CN111606902A - Ester pyrazole bithiazole amine compound and preparation method and application thereof - Google Patents

Abstract

The invention discloses an ester pyrazole bithiazole amine compound, a preparation method and application thereof, wherein the structural general formula of the compound is as follows:

. The compound is a double five-membered azacyclo bifunctional compound, is convenient for realizing high-flux synthesis and diversified derivation of thiazolylamine and pyrazole, and can be widely applied to research, development and production of thiazole dipyrazole medicaments.

Description

Ester pyrazole bithiazole amine compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to ester pyrazole isothiazolamine and a preparation method and application thereof.

Background

Thiazole and pyrazole are common compound groups in medicinal chemistry, and the generated derivatives have good biological activity, such as cancer cell migration resistance, antifungal property and anti-proliferation property. The aromatic ring-thiazole-pyrazole organic acid is used as a pharmaceutically active intermediate, and an intermediate with different substituent groups on the aromatic ring needs to be synthesized. The current route for the synthesis of aromatic ring-thiazole-pyrazole organic acids is to perform amide condensation of aromatic (heteroaromatic-containing) acids with different substituents with aminothiazolones, and then perform claisen condensation, pyrazole cyclization and ester hydrolysis reactions, respectively (Long Ye, John M. Knapp, Panjamaporon Sangwung, James C. Fettinger, A.S. Verkman, and Mark J. Kurth, pyrazolythizolyloles. DELTA.F 508-cysteine fibers, transfer membrane reactor Regulator and reactor with improved hydrogenation reaction J. Med. chem. 2010, 53, 3772-3781). In the method, the structural diversification is realized in the early stage of synthesis, and the synthesis of a target product with different substituents is repeated from the synthesis of raw materials, so that the reaction economy is not high. Therefore, the method for efficiently synthesizing the aromatic ring-thiazole-pyrazole organic acid is of great significance to the discovery of medicaments and the research on the structure-activity relationship of compounds and proteins.

Disclosure of Invention

In order to improve the synthesis efficiency of the aromatic ring-thiazole-pyrazole organic acid, according to one aspect of the invention, an ester pyrazole bithiazole amine compound is provided, and the structural general formula of the compound is as follows:

，

wherein R is¹-R²At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, aromatic radical (benzene ring and substituted benzene ring), R³-R⁶At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl groups, aromatic groups (benzene rings and substituted benzene rings).

According to another aspect of the present invention, there is provided a method for preparing the ester pyrazole bithiazole amine compound, the method employs an amino protection strategy, after a pyrazole ring is constructed, the amino group on the thiazole ring is released, so as to facilitate the diversity of the later-stage amino amide condensation reaction, and after the hydrolysis of the ester group on the pyrazole ring, the method can further perform diversity derivatization, and comprises the following steps:

first, compound 1 and (Boc)₂Performing amino protection reaction on O (di-tert-butyl dicarbonate) to obtain a compound 2, performing claisen condensation reaction on the compound 2 and diethyl oxalate to obtain a compound 3, performing pyrazole cyclization reaction on the compound 3 and hydrazine hydrate to obtain a compound 4, and performing deprotection reaction on the compound 4 under the action of TFA (trifluoroacetic acid) to obtain a compound 5; the reaction route is as follows:

，

wherein R is¹-R²At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, aromatic radical (benzene ring and substituted benzene ring), R³-R⁶At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl groups, aromatic groups (benzene rings and substituted benzene rings).

According to another aspect of the invention, the application of the ester pyrazole isothiazolamine compound in synthesis of aromatic ring-thiazole-pyrazole organic acid (compound 7) is further provided, namely, the compound 5 is subjected to amide condensation reaction with aromatic (heteroaromatic) acid with different substituents, and then subjected to ester hydrolysis reaction to obtain aromatic ring-thiazole-pyrazole organic acid; the reaction route is as follows:

wherein R is¹-R²At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, aromatic radical (benzene ring and substituted benzene ring), R³-R⁶At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, aryl (benzene ring and substituted benzene ring), R⁷At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, halogen, aromatic base (benzene ring and substituted benzene ring).

Therefore, the invention provides a novel ester pyrazole bithiazole amine compound, and a preparation method and application thereof. The compound is a double five-membered azacyclo bifunctional compound, is convenient for realizing high-flux synthesis and diversified derivation of thiazolylamine and pyrazole, and can be widely applied to research, development and production of thiazole dipyrazole medicaments.

Drawings

FIG. 1 is a drawing of Compound 5¹H NMR spectrum;

FIG. 2 is a HRMS profile of a bioactive compound.

Detailed Description

The present invention is further illustrated by the following specific examples, which are only intended to illustrate the invention and not to limit the scope of the invention, and all other examples obtained by a person skilled in the art based on the examples of the present invention shall fall within the scope of the protection of the present invention.

Synthesis of the Compound of example 1

The structural formula of the compound is as follows:

，

wherein in the example compounds R¹=CH₃，R²=R⁴=R⁵=R⁶=H,R³=Et。

The compounds can be prepared by the following preparation schemes, the reaction schemes are as follows:

。

the specific synthesis steps are as follows:

(a) preparation of Compound 2

Compound 1 (8.1 g, 51.9 mmol) was added to tetrahydrofuran THF (260 ml) under ice bath, followed by addition of triethylamine (28.86 ml, 207.62 mmol) and 4-dimethylaminopyridine DMAP (95.12 mg, 778.57. mu. mol), respectively, and after 10 min, di-tert-butyl dicarbonate (Boc) was added dropwise₂O (71.62 ml, 311.43 mmol), stirring was continued for 10 min, the ice bath was removed and the reaction was heated to reflux for 5 h. Filtering by suction to obtain filtrate, removing solvent to obtain solid, drying, dissolving with DMF, adding water, filtering, and drying to obtain white solid compound 2 (13.3 g, yield 100%).¹H NMR （600 MHz，Chloroform-d） 11.31（s，1H），2.69（s，3H），2.50（s，3H），1.56（s，9H）。

(b) Preparation of Compound 3

Dissolving the compound 2 (13.3 g, 51.89 mmol) in dry THF (240 mL), adding the solution into a dry THF solution of lithium bis (trimethylsilyl) amide LHDMS (1M in THF, 92.2 mL) at-50 to-80 ℃, stirring and reacting for 45 min under the protection of nitrogen, adding diethyl oxalate (14.07 mL, 103.78 mmol), and continuing to react for 5 h. Returning to room temperature, rotary evaporation to remove THF, solid grinding into powder, adding water, using 1M HCl to adjust pH to weak acidity, filtering, drying to obtain yellow solid compound 3 (15.5 g yield 83.8%).¹H NMR（600 MHz，Methanol-d ₄） 4.35（d，J= 8.1 Hz，1H），4.06（s，2H），2.54（s，3H），1.55（s，9H），1.28（s，3H）。

(c) Preparation of Compound 4

Compound 3 (15.5 g, 43.49 mmol) was dissolved in ethanol (217.45 ml), and hydrazine hydrate (2.54 ml, 52.19 mmol) was added thereto, followed by heating under reflux for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered to obtain a filtrate, and the filtrate was evaporated to remove the solvent and dried to obtain compound 4 (14.1 g, yield 93%) as a yellow solid.¹H NMR（600 MHz，DMSO-d ₆） 11.53 （s，1H），6.92（s，1H），4.32（t，J= 7.1 Hz，2H），2.38（s，3H），1.49 （s，9H），1.32（t，J= 7.0 Hz，3H）。

(d) Preparation of Compound 5

Compound 4 (14.1 g, 40 mmol) was dissolved in dichloromethane DCM (200 ml), and TFA (44.4 ml, 598.1 mmol) was added and reacted at room temperature for 3 h. Removing solvent by rotary evaporation, and adding saturated NaHCO₃Then, the reaction mixture was filtered with suction and dried to obtain Compound 5 (7.79 g, yield 78.9%) as a yellow solid.¹H NMR（600 MHz，DMSO-d ₆） 9.36（s，2H），7.03（s，1H），4.34 – 4.29（m，2H），1.30（t，J= 7.1 Hz，3H）。

EXAMPLE 2 use of Compounds in the Synthesis of aromatic Ring-thiazole-pyrazole organic acids

The structural general formula of the aromatic ring-thiazole-pyrazole organic acid compound is as follows:

。

in the above formula, R⁷At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, halogen, aromatic base (benzene ring and substituted benzene ring); the reaction route is as follows:

。

the specific synthesis steps are as follows:

(a) preparation of Compound 6

Dissolving aromatic acid (1 equiv) with different substituents in DMF, reacting with CDI (1.3 euquiv) for 30min, adding compound 5 (1 equiv), and heating under reflux for 15 h. After the reaction is finished, cooling to room temperature, adding water, filtering to obtain a solid, and drying to obtain the compound 6, wherein the yield is 80%.

When R is⁷When H, the compound has the structural formula:

。

¹H NMR（600 MHz，Methanol-d ₄） 8.02（d，J= 7.7 Hz，2H），7.63（t，J= 7.4 Hz，1H），7.55 （t，J= 7.6 Hz，2H），6.97（s，1H），4.40（q，J= 7.2 Hz，2H），2.48（s，3H），1.40（q，J= 7.0 Hz，3H）。

when R is⁷Is 4-CH₃The structural formula of the compound is as follows:

。

¹H NMR（600 MHz，Methanol-d ₄） 7.92（d，J= 7.6 Hz，2H），7.36（t，J= 7.7 Hz，2H），4.40（q，J= 7.3 Hz，2H），2.50（s，3H），2.43（d，J= 6.7 Hz，3H），1.40 （t，J= 7.2Hz，3H）。

when R is⁷When the structure is 2-Br, the compound formula is as follows:

。

¹H NMR（600 MHz，Methanol-d ₄） 7.72（d，J= 8.0 Hz，1H），7.57（d，J= 7.9 Hz，1H），7.50（s，1H），7.45（d，J= 8.3 Hz，1H），6.99（s，1H），4.40（q，J= 7.8， 7.3 Hz，2H），2.48（s，3H），1.41（d，J= 7.8 Hz，3H）。

(b) preparation of Compound 7

Compound 6 (1 equiv) was dissolved in THF, and 1M NaOH (1 equiv) solution was added to react at room temperature for 48 hours. Removing THF by rotary evaporation, extracting to remove impurities, collecting aqueous phase, adding 1M HCl to weak acidity, filtering, and oven drying to obtain compound 7 with yield of 75%.

When R is⁷When H, the compound has the structural formula:

。

¹H NMR（600 MHz，Methanol-d ₄） 8.02（d，J= 7.5 Hz，2H），7.63（t，J= 7.4 Hz，1H），7.55（t，J= 7.3 Hz，2H），6.86（d，J= 5.5 Hz，1H），2.50（s，3H）。

when R is⁷Is 4-CH₃The structural formula of the compound is as follows:

。

¹H NMR（600 MHz，Methanol-d ₄） 7.93（s，2H），7.38（s，2H），6.99（s，1H），2.51 s，3H），2.44（s，3H）。

when R is⁷When the structure is 2-Br, the compound formula is as follows:

。

¹H NMR（600 MHz，Methanol-d ₄） 7.73（s，1H），7.48（d，J= 34.1 Hz，2H），7.00（s，1H）， 2.51（d，J= 16.5 Hz，3H）。

the above description is only a preferred embodiment of the present invention, and should not be taken as limiting the invention, and all modifications, equivalents, improvements and the like that are included in the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (4)

1. An ester pyrazole bithiazole amine compound has a structural general formula as follows:

，

wherein R is¹-R²At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, aromatic radical (benzene ring and substituted benzene ring), R³-R⁶At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl groups, aromatic groups (benzene rings and substituted benzene rings).

2. The method for preparing an esterpyrazole bithiazole amine compound according to claim 1, which comprises:

first, compound 1 and (Boc)₂Performing amino protection reaction on O (di-tert-butyl dicarbonate) to obtain a compound 2, performing claisen condensation reaction on the compound 2 and diethyl oxalate to obtain a compound 3, performing pyrazole cyclization reaction on the compound 3 and hydrazine hydrate to obtain a compound 4, and performing deprotection reaction on the compound 4 under the action of TFA (trifluoroacetic acid) to obtain a compound 5; the reaction route is as follows:

，

wherein R is¹-R²At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, aromatic radical (benzene ring and substituted benzene ring), R³-R⁶At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl groups, aromatic groups (benzene rings and substituted benzene rings).

3. Use of an esterpyrazole bithiazole amine compound as claimed in claim 1 for the synthesis of aromatic ring-thiazole-pyrazole organic acids.

4. Use according to claim 3, wherein the aromatic ring-thiazole-pyrazole organic acid is synthesized by the following route: the compound 5 firstly generates amide condensation reaction with aromatic (containing heteroaromatic) acid with different substituent groups, and then aromatic ring-thiazole-pyrazole organic acid (compound 7) is obtained through ester hydrolysis reaction; the reaction route is as follows:

，

wherein R is¹-R²At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, aromatic radical (benzene ring and substituted benzene ring), R³-R⁶At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, aryl (benzene ring and substituted benzene ring), R⁷At least comprising hydrogen and C₁-C₄Saturated or unsaturated alkyl, saturated or unsaturated alkoxy, halogen, aromatic base (benzene ring and substituted benzene ring).

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