CN103193582B - Preparation method of cyclopropane compounds - Google Patents
Preparation method of cyclopropane compounds Download PDFInfo
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- CN103193582B CN103193582B CN201310130880.XA CN201310130880A CN103193582B CN 103193582 B CN103193582 B CN 103193582B CN 201310130880 A CN201310130880 A CN 201310130880A CN 103193582 B CN103193582 B CN 103193582B
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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
Due to the physicochemical property that cyclopropanes compound is special, make cyclopropanes compound have important using value in the field such as medical, agriculture, a lot of pharmaceutical activity molecule is all cyclopropanes compound or derives from cyclopropane.In organic chemistry, cyclopropanes compound can as important intermediate.
The method preparing cyclopropanes compound at present in organic synthesis mainly contains the cycloaddition of metal catalytic, intramolecular substitution reaction, rearrangement reaction and Simmons-Smith cyclopropanization reaction etc.Wherein Simmons-Smith cyclopropanization reaction is a kind of Cyclopropanated method of effectively alkene, and by being added into acid or alcohol in reaction system, such as trifluoroacetic acid, greatly can improve the efficiency of cyclopropanization reaction.But the method often needs excessive acid, maintain high reactivity.Such as: for the toluylene of inertia, the trifluoroacetic acid of use 4 equivalent is needed just can to obtain higher cyclopropane compound productive rate.In addition, the use of a large amount of acid, makes system slant acidity, causes the method to be not too applicable to acid-sensitive compounds.Therefore, develop a kind of Cyclopropanation process of the acid of catalytic amount that uses and seem particularly necessary.
Summary of the invention
The object of this invention is to provide a kind of preparation method of cyclopropanes compound, the substrate spectrum of the method is wide, reaction conditions is gentle, easy and simple to handle, productive rate is high, is a kind of method with industrial production potential,
Shown in formula I provided by the present invention, the preparation method of cyclopropanes compound, comprises the steps:
Alkene shown in formula II through cyclopropanization reaction, namely obtains cyclopropanes compound shown in 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 formula II, R
1, R
2, R
3and R
4all be selected from any one in hydrogen atom, methyl, ethyl, n-pentyl, n-octyl, phenyl, siloxy, substituted alkyl and substituted-phenyl; Described substituted alkyl to be carbonatoms be 1 ~ 8 alkyl, the substituting group in described substituted alkyl is hydroxyl, siloxy, ester group or phenyl; Described substituted-phenyl is monosubstituted phenyl or disubstituted phenyl, and the substituting group in described substituted-phenyl is methyl, normal-butyl, the tertiary butyl, methoxyl group, ester group, cyano group, fluorine atom, chlorine atom or bromine atoms.
In above-mentioned preparation method, the solvent of described cyclopropanization reaction is any one in methylene dichloride, trichloromethane, 1,2-ethylene dichloride, toluene, acetonitrile and normal hexane.
In above-mentioned preparation method, the temperature of described cyclopropanization reaction is-40 ~ 40 DEG C, specifically can be 25 DEG C; 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.
In above-mentioned preparation method, described acid is any one in trichoroacetic acid(TCA), trifluoroacetic acid, pyruvic acid, acetic acid, acetoxy acid, methoxyacetic acid, phenylformic acid, 2,4,6-Trichlorophenols and trifluoroethanol.
In above-mentioned preparation method, described ether is any one in ether, tetrahydrofuran (THF), dioxane, t-butyl methyl ether, n-butyl ether, 1,2-glycol dimethyl ether, 1-methoxyl group-2-acetoxyl group ethane and 2-ethyl methoxyacetate.
In above-mentioned preparation method, shown in described zinc ethyl, described methylene iodide, described acid, described ether and formula II, the mol ratio of alkene is 1 ~ 3:2 ~ 6:0 ~ 3:0 ~ 10:1, and the addition of described acid and described ether is all non-vanishing, specifically can be 2:4:0.2:1:1.
In above-mentioned preparation method, the volumetric molar concentration of alkene shown in formula II in the reaction system of described cyclopropanization reaction is 0.05 ~ 0.5 mol/L, as 0.15 mol/L.
In above-mentioned preparation method, first dilute hydrochloric acid or saturated solution of sodium bicarbonate cancellation reaction that concentration is 0.1 ~ 1.0 mol/L is added, add water again to dilute, then extract with organic solvent, the organic phase siccative obtained after extraction carries out drying, cross and filter siccative, organic phase is spin-dried for rear column chromatography for separation and obtains cyclopropanes compound, as being that eluent carries out column chromatography with Skellysolve A;
Described organic solvent is methylene dichloride or ether;
Described siccative is sodium sulfate or magnesium sulfate.
The preparation method of cyclopropanes compound provided by the invention, with the alkene of different structure for substrate, zinc ethyl solution and methylene iodide is adopted to be methylene reagents, in the trichoroacetic acid(TCA) of catalytic amount and 1 of equivalent, under 2-glycol dimethyl ether synergy, final high yield obtains cyclopropane compound.The gentle safety of the method reaction conditions, be easy to a large amount of operation, substrate use range is wide, and productive rate is high, has larger industrialization potential.Cyclopropanes compound provided by the present invention is the important feature unit of the important pharmaceutical intermediate of a class and medicine, as it prepares medicine roflumilast (roflumilast) by the organic synthesis that etherificate and esterification etc. are ripe, be used for the treatment of chronic obstructive pulmonary disease (COPD), in this way in synthesis cyclopropanes compound, there is important using value.
Embodiment
The experimental technique used in following embodiment if no special instructions, is ordinary method.
Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment 1, synthesis of trans 1-methyl-2-cyclo-propane (see structural formula I-a)
Under room temperature under nitrogen environment, the methylene dichloride (2.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (2.0mL, 2.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (1.0mL) dropwise of methylene iodide (1.080g, 4.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0326g, 0.20mmol) join in reaction solution with methylene dichloride (1.0mL) solution of DME (0.090g, 1.0mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (1.0mL) dropwise of alkene (shown in formula II-a) (0.121g, 1.0mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (10mL) cancellation is reacted, and water (10mL) dilutes, CH
2cl
2(10mL x3) extracts three times, merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A), obtains 0.1012g colourless liquid cyclopropane (shown in formula I-a), yield 77%.
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-cyclo-propane base)-methyl alcohol (formula I-b)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-b) (0.069g, 0.5mmol) joins in reaction solution.Then schlenk pipe is transferred in the oil bath pan of 25 ° of C and react 2h, use saturated NaHCO
3solution (5mL) cancellation is reacted, stirred at ambient temperature 20min, 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 brine washing.Organic phase is through Na
2sO
4after drying, filter, concentrated, column chromatography purification (silica gel, eluent is: petrol ether/ethyl acetate=10/1-5/1), obtains 0.0716g colourless liquid cyclopropane (shown in formula I-b), yield 97%.
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-cyclo-propane (formula I-c)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-c) (0.124g, 0.5mmol) joins in reaction solution.Then schlenk pipe is transferred in the oil bath pan of 25 ° of C and react 18h, saturated NH
4cl (10mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (eluent is: Skellysolve A/methylene dichloride=10/1), obtains 0.1251g colourless liquid cyclopropane (shown in formula I-c), yield 95%.
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 room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-d) (0.1073g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A/ether=50/1), obtains 0.1053g white solid cyclopropane (shown in formula I-d), yield 94%.
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 (see structural formula I-e)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-e) (0.1560g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A/methylene dichloride=5/1), obtains 0.1501g colourless liquid cyclopropane (shown in formula I-e), yield 97%.
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 (see structural formula I-f)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-f) (0.093g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 24h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A/methylene dichloride=30/1), obtains 0.069g colourless liquid cyclopropane (shown in formula I-f), yield 71%.
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 (see structural formula I-g)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-g) (0.075g, 0.5mmol) joins in reaction solution.Then schlenk pipe is transferred in the oil bath pan of 25 ° of C and react 4h, use saturated NaHCO
3solution (5mL) cancellation is reacted, stirred at ambient temperature 20min, 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 wash.Organic phase is through Na
2sO
4after drying, filter, concentrated, column chromatography purification (silica gel, eluent is: petrol ether/ethyl acetate=10/1), obtains 0.078g colourless liquid cyclopropane (shown in formula I-g), yield 99%.
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 room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-h) (0.060g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A), obtains 0.0612g colourless liquid cyclopropane (shown in formula I-h), yield 94%.
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, to bromophenyl cyclopropane (see structural formula I-i)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-i) (0.094g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A), obtains 0.070g colourless liquid cyclopropane (shown in formula I-i), yield 71%.
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-cyclo-propane (see structural formula I-j)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-j) (0.060g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A), obtains 0.0542g colourless liquid cyclopropane (shown in formula I-i), yield 82%.
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 room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-k) (0.079g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 18h, 0.1N HCl (5mL) cancellation is reacted, CH
2cl
2(10mL x3) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A), obtains 0.0802g colourless liquid cyclopropane (shown in formula I-k), yield 93%.
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 (see structural formula I-l)
Under room temperature under nitrogen environment, the methylene dichloride (1.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (1.0mL, 1.0mmol) (1.0M in hexane).After-40 ° of C cool 5min, methylene dichloride (0.5mL) dropwise of methylene iodide (0.540g, 2.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.0163g, 0.10mmol) join in reaction solution with methylene dichloride (0.5mL) solution of DME (0.045g, 0.5mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (0.5mL) dropwise of alkene (formula II-l) (0.104g, 0.5mmol) joins in reaction solution.Then schlenk pipe is transferred in the oil bath pan of 25 ° of C and react 3h, use saturated NaHCO
3solution (5mL) cancellation is reacted, stirred at ambient temperature 20min, 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 wash.Organic phase is through Na
2sO
4after drying, filter, concentrated, column chromatography purification (silica gel, eluent is: Skellysolve A, containing 1% triethylamine), obtains 0.0995g colourless liquid cyclopropane (shown in formula I-l), yield 90%.
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, synthesis Roflumilast(see structural formula V) key intermediate (see structural formula I-m)
Under 0 ° of C, thionyl chloride (9.52g, 80.0mmol) dropwise adds in the methanol solution (50mL) of PCA (3.08g, 20.0mmol) (such as formula III Suo Shi), 30min consuming time.After 50 ° of C stir 8h, cool to room temperature, concentrated, residuum is dissolved in anhydrous propanone (30mL), then adds K
2cO
3(13.8g, 100.0mmol).Stirred at ambient temperature 10min, adds allyl bromide 98 (7.26g, 60.0mmol).Reaction solution at room temperature reacts and spends the night, concentrated removing acetone, and regulate aqueous solution pH=7 with 1N HCl, EtOAc (30mL x3) extracts three times, merges organic phase brine and washs, Na
2sO
4drying, filters, and concentrated, column separating purification (silica gel, eluent: petrol ether/ethyl acetate=20/1), obtains 4.76g colourless liquid (shown in formula IV compound), productive rate 96%.
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.
Compound (shown in formula IV) (4.60g, 18.5mmol) is added, 10%Pd/C (0.64g), K in round-bottomed flask
2cO
3(20g) with methyl alcohol (180g), reaction solution stirs 5h at 50 ° of C, diatomite filtration, DCM (20mL) rinse, concentrated removing methyl alcohol, regulates pH=7 with 1N HCl (~ 150mL), DCM (30mLx2) extracting twice, after merging organic phase, use water and brine It successively, Na
2sO
4drying, filters, and concentrated, column separating purification (silica gel, eluent: petrol ether/ethyl acetate=20/1), obtain 2.64g white solid (shown in formula II-m compound), yield is 69%.
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 room temperature under nitrogen environment, the methylene dichloride (14.0mL) of fresh distillation joins in schlenk pipe, then adds zinc ethyl solution (14.0mL, 14.0mmol) (1.0M in hexane).After-40 ° of C cool 10min, methylene dichloride (7.0mL) dropwise of methylene iodide (7.50g, 28.0mmol) joins in schlenk pipe.After-40 ° of C react 1h, trichoroacetic acid(TCA) (0.228g, 1.40mmol) join in reaction solution with methylene dichloride (7.0mL) solution of DME (0.631g, 7.0mmol), temperature of reaction is raised to-15 ° of C and stirs 1h at such a temperature.Under-15 ° of C, methylene dichloride (7.0mL) dropwise of alkene (formula II-m) (1.46g, 0.5mmol) joins in reaction solution.Then transferred to by schlenk pipe in the oil bath pan of 25 ° of C and react 24h, 0.1N HCl (100mL) cancellation is reacted, CH
2cl
2(20mL x4) extracts, and merges organic phase brine washing, Na
2sO
4drying, filters, concentrated, column chromatography purification (silica gel, eluent: petrol ether/ethyl acetate=20/1), obtains 1.39g white solid cyclopropane (shown in formula I-m), yield 89%.
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), 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.
As shown in aforesaid equation, shown in the formula I-m of the present embodiment synthesis, cyclopropane compound may be used for synthesizing important medicine intermediate Roflumilast, shown in V.
Claims (6)
1. the preparation method of cyclopropanes compound shown in formula I, comprises the steps:
Alkene shown in formula II through cyclopropanization reaction, namely obtains cyclopropanes compound shown in 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;
Shown in described zinc ethyl, described methylene iodide, described acid, described ether and formula II, the mol ratio of alkene is 1 ~ 3:2 ~ 6:0 ~ 3:0 ~ 10:1, and the addition of described acid and described ether is all non-vanishing;
Described acid is any one in trichoroacetic acid(TCA), trifluoroacetic acid, pyruvic acid, acetic acid, acetoxy acid, methoxyacetic acid, phenylformic acid, 2,4,6-Trichlorophenols and trifluoroethanol;
Described ether is any one in ether, tetrahydrofuran (THF), dioxane, t-butyl methyl ether, n-butyl ether, 1,2-glycol dimethyl ether, 1-methoxyl group-2-acetoxyl group ethane and 2-ethyl methoxyacetate;
In formula I and formula II, R
1, R
2, R
3and R
4all be selected from any one in hydrogen atom, methyl, ethyl, n-pentyl, n-octyl, phenyl, siloxy, substituted alkyl and substituted-phenyl; Described substituted alkyl to be carbonatoms be 1 ~ 8 alkyl, the substituting group in described substituted alkyl is hydroxyl, siloxy, ester group or phenyl; Described substituted-phenyl is monosubstituted phenyl or disubstituted phenyl, and the substituting group in 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, is characterized in that: the solvent of described cyclopropanization reaction is any one in methylene dichloride, trichloromethane, 1,2-ethylene dichloride, toluene, acetonitrile and normal hexane.
3. preparation method according to claim 1 and 2, is characterized in that: the temperature of described cyclopropanization reaction is-40 ~ 40 DEG C; The time of described cyclopropanization reaction is 2 ~ 48 hours.
4. preparation method according to claim 1, is characterized in that: the volumetric molar concentration of alkene shown in formula II in the reaction system of described cyclopropanization reaction is 0.05 ~ 0.5 mol/L.
5. want the preparation method described in 1 according to right, it is characterized in that: described method also comprise cyclopropanes compound shown in formula I is extracted, the step of dry and column chromatography for separation.
6. want the preparation method described in 5 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 magnesium sulfate;
The eluent of described column chromatography for separation is Skellysolve A.
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