A method for synthesizing a beta-cyanopyrazole compound

Abstract

The application discloses a synthesis method of a beta-cyano pyrazole compound. The Michael addition product of hydrazine hydrate to cyano-substituted olefin is obtained, and after salt formation by adding acid, stable 3-amino-1H-hydrogenated pyrazole or its salt type is obtained by alkaline treatment or heating treatment. Then, the stable synthon is reacted with a 1,3-dicarbonyl compound or an equivalent 1,3-diimine compound to obtain a beta-cyano-substituted pyrazole ring compound. After further conversion, the molecules of Rociitinib or Baricitinib can be obtained. The application avoids the use of expensive transition metal catalysts, avoids the use of unstable intermediates, shortens the reaction route, and greatly improves the amplification and industrial production efficiency of the process.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and relates to the synthesis of β-cyanopyrazole compounds, particularly to a method for synthesizing cyanosubstituted pyrazole compounds using 3-amino-1H-hydropyrazole or its salt as an equivalent synthon of β-hydrazinopropionitrile. Background Technology

[0002] The Janus kinase (JAK) family plays a role in the cytokine-dependent regulation of cell proliferation and function involved in immune responses. Blocking signal transduction at the JAK kinase level offers promise for the development of treatments for inflammatory diseases, autoimmune diseases, myeloproliferative disorders, and cancer. In 2011, the world's first JAK inhibitor, ruxolitinib, was approved by the FDA for the treatment of intermediate- to high-risk myelofibrosis patients. Subsequently, Novartis and Inset developed applications of ruxolitinib in multiple areas, and it has been successfully used for dozens of diseases, including atopic dermatitis, graft-versus-host disease, polycythemia vera, and primary myelofibrosis. It has also received FDA Emergency Use Authorization (EUA) for invasive mechanical ventilation or ECMO. In June 2022, baricitinib became the first FDA-approved systemic therapy for alopecia areata.

[0003] Ruxolitinib and baricitinib, two blockbuster JAK inhibitors, share a common structural feature—both contain a β-cyano-substituted pyrazole ring. Despite growing market demand for these two drugs, there are still relatively few reported synthetic methods for this class of compounds.

[0004] Inset reported a method to obtain the target pyrazole structure (WO2009114512) by coupling a protected pyrazole borate (ester) with a halide followed by deprotection and Michael addition. This coupling reaction used an expensive palladium catalyst, and the nitrogen on the pyrazole ring required both protection and deprotection, resulting in a lengthy route and high production costs.

[0005] Patent CN113292569 also reports a similar method for synthesis using the noble metal palladium as a catalyst.

[0006] It is worth mentioning that patent WO2022040180 reports a cyclization reaction of alkyl-substituted hydrazine compounds with 1,3-dialdehyde or 1,3-diimine compounds to obtain the target pyrazole structure. This method avoids the use of precious metals, has a high degree of convergence, and is more efficient. However, alkyl-substituted hydrazine compounds obtained by Michael addition of hydrated hydrazine are highly susceptible to intramolecular or intermolecular addition reactions due to the presence of the cyano group. Once a chain reaction is initiated, the purity and content of the product decrease drastically. Due to the instability of this intermediate, adding acid to the solution to form its salt form can temporarily stabilize the product. However, in practical applications, the stability is still limited, which is not conducive to the storage of intermediates for industrial-scale production.

[0007] In addition, Chia Tai Tianqing Pharmaceutical reported another synthetic method that uses pyrazolone and 1,3-dialdehyde to construct a pyrazolone ring structure. The resulting carboxyl-substituted intermediate still needs to undergo three transformation steps to obtain the target cyano compound. The route is too long, and the amines at other positions need to be protected by protecting groups (WO2017114461).

[0008] Therefore, it is particularly important to continue developing a simple, efficient, cost-controllable method for synthesizing β-cyanopyrazole compounds that is conducive to large-scale production. Summary of the Invention

[0009] To address the aforementioned problems, this invention provides a method for synthesizing β-cyanopyrazole compounds. This method avoids the use of expensive transition metal catalysts and unstable intermediates, shortens the reaction route, and greatly improves the scalability and industrial production efficiency of the process.

[0010] To achieve the above objectives, the present invention adopts the following technical solution:

[0011] First, hydrazine hydrate undergoes a Michael addition reaction with a cyano-substituted olefin. After adding acid to form a salt, the product is subjected to alkali treatment or heating to obtain a stable 3-amino-1H-hydropyrazole or its salt form. Subsequently, the stable synthon is reacted with a 1,3-dicarbonyl compound or its equivalent 1,3-diimine compound to obtain a β-cyano-substituted pyrazole ring compound. After further transformation, ruxolitinib or baricitinib molecules can be obtained.

[0012] This invention provides a method for synthesizing β-cyanopyrazole compounds, the method comprising the following steps:

[0013] (a) The substance represented by formula (Ⅰ) reacts with hydrazine to give the intermediate of the compound represented by formula (Ⅱ), and then the reaction continues to give the compound represented by formula (Ⅲ).

[0014] Among them, the compound represented by formula (Ⅰ):

[0015] The compound represented by formula (II):

[0016] The compound represented by formula (Ⅲ):

[0017] (b) The substance represented by formula (Ⅲ) reacts with the substance represented by formula (Ⅳ) in a solvent to obtain the compound represented by formula (Ⅴ);

[0018] Among them, the compound represented by formula (Ⅳ):

[0019] The compound represented by formula (V):

[0020] In the formula, R1 and R2 are either any alkyl or cycloalkyl or hydrogen, or R1 and R2 are connected to each other to form a 3-8 membered ring; R3 is any alkyl, cycloalkyl or aromatic ring; HX is any inorganic or organic acid; Y1 and Y2 are atoms of oxygen or nitrogen forming 1,3-dicarbonyl or 1,3-diimine or other equivalent compounds.

[0021] As a preferred embodiment of the present invention, step a) specifically involves: reacting the substance shown in formula (Ⅰ) with hydrazine to obtain the substance shown in formula (Ⅱ), adding a solvent to mix, and stirring at 0-100°C until the reaction is complete. The reaction solution is then extracted, washed, and concentrated to obtain the compound shown in formula (Ⅲ).

[0022] In a preferred embodiment of the present invention, in step a), the solvent includes a protic solvent or an aprotic solvent, or no solvent is used. Examples include DCM, DMF, DMSO, acetonitrile, water, alcohols, and other protic or aprotic solvents.

[0023] As a preferred embodiment of the present invention, the solvent is one of DCM, DMF, DMSO, acetonitrile, water or alcohol.

[0024] As a preferred embodiment of the present invention, in step a), the reaction reagent used is hydrazine hydrate and any inorganic or organic acid that can form a salt with hydrazine hydrate, and the base used to neutralize the free amine is any inorganic or organic base.

[0025] In a preferred embodiment of the present invention, in step b), the reaction temperature is 0 to 100°C.

[0026] As a preferred embodiment of the present invention, in step b), the solvent is methanol or ethanol or DMF, DMSO or water or an aprotic solvent.

[0027] In a preferred embodiment of the present invention, in step b), the reaction temperature is 0 to 100°C.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1) The synthesis method of the present invention is different from the prior art in terms of starting materials, process route and post-processing. Moreover, the raw materials of the present invention are simple and readily available, low in cost and easy to operate.

[0030] 2) This invention avoids the use of expensive transition metal catalysts, which greatly reduces production costs.

[0031] 3) This invention avoids the purification and separation operations of unstable intermediate alkyl-substituted hydrazine, thus improving the operability for industrial scale-up.

[0032] 4) The process route of the present invention is relatively short, and the post-processing does not require the use of column chromatography to purify and separate the product. Most steps can be carried directly into the next reaction without purifying the crude product, which saves production costs, improves production efficiency, and is suitable for industrial mass production as well as laboratory small-scale preparation. Attached Figure Description

[0033] Figure 1 This is the process route diagram of the present invention.

[0034] Figure 2 This is the hydrogen spectrum of Example 2. Detailed Implementation

[0035] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0036] In this invention, all raw materials, reagents, or equipment used can be purchased from the market.

[0037] Example 1

[0038] See Figure 1 This embodiment provides a method for synthesizing 3-methyl-3-(4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)butyronitrile.

[0039] a) Trimethylcrotonitrile (16.2 g, 0.2 mol) was added to a reaction flask, and 80% hydrazine hydrate (12.6 g, 0.4 mol) was added dropwise at 0–30 °C. The reaction was maintained at this temperature for 10 hours until completion. 20 mL of saturated brine and 20 mL of dichloromethane were added to the reaction solution, and the layers were separated. The aqueous layer was extracted once with dichloromethane, and the organic phases were combined. The solution was washed once with saturated brine, and the solvent was removed. The resulting crude 3-hydrazino-3-methylbutyronitrile was heated to 50–60 °C and stirred for 2 hours to obtain 18.3 g of the product 5,5-dimethyl-3-amino-4,5-dihydro-1H-pyrazole. The crude product can be used directly in the next reaction without further purification. (Product mass spectrometry molecular weight: M) + +H=114.1).

[0040] b) Take the product obtained in the previous step, 5,5-dimethyl-3-amino-4,5-dihydro-1H-pyrazole dihydrochloride (11.3 g, 0.1 mol), and 2-(pyrimidin-4-yl)malondialdehyde (15.0 g, 0.1 mol), and add them to the solvent DMF (100 mL). Incubate at 25–35 °C for 10 hours until the reaction is complete. Add the reaction solution to 300 mL of water and extract twice with 300 mL of ethyl acetate. Combine the organic phases, wash twice with water and saturated brine, dry with anhydrous sodium sulfate, and remove the solvent to obtain 19.3 g of the product 3-methyl-3-(4-(pyrimidin-4-yl)-1H-pyrazole-1-yl)butyronitrile. (Product mass spectrometry molecular weight: M) + +H=228.1).

[0041] Example 2

[0042] See Figure 1 This embodiment provides a method for synthesizing (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate.

[0043] a) Add 3-cyclopentylacrylonitrile (34.6 g, 0.29 mol) to a reaction flask, and add 80% hydrazine hydrate (36.3 g, 0.58 mol) dropwise at 0–30 °C. After the addition is complete, maintain the temperature for 10 hours to complete the reaction. Add 40 mL of saturated saline and 40 mL of dichloromethane to the reaction solution, allowing the layers to separate. Extract the aqueous layer once with dichloromethane, combine the organic phases, wash once with saturated saline, remove the solvent, add 100 mL of acetonitrile and 100 mL of water, and add dropwise L-tartaric acid solution (43.5 g L-tartaric acid dissolved in 70 g of water and 70 mL of acetonitrile). Solid (R)-3-cyclopentyl-3-hydrazinopropionitrile tartrate precipitates. Heat the reaction solution to 60–80 °C and stir for 5 hours. Filter to collect the solid, and dry to obtain 36 g of product (R)-5-cyclopentyl-3-amino-4,5-dihydro-1H-pyrazole tartrate. (see Figure 2( 1 ¹H NMR (D₂O, 500MHz) δppm 3.85 (dd, 1H), 3.10 (s, 1H), 2.85 (dd, 1H), 2.13 (m, 1H), 1.80 (m, 2H), 1.60 (m, 4H), 1.20 (m, 1H); Product mass spectrometry molecular weight: M + +H=154.1).

[0044] b) (R)-5-cyclopentyl-3-amino-4,5-dihydro-1H-pyrazole tartrate (30.3 g, 0.1 mol) and (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allyl)-N-methylmethylammonium fluoroborate (33.1 g, 0.1 mol) were added to the solvent ethanol (150 mL), and the reaction was carried out at 30-40 °C for 3 hours until the reaction was completed. The reaction solution was added to 500 mL of water, extracted twice with 300 mL of dichloromethane, and the combined organic phases were washed twice with water. The mixture was concentrated to dryness, and then 500 mL of dichloromethane and 50 mL of isopropanol were added. With stirring, 12.7 g (0.11 mol) of 85% phosphoric acid aqueous solution was added, precipitating a solid. After drying, 32 g of the product (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate was obtained. 1 HNMR (DMSO-d6, 500MHz) δppm 12.10 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.36 (s 1H), 7.58(dd, 1H), 6.97(d, 1H), 4.52(td, 1H), 3.25(dd, 1H), 3.16(dd, 1H), 2.41, (m , 1H), 1.79(m, 1H), 1.59(m, 1H), 1.51(m, 2H), 1.42(m, 1H), 1.29(m, 2H), 1.18(m, 1H); 13 C NMR (DMSO-d6, 125MHz) d ppm 152.1, 150.8, 149.8, 139.2, 131.0, 126.8, 120.4, 118.1, 112.8, 99.8, 62.5, 44.3, 29.1, 29.0, 24.9, 24.3, 22.5); Product mass spectrometry molecular weight: M + +H=307.2).

[0045] It is evident that the synthesis method of this invention differs from existing technologies in terms of starting materials, process route, and post-processing. Furthermore, the raw materials of this invention are simple and readily available, low in cost, easy to operate, and have a shorter process route. Post-processing does not require column chromatography to purify and separate the product, and most steps can be carried directly into the next reaction without purifying the crude product, thus saving production costs, improving production efficiency, and making it suitable for large-scale industrial production as well as small-scale laboratory preparation.

[0046] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing β-cyanopyrazole compounds, characterized in that, The synthesis method includes the following steps: (a) The substance represented by formula (I) reacts with hydrazine to give the intermediate of the compound represented by formula (II), and then the reaction continues to give the compound represented by formula (III); Among them, the compound represented by formula (Ⅰ): ; The compound represented by formula (II): ; The compound represented by formula (Ⅲ): ; (b) The substance represented by formula (Ⅲ) reacts with the substance represented by formula (Ⅳ) in a solvent to obtain the compound represented by formula (Ⅴ); Among them, the compound represented by formula (Ⅳ) is 2-(pyrimidin-4-yl)malondialdehyde or (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allyl)-N-methylammonium fluoroborate; The compound represented by formula (V): ; In the formula, R1 and R2 are either any alkyl or cycloalkyl or hydrogen, or R1 and R2 are connected to each other to form a 3-8 membered ring; R3 is an aromatic ring; HX is any inorganic or organic acid.

2. The method for synthesizing a β-cyanopyrazole compound according to claim 1, characterized in that, Step a) specifically involves reacting the substance shown in formula (Ⅰ) with hydrazine to obtain the substance shown in formula (Ⅱ), adding a solvent to mix, and stirring at 0~100℃ until the reaction is complete. The reaction solution is then extracted, washed, and concentrated to obtain the compound shown in formula (Ⅲ).

3. The method for synthesizing a β-cyanopyrazole compound according to claim 2, characterized in that, In step a), the solvent includes a protic solvent or an aprotic solvent, or no solvent is used.

4. The method for synthesizing a β-cyanopyrazole compound according to claim 3, characterized in that, The solvent is one of DCM, DMF, DMSO, acetonitrile, water, or alcohol.

5. The method for synthesizing a β-cyanopyrazole compound according to claim 1, characterized in that, In step a), the reaction reagent used is hydrazine hydrate or an organic or inorganic acid salt of a compound containing hydrazine hydrate.

6. The method for synthesizing a β-cyanopyrazole compound according to claim 1, characterized in that, In step b), the reaction temperature is 0~100℃.

7. The method for synthesizing a β-cyanopyrazole compound according to claim 1, characterized in that, In step b), the solvent is methanol, ethanol, DMF, DMSO, or water.

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