CN116969949A - Synthesis method of intermediate impurity of ibrutinib - Google Patents
Synthesis method of intermediate impurity of ibrutinib Download PDFInfo
- Publication number
- CN116969949A CN116969949A CN202310337334.7A CN202310337334A CN116969949A CN 116969949 A CN116969949 A CN 116969949A CN 202310337334 A CN202310337334 A CN 202310337334A CN 116969949 A CN116969949 A CN 116969949A
- Authority
- CN
- China
- Prior art keywords
- compound
- ibt217
- ibrutinib
- water
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 31
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 title claims abstract description 31
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 31
- 239000012535 impurity Substances 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000004451 qualitative analysis Methods 0.000 abstract description 3
- 238000004445 quantitative analysis Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- -1 4-phenoxyphenyl Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a synthesis method of intermediate impurities of ibrutinib, which comprises the following steps: reacting the intermediate 1 with concentrated sulfuric acid in the presence of water to obtain a compound IBT217-1; the compound IBT217-1 reacts with the intermediate 2 in an organic solvent to obtain a compound IBT217, and the compound IBT217 is a target product. Compared with the direct heating method that the intermediate 1 cannot be effectively converted into the compound IBT217-1, the method successfully converts the intermediate 1 into the compound IBT217-1 through reasonable conditions and steps, and further prepares the impurity compound IBT217, the synthesis conditions are stable, the post-treatment mode of the preparation process is simple, the purity of the obtained product is high, the yield is high, and mass preparation is easy to realize; the synthesis method has great significance on the research on the quality and the impurity of ibrutinib, can be used for qualitative and quantitative analysis of the impurity in ibrutinib production, and provides a guarantee for the medication safety of ibrutinib.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy, in particular to a method for synthesizing intermediate impurities of ibutinib.
Background
Ibrutinib (ibrutinib) is a targeted anticancer new drug developed by the co-operation of Johnson company and pharma cycles company, and is approved by the united states Food and Drug Administration (FDA) for marketing at 11/13 2013, under the trade name Imbruvica, and is used for the treatment of mantle cell lymphoma (mantle cell lymphoma, MCL). Chemical name of ibrutinib: 1- [3 (R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ]]Pyrimidin-1-yl]Piperidin-1-yl]-2-propen-1-one; the molecular formula: c (C) 25 H 24 N 6 O 2 。
The publication No. CN101610676B (application No. CN 200680056438.5) discloses a method for synthesizing ibrutinib, and the synthesis process is shown in figure 1. In this synthesis, compound 4 was suspended in formamide and heated at 180 ℃ under nitrogen for 4 hours, the reaction mixture was cooled to 30 ℃ and then water was added, the solids were collected, washed thoroughly with water, methanol in sequence, and air dried to give compound 3. The applicant found that when repeating the synthesis method, the cyano group of the compound 4 is hydrolyzed to obtain carboxyl during the reaction process, and the carboxyl reacts with the amino group of the compound 3 to generate an impurity compound IBT217, and the structural formula is as follows:
the compound IBT217 has a plurality of active amino sites, and in the subsequent synthesis reaction of ibrutinib, namely, when the compound 3 reacts with acryloyl chloride to obtain ibrutinib, the active amino group easily reacts with the acryloyl chloride to obtain impurities similar to ibrutinib in structure but large in molecular weight, and the impurities with large molecular weight are difficult to remove and refine in the purification process of the crude product, so that the purity of the target product is influenced. The control of the impurity compound IBT217 content in the intermediate stage is an effective means of controlling the impurity content of the final product, which requires further investigation of the properties of the compound IBT217, however, the synthesis method of the impurity compound IBT217 is not disclosed in the prior art, the yield of the compound obtained by the mother liquor enrichment method in the reaction process is extremely low, and the compound needs to be purified for many times, and the cost is high.
Therefore, the impurity compound IBT217 is synthesized, has great significance on the quality and impurity research of ibrutinib, can be used for qualitative and quantitative analysis of impurities in ibrutinib production, and provides guarantee for the medication safety of ibrutinib.
Disclosure of Invention
Aiming at the current state of the art, the invention provides a synthesis method of intermediate impurities of ibrutinib, which can directionally synthesize an impurity compound IBT217, and the obtained product has high purity and high yield.
The technical scheme adopted for solving the technical problems is as follows:
a synthesis method of intermediate impurities of ibrutinib comprises the following steps:
(1) Reacting the intermediate 1 with concentrated sulfuric acid in the presence of water to obtain a compound IBT217-1;
(2) The compound IBT217-1 reacts with the intermediate 2 in an organic solvent to obtain a compound IBT217, the compound IBT217 is the target product,
preferably, in step (1), intermediate 1 is mixed with concentrated sulfuric acid, then heated directly to 105-110 ℃ and stirred for a period of time, cooled to room temperature and slowly dripped into water.
Preferably, after the water is added dropwise, the reaction solution is heated to reflux, the reflux reaction is kept at a temperature, the reaction solution is cooled to room temperature after the reflux reaction is finished, and the stirring is continued at the room temperature for a period of time.
Preferably, the heat preservation reflux reaction time is 1.5-2.5 h, and the heat preservation stirring time is 30-60 minutes.
Preferably, after the heat preservation and stirring are finished, suction filtration is carried out, the obtained solid is leached by water, and the wet product is dried at 50-60 ℃ to obtain the compound IBT217-1.
Preferably, in step (2), the compound IBT217-1, N-dimethylformamide, 4-dimethylaminopyridine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is mixed, stirred for a period of time, and then the intermediate 2 is added in portions and reacted at room temperature.
Preferably, after the reaction is completed, water is added to the reaction system at 25 to 30 ℃ and stirring is continued for 30 to 60 minutes.
Preferably, the obtained reaction solution is filtered by suction, and is continuously rinsed by water, and the obtained wet product is dried to obtain the compound IBT217.
Compared with the prior art, the invention has the advantages that: compared with the direct heating method that the intermediate 1 cannot be effectively converted into the compound IBT217-1, the method successfully converts the intermediate 1 into the compound IBT217-1 through reasonable conditions and steps, and further prepares the impurity compound IBT217, the synthesis conditions are stable, the post-treatment mode of the preparation process is simple, the purity of the obtained product is high, the yield is high, and mass preparation is easy to realize; the synthesis method has great significance on the research on the quality and the impurity of ibrutinib, can be used for qualitative and quantitative analysis of the impurity in ibrutinib production, and provides a guarantee for the medication safety of ibrutinib.
Drawings
FIG. 1 is a schematic diagram of a structure of the background art of the invention;
FIG. 2 is a mass spectrum of the compound IBT217-1 obtained in the examples of the invention;
FIG. 3 is a mass spectrum of the compound IBT217 obtained in the examples of the invention;
FIG. 4 is an HPLC chart of the compound IBT217 obtained in the examples of the present invention.
Detailed Description
The invention is described in further detail below with reference to the embodiments of the drawings.
The method for synthesizing the intermediate impurity of ibrutinib in the embodiment comprises the following steps:
(1) Synthesis of IBT217-1
15.0mL of concentrated sulfuric acid is added into a clean and dry 100.0mL four-necked flask at the temperature of 25-30 ℃, then 10.0g of intermediate 1 is added, the temperature is directly raised to 110 ℃ (internal temperature is 108 ℃), the mixture is kept at 105-110 ℃ and stirred for 1-2 h, and then the mixture is cooled to the room temperature of 25-30 ℃. Slowly adding water dropwise at room temperature (the water adding process needs to pay attention to obvious heat release, the temperature is controlled at 25-100 ℃), after the dripping is finished, heating the reaction liquid to reflux, keeping the temperature for 2 hours, and slowly cooling the reaction liquid to 25-30 ℃ after the reflux is finished. And stirring is continued for 30-60 minutes at 25-30 ℃. Filtering after the heat preservation and stirring are finished, leaching with 30.0mL of water, and drying the wet product at 50-60 ℃; yield 75%;
(2) Synthesis of IBT217
10.0mL of N, N-Dimethylformamide (DMF), IBT217-11.0g of 4-Dimethylaminopyridine (DMAP) 0.04g and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) 1.5g were placed in a clean, dry 100.0mL four-necked flask at 25-30 ℃. After the addition, stirring is continued for 30-60 min at 25-30 ℃, and then 1.02g of intermediate 2 is added in 3 batches. The reaction mixture was stirred at 25 to 30℃and TLC measurements were performed every 0.5h (the solvent used for the measurements was methylene chloride: methanol=19:1 by volume) until the starting material was completely reacted. After the reaction is finished, 100.0mL of water is added into the reaction system at the temperature of 25-30 ℃ and stirring is continued for 30-60 min. Suction filtration and continuous leaching with 50.0mL of water are carried out to obtain 4.2g of wet product, and the wet product is dried at 50 ℃ to obtain 1.75g of white solid with the yield of 91.2%.
As shown in FIG. 2, the structure of the compound IBT217-1 can be confirmed; as shown in fig. 3, the structure of compound IBT217 can be confirmed. As shown in fig. 4, it can be known that the purity of the resultant product compound IBT217 is 99.06%.
Claims (8)
1. The synthesis method of the intermediate impurity of ibrutinib is characterized by comprising the following steps of:
(1) Reacting the intermediate 1 with concentrated sulfuric acid in the presence of water to obtain a compound IBT217-1;
(2) The compound IBT217-1 reacts with the intermediate 2 in an organic solvent to obtain a compound IBT217, the compound IBT217 is the target product,
2. the method for synthesizing intermediate impurities of ibrutinib according to claim 1, wherein: in the step (1), after the intermediate 1 is mixed with concentrated sulfuric acid, the temperature is directly raised to 105-110 ℃, the mixture is stirred for a period of time, and water is slowly dripped after the mixture is cooled to room temperature.
3. The method for synthesizing intermediate impurities of ibrutinib according to claim 2, wherein: after the water is added dropwise, the reaction solution is heated to reflux, and the reflux reaction is carried out at the reflux temperature, cooled to room temperature after the reflux reaction is finished, and kept at the room temperature for a period of time.
4. A process for the synthesis of intermediate impurities of ibrutinib according to claim 3, characterized in that: the reflux reaction time is 1.5-2.5 h, and the heat preservation stirring time is 30-60 minutes.
5. A process for the synthesis of intermediate impurities of ibrutinib according to claim 3, characterized in that: and (3) after the heat preservation and stirring are finished, carrying out suction filtration, leaching the obtained solid by using water, and drying the wet product at 50-60 ℃ to obtain the compound IBT217-1.
6. Process for the synthesis of intermediate impurities of ibrutinib according to any one of claims 1 to 5, characterized in that: in the step (2), the compound IBT217-1, N-dimethylformamide, 4-dimethylaminopyridine and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are mixed, stirred for a period of time, and then the intermediate 2 is added in portions for reaction at room temperature.
7. The method for synthesizing intermediate impurities of ibrutinib according to claim 6, wherein: after the reaction is finished, water is added into the reaction system at the temperature of 25-30 ℃ and stirring is continued for 30-60 min.
8. The method for synthesizing intermediate impurities of ibrutinib according to claim 7, wherein: the obtained reaction liquid is filtered by suction, and is continuously rinsed by water, and the obtained wet product is dried to obtain the compound IBT217.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310337334.7A CN116969949A (en) | 2023-03-31 | 2023-03-31 | Synthesis method of intermediate impurity of ibrutinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310337334.7A CN116969949A (en) | 2023-03-31 | 2023-03-31 | Synthesis method of intermediate impurity of ibrutinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116969949A true CN116969949A (en) | 2023-10-31 |
Family
ID=88483844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310337334.7A Pending CN116969949A (en) | 2023-03-31 | 2023-03-31 | Synthesis method of intermediate impurity of ibrutinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116969949A (en) |
-
2023
- 2023-03-31 CN CN202310337334.7A patent/CN116969949A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN114014787A (en) | Asymmetric synthesis method for preparing (2S,3R) -p-methylsulfonylphenylserine ethyl ester | |
| CN1109017C (en) | Preparation of 1.1-cyclohexyl oxalic amide | |
| WO2024040995A1 (en) | Synthesis method for n-methyl-3-substituted methyl-4-pyrazolecarboxamide derivative and n-methyl-3-substituted methyl-4-pyrazole formic acid | |
| CN103626772A (en) | Synthetic method for temozolomide and intermediate | |
| CN113710655B (en) | Method for purifying haloperidol | |
| CN116969949A (en) | Synthesis method of intermediate impurity of ibrutinib | |
| CN104193674A (en) | Synthesis method of flunixin meglumine | |
| CN102260241A (en) | Industrial preparation method of thalidomide of crystal form alpha | |
| CN114213337A (en) | Production process of benzimidazole drug intermediate | |
| CN1800166A (en) | Ornidazole optical antimer preparation and purification method | |
| CN108503600B (en) | Polysubstituted quinoxaline derivative and preparation method thereof | |
| CN109293631B (en) | Preparation method of 3-amino-N- (2, 6-dioxo-3-piperidyl) -phthalimide compound | |
| CN114516827A (en) | Method for reducing content of indobufen genotoxic impurities | |
| CN102344392B (en) | Method for refining histone deacetylase (HDAC) inhibitor vorinostat | |
| CN112898204A (en) | Synthesis method of N-benzyloxycarbonyl-L-histidine | |
| Yamasaki et al. | A Convenient Method for the Preparation of N-β Alanyldopamine as a Substrate of Phenoloxidase | |
| CN109134385B (en) | Method for purifying uracil compounds | |
| CN102030684A (en) | Clean production method for symmetrical N,N'-dialkylurea | |
| CN111925298B (en) | 4-CNAB and preparation method thereof | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| CN112174966B (en) | New method for preparing piroxicam hydrochloride | |
| CN111995618B (en) | Preparation method of neratinib impurity G | |
| CN111269138B (en) | Method for efficiently preparing propacetamol hydrochloride for injection | |
| CN114105961B (en) | Preparation method of IDO1 inhibitor (LY-3381916) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |