CN106083804A - A kind of synthetic method of octatomic ring lactone compound - Google Patents
A kind of synthetic method of octatomic ring lactone compound Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
A kind of synthetic method of octatomic ring lactone compound, belongs to field of pharmaceutical chemistry technology, mixes with acyl chlorides and react after first alcohol being dissolved in anhydrous methylene chloride, obtains malonic acid compounds；Again malonic acid compounds is dissolved in after anhydrous methylene chloride with allyl acetate generation olefin cross coupling reaction, obtain acetoxyl group malonic acid compounds；Last under the catalysis of palladium and triphenylphosphine, with anhydrousN,NDimethylformamide makees solvent, and the acetoxyl group malonic acid compounds that concentration is 0.1M～0.3M carries out inner molecular reaction, obtains octatomic ring lactone compound.This technological operation is simple, needs to be simply mixed substrate and catalyst, it is possible to obtain octatomic ring compound.This technique goes for the preparation of different product, as there being the product of ester group, sulfuryl and methyl at octatomic ring diverse location.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to the preparation method of octatomic ring lactone compound.
Background technology
Octatomic ring lactone is that in nature a class is important and characteristic heterocycle compound.In nature,
Some plants or Marine microorganism all can produce the compound containing octatomic ring lactone structure, and wherein most all has
Certain biological activity.By analyzing the research of recent domestic this respect, it has been found that some marine actinomycetes, ocean chain
Some compounds containing octatomic ring lactone structure that coccus metabolism produces have cytotoxicity to cancerous cell, and carry from Pericarppium Armeniacae Amarum
The compound containing octatomic ring lactone structure taken has the strongest inhibitory action to leukemia tumor cells.Nowadays, domestic
Octatomic ring lactone, Effect of Anti cancer drug when, is given by outer chemist, biologist as important research direction
Pay attention to.
Object of study is a kind of octatomic ring lactone with cis-double bonds herein, and its structural formula is as follows:
Synthetic method containing cis-double bonds octatomic ring lactone compound has as follows now:
1. lactonization reaction:
Lactonization reaction, is the relatively conventional organic chemical reactions of a class, is that the hydroxyl carboxylic acid group with same a part is in condensation
The effect of reagent is lower be there is dehydration and generates the reaction of octatomic ring lactone.
The lactonization reaction of octatomic ring, is the slowest, than the lactonization reaction of hexatomic ring in all of lactonization reaction
Wanting slow 20000 times (JACS, 1977,99,2591), and the concentration requirement reacted is the lowest, ordinary circumstance is left at 0.001M
Right.Further, also can be with the by-product of intermolecular lactonization reaction during synthesis target product.At this in reaction, need
Preparation containing the substrate of cis-double bonds, generally under, the preparation of this substrate needs multistep reaction, and relatively difficult.
Lactonization reaction formula is as follows:
2. cultural care (RCM):
Olefin metathesis reaction, refers to carbon-carbon double bond or carbon carbon three under the olefin cross coupling catalyst containing noble metal is catalyzed
The organic chemical reactions process that key cuts off and recombinates, is the most the more commonly used a kind of carbon skeleton transformation means.Mesh can be utilized
Two double bonds in mark product, obtain so that carrying out cultural care with Hoveyda-Grubbs second filial generation catalyst
Product.But this reaction is just like inferior shortcoming: easily produce dimer or the polymer of 16 rings, reduce the yield of reaction；
And need at high dilute concentration (10-3M-10-5M) react under；And noble metal, such as ruthenium, rhodium etc., extremely difficult from product
Completely remove.
The reaction equation of cultural care is as follows:
Summary of the invention
It is an object of the invention to propose a kind of palladium chtalyst cyclization easy and simple to handle, that yield is high, by-product is few and synthesize eight yuan
The synthetic method of macrolide compounds.
The present invention comprises the steps:
1) mix with acyl chlorides after alcohol being dissolved in anhydrous methylene chloride and react, obtain malonic acid compounds；
2) malonic acid compounds is dissolved in after anhydrous methylene chloride with allyl acetate generation olefin cross coupling reaction, obtain
Acetoxyl group malonic acid compounds；
3) under the catalysis of palladium and triphenylphosphine, with anhydrousN,N-dimethylformamide makees solvent, by concentration be 0.1M～
The acetoxyl group malonic acid compounds of 0.3M carries out inner molecular reaction, obtains octatomic ring lactone compound.
Present invention process has the following advantages:
1. concentration range when reacting in acetoxyl group malonic acid compounds conducting molecule in the step 3) of this technological requirement
For 0.1M～0.3M, it is not necessary to the dilutest concentration, this requires the dilutest with traditional lactonization reaction and cultural care
Concentration formed sharp contrast.
2. this technique goes for the preparation of different product, as having ester group, sulfuryl and methyl at octatomic ring diverse location
Product.
3. this technological operation is simple, needs to be simply mixed substrate and catalyst, it is possible to obtain octatomic ring compound.
Detailed description of the invention
One, example 1, synthesis (methyl (Z)-2-oxo 3,4,7,8-tetrahydrochysene-2H-oxocine-3-carboxylic acid, operative employee
Process flow is as follows:
Step 1) particularly as follows:
1. from baking oven, take out 100 mL cleaning flasks, under argon state, be cooled to room temperature, in reaction bulb, add dichloromethane
5mL and Isosuccinic acid hydrogen 1.0g(8.5mmol), and in whipping process add a DMF, ice bath after 5 minutes slowly to
Reaction bulb adds oxalyl chloride 1.2g(9.4mmol), remove ice bath, room temperature reaction 2 hours, obtain by Rotary Evaporators evaporation and concentration
To methylmalonate acyl chlorides.
2. from baking oven, take out 100 mL round-bottomed flasks, under argon state, be cooled to room temperature, add dichloromethane 5 mL with
And 3-butene-1-ol 0.41g(5.7mmol), add under stirringN,N-Diisopropylethylamine (DIEA) 1.5 g
(11.4mmol), and ice bath 5 minutes, it is slowly added into the methylmalonate acyl chlorides produced in step, reaction bulb has a large amount of white
Acid mist occurs, is stirred at room temperature 8 hours, adds saturated sodium bicarbonate solution 5 mL and washes and use dichloromethane solution 3 X 5 mL to extract
Take, take organic layer Rotary Evaporators evaporation and concentration, obtain crude product and cross post separation, obtain compound butyl-3-alkene-1-ylmethyl third
Diacid 1.9 g(productivity 79 %), for colourless liquid.
The compound obtained by nuclear magnetic data proof is butyl-3-alkene-1-ylmethyl malonic acid:1H NMR (600 MHz,
CDCl3) δ 5.79 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.13 (dd, J = 17.3, 1.6 Hz,
1H), 5.10 (dd, J = 10.2, 1.5 Hz, 1H), 4.22 (t, J = 6.7 Hz, 2H), 3.76 (s, 3H),
3.40 (s, 2H), 2.44 – 2.40 (m, 2H)。
Step 2) particularly as follows: take out 100 mL round-bottomed flasks from baking oven, it is cooled to room temperature under argon state, takes dichloromethane
Alkane 5 mL and Hoveyda-Grubbs second filial generation catalyst (HG-2) 0.09 g(0.14 mmol) join in round-bottomed flask,
Stir five minutes.Take dichloromethane 2 mL, butyl-3-alkene-1-ylmethyl malonic acid 0.3 g(1.7 mmol) and allyl acetate
0.5g(5.1mmol) after mix homogeneously, it is slowly added in reaction bulb.React 6 hours under room temperature, cross post isolated product 5-
Methylpent-3-alkene-1-ylmethyl malonic acid 0.4 g(productivity 56 %), for faint yellow color grease.
EIsomer:1H NMR (600 MHz, CDCl3) δ 5.77 – 5.71 (m, 1H), 5.70 – 5.64
(m, 1H), 4.53 (dd, J = 6.0, 1.1 Hz, 2H), 4.21 (t, J = 6.7 Hz, 2H), 3.76 (s,
3H), 3.39 (s, 2H), 2.43 (q, J = 6.6, 1.1 Hz, 2H), 2.07 (s, 3H)。
ZIsomer (diagnostic peaks only):1H NMR (600 MHz, CDCl3) δ 4.64 – 4.62
(m, 2H), 2.50 (q, J = 6.8 Hz, 2H)。
Step 3), particularly as follows: take out a clean tube sealing from baking oven, is cooled to room temperature under argon state.Successively to tube sealing
Middle additionN,N-dimethylformamide 3 mL, palladium 12 mg(0.053 mmol) and triphenylphosphine 55 mg(0.21
Mmol), stirring at normal temperature 10 minutes.5-methylpent-3-alkene-1-ylmethyl malonic acid 150 mg(0.61 is added in tube sealing
Mmol, 0.2M), and with 2 mL DMF shower tube sealing inwalls, it is ensured that raw material is completely added to bottom tube sealing.It is heated to 90 DEG C, and
Isothermal reaction 10 hours.Extract by 5 mL ethyl acetate, and with 3 part of 5 mL saturated sodium bicarbonate solution washing, take organic layer
Be dried with anhydrous sodium sulfate, cross leaching organic solution evaporation and concentration, obtain crude mixture, cross post isolated (methyl (Z)-
2-oxo 3,4,7,8-tetrahydrochysene-2H-oxocine-3-carboxylic acid (31 mg) and its hexatomic ring isomer methyl-2-oxygen
Generation-4-vinyl tetrahydrochysene-2H-pyrans-3-carboxylate methyl ester 30mg, gross production rate is 55 %, is all yellow liquid.
(methyl (Z)-2-oxo 3,4,7,8-tetrahydrochysene-2 H-oxocine-3-carboxylic acid:1H NMR (400 MHz,
CDCl3) δ 6.12 – 6.00 (m, 1H), 5.80 (dt, J = 11.1, 7.9 Hz, 1H), 4.76 – 4.67
(m, 1H), 3.82 (dd, J = 6.2, 2.7 Hz, 1H), 3.75 (s, 3H), 2.93 (ddd, J = 12.9,
9.8, 6.2 Hz, 1H), 2.50 – 2.36 (m, 2H), 2.16 – 2.06 (m, 1H), 1.71 – 1.61 (m,
1H), 1.51 – 1.35 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H)。
(3S*, 4S*)-methyl-2-oxo-4-vinyl tetrahydrochysene-2 H-pyrans-3-carboxylate methyl ester:1H NMR
(600 MHz, CDCl3) δ 5.72 (ddd, J = 17.4, 10.4, 7.3 Hz, 1H), 5.20 – 5.12 (m,
2H), 4.45 (dt, J = 11.6, 4.7 Hz, 1H), 4.39 (ddd, J = 11.5, 10.0, 3.8 Hz, 1H),
3.79 (s, 2H), 3.38 (d, J = 10.4 Hz, 1H), 3.10 – 3.02 (m, 1H), 2.12 – 2.05 (m,
2H)。
The reaction equation of this example is as follows:
Two, example 2, synthesis (Z)-3-(tert-butyl group base sulfonyl)-3,4,7,8-tetrahydrochysene-2 H-oxocin-2-ketone, specifically grasps
Make flow process as follows:
200 mL THF, 2-methyl-2-propanethiol 26.2 mL(20.96 g is added in 500 mL round-bottomed flasks, 0.23
Mol), sodium tert-butoxide 22.33 g(0.23 mol), by 30 mL THF and methyl bromoacetate 21.5 mL (35.55 g, 0.23
Mol) pour in 50 mL Dropping funnels and mix, drip in round-bottomed flask, react 3 h.After reaction terminates, organic facies is first with full
Extract with sodium bicarbonate solution, then be dried with anhydrous sodium sulfate, sucking filtration, and revolve steaming and obtain the first step thick product tertiary butylthio of 2-()
Ethyl acetate 36.8g, yield 98%.
The tertiary butylthio of 2-() ethyl acetate:1H NMR (600 MHz, CDCl3) δ 3.74 (s, 3H), 3.31 (s,
2H), 1.35 (s, 9H)。
In 250 mL round-bottomed flask, add 150 mL DCM, add first step product 10 g(62 mmol), between adding
Chloroperoxybenzoic acid 31.5 g(155 mmol), reaction is overnight.After reaction terminates, sucking filtration, the liquid obtained, with 10% sulfur for sulfur
Acid sodium solution extracts three times, then extracts three times with saturated sodium bicarbonate.Finally it is dried with anhydrous sodium sulfate, sucking filtration, and revolves and steam
To thick product.Take a small amount of crude product, be dissolved in ethyl acetate, carry out thin-layer chromatographic analysis, crude product is filled sample and crosses post, process and obtain the
Secondary product methyl 2-(tert. butylsulfonyl) ethyl acetate 7.8g, yield 65%.
Methyl 2-(tert. butylsulfonyl) ethyl acetate:1H NMR (600 MHz, CDCl3) δ 3.98 (s, 2H),
3.83 (s, 3H), 1.46 (s, 9H)。
In 100mL round-bottomed flask, add 8 mL 1M NaOH, add second step product 1.5 g(7.7 mmol), instead
Should be overnight.After reaction terminates, extract 3 times with ether, collect aqueous phase, then with sulphuric acid regulation aqueous phase to pH1, extract by ethyl acetate
Taking, collect organic facies, be dried with anhydrous sodium sulfate, rotation is steamed, and obtains white solid product 2-(tert. butylsulfonyl) acetic acid
1.03g, yield 74%.
2-(tert. butylsulfonyl) acetic acid:1H NMR (600 MHz, CDCl3) δ 4.03 (s, 1H), 1.50 (s,
5H)。
Step 1) particularly as follows:
1. from baking oven, take out 250 mL cleaning flasks, under argon state, be cooled to room temperature, in reaction bulb, add dichloromethane
10 mL and 2-(tert. butylsulfonyl) acetic acid 756 mg(4.19 mmol), and in whipping process, add a DMF, ice bath
In reaction bulb, oxalyl chloride 580 mg(4.57 mmol is slowly added after 5 minutes), remove ice bath, room temperature reaction 2 hours, with rotation
Turn evaporimeter evaporation and concentration and obtain 2-(tert. butylsulfonyl) chloroacetic chloride.
2. from baking oven, take out 250 mL round-bottomed flasks, under argon state, be cooled to room temperature, add dichloromethane 10 mL
And compound 3-butene-1-ol 200 mg(2.77 mmol), add under stirringN,N-Diisopropylethylamine (DIEA)
718 mg(5.54 mmol), and ice bath 5 minutes, it is slowly added into the 2-(tert. butylsulfonyl newly produced in top) chloroacetic chloride, instead
Answer and bottle have a large amount of white acid mist occur, be stirred at room temperature 8 hours, add saturated sodium bicarbonate solution 10 mL and wash and use 3 parts,
10 mL/ part dichloromethane solutions extract, and take organic layer Rotary Evaporators evaporation and concentration, obtain crude product and cross post separation,
To compound butyl-3-alkene-1-base-2-(tert. butylsulfonyl) ethyl acetate 350mg, yield 54%, for brown liquid.
Butyl-3-alkene-1-base-2-(tert. butylsulfonyl) ethyl acetate:1H NMR (400 MHz, CDCl3) δ 5.78
(ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.15 – 5.04 (m, 2H), 4.25 (t, J = 6.8 Hz,
2H), 3.93 (s, 2H), 2.47 – 2.39 (m, 2H), 1.44 (s, 9H)。
Step 2) particularly as follows: take out 100 ml round-bottomed flasks from baking oven, it is cooled to room temperature under argon state, takes dichloromethane
Alkane 4 mL and Hoveyda-Grubbs second filial generation catalyst (HG-2) 33 mg(0.053 mmol) join in round-bottomed flask,
Stir five minutes.Take dichloromethane 2 mL, butyl-3-alkene-1-base-2-(tert. butylsulfonyl) ethyl acetate 250 mg(1.07
Mmol) and allyl acetate 321 mg(3.21 mmol) after mix homogeneously, be slowly added in reaction bulb.6 are reacted under room temperature
Hour, cross post isolated product 5-methylpent-3-alkene-1-base-2-(tert. butylsulfonyl) ethyl acetate 131mg, yield
40%, for brown oil.E isomer: 1H NMR (600 MHz, CDCl3) δ 5.80 – 5.74 (m, 1H),
5.73 – 5.67 (m, 1H), 4.54 (dd, J = 6.1, 1.1 Hz, 2H), 4.28 (td, J = 6.7, 1.4
Hz, 2H), 3.97 (s, 2H), 2.48 (q, J = 6.7 Hz, 2H), 2.08 (s, 3H), 1.47 (s, 9H).Z isomer (diagnostic peaks only): 1H NMR (600 MHz, CDCl3) δ 4.64 (d, J = 5.5
Hz, 2H), 3.98 (s, 2H), 2.54 (q, J = 6.5 Hz, 2H), 2.07 (s, 3H).。
Step 3), particularly as follows: take out a clean tube sealing from baking oven, is cooled to room temperature under argon state.Successively to tube sealing
Middle additionN,N-Dimethylformamide 1 mL, palladium 5.7 mg(0.026 mmol) and triphenylphosphine 14 mg(0.052
Mmol), stirring at normal temperature 10 minutes.Admixture 5-methylpent-3-alkene-1-base-2-(tert. butylsulfonyl in tube sealing) acetic acid second
Ester 80 mg(0.26 mmol, 0.3M), and with 1 mL DMF shower tube sealing inwall, it is ensured that raw material is completely added to bottom tube sealing.
It is heated to 110 DEG C, and isothermal reaction 10 hours.With 5 mL ethyl acetate extractions, and with 3 × 5 mL saturated sodium bicarbonate solutions
Washing, takes organic layer anhydrous sodium sulfate and is dried, and crosses leaching organic solution evaporation and concentration, obtains crude mixture, crosses post and separates
Obtain (Z)-3-(tert. butylsulfonyl)-3,4,7,8-tetrahydrochysene-2H-oxocin-2-ketone 53 mg, for colorless solid and
Its hexatomic ring isomer (3S, 4S)-3-(tert. butylsulfonyl)-4-vinyl tetrahydrochysene-2 H-pyran-2-one (2 mg) is
Colorless liquid, gross production rate is 86 %.
(Z)-3-(tert. butylsulfonyl)-3,4,7,8-tetrahydrochysene-2 H-oxocin-2-ketone: 1H NMR (600 MHz,
CDCl3) δ 6.00 – 5.94 (m, 1H), 5.77 – 5.71 (m, 1H), 4.60 (t, J = 11.5 Hz, 1H),
4.28 – 4.22 (m, 1H), 4.05 (dd, J = 12.3, 4.2 Hz, 1H), 3.37 (q, J = 11.8 Hz,
1H), 2.87 – 2.77 (m, 1H), 2.62 (ddd, J = 11.3, 6.8, 4.3 Hz, 1H), 2.13 (dd, J
= 14.3, 8.4 Hz, 1H), 1.48 (s, 9H)。
(3S *, 4S *)-3-(tert. butylsulfonyl)-4-vinyl tetrahydrochysene-2H-pyran-2-one:1H NMR (400
MHz, CDCl3) δ 5.80 (ddd, J = 17.4, 10.2, 7.3 Hz, 1H), 5.22 – 5.15 (m, 2H),
4.38 (dt, J = 11.4, 4.7 Hz, 1H), 4.16 – 4.14 (m, 1H),4.05 – 4.03 (d, J = 4.2
Hz, 1H), 3.61 – 3.54 (dddd, J = 8.7, 7.2, 5.1, 2.3 Hz, 1H), 2.34 – 2.26
(dddd, J = 15.0, 7.0, 5.0, 3.2 Hz, 2H), 1.49 (s, 9H)。
The reaction equation of this example is as follows:
Three, example 3, synthesis (Z)-3-(tert. butylsulfonyl)-8-methyl 3,4,7,8 tetrahydrochysene-2H-oxocin-2-ketone, specifically grasp
Make flow process as follows:
Step 1) particularly as follows:
1. from baking oven, take out 250 mL cleaning flasks, under argon state, be cooled to room temperature, in reaction bulb, add dichloromethane
10 mL and 2-(tert. butylsulfonyl) acetic acid 4.00 g(22.2 mmol), and in whipping process, add a DMF, ice bath
In reaction bulb, oxalyl chloride 3.10 g(24.4 mmol is slowly added after 5 minutes), remove ice bath, room temperature reaction 2 hours, with rotation
Turn evaporimeter evaporation and concentration and obtain 2-(tert. butylsulfonyl) chloroacetic chloride.
2. from baking oven, take out 250 mL round-bottomed flasks, under argon state, be cooled to room temperature, add dichloromethane 10 mL
And compound 4-amylene-2-alcohol 1.27 g(14.8 mmol), add under stirringN,N-Diisopropylethylamine (DIEA)
3.83 g(29.6 mmol), and ice bath 5 minutes, it is slowly added into the 2-(tert. butylsulfonyl newly produced in top) chloroacetic chloride, instead
Answer and bottle has a large amount of white acid mist occur, be stirred at room temperature 8 hours, add saturated sodium bicarbonate solution 10 mL and wash and use dichloro
Dichloromethane 3 × 10 mL extracts, and takes organic layer Rotary Evaporators evaporation and concentration, obtains crude product and crosses post separation, obtains compound
Amyl-4-alkene-2-base-2-(tert. butylsulfonyl) ester 2.23 g, yield 40%, for brown liquid.1H NMR (400 MHz,
CDCl3) δ 5.87 – 5.65 (m, 1H), 5.13 – 5.06 (m, 2H), 5.06 – 5.02 (m, 1H), 3.92
(s, 2H), 2.47 – 2.27 (m, 2H), 1.44 (s, 9H), 1.28 (d, J = 6.3 Hz, 3H)。
Step 2) particularly as follows: take out 100 ml round-bottomed flasks from baking oven, it is cooled to room temperature under argon state, takes dichloromethane
Alkane 10 mL and Hoveyda-Grubbs second filial generation catalyst (HG-2) 112 mg(0.179 mmol) join round-bottomed flask
In, stir five minutes.Take dichloromethane 5 mL, amyl-4-alkene-2-base-2-(tert. butylsulfonyl) ester 2.23 g(8.96 mmol)
And allyl acetate 2.69 g(26.9 mmol) after mix homogeneously, be slowly added in reaction bulb.React 6 hours under room temperature,
Cross post isolated product 6-acetoxyl group hex-4-alkene-2-base 2-(tert. butylsulfonyl) ethyl acetate 1.18 g, yield 41%,
For brown oil.
EIsomer:1H NMR (600 MHz, CDCl3) δ 5.74 (dt, J = 14.9, 7.0 Hz, 1H),
5.70 – 5.60 (m, 1H), 5.06 (q, J = 6.3 Hz, 1H), 4.52 (d, J = 6.1 Hz, 2H), 3.94
(s, 2H), 2.45 – 2.39 (m, 1H), 2.36 (t, J = 6.5 Hz, 1H), 2.06 (s, 3H), 1.46
(s, 9H), 1.29 (d, J = 6.3 Hz, 3H)。
Z Isomer (diagnostic peaks only):1H NMR (600 MHz, CDCl3) δ 4.63 (d, J
= 5.4 Hz, 2H), 4.52 (d, J = 6.1 Hz, 2H), 3.95 (s, 2H)。
Step 3), particularly as follows: take out a clean tube sealing from baking oven, is cooled to room temperature under argon state.Successively to tube sealing
Middle additionN,N-Dimethylformamide 8 mL, palladium 21 mg(0.094 mmol) and triphenylphosphine 98 mg(0.038
Mmol), stirring at normal temperature 10 minutes.Admixture 6-acetoxyl group hex-4-alkene-2-base 2-(tert. butylsulfonyl in tube sealing) acetic acid
Ethyl ester 300 mg(0.937 mmol, 0.1M), and with 2 mL DMF shower tube sealing inwalls, it is ensured that raw material is completely added at the bottom of tube sealing
Portion.It is heated to 110 DEG C, and isothermal reaction 10 hours.With 10 mL ethyl acetate extractions, and with 3 × 10 mL saturated sodium bicarbonates
Solution is washed, and takes organic layer anhydrous sodium sulfate and is dried, and crosses leaching organic solution evaporation and concentration, obtains crude mixture, crosses post
Isolated (Z)-3-(tert. butylsulfonyl)-8-methyl 3,4,7,8 tetrahydrochysene-2 H-oxocin-2-ketone 116 mg, for colourless
Solid, shaped and its hexatomic ring isomer (3S, 4S)-3-(tert. butylsulfonyl)-6-methyl-4-vinyl tetrahydrochysene-2 H -
Pyran-2-one 32 mg is colorless liquid, and gross production rate is 65 %.
(Z)-3-(tert. butylsulfonyl)-8-methyl 3,4,7,8 tetrahydrochysene-2 H-oxocin-2-ketone: 1H NMR (600
MHz, CDCl3) δ 5.91 (dddd, J = 11.1, 8.5, 7.3, 1.2 Hz, 1H), 5.68 (dddd, J =
11.0, 10.1, 6.8, 2.0 Hz, 1H), 4.88 (dqd, J = 11.0, 6.3, 1.4 Hz, 1H), 3.99
(dd, J = 12.4, 4.1 Hz, 1H), 3.34 (tdd, J = 12.2, 10.1, 1.2 Hz, 1H), 2.63 –
2.51 (m, 2H), 2.11 (ddd, J = 14.1, 8.4, 1.4 Hz, 1H), 1.45 (s, 9H), 1.42 (d, J
= 6.3 Hz, 3H)。
(3S*, 4S*)-3-(tert. butylsulfonyl)-6-methyl-4-vinyl tetrahydrochysene-2 H-pyran-2-one:1H NMR
(600 MHz, CDCl3) δ 5.79 (ddd, J = 17.0, 10.2, 7.8 Hz, 1H), 5.27 – 5.06 (m,
2H), 4.80 (ddd, J = 11.4, 6.2, 1.9 Hz, 1H), 4.13 (d, J = 3.5 Hz, 1H), 3.66 –
3.55 (m, 1H), 2.21 (ddd, J = 14.2, 7.8, 1.9 Hz, 1H), 1.53 (s, 9H), 1.42 (d, J
= 6.2 Hz, 3H)。
The reaction equation of this example is as follows:
Claims (1)
1. a kind of synthetic method of octatomic ring lactone compound, it is characterised in that comprise the following steps:
1) mix with acyl chlorides after alcohol being dissolved in anhydrous methylene chloride and react, obtain malonic acid compounds；
2) malonic acid compounds is dissolved in after anhydrous methylene chloride with allyl acetate generation olefin cross coupling reaction, obtain
Acetoxyl group malonic acid compounds；
3) under the catalysis of palladium and triphenylphosphine, with anhydrousN,N-dimethylformamide makees solvent, by concentration be 0.1M～
The acetoxyl group malonic acid compounds of 0.3M carries out inner molecular reaction, obtains octatomic ring lactone compound.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110218203A (en) * | 2019-05-20 | 2019-09-10 | 扬州大学 | The synthetic method of 8 substitution -3,4,7,8- tetrahydro -2H- oxo octyl- 2- ketone octatomic rings |
| CN111704600A (en) * | 2020-05-26 | 2020-09-25 | 扬州大学 | Z-olefin-containing tert-butyl sulfonyl substituted 9-10-membered ring compound and synthesis method thereof |
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| JP2001122867A (en) * | 1999-10-26 | 2001-05-08 | Kuraray Co Ltd | Method for producing lactone derivative |
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| JP2001122867A (en) * | 1999-10-26 | 2001-05-08 | Kuraray Co Ltd | Method for producing lactone derivative |
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| BAOQIANG WAN ET AL.: "Palladium-Catalyzed Highly Chemo-, Regio- and Stereoselective Synthesis of Eight- to Ten-Membered Lactones from Allenyl 3-Oxoalkanoates and Organic Halides", 《ADV. SYNTH. CATAL.》 * |
| FRIESEN, R. W.: "《e-EROS Encyclopedia of Reagents for Organic Synthesis》", 15 April 2001 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218203A (en) * | 2019-05-20 | 2019-09-10 | 扬州大学 | The synthetic method of 8 substitution -3,4,7,8- tetrahydro -2H- oxo octyl- 2- ketone octatomic rings |
| CN111704600A (en) * | 2020-05-26 | 2020-09-25 | 扬州大学 | Z-olefin-containing tert-butyl sulfonyl substituted 9-10-membered ring compound and synthesis method thereof |
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