Method for preparing intermediate of Bruton's tyrosine kinase degradation agent

Abstract

The invention discloses a method for preparing an intermediate of a Bruton's tyrosine kinase degradation agent, in particular a method for preparing 3-((4-(4-(1, 3-dioxolane-2-yl) piperidine-1-yl) phenyl) amino) propionic acid, and the method is high in yield, few in by-product and suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing an intermediate of a Bruton's tyrosine kinase degrading agent. Background Technology

[0002] Bruton's tyrosine kinase (BTK) belongs to the Tec tyrosine kinase family and is primarily expressed in most hematopoietic cells, such as B cells. BTK plays an important role in the B cell receptor (BCR) and FcR signaling pathways, which are involved in B cell development and differentiation. Inhibition of BTK has been shown to affect cancer development (B-cell malignancies). Other strategies for inhibiting BTK have also been reported, such as degradation of BTK. International publication WO2021219070 discloses BTK degrading agents, such as compound A having the following chemical structure:

[0003]

[0004] Compound A

[0005] Compound Z4a is an important intermediate in the production of compound A:

[0006]

[0007] Compound Z4a Summary of the Invention

[0008] The purpose of this invention is to provide a preparation method that can increase the yield of an intermediate of the BTK degrading agent, namely the yield of compound Z4a, thereby increasing the yield of the compound raw material of BTK degrading agent compound A.

[0009] According to one aspect of the present invention, a method for preparing an intermediate for a BTK degrading agent is provided.

[0010] According to another aspect of the present invention, a method is provided for preparing an intermediate compound Z4a for BTK degradation agents.

[0011] In one embodiment, the method further includes adding compound Z4a-INT3:

[0012]

[0013] Compound Z4a-INT3,

[0014] The compound Z4a was synthesized by reacting it with an acid.

[0015] In one embodiment, the acid is acetic acid.

[0016] In one embodiment, the method further includes compound Z4a-INT1 and compound Z4a-INT2:

[0017]

[0018] Compound Z4a-INT1, and

[0019]

[0020] Compound Z4a-INT2,

[0021] The compound Z4a-INT3 was synthesized by reacting urea with urea in an acid.

[0022] In one embodiment, the acid is acetic acid.

[0023] In one embodiment, the method further includes adding compound Z4c

[0024]

[0025] Compound Z4c,

[0026] Compounds Z4a-INT1 and Z4a-INT2 were synthesized by reacting with acrylic acid. Detailed Implementation

[0027] The preparation method of compound Z4a of the present invention will be described in detail below.

[0028] Example 1: 3-((4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)amino)propionic acid

[0029] Step 1: 3,3'-((4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)azadiyl)dipropionic acid:

[0030] and

[0031] 3-((4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)amino)propionic acid:

[0032]

[0033] The synthesis route for step one:

[0034]

[0035] A nitrogen-inert reactor was charged with a tetrahydrofuran (100 mL) solution of compound Z4c (10 g). The solution was concentrated. Cyclopentyl methyl ether (CPME) (170 g) was added. The water content was reduced to <0.5% (by weight). Acrylic acid (5.7 g) was added to the reactor. The solution was then heated to 60 °C and stirred for 24 hours.

[0036] Step 2: 3-((4-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)phenyl)amino)propionic acid

[0037] The synthetic route for step two:

[0038]

[0039] Urea (5.3 g) and acetic acid (32 g) were sequentially introduced into the nitrogen inerting reactor. The temperature was raised to 100°C over 3 hours and maintained at that temperature for 48 hours.

[0040] The reaction was cooled to 50°C, and isopropanol (80 g) was added over 6 hours to precipitate a solid. The slurry was aged at 50°C for 6 hours, then cooled to 10°C over 4 hours. The slurry was aged at 10°C for 12 hours, then filtered to provide a wet filter cake. The wet filter cake was washed with isopropanol (20 g).

[0041] The wet filter cake was transferred back to the reactor and dissolved in acetic acid (70 g) at 90°C, then cooled to 50°C. The slurry was aged at 50°C for 6 hours, followed by the addition of isopropanol (90 g) at 50°C for 6 hours. After continuous stirring for 6 hours, the temperature was adjusted to 10°C over 4 hours, and the reaction was continued with stirring for 12 hours. The slurry was filtered to provide a wet filter cake. The wet filter cake was washed with isopropanol (20 g).

[0042] The wet filter cake was dried under vacuum at 60°C for 24 hours. Drying was considered complete when the loss-on-drying (LOD) did not exceed 3.0% by weight. The yield was 60%.

[0043] In the foregoing, the invention has been described in detail through general description, specific examples, and tests. Modifications or improvements made without departing from the spirit of the invention fall within its scope of protection. The scope of the invention is intended to be defined by the appended claims and their equivalents.

Claims

1. A method for preparing compound Z4a, comprising: Z4A-INT3: The compound Z4a was synthesized by reacting it with an acid.

2. The method according to claim 1, wherein the acid is acetic acid.

3. The method of claim 2, further comprising: compound Z4a-INT1: Compound Z4a-INT2 The compound Z4a-INT3 was synthesized by reacting urea with urea in an acid.

4. The preparation method according to claim 3, wherein the acid is acetic acid.

5. The preparation method according to claim 4, further comprising: compound Z4c: Compounds Z4a-INT1 and Z4a-INT2 were synthesized by reacting with acrylic acid.

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