CN104774177A - Polycyclic benzyl alcohol derivative with optical activity - Google Patents

Polycyclic benzyl alcohol derivative with optical activity Download PDF

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Publication number
CN104774177A
CN104774177A CN201510174291.0A CN201510174291A CN104774177A CN 104774177 A CN104774177 A CN 104774177A CN 201510174291 A CN201510174291 A CN 201510174291A CN 104774177 A CN104774177 A CN 104774177A
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atom
dihydroquinoline
many rings
salt
substitute
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Inventor
陈永正
崔宝东
韩文勇
周晓建
郑代军
卓俊睿
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Zunyi Medical University
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Zunyi Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring

Abstract

The invention discloses a polycyclic benzyl alcohol derivative with optical activity shown in a chemical formula [C-3] or a salt of the polycyclic benzyl alcohol derivative. The chemical formula is shown in the description.

Description

One has optically active many rings benzylalcohol derivative
Technical field
The present invention relates to and there is optically active many rings benzylalcohol derivative.Concrete, the present invention relates to and there is optically active 1,2,3,4-tetrahydroquinoline-4-alcohol derivate or its salt and there is optically active chirality 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol derivate or its salt.
Background technology
Chirality benzylalcohol containing active function groups is the important feature unit synthesizing the chemical of many structure diversifications, medicine and agricultural chemicals, because this compounds can be derived as a lot of pharmaceutical intermediates by a series of chemical conversions of hydroxyl.Especially, tetrahydroquinoline-4-alcohol and 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol, as important molecular skeleton, are extensively present in a lot of pharmaceutical activity molecules, play a part very important in pharmaceutical chemistry.Such as, 1,2,3,4-tetrahydroquinoline-4-alcohol compound is the key intermediate synthesizing phosphodiesterase inhibitor (PED4) 1, glucocorticoid agonists 3 and Cannabined receptor 2 agonist 4.The derivative of 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol, as the one of benzo-aza cycloheptatriene derivative, is a kind of non-peptide vasopressin V 2 Receptor Antagonists that can be oral, and is used as diuretic(s) and is carrying out clinical trial.Usually, from the viewpoint of the pharmacologically active and side effect etc. of medicine, there is optically active drug molecule better than the clinical effectiveness of its raceme.Therefore, searching synthesis has the effective ways of optically active tetrahydroquinoline-4-alcohol, 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol and their derivative is very necessary.
In prior art, the report about the synthesis of chiral tetrahydroquinoline-4-alcohol, 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol compounds is little.Wherein, tetrahydroquinoline-4-the alcohol of chirality and derivative thereof can by 2,3, the chiral oxazaborolidine reduction of-dihydro-quinolinone or using the complex compound of metal Ru and chiral diamine ligands as catalyzer, under hydrogen donor existent condition, obtained by asymmetric transfer hydrogenation.But often reaction conditions is harsher to utilize metal reagent iridium and borane gases to prepare chipal compounds, and metal reagent is expensive, thus production difficulty and cost higher.In addition, also useful fungi cunninghamella elegansthe tetrahydroquinoline that N-replaces is converted into the method for tetrahydroquinoline-4-alcohol, but the productive rate of the method is very low.Therefore, a kind of method of 1,2,3,4-tetrahydroquinoline-4-alcohol, 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol and their derivative that convenient preparation optical purity is high is in a mild condition needed badly.
In the present invention, many rings benzalcohol derivatives refers to many rings benzylalcohol and derivative thereof, tetrahydroquinoline alcohol compound refers to tetrahydroquinoline alcohol and derivative thereof, 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol compound refers to 2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol and derivative thereof.
Summary of the invention
The invention provides a kind of preparation method with optically active many rings benzalcohol derivatives, comprising:
1, add compound or its salt, enzyme and the acry radical donor as shown in chemical formula [C-1] in organic solvent, stir under the temperature of reaction of 0 DEG C-100 DEG C;
Wherein * represents chiral carbon atom;
Ring A is the phenyl ring that can be substituted;
X is-CH 2-or-CH 2cH 2-;
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; H, D, F, Cl, Br, I, CHO, N (Ar 1) 2, N (R 2) 2, C (=O) Ar 1, P (Ar 1) 2, P (=O) (Ar 1) 2, S (=O) Ar 1, S (=O) 2ar 1, CR 1=CR 1ar 1, CN, NO 2, Si (R 1) 3, B (OAr 1) 2, B (OR 1) 2, OSO 2r 1, OH, has the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or has branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, and they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by R 1c=CR 1, C=C, Si (R 1) 2, Ge (R 1) 2, Sn (R 1) 2, C=O, C=S, C=Se, C=NR 1, P (=O) (R 1), SO, SO 2, NR 1, O, S or CONR 1substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
Ar 1, occur identical or different each time, be fragrance or the hetero-aromatic ring system with 5 to 30 aromatic ring atom, it can by more than one non-aryl R 2replace; Here, two group Ar of identical nitrogen or phosphorus atom are bonded to 1can also by singly-bound or by being selected from B (R 1), C (R 1) 2, Si (R 1) 2, C=O, C=NR 1, C=C (R 1) 2, O, S, S=O, SO 2, N (R 1), P (R 1) and P (=O) R 1bridging be connected to each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute; Here the substituent R that two or more is adjacent 1fat or the aromatic ring of single or many rings can also be formed each other;
2, be separated and obtain there is optically active many rings benzylalcohol derivative or its salt and there is optically active many rings benzylalcohol or its salt.
In compound or its salt shown in the preferred described chemical formula [C-1] of the present invention,
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
More preferably in the compound or its salt shown in described chemical formula [C-1],
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
More preferably in the compound or its salt shown in described chemical formula [C-1],
R 1h or halogen (Cl, Br or I);
R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
More preferably in the compound or its salt shown in described chemical formula [C-1],
Ring A is phenyl ring;
When X is-CH 2-, R 1when being H, R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl; When X is-CH 2-, R 1when being Cl or Br, R 2tertbutyloxycarbonyl (Boc);
When X is-CH 2cH 2-, R 1when being H, R 2carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl.
Described organic solvent can be hydrocarbon, heterogeneous ring compound, alcohol, aldehyde, ketone, ether, acid, ester, amine, nitrile, sulfone and/or sulfoxide, such as, in hexanaphthene, normal hexane, benzene, toluene, pyridine, ethanol, propionic aldehyde, acetone, ether, tetrahydrofuran (THF), butyric acid, ethyl acetate, aniline, acetonitrile, dimethyl sulfone, methyl-sulphoxide one or more; Preferred hydrocarbons, alcohol, ketone, ether, ester and/or nitrile, such as, in hexanaphthene, normal hexane, benzene, toluene, ethanol, acetone, ether, ethyl acetate, acetonitrile one or more; More preferably hydrocarbon, ether and/or nitrile, such as, in hexanaphthene, normal hexane, n-dodecane, n-hexadecane, benzene, toluene, p-Xylol, o-Xylol, m-xylene, ether, methyl ethyl ether, methyl tertiary butyl ether, diisopropyl ether, acetonitrile one or more; More preferably ether, such as, in methyl ethyl ether, methyl tertiary butyl ether, diisopropyl ether one or more.
Described enzyme obtains by commercial means, also can oneself prepare, preferred fat enzyme and/or lytic enzyme, more preferably lipase, more preferably enzyme novozyme435, the wild lipase A in sky ( amano Lipasea), lipase RM IM( lipaserM IM) and/or lipase TL IM( lipasetL IM).More preferably above-mentioned enzyme is immobilized enzyme.
Described acry radical donor can be acid anhydrides, carboxylic acid halides and/or ester, such as, in diacetyl oxide, acetyl bromide, acrylate chloride, ethyl acetate, vinyl chloroacetate one or more; Preferred anhydrides, acyl chlorides and/or ester, such as, in diacetyl oxide, acrylate chloride, ethyl acetate, vinyl chloroacetate one or more; More preferably ester, such as ethyl acetate, vinyl chloroacetate, vinyl-acetic ester, methylvinyl acetate, acetic acid are to one or more in chlorobenzene ester; More preferably vinyl acetate, such as vinyl-acetic ester, chloracetic acid vinyl acetate, CH 2=CHCOO (CH 2) 5cOOCH=CH 2, propionate, vinyl acrylate, CH 2=CHCH 2cOOCH=CH 2, n-caproic acid vinyl acetate, positive undeeanoic acid vinyl acetate, n Propanoic acid vinyl acetate, one or more in vinyl chloroacetate; More preferably vinyl acetate and/or vinyl chloroacetate.
Described temperature of reaction is 0 DEG C-100 DEG C, preferably 10 DEG C-60 DEG C, more preferably 20 DEG C-40 DEG C, more preferably 25 DEG C-40 DEG C.
Described stirring can use various agitator to realize, such as, use magnetic stirring apparatus and mechanical stirrer.The preferred 20-500rpm of speed of described stirring, more preferably 50-400rpm.Described stirring preferably carries out 2 hours-3 days, more preferably carries out 4 hours-2 days, more preferably carries out 5 hours-1 day, more preferably carries out 6 hours-14 hours.
In order to prevent the volatilization of reactant and solvent, first step of described method is preferably carried out in airtight container.
The method that described separation can adopt various the art ordinary person to understand is carried out, such as, adopt the methods such as chromatogram, crystallization, chromatography, filtration.Preferably be separated by the method for chromatogram and/or chromatography.Preferably be separated with column chromatography.
There is described in method according to the present invention obtains optically active many rings benzylalcohol derivative or its salt and described there is optical purity >=90%ee arbitrary in optically active many rings benzylalcohol or its salt, more preferably its arbitrary optical purity >=95%ee, more preferably its arbitrary optical purity >=97%ee, more preferably its arbitrary optical purity >=98%ee, more preferably its arbitrary optical purity >=99%ee.Also preferably described in have optically active many rings benzylalcohol derivative or its salt and the described optical purity with optically active many rings benzylalcohol or its salt all >=90%ee, more preferably its optical purity all >=95%ee, more preferably its optical purity all >=97%ee, more preferably its optical purity all >=98%ee, more preferably its optical purity all >=99%ee.
Preparation method's reaction conditions gentleness with optically active compound provided by the present invention, proper temperature, easy to operate, equipment is simple, is separated easy; Reaction is carried out in organic solvent, and enzyme activity is stablized; Prepare product optical purity high.
The invention also discloses and a kind of as shown in chemical formula [C-2], there is optically active many rings benzylalcohol or its salt,
Wherein ring A is the phenyl ring that can be substituted;
X is-CH 2-or-CH 2cH 2-;
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; H, D, F, Cl, Br, I, CHO, N (Ar 1) 2, N (R 2) 2, C (=O) Ar 1, P (Ar 1) 2, P (=O) (Ar 1) 2, S (=O) Ar 1, S (=O) 2ar 1, CR 1=CR 1ar 1, CN, NO 2, Si (R 1) 3, B (OAr 1) 2, B (OR 1) 2, OSO 2r 1, OH, has the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or has branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, and they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by R 1c=CR 1, C=C, Si (R 1) 2, Ge (R 1) 2, Sn (R 1) 2, C=O, C=S, C=Se, C=NR 1, P (=O) (R 1), SO, SO 2, NR 1, O, S or CONR 1substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
Ar 1, occur identical or different each time, be fragrance or the hetero-aromatic ring system with 5 to 30 aromatic ring atom, it can by more than one non-aryl R 2replace; Here, two group Ar of identical nitrogen or phosphorus atom are bonded to 1can also by singly-bound or by being selected from B (R 1), C (R 1) 2, Si (R 1) 2, C=O, C=NR 1, C=C (R 1) 2, O, S, S=O, SO 2, N (R 1), P (R 1) and P (=O) R 1bridging be connected to each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute; Here the substituent R that two or more is adjacent 1fat or the aromatic ring of single or many rings can also be formed each other.
The present invention is preferably described to be had in optically active many rings benzylalcohol or its salt as shown in chemical formula [C-2],
R 2, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention is more preferably described to be had in optically active many rings benzylalcohol or its salt as shown in chemical formula [C-2],
R 2, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention is more preferably described to be had in optically active many rings benzylalcohol or its salt as shown in chemical formula [C-2],
R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
The present invention is more preferably described to be had in optically active many rings benzylalcohol or its salt as shown in chemical formula [C-2],
Ring A is phenyl ring;
When X is-CH 2-, R 1when being H, R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl; When X is-CH 2-, R 1when being Cl or Br, R 2tertbutyloxycarbonyl (Boc);
When X is-CH 2cH 2-, R 1when being H, R 2carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl.
Optical purity >=the 90%ee of the preferred above-mentioned many rings benzylalcohol of the present invention or its salt, more preferably optical purity >=the 95%ee of described many rings benzylalcohol or its salt, more preferably optical purity >=the 97%ee of described many rings benzylalcohol or its salt, more preferably optical purity >=the 98%ee of described many rings benzylalcohol or its salt, the more preferably optical purity >=99%ee of described many rings benzylalcohol or its salt.
The invention also discloses and a kind of as shown in chemical formula [C-3], there is optically active many rings benzylalcohol derivative or its salt,
Wherein ring A is the phenyl ring that can be substituted;
X is-CH 2-or-CH 2cH 2-;
R 1h or halogen (Cl, Br or I);
R 2and R 3, occur identical or different each time; H, D, F, Cl, Br, I, CHO, N (Ar 1) 2, N (R 2) 2, C (=O) Ar 1, P (Ar 1) 2, P (=O) (Ar 1) 2, S (=O) Ar 1, S (=O) 2ar 1, CR 1=CR 1ar 1, CN, NO 2, Si (R 1) 3, B (OAr 1) 2, B (OR 1) 2, OSO 2r 1, OH, has the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or has branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, and they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by R 1c=CR 1, C=C, Si (R 1) 2, Ge (R 1) 2, Sn (R 1) 2, C=O, C=S, C=Se, C=NR 1, P (=O) (R 1), SO, SO 2, NR 1, O, S or CONR 1substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
Ar 1, occur identical or different each time, be fragrance or the hetero-aromatic ring system with 5 to 30 aromatic ring atom, it can by more than one non-aryl R 2replace; Here, two group Ar of identical nitrogen or phosphorus atom are bonded to 1can also by singly-bound or by being selected from B (R 1), C (R 1) 2, Si (R 1) 2, C=O, C=NR 1, C=C (R 1) 2, O, S, S=O, SO 2, N (R 1), P (R 1) and P (=O) R 1bridging be connected to each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute; Here the substituent R that two or more is adjacent 1fat or the aromatic ring of single or many rings can also be formed each other.
The present invention is preferably described to be had in optically active many rings benzylalcohol derivative or its salt as shown in chemical formula [C-3],
R 2and R 3, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention is more preferably described to be had in optically active many rings benzylalcohol derivative or its salt as shown in chemical formula [C-3],
R 2and R 3, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention is more preferably described to be had in optically active many rings benzylalcohol derivative or its salt as shown in chemical formula [C-3],
R 2and R 3, occurring identical or different each time, is methyl, chloromethyl, n-pentyl ,-(CH 2) 5cOOCH=CH 2, positive decyl, the tertiary butyl, tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
The present invention is more preferably described to be had in optically active many rings benzylalcohol derivative or its salt as shown in chemical formula [C-3],
Wherein ring A is phenyl ring;
When X is-CH 2-, R 1h, R 2when being tertbutyloxycarbonyl (Boc), R 3methyl, chloromethyl, n-pentyl ,-(CH 2) 5cOOCH=CH 2, positive decyl, the tertiary butyl;
When X is-CH 2-, R 1h, R 2carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or during 2-furanylcarbonyl, R 3it is chloromethyl;
When X is-CH 2-, R 1cl or Br, R 2when being tertbutyloxycarbonyl (Boc), R 3it is chloromethyl;
When X is-CH 2cH 2-, R 1h, R 2when being carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl, R 3it is chloromethyl.
Optical purity >=the 90%ee of the preferred above-mentioned many rings benzylalcohol derivative of the present invention or its salt, more preferably optical purity >=the 95%ee of described many rings benzylalcohol derivative or its salt, more preferably optical purity >=the 97%ee of described many rings benzylalcohol derivative or its salt, more preferably optical purity >=the 98%ee of described many rings benzylalcohol derivative or its salt, the more preferably optical purity >=99%ee of described many rings benzylalcohol derivative or its salt.
Present invention also offers a kind of preparation method with optically active composition, comprising:
Add compound or its salt, enzyme and the acry radical donor as shown in chemical formula [C-4] in organic solvent, stir under the temperature of reaction of 0 DEG C-100 DEG C;
Wherein * represents chiral carbon atom;
Ring A is the phenyl ring that can be substituted;
X is-CH 2-or-CH 2cH 2-;
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; H, D, F, Cl, Br, I, CHO, N (Ar 1) 2, N (R 2) 2, C (=O) Ar 1, P (Ar 1) 2, P (=O) (Ar 1) 2, S (=O) Ar 1, S (=O) 2ar 1, CR 1=CR 1ar 1, CN, NO 2, Si (R 1) 3, B (OAr 1) 2, B (OR 1) 2, OSO 2r 1, OH, has the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or has branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, and they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by R 1c=CR 1, C=C, Si (R 1) 2, Ge (R 1) 2, Sn (R 1) 2, C=O, C=S, C=Se, C=NR 1, P (=O) (R 1), SO, SO 2, NR 1, O, S or CONR 1substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
Ar 1, occur identical or different each time, be fragrance or the hetero-aromatic ring system with 5 to 30 aromatic ring atom, it can by more than one non-aryl R 2replace; Here, two group Ar of identical nitrogen or phosphorus atom are bonded to 1can also by singly-bound or by being selected from B (R 1), C (R 1) 2, Si (R 1) 2, C=O, C=NR 1, C=C (R 1) 2, O, S, S=O, SO 2, N (R 1), P (R 1) and P (=O) R 1bridging be connected to each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute; Here the substituent R that two or more is adjacent 1fat or the aromatic ring of single or many rings can also be formed each other.
In compound or its salt shown in the preferred described chemical formula [C-4] of the present invention,
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
More preferably in the compound or its salt shown in described chemical formula [C-4],
R 1h or halogen (Cl, Br or I);
R 2, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
More preferably in the compound or its salt shown in described chemical formula [C-4],
R 1h or halogen (Cl, Br or I);
R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
More preferably in the compound or its salt shown in described chemical formula [C-4],
Ring A is phenyl ring;
When X is-CH 2-, R 1when being H, R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl; When X is-CH 2-, R 1when being Cl or Br, R 2tertbutyloxycarbonyl (Boc);
When X is-CH 2cH 2-, R 1when being H, R 2carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl.
Described organic solvent can be hydrocarbon, heterogeneous ring compound, alcohol, aldehyde, ketone, ether, acid, ester, amine, nitrile, sulfone and/or sulfoxide, such as, in hexanaphthene, normal hexane, benzene, toluene, pyridine, ethanol, propionic aldehyde, acetone, ether, tetrahydrofuran (THF), butyric acid, ethyl acetate, aniline, acetonitrile, dimethyl sulfone, methyl-sulphoxide one or more; Preferred hydrocarbons, alcohol, ketone, ether, ester and/or nitrile, such as, in hexanaphthene, normal hexane, benzene, toluene, ethanol, acetone, ether, ethyl acetate, acetonitrile one or more; More preferably hydrocarbon, ether and/or nitrile, such as, in hexanaphthene, normal hexane, n-dodecane, n-hexadecane, benzene, toluene, p-Xylol, o-Xylol, m-xylene, ether, methyl ethyl ether, methyl tertiary butyl ether, diisopropyl ether, acetonitrile one or more; More preferably ether, such as, in methyl ethyl ether, methyl tertiary butyl ether, diisopropyl ether one or more.
Described enzyme obtains by commercial means, also can oneself prepare, preferred fat enzyme and/or lytic enzyme, more preferably lipase, more preferably enzyme novozyme435, the wild lipase A in sky ( amano Lipasea), lipase RM IM( lipaserM IM) and/or lipase TL IM( lipasetL IM).More preferably above-mentioned enzyme is immobilized enzyme.
Described acry radical donor can be acid anhydrides, carboxylic acid halides and/or ester, such as, in diacetyl oxide, acetyl bromide, acrylate chloride, ethyl acetate, vinyl chloroacetate one or more; Preferred anhydrides, acyl chlorides and/or ester, such as, in diacetyl oxide, acrylate chloride, ethyl acetate, vinyl chloroacetate one or more; More preferably ester, such as ethyl acetate, vinyl chloroacetate, vinyl-acetic ester, methylvinyl acetate, acetic acid are to one or more in chlorobenzene ester; More preferably vinyl acetate, such as vinyl-acetic ester, chloracetic acid vinyl acetate, CH 2=CHCOO (CH 2) 5cOOCH=CH 2, propionate, vinyl acrylate, CH 2=CHCH 2cOOCH=CH 2, n-caproic acid vinyl acetate, positive undeeanoic acid vinyl acetate, n Propanoic acid vinyl acetate, one or more in vinyl chloroacetate; More preferably vinyl acetate and/or vinyl chloroacetate.
Described temperature of reaction is 0 DEG C-100 DEG C, preferably 10 DEG C-60 DEG C, more preferably 20 DEG C-40 DEG C, more preferably 25 DEG C-40 DEG C.
Described stirring can use various agitator to realize, such as, use magnetic stirring apparatus and mechanical stirrer.The preferred 20-500rpm of speed of described stirring, more preferably 50-400rpm.In the present invention, rpm representative " rev/min ".Described stirring preferably carries out 2 hours-3 days, more preferably carries out 4 hours-2 days, more preferably carries out 5 hours-1 day, more preferably carries out 6 hours-14 hours.
In order to prevent the volatilization of reactant and solvent, described method is preferably carried out in airtight container.
Method according to the present invention obtains in composition containing having optically active many rings benzylalcohol derivative or its salt and having in optically active many rings benzylalcohol or its salt, preferably arbitrary in them optical purity >=90%ee, more preferably its arbitrary optical purity >=95%ee, more preferably its arbitrary optical purity >=97%ee, more preferably its arbitrary optical purity >=98%ee, more preferably its arbitrary optical purity >=99%ee.Also preferably described in have optically active many rings benzylalcohol derivative or its salt and described in have the optical purity of optically active many rings benzylalcohol or its salt all >=90%ee, more preferably its optical purity all >=95%ee, more preferably its optical purity all >=97%ee, more preferably its optical purity all >=98%ee, more preferably its optical purity all >=99%ee.
Preparation method's reaction conditions gentleness with optically active composition provided by the present invention, proper temperature, easy to operate, equipment is simple; Reaction is carried out in organic solvent, and enzyme activity is stablized; Prepared by the chipal compounds optical purity that obtains in composition high.
One has optically active many rings benzylalcohol based composition, it is characterized in that said composition is containing, for example the many rings benzylalcohol shown in chemical formula [C-5] or its salt,
Many rings benzylalcohol derivative as shown in chemical formula [C-6] or its salt,
Organic solvent and enzyme;
Wherein ring A is the phenyl ring that can be substituted;
X is-CH 2-or-CH 2cH 2-;
R 1h or halogen (Cl, Br or I);
R 2and R 3, occur identical or different each time; H, D, F, Cl, Br, I, CHO, N (Ar 1) 2, N (R 2) 2, C (=O) Ar 1, P (Ar 1) 2, P (=O) (Ar 1) 2, S (=O) Ar 1, S (=O) 2ar 1, CR 1=CR 1ar 1, CN, NO 2, Si (R 1) 3, B (OAr 1) 2, B (OR 1) 2, OSO 2r 1, OH, has the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or has branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, and they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by R 1c=CR 1, C=C, Si (R 1) 2, Ge (R 1) 2, Sn (R 1) 2, C=O, C=S, C=Se, C=NR 1, P (=O) (R 1), SO, SO 2, NR 1, O, S or CONR 1substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
Ar 1, occur identical or different each time, be fragrance or the hetero-aromatic ring system with 5 to 30 aromatic ring atom, it can by more than one non-aryl R 2replace; Here, two group Ar of identical nitrogen or phosphorus atom are bonded to 1can also by singly-bound or by being selected from B (R 1), C (R 1) 2, Si (R 1) 2, C=O, C=NR 1, C=C (R 1) 2, O, S, S=O, SO 2, N (R 1), P (R 1) and P (=O) R 1bridging be connected to each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute; Here the substituent R that two or more is adjacent 1fat or the aromatic ring of single or many rings can also be formed each other.
The present invention is preferably in described many rings benzylalcohol as shown in chemical formula [C-5] or its salt,
R 2, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention more preferably the present invention preferably in described alcohol as shown in chemical formula [C-5] or its salt,
R 2, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention more preferably the present invention preferably in described many rings benzylalcohol as shown in chemical formula [C-5] or its salt,
R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
The present invention more preferably the present invention preferably in described many rings benzylalcohol as shown in chemical formula [C-5] or its salt,
Ring A is phenyl ring;
When X is-CH 2-, R 1when being H, R 2tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl; When X is-CH 2-, R 1when being Cl or Br, R 2tertbutyloxycarbonyl (Boc);
When X is-CH 2cH 2-, R 1when being H, R 2carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl.
The present invention is preferably in described many rings benzylalcohol derivative as shown in chemical formula [C-5] or its salt,
R 2and R 3, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention is more preferably in described many rings benzylalcohol derivative as shown in chemical formula [C-6] or its salt,
R 2and R 3, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
The present invention is more preferably in described many rings benzylalcohol derivative as shown in chemical formula [C-6] or its salt,
R 2and R 3, occurring identical or different each time, is methyl, chloromethyl, n-pentyl ,-(CH 2) 5cOOCH=CH 2, positive decyl, the tertiary butyl, tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
The present invention is more preferably in described many rings benzylalcohol derivative as shown in chemical formula [C-6] or its salt,
Wherein ring A is phenyl ring;
When X is-CH 2-, R 1h, R 2when being tertbutyloxycarbonyl (Boc), R 3methyl, chloromethyl, n-pentyl ,-(CH 2) 5cOOCH=CH 2, positive decyl, the tertiary butyl;
When X is-CH 2-, R 1h, R 2carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or during 2-furanylcarbonyl, R 3it is chloromethyl;
When X is-CH 2-, R 1cl or Br, R 2when being tertbutyloxycarbonyl (Boc), R 3it is chloromethyl;
When X is-CH 2cH 2-, R 1h, R 2when being carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl, R 3it is chloromethyl.
Described organic solvent can be hydrocarbon, heterogeneous ring compound, alcohol, aldehyde, ketone, ether, acid, ester, amine, nitrile, sulfone and/or sulfoxide, such as, in hexanaphthene, normal hexane, benzene, toluene, pyridine, ethanol, propionic aldehyde, acetone, ether, tetrahydrofuran (THF), butyric acid, ethyl acetate, aniline, acetonitrile, dimethyl sulfone, methyl-sulphoxide one or more; Preferred hydrocarbons, alcohol, ketone, ether, ester and/or nitrile, such as, in hexanaphthene, normal hexane, benzene, toluene, ethanol, acetone, ether, ethyl acetate, acetonitrile one or more; More preferably hydrocarbon, ether and/or nitrile, such as, in hexanaphthene, normal hexane, n-dodecane, n-hexadecane, benzene, toluene, p-Xylol, o-Xylol, m-xylene, ether, methyl ethyl ether, methyl tertiary butyl ether, diisopropyl ether, acetonitrile one or more; More preferably ether, such as, in methyl ethyl ether, methyl tertiary butyl ether, diisopropyl ether one or more.
Described enzyme obtains by commercial means, also can oneself prepare, preferred fat enzyme and/or lytic enzyme, more preferably lipase, more preferably enzyme novozyme435, the wild lipase A in sky ( amano Lipasea), lipase RM IM( lipaserM IM) and/or lipase TL IM( lipasetL IM).More preferably above-mentioned enzyme is immobilized enzyme.
In the preferred composition of the present invention, optical purity >=90%ee arbitrary in preferred described many rings benzylalcohol or its salt and described many rings benzylalcohol derivative or its salt, more preferably its arbitrary optical purity >=95%ee, more preferably its arbitrary optical purity >=97%ee, more preferably its arbitrary optical purity >=98%ee, more preferably its arbitrary optical purity >=99%ee.Also the optical purity of preferred described many rings benzylalcohol or its salt and described many rings benzylalcohol derivative or its salt all >=90%ee, more preferably its optical purity all >=95%ee, more preferably its optical purity all >=97%ee, more preferably its optical purity all >=98%ee, more preferably its optical purity all >=99%ee.
In the preferred composition of the present invention, the molar ratio of described many rings benzylalcohol or its salt and described many rings benzylalcohol derivative or its salt is in the scope of 1:2 to 2:1, more preferably in the scope of 1:1.5 to 1.5:1, more preferably in the scope of 1:1.2 to 1.2:1, more preferably in the scope of 1:1.1 to 1.1:1.
Embodiment
The present invention is described in detail below in conjunction with a series of embodiment.Embodiment just further illustrates of the present invention, not for limiting the present invention.
The invention provides a kind of preparation method with optically active many rings benzalcohol derivatives, comprising:
1, add compound or its salt, enzyme and the acry radical donor as shown in chemical formula [C-1] in organic solvent, stir 2 hours-3 days under the temperature of reaction of 0 DEG C-100 DEG C;
2, be separated and obtain there is optically active alcohol derivate or its salt and there is optically active alcohol or its salt.
Such as, 1,2,3,4-tetrahydroquinoline-4-alcohol derivate of 1 mmol racemization is dissolved in 20 mL methyl tertiary butyl ethers, then adds 120 mg immobilized lipases novozyme435 and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions.Then be separated with column chromatography, obtain r-1,2,3,4-tetrahydroquinoline-4-ester derivative and s-1,2,3,4-tetrahydroquinoline-4-alcohol derivate.
The present invention is by by 1; 2; 3; 4-tetrahydroquinoline-4-alcohol compound (or 2; 3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol compound) be dissolved in organic solvent; then enzyme and acry radical donor reagent is added; under the katalysis of enzyme, 1,2; 3; 4-tetrahydroquinoline-4-alcohol compound (or 2,3,4; 5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol compound) and acry radical donor reagent there is asymmetric transesterification, obtain and there is optical purity high (high ee value) r-1,2,3,4-tetrahydroquinoline-4-alcohol derivate or its salt and s-1,2,3,4-tetrahydroquinoline-4-alcohol or its salt (or r-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol derivate or its salt and s-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol or its salt), and with simple column chromatography and separable acquisition.
In the present invention, the optical purity high performance liquid phase of product records, and the calculation formula of producing optical purity is: ee%=( r- s)/( r+ s) × 100%, wherein srepresentative s-1,2,3,4-tetrahydroquinoline-4-alcohol derivate or its salt (or s-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol or its salt) amount of substance, rrepresentative r-1,2,3,4-tetrahydroquinoline-4-ester derivative (or r-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol derivate or its salt) amount of substance.
embodiment 1:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml methyl tertiary butyl ethers novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 51%, ee value 99%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 49%, ee value 98%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate: 1h NMR (300 MHz, dmso- d 6): δ7.63 (d, j=8.1 Hz, 1H), 7.35 (d, j=6.6 Hz, 1H), 7.20-7.15 (m, 1H); 7.06-7.00 (m, 1H), 5.36 (s, 1H); 4.56 (s, 1H), 3.83-3.76 (m; 1H), 3.60-3.53 (m, 1H); 1.98-1.93 (m, 1H), 1.80-1.76 (m; 1H), 1.47 (s, 9H); 13c NMR (75 MHz, dmso- d 6): δ152.9,137.1,132.5,127.8,126.7,122.9,122.7,80.2,64.1,40.9,32.1,27.9.
The nuclear magnetic data of R-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate: 1h NMR (300 MHz, cdcl 3): δ7.83 (d, j=8.7 Hz, 1H), 7.31-7.26 (m, 2H), 7.05 (m, j=7.5 Hz, 1H), 6.03 (t, j=3.9 Hz, 1H), 4.18-4.11 (m, 1H), 4.06 (s, 2H), 3.60-3.50 (m, 1H), 2.17-2.12 (m, 2H), 1.54 (s, 9H); 13c NMR (75 MHz, cdcl 3): δ166.8,153.4,138.8,129.5,128.9,125.1,123.6,123.4,81.5,70.0,41.1,40.3,29.2,28.3.
embodiment 2:
1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-the Ji)-ethyl ketone of 1 mmol (191 mg) racemization is added, 120 mg immobilized lipases in 20 ml methyl tertiary butyl ethers novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-Ji)-ethyl ketone and rthe composition of-1-ethanoyl-1,2,3,4-tetrahydroquinoline-2'-Mono Chloro Acetic Acid-4-ester.Can composition for separating with column chromatography, obtain pure s-1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-Ji)-ethyl ketone (productive rate 44%, ee value 99%) and r-1-ethanoyl-1,2,3,4-tetrahydroquinoline-2'-Mono Chloro Acetic Acid-4-ester (productive rate 40%, ee value 96%).
R 1=H, R 2=ethanoyl (Ac), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-Ji)-ethyl ketone: 1h NMR (300 MHz, DMSO- d 6): δ7.50-7.41 (m, 2H), 7.24-7.19 (m, 1H), 7.16-7.11 (m, 1H), 5.43-5.42 (d, j=7.3Hz, 1H), 4.58-4.53 (m; 1H), 3.91-3.84 (m, 1H); 3.54-3.50 (m; 1H), 2.16 (s, 3H); 2.13-2.04 (m; 1H), 1.78-1.71 (m, 1H); 13c NMR (75 MHz, DMSO- d 6): δ169.3,137.3,127.0,126.7,124.1,123.9,64.2,32.9,23.3.
The nuclear magnetic data of R-1-ethanoyl-1,2,3,4-tetrahydroquinoline-2'-Mono Chloro Acetic Acid-4-ester: 1h NMR (400 MHz, cdcl 3): δ7.33 (m, 3H), 7.20-7.16 (m, 1H), 6.00 (t, j=4.4 Hz, 1H), 4.07-4.01 (m, 3H), 3.79-3.69 (m, 1H), 2.26 (s, 3H), 2.23-2.18 (m, 2H); 13c NMR (100 MHz, cdcl 3): δ169.9,166.8,139.0,129.1,129.0,125.3,124.5,69.9,41.0,39.8,30.1,23.4.
embodiment 3:
In 20 ml methyl tertiary butyl ethers, add 1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-the Ji)-benzophenone of 1 mmol (253 mg) racemization, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-Ji)-benzophenone and r-1-benzoyl-1,2,3,4-tetrahydroquinoline-2 ' composition of-Mono Chloro Acetic Acid-4-ester.Can composition for separating with column chromatography, obtain pure s-1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-Ji)-benzophenone (productive rate 34%, ee value 99%) and r-1-benzoyl-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester (productive rate 49%, ee value 99%).
R 1=H, R 2=benzoyl (Bz), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-1-(4-hydroxyl-3,4-dihydroquinoline-1 (2H)-Ji)-benzophenone: 1h NMR (400 MHz, dmso- d 6): δ7.42-7.37 (m, 2H), 7.33-7.30 (m, 4H), 7.06-7.02 (m, 1H), 6.95-6.91 (m, 1H), 6.79-6.77 (m, 1H), 5.51 (d, j=5.6 Hz, 1H), 4.71-4.67 (m, 1H), 3.92-3.85 (m, 1H), 3.67-3.60 (m, 1H), 2.18-2.10 (m, 1H), 1.86-1.78 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ169.8,137.9,136.9,134.6,130.5,128.6,128.5,127.8,126.9,124.8,124.5,64.5,42.2,33.3.
R-1-benzoyl-1,2,3,4-tetrahydroquinoline-2 ' nuclear magnetic data of-Mono Chloro Acetic Acid-4-ester: 1h NMR (400 MHz, cdcl 3): δ7.43-7.39 (m, 3H), 7.36-7.30 (m, 3H), 7.08-7.05 (m, 2H), 6.92-6.91 (m, 1H), 6.12 (t, j=4.2 Hz, 1H), 4.16-4.11 (m, 1H), 4.09 (s, 2H), 3.90-3.85 (m, 1H), 2.31-2.26 (m, 2H); 13c NMR (100 MHz, cdcl 3): δ170.5,166.9,139.1,135.6,130.6,129.2,128.7,128.5,128.3,126.5,125.1,124.8,69.8,41.3,41.0,29.9.
embodiment 4:
In 20 ml methyl tertiary butyl ethers, 4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylic acid phenyl ester adding 1 mmol (269 mg) racemization is dissolved in, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid phenyl ester and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylic acid phenyl ester.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid phenyl ester (productive rate 46%, ee value 97%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylic acid phenyl ester (productive rate 43%, ee value 92%).
R 1=H, R 2=carbobenzoxy, R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid phenyl ester: 1h NMR (400 MHz, DMSO- d 6): δ7.74 (d, j=8.4 Hz, 1H), 7.43-7.39 (m, 3H), 7.26-7.20 (m, 4H), 7.12-7.08 (m, 1H), 5.47 (d, j=4.8 Hz, 1H), 4.66-4.62 (m, 1H), 4.02-3.97 (m, 1H), 3.79-3.77 (m, 1H), 2.14-2.09 (m, 1H), 1.89-1.86 (m, 1H); 13c NMR (100 MHz, DMSO- d 6): δ152.9,151.4,136.8,133.8,129.8,128.3,127.5,126.00,124.1,123,3,122.4,64.5,42.1,32.5.
The nuclear magnetic data of R-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylic acid phenyl ester: 1h NMR (400 MHz, CDCl 3): δ7.96 (d, j=8.4 Hz, 1H), 7.43-7.33 (m, 4H), 7.27-7.23 (m, 1H), 7.19-7.12 (m, 3H), 6.10 (t, j=4.0 Hz, 1H), 4.14-4.11 (m, 1H), 4.10 (s, 2H), 3.84-3.77 (m, 1H), 2.31-2.26 (m, 2H); 13c NMR (400 MHz, CDCl 3): δ166.9,153.0,150.8,137.9,129.7,129.5,129.4,125.9,125.6,124.4,123.5,121.7,69.7,41.1,40.6,29.1.
embodiment 5:
In 20 ml methyl tertiary butyl ethers, add 4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester of 1 mmol (283 mg) racemization, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester (productive rate 46%, ee value 97%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester (productive rate 43%, ee value 92%).
R 1=H, R 2=carbobenzoxy-(Cbz) (Cbz), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester: 1h NMR (400 MHz, dmso- d 6): δ7.71 (d, j=8.0 Hz, 1H), 7.41-7.31 (m, 6H), 7.19-7.16 (m, 1H), 7.07-7.03 (m, 1H), 5.42 (d, j=5.2 Hz, 1H), 5.18 (s; 2H), 4.58-4.56 (m, 1H); 3.90-3.85 (m; 1H), 3.67-3.65 (m, 1H); 1.99-1.96 (m; 1H), 1.80-1.78 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ154.2,137.1,136.9,133.3,128.9,128.4,128.3,128.2,127.4,123.6,123.1,67.3,64.5,41.6,32.4.
The nuclear magnetic data of R-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylic acid benzyl ester: 1h NMR (400 MHz, cdcl 3): δ7.92 (d, j=8.8 Hz, 1H), 7.42-7.26 (m, 7H), 7.11-7.07 (m, 1H), 6.03 (t, j=3.8 Hz, 1H), 5.26 (s, 2H), 4.25-4.20 (m, 1H), 4.05 (s, 2H), 3.69-3.61 (m, 1H), 2.19-2.14 (m, 2H); 13c NMR (100 MHz, cdcl 3): δ166.8,154.2,138.3,136.0,129.7,129.3,128.6,128.3,128.1,125.2,123.9,123.4,69.8,67.9,41.1,40.5,28.9.
embodiment 6:
In 20 ml methyl tertiary butyl ethers, add 6-bromo-4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (327 mg) racemization, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-6-bromo-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of the bromo-4-of-6-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-6-bromo-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 29%, ee value 99%) and rthe bromo-4-of-6-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 35%, ee value 97%).
R 1=Br, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-6-bromo-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate: 1h NMR (400 MHz, dmso- d 6): δ7.60 (d, j=9.2 Hz, 1H), 7.48 (d, j=2.8 Hz, 1H), 7.33 (dd, j=9.2 Hz, 2.8 Hz, 1H), 5.55 (d, j=5.6 Hz, 1H), 4.55-4.51 (m; 1H), 3.77-3.70 (m, 1H); 3.56-3.50 (m; 1H), 1.99-1.93 (m, 1H); 1.73-1.70 (m; 1H), 1.44 (s, 9H); 13c NMR (100 MHz, dmso- d 6): δ153.1,136.8,135.7,130.3,129.8,125.5,115.2,81.1,64.3,41.6,32.1,28.3.
The nuclear magnetic data of the bromo-4-of R-6-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate: 1h NMR (400 MHz, cdcl 3): δ7.75 (d, j=8.8 Hz, 1H), 7.41-7.36 (m, 2H), 5.94 (t, j=4.0 Hz, 1H), 4.14-4.08 (m, 3H), 3.54-3.50 (m, 1H), 2.14-2.10 (m, 2H), 1.53 (s, 9H); 13c NMR (100 MHz, cdcl 3): δ166.7,153.1,137.8,131.9,131.8,126.9,125.3,115.9,81.9,69.3,41.0,40.3,28.8,28.3.
embodiment 7:
In 20 ml methyl tertiary butyl ethers, add 6-chloro-4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (283 mg) racemization, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-6-chloro-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of the chloro-4-of-6-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-6-chloro-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 48%, ee value 97%) and rthe chloro-4-of-6-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 42%, ee value 99%).
R 1=Cl, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-6-chloro-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate: 1h NMR (400 MHz, dmso- d 6): δ7.65 (d, j=9.2 Hz, 1H), 7.35 (d, j=2.0 Hz, 1H), 7.20 (dd, j=9.0 Hz, 2.6 Hz, 1H), 5.55 (d, j=5.5 Hz, 1H), 4.55-4.50 (m; 1H), 3.77-3.71 (m, 1H); 3.57-3.51 (m; 1H), 1.98-1.93 (m, 1H); 1.75-1.70 (m; 1H), 1.44 (s, 9H); 13c NMR (100 MHz, dmso- d 6): δ153.2,136.3,135.3,127.4,127.1,127.0,125.1,81.1,64.3,41.6,32.1,28.3.
The nuclear magnetic data of the chloro-4-of R-6-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate: 1h NMR (400 MHz, cdcl 3): δ7.81 (d, j=8.8 Hz, 1H), 7.27-7.22 (m, 2H), 5.94 (t, j=4.2 Hz, 1H), 4.19-4.09 (m, 1H), 4.08 (s, 2H), 3.56-3.49 (m, 1H), 2.14-2.10 (m, 2H), 1.54 (s, 9H); 13c NMR (100 MHz, cdcl 3): δ166.7,153.1,137.3,128.9,128.4,126.6,124.9,81.9,69.3,41.0,40.3,28.9,28.3.
embodiment 8:
In 20 ml methyl tertiary butyl ethers, 1-benzenesulfonyl-1,2,3, the 4-tetrahydroquinoline-4-alcohol adding 1 mmol (289 mg) racemization is dissolved in, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline-4-alcohol and rthe composition of-1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester.Can composition for separating with column chromatography, obtain pure s-1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline-4-alcohol (productive rate 48%, ee value 99%) and r-1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester (productive rate 47%, ee value 99%).
R 1=H，R 2=-SO 2C 6H 5，R 3=-C(=O)-CH 2Cl，X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline-4-alcohol: 1h NMR (400 MHz, dmso- d 6): δ7.66-7.60 (m, 4H), 7.55-7.51 (m, 2H), 7.34-7.32 (m, 1H), 7.24-7.20 (m, 1H), 7.12-7.08 (m, 1H), 5.37 (d, j=5.2 Hz, 1H), 4.22-4.19 (m, 1H), 4.00-3.93 (m, 1H), 3.75-3.68 (m, 1H), 1.72-1.67 (m, 1H), 1.62-1.58 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ139.2,135.7,133.9,133.4,129.9,129.5,128.0,127.2,124.7,122.5,63.6,43.2,30.9.
The nuclear magnetic data of R-1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester: 1h NMR (400 MHz, cdcl 3): δ7.91 (d, j=8.4 Hz, 1H), 7.64-7.54 (m, 3H), 7.45-7.32 (m, 3H), 7.26-7.12 (m, 2H), 5.76 (t, j=3.6 Hz, 1H), 4.26-4.20 (m, 1H), 3.88 (d, j=4Hz 2H), 3.69-3.61 (m, 1H), 1.92-1.82 (m, 1H), 1.81-1.73 (m, 1H); 13c NMR (100 MHz, cdcl 3): δ166.6,139.1,136.9,133.2,130.4,129.8,129.2,127.0,125.6,125.0,123.6,68.8,42.2,40.6,27.1.
embodiment 9:
In 20 ml methyl tertiary butyl ethers, add 4-hydroxyl-3,4-dihydroquinoline-1 (2H)-furans-2-ketone of 1 mmol (243 mg) racemization, 120 mg immobilized lipases novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-furans-2-ketone and rthe composition of-1-(furans-2-carbonyl)-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-furans-2-ketone (productive rate 40%, ee value 99%) and r-1-(furans-2-carbonyl)-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester (productive rate 46%, ee value 99%).
R 1=H, R 2=2-furanylcarbonyl, R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-furans-2-ketone: 1h NMR (400 MHz, dmso- d 6): δ7.71-7.44 (m, 2H), 7.13-7.06 (m, 2H), 6.96 (d, j=7.6 Hz, 1H), 6.82 (d, j=3.6 Hz, 1H), 6.56-6.55 (m, 1H), 5.51 (d, j=5.6 Hz, 1H), 4.65-4.60 (m, 1H), 4.02-3.94 (m, 1H), 3.70-3.64 (m, 1H), 2.14-2.10 (m, 1H), 1.81-1.77 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ159.6,147.9,145.4,137.4,134.5,127.8,127.1,124.7,123.5,116.8,112.0,64.3,42.1,33.3.
The nuclear magnetic data of R-1-(furans-2-carbonyl)-1,2,3,4-tetrahydroquinoline-2 ＇-Mono Chloro Acetic Acid-4-ester: 1h NMR (400 MHz, cdcl 3): δ7.39-7.37 (m, 2H), 7.21-7.13 (m, 2H), 7.08-7.06 (m, 1H), 6.86 (d, j=3.6 Hz, 1H), 6.45-6.43 (m, 1H), 6.09 (t, j=4.2 Hz, 1H), 4.23-4.18 (m, 1H), 4.06 (s, 2H), 3.92-3.85 (m, 1H), 2.30-2.26 (m, 2H); 13c NMR (100 MHz, cdcl 3): δ166.8,159.9,147.5,144.5,138.8,129.3,128.9,126.8,125.1,123.9,117.4,111.6,69.6,41.0,40.6,30.0.
embodiment 10:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added in 0.5 ml methyl tertiary butyl ether, 5 mg days wild lipase As ( amano Lipasea), and 0.25 mmol vinyl chloroacetate, under the temperature of reaction of 30 DEG C, stir 8 hours under 400 rpm conditions, obtain containing methyl tertiary butyl ether, open country, sky lipase A ( amano Lipasea), s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 62%, ee value 53%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 38%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
The wild lipase A in enzyme=sky ( amano Lipasea), organic solvent=methyl tertiary butyl ether
embodiment 11:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added, 5 mg lipase RM IM(in 0.5 ml methyl tertiary butyl ether lipaserM IM), and 0.25 mmol vinyl chloroacetate, under the temperature of reaction of 30 DEG C, stir 8 hours under 400 rpm conditions, obtain containing methyl tertiary butyl ether, lipase RM IM( lipaserM IM), s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 62%, ee value 58%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 38%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=lipase RM IM( lipaserM IM), organic solvent=methyl tertiary butyl ether
embodiment 12:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added, 5 mg lipase TL IM(in 0.5 ml methyl tertiary butyl ether lipasetL IM), and 0.25 mmol vinyl chloroacetate, under the temperature of reaction of 30 DEG C, stir 8 hours under 400 rpm conditions, obtain containing methyl tertiary butyl ether, lipase TL IM( lipasetL IM), s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 35%, ee value 99%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 65%, ee value 48%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=lipase TL IM( lipasetL IM), organic solvent=methyl tertiary butyl ether
embodiment 13:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml diisopropyl ether novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing diisopropyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 46%, ee value 99%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 54%, ee value 95%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=diisopropyl ether
embodiment 14:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml acetonitriles novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing acetonitrile, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 52%, ee value 92%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 48%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=acetonitrile
embodiment 15:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml toluene novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing toluene, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 58%, ee value 78%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 42%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=toluene
embodiment 16:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml normal hexanes novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing normal hexane, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 74%, ee value 33%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 26%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=normal hexane
embodiment 17:
N-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol of 1 mmol racemization is added, 120 mg immobilized lipases in 20 ml methyl tertiary butyl ethers novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-N-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol and r-the composition of N-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester.Composition can be separated with column chromatography, obtains pure s-N-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol (productive rate 40%, ee value 98%) and r-n-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester (productive rate 42%, ee value 97%).
R 1=H, R 2=benzoyl (Bz), R 3=-C (=O)-CH 2cl, X=-CH 2cH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-N-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol: 1h NMR (400 MHz, dmso- d 6): δ7.59-7.40 (m, 1H), 7.28-7.05 (m, 6H), 6.93-6.90 (m, 1H), 6.64-6.54 (m, 1H), 5.56 (d, j=4.0 Hz, 1H), 4.93 (d, j=12.0 Hz, 1H), 4.66 (d, j=16.0 Hz, 1H), 2.67-2.61 (m, 1H), 2.13-2.10 (m, 1H), 1.97-1.90 (m, 1H), 1.73-1.62 (m, 1H), 1.50-1.54 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ168.4,142.9,140.5,136.7,129.8,128.4,128.1,127.9,127.3,127.2,125.4,70.1,46.6,36.0,26.3.
The nuclear magnetic data of R-N-benzoyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester: 1h NMR (400 MHz, cdcl 3): δ7.31-7.12 (m, 7H), 7.02-6.94 (m, 1H), 6.65-6.62 (m, 1H), 6.25-6.11 (m, 1H), 5.12-4.84 (m, 1H), 4.25 (s, 1H), 4.05-3.91 (m, 1H), 2.85 (t j=12.0 Hz, 1H), 2.27-2.12 (m, 2H), 1.82-1.79 (m, 2H); 13c NMR (100 MHz, cdcl 3): δ169.6,166.3,135.4,131.3,129.8,129.4,128.7,128.2,127.8,127.6,127.2,123.6,74.7,46.4,41.0,31.7,25.4.
embodiment 18:
N-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml methyl tertiary butyl ethers novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-N-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol and r-the composition of N-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester.Composition can be separated with column chromatography, obtains pure s-N-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol (productive rate 39%, ee value 96%) and r-n-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester (productive rate 43%, ee value 98%).
R 1=H, R 2=2-furanylcarbonyl, R 3=-C (=O)-CH 2cl, X=-CH 2cH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-N-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol: 1h NMR (400 MHz, dmso- d 6): δ7.67-7.63 (m, 2H), 7.40-7.37 (m, 1H), 7.19-7.17 (m, 1H), 7.00-6.98 (m, 1H), 6.34 (s, 1H), 5.63 (s, 1H), 5.51 (d j=4.0 Hz, 1H), 4.70-4.67 (m; 1H), 4.61-4.58 (m, 1H); 2.64-2.58 (m, 1H), 2.04-2.01 (m; 1H), 1.89-1.85 (m, 1H); 1.71-1.68 (m; 1H), 1.50-1.45 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ157.3,147.0,145.4,143.9,140.0,128.4,127.9,127.6,125.6,115.9,111.6,69.8,46.6,36.1,26.3.
The nuclear magnetic data of R-N-(2-furancarbonyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester: 1h NMR (400 MHz, cdcl 3): δ7.52-7.41 (m, 1H), 7.37-7.26 (m, 2H), 7.08 (d, j=8.0 Hz, 1H), 6.20 (s, 1H), 5.92 (d, j=8.0 Hz, 1H), 5.72 (d, j=4.0 Hz, 1H), 4.98-4.95 (m, 1H), 4.23-3.28 (m, 2H), 2.86-2.83 (m, 1H), 2.44-2.31 (m, 2H), 1.84-1.71 (m, 3H); 13c NMR (100 MHz, cdcl 3): δ166.5,157.8,147.1,144.4,142.4,135.8,131.5,129.8,129.0,128.2,116.3,111.1,74.7,47.8,40.6,30.1,23.1.
embodiment 19:
N-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml methyl tertiary butyl ethers novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-N-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol and r-the composition of N-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester.Composition can be separated with column chromatography, obtains pure s-N-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol (productive rate 44%, ee value 90%) and r-n-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester (productive rate 41%, ee value 93%).
R 1=H, R 2=carbobenzoxy-(Cbz) (Cbz), R 3=-C (=O)-CH 2cl, X=-CH 2cH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
The nuclear magnetic data of S-N-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-alcohol: 1h NMR (400 MHz, dmso- d 6): δ7.61-7.59 (m, 1H), 7.42-7.40 (m, 1H), 7.30-7.15 (m, 7H), 5.48 (s, 1H), 5.18-5.11 (m, 1H), 5.02-4.99 (m, 1H), 4.63 (d j=12.0 Hz, 1H), 4.21 (d, j=12.0 Hz, 1H), 2.64-2.61 (m, 1H), 2.04-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.46-1.41 (m, 1H); 13c NMR (100 MHz, dmso- d 6): δ154.1,143.2,138.9,137.3,128.9,128.7,128.3,128.1,127.4,127.1,125.3,70.0,66.6,48.0,36.1,26.4.
The nuclear magnetic data of R-N-(carbobenzoxy-(Cbz))-2,3,4,5-tetrahydrochysene-1H-benzo [b] azepines-5-(2-Mono Chloro Acetic Acid) ester: 1h NMR (400 MHz, cdcl 3): δ7.47-7.34 (m, 3H), 7.29-7.19 (m; 6H), 6.00-5.92 (m, 1H); 5.31-5.02 (m, 2H), 4.48-4.09 (m; 1H), 3.73-3.50 (m, 2H); 2.88-2.74 (m, 1H), 2.36-2.13 (m; 2H), 1.74-1.65 (m, 2H); 13c NMR (100 MHz, cdcl 3): δ166.3,154.5,141.6,136.6,135.3,130.7,129.4,128.5,128.4,128.0,127.7,127.3,67.3,66.9,48.9,40.6,30.0,23.0.
embodiment 20:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added, 5 mg immobilized lipases in 0.5 ml methyl tertiary butyl ether novozyme435, and 0.25 mmol vinyl-acetic ester, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and r-4-acetoxy-3, the composition of 4-dihydroquinoline-1 (2H)-carboxylate.Composition can be separated with column chromatography, obtains pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 52%, ee value 99%) and r-4-acetoxy-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 48%, ee value 98%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 3, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
embodiment 21:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added, 5 mg immobilized lipases in 0.5 ml methyl tertiary butyl ether novozyme435, and 0.25 mmol CH 2=CHCOO (CH 2) 5cOOCH=CH 2, under the temperature of reaction of 30 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(the positive hexylyloxy of 6-(acryloxy))-3,4-dihydroquinoline-1 (2H)-carboxylate.Composition can be separated with column chromatography, obtains pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 57%, ee value 84%) and r-4-(the positive hexylyloxy of 6-(acryloxy))-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 43%, ee value 98%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=CH 2=CHCOO (CH 2) 5cO-, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
embodiment 22:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added, 5 mg immobilized lipases in 0.5 ml methyl tertiary butyl ether novozyme435, and 0.25 mmol n-caproic acid vinyl acetate, under the temperature of reaction of 60 DEG C, stir 8 hours under 300 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-positive hexylyloxy-3,4-dihydroquinoline-1 (2H)-carboxylate.Composition can be separated with column chromatography, obtains pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 80%, ee value 26%) and r-4-positive hexylyloxy-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 20%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=n-pentyl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
embodiment 23:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 0.05 mmol (12.5 mg) racemization is added, 5 mg immobilized lipases in 0.5 ml methyl tertiary butyl ether novozyme435, and the positive undeeanoic acid vinyl acetate of 0.25 mmol, under the temperature of reaction of 50 DEG C, stir 15 hours under 500 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-positive undecanoyl oxygen base-3,4-dihydroquinoline-1 (2H)-carboxylate.Composition can be separated with column chromatography, obtains pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 67%, ee value 33%) and r-4-positive undecanoyl oxygen base-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 33%, ee value 99%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=positive decyl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
embodiment 24:
4-hydroxyl-3,4-dihydroquinoline-1 (the 2H)-carboxylate of 1 mmol (249 mg) racemization is added, 120 mg immobilized lipases in 20 ml toluene novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 100 DEG C, stir 2 hours under 400 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 51%, ee value 98%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 49%, ee value 98%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=toluene+normal hexane
embodiment 25:
The 4-hydroxyl-3 of 1 mmol (249 mg) racemization is added in the mixing solutions of 10 ml toluene and 10 ml normal hexanes, 4-dihydroquinoline-1 (2H)-carboxylate, 60 mg lipase RM IM(Lipase RM IM) and 60 mg lipase TL IM( lipasetL IM), and 3 mmol vinyl chloroacetates, under the temperature of reaction of 0 DEG C, stir 3 days under 100 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 44%, ee value 95%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 43%, ee value 96%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=lipase RM IM+ lipase TL IM, organic solvent=methyl tertiary butyl ether
embodiment 26:
1 mmol (249 mg) 4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate is added, 120 mg immobilized lipases in 20 ml methyl tertiary butyl ethers novozyme435, and 3 mmol vinyl chloroacetates, under the temperature of reaction of 20 DEG C, stir 2 days under 250 rpm conditions, obtain containing methyl tertiary butyl ether, immobilized lipase novozyme435, s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate and rthe composition of-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate.Can composition for separating with column chromatography, obtain pure s-4-hydroxyl-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 51%, ee value 99%) and r-4-(2-chloroethene acyloxy)-3,4-dihydroquinoline-1 (2H)-carboxylate (productive rate 49%, ee value 98%).
R 1=H, R 2=tertbutyloxycarbonyl (Boc), R 3=-C (=O)-CH 2cl, X=-CH 2-
Enzyme=immobilized lipase novozyme435, organic solvent=methyl tertiary butyl ether
Although describe in detail invention has been in conjunction with embodiment, concerning those skilled in the art, it is apparent for making various changes and modifications it under the prerequisite not departing from its scope.Embodiment described herein is only exemplary, and it is not intended to limit the present invention.Many changes of the present invention disclosed herein and amendment are possible, and fall into scope of the present invention.Therefore, protection domain not limit by the specification sheets of stating above, it only limited by appended claim, and its scope comprises all Equivalents of claim theme.Each claim is incorporated to specification sheets as embodiments of the present invention.Thus, claim is further instruction book, and is the increase to the preferred embodiment for the present invention.The disclosure of all patents quoted herein, patent application and publication is incorporated herein by reference, in exemplary, the program comprising that they provide or other detailed supplementing.

Claims (6)

1. as shown in chemical formula [C-3], there is optically active many rings benzylalcohol derivative or its salt,
Wherein ring A is the phenyl ring that can be substituted;
X is-CH 2-or-CH 2cH 2-;
R 1h or halogen (Cl, Br or I);
R 2and R 3, occur identical or different each time; H, D, F, Cl, Br, I, CHO, N (Ar 1) 2, N (R 2) 2, C (=O) Ar 1, P (Ar 1) 2, P (=O) (Ar 1) 2, S (=O) Ar 1, S (=O) 2ar 1, CR 1=CR 1ar 1, CN, NO 2, Si (R 1) 3, B (OAr 1) 2, B (OR 1) 2, OSO 2r 1, OH, has the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or has branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, and they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by R 1c=CR 1, C=C, Si (R 1) 2, Ge (R 1) 2, Sn (R 1) 2, C=O, C=S, C=Se, C=NR 1, P (=O) (R 1), SO, SO 2, NR 1, O, S or CONR 1substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
Ar 1, occur identical or different each time, be fragrance or the hetero-aromatic ring system with 5 to 30 aromatic ring atom, it can by more than one non-aryl R 2replace; Here, two group Ar of identical nitrogen or phosphorus atom are bonded to 1can also by singly-bound or by being selected from B (R 1), C (R 1) 2, Si (R 1) 2, C=O, C=NR 1, C=C (R 1) 2, O, S, S=O, SO 2, N (R 1), P (R 1) and P (=O) R 1bridging be connected to each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute; Here the substituent R that two or more is adjacent 1fat or the aromatic ring of single or many rings can also be formed each other.
2. there is optically active many rings benzylalcohol derivative or its salt as claimed in claim 1, it is characterized in that:
R 2and R 3, occur identical or different each time; Be have the straight chained alkyl of 1 to 40 C atom, unbranched alkoxy or thio alkoxy, or have branching or cyclic alkyl, alkoxyl group or the thio alkoxy of 3 to 40 C atoms, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute, and one of them above H atom can by D, F, Cl, Br, I, CN or NO 2substitute; Or there is fragrance or the hetero-aromatic ring system of 5 to 60 aromatic ring atom, it can by more than one non-aryl R 2replace, the described non-aryl R that two or more is adjacent 2the fatty ring system of single or many rings can also be formed each other;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
3. there is optically active many rings benzylalcohol derivative or its salt as claimed in claim 2, it is characterized in that:
R 2and R 3, occur identical or different each time; Be straight chained alkyl or the unbranched alkoxy with 1 to 10 C atom, or have the branching of 3 to 15 C atoms or cyclic alkyl or alkoxyl group, they can by more than one radicals R 1replace, one of them above non-adjacent CH 2group can by C=O or SO 2substitute;
R 1, occur identical or different each time, be H or the fat with 1 to 20 C atom, fragrance and/or assorted aryl, one of them above H atom can by D, F, Cl, Br, I, CN or NO in addition 2substitute.
4. there is optically active many rings benzylalcohol derivative or its salt as claimed in claim 3, it is characterized in that:
R 2and R 3, occurring identical or different each time, is methyl, chloromethyl, n-pentyl ,-(CH 2) 5cOOCH=CH 2, positive decyl, the tertiary butyl, tertbutyloxycarbonyl (Boc), carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or 2-furanylcarbonyl.
5. there is optically active many rings benzylalcohol derivative or its salt as claimed in claim 4, it is characterized in that:
Wherein ring A is phenyl ring;
When X is-CH 2-, R 1h, R 2when being tertbutyloxycarbonyl (Boc), R 3methyl, chloromethyl, n-pentyl ,-(CH 2) 5cOOCH=CH 2, positive decyl, the tertiary butyl;
When X is-CH 2-, R 1h, R 2carbobenzoxy, carbobenzoxy-(Cbz) (Cbz), ethanoyl (Ac), benzoyl (Bz), benzyl (Bn) ,-SO 2c 6h 5or during 2-furanylcarbonyl, R 3it is chloromethyl;
When X is-CH 2-, R 1cl or Br, R 2when being tertbutyloxycarbonyl (Boc), R 3it is chloromethyl;
When X is-CH 2cH 2-, R 1h, R 2when being carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz) or 2-furanylcarbonyl, R 3it is chloromethyl.
6. as described in above-mentioned arbitrary claim, there is optically active many rings benzylalcohol derivative or its salt, it is characterized in that the optical purity >=90%ee of described many rings benzylalcohol derivative or its salt.
CN201510174291.0A 2015-04-14 2015-04-14 Polycyclic benzyl alcohol derivative with optical activity Pending CN104774177A (en)

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