CN105315159B - A kind of method for splitting of compound - Google Patents
A kind of method for splitting of compound Download PDFInfo
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- CN105315159B CN105315159B CN201410415353.8A CN201410415353A CN105315159B CN 105315159 B CN105315159 B CN 105315159B CN 201410415353 A CN201410415353 A CN 201410415353A CN 105315159 B CN105315159 B CN 105315159B
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Abstract
The invention provides a kind of method for splitting of compound.Method for splitting of the present invention, it is easy to operate, without especially being reacted using the intermediate for possessing optical siomerism, it is possible to simply and effectively split and obtain (S) 3 chipal compounds, new selection is provided for the chiral resolution of related compound.
Description
Technical field
The present invention relates to a kind of method for splitting of compound.
Background technology
Chiral factor biology, chemistry and other it is multi-field in all there is extremely important influence power.With organising
Learn and biochemical development, the Chiral properties of compound have started to more and more be paid attention to.Numerous researchs show, different
Optical isomer may have completely different physiologically active, transporting mechanism, metabolic rate and toxicity, absorb, distribution and
Also it is not quite similar in terms of excretion.
Chiral resolution (Chiral resolution), also known as optical resolution (Optical resolution) or racemic
Body is split, and is in spatial chemistry, to separate method of the racemic compound as two different mirror image isomerism things.Generally make
Method for splitting has crystallization Split Method, chemical resolution method, enzymatic isolation method and column chromatography etc., wherein, chemical resolution method is normal
Reaction is participated in using a pure optical activity isomer, forms diastereomer, then diastereomer backward reaction is sloughed to pure light
Active isomer.But and not all compound can find suitable optical activity isomer and participate in reaction, if can
Find a kind of method that compound can be just split without using specific optical activity isomer, it will provide newly for chiral separation method
Thinking and selection.
The content of the invention
It is an object of the invention to provide a kind of chiral separation method of compound.
Specifically, the invention provides the method for splitting of (S) -3 compound as follows, reaction path are as follows：
Rac-3 isRacemic modification；
R1 is selected from phenyl ring, substituted benzene ring or five yuan or hexa-member heterocycle, R2 and is selected from C1-C4 alkyl, and R3 is selected from H or C1-C4 alkane
Base.
Further, the substituent of the substituted-phenyl is selected from halogen or nitro, and substituent quantity is 1~3.
Further, the halogen is selected from F, Cl or Br.
Further, substituent quantity is 1 or 2.
Further, the C1-C4 alkyl is selected from methyl or ethyl.
Further, concrete operation step is as follows：
Rac-3 is taken to add aldehyde 4, diphenylprolinol silicon ether IIa and glacial acetic acid, reaction is carried out, monitored with TLC at room temperature
Terminate to reaction, concentrate simultaneously silica gel column chromatography (PE/EA=10：1) the isolated MBH products (S) -3 of priority and chiral tetrahydrochysene pyrrole
Mutter alcohol product 5.
Further, Rac-3 preparation method is：
Wherein, the concrete operation step of Rac-3 preparation methods is as follows：
Nitroolefin 1 and carbonyls 2 make solvent in the presence of DMAP with MeCN, are stirred at room temperature to obtain MBH additions production
Thing rac-3.
MBH is Belize-Harry Hillman reaction.
Further, nitroolefin shown in formula 1：Carbonyls shown in formula 2：DMAP：Aldehyde shown in formula 4：Catalyst：Ice
Acetic acid=0.5-1.0mmol:1.0mmol：0.05-0.2mmol：1.0-2.0mmol：0.1-0.3mmol：0.1-0.2mmol.
Preferably, nitroolefin shown in formula 1:Carbonyls shown in formula 2：DMAP：Aldehyde shown in formula 4：Catalyst：Glacial acetic acid
=0.5mmol:1.0mmol：0.05mmol：1.0mmol：0.1mmol：0.1mmol.
Method for splitting of the present invention, it is easy to operate, without especially being reacted using the intermediate for possessing optical siomerism, so that it may
Simply and effectively to split to obtain (S) -3 chipal compounds, new selection is provided for the chiral resolution of related compound.
Below by way of embodiment, the present invention is described in further detail, but is not intended to limit the present invention, ability
Field technique personnel can be variously modified and deform according to the present invention, without departing from the spirit of the present invention, all should belong to this
Invention scope of the following claims.
Embodiment
1 method for splitting of the present invention of embodiment
Nitroolefin 1 (0.5mmol) and active carbonyls 2 (1.0mmol) DMAP (6.1mg,
In the presence of 0.05mmol), solvent is done with MeCN, 30min is stirred at room temperature and obtains MBH addition compound products rac-3.Then one kettle way adds
Enter aldehyde 4 (1.0mmol), diphenylprolinol silicon ether IIa (32.5mg, 0.1mmol) and glacial acetic acid (6.0mg, 0.1mmol).Instead
It should at room temperature carry out, reaction process is monitored with TLC.Concentrate simultaneously silica gel column chromatography (PE/EA=10：1) the isolated MBH of priority
Product (S) -3 and chiral oxinane alcohol product 5.
Each particular compound split is as follows：
(d, J=7.6Hz, 2H), 5.35 (d, J=4.8Hz, 1H), 5.18 (dd, J=9.6Hz, J=6.0Hz, 1H), 5.07 (d, J=
5.6Hz, 1H), 4.26-4.20 (m, 2H), 4.03 (br s, 1H), 3.16 (t, J=11.6Hz, 1H), 1.97-1.94 (m, 1H),
1.24 (t, J=7.2Hz, 3H), 0.86 (d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=
167.95,137.63,129.11,128.07,128.00,98.15,89.72,69.35,62.29,48.19,39.32,15.50,
13.85ppm；ESI HRMS:Calculated value C15H19NO6+ Na 332.1110, measured value 332.1112.
[α]D 20+ 108.4 (c=0.21in CH2Cl2).
1H), 7.31-7.19 (m, 3H), 5.30 (br s, 2H), 5.10 (d, J=4.8Hz, 1H), 4.34 (br s, 1H), 4.30-4.23
(m, 2H), 2.12-2.05 (m, 1H), 1.25 (t, J=6.8Hz, 3H), 0.88 (d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR
(100MHz,CDCl3):δ=167.89,130.43,130.26,129.13,128.32,127.67,127.40,98.39,
95.33,83.64,69.98,68.89,62.38,15.08,13.88ppm；ESI HRMS:calcd.For C15H18ClNO6+Na
366.0720 measured value 366.0716.
(S)-3b：Spectral data is consistent with racemic product 3b.Yield：39% (55.7mg) is efficient
Liquid phase CelluCoat posts measure ee values 98% (5%2-propanol/n-hexane, 1mL/min), UV 220nm, tminor=
13.24min,tmajor=14.23min. optically-actives：[α]D 20+ 86.2 (c=0.11in CH2Cl2).
7.20 (s, 1H), 7.10-7.08 (m, 1H), 5.34 (dd, J=7.6Hz, J=4.4Hz, 1H), 5.13 (dd, J=10.4Hz, J
=6.0Hz, 1H), 5.04 (d, J=5.6Hz, 1H), 4.28-4.21 (m, 2H), 3.46 (d, J=4.0Hz, 1H), 3.21-3.15
(m, 1H), 1.95-1.85 (m, 1H), 1.26 (t, J=7.2Hz, 3H), 0.87 (d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR
(100MHz,CDCl3):δ=167.64,139.71,135.02,130.40,128.41,128.09,126.32,97.82,
88.98,69.60,62.34,47.65,39.49,15.36,13.87ppm；High resolution mass spectrum ESI HRMS:Calculated value
C15H18ClNO6+ Na 366.0720, measured value 366.0723.
2-propanol/n-hexane,1mL/min),UV 220nm,tminor=10.13min, tmajor=19.33min. optically-actives：
[α]D 20+ 97.6 (c=0.15in CH2Cl2).
δ=7.35 (d, J=8.0Hz, 2H), 7.14 (d, J=7.6Hz, 2H), 5.33 (d, J=6.8Hz, 1H), 5.13 (dd, J=
10.0Hz, J=6.0Hz, 1H), 5.06 (d, J=5.6Hz, 1H), 4.26-4.20 (m, 2H), 4.06 (br s, 1H), 3.15 (t,
J=11.2Hz, 1H), 1.95-1.89 (m, 1H), 1.24 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H) ppm；Carbon
Spectrum13C NMR(100MHz,CDCl3):δ=166.80,135.12,132.96,128.34,128.31,96.94,88.37,
68.25,61.35,46.58,38.26,14.41,12.82ppm；High resolution mass spectrum ESI HRMS:Calculated value C15H18ClNO6+Na
366.0720 measured value 366.0723.
(S)-3d:Spectral data yields consistent with racemic product 3d:38% (54.3mg) efficient liquid phase AD-H posts determine
Ee values 98% (10%2-propanol/n-hexane, 1mL/min), UV 220nm, tminor=16.01min, tmajor=
30.78min. optically-actives：[α]D 20+ 82.4 (c=0.12in CH2Cl2).
CDCl3):δ=7.44 (s, 1H), 7.31-7.21 (m, 2H), 5.28 (br s, 2H), 5.07 (d, J=4.4Hz, 1H), 4.32-
4.23 (m, 2H), 4.09 (br s, 1H), 3.92-3.80 (m, 1H), 2.05 (br s, 1H), 1.25 (t, J=7.2Hz, 3H),
0.87 (d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=167.68,134.37,130.25,
130.08,128.07,127.74,127.67,98.19,95.18,83.25,69.86,69.01,62.44,14.99,
13.88ppm；High resolution mass spectrum ESI HRMS:calcd.For C15H17Cl2NO6+ Na 400.0331, measured value 400.0328.
Optically-active：[α]D 20+ 76.9 (c=0.21in CH2Cl2).
CDCl3):δ=7.45 (d, J=8.4Hz, 1H), 7.37 (s, 1H), 7.24-7.23 (m, 1H), 7.14 (d, J=7.6Hz, 1H),
5.32 (d, J=7.2Hz, 1H), 5.15 (dd, J=9.6Hz, J=5.6Hz, 1H), 5.07 (d, J=5.6Hz, 1H), 4.44 (br
S, 1H), 4.25-4.20 (m, 2H), 3.14 (t, J=11.2Hz, 1H), 1.97-1.89 (m, 1H), 1.24 (t, J=7.2Hz,
3H), 0.87 (d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=166.91,139.13,130.29,
129.95,129.64,125.83,122.14,96.99,88.27,68.11,61.41,46.89,38.22,14.52,
12.82ppm；High resolution mass spectrum ESI HRMS:Calculated value C15H18BrNO6+ Na 410.0215, measured value 410.0211.
(S)-3f：Spectral data is consistent with racemic product 3f.Yield：41% (67.7mg) is high
Imitate liquid phase AD-H posts measure ee values 90% (15%2-propanol/n-hexane, 1mL/min), UV 220nm, tminor=
9.80min,tmajor=18.88min. optically-actives：[α]D 20+ 65.8 (c=0.16in CH2Cl2).
CDCl3):δ=7.50 (d, J=7.6Hz, 2H), 7.08 (d, J=7.6Hz, 2H), 5.33 (d, J=4.0Hz, 1H), 5.12
(dd, J=9.6Hz, J=6.0Hz, 1H), 5.05 (d, J=5.2Hz, 1H), 4.25-4.21 (m, 2H), 4.08 (br s, 1H),
3.14 (t, J=11.2Hz, 1H), 1.95-1.88 (m, 1H), 1.24 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H)
ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=166.80,135.66,131.29,128.65,121.05,96.91,
88.26,68.27,61.36,46.65,38.23,14.40,12.82ppm；High resolution mass spectrum ESI HRMS:Calculated value
C15H18BrNO6+ Na 410.0215, measured value 410.0217.
min,tmajor=32.45min. optically-actives：[α]D 20+ 87.2 (c=0.16in CH2Cl2).
CDCl3):δ=7.19-7.16 (m, 2H), 7.08-7.04 (m, 2H), 5.35-5.33 (m, 1H), 5.13 (dd, J=9.6Hz, J
=6.0Hz, 1H), 5.06 (d, J=5.6Hz, 1H), 4.29-4.17 (m, 3H), 3.15 (t, J=11.2Hz, 1H), 1.96-
1.90 (m, 1H), 1.24 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR(100MHz,
CDCl3):δ=167.93,162.36 (d, JCF=246Hz), 133.38 (d, JCF=3Hz), 129.59 (d, JCF=8Hz),
116.14(d,JCF=21Hz), 98.08,89.76,69.19,62.38,47.57,39.35,15.49,13.84ppm；High-resolution
Mass spectrum ESI HRMS:Calculated value C15H18FNO6+ Na 350.1016, measured value 350.1011.
(S)-3h:Spectral data yields consistent with racemic product 3h:36% (48.5mg) efficient liquid phase AD-H posts determine
Ee values 99% (15%2-propanol/n-hexane, 1mL/min), UV 220nm, tminor=12.73min, tmajor=
24.56min. optically-actives：[α]D 20+ 75.4 (c=0.20in CH2Cl2).
7.67 (t, J=7.6Hz, 1H), 7.51-7.47 (m, 2H), 5.35-5.21 (m, 2H), 5.12 (d, J=5.2Hz, 1H), 4.32-
4.18 (m, 3H), 4.03 (br s, 1H), 2.08 (br s, 1H), 1.25 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz,
3H)ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=167.62,133.51,133.05,128.91,128.08,125.19,
124.96,97.91,95.17,88.35,83.98,69.70,62.52,13.85,13.43ppm；High resolution mass spectrum ESI HRMS:
Calculated value C15H18N2O8+ H355.1141, measured value 355.1145.
tmajor=34.45min. optically-actives：[α]D 20+ 91.6 (c=0.16in CH2Cl2).
CDCl3):δ=8.25 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 5.35 (dd, J=6.8Hz, J=4.4Hz,
1H), 5.18 (dd, J=10.0Hz, J=6.0Hz, 1H), 5.10 (d, J=5.6Hz, 1H), 4.31-4.19 (m, 2H), 3.80
(d, J=3.6Hz, 1H), 3.34 (t, J=11.2Hz, 1H), 2.01-1.95 (m, 1H), 1.26 (t, J=7.2Hz, 3H), 0.86
(d, J=6.4Hz, 3H) ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=167.58,147.73,145.19,129.08,
124.39,97.64,88.44,69.45,62.51,47.80,39.45,15.31,13.86ppm；High resolution mass spectrum ESI HRMS:
Calculated value C15H18N2O8+ Na 377.0961, measured value 377.0958.
min,tmajor=24.45min. optically-actives：[α]D 20+ 65.8 (c=0.22in CH2Cl2).
Claims (4)
1. the method for splitting of (S) -3 compound as follows, it is characterised in that：Reaction path is as follows：
Rac-3 isRacemic modification；
R1Selected from phenyl ring, substituted benzene ring or five yuan or hexa-member heterocycle, R2Selected from C1-C4 alkyl, R3Selected from H or C1-C4 alkyl；
Wherein, the substituent of the substituted-phenyl is selected from halogen or nitro；The halogen is selected from F, Cl or Br；Substituent quantity is
1 or 2；
Concrete operation step is as follows：
Rac-3 is taken to add aldehyde 4, diphenylprolinol silicon ether and glacial acetic acid, reaction is carried out, monitored with TLC to reaction at room temperature
Terminate, concentrate and pass through silica gel column chromatography, petrol ether/ethyl acetate=10：The isolated MBH products (S) -3 of 1 elution and chirality
Oxinane alcohol product 5；
Rac-3 preparation method is：
Nitroolefin 1 and carbonyls 2 make solvent in the presence of DMAP with MeCN, are stirred at room temperature to obtain MBH addition compound products
Rac-3。
2. method for splitting according to claim 1, it is characterised in that：The C1-C4 alkyl is selected from methyl or ethyl.
3. method for splitting according to claim 1, it is characterised in that：Nitroolefin shown in formula 1：Carbonyl compound shown in formula 2
Thing：DMAP：Aldehyde shown in formula 4：Diphenylprolinol silicon ether：Glacial acetic acid=0.5-1.0mmol:1.0mmol：0.05-0.2mmol：
1.0-2.0mmol：0.1-0.3mmol：0.1-0.2mmol.
4. method for splitting according to claim 3, it is characterised in that：Nitroolefin shown in formula 1:Carbonyl compound shown in formula 2
Thing：DMAP：Aldehyde shown in formula 4：Diphenylprolinol silicon ether：Glacial acetic acid=0.5mmol:1.0mmol：0.05mmol：1.0mmol：
0.1mmol：0.1mmol.
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| CN105315248A (en) * | 2014-06-26 | 2016-02-10 | 成都中医药大学 | Tetrahydropyranol series chiral compound, synthesis method therefor and use of tetrahydropyranol series chiral compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105315248A (en) * | 2014-06-26 | 2016-02-10 | 成都中医药大学 | Tetrahydropyranol series chiral compound, synthesis method therefor and use of tetrahydropyranol series chiral compound |
Non-Patent Citations (1)
| Title |
|---|
| Asymmetric One-Pot Four-Component Coupling Reaction: Synthesis of Substituted Tetrahydropyrans Catalyzed by Diphenylprolinol Silyl Ether;Hayato Ishikawa等;《Angew. Chem.》;20110324;第123卷;3858-3863 * |
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