One-pot synthesis method for substituted indane compounds

Abstract

The invention discloses one-pot synthesis method for a substituted indane compound. The method comprises the following steps: slowly and dropwise adding a mixed solution dissolved with far-end double-bond aryl halide and PEPPSI into a mixed solution of a phenylmagnesium bromide Grignard reagent and iodoisopropane, and stirring the reaction solution at a room temperature for 5-15 minutes; and quenching the reaction solution with a saturated NH4Cl solution, conducting extracting with ethyl acetate, washing the organic phase with saturated edible salt water, carrying out drying with anhydrous sodium sulfate, concentrating the organic phase, and carrying out column chromatography separation to obtain the substituted indane compound. According to the method, the transition metal salt PEPPSI andiodoisopropane in a catalytic system are commercial products; a catalytic reaction is conducted under mild conditions and is easy to operate; the related reaction can synthesize the target compound by using a one-pot process, so material resources and human resources can be further saved, and the social necessary labor time for synthesizing the target compound is shortened; and the cyclized coupling product synthesized by using the method has potential pharmaceutical activity and also has important reference value for the industry.

Description

technical field

[0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a transition metal palladium-catalyzed free radical cyclization coupling reaction, that is, a preparation method for selectively constructing substituted dihydroindene compounds in one pot. Background technique

[0002] Substituted indanes are an important class of pharmaceutical intermediates, and they have a wide range of pharmaceutical activities. The substituted dihydroindane derivatives shown below have been proven to have a high inhibitory effect on the calcium influx of nerve cells (see: B.S.Orlek, J.D.Harling, WO 9621641, 1996), so these compounds can be used as nerve cells. Calcium influx inhibitors have potential pharmacological activity on mammals, especially human brain cells related diseases caused by calcium accumulation, such as migraine, epilepsy, paralytic dementia, senile dementia, and emotional disorders.

[0003]

[0004] ...

Examples

Embodiment 1

[0036] Example 1 Synthesis of 1-(4-methoxybenzyl)-2,3-dihydro-1H-indene (1)

[0037]

[0038] Slowly add the compound 1-(3-ene-butyl )-2-iodobenzene (633mg, 3mmol) and PEPPSI (40.8mg, 0.06mmol) in 3mL THF mixed solution, the reaction solution was stirred at room temperature for 5 minutes. The reaction solution was saturated with NH 4 Cl solution was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by column chromatography (eluent: PE:EA=100:1) to obtain compound 1 (489mg, 85%) as a colorless oil. 1 H NMR (CDCl 3 ,400MHz,ppm):δ=7.23-6.83(m,8H),3.81(s,3H), 3.46-3.36(m,1H),3.07(dd,J=13.7Hz; 5.8Hz,1H),2.93- 2.74 (m,2H),2.65(dd,J=13.7Hz;9.3Hz,1H),2.20-2.09(m,1H), 1.82-1.69(m,1H).

Embodiment 2

[0039] Example 2 Synthesis of tert-butyl((3-(4-methoxybenzyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane(2)

[0040]

[0041] The compound tert-butyl ((1-(2- A mixed solution of iodophenyl)but-3-en-1-yl)oxy)dimethylsilane (250mg, 0.64mmol) and PEPPSI (17.4mg, 0.025mmol) in 4mL THF was stirred at room temperature for 5 minutes. The reaction solution was saturated with NH 4 The Cl solution was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by column chromatography (eluent: PE:EA=100:1) to obtain compound 2 (114mg, 50%) as a colorless oil. 1H NMR (CDCl 3 ,400MHz,ppm): δ=7.28-6.76(m,8H),5.01(t,J=7.4Hz,1H),3.79(s,3H), 3.20-2.92(m,3H),2.10-1.54(m ,2H),0.98(s,9H),0.21(s,6H).

Embodiment 3

[0042] Example 3 Synthesis of 1-methoxy-3-(4-methoxybenzyl)-2,3-dihydro-1H-indene(3)

[0043]

[0044] Add compound 1-iodo-2-(pent-4-ene-2- Base) a mixed solution of benzene (237mg, 0.82mmol) and PEPPSI (11.1mg, 0.0164mmol) in 3 mL THF, and the reaction solution was stirred at room temperature for 5 minutes. The reaction solution was saturated with NH 4 Cl solution was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by column chromatography (eluent: PE:EA=100: 1) to obtain compound 3 (82mg, 45%) as a colorless oil. 1 H NMR (CDCl 3 , 400MHz,ppm):δ=7.62-6.86(m,8H),5.81-5.06(m,1H),5.81-5.06(m,2H),4.49-4.38(m,1H),3.90(s,3H) ,3.17(s,3H),2.50- 2.26(m,2H).

[0045] The transition metal salt PEPPSI ([1,3-bis(2,6-diisopropylphenyl) imidazol-2-yl subunit] (3-chloropyridyl) palladium dichloride (II) in the catalytic system of this...

technical field

[0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a transition metal palladium-catalyzed free radical cyclization coupling reaction, that is, a preparation method for selectively constructing substituted dihydroindene compounds in one pot. Background technique

[0002] Substituted indanes are an important class of pharmaceutical intermediates, and they have a wide range of pharmaceutical activities. The substituted dihydroindane derivatives shown below have been proven to have a high inhibitory effect on the calcium influx of nerve cells (see: B.S.Orlek, J.D.Harling, WO 9621641, 1996), so these compounds can be used as nerve cells. Calcium influx inhibitors have potential pharmacological activity on mammals, especially human brain cells related diseases caused by calcium accumulation, such as migraine, epilepsy, paralytic dementia, senile dementia, and emotional disorders.

[0003]

[0004] ...

Examples

Embodiment 1

[0036] Example 1 Synthesis of 1-(4-methoxybenzyl)-2,3-dihydro-1H-indene (1)

[0037]

[0038] Slowly add the compound 1-(3-ene-butyl )-2-iodobenzene (633mg, 3mmol) and PEPPSI (40.8mg, 0.06mmol) in 3mL THF mixed solution, the reaction solution was stirred at room temperature for 5 minutes. The reaction solution was saturated with NH 4 Cl solution was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by column chromatography (eluent: PE:EA=100:1) to obtain compound 1 (489mg, 85%) as a colorless oil. 1 H NMR (CDCl 3 ,400MHz,ppm):δ=7.23-6.83(m,8H),3.81(s,3H), 3.46-3.36(m,1H),3.07(dd,J=13.7Hz; 5.8Hz,1H),2.93- 2.74 (m,2H),2.65(dd,J=13.7Hz;9.3Hz,1H),2.20-2.09(m,1H), 1.82-1.69(m,1H).

Embodiment 2

[0039] Example 2 Synthesis of tert-butyl((3-(4-methoxybenzyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane(2)

[0040]

[0041] The compound tert-butyl ((1-(2- A mixed solution of iodophenyl)but-3-en-1-yl)oxy)dimethylsilane (250mg, 0.64mmol) and PEPPSI (17.4mg, 0.025mmol) in 4mL THF was stirred at room temperature for 5 minutes. The reaction solution was saturated with NH 4 The Cl solution was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by column chromatography (eluent: PE:EA=100:1) to obtain compound 2 (114mg, 50%) as a colorless oil. 1H NMR (CDCl 3 ,400MHz,ppm): δ=7.28-6.76(m,8H),5.01(t,J=7.4Hz,1H),3.79(s,3H), 3.20-2.92(m,3H),2.10-1.54(m ,2H),0.98(s,9H),0.21(s,6H).

Embodiment 3

[0042] Example 3 Synthesis of 1-methoxy-3-(4-methoxybenzyl)-2,3-dihydro-1H-indene(3)

[0043]

[0044] Add compound 1-iodo-2-(pent-4-ene-2- Base) a mixed solution of benzene (237mg, 0.82mmol) and PEPPSI (11.1mg, 0.0164mmol) in 3 mL THF, and the reaction solution was stirred at room temperature for 5 minutes. The reaction solution was saturated with NH 4 Cl solution was quenched, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by column chromatography (eluent: PE:EA=100: 1) to obtain compound 3 (82mg, 45%) as a colorless oil. 1 H NMR (CDCl 3 , 400MHz,ppm):δ=7.62-6.86(m,8H),5.81-5.06(m,1H),5.81-5.06(m,2H),4.49-4.38(m,1H),3.90(s,3H) ,3.17(s,3H),2.50- 2.26(m,2H).

[0045] The transition metal salt PEPPSI ([1,3-bis(2,6-diisopropylphenyl) imidazol-2-yl subunit] (3-chloropyridyl) palladium dichloride (II) in the catalytic system of this...

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