CN104163759B - The novel synthesis of the acid of card dragon, Caronic anhydride - Google Patents
The novel synthesis of the acid of card dragon, Caronic anhydride Download PDFInfo
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- CN104163759B CN104163759B CN201410364816.2A CN201410364816A CN104163759B CN 104163759 B CN104163759 B CN 104163759B CN 201410364816 A CN201410364816 A CN 201410364816A CN 104163759 B CN104163759 B CN 104163759B
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- GUANXMKKWAKGCE-UHFFFAOYSA-N CC(C)(C1C[O](C)C(c2ccccc2)=O)C1C(O)=O Chemical compound CC(C)(C1C[O](C)C(c2ccccc2)=O)C1C(O)=O GUANXMKKWAKGCE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to carane aldehydic acid lactone, block the novel synthesis of imperial acid and Caronic anhydride. Adopting the protected prenol of hydroxyl is starting material, then by the addition of two keys is generated to three-membered ring key intermediate, next to ethyl ester and protecting group hydrolysis, then obtains respectively carane aldehydic acid lactone and the acid of card dragon by controlling oxidizing condition. Have mild condition, production security is high, is easy to suitability for industrialized production; Without metallic residue and other, environment there is is the waste liquid of pollution, waste residue, waste gas generates; The advantage such as can effectively reduce costs.
Description
Patent application of the present invention is divisional application, and the application number of original bill is 201110247811.8, and the applying date is August 24 in 2011Day, denomination of invention is: the novel synthesis of carane aldehydic acid lactone, the acid of card dragon, Caronic anhydride and key intermediate thereof.
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 (Caronaldehydicacidhemiacetal) is to produce the highest bromine of virulence in current chrysanthemum ester insecticideThe important intermediate of Cyano chrysanthemate (molecular formula is as follows), is widely used in agricultural chemicals and field of medicaments, and its molecular formula is as follows.
Blocking imperial acid is the raw material of producing the third orgotein enzyme inhibitor boceprevir important intermediate Caronic anhydride, also extensively should simultaneouslyWith with agricultural chemicals and other organic synthesis fields, their chemical formula is as follows:
The general synthetic route of carane aldehydic acid lactone is as follows at present:
This route is synthetic carane aldehydic acid lactone taking chrysanthemumic acid ethyl ester as starting material, and this raw material manufacturer is less, on the high side. ConnecingIn the oxidation reaction of getting off, use ozone as oxidant, power consumption is large, and operational hazards easily sets off an explosion, and ozone is to ring simultaneouslyBorder pollutes.
The general synthetic route of Caronic anhydride is as follows at present:
The dragon acid taking chrysanthemumic acid ethyl ester as starting material Synthesis Card equally in this route, this raw material manufacturer is less, on the high side. ?The a large amount of potassium permanganate using in ensuing oxidation reaction is as oxidant, and operational hazards is held fire hazardous, generates simultaneouslyA large amount of containing manganese residues to environment. In oxidation reaction, the use amount of acetone is very large simultaneously, and cannot after reclaimingContinue to use in this reaction, production cost is improved greatly.
Summary of the invention
The object of the invention is to overcome defect of the prior art, a kind of synthetic carane aldehydic acid lactone, the acid of card dragon and the acid of card dragon are providedThe method of acid anhydride. With more economical, safer, more the method for environmental protection realizes the manufacture of this product, improves yield and quality,Reduce costs, economize on resources and the energy.
It is starting material that the present invention adopts the protected prenol of hydroxyl, generates in the middle of three-membered ring key by the addition to two keysBody, next to ethyl ester and protecting group hydrolysis, then obtains respectively carane aldehydic acid lactone and the acid of card dragon by controlling oxidizing condition. ?Obtain Caronic anhydride by the cyclization of card dragon acid afterwards. General reaction route is as follows:
First this provide a kind of 3-methylol-2, and the synthetic method of 2-dimethyl ethylene-acetic acid, comprises the following steps:
1) taking the protected prenol of hydroxyl (I) as raw material; Two keys of raw material are added with the compound of formula (II)Become reaction, obtain three-membered ring intermediate (III);
2) to the reaction that is hydrolyzed of the ethoxycarbonyl on three-membered ring intermediate (III), and deprotection base R, 3-methylol obtained-2,2-dimethyl ethylene-acetic acid (IV);
Reaction scheme is as follows:
In formula: R is blocking group; R1Replace or unsubstituted alkyl, optionally replace or unsubstituted assorted alkyl, appoint for optionalChoose generation or unsubstituted cycloalkyl, optionally replacement or unsubstituted Heterocyclylalkyl, optionally replacement or unsubstituted aryl and optionalReplace 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 select but be not limited to acetyl group, benzoyl or substituted benzoyl (as p-nitrophenyl formoxyl,M-nitro benzoyl, to methoxybenzoyl base); Described alkyl ether protecting group can be selected but be not limited to benzyl, triphenylMethyl or THP trtrahydropyranyl; Described silicon ethers protecting group can be selected but be not limited to trimethyl silicon based or the dimethyl tert-butyl group is silica-based.
Preferably, R1For methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group or benzyl; Most preferably be ethyl.
Step 1) in, described addition reaction is taking copper class catalyst as catalyst, and reaction dissolvent is selected from dichloroethanes, carreneOr one or more mixing in toluene, reaction temperature is 25～110 DEG C.
Preferably, described copper class catalyst is selected from metallic copper, stannous chloride, cuprous bromide, cuprous iodide, TFMS AsiaOne or more in copper, copper sulphate, Schweinfurt green, fluoroform sulphonyl copper and copper 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 copperThe weight ratio of class catalyst and raw material 1-RO base-3-methyl-3-butylene is (0.01～0.5): 1.
Step 2) in, described hydrolysis condition is the popular response condition that is hydrolyzed ethoxycarbonyl in this area, for example: described waterSolution reacts in the aqueous solution of NaOH carries out, and reaction temperature is preferably 50 DEG C. In described sodium hydrate aqueous solution, contain hydrogen-oxygenChange sodium 15～30wt%. Described deprotection base R, can adopt in this area and remove accordingly according to the blocking group of specifically selectingThe method of protecting group.
Further, the synthetic method of carane aldehydic acid lactone provided by the present invention, comprises step: make 3-methylol-2,2-bis-Methyl ethylene-acetic acid is soluble in water, and regulating pH value is 7～11, then carries out oxidation reaction; The condition of described oxidation reactionFor: at-5～15 DEG C, add organic solvent, KBr and tetramethyl piperidine oxide, and drip the water-soluble of cloroxLiquid; Then react temperature to 20～25 DEG C that raise; Completely rear separation of oxidation reaction obtains product carane aldehydic acid lactone. Wherein:
Tetramethyl piperidine oxide 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 KBr, tetramethyl piperidine oxide and the aqueous solution of cloroxFor 1:(0.1～0.5): (50～100), are preferably 1:(0.2～0.4): (50～100); Described aqueous sodium hypochlorite solutionIn chlorinity be 5～15wt%; The envelope-bulk to weight ratio of described organic solvent and tetramethyl piperidine oxide 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, pour reaction system into 0 DEG C of following sodium sulfite aqueous solution, use hydrochloric acidRegulate pH to 5, re-use ethyl acetate extraction, the organic phase extracting is dry, and then removal of solvent under reduced pressure, can obtainProduct carane aldehydic acid lactone.
Described 3-methylol-2,2-dimethyl ethylene-acetic acid can adopt above-mentioned any one synthetic 3-hydroxyl provided by the present inventionMethyl-2, the method preparation of 2-dimethyl ethylene-acetic acid (IV). Wherein, described step 2) in, to three-membered ring intermediateEthoxycarbonyl in (III) is hydrolyzed after reaction deprotection base, does not carry out post processing, directly lowers the temperature and regulates its pH valueBe 7～11, then carry out follow-up oxidation 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-dimethylEthylene-acetic acid is soluble in water, and regulating pH value is 8～10, then carries out oxidation reaction; The condition of described oxidation reaction is:At-5～15 DEG C, add organic solvent, KBr and tetramethyl piperidine oxide, and drip the aqueous solution of clorox,Then stir 10～50min, then regulate pH value to 4～7, drip the aqueous solution of sodium chlorite, after dropwising, react;Completely rear separation of oxidation reaction obtains the acid of product card dragon. Wherein:
Tetramethyl piperidine oxide 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; KBr, tetramethyl piperidine oxide, the aqueous solution of clorox and the water of sodium chloriteWeight proportion between solution is 1:(0.1～0.5): (50～100): (30～100), are preferably 1:(0.2～0.4):(50～100): (30～100); Chlorinity in the aqueous solution of described aqueous sodium hypochlorite solution and sodium chlorite is respectively 5～15wt%; The envelope-bulk to weight ratio of described organic solvent and tetramethyl piperidine oxide 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, pour reaction system into 0 DEG C of following sodium sulfite aqueous solution, use hydrochloric acidRegulate pH to 1, re-use ethyl acetate extraction, the organic phase extracting is dry, and then removal of solvent under reduced pressure, can obtainThe acid of product card dragon.
Described 3-methylol-2,2-dimethyl ethylene-acetic acid can adopt above-mentioned any one synthetic 3-hydroxyl provided by the present inventionMethyl-2, the method preparation of 2-dimethyl ethylene-acetic acid (IV). Wherein, described step 2) in, to three-membered ring intermediateEthoxycarbonyl in (III) is hydrolyzed after reaction deprotection base, does not carry out post processing, directly lowers the temperature and regulates its pH valueBe 8～10, then carry out follow-up oxidation 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 cyclization anti-Should obtain product Caronic anhydride; The acid of described card dragon is prepared by the method that adopts above-mentioned any one Synthesis Card dragon acid.
Preferably, described ring-closure reaction, taking aceticanhydride as solvent, carries out under the reflux temperature of aceticanhydride, and the reaction time is 2-4h.
The synthetic route of above-mentioned Caronic anhydride is as follows:
Compared with prior art, above-mentioned carane aldehydic acid lactone provided by the present invention, the synthetic method of blocking imperial acid and Caronic anhydride, toolThere is following advantage:
1) mild condition, production security is high, is easy to suitability for industrialized production;
2) without metallic residue and other, environment there is is the waste liquid of pollution, waste residue, waste gas generates;
3) supplementary material is all cheap and easy to get, can effectively reduce costs.
Detailed description of the invention
Further set forth the present invention below in conjunction with embodiment. Should be understood that these embodiment are only for the present invention is described, and unrestrictedScope of the present invention.
Embodiment 1a
The preparation of intermediate III a:
In reaction bulb, add intermediate compound I a (54g), (catalyst is the cuprous complexing with cyanophenyl 1:1 of TFMS to copper catalystThing) (0.5g), dichloroethanes 200ml, is warming up to 60-65 DEG C. Be dissolved in two to dripping 48 grams of ethyl diazoacetate II in systemThe solution of chloroethanes 100ml drips off under the condition of warm 60-85 DEG C within keeping. Dripping off rear continuation stirs 30 minutes. DecompressionDistillation, the cut of collecting 117-120 DEG C/1kPa obtains intermediate III a60g.
Trans IIIa nuclear-magnetism:
1HNMRδ4.18(dd,J＝12,7Hz1H),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 catalyst complex compound with cyanophenyl 1:1 cuprous for TFMS, catalyst and raw material IThe weight ratio of b 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IcWeight ratio be 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IdWeight ratio be 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IeWeight ratio be 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IfWeight ratio be 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IgWeight ratio be 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IhWeight ratio be 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 catalyst is the cuprous complex compound with cyanophenyl 1:1 of TFMS, catalyst and raw material IiWeight ratio be 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 IV:
Intermediate III (8.3g), water (9ml) mixes. Stirring is warming up to 50 DEG C, adds the NaOH of 28wt% water-solubleLiquid (24.2g). At 50 DEG C, be incubated 2 hours. Obtain the water of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid)Solution. 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, suitablely dryEster products in formula. The remaining aqueous solution is regulated to pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to obtain
Nuclear magnetic data is as follows:
Ester products in cis:
1HNMR(400MHz,CDCI3)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:
1HNMR(400MHz,CDCl3)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 IV:
Intermediate III b (10g), 6N hydrochloric acid (5ml), oxolane (30ml) mixes. Stirring at room temperature 1 hour, decompression is steamedGo after oxolane, add the sodium hydrate aqueous solution (40g) of 28wt%. At 50 DEG C, be incubated 2 hours. Obtain intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid) the aqueous solution. 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, suitablely dryEster products in formula. The remaining aqueous solution is regulated to pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to obtain
Nuclear magnetic data is with implementing 2a.
Embodiment 2c
The preparation of intermediate IV:
Operation embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2d
The preparation of intermediate IV:
Intermediate III d (12g), ethanol (100ml) mixes. Add 10%Pd-C catalyst (1.0g), logical hydrogen is to formerMaterial disappears. Filter, ethanol is removed in decompression, stirs and is warming up to 50 DEG C, adds the sodium hydrate aqueous solution (24. of 28wt%2g). At 50 DEG C, be incubated 2 hours. 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, suitablely dryEster products in formula. The remaining aqueous solution is regulated to pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to obtain
Nuclear magnetic data is consistent with embodiment 2a.
Embodiment 2e
The preparation of intermediate IV:
Operation embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2e
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2f
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2h
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2i
The preparation of intermediate 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 in embodiment 2a-2i is raw material reaction liquid.
In the aqueous solution of the above-mentioned intermediate compound IV that cools to 5 DEG C, add 50% sulphur acid for adjusting pH to 8-10, add acetonitrile 5mL,0.3 gram of KBr. Add tetramethyl piperidine oxide 0.1g, drip 12% clorox the aqueous solution (chlorinity 10%,Approximately use 20 grams).
Be warmed up to 20-25 DEG C, continue to stir 30 minutes, reaction system is poured into the sodium sulfite aqueous solution of 0 DEG C, adjust with hydrochloric acidJoint pH to 5, makes to be extracted with ethyl acetate, anhydrous sodium sulfate drying, and 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(brs,1H),5.13-5.87(m,1H)。
IR:Vmax(neat):3300,1720cm-1，MS:m/z127(M-15)+and67(100％)。
Embodiment 4
The preparation of card dragon acid:
The aqueous solution that obtains intermediate compound IV in embodiment 2a-2i is raw material reaction liquid.
In the aqueous solution of the above-mentioned intermediate compound IV that cools to 5 DEG C, add 50% sulphur acid for adjusting pH to 8-10, add acetonitrile 5mL, bromineChange 0.3 gram, potassium. Add tetramethyl piperidine oxide 0.1g, (chlorinity 10%, approximately makes the aqueous solution of the clorox of dropping 12%With 20 grams). Stir 20 minutes. Regulate pH value to 4-7, drip 25% sodium chlorite aqueous solution 16g. 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, made to be extracted with ethyl acetate anhydrous sulphurAcid sodium is dry, and removal of solvent under reduced pressure obtains the imperial sour 2g of card.
1HNMR(300MHz,CD3OD)；cis-isomer1.25(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:
In reaction bulb, add aceticanhydride 200ml, block imperial sour 100g, add hot reflux 3 hours, after unnecessary aceticanhydride is removed in decompression, decompression is steamedHeat up in a steamer to obtain Caronic anhydride 70g, productive rate > 80%.
m.p.:53-55℃。1HNMR(300MHz,CDCI3)1.32(s,3H),1.41(s,3H).2.65(s,2H)。
Claims (10)
1. a synthetic method of blocking dragon acid, comprises the following steps:
1) taking the protected prenol of hydroxyl (I) as raw material; Two keys of raw material are added with the compound of formula (II)Become reaction, obtain three-membered ring intermediate (III);
2) to the reaction that is hydrolyzed of the ethoxycarbonyl on three-membered ring intermediate (III), and deprotection base R, 3-methylol obtained-2,2-dimethyl ethylene-acetic acid (IV);
3) make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating pH value is 8～10, is then oxidizedReaction; The condition of described oxidation reaction is: at-5～15 DEG C, add acetonitrile, KBr and tetramethyl piperidine oxygenCompound, and drip the aqueous solution of clorox, then stir 10～50min; Regulate again pH value to 4～7, dripThe aqueous solution of sodium chlorite, reacts after dropwising; Completely rear separation of oxidation reaction obtains the acid of product card dragon;
Step 1) and step 2) reaction scheme as follows:
In formula: R is blocking group; R1Replace or unsubstituted alkyl, optionally replace or unsubstituted assorted alkyl, appoint for optionalChoose generation or unsubstituted cycloalkyl, optionally replacement or unsubstituted Heterocyclylalkyl, optionally replacement or unsubstituted aryl and optionalReplace or unsubstituted heteroaryl;
Wherein, tetramethyl piperidine oxide and 3-methylol-2, the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5):1; Weight proportion between KBr, tetramethyl piperidine oxide, the aqueous solution of clorox and the aqueous solution of sodium chlorite is 1:(0.1～0.5): (50～100): (30～100); Chlorinity in the aqueous solution of described aqueous sodium hypochlorite solution and sodium chloriteBe respectively 5～15wt%.
2. the synthetic method of card dragon as claimed in claim 1 acid, is characterized in that, R is selected from ester class protecting group, alkyl ether is protectedProtect base and silicon ethers protecting group.
3. the synthetic method of card dragon as claimed in claim 2 acid, is characterized in that, described ester class protecting group is selected from acetyl group, benzeneFormoxyl 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 the dimethyl tert-butyl group is silica-based.
4. the synthetic method of card dragon as claimed in claim 1 acid, is characterized in that R1For methyl, ethyl, n-pro-pyl, isopropylBase, normal-butyl, the tert-butyl group or benzyl.
5. the synthetic method of card dragon acid as claimed in claim 1, is characterized in that step 1) described in addition reaction with copperClass catalyst is catalyst, and reaction dissolvent is selected from one or more the mixing in dichloroethanes, carrene or toluene,Reaction temperature is 25～110 DEG C.
6. the synthetic method of card dragon as claimed in claim 5 acid, is characterized in that, described copper class catalyst is selected from metallic copper, chlorineChange that cuprous, cuprous bromide, cuprous iodide, TFMS are cuprous, copper sulphate, Schweinfurt green, fluoroform sulphonyl copper andOne or more in copper chloride.
7. the synthetic method of the dragon of the card as described in claim 5 or 6 acid, is characterized in that described raw material and formula (II) compoundMol ratio be (0.5～1.5): 1, the weight ratio of copper class catalyst and raw material is (0.01～0.5): 1.
8. the synthetic method of card dragon as claimed in claim 1 acid, is characterized in that described step 2) in, in the middle of three-membered ringEthoxycarbonyl on body (III) is hydrolyzed after reaction deprotection base, does not carry out post processing, directly lowers the temperature and regulates itPH value is 8～10, then carries out follow-up oxidation reaction.
9. a synthetic method for Caronic anhydride, comprises step: adopt as sour in described Synthesis Card dragon arbitrary in claim 1-8Method prepares the acid of card dragon; Use the imperial acid of described card to carry out ring-closure reaction and obtain product Caronic anhydride.
10. the synthetic method of Caronic anhydride as claimed in claim 9, is characterized in that, described ring-closure reaction is taking aceticanhydride as solvent,Under the reflux temperature of aceticanhydride, carry out, the reaction time is 2～4h.
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| CN114163375B (en) * | 2021-12-10 | 2023-09-05 | 浙江新和成股份有限公司 | Synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or derivative thereof |
| CN114539048B (en) * | 2022-02-18 | 2023-09-08 | 新发药业有限公司 | Carlong anhydride intermediate and preparation method of Carlong anhydride |
| 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 |
| WO2023175526A1 (en) * | 2022-03-16 | 2023-09-21 | Laurus Labs Limited | Process for preparation of azabicyclo [3.1.0] hexane intermediates |
| 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 |
| 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 |
| 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 |
| 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 |
| CN115304538A (en) * | 2022-08-16 | 2022-11-08 | 北京京宇复瑞科技集团有限责任公司 | Method for preparing 6,6-dimethyl-3-azabicyclo [3.1.0] hexane from isopentenol |
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