CN1379748A - Process for preparing optically active alpha-hydroxy acids and derivatives thereof - Google Patents

Process for preparing optically active alpha-hydroxy acids and derivatives thereof Download PDF

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CN1379748A
CN1379748A CN99817025.9A CN99817025A CN1379748A CN 1379748 A CN1379748 A CN 1379748A CN 99817025 A CN99817025 A CN 99817025A CN 1379748 A CN1379748 A CN 1379748A
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alkyl
replace
dioxolane
general formula
ketone
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汪炳钧
张家文
詹德品
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Scinopharm Singapore Pte Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The present invention provides a process for preparing optically active α-hydroxy acids and derivatives thereof by subjecting the alkylated 1, 3-dioxolanones of formula (IV) wherein R1 and R2 are the same or different and are each independently H or C1-6 alkyl; R5 is H, C1-16 alkyl, or unsubstituted or substituted phenyl; and R6 is C1-8 alkyl, C2-7 alkenyl or unsubstituted or substituted benzyl, to either alcoholysis or hydrolysis, in which the alkylated 1,3-dioxolanones are obtained by using 10-camphorsulfonamide as a chiral auxiliary.

Description

The preparation method of optically active alpha-hydroxy acids and its derivative
Invention field
The present invention relates to the preparation method of a kind of optically active alpha-hydroxy acids and its derivative.Alpha hydroxy acid is to be used for the synthetic important intermediate that is used for the organic compound of medicine and industrial application.More particularly, the present invention relates to by 1, the method that 3-dioxolane ketone (dioxolanone) enantio-selectivity ground synthesizes alpha hydroxy acid, described method adopt the 10-camphor sulfonamide as chiral auxiliary(reagent).
Background of invention
The alpha hydroxy acid of optically-active is the structural subunit of many natural products, as motuportin, integerrimine, Monocrotaline and eremantholide A.Alpha hydroxy acid and its derivative are to be used for the synthetic important intermediate that is used for the organic compound of medicine and industrial application.Many useful synthetic methods that are used to prepare the alpha-branched alpha hydroxy acid of enantiomer-pure had been developed already.Usually, optically active alpha-hydroxy acids obtains by microbial process, and enzymic synthesis and enantio-selectivity synthetic method adopt chiral auxiliary(reagent).
Microbial process adopts microorganism that the precursor of alpha hydroxy acid is changed into alpha hydroxy acid and its derivative as the compound that contains oxo group or hydroxyl.For example, United States Patent (USP) 5,326,702 disclose the method for a kind of biosynthesizing Alpha-hydroxy acid amides or alpha hydroxy acid, this method is included in sulfite ion, heavy sulfite ion or SODIUM HYDROSULPHITE radical ion and exists down, alpha-hydroxy nitrile or aldehyde with produce acid amides or sour microorganism by corresponding alpha-hydroxy nitrile and react.Relevant prior art United States Patent (USP) 5,371,014,5,508,181,5,756,306 and 5,273,895 also are incorporated herein by reference.But, when adopting microbial process, be difficult to from the fermenting broth substratum, isolate product.The purge process of product is very complicated and with high costs.Fermenting process produces a large amount of environmentally harmful refuses usually.This needs other treating processes, thereby is uneconomic.
United States Patent (USP) 5,098,841 disclose the butyro-enantiomorph preparation method of a kind of 2-hydroxy-4-phenyl, and this method is included in electron donor(ED) and enzyme/substrate system exists down, with lactate dehydrogenase reductase 12-oxo-4-phenylbutyric acid.Relevant prior art adopts the enzymic synthesis method, as United States Patent (USP) 5,273, and 895,5,523,223,5,686,275 and 5,770,410, these documents also are incorporated herein by reference.But the cost of enzyme is very high.Therefore, enzymic synthesis method needs the expensive cofactor of stoichiometry.In addition, the polarimetry purity by enzymic synthesis acquisition enantio-selectivity product is very relevant with substrate.
United States Patent (USP) 5; 488; 131 disclose a kind of synthetic method that can be used for the compound with predetermined chirality of asymmetric synthesis; this method comprises that the enantiomorph with pseudo-ephedrine carries out the acylations processing; alpha-carbon to adducts carries out the alkylation processing then; wherein, alkylation process is to carry out in the stereoselectivity mode, and is derived by the auxiliary pseudo-ephedrine of chirality.Adopt chiral auxiliary(reagent) to carry out enantio-selectivity synthetic related art such as United States Patent (USP) 4,983,766,5,512,682,5,512,688,5,516,930,5,578,730,5,760,237 and 5,919,949 also are incorporated herein by reference.Adopt these enantio-selectivity synthetic methods to also have some other defective, for example, the enantio-selectivity of product is lower, and chiral auxiliary(reagent) is very expensive and can not scale operation; And be difficult to reclaim chiral auxiliary(reagent).Therefore, people still wish to develop more efficiently method to produce optically-active compound.
Utilize the enantio-selectivity of 10-camphor sulfonamide, we have found a kind ofly to pass through 1, and 3-dioxolane ketone enantio-selectivity ground synthesizes the method for alpha hydroxy acid and its derivative, and described method adopts the 10-camphorsulfonic acid as chiral auxiliary(reagent).There is not the defective that can run in the prior art in method of the present invention, and has such as advantages such as the high antimer selectivity of product and high chemical yields.And then, (S) type and (R) the 10-camphor sulfonamide chiral auxiliary(reagent) of type can carry out suitability for industrialized production on a large scale, and, in described method, be easy to reclaim with high yield this chiral auxiliary(reagent).Therefore, method of the present invention has advantages such as high antimer selectivity, efficient, economy and easy handling.
Summary of the invention
The present invention relates to a kind ofly pass through 1,3-dioxolane ketone prepares the method for alpha hydroxy acid and its derivative, and described method adopts the 10-camphor sulfonamide as chiral auxiliary(reagent).1,3-dioxolane ketone is by the preparation of dialkoxy acetal catalyzing and condensing process, and described dialkoxy acetal is handled through alpha hydroxy acid by chiral auxiliary(reagent) 10-camphor sulfonamide and obtained.1,3-dioxolane ketone is enantio-selectivity, thereby can be further used for producing optically-active compound, as alpha hydroxy acid and its derivative.To 1,3-dioxolane ketone carries out alkylation to be handled, and carries out alcoholysis or hydrolysis then, to produce single and dibasic alpha hydroxy acid and its derivative and 10-camphor sulfonamide.The 10-camphor sulfonamide is easy to reclaim.Detailed Description Of The Invention
The present invention relates to a kind ofly pass through 1,3-dioxolane ketone enantio-selectivity ground synthesizes the method for alpha hydroxy acid and its derivative, and described method adopts the 10-camphor sulfonamide as chiral auxiliary(reagent).
Usually, the present invention's method of being used to prepare optically active alpha-hydroxy acids may further comprise the steps:
(a) the 10-camphor sulfonamide of following general formula I and the alkane of alkoxyl group replacement are reacted
Figure A9981702500121
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, the dialkoxy acetal of formation general formula I I
Figure A9981702500122
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 3And R 4Can be identical or different, be C independently of one another 1-4Alkyl;
(b) the dialkoxy acetal of general formula I I and the alpha hydroxy acid with following general formula are reacted
Figure A9981702500123
Wherein, R 5Be H, C 1-6Alkyl, or the phenyl that does not replace or replace form 1 of general formula III, 3-dioxolane ketone
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be H, C 1-6Alkyl, or the phenyl that does not replace or replace;
(c) make 1 of general formula III, 3-dioxolane ketone and alkylating reagent reaction form the alkylation 1 of general formula I V, 3-dioxolane ketone
Figure A9981702500131
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be H, C 1-6Alkyl, or the phenyl that does not replace or replace, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace;
(d) make the alkylating 1 of general formula I V, 3-dioxolane ketone carries out
(i) work as R 5During for hydrogen, alcoholysis, the alpha hydroxy acid derivative of formation 10-camphor sulfonamide and general formula V
Figure A9981702500132
Wherein, R 7Be C 1-6Alkyl, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace,
Or
(ii) work as R 5Be C 1-6When alkyl or the phenyl that do not replace or replace, hydrolysis forms the alpha hydroxy acid of 10-camphor sulfonamide and general formula VI
Figure A9981702500133
Wherein, R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace.
The raw material that is used for the inventive method is that the 10-camphor sulfonamide of general formula I is known, and can be obtained by prior art.In step (a), the alkane that the 10-camphor sulfonamide of general formula I and alkoxyl group replace reacts, and forms the dialkoxy acetal of general formula I I.This is reflected at and well known to a person skilled in the art that catalyzer and solvent carry out under existing or not existing.Usually the catalyzer that adopts for example is a tosic acid (p-TSA), and solvent for example is an alcohol, as methyl alcohol.In a preferred embodiment of the invention, the alkane of alkoxyl group replacement is (CH 3O) 3CH.
In step (b), make the dialkoxy acetal of the general formula I I that produces by step (a) and have general formula R 5The condensation reaction that the alpha hydroxy acid of C (OH) COOH carries out Louis acid catalysis produces 1 of general formula III, 3-dioxolane ketone, wherein, R 5Be H, C 1-6Alkyl or the phenyl dioxolane ketone that does not replace or replace.The reaction conditions of the condensation reaction of Louis acid catalysis is known in the art.Can be with reference to following document: Farines, M.; Soulier, J.Bull.Soc.Chim.Fr.1970,332; Petasis, N.A.; Lu, S.-P.J.Am.Chem.Soc.1995,117,6394; Pearson, W.H.; Cheng, M.-C.J.Org Chem.1987,52,1353; And Hoye, T.R.; Peterson, B.H.; Miller, J.D.J.Org.Chem.1987,52,1351.In embodiments of the invention, dialkoxy acetal and the acid of alpha hydroxy acid preferred alcohol, lactic acid and tussol reaction are reflected under the inert atmosphere and carry out, temperature of reaction for approximately-35 ℃ to-60 ℃ approximately, be reflected at ether as solvent and carry out under existing.The Lewis acid of Cai Yonging is BF in a preferred embodiment of the invention 3OEt 2
Because the 10-camphor sulfonamide of general formula I has enantio-selectivity, therefore, 1 of general formula III, 3-dioxolane ketone also has enantio-selectivity, 1 of general formula III, the enantioselectivity of 3-dioxolane ketone are suitable for preparing optically-active compound such as alpha hydroxy acid and its derivative very much.
Work as R 5During for H, the reaction of step (b) can produce the by product 1 of a spot of general formula III a, 3-dioxolane ketone:
Figure A9981702500141
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl.1 of general formula III and IIIa, 3-dioxolane ketone is diastereomeric chipal compounds.General formula III pure 1,3-dioxolane ketone can obtain by recrystallization, perhaps by column chromatography by 1 of general formula III a, a small amount of isomer separation of 3-dioxolane ketone is come out.The condition of recrystallization and column chromatography is well known to a person skilled in the art.
Work as R 5Be C 1-6When alkyl or the phenyl that do not replace or replace, 1 of general formula III, 3-dioxolane ketone is single product.1, the stereochemistry of 3-dioxolane ketone can be confirmed by the conventional known method that adopts in the prior art, as X ray crystal analysis and nuclear Wo Haosi effect (NOE) experiment.
In the alkylated reaction of step (c), 1 of general formula III, thus 3-dioxolane ketone and alkylating reagent react the alkylation 1 that forms general formula I V, 3-dioxolane ketone, described alkylating reagent such as R 6X, wherein, R 6Be C 1-C 8Alkyl, C 2-C 8Alkenyl or the benzyl that does not replace or replace, X is a leavings group dioxolane ketone.Preferably, alkylating reagent is halogenide or sulfonate.Alkylated reaction carries out to room temperature at-110 ℃, preferably-100 ℃ to 0 ℃, more preferably-100 ℃ to-45 ℃, first-selected-100 ℃ to-78 ℃, alkylated reaction carries out in the presence of highly basic, as di-isopropyl lithamide (lithium diisopropylamide) (LDA), being reflected at solvent exists or does not exist and carry out.Have found that when the addition reaction of taking off alpha proton reaction and alkylating reagent under-100 ℃ was increased to-78 ℃ then, the stereoselectivity of product and yield all can improve.In alkylated reaction, by 400 MHz 1H NMR measures and does not detect the diastereomer isomer.The alkylation 1 of general formula I V, 3-dioxolane ketone have excellent cis-selectivity.The alkylation 1 of general formula I V, the stereochemistry of 3-dioxolane ketone can adopt conventional square tube formula such as X ray crystal analysis to detect.
In step (d), the alkylation 1 of general formula I V, 3-dioxolane ketone can further carry out alcoholysis or hydrolysis, with the alpha hydroxy acid of production general formula VI and the derivative of its general formula V.Work as R 5During for H, alkylating product carries out the alcoholysis of step (I).In embodiments of the invention, the process of alcoholysis is at absolute alcohol (general formula R 7OH, wherein R 7Be C 1-6Alkyl) as in the ethanol, by the alkylation 1 of heating-type IV, 3-dioxolane ketone and anhydrous hydrogen chloride carry out.In alcoholysis process, also can produce the 10-camphor sulfonamide of general formula I.Can be according to the alpha hydroxy acid derivative of ordinary method such as column chromatography separation and purifying general formula VI.Thereby reclaim the 10-camphor sulfonamide.Step (d) reaction scheme (i) is as follows:
Figure A9981702500161
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be H, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace, R 7Be C 1-6Alkyl.
Work as R 5Be C 1-6When alkyl or the phenyl that do not replace or replace, the alkylation 1 of general formula I V, 3-dioxolane ketone carries out step hydrolytic process (ii).The conventional condition that adopts in hydrolysising condition and the prior art.In a preferred embodiment of the invention, make the alkylating 1 of general formula I V, 3-dioxolane ketone and a kind of highly basic such as sodium hydroxide react in the presence of as the alcohol of solvent such as methyl alcohol and are hydrolyzed.In hydrolytic process, also can produce the 10-camphor sulfonamide of general formula I, can separate and recovery 10-camphor sulfonamide by ordinary method such as extraction process.The purifying of alpha hydroxy acid can be undertaken by concentrating.Step (d) reaction scheme (ii) is as implied above:
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be C 1-6Alkyl or the phenyl that does not replace or replace, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace.
Alpha hydroxy acid and its derivative are to be used for the synthetic important intermediate that is used for the optically-active organic compound of medicine and industrial application.
Further describe method of the present invention by following embodiment, these embodiment only are used to illustrate the present invention, are not limiting the scope of the invention.
Abbreviation: Me is a methyl, and Et is an ethyl, and Ac is COCH 3
Embodiment
Embodiment 1
Embodiment 1 explanation is prepared the dialkoxy acetal of general formula I I by the 10-camphor sulfonamide of general formula I.(1R)-and N, N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin
Figure A9981702500171
At room temperature, with (1S)-(+)-N of 30g, the tosic acid (p-TSA) of N-di-isopropyl-10-camphor sulfonamide, 1g and the CH (OCH of 84mL 3) 3In the methyl alcohol of 150mL, stirred 84 hours.Saturated sodium bicarbonate (aqueous solution) with 100mL stops reaction, and decompression steams methyl alcohol.(3 * 100mL) extract with ethyl acetate with resistates.With the organic phase salt water washing after merging, with sodium sulfate (solid) drying, vacuum-evaporation, with resistates column chromatography purifying (SiO 2, hexane-ethyl acetate 8: 1, adds 1～2%N (C 2H 5) 3), obtaining (1R)-N of 31.46g (85%), N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two rings [2.2.1] heptan-1-yl) Toluidrin is a kind of white solid.
mp＝73.8-74.6℃；
[α] D 25+16.54(c1.00，CHCl 3)；
IR(KBr)2973，2871，2836，1748，1460，1402，1377，1330，1199，1136cm -1。
1H NMR (CDCl 3, 400 MHz) and δ 3.70 (septet, J=6.8Hz, 2H), 3.46 (d, J=15.6Hz, 1H), 3.30 (s, 3H), 3.13 (s, 3H), 2.72 (d, J=15.6Hz), 2.29 (td, J=12.6, J=5.2Hz, 1H), 2.16 (dt, J=13.2, J=3.6Hz, 1H), 1.91 (ddd, J=7.7, J=7.7, J=3.6Hz), 1.84-1.76 (m, 1H), 1.63 (t, J=4.8Hz, 1H), 1.30 (d, J=6.8Hz, 6H), 1.29 (d, J=6.8Hz, 6H), 1.28-1.22 (m, 1H), 1.18 (d, J=13.2Hz, 1H), 0.99 (s, 3H), 0.88 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ108.5，53.3，52.1，51.1，49.4，48.2，47.4，43.0，41.2，27.0，24.7，22.4，22.2，21.5，20.4；
Analytical calculation value C 18H 35NO 4S:C, 59.80; H, 9.76; N, 3.87; S, 8.87.Measured value: C, 60.07; H, 9.60; N, 4.22; S, 8.51.
Embodiment 2a-d
The embodiment 2a-d explanation condensation reaction by Louis acid catalysis prepares 1 of general formula III and IIIa, 3-dioxolane ketone by the dialkoxy acetal of general formula I I.It is as follows that dialkoxy acetal and alpha hydroxy acid carry out the general process of condensation reaction of Louis acid catalysis:
Under argon atmospher and-50 ℃, in 10 minutes, methylene dichloride (1mL) solution of dialkoxy acetal (1mmol) is added to alpha hydroxy acid and BF 3-O (C 2H 5) 2In (1.6 equivalent) mixture in ether.After 30 to 60 minutes, use (C at stir about 2H 5) 3N (0.6mL) stopped reaction.Solution is poured in the 5mL frozen water, with ether (3 * 20mL) extractions.With the organic phase salt water washing after merging, use dried over sodium sulfate, vacuum-evaporation is with resistates column chromatography purifying (SiO 2, hexane-ethyl acetate, 6: 1), obtain 1, the condensation product of 3-dioxolane ketone.
Embodiment 2a (1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1]-heptan-the 1-yl] Toluidrin
By (1R)-N, N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin and oxyacetic acid (2.2 equivalent) carry out condensation reaction and prepare title compound.
74% yield
mp＝140.3-140.7℃；
[α] D 25-7.99(c1.00，CHCl 3)；
IR(KBr)cm -1?2974，2879，1806，1468，1394，1281，1258，1338，1258，1243，1198，1154；
1H NMR (CDCl 3, 400MHz) δ 4.44 (d, J=14.2Hz, 1H), 4.28 (d, J=14.2Hz, 1H), 3.68 (septet, J=6.8Hz, 2H), 3.30 (d, J=13.2Hz, 1H), 2.56 (d, J=13.2Hz, 1H), 2.38-2.26 (m, 2H), 1.80-1.90 (m, 3H), 1.76 (d, J=13.6Hz, 1H), 1.39-1.38 (m, 1H), 1.28 (d, J=6.8, Hz, 3H), 1.27 (d, J=6.8,3H), 0.99 (s, 3H), 0.87 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ171.0，119.2，64.7，54.6，52.4，48.3，45.5，44.0，26.1，26.6，22.36，22.2，20.5，20.1，
Analytical calculation value C 18H 31NO 5S:C, 57.88; H, 8.37; N, 3.75; S, 8.59. measured value: C, 57.36; H, 8.34; N, 3.65; S, 8.61.
Embodiment 2b (1R, 2R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two rings [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500191
Title compound for preparation (1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] by product in the Toluidrin process.
mp＝139.9-140.2℃；
[α] D 25-13.35(c1.00，CHCl 3)；
IR(KBr)2997，2968，2934，1800，1458，1333，1270，1240，1199，1174，1136cm -1；
1H NMR (CDCl 3, 400MHz) δ 4.42 (d, J=14.6Hz, 1H), 4.11 (d, J=14.6Hz, 1H), 3.69 (septet, J=6.8Hz, 2H), 3.17 (d, J=14Hz, 1H), 2.59 (d, J=14Hz, 1H), 2.50-2.40 (m, 1H), 2.26 (dt, J=13.2,2.8Hz, 1H), 1.84-1.72 (m, 3H), 1.69 (d, J=14Hz, 1H), 1.38-1.30 (m, 1H), 1.27 (d, J=7.2Hz, 12H); 1.00 (s, 3H); 0.88 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ172.2，118.3，62.9，54.8，52.3，50.8，48.3，44.8，44.2，26.5，25.2，22.3，22.2，20.4，20.1；
Analytical calculation value C 18H 31NO 5S:C, 57.88; H, 8.37; N, 3.75; S, 8.59. measured value: C, 57.76; H, 8.24; N, 3.92; S, 8.24.Embodiment 2c (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500201
Title compound is by (1R)-N, and N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two rings [2.2.1] heptan-1-yl) Toluidrin and racemic lactic acid (4.5 equivalent) carry out condensation prepared.
77% yield;
mp＝94.4-94.6℃；
[α] D 25+6.36(c1.00，CHCl 3)；
IR (net value) 2973,2949,2879,1794,1370,1334,1133,976,658cm -1
1H NMR (CDCl 3, 400MHz) δ 4.43 (q, J=6.4Hz, 1H), 3.70 (septets, J=6.4Hz, 2H), 3.30 (d, J=13.2Hz, 1H), 2.56 (d, J=13.2Hz, 1H), 2.39 (ddd, J=13.2,9.6,3.6Hz, 1H), 2.29 (dt, 1H, J=9.6,3.6Hz, 1H), 1.92 (td, J=13.2,3.6Hz, 1H), and 1.85-1.80 (m, 2H), 1.71 (d, J=13.2Hz, 1H), 1.53 (d, J=6.4Hz, 1H), 1.38-1.22 (m, 1H), 1.29 (d, J=6.4Hz, 6H), and 1.1.27 (d, J=6.4Hz, 6H), 1.02 (s, 3H), 0.90 (s, 3H);
13C NMR (CDCl 3, 100.6MHz) δ 173.0,116.2, and 70.6,53.7,52.1,50.7,48.2,44.2,43.9,26.6,26.1,22.4,22.2,20.5,20.2,15.4; MS (EI) m/z (relative intensity) 387 (M +, 0.1), 372 (3), 223 (21), 215 (7), 151 (100), 123 (47), 109 (56), 81 (35);
HRMS calculated value C 19H 33O 5NS (M +-Me) m/z 372.1842, measured value 372.1847;
Analytical calculation value C 19H 33O 5NS:C, 58.89; H, 8.58; N, 3.61; S, 8.27; Measured value: C, 58.79; H, 8.34; N, 3.64; S, 8.30.
Embodiment 2d (1R.2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500211
Title compound is by (1R)-N, and N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two rings [2.2.1] heptan-1-yl) Toluidrin carries out condensation reaction with racemize tussol (2.2 equivalent) and prepares.
56% yield;
Silica gel column chromatography (hexane-ethyl acetate, 6: 1);
mp＝112.3-112.6℃；
[α]D 25+2.29(c1.00，CHCl 3)；
IR(KBr)3070，2970，2879，1799，1458，1335，1121，977，774cm -1；
1H NMR (CDCl 3, 400MHz) δ 7.61-7.59 (m, 2H), 7.36-7.32 (m, 3H), 5.36 (s, 1H), 3.43 (septet, J=6.9Hz, 1H), 3.28 (d, J=13.7Hz, 1H), 2.53 (d, J=13.7Hz, 1H), 2.46 (dt, J=13.4,4.0Hz, 1H), 2.34-2.29 (m, 1H), 2.09 (dt, J=5.1,13.4Hz, 1H), 1.90-1.80 (m, 4H), 1.41-1.35 (m, 1H), 1.16 (d, J=6.9Hz, 6H), 1.22 (d, J=6.9Hz, 6H), 1.07 (s, 3H), 0.94 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ170.2，133.4，128.6，128.3，127.3，116.6，75.0，53.9，51.7，50.6，48.0，44.2，44.0，26.6，25.7，22.7，21.6，20.6，20.2；
MS (EI) m/z (relative intensity) 449 (M +, 0.04), 434 (4), 284 (7), 257 (10), 151 (100), 123 (42), 109 (60), 93 (21), 81 (38), 67 (21);
HRMS calculated value C 24H 35O 5NS (M +-Me) m/z 434.1999, measured value 434.2003;
Analytical calculation value C 24H 35O 5NS:C, 64.11; H, 7.85; N, 3.12; S, 7.13; Measured value: C, 64.00; H, 7.64; N, 3.27; S, 7.16.
Embodiment 3a-i
1 of embodiment 3a-i explanation general formula III, the alkylation process of 3-dioxolane ketone, wherein, R 5Be hydrogen.
Embodiment 3a (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Under argon atmospher, under 0 ℃, by diisopropylamine (0.14mL, 1.0mmol) and n-butyllithium solution (2.2M hexane solution, 0.44mL) (1.0mL) solution of tetrahydrofuran (THF) (THF) of preparation di-isopropyl lithamide (LDA).After stirring 30 hours, add hexamethylphosphoramide (HMPA) (1.2 equivalent), and be cooled to-78 ℃.In 20 minutes, add (1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] THF (1.0mL) solution of Toluidrin (0.8mmol), mixture was stirred 30 minutes, add methyl halogenide (1.5 equivalent) then.With mixture restir 1 hour.In mixture, add 1%H 2C 2O 4(aqueous solution) (1mL) and be warming up to 0 ℃ uses 1%H 2C 2O 4(aqueous solution) is neutralized to pH=6～7.With the solution ethyl acetate extraction, dried over sodium sulfate is used in the salt water washing of the organic phase after the merging, and vacuum-evaporation with the resistates silica gel chromatography, obtains title compound.The non-enantiomer selectivity of product is 93.5%.
77% yield;
Silica gel column chromatography (hexane-ethyl acetate, 6: 1);
mp＝106.0-107.0℃；
[α]D 25-17.67(c1.00，CHCl 3)；
IR(KBr)3002，2973，2886，1801，1457，1413，1375，1328，1283，1257，1240，1200，1154，1117，1034cm -1；
1H NMR (CDCl 3, 400MHz) δ 4.60 (quat, J=6.8Hz, 1H), 3.68 (septet, J=6.8Hz, 2H), 3.28 (d, J=13.6Hz, 1H), 2.55 (d, J=13.6Hz, 1H), and 2.37-2.24 (m, 2H), 1.90-1.76 (m, 4H), (1.43 d, J=7.2Hz 3H), and 1.40-1.30 (m, 1H), 1.271 (d, J=6.8, Hz, 6H), 1.268 (d, J=6.8,6H), 1.00 (s, 3H), 0.87 (s, 3H); 13C NMR (CDCl 3, 100.6MHz) δ 173.7,117.5, and 72.3,54.8,52.5,51.2,48.3,47.2,44.1,26.6,25.9,22.5,22.2,20.6,20.2,19.0;
Analytical calculation value C 19H 33O 5NS:C, 58.89; H, 8.58; N, 3.61; S, 8.27; Measured value: C, 58.87; H, 8.50; N, 3.91; S, 8.65.
Embodiment 3b
Repeat embodiment 3a, just do not add HMPA, temperature of reaction is increased to right-78 ℃ from-100 ℃.The yield of title compound is 84%, and non-enantiomer selectivity is greater than 98%.
Embodiment 3c
Repeat embodiment 3a, just temperature of reaction is increased to right-78 ℃ from-100 ℃.The yield of title compound is 86%, and non-enantiomer selectivity is greater than 98%.
Embodiment 3d (1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-[5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone]-7,7-dimethyl two rings [2.2.11 heptan-1-yl } Toluidrin
Under argon atmospher, under 0 ℃, by diisopropylamine (0.14mL, 1.0mmol) and n-butyllithium solution (2.2M hexane solution, 0.44mL) (1.0mL) solution of tetrahydrofuran (THF) (THF) of preparation di-isopropyl lithamide (LDA).After stirring 30 hours, reaction mixture is cooled to-100 ℃.In 20 minutes, add (1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7, THF (1.0mL) solution of 7-dimethyl-two ring [2.2.1) heptan-1-yl] Toluidrin (0.8mmol), mixture was stirred 30 minutes, add allyl halide (1.5 equivalent) then.Mixture is heated up right-78 ℃ again, restir 1 hour.In mixture, add 1%H 2C 2O 4(aqueous solution) (1mL) and be warming up to 0 ℃ uses 1%H 2C 2O 4(aqueous solution) is neutralized to pH=6～7.With the solution ethyl acetate extraction, dried over sodium sulfate is used in the salt water washing of the organic phase after the merging, and vacuum-evaporation with the resistates silica gel chromatography, obtains title compound.The non-enantiomer selectivity of product is greater than 98%.
76% yield;
Silica gel column chromatography (hexane-ethyl acetate, 6: 1);
mp＝149.5-151.4℃；
[α]D 25-3.77(c1.00，CHCl 3)；
IR(KBr)3007，2973，2881，1798，1332，1283，1240，1201，1153，1136cm -1。
1H NMR (CDCl 3, 400MHz) δ 5.74-5.85 (m, 1H), 5.20-5.13 (m, 2H), 4.62 (dd, J=6.8, J=4.8Hz, 1H), 3.68 (septet, J=6.8Hz, 2H), 3.29 (d, J=13.6Hz, 1H), 2.64-2.50 (m, 1H), 2.56 (d, J=13.6,1H), 2.62-2.54 (m, 1H), 2.48-2.23 (m, 2H), 1.90-1.73 (m, 4H), 1.38-1.30 (m, 1H, 1.28 (d, J=6.8Hz, 6H), 1.27 (d, J=6.8Hz, 6H), 0.99 (s, 3H), 0.86 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ172.3，132.1，118.9，117.6，75.8，54.7，52.3，51.0，48.2，47.2，43.8，36.7，26.4，25.7，22.4，22.0，20.4，20.0；
Analytical calculation value C 21H 35O 5NS:C, 60.99; H, 8.53; N, 3.39; S, 7.75; Measured value: C, 60.65; H, 8.85; N, 3.27; S, 7.90.
Embodiment 3e
Repeat embodiment 3d, just add HMPA.The yield of title compound is 76%, and non-enantiomer selectivity is greater than 98%.
Embodiment 3f (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-1 ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500241
Under argon atmospher, under 0 ℃, by diisopropylamine (0.14mL, 1.0mmol) and n-butyllithium solution (2.2M hexane solution, 0.44mL) (1.0mL) solution of tetrahydrofuran (THF) (THF) of preparation di-isopropyl lithamide (LDA).After stirring 30 hours, add hexamethylphosphoramide (HMPA) (1.2 equivalent), and be cooled to-78 ℃.In 20 minutes, add (1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] THF (1.0mL) solution of Toluidrin (0.8mmol), mixture was stirred 30 minutes, add ethyl halogenide (1.5 equivalent) then.With mixture restir 1 hour.In mixture, add 1%H 2C 2O 4(aqueous solution) (1mL) and be warming up to 0 ℃ uses 1%H 2C 2O 4(aqueous solution) is neutralized to pH=6～7.With the solution ethyl acetate extraction, dried over sodium sulfate is used in the salt water washing of the organic phase after the merging, and vacuum-evaporation with the resistates silica gel chromatography, obtains title compound.The non-enantiomer selectivity of product＞98%.(1S)-(+)-and N, the recovery yield of N-di-isopropyl-10-camphor sulfonamide is 57%.
36% yield.
Silica gel column chromatography (hexane-ethyl acetate, 6: 1); Mp=143.1-143.8 ℃;
[α]D 25-7.17(c1.00，CHCl 3)；
IR(KBr)3002，2968，2949，2891，1800，1328，1238，1155，1136cm -1；
1H NMR (CDCl 3, 400MHz) δ 4.49 (dd, J=6.6, J=4.8Hz, 1H), 3.69 (septets, J=6.8Hz, 2H), 3.30 (d, J=13.6,1H), 2.57 (d, J=13.6Hz, 1H), 2.36-2.24 (m, 2H), 1.93-1.68 (m, 6H), 1.39-1.31 (m, 1H), 1.284 (d, J=6.8Hz, 6H), 1.278 (d, J=13.6Hz, 6H), 1.006 (s, 3H), 1.004 (t, J=7.2Hz, 3H), 0.87 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ173.0，117.5，77.2，54.8，52.4，51.1，48.3，47.0，43.9，26.5，25.72，25.68，22.5，22.1，20.5，20.1，9.3；
Analytical calculation value C 20H 35O 5NS:C, 59.82; H, 8.79; N, 3.49, S, 7.99; Measured value: C, 59.82; H, 8.77; N, 3.77; S, 7.96.
Embodiment 3g
Repeat embodiment 3f, just temperature of reaction increases to-78 ℃ from-100 ℃.The yield of title compound is 65%, non-enantiomer selectivity＞98%.
Embodiment 3h (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-phenyl methyl-1 ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500261
Under argon atmospher, under 0 ℃, by diisopropylamine (0.14mL, 1.0mmol) and n-butyllithium solution (2.2M hexane solution, 0.44mL) (1.0mL) solution of tetrahydrofuran (THF) (THF) of preparation di-isopropyl lithamide (LDA).After stirring 30 hours, add hexamethylphosphoramide (HMPA) (1.2 equivalent), and be cooled to-78 ℃.In 20 minutes, add (1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] THF (1.0mL) solution of Toluidrin (0.8mmol), mixture was stirred 30 minutes, add benzyl halogenide (1.5 equivalent) then.Mixture is warming up to-45 ℃, and with mixture restir 1 hour.In mixture, add 1%H 2C 2O 4(aqueous solution) (1mL) and be warming up to 0 ℃ uses 1%H 2C 2O 4(aqueous solution) is neutralized to pH=6～7.With the solution ethyl acetate extraction, dried over sodium sulfate is used in the salt water washing of the organic phase after the merging, and vacuum-evaporation with the resistates silica gel chromatography, obtains title compound.The non-enantiomer selectivity of product＞98%.
60% yield;
Silica gel column chromatography (hexane-ethyl acetate, 6: 1);
mp＝106.3-161.0℃；
[α]D 25+1.78(c1.00，CHCl 3)；
IR(KBr)2992，2944，2886，1787，1336，1240，1199，1149，1134cm -1；
1H NMR (CDCl 3, 400MHz) δ 7.30-7.20 (m, 5H), 4.83 (t, J=5.2Hz, 1H), 3.67 (septets, J=6.8Hz, 2H), 3.25 (d, J=13.2Hz, 1H), 3.25 (d, J=13.2Hz, 1H), 3.08 (d, J=5.2Hz, 2H), 2.51 (d, J=13.2Hz, 1H), 2.42 (m, 1H, 1.82 (td, J=12.6,1H), 1.76-1.60 (m, 3H), 1.26 (d, J=6.8Hz, 12H), 1.30-1.18 (m, 1H), 1.16 (d, J=13.6Hz, 1H), 0.91 (s, 3H), 0.8 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ172.5，136.2，129.8，128.3，126.9，118.0，77.4，54.8，52.4，51.0，48.3，45.9，43.7，38.1，26.4，25.7，22.5，22.0，20.4，20.1；
Analytical calculation value C 25H 37O 5NS:C, 64.76; H, 8.04; N, 3.02; S, 6.92; Measured value: C, 64.76; H, 8.00; N, 3.43; S, 7.11.
Embodiment 3i
Repeat embodiment 3h, just temperature of reaction increases to-78 ℃ from-100 ℃.The yield of title compound is 70%, diastereomer isomer＞98%.
Embodiment 4a-g
1 of embodiment 4a-g explanation general formula III, the alkylation process of 3-dioxolane ketone, wherein, R 5Be methyl or phenyl.The conventional process of alkylation is as follows:
Under argon atmospher, under 0 ℃, by diisopropylamine (0.14mL, 1.0mmol) and n-butyllithium solution (2.2M hexane solution, 0.44mL) (1.0mL) solution of tetrahydrofuran (THF) (THF) of preparation di-isopropyl lithamide (LDA).After stirring 30 hours, reactant is cooled to-100 ℃.In 20 minutes, add 1 of general formula III, THF (1.0mL) solution of 3-dioxolane ketone (0.8mmol) stirs mixture 30 minutes, adds alkylating reagent (1.5 equivalent) then.Mixture is warming up to-78 ℃, and with mixture restir 1 hour.In mixture, add 1%H 2C 2O 4(aqueous solution) (1mL) and be warming up to 0 ℃ uses 1%H 2C 2O 4(aqueous solution) is neutralized to pH=6～7.With the solution ethyl acetate extraction, dried over sodium sulfate is used in the salt water washing of the organic phase after the merging, and vacuum-evaporation with silica gel column chromatography (hexane-ether 4: 1) purifying, obtains title compound with resistates.
Embodiment 4a (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500271
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and ethyl halogenide carries out the prepared in reaction title compound.The non-enantiomer selectivity of product＞98%.
79% yield;
mp＝185.4-185.5℃；
[α] D 25+9.52(c1.00，CHCl 3)；
IR(KBr)3007，2977，1796，1635，1458，1330，1189，1148，1135，1115，983，774cm -1；
1H NMR (CDCl 3, 400 MHz) and δ 3.69 (septet, J=6.4Hz, 2H), 3.28 (d, J=13.2Hz, 1H), 2.58 (d, J=13.2Hz, 1H), 2.35-2.24 (m, 2H), 2.06-1.98 (m, 1H), 1.84-1.68 (m, 5H), 1.48 (s, 3H), 1.38-1.21 (m, 1H), 1.33 (d, J=6.4Hz, 6H), 1.28 (d, J=6.4Hz, 6H), 1.02 (s, 3H), 1.0 (t, J=8.0Hz, 3H), 0.91 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ174.74，115.1，80.7，54.1，51.8，50.4，48.0，46.5，44.10，30.36，26.36，25.6，22.5，21.7，20.4，20.0，19.7，7.2；
MS (EI) m/z (relative intensity) 415 (M +, 67), 267 (22), 251 (20), 171 (29), 151 (100), 109 (63), 86 (61), 55 (77);
HRMS calculated value C 21H 37O 5NS (M +-Me) m/z 400.2163, measured value 400.2154;
Analytical calculation value C 21H 37O 5NS:C, 60.69; H, 8.90; N, 3.37; S, 7.72; Measured value: C, 60.59; H, 8.71; N, 3.43; S, 7.78.
Embodiment 4b (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-propyl group-1 ', 3 '-dioxolane-4 '-ketone) 7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and propyl group halides prepared in reaction title compound.The non-enantiomer selectivity of product＞98%.
67% yield;
mp＝191.6-191.8℃；
[α] D 25+2.17(c1.00，CHCl 3)；
IR(KBr)2965，2877，1798，1635，1334，1187，1114，1039，982，775，660cm -1；
1H NMR (CDCl 3, 400MHz) δ 3.69 (septet, J=6.4Hz, 2H), 3.27 (d, J=13.6Hz, 1H), 2.58 (d, J=13.6Hz, 1H), 2.34-2.23 (m, 2H), 2.06-1.99 (m, 1H), 1.84-1.76 (m, 3H), 1.71-1.21 (m, 5H), 1.49 (s, 3H), 1.29 (d, J=6.4Hz, 6H), 1.27 (d, J=6.4Hz, 6H), 1.01 (s, 3H), 0.93 (t, J=7.2Hz, 3H), 0.91 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ174.9，115.3，80.6，54.3，51.9，50.4，48.1，46.5，44.3，39.8，26.4，25.7，22.6，21.8，20.5，20.5，20.1，16.4，14.1；
MS (EI) m/z (relative intensity) 429 (M +, 0.2), 151 (32), 123 (15), 109 (25), 86 (75), 84 (100), 69 (9);
HRMS calculated value C 22H 39O 5NS (M +-Me) m/z 414.2349, measured value 414.2290;
Analytical calculation value C 22H 39O 5NS:C, 61.51; H, 9.15; N, 3.26; S, 7.46; Measured value: C, 61.60; H, 9.37; N, 3.34 S, 7.61.
Embodiment 4c (1R 2S, 5 ' R)-N, the N-di-isopropyl-2-spiral shell-2 '-[5 '-methyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone]-7,7-dimethyl two rings [2.2.1] heptan-1-yl] Toluidrin
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and allyl halide prepared in reaction title compound.The non-enantiomer selectivity of product＞98%.
78% yield;
mp＝177,7-177.8℃；
[α] D 25+18.65(c1.00，CHCl 3)；
IR(KBr)3007，2971，1798，1645，1332，1247，1185，1146，984，919，774，660cm -1；
1H NMR (CDCl 3, 400MHz) δ 5.87-5.76 (m, 1H), 5.21-5.14 (m, 2H), 3.69 (septets, J=6.8Hz, 2H), 3.27 (d, J=14.0Hz, 1H), 2.57 (d, J=14.0Hz, 1H), 2.51-2.29 (m, 4H), 2.06-1.98 (m, 1H), 1.85-1.77 (m, 3H), 1.55 (s, 3H), 1.38-1.23 (m, 1H), 1.28 (d, J=6.8Hz, 6H), 1.27 (d, J=6.8Hz, 6H), 1.01 (s, 3H), 0.91 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ174.3，131.1，119.7，115.5，80.1，54.3，51.9，50.5，48.1，46.6，44.2，41.9，26.4，25.7，22.6，21.8，20.6，20.5，20.1；
MS (EI) m/z (relative intensity) 427 (M +, 0.13), 316 (3), 300 (2), 263 (16), 215 (16), 151 (100), 123 (40), 109 (67), 81 (36), 67 (25);
HRMS calculated value C 22H 37O 5NS (M +-Me) m/z 412.2174, measured value 412.2147;
Analytical calculation value C 22H 37O 5NS:C, 61.80; H, 8.72; N, 3.28; S, 7.50; Measured value: C, 61.57; H, 8.52; N, 3.36; S, 7.51.
Embodiment 4d (1R.2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-butyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500301
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and butyl halogenide prepared in reaction title compound.The non-enantiomer selectivity of product＞98%.
74% yield;
mp＝148.3-148.5℃；
[α]D 25+5.13(c1.0，CHCl 3)；
IR(KBr)2963，2939，2876，1794，1338，1148，1137，978，778，661cm -1；
1H NMR (CDCl 3, 400MHz) δ 3.69 (septet, J=6.4Hz, 2H), 3,27 (d, J=13.6Hz, 1H), 2.58 (d, J=13.6Hz, 1H), 2.35-2.23 (m, 2H), and 2.06-1.99 (m, 1H), 1.82-1.75 (m, 3H), 1.71-1.64 (m, 2H), 1.49 (s, 3H), 1.39-1.27 (m, 3H), 1.29 (d, J=6.4Hz, 6H), 1.27 (d, J=6.4Hz, 6H), 1.02 (s, 3H), 0.92-0.88 (m, 5H), 0.91 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ175.0，115.3，80.6，54.3，52.0，50.6，48.2，46.6，44.3，37.3，26.5，25.8，25.1，22.7，22.6，22.0，20.6，20.5，20.2，13.6；
MS (EI) m/z (relative intensity) 443 (M +, 0.3), 279 (12), 215 (14), 151 (100), 123 (42), 86 (46) .81 (35), 67 (20);
HRMS calculated value C 23H 41O 5NS (m --Me) m/z 428.2464, measured value 428.2476;
Analytical calculation value C 23H 41O 5NS:C, 62.27; H, 9.32; N, 3.16.S, 7.23; Measured value: C, 62.15; H, 9.37; N, 3.34; S, 7.33.
Embodiment 4e (1 R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-phenyl methyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and benzyl halogenide prepared in reaction title compound.The non-enantiomer selectivity of product＞98%.
82% yield;
mp＝130.4-130.6℃；
[α]D 25+32.33(c1.0，CHCl 3)；
IR(KBr)3061，3027，2997，2973，2944，2881，1790，1333，1179，1146，1119，797cm -1；
1H NMR (CDCl 3, 400MHz) δ 7.32-7.22 (m, 5H), 3.66 (septets, J=6.8Hz, 2H), 3.22 (d, J=14.0Hz, 1H), 3.14 (d, J=14.8Hz, 1H), 2.88 (d, J=14.8Hz, 1H), 2.60 (d, J=14.0Hz, 1H), 2.28-2.20 (m, 2H), 2.13-2.06 (m, 1H), 1.83-1.76 (m, 2H), (1.56 d, J=13.2Hz) 1H), 1.44 (s, 3H), 1.41-1.42 (m, 1H), 1.26 (d, J=6.8Hz, 6H), 1.25 (d, J=6.8Hz, 6H), 1.02 (s, 3H), 0.92 (s, 3H);
13C?NMR(CDCl 3，100.6MHz)δ174.6，135.3，130.4，128.3，127.1，116.5，81.4，54.6，51.9，50.6，48.2，46.1，44.4，43.8，26.4，25.7，22.9，21.9，21.6，20.8，20.2；
MS (ED m/z (relative intensity) 447 (M +, 1.4), 313 (100), 300 (17), 215 (56), 151 (61), 123 (12), 109 (10);
HRMS calculated value C 26H 39O 5NS (M +-Me) m/z 477.2584, measured value 477.2517;
Analytical calculation value C 26H 39O 5NS:C, 65.38; H, 6.71; N, 2.93; S, 6.71; Measured value: C, 65.42; H, 6.85; N, 3.03; S, 6.73.
Embodiment 4f (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin
Figure A9981702500321
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and methyl halogenide prepared in reaction title compound.The non-enantiomer selectivity of product＞98%.
76% yield;
mp＝142.2-142.4℃；
[α] D 25-18.55(c1.0，CHCl 3)；
IR(KBr)3060，2982，2880，1791，1639，1394cm -1；
1H?NMR(CDCl 3，400MHz)δ7.69-7.71(m，2H)，7.35-7.23(m，3H)，3.09(d，J＝14Hz，1H，2.95(b，2H)，2.50-2.45(m，1H)，2.45(d，J＝14Hz，1H)，2.30-2.23(m，1H)，2.11-2.04(m，1H)，1.94-1.78(m，3H)，1.70(m，3H)，1.42-1.36(m，1H)，1.15(s，3H)，1.02(d，J＝6.4Hz，6H)，0.94(d，J＝6.4Hz，6H，0.93(s，3H)；
13C?NMR(CDCl 3，100.6MHz)δ?172.7，140.6，128.0，127.1，124.1，115.9，79.8，54.2?51.2，50.4，47.5，46.6，44.2，30.5，26.5，25.3，22.8，21.0，20.5，20.0；
MS (EI) m/z (relative intensity) 464 (M -+ 1,1.08), 448 (11), 316 (27), 299 (46), 271 (28), 151 (100), 70 (50);
HRMS calculated value C 25H 37NO 5S (M +) m/z 463.2392, measured value 463.2400;
Analytical calculation value C 25H 37NO 5S:C, 64.76; H, 8.04; N, 3.02; S, 6.92; Measured value: C, 64.76; H, 8.07; N, 3.03; S, 6.92.
Embodiment 4g (1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-(5 '-phenyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl } Toluidrin
Figure A9981702500331
According to conventional process, by (1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-phenyl-1 ', 3 '-dioxolane 4 '-ketone)-7,7-dimethyl-two ring [2.2.1] heptan-1-yl] Toluidrin and allyl halide prepared in reaction title compound.The non-enantiomer selectivity 98% of product.
84% yield;
mp＝147.5-147.7℃；
[α] D 25-19.64(c1.0，CHCl 3)；
IR(KBr)2958，2880，1793，1640，1615，1338，1120，977，936，702，664cm -1；
1H?NMR(CDCl 3，400MHz)δ7.69-7.67(m，2H)，7.35-7.22(m，3H)，5.63-5.53(m，1H)，5.08-4.97(m，2H)，3.07(d，J＝13.2Hz，1H)，2.91(b，2H)，2.66(d，J＝7.2Hz，2H)，2.49-2.44(m，1H)，2.45(d，J＝13.2Hz，1H)，2.27-2，20(m，1H)，2.14-2.06(m，1H)，1.90-1.78(m，1H)，1.40-1.33(m，1H)，1.15(s，3H)，1.02(d，J＝6.4Hz，6H)，0.94(d，J＝6.4Hz，6H)，0.93(s，3H)；
13C?NMR(CDCl 3，100.6MHz)δ171.0，138.2，130.1，127.4，126.7，124.1，119.4，115.9，81.6，53.9，51.0，49.9，46.9，46.5，46.4，43.5，26.0，24.9，22.4，20.4，20.0，19.5；
MS (EI) m/z (relative intensity) 490 (M ++ 1,4.52), 420 (54), 316 (55), 215 (32), 151 (71), 105 (100), 77 (68), 43 (29);
HRMS calculated value C 27H 39NO 5S (M +) m/z 489.2549, measured value 489.2556;
Analytical calculation value C 27H 39NO 5S:C, 66.23; H, 8.03; N, 2.82; S, 6.55. measured value: C, 66.25; H, 8.08; N, 2.87; S, 6.53.
Embodiment 5
Embodiment 5 explanation general formula I V's is alkylating 1, and 3-dioxolane keto-alcohol is separated and formed the alcoholysis process of the 10-camphor sulfonamide of the alpha hydroxy acid derivative of general formula VI and general formula I.(2R)-2-hydroxyl-3-phenylpropionic acid ethyl ester
Figure A9981702500341
The anhydrous chlorides of rase hydrogen blistering is passed through (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 ' phenyl methyl-1 ',-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin (464mg, dehydrated alcohol 1mmol) (4mL) solution 10 minutes.After refluxing 6 hours, with the solution cooling, pour in the saturated sodium bicarbonate (aqueous solution), use twice of extracted with diethyl ether.Dried over mgso is used in the salt water washing of organic phase after the merging, concentrates.Crude product column chromatography purifying (SiO 2, hexane-ethyl acetate, 6: 1), obtain the title compound of 161mg (83%), and reclaim (1S)-(+)-N, N-di-isopropyl-1-camphor sulfonamide (287mg, 91%).
[α] D 25+22.21(c3.85，CHCl 3)；
IR (net value) 3471 (b), 3085,3060,3030,2982,2939,1733,1604,1497,1455,1370,1201,1096,1031cm -1
1H NMR (CDCl 3, 400MHz) δ 7.19-7,30 (m, 5H), 4.42 (dd, J=6.4, J=4.4Hz, 1H), 4.2 (quartet, J=7.2Hz, 2H), 3.11 (dd, J=13.6, J=4.4Hz, 1H), 2.95 (dd, J=13.6, J=6.4Hz, 1H), 1.26 (t, J=7.2Hz, 3H);
13C?NMR(CDCl 3，100.6MHz)δ174.1，136.3，129.4，128.2，126.7，71.1，61.5，40.4，14.0。
Embodiment 6a-c
Embodiment 6a-c explanation general formula I V's is alkylating 1, and the hydrolysis of 3-dioxolane ketone forms the alpha hydroxy acid of general formula V and the 10-camphor sulfonamide of general formula I.The conventional process of hydrolysis is as follows:
Will be alkylating 1 at the 1g of the methyl alcohol of 4mL, the 1N sodium hydroxide (aqueous solution) of the solution of 3-dioxolane ketone and 1mL is 60 ℃ of heating 4 hours down.After with the solution cooling, vacuum steams methyl alcohol.With resistates water (5mL) dilution, with ethyl acetate extraction (2 * 10mL).With the organic phase dried over sodium sulfate, concentrate, reclaim the 10-camphor sulfonamide.The pH value of water layer is adjusted to 2 with concentrated hydrochloric acid aqueous solution, under reduced pressure steams solvent again.Resistates is dissolved in the 10mL ether, removes by filter salt (NaCl).With the solution dried over sodium sulfate that forms, concentrate, obtain required alpha hydroxy acid.
Embodiment 6a (2R)-2-hydroxy-2-methyl butyric acid
Figure A9981702500351
By hydrolysis (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-5 '-methyl isophthalic acid ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin makes title compound.The yield of title compound is 97% (1S)-(+)-N, and the rate of recovery of N-di-isopropyl-10-camphor sulfonamide is 96%;
mp＝72.4-72.6℃；
[α] D 25-7.03(c1.4，0.2N?NaOH)；
IR(KBr)3447，3343，2981-2583(b)，1737cm -1；
1H?NMR(CDCl 3，400MHz)δ7.02(b，1H)，1.84-1.66(m，2H)，1.43(s，3H)，0.90(t，J＝7.3Hz，3H)；
13C?NMR(CDCl 3，100.6MHz)δ181.8，75.2，32.9，25.4，7.8；
MS (EI) m/z (relative intensity) 118 (M +, 2), 73 (100), 71 (14), 57 (42), 55 (90).
Embodiment 6b (2R)-2-hydroxy-2-methyl caproic acid
Figure A9981702500361
By hydrolysis (1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-butyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin makes title compound.
The yield of title compound is 98% (1S)-(+)-N, and the rate of recovery of N-di-isopropyl-10-camphor sulfonamide is 92%;
mp＝67.8-67.9℃；
[α] D 23-8.12(c0.85，H 2O)；
IR (net value) 3457,3421,2961-2578 (b), 1735cm -1
1H?NMR(CDCl 3，400MHz)δ7.10(b，1H)，1.78-1.62(m，2，H)，1.43(s，3H)，1.31-1.13(m，4H)，0.86(t，J＝6.96Hz，3H)；
13C?NMP，(CDCl 3，100.6MHz)δ161.8，74.9，39.7，25.8，25.7，22.7，13.8；
MS (EI) m/z (relative intensity) 146 (M +, 39.51), 128 (44), 122 (42), 85 (59), 55 (100).
Embodiment 6c (2S)-2-hydroxyl-2-phenyl-4-pentenoic acid By hydrolysis (1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-(5 '-phenyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin makes title compound.
The yield of title compound is 94%, (1S)-(+)-N, the rate of recovery of N-di-isopropyl-10-camphor sulfonamide is 93%;
mp＝132.1-132.3℃；
[α] D 26+29.54(c1.0，CHCl 3)；
IR (net value) 3423,3080,2915,1725,1640cm -1
1H?NMR(CDCl 3，400MHz)δ7.61-7.60(m，2H)，7.37-7.24(m，3H)，5.81-5.71(m，2H)，5.25-5.81(m，2H)，3.02(dd?J＝14，J＝7.2Hz，1H)，2.79(dd，J＝14，J＝7.2Hz，1H)；
13C?NMR(CDCl 3，100.6MHz)δ178.5，140.2，131.7，128.4，128.2，125.5，120.4，77.8，44.1。
Principle of the present invention has been instructed in the description of above specification sheets, and these embodiment only are used for illustration purpose, is appreciated that the present invention will comprise all useful variations, change and modification, as the described protection domain of claims.

Claims (12)

1. the preparation method of an alpha hydroxy acid and its derivative, this method comprise the steps: to make the alkylating 1 of general formula I V, and 3-dioxolane ketone carries out
Figure A9981702500021
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl; R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace; R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace;
(i) work as R 5During for hydrogen, alcoholysis, the alpha hydroxy acid derivative of formation general formula V
Figure A9981702500022
Wherein, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace, R 7Be C 1-6Alkyl, and separate the product that forms;
Perhaps
(ii) work as R 5Be C 1-6When alkyl or the phenyl that do not replace or replace, hydrolysis forms the alpha hydroxy acid of general formula VI
Figure A9981702500023
Wherein, R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace, and separate the product (V) that forms and (VI).
2. according to the method for claim 1, it also comprises the alkylation 1 of producing general formula I V, the step of 3-dioxolane ketone,
Figure A9981702500031
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl; R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace; And R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace, this step is to make 1 of general formula III, 3-dioxolane ketone
Figure A9981702500032
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be hydrogen, C 1-16Alkyl or the phenyl that does not replace or replace,
With general formula R 6The alkylating reagent reaction of X, wherein, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace, X is a leavings group, and separates the product (IV) that forms.
3. according to the method for claim 2, also comprise 1 of production general formula III, the step of 3-dioxolane ketone,
Figure A9981702500033
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be hydrogen, C 1-16Alkyl or the phenyl that does not replace or replace, this step is the dialkoxy acetal that makes general formula I I
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 3And R 4Can be identical or different, be C independently of one another 1-4Alkyl;
Alpha hydroxy acid reaction with following general formula
Figure A9981702500042
Wherein, R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace, and separate the product (III) that forms.
4. according to the method for claim 3, also comprise the step of the dialkoxy acetal of producing general formula I I,
Figure A9981702500043
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 3And R 4Can be identical or different, be C independently of one another 1-4Alkyl; This step is the 10-camphor sulfonamide that makes general formula I
Figure A9981702500044
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl,
With the alkane reaction of alkoxyl group replacement, and separate the product (II) that forms.
5. according to the process of claim 1 wherein, wherein produce the 10-camphor sulfonamide and the recovery of general formula I as product
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl.
6. according to the method for claim 2, wherein, wherein produce 1 of by product general formula III a, 3-dioxolane ketone separates this by product then
Figure A9981702500052
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl.
7. according to the process of claim 1 wherein that described product is selected from:
(2R)-2-hydroxyl-3-phenylpropionic acid ethyl ester,
(2R)-2-hydroxy-2-methyl butyric acid,
(2R)-2-hydroxy-2-methyl caproic acid and
(2S)-2-hydroxyl-2-phenyl-4-pentenoic acid.
8. according to the method for claim 2, wherein, the described alkylation 1 of general formula I V, 3-dioxolane ketone is selected from:
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-[5 '-(the third-2 " thiazolinyl)-1 ' ,-3 '-dioxolane-4 '-ketone]-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-1 ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 ' phenyl methyl-1 ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-ethyl-5 '-methyl isophthalic acid ' ,-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-propyl group-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-2-spiral shell-2 '-[5 '-methyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone]-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-butyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' R)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-phenyl methyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl-5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin and
(1R, 2S, 5 ' S)-N, the N-di-isopropyl-2-spiral shell-2 '-(5 '-phenyl-5 '-(the third-2 " thiazolinyl)-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two rings [2.2.1] heptan-1-yl } Toluidrin.
9. according to the method for claim 3, wherein, 1 of general formula III, 3-dioxolane ketone is selected from:
(1R, 2S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(1 '-3 '-dioxolane-4 '-ketone)-7,7-dimethyl two rings [2.2.1] heptan-1-yl] Toluidrin,
(1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-methyl isophthalic acid ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin and
(1R, 2S, 5 ' S)-N, the N-di-isopropyl-[2-spiral shell-2 '-(5 '-phenyl-1 ', 3 '-dioxolane-4 '-ketone)-7,7-dimethyl two ring [2.2.1] heptan-1-yl] Toluidrin.
10. according to the method for claim 4, wherein, the dialkoxy acetal of general formula I I is (1R)-N, N-di-isopropyl-(2,2-dimethoxy-7,7-dimethyl two ring [2.2.1] heptan-1-yl) Toluidrin.
11. according to the method for claim 2, wherein said being reflected at-100 ℃ carried out under-45 ℃.
12. the preparation method of an optically active alpha-hydroxy acids, this method may further comprise the steps:
(a) in the presence of pure and mild tosic acid, the 10-camphor sulfonamide of general formula I and the alkane of alkoxyl group replacement are reacted, form the dialkoxy acetal of general formula I I
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 3And R 4Can be identical or different, be C independently of one another 1-4Alkyl;
(b) in the presence of ether and Lewis acid, make the dialkoxy acetal and alpha hydroxy acid reaction of general formula I I with following general formula
Figure A9981702500073
Wherein, R 5Be H, C 1-6Alkyl, or the phenyl that does not replace or replace form 1 of general formula III, 3-dioxolane ketone
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace;
(c) at highly basic and optionally in the presence of the hexamethylphosphoramide ,-100 ℃ under 0 ℃, make 1 of general formula III, 3-dioxolane ketone reacts with alkylating reagent, the alkylation 1 of formation general formula I V, 3-dioxolane ketone
Wherein, R 1And R 2Can be identical or different, be H or C independently of one another 1-6Alkyl, R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace, R 6Be C 1-8Alkyl, C 2-7Alkenyl or the benzyl that does not replace or replace;
(d) make the alkylating 1 of general formula I V, 3-dioxolane ketone carries out
(i) work as R 5During for hydrogen, alcoholysis, the alpha hydroxy acid derivative of formation general formula V
Wherein, R 7Be C 1-6Alkyl, R 6Be C 1-8Alkyl, C 2-7Alkenyl or not replacement
Or the benzyl that replaces,
Or
(ii) work as R 5Be C 1-6When alkyl or the phenyl that do not replace or replace, hydrolysis, shape
Become the alpha hydroxy acid of general formula VI
Figure A9981702500091
Wherein, R 5Be H, C 1-6Alkyl or the phenyl that does not replace or replace, R 6Be C 1-8Alkyl, C 2-7Alkenyl or benzyl that does not replace or replace and the 10-camphor sulfonamide that reclaims general formula I.
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CN102234255A (en) * 2010-05-07 2011-11-09 国立清华大学 Preparation method of 2-morpholinoisobornane-10-thoil and intermediates formed thereby
CN102234255B (en) * 2010-05-07 2013-05-08 国立清华大学 Preparation method of 2-morpholinoisobornane-10-thoil and intermediates formed thereby

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