CN103193582A - Preparation method of cyclopropane compounds - Google Patents
Preparation method of cyclopropane compounds Download PDFInfo
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- CN103193582A CN103193582A CN201310130880XA CN201310130880A CN103193582A CN 103193582 A CN103193582 A CN 103193582A CN 201310130880X A CN201310130880X A CN 201310130880XA CN 201310130880 A CN201310130880 A CN 201310130880A CN 103193582 A CN103193582 A CN 103193582A
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Abstract
The invention discloses a preparation method of cyclopropane compounds. The structural formula of the cyclopropane compounds is shown in a formula I. According to the preparation method, olefins shown as a formula II have cyclopropanation reaction under the actions of a methylene transfer agent and an additive to generate cyclopropane compounds shown as the formula I, wherein the methylene transfer agent is a mixture of diethylzinc and diiodomethane, and the additive is a mixture of acid and ether. According to the preparation method provided by the invention, olefins with different structures are taken as substrates, and the mixture of diethylzinc solution and diiodomethane is taken as the methylene agent, so that the cyclopropane compounds are finally obtained with high yield under the synergistic effect of catalytic amount of trichloroacetic acid and equivalent amount of 1, 2-dimethoxyethane. The preparation method is mild and safe in reaction conditions, easy for large-scale operation, wide in the using range of the substrates and high in yield and has great industrialization potential.
Description
Technical field
The present invention relates to a kind of preparation method of cyclopropanes compound.
Background technology
Because cyclopropanes compound special physicochemical character, make the cyclopropanes compound have important using value in fields such as medicine, agriculturals, much the pharmaceutical activity molecules all are the cyclopropanes compounds or derive from cyclopropane.In organic chemistry, the cyclopropanes compound can be used as important intermediate.
The method for preparing at present the cyclopropanes compound in organic synthesis mainly contains the cycloaddition of metal catalytic, intramolecular substitution reaction, rearrangement reaction and Simmons-Smith cyclopropanization reaction etc.Wherein the Simmons-Smith cyclopropanization reaction is the Cyclopropanated method of a kind of effectively alkene, by be added into acid or alcohol in reaction system, such as trifluoroacetic acid, can greatly improve the efficient of cyclopropanization reaction.But this method often needs excessive acid, keeps high reactivity.Such as: for the toluylene of inertia, need to use the trifluoroacetic acid of 4 equivalents just can obtain higher cyclopropane compound productive rate.In addition, the use of a large amount of acid makes the system slant acidity to cause this method not too to be fit to acid-sensitive compounds.Therefore, a kind of Cyclopropanation process of the acid of catalytic amount that uses of exploitation seems particularly necessary.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of cyclopropanes compound, the substrate scope of this method is wide, reaction conditions is gentle, easy and simple to handle, productive rate is high, is a kind of method with suitability for industrialized production potentiality,
The preparation method of cyclopropanes compound comprises the steps: shown in the formula I provided by the present invention
Alkene shown in the formula II through cyclopropanization reaction, namely obtains cyclopropanes compound shown in the formula I under the effect of methylene radical transfering reagent and additive;
Described methylene radical transfering reagent is the mixture of zinc ethyl and methylene iodide, and described additive is the mixture of acid and ether;
In formula I and the formula II, R
1, R
2, R
3And R
4All be selected from hydrogen atom, methyl, ethyl, n-pentyl, n-octyl, phenyl, siloxy, substituted alkyl and the substituted-phenyl any; Described substituted alkyl is that carbonatoms is 1～8 alkyl, and the substituting group in the described substituted alkyl is hydroxyl, siloxy, ester group or phenyl; Described substituted-phenyl is monosubstituted phenyl or disubstituted phenyl, and the substituting group in the described substituted-phenyl is methyl, normal-butyl, the tertiary butyl, methoxyl group, ester group, cyano group, fluorine atom, chlorine atom or bromine atoms.
Among the above-mentioned preparation method, the solvent of described cyclopropanization reaction is methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride, toluene, acetonitrile and the normal hexane any.
Among the above-mentioned preparation method, the temperature of described cyclopropanization reaction is-40～40 ℃, specifically can be 25 ℃; The time of described cyclopropanization reaction is 2～48 hours, specifically can be 2 hours～24 hours, 2 hours, 3 hours, 4 hours, 18 hours or 24 hours.
Among the above-mentioned preparation method, described acid is trichoroacetic acid(TCA), trifluoroacetic acid, pyruvic acid, acetic acid, acetoxy acid, methoxyacetic acid, phenylformic acid, 2,4, in 6-Trichlorophenol and the trifluoroethanol any.
Among the above-mentioned preparation method, described ether is ether, tetrahydrofuran (THF), dioxane, t-butyl methyl ether, n-butyl ether, 1, in 2-glycol dimethyl ether, 1-methoxyl group-2-acetoxyl group ethane and the 2-methoxyacetic acid ethyl ester any.
Among the above-mentioned preparation method, the mol ratio of alkene is 1～3:2～6:0～3:0～10:1 shown in described zinc ethyl, described methylene iodide, described acid, described ether and the formula II, and the addition of described acid and described ether is all non-vanishing, specifically can be 2:4:0.2:1:1.
Among the above-mentioned preparation method, the volumetric molar concentration of alkene shown in the formula II in the reaction system of described cyclopropanization reaction is 0.05～0.5 mol, as 0.15 mol.
Among the above-mentioned preparation method, at first add dilute hydrochloric acid or saturated solution of sodium bicarbonate cancellation reaction that concentration is 0.1～1.0 mol, add water again and dilute, extract with organic solvent then, the organic phase that obtains after the extraction is carried out drying with siccative, remove by filter siccative, organic phase is spin-dried for the back column chromatography for separation and obtains the cyclopropanes compound, as being that eluent carries out column chromatography with the Skellysolve A;
Described organic solvent is methylene dichloride or ether;
Described siccative is sodium sulfate or sal epsom.
The preparation method of cyclopropanes compound provided by the invention, alkene with different structure is substrate, adopting zinc ethyl solution and methylene iodide is methylene reagents, at 1 of the trichoroacetic acid(TCA) of catalytic amount and equivalent, under the 2-glycol dimethyl ether synergy, final high yield obtains cyclopropane compound.The gentle safety of this method reaction conditions is easy to a large amount of operations, and the substrate use range is wide, and the productive rate height has bigger industrialization potentiality.Cyclopropanes compound provided by the present invention is the important structure unit of the important pharmaceutical intermediate of a class and medicine, can prepare medicine roflumilast (roflumilast) by the organic synthesis of maturations such as etherificate and esterification as it, be used for the treatment of chronic obstructive pulmonary disease (COPD), be worth so this method has important use in synthetic cyclopropanes compound.
Embodiment
Employed experimental technique is ordinary method if no special instructions among the following embodiment.
Used material, reagent etc. if no special instructions, all can obtain from commercial channels among the following embodiment.
Embodiment 1, synthesis of trans 1-methyl-2-benzyl ring propane (see structural formula I-a)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (2.0mL) joins in the schlenk pipe, adds zinc ethyl solution (2.0mL, 2.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (1.080g, methylene dichloride 4.0mmol) (1.0mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0326g, 0.20mmol) and DME (0.090g, methylene dichloride 1.0mmol) (1.0mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (0.121g, methylene dichloride 1.0mmol) (1.0mL) solution dropwise joins in the reaction solution alkene (shown in formula II-a).Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (10mL) cancellation reaction, water (10mL) dilution, CH
2Cl
2(10mL x3) extraction three times merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A), obtain 0.1012g colourless liquid cyclopropane (shown in formula I-a), yield 77%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.27-7.19 (m, 2H), 7.11 (t, J=7.2Hz, 1H), 7.02 (d, J=7.2Hz, 2H), 1.56 (dt, J=8.8,4.8Hz, 1H), 1.17 (d, J=6.0Hz, 3H), 1.10-0.99 (m, 1H), 0.91-0.82 (m, 1H), 0.76-0.69 (m, 1H);
13C NMR (100MHz, CDCl
3) δ 144.3,128.4,125.6,125.3,24.5,19.3,18.2,17.8.
Embodiment 2, synthesis of trans (2-benzyl ring propyl)-methyl alcohol (the formula I-b)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-b) (0.069g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 2h, use saturated NaHCO
3Solution (5mL) cancellation reaction is stirred 20min under the room temperature, after water (10mL) dilution, and CH
2Cl
2(15mL x2) extracting twice merges organic interdependent time and uses saturated NH
4Cl solution (10mL), saturated Na
2SO
3Solution (10mL), saturated NaHCO
3(10mLx2) with the brine washing.Organic phase is through Na
2SO
4After the drying, filter, concentrate, (silica gel, eluent is column chromatography purification: petrol ether/ethyl acetate=10/1-5/1), obtain 0.0716g colourless liquid cyclopropane (shown in formula I-b), yield 97%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.25 (t, J=7.2Hz, 2H), 7.15 (t, J=7.2Hz, 1H), 7.06 (d, J=7.2Hz, 2H), 3.66-3.53 (m, 2H), 1.81 (dt, J=9.2,4.8Hz, 1H), 1.74 (br s, 1H), 1.50-1.39 (m, 1H), 1.01-0.86 (m, 2H);
13C NMR (100MHz, CDCl
3) δ 142.6,128.5,126.0,125.8,66.7,25.5,21.5,14.1.
Embodiment 3, synthesis of trans 1-[(tertiary butyl dimethyl Si base) methyl]-2-benzyl ring propane (the formula I-c)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-c) (0.124g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, saturated NH
4Cl (10mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (eluent is column chromatography purification: Skellysolve A/methylene dichloride=10/1), obtain 0.1251g colourless liquid cyclopropane (shown in formula I-c), yield 95%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.32-7.21 (m, 2H), 7.14 (t, J=7.2Hz, 1H), 7.07 (d, J=7.2Hz, 2H), 3.72 (dd, J=10.8,5.6Hz, 1H), 3.62 (dd, J=10.8,6.0Hz, 1H), 1.80 (dt, J=8.4,4.0Hz, 1H), 1.41-1.31 (m, 1H), 0.97-0.88 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H);
13C NMR (100MHz, CDCl
3) δ 143.3,128.5,126.1,125.6,66.1,26.2,25.5,21.0,18.7,13.9 ,-4.9.
Embodiment 4, trans 1-p-methoxyphenyl-2-phenyl-cyclopropane (see structural formula I-d)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-d) (0.1073g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A/ether=50/1), obtain 0.1053g white solid cyclopropane (shown in formula I-d), yield 94%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.28 (t, J=7.6Hz, 2H), 7.17 (t, J=7.2Hz, 1H), 7.13 (d, J=7.2Hz, 2H), 7.08 (d, J=8.4Hz, 2H), 6.84 (d, J=8.8Hz, 2H), 3.79 (s, 3H), 2.17-2.04 (m, 2H), 1.39 (dd, J=7.6,6.8Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 158.0,142.9,134.7,128.6,127.1,125.9,125.8,114.0,55.5,27.7,27.6,18.1; HRMS Calcd for C
16H
17O (M+H): 225.1274; Found:225.1270.
Embodiment 5,3-(2-octyl cyclopropyl) methyl caprylate (sees structural formula I-e)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-e) (0.1560g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A/methylene dichloride=5/1), obtain 0.1501g colourless liquid cyclopropane (shown in formula I-e), yield 97%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 3.66 (s, 3H), 2.30 (t, J=7.6Hz, 2H), 1.64-1.57 (m, 2H), 1.42-1.04 (m, 24H), 0.87 (t, J=6.8Hz, 3H), 0.40-0.30 (m, 2H), 0.16-0.09 (m, 2H);
13C NMR (100MHz, CDCl
3) δ 174.6,51.7,34.6,34.5,34.3,32.1,29.9,29.82,29.75,29.6,29.5,29.4,25.2,22.9,19.0,18.9,14.4,12.0; HRMS Calcd for C
20H
39O
2(M+H): 311.2945; Found:311.2946.
Embodiment 6, cis 1,2-phenylbenzene cyclopropane (is seen structural formula I-f)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-f) (0.093g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 24h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A/methylene dichloride=30/1), obtain 0.069g colourless liquid cyclopropane (shown in formula I-f), yield 71%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.17-7.04 (m, 6H), 6.98 (d, J=7.6Hz, 4H), 2.52 (dd, J=8.4,6.4Hz, 2H), 1.50 (td, J=8.8,5.6Hz, 1H), 1.41 (td, J=6.4,5.6Hz, 1H);
13C NMR (100MHz, CDCl
3) δ 138.6,129.2,127.8,125.8,24.5,11.6.
Embodiment 7, cis 2-hexyl-1-carboxymethyl cyclopropane (is seen structural formula I-g)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-g) (0.075g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 4h, use saturated NaHCO
3Solution (5mL) cancellation reaction is stirred 20min under the room temperature, after water (10mL) dilution, and CH
2Cl
2(15mL x2) extracting twice merges organic interdependent time and uses saturated NH
4Cl solution (10mL), saturated Na
2SO
3Solution (10mL), saturated NaHCO
3(10mL x2) and brine washing.Organic phase is through Na
2SO
4After the drying, filter, concentrate, (silica gel, eluent is column chromatography purification: petrol ether/ethyl acetate=10/1), obtain 0.078g colourless liquid cyclopropane (shown in formula I-g), yield 99%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 3.63 (dd, J=10.8,7.2Hz, 1H), 3.57 (dd, J=10.8,8.4Hz, 1H), 1.49-1.15 (m, 11H), 1.15-1.03 (m, 1H), 0.90-0.80 (m, 1H), 0.87 (t, J=6.8Hz, 3H), 0.69 (td, J=8.4,4.8Hz, 1H) ,-0.05 (q, J=5.2Hz, 1H);
13C NMR (100MHz, CDCl
3) δ 63.5,32.1,30.3,29.4,28.8,22.9,18.3,16.4,14.3,9.7.
Embodiment 8, benzo [2,3] dicyclo [3.1.0] hexane (see structural formula I-h)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-h) (0.060g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A), obtain 0.0612g colourless liquid cyclopropane (shown in formula I-h), yield 94%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.33-7.28 (m, 1H), 7.18-7.05 (m, 3H), 3.19 (dd, J=16.8,6.8Hz, 1H), 2.94 (d, J=16.8Hz, 1H), 2.40-2.33 (m, 1H), 1.90-1.81 (m, 1H), 1.06 (td, J=8.0,4.4Hz, 1H), 0.07 (td, J=4.4,3.6Hz, 1H);
13C NMR (100MHz, CDCl
3) δ 147.3,142.2,126.1,125.7,125.5,123.6,35.7,24.1,16.9,16.2.
Embodiment 9, the bromophenyl cyclopropane (is seen structural formula I-i)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-i) (0.094g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A), obtain 0.070g colourless liquid cyclopropane (shown in formula I-i), yield 71%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.36 (d, J=8.4Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 1.90-1.81 (m, 1H), 1.10-0.94 (m, 2H), 0.70-0.63 (m, 2H);
13C NMR (100MHz, CDCl
3) δ 143.3,131.4,127.6,119.0,15.2,9.6; HRMS Calcd for C
9H
8Br (M-H): 194.9804; Found:194.9804.
Embodiment 10,1-methyl isophthalic acid-benzyl ring propane (is seen structural formula I-j)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-j) (0.060g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A), obtain 0.0542g colourless liquid cyclopropane (shown in formula I-i), yield 82%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.31-7.22 (m, 4H), 7.18-7.12 (m, 1H), 1.40 (s, 3H), 0.88-0.84 (m, 2H), 0.75-0.70 (m, 2H);
13C NMR (100MHz, CDCl
3) δ 147.3,128.4,126.9,125.6,25.9,19.9,15.9.
Embodiment 11,1-phenyl dicyclo [4.1.0] pentane (see structural formula I-k)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-k) (0.079g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 18h, 0.1N HCl (5mL) cancellation reaction, CH
2Cl
2(10mL x3) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent is column chromatography purification: Skellysolve A), obtain 0.0802g colourless liquid cyclopropane (shown in formula I-k), yield 93%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.31-7.22 (m, 4H), 7.18-7.11 (m, 1H), 2.14-2.00 (m, 2H), 1.98-1.89 (m, 1H), 1.73-1.61 (m, 1H), 1.52-1.17 (m, 5H), 0.94 (dd, J=9.2,4.4Hz, 1H), 0.63 (t, J=5.2Hz, 1H);
13C NMR (100MHz, CDCl
3) δ 149.8,128.4,127.6,125.6,31.7,24.7,24.2,21.88,21.87,19.2,18.5.
Embodiment 12, synthesizing cis 2-methyl isophthalic acid-phenyl-1-(trimethylsiloxy group) cyclopropane (sees structural formula I-l)
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (1.0mL) joins in the schlenk pipe, adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 5min, (0.540g, methylene dichloride 2.0mmol) (0.5mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) and DME (0.045g, methylene dichloride 0.5mmol) (0.5mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-l) (0.104g, methylene dichloride 0.5mmol) (0.5mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 3h, use saturated NaHCO
3Solution (5mL) cancellation reaction is stirred 20min under the room temperature, after water (10mL) dilution, and CH
2Cl
2(15mL x2) extracting twice merges organic interdependent time and uses saturated NH
4Cl solution (10mL), saturated Na
2SO
3Solution (10mL), saturated NaHCO
3(10mL x2) and brine washing.Organic phase is through Na
2SO
4After the drying, filter, concentrate, column chromatography purification (silica gel, eluent is: Skellysolve A contains 1% triethylamine) obtains 0.0995g colourless liquid cyclopropane (shown in formula I-l), yield 90%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.37-7.25 (m, 4H), 7.25-7.17 (m, 1H), 1.38 (dd, J=9.6,6.0Hz, 1H), 1.29 (d, J=6.0Hz, 3H), 1.08-0.97 (m, 1H), 0.80 (t, J=6.4Hz, 1H), 0.14 (s, 9H);
13C NMR (100MHz, CDCl
3) δ 146.1,128.2,126.0,124.8,61.1,23.1,22.4,13.1,1.3.
Embodiment 13, synthetic Roflumilast(see the structural formula V) key intermediate (see structural formula I-m)
Under 0 ° of C, thionyl chloride (9.52g, 80.0mmol) dropwise add 3,4-resorcylic acid (3.08g, 20.0mmol) in the methanol solution of (shown in III) (50mL), 30min consuming time.After 50 ° of C stirred 8h, cool to room temperature concentrated, and residuum is dissolved in the anhydrous propanone (30mL), adds K then
2CO
3(13.8g, 100.0mmol).Stir 10min under the room temperature, and the adding allyl bromide 98 (7.26g, 60.0mmol).Reaction solution at room temperature reacts and spends the night, and concentrates to remove acetone, regulates aqueous solution pH=7 with 1N HCl, and EtOAc (30mL x3) extraction three times merges organic phase and washs Na with brine
2SO
4Drying is filtered, and concentrates column separating purification (silica gel, eluent: petrol ether/ethyl acetate=20/1), obtain 4.76g colourless liquid (compound shown in the formula IV), productive rate 96%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.64 (dd, J=8.8,2.0Hz, 1H), 7.56 (d, J=2.0Hz, 1H), 6.89 (d, J=8.8Hz, 1H), 6.15-6.01 (m, 2H), 5.48-5.39 (m, 2H), 5.34-5.27 (m, 2H), 4.69-4.63 (m, 4H), 3.88 (s, 3H);
13C NMR (100MHz, CDCl
3) δ 167.0,152.6,148.1,133.1,132.9,123.9,122.9,118.3,118.2,114.7,112.5,70.0,69.8,52.2; HRMS Calcd for C
14H
17O
4(M+H): 249.1121; Found:249.1123.
Add in the round-bottomed flask compound (shown in the formula IV) (4.60g, 18.5mmol), 10%Pd/C (0.64g), K
2CO
3(20g) and methyl alcohol (180g), reaction solution stirs 5h, diatomite filtration, DCM (20mL) rinse at 50 ° of C, concentrate and to remove methyl alcohol, with 1N HCl (～150mL) regulate pH=7, DCM (30mLx2) extracting twice, after merging organic phase, water and salt solution washing successively, Na
2SO
4Drying is filtered, and concentrates, and (silica gel, eluent: petrol ether/ethyl acetate=20/1), obtain 2.64g white solid (compound shown in formula II-m), yield is 69% to column separating purification.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.62 (dd, J=8.4,1.6Hz, 1H), 7.54 (d, J=1.6Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.25 (s, 1H), 6.10-5.97 (m, 1H), 5.47-5.39 (m, 1H), 5.32 (d, J=10.4Hz, 1H), 4.63 (d, J=5.2Hz, 2H), 3.87 (s, 3H);
13C NMR (100MHz, CDCl
3) δ 167.0,150.4,145.3,132.5,124.5,122.4,119.0,114.5,113.3,70.1,52.2; HRMS Calcd for C
11H
13O
4(M+H): 209.0808; Found:209.0803.
Under the room temperature nitrogen environment, the methylene dichloride of fresh distillation (14.0mL) joins in the schlenk pipe, adds zinc ethyl solution (14.0mL, 14.0mmol) (1.0M in hexane) then.Behind-40 ° of C cooling 10min, (7.50g, methylene dichloride 28.0mmol) (7.0mL) solution dropwise joins in the schlenk pipe methylene iodide.Behind-40 ° of C reaction 1h, trichoroacetic acid(TCA) (0.228g, 1.40mmol) and DME (0.631g, methylene dichloride 7.0mmol) (7.0mL) solution joins in the reaction solution, temperature of reaction is raised to-15 ° of C and stirs 1h under this temperature.Under-15 ° of C, (the formula II-m) (1.46g, methylene dichloride 0.5mmol) (7.0mL) solution dropwise joins in the reaction solution alkene.Then the schlenk pipe is transferred in the oil bath pan of 25 ° of C and reacted 24h, 0.1N HCl (100mL) cancellation reaction, CH
2Cl
2(20mL x4) extraction merges organic phase brine washing, Na
2SO
4Drying is filtered, and concentrates column chromatography purification (silica gel, eluent: petrol ether/ethyl acetate=20/1), obtain 1.39g white solid cyclopropane (shown in formula I-m), yield 89%.
The structural identification result is as follows:
1H NMR (400MHz, CDCl
3) δ 7.62 (dd, J=8.4,1.6Hz, 1H), 7.50 (d, J=1.6Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.16 (s, 1H), 3.92 (d, J=6.8Hz, 2H), 3.87 (s, 3H), and 1.35-1.22 (m, 1H), 0.71-0.61 (m, 2H), 0.40-0.31 (m, 2H);
13C NMR (100MHz, CDCl
3) δ 167.1,150.4,145.7,124.2,122.2,114.2,113.0,74.3,52.1,10.3,3.5; HRMS Calcd for C
12H
15O
4(M+H): 223.0965; Found:223.0962.
Shown in above-mentioned equation, cyclopropane compound can be for the synthesis of important medicine intermediate Roflumilast, shown in V shown in formula I-m that present embodiment synthesizes.
Claims (9)
1. the preparation method of cyclopropanes compound shown in the formula I comprises the steps:
Alkene shown in the formula II through cyclopropanization reaction, namely obtains cyclopropanes compound shown in the formula I under the effect of methylene radical transfering reagent and additive;
Described methylene radical transfering reagent is the mixture of zinc ethyl and methylene iodide, and described additive is the mixture of acid and ether;
In formula I and the formula II, R
1, R
2, R
3And R
4All be selected from hydrogen atom, methyl, ethyl, n-pentyl, n-octyl, phenyl, siloxy, substituted alkyl and the substituted-phenyl any; Described substituted alkyl is that carbonatoms is 1～8 alkyl, and the substituting group in the described substituted alkyl is hydroxyl, siloxy, ester group or phenyl; Described substituted-phenyl is monosubstituted phenyl or disubstituted phenyl, and the substituting group in the described substituted-phenyl is methyl, normal-butyl, the tertiary butyl, methoxyl group, ester group, cyano group, fluorine atom, chlorine atom or bromine atoms.
2. preparation method according to claim 1, it is characterized in that: the solvent of described cyclopropanization reaction is methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride, toluene, acetonitrile and the normal hexane any.
3. preparation method according to claim 1 and 2, it is characterized in that: the temperature of described cyclopropanization reaction is-40～40 ℃; The time of described cyclopropanization reaction is 2～48 hours.
4. according to each described preparation method among the claim 1-3, it is characterized in that: described acid is trichoroacetic acid(TCA), trifluoroacetic acid, pyruvic acid, acetic acid, acetoxy acid, methoxyacetic acid, phenylformic acid, 2, in 4,6-Trichlorophenol and the trifluoroethanol any.
5. according to each described preparation method among the claim 1-4, it is characterized in that: described ether is ether, tetrahydrofuran (THF), dioxane, t-butyl methyl ether, n-butyl ether, 1, in 2-glycol dimethyl ether, 1-methoxyl group-2-acetoxyl group ethane and the 2-methoxyacetic acid ethyl ester any.
6. according to each described preparation method among the claim 1-5, it is characterized in that: the mol ratio of alkene is 1～3:2～6:0～3:0～10:1 shown in described zinc ethyl, described methylene iodide, described acid, described ether and the formula II, and the addition of described acid and described ether is all non-vanishing.
7. according to each described preparation method among the claim 1-6, it is characterized in that: the volumetric molar concentration of alkene shown in the formula II in the reaction system of described cyclopropanization reaction is 0.05～0.5 mol.
8. want each described preparation method among the 1-7 according to right, it is characterized in that: described method also comprise to cyclopropanes compound shown in the formula I extract, the step of drying and column chromatography for separation.
9. want 8 described preparation methods according to right, it is characterized in that: the solvent of described extraction is methylene dichloride or ether;
The siccative of described drying is sodium sulfate or sal epsom;
The eluent of described column chromatography for separation is Skellysolve A.
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| Title |
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| JON C. LORENZ ET AL.: "A Novel Class of Tunable Zinc Reagents (RXZnCH2Y) for Efficient Cyclopropanation of Olefins", 《J. ORG. CHEM.》, vol. 69, 17 December 2003 (2003-12-17), pages 327 - 334 * |
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