A process for the preparation of trans-cyclobutane-1,2-dicarboxylic acid

Abstract

The application discloses a preparation method of trans-cyclobutane-1,2-dicarboxylic acid (a compound of formula I), which adopts a continuous reaction device, uses cyclobutane-1,2-dicarboxylic anhydride (a compound of formula II) as raw material, and obtains trans-cyclobutane-1,2-dicarboxylic acid through one-step reaction under high-temperature and high-pressure conditions. The process is safe, simple, easy to enlarge, high in yield, low in cost, and capable of realizing continuous large-scale production and preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of trans-cyclobutane-1,2-dicarboxylic acid. BACKGROUND

[0002] The research of drugs for treating hematological malignancies has been an important research topic at home and abroad. AMG-176 compound developed by Amgen Company is a selective MCL-1 inhibitor, which has shown efficacy in various hematological malignancies. At present, this compound has entered the clinical research stage, bringing new hope for the treatment of hematological malignancies. Trans-cyclobutane-1,2-dicarboxylic acid is an important intermediate for synthesizing AMG-176.

[0003]

[0004] The synthesis method of trans-cyclobutane-1,2-dicarboxylic acid is disclosed in the document Tetrahedron: Asymmetry, 14(1), 127-137; 2003, and the synthesis route is as shown below:

[0005]

[0006] Reagents and conditions: (a) SOCl2, Br2, methanol, 80℃, 10h; (b) KCN, methanol, 75℃, 56h, two-step yield: 71%; (c) 6M HCl, reflux, 12h, yield: 62%; (d) 180℃, 2.5h, trans: cis (70:30) two-step yield: 62%; (e) 12M HCl, 120℃, 6days, yield 54%.

[0007] The document discusses in detail the method for preparing compound of formula 8 from compound of formula 12 (isomer mixture) in the document, and the compound of formula 8 is the compound of formula I (trans-cyclobutane-1,2-dicarboxylic acid) mentioned in the present application. In the synthesis route, the second step reaction needs to use the toxic potassium cyanide, and there is a great safety risk in the production process; the last step isomerization reaction needs to be reacted under high temperature condition of strong acid system for a long time, and the reaction equipment is required to be high, and the yield of trans configuration is low, only 54%, so this process route is not suitable for industrial production.

[0008] Therefore, it is of great significance to develop a safe, simple, easy to scale up, high yield and low cost process of trans-cyclobutane-1,2-dicarboxylic acid. SUMMARY

[0009] The present application aims to provide a continuous synthesis method of trans-cyclobutane-1,2-dicarboxylic acid, so as to solve the problems in the prior art that potassium cyanide, a toxic product, is needed in the synthesis process of trans-cyclobutane-1,2-dicarboxylic acid, and there are great safety risks in industrial production, and the isomerization reaction, a key step, has high requirements on equipment and a too long reaction period.

[0010] In one aspect, the present application provides a preparation method of a compound of formula I:

[0011]

[0012] The method comprises the following operations:

[0013] 1) dissolving base 1 in water to prepare a base solution, adding the compound of formula II, stirring and dissolving, and then pumping into a continuous reactor for reaction;

[0014] 2) after the reaction is completed, adding acid 1 to the system for acidification treatment to obtain the compound of formula I.

[0015] Preferably, the base 1 is one or more of sodium hydroxide, potassium hydroxide or lithium hydroxide;

[0016] Preferably, the acid 1 is one or more of hydrochloric acid, sulfuric acid, hydrobromic acid or hydroiodic acid;

[0017] Preferably, the solvent used is one or more of water, dioxane, ethanol, methanol or tetrahydrofuran; more preferably, the solvent used is water;

[0018] Preferably, the molar ratio of the compound of formula II to the base 1 ranges from 1:2 to 1:5;

[0019] Preferably, the continuous reactor is a micro-channel reactor, a tube reactor or a plate reactor;

[0020] Preferably, the reaction liquid is pumped into the continuous reactor for reaction, and the reaction temperature ranges from 150 to 300 DEG C, and the pressure ranges from 2 to 8 Mpa;

[0021] Preferably, the continuous reactor is made of stainless steel, silicon carbide, titanium or hastelloy;

[0022] Preferably, after the reaction is completed, the compound of formula I is obtained by recrystallization purification using an ethyl acetate / n-heptane system for post-treatment.

[0023] Beneficial effects

[0024] The present application aims at overcoming the problems in the prior art, such as the need of using the toxic potassium cyanide in the reaction process, high requirement for equipment, and too long production cycle, and provides a safe, simple, easy-to-scale-up, high-yield, and low-cost process. The process takes cyclobutane-1,2-dicarboxylic anhydride as a raw material, and selects a continuous reaction device, so that the industrial production can be carried out without using complex equipment such as a high-pressure reaction kettle, and trans-1,2-cyclobutane dicarboxylic acid can be obtained in one step with a yield of more than 90%. Compared with the process in the literature, the synthesis difficulty is reduced, the production cycle is greatly shortened, and the production cost is reduced. In summary, the technical scheme provided by the present application is suitable for industrial production and has high economic benefits. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to more clearly illustrate the technical schemes in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the present application.

[0026] Figure 1 A continuous reaction schematic diagram for preparing the compound of formula I from the compound of formula II according to the present application;

[0027] Figure 2 A HPLC spectrum of the trans / cis-cyclobutane-1,2-dicarboxylic acid mixture (cis:trans = 19:70) of Example 1 of the present application; 1 H NMR spectrum;

[0028] Figure 3 A HPLC spectrum of the final product of Example 1 of the present application; 1 H NMR spectrum;

[0029] Figure 4 A HPLC spectrum of the final product of Example 1 of the present application;

[0030] Figure 5 A MS spectrum of the final product of Example 1 of the present application. DETAILED DESCRIPTION

[0031] The present application will be further illustrated by specific embodiments, which are implemented on the premise of the technical scheme of the present application, and it should be understood that these embodiments are only used to illustrate the present application and not to limit the scope of the present application.

[0032] Example 1

[0033]

[0034] Preparation of the compound of formula I:

[0035] 500L reaction kettle, add water (290 kg), under stirring, add sodium hydroxide (63.07 kg, 1576.96 mol, 2.2 eq.), control the temperature at 60-70 °C, prepare the alkali solution, and reserve. Add the compound of formula II (90.40 kg, 716.8 mol, 1.0 eq.) into the reaction kettle, and stir until dissolved. Cool the reaction solution to room temperature, and deliver into the continuous reactor by the plunger pump, the temperature of the pipeline is 200 °C, the pressure is 2 Mpa, and the reaction solution is delivered for 60 h. Detect the conversion of the raw material by HPLC, and the reaction is completed. Draw the reaction solution into the reaction kettle, add activated carbon (5 kg), heat to 60-70 °C, and stir to decolorize. After cooling, filter, remove the residue, transfer the mother liquor into the reaction kettle, control the internal temperature at 25-45 °C, and adjust the pH to 1 by concentrated hydrochloric acid. Concentrate and evaporate the solvent water under reduced pressure until the system becomes a paste, and evaporate with toluene for three times. Add tetrahydrofuran at 40-45 °C to make a paste, after cooling, filter, and concentrate to remove tetrahydrofuran. After dissolving in ethyl acetate, slowly add n-heptane to crystallize, filter, and obtain the compound of formula I as a white solid 92.96 kg with a yield of 90%.

[0036] 1 HNMR (400 MHz, D2O) (ppm): 3.4073-3.3701 (m, 2H), 2.1240-2.1032 (m, 4H); (ESI-TOF) m / z: [M-H]+calcd for C6H8O4: 144; found: 143; GC detection purity is 98.76%.

[0037] Comparative Example 1

[0038]

[0039] The results of the investigation of base 1, acid 1, temperature, and pressure are shown in Table 1 according to the method of Reference Example 1.

[0040] Table 1

[0041]

Claims

1. A method for preparing a compound of formula I, characterized in that: The following operations are included: 1) Alkali 1 is dissolved in water to prepare an alkali solution, the compound of formula II is added, stirred and dissolved, and then pumped into a continuous reactor for reaction; 2) After the reaction is completed, acid 1 is added to the system for acidification to obtain the compound of formula I; Wherein, the molar ratio of the compound of formula II to base 1 is in the range of 1:2 to 1:5; The base 1 is selected from one or more of sodium hydroxide, potassium hydroxide or lithium hydroxide; The acid 1 is selected from one or more of hydrochloric acid, sulfuric acid, hydrobromic acid or hydroiodic acid; The continuous reactor is a microchannel reactor, a tubular reactor or a plate reactor; The reaction temperature range is 150-300°C; the pressure range is 2-8 MPa.

2. The preparation method according to claim 1, wherein: The solvent used is selected from one or more of water, dioxane, ethanol, methanol or tetrahydrofuran.

3. The preparation method according to claim 1, wherein: The solvent used was water.

4. The preparation method according to claim 1, wherein: The continuous reactor is made of stainless steel, silicon carbide, titanium or Hastelloy.

5. The preparation method according to claim 1, wherein: After the reaction is completed, the compound of formula I is prepared by recrystallization and purification using an ethyl acetate / n-heptane system.

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