CN110790652A - Imatinib intermediate, synthetic method thereof and intermediate - Google Patents
Imatinib intermediate, synthetic method thereof and intermediate Download PDFInfo
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to an erlotinib intermediate, a synthetic method thereof and an intermediate. The synthesis method of the Aleptinib intermediate adopts 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid as a raw material, the raw material is cheap and easy to obtain, the reaction steps are short, the reaction time is short, the chemical purity of the product can reach more than 98.150%, the yield can reach more than 90.73%, and the synthesis method has good industrial prospect.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an erlotinib intermediate, a synthetic method thereof and an intermediate.
Background
Lung cancer is one of the more prevalent cancers, while non-small cell lung cancer accounts for 80% of all lung cancers. Currently, the traditional chemotherapy method for the non-small cell lung cancer generally adopts crizotinib, and part of patients are insensitive to the crizotinib. The etanertinib is still effective in patients who have failed the chemotherapy of crizotinib. The Alletinib is an innovative drug invented by Chugai pharmaceutical, a division of Roche pharmaceutical, has been qualified as a U.S. FDA breakthrough therapeutic drug, is rapidly approved as a new oral anti-lung cancer drug, and is used for treating advanced (metastatic) non-small cell lung cancer (NSCLC) with ALK gene mutation or treating crizotinib-resistant patients.
6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -one is used as a key intermediate for synthesizing the alendronic acid. In the prior art, the main synthesis method is, for example, that 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid is used as a starting material, and methoxy group is introduced, brominated and cyclized to generate the compound disclosed in US2013/143877A 1. As the raw material 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid is not industrially produced, the cost is high, the comprehensive yield is only 35-40%, and the industrial production is not facilitated.
In order to overcome the defects of the prior art, the application provides a brand new synthesis method, the method selects 2- (4-hydroxy-5-methoxy-2-propyl phenyl) acetic acid as a raw material, the raw material is easy to obtain, the industrial production is facilitated, the chemical purity of the product can reach more than 98.150%, the yield can reach more than 90.73%, and the method has good industrial prospect.
Disclosure of Invention
The invention aims to provide an erlotinib intermediate, a synthesis method thereof and an intermediate, so as to improve the purity and yield of a product.
In order to solve the technical problem, the invention provides a synthesis method of 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone, which comprises the following steps: two reactions carried out one after the other; removing methanol by rotary evaporation; and drying to obtain the 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one; wherein the first reaction is to prepare an intermediate by 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, paraformaldehyde, (1S) - (+) -10-camphorsulfonic acid and anhydrous methanol; and (4) secondary reaction, namely mixing the intermediate with Triton B, methyl iodide and hydrogen bromide to react.
Further, the reaction formula of the first reaction is as follows:
further, the molar ratio of the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, the paraformaldehyde, and the (1S) - (+) -10-camphorsulfonic acid is 1: 1-1.2: 1.5-2.
Further, the primary reaction comprises: adding the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, paraformaldehyde, (1S) - (+) -10-camphorsulfonic acid and anhydrous methanol to a single-neck round bottom flask to form a reaction mixture; placing the reaction mixture in a preheated oil bath, and heating and reacting under stirring; cooled to room temperature for filtration through buchner funnel, celite pad; washing with anhydrous methanol to remove insoluble solids; and drying to obtain the intermediate.
Further, the temperature of the preheating oil bath is 120-140 ℃.
Further, the reaction formula of the secondary reaction is as follows:
further, the molar ratio of the intermediate, methyl iodide and hydrogen bromide is 1: 0.1: 2-4.
Further, the secondary reaction comprises: adding the intermediate into a three-neck round-bottom flask, and connecting the intermediate with a calcium oxide drying tube through a reflux condenser; adding absolute methanol and stirring; dropwise adding Triton B, and continuously stirring; adding methyl iodide at room temperature, heating, stirring and refluxing; adding hydrogen bromide, and continuously heating, stirring and refluxing; and cooling to room temperature.
In a second aspect, the present invention also provides a 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one having the formula:
in a third aspect, the invention also provides an intermediate for synthesizing 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one,
the intermediate has the structural formula:
the synthesis method has the beneficial effects that the synthesis method adopts 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid as a raw material to prepare 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone, namely an alentinib intermediate, the raw material is cheap and easy to obtain, the reaction step is short, the reaction time is short, the chemical purity of the product can reach more than 98.150%, the yield can reach more than 90.73%, and the synthesis method has a good industrial prospect.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a process flow diagram of the synthetic method of the present invention.
Detailed Description
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
Example 1
As shown in fig. 1, this example 1 provides 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one (i.e., an ailutinib intermediate) comprising the steps of: step S1, two reactions carried out successively; step S2, removing methanol by rotary evaporation; and step S3, drying to obtain the 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one; wherein in step S11, a reaction is carried out, namely, an intermediate is prepared from 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, paraformaldehyde, (1S) - (+) -10-camphorsulfonic acid and anhydrous methanol; and in the step S12, carrying out secondary reaction, namely mixing the intermediate with Triton B, methyl iodide and hydrogen bromide to react.
The synthesis method of the embodiment 1 selects 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid as a raw material, the raw material is cheap and easy to obtain, the reaction step is short, the reaction time is short, the chemical purity of the product can reach more than 98.150%, the yield can reach more than 90.73%, and the method has a good industrial prospect.
As an alternative to the primary reaction.
The primary reaction comprises the following steps: step S111, adding the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid and paraformaldehyde ((CH)2O)n) (1S) - (+) -10-Camphorsulfonic acid (Camphorsylfonic acid) and anhydrous methanol were added to a single-necked round bottom flask equipped with a magnetic stirrer to form a reaction mixture; step S112, placing the reaction mixture in a preheated oil bath, and heating for 40 minutes under the condition of stirring to perform reaction; step S113, cooling to room temperature, to filter through a Buchner funnel, 10g of a Celite pad; step S114, washing with anhydrous methanol to remove insoluble solids; and step S115, drying to obtain the intermediate.
Specifically, the reaction formula of the first reaction is as follows:
optionally, the molar ratio of the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, paraformaldehyde, and (1S) - (+) -10-camphorsulfonic acid is 1: 1-1.2: 1.5-2.
Optionally, the temperature of the pre-heating oil bath is 120-140 ℃, preferably 130 ℃.
As an alternative embodiment of the secondary reaction.
The secondary reaction comprises the following steps: step S121, adding the intermediate into a three-neck round-bottom flask with a magnetic stirrer inside, and connecting the intermediate with a calcium oxide drying tube through a reflux condenser; step S122, adding 500ml of anhydrous methanol and stirring for 1 hour; step S123, adding Triton B (benzyl trimethyl ammonium hydroxide) dropwise, and continuing stirring for 10 minutes; step S124, slowly adding methyl iodide (Mel) at room temperature, heating, stirring and refluxing for 8 hours; step S125, adding hydrogen bromide, and continuing heating, stirring and refluxing for 2 hours; and step S126, cooling to room temperature.
Specifically, the reaction formula of the secondary reaction is as follows:
optionally, the molar ratio of the intermediate, methyl iodide and hydrogen bromide is 1: 0.1: 2-4.
In this example 1, the used anhydrous methanol and Triton B are both solvents, so that the reactants are fully dissolved to increase the reaction rate, and do not act as reactants or participate in the two reactions, therefore, the amount of the reactants can be adjusted by itself according to the amount of the reactants, and is not specifically specified.
Example 2
Based on example 1, this example 2 provides 1- (4-nitrophenyl) piperidin-2-one, wherein the structural formula of the 1- (4-nitrophenyl) piperidin-2-one is:
for the specific structure and implementation of 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one, reference is made to the relevant discussion of example 1, and no further description is given here.
Example 3
Based on example 1, this example 3 provides an intermediate for the synthesis of 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one, said intermediate having the formula:
for the specific structure and implementation of the intermediate, refer to the related discussion of embodiment 1, and are not described herein again.
Example 4
(1) 208.25g of 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, 90g of paraformaldehyde, 348.45g of (1S) - (+) -10-camphorsulfonic acid and 500ml of anhydrous methanol are sequentially added into a single-neck round-bottom flask with a magnetic stirring rod for reaction; then the reaction mixture was placed in a preheated oil bath at 120 ℃ and heated with stirring for 40 minutes; the reaction mixture was cooled to room temperature and filtered through a buchner funnel with a 10g pad of celite, washed with dry methanol to remove insoluble solids, and dried to give an intermediate.
(2) The intermediate was placed in a three-necked round-bottomed flask equipped with a magnetic stirrer, the top of the reflux condenser was connected to a calcium oxide drying tube, 500ml of anhydrous methanol was added thereto and stirred for 1 hour, then 200ml of commercially available Triton B (containing 40% methanol solution) was added dropwise to the solution and stirred for 10 minutes, 14.19g of methyl iodide was slowly added at room temperature, and stirred under heating under reflux for 8 hours, 161.8g of hydrogen bromide was added thereto and stirred under reflux for 2 hours. Cooled to room temperature and methanol was removed by rotary evaporation. Drying to obtain the product 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone. (6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one 261.75g in mass, 98.150% purity, 90.73% yield).
Example 5
(1) 208.25g of 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, 99g of paraformaldehyde, (1S) - (+) -10-camphorsulfonic acid 418.1g and 500ml of anhydrous methanol were sequentially added to a single-necked round-bottomed flask equipped with a magnetic stir bar. The reaction mixture was placed in a preheated oil bath at 130 ℃ and heated with stirring for 40 minutes. The reaction mixture was then cooled to room temperature and filtered through a buchner funnel with a 10g pad of celite and washed with dry methanol to remove insoluble solids, which was dried to give an intermediate.
(2) Putting the intermediate into a three-neck round-bottom flask provided with a magnetic stirrer, connecting a calcium oxide drying tube to the top of a reflux condenser, adding 500ml of anhydrous methanol, stirring for 1 hour, then dropwise adding 200ml of commercially available Triton B (containing 40% methanol solution) into the solution, continuously stirring for 10 minutes, slowly adding 14.19g of methyl iodide at room temperature, heating, stirring and refluxing for 8 hours, adding 242.7g of hydrogen bromide, and continuously heating, stirring and refluxing for 2 hours; cooling to room temperature and removing the methanol by rotary evaporation; drying to obtain the product. (product 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one 261.4g in mass, 99.216% in purity, 91.59% in yield).
Example 6
(1) 208.25g of 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, 108g of paraformaldehyde, 464.6g of (1S) - (+) -10-camphorsulfonic acid and 500ml of anhydrous methanol were sequentially added to a single-necked round-bottomed flask equipped with a magnetic stir bar. The reaction mixture was placed in a pre-heated oil bath at 140 ℃ and heated with stirring for 40 minutes. The reaction mixture was then cooled to room temperature and filtered through a buchner funnel with a 10g pad of celite and washed with dry methanol to remove insoluble solids, which was dried to give an intermediate.
(2) Putting the intermediate into a three-neck round-bottom flask with a magnetic stirrer, connecting a calcium oxide drying tube to the top of a reflux condenser, adding 500ml of anhydrous methanol, stirring for 1 hour, then dropwise adding 200ml of commercially available Triton B (containing 40% methanol solution) into the solution, continuously stirring for 10 minutes, slowly adding 14.19g of methyl iodide at room temperature, heating, stirring and refluxing for 8 hours, adding 323.6g of hydrogen bromide, and continuously heating, stirring and refluxing for 2 hours; cooling to room temperature and removing the methanol by rotary evaporation; drying to obtain the product. (the product 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one has a mass of 261.99g, a purity of 99.338%, and a yield of 91.91%).
Example 7
In example 7, the influence factors on the purity and yield of the synthesized product were investigated, as shown in Table 1. That is, in the synthesis process of 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone (i.e. the intermediate of Alletinib), when the content of 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid is unchanged, the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid can be fully reacted by increasing the content of paraformaldehyde, (1S) - (+) -10-camphorsulfonic acid, hydrogen bromide and the like, thereby improving the purity and yield of the product.
Table 1 amount of main components and synthetic effect of the present application
In conclusion, the Aleptinib intermediate and the synthesis method thereof, and the intermediate adopt 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid as a raw material, the raw material is cheap and easy to obtain, the reaction steps are short, and the reaction time is short; by reasonably setting the content ratio of each component, the purity and the yield of the product can be effectively improved, the chemical purity of the product can reach more than 98.150 percent, the yield can reach more than 90.73 percent, even the purity can reach 99.338 percent, and the yield can reach 91.91 percent; has better industrial prospect and is suitable for large-scale production and standardized operation. In addition, the high-purity 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone is more suitable for being used as an intermediate for synthesizing the alendronic, and the ineffective components in the alendronic can be reduced, so that the drug effect is ensured.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (10)
1. A method for synthesizing 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone is characterized by comprising the following steps:
two reactions carried out one after the other;
removing methanol by rotary evaporation; and
drying to obtain the 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -one; wherein
A first reaction, namely preparing an intermediate by 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, paraformaldehyde and (1S) - (+) -10-camphorsulfonic acid;
and (4) secondary reaction, namely mixing the intermediate with methyl iodide and hydrogen bromide to react.
2. The method of synthesis according to claim 1,
the reaction formula of the primary reaction is as follows:
3. the method of synthesis according to claim 1,
the molar ratio of the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid to the paraformaldehyde to the (1S) - (+) -10-camphorsulfonic acid is 1: 1-1.2: 1.5-2.
4. The method of synthesis according to claim 1,
the primary reaction comprises the following steps:
adding the 2- (4-hydroxy-5-methoxy-2-propylphenyl) acetic acid, paraformaldehyde, (1S) - (+) -10-camphorsulfonic acid and anhydrous methanol to a single-neck round bottom flask to form a reaction mixture;
placing the reaction mixture in a preheated oil bath, and heating and reacting under stirring;
cooled to room temperature for filtration through buchner funnel, celite pad;
washing with anhydrous methanol to remove insoluble solids; and
and drying to obtain the intermediate.
5. The method of synthesis according to claim 4,
the temperature of the preheating oil bath is 120-140 ℃.
6. The method of synthesis according to claim 1,
the reaction formula of the secondary reaction is as follows:
7. the method of synthesis according to claim 1,
the molar ratio of the intermediate to the methyl iodide to the hydrogen bromide is 1: 0.1: 2-4.
8. The method of synthesis according to claim 1,
the secondary reaction comprises the following steps:
adding the intermediate into a three-neck round-bottom flask, and connecting the intermediate with a calcium oxide drying tube through a reflux condenser;
adding absolute methanol and stirring;
dropwise adding Triton B, and continuously stirring;
adding methyl iodide at room temperature, heating, stirring and refluxing;
adding hydrogen bromide, and continuously heating, stirring and refluxing; and
and cooling to room temperature.
9. A6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalen-2 (1H) -one having the formula:
10. an intermediate for synthesizing 6-bromo-7-methoxy-1, 1-dimethyl-3, 4-dihydronaphthalene-2 (1H) -ketone,
the intermediate has the structural formula:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113233964A (en) * | 2021-05-14 | 2021-08-10 | 武汉工程大学 | Synthesis method of 5-methoxy-2-tetralone |
| CN113336633A (en) * | 2021-05-14 | 2021-09-03 | 武汉工程大学 | Synthetic method of 5-hydroxy-2-tetralone |
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| CN113336633A (en) * | 2021-05-14 | 2021-09-03 | 武汉工程大学 | Synthetic method of 5-hydroxy-2-tetralone |
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Application publication date: 20200214 |