阅读说明：本技术 一种格拉斯吉布关键中间体的制备方法 (Preparation method of key intermediate of Gerastib ) 是由 夏青青 于 2020-12-08 设计创作，主要内容包括：本发明公开了一种格拉斯吉布关键中间体的制备方法,包括以下步骤：S1、向丙烯酸中依次加入4A分子筛、乙腈、结构式1所示化合物,进行狄尔斯-阿尔德反应,得到中间产物；S2、将中间产物加入至甲醇中,混合均匀后,再缓慢加入甲醇钠,在搅拌条件下进行开环反应,TLC检测原料反应完全后,降温至0～5℃,采用中和试剂调节pH至6～7,浓缩甲醇,萃取,合并有机相,洗涤,干燥,浓缩,即得粗品；S3、将上述粗品经硅胶柱层析进行分离纯化,即得所述格拉斯吉布关键中间体；其中,所述格拉斯吉布关键中间体为结构式3a所示化合物。本发明一种格拉斯吉布关键中间体的制备方法,工艺简单、安全、环保,保证开环反应顺利进行的同时避免了副产物酰胺的生成。(The invention discloses a preparation method of a Glassy gibb key intermediate, which comprises the following steps: s1, sequentially adding a 4A molecular sieve, acetonitrile and a compound shown in a structural formula 1 into acrylic acid, and carrying out Diels-Alder reaction to obtain an intermediate product; s2, adding the intermediate product into methanol, mixing uniformly, then slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, after TLC detection raw material completely reacts, cooling to 0-5 ℃, adjusting the pH to 6-7 by using a neutralizing reagent, concentrating methanol, extracting, combining organic phases, washing, drying and concentrating to obtain a crude product; s3, separating and purifying the crude product by silica gel column chromatography to obtain the key intermediate of the Gerasagiline; wherein the key intermediate of the Gerasagiline is a compound shown in a structural formula 3 a. The preparation method of the key intermediate of the Gerastib has the advantages of simple process, safety and environmental protection, ensures that the ring-opening reaction is smoothly carried out, and simultaneously avoids the generation of by-product amide.)

1. A preparation method of a key intermediate of Gerastib is characterized by comprising the following steps:

s1, sequentially adding a 4A molecular sieve, acetonitrile and a compound shown in a structural formula 1 into acrylic acid, and carrying out Diels-Alder reaction to obtain an intermediate product; wherein the intermediate product is a mixture of a compound shown in a structural formula 2a and a compound shown in a structural formula 2 b;

s2, adding the intermediate product into methanol, mixing uniformly, then slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, after TLC detection raw material completely reacts, cooling to 0-5 ℃, adjusting the pH to 6-7 by using a neutralizing reagent, concentrating methanol, extracting, combining organic phases, washing, drying and concentrating to obtain a crude product; wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b;

s3, separating and purifying the crude product by silica gel column chromatography to obtain the key intermediate of the Gerasagiline; wherein the key intermediate of the Gerasagiline is a compound shown in a structural formula 3 a;

wherein, the structural formula 1 is:

structural formula 2a is:

structural formula 2b is:

structural formula 3a is:

structural formula 3b is as follows:

2. the process of claim 1, wherein the organic solvent used in step S1 is acetonitrile.

3. The method for preparing the key intermediate of Gerastib as claimed in claim 1, wherein the ring-opening reaction temperature in step S2 is-5-10 ℃.

4. The method of claim 1, wherein in step S2, the molar ratio of sodium methoxide to intermediate is 0.4-0.5: 1.

5. the method of claim 1, wherein in step S2, the neutralization reagent is 1mol/L hydrochloric acid.

6. The process of claim 1, wherein in step S2, the grignard key intermediate is extracted 2 times with ethyl acetate.

7. The method of claim 1, wherein the step S2 comprises washing with water 1 time, and then washing with supersaturated brine 1 time.

Technical Field

The invention relates to the technical field of preparation methods of a glasgrib key intermediate, and particularly relates to a preparation method of a glasgrib key intermediate.

Background

Acute Myeloid Leukemia (AML), the most common malignant leukemia in adults, is the one of the lowest survival types of leukemia. Glasgibb (its english name is glasdegib) was found to have a good therapeutic effect on AML. The key intermediates used in the prior art for the preparation of glasgibos are compounds of formula 3a, formula 3a being as follows:

in the prior art, the preparation method of the key intermediate is shown in figure 1, and after a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3b is prepared, a purified key intermediate is obtained through column chromatography; however, in this method, the ring-opening reaction cannot be performed when the ammonia gas concentration is too low, and the by-product amide is easily produced when the ammonia gas concentration is too high.

Disclosure of Invention

The invention aims to overcome the defects and provides a preparation method of the key intermediate of the Gerastib, which has the advantages of simple process, safety and environmental protection, ensures that the ring-opening reaction is smoothly carried out and simultaneously avoids the generation of by-product amide.

In order to achieve the purpose, the invention provides the following technical scheme that the preparation method of the key intermediate of the Gerastib comprises the following steps:

s1, sequentially adding a 4A molecular sieve, acetonitrile and a compound shown in a structural formula 1 into acrylic acid, and carrying out Diels-Alder reaction to obtain an intermediate product; wherein the intermediate product is a mixture of a compound shown in a structural formula 2a and a compound shown in a structural formula 2 b;

s2, adding the intermediate product into methanol, mixing uniformly, then slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, after TLC detection raw material completely reacts, cooling to 0-5 ℃, adjusting the pH to 6-7 by using a neutralizing reagent, concentrating methanol, extracting, combining organic phases, washing, drying and concentrating to obtain a crude product; wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b;

s3, separating and purifying the crude product by silica gel column chromatography to obtain the key intermediate of the Gerasagiline; wherein the key intermediate of the Gerasagiline is a compound shown in a structural formula 3 a;

wherein, the structural formula 1 is:

structural formula 2a is:

structural formula 2b is:

structural formula 3a is:

structural formula 3b is:

preferably, the organic solvent in step S1 is acetonitrile.

Preferably, in the step S2, the ring-opening reaction temperature is-5 to 10 ℃.

When the ring-opening reaction temperature exceeds 10 ℃, partial intermediate product is hydrolyzed, and when the ring-opening reaction temperature exceeds 20 ℃, half of the intermediate product is hydrolyzed.

Preferably, in the step S2, the molar ratio of sodium methoxide to intermediate product is 0.4-0.5: 1.

preferably, in the step S2, the neutralizing agent is 1mol/L hydrochloric acid.

Preferably, in the step S2, 2 times of extraction is performed by ethyl acetate.

Preferably, in step S2, the washing is performed 1 time with water and then 1 time with supersaturated brine.

Compared with the prior art, the invention has the beneficial effects that: the preparation method of the key intermediate of the Gerastib has the advantages of simple process, safety and environmental protection, ensures that the ring-opening reaction is smoothly carried out, and simultaneously avoids the generation of by-product amide.

Drawings

FIG. 1 is a schematic diagram of a prior art process for the preparation of a key intermediate of Gerastib;

FIG. 2 is a schematic diagram of a process for the preparation of a key intermediate of Gerastib in the present invention.

Detailed Description

In order to make the technical means of the implementation of the present invention, and the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments.

Example 1

This example provides a process for preparing a compound of formula 1, comprising the steps of:

taking a 100L reaction kettle, washing, drying, taking 4.5kg of the compound shown in the structural formula 4, dissolving in acetonitrile (35L), adding 6.64kg of potassium carbonate, stirring for 30 minutes, adding 5.0kg of 4-bromobutene, heating to reflux for about 6 hours (based on TLC), filtering, and concentrating the filtrate to obtain 6.5kg of the compound shown in the structural formula 1.

Wherein, structural formula 4 is:

wherein, the structural formula 1 is: (ii) a

The specific reaction formula is as follows:

example 2

This example provides a method for preparing an intermediate product, comprising the steps of:

adding 661.7g of acrylic acid into a cleaned and dried reaction kettle, adding 7.2L of acetonitrile and a 4A molecular sieve (360g), stirring for 30 minutes under the protection of nitrogen, dropwise adding 1.2kg of a compound shown in a structural formula 1, wherein heat release occurs in the dropwise adding process, controlling the temperature below 40 ℃, completing dropwise adding within about 1 hour, stirring for 18 hours at room temperature after completing dropwise adding, filtering, washing a filter cake with 500ml of acetonitrile, and combining a filtrate and a washing solution, concentrating and drying to obtain 1.146kg of an intermediate product; wherein the intermediate product is a mixture of a compound shown in a structural formula 2a and a compound shown in a structural formula 2 b.

Wherein, the structural formula 1 is:

structural formula 2a is:

structural formula 2b is:

example 3

The embodiment provides a preparation method of a glasgibb key intermediate, which comprises the following steps: adding 1L of methanol and an intermediate product (250g, 1.08mol) into a 5L reaction kettle in sequence, slowly adding sodium methoxide, carrying out ring-opening reaction under the condition of stirring, wherein the ring-opening reaction temperature is between-5 and 10 ℃, detecting that raw materials are completely reacted by TLC, adding 28.0g of sodium methoxide in total during the reaction process, then cooling to 0 ℃, dropwise adding 1mol/L hydrochloric acid to adjust the pH to 6 to 7, controlling the temperature to be below 5 ℃, concentrating the methanol, adding ethyl acetate to extract twice (500ml multiplied by 2), washing once (1L), washing with saturated saline (1L), drying with anhydrous sodium sulfate, concentrating to dryness to obtain 1.2kg of crude product (wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b), and mixing with silica gel (300g) to pass through a column. Gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 10: 1 to 5: 1, 40g of the compound with the structural formula 3(b) is collected, gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 5: 1 to 1: 1, and 36g of the compound with the structural formula 3(a) is collected, namely the key intermediate of the Gerasagiline.

The intermediate product in this example is the intermediate product obtained in example 2.

Example 4

The embodiment provides a preparation method of a glasgibb key intermediate, which comprises the following steps: adding 28L of methanol and an intermediate product (5.646g and 24.4mol) into a 100L reaction kettle in sequence, slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, wherein the ring-opening reaction temperature is between-5 and 10 ℃, detecting the reaction of raw materials by TLC (thin-layer chromatography), adding 566g of sodium methoxide in total during the reaction process, then cooling to 0 ℃, dropwise adding 1mol/L hydrochloric acid to adjust the pH to 6 to 7, controlling the temperature to be below 5 ℃, concentrating the methanol, adding ethyl acetate to extract twice (8L multiplied by 2), washing once (10L), washing with saturated saline (10L), drying with anhydrous sodium sulfate, concentrating to dryness to obtain 2.8kg of crude product (wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b), and mixing with silica gel (4kg) to pass through a column. Gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 10: 1 to 5: 1, 1.1kg of the compound with the structural formula 3(b) is collected, gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 5: 1 to 1: 1, and 1.05kg of the compound with the structural formula 3(a) is collected, and the gelase gibb key intermediate is obtained. Of these, 190L of petroleum ether and 140L of ethyl acetate were used in total.

The intermediate product in this example is the intermediate product obtained in example 2.

Example 5

The embodiment provides a preparation method of a glasgibb key intermediate, which comprises the following steps: adding 28L of methanol and an intermediate product (5.646g and 24.4mol) into a 100L reaction kettle in sequence, slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, wherein the ring-opening reaction temperature is 12 ℃, TLC (thin layer chromatography) detection is carried out to completely react raw materials, adding 566g of sodium methoxide in total during the reaction process, then cooling to 0 ℃, dropwise adding 1mol/L hydrochloric acid to adjust the pH to 6-7, controlling the temperature to be below 5 ℃, concentrating the methanol, adding ethyl acetate to extract twice (8L multiplied by 2), washing once (10L), washing with saturated salt water (10L), drying with anhydrous sodium sulfate, concentrating to dryness to obtain 2.1kg of crude product (wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b), and mixing with silica gel (4kg) to pass through a column. Gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 10: 1 to 5: 1, 0.82kg of the compound with the structural formula 3(b) is collected, gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 5: 1 to 1: 1, and 0.79kg of the compound with the structural formula 3(a) is collected, and the gelase gibb key intermediate is obtained.

The intermediate product in this example is the intermediate product obtained in example 2.

The difference between the preparation of the glasgibus key intermediate in this example and the preparation of the glasgibus key intermediate in example 4 is that the ring-opening reaction temperature in this example is greater than 10 ℃.

Example 6

The embodiment provides a preparation method of a glasgibb key intermediate, which comprises the following steps: adding 28L of methanol and an intermediate product (5.646g and 24.4mol) into a 100L reaction kettle in sequence, slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, wherein the ring-opening reaction temperature is 25 ℃, TLC (thin layer chromatography) detection is carried out to completely react raw materials, adding 566g of sodium methoxide in total during the reaction process, then cooling to 0 ℃, dropwise adding 1mol/L hydrochloric acid to adjust the pH to 6-7, controlling the temperature to be below 5 ℃, concentrating the methanol, adding ethyl acetate to extract twice (8L multiplied by 2), washing once (10L), washing with saturated salt water (10L), drying with anhydrous sodium sulfate, concentrating to dryness to obtain 1.5kg of crude product, mixing the crude product with silica gel (4kg) to pass through a column, wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b. Gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 10: 1 to 5: 1, 0.60kg of the compound with the structural formula 3(b) is collected, gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 5: 1 to 1: 1, and 0.56kg of the compound with the structural formula 3(a) is collected, and the gelase gibb key intermediate is obtained.

The intermediate product in this example is the intermediate product obtained in example 2.

The difference between the preparation method of the glasgibag key intermediate in this example and the preparation method of the glasgag key intermediate in example 4 is that the ring-opening reaction temperature in this example is 25 ℃.

From the comparison of examples 3, 4 and 5, it is known that when the ring-opening reaction temperature exceeds 10 ℃, partial hydrolysis of the intermediate products (the compound represented by the structural formula 2a and the compound represented by the structural formula 2 b) occurs, and when the ring-opening reaction temperature exceeds 20 ℃, half of the intermediate products are hydrolyzed, which affects the yield of the final glatiramer key intermediate (the compound represented by the structural formula 3 a).

Example 7

The embodiment provides a preparation method of a glasgibb key intermediate, which comprises the following steps: adding 28L of methanol and an intermediate product (5.646g and 24.4mol) into a 100L reaction kettle in sequence, slowly adding sodium methoxide, carrying out ring-opening reaction under the stirring condition, wherein the ring-opening reaction temperature is between-5 and 10 ℃, detecting that raw materials react completely by TLC (thin layer chromatography), adding 593g of sodium methoxide in total in the reaction process, then cooling to 0 ℃, dropwise adding 1mol/L hydrochloric acid to adjust the pH to 6 to 7, controlling the temperature to be below 5 ℃, concentrating the methanol, adding ethyl acetate to extract twice (8L multiplied by 2), washing once (10L) with water, washing with saturated saline (10L), drying with anhydrous sodium sulfate, concentrating to dryness to obtain 2.93kg of crude product (wherein the crude product is a mixture of a compound shown in a structural formula 3a and a compound shown in a structural formula 3 b), and mixing with silica gel (4kg) to pass through a column. Gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 10: 1 to 5: 1, 1.15kg of the compound with the structural formula 3(b) is collected, gradient change of the eluent is that the petroleum ether and the ethyl acetate are in a volume ratio of 5: 1 to 1: 1, and 1.10kg of the compound with the structural formula 3(a) is collected, and the gelase gibb key intermediate is obtained.

The intermediate product in this example is the intermediate product obtained in example 2.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.