CN111138420A

CN111138420A - C13Isotope labeled lapatinib synthesis method

Info

Publication number: CN111138420A
Application number: CN202010084702.8A
Authority: CN
Inventors: 邓德轩
Original assignee: Beijing Kaijite Pharmaceutical Technology Development Co Ltd
Current assignee: Beijing Kaijite Pharmaceutical Technology Development Co Ltd
Priority date: 2020-02-10
Filing date: 2020-02-10
Publication date: 2020-05-12

Abstract

The invention relates to the technical field of drug synthesis, in particular to a C¹³A method for synthesizing isotopically labeled lapatinib. The method comprises the following steps: carrying out nitration reaction on the compound 1 to obtain a compound 2; the compound 2 is hydrolyzed to obtain a compound 3; the compound 3 is subjected to chlorination reaction to obtain a compound 4; the compound 4 is subjected to substitution reaction to obtain a compound 5; the compound 5 is subjected to reduction reaction to obtain a compound 6; the compound 6 is subjected to substitution reaction to obtain a compound 7; compound 7 is coupled to obtain C¹³Labeling lapatinib internal standard isotope labeling substance. The method has the advantages of simple technical route, mild conditions, no use of reagents with high danger and high separation difficulty, environmental protection and high application value.

Description

C13Isotope labeled lapatinib synthesis method

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a C¹³A method for synthesizing isotopically labeled lapatinib.

Background

Lapatinib is a new breast cancer targeted therapy drug developed by glatiramer britain, is a tyrosine kinase inhibitor, and can effectively inhibit the activities of human epidermal growth factor receptor-1 (ErbB1) and human epidermal growth factor receptor-2 (ErbB2) tyrosine kinase. It is unique in that it can act in a variety of ways to inhibit or kill tumor cells by preventing breast cancer cells from receiving signals necessary for growth. Currently, in China, lapatinib is mainly used as a first-line treatment drug for trastuzumab-resistant patients. As stable isotopes of C¹³The marked lapatinib internal label isotope marker is widely applied to lapatinib pharmacy and clinical research and has wide application prospect, so that research on a synthetic method of the lapatinib internal label isotope marker has important significance on clinical application of the lapatinib internal label isotope marker.

Disclosure of Invention

In view of the above technical problems, the present invention provides a method for preparing C¹³The synthesis method of the labeled lapatinib internal standard isotope label has the advantages of simple technical route, mild conditions, no use of reagents with high risks and high separation difficulty, environmental friendliness and high application value.

The present invention relates to the preparation of the following compounds:

the following synthetic route is specifically adopted:

the method specifically comprises the following steps:

step a): carrying out nitration reaction on the compound 1 to obtain a compound 2;

step b): hydrolyzing the compound 2 to obtain a compound 3;

step c): performing chlorination reaction on the compound 3 to obtain a compound 4;

step d): carrying out substitution reaction on the compound 4 to obtain a compound 5;

step e): carrying out reduction reaction on the compound 5 to obtain a compound 6;

step f): carrying out substitution reaction on the compound 6 to obtain a compound 7;

step g): the compound 7 is subjected to coupling reaction to obtain C¹³Isotopically labeled lapatinib.

Further, the step a) is as follows: carrying out nitration reaction by using the compound 1 as a reaction substrate and potassium nitrate as a nitration reagent to obtain a compound 2.

Further, the hydrolysis reagent in step b) is one of potassium hydroxide, sodium hydroxide or tetrabutylammonium hydroxide.

Further, the reaction conditions of the hydrolysis reaction of the step b) are 70-80 ℃, and preferably 80 ℃.

Further, the step c) is as follows: and taking the compound 3 as a reaction substrate, adding NCS as a chlorination reagent, and carrying out chlorination reaction to obtain a compound 4.

Further, the step d) is as follows: and (3) taking the compound 4 as a reaction substrate, and adding potassium carbonate and acetonitrile to perform substitution reaction to obtain a compound 5.

Further, in the step e), the compound 5 is used as a reaction substrate, and iron powder and ammonium chloride are added into the reaction substrate to perform reduction reaction in an ethanol solution to obtain a compound 6.

Further, the step f) is as follows: and (3) taking the compound 6 as a reaction substrate, adding 6-iodo-4-chloroquinazoline and isopropanol, and carrying out substitution reaction to obtain a compound 7.

Further, the step g) is as follows: taking the compound 7 as a reaction substrate, adding lapatinib furan boronic acid intermediate, dioxane, water, a catalyst and potassium acetate to perform coupling reaction to obtain C¹³Isotopically labeled lapatinib.

Further, the catalyst in the step g) is palladium tetratriphenylphosphine, and the chemical formula of the Lapatinib furoic acid intermediate is as follows:

the invention has the beneficial effects that: the method has the advantages of simple technical route, cheap and easily-obtained raw materials, mild reaction conditions, easy monitoring, no use of reagents with high separation difficulty, environmental protection, high application value and suitability for industrial large-scale production.

Detailed Description

The technical solution of the present invention will be described in detail with reference to the specific embodiments. The following examples are only for illustrating the technical solutions of the present invention more clearly, and therefore are only examples, and the protection scope of the present invention is not limited thereby.

The invention relates to a compound C¹³Method for synthesizing isotopically labeled lapatinib, the C¹³The chemical formula of isotopically labeled lapatinib is as follows:

the invention provides a compound C¹³The synthesis method of isotopically labeled lapatinib comprises the following reaction route:

the method comprises the following steps:

step b): hydrolyzing the compound 2 to obtain a compound 3;

step g): compound 7 is coupled to obtain C¹³Labeling lapatinib internal standard isotope labeling substance.

The following are specific examples of the present invention:

example 1

Step a): synthesis of Compound 2

Adding the compound 1(1.00g, 0.09mmol) and 50ml of n-hexane into a 100ml single-neck flask, cooling to 5 ℃, adding potassium nitrate (1.00g,0.11 mol) while stirring, reacting for 12h, pouring the system into a mixed solution of 50ml of dichloromethane and 50ml of ice water, stirring for 10min, separating an organic phase, and performing column chromatography purification by evaporation to obtain a product compound 2(754mg), wherein the yield is 54.0%.

Example 2

Step b): synthesis of Compound 3

Adding 2ml of compound 2(600mg, 0.038mmol) water into a 100ml reaction bottle, adding 10ml of tetrahydrofuran and 10ml of tetrabutylammonium hydroxide, heating to 80 ℃ for reaction for 3 hours, cooling to room temperature, extracting the system with dichloromethane three times, 50ml each time, combining organic phases, evaporating to dryness, and purifying by column chromatography to obtain a product compound 3(517mg), wherein: 97.5 percent.

Example 3

Step c): synthesis of Compound 4

Compound 3(500mg, 0.036mmol) was dissolved in 10ml acetonitrile and 10ml glacial acetic acid and NCS (470mg, 0.031mmol) was added and stirred at 80 ℃ until dissolved. The reaction system was stirred for 1 hour, 2ml of water was added, and the resulting mixture was purified by column chromatography to dryness to give the product compound 4(397mg) in yield: and (3.8).

Example 4

Step d): synthesis of Compound 5

Compound 4(400mg, 0.023mmol) and 3-fluorobenzyl bromide (440mg, 0.023mmol) acetonitrile 50ml are added into a 100ml reaction flask, anhydrous potassium carbonate (635mg,0.046mmol) is added, the system reacts for 3 hours at 80 ℃, then the filtration is carried out, the filter cake is rinsed by 20ml acetonitrile, the filtrate is evaporated to dryness, and the column chromatography purification is carried out to obtain the product compound 5(415mg), the yield: 64.1 percent.

Example 5

Step e): synthesis of Compound 6

Adding a compound 5(600mg, 0.021mmol), iron powder (597mg, 0.11mmol) and ammonium chloride (590mg, 0.11mmol) into a 100ml reaction bottle, adding 50ml of ethanol and 5ml of water, reacting at 80 ℃ for 6 hours, cooling to room temperature after the reaction is finished, filtering, rinsing a filter cake with 20ml of ethanol, adding 50ml of dichloromethane into the filter cake, stirring for 20 minutes, filtering, evaporating the filtrate to dryness, and purifying by column chromatography to obtain a product compound 6 (303mg), wherein the yield is as follows: 56.5 percent.

Example 6

Step f): synthesis of Compound 7

Adding a compound 6(300mg, 0.012mmol) and 6-iodo-4-chloroquinazoline (345mg, 0.012mmol) into a three-necked flask, adding isopropanol, reacting at 80 ℃ for 3 hours, cooling to room temperature after the reaction is finished, filtering, rinsing a filter cake with 20ml of cold isopropanol, and drying the filter cake to obtain a compound 7(501mg) with yield: 83.2 percent.

Example 7

Step g): c¹³Synthesis of isotopically labeled lapatinib

Adding a compound 7(500mg, 0.099mmol) and a lapatinib furanboronic acid intermediate (247mg, 0.099mmol) into a three-necked flask, adding 20ml of dioxane, 2ml of water, palladium tetratriphenylphosphine (15mg, 0.0099mmol), adding potassium acetate (192mg, 0.02mmol) to provide an alkaline environment, reacting at 80 ℃ for 3 hours, cooling to room temperature after the reaction is finished, filtering, and purifying a filtrate evaporation system by column chromatography to obtain a product C¹³Labeled lapatinib internal standard isotope label (269mg), yield: 52.5 percent.

Wherein the lapatinib furanboronic acid intermediate is:

。

Claims

1. c¹³The method for synthesizing isotopically labeled lapatinib is characterized by comprising the following steps of:

in the step a), carrying out nitration reaction on the compound 1 to obtain a compound 2;

step b), carrying out hydrolysis reaction on the compound 2 to obtain a compound 3;

in the step c), the compound 3 is subjected to chlorination reaction to obtain a compound 4;

in the step d), the compound 4 is subjected to substitution reaction to obtain a compound 5;

step e), carrying out reduction reaction on the compound 5 to obtain a compound 6;

step f), carrying out substitution reaction on the compound 6 to obtain a compound 7;

step g) coupling of the compound 7 to give C¹³Isotopically labeled lapatinib.

2. A compound of claim 1¹³The method for synthesizing isotopically labeled lapatinib is characterized in that the step a) is as follows: carrying out nitration reaction by using the compound 1 as a reaction substrate and potassium nitrate as a nitration reagent to obtain a compound 2.

3. A compound of claim 1¹³The synthesis method of isotopically labeled lapatinib is characterized by comprising the following steps: the hydrolysis reaction reagent in the step b) is one of potassium hydroxide, sodium hydroxide or tetrabutylammonium hydroxide.

4. A compound of claim 3¹³The synthesis method of isotopically labeled lapatinib is characterized by comprising the following steps: the hydrolysis temperature of the step b) is 70-80 ℃.

5. A compound of claim 1¹³The method for synthesizing isotopically labeled lapatinib is characterized in that the step c) comprises the following steps: and taking the compound 3 as a reaction substrate, adding NCS as a chlorination reagent, and carrying out chlorination reaction to obtain a compound 4.

6. A compound of claim 1¹³A method for synthesizing isotopically labeled lapatinib is characterized in that,the step d) is as follows: and (3) taking the compound 4 as a reaction substrate, and adding potassium carbonate and acetonitrile to perform substitution reaction to obtain a compound 5.

7. A compound of claim 1¹³The method for synthesizing isotopically labeled lapatinib is characterized in that the step e) is as follows: and taking the compound 5 as a reaction substrate, adding iron powder and ammonium chloride into the reaction substrate, and carrying out reduction reaction in an ethanol solution to obtain a compound 6.

8. A process as claimed in claim 7¹³The method for synthesizing isotopically labeled lapatinib is characterized in that the step f) is as follows: and (3) taking the compound 6 as a reaction substrate, adding 6-iodo-4-chloroquinazoline and isopropanol, and carrying out substitution reaction to obtain a compound 7.

9. The method for synthesizing C13 isotopically labeled lapatinib of claim 1, wherein: the step g) is as follows: taking the compound 7 as a reaction substrate, adding lapatinib furan boronic acid intermediate, dioxane, water, a catalyst and potassium acetate to perform coupling reaction to obtain C¹³Isotopically labeled lapatinib.

10. The method of claim 9, wherein the method for synthesizing C13 isotopically labeled lapatinib comprises the following steps: the catalyst in the step g) is palladium tetratriphenylphosphine, and the chemical formula of the Lapatinib furanoate intermediate is as follows:

。