CN102952011B - New synthetic method of carane aldehyde acid lactone - Google Patents
New synthetic method of carane aldehyde acid lactone Download PDFInfo
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- CN102952011B CN102952011B CN201110247811.8A CN201110247811A CN102952011B CN 102952011 B CN102952011 B CN 102952011B CN 201110247811 A CN201110247811 A CN 201110247811A CN 102952011 B CN102952011 B CN 102952011B
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- QHAPONCMFJQXEN-UHFFFAOYSA-N CC(C)(C1C(O)O2)C1C2=O Chemical compound CC(C)(C1C(O)O2)C1C2=O QHAPONCMFJQXEN-UHFFFAOYSA-N 0.000 description 1
- MBCPNFHFYXLONQ-UHFFFAOYSA-N CC(C)=CCOC(c(cc1)ccc1[N+]([O-])=O)=O Chemical compound CC(C)=CCOC(c(cc1)ccc1[N+]([O-])=O)=O MBCPNFHFYXLONQ-UHFFFAOYSA-N 0.000 description 1
- LDQXBTVZCXAIIB-UHFFFAOYSA-N CCOC(C1C(C)(C)C1COC(c(cc1)ccc1[N+]([O-])=O)=O)=O Chemical compound CCOC(C1C(C)(C)C1COC(c(cc1)ccc1[N+]([O-])=O)=O)=O LDQXBTVZCXAIIB-UHFFFAOYSA-N 0.000 description 1
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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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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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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 current chrysanthemum ester insecticide, be widely used in agricultural chemicals and field of medicaments, its molecular formula is as follows.
Carane aldehydic acid lactone
Deltamethrin
Block the raw material that imperial acid is production third orgotein enzyme inhibitors boceprevir important intermediate Caronic anhydride, simultaneously also widespread use and agricultural chemicals and other organic synthesis fields, their chemical formula is as follows:
Block imperial sour Caronic anhydride
The general synthetic routes of current carane aldehydic acid lactone is as follows:
This route take ethyl chrysanthemate as starting material synthesis carane aldehydic acid lactone, and this raw material production producer is less, on the high side.In ensuing oxidizing reaction, use ozone as oxygenant, power consumption is large, and operational hazards easily sets off an explosion, and ozone is to environment simultaneously.
Current Caronic anhydride general synthetic routes is as follows:
Same in this route take ethyl chrysanthemate as the acid of starting material Synthesis Card dragon, and this raw material production producer is less, on the high side.The a large amount of potassium permanganate used in ensuing oxidizing reaction is as oxygenant, and operational hazards holds fire hazardous, and a large amount of manganese residues that contain simultaneously generated are to environment.The usage quantity of acetone is very large in the oxidation reaction simultaneously, and cannot continue after reclaiming to use in the present reaction, and production cost is improved greatly.
Summary of the invention
The object of the invention is to overcome defect of the prior art, provide a kind of and synthesize carane aldehydic acid lactone, the acid of card dragon and the method for Caronic anhydride.With more economical, safer, the method for more environmental protection realizes the manufacture of this product, improves yield and quality, reduces costs, economize on resources and the energy.
The present invention adopts the protected prenol of hydroxyl to be starting material, by generating triatomic ring key intermediate to the addition of double bond, next to ethyl ester and protecting group hydrolysis, then obtains carane aldehydic acid lactone and the acid of card dragon respectively by controlled oxidization condition.Cyclization finally by the acid of card dragon obtains Caronic anhydride.General reaction route is as follows:
Originally provide firstly a kind of synthetic method of 3-methylol-2,2-Dimethvlcvclopropvl formic acid, comprise the following steps:
1) with the protected prenol of hydroxyl (I) for raw material; With the compound of formula (II), addition reaction is carried out to the double bond of raw material, obtain triatomic ring intermediate (III);
2) ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed reaction, and deprotection base R, obtain 3-methylol-2,2-Dimethvlcvclopropvl formic acid (IV);
Reaction scheme is as follows:
In formula: R is blocking group; R
1for optional substituted or unsubstituted alkyl, optional substituted or unsubstituted assorted alkyl, optional substituted or unsubstituted cycloalkyl, optional substituted or unsubstituted Heterocyclylalkyl, optional substituted or unsubstituted aryl and optional substituted or unsubstituted heteroaryl.
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 (as p-nitrophenyl formyl radical, m-nitro benzoyl, 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 be selected but be not limited to trimethyl silicon based or dimethyl tertiary butyl is silica-based.
Preferably, R
1for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl or benzyl; Most preferably be ethyl.
Step 1) in, described addition reaction is with copper class catalyzer for catalyzer, and reaction solvent is selected from one or more the mixing in ethylene dichloride, methylene dichloride or toluene, and temperature of reaction is 25 ~ 110 DEG C.
Preferably, described copper class catalyzer be selected from that metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, trifluoromethanesulfonic acid are cuprous, one or more in copper sulfate, neutralized verdigris, fluoroform sulphonyl copper and cupric chloride.
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 hydrolyzed ethyl base in this area, such as: described hydrolysis reaction carries out in the aqueous solution of sodium hydroxide, and temperature of reaction is preferably 50 DEG C.Containing sodium hydroxide 15 ~ 30wt% in described aqueous sodium hydroxide solution.Described deprotection base R, can adopt the method for corresponding deprotection base in this area according to the blocking group specifically selected.
Further, the synthetic method of carane aldehydic acid lactone provided by the present invention, comprises step: make 3-methylol-2,2-Dimethvlcvclopropvl formic acid soluble in water, adjust ph is 7 ~ 11, then carries out oxidizing reaction; The condition of described oxidizing reaction is: at-5 ~ 15 DEG C, adds organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drips the aqueous solution of clorox; Then raised temperature to 20 ~ 25 DEG C are reacted; Oxidizing reaction is separated completely afterwards and obtains product carane aldehydic acid lactone.Wherein:
The mass ratio of tetramethyl piperidine oxide compound and 3-methylol-2,2-Dimethvlcvclopropvl formic acid is (0.01 ~ 0.5): 1, is preferably (0.01 ~ 0.2): 1; Potassium Bromide, weight proportion between tetramethyl piperidine oxide compound and the aqueous solution of clorox are 1: (0.1 ~ 0.5): (50 ~ 100), are preferably 1: (0.2 ~ 0.4): (50 ~ 100); Cl content in 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.
Preferably, described organic solvent is selected from acetonitrile or ethyl acetate.
Described separation method can be: after reacting completely, and reaction system is poured into the sodium sulfite aqueous solution of less than 0 DEG C, with salt acid for adjusting pH to 5, re-use extraction into ethyl acetate, the organic phase extracted is dry, and then removal of solvent under reduced pressure, can obtain product carane aldehydic acid lactone.
Described 3-methylol-2,2-Dimethvlcvclopropvl formic acid can adopt the method preparation of any one synthesis 3-methylol-2,2-Dimethvlcvclopropvl formic acid (IV) above-mentioned provided by the present invention.Wherein, described step 2) in, the ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed and reacts and after deprotection base, do not carry out aftertreatment, directly lower the temperature and regulate its pH value to be 7 ~ 11, then carrying 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, comprises step: make 3-methylol-2,2-Dimethvlcvclopropvl formic acid soluble in water, adjust ph is 8 ~ 10, then carries out oxidizing reaction; The condition of described oxidizing reaction is: at-5 ~ 15 DEG C, adds organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drips the aqueous solution of clorox, then 10 ~ 50min is stirred, adjust ph to 4 ~ 7 again, drip the aqueous solution of Textone, react after dropwising; Oxidizing reaction is separated completely afterwards and obtains product carane aldehydic acid lactone.Wherein:
The mass ratio of tetramethyl piperidine oxide compound and 3-methylol-2,2-Dimethvlcvclopropvl formic acid is (0.01 ~ 0.5): 1, is 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), is 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.
Preferably, described organic solvent is selected from acetonitrile or ethyl acetate.
Described separation method can be: after reacting completely, and reaction system is poured into the sodium sulfite aqueous solution of less than 0 DEG C, with salt acid for adjusting pH to 1, re-use extraction into ethyl acetate, the organic phase extracted is dry, and then removal of solvent under reduced pressure, can obtain product carane aldehydic acid lactone.
Described 3-methylol-2,2-Dimethvlcvclopropvl formic acid can adopt the method preparation of any one synthesis 3-methylol-2,2-Dimethvlcvclopropvl formic acid (IV) above-mentioned provided by the present invention.Wherein, described step 2) in, the ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed and reacts and after deprotection base, do not carry out aftertreatment, directly lower the temperature and regulate its pH value to be 8 ~ 10, then carrying 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 acid of card dragon carry out ring-closure reaction and obtain product Caronic anhydride; The acid of described card dragon prepares by adopting the method for any one Synthesis Card dragon acid above-mentioned.
Preferably, described ring-closure reaction take aceticanhydride as solvent, carries out under the reflux temperature of aceticanhydride, 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 the imperial acid of above-mentioned carane aldehydic acid lactone provided by the present invention, card and Caronic anhydride, has the following advantages:
1) mild condition, production security is high, is easy to suitability for industrialized production;
2) without metallic residue and other environment had to the waste liquid of pollution, waste residue, waste gas generates;
3) supplementary material is all cheap and easy to get, can effectively reduce costs.
Embodiment
The present invention is set forth further below in conjunction with embodiment.Should be understood that these embodiments are only for illustration of the present invention, but not limit the scope of the invention.
Embodiment 1a
The preparation of intermediate III a:
Add intermediate la (54g) in reaction flask, copper catalyst (catalyzer is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid) (0.5g), ethylene dichloride 200ml, is warming up to 60-65 DEG C.In system, drip the solution that ethyl diazoacetate II48 gram is dissolved in ethylene dichloride 100ml, drip off under the condition of warm 60-85 DEG C within keeping.Drip off rear continuation stirring 30 minutes.Underpressure distillation, the cut collecting 117-120 DEG C/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 is complex compound that is cuprous for trifluoromethanesulfonic acid and cyanophenyl 1: 1, and the weight ratio of catalyzer and raw material Ib is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ic is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Id is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ie is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material If is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ig is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ih is 0.01, and 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 is the cuprous complex compound with cyanophenyl 1: 1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ii is 0.01, and 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 DEG C, adds the aqueous sodium hydroxide solution (24.2g) of 28wt%.2 hours are incubated at 50 DEG C.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-Dimethvlcvclopropvl formic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, adjust ph to 9, extraction into ethyl acetate, dry cis cinnamate ester product.By remaining aqueous solution adjust ph to 1, extraction into ethyl acetate, drying is concentrated to obtain trans-compound IV
Nuclear magnetic data is as follows:
Cis cinnamate ester product:
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 temperature 1 hour, after pressure reducing and steaming tetrahydrofuran (THF), adds the aqueous sodium hydroxide solution (40g) of 28wt%.2 hours are incubated at 50 DEG C.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-Dimethvlcvclopropvl formic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, adjust ph to 9, extraction into ethyl acetate, dry cis cinnamate ester product.By remaining aqueous solution adjust ph to 1, extraction into ethyl acetate, drying is concentrated to obtain trans-compound IV
Nuclear magnetic data is with implementing 2a.
Embodiment 2c
The preparation of intermediate compound IV:
Behaviour's acting 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 disappears to raw material.Filter, decompression removing ethanol, stirs and is warming up to 50 DEG C, add the aqueous sodium hydroxide solution (24.2g) of 28wt%.2 hours are incubated at 50 DEG C.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-Dimethvlcvclopropvl formic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, adjust ph to 9, extraction into ethyl acetate, dry cis cinnamate ester product.By remaining aqueous solution adjust ph to 1, extraction into ethyl acetate, drying is concentrated to obtain trans-compound IV
Nuclear magnetic data is consistent with embodiment 2a.
Embodiment 2e
The preparation of intermediate compound IV:
Behaviour's acting embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2e
The preparation of intermediate compound IV:
Behaviour's acting embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2f
The preparation of intermediate compound IV:
Behaviour's acting embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2h
The preparation of intermediate compound IV:
Behaviour's acting embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2i
The preparation of intermediate compound IV:
Behaviour's acting embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 3
The preparation of carane aldehydic acid lactone:
The aqueous solution obtaining intermediate compound IV in embodiment 2a-2i is raw material reaction liquid.
Add 50% sulphur acid for adjusting pH to 8-10 to above-mentioned cooling in the aqueous solution of the intermediate compound IV of 5 DEG C, add acetonitrile 5mL, Potassium Bromide 0.3 gram.Add tetramethyl piperidine oxide compound 0.1g, drip the aqueous solution (cl content 10% about uses 20 grams) of the clorox of 12%.
Be warmed up to 20-25 DEG C, continue stirring 30 minutes, reaction system is poured into the sodium sulfite aqueous solution of 0 DEG C, with salt acid for adjusting pH to 5, make to be extracted with ethyl acetate, 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 obtaining intermediate compound IV in embodiment 2a-2i is raw material reaction liquid.
Add 50% sulphur acid for adjusting pH to 8-10 to above-mentioned cooling in the aqueous solution of the intermediate compound IV of 5 DEG C, add acetonitrile 5mL, Potassium Bromide 0.3 gram.Add tetramethyl piperidine oxide compound 0.1g, drip the aqueous solution (cl content 10% about uses 20 grams) of the clorox of 12%.Stir 20 minutes.Adjust ph, to 4-7, drips the sodium chlorite aqueous solution 16g of 25%.Drip off rear stirring 2 hours.
Reaction system is poured into the sodium sulfite aqueous solution of 0 DEG C, with salt acid for adjusting pH to 1, make to be extracted with ethyl acetate, 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 reaction flask, block imperial sour 100g, reflux 3 hours, after the aceticanhydride that decompression removing is unnecessary, underpressure distillation obtains Caronic anhydride 70g, productive rate > 80%.
m.p.：53-55℃。
1H NMR(300MHz，CDCl
3)1.32(s，3H)，1.41(s，3H).2.65(s，2H)。
Claims (9)
1. a synthetic method for carane aldehydic acid lactone, comprises the following steps:
1) with the protected prenol of hydroxyl (I) for raw material; With the compound of formula II, addition reaction is carried out to the double bond of raw material, obtain triatomic ring intermediate (III);
2) ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed reaction, and deprotection base R, obtain 3-methylol-2,2-Dimethvlcvclopropvl formic acid (IV);
3) make 3-methylol-2,2-Dimethvlcvclopropvl formic acid soluble in water, adjust ph is 7 ~ 11, then carries out oxidizing reaction; The condition of described oxidizing reaction is: at-5 ~ 15 DEG C, and add organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox, then raised temperature to 20 ~ 25 DEG C are reacted; Oxidizing reaction is separated completely afterwards and obtains product carane aldehydic acid lactone;
Step 1) and 2) reaction scheme as follows:
In formula: R is blocking group; R
1for optional substituted or unsubstituted alkyl, optional substituted or unsubstituted assorted alkyl, optional substituted or unsubstituted cycloalkyl, optional substituted or unsubstituted Heterocyclylalkyl, optional substituted or unsubstituted aryl and optional substituted or unsubstituted heteroaryl.
2. the synthetic method of carane aldehydic acid lactone as claimed in claim 1, it is characterized in that, R is selected from ester class protecting group, alkyl ether protecting group and silicon ethers protecting group.
3. the synthetic method of carane aldehydic acid lactone as claimed in claim 2, it 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 is selected from trimethyl silicon based or dimethyl tertiary butyl is silica-based.
4. the synthetic method of carane aldehydic acid lactone as claimed in claim 1, is characterized in that, R
1for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl or benzyl.
5. the synthetic method of carane aldehydic acid lactone as claimed in claim 1, it is characterized in that, step 1) described in addition reaction with copper class catalyzer for catalyzer, reaction solvent is selected from one or more the mixing in ethylene dichloride, methylene dichloride or toluene, and temperature of reaction is 25 ~ 110 DEG C.
6. the synthetic method of carane aldehydic acid lactone as claimed in claim 5, 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, one or more in copper sulfate, neutralized verdigris, fluoroform sulphonyl copper and cupric chloride.
7. the synthetic method of the carane aldehydic acid lactone as described in claim 5 or 6, 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 carane aldehydic acid lactone as claimed in claim 1, it is characterized in that, the mass ratio of tetramethyl piperidine oxide compound and 3-methylol-2,2-Dimethvlcvclopropvl formic acid is (0.01 ~ 0.5): 1; Potassium Bromide, weight proportion between tetramethyl piperidine oxide compound and the aqueous solution of clorox are 1:(0.1 ~ 0.5): (50 ~ 100); Cl content in described aqueous sodium hypochlorite solution is 5 ~ 15wt%.
9. the synthetic method of carane aldehydic acid lactone as claimed in claim 1; it is characterized in that; described step 2) in; to the ethoxycarbonyl on triatomic ring intermediate (III) be hydrolyzed reaction and deprotection base after; do not carry out aftertreatment; direct cooling also regulates its pH value to be 7 ~ 11, then carries out follow-up oxidizing reaction.
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| CN114105859B (en) * | 2022-01-27 | 2022-05-03 | 南京桦冠生物技术有限公司 | Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
| CN114539046B (en) * | 2022-03-07 | 2023-08-29 | 浙江新和成股份有限公司 | Process for preparing caronic acid and caronic anhydride |
| CN114634410B (en) * | 2022-03-25 | 2023-05-23 | 杭州国瑞生物科技有限公司 | Preparation method of paciclovir intermediate |
| CN114702431B (en) * | 2022-05-10 | 2023-06-23 | 浙江江北药业有限公司 | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
| CN114933523A (en) * | 2022-05-23 | 2022-08-23 | 南通雅本化学有限公司 | Process for the preparation of caronic acid and its derivatives |
| CN114933580A (en) * | 2022-05-23 | 2022-08-23 | 南通雅本化学有限公司 | Process for the preparation of caronic anhydride |
| CN115028527A (en) * | 2022-05-28 | 2022-09-09 | 汉瑞药业(荆门)有限公司 | Preparation method of 3-hydroxymethyl-2, 2-dimethylcyclopropanecarboxylic acid |
| CN115322167B (en) * | 2022-08-15 | 2023-06-30 | 淄博矿业集团有限责任公司 | Preparation method of antiviral drug intermediate |
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