raw material 4,4 '-dimethoxy-5,6, and 5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid esters are raceme, S type and R type isomer respectively account for 50%.
Summary of the invention
The novel chiral 4 that provides a class to have single particular configuration is provided the object of the invention, 4 '-dimethoxy-5,6, and 5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid derivatives and preparation method thereof make its preparation method that higher yields be arranged.
Novel chiral 4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid derivatives have following general structure:
R wherein
1Be Me, Et, n-Pr, i-Pr, n-Bu-, alkyl such as i-Bu-;
R
2For
R
3Be H, Me, CH
2Ph, i-Pr, CH
2CH (CH
3)
2, i-Bu, CH
2OH, CH
2(CH
3) OH, CH
2CH
2OH, CH
2CH
2CH
2OH, 4-HO-Ph-CH
2Etc. natural a-amino acid residue.
Two phenyl ring planar that on behalf of the biphenyl axle, S, R connected respectively are oriented to the configuration of S structure and R configuration or corresponding chiral carbon.
It specifically can be following compounds, but is not limited to following compounds:
The present invention takes the configuration conversion novel method to realize the object of the invention, and the preparation route of chirality α-biphenyl dicarboxylic acid derivatives is as follows:
1) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate dimethyl ester heating hydrolysis 4-10h in 10% potassium hydroxide aqueous solution, hydrochloric acid is adjusted to pH 1-4, filtration drying gets 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate (B);
2) 4,4 '-dimethoxy-5,6 ,-5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate 100-140 ℃ of following reaction 4-8h in diacetyl oxide, after the evaporated under reduced pressure 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid anhydride (C).
3) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid anhydride and Fatty Alcohol(C12-C14 and C12-C18) be such as reactions such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinols, and make solvent with corresponding alcohol, reflux 10-20h, that crystallisation by cooling can obtain is corresponding 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formic acid (D);
4) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formic acid is with CH
2Cl
2Being solvent, down reacting 4-10h with sulfur oxychloride at 15-60 ℃, solvent evaporated obtains 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formyl chloride (E).
5) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formyl chloride at inert solvent such as CH
2Cl
2In; under sour agent triethylamine existence of bundle and nitrogen protection; in 15-60 ℃ preferred 20 ℃; respectively with (S)-2-amino alcohol, (R)-2-amino alcohol reaction response 2-15h after; through saturated aqueous sodium carbonate, 5% aqueous hydrochloric acid, saturated sodium-chloride water solution washing reaction liquid, anhydrous sodium sulfate drying; solvent evaporated, crystallization in methyl alcohol, the ethanol can obtain target compound I, II behind the recrystallization.
Fatty Alcohol(C12-C14 and C12-C18) is including, but not limited to following alcohol in above-mentioned: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol.(S)-2-amino alcohol and (R) in above-mentioned-2-amino alcohol is respectively including, but not limited to following amino alcohol: (S)-2-aminopropanol, (R)-2-aminopropanol, (S)-2-amino-3-phenyl propanol, (R)-2-amino-3-phenyl propanol, (S)-dried meat aminopropanol, and directly reduce resulting chirality 2-amino alcohol by other natural chirals through carboxyl.
Meaning of the present invention be to provide a kind axle chirality 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid derivatives and synthetic method thereof; This kind axle chirality biphenol compound of the present invention and derivative thereof are single R or S configuration, and the pro-drug that can be used as treatment viral hepatitis and hepatic insufficiency is developed.Owing to do not contain enantiomorph, can improve the efficacy of medicine well and reduce Side effects of pharmaceutical drugs; Synthetic method of the present invention is through the configuration conversion of axle chiral centre, need through resolution process can be directly with higher yield synthesize respectively S and R configuration axle chirality 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid derivatives, simple synthetic method is feasible.
Description of drawings is synthetic target compound 3 (R
1Be CH
2CH
3, R
3Be CH
3) monocrystalline X-ray crystalline structure figure.
Embodiment
For the present invention is more described in detail, it is as follows to give an actual example:
Embodiment: 1) 4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acids (B) are synthetic
Compound 4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid dimethyl ester 1000g (2.4mol) add 95% ethanol 600mL and 82% potassium hydroxide 480g (7.04mol), reflux 7h, TLC detects, and reacts to the disappearance of raw material point cooling, to pH 2, suction filtration is collected filter cake with 10% hydrochloric acid, dry white solid 4, the 4 '-dimethoxy-5,6 of getting, 5 ', 6 '-two methylene-dioxy biphenyl dicarboxylic acid 910g, yield 97%.
2) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid anhydride (C) is synthetic
Get compound (B) 800g (2.04mol), add the 2.40L acetic anhydride, nitrogen protection; bathe temperature and react 6h down for 140 ℃, decompression steams acetic acid and excessive acetic anhydride, adds dry toluene 150mL; reduce to suction filtration after the room temperature, with toluene wash (2 * 50mL) filter cakes, after the drying compound 4; 4 '-dimethoxy-5; 6,5 ', 6 '-secondary methylenedioxy group biphenyl-2; 2 '-dicarboxylic acid anhydride (C) 702g, yield 92%.m.p.263-265℃。
3) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-third oxygen formyl radical-2 '-formic acid (D-1) is synthetic
With compound 4; 4 '-dimethoxy-5; 6; 5 '; 6 '-secondary methylenedioxy group biphenyl-2; 2 '-dicarboxylic acid anhydride (C) 53g (0.142mol) and DMAP 100mg (0.8mmol) add in the 500mL n-propyl alcohol, under the nitrogen protection, and reflux 20h; TLC detects (developping agent: methylene dichloride/sherwood oil/methyl alcohol=10/2/2); react completely, get compound dimethoxy-5,6 after cooling, crystallization, suction filtration, the drying; 5 '; 6 '-secondary methylenedioxy group biphenyl-2-third oxygen formyl radical-2 '-formic acid 50g, yield 81.3%, 204 ℃ of fusing points.
1H NMR(300MHz，CDCl
3)δ0.79(t，J＝7.5，3H，CH
3)，1.45(m，2H，CH
2CH
2CH
3)，3.96(s，3H，OCH
3)，3.97(s，3H，OCH
3)，4.02(t，J＝7.5，2H，OCH
2CH
2CH
3)，5.95-5.99(m，4H，2×OCH
2O)，7.38(s，1H，ArH)，7.44(s，1H，ArH).ESI-MS(m/s)431[M-H
+]
-
4) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-fourth oxygen formyl radical-2 '-formic acid (D-2) is synthetic
With compound 4; 4 '-dimethoxy-5; 6; 5 '; 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid anhydride (C) 40g (0.107mol) and DMAP 100mg (0.8mmol) add in the 400mL propyl carbinol, under the nitrogen protection; reflux 20h; TLC detects (developping agent: methylene dichloride/sherwood oil/methyl alcohol=10/2/2), react completely, get white, needle-shaped crystals 4 after cooling, crystallization, suction filtration, the drying; 4 '-dimethoxy-5; 6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-fourth oxygen formyl radical-2 '-formic acid (D-2) 42g; yield 87.7%, mp 188.
1H NMR(300MHz，CDCl
3)δ0.84(t，J＝7.5，3H，CH
3)，1.14-1.22(m，2H，CH
2CH
2CH
2CH
3)，1.36-1.45(m，2H，CH
2CH
2CH
2CH
3)，3.96(s，3H，OCH
3)，3.97(s，3H，OCH
3)，4.03-4.08(m，2H，OCH
2CH
2CH
2CH
3)，5.95-5.99(m，4H，2×OCH
2O)，7.38(s，1H，ArH)，7.44(s，1H，ArH).ESI-MS(m/s)431[M-H
+]
-
5) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-isobutyl oxygen formyl radical-2 '-formic acid (D-3) is synthetic
With compound 4; 4 '-dimethoxy-5; 6; 5 '; 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid anhydride (C) 43g (0.12mol) and DMAP 100mg (0.08mmol) add in the 400mL isopropylcarbinol, under the nitrogen protection; reflux 21h; TLC detects (developping agent: methylene dichloride/sherwood oil/methyl alcohol=10/2/2), react completely, get white crystallization 4 after cooling, crystallization, suction filtration, the drying; 4 '-dimethoxy-5; 6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-isobutyl oxygen formyl radical-2 '-formic acid (D-3) 44g; yield 85.3%, fusing point 196-200 ℃.
1H NMR(300MHz，CDCl
3)δ0.79(d，J＝6.6，6H，2×CH
3)，1.73(m，1H，CH
2CH(CH
3)
2)，3.86(d，J＝6.6，2H，OCH
2CH(CH
3)
2)，3.96(s，3H，OCH
3)，3.97(s，3H，OCH
3)，5.95-5.99(m，4H，2×OCH
2O)，7.38(s，1H，ArH)，7.44(s，1H，ArH).ESI-MS(m/s)445[M-H
+]
-
6) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-methoxycarbonyl base-2 '-formyl chloride (E-1) is synthetic
Get compound 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-methoxycarbonyl base-2 '-formic acid 10g (26mmol), add in the 100mL methylene dichloride, drip SOCl
22 of 20mL and DMF, reflux 5h under the nitrogen protection, decompression steams solvent and other volatile matters, adds dry toluene 25mL behind the evaporate to dryness, and the continuation decompression is steamed to doing, and gets 104 ℃ of little yellow solid 10g. fusing points, yield 97%.IR (cm
-1) 1765,1716,1634,1585.
7) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-ethoxycarbonyl-2 '-formyl chloride (E-2) is synthetic
Get compound 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-ethoxycarbonyl-2 '-formic acid 11g (26mmol), add in the 100mL methylene dichloride, drip SOCl
22 of 20mL and DMF, reflux 5h under the nitrogen protection, decompression steams solvent and other volatile matters, adds dry toluene 25mL behind the evaporate to dryness, and the continuation decompression is steamed to doing, and gets 104 ℃ of little yellow solid 11.1g. fusing points, yield 97%.IR (cm
-1) 1765,1716,1634,1585.
8) 4,4 '-dimethoxy-5,6,5 ', 6 '-the different third oxygen formyl radical-2 of secondary methylenedioxy group biphenyl-2-'-formyl chloride (E-3) is synthetic
Get compound 4,4 '-dimethoxy-5,6,5 ', 6 '-the different third oxygen formyl radical-2 of secondary methylenedioxy group biphenyl-2-'-formic acid 10g (23mmol), add in the 100mL methylene dichloride, drip SOCl
22 of 20mL and DMF, reflux 5h under the nitrogen protection, decompression steams solvent and other volatile matters, adds dry toluene 30mL behind the evaporate to dryness, and the continuation decompression is steamed to doing, and gets 116 ℃ of little yellow solid 10.5g. fusing points, yield 93%.IR (cm
-1) 1764,1716,1635,1585.
9) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-fourth oxygen formyl radical-2 '-formyl chloride (E-4) is synthetic
Get compound 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-fourth oxygen formyl radical-2 '-formic acid 10g (22mmol), add in the 100mL methylene dichloride, drip SOCl
22 of 20mL and DMF heat back under the nitrogen protection and heat up in a steamer 4h, and decompression steams solvent and other volatile matters, adds dry toluene 40mL behind the evaporate to dryness, and the continuation decompression is steamed extremely and done, and gets little yellow solid 10g. yield 97%.IR (cm
-1) 1747,1712,1637,1593.
10) 4,4 '-dimethoxy-5,6,5 ', 6 '-the different oxygen formyl radical-2 of secondary methylenedioxy group biphenyl-2-'-formyl chloride (E-5) is synthetic
Get compound 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-isobutyl oxygen formyl radical-2 '-formic acid 11g (24mmol), add in the 100mL methylene dichloride, drip SOCl
22 of 20mL and DMF heat back under the nitrogen protection and heat up in a steamer 4h, and decompression steams solvent and other volatile matters, adds dry toluene 40mL behind the evaporate to dryness, and the continuation decompression is steamed extremely and done, and gets little yellow solid 10.8g. yield 94%.IR (KBr compressing tablet, cm
-1) 1762,1712,1639,1587.
11) synthetic (R of target compound 1
1Be CH
3, R
3Be CH
3):
Get (S)-2-aminopropanol (2.25g; 30mmol) be dissolved in the 25mL methylene dichloride; add triethylamine (10mL), drip 4,4 in the ice bath '-dimethoxy-5; 6; 5 ', 6 '-secondary methylenedioxy group biphenyl-2-methoxycarbonyl base-2 '-formyl chloride 12g (28.4mmol) is dissolved in the solution that the 50mL methylene dichloride is made, argon shield; stir 10h under the room temperature; in reaction solution impouring 100mL water, 5% hydrochloric acid is regulated water to pH3, organic phase washing (2 * 100); saturated common salt washing (1 * 100); behind the anhydrous sodium sulfate drying; rotary evaporation is to doing, and recrystallization gets white solid 9.1g in the dehydrated alcohol, mp.160 ℃; yield 69%, [α]
D 25=-31.0～-33.1 ° (c=0.042, EtOH), ESI-MS m/z=462, [M+H
+].
1H NMR (300MHz, CDCl
3) δ 7.23,7.04 each (s, 1H, ArH), 6.25 (bd, 1H, NH), 6.06-5.95 (m, 4H, 2 * OCH
2O), and 4.05-4.10 (m, 1H, NCH), and 3.97,3.95each (s, 3H, OCH
3), 3.40-3.30 (m, 1H, CH
aOH), 3.19-3.11 (m, 1H, CH
bOH), 2.60 (bs, 1H, OH), 0.96 (d, J=6.6Hz, 3H, CH
3).
12) synthetic (R of target compound 3
1Be CH
2CH
3, R
3Be CH
3):
Get (S)-2-aminopropanol (2.31g; 30.8mmol) be dissolved in the 25mL methylene dichloride; add triethylamine (10mL), drip 4,4 in the ice bath '-dimethoxy-5; 6; 5 ', 6 '-secondary methylenedioxy group biphenyl-2-ethoxycarbonyl-2 '-formyl chloride 12g (27.5mmol) is dissolved in the solution that the 50mL methylene dichloride is made, argon shield; stir 10h under the room temperature; in reaction solution impouring 100mL water, 5% hydrochloric acid is regulated water to pH3, organic phase washing (2 * 100); saturated common salt washing (1 * 100); behind the anhydrous sodium sulfate drying; rotary evaporation is to doing, and recrystallization gets white solid 10.0g in the dehydrated alcohol, 138～140 ℃ of fusing points; yield 81%, [α]
D 25=94.3～98.0 ° of (c=0.045, EtOH) .ESI-MS m/z=476.NMR and monocrystalline X-diffraction result are as follows:
The NMR data analysis of compound 3:
Compound 3
1H NMR data
| Chemical shift (ppm) | Multiplicity | Coupling constant (Hz) | Proton number | 1H- 1H COSY | Corresponding proton |
| 7.27 | s | / | 1 | / | H-4 |
| 7.09 | s | / | 1 | / | H-9 |
| 6.31 | d | 6.95 | 1 | H-21 | N-H |
| 6.02 | dd | 1.46，11.71 | 2 | / | H-13 |
| 5.95 | dd | 1.46，1.83 | 2 | / | H-18 |
| 4.21 | q | 6.95 | 2 | H-17 | H-16 |
| 3.97 | s | / | 3 | / | H-14Δ |
| 3.95 | s | / | 3 | / | H-19Δ |
| 3.94 | m | / | 1 | H-22，H-23，N-H | H-21 |
| 3.57～3.37 | m | / | 2 | H-21 | H-23 |
| 2.94 | s | / | 1 | / | -OH |
| 1.17 | t | 6.95 | 3 | H-16 | H-17 |
| 0.75 | d | 6.95 | 3 | H-21 | H-22 |
Annotate: s, unimodal; D, doublet; Dd, double doublet; T, triplet; Q, quartet; M, multiplet.
Δ is represented commutative
Compound 3
13C NMR data
| The carbon sequence number | Chemical shift (ppm) | Carbon progression | HSQC | HMBC |
| 1 | 147.73 | Season | / | H-4，H-13 |
| 2 | 138.32 | Season | / | H-4，H-13 |
| 3 | 143.00 | Season | / | H-4 |
| 4 | 110.45 | Uncle | H-4 | / |
| 5 | 124.90 | Season | / | H-4 |
| 6 | 110.06 | Season | / | H-4 |
| 7 | 108.21 | Season | / | H-9 |
| 8 | 129.80 | Season | / | H-9 |
| 9 | 108.42 | Uncle | H-9 | / |
| 11 | 136.46 | Season | / | H-9，H-18 |
| 12 | 146.41 | Season | / | H-9，H-18 |
| 13 | 102.69 | Secondary | H-13 | / |
| 14Δ | 56.75 | Primary | H-14 | / |
| 15 | 167.09 | Season | / | H-4，H-16 |
| 16 | 61.47 | Secondary | H-16 | H-17 |
| 17 | 13.97 | Primary | H-17 | H-16 |
| 18 | 102.16 | Secondary | H-18 | / |
| 19△ | 56.43 | Primary | H-19 | / |
| 20 | 168.51 | Season | / | H-9，N-H |
| 21 | 48.25 | Uncle | H-21 | N-H，H-23，H-22 |
| 22 | 16.29 | Primary | H-22 | N-H，H-21，H-23 |
| 23 | 67.28 | Secondary | H-23 | H-22 |
Annotate: △ represents commutative
13) synthetic (R of target compound 7
1For-CH (CH
3) CH
3, R
3Be CH
3)
Get (S)-2-aminopropanol (2.25g; 30mmol) be dissolved in the 25mL methylene dichloride, add triethylamine (10mL), drip 4 in the ice bath; 4 '-dimethoxy-5; 6,5 ', 6 '-the different third oxygen formyl radical-2 of secondary methylenedioxy group biphenyl-2-'-formyl chloride 13.5g (30mmol) is dissolved in the solution that the 50mL methylene dichloride is made; under the nitrogen protection; stirring at room 7h, in reaction solution impouring 100mL water, 5% hydrochloric acid is regulated water to pH3; organic phase washing (2 * 100); saturated common salt washing (1 * 100); behind the anhydrous sodium sulfate drying, rotary evaporation is to doing, and recrystallization gets white solid 10.5g in the dehydrated alcohol; mp.184 ℃; yield 72%, ESI-MS, m/z=490[M+H
+] .[α]
D 25=7.1-9.5 ° of (c=0.024, CH
3OH).
1H NMR (300MHz, CDCl
3) δ 7.21,7.10each (s, 1H, ArH), 6.30 (bd, 1H, NH), 6.06-5.95 (m, 4H, 2 * OCH
2O), 5.07 (m, 1H, CHMe
2), 3.97,3.95each (s, 3H, OCH
3), 3.54-3.67 (m, 2H, CH
2), 2.74 (bs, 1H, NCH), 1.07 (d, J=6.3Hz, 3H, CH
3), 1.11 (dd, J
1=6.3Hz, J
2=1.2Hz 3H, CH
3).
14) synthetic (R of target compound 13
1For-CH
2CH
3, R
3Be CH
2Ph)
Get (S)-2-aminophenylpropyl alcohol (3.0g; 20mmol) be dissolved in the 25mL methylene dichloride; add triethylamine (10mL), drip 4,4 in the ice bath '-dimethoxy-5; 6; 5 ', 6 '-secondary methylenedioxy group biphenyl-2-ethoxycarbonyl-2 '-formyl chloride 8.7g (20mmol) is dissolved in the solution that the 50mL methylene dichloride is made, under the nitrogen protection; stirring at room 7h; in reaction solution impouring 100mL water, 5% hydrochloric acid is regulated water to pH3, organic phase washing (2 * 100); saturated common salt washing (1 * 100mL); behind the anhydrous sodium sulfate drying; rotary evaporation is to doing, and recrystallization gets white solid 8.47g in the dehydrated alcohol, mp.144 ℃; yield 77%, [α]
D 28=33.1～35.5 ° (c=0.042, EtOH), ESI-MS, m/z=552[M+H
+].
1H NMR (300MHz, CDCl
3) δ 7.25-7.05 (s, 7H, ArH), 6.40 (bd, 1H, NH), 5.97-5.94 (m, 4H, 2 * OCH
2O), 4.24-4.09 (m, 3H, OCH
2CH
3, NCH), 3.96,3.94each (s, 3H, OCH
3), 3.40-3.60 (m, 2H, CH
2OH), 2.53 (m, 3H, CH
2Ph, OH), 1.28 (t, J=7.2Hz, 3H, CH
3).
Used analytical instrument and model:
1H NMR,
13C NMR and 2D NMR measure with Bruker Ax300, and ESI-MS measures with LC-DSD-trap-SL, and optical value is measured and taked the PE-341 polarimeter to measure.
Claims (5)
- Chirality 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid derivatives, it is characterized in that, its contain represented (S)-4,4 of following general formula '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid derivatives, (R)-4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid derivatives:
R wherein 1Be Me, Et, n-Pr, i-Pr, n-Bu, i-Bu;R 2For
R 3Be H, Me, CH 2Ph, i-Pr, CH 2CH (CH 3) 2, i-Bu, CH 2OH, CH 2(CH 3) OH, CH 2CH 2OH, CH 2CH 2CH 2OH, 4-HO-Ph-CH 2Two phenyl ring planar that on behalf of the biphenyl axle, S, R connected respectively are oriented to the configuration of S structure and R configuration or corresponding chiral carbon. - 2. biphenyl derivatives as claimed in claim 1 is characterized in that it specifically can be following compounds, but is not limited to following compounds:
- 3. compounds process for production thereof as claimed in claim 1 is characterized in that, realizes by the following method:1) .4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate dimethyl ester heating hydrolysis 4-10h in 10% potassium hydroxide aqueous solution, hydrochloric acid is adjusted to pH1-4, filtration drying gets 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate;2) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate 100-140 ℃ of reaction 4-8h down in diacetyl oxide, after the evaporated under reduced pressure 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dioctyl phthalate;3) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2,2 '-dicarboxylic acid anhydride and Fatty Alcohol(C12-C14 and C12-C18) be such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol reaction, and make solvent with corresponding alcohol, reflux 10-20h, that crystallisation by cooling can obtain is corresponding 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formic acid;4) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formic acid is with CH 2Cl 2Being solvent, down reacting 4-10h with sulfur oxychloride at 15-60 ℃, solvent evaporated obtains 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formyl chloride;5) 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group biphenyl-2-alkoxyl formyl-2 '-formyl chloride at inert solvent such as CH 2Cl 2In; under sour agent triethylamine existence of bundle and nitrogen protection; in 15-60 ℃ preferred 20 ℃; respectively with (S)-2-amino alcohol, (R)-2-amino alcohol reaction response 2-15h after; through saturated aqueous sodium carbonate, 5% aqueous hydrochloric acid, saturated sodium-chloride water solution washing reaction liquid, anhydrous sodium sulfate drying; solvent evaporated, crystallization in methyl alcohol, the ethanol can obtain target compound I, II behind the recrystallization.
- 4. compounds process for production thereof as claimed in claim 3; it is characterized in that; 3), 4), 5) in the step, the 2-alkoxyl formyl is meant 2-methoxycarbonyl base, 2-ethoxycarbonyl, the 2-third oxygen formyl radical, the different third oxygen formyl radical of 2-, 2-fourth oxygen formyl radical, 2-isobutyl oxygen formyl radical.
- 5. compounds process for production thereof as claimed in claim 3 is characterized in that, (S)-and the 2-amino alcohol is meant (S)-2-aminopropanol, (S)-2-aminophenylpropyl alcohol, (R)-the 2-amino alcohol is corresponding (S)-2-amino alcohol enantiomer.
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| CN107488162A (en) * | 2015-10-19 | 2017-12-19 | 中国医学科学院药物研究所 | A kind of bicyclic alcohol derivatives and its preparation and application |
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| US5504221A (en) * | 1995-03-02 | 1996-04-02 | Development Center For Biotechnology | Method for resolving racemic compounds |
| KR100344099B1 (en) * | 1996-11-13 | 2003-09-26 | 김재철 | Novel biphenyldicarboxylate derivative and method for manufacturing the same |
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| CN107488162B (en) * | 2015-10-19 | 2020-09-18 | 中国医学科学院药物研究所 | Bicyclic alcohol derivatives, and preparation and application thereof |
| WO2021103749A1 (en) * | 2019-11-28 | 2021-06-03 | 中国医学科学院药物研究所 | Left-handed bicyclic morpholine and salt thereof, preparation method therefor, pharmaceutical composition, and application |
| RU2819002C1 (en) * | 2019-11-28 | 2024-05-08 | Инститьют Оф Материя Медика, Чайниз Экедеми Оф Медикал Сайенсез | Levorotatory bicyclic morpholine and salt thereof, method for preparation, pharmaceutical composition and use thereof |
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