CN101289393A - (S) or (R)-6,8-dialkylcarbonyl acyloxy caprylate, preparation method and applications thereof - Google Patents
(S) or (R)-6,8-dialkylcarbonyl acyloxy caprylate, preparation method and applications thereof Download PDFInfo
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Abstract
The invention discloses a compound (S) or (R)-6, 8-dialkyl carbonyl acyloxy octoate which is showed in graph I and also discloses a preparation method thereof. The compound (S) or (R)-6-alkyl carbonyl acyloxy-8-alkoxy octoate showed in graph II can react with anhydride in organic solution with the existence of lewis acid. The invention also discloses the application of the (S) or (R)-6-alkyl carbonyl acyloxy-8-alkoxyl octoate in the producing of intermediate. The compound that the invention discloses can obtain the key intermediate (S) or (R)-6, 8- dialkyl octoate in producing the (S) or (R) lipoic acid with high yield, wherein, R1 stands for the alkyl of C1-C6 or the naphthenic base of C5-C7; R2 stands for the phenyl or the alkyl of C1-C4; R3 stands for the benzyl PhCH2- or the alkyl of C1-C4; R4 stands for the alkyl of C1-C2.
Description
Technical field
The present invention relates to novel compound (S) or (R)-6,8-dialkyl group carbonyl acyloxy octanoate and its production and application.
Background technology
(S) or (R)-6,8-dihydroxyl octanoate for synthetic (S) or (R)-key intermediate of Thioctic Acid.At present, existing many pieces of its synthetic methods of bibliographical information.
[Page P.C.B such as Page, Rayner C.M., Sutherland L.O., J.Chem.Soc., Perkin Trans.1,1615 (1990)] by Sharpless epoxidation 2, with the Red-Al reduction, obtain (S)-1,3-dihydroxyl-8-nonene behind the 8-nonadienol, the back obtains (S)-6 by the oxidation terminal double link, and the 8-dihydroxyl is sad.[GewaldR. such as Gewald, Laban G., US6013833] usefulness Ru-(S)/(R)-BINAP asymmetric reduction 6-carbonyl-1, the 6-position carbonyl of 8-suberate obtains (S)/(R)-3-hydroxyl suberic acid diester, selective reduction 8-position ester group obtains (S) or (R)-6,8-dihydroxyl octanoate again.Adopt asymmetry catalysis method preparation (R) though-Thioctic Acid has research more, because high precious metal and reagent price is restricted the application of this method.
[Adger B. such as Adger, Bes M.T., Grogan G., McCague R., Bioorg.Med.Chem, 5,253 (1997) .] report 2-(2 '-the acetoxyl group ethyl) pimelinketone, through its (R)-configuration of enzyme (Baeyer-Villigermonooxygenase) selective oxidation, get (R)-ε-(2-acetyl oxygen ethyl)-6-caprolactone (20), get (R)-6,8-dihydroxyl octanoate after the alcoholysis open loop.Bezbarua etc. [Bezbarua M.S, Synthesis, 11,1289 (1996)] obtain (S)-6-hydroxyl-8-methoxyl group octanoate with the 6-position carbonyl of bread yeast reduction 6-carbonyl-8-methoxyl group octanoate, get (S)-6,8-dihydroxyl octanoate behind the demethylation.Adopt microbial method can obtain the optical isomer of based on very high purity, but, therefore be unfavorable for mass preparation because this method space-time yield (time-space yield) is generally all lower.
Summary of the invention
The objective of the invention is to disclose a class and can high yield make the key intermediate (S) of preparation (S) or (R)-Thioctic Acid or (R)-6, the compound (S) of 8-dihydroxyl octanoate or (R)-6,8-dialkyl group carbonyl acyloxy octanoate.
Compound of the present invention is suc as formula shown in the I:
Wherein, R
1Represent C
1-C
6Alkyl or C
5-C
7Cycloalkyl; R
2Represent phenyl or C
1-C
4Alkyl; R
4Represent C
1Or C
2Alkyl.
Another object of the present invention is to disclose compound of the present invention (S) or (R)-6, the preparation method of 8-dialkyl group carbonyl acyloxy octanoate, its comprise the steps: with suc as formula the compound shown in the II (S) or (R)-6-alkyl oxycarbonyl acyloxy-8--oxyl octanoate in the presence of lewis acidic, gets final product with anhydride reaction in organic solvent;
Wherein, R
1Represent C
1-C
6Alkyl or C
5-C
7Cycloalkyl; R
2Represent phenyl or C
1-C
4Alkyl; R
3Represent phenmethyl PhCH
2-or C
1-C
4Alkyl.
What wherein, described Lewis acid was preferable is boron trihalides or aluminum trihalide.The consumption of boron trihalides is preferable be suc as formula the compound shown in the II (S) or (R)-1～10 times of 6-alkyl oxycarbonyl acyloxy-sad molar weight of 8--oxyl.The consumption of aluminum trihalide is preferable be suc as formula the compound shown in the II (S) or (R)-10～30 times of 6-alkyl oxycarbonyl acyloxy-sad molar weight of 8--oxyl.
What wherein, described acid anhydrides was preferable is diacetyl oxide or propionic anhydride.Acid anhydrides can be simultaneously as the solvent that reacts.Acid anhydrides is during as solvent, and its consumption can be suc as formula the compound shown in the II (S) or (R)-20～50 times of 6-alkyl oxycarbonyl acyloxy-sad molar weight of 8--oxyl.
Wherein, what described organic solvent was preferable is methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, ether, acetonitrile, diacetyl oxide, ethyl acetate, propyl acetate and the butylacetate; What the temperature of reaction was preferable is-20 ℃～100 ℃, and better is-10 ℃～50 ℃; What the time of reaction was preferable is 0.5～48 hour.
Wherein, suc as formula the compound shown in the II (S) or (R)-preparation method of 6-alkyl oxycarbonyl acyloxy-8--oxyl octanoate can be referring to the patent application of submitting on April 18th, 2007 " (S) or (R)-6-alkyl oxycarbonyl acyloxy-8--oxyl octanoate and preparation method thereof " (number of patent application is 200710039642.2), its concrete grammar is as follows: (S) that will be shown in formula III or (R)-6-hydroxyl-8--oxyl octanoate compounds carries out esterification, gets final product;
Wherein, R
1Represent C
1-C
6Alkyl or C
5-C
7Cycloalkyl; R
3Represent phenmethyl PhCH
2-or C
1-C
4Alkyl.
Wherein, described esterification can adopt multiple mode, and preferable selects following four kinds:
1. in the organic solvent, under the effect of alkali, compound (S) that will be shown in formula III or (R)-6-hydroxyl-8--oxyl octanoate and anhydride reaction get final product.
What wherein, described acid anhydrides was preferable is diacetyl oxide, propionic anhydride, butyryl oxide or benzoyl oxide; Described alkali is the mixture of triethylamine, pyridine and derivative thereof (as lutidine etc.), 4-Dimethylamino pyridine (DMAP), Isopropylamine, sodium alkoxide or above-claimed cpd; What described organic solvent was preferable is that halohydrocarbon, aromatic hydrocarbon, alkane, ethers are like methylene dichloride, trichloromethane, 1,2-ethylene dichloride, benzene,toluene,xylene, chlorobenzene, normal hexane, hexanaphthene, tetrahydrofuran (THF), ether, isopropyl ether, N, dinethylformamide or dimethyl sulfoxide (DMSO) etc.
2. in the organic solvent, under catalyst action, compound (S) that will be shown in formula III or (R)-6-hydroxyl-8--oxyl octanoate and carboxylic acid reaction get final product.
Wherein, what described acid was preferable is formic acid, acetate, propionic acid, butyric acid or phenylformic acid, and that described catalyzer is preferable is hydrochloric acid, sulfuric acid, acetate, Hydrogen bromide, tosic acid, Phenylsulfonic acid, chlorsulfonic acid, boron trifluoride, dicyclohexylcarbodiimide (DCC) or diethylazodicarboxylate; What described organic solvent was preferable is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, benzene,toluene,xylene, chlorobenzene, N, dinethylformamide or dimethyl sulfoxide (DMSO).
3. in the solvent, under the effect of alkali, compound (S) that will be shown in formula III or (R)-6-hydroxyl-8--oxyl octanoate and acyl chloride reaction get final product.
What wherein, described acyl chlorides was preferable is Acetyl Chloride 98Min., propionyl chloride, butyryl chloride or Benzoyl chloride; Described alkali can be organic bases, preferable triethylamine, pyridine, N, accelerine, N, the mixture of N-Dimethylamino pyridine or above-claimed cpd of being selected from; Described preferred solvents be halohydrocarbon, ethers or alkane, as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF), ether, isopropyl ether, hexane or hexanaphthene etc.
4. under the effect of catalyzer, compound (S) that will be shown in formula III or (R)-6-hydroxyl-8--oxyl octanoate and carboxylicesters reaction get final product.
What wherein, described carboxylicesters was preferable is methyl acetate, methyl propionate, methyl-butyrate, methyl benzoate, ethyl acetate, ethyl propionate, ethyl butyrate or ethyl benzoate; Described catalyzer can be protonic acid commonly used, and wherein preferable is sulfuric acid, hydrochloric acid, Hydrogen bromide, acetate, propionic acid, butyric acid, tosic acid, Phenylsulfonic acid, methylsulfonic acid or sodium alkoxide etc.
Wherein, described shown in formula III (S) or (R)-6-hydroxyl-8--oxyl octanoate compounds can make according to the method in the patent application of submitting on December 6th, 2006 " (S) or (R)-6-hydroxyl-8--oxyl sad and ester, its salt and its acid amides and its production and application " (number of patent application is 200610119227.3), its concrete steps are:
(1) preparation (S) or (R)-6-hydroxyl-8--oxyl is sad
Method one: in basic solution, hydrolysis is suc as formula (S) shown in the IV-or (R)-ε-(2-hydrocarbon oxygen ethyl)-6-caprolactone, makes suc as formula the compound shown in the V (S) or (R)-6-hydroxyl-8--oxyl octylate, carries out acidifying with acid again, gets final product.
Wherein, R
3Be C
1-C
4Alkyl or phenmethyl-CH
2Ph, styroyl-C
2H
4Ph.
Wherein, the alkali in the described basic solution can be selected from oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal; Solvent in the described basic solution is a water, or the mixed solvent of water and organic solvent composition.What wherein, organic solvent was preferable is the mixed solvent of water-miscible organic solvent, organic inert solvent or above-mentioned solvent composition.Wherein, that described water-miscible organic solvent is preferable is methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) Huo diox, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO); What described organic inert solvent was preferable is methylene dichloride, trichloromethane, 1,2-ethylene dichloride or toluene, dimethylbenzene or chlorobenzene etc.
Wherein, what the temperature of reaction of described hydrolysis reaction was preferable is-10 ℃～100 ℃, and better is 10 ℃～50 ℃; What the reaction times of hydrolysis reaction was preferable is 0.5～24 hour, and better is 5～15 hours.
What wherein, described acid was preferable is sulfuric acid, Hydrogen bromide, hydrochloric acid, Phenylsulfonic acid or tosic acid.
Method two: in acidity or neutral solution, hydrolysis gets final product suc as formula (S) shown in the IV-or (R)-ε-(2-hydrocarbon oxygen ethyl)-6-caprolactone.
Wherein, sour preferable in the described acidic solution is sulfuric acid, hydrochloric acid, acetate, tosic acid or methylsulfonic acid etc.The solvent in the described acidic solution and the temperature and time of hydrolysis reaction, with above-mentioned in basic solution through hydrolysis reaction preparation suc as formula the compound shown in the V (S) or (R)-6-hydroxyl-8--oxyl octylate solvent for use and temperature of reaction are identical with time range.
In above-mentioned two kinds of methods, described suc as formula (S) shown in the IV-or (R)-ε-(2-hydrocarbon oxygen ethyl)-6-caprolactone, wherein R
3Be phenmethyl-CH
2Ph, its preparation method can be with reference to the method [Liu C., Coward J.K., J.Med.Chem., 34,2094 (1991)] of Liu etc.Described suc as formula (S) shown in the IV-or (R)-ε-(2-hydrocarbon oxygen ethyl)-6-caprolactone, wherein R
3Be C
1-C
4Alkyl and styroyl-C
2H
4Ph, its preparation method can be referring to the patent application of submitting on October 31st, 2006 " (S)-or (R)-ε-(2-alkoxyl oxygen alkyl ethyl)-6-caprolactone and its production and application ", and number of patent application is 200610117814.9, and its synthetic route is suc as formula shown in the VI:
Wherein, TADDOL is α, α, α ', α '-four aryl-1,3-dioxolane-4,5-dimethanol, R
1Be C
1-C
4Alkyl or styroyl-C
2H
4Ph, n=1,1.5 or 2.
These method concrete steps are as follows:
1. with the compound α shown in the formula VII, α, α ', α '-four aryl-1,3-dioxolane-4,5-dimethanol (TADDOL) forms the inclusion compound shown in the formula IX with the racemization 2-shown in the formula VIII (2-alkoxyl oxygen alkyl ethyl) pimelinketone:
Wherein, TADDOL is α, α, α ', α '-four aryl-1,3-dioxolane-4,5-dimethanol; Ar is the phenyl ring that phenyl ring, naphthalene nucleus or methoxyl group replace; R
3=R
4, be H, C
1-C
2Alkyl, or R
3-R
4=(CH
2)
4, (CH
2)
5R
1Be C
1-C
4Alkyl or styroyl-C
2H
4Ph; N=1,1.5 or 2.
Wherein, described α, α, α ', α '-four aryl-1,3-dioxolane-4,5-dimethanol (TADDOL) can be by prior art document [Seebach VD., Hel.Chim.Acta, 70,954 (1987); Beck.A.K., Chimia, 45,238 (1991)] method preparation.
Wherein, described 2-(2-alkoxyl oxygen alkyl ethyl) pimelinketone can be made through simple derivatize by 2-(2-chloroethyl) pimelinketone (CN1272487A).
In this method, inclusion compound can be by prior art document [Tsunoda T., Tetrahedron Lett, 38 (44), 7759 (1997); Kaku H., Heterocycles, 55 (5), 847 (2001); Kaku H., Chem.Lett., 33 (5), 516 (2004)] the method preparation.In the inclusion compound of this method, TADDOL is host molecule (Host), and 2-(2-alkoxyl oxygen alkyl ethyl) pimelinketone is guest molecule (Guest).
2. by guest molecule 2-(2-alkoxyl oxygen alkyl ethyl) pimelinketone and host molecule α in the inclusion compound shown in column chromatography for separation method or the distillation under vacuum separate type VIII, α, α ', α '-four aryl-1,3-dioxolane-4, the 5-dimethanol makes (R) shown in the formula X-or (S)-2-(2-alkoxyl oxygen alkyl ethyl) pimelinketone;
Wherein, R
1Be C
1-C
4Alkyl, styroyl-C
2H
4Ph.
In this method, described column chromatography for separation method can be operated by prior art document [Tsunoda T., TetrahedronLett, 38 (44), 7759 (1997)].In this method, described distillation under vacuum can be with reference to prior art document [Kaupp, G., Angew.Chem.Int.Ed.Engl., 728 (1994); Toda F.J., Chem.Soc.Chem.Commun., 1238 (1993)] operation.
3. (R) shown in the formula X-or (S)-2-(2-alkoxyl oxygen alkyl ethyl) pimelinketone and oxygenant are carried out the Baeyer-Villiger oxidizing reaction, make the compound shown in the formula IV (S)-or (R)-ε-(2-alkoxyl oxygen alkyl ethyl)-6-caprolactone.
In this method, described Baeyer-Villiger oxidizing reaction is that [Volume 9,73 for Hassall C.H., Organic Reactions for techniques well known; Krow G.R., Organic Reactions, Volume 43,251].
In this method, what described oxygenant was preferable is peroxy acid, and described peroxy acid is preferable is hydrogen peroxide, metachloroperbenzoic acid, Peracetic Acid, peroxide trifluoracetic acid, single peroxide maleic acid, peroxyformic acid, peroxybenzoic acid, singly cross phthalic acid, cross p-nitrobenzoic acid, single dextrocamphoric acid or peroxybenzoic acid ortho-sulfonic acid crossed.When oxygenant is hydrogen peroxide, can adds dehydrating agent acetic anhydride or MALEIC ANHYDRIDE and improve the peroxide reagent concentration.
In this method, what described Baeyer-Villiger oxidizing reaction was preferable carries out in inert solvent.That described inert solvent is preferable is methylene dichloride, trichloromethane, ethylene dichloride or R
5COOR
6The ester class, R wherein
5Be C
1～C
4Alkyl, R
6Be C
1～C
6Alkyl.
In this method, what the temperature of reaction of described Baeyer-Villiger oxidizing reaction was preferable is-20 ℃～50 ℃, and better is 0 ℃～40 ℃; What the reaction times was preferable is 5～56 hours, and better is 6～35 hours.
(2) preparation (S) or (R)-6-hydroxyl-8--oxyl octanoate
With (S) or (R)-the sad and alcohol of 6-hydroxyl-8--oxyl carries out esterification, gets final product.Wherein, described esterification mode is preferable be (S) or (R)-6-hydroxyl-8--oxyl sad with alcohol azeotropic band water in organic solvent; Or produce by DCC reagent (dicyclohexylcarbodiimide) dehydration with alcohol; Or, react with alcohol again by phosphinylidyne diimidazole (CDI) isoreactivity acid amides activating carboxy acid.Described alcohol can be selected from C
1～C
6Alkyl alcohol, C
5～C
7Cycloalkyl alcohol.
Perhaps, will carry out the lactone alcoholysis, also can make (S) or (R)-6-hydroxyl-8--oxyl octanoate suc as formula (S) shown in the IV-or (R)-ε-(2-hydrocarbon oxygen ethyl)-6-caprolactone.Wherein, described alcohol can be selected from C
1～C
6Alkyl alcohol, C
5～C
7Cycloalkyl alcohol.
Further purpose of the present invention is to disclose compound of the present invention (S) or (R)-6,8-dialkyl group carbonyl acyloxy octanoate at synthetic preparation intermediate (S) or (R)-6, the application in the 8-dihydroxyl octanoate.Synthetic method can be: hydrolysis (S) or (R)-6, and behind whole ester groups of 8-dialkyl group carbonyl acyloxy octanoate, the esterification terminal carboxyl(group) can make (S) or (R)-6,8-dihydroxyl octanoate, synthetic route is as follows:
Wherein, hydrolysis, esterif iotacation step experiment condition is routinely carried out.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: compound of the present invention (S) or (R)-6,8-dialkyl group carbonyl acyloxy octanoate can high yield makes the key intermediate (S) of preparation (R) or (S)-Thioctic Acid or (R)-6,8-dihydroxyl octanoate.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Embodiment 1～7
Table 1 has provided structure compound shown by formula I (S) or (R)-6, the embodiment 1～7 of 8-dialkyl group carbonyl acyloxy octanoate.
Table 1 (S) or (R)-6-alkyl oxycarbonyl acyloxy-8--oxyl octanoate embodiment 1～7
| Embodiment | Structural formula | Steric configuration | R 1 | R 2 | R 4 |
| 1 | Formula I | S | -CH 3 | Phenyl | -CH 3 |
| 2 | Formula I | R | -(CH 2) 2CH 3 | -CH 3 | -CH 3 |
| 3 | Formula I | R | -(CH 2) 5CH 3 | -(CH 2) 3CH 3 | -CH 3 |
| 4 | Formula I | S | -CH 2CH 3 | -CH 2CH 3 | -CH 2CH 3 |
| 5 | Formula I | R | The pentamethylene base | -CH 3 | -CH 2CH 3 |
| 6 | Formula I | S | Cyclohexyl | -CH 3 | -CH 3 |
| 7 | Formula I | S | The suberane base | -CH 2CH 3 | -CH 2CH 3 |
Method embodiment 1 preparation (S)-6,8-diacetoxy methyl caprylate
(S)-6-acetoxyl group-8-methoxyl group methyl caprylate 1.1g (4.5mmol) is dropped in the 100ml eggplant type bottle, add diacetyl oxide 20ml.The ice bath cooling slowly splashes into boron trifluoride ether solution 4.3ml (33.9mmol) down, the about 10 ℃ of reaction 5h of controlled temperature.Reaction mixture is poured in the frozen water, use ethyl acetate 15ml * 3 aqueous layer extracted after stirring 15min, merge concentrate behind the organic layer oily matter, this oily matter is dissolved in ethyl acetate 20ml, stir and add saturated sodium bicarbonate aqueous solution down to no longer including the bubble generation, leave standstill and tell organic layer, water layer extracts with ethyl acetate 15ml.Steaming removes organic solvent and gets light yellow oil,, obtains (S)-6 by column chromatography purification, 8-diacetoxy methyl caprylate 0.70g, yield 57.0%.
[α]
D 25+12.5°(CH
2Cl
2)。
1HNMR(CDCl
3，400MHz)δ：4.96(1H)，4.07(2H)，3.64(3H)，2.29(2H)，2.01(6H)，1.89-1.24(8H)。
MS(m/z)：274。
13CNMR(CDCl
3，75MHz，DEPT)δ：173.72，170.81，170.48，70.87，60.74，51.33，33.86，33.80，33.04，24.66，20.77。
Method embodiment 2 preparation (S)-6,8-diacetoxy methyl caprylate
(S)-6-acetoxyl group-8-methoxyl group methyl caprylate 0.2g (0.81mmol) is dropped in the 25ml eggplant type bottle, add diacetyl oxide 4ml.The ice bath cooling slowly splashes into boron trifluoride ether solution 1.0ml (8.1mmol) down, controlled temperature is about-20 ℃ of reaction 48h, add less water to reaction mixture, with ethyl acetate 10ml * 3 aqueous layer extracted, merge organic layer, stirring down, the adding saturated sodium bicarbonate aqueous solution leaves standstill to no longer including the bubble generation, tell organic layer, water layer extracts with ethyl acetate 10ml.Steaming removes organic solvent and gets light yellow oil,, obtains (S)-6 by column chromatography purification, 8-diacetoxy methyl caprylate 0.08 gram, and yield 35.1%, qualification result is with method embodiment 1.
Method embodiment 3 preparation (S)-6,8-diacetoxy butyl caprylate
(S)-6-acetoxyl group-8-methoxyl group butyl caprylate 1.0g (3.5mmol) is dropped in the 100ml eggplant type bottle, add diacetyl oxide 6ml, methylene dichloride 15ml, the ice bath cooling slowly splashes into boron trifluoride ether solution 3.9ml (30.8mmol) down, controlled temperature is about 15 ℃, reaction 3.5h.Reaction mixture is poured in the frozen water, use methylene dichloride 15ml * 3 aqueous layer extracted after stirring 15min, merge concentrate behind the organic layer oily matter, this oily matter is dissolved in ethyl acetate 20ml, stir and add saturated sodium bicarbonate aqueous solution down to no longer including the bubble generation, leave standstill, tell organic layer, water layer extracts with ethyl acetate 15ml.Steaming removes organic solvent and gets light yellow oil,, obtains (S)-6 by column chromatography purification, 8-diacetoxy butyl caprylate 0.63g, and yield 57.0%, qualification result is as follows:
[α]
D 25+11.6°(CH
2Cl
2)
1HNMR(CDCl
3，400MHz)δ：4.97(1H)，4.09(2H)，4.07(2H)，2.29(2H)，2.04(6H)，1.90-1.33(12H)，0.94(2H)。
MS(m/z)：316.07，274.18，257.09。
Method embodiment 4 preparation (S)-6,8-diacetoxy butyl caprylate
(S)-6-acetoxyl group-8-methoxyl group butyl caprylate 1.0g (3.5mmol) is dropped in the 100ml eggplant type bottle, add diacetyl oxide 6ml, trichloromethane 15ml, the ice bath cooling slowly splashes into boron trifluoride ether solution 4.4ml (35.0mmol) down, and controlled temperature is about-10 ℃ of reaction 24h.Reaction mixture is poured in the frozen water, with methylene dichloride 15ml * 3 aqueous layer extracted, merge concentrate behind the organic layer oily matter, this oily matter is dissolved in ethyl acetate 20ml, stir and add saturated sodium bicarbonate aqueous solution down to no longer including the bubble generation, leave standstill and tell organic layer, water layer extracts with ethyl acetate 15ml.Steaming removes organic solvent and gets light yellow oil,, obtains (S)-6 by column chromatography purification, 8-diacetoxy butyl caprylate 0.35g, and yield 32.0%, qualification result is with method embodiment 3.
Method embodiment 5 preparation (R)-6-acetoxyl group-8-propionyloxy propyl caprylates
(R)-6-acetoxyl group-8-methoxyl group propyl caprylate 0.9g (3.3mmol) is dropped in the 50ml eggplant type bottle, add propionic anhydride 10ml, ether 10ml.The ice bath cooling slowly splashes into boron tribromide 0.82g (3.3mmol) down, and controlled temperature is about 0 ℃ of reaction 0.5h.Stir down reaction mixture is poured in the frozen water, use ether 15ml * 2 aqueous layer extracted behind the standing demix, merge organic layer and remove organic solvent under reduced pressure and get oily matter, this oily matter is dissolved in ethyl acetate 20ml, stir and add solid sodium bicarbonate down to no longer including the bubble generation, leave standstill, tell organic layer, water layer extracts with ethyl acetate 15ml.Steaming removes organic solvent and gets light yellow oil,, obtains (R)-6-acetoxyl group-8-propionyloxy propyl caprylate 0.13 by column chromatography purification, yield 13.0%, and qualification result is as follows:
[α]
D-11.2°(CH
2Cl
2)。
1HNMR(CDCl
3，400MHz)δ：4.97(1H)，4.09(2H)，3.98(2H)，2.29(2H)，2.25(2H)，2.04(3H)，1.80-1.29(10H)，1.14(3H)，0.94(3H)。
MS(m/z)：316.07。
Method embodiment 6 preparation (R)-6,8-two propionyloxy methyl caprylates
(R)-6-propionyloxy-8-propoxy-methyl caprylate 0.5g (1.7mmol) is dropped in the 25ml eggplant type bottle, add propionic anhydride 8ml, propyl acetate 15ml.Add aluminum chloride 6.9g (51.0mmol) and 2.0g sodium iodide under the room temperature, be warming up to and be about 100 ℃ of reaction 3h.Cooling reaction system, reaction system is slowly poured in the 15ml dilute hydrochloric acid (10%), with propyl acetate 15ml * 2 aqueous layer extracted, remove partial solvent under reduced pressure to remaining 20ml approximately after merging organic layer, stir and add saturated sodium bicarbonate aqueous solution down to no longer including the bubble generation, leave standstill, tell organic layer, water layer extracts with propyl acetate 15ml * 2.Steam except that passing through column chromatography purification behind the organic solvent, obtain (R)-6,8-two propionyloxy methyl caprylate 0.12g, yield 23.0%, qualification result is as follows:
1HNMR(CDCl
3，400MHz)δ：4.77(1H)，4.09(2H)，3.63(3H)，2.29(4H)，2.24(2H)，1.82-1.10(14H)。
MS(m/z)：302。
Method embodiment 7 preparation (R)-6,8-diacetoxy ethyl octylate
(R)-6-acetoxyl group-8-oxyethyl group ethyl octylate 0.3g (1.1mmol) is dropped in the 25ml eggplant type bottle, add acetonitrile 15ml, diacetyl oxide 2ml adds alchlor 5.9g (22mmol) in reaction system, is warming up to be about 50 ℃ of reaction 6h.Cooling reaction system, to wherein slowly adding about 15ml dilute hydrochloric acid (10%), after removing low boiling point solvent under reduced pressure, with ethyl acetate 15ml * 2 aqueous layer extracted, merge organic layer, stirring down, the adding saturated sodium bicarbonate aqueous solution leaves standstill to no longer including the bubble generation, tell organic layer, water layer extracts with ethyl acetate 15ml * 2.Steam except that passing through column chromatography purification behind the organic solvent, obtain (R)-6,8-diacetoxy ethyl octylate 0.05, yield 15%, qualification result is as follows:
[α]
D 25-12.1°(CH
2Cl
2)。
1HNMR(CDCl
3，400MHz)δ：4.97(1H)，4.09(2H)，4.07(2H)，2.29(2H)，2.04(6H)，1.90-1.33(8H)，1.10(3H)。
MS(m/z)：288。
Method embodiment 8 preparation (R)-6, the sad ring pentyl ester of 8-diacetoxy
(the R)-6-acetoxyl group-sad ring pentyl ester of 8-methoxyl group 0.5g (1.7mmol) is dropped in the 50ml eggplant type bottle, add diacetyl oxide 5ml, 1,2-ethylene dichloride 15ml.The ice bath cooling slowly adds boron trichloride 1.0g (8.5mmol) down, and controlled temperature is about 30 ℃ of reaction 5h.After wherein slowly add a small amount of frozen water, stirring 12min, steam, with ethyl acetate 15ml * 2 aqueous layer extracted except that low boiling point solvent, merge organic layer, stirring down, the adding saturated sodium bicarbonate aqueous solution leaves standstill to no longer including the bubble generation, tell organic layer, water layer extracts with ethyl acetate 15ml * 2.Steam except that passing through column chromatography purification behind the organic solvent, obtain (R)-6, the sad ring pentyl ester of 8-diacetoxy, qualification result is as follows:
MS(m/z)：328。
Method embodiment 9 preparation (S)-6, the sad cyclohexyl of 8-propionyloxy
The sad cyclohexyl 0.12g of (S)-6-propionyloxy-8-benzyloxy (0.3mmol) is dropped in the 25ml eggplant type bottle, add propionic anhydride 3ml, propyl acetate 10ml, ethyl acetate 5ml.The ice bath cooling slowly splashes into boron tribromide 0.38g (1.5mmol) down, control-10 ℃ of reaction 6h, reaction system is slowly poured in a small amount of frozen water, leave standstill the back layering, water layer extracts with propyl acetate 15ml * 2, steam and remove the part organic solvent, in residuum, add saturated sodium bicarbonate aqueous solution under stirring and generate, leave standstill to no longer including bubble, tell organic layer, water layer merges organic solvent with propyl acetate 15ml * 2 extractions, steams after the dried over mgso and removes organic solvent, pass through column chromatography purification, obtain (S)-6, the sad cyclohexyl 0.06g of 8-propionyloxy, yield 56%.
MS(m/z)：370。
Method embodiment 10 preparation (R)-6, the sad ring heptyl ester of 8-diacetoxy
(the R)-6-acetoxyl group-sad ring heptyl ester of 8-methoxyl group 1.2g (3.7mmol) is dropped in the 25ml eggplant type bottle, add diacetyl oxide 2ml, add butylacetate 5ml, the ice bath cooling slowly splashes into boron trifluoride ether solution 1.5ml (11.8mmol) down, control 0 ℃ of reaction 15h, reaction system is slowly poured in a small amount of frozen water, leave standstill the back layering, water layer steams and removes the part organic solvent with ethyl acetate 15ml * 2 extractions, stir and in residuum, add saturated sodium bicarbonate aqueous solution down to no longer including the bubble generation, leave standstill, tell organic layer, water layer extracts with ethyl acetate 15ml * 2, merge organic solvent, steam after the dried over mgso and remove organic solvent,, obtain (R)-6 by column chromatography purification, the sad ring heptyl ester of 8-diacetoxy, qualification result is as follows:
MS(m/z)：356。
Method embodiment 11 preparation (the R)-6-penta acyloxy-sad own ester of 8-acetoxyl group
The sad own ester 0.82g of (R)-6-penta acyloxy-8-butoxy (2.0mmol) is dropped in the 50ml eggplant type bottle, add diacetyl oxide 3ml, ethyl acetate 20ml.In system, add aluminium triiodide 7.9g (20mmol), keep temperature to be about 50 ℃ of reaction 3h, steaming removes low boiling point solvent after wherein slowly adding a small amount of ice-cold dilute hydrochloric acid (10%), stirring 12min, with ethyl acetate 15ml * 2 aqueous layer extracted, merge organic layer, steam except that behind the organic solvent residuum is dissolved in the 15ml ethyl acetate, add saturated sodium bicarbonate aqueous solution under stirring and generate, leave standstill to no longer including bubble, tell organic layer, water layer extracts with ethyl acetate 15ml * 2.Steam except that passing through column chromatography purification behind the organic solvent, obtain the sad own ester of (R)-6-penta acyloxy-8-acetoxyl group, qualification result is as follows:
MS(m/z)：386。
Method embodiment 12 preparation (R)-6-benzoyloxy-8-acetoxyl group methyl caprylates
(R)-6-benzoyloxy-8-propoxy-methyl caprylate 1.2g (3.6mmol) is dropped in the 25ml eggplant type bottle, add diacetyl oxide 3ml, ether 10ml.In system, add boron trifluoride ether solution 1.6ml (12.6mmol), react 0.5h under the room temperature, after wherein slowly add a small amount of frozen water, stirring 12min, steam, with ethyl acetate 15ml * 2 aqueous layer extracted except that low boiling point solvent, merge organic layer, steam except that behind the organic solvent residuum is dissolved in the 15ml ethyl acetate, add saturated sodium bicarbonate aqueous solution under stirring and generate, leave standstill to no longer including bubble, tell organic layer, water layer extracts with ethyl acetate 15ml * 2.Steam except that passing through column chromatography purification behind the organic solvent, obtain (R)-6-benzoyloxy-8-acetoxyl group methyl caprylate, yield 45%, qualification result is as follows:
1HNMR(CDCl
3，400MHz)δ：8.04-8.01(2H)，7.54-7.25(3H)，5.24(1H)，4.08(2H)，3.62(3H)，2.29(2H)，2.01(3H)，1.97-1.40(8H)。
MS(m/z)：336。
Application Example preparation (S)-6,8-dihydroxyl butyl caprylate
(S)-6-hydroxyl-8-methoxyl group butyl caprylate 2.7g is dissolved in methylene dichloride 50ml, adds diacetyl oxide 1.7g, triethylamine 2.3g, stir 3h under the room temperature.With hydrochloric acid (15%) 15ml washing, saturated sodium bicarbonate aqueous solution 15ml washing divides water-yielding stratum with reaction solution, organic layer with anhydrous magnesium sulfate drying after, filter, concentrate (S)-6-acetoxyl group-8-methoxyl group butyl caprylate.
(S)-6-acetoxyl group-8-methoxyl group butyl caprylate is dissolved in ethyl acetate 50ml, add diacetyl oxide 15.5ml, controlled temperature slowly drips boron trifluoride ether solution 10ml less than 10 ℃, continues to react 8h under this temperature, make (S)-6,8-diacetoxy butyl caprylate.Pour reaction mixture into frozen water 10ml, taking-up is used for analyzing on a small quantity.The ice bath cooling adds the KOH aqueous solution (3mol/L) 30ml, methyl alcohol 30ml down, rises to stirring at room 3h, steams and removes low boiling point solvent, with hydrochloric acid (25%) regulation system pH about 2, with propyl carbinol 25ml * 3 extractions, remove partial solvent under reduced pressure behind the merging organic layer, to remaining 10ml approximately.
In residuum, add hexanaphthene 70ml, splash into 4～5 concentrated hydrochloric acids, reaction solution is washed with saturated sodium bicarbonate solution 30ml, divide water-yielding stratum, the organic layer dried over mgso is filtered, get 2.0g oily matter [yield 78.5% calculates with (S)-6-hydroxyl-8-methoxyl group butyl caprylate] after concentrating.
[α]
D 25-2.6°(c＝1.5，CH
2Cl
2)。
1HNMR(CDCl
3，400MHz)δ：4.06(2H)，3.89-3.80(3H)，2.4(br，2H)，2.30(2H)，1.71-1.34(12H)。
MS(m/z)：233，215，144。
Claims (10)
1. a class compound shown by formula I (S) or (R)-6,8-dialkyl group carbonyl acyloxy octanoate;
Wherein, R
1Represent C
1-C
6Alkyl or C
5-C
7Cycloalkyl; R
2Represent phenyl or C
1-C
4Alkyl;
R
4Represent C
1Or C
2Alkyl.
2. compound according to claim 1 (S) or (R)-6, the preparation method of 8-dialkyl group carbonyl acyloxy octanoate, it is characterized in that: will be suc as formula the compound shown in the II (S) or (R)-6-alkyl oxycarbonyl acyloxy-8--oxyl octanoate in the presence of lewis acidic, gets final product with anhydride reaction in organic solvent;
Wherein, R
1Represent C
1-C
6Alkyl or C
5-C
7Cycloalkyl; R
2Represent phenyl or C
1-C
4Alkyl;
R
3Represent phenmethyl PhCH
2-or C
1-C
4Alkyl.
3. preparation method according to claim 2 is characterized in that: described Lewis acid is boron trihalides or aluminum trihalide.
4. preparation method according to claim 3 is characterized in that: the consumption of described boron trihalides for suc as formula the compound shown in the II (S) or (R)-1～10 times of 6-alkyl oxycarbonyl acyloxy-sad molar weight of 8--oxyl;
The consumption of described aluminum trihalide be suc as formula the compound shown in the II (S) or (R)-10～30 times of 6-alkyl oxycarbonyl acyloxy-sad molar weight of 8--oxyl.
5. preparation method according to claim 2 is characterized in that: described acid anhydrides is diacetyl oxide or propionic anhydride.
6. preparation method according to claim 2 is characterized in that: described organic solvent is methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, ether, acetonitrile, diacetyl oxide, ethyl acetate, propyl acetate and the butylacetate.
7. preparation method according to claim 2 is characterized in that: the temperature of described reaction is-20 ℃～100 ℃.
8. preparation method according to claim 7 is characterized in that: described temperature is-10 ℃～50 ℃.
9. preparation method according to claim 2 is characterized in that: the time of described reaction is 0.5～48 hour.
10. compound according to claim 1 (S) or (R)-6,8-dialkyl group carbonyl acyloxy octanoate at synthetic preparation intermediate (S) or (R)-6, the application in the 8-dihydroxyl octanoate.
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