CN102827030B - Preparation method of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate - Google Patents
Preparation method of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
The invention relates to a preparation method of (3R, 5R)-3,5-dihydroxy-6-methyl cyan-caproate (I) and belongs to the technical field of pharmaceutical chemistry. The preparation method concretely comprises the following steps of: firstly, carrying out asymmetric catalysis alcoholysis on 3-siloxy cyclopentane anhydride (II) to prepare (R)-3-siloxy-5-alkoxy-5-oxo-pentanoate (III); secondly, condensing the (R)-3-siloxy-5-alkoxy-5-oxo-pentanoate (III) and methyl cyanoacetate to prepare (R)-2-cyano-3-oxo-5-siloxy diethyl pimelate (IV); thirdly, carrying out decarboxylation on the (R)-2-cyano-3-oxo-5-siloxy diethyl pimelate (IV) to prepare (R)-3-hydroxy-5-oxo-6-benzyl cyanohexanoate (V) by using desilicication protective groups; and fourthly, carrying out asymmetric reduction on the (R)-3-hydroxy-5-oxo-6-benzyl cyanohexanoate to prepare a product of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate (I). The preparation method is mild in reaction conditions, simple and convenient to operate, high in stereoselectivity, environment-friendly, and suitable for industrial production; and products have high yield, the used chiral catalyst is small in dosage and can be recovered with fix quantify, raw materials which are easily obtained are low in cost, and particularly hypertoxic cyanides are avoided.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to one (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate.
Background technology
Compound (3
r, 5
r)-3,5-dihydroxyl-6-cyano group capronate (
) structural formula as follows:
R in formula
1for C
1~ C
6fatty alkyl, C
3~ C
6cycloalkyl, C
2~ C
6thiazolinyl, aralkyl or arylalkenyl, or be the optional substitutive derivative of above-mentioned group.
(3
r, 5
r)-3,5-dihydroxyl-6-cyano group capronate (
) be the key intermediate of preparing blood lipid-lowering medicine atorvastatincalcuim.Atorvastatincalcuim (trade(brand)name: Lipitor
?) be a kind of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, there is adjusting blood fat, suppress blood vessel endothelium inflammation, stablize atheromatous plaque, improve function of vascular endothelium, delay the effects such as atherosclerosis, anti-inflammatory, antithrombotic, from listing, just caused in the world the concern of numerous drugmakers, 2011, its market sales revenue reached 11,900,000,000 dollars, was situation of selling well medicine then.
U.S. Pat 5155251A has reported take chiral epoxy butyric ester as starting raw material, the open loop of process metal cyanides, and Claisen ester condensation, asymmetric reduction acquisition intermediate (
) method.World patent WO 2003053950 is by chiral epoxy butyric ester Yu Geshi reagent open, Boc protection, iodine bromide IBr addition hydrolysis, eliminates cyclization, potassium cyanide ring opening synthesis intermediate (
).World patent WO 2003106415 is by potassium cyanide to epoxy chloropropane open loop, and the hydrolysis of nitrilase asymmetry catalysis builds chiral, secondary alcohols fragment.Greenberg W. A. etc. (P.N.A.S.,
2004,
110, 5788-5793.) the asymmetric aldol reaction of multistep by enzyme deoxyribose phosphate aldolase (DERA) catalysis monochloroacetaldehyde obtains chiral diol fragment, then react with sodium cyanide acquisition intermediate (
).This route productive rate is higher, but aldol condensation enzyme obtains difficulty.Jiang Chengjun etc. (Chinese Journal of Pharmaceuticals,
2009,
40, 486.) and utilize chiral epichlorohydrin for raw material, sodium cyanide open loop, alcoholysis, TMS protection, sodium cyanide replaces, deprotection, Claisen ester condensation, asymmetric reduction acquisition intermediate (
).Above synthetic route all needs to use hypertoxic prussiate, and severe reaction conditions is high to equipment and labour protection requirement, complicated operation.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provides that one avoids using hypertoxic prussiate, route is short, simple to operate, reaction conditions is gentle, productive rate is high, environment amenable (3
r, 5
r)-3,5-dihydroxyl-6-cyano group capronate (
) preparation method.
One (3 provided by the invention
r, 5
r)-3,5-dihydroxyl-6-cyano group capronate (
) preparation method, concrete steps are as follows:
(1) by 3-siloxy chaulmoogric acid acid anhydride (structural formula see (
) formula) under chiral catalyst catalysis, with alcohol R
1oH carries out asymmetric alcohol
Solution reaction preparation (
r)-3-siloxy-5-alkoxyl group-5-oxopentanoic acid (
);
(2) under condensing agent effect,
(structural formula is shown in cyanoacetate
a) condensation preparation (
r)-2-cyano group-3-oxo-5-siloxy pimelic acid diester (
);
(3)
through decarboxylation, desiliconization protecting group obtain (
r)-3-hydroxyl-5-oxo-6-cyano group capronate (
);
(4) under reductive agent and chiral adjuvant effect,
reduction obtains (3
r, 5
r)-3,5-dihydroxyl-6-cyano group capronate (
).
Its synthetic route is as follows:
R in formula
1oH is selected from C
1~ C
6fatty alcohol, C
3~ C
6cycloalkyl alcohol, C
2~ C
6in enol aralkyl alcohol or aryl enol, any, or be the optional substitutive derivative of above-mentioned alcohol;
R
2, R
3, R
4be selected from C
1~ C
6fatty alkyl, C
3~ C
6cycloalkyl, C
2~ C
6in thiazolinyl, aralkyl or aryl alkenyl, any, or be the optional substitutive derivative of above-mentioned group;
R
5be selected from C
1~ C
6fatty alkyl, C
3~ C
6cycloalkyl, C
2~ C
6in thiazolinyl, aralkyl or aryl alkenyl, any, or be the optional substitutive derivative of above-mentioned group.
In the present invention, in the thiourea derivatives that reactions steps (1) chiral catalyst used is quinine or the sulfonic acid amide derivatives of quinine any one.The mol ratio of 3-siloxy chaulmoogric acid acid anhydride/alcohol/chiral catalyst is 1:(1.1 ~ 10): (0.01 ~ 0.5), temperature of reaction is-78 ~ 50 ℃, the reaction times is 1 ~ 480 h; Organic solvent used is toluene, tetracol phenixin, chloroform, methylene dichloride, ethylene dichloride, ether, tetrahydrofuran (THF), methyl tertiary butyl ether, dioxane, can be single solvent, can be also mixed solvent, and its proportion of composing does not have special stipulation.
In the present invention, reactions steps (2) condensation reagent used is any one in sulfur oxychloride, oxalyl chloride, phosgene, trichloromethylchloroformate, triphosgene, phosphorus oxychloride, trifluoro-acetic anhydride, chloro-formic ester, Acetyl Chloride 98Min., pyrocarbonate, cyanogen substituted phosphate, dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride.In reactions steps (2), condensation reaction is carried out under alkaline condition, alkali used is mineral alkali or organic bases, wherein mineral alkali used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, salt of wormwood any one, organic bases used be in triethylamine, diisopropyl ethyl amine, DBU, DBN, sodium methylate, sodium ethylate, sodium tert-butoxide, n-Butyl Lithium, tert-butyl lithium, LDA or HMDSLi any one.
/the mol ratio of cyanoacetate/condensation reagent/alkali is 1:(1.1 ~ 2.0): (1.0 ~ 3.0): (1.1 ~ 5.0); Organic solvent used is selected from toluene, chloroform, methylene dichloride, ethylene dichloride, ether, tetrahydrofuran (THF), methyl tertiary butyl ether, dioxane or DMF any; Temperature of reaction is 0 ~ 100 ℃.
In step of the present invention (3), decarboxylation, desiliconization protecting group reaction substep completes or a step completes.
In the present invention; step (3) substep completes; under acid or alkali effect; first carry out decarboxylic reaction; adopt again desiliconization protecting group reagent; wherein inorganic acid alkali used is selected from hydrochloric acid, sulfuric acid, lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood any one during decarboxylic reaction, organic acids and base used be in formic acid, trifluoracetic acid, tosic acid, camphorsulfonic acid, triethylamine, DBU or DBN any one
the mol ratio of/hydrolysis decarboxylation agent is 1:(1.0 ~ 10.0); Temperature of reaction is 0 ~ 200 ℃.
In the present invention, when reactions steps (3) one steps complete, de-ester group used and desiliconization protecting group reagent are alkali metal halide,
the mol ratio of/de-ester group reagent is 1:(1.0 ~ 3.0).Organic solvent used is any one in DMF, DMA or DMSO; Temperature of reaction is 50 ~ 200 ℃.
In the present invention, reactions steps (4) reductive agent used is sodium borohydride, POTASSIUM BOROHYDRIDE, red aluminium or H
2, chiral adjuvant is diethyl methoxyl group borine or boron triethyl,
/also the mol ratio of original reagent/chiral adjuvant is 1:(0.5 ~ 3.0): (1.0 ~ 3.0), organic solvent used is any one or two kinds of in ether, tetrahydrofuran (THF), methyl tertiary butyl ether, methylene dichloride, methyl alcohol or dioxane; Temperature of reaction is-78 ~ 100 ℃.
The present invention has overcome many deficiencies of prior art, reaction conditions gentleness, and easy and simple to handle, raw material is cheap and easy to get, and products therefrom has high yield, and highly-solid selectively is especially avoided using hypertoxic prussiate, environmentally friendly, has good industrial prospect.
Embodiment
Following embodiment can illustrate content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment
1
Step 1: the tertiary fourth hexichol siloxy-5-of preparation (R)-3-methoxyl group-5-oxopentanoic acid (
)
The tertiary fourth hexichol of 3--siloxy chaulmoogric acid acid anhydride (
)1.1 g (3 mmol, 1.0 eq), methyl alcohol 1.2 mL (30 mmol, 10 eq), quinine Thiourea catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL methyl tertiary butyl ethers, under nitrogen atmosphere 0
oc reaction 24 hours, concentrating under reduced pressure, column chromatography purification, obtain the tertiary fourth hexichol siloxy-5-of colorless oil 3-methoxyl group-5-oxopentanoic acid (
)(1.16 g, 2.9 mmol), productive rate 97%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.04?(s,?9H),?2.55-2.68?(m,?4H),?3.57?(s,?3H),?4.50-4.56?(m,?1H),?7.36-7.47?(m,?6H),?7.68?(d,?
J?=?6.8?Hz,?4H),?10.07?(br?s,?1H)?ppm.?MS?(ESI):?399?(M-H
+)；
Step 2: the tertiary fourth hexichol of preparation (R)-2-cyano group-3-oxo-5-siloxy NSC 52563 (
)
The tertiary fourth hexichol siloxy-5-of 3-methoxyl group-5-oxopentanoic acid (
)800 mg (2 mmol, 1.0 eq), oxalyl chloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL methylene dichloride, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL acetonitriles to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq), finishes 40
oc reaction 24 hours, stopped reaction, concentrating under reduced pressure, obtains red-brown oily matter, column chromatography purification, obtain the tertiary fourth hexichol of brown color oily matter 2-cyano group-3-oxo-5-siloxy NSC 52563 (
)(645 mg, 1.16 mmol), productive rate 58%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.02?(s,?9H),?2.51?(dd,?
J?=?6.4,?15.2?Hz,?1H),?2.57?(dd,?
J?=?5.6,?15.2?Hz,?1H),?2.86?(dd,?
J?=?5.6,?14.4?Hz,?1H),?2.94?(dd,?
J?=?7.2,?14.4?Hz,?1H),?3.56?(s,?3H),?3.86?(s,?3H),?4.58-4.64?(m,?1H),?7.36-7.46?(m,?6H),?7.65-7.67?(m,?4H),?13.38?(s,?1H)?ppm.?MS?(ESI):?480?(M-H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
)
The tertiary fourth hexichol of 2-cyano group-3-oxo-5-siloxy Methyl glutarate (
)558 mg (1.16 mmol, 1.0 eq), sodium hydroxide 56 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL methyl alcohol reflux 10 hours, hcl acidifying, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown color oily matter.Add hydrogen fluoride (1.0 M in THF, 3.0 eq) to be dissolved in tetrahydrofuran (THF) room temperature reaction 24 hours, stopped reaction, be spin-dried for solvent, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.46 mmol), overall yield 40%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.55?(d,?
J?=?6.4?Hz,?2H),?2.75?(dd,?
J?=?4.0,?16.0?Hz,?1H),?2.82?(dd,?
J?=?8.0,?16.0?Hz,?1H),?3.60?(s,?2H),?3.72?(s,?3H),?4.46-4.52?(m,?1H)?ppm.?MS?(ESI):?184?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group methyl caproate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
)(86 mg, 0.46 mmol) be dissolved in 2 mL tetrahydrofuran (THF)s and 0.5 mL methyl alcohol,-78 ℃ drip diethyl methoxyl group borine 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add lithium borohydride 20 mg (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group methyl caproate (
) (70 mg, 0.37 mmol), productive rate 81%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.74-1.77?(m,?2H),?2.52-2.56?(m,?4H),?3.74?(s,?3H),?4.19-4.24?(m,?1H),?4.29-4.36?(m,?1H)?ppm.?MS?(ESI):?188?(M+H
+)。
Embodiment
2
Step 1: the tertiary fourth hexichol siloxy-5-of preparation (R)-3-benzyloxy-5-oxopentanoic acid (
)
The tertiary fourth hexichol of 3-siloxy chaulmoogric acid acid anhydride (
)1.1 g (3 mmol, 1.0 eq), benzylalcohol 3.1 mL (30 mmol, 10 eq), quinine sulfonamides catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL tetrahydrofuran (THF)s room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtain the tertiary fourth hexichol siloxy-5-of colorless oil 3-benzyloxy-5-oxopentanoic acid (
)(1.4 g, 2.9 mmol), productive rate 97%.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.01?(s,?9H),?2.54-2.69?(m,?4H),?4.49-4.55?(m,?1H),?4.97?(d,?
J?=?12.0?Hz,?1H),?5.03?(d,?
J?=?12.0?Hz,?1H),?7.25-7.44?(m,?11H),?7.64-7.67?(m,?4H)?ppm.?MS?(ESI):?477?(M+H
+)；
Step 2: the tertiary fourth hexichol of preparation (R)-2-cyano group-3-oxo-5-siloxy pimelic acid methylbenzyl ester (
)
The tertiary fourth hexichol siloxy-5-of 3-benzyloxy-5-oxopentanoic acid (
)952 mg (2 mmol, 1.0 eq), oxalyl chloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL tetrahydrofuran (THF)s, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL acetonitriles to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq), finish reaction 24 hours, concentrating under reduced pressure, obtain red-brown oily matter, column chromatography purification, the tertiary fourth hexichol of brown color oily matter (R)-2-cyano group-3-oxo-5-siloxy pimelic acid methylbenzyl ester (
)(645 mg, 1.16 mmol), productive rate 58%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.01?(s,?9H),?2.53-2.64?(m,?2H),?2.84?(dd,?
J?=?4.2,?14.0?Hz,?1H),?2.80?(dd,?
J?=?5.2,?14.0?Hz,?1H),?2.94?(dd,?
J?=?7.2,?14.0?Hz,?1H),?3.86?(s,?3H),?4.58-4.64?(m,?1H),?4.97?(d,?
J?=?12.4?Hz,?1H),?5.01?(d,?
J?=?12.4?Hz,?1H),?7.24-7.44?(m,?11H),?7.62-7.66?(m,?4H),?13.36?(s,?1H).?MS?(ESI):?556?(M-H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
)
(the R)-tertiary fourth hexichol of 2-cyano group-3-oxo-5-siloxy pimelic acid methylbenzyl ester (
)645 mg (1.16 mmol, 1.0 eq), potassium hydroxide 56 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL tetrahydrofuran (THF)s reflux 10 hours, hcl acidifying, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
), (124 mg, 0.475 mmol), overall yield 41%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.60?(d,?
J?=?6.4?Hz,?2H),?2.73?(dd,?
J?=?4.0,?16.4?Hz,?1H),?2.81?(dd,?
J?=?8.0,?16.4?Hz,?1H),?3.56?(s,?2H),?4.47-4.54?(m,?1H),?5.16?(s,?2H),?7.33-7.40?(m,?5H).?MS?(ESI):?260?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group benzyl hexanoate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
) (124 mg, 0.475 mmol) be dissolved in 2 mL toluene and 0.5 mL methyl alcohol,-78 ℃ drip boron triethyl 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add POTASSIUM BOROHYDRIDE 26 mg (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group benzyl hexanoate (
), productive rate 77%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.74?(m,?2H),?2.53-2.62?(m,?4H),?4.20-4.27?(m,?1H),?4.33-4.38?(m,?1H),?5.16?(s,?2H),?7.36?(m,?5H).?MS?(ESI):?262?(M-H
+)。
Embodiment 3
Step 1: preparation (R)-3-tertiary fourth two silyloxies-5-methoxyl group-5-oxopentanoic acid (
)
The tertiary fourth two silyloxy chaulmoogric acid acid anhydrides of 3-(
)0.73 g (3 mmol, 1.0 eq), methyl alcohol 1.2 mL (30 mmol, 10 eq), quinine ureas catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL methylene dichloride room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtain colorless oil 3-tertiary fourth two silyloxies-5-methoxyl group-5-oxopentanoic acid (
)(0.8 g, 2.9 mmol), productive rate 97%.
1H-NMR?(400?MHz,?CDCl
3)?δ?0.06?(s,?3H),?0.07?(s,?3H),?0.84?(s,?9H),?2.55-2.69?(m,?4H),?3.68?(s,?3H),?4.51-4.57?(m,?1H),?11.07?(br?s,?1H)?ppm.?MS?(ESI):?275?(M-H
+)；
Step 2: the tertiary fourth two silyloxy NSC 52563 of preparation (R)-2-cyano group-3-oxo-5-(
)
3-tertiary fourth two silyloxies-5-methoxyl group-5-oxopentanoic acid (
)552 mg (2 mmol, 1.0 eq), oxalyl chloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL ethylene dichloride, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL acetonitriles to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq), finishes reaction 24 hours, concentrating under reduced pressure, red-brown oily matter, column chromatography purification, obtain the tertiary fourth two silyloxy NSC 52563 of brown color oily matter 2-cyano group-3-oxo-5-(
)(370 mg, 1.04 mmol), productive rate 52%.
1H-NMR?(400?MHz,?CDCl
3)?δ?-0.003?(s,?3H),?0.02?(s,?3H),?0.81?(s,?9H),?2.52?(dd,?
J?=?6.0,?15.2?Hz,?1H),?2.57?(dd,?
J?=?6.0,?16.0?Hz,?1H),?2.77?(dd,?
J?=?5.2,?13.6?Hz,?1H),?2.89?(dd,?
J?=?7.2,?14.0?Hz,?1H),?3.65?(s,?3H),?3.86?(s,?3H),?4.50-4.56?(m,?1H),?13.52?(s,?1H)?ppm.?MS?(ESI):?356?(M-H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
)
The tertiary fourth two silyloxy Methyl glutarates of 2-cyano group-3-oxo-5-(
)414 mg (1.16 mmol, 1.0 eq), potassium tert.-butoxide 78 mg (1.39 mmol, 1.2 eq) be dissolved in the 10 mL trimethyl carbinols reflux 10 hours, hcl acidifying, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, stopped reaction, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtain brown color oily matter, add TBAF (1.0 M in THF, 3.0 eq) to be dissolved in tetrahydrofuran (THF), room temperature reaction 24 hours, be spin-dried for solvent, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.45 mmol), overall yield 39%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.55?(d,?
J?=?6.4?Hz,?2H),?2.75?(dd,?
J?=?4.0,?16.0?Hz,?1H),?2.82?(dd,?
J?=?8.0,?16.0?Hz,?1H),?3.60?(s,?2H),?3.72?(s,?3H),?4.46-4.52?(m,?1H)?ppm.?MS?(ESI):?184?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group methyl caproate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.45 mmol) be dissolved in 2 mL tetrahydrofuran (THF)s and 0.5 mL methyl alcohol,-78 ℃ drip diethyl methoxyl group borine 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add sodium borohydride 22 mg (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group methyl caproate (
) (70 mg, 0.37 mmol), productive rate 81%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.74-1.77?(m,?2H),?2.52-2.56?(m,?4H),?3.74?(s,?3H),?4.19-4.24?(m,?1H),?4.29-4.36?(m,?1H)?ppm.?MS?(ESI):?188?(M+H
+)。
Embodiment
4
Step 1: preparation (R)-3-tertiary fourth two silyloxies-5-methoxyl group-5-oxopentanoic acid (
)
The tertiary fourth two silyloxy chaulmoogric acid acid anhydrides of 3-(
) 0.73 g (3 mmol, 1.0 eq), methyl alcohol 1.2 mL (30 mmol, 10 eq), quinine Thiourea catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL methyl tertiary butyl ethers room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtain colorless oil 3-tertiary fourth two silyloxies-5-methoxyl group-5-oxopentanoic acid (
)(0.8 g, 2.9 mmol), productive rate 97%.
1H-NMR?(400?MHz,?CDCl
3)?δ?0.06?(s,?3H),?0.07?(s,?3H),?0.84?(s,?9H),?2.55-2.69?(m,?4H),?3.68?(s,?3H),?4.51-4.57?(m,?1H),?11.07?(br?s,?1H)?ppm.?MS?(ESI):?275?(M-H
+)；
Step 2: the tertiary fourth two silyloxy NSC 52563 of preparation (R)-2-cyano group-3-oxo-5-(
)
3-tertiary fourth two silyloxies-5-methoxyl group-5-oxopentanoic acid (
)552 mg (2 mmol, 1.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq) be dissolved in 10 mL DMF, add triethylamine 0.55 mL (4 mmol, 3.0 eq), room temperature reaction 1 hour, add diethylpyrocarbonate 0.35 mL (2.4 mmol, 1.2 eq), 50 ° of C react 24 hours, concentrating under reduced pressure, red-brown oily matter, column chromatography purification, obtain the tertiary fourth two silyloxy NSC 52563 of brown color oily matter 2-cyano group-3-oxo-5-(
)(370 mg, 1.04 mmol), productive rate 52%.
1H-NMR?(400?MHz,?CDCl
3)?δ?-0.003?(s,?3H),?0.02?(s,?3H),?0.81?(s,?9H),?2.52?(dd,?
J?=?6.0,?15.2?Hz,?1H),?2.57?(dd,?
J?=?6.0,?16.0?Hz,?1H),?2.77?(dd,?
J?=?5.2,?13.6?Hz,?1H),?2.89?(dd,?
J?=?7.2,?14.0?Hz,?1H),?3.65?(s,?3H),?3.86?(s,?3H),?4.50-4.56?(m,?1H),?13.52?(s,?1H)?ppm.?MS?(ESI):?356?(M-H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
)
The tertiary fourth two silyloxy Methyl glutarates of 2-cyano group-3-oxo-5-(
)414 mg (1.16 mmol, 1.0 eq), trifluoracetic acid 36 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL ethanol, reflux 10 hours, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, stopped reaction, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtain brown color oily matter, add TBAF (1.0 M in THF, 3.0 eq) to be dissolved in tetrahydrofuran (THF), room temperature reaction 24 hours, be spin-dried for solvent, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.45 mmol), overall yield 39%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.55?(d,?
J?=?6.4?Hz,?2H),?2.75?(dd,?
J?=?4.0,?16.0?Hz,?1H),?2.82?(dd,?
J?=?8.0,?16.0?Hz,?1H),?3.60?(s,?2H),?3.72?(s,?3H),?4.46-4.52?(m,?1H)?ppm.?MS?(ESI):?184?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group methyl caproate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.45 mmol) be dissolved in 2 mL methylene dichloride and 0.5 mL methyl alcohol,-78 ℃ drip boron triethyl 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add sodium borohydride 22 mg (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group methyl caproate (
) (70 mg, 0.37 mmol), productive rate 81%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.74-1.77?(m,?2H),?2.52-2.56?(m,?4H),?3.74?(s,?3H),?4.19-4.24?(m,?1H),?4.29-4.36?(m,?1H)?ppm.?MS?(ESI):?188?(M+H
+)。
Embodiment
5
Step 1: the tertiary fourth hexichol siloxy-5-of preparation (R)-3-benzyloxy-5-oxopentanoic acid (
)
The tertiary fourth hexichol of 3-siloxy chaulmoogric acid acid anhydride (
)1.1 g (3 mmol, 1.0 eq), benzylalcohol 3.1 mL (30 mmol, 10 eq), quinine Thiourea catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL dioxane room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtain the tertiary fourth hexichol siloxy-5-of colorless oil 3-benzyloxy-5-oxopentanoic acid (
)(1.4 g, 2.9 mmol), productive rate 97%.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.01?(s,?9H),?2.54-2.69?(m,?4H),?4.49-4.55?(m,?1H),?4.97?(d,?
J?=?12.0?Hz,?1H),?5.03?(d,?
J?=?12.0?Hz,?1H),?7.25-7.44?(m,?11H),?7.64-7.67?(m,?4H)?ppm.?MS?(ESI):?477?(M+H
+)；
Step 2: the tertiary butyl benzyl of preparation (R)-2-cyano group-3-oxo-5-tertiary fourth hexichol siloxy pimelic acid (
)
The tertiary fourth hexichol siloxy-5-of 3-benzyloxy-5-oxopentanoic acid (
)952 mg (2 mmol, 1.0 eq), oxalyl chloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL toluene, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL acetonitriles to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), the cyanoacetic acid tert-butyl ester 0.34 mL (2.4 mmol, 1.2 eq), finishes reaction 24 hours, concentrating under reduced pressure, red-brown oily matter, column chromatography purification, obtain the tertiary butyl benzyl of brown color oily matter 2-cyano group-3-oxo-5-tertiary fourth hexichol siloxy pimelic acid (
)(599 mg, 1.0 mmol), productive rate 50%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.01?(s,?9H),?1.53?(s,?9H),?2.53?(dd,?
J?=?6.8,?15.6?Hz,?1H),?2.57?(dd,?
J?=?5.6,?15.6?Hz,?1H),?2.80?(dd,?
J?=?5.2,?14.0?Hz,?1H),?2.92?(dd,?
J?=?7.6,?14.0?Hz,?1H),?4.57-4.63?(m,?1H),?4.95?(d,?
J?=?12.4?Hz,?1H),?5.00?(d,?
J?=?12.4?Hz,?1H),?7.23-7.25?(m,?2H),?7.31-7.44?(m,?9H),?7.63-7.70?(m,?4H),?13.69?(s,?1H).?MS?(ESI):?598?(M-H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
)
The tertiary butyl benzyl of the tertiary fourth hexichol of 2-cyano group-3-oxo-5-siloxy pentanedioic acid (
)695 mg (1.16 mmol, 1.0 eq), sodium-chlor 81 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL DMF, in 2 mL water, heating reflux reaction 4 hours, 100 mL ethyl acetate extractions, 50 mL × 4 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
) (124 mg, 0.475 mmol), productive rate 38%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.60?(d,?
J?=?6.4?Hz,?2H),?2.73?(dd,?
J?=?4.0,?16.4?Hz,?1H),?2.81?(dd,?
J?=?8.0,?16.4?Hz,?1H),?3.56?(s,?2H),?4.47-4.54?(m,?1H),?5.16?(s,?2H),?7.33-7.40?(m,?5H).?MS?(ESI):?260?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group methyl caproate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
) (124 mg, 0.475 mmol) be dissolved in 2 mL ether and 0.5 mL methyl alcohol,-78 ℃ drip diethyl methoxyl group borine 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add red aluminum solutions 0.57 mL (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group benzyl hexanoate (
), productive rate 77%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.74?(m,?2H),?2.53-2.62?(m,?4H),?4.20-4.27?(m,?1H),?4.33-4.38?(m,?1H),?5.16?(s,?2H),?7.36?(m,?5H).?MS?(ESI):?262?(M-H
+)。
Embodiment
6
Step 1: the tertiary fourth two silyloxies-5-[(E of preparation (R)-3-)-3-benzene allyloxy]-5-oxopentanoic acid (
)
The tertiary fourth two silyloxy chaulmoogric acid acid anhydrides of 3-(
)0.73 g (3 mmol, 1.0 eq), trans styryl carbinol 1.2 g (9 mmol, 3.0 eq), quinine Thiourea catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL toluene room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtains the tertiary fourth two silyloxies-5-[(E of colorless oil (R)-3-)-3-benzene allyloxy]-5-oxopentanoic acid (
)(0.98 g, 2.6 mmol), productive rate 87%.
1H-NMR?(400?MHz,?CDCl
3)?δ?0.09?(s,?6H),?0.85?(s,?9H),?2.58-2.69?(m,?4H),?4.55-4.62?(m,?1H),?4.70-4.79?(m,?2H),?6.28?(dt,?
J?=?6.4,?16.0?Hz,?1H),?6.66?(d,?
J?=?16.0?Hz,?1H),?7.25-7.28?(m,?1H),?7.31-7.35?(m,?2H),?7.38-7.40?(m,?2H),?10.96?(br?s,?1H)?ppm.?
13C-NMR?(100?MHz,?CDCl
3)?δ?-4.97,?-4.92,?17.83,?25.59,?42.20,?42.32,?65.20,?66.03,?122.84,?126.58,?128.05,?128.55,?134.40,?136.09,?170.66,?177.11?ppm.?MS?(ESI):?379?(M+H
+)；
Step 2: the tertiary fourth two silyloxy pimelic acid benzene allyl methyl esters of preparation (R)-2-cyano group-3-oxo-5-(
)
(R) the tertiary fourth two silyloxies-5-[(E of-3-)-3-benzene allyloxy]-5-oxopentanoic acid (
)760 mg (2 mmol, 1.0 eq), sulfur oxychloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL chloroforms, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL acetonitriles to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq), finish reaction 24 hours, concentrating under reduced pressure, obtain red-brown oily matter, column chromatography purification, the tertiary fourth two silyloxy pimelic acid benzene allyl methyl esters of brown color oily matter (R)-2-cyano group-3-oxo-5-(
)(441 mg, 0.96 mmol), productive rate 48%.MS?(ESI):?458?(M-H
+)；
Step 3:R)-3-hydroxyl-5-oxo-6-cyano group caproic acid cinnamic ester (
)
The tertiary fourth two silyloxy pimelic acid benzene allyl methyl esters of (R)-2-cyano group-3-oxo-5-(
)532 mg (1.16 mmol, 1.0 eq), salt of wormwood 96 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL acetonitriles reflux 10 hours, hcl acidifying, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown color oily matter.Add pyridine hydrogen fluoride (1.0 M in THF, 3.0 eq) to be dissolved in tetrahydrofuran (THF) room temperature reaction 24 hours, stopped reaction, be spin-dried for solvent, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group caproic acid cinnamic ester (
) (86 mg, 0.45 mmol), overall yield 39%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.57?(d,?
J?=?6.0?Hz,?2H),?2.73?(dd,?
J?=?4.0,?16.4?Hz,?1H),?2.81?(dd,?
J?=?8.0,?16.4?Hz,?1H),?3.59?(s,?2H),?4.47-4.54?(m,?1H),?4.76?(d,?
J?=?6.4?Hz,?2H),?6.26?(dt,?
J?=?6.4,?16.0?Hz,?1H),?6.66?(d,?
J?=?16.0?Hz,?1H),?7.24-7.39?(m,?5H)?ppm.?MS?(ESI):?286?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group caproic acid cinnamic ester (
)
(R)-3-hydroxyl-5-oxo-6-cyano group caproic acid cinnamic ester (
) (126 mg, 0.475 mmol) be dissolved in 2 mL dioxane and 0.5 mL methyl alcohol,-78 ℃ drip diethyl methoxyl group borine 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add sodium borohydride 22 mg (0.57 mmol, 1.2 eq), finish, 50 ℃ are reacted 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group caproic acid cinnamic ester (
), productive rate 76%.MS?(ESI):?288?(M-H
+)。
Embodiment
7
Step 1: preparation (R)-3-tertiary fourth two silyloxies-5-positive propoxy-5-oxopentanoic acid (
)
The tertiary fourth two silyloxy chaulmoogric acid acid anhydrides of 3-(
)0.73 g (3 mmol, 1.0 eq), n-propyl alcohol 2.3 mL (30 mmol, 10.0 eq), quinine amides catalyzer 0.3 mmol(0.1 eq) be dissolved in 150 mL ether room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtain colorless oil (R)-3-tertiary fourth two silyloxies-5-positive propoxy-5-oxopentanoic acid (
)(0.82 g, 2.7 mmol), productive rate 90%.
1H-NMR?(400?MHz,?CDCl
3)?δ?0.06?(s,?3H),?0.06?(s,?3H),?0.07?(s,?3H),?0.84?(s,?9H),?2.55-2.69?(m,?4H),?3.68?(s,?3H),?4.51-4.57?(m,?1H),?11.07?(br?s,?1H)?ppm.?
13C-NMR?(100?MHz,?CDCl
3)?δ?-5.03,?-4.96,?10.34,?17.83,?21.85,?25.58,?42.24,?42.36,?66.07,?66.22,?171.04,?177.23?ppm.?MS?(ESI):?305?(M+H
+)；
Step 2: the tertiary fourth two silyloxy pimelic acid first propyl ester of preparation (R)-2-cyano group-3-oxo-5-(
)
(R)-3-tertiary fourth two silyloxies-5-positive propoxy-5-oxopentanoic acid (
)710 mg (2 mmol, 1.0 eq), oxalyl chloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL dioxane, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL tetrahydrofuran (THF)s to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq), finish reaction 24 hours, concentrating under reduced pressure, obtain red-brown oily matter, column chromatography purification, the tertiary fourth two silyloxy pimelic acid first propyl ester of brown color oily matter (R)-2-cyano group-3-oxo-5-(
)(331 mg, 0.86 mmol), productive rate 43%.
1H-NMR?(400?MHz,?CDCl
3)?δ?0.02?(s,?3H),?0.05?(s,?3H),?0.83?(s,?9H),?0.93?(t,?
J?=?7.6?Hz,?3H),?1.60-1.69?(m,?2H),?2.54?(dd,?
J?=?6.0,?15.2?Hz,?1H),?2.59?(dd,?
J?=?6.0,?15.2?Hz,?1H),?2.80?(dd,?
J?=?5.2,?13.6?Hz,?1H),?2.92?(dd,?
J?=?7.6,?13.6?Hz,?1H),?3.88?(s,?3H),?4.03?(t,?
J?=?6.8?Hz,?2H),?4.52-4.59?(m,?1H),?13.54?(s,?1H)?ppm.?
13C-NMR?(100?MHz,?CDCl
3)?δ?-5.17,?-5.00,?10.33,?17.76,?21.83,?25.51,?42.56,?53.02,?66.30,?66.73,?82.75,?114.45,?170.33,?170.57,?187.69?ppm.?MS?(ESI):?384?(M-H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group n-propyl hexylate (
)
The tertiary fourth two silyloxy pimelic acid first propyl ester of (R)-2-cyano group-3-oxo-5-(
)447 mg (1.16 mmol, 1.0 eq), tosic acid 221 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL methyl alcohol, reflux 5 hours, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtain brown color oily matter, add TBAF (1.0 M in THF, 3.0 eq) to be dissolved in tetrahydrofuran (THF), room temperature reaction 24 hours, be spin-dried for solvent, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group n-propyl hexylate (
) (96 mg, 0.45 mmol), overall yield 39%.
1H-NMR?(400?MHz,?CDCl
3)?δ?0.92?(t,?
J?=?7.2?Hz,?3H),?1.60-1.68?(m,?2H),?2.51-2.57?(m,?2H),?2.72?(dd,?
J?=?4.0,?16.0?Hz,?1H),?2.80?(dd,?
J?=?8.0,?16.0?Hz,?1H),?3.62?(s,?2H),?4.05?(t,?
J?=?6.8?Hz,?2H),?4.41-4.50?(m,?1H).
?13C-NMR?(100?MHz,?CDCl
3)?δ?10.24,?21.77,?33.08,?40.37,?47.79,?64.26,?66.57,?113.58,?171.91,?196.89?ppm.?MS?(ESI):?214?(M+H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group n-propyl hexylate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group benzyl hexanoate (
) (124 mg, 0.475 mmol) be dissolved in 2.5 mL methyl alcohol,-78 ℃ drip diethyl methoxyl group borine 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add POTASSIUM BOROHYDRIDE 25 mg (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group n-propyl hexylate (
), productive rate 79%.MS?(ESI):?216?(M+H
+)。
Embodiment
8
Step 1: preparation (R)-3-tri-isopropyl siloxy-5-methoxyl group-5-oxopentanoic acids (
)
3-tri-isopropyl siloxy chaulmoogric acid acid anhydrides (
)0.91 g (3 mmol, 1.0 eq), methyl alcohol 1.2 mL (30 mmol, 10 eq), quinine Thiourea catalyzer 0.3 mmol (0.1 eq) is dissolved in 150 mL tetracol phenixin, room temperature reaction 12 hours under nitrogen atmosphere, concentrating under reduced pressure, column chromatography purification, obtain colorless oil 3-tri-isopropyl siloxy-5-methoxyl group-5-oxopentanoic acids (
)(0.97 g, 2.9 mmol), productive rate 97%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.03?(s,?3H),?1.04?(s,?18H),?2.59-2.74?(m,?4H),?3.65?(s,?3H),?4.60-4.66?(m,?1H),?10.03?(br?s,?1H).?
13C-NMR?(100?MHz,?CDCl
3)?δ?12.34,?17.91,?42.00,?42.03,?51.57,?66.23,?171.36,?176.83?ppm.?MS?(ESI):?319?(M+H
+)；
Step 2: preparation (R)-2-cyano group-3-oxo-5-tri-isopropyl siloxy NSC 52563 (
)
3-tri-isopropyl siloxy-5-methoxyl group-5-oxopentanoic acids (
)672 mg (2 mmol, 1.0 eq), oxalyl chloride 0.29 mL (3 mmol, 1.5 eq), 2 DMF are dissolved in 2 mL ether, react 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add 2 mL toluene to dissolve, drip triethylamine 0.55 mL (4 mmol, 2.0 eq), methyl cyanoacetate 0.22 mL (2.4 mmol, 1.2 eq), finishes reaction 24 hours, concentrating under reduced pressure, red-brown oily matter, column chromatography purification, obtain brown color oily matter 2-cyano group-3-oxo-5-tri-isopropyl siloxy NSC 52563 (
)(415 mg, 1.04 mmol), productive rate 52%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.03?(s,?3H),?1.04?(s,?18H),?2.60?(dd,?
J?=?6.8,?15.2?Hz,?1H),?2.66?(dd,?
J?=?5.2,?15.2?Hz,?1H),?2.93?(d,?
J?=?6.4?Hz,?2H),?3.67?(s,?3H),?3.88?(s,?3H),?4.68-4.74?(m,?1H),?13.57?(s,?1H).
?13C-NMR?(100?MHz,?CDCl
3)?δ?12.41,?17.87,?17.89,?42.26,?42.59,?51.66,?53.01,?66.97,?82.65,?114.38,?170.33,?170.86,?187.51?ppm.?MS?(ESI):?400?(M+H
+)；
Step 3: preparation (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
)
2-cyano group-3-oxo-5-tri-isopropyl siloxy Methyl glutarates (
)463 mg (1.16 mmol, 1.0 eq), sodium hydroxide 56 mg (1.39 mmol, 1.2 eq) be dissolved in 10 mL methyl alcohol reflux 10 hours, hcl acidifying, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtains brown viscous fluid.Add 5 mL DMF, reflux 3 hours, adds 30 mL water, 30 mL × 4 ethyl acetate extractions, combined ethyl acetate layer, 50 mL × 2 saturated common salt water washings, anhydrous MgSO
4dry, elimination siccative, concentrating under reduced pressure, obtain brown color oily matter, add TBAF (1.0 M in THF, 3.0 eq) to be dissolved in tetrahydrofuran (THF), room temperature reaction 24 hours, be spin-dried for solvent, column chromatography purification, obtain brown color oily matter (R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.45 mmol), overall yield 39%.
1H-NMR?(400?MHz,?CDCl
3)?δ?2.55?(d,?
J?=?6.4?Hz,?2H),?2.75?(dd,?
J?=?4.0,?16.0?Hz,?1H),?2.82?(dd,?
J?=?8.0,?16.0?Hz,?1H),?3.60?(s,?2H),?3.72?(s,?3H),?4.46-4.52?(m,?1H)?ppm.?MS?(ESI):?184?(M-H
+)；
Step 4: preparation (3R, 5R)-3,5-dihydroxyl-6-cyano group methyl caproate (
)
(R)-3-hydroxyl-5-oxo-6-cyano group methyl caproate (
) (86 mg, 0.45 mmol) be dissolved in 2 mL tetrahydrofuran (THF)s and 0.5 mL methyl alcohol,-78 ℃ drip diethyl methoxyl group borine 0.57 mL (1.0 M in THF, 1.2 eq), finish, react 1 hour, add sodium borohydride 22 mg (0.57 mmol, 1.2 eq), finish, react 5 hours, add the mixing of 0.5 mL Glacial acetic acid and 0.5 mL methyl alcohol to be dissolved in cancellation reaction, add 1.0 mL 30% hydrogen peroxide, rise to room temperature reaction 2 hours, add 60 mL ethyl acetate, use successively 5% sodium hydrogen carbonate solution of 20 mL × 2, 20 mL × 3 saturated common salt water washings, anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain brown oil (3R, 5R)-3, 5-dihydroxyl-6-cyano group methyl caproate (
) (70 mg, 0.37 mmol), productive rate 81%.
1H-NMR?(400?MHz,?CDCl
3)?δ?1.74-1.77?(m,?2H),?2.52-2.56?(m,?4H),?3.74?(s,?3H),?4.19-4.24?(m,?1H),?4.29-4.36?(m,?1H)?ppm.?MS?(ESI):?188?(M+H
+)。
Claims (7)
1. one kind (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, is characterized in that concrete steps are as follows:
(1) under chiral catalyst catalysis, 3-siloxy chaulmoogric acid acid anhydride and alcohol carry out asymmetric alcoholysis react preparation (
r)-3-siloxy
-5-alkoxyl group-5-oxopentanoic acid, described alcohol is selected from C
1~ C
6fatty alcohol, C
3~ C
6cycloalkyl alcohol, C
2~ C
6in enol, aralkyl alcohol or aryl enol any;
(2) under condensation reagent effect, (
r)-3-siloxy-5-alkoxyl group-5-oxopentanoic acid and cyanoacetate carry out condensation reaction systems
Standby (
r)-2-cyano group-3-oxo-5-siloxy pimelic acid diester;
(3) (
r)-2-cyano group-3-oxo-5-siloxy pimelic acid diester is through decarboxylation, the preparation of desiliconization protecting group (
r)-3-hydroxyl-5-oxo-6-cyano group capronate;
(4) under chiral adjuvant effect, (
r)-3-hydroxyl-5-oxo-6-cyano group capronate and reductive agent carry out asymmetric reduction reaction and prepare (3
r, 5
r)-3,5-dihydroxyl-6-cyano group capronate.
2. according to claim 1 (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, is characterized in that: in described step (1), 3-siloxy chaulmoogric acid acid anhydride structural formula is:
R in formula
2, R
3, R
4be selected from respectively C
1~ C
6fatty alkyl, C
3~ C
6cycloalkyl, C
2~ C
6any in thiazolinyl, aralkyl or arylalkenyl, or be the optional substitutive derivative of above-mentioned group.
3. according to claim 1 (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, it is characterized in that: in the thiourea derivatives that described in step (1), chiral catalyst is quinine or the sulfonic acid amide derivatives of quinine any, the mol ratio of described 3-siloxy chaulmoogric acid acid anhydride/alcohol/chiral catalyst is 1:(1.1 ~ 10): (0.01 ~ 0.5).
4. according to claim 1 (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, is characterized in that: in step (2), the structural formula of described cyanoacetate as
ashown in:
R in formula
5for C
1~ C
6fatty alkyl, C
3~ C
6cycloalkyl, C
2~ C
6in thiazolinyl, aralkyl or arylalkenyl any.
5. according to claim 1 (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, is characterized in that: condensation reagent described in step (2) is any one in sulfur oxychloride, oxalyl chloride, phosgene, trichloromethylchloroformate, triphosgene, phosphorus oxychloride, trifluoro-acetic anhydride, chloro-formic ester, Acetyl Chloride 98Min., pyrocarbonate, cyanogen substituted phosphate, dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride; In described step (2), condensation reaction is carried out under alkaline condition, alkali used is mineral alkali or organic bases, wherein mineral alkali used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, salt of wormwood any one, organic bases used be in triethylamine, diisopropyl ethyl amine, DBU, DBN, sodium methylate, sodium ethylate, sodium tert-butoxide, n-Butyl Lithium, tert-butyl lithium, LDA or HMDSLi any one; (
r)-3-siloxy-5-alkoxyl group-5-oxopentanoic acid
/the mol ratio of cyanoacetate/condensation reagent/alkali is 1:(1.1 ~ 2.0): (1.0 ~ 3.0): (1.1 ~ 5.0).
6. according to claim 1 (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, is characterized in that: in step (3), decarboxylation, desiliconization protecting group reaction substep completes or a step completes; When described reaction substep completes, first hydrolysis decarboxylation under acid or alkali effect, then adopt desiliconization protecting group reagent desiliconization protecting group, described (
r)-2-cyano group-3-oxo-5-siloxy pimelic acid diester
/the mol ratio of hydrolysis decarboxylation agent is 1:(1.0 ~ 10.0); When described reaction one step completes, reagent is alkali metal halide, described (
rthe mol ratio of)-2-cyano group-3-oxo-5-siloxy pimelic acid diester/alkali metal halide is 1:(1.0 ~ 3.0).
7. according to claim 1 (3
r, 5
r)-3, the preparation method of 5-dihydroxyl-6-cyano group capronate, is characterized in that: in step (4), described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, red aluminium or H
2, described chiral adjuvant is methoxyl group diethyl borine or boron triethyl; Described (
r)-3-hydroxyl-5-oxo-6-cyano group capronate
/also the mol ratio of original reagent/chiral adjuvant is 1:(0.5 ~ 3.0): (1.0 ~ 3.0).
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| CN107573260A (en) * | 2017-07-27 | 2018-01-12 | 浙江工业大学 | A kind of preparation method of α cyano group β carbonyl propionic acid ester type compounds |
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| WO2004094343A1 (en) * | 2003-04-22 | 2004-11-04 | Biocon Limited | NOVEL PROCESS FOR STEREOSELECTIVE REDUCTION OF ß-KETOESTERS |
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