CN109734662A - A kind of trifluoromethyl substituted-dihydro isoquinolinone derivatives and preparation method thereof - Google Patents

Abstract

The invention discloses a kind of trifluoromethyl substituted-dihydro isoquinolinone derivatives and preparation method thereof, use the alkali of equivalent, using Togni reagent and N- methyl-N- allyl benzene formamide as reactant, DMF is as solvent, temperature is controlled at 80-100 DEG C, obtains trifluoromethyl substituted-dihydro isoquinolines product through column chromatography for separation after reaction 12-24 h.The present invention provide for the first time it is a kind of using N- methyl-N- allyl benzene formamide cheap and easy to get as starting material, be not necessarily to additional transition-metal catalyst, efficiently synthesize the new method of dihydro-isoquinoline ketone trifluoromethyl derivative compound.This method advantages such as mild, easy to operate with reaction condition.

Description

A kind of trifluoromethyl substituted-dihydro isoquinolinone derivatives and preparation method thereof

Technical field

The present invention relates to the field of chemical synthesis, and in particular to a kind of preparation of trifluoromethyl substituted-dihydro isoquinolines.

Background technique

Trifluoromethyl is present in many bioactive molecules, it have enhancing molecule chemistry with metabolic stability, Improve lipophilicity and improves the characteristics such as the selectivity in conjunction with large biological molecule.Therefore, trifluoro is introduced in small organic molecule The synthetic method of methyl receives the extensive concern of organic chemist and Pharmaceutical Chemist.Present invention firstly provides a kind of trifluoros It is different to provide a kind of mild, cheap method synthesis trifluoromethyl substituted-dihydro for the preparation method of methyl substituted-dihydro isoquinolines Quinolinone.The synthesising method reacting condition is mild, opens wide system operation in air under the conditions of 80-100 DEG C, and handy and safe is former Material and alkali are cheap and easy to get, are a kind of environmental-friendly synthetic methods.

Summary of the invention

It realizes the technical scheme is that a kind of trifluoromethyl substituted-dihydro isoquinolines, structure are as follows:

Wherein, R¹For chlorine, bromine, iodine, methyl, methoxyl group, ethyl, isopropyl, tert-butyl；R²For methyl, ethyl, isopropyl, uncle Butyl；R³For hydrogen, methyl, ester group.

The preparation method of the trifluoromethyl substituted-dihydro isoquinolines, steps are as follows: by N- methyl-N- allyl benzene first Amide, Togni reagent, sodium acetate are added heated at constant temperature in reaction tube and are stirred to react, and obtain trifluoromethyl substituted-dihydro isoquinolin Ketone.

The structure of the N- methyl-N- allyl benzene formamide is as follows:

Wherein, R¹For chlorine, bromine, iodine, methyl, methoxyl group, ethyl, isopropyl, tert-butyl；R²For methyl, ethyl, isopropyl, uncle Butyl；R³For hydrogen, methyl, ester group.

The solvent is DMF, and alkali is sodium acetate.

N- methyl-N- allyl benzene the formamide, Togni reagent, sodium acetate molar ratio be 1:(1-2): (2-3).

The reaction temperature is 80-100 DEG C, and the reaction time is 12-24 h.

The reaction formula of preparation method of the present invention is as follows:

。

The beneficial effects of the present invention are: the present invention provides a kind of preparation sides of trifluoromethyl substituted-dihydro isoquinolines Method, the method directly carry out in air, efficiently synthesize trifluoromethyl substituted-dihydro isoquinolin using raw material cheap and easy to get Ketone product.It is easy to operate and safe involved in this method, have the advantages that reaction condition mild, be good economy performance, environmental-friendly.

Specific embodiment

Below in conjunction with the embodiment of the present invention, technical solution of the present invention is clearly and completely described, it is clear that institute The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, Those of ordinary skill in the art's every other embodiment obtained under that premise of not paying creative labor, belongs to this hair The range of bright protection.

Embodiment 1

The preparation method of trifluoromethyl substituted-dihydro isoquinolines, steps are as follows:

N- methyl-N-(2- methacrylic is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni reagent (0.6 mmol), sodium acetate (1.5mmol) stir 12 hours, the isolated final product of column chromatography silica gel, with N- at 80 DEG C Methyl-N-(2- methacrylic) benzamide mole be 100 % meter, 91 % of Yield of final product.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 8.14 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (td, J = 7.6, 1.6 Hz, 1H), 7.39 (td, J = 7.6, 1.2 Hz, 1H), 7.31 (dd, J = 7.6, 1.2 Hz, 1H), 3.55 (d, J = 13.2 Hz, 1H), 3.39 (d, J = 13.2 Hz, 1H), 3.17 (s, 3H), 2.57-2.26 (m, 2H), 1.55 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.37, 144.20, 132.26, 128.89, 128.02, 127.70, 126.11 (q, J = 279.8 Hz), 123.74, 57.15, 41.32 (q, J = 27.0 Hz), 35.19 (d, J = 1.3 Hz), 35.05, 22.11 ¹⁹F NMR (376 MHz, CDCl₃) δ -59.78. HRMS Calcd. for C₁₃H₁₅F₃NO [M + H]⁺ :258.1100, Found 258.1083。

Embodiment 2

The preparation method of trifluoromethyl substituted-dihydro isoquinolines, steps are as follows:

The chloro- N- methyl-N-(2- methacrylic of 4- is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni Reagent (0.7 mmol), sodium acetate (1 mmol) stir 24 hours, the isolated final product of column chromatography silica gel at 80 DEG C, By the chloro- N- methyl-N-(2- methacrylic of 4-) benzamide mole be 100 % in terms of, 82 % of Yield of final product.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 3.55 (d, J = 13.2 Hz, 1H), 3.40 (d, J = 13.2 Hz, 1H), 3.16 (s, 3H), 2.57-2.26 (m,2H), 1.54 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.54, 145.90, 138.53, 128.11, 126.53, 125.93 (q, J = 279.8 Hz), 124.24, 57.02, 41.17 (q, J = 27.3 Hz) 35.34, 35.06, 22.03. ¹⁹F NMR (376 MHz, CDCl₃)δ-59.76. HRMS Calcd. for C₁₃H₁₄ClF₃NO [M + H]⁺: 292.0711, Found 292.0693。

Embodiment 3

The preparation method of trifluoromethyl substituted-dihydro isoquinolines, steps are as follows:

3- chloro-n-methyl-N-(2- methacrylic is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni examination Agent (0.6 mmol), sodium acetate (2mmol) stir 12 hours, the isolated final product of column chromatography silica gel at 100 DEG C, with 3- chloro-n-methyl-N-(2- methacrylic) benzamide mole be 100 % meter, 73 % of Yield of final product.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.17 (s, 3H), 2.54-2.27 (m, 2H), 1.54 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.15, 142.34, 133.98, 132.14, 129.65, 128.78, 125.94 (q, J = 279.8 Hz), 125.61, 57.21, 41.20 (q, J = 27.2 Hz), 35.13, 35.02, 22.16. ¹⁹F NMR (376 MHz, CDCl₃) δ -59.94. HRMS Calcd. for C₁₃H₁₄ClF₃NO [M + H]⁺: 292.0711, Found 292.0690。

Embodiment 4

The preparation method of the dihydro-isoquinoline ketone of trifluoromethylation, steps are as follows:

The bromo- N- methyl-N-(2- methacrylic of 4- is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni examination Agent (0.7 mmol), sodium acetate (1.5mmol) stir 12 hours, the isolated final product of column chromatography silica gel at 80 DEG C, with The bromo- N- methyl-N-(2- methacrylic of 4-) benzamide mole be 100 % meter, Yield of final product 69%.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J = 8.4Hz, 1H), 7.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 1.6Hz, 1H), 3.55 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.2 Hz, 1H), 3.16 (s, 3H), 2.57-2.26 (m, 2H), 1.54 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.64, 146.05, 131.12, 130.76, 127.17, 127.12, 126.97, 127.86 (q, J = 279.8 Hz), 56.98, 41.19 (q, J = 27.3 Hz), 35.32, 35.09, 22.04. ¹⁹F NMR (376 MHz, CDCl₃) δ -59.77. HRMS Calcd for C₁₃H₁₄BrF₃NO [M + H]⁺: 336.0205, Found 336.0193。

Embodiment 5

The preparation method of the dihydro-isoquinoline ketone of trifluoromethylation, steps are as follows:

The iodo- N- methyl-N-(2- methacrylic of 4- is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni examination Agent (0.6 mmol), sodium acetate (1 mmol) stir 24 hours, the isolated final product of column chromatography silica gel at 80 DEG C, with The iodo- N- methyl-N-(2- methacrylic of 4-) benzamide mole be 100 % meter, Yield of final product 72%.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.16 (s, 3H), 2.56 - 2.24 (m, 2H), 1.54 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.81, 145.96, 137.15, 133.09, 130.62, 127.54, 125.92(d, J = 279.0 Hz), 99.69, 56.91, 41.20(q, J = 27.3 Hz), 35.17, 35.10, 22.01. ¹⁹F NMR (376 MHz, CDCl₃) δ -59.77. HRMS Calcd for C₁₃H₁₄IF₃NO [M + H]⁺: 384.0067, Found 384.0060。

Embodiment 6

The preparation method of the dihydro-isoquinoline ketone of trifluoromethylation, steps are as follows:

The bromo- N- methyl-N-(2- methacrylic of 3- is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni examination Agent (1 mmol), sodium acetate (1 mmol) stir 24 hours, the isolated final product of column chromatography silica gel, with 3- at 80 DEG C Bromo- N- methyl-N-(2- methacrylic) benzamide mole be 100 % meter, Yield of final product 69%.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.4, 2.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.54 (d, J = 12.8 Hz, 1H), 3.38 (d, J = 12.8 Hz, 1H), 3.17 (s, 3H), 2.54-2.26 (m, 2H), 1.54 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.04, 142.86, 135.10, 131.83, 129.84, 125.92 (q, J = 279.8 Hz), 125.82, 121.92, 57.15, 41.22 (q, J = 27.0 Hz), 35.17, 35.10, 22.12. ¹⁹F NMR (376 MHz, CDCl₃) δ -59.73. HRMS Calcd for C₁₃H₁₄BrF₃NO [M + H]⁺: 336.0205, Found 336.0195。

Embodiment 7

The preparation method of the dihydro-isoquinoline ketone of trifluoromethylation, steps are as follows:

N- methyl-N- allyl benzene formamide (0.5 mmol) is added in 10 mL reaction tubes, Togni reagent (0.8 mmol), Sodium acetate (1 mmol) stirs 16 hours, the isolated final product of column chromatography silica gel at 80 DEG C, with N- methyl-N- allyl Yl-benzamide mole is 100 % meter, Yield of final product 81%.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 8.10 (dd, J = 7.6, 1.2 Hz, 1H), 7.47(td, J = 7.2, 1.6 Hz, 1H), 7.40 (td, J = 7.6, 1.2 Hz, 1H), 7.22 (d, td, J = 7.2 Hz, 1H), 3.86 (dd, J =12.8, 3.6 Hz, 1H), 3.47 (dd, J =12.8, 2.4 Hz, 1H), 3.29- 3.24 (m, 1H), 3.18 (s, 3H), 2.63-2.26 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 164.29, 139.72, 132.20, 128.66, 128.58, 128.06, 126.23 (q, J = 279.8 Hz), 126.42, 51.04, 36.91, 35.36, 32.44. ¹⁹F NMR (376 MHz, CDCl₃) δ -63.70. HRMS Calcd for C₁₂H₁₃F₃NO [M + H]⁺: 244.0944, Found 244.0959。

Embodiment 8

The preparation method of the dihydro-isoquinoline ketone of trifluoromethylation, steps are as follows:

N- ethyl-N-(2- methacrylic is added in 10 mL reaction tubes) benzamide (0.5 mmol), Togni reagent (0.8 mmol), sodium acetate (1 mmol) stir 24 hours, the isolated final product of column chromatography silica gel, with N- at 80 DEG C Ethyl-N-(2- methacrylic) benzamide mole be 100 % meter, Yield of final product 78%.

Specific structure is as follows:

¹H NMR (400 MHz, CDCl₃) δ 8.13 (dd, J = 7.6, 1.2 Hz, 1H), 7.50 (td, J = 7.6, 1.6 Hz, 1H), 7.39 (td, J = 7.6, 1.2 Hz, 1H), 7.31 (d, J = 7.6 Hz), 3.80 (m, 1H), 3.54 (d, J =12.8 Hz, 1H), 3.54-3.45 (m, 1H), 3.39 (d, J =12.8 Hz, 1H), 2.57-2.30 (m, 2H), 1.56 (s, 3 H), 1.23 (t, J =7.2 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.71, 143.91, 132.23, 128.89, 128.25, 127.68, 126.14 (q, J = 279.8 Hz), 123.80, 55.14, 42.21, 41.02 (q, J = 27.0 Hz), 35.07, 22.13, 12.44.¹⁹F NMR (376 MHz, CDCl₃) δ -59.64. HRMS Calcd for C₁₄H₁₇F₃NO [M + H]⁺: 272.1257, Found 272.1278。

The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.

Claims (7)

1. a kind of trifluoromethyl substituted-dihydro isoquinolines, it is characterised in that structural formula is as follows:

Wherein, R¹For chlorine, bromine, iodine, methyl, methoxyl group, ethyl, isopropyl, tert-butyl；R²For methyl, ethyl, isopropyl, tertiary fourth Base；R³For hydrogen, methyl, ester group.

2. the preparation method of trifluoromethyl substituted-dihydro isoquinolines, characterization step are as follows: by N- methyl-N- allyl benzene first Amide, Togni reagent, sodium acetate are added heated at constant temperature in reaction tube and are stirred to react, and obtain trifluoromethyl substituted-dihydro isoquinolin Ketone derivatives.

3. the preparation method of trifluoromethyl substituted-dihydro isoquinolines according to claim 2, it is characterised in that the N- The structural formula of methyl-N- allyl benzene formamide is as follows:

Wherein, R¹For chlorine, bromine, iodine, methyl, methoxyl group, ethyl, isopropyl, tert-butyl；R²For methyl, ethyl, isopropyl, tertiary fourth Base；R³For hydrogen, methyl, ester group.

4. the preparation method of trifluoromethyl substituted-dihydro isoquinolines according to claim 2, it is characterised in that: described molten Agent is DMF, and alkali is sodium acetate.

5. the preparation method of trifluoromethyl substituted-dihydro isoquinolines according to claim 2, it is characterised in that: the N- Methyl-N- allyl benzene formamide, Togni reagent, sodium acetate molar ratio be 1:(1-2): (2-3).

6. the preparation method of trifluoromethyl substituted-dihydro isoquinolines according to claim 2, which is characterized in that reaction temperature Degree is 80-100 DEG C, and the reaction time is 12-24 h.

7. according to the preparation method of the described in any item trifluoromethyl substituted-dihydro isoquinolines of claim 2-6, feature exists It is as follows in the structure of the trifluoromethyl substituted-dihydro isoquinolines:

Wherein, R¹For chlorine, bromine, iodine, methyl, methoxyl group, ethyl, isopropyl, tert-butyl；R²For methyl, ethyl, isopropyl, tertiary fourth Base；R³For hydrogen, methyl, ester group.