CN112961090A - Key intermediate for synthesizing Alpelisib and preparation method thereof - Google Patents
Key intermediate for synthesizing Alpelisib and preparation method thereof Download PDFInfo
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- CN112961090A CN112961090A CN201911289330.6A CN201911289330A CN112961090A CN 112961090 A CN112961090 A CN 112961090A CN 201911289330 A CN201911289330 A CN 201911289330A CN 112961090 A CN112961090 A CN 112961090A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C07B2200/07—Optical isomers
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Abstract
The invention relates to a novel compound shown in a formula I, which is a key intermediate for synthesizing an inhibitor Alpelisib of PI 3K. The synthesis process is simple, the obtained product has high purity and mild reaction conditions, and the compound shown in the formula I can be quickly and effectively prepared by using the method.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a key intermediate for synthesizing a PI3K inhibitor Alpelisib and a preparation method thereof.
Background
Alpelisib (BYL719) was developed by Nowa, and the US FDA approved the Alpelisib tablet of Nowa on 24/5/2019 (Specification: 50mg, 150mg, 200mg)Trade name of
It is used in combination with fulvestrant in the treatment of advanced metastatic breast cancer carrying a PIK3CA mutation in hormone receptor positive (HR +)/human epidermal growth factor receptor 2 negative (HER2-) negative in both men and postmenopausal women. Alpelisib is the first PI3K (specifically PI3K α) inhibitor to treat this type of breast cancer.
The compound shown in the formula I is a key intermediate in the synthesis of Alpelisib, and the chemical structures of the compound shown in the formula I and the Alpelisib are respectively shown as follows:
there is still a need for improvement in the compounds of formula I and their preparation.
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 compound shown as a key intermediate formula I for synthesizing Alpelisib, which has the advantages of simple process, high purity and mild reaction conditions, and a preparation method and application thereof.
In a first aspect of the invention, there is provided a compound of formula I,
the compound is a brand new compound, and at present, no literature report exists.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I. According to an embodiment of the invention, the method comprises: a compound represented by the formula A (Cas No. 717094-71-8) was reacted with di-tert-butyl dicarbonate ((Boc)2O) and triethylamine so as to prepare the compound shown in the formula I. The synthetic route for the compounds of formula I can be shown as follows:
the inventor finds that the compound shown in the formula I can be quickly and effectively prepared by using the method, and the preparation method has mild reaction conditions and is easy to realize industrial scale-up production.
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.
According to an embodiment of the present invention, a compound of formula A is reacted with di-tert-butyl dicarbonate ((Boc)2The contact manner of O), triethylamine is not particularly limited. Thus, the compound represented by the formula A and di-tert-butyl dicarbonate ((Boc) can be extracted2O) and triethylamine contact efficiency, thereby accelerating the reaction speed and further improving the efficiency of preparing the compound shown in the formula I by using the method.
According to an embodiment of the invention, the reaction of the invention comprises the following steps: adding the compound shown in the formula A and triethylamine in the dichloromethane in sequence under the stirring state, keeping stirring, and slowly dripping (Boc) at about 0 DEG C2And O, heating to 30-40 ℃, stirring and reacting for 1.5-2.5 hours. Adding 10% citric acid solution, washing for 3 times, separating organic layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain brown oily substance, dissolving the oily substance with C1-C6 straight chain or branched chain alcohol, adding acetone, stirring, recrystallizing, and filtering to obtain the compound shown in formula I.
According to an embodiment of the invention, the reaction of the invention further comprises the steps of: adding the compound shown in the formula A and triethylamine in the dichloromethane in sequence at 0 ℃ under the stirring state, keeping stirring, and slowly dropwise adding (Boc) at about 0 DEG C2O, temperature risingStirring and reacting for 1.5-2.5 hours at the temperature of 30-40 ℃. Adding 10% citric acid solution, washing for 3 times, separating organic layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain brown oily substance, adding C1-C6 straight chain or branched chain alcohol to dissolve oily substance, adding acetone, stirring, cooling, standing for recrystallization overnight, precipitating a large amount of solid the next day, filtering, and vacuum drying to obtain the compound shown in formula I.
According to an embodiment of the present invention, in the above step, the compound represented by the formula A, triethylamine, (Boc)2The molar ratio of O is 1 (2.5-5) to 1.5-3, preferably a compound represented by the formula A, triethylamine, (Boc)2The molar ratio of O is 1:3.0: 2.2. 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 above step, it is preferable to use a compound represented by formula A, triethylamine, (Boc)2The reaction is stirred for 2h under the contact of O.
According to an embodiment of the present invention, in the above step, the C1-C6 linear or branched alcohol is one selected from methanol, ethanol, isopropanol, and tert-butanol, and preferably the C1-C6 linear or branched alcohol is one selected from methanol, ethanol, and tert-butanol.
According to an embodiment of the present invention, in the above step, the volume ratio of the C1-C6 linear or branched alcohol to acetone is 1:3.
According to an embodiment of the present invention, in the above step, the mixed solvent for recrystallization is at least two selected from methanol, acetone, dichloromethane, and petroleum ether, preferably the solvent for recrystallization is a mixed solvent selected from methanol and acetone, and more preferably the volume ratio of methanol to acetone is 3:1 (v/v).
In a third aspect of the invention, the invention provides a compound shown as a formula I for pharmaceutical use. The compound shown in the formula I is used as a key intermediate for synthesizing an inhibitor Alpelisib of PI 3K.
The synthesis process is simple, the obtained product has high purity and mild reaction conditions, and the compound shown in the formula I can be quickly and effectively prepared by using the method.
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 of formula I
The compound of formula A (15.8g, 0.1mol) and triethylamine (30.3g, 0.3mol) were added to dichloromethane (200mL) with stirring at 0 deg.C, then stirred, and slowly added dropwise (Boc) at about 0 deg.C2O (48.0g, 0.22mol), heated to 36 ℃ and stirred for 2 hours. And (3) adding 10% citric acid solution for washing (300mL for 3 times), separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain brown oily matter, adding 40mL of methanol to dissolve the oily matter while the oily matter is hot, adding 120mL of acetone, stirring uniformly, cooling, standing for recrystallization overnight, precipitating a large amount of solid the next day, filtering, and drying in vacuum to obtain the compound shown in the formula I, wherein the content is 32.2g, the yield is 89.8%, and the HPLC purity is 98.2%.
LC-MS(APCI):m/z＝359.3(M+1)+。
EXAMPLE 2 Synthesis of Compound of formula I
The compound of formula A (15.8g, 0.1mol) and triethylamine (25.3g, 0.25mol) were added to dichloromethane (180mL) sequentially with stirring at 0 deg.C, then kept under stirring and slowly added dropwise (Boc) at about 0 deg.C2O (32.7g, 0.15mol), and the reaction was stirred at 40 ℃ for 1.5 hours. And (3) adding 10% citric acid solution for washing (300mL for 3 times), separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain brown oily matter, adding 40mL of ethanol while the oily matter is hot to dissolve, adding 120mL of acetone, uniformly stirring, cooling, standing for recrystallization overnight, precipitating a large amount of solid the next day, filtering, and drying in vacuum to obtain the compound shown in the formula I, wherein the amount of the compound is 31.5g, the yield is 87.9%, and the HPLC purity is 98.4%.
EXAMPLE 3 Synthesis of Compound of formula I
The compound of formula A (15.8g, 0.1mol) and triethylamine (50.6g, 0.5mol) were added to dichloromethane (250mL) with stirring at 0 deg.C, then stirred, and slowly added dropwise (Boc) at about 0 deg.C2O (65.5g, 0.3mol), heated to 30 ℃ and stirred for 2.5 hours. And (3) adding 10% citric acid solution for washing (360mL for 3 times), separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain brown oily matter, adding 40mL of isopropanol while the oily matter is hot to dissolve, adding 120mL of acetone, uniformly stirring, cooling, standing for recrystallization overnight, precipitating a large amount of solid the next day, filtering, and drying in vacuum to obtain the compound shown in the formula I, wherein the obtained amount is 32.3g, the yield is 90.2%, and the purity of HPLC is 97.8%.
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 compound of the formula I, wherein,
2. the compound of formula I as claimed in claim 1, wherein the compound of formula A is contacted with di-tert-butyl dicarbonate and triethylamine to prepare the compound of formula I,
3. the method of claim 2, comprising the steps of: and under the stirring state, sequentially adding the compound shown in the formula A and triethylamine into dichloromethane, keeping stirring, slowly dropwise adding di-tert-butyl dicarbonate at about 0 ℃, heating to 30-40 ℃, and stirring for reaction for 1.5-2.5 hours. Adding 10% citric acid solution, washing for 3 times, separating organic layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain brown oily substance, dissolving the oily substance with C1-C6 straight chain or branched chain alcohol, adding acetone, stirring, recrystallizing, filtering, and drying to obtain the compound shown in formula I.
4. The method according to claim 3, wherein the compound represented by formula A, triethylamine and di-tert-butyl dicarbonate are contacted and stirred for reaction for 2 hours.
5. The method of claim 3, wherein the molar ratio of the compound of formula A to the triethylamine to the di-tert-butyl dicarbonate is 1 (2.5-5) to (1.5-3).
6. The method according to claim 5, wherein the molar ratio of the compound represented by formula A to the triethylamine to the di-tert-butyl dicarbonate is 1:3.0: 2.2.
7. The method of claim 3, wherein the C1-C6 linear or branched alcohol is one selected from methanol, ethanol, isopropanol, and tert-butanol.
8. The method of claim 7, wherein the C1-C6 linear or branched alcohol is one selected from methanol, ethanol, or tert-butanol.
9. The method of claim 3, wherein the volume ratio of the C1-C6 linear or branched alcohol to acetone is 1:3.
10. A compound of formula I according to claim 1, characterized in that it is used as a key intermediate in the synthesis of Alpelisib.
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| CN201911289330.6A CN112961090A (en) | 2019-12-13 | 2019-12-13 | Key intermediate for synthesizing Alpelisib and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103619840A (en) * | 2011-06-21 | 2014-03-05 | 诺华股份有限公司 | Polymorphs of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide |
| CN104844589A (en) * | 2014-12-26 | 2015-08-19 | 中国科学院合肥物质科学研究院 | Novel PI3K (phosphatidyl inositol 3-kinase) inhibitor |
| CN106083840A (en) * | 2011-03-03 | 2016-11-09 | 诺华股份有限公司 | The synthesis of 2 carbamyl ring semicarbazide derivatives |
-
2019
- 2019-12-13 CN CN201911289330.6A patent/CN112961090A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083840A (en) * | 2011-03-03 | 2016-11-09 | 诺华股份有限公司 | The synthesis of 2 carbamyl ring semicarbazide derivatives |
| CN103619840A (en) * | 2011-06-21 | 2014-03-05 | 诺华股份有限公司 | Polymorphs of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide |
| CN104844589A (en) * | 2014-12-26 | 2015-08-19 | 中国科学院合肥物质科学研究院 | Novel PI3K (phosphatidyl inositol 3-kinase) inhibitor |
Non-Patent Citations (4)
| Title |
|---|
| JEKATERINA IVANOVA: "Access to NH-aziridine-2-carboxamides through Davidsen acylimidodicarbonate activation", 《C. R. CHIMIE》 * |
| PASCAL FURET ET AL.: "Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| STEVEN K. DAVIDSEN ET AL.: "Di-tert-butyl JV-Acylimidodicarbonates as Isolable Acylating Agents： Mild Conversion Primary Carboxamides to Substituted Amidesof", 《J. ORG. CHEM.》 * |
| VON LEIF GREHN ET AL.: "Erschopfende tert-Butoxycarbonylierung von Peptid-Stickstoffatomen", 《ANGEW. CHEM.》 * |
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Application publication date: 20210615 |