CN1247592C - Optics decomposing method for coumarin dimer - Google Patents
Optics decomposing method for coumarin dimer Download PDFInfo
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- CN1247592C CN1247592C CN 01126762 CN01126762A CN1247592C CN 1247592 C CN1247592 C CN 1247592C CN 01126762 CN01126762 CN 01126762 CN 01126762 A CN01126762 A CN 01126762A CN 1247592 C CN1247592 C CN 1247592C
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Abstract
The present invention relates to an optics decomposing method for coumarin dimers, which makes optically pure TADDOL-6 selectively combined with an antimer of racemic coumarin dimers to form separated molecular crystals; after processing, N, N-dimethylformamide and products released by the reaction to the N, N-dimethylformamide are used, and then, the optics active coumarin dimers are obtained by post processing. The method has the advantages of simple operation, high repetitiveness, economy and easy recycle of chiral separation reagents. High efficiency optics decomposability to racemic bodies is realized, and the coumarin dimers are suitable for large-scale preparation.
Description
Technical field
The present invention relates to the optical isomer new method for splitting in the chiral technology.
Background technology
In four kinds of photosynthetic dimer 2-5 of tonka bean camphor 1, have only anti-head-to-head dimer 5 (the following coumarin dimer that all abbreviates as) to have optical activity.In coumarin dimer 5 molecules, both had C
2Symmetric tetra-atomic ring skeleton, but simultaneously lactone again open loop be derivatized to a series of compound [Yonezawa, N. with multiple functional group; Hasegawa, M.Bull.Chem.Soc.Jpn.1983,56,367-368].As can be used for building-up reactions [Hayashi, the M. of catalytic amino acid by the Rh complex compound of its deutero-biphosphine ligand; Hashimoto, Y.; Takezaki, H.; Watanabe, Y.; Saigo, K.Tetrahedron:Asymmetry 1998,1863-1866]; It and some diamine compounds optically active polymeric amide that has that forms of deriving has good chiral recognition ability, and the chiral stationary phase that has been used as high performance liquid chromatography (HPLC) is used for separating chiral compound [Saigo, K.; Chen, Y.; Yonezawa, N.; Kanoe, T.; Tachibuna, K.; Hasegawa, M.Macromolecules 1986,19,1552-1558] [Chen, Y.; Saigo, K.; Yonezawa, N.; Hasegawa, M.Bull.Chem.Soc.Jpn.1987,60,1895-1902] [Chen, Y.; Saigo, K.; Yonezawa, N.; Tachibana, K.Bull.Chem.Soc.Jpn.1987,60,3341-3345] [Chen, Y.; Shiao, M-T.Bull.Chem.Soc.Jpn.1992,65,3423-3429].Therefore optical purity coumarin dimer 5 will be a kind of chiral synthon and chiral ligand synthetic key intermediate with significant application value.Wherein the structural formula of 1-5 is as follows respectively:
The high-level efficiency of racemize coumarin dimer (±)-5 is three-dimensional single-minded synthesizes and was seen in report [Kraus, C.H. in 1966; Farid, S.and Schenk, G.O.Chem.Ber.1966,99,625], reaction formula is:
And its optical resolution to 1985 year just realizes [Saigo, K. first; Yonezawa, N.; Sekimoto, K.; Hasegawa, M.; Ueno, K.; Nakani sh, H.Bull.Chem.Soc.Jpn.1985,58,1000-1005], this method is at first reacted the acid amides non-enantiomer derivative that forms open loop by racemic coumarin dimer (±)-5 and optical purity α-Ben Yian, adopt the method for fractional crystallization again, obtain single optical isomer, obtain optical purity 5 through hydrolysis and ring closure reaction then, the shortcoming of this method is to need to transform through the multistep chemical reaction, step is long, efficient is low, and needs the optical purity α-Ben Yian of two molar equivalents, the report that does not also have the resolution reagent α-Ben Yian to reclaim.Another method that obtains optical purity coumarin dimer 5 is to utilize optically active TADDOL (-)-6a (i.e. (R, R)-(-) trans-4,5-pair-(hydroxy benzophenone base)-2,2-dimethyl-1, the 3-dioxolane) forms molecular crystal with tonka bean camphor 1, obtain the molecular crystal that optical purity dimer 5 and (-)-6a form by solid-state light reaction is three-dimensional then, the yield of reaction and enantioselectivity be near 100%[Tanaka single-mindedly, K.; Toda, F.; Mochizuki, E.; Yasui, N.; Kai, Y.; Miyahara, K.H.Angew.Chem.Int.Ed.1999,38,3523-3525], still, the first step (-)-6a and tonka bean camphor 1 form the extremely difficult control of condition of molecular crystal in this method, poor repeatability, and yield is low, and the solid-state light reaction of second step is difficult to realize a large amount of preparations.Because the present preparation method difficulty of optical purity coumarin dimer 5, therefore influenced the application in producing of its exploitation in asymmetry catalysis research and futurity industry.
Summary of the invention
For the problem of the preparation method difficulty that solves above-mentioned optical purity coumarin dimer 5, the invention provides easy, the optical isomer new method for splitting efficiently of a kind of racemize coumarin dimer (±)-5.
The present invention is according to the supramolecular chemistry principle, utilize the weak interaction between the additional mutually and group on the three-dimensional space between main body (HOST) molecule and object (GUEST) molecule, the two optionally forms stable molecular crystal by molecular recognition, thereby has realized the high-level efficiency optical resolution to racemic modification.
Method of the present invention is in organic solvent, optically pure 6 with racemize coumarin dimer (±)-5 reaction, wherein optically pure 6 with the mol ratio of racemize coumarin dimer (±)-5 be 1-3: 1, temperature of reaction 0-150 ℃, reaction times 2-10h, the molecular crystal that obtains of reaction from mother liquor, separate out and with organic solvent once more recrystallization obtain optical purity molecular crystal A ' or A, described optically pure 6 is (+)-6 or (-)-6, (+)-6 structural formula is
The structural formula of (-)-6 is
R or R ' are H, C in the formula
1～C
10Alkyl, cycloalkyl, phenyl or substituted-phenyl Ar be phenyl, substituted-phenyl or naphthyl, the substituting group of described substituted-phenyl is C
1～C
3Hydroxyalkyl, C
1～C
3Thiazolinyl, C
1～C
3Alkyl, hydroxyl, benzyloxy, dimethylin etc.; Described A ' is 2 (+)-6 (+)-5, and described A is 2 (-)-6 (-)-5, and the structural formula of described optically pure coumarin dimer (+)-5 is
The structural formula of (-)-5 is
In the above-mentioned reaction, preferential R or R ' are H, C
1～C
6Alkyl, cycloalkyl, phenyl or substituted-phenyl; The concrete structure of preferential (+)-6 or (-)-6 is for example shown in (+)-6a～u and (-)-6a～u:
(+)-6 TADDOLs?6a-u (-)-6
(+)6R R′ Ar (-)-6R R′ Ar
a Me Me Ph a Me Me Ph
b Me Ph Ph b Me Ph Ph
c (CH
2)
4 Ph c (CH
2)
4 Ph
d (CH
2)
5 Ph d (CH
2)
5 Ph
e Me Me 1-Nph e Me Me 1-Nph
f Me Me 2-Nph f Me Me 2-Nph
g Ph Ph Ph g Ph Ph Ph
h Ph H Ph h Ph H Ph
i tBu H Ph i tBu H Ph
j Me Me 3，5-Me
2C
6H
3 j Me Me 3，5-Me
2C
6H
3
k Et Et Ph k Et Et Ph
l Et Et?3，5-Me
2C6H
3 l Et Et 3，5-Me
2C
6H
3
m Me Me 4-HOC
6H
4 m Me Me 4-HOC
6H
4
n Me Me?4-C
6H
5CH
2OC
6H
4 n Me Me 4-C
6H
5CH
2OC
6H
4
O H H 4-(Me
2N)C
6H
4 o H H 4-(Me
2N)C
6H
4
p 4-(HOCH
2)C
6H
4 H Ph p 4-(HOCH
2)C
6H
4 H Ph
q 4-(CH
2＝CH)C
6H
4?H Ph q 4-(CH
2＝CH)C
6H
4?H Ph
r 4-(CH
2＝CH)C
6H
4?H 1-Nph r 4-(CH
2＝CH)C
6H
4?H 1-Nph
s 4-(CH
2＝CH)C
6H
4?H 2-Nph s 4-(CH
2＝CH)C
6H
4?H 2-Nph
t 4-(CH
2＝CH)C
6H
4?Me Ph t 4-(CH
2＝CH)C
6H
4?Me Ph
u 4-(CH
2＝CH)C
6H
4?Ph Ph u 4-(CH
2＝CH)C
6H
4?Ph Ph
Above-mentioned organic solvent ethyl acetate, benzene, toluene, ether, tetrahydrofuran (THF), acetonitrile, methylene dichloride, chloroform or acetone.
In this method, the preferred reaction raw material is (+)-6 and racemize coumarin dimer (±)-5, and described (+)-6 as previously mentioned; Perhaps the preferred reaction raw material is (-)-6 and racemize coumarin dimer (±)-5, and described (-)-6 as previously mentioned.
Preferably with the optical purity molecular crystal A ' or the A N that obtain, the mixed solvent recrystallization of dinethylformamide (DMF) and water, form new molecular crystal C ' or C, reclaim molecular crystal C ' or C, the mother liquor of reaction concentrates the back recrystallization and obtains optically pure (-)-5 or (+)-5, described C ' is (+)-6DMF, and described C is (-)-6DMF, and described A ', A, (-)-5 or (+)-5 are as previously mentioned.The volume ratio of preferred DMF/ water is 2-5: 1, and per 1 mole of A ' or A need 5-10 to rise solvent, and the amount that increases solvent does not hinder reaction, and the recrystallization temperature of reaction is 0-150 ℃, reaction times 1-10h.
Preferably after concentrating, unreacted (-)-5 or (+)-5 use DMF/H with staying in the reaction of the above-mentioned the first step in the mother liquor
2The O recrystallization, recrystallization gets optically pure (-)-5 or (+)-5 after the filtering and concentrating.[α] of described (+)-5
D 21=+9.0, condition determination: c=1.00, solvent: benzene; [α] of described (-)-5
D 21=-9.0, condition determination: c=1.00, solvent: benzene.
Preferably repeated use is reclaimed in (+)-6 or (-)-6, described (+)-6 or (-)-6 as previously mentioned.
Specifically:
Optically pure 6 optionally with racemize coumarin dimer (±)-5 in (+)-5 or (-)-5 enantiomorph combine when forming molecular crystal, the yield of the molecular crystal that this reaction obtains can reach 85-90%, enantiomeric excess (ee) can reach 88.5-92%.Wherein reactant is (+)-6 o'clock, and it combines with (+)-5, the molecular crystal that obtains from mother liquor, separate out and with organic solvent once more recrystallization promptly obtain optical purity molecular crystal A ', i.e. 2 (+)-6 (+)-5, (-)-5 then are retained in the mother liquor; Reactant is (-)-6 o'clock, and it combines with (-)-5, the molecular crystal that obtains from mother liquor, separate out and with organic solvent once more recrystallization promptly obtain optical purity molecular crystal A, i.e. 2 (-)-6 (-)-5, (+)-5 enantiomorph then is retained in the mother liquor.
With molecular crystal A ' or A N, during the mixed solvent recrystallization of dinethylformamide (DMF) and water, when wherein reactant is A ', by reaction (+)-6 discharge (+)-5 backs and and N, dinethylformamide (DMF) forms new molecular crystal C ', i.e. (+)-6DMF reclaims molecular crystal C ' then, the mother liquor of reaction concentrate the back with ethyl acetate/normal hexane recrystallization promptly with the yield of 60-80% and＞99% enantiomeric excess obtains (+)-5, [α] of (+)-5
D 21=+9.0 (c=1.00, benzene); When reactant is A, discharge back, (-)-5 and form new molecular crystal C by reaction (-)-6 with DMF, i.e. (-)-6DMF, reclaim molecular crystal C then, the mother liquor of reaction concentrate the back with ethyl acetate/normal hexane recrystallization promptly with the yield of 60-80% and＞99% enantiomeric excess obtains (-)-5, [a] of (-)-5
D 21=-9.0 (c=1.00, benzene).
Stay after the reaction of the above-mentioned the first step in the mother liquor and to use DMF/H after unreacted (-)-5 or (+)-5 concentrate
2(2-5: 1) during recrystallization, wherein a small amount of optically pure 6 form molecular crystal C ' with DMF or C removes, filtrate concentrates the back and promptly obtains optically pure (-)-5 or (+)-5, yield 60-80%, enantiomeric excess＞99% with ethyl acetate/normal hexane recrystallization O.
Merge resulting molecular crystal C ' twice, to wash with water behind the acetic acid ethyl dissolution, removing desolvates can reclaim (+)-6; Merge resulting molecular crystal C twice, to wash with water behind the acetic acid ethyl dissolution, removing desolvates can reclaim (-)-6.The above-mentioned rate of recovery can＞90%, and reusable, do not influence it and split efficient.
In the raw material of the present invention, racemize coumarin dimer 5 can be according to document [Kraus, C.H.; Farid, S.and Schenk, G.O.Chem.Ber.1966,99,625] the method high-level efficiency three-dimensional single-minded synthetic.
The present invention uses the resolution reagent that is easy to get that the coumarin dimer racemic modification with tetra-atomic ring skeleton is split, and method for splitting of having reported more or preparation method have following advantage:
1. method for splitting is different from existent method (as forming non-mapping derivative, direct reaction to light).Present method is according to the supramolecular chemistry principle, utilize the weak interaction between the additional mutually and group on the three-dimensional space between host molecule and the guest molecule, the two optionally forms stable molecular crystal by molecular recognition, thereby has realized the high-level efficiency optical resolution to racemic modification.
2. method economy.Optical resolution can be carried out to 1 mole of racemic modification in chiral selectors (+)-6 or (-)-6 that need only 1 mole, and chiral selectors reclaims (rate of recovery＞90%) easily, reusable and do not influence fractionation efficient, so the consumption of resolution reagent is very low.
3. it is higher to split efficient.Because high molecule distinguishability is arranged, cause isolating (-)-5 and (+)-5 isomer to have very high optical purity (88.5%-92%ee), need only a recrystallization, the enantiomeric excess of chirality coumarin dimer 5 can reach＞and 99%, total recovery reaches 60-80%..
4. simple to operate, good reproducibility can prepare in a large number.The involved operation of the inventive method is as filtering, extraction, and recrystallizations etc. all belong to the simple operations in the organic synthesis.Scale-up is the result show, therefore the be not put to the test influence of scale of the yield of product and optical purity is used in a large amount of preparations.
Description of drawings
Reaction method of the present invention such as accompanying drawing are illustrated in figures 1 and 2.
Fig. 1 is to be the reaction method of raw material with (+)-6 and racemize coumarin dimer 5, among the figure:
A ' is a molecular crystal 2 (+)-6 (+)-5; B ' is a mother liquor;
C ' is molecular crystal (+)-6DMF; D is DMF/H
2O (5: 1) recrystallization
E is for filtering, and filtrate concentrates; F is ethyl acetate/normal hexane recrystallization;
G is an ethyl acetate extraction, washing.
Fig. 2 is to be the reaction method of raw material with (-)-6 and racemize coumarin dimer 5, among the figure:
A is a molecular crystal 2 (-)-6 (-)-5; B is a mother liquor;
C is molecular crystal (-)-6DMF; D is DMF/H
2O (5: 1) recrystallization
E is for filtering, and filtrate concentrates; F is ethyl acetate/normal hexane recrystallization;
G is an ethyl acetate extraction, washing.
Embodiment
Help to understand the present invention by following examples, but be not limited to the present invention.
The high-level efficiency of embodiment one racemize coumarin dimer (±)-5 is three-dimensional single-minded synthetic
250mL benzene (analytical pure) solution that in a 250mL liquid phase photoreactor, adds 29.0g tonka bean camphor 1,5.04g benzophenone, earlier in system, blasted argon gas 0.5 hour, carried out illumination 10 hours with 400W Hg Lamp then, stopped reaction, the white crystal suction filtration of separating out is got the 21.5g product, 6.40g white crystal (±)-5 again after filtrate concentrates, total recovery is 96.0%.m.p.176-177℃；IR(KBr，cm
-1)：v＝1760，1490，1450，775，765cm
-1；
1H?NMR(CDCl
3，300MHz)：δ＝3.90(4H，d)，7.1-7.4(8H，m)。Recyclable benzophenone 4.57g of while, the rate of recovery is 91.4%.
The method for optical resolution of embodiment two coumarin dimers
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 9.34g (20mmol) (-)-6a respectively, 5.85g (20mmol) racemize coumarin dimer (±)-5 and 120mL ethyl acetate, said mixture is reflux 4 hours under agitation, be cooled to room temperature then, filter the flakes white crystalline solid that is generated, and carry out recrystallization once more with ethyl acetate (100mL), resulting white crystal (9.20g, 75%) is through being characterized by 2: 1 the molecular crystal A that (-)-6a and coumarin dimer (-)-5 form
a: 2 (-)-6a (-)-5.M.p.228-232 ℃; [α]
D 21=-72.0 ℃ (c=1.00, benzene); [α]
435 21=-157.5 ℃ (c=1.00, benzene);
1H NMR (CDCl
3.300MHz): δ=1.05 (12H, s), 3.9-4.0 (8H, m), 4.60 (4H, s), 7.1-7.6 (48H, m); C
80H
72O
12, calculated value: C, 71.37%; H, 3.99%.Measured value: C, 71.64%; H, 3.82%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 9.85g (20mmol) (-)-6b respectively, 5.85g (20mmol) racemize coumarin dimer (±)-5 and 120mL ethyl acetate, said mixture is reflux 4 hours under agitation, be cooled to room temperature then, filter the flakes white crystalline solid that is generated, and carry out recrystallization once more with ethyl acetate (100mL), resulting white crystal (8.94g, 70%) is through being characterized by 2: 1 the molecular crystal A that (-)-6b and coumarin dimer (-)-5 form
b: 2 (-)-6b (-)-5.M.p.198-202 ℃; [α] D25=-24.3 (c=1.00, chloroform); [α] 36525=-63.8 (c=1.00, chloroform); 1H NMR (CDCl3,300MHz): δ=1.3-1.5 (16H, s), 3.6-4.0 (8H, m), 4.7 (4H, s), 7.2-7.7 (48H, m); C84H76O12, calculated value: C, 78.97%; H, 6.00%.Measured value: C, 78.88%; H, 6.02%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 10.13g (20mmol) (-)-6c, other condition during with aforementioned (-)-6a is identical, resulting white crystal (9.79g, 75%) is through being characterized by 2: 1 the molecular crystal A that (-)-6c and coumarin dimer (-)-5 form
c: 2 (-)-6c (-)-5.M.p.226--230 ℃; [α] D25=-65.1 (c=1.00, chloroform); 1H NMR (CDCl3,300MHz): δ=1.1-1.6 (20H, m), 3.9-4.1 (44H, m), 4.55 (4H, s), 7.1-7.6 (48H, m).C86H80O12, calculated value: C, 79.12%; H, 6.18%.Measured value: C, 79.21%; H, 6.23%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 10.13g (20mmol) (-)-6d, other condition during with aforementioned (-)-6a is identical, resulting white crystal (9.79g, 75%) is through being characterized by 2: 1 the molecular crystal A that (-)-6d and coumarin dimer (-)-5 form
d: 2 (-)-6d (-)-5.M.p.226--230 ℃; [α] D25=-65.1 (c=1.00, chloroform); 1H NMR (CDCl3,300MHz): δ=1.1-1.6 (20H, m), 3.9-4.1 (44H, m), 4.55 (4H, s), 7.1-7.6 (48H, m).C86H80O12, calculated value: C, 79.12%; H, 6.18%.Measured value: C, 79.21%; H, 6.23%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 13.33g (20mmol) (-)-6e, other condition during with aforementioned (-)-6a is identical, resulting white crystal (12.68g, 78%) is through being characterized by 2: 1 the molecular crystal A that (-)-6e and coumarin dimer (-)-5 form
e: 2 (-)-6e (-)-5.M.p.222--225 ℃; [α]
D 25=-245.3 (c=1.00, ethyl acetate);
1H NMR (CDCl
3, 300MHz): δ=0.19 (4H, s), 3.9-4.0 (4H, s), 5.45 (4H, s), 7.2-7.6 (48H, m), 8.3-8.8 (56H, m) .C
112H
88O
12Calculated value: C, 82.74%; H, 5.46%.Measured value: C, 82.62%; H, 5.40%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 10.30g (20mmol) (-)-6h, other condition during with aforementioned (-)-6a is identical, resulting white crystal (9.91g, 75%) is through being characterized by 2: 1 the molecular crystal A that (-)-6h and coumarin dimer (-)-5 form
h: 2 (-)-6h (-)-5.M.p.198--202 ℃; [α]
D 25=-19.8 (c=1.00, chloroforms);
1H NMR (CDCl
3.300MHz): δ=2.15 (2H, s), 3.27 (2H, s), 3.9-4.0 (4H, m), 5.1-5.4 (6H, m), 7.0-7.7 (58H, m).C
88H
72O
12, calculated value: C, 79.98%; H, 5.49%.Measured value: C, 80.04%; H, 5.40%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 17.82g (20mmol) (-)-6n, other condition during with aforementioned (-)-6a is identical, resulting white crystal (8.60g, 80%) is through being characterized by 2: 1 the molecular crystal A that (-)-6n and coumarin dimer (-)-5 form
n: 2 (-)-6n (-)-5.M.p.206--208 ℃; [α]
D 25=-43.0 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=1.05 (12H, s), 3.9-4.0 (8H, m), 4.48 (4H, s), 5.01 (8H, s), 5.06 (8H, s), 6.8-7.0 (16H, m), 7.10-7.50 (64H, m) .C
136H
120O
20, calculated value: C, 78.74%; H, 5.83%.Measured value: C, 78.54%; H, 5.80%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 12.20g (20mmol) (-)-6o respectively, 5.85g (20mmol) racemize coumarin dimer (±)-5 and 120mL ethyl acetate, said mixture is reflux 4 hours under agitation, be cooled to room temperature then, filter the flakes white crystalline solid that is generated, and carry out recrystallization once more with ethyl acetate (100mL), resulting white crystal (12.0g, 80%) is through being characterized by 2: 1 the molecular crystal A that (-)-6o and coumarin dimer (-)-5 form
o: 2 (-)-6o (-)-5.M.p.164--168 ℃; [α]
D 25=-53.4 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=2.54 (4H, s), 2.90 (48H, d), 3.90 (4H, d), 4.63 (4H, s), 4.95 (4H, s), 6.5-6.7 (16H, d), 7.1-7.4 (24H, m).C
92H
101N
4O
12, calculated value: C, 75.79%; H, 7.19%; N, 3.84%.Measured value: C, 75.70%; H, 7.09%; N, 3.76%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Be equipped with in the round-bottomed flask of 250mL of reflux condensing tube one, add 10.90g (40mmol) (-)-6p respectively, 5.85g (20mmol) racemize coumarin dimer (±)-5 and 120mL toluene or methylene dichloride, said mixture is reflux 2 hours under agitation, be cooled to room temperature then, filter the flakes white crystalline solid that is generated, and carry out recrystallization once more with toluene or methylene dichloride (100mL), resulting white crystal (11.05g, 80%) is through being characterized by 2: 1 the molecular crystal A that (-)-6p and coumarin dimer (-)-5 form
p: 2 (-)-6p (-)-5.M.p.158--162 ℃; [α]
D 25=-24.2 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=1.66 (2H, t), 2.25,3.36 (4H, s), 3.90 (4H, d), 4.61 (4H, d), 5.12 (2H, d), 5.16 (2H, s), 5.30 (2H, d), 7.1-7.5 (56H, m) .C
90H
76O
14, calculated value: C, 78.24%; H, 5.54%.Measured value: C, 78.35%; H, 5.48%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
In the round-bottomed flask of 250mL, add 10.81g (20mmol) (-)-6q respectively, 5.85g (20mmol) racemize coumarin dimer (±)-5 and 120mL acetone or tetrahydrofuran (THF), said mixture low-grade fever reaction under agitation 10 hours, be cooled to room temperature then, filter the flakes white crystalline solid that is generated, and carry out recrystallization once more with acetone or tetrahydrofuran (THF) (100mL), resulting white crystal (10.3g, 75%) is through being characterized by 2: 1 the molecular crystal A that (-)-6q and coumarin dimer (-)-5 form
o: 2 (-)-6q (-)-5.M.p.138--140 ℃; [α]
D 25=-55.3 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=2.15,3.26 (4H, s), 3.90 (4H, d), 5.1-5.2 (4H, m), 5.22 (2H, dd), 5.31 (2H, d), 5.70 (2H, dd), 6.65 (2H, dd), 7.1-7.6 (56H, m) .C
93H
76O
12, calculated value: C, 80.44%; H, 5.58%.Measured value: C, 80.34%; H, 5.50%.Coumarin dimer (+)-5 item is stayed in the mother liquor.
Embodiment three coumarin dimer esterification by ring opening carry out HPLC and measure
With above-mentioned molecular crystal A
a10.0g use 5mL DMF/H
2O (5: 1) carries out recrystallization, forms colourless acicular crystal C
a(8.6g, 99%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 2.1g clear crystal (-)-5, yield 89%, ee＞99%;
With above-mentioned molecular crystal A
d10.0g use 5mL DMF/H
2O (5: 1) row recrystallization forms colourless acicular crystal C
d(8.43g, 95%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 2.00g clear crystal (-)-5, yield 89%, ee＞99%;
With above-mentioned molecular crystal A
e10.0g use 5mL DMF/H
2O (5: 1) carries out recrystallization, forms colourless acicular crystal C
e(8.73g, 96%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 1.70g clear crystal (-)-5, yield 95%, ee＞99%;
With above-mentioned molecular crystal A
h10.0g use 5mL DMF/H
2O (5: 1) carries out recrystallization, forms colourless acicular crystal C
h(8.54g, 96%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 2.10g clear crystal (-)-5, yield 95%, ee＞99%;
With above-mentioned molecular crystal A
n10.4g use 5mL DMF/H
2O (5: 1) carries out recrystallization, forms colourless acicular crystal C
n(9.06g, 94%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 1.30g clear crystal (-)-5, yield 88%, ee＞99%;
With above-mentioned molecular crystal A
o7.56g use 5mL DMF/H
2O (5: 1) carries out recrystallization, forms colourless acicular crystal C
o(6.28g, 92%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 1.31g clear crystal (-)-5, yield 90%, ee＞99%;
With above-mentioned molecular crystal A
p6.90g use 5mL DMF/H
2O (5: 1) carries out recrystallization, forms colourless acicular crystal C
p(5.87g, 95%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 1.30g clear crystal (-)-5, yield 89%, ee＞99%;
With above-mentioned molecular crystal A
q6.90g use 10mL DMF/H
2O (2: 1) carries out recrystallization, forms colourless acicular crystal C
q(5.65g, 92%) filters, and concentrated filtrate, resistates are used ethyl acetate/normal hexane recrystallization again, obtain 1.34g clear crystal (-)-5, yield 80%, ee＞99%, m.p.168.5-169 ℃; [α]
D 21=-9.0 (c=1.00, benzene); [α]
435 21=-65.8 (c=1.00, benzene); IR (KBr, cm
-1): v=1760,1490,1450,775,765cm
-1 1H NMR (CDCl
3, 300MHz): δ=3.90 (4H, d), 7.1-7.4 (8H, m);
More than obtaining derive again ester cpds 7 for open loop of clear crystal (-)-5 carries out HPLC and measures.
(+)-5 derive for the reaction formula of the ester cpds (+)-7 of open loop as follows:
(condition determination: the Japanese chirality AD of DaCheng Co., Ltd post (Chiralcel AD Column), eluent are Virahol/normal hexane=15: 85, and flow velocity is 0.80mL/min, retention time: t
(+)=8.00min, t
(-)=11.24min.).
The recovery of embodiment four resolution reagents (-)-6
Colourless acicular crystal C with above-mentioned gained
a5.40g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6a 4.50g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.195-196 ℃; [α]
D 21=-87.0 ° (c=1.00, benzene); [α]
435 21=-183.0 ° (c=1.00, benzene);
1H NMR (CDCl
3, 300MHz): δ=1.0 (6H, s), 3.95 (2H, s), 4.60 (2H, s), 7.2-7.6 (20H, m);
Colourless acicular crystal C with above-mentioned gained
d5.80g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6d 4.80g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.195-196 ℃; [α]
D 25=-74.4 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=1.1-1.6 (10H, m), 3.95 (20H, s), 4.55 (2H, s), 7.1-7.6 (20H, m).
Colourless acicular crystal C with above-mentioned gained
e7.40g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6e 6.54g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.195-196 ℃; [α]
D 25=-283.4 (c=1.00, ethyl acetate);
1H NMR (CDCl
3, 300MHz): δ=0.19 (2H, s), 5.45 (2H, s), 7.40 (20H, br), 8.28-8.74 (28H, m).
Colourless acicular crystal C with above-mentioned gained
h5.88g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6h 4.85g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.173-174 ℃; [α]
D 25=-22.6 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=2.15 (1H, s), 3.27 (1H, s), 5.13 (1H, d), 5.18 (1H, s), 5.33 (1H, d), 7.0-7.7 (25H, m).
Colourless acicular crystal C with above-mentioned gained
n9.64g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6n 8.46g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.176-178 ℃; [α]
D 25=-49.2 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=1.05 (6H, s), 4.00 (2H, s), 4.48 (2H, s), 5.01 (4H, s), 5.06 (4H, s), 6.8-7.0 (8H, m), 7.20-7.50 (28H, m).
Colourless acicular crystal C with above-mentioned gained
o6.83g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6o 6.05g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.135-137 ℃; [α]
D 25=-61.0 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=2.54 (2H, s), 2.90 (24H, d), 4.63 (2H, s), 4.95 (2H, s), 6.5-6.7 (8H, d), 7.2-7.4 (8H, d).
Colourless acicular crystal C with above-mentioned gained
p6.20g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6p 5.42g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.128-132 ℃; [α]
D 25=-28.2 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=1.66 (1H, t), 2.25,3.36 (2H, 2s), 4.61 (2H, d), 5.12 (1H, d), 5.16 (1H, s), 5.30 (1H, d), 7.13-7.54 (24H, m).
Colourless acicular crystal C with above-mentioned gained
q6.14g to wash (8mL * 3), anhydrous sodium sulfate drying behind the 15mL acetic acid ethyl dissolution with water three times; Remove desolvate white solid (-)-6q 5.36g, the rate of recovery＞90%, further recrystallization is promptly reusable.M.p.104-105 ℃; [α]
D 25=-63.2 (c=1.00, chloroforms);
1H NMR (CDCl
3, 300MHz): δ=2.15,3.26 (2H, 2s), 5.1-5.2 (2H, m), 5.22 (1H, dd), 5.31 (1H, d), 5.70 (1H, dd), 6.65 (1H, dd), 7.12-7.56 (24H, m).
Claims (9)
1. the method for optical resolution of a coumarin dimer, it is characterized in that in organic solvent, optically pure 6 with racemize coumarin dimer (±)-5 reaction, wherein optically pure 6 with the mol ratio of racemize coumarin dimer (±)-5 be 1-3: 1, temperature of reaction 0-150 ℃, reaction times 2-10h, the molecular crystal that obtains of reaction from mother liquor, separate out and with organic solvent once more recrystallization obtain optical purity molecular crystal A ' or A, described optically pure 6 is (+)-6 or (-)-6, (+)-6 structural formula be (+)-
The structural formula of (-)-6 be (-)-
R or R ' are H, C in the formula
1～C
10Alkyl, cycloalkyl, phenyl or substituted-phenyl; Ar is phenyl, substituted-phenyl or naphthyl, and the substituting group of described substituted-phenyl is C
1～C
3Hydroxyalkyl, C
1～C
3Thiazolinyl, C
1～C
3Alkyl, hydroxyl, benzyloxy, dimethylin; Described A ' is 2 (+)-6 (+)-5, and described A is 2 (-)-6 (-)-5, the structural formula of described optically pure coumarin dimer (+)-5 be (+)-
The structural formula of (-)-5 be (-)-
2. the method for optical resolution of coumarin dimer as claimed in claim 1, it is characterized in that optical purity molecular crystal A ' or A mixed solvent recrystallization with DMF/ water, form new molecular crystal C ' or C, reclaim molecular crystal C ' or C, the mother liquor of reaction concentrates the back recrystallization and obtains optically pure (-)-5 or (+)-5, described C ' is (+)-6DMF, and described C is (-)-6DMF, and described A ', A, (-)-5 or (+)-5 are according to claim 1.
3. the method for optical resolution of coumarin dimer as claimed in claim 2, the volume ratio that it is characterized in that DMF/ water is 2-5: 1.
4. the method for optical resolution of coumarin dimer as claimed in claim 1 is characterized in that reaction raw materials is (+)-6 and racemize coumarin dimer (±)-5, and described (+)-6 according to claim 1.
5. the method for optical resolution of coumarin dimer as claimed in claim 1 is characterized in that reaction raw materials is (-)-6 and racemize coumarin dimer (±)-5, and described (-)-6 according to claim 1.
6. the method for optical resolution of coumarin dimer as claimed in claim 1 is characterized in that described organic solvent is ethyl acetate, benzene, toluene, ether, tetrahydrofuran (THF), acetonitrile, methylene dichloride, chloroform or acetone.
7. the method for optical resolution of coumarin dimer as claimed in claim 1 is characterized in that staying in the reaction (1) in the mother liquor and to use DMF/H after unreacted (-)-5 or (+)-5 concentrate
2The O recrystallization, recrystallization gets optically pure (-)-5 or (+)-5 after the filtering and concentrating.
8. the method for optical resolution of coumarin dimer as claimed in claim 1 is characterized in that [α] of described (+)-5
D 21=+9.0, condition determination: c=1.00, solvent: benzene; [α] of described (-)-5
D 21=-9.0, condition determination: c=1.00, solvent: benzene.
9. the method for optical resolution of coumarin dimer as claimed in claim 1, it is characterized in that (+)-6 or (-)-6 reclaim and reuse, described (+)-6 or (-)-6 is according to claim 1.
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