CN102952011A - New synthetic method of carane aldehyde acid lactone, caronic acid, caronic anhydride and key intermediates thereof - Google Patents
New synthetic method of carane aldehyde acid lactone, caronic acid, caronic anhydride and key intermediates thereof Download PDFInfo
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Abstract
The invention relates to a new synthetic method of carane aldehyde acid lactone, caronic acid, caronic anhydride and key intermediates thereof. The method comprises using hydroxy protected isoamyl alcohol as initial materials, performing an addition of a double bond to generate a key intermediate with a three-membered ring, hydrolyzing ethyl ester and protective groups, and then controlling oxidation conditions to obtain the carane aldehyde acid lactone and the caronic acid respectively. The method has advantages of mild condition, high production security, easy industrial production, no metal residues, and no other waste liquid, waste residue and exhaust gas that pollut the environment, and can effectively reduce cost.
Description
Technical field
The present invention relates to the novel synthesis of carane aldehydic acid lactone, the acid of card dragon, Caronic anhydride and key intermediate thereof.
Background technology
Carane aldehydic acid lactone (Caronaldehydic acid hemiacetal) is the important intermediate of producing the Deltamethrin (molecular formula is as follows) that virulence is the highest in the present chrysanthemum ester insecticide, is widely used in agricultural chemicals and field of medicaments, and its molecular formula is as follows.
Carane aldehydic acid lactone
Deltamethrin
Blocking imperial acid is the raw material of producing the third orgotein enzyme inhibitors boceprevir important intermediate Caronic anhydride, and the while is widespread use and agricultural chemicals and other organic synthesis fields also, and their chemical formula is as follows:
Block imperial sour Caronic anhydride
The general synthetic route of carane aldehydic acid lactone is as follows at present:
This route is synthetic carane aldehydic acid lactone take the chrysanthemumic acid ethyl ester as starting material, and this raw material production producer is less, on the high side.Use ozone as oxygenant in ensuing oxidizing reaction, power consumption is large, and operational hazards easily sets off an explosion, and ozone is to environment simultaneously.
The general synthetic route of Caronic anhydride is as follows at present:
The equally dragon acid take the chrysanthemumic acid ethyl ester as the starting material Synthesis Card in this route, this raw material production producer is less, on the high side.The a large amount of potassium permanganate that uses in ensuing oxidizing reaction is as oxygenant, and operational hazards easily causes fire, and what generate simultaneously contains manganese residue in a large number to environment.The usage quantity of acetone is very large in oxidizing reaction simultaneously, and can't continue after reclaiming to use in this reaction, and production cost is improved greatly.
Summary of the invention
The objective of the invention is to overcome defective of the prior art, the method for a kind of synthetic carane aldehydic acid lactone, the imperial acid of card and Caronic anhydride is provided.With more economical, safer, more the method for environmental protection realizes the manufacture of this product, improves yield and quality, reduces cost, economizes on resources and the energy.
It is starting material that the present invention adopts the protected prenol of hydroxyl, generates the triatomic ring key intermediate by the addition to two keys, next to ethyl ester and protecting group hydrolysis, obtains respectively carane aldehydic acid lactone and the acid of card dragon by the control oxidizing condition again.The at last cyclization by the acid of card dragon obtains Caronic anhydride.The general reaction route is as follows:
This at first provides a kind of 3-methylol-2, and the synthetic method of 2-dimethyl ethylene-acetic acid comprises the following steps:
1) take the protected prenol of hydroxyl (I) as raw material; With the compound of formula (II) two keys of raw material are carried out addition reaction, obtain triatomic ring intermediate (III);
2) to the reaction that is hydrolyzed of the ethoxycarbonyl on the triatomic ring intermediate (III), and deprotection base R, 3-methylol-2 obtained, 2-dimethyl ethylene-acetic acid (IV);
Reaction scheme is as follows:
In the formula: R is blocking group; R
1For choosing replacement or unsubstituted alkyl wantonly, choose replacement or unsubstituted assorted alkyl wantonly, choose replacement or unsubstituted cycloalkyl wantonly, choose replacement or unsubstituted Heterocyclylalkyl wantonly, choose replacement or unsubstituted aryl wantonly and choosing replacement or unsubstituted heteroaryl wantonly.
Preferably, described blocking group R is selected from ester class protecting group, alkyl ether protecting group and silicon ethers protecting group.Further, described ester class protecting group can be selected but be not limited to ethanoyl, benzoyl or substituted benzoyl (such as the p-nitrophenyl formyl radical, m-nitro benzoyl is to anisoyl); Described alkyl ether protecting group can be selected but be not limited to benzyl, triphenyl methane base or THP trtrahydropyranyl; Described silicon ethers protecting group can select but be not limited to trimethyl silicon based or the dimethyl tertiary butyl silica-based.
Preferably, R
1Be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl or benzyl; Most preferably be ethyl.
Step 1) in, described addition reaction is take copper class catalyzer as catalyzer, and reaction solvent is selected from one or more the mixing in ethylene dichloride, methylene dichloride or the toluene, and temperature of reaction is 25～110 ℃.
Preferably, described copper class catalyzer be selected from that metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, trifluoromethanesulfonic acid are cuprous, in copper sulfate, neutralized verdigris, fluoroform sulphonyl copper and the cupric chloride one or more.
Preferably, the mol ratio of raw material 1-RO base-3-methyl-3-butylene and formula (II) compound is (0.5～1.5): 1, and the weight ratio of copper class catalyzer and raw material 1-RO base-3-methyl-3-butylene is (0.01～0.5): 1.
Step 2) in, described hydrolysis reaction condition is the popular response condition of hydrolysis ethoxycarbonyl in this area, and for example: described hydrolysis reaction carries out in the aqueous solution of sodium hydroxide, and temperature of reaction is preferably 50 ℃.Contain sodium hydroxide 15～30wt% in the described aqueous sodium hydroxide solution.Described deprotection base R can be according to the method for corresponding deprotection base in blocking group employing this area of specifically selecting.
Further, the synthetic method of carane aldehydic acid lactone provided by the present invention comprises step: make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating the pH value is 7～11, then carries out oxidizing reaction; The condition of described oxidizing reaction is: under-5～15 ℃, add organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox; Then ℃ react temperature to 20～25 that raise; Oxidizing reaction obtains product carane aldehydic acid lactone fully rear the separation.Wherein:
Tetramethyl piperidine oxide compound and 3-methylol-2, the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1, be preferably (0.01～0.2): 1; Weight proportion between the aqueous solution of Potassium Bromide, tetramethyl piperidine oxide compound and clorox is 1: (0.1～0.5): (50～100) are preferably 1: (0.2～0.4): (50～100); Cl content in the described aqueous sodium hypochlorite solution is 5～15wt%; The envelope-bulk to weight ratio of described organic solvent and tetramethyl piperidine oxide compound is (0.5～50): 1ml/g.
Better, described organic solvent is selected from acetonitrile or ethyl acetate.
Described separation method can be: after reacting completely, pour reaction system into below 0 ℃ sodium sulfite aqueous solution, with salt acid for adjusting pH to 5, re-use ethyl acetate extraction, the organic phase that extracts is dry, and then removal of solvent under reduced pressure can obtain product carane aldehydic acid lactone.
Described 3-methylol-2,2-dimethyl ethylene-acetic acid can adopt above-mentioned any one synthetic 3-methylol-2 provided by the present invention, the method preparation of 2-dimethyl ethylene-acetic acid (IV).Wherein, described step 2) in, the ethoxycarbonyl on the triatomic ring intermediate (III) is hydrolyzed behind reaction and the deprotection base, does not carry out aftertreatment, directly lowering the temperature and regulating its pH value is 7～11, then carries out follow-up oxidizing reaction.
The synthetic route of above-mentioned carane aldehydic acid lactone is as follows:
Further, the synthetic method of card dragon provided by the present invention acid, comprise step: make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating the pH value is 8～10, then carries out oxidizing reaction; The condition of described oxidizing reaction is: under-5～15 ℃, add organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox, then stir 10～50min, re-adjustment pH value to 4～7, the aqueous solution of dropping Textone reacts after dropwising; Oxidizing reaction obtains product carane aldehydic acid lactone fully rear the separation.Wherein:
Tetramethyl piperidine oxide compound and 3-methylol-2, the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1, be preferably (0.01～0.2): 1; Weight proportion between the aqueous solution of Potassium Bromide, tetramethyl piperidine oxide compound, clorox and the aqueous solution of Textone is 1: (0.1～0.5): (50～100): (30～100) are preferably 1: (0.2～0.4): (50～100): (30～100); Cl content in the aqueous solution of described aqueous sodium hypochlorite solution and Textone is respectively 5～15wt%; The envelope-bulk to weight ratio of described organic solvent and tetramethyl piperidine oxide compound is (0.5～50): 1ml/g.
Better, described organic solvent is selected from acetonitrile or ethyl acetate.
Described separation method can be: after reacting completely, pour reaction system into below 0 ℃ sodium sulfite aqueous solution, with salt acid for adjusting pH to 1, re-use ethyl acetate extraction, the organic phase that extracts is dry, and then removal of solvent under reduced pressure can obtain product carane aldehydic acid lactone.
Described 3-methylol-2,2-dimethyl ethylene-acetic acid can adopt above-mentioned any one synthetic 3-methylol-2 provided by the present invention, the method preparation of 2-dimethyl ethylene-acetic acid (IV).Wherein, described step 2) in, the ethoxycarbonyl on the triatomic ring intermediate (III) is hydrolyzed behind reaction and the deprotection base, does not carry out aftertreatment, directly lowering the temperature and regulating its pH value is 8～10, then carries out follow-up oxidizing reaction.
The synthetic route of above-mentioned card dragon acid is as follows:
Further, the invention also discloses a kind of synthetic method of Caronic anhydride, comprise step: make the imperial acid of card carry out ring-closure reaction and obtain the product Caronic anhydride; The acid of described card dragon is prepared by the method that adopts above-mentioned any one Synthesis Card dragon acid.
Better, described ring-closure reaction carries out under the reflux temperature of aceticanhydride take aceticanhydride as solvent, and the reaction times is 2-4h.
The synthetic route of above-mentioned Caronic anhydride is as follows:
Compared with prior art, the synthetic method of above-mentioned carane aldehydic acid lactone provided by the present invention, the imperial acid of card and Caronic anhydride has the following advantages:
1) mild condition, production security is high, is easy to suitability for industrialized production;
2) environment there is the waste liquid of pollution without metallic residue and other, waste residue, waste gas generates;
3) equal inexpensive being easy to get of supplementary material can effectively be reduced cost.
Embodiment
Further set forth the present invention below in conjunction with embodiment.Should be understood that these embodiment only are used for explanation the present invention, but not limit the scope of the invention.
Embodiment 1a
The preparation of intermediate III a:
Add intermediate la (54g) in the reaction flask, copper catalyst (catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl) (0.5g), ethylene dichloride 200ml is warming up to 60-65 ℃.In system, drip the solution that ethyl diazoacetate II48 gram is dissolved in ethylene dichloride 100ml, within keeping, drip off under warm 60-85 ℃ the condition.Dripping off rear continuation stirred 30 minutes.Underpressure distillation, the cut of collecting 117-120 ℃/1kPa obtains intermediate III a 60g.
Trans IIIa nuclear-magnetism:
1HNMR?δ4.18(dd，J＝12，7Hz?1H)，4.13(m，2H)，4.00(dd，J＝12，8Hz，1H)，2.07(s，3H)，1.73(ddd，J＝8，7，5.5Hz，1H)，1.43(d，J＝5.5Hz，1H)，1.27(s，3H)，1.26(t，J＝7Hz，3H)，1.19(s，3H)
Cis IIIa nuclear-magnetism:
1HNMR：δ4.50(dd，J＝12，7Hz，1H)，4.39(dd，J＝12，8Hz，1H)，4.11(m，2H)，2.06(s，3H)，1.60(d，J＝9Hz，1H)，1.44(ddd，J＝9.8，7Hz，1H)，1.27(s，3H)，1.25(t，J＝7Hz，3H)，1.19(s，3H)
Embodiment 1b
The preparation of intermediate III b:
Operation is with example Ia: wherein catalyzer for for trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Ib is 0.01, the mol ratio of raw material Ib and ethyl diazoacetate II is 1: 1.5.
Trans IIIb nuclear-magnetism:
1HNMR：δ4.12(m，2H)，3.74(dd，J＝11，6Hz，1H)，3.53(dd，J＝11，8Hz，1H)，1.66(ddd，J＝8，6，5.5Hz，1H)，1.33(d，J＝5Hz，1H)，1.26(t，J＝7Hz，3H)，1.23(s，3H)，1.18(s，3H)，0.10(s，9H)
Cis IIIb nuclear-magnetism:
1HNMR：δ4.08(m，2H)，3.91(dd，J＝6.5，2.5Hz，2H)，1.52(d，J＝9Hz，1H)，1.40(ddd，J＝9，6.52.5Hz，1H)，1.25(s，3H)，1.25(t，J＝7Hz，3H)，1.18(s，3H)，0.10(s，9H)
Embodiment 1c
The preparation of intermediate III c:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Ic is 0.01, the mol ratio of raw material Ic and ethyl diazoacetate II is 1: 1.5.
Trans IIIc nuclear-magnetism:
1HNMR：δ4.12(m，2H)，3.77(dd，J＝11，6Hz，1H)，3.55(dd，J＝11，8Hz，1H)，1.63(ddd，J＝9，6，5Hz，1H)，1.35(d，J＝5Hz，1H)，1.24(t，J＝7Hz，3H)，1.22(s，3H)，1.18(s，3H)，0.89(s，9H)，0.06(s，3H)，0，05(s，3H)
Cis IIIc nuclear-magnetism:
1HNMR：δ4.08(m，2H)，3.96(dd，J＝11，7Hz，1H)，3.90(dd，J＝11，6.5Hz，1H)，1.52(d，J＝9Hz，1H)，1.40(ddd，J＝9，7，6.5Hz，1H)，1.25(s，3H)，1.25(t，J＝7Hz，3H)，1.18(s，3H)，0.89(s，9H)，0.06(s，3H)，0.05(s，3H)
Embodiment 1d
The preparation of intermediate III d:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Id is 0.01, the mol ratio of raw material Id and ethyl diazoacetate II is 1: 1.5.
Trans IIId nuclear-magnetism:
1HNMR：δ7.35-7.25(m，5H)，4.50(d，J＝1Hz，2H)，4.11(m，2H)3.61(dd，J＝11，6Hz，1H)，3.38(dd，J＝11，8.5Hz，1H)，1.75(ddd，J＝8.5，6，5Hz，1H)，1.36(d，J＝5Hz，1H)，1.25(t，J＝7Hz，3H)，1.24(s，3H)，1.18(s，3H)
Cis IIId nuclear-magnetism:
1HNMR：δ7.35-7.25(m，5H)，4.52(d，J＝1Hz，2H)，4.11(m，2H)，3.86(dd，J＝10.5，5Hz，1H)，3.78(dd，J＝10.5，4.5Hz，1H)，1.57(d，J＝9Hz，1H)，1.44(ddd，J＝9，5，5.5，1H)，1.25(s，3H)，1.24(t，J＝7Hz，3H)，1，19(s，3H).
Embodiment 1e
The preparation of intermediate III e:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Ie is 0.01, the mol ratio of raw material Ie and ethyl diazoacetate II is 1: 1.5.
Trans IIIe nuclear-magnetism:
1HNMR：δ7.50-7.40(m，6H)，7.35-7.15(m，9H)，4，10(m，2H)，3.31(dd，J＝10，6Hz，1H)，2.85(dd，J＝10，8.5Hz，1H)，1.75(ddd，J＝8.5，6，5Hz，1H)，1.32(d，J＝5Hz，1H)，1，28(t，J＝7Hz，3H)，1，26(s，3H)，1.02(s，3H)
Cis IIIe nuclear-magnetism:
1HNMR：δ7.50-7.40(m，6H)，7.35-7.15(m，9H)，3.98(m，2H)，3.43(dd，J＝7，0.5Hz，2H)，1.50(d，J＝9Hz，1H)，1.37(dt，J＝9，7Hz，1H)，1.18(s，3H)，1.17(t，J＝7Hz，3H)，1.09(s，3H).
Embodiment 1f
The preparation of intermediate III f:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material If is 0.01, the mol ratio of raw material And if ethyl diazoacetate II is 1: 1.5.
Trans IIIf nuclear-magnetism:
1HNMR：δ8.10-8.00(m，2H)，7.62-7.38(m，3H)，4.48(dd，J＝12，7Hz，1H)，4.23(dd，J＝12，9Hz，1H)，4.14(m，2H)，1.88(ddd，J＝9，7，5Hz，1H)，1.53(d，J＝5Hz，1H)，1.27(s，3H)，1.26(t，J＝7Hz，3H)，1.26(s，3H)
Cis IIIf nuclear-magnetism:
1HNMR：δ8.10-8.00(m，2H)，7.62-7.38(m，3H)，4.73(ddd，J＝22，7，1Hz，1H)，4.68(ddd，J＝22，5.5，2Hz，1H)，4.10(m，2H)，1.75-1.52(m，2H)，1.35(s，3H)，1.26(t，J＝7Hz，3H)，1.22(s，3H)
Embodiment 1g
The preparation of intermediate III g:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Ig is 0.01, the mol ratio of raw material Ig and ethyl diazoacetate II is 1: 1.5.
Trans IIIg nuclear-magnetism:
1HNMR：δ8.35-8.15(m，4H)，4.53(dd，J＝12，7Hz，1H)，4，32(dd，J＝12，9Hz，1H)，4.14(m，2H)，1.90(ddd，J＝9，7，5Hz，1H)，1.58(d，J＝5Hz，1H)，1.30(t，J＝7Hz，3H)，1.27(s，3H)，1.26(s，3H)
Cis IIIg nuclear-magnetism:
1HNMR：δ8.35-8.15(m，4H)，4.80(dd，J＝22，7Hz，1H)，4.75(dd，J＝22，7，1Hz，1H)，4.11(q，J＝7Hz，2H)，1.65(d，J＝9Hz，1H)，1.64(ddd，J＝9，7，7Hz，1H)，1.35(s，3H)，1.25(t，J＝7Hz，3H)，1.24(s，3H)
Embodiment 1h
The preparation of intermediate III h:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Ih is 0.01, the mol ratio of raw material Ih and ethyl diazoacetate II is 1: 1.5.
Trans IIIh nuclear-magnetism:
1HNMR：δ8.85(td，J＝2，1Hz，1H)，8.43(ddd，J＝8，4，1Hz，1H)，8.38(ddd，J＝8，2，1Hz，1H)，7.68(td，J＝8，1Hz，1H)，4.53(dd，J＝12，7Hz，1H)，4.33(dd，J＝12，8Hz，1H)，4.16(m，2H)，1.92(ddd，J＝8，7，5Hz，1H)，1.59(d，J＝5Hz，1H)，1.30(s，6H)，1.28(t，J＝7Hz，3H)
Cis IIIh nuclear-magnetism:
1HNMR：δ8.85(td，J＝2，1Hz，1H)，8.43(ddd，J＝8，4，1Hz，1H)，8.38(ddd，J＝8，2，1Hz，1H)，7.68(td，J＝8，1Hz，1H)，4.81(dd，J＝18，7Hz，1H)，4.77(dd，J＝18，6，1Hz，1H)，4.11(m，2H)，1.65(d，J＝9Hz，1H)，1.64(ddd，J＝9，7，6Hz，1H)，1.35(s，3H)，1.28(t，J＝7Hz，3H)，1.26(s，3H)
Embodiment 1i
The preparation of intermediate III i:
Operation is with example Ia: wherein catalyzer be trifluoromethanesulfonic acid cuprous with 1: 1 complex compound of cyanophenyl, the weight ratio of catalyzer and raw material Ii is 0.01, the mol ratio of raw material Ii and ethyl diazoacetate II is 1: 1.5.
Trans IIIi nuclear-magnetism:
1HNMR：δ7.99(dt，J＝9，2Hz，2H)，6.93(dt，J＝9，2Hz，2H)，4.46(dd，J＝12，7Hz，1H)，4.20(dd，J＝12，8Hz，1H)，4.14(m，2H)，3.87(s，3H)，1.87(ddd，J＝8，7，5Hz，1H)，1.52(d，J＝5Hz，1H)，1.27(s，3H)，1.26(t，J＝7Hz，3H)，1.25(s，3H)
Cis IIIi nuclear-magnetism:
1HNMR：δ7.99(dt，J＝9，2Hz，2H)，6.91(dt，J＝9，2Hz，2H)，4.70(dd，J＝22，7Hz，1H)，4.65(ddd，J＝22，6，2Hz，1H)，4.11(m，2H)，3.86(s，3H)，1.62(d，J＝6Hz，1H)，1.60(m，1H)，1.34(s，3H)，1.25(t，J＝7Hz，3H)，1.22(s，3H)
Embodiment 2a
The preparation of intermediate compound IV:
Intermediate III (8.3g), water (9ml) mixes.Stirring is warming up to 50 ℃, drips the aqueous sodium hydroxide solution (24.2g) that adds 28wt%.Insulation is 2 hours under 50 ℃.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, regulate pH value to 9, ethyl acetate extraction, the dry interior ester products of cis that gets.The remaining aqueous solution is regulated pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to get
Nuclear magnetic data is as follows:
Ester products in the cis:
1H?NMR(400MHz，CDCI
3)1.16(s，3H)，1.17(s，3H)，1.93(d，1H，J＝6.3Hz)，2.05(dd，1H，J＝8.7，3.1Hz)，4.14(d，1H，J＝9.9Hz)，4.35(dd，1H，J＝9.9，5.5Hz)。
Trans-compound IV:
1H?NMR(400MHz，CDCl
3)δ1.21(s，3H)，1.26(s，3H)，1.41(d，1H，J＝5.5Hz)，1.79-1.63(m，1H)，1.90(br，1H)，3.67(d，J＝7.4Hz，2H)，9.3-9.8(br，1H)。
Embodiment 2b
The preparation of intermediate compound IV:
Intermediate III b (10g), 6N hydrochloric acid (5ml), tetrahydrofuran (THF) (30ml) mixes.Stirring at room 1 hour behind the pressure reducing and steaming tetrahydrofuran (THF), adds the aqueous sodium hydroxide solution (40g) of 28wt%.Insulation is 2 hours under 50 ℃.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, regulate pH value to 9, ethyl acetate extraction, the dry interior ester products of cis that gets.The remaining aqueous solution is regulated pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to get
Nuclear magnetic data is with implementing 2a.
Embodiment 2c
The preparation of intermediate compound IV:
Operation embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2d
The preparation of intermediate compound IV:
Intermediate III d (12g), ethanol (100ml) mixes.Add 10%Pd-C catalyzer (1.0g), logical hydrogen to raw material disappears.Filter, ethanol is removed in decompression, stirs and is warming up to 50 ℃, drips the aqueous sodium hydroxide solution (24.2g) that adds 28wt%.Insulation is 2 hours under 50 ℃.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, regulate pH value to 9, ethyl acetate extraction, the dry interior ester products of cis that gets.The remaining aqueous solution is regulated pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to get
Nuclear magnetic data is consistent with embodiment 2a.
Embodiment 2e
The preparation of intermediate compound IV:
Operation embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2e
The preparation of intermediate compound IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2f
The preparation of intermediate compound IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2h
The preparation of intermediate compound IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2i
The preparation of intermediate compound IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 3
The preparation of carane aldehydic acid lactone:
The aqueous solution that obtains intermediate compound IV among the embodiment 2a-2i is raw material reaction liquid.
Add 50% sulphur acid for adjusting pH to 8-10 to above-mentioned cooling in 5 ℃ the aqueous solution of intermediate compound IV, add acetonitrile 5mL, Potassium Bromide 0.3 restrains.Add tetramethyl piperidine oxide compound 0.1g, the aqueous solution of the clorox of dropping 12% (cl content 10% approximately uses 20 grams).
Be warmed up to 20-25 ℃, continue to stir 30 minutes, reaction system is poured into 0 ℃ sodium sulfite aqueous solution, with salt acid for adjusting pH to 5, use ethyl acetate extraction, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains carane aldehydic acid lactone 2g.
1HNMR(300MHz，CDCI3)1.20(s，6H)，2.10(s，2H)，5.50(br?s，1H)，5.13-5.87(m，1H)。
IR：Vmax(neat)：3300，1720cm-1，MS：m/z?127(M-15)+and?67(100％)。
Embodiment 4
The preparation of card dragon acid:
The aqueous solution that obtains intermediate compound IV among the embodiment 2a-2i is raw material reaction liquid.
Add 50% sulphur acid for adjusting pH to 8-10 to above-mentioned cooling in 5 ℃ the aqueous solution of intermediate compound IV, add acetonitrile 5mL, Potassium Bromide 0.3 restrains.Add tetramethyl piperidine oxide compound 0.1g, the aqueous solution of the clorox of dropping 12% (cl content 10% approximately uses 20 grams).Stirred 20 minutes.Regulate the pH value to 4-7, drip 25% sodium chlorite aqueous solution 16g.Drip off rear stirring 2 hours.
Reaction system poured into 0 ℃ sodium sulfite aqueous solution, with salt acid for adjusting pH to 1, use ethyl acetate extraction, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains the imperial sour 2g of card.
1H?NMR(300MHz，CD
3OD)；cis-isomer?1.25(s，3H)，1.41(s，3H)，1.95(s，2H)；trans-isomer81.31(s，6H)，2.20(s，2H)。
Embodiment 5
The preparation of Caronic anhydride:
Add aceticanhydride 200ml in the reaction flask, block imperial sour 100g, reflux 3 hours, underpressure distillation got Caronic anhydride 70g, productive rate＞80% after unnecessary aceticanhydride was removed in decompression.
m.p.：53-55℃。
1H?NMR(300MHz，CDCl
3)1.32(s，3H)，1.41(s，3H).2.65(s，2H)。
Claims (17)
1. 3-methylol-2, the synthetic method of 2-dimethyl ethylene-acetic acid comprises the following steps:
1) take the protected prenol of hydroxyl (I) as raw material; With the compound of formula (II) two keys of raw material are carried out addition reaction, obtain triatomic ring intermediate (III);
2) to the reaction that is hydrolyzed of the ethoxycarbonyl on the triatomic ring intermediate (III), and deprotection base R, 3-methylol-2 obtained, 2-dimethyl ethylene-acetic acid (IV);
Reaction scheme is as follows:
In the formula: R is blocking group; R
1For choosing replacement or unsubstituted alkyl wantonly, choose replacement or unsubstituted assorted alkyl wantonly, choose replacement or unsubstituted cycloalkyl wantonly, choose replacement or unsubstituted Heterocyclylalkyl wantonly, choose replacement or unsubstituted aryl wantonly and choosing replacement or unsubstituted heteroaryl wantonly.
2. 3-methylol-2 as claimed in claim 1, the synthetic method of 2-dimethyl ethylene-acetic acid is characterized in that, R is selected from ester class protecting group, alkyl ether protecting group and silicon ethers protecting group.
3. 3-methylol-2 as claimed in claim 2, the synthetic method of 2-dimethyl ethylene-acetic acid is characterized in that, described ester class protecting group is selected from ethanoyl, benzoyl or substituted benzoyl; Described alkyl ether protecting group is selected from benzyl, triphenyl methane base or THP trtrahydropyranyl; Described silicon ethers protecting group be selected from trimethyl silicon based or the dimethyl tertiary butyl silica-based.
4. 3-methylol-2 as claimed in claim 1, the synthetic method of 2-dimethyl ethylene-acetic acid is characterized in that, R1 is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl or benzyl.
5. 3-methylol-2 as claimed in claim 1, the synthetic method of 2-dimethyl ethylene-acetic acid is characterized in that step
1) addition reaction described in is take copper class catalyzer as catalyzer, and reaction solvent is selected from one or more the mixing in ethylene dichloride, methylene dichloride or the toluene, and temperature of reaction is 25～110 ℃.
6. 3-methylol-2 as claimed in claim 5, the synthetic method of 2-dimethyl ethylene-acetic acid, it is characterized in that, described copper class catalyzer is selected from that metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, trifluoromethanesulfonic acid are cuprous, in copper sulfate, neutralized verdigris, fluoroform sulphonyl copper and the cupric chloride one or more.
7. such as claim 5 or 6 described 3-methylols-2, the synthetic method of 2-dimethyl ethylene-acetic acid, it is characterized in that, the mol ratio of described raw material and formula (II) compound is (0.5～1.5): 1, and the weight ratio of copper class catalyzer and raw material is (0.01～0.5): 1.
8. the synthetic method of a carane aldehydic acid lactone, comprise step: make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating the pH value is 7～11, then carries out oxidizing reaction; The condition of described oxidizing reaction is: under-5～15 ℃, add organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox, ℃ react temperature to 20～25 that then raise; Oxidizing reaction obtains product carane aldehydic acid lactone fully rear the separation.
9. the synthetic method of carane aldehydic acid lactone as claimed in claim 8 is characterized in that, tetramethyl piperidine oxide compound and 3-methylol-2, and the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1; Weight proportion between the aqueous solution of Potassium Bromide, tetramethyl piperidine oxide compound and clorox is 1: (0.1～0.5): (50～100); Cl content in the described aqueous sodium hypochlorite solution is 5～15wt%.
10. the synthetic method of carane aldehydic acid lactone as claimed in claim 8 or 9 is characterized in that, described 3-methylol-2, and 2-dimethyl ethylene-acetic acid adopts and makes such as arbitrary described synthetic method among the claim 1-7.
11. the synthetic method of carane aldehydic acid lactone as claimed in claim 10; it is characterized in that; described step 2) in; to the ethoxycarbonyl on the triatomic ring intermediate (III) be hydrolyzed the reaction and the deprotection base after; do not carry out aftertreatment; directly lowering the temperature and regulating its pH value is 7～11, then carries out follow-up oxidizing reaction.
12. a synthetic method of blocking dragon acid, comprise step: make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating the pH value is 8～10, then carries out oxidizing reaction; The condition of described oxidizing reaction is: under-5～15 ℃, add acetonitrile, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox, then stir 10～50min; Re-adjustment pH value to 4～7, the aqueous solution of dropping Textone reacts after dropwising; Oxidizing reaction obtains product carane aldehydic acid lactone fully rear the separation.
13. the synthetic method of card dragon as claimed in claim 12 acid is characterized in that, tetramethyl piperidine oxide compound and 3-methylol-2, and the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1; Weight proportion between the aqueous solution of Potassium Bromide, tetramethyl piperidine oxide compound, clorox and the aqueous solution of Textone is 1: (0.1～0.5): (50～100): (30～100); Cl content in the aqueous solution of described aqueous sodium hypochlorite solution and Textone is respectively 5～15wt%.
14. the synthetic method such as claim 12 or 13 described card dragon acid is characterized in that, described 3-methylol-2, and 2-dimethyl ethylene-acetic acid adopts and makes such as arbitrary described synthetic method among the claim 1-7.
15. the synthetic method of card dragon as claimed in claim 14 acid; it is characterized in that; described step 2) in; to the ethoxycarbonyl on the triatomic ring intermediate (III) be hydrolyzed the reaction and the deprotection base after; do not carry out aftertreatment; directly lowering the temperature and regulating its pH value is 8～10, then carries out follow-up oxidizing reaction.
16. the synthetic method of a Caronic anhydride comprises step: make the imperial acid of card carry out ring-closure reaction and obtain the product Caronic anhydride; The acid of described card dragon is by adopting the method such as arbitrary described Synthesis Card dragon acid among the claim 12-15 to prepare.
17. the synthetic method of Caronic anhydride as claimed in claim 16 is characterized in that, described ring-closure reaction carries out under the reflux temperature of aceticanhydride take aceticanhydride as solvent, and the reaction times is 2～4h.
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