Monofluorodiarylsulfonylethylamine derivative and preparation method thereof

Abstract

The invention provides a monofluoro diaryl sulfuryl ethylamine derivative and a preparation method thereof. The monofluorodiarylsulfonylethylamine derivative as shown in a formula (I) in the specification, wherein Ar is selected from substituted or unsubstituted aryl groups of C6 to C10. The preparation method of the monofluoro diaryl sulfurylethylamine derivative has the advantages of mild reaction conditions, simple reaction steps, high conversion rate, easiness in amplification production and the like, the obtained novel monofluoro diaryl sulfurylethylamine is a fluorine-containing synthon with synthesis application potential, and the novel monofluoro diaryl sulfurylethylamine derivative is prepared by simple conversion, so that the yield of the monofluoro diaryl sulfurylethylamine derivative is greatly improved. Fluorine-containing compounds with various and complex structures can be obtained, and the method has a wide application prospect. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a class of monofluorodiarylsulfoneethylamine derivatives and a preparation method thereof. Background Art

[0002] In the study of medicinal chemistry, since the introduction of fluorine atoms can change the physical, chemical and biological activities of the parent compound, thus giving fluorine-containing organic compounds unique properties, fluorine-containing organic compounds have been rapidly developed in the fields of medicine, pesticides, materials, etc. Since the 1970s, compounds containing single fluorine atoms have a pivotal position. Traditionally, the construction of single fluorine-substituted compounds mainly uses nucleophilic fluorination reagents such as KF and electrophilic fluorination reagents such as NFSI and Selectfluor to introduce fluorine atoms into non-fluorine parent compounds. How to control the selectivity of the reaction has become a challenging topic; at the same time, using single fluorine-substituted reagents through efficient transformation reactions is another effective synthetic strategy for constructing single fluorine compounds. (P. Champagne, J. Desroches, J. Hamel, M. Vandamme, J. Paquin, Chem. Rev., 2015, 115, 9073-9174; T. Ahrens, J.K ohlmann, M. Ahrens, T. Braun, Chem. Rev., 2015, 115, 931-972; C. Ni, J. Hu, Chem. Soc. Rev., 2016, 45, 5441-5454).

[0003] Compared with the widespread application of difluoromethyl and trifluoromethyl reagents in fluorine-containing organic synthesis, the research on the use of monofluoro substitution reagents to construct monofluoro compounds is still very limited, and the monofluoro substitution reagents that have been reported and applied to the synthesis of fluorine-containing compounds are also relatively rare. (F.Ullah, G.-L.Zhao, L.Deiana, M.Zhu, P.Dziedzic, I.Ibrahem, P.Hammar, J.Sun, A.Cordova, Chem.Eur.J., 2009, 15, 10013-10017; T.Furukawa, J.Kawazoe, W.Zhang, T.Nishimine, E.Tokunage, T.Matsumoto, M.Shiro, N.Shibata, Angew.Chem.Int.Ed., 2011, 50, 9684-9688) Therefore, developing a direct and effective method for preparing new monofluoro-substituted reagents has important significance and application potential in the fields of organic synthesis and medicinal chemistry. Summary of the invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide a novel monofluorodiarylsulfoneethylamine derivative and a preparation method thereof. The preparation method has the advantages of mild reaction conditions, simple reaction steps, high conversion rate, easy scale-up production, etc. The obtained novel monofluorodiarylsulfoneethylamine has multiple synthetic uses and can be converted into fluorine-containing compounds with diverse and complex structures through simple reactions, and has broad application prospects.

[0005] The present invention provides a monofluorodiarylsulfoneethylamine derivative, as shown in formula (I):

[0006]

[0007] Wherein, Ar is selected from substituted and unsubstituted C6-C10 aryl groups;

[0008] The Ar is selected from one of formula (1) to formula (12):

[0009]

[0010]

[0011] The monofluorodiarylsulfoneethylamine derivative is one of the formulas L-1 to L-12:

[0012]

[0013] The monofluorodiarylsulfoneethylamine derivative is preferably selected from the formula L-1, L-5 to L-7:

[0014]

[0015]

[0016] The present invention provides a method for preparing a monofluorodiarylsulfoneethylamine derivative of formula (I), comprising the following steps:

[0017]

[0018] Wherein, Ar is selected from substituted and unsubstituted C6-C10 aryl groups;

[0019] Step (1): adding a base and formaldehyde to a monofluorodiarylsulfonemethane (II) solution to prepare a compound of formula (III): in the step (1), the molar ratio of the compound of formula (II) to the base is 1:1-1:2; the molar ratio of the compound of formula (II) to formaldehyde is 1:1-1:2; the base is selected from one of the inorganic bases of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, cesium carbonate, and potassium tert-butoxide; the reaction temperature is 0-25°C, and the reaction uses an organic solvent selected from one of dichloromethane, chloroform, acetone, benzene, and toluene.

[0020] Step (2): in the presence of a base, adding an acid anhydride or an acid chloride to a compound of formula (III) to prepare a compound of formula (IV); in the step (2), the acid anhydride or the acid chloride used in the reaction is selected from one of trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, and p-trifluoromethylbenzenesulfonyl chloride; the molar ratio of the compound of formula (III) to the acid anhydride or the acid chloride is 1:1 to 1:2; the base is selected from one of triethylamine, pyridine, 2,6-lutidine, hexahydropyridine, 4-dimethylaminopyridine, DBU, and DBACO; the solvent is one of dichloromethane, chloroform, ether, acetone, benzene, toluene, acetonitrile, DMF, and DMSO; and the reaction temperature is 0 to 50°C.

[0021] Step (3): Sodium azide is added to the solution of the compound of formula (IV), and then nitrogen is removed by reduction to prepare a monofluorodiarylsulfoneethylamine derivative of formula (I): the molar ratio of the compound of formula (IV) to sodium azide is 1:1 to 1:2; the reduction reaction catalyst is one of Pd / C, Pt / C, Raney Ni, and sodium sulfide; the solvent is one or more of methanol, ethanol, and water; and the reaction temperature is room temperature.

[0022] Step (4): In the presence of an oxidizing agent, oxidizing the compound of formula (III) to prepare a compound of formula (V): the reaction reagent is selected from CrO 3 · One of 2Py, DCC, DMSO, oxalyl chloride, acetic anhydride, triisopropoxyaluminum, pyridinium chlorochromate, pyridinium dichromate, 4-dimethylaminopyridine, and DMP; the solvent is one of dichloromethane, DMSO, acetone, DMF, acetonitrile, and chloroform; the reaction temperature is 0 to 30°C.

[0023] Step (5): The compound of formula (V) is subjected to reductive amination to prepare a monofluorodiarylsulfoneethylamine derivative of formula (I): the reducing agent is selected from one of Pd / C, Pt / C, Raney Ni, and sodium cyanoborohydride; the catalyst is selected from Co@CN(800); and the solvent is ethanol or methanol. DETAILED DESCRIPTION

[0024] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0025] The present invention provides a monofluorodiarylsulfoneethylamine compound, as shown in formula (I):

[0026]

[0027] Wherein, Ar is selected from substituted and unsubstituted C6-C10 aryl groups;

[0028] The preparation method thereof comprises the following steps:

[0029]

[0030] Step (1): adding a base and formaldehyde to a monofluorodiarylsulfonemethane (II) solution to prepare a compound of formula (III): in the step (1), the molar ratio of the compound of formula (II) to the base is 1:1-1:2; the molar ratio of the compound of formula (II) to formaldehyde is 1:1-1:2; the base is selected from one of the inorganic bases of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, cesium carbonate, and potassium tert-butoxide; the reaction temperature is 0-25°C, and the reaction uses an organic solvent selected from one of dichloromethane, chloroform, acetone, benzene, and toluene.

[0031] Step (2): in the presence of a base, adding an acid anhydride or an acid chloride to a compound of formula (III) to prepare a compound of formula (IV); in the step (2), the acid anhydride or the acid chloride used in the reaction is selected from one of trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, and p-trifluoromethylbenzenesulfonyl chloride; the molar ratio of the compound of formula (III) to the acid anhydride or the acid chloride is 1:1 to 1:2; the base is selected from one of triethylamine, pyridine, 2,6-lutidine, hexahydropyridine, 4-dimethylaminopyridine, DBU, and DBACO; the solvent is one of dichloromethane, chloroform, ether, acetone, benzene, toluene, acetonitrile, DMF, and DMSO; and the reaction temperature is 0 to 50°C.

[0032] Step (3): Sodium azide is added to the solution of the compound of formula (IV), and then nitrogen is removed by reduction to prepare a monofluorodiarylsulfoneethylamine derivative of formula (I): the molar ratio of the compound of formula (IV) to sodium azide is 1:1 to 1:2; the reduction reaction catalyst is one of Pd / C, Pt / C, Raney Ni, and sodium sulfide; the solvent is one or more of methanol, ethanol, and water; and the reaction temperature is room temperature.

[0033] Step (4): In the presence of an oxidizing agent, oxidizing the compound of formula (III) to prepare a compound of formula (V): the reaction reagent is selected from CrO 3 · One of 2Py, DCC, DMSO, oxalyl chloride, acetic anhydride, triisopropoxyaluminum, pyridinium chlorochromate, pyridinium dichromate, 4-dimethylaminopyridine, and DMP; the solvent is one of dichloromethane, DMSO, acetone, DMF, acetonitrile, and chloroform; the reaction temperature is 0 to 30°C.

[0034] Step (5): subjecting the compound of formula (V) to reductive amination to prepare a monofluorodiarylsulfoneethylamine derivative of formula (I): the reducing agent is selected from one of Pd / C, Pt / C, Raney Ni, and sodium cyanoborohydride; the solvent is ethanol or methanol.

[0035] Example 1: Preparation of 2-fluoro-2,2-diphenylsulfone ethanol

[0036] Fluorodiphenylsulfonemethane (15.7 g, 50 mmol) and 100 mL of dichloromethane were added to a three-necked flask. Formaldehyde aqueous solution (37%) and potassium carbonate (8.28 g, 60 mmol) were added at 0°C. The mixture was stirred for 6 to 8 hours. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate, and then purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain 16.3 g of the product 2-fluoro-2,2-diphenylsulfoneethanol with a yield of 91%. 1 H NMR (500 MHz, CDCl 3 )δ7.97(d,J=7.7Hz,4H),7.75(dd,J=10.9,4.1Hz,2H),7.58(t,J=7.8Hz,4H),4.28(d,J=9.1Hz,2H),2.98(s,1H). 13 C NMR (126 MHz, CDCl 3 )δ135.7,134.6,130.9,129.2,111.3(d,J=268.9Hz),60.6(d,J=22.7Hz),111.0,21.5. 19 F NMR (470 MHz, CDCl 3)δ-147.76(t,J=11.1Hz).HRMS(ESI)m / z calcd.forC 14 H 13 FO 5 S 2 [M+H] + =345.0261; found 345.0261.

[0037] Example 2: Preparation of 2-fluoro-2,2-di(4-methylphenylsulfone)ethanol

[0038] According to the preparation method in Example 1, 16.95 g of the compound 2-fluoro-2,2-di(4-methylphenylsulfone)ethanol was prepared, with a yield of 91%.

[0039] Example 3: Preparation of 2-fluoro-2,2-di(naphthalene-2-sulfone)ethanol

[0040] According to the preparation method in Example 1, 21.11 g of the compound 2-fluoro-2,2-di(naphthalene-2-sulfone)ethanol was prepared, with a yield of 95%.

[0041] Example 4: Preparation of 2-fluoro-2,2-di(4-methoxyphenylsulfone)ethanol

[0042] The compound 2-fluoro-2,2-di(4-methoxyphenylsulfone)ethanol (18.2 g) was prepared by referring to the preparation method in Example 1 with a yield of 91%.

[0043] Example 5: Preparation of 2-fluoro-2,2-di(4-fluorophenylsulfone)ethanol

[0044] The compound 2-fluoro-2,2-di(4-fluorophenylsulfone)ethanol (15.9 g) was prepared by referring to the preparation method in Example 1 with a yield of 84%.

[0045] Example 6: Preparation of 2-fluoro-2,2-diphenylsulfone trifluoromethanesulfonate

[0046] 2-Fluoro-2,2-diphenylsulfoneethanol: 13.8 g, 40 mmol) and 100 mL of dichloromethane were added to a three-necked flask, and trifluoromethanesulfonic anhydride (8.1 mL, 48 mmol) was added dropwise at 30°C. After stirring for 10 minutes, 2,6-lutidine (5.2 g, 48 mmol) was added dropwise; the reaction was continued with stirring for 6 hours, the reaction was quenched with water, the organic phase was washed with brine, and then dried over anhydrous sodium sulfate, the organic phase was concentrated, and column chromatography (petroleum ether / ethyl acetate = 4:1) was performed to obtain the product 2-fluoro-2,2-diphenylsulfone trifluoromethanesulfonate 16.0 g, with a yield of 84%. 1 H NMR (500 MHz, CDCl 3)δ8.07-7.92(m,4H),7.79(t,J=7.5Hz,2H),7.61(t,J=7.9Hz,4H),5.25(d,J=16.9Hz,2H). 13 C NMR (126 MHz, CDCl 3 )δ136.2,134.6,131.1,118.2(q,J=320.1Hz),110.1(d,J=277.2Hz),69.3(d,J=18.9Hz). 19 F NMR (470 MHz, CDCl 3 )δ-74.05,-149.00(t,J=16.9Hz).HRMS(ESI)m / z calcd.for C 15 H 12 F 4 O 7 S 3 [M+H] + =475.9681; found 475.9684.

[0047] Example 7: Preparation of 2-fluoro-2,2-bis(4-methylphenylsulfone)trifluoromethanesulfonate

[0048] According to the preparation method in Example 6, 18.56 g of compound 2-fluoro-2,2-di(4-methylphenylsulfone)trifluoromethanesulfonate was prepared, with a yield of 92%.

[0049] Example 8: Preparation of 2-fluoro-2,2-di(naphthalene-2-sulfone) trifluoromethanesulfonate

[0050] 19.8 g of the compound 2-fluoro-2,2-di(naphthalene-2-sulfone) trifluoromethanesulfonate was prepared by referring to the preparation method in Example 6 with a yield of 86%.

[0051] Example 9: Preparation of 2-fluoro-2,2-bis(4-fluorophenylsulfone)trifluoromethanesulfonate

[0052] The compound 2-fluoro-2,2-di(4-fluorophenylsulfone)trifluoromethanesulfonate (17.4 g) was prepared by referring to the preparation method in Example 5 with a yield of 85%.

[0053] Example 10: Preparation of 2-fluoro-2,2-diphenylsulfoneethylamine

[0054] 2-Fluoro-2,2-diphenylsulfone trifluoromethanesulfonate (19.1 g, 40 mmol) and 150 mL DMF were added to a three-necked flask. Sodium azide (3.4 g, 52 mmol) was added to the solution in batches at room temperature. The reaction was stirred overnight, quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with brine again, dried over anhydrous sodium sulfate, and concentrated for the next reduction reaction. 10% Pd / C (500 mg) was added to the methanol solution of the azide compound at room temperature, and a hydrogen balloon was added to the reaction flask. TLC detected that the reaction raw materials completely disappeared. The mixture was filtered and concentrated under reduced pressure to obtain 13.4 g of the compound 2-fluoro-2,2-diphenylsulfoneethylamine, with a two-step yield of 98%. 1 H NMR (500 MHz, CDCl 3 )δ7.97-7.89(m,4H),7.81-7.70(m,2H),7.58(t,J=7.9Hz,4H),3.60(d,J=11.2Hz,2H),2.93(d,J=29.3Hz,2H). 13 C NMR (126 MHz, CDCl 3 )δ135.4,134.9,130.8,129.2,112.4(d,J=266.2Hz),43.5(d,J=20.6Hz). 19 F NMR (470 MHz, CDCl 3 )δ-144.48(t,J=11.2Hz).HRMS(ESI)m / z calcd.for C 14 H 14 FNO 4 S 2 [M+H] + =343.0348; found 343.0350.

[0055] Example 11: Preparation of 2-fluoro-2,2-di(4-methylphenylsulfonyl)ethylamine

[0056] The compound 2-fluoro-2,2-di(4-methylphenylsulfonyl)ethylamine (14.6 g) was prepared by referring to the preparation method in Example 10 with a yield of 96%.

[0057] Example 12: Preparation of 2-fluoro-2,2-di(naphthalene-2-sulfone)ethylamine

[0058] The compound 2-fluoro-2,2-di(naphthalene-2-sulfone)ethylamine (16.3 g) was prepared by referring to the preparation method in Example 10 with a yield of 92%.

[0059] Example 13: Preparation of 2-fluoro-2,2-di(4-fluorophenylsulfone)ethylamine

[0060] The compound 2-fluoro-2,2-di(4-fluorophenylsulfone)ethylamine (13.6 g) was prepared by referring to the preparation method in Example 10 with a yield of 90%.

[0061] Example 14: Preparation of 2-fluoro-2,2-bis(4-methoxyphenylsulfone)acetaldehyde

[0062] Under argon protection, DMP (31.9 g, 75 mmol) was added to a dichloromethane solution (400 ml) of 2-fluoro-2,2-bis(4-methoxyphenylsulfone)ethanol (20.2 g, 50 mmol). The mixture was stirred at room temperature for 2 h. TLC detected that the reaction was complete, and the reaction was quenched by adding sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution. It was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (petroleum ether: ethyl acetate: = 10:1) to obtain 18.3 g of the compound 2-fluoro-2,2-bis(4-methoxyphenylsulfone)acetaldehyde, with a yield of 91%. 1 H NMR (400 MHz, CDCl 3 )δ9.88(s,1H),8.08-8.03(m,2H),7.95(td,J=7.9,3.6Hz,2H),7.73-7.66(m,4H),3.78(s,6H). 19 FNMR (470MHz, CDCl 3 )δ-134.8.

Claims

1. A monofluorodiarylsulfoneethylamine derivative, characterized in that: The structural formula is shown in formula (I): Wherein, Ar is selected from substituted or unsubstituted C6-C10 aryl groups.

2. The monofluorodiarylsulfoneethylamine derivative according to claim 1, characterized in that The Ar is selected from one of formula (1) to formula (12):

3. The monofluorodiarylsulfoneethylamine derivative according to claim 1, characterized in that: As shown in one of formula L-1 to formula L-12:

4. The monofluorodiarylsulfoneethylamine derivative according to claim 3, characterized in that: Preferably selected from formula L-1, L-5 to L-7:

5. A method for synthesizing a monofluorodiarylsulfoneethylamine derivative of formula (I), characterized in that: The following steps are involved: Step (1): adding a base and formaldehyde to a solution of monofluorodiarylsulfonemethane (II) to prepare a compound of formula (III); Step (2): In the presence of a base, adding an acid anhydride or an acid chloride to the compound of formula (III) to prepare a compound of formula (IV); Step (3): Sodium azide is added to the solution of the compound of formula (IV), and then nitrogen is removed by reduction to prepare a monofluorodiarylsulfoneethylamine derivative of formula (I): Step (4): oxidizing the compound of formula (III) in the presence of an oxidizing agent to prepare a compound of formula (V); Step (5): subjecting the compound of formula (V) to reductive amination to prepare a monofluorodiarylsulfoneethylamine derivative of formula (I). Wherein, Ar is selected from substituted or unsubstituted C6-C10 aryl groups.

6. The preparation method according to claim 5, characterized in that: In the step (1), the molar ratio of the compound of formula (II) to the base is 1:1-1:2; the molar ratio of the compound of formula (II) to formaldehyde is 1:1-1:2, the base is selected from one of the inorganic bases of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, cesium carbonate, and potassium tert-butoxide, the reaction temperature is 0-25°C, and the organic solvent used in the reaction is selected from one of dichloromethane, chloroform, acetone, benzene, and toluene.

7. The preparation method according to claim 5, characterized in that: In the step (2), the acid anhydride or acyl chloride used in the reaction is selected from one of trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, and p-trifluoromethylbenzenesulfonyl chloride; the molar ratio of the compound of formula (III) to the acid anhydride or acyl chloride is 1:1 to 1:2; the base is selected from one of triethylamine, pyridine, 2,6-lutidine, hexahydropyridine, 4-dimethylaminopyridine, DBU, and DBACO; the solvent is one of dichloromethane, chloroform, ether, acetone, benzene, toluene, acetonitrile, DMF, and DMSO; and the reaction temperature is 0 to 50°C.

8. The preparation method according to claim 5, characterized in that: In the step (3), the molar ratio of the compound of formula (IV) to sodium azide is 1:1 to 1:2; the reduction reaction catalyst is one of Pd / C, Pt / C, Raney Ni, and sodium sulfide; the solvent is one or more of methanol, ethanol, and water; and the reaction temperature is room temperature.

9. The preparation method according to claim 5, characterized in that: In the step (4), the reaction reagent is selected from one of CrO3·2Py, DCC, DMSO, oxalyl chloride, acetic anhydride, triisopropoxyaluminum, pyridinium chlorochromate, pyridinium dichromate, 4-dimethylaminopyridine, and DMP; the solvent is one of dichloromethane, DMSO, acetone, DMF, acetonitrile, and chloroform; and the reaction temperature is 0 to 30°C.

10. The preparation method according to claim 5, characterized in that: In the step (5), the reducing agent is selected from one of Pd / C, Pt / C, Raney Ni, and sodium cyanoborohydride; the catalyst is selected from Co@CN(800); and the solvent is ethanol or methanol.

Images