CN112480072A - Preparation method of anticancer medicine - Google Patents
Preparation method of anticancer medicine Download PDFInfo
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- CN112480072A CN112480072A CN202011388608.8A CN202011388608A CN112480072A CN 112480072 A CN112480072 A CN 112480072A CN 202011388608 A CN202011388608 A CN 202011388608A CN 112480072 A CN112480072 A CN 112480072A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a preparation method of anticancer Laolatinib, which is characterized by comprising the following steps: dissolving the compound of the formula A in an organic solvent, adding a condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 ℃, carrying out heat preservation reaction for 2-3h, carrying out TLC detection on the reaction, cooling to room temperature, adding an ammonium chloride solution to carry out quenching reaction, and extracting and separating to obtain Laratinib; the structural formula of the compound of the formula A is
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an anticancer drug, and more particularly relates to a preparation method of an anticancer drug Laolatinib.
Background
Loratinib (Lorlatinib), the Chinese name (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-4, 8- (methine bridge) pyrazolo [4, 3-H ] [2, 5, 11] benzoxadiazatetetradecyl ring-3-carbonitrile, the name of England chemical (10R) -7-amino-12-fluoro-2, 10, 16-trimethy-15-oxo-10, 15, 16, 17-tetrahydro-2H-4, 8- (meta) pyrazolo [4, 3-H ] [2, 5, 11] benzodiazepine-cyclotene-3-carbonitrile. Laolatinib (loratinib) is produced by Pfizer, Calif
Limited corporation, approved by the United states FDA and marketed at 11/2 of 2018, is a third generation new drug for treating non-small cell lung cancer (NSCLC), has strong inhibitory effects on Anaplastic Lymphoma Kinase (ALK) and c-ROS proto-oncogene 1(c-ROS oncogene 1, ROS1) dual Receptor Tyrosine Kinase (RTK), and is used for treating patients who have been treated with at least one ALK inhibitor, such as first generation ALK inhibitor crizotinib (crizotinib) or second generation ALK inhibitor ceritinib (ceritinib) and alcaine (alitinib) but continue to progress in ALK-positive and (or) ROS 1-positive metastatic NSCLC.
The preparation method of Laolatinib in the prior art is not described in many ways, and the method mainly comprises the following steps:
(1) also disclosed are compounds of formula A
The preparation method is characterized in that HATU is used as a condensing agent, DIPEA is used as an alkali promoter, DMF is used as a solvent, and the reaction is carried out at a low temperature, so that the yield is only 29%;
(2) with the formula A
The method is characterized in that HATU is used as a condensing agent, DIPEA is used as an alkali promoter, DMF is used as a solvent, and the reaction is carried out for 4 to 5 hours under the condition of heating (60 to 70 ℃), so that the yield can reach about 78 percent.
(3) Or a salt of a compound of formula A
The raw material is COMU as condensing agent, TEA as alkali accelerating agent and DMF/THF as solvent, the yield is lower than 60%.
The above-mentioned processes, in addition to the low yield of the product loratinib, all present the problem of large quantities of the condensing agent and the alkali promoter, thus resulting in low overall catalytic efficiency, causing a large amount of waste of the condensing agent and the alkali promoter, which is disadvantageous from the economic point of view, and in addition, the large quantities of the condensing agent and the alkali promoter are used, which inevitably results in more complicated post-treatment operations and difficult purification, and is not favorable for the industrial development from the long-term point of view.
Disclosure of Invention
Objects of the inventionIn order to overcome a series of defects existing in the synthesis of anticancer drug Laratinib in the prior art, the preparation method of the anticancer drug Laratinib is provided, and is characterized by comprising the following steps: dissolving the compound of formula A in an organic solvent, and adding a condensing agent TBTU (O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate) and an alkali promoter DBU (1, 8-diazabicyclo [5.4.0 ]]-undec-7-ene), stirring uniformly, heating the system to 40-60 ℃, carrying out heat preservation reaction for 2-3h, detecting the reaction by TLC (thin layer chromatography), cooling to room temperature, adding an ammonium chloride solution to carry out quenching reaction, and extracting and separating to obtain Laolatinib; the structural formula of the compound of the formula A is
According to the preparation method of the anticancer drug Laolatinib, the organic solvent is selected from DMF, DMSO, acetonitrile, toluene or xylene
According to the preparation method of the anti-cancer drug Laolatinib, the organic solvent is preferably DMF.
According to the preparation method of the anticancer drug Laolatinib, the feeding molar ratio of the compound shown as the formula A, TBTU and DBU is 1: 0.5-1.5: 0.1 to 1.
According to the preparation method of the anti-cancer drug Laolatinib, the extracting agent is selected from one or more of ethyl acetate, dichloromethane or toluene.
According to the preparation method of the anticancer drug Laolatinib, the ammonium chloride solution is preferably a saturated ammonium chloride solution.
According to the preparation method of the anticancer drug Laolatinib, the separation method comprises the following steps: and collecting the extracted organic phase, concentrating under reduced pressure to obtain a solid, washing by using n-hexane, and drying in vacuum to obtain the Laolatinib.
Further, the invention also provides an application of TBTU in preparing an anticancer drug, preferably, the anticancer drug is Laratinib.
The main contributions of the present invention with respect to the prior art are the following:
according to the invention, the specific TBTU is used as the condensing agent, the specific DBU is used as the alkali promoter, and the condensing agent and the alkali promoter are used in combination, so that compared with the prior art, the consumption of the condensing agent and the alkali promoter used in the invention is obviously reduced, the reaction time is shorter, but the reaction yield is far higher than that of the prior art, namely, compared with the prior art, the method for preparing Lauratinib is more economic and environment-friendly, can ensure higher yield, and is very suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present disclosure more apparent, the technical solutions of the embodiments of the present disclosure are clearly and completely described. It is to be understood that the described embodiments are only a few embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the disclosure without any inventive step, are within the scope of protection of the disclosure.
The invention provides a preparation method of anticancer Laolatinib, which is characterized by comprising the following steps: dissolving the compound of formula A in an organic solvent, and adding a condensing agent TBTU (O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate) and an alkali promoter DBU (1, 8-diazabicyclo [5.4.0 ]]-undec-7-ene), stirring uniformly, heating the system to 40-60 ℃, carrying out heat preservation reaction for 2-3h, detecting the reaction by TLC (thin layer chromatography), cooling to room temperature, adding an ammonium chloride solution to carry out quenching reaction, and extracting and separating to obtain Laolatinib; the structural formula of the compound of the formula A is
According to the preparation method of the anticancer drug Laolatinib, the organic solvent is selected from DMF, DMSO, acetonitrile, toluene or xylene
According to the preparation method of the anti-cancer drug Laolatinib, the organic solvent is preferably DMF.
According to the preparation method of the anticancer drug Laolatinib, the feeding molar ratio of the compound shown as the formula A, TBTU and DBU is 1: 0.5-1.5: 0.1 to 1.
According to the preparation method of the anti-cancer drug Laolatinib, the extracting agent is selected from one or more of ethyl acetate, dichloromethane or toluene.
According to the preparation method of the anticancer drug Laolatinib, the ammonium chloride solution is preferably a saturated ammonium chloride solution.
According to the preparation method of the anticancer drug Laolatinib, the separation method comprises the following steps: and collecting the extracted organic phase, concentrating under reduced pressure to obtain a solid, washing by using n-hexane, and drying in vacuum to obtain the Laolatinib.
Further, the invention also provides an application of TBTU in preparing an anticancer drug, preferably, the anticancer drug is Laratinib.
Example 1
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of a condensing agent TBTU and 0.1mol of an alkali promoter DBU, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2h, detecting the reaction completion by TLC, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution for quenching reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate for extraction (100ml multiplied by 3), collecting an organic layer, carrying out reduced pressure distillation on the organic layer, completely removing the solvent to obtain a solid crude product, washing by using 200ml of n-hexane, and carrying out vacuum drying to obtain a target product Laratinib, wherein the yield is 87.8%, and the purity is 98.2%.
Example 2
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.15mol of a condensing agent TBTU and 50mmol of an alkali promoter DBU, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 3h, detecting by TLC that the reaction is finished, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution to quench the reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate to extract (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing by using 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 89.4%, and the purity is 97.4%.
Example 3
Adding 0.1mol of the compound of the formula A into 200ml of toluene, adding 50mmol of condensing agent TBTU and 0.1mol of alkali promoter DBU, slowly stirring until the system is uniformly mixed, then heating the system to 60 ℃, keeping the temperature for reaction for 3h, detecting by TLC that the reaction is finished, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution to quench the reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate to extract (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing by using 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 88.0%, and the purity is 98.1%.
Example 4
Adding 0.1mol of the compound of the formula A into 200ml of toluene, adding 0.1mol of condensing agent TBTU and 10mol of alkali promoter DBU, slowly stirring until the system is uniformly mixed, then heating the system to 40 ℃, keeping the temperature for reaction for 3h, detecting by TLC that the reaction is finished, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution to quench the reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate to extract (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing by using 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 85.8%, and the purity is 97.5%.
Comparative example 1
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of a condensing agent HATU and 0.1mol of an alkali promoter DIPEA, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2h, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution for quenching reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate for extraction (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing with 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 62.8%, and the purity is 79.6%.
Comparative example 2
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of a condensing agent HATU and 0.1mol of an alkali promoter DBU, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2h, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution for quenching reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate for extraction (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing with 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 70.4%, and the purity is 81.5%.
Comparative example 3
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of a condensing agent TBTU and 0.1mol of an alkali promoter DIPEA, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2h, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution for quenching reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate for extraction (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing with 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 77.5%, and the purity is 81.8%.
Comparative example 4
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of a condensing agent TBTU and 0.1mol of an alkali promoter TEA, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2h, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution to quench the reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate to extract (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing with 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 72.7%, and the purity is 83.9%.
Comparative example 5
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of condensing agent COMU and 0.1mol of alkali promoter TEA, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2 hours, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution to quench the reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate to extract (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing with 200ml of n-hexane, and drying in vacuum to obtain the target product Laratinib, wherein the yield is 58.3%, and the purity is 66.7%.
Comparative example 6
Adding 0.1mol of the compound of the formula A into 200ml of DMF, adding 0.1mol of condensing agent COMU and 0.1mol of alkali promoter DBU, slowly stirring until the system is uniformly mixed, then heating the system to 50 ℃, preserving heat for reaction for 2h, slowly cooling the system to room temperature, adding 100ml of saturated ammonium chloride solution for quenching reaction, continuously stirring for 20min, standing for 5min, adding ethyl acetate for extraction (100ml multiplied by 3), collecting an organic layer, distilling the organic layer under reduced pressure, completely removing the solvent to obtain a solid crude product, washing with 200ml of n-hexane, and drying in vacuum to obtain a target product Laratinib, wherein the yield is 60.7%, and the purity is 68.3%.
Finally, it should be noted that: it should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the scope of the invention.
Claims (5)
1. The preparation method of the anticancer drug Laolatinib is characterized by comprising the following steps: dissolving the compound of the formula A in an organic solvent, adding a condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 ℃, carrying out heat preservation reaction for 2-3h, carrying out TLC detection on the reaction, cooling to room temperature, adding an ammonium chloride solution to carry out quenching reaction, and extracting and separating to obtain Laratinib; the structural formula of the compound of the formula A is
2. The process for the preparation of the anticancer drug Lauratinib, according to claim 1, wherein the organic solvent is selected from DMF, DMSO, acetonitrile, toluene or xylene, preferably DMF.
3. The process for the preparation of the anticancer drug Lauratinib according to claim 1 or 2, wherein the molar ratio of the compound of formula A, TBTU and DBU is 1: 0.5-1.5: 0.1 to 1.
4. The process for the preparation of the anticancer drug Lauratinib according to any one of claims 1 to 3, wherein the extractant is selected from one or more of ethyl acetate, dichloromethane or toluene.
5. The process for the preparation of the anticancer drug Laratinib according to any one of claims 1-4, said isolation process is: and collecting the extracted organic phase, concentrating under reduced pressure to obtain a solid, washing by using n-hexane, and drying in vacuum to obtain the Laolatinib.
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| CN112457293A (en) * | 2020-11-30 | 2021-03-09 | 商河探荣新技术开发中心 | Application of TBTU in preparation of anti-cancer drugs |
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