A compound, preparation method and application thereof

Abstract

The application discloses a compound and a preparation method and application thereof, and relates to the technical field of medicine synthesis. The compound is {[(2S)-1-{[4-(3,5-dimethylisoxazole-4-yl)-2-nitrophenyl]amino}propan-2-yl]amino}methane acid-2-methylpropan-2-yl ester, which is prepared by using 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole and ((S)-1-aminopropan-2-yl) tert-butyl carbamate as main raw materials and by performing a nucleophilic substitution reaction in the presence of an alkali; and the compound is applied to prepare a medical intermediate of SGC-CBP30 by performing a deprotection reaction in the presence of an acid. The preparation method is simple in process, low in equipment investment, mild in reaction condition, easy to control, high in yield and suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a compound, a preparation method and application thereof. BACKGROUND

[0002] SGC-CBP30 is a potent CBP / P300 inhibitor. CBP / EP300 bromodomain is related to diseases such as acute myeloid leukemia (AML), inflammation and neurodegenerative diseases, and is considered to be the most promising non-BET bromodomain target. Studies have shown that SGC-CBP30 has good therapeutic effect on cancer and inflammatory diseases.

[0003] (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (Formula D) is a key intermediate for preparing SGC-CBP30. The literature Journal of the American Chemical Society, 136(26), 9308-9319, 2014 reported that the intermediate can be prepared from 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (Formula A) and (2S)-propane-1,2-diamine (Formula B-1) as raw materials. The preparation method produces a large amount of regioselective by-products (Formula E), resulting in low utilization of raw materials, and the yield is only 41%. At the same time, the method uses column chromatography for purification, which is complex and not suitable for industrial production. The preparation method is as follows:

[0004] SUMMARY

[0005] The present application aims to provide a compound, a preparation method and application thereof, which uses 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole and ((S)-1-aminopropan-2-yl) tert-butyl carbamate as main raw materials, and a nucleophilic substitution reaction occurs in the presence of a base to obtain a compound shown as Formula III. The compound shown as Formula III is used to prepare a pharmaceutical intermediate (a compound shown as Formula IV) of SGC-CBP30 by a deprotection reaction in the presence of an acid, so as to solve the technical problems of low utilization of raw materials, many by-products and unsuitability for industrial production in the preparation of the existing pharmaceutical intermediate of SGC-CBP30.

[0006] To solve the above technical problems, the present application adopts the following technical scheme:

[0007] A compound, the structure of which is shown as Formula III or each optical isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:

[0008] .

[0009] The chemical name of the compound shown in formula III is {[(2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-yl]amino}methane acid-2-methylpropan-2-yl ester.

[0010] A preparation method suitable for the preparation of the compound, comprising the following contents:

[0011] The compound I and the compound II undergo a nucleophilic substitution reaction in the presence of a base in a solvent to obtain the compound shown in formula III;

[0012] The reaction formula is as follows:

[0013] .

[0014] The present application uses 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (compound I) and ((S)-1-aminopropan-2-yl) tert-butyl carbamate (compound II) as raw materials, and a SNAr nucleophilic aromatic substitution reaction occurs in the presence of a base to obtain {[(2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-yl]amino}methane acid-2-methylpropan-2-yl ester (a compound shown in formula III).

[0015] The present application directly uses the chiral raw material ((S)-1-aminopropan-2-yl) tert-butyl carbamate (compound II), and no operation of a chiral center is involved in the synthesis (the SNAr occurs on the N of the amine, far away from the chiral C), which ensures the optical purity of the compound shown in formula III, avoids a complex chiral synthesis or a separation step, and only uses an acid and a base. The preparation method of the present application only uses a base and does not involve a noble metal catalyst, significantly reduces the cost, has a mild reaction condition and can be carried out at room temperature, and has a high yield of 95.9%.

[0016] Further, the molar ratio of the compound I to the compound II is 1:0.8-3.0.

[0017] Further, the base includes one or both of N,N-diisopropylethylamine or potassium carbonate.

[0018] When the base includes N,N-diisopropylethylamine and potassium carbonate, the mass ratio of N,N-diisopropylethylamine to potassium carbonate is 0.8-1:1.

[0019] Further, the solvent includes one or both of tetrahydrofuran or N,N-dimethylformamide.

[0020] One application of the compound in the preparation of an SGC-CBP30 pharmaceutical intermediate.

[0021] Further, the preparation of the SGC-CBP30 pharmaceutical intermediate includes the following contents:

[0022] The compound shown in formula III is subjected to removal of the protecting group in the presence of an acid in a solvent to obtain the intermediate shown in formula IV;

[0023] The reaction is as follows:

[0024] .

[0025] The application removes the Boc protection of the compound shown in formula III under acidic conditions to obtain (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (the intermediate shown in formula IV), and the intermediate shown in formula IV is an important SGC-CBP30 pharmaceutical intermediate. The compound shown in formula III is a chiral compound, and the preparation of the SGC-CBP30 pharmaceutical intermediate from the compound shown in formula III does not involve the operation of the chiral center in the reaction, thereby ensuring the optical purity of the final product and avoiding the complex chiral synthesis or separation steps. Only an acid is used, and no noble metal catalyst is involved, thereby significantly reducing the cost; the reaction condition is mild, and the reaction can be carried out at room temperature; and the yield is high, and can reach 96.1%.

[0026] Further, the molar ratio of the compound I and the base is 1:2-4; and the molar ratio of the compound shown in formula III and the acid is 1:1-10.

[0027] Further, the acid includes one of hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid.

[0028] Further, the solvent of the reaction includes one or both of methanol and dichloromethane.

[0029] Compared with the prior art, the application has the following beneficial effects:

[0030] The application provides a new structure intermediate compound {[(2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-yl]amino}methane acid-2-methylpropan-2-yl ester (the compound shown in formula III), which is prepared from 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole and ((S)-1-aminopropan-2-yl) tert-butyl carbamate in the presence of a base. The application removes (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (an important SGC-CBP30 pharmaceutical intermediate) from the compound shown in formula III under acidic conditions. The preparation method of the application has the advantages of simple process, less equipment investment, mild reaction condition, easy control, high yield and strong process amplification feasibility. DETAILED DESCRIPTION

[0031] Example 1

[0032] Into a 5L reaction flask was placed 112.0g of 4-(4-fluoro-3-nitrophenyl)-3,5- dimethylisoxazole, 99.4g of tert-butyl ((S)-1-aminopropan-2-yl)carbamate, 2.8L of tetrahydrofuran, 215g of N,N-diisopropylethylamine, stirred and warmed, and refluxed for 2h. 0.6L of N,N-dimethylformamide and 228.4g of potassium carbonate were added, and refluxed for 4h. The tetrahydrofuran was removed by concentration under reduced pressure, 2L of water and 2L of ethyl acetate were added, stirred, and separated into layers. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate C (177.5g, yield 95.9%).

[0033] 1 H NMR (400MHz, Chloroform-d) δ 8.39-8.30 (m, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 10.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.58-4.49 (m, 1H), 4.07-3.96 (m, 1H), 3.53-3.48 (m, 1H), 3.40-3.31 (m, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 1.46 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H).

[0034] Into a 5L reaction flask was placed 177.5g of intermediate C, 1L of methanol, and 1L of dichloromethane, stirred and dissolved, and 0.4L of 6mol / L hydrochloric acid was added dropwise. The reaction was allowed to proceed at room temperature for 18h. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, stirred, and separated into layers. The water layer was adjusted to pH > 8 with potassium carbonate solution, 1L of dichloromethane was added, stirred, and separated into layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (126.8g, yield 96.1%).

[0035] 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 9.0, 2.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.46 - 3.26 (m, 2H), 3.25 - 3.12 (m, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 1.25 (d, J = 6.0 Hz, 3H).

[0036] Example 2

[0037] Into a 5L reaction flask was placed 112.0g of 4-(4-fluoro-3-nitrophenyl)-3,5- dimethylisoxazole, 66.1g of tert-butyl ((S)-1-aminopropan-2-yl)carbamate, 2.8L of tetrahydrofuran, 215g of N,N-diisopropylethylamine, stirred and warmed, and refluxed for 2h. 0.6L of N,N-dimethylformamide, 228.4g of potassium carbonate was added, and refluxed for 4h. The tetrahydrofuran was removed by concentration under reduced pressure, 2L of water and 2L of ethyl acetate were added, stirred, and separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate C (152.0g, yield 82.1%).

[0038] Into a 5L reaction flask was placed 152.0g of intermediate C, 1L of methanol, and 1L of dichloromethane, stirred and dissolved, and 65mL of 6mol / L hydrochloric acid was added dropwise, and reacted at room temperature for 18h. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, stirred, and separated. The water layer was adjusted to pH>8 with potassium carbonate solution, 1L of dichloromethane was added, stirred, and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (106.6g, yield 94.3%).

[0039] Example 3

[0040] Into a 5L reaction flask was placed 112.0g of 4-(4-fluoro-3-nitrophenyl)-3,5- dimethylisoxazole, 66.1g of tert-butyl ((S)-1-aminopropan-2-yl)carbamate, 2.8L of tetrahydrofuran, 215g of N,N-diisopropylethylamine, stirred and warmed, and refluxed for 2h. 0.6L of N,N-dimethylformamide, 228.4g of potassium carbonate was added, and refluxed for 4h. The tetrahydrofuran was removed by concentration under reduced pressure, 2L of water and 2L of ethyl acetate were added, stirred, and separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate C (152.0g, yield 82.1%).

[0038] Into a 5L reaction flask was placed 152.0g of intermediate C, 1L of methanol, and 1L of dichloromethane, stirred and dissolved, and 65mL of 6mol / L hydrochloric acid was added dropwise, and reacted at room temperature for 18h. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, stirred, and separated. The water layer was adjusted to pH>8 with potassium carbonate solution, 1L of dichloromethane was added, stirred, and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (106.6g, yield 94.3%).

[0039] Example 3

[0040] Into a 5L reaction flask was placed 112.0g of 4-(4-fluoro-3-nitrophenyl)-3,5- dimethylisoxazole, 66.1g of tert-butyl ((S)-1-aminopropan-2-yl)carbamate, 2.8L of tetrahydrofuran, 215g of N,N-diisopropylethylamine, stirred and warmed, and refluxed for 2h. 0.6L of N,N-dimethylformamide, 228.4g of potassium carbonate was added, and refluxed for 4h. The tetrahydrofuran was removed by concentration under reduced pressure, 2L of water and 2L of ethyl acetate were added, stirred, and separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate C (152.0g, yield 82.1%).

[0041] To a 5L reaction flask was added 171.3g of Intermediate C, 2L of dichloromethane, and stirred to dissolve. 200g of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed at room temperature for 8 hours. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, and stirred and separated. The aqueous layer was adjusted to pH > 8 with potassium carbonate solution, 1L of dichloromethane was added, stirred and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (115.4g, yield 90.6%).

[0042] Example 4

[0043] To a 5L reaction flask was added 171.3g of Intermediate C, 2L of dichloromethane, and stirred to dissolve. 200g of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed at room temperature for 8 hours. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, and stirred and separated. The aqueous layer was adjusted to pH > 8 with potassium carbonate solution, 1L of dichloromethane was added, stirred and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (115.4g, yield 90.6%).

[0044] To a 5L reaction flask was added 171.3g of Intermediate C, 2L of dichloromethane, and stirred to dissolve. 200g of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed at room temperature for 8 hours. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, and stirred and separated. The aqueous layer was adjusted to pH > 8 with potassium carbonate solution, 1L of dichloromethane was added, stirred and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (115.4g, yield 90.6%).

[0045] Example 5

[0046] To a 5L reaction flask was added 171.3g of Intermediate C, 2L of dichloromethane, and stirred to dissolve. 200g of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed at room temperature for 8 hours. The organic solvent was removed by concentration under reduced pressure, 1L of water and 1L of dichloromethane were added, and stirred and separated. The aqueous layer was adjusted to pH > 8 with potassium carbonate solution, 1L of dichloromethane was added, stirred and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (115.4g, yield 90.6%).

[0047] Into a 5L reaction flask was added 170.5g of intermediate C, 2L of dichloromethane, stirred to dissolve, added 150g of p-toluenesulfonic acid, reacted at room temperature for 18h. The organic solvent was removed by concentration under reduced pressure, added 1L of water and 1L of dichloromethane, stirred, separated. The water layer was adjusted to pH>8 with potassium carbonate solution, added 1L of dichloromethane, stirred, separated. The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the target compound (2S)-1-{[4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl]amino}propan-2-amine (114.4g, yield 90.2%).

[0048] Finally, it should be pointed out that the above preferred embodiments are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present application.

Claims

1. A compound, characterized in that, A compound as shown in formula III or each optical isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof: 。 2. A process for the preparation of a compound as claimed in claim 1, characterized in that, The application relates to a preparation method of SGC-CBP30 medical intermediates. The nucleophilic substitution reaction of compound I and compound II in the presence of a base in a solvent obtains a compound as shown in formula III; The general reaction formula is as follows: 。 3. The production method according to claim 2, characterized by, The molar ratio of compound I and compound II is 1:0.8-3.

0.

4. The preparation method according to claim 2, characterized in that, The base includes one or both of N,N-diisopropyl ethylamine and potassium carbonate.

5. The preparation method according to claim 2, characterized in that, The solvent includes one or both of tetrahydrofuran and N,N-dimethylformamide.

6. Use of a compound as claimed in claim 1 in the preparation of SGC-CBP30 medical intermediates.

7. Use according to claim 6, characterized in that, The preparation of SGC-CBP30 medical intermediates includes the following steps: The deprotection of the compound as shown in formula III in the presence of an acid in a solvent obtains an intermediate as shown in formula IV; The general reaction formula is as follows: 。 8. Use according to claim 7, characterized in that, The molar ratio of compound I and the base is 1:2-4; the molar ratio of the compound as shown in formula III and the acid is 1:1-10.

9. Use according to claim 7, characterized in that, The acid includes one of hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid.

10. Use according to claim 7, characterized in that, The solvent of the reaction includes one or both of methanol and dichloromethane.

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