CN111004257A - Method for preparing RET inhibitor Selpercatinib - Google Patents
Method for preparing RET inhibitor Selpercatinib Download PDFInfo
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- CN111004257A CN111004257A CN201911348328.1A CN201911348328A CN111004257A CN 111004257 A CN111004257 A CN 111004257A CN 201911348328 A CN201911348328 A CN 201911348328A CN 111004257 A CN111004257 A CN 111004257A
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 229940121610 selpercatinib Drugs 0.000 title claims abstract description 31
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 title claims abstract description 26
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- 239000007787 solid Substances 0.000 claims description 29
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
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- 229940125782 compound 2 Drugs 0.000 claims description 8
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- IDXKJSSOUXWLDB-UHFFFAOYSA-N 2-[4-(4-ethoxy-6-oxo-1h-pyridin-3-yl)-2-fluorophenyl]-n-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide Chemical compound CCOC1=CC(=O)NC=C1C(C=C1F)=CC=C1CC(=O)NC1=NOC(C(C)(C)C(F)(F)F)=C1 IDXKJSSOUXWLDB-UHFFFAOYSA-N 0.000 description 1
- KOLQINCWMXQEOF-UHFFFAOYSA-N 2-[6-(6,7-dimethoxyquinolin-3-yl)pyridin-3-yl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]acetamide Chemical compound COC=1C=C2C=C(C=NC2=CC=1OC)C1=CC=C(C=N1)CC(=O)NC1=CC(=NO1)C(C(F)(F)F)(C)C KOLQINCWMXQEOF-UHFFFAOYSA-N 0.000 description 1
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- GBLBJPZSROAGMF-RWYJCYHVSA-N CO[C@@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 Chemical compound CO[C@@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 GBLBJPZSROAGMF-RWYJCYHVSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing RET inhibitor Selpercatinib. The preparation method has the advantages of milder halogenation reaction conditions, simpler reaction operation steps and post-treatment, fewer reaction steps, greatly improved total yield of the reaction and product purity of more than 99.0%.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for preparing a RET inhibitor Selpercatinib.
Background
RET is a protooncogene (The transfected REarranged gene). RET receptor tyrosine kinase is an oncogene that appears in various cancers including non-small cell lung cancer (NSCLC), Medullary Thyroid Cancer (MTC), etc., abnormal activation of which is a key driver leading to growth and proliferation of various solid tumors, and it has been found that various diseases occur in close relation to RET gene mutation, such as NSCLC, MTC, multiple endocrine adenomatosis type 2 (multiple endocrine neoplasma ii, MEN2), Papillary Thyroid Cancer (PTC), megacolon congenital, lung adenocarcinoma, etc.
RET gene variation includes gene fusion and activating point mutations, which can lead to excessive activation of the RET signaling pathway and uncontrolled cell growth. RET gene fusions occur in 2% of non-small cell lung cancers (NSCLC), 10-20% of thyroid cancers and a few other cancer types. Whereas activating RET point mutations occur in 60% of patients with Medullary Thyroid Carcinoma (MTC). Cancers carrying the variation of the RET gene are largely dependent on abnormal activation of this protein kinase to promote their proliferation and growth, and thus these cancers are very sensitive to RET inhibitors.
At present, selective and specific medicines and therapies aiming at RET are not approved by regulatory agencies such as FDA, and no selective RET inhibitor is on the market all over the world. A total of 17 selective RET inhibitor drugs are currently under investigation, with 2 in phase 2, 3 in phase 1, 6 in Discovery stage, and 6 reported without progression. The selective Ret inhibitor drugs associated with tumor indications entered 3 out of 3 in the clinic, with stage 2 clinic 1 (selpercatinib/LOXO-292), and stage 1 clinic 2 (pralseatinib/BLU-667, BOS-172738). Another 2 drugs, BOS-589 (phase 2 clinical), GSK-3179106 (phase 1 clinical), are used in intestinal diseases such as irritable bowel syndrome, gastrointestinal pain, inflammatory bowel disease.
Selpercatinib is a highly specific, potent oral RET inhibitor obtained when LOXO Oncology is purchased from gifts. It can inhibit not only the natural RET signaling pathway but also the acquired resistance mechanisms that may occur. It has been identified by FDA-granted breakthrough therapy to treat NSCLC patients carrying RET gene fusions and MTC patients carrying RET activating mutations, as well as patients with advanced thyroid cancer carrying RET gene fusions. From the current clinical test, the treatment effect is very good and more accurate, and the biochemical index remission rate obtains a good result. In addition, the compound is effective not only for patients with RET gene mutation, but also for patients with RET gene fusion. Finally, of particular interest is the very low side effects. The structural formula of the high-selectivity RET gene mutation inhibitor Selpercatinib is a compound shown as a formula I:
the current method for preparing the RET inhibitor Selpercatinib still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a method for preparing the RET inhibitor Selpercatinib, which has the advantages of few synthesis steps, mild reaction conditions, high reaction yield in each step, simplicity and convenience in operation, high total yield of reaction products and high purity of the obtained products.
In one aspect of the invention, the invention provides a method for preparing a compound RET inhibitor Selpercatinib shown in formula I. According to an embodiment of the invention, the method comprises:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting a compound of formula 3 with a compound of formula 4 to obtain a compound of formula I,
the inventor finds that the method adopts the existing easily-obtained drug intermediate (compound 1) and obtains the target compound Selpercatinib after halogenation reaction and reductive amination, the halogenation reaction condition is milder, the reaction operation steps and the post-treatment are simpler and more convenient, the reaction steps are fewer, the total yield of the reaction is greatly improved, and the product purity reaches more than 99.0%.
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and may be, for example, mechanical stirring, that is, stirring under the action of a mechanical force.
Herein, a "compound of formula N" is also sometimes referred to herein as "compound N", where N is any integer from 1 to 4, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to an embodiment of the present invention, the above method for preparing the compound represented by formula 3, the compound represented by formula I, may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the raw materials for preparing the compound represented by formula 3, the compound represented by formula I is not particularly limited, and it may be prepared by any known method or may be commercially available.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, the compound represented by formula 2, K2CO3、Bu4The contact manner of NBr is not particularly limited. Preferably, the solvent of the reaction is selected from acetone. Thus, the compound represented by the formula 1, the compound represented by the formula 2, and K can be promoted2CO3、Bu4The NBr contact efficiency accelerates the reaction speed, and further improves the efficiency of preparing the compound shown in the formula 3 by using the method.
According to an embodiment of the present invention, in the step (1), the following steps are included: adding compound 1, compound 2 and K into acetone2CO3And Bu4NBr was stirred and heated to reflux. Filtering the reaction solution, concentrating the filtrate, pulping and purifying the obtained solid by using ethyl acetate, filtering the solid, and drying to obtain the compound shown in the formula 3. Thus, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to an embodiment of the present invention, in step (1), formula 1A compound represented by the formula 22CO3、Bu4The molar ratio of NBr is 1 (1.0-1.3): (1.1-1.4): 0.005-0.015), preferably 1,2, K2CO3、Bu4The molar ratio of NBr was 1:1.2:1.2: 0.01. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (1), the compound represented by formula 1, the compound represented by formula 2, and K may be reacted at 60 ℃2CO3、Bu4NBr contact reaction is carried out for 11-14 hours, and the preferable reaction time is 12 hours.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: to acetone (300mL) was added Compound 1(33.2g, 0.1mol), Compound 2(18.4g, 0.12mol), and K2CO3(16.6g, 0.12mol) and tetrabutylammonium bromide (Bu4NBr) (3.2g, 0.01mol), heated with stirring, and reacted at 60 ℃ under reflux for 12 h. Filtering the reaction solution, concentrating the filtrate, pulping the obtained solid with ethyl acetate (120mL), purifying, filtering the solid, and drying to obtain the compound shown in the formula 3.
According to an embodiment of the present invention, in the step (2), the compound represented by formula 3, the compound represented by formula 4, HOAc, NaBH3The contact manner of CN is not particularly limited. Preferably, the solvent of the reaction is selected from CH2ClCH2A mixed solvent of Cl and MeOH. Thus, the compound represented by the formula 3, the compound represented by the formula 4, HOAc, NaBH can be promoted3CN contact efficiency, reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula I by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the following steps are included: mixing compound 3, compound 4, HOAc and NaBH3CN addition of CH2ClCH2Cl and MeOH, the mixture was stirred and the reaction was stirred. After the reaction solution was cooled to room temperature, saturated NaHCO was added3After the solution was adjusted to pH 10, DCM and MeOH were added and extracted. Drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, pulping the obtained solid with ethyl acetate, and purifyingAnd filtering and drying the solid to obtain the compound Selpercatinib shown in the formula I. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to an embodiment of the invention, in step (2), compound 3, compound 4, HOAc, NaBH3The molar ratio of CN is 1 (1.0-1.4) to 1.1-1.5 (1.2-1.5), preferably 3, 4, HOAc, NaBH3The molar ratio of CN is 1:1.2: 1.3. therefore, the utilization rate of reactants is high, the waste of raw materials and reality can not be caused, and the yield and the purity of the target compound are high.
According to an embodiment of the present invention, in step (2), compound 3, compound 4, HOAc, NaBH3CN and CH2ClCH2And stirring and heating the mixture of Cl and MeOH to 70-85 ℃, stirring and reacting for 3-7 h, preferably stirring and heating the mixture to 80 ℃, and stirring and reacting for 4 h. Thereby, the compound 3, the compound 4, HOAc, NaBH can be improved3CN is contacted, so that the efficiency of preparing the compound shown in the formula I by using the method is further improved.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: compound 3(40.5g, 0.1mol), compound 4(16.5g, 0.12mol), HOAc (7.8g, 0.13mol), NaBH3CN (40.5g, 0.13mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 80 deg.C and the reaction stirred for 4 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase is dried by anhydrous sodium sulfate and then concentrated under reduced pressure, the obtained solid is pulped and purified by ethyl acetate (400mL), and the solid is filtered and dried to obtain the compound Selpercatinib shown in the formula I.
According to the examples of the present invention, the synthetic route of the compound Selpercatinib of formula I can be as follows:
the preparation method of Selpercatinib reported in the prior art uses 1, 2-dimethyloxirane and hydroxyl in a compound 1 for alkylation, the reaction is a high-temperature and high-pressure tube sealing reaction, the danger is high, and the requirements on reaction equipment and operators are high during industrialization. The preparation method of Selpercatinib adopts the existing easily obtained drug intermediate (compound 1), and the target compound Selpercatinib is obtained after the halogenation reaction and the reduction ammoniation, the halogenation reaction condition is milder, the reaction operation steps and the post-treatment are simpler and more convenient, the reaction steps are fewer, the total yield of the reaction is greatly improved, and the product purity reaches more than 99.0 percent.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 3
To acetone (300mL) was added Compound 1(33.2g, 0.1mol), Compound 2(18.4g, 0.12mol), and K2CO3(16.6g, 0.12mol) and tetrabutylammonium bromide (3.2g, 0.01mol), heated with stirring and reacted at 60 ℃ under reflux for 12 h. The reaction solution was filtered, the filtrate was concentrated, and the obtained solid was purified by slurrying with ethyl acetate (120mL), and the solid was filtered and dried to obtain a compound represented by formula 3 in an amount of 32.6g with a yield of 80.7%.
LC-MS(APCI):m/z＝405.4(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
To acetone (300mL) was added Compound 1(33.2g, 0.1mol), Compound 2(15.3g, 0.1mol), and K2CO3(15.2g, 0.11mol) and Bu4NBr (1.6g, 0.005mol), heated with stirring, reacted at 60 ℃ under reflux for 11 h. The reaction solution was filtered, the filtrate was concentrated, and the obtained solid was purified by slurrying with ethyl acetate (120mL), and the solid was filtered and dried to obtain the compound represented by formula 3 in an amount of 31.2g with a yield of 77.1%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
To acetone (300mL) was added Compound 1(33.2g, 0.1mol), Compound 2(19.9g, 0.13mol), and K2CO3(19.3g, 0.14mol) and Bu4NBr (4.8g, 0.015mol), heated with stirring, was reacted at 60 ℃ under reflux for 14 h. The reaction solution was filtered, the filtrate was concentrated, and the obtained solid was purified by slurrying with ethyl acetate (120mL), and the solid was filtered and dried to obtain a compound represented by formula 3 in an amount of 30.4g with a yield of 75.2%.
Example 4 Synthesis of Selpercatinib Compound of formula I
Compound 3(40.5g, 0.1mol), compound 4(16.5g, 0.12mol), HOAc (7.8g, 0.13mol), NaBH3CN (40.5g, 0.13mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 80 deg.C and the reaction stirred for 4 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting solid was purified by slurrying with ethyl acetate (400mL), the solid was filtered and dried to give the compound Selpercatinib of formula I in an amount of 41.4g, yield 78.8% and HPLC purity 99.5%.
LC-MS(APCI):m/z＝526.4(M+1)+。
Example 5 Synthesis of Selpercatinib Compound of formula I
Compound 3(40.5g, 0.1mol), compound 4(13.7g, 0.1mol), HOAc (6.6g, 0.11mol), NaBH3CN (7.5g, 0.12mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 70 deg.C and the reaction stirred for 7 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting solid was purified by slurrying with ethyl acetate (400mL), the solid was filtered and dried to give the compound Selpercatinib of formula I in an amount of 40.1g, yield 76.3% and HPLC purity 99.2%.
Example 6 Synthesis of Selpercatinib Compound of formula I
Combining compound 3(40.5g, 0.1mol)Substance 4(19.2g, 0.14mol), HOAc (9.0g, 0.15mol), NaBH3CN (9.4g, 0.15mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 85 deg.C, and the reaction stirred for 3 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting solid was purified by slurrying with ethyl acetate (400mL), filtered and dried to give the compound Selpercatinib of formula I in an amount of 39.4g, a yield of 75.0% and an HPLC purity of 99.3%.
Example 7 Synthesis of Selpercatinib Compound of formula I
A mixture of compound 3(40.5g, 0.1mol), compound 4(13.0g, 0.095mol), HOAc (6.0g, 0.1mol), NaBH3CN (6.9g, 0.11mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 80 deg.C and the reaction stirred for 4 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting solid was purified by slurrying with ethyl acetate (400mL), filtered and dried to give the compound Selpercatinib of formula I in an amount of 23.6g, yield 44.9% and HPLC purity 97.8%.
Example 8 Synthesis of Selpercatinib Compound of formula I
Compound 3(40.5g, 0.1mol), compound 4(20.6g, 0.15mol), HOAc (10.8g, 0.18mol), NaBH3CN (11.3g, 0.18mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 80 deg.C and the reaction stirred for 4 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting solid was purified by slurrying with ethyl acetate (400mL), filtered and dried to give the compound Selpercatinib of formula I in an amount of 34.8g, a yield of 66.2% and an HPLC purity of 98.2%.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A method of preparing the RET inhibitor Selpercatinib, comprising:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting a compound of formula 3 with a compound of formula 4 to obtain a compound of formula I,
2. the method according to claim 1, wherein in step (1), the following steps are included: adding compound 1, compound 2 and K into acetone2CO3And Bu4NBr, stirring and heating, carrying out reflux reaction, filtering the reaction solution, concentrating the filtrate, pulping the obtained solid by using ethyl acetate, purifying, filtering the solid, and drying to obtain the compound shown in the formula 3.
3. The method of claim 2The method of (1), wherein in the step (1), the compound represented by the formula 1, the compound represented by the formula 2, and K2CO3、Bu4The molar ratio of NBr is 1 (1.0-1.3) to 1.1-1.4 to 0.005-0.015.
4. The method according to claim 3, wherein in the step (1), the compound represented by formula 1, the compound represented by formula 2, K2CO3、Bu4The molar ratio of NBr was 1:1.2:1.2: 0.01.
5. The method according to claim 2, wherein the compound represented by formula 1, the compound represented by formula 2, and K are reacted at 60 ℃ in step (1)2CO3、Bu4NBr contact reaction is carried out for 11-14 hours, and the preferable reaction time is 12 hours.
6. The method of claim 1, wherein in step (2), the following steps are included: mixing compound 3, compound 4, HOAc and NaBH3CN addition of CH2ClCH2Cl and MeOH, the mixture was stirred and the reaction was stirred. After the reaction solution was cooled to room temperature, saturated NaHCO was added3After the solution was adjusted to pH 10, DCM and MeOH were added and extracted. Drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, pulping and purifying the obtained solid by using ethyl acetate, filtering the solid, and drying to obtain the compound Selpercatinib shown in the formula I.
7. The method of claim 6, wherein in step (2), Compound 3, Compound 4, HOAc, NaBH3The molar ratio of CN is 1 (1.0-1.4) to 1.1-1.5 to 1.2-1.5.
8. The method of claim 7, wherein in step (2), Compound 3, Compound 4, HOAc, NaBH3The molar ratio of CN is 1:1.2: 1.3.
9. the method of claim 6The method is characterized in that in the step (2), the compound 3, the compound 4, HOAc, NaBH3CN and CH2ClCH2And stirring and heating the mixture of Cl and MeOH to 70-85 ℃, stirring and reacting for 3-7 h, preferably stirring and heating the mixture to 80 ℃, and stirring and reacting for 4 h.
10. The method according to claims 1-9, characterized in that: in the step (1), the method comprises the following steps: to acetone (300mL) was added Compound 1(33.2g, 0.1mol), Compound 2(18.4g, 0.12mol), and K2CO3(16.6g, 0.12mol) and tetrabutylammonium bromide (3.2g, 0.01mol), heated with stirring and reacted at 60 ℃ under reflux for 12 h. Filtering the reaction solution, concentrating the filtrate, pulping and purifying the obtained solid by using ethyl acetate (120mL), filtering the solid, and drying to obtain a compound shown in a formula 3;
in the step (2), the method comprises the following steps: compound 3(40.5g, 0.1mol), compound 4(16.5g, 0.12mol), HOAc (7.8g, 0.13mol), NaBH3CN (40.5g, 0.13mol) was added to CH2ClCH2Cl (400mL) and MeOH (250mL), stirred and warmed to 80 deg.C and the reaction stirred for 4 h. After the reaction solution was cooled to room temperature, saturated NaHCO was added3The solution was then adjusted to pH 10 and extracted by addition of DCM (400mL) and MeOH (40 mL). The organic phase is dried by anhydrous sodium sulfate and then concentrated under reduced pressure, the obtained solid is pulped and purified by ethyl acetate (400mL), and the solid is filtered and dried to obtain the compound Selpercatinib shown in the formula I.
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| CN110156803A (en) * | 2017-02-27 | 2019-08-23 | 北京赛特明强医药科技有限公司 | Dioxanes and quinolines and the preparation method and application thereof |
| CN110382494A (en) * | 2016-10-10 | 2019-10-25 | 阿雷生物药品公司 | Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor |
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| CN110156803A (en) * | 2017-02-27 | 2019-08-23 | 北京赛特明强医药科技有限公司 | Dioxanes and quinolines and the preparation method and application thereof |
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Denomination of invention: Method for preparing RET inhibitor Selpercatinib Granted publication date: 20210629 Pledgee: Wuhan Optics Valley Small and Medium Duty Venture Capital Co.,Ltd. Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2024110000096 |