CN113861120A - Preparation method of dacomitinib - Google Patents
Preparation method of dacomitinib Download PDFInfo
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- CN113861120A CN113861120A CN202111281340.2A CN202111281340A CN113861120A CN 113861120 A CN113861120 A CN 113861120A CN 202111281340 A CN202111281340 A CN 202111281340A CN 113861120 A CN113861120 A CN 113861120A
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- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 title claims abstract description 38
- 229950002205 dacomitinib Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- QRZFUQFQXCRJRR-UHFFFAOYSA-N 4-n-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine Chemical compound C=12C=C(N)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 QRZFUQFQXCRJRR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- CJOJDNRJDBWZKM-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine Chemical compound N1=CN=C2C=C(F)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 CJOJDNRJDBWZKM-UHFFFAOYSA-N 0.000 claims abstract description 4
- DSQHWBRYZUFZDY-FXRZFVDSSA-N (e)-4-piperidin-1-ylbut-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)\C=C\CN1CCCCC1 DSQHWBRYZUFZDY-FXRZFVDSSA-N 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- 239000008213 purified water Substances 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- VKEKKVCWODTGAP-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine Chemical compound C=12C=C([N+]([O-])=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 VKEKKVCWODTGAP-UHFFFAOYSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims 3
- 230000010933 acylation Effects 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 35
- 238000006722 reduction reaction Methods 0.000 abstract description 10
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 abstract description 9
- 238000006482 condensation reaction Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- -1 3-chloro-4-fluorophenyl Chemical group 0.000 abstract description 3
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 238000006198 methoxylation reaction Methods 0.000 abstract description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000779 smoke Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- QEUXJCPXSNFBHX-UHFFFAOYSA-N 7-fluoro-6-nitroquinazolin-4-amine Chemical compound FC1=C([N+]([O-])=O)C=C2C(N)=NC=NC2=C1 QEUXJCPXSNFBHX-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of dacomitinib, which comprises the following steps: (N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine) is subjected to methoxylation reaction in an alkali/methanol system to obtain a compound 02(N- (3-chloro-4-fluorophenyl) -7-methoxy-6-nitroquinazolinamine-4-amine); the compound 02 and hydrazine hydrate are subjected to reduction reaction to obtain a compound 03(N- (3-chloro-4-fluorophenyl) -7-methoxyl-6-aminoquinazoline-4-amine); the compound 03 and the acyl chloride compound 11((2E) -4- (1-piperidyl) -2-butenoic acid hydrochloride) are subjected to condensation reaction in an N-methylpyrrolidone solvent to obtain a crude product, and then the crude product is refined in an ethanol water solution to obtain the cotinib. The preparation method of the invention avoids using a large amount of solvent as a reaction solvent, thereby reducing the generation of waste liquid as much as possible and being more environment-friendly; the method has the advantages of easily available and safe raw materials, high overall yield and high purity of the route, can effectively avoid the defects of difficult availability and low yield of the raw materials and the catalyst, is favorable for realizing industrialization, and reduces the generation cost.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of dacomitinib
Background
Dacomitinib (Dacomitinib), chemical name (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] - -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide, marketed in china in 2019. Dacomitinib was originally developed by Hurrill, and was licensed to SFJ Pharmaceuticals for collaborative development in 2012. Dacomitinib was approved as a single drug in china for first-line treatment of locally advanced or metastatic non-small cell lung cancer patients with Epidermal Growth Factor Receptor (EGFR) exon 19 deletion mutation or exon 21L 858R substitution mutation.
CN1972688B describes the original process for synthesizing dacomitinib from N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine. The original research process uses heavy metal catalyst and hydrogen for reduction when reducing the nitro group on the benzene ring, and has high cost, long reaction time and easy explosion gas hidden trouble. The oxalyl chloride is used in the amino condensation reaction of the original research process, is very sensitive to air humidity and has unpleasant smell, and the reaction is too violent, so the method is not friendly and safe to the environment. Thirdly, the method of catalytic hydrogenation reduction of nitro groups is difficult to control: when conditions are not well controlled, small amounts of dechlorinated impurities are formed, which are difficult to remove in downstream steps. This dechlorination reaction is extremely sensitive to palladium catalysts, with trace amounts of catalyst remaining in the hydrogenator sufficient to result in the formation of dechlorinated impurities. Finally, due to the properties of the intermediates and the bulk drugs, the solubility of the intermediates and the bulk drugs in most solvents is very low, a large amount of solvents are consumed in the original grinding and synthesizing route, the environment is polluted, the bottleneck of capacity is reduced, and the cost is high. The invention avoids the use of noble metal, flammable and explosive gas and impurities caused by incomplete catalytic hydrogenation reaction, and has obvious advantage of reducing the use amount of the solvent.
Disclosure of Invention
According to the invention, high-purity dacomitinib is obtained by combining methyl oxidation substitution reaction, reduction reaction, condensation reaction and recrystallization with water, and the yield is high, so that the cost of treating non-small molecular lung cancer by using dacomitinib as the first-line second-generation drug is greatly reduced, and the preparation method is suitable for industrial production. The synthetic route is as follows:
(i) specifically, the compound 01(N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine) undergoes a methoxylation reaction in an alkali/methanol system to obtain a compound 02(N- (3-chloro-4-fluorophenyl) -7-methoxy-6-nitroquinazolin-4-amine);
(ii) specifically, the compound 02 and hydrazine hydrate undergo reduction reaction to obtain a compound 03(N- (3-chloro-4-fluorophenyl) -7-methoxy-6-aminoquinazoline-4-amine);
(iii) specifically, the compound 03 and the acyl chloride compound 11 are subjected to condensation reaction in an N-methyl pyrrolidone solvent to obtain a crude product, and then the crude product is refined in an ethanol water solution to obtain the cotinib.
The preparation method comprises the steps of methyl oxidation substitution reaction, reduction reaction, condensation reaction and recrystallization combined with water to obtain the dacomitinib with high purity and higher yield, so that the cost of the dacomitinib used as the first-line second-generation medicament for treating the non-small molecular lung cancer is greatly reduced, and the preparation method is suitable for industrial production.
Further, the base in step 1 is selected from one or more of sodium hydroxide, potassium carbonate, sodium methoxide and sodium carbonate, and is preferably sodium hydroxide.
Further, the reaction temperature of the methoxylation reaction in the step 1 is 25 ℃ to 65 ℃, preferably 50 ℃ to 65 ℃.
Further, the molar ratio of the compound 01 to the base in the step 1 is 1.0:1.0 to 1.0:3.0, and the preferred molar ratio is 1.0:2.0 to 1.0: 2.5.
Further, the reduction reaction of step 2 is: hydrazine hydrate is used as a reducing agent, and the compound 02 is subjected to reduction reaction in the presence of a catalyst and under the condition of an organic solvent to generate a compound 03. Optionally, the organic solvent in step 2 is selected from one or more of 1, 4-dioxane, N-dimethylformamide, N-methylpyrrolidone and tetrahydrofuran, and is preferably tetrahydrofuran solvent; the catalyst is preferably ferric trichloride; optionally, the molar ratio of compound 02 to reducing agent is 1.0:5.0 to 1.0:12.0, preferably the molar ratio is 1.0: 8.0; optionally, the reaction temperature of the step 2 is 45-70 ℃, preferably 55-65 ℃.
Compared with the prior art that the heavy metal catalyst and hydrogen are used for reducing the nitro group on the benzene ring, the cost is high, the reaction time is long, and high-pressure gas hidden danger exists, the hydrazine hydrate reduction method can quickly and efficiently complete the reaction, and the cost is much lower.
Further, after the reaction of the compound 02 with the reducing agent in the step 2 is finished, thermal filtration and concentration are carried out, and then the mixture is poured into a crystallization solvent for crystallization. Wherein, the crystallization solvent is methanol, ethanol, tetrahydrofuran or drinking water, preferably drinking water; the mass ratio of the compound 02 to water is 1: 8 to 1: 15, preferably 1: 10.
further, step 3 is: firstly, carrying out acyl chlorination reaction on the compound 11 and a chlorinating reagent, then carrying out condensation reaction on the compound 11 and the compound 03, adjusting the pH value of a system after the reaction is finished, and cooling and crystallizing to obtain a crude product of the cotinib. In the above synthetic route of the present invention, compound 03 is directly condensed with compound 11, so that the whole synthetic route is simpler than the original synthetic route.
Further, the chlorinating agent is selected from one or more of thionyl chloride, phosphorus oxychloride and oxalyl chloride, and is preferably thionyl chloride; the method has the advantages that the chlorination by using the thionyl chloride is more stable and efficient, the reaction operation is simple, the thionyl chloride is more easily controlled than the method for preparing acyl chloride by using phosphorus oxychloride, the method is environment-friendly, and the safety is high.
Further, the reaction solvent is preferably N-methylpyrrolidone.
Further, the molar ratio of compound 11 to chlorinating agent is 1.0:0.8 to 1.0:1.3, preferably 1.1: 1.0; the reaction temperature of the acyl chlorination reaction is-10 ℃ to 15 ℃, and is preferably-5 ℃ to 5 ℃; the molar ratio of compound 03 to compound 11 is 1.0:1.0 to 1.0:1.5, preferably 1.0: 1.3.
Further, the protic solvent used for quenching in step 3 is one or more of water, methanol and ethanol, and preferably, water is used as a quenching agent. The temperature of the quenching is-20 ℃ to 10 ℃, preferably-5 ℃ to 5 ℃.
Further, step 3 also includes recrystallization. In the above recrystallization, the mass ratio of the recrystallization solvent to the compound 04 is 10:1 to 20:1, preferably, the mass ratio is 12: 1; the refined solvent is selected from ethyl acetate, ethanol, methanol and isopropanol, and preferably ethanol; the temperature of the recrystallization is 40 ℃ to 80 ℃, preferably 60 ℃ to 70 ℃.
Further, the mixed solvent used in the preparation of dacomitinib in step 4 is methanol/water, ethanol/water, tetrahydrofuran/water, 2-methyltetrahydrofuran/water, isopropanol/water, preferably, ethanol/water; the volume ratio of the organic solvent to the water in the mixed solvent is 10:1 to 20:1, preferably 15: 1; the refining temperature is 40 ℃ to 80 ℃, preferably 60 ℃ to 70 ℃.
In addition, the synthetic process route of the invention avoids and solves the defect of using a large amount of solvent as a reaction solvent, thereby reducing the generation of waste liquid as much as possible and being more environment-friendly.
The preparation method has the advantages of simple process, easily available raw materials, safety, strong operability, high overall yield of the route, high purity, economy, environmental protection, contribution to realizing industrialization and reduction of the production cost, and can effectively avoid the defects of unavailable raw materials and catalysts and low yield.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the instrumentalities and methods described in the specification.
For a better understanding and practice, the present invention is described in detail below.
Drawings
FIG. 1 is a high resolution mass spectrum of dacomitinib;
FIG. 2 is a 1H-NMR spectrum of dacomitinib prepared in example 7;
FIG. 3 is an HPLC chromatogram of dacomitinib prepared in example 7;
FIG. 4 is an HPLC chromatogram of dacomitinib prepared in example 8.
Detailed Description
The technical solutions of the present invention are further described below by examples, which are illustrative and do not limit the scope of the present invention. The technical features of the invention are equally replaced by the prior art according to the teaching of the invention and the technical scope of the invention is also covered by the technical personnel in the technical field.
The chromatographic conditions for purity measurement of the following intermediates and dacomitinib are as follows (the intermediates and the bulk drug analysis methods are the same):
HPLC instrument model: agilent 1260 high performance liquid chromatograph
Chromatographic conditions are as follows: XDB-C18(250 mm. times.4.6 mm, 5 μm)
EXAMPLE 1 preparation of Compound 02
1.6L of methanol was put into a 5L reaction flask, 71.3g of sodium hydroxide was added to the reaction solution in portions with mechanical stirring, and stirring was continued until it became clear. And adding the compound 01(300g) into the solution, heating to reflux reaction after the addition is finished, and starting to dissolve and clear for 3-4 h. And after the reaction is finished, cooling to 50-60 ℃, adding 2.1L of water into the reaction system, stirring and cooling to 20-30 ℃, stirring for 1-2 h, filtering, washing a filter cake with water for 2 times, leaching with methanol once, drying at 50-60 ℃ by air blast until the weight of the filter cake is constant to obtain 143.0g of yellow solid compound 02, wherein the yield is 92.0%. The purity is 99.64%.
Example 2 preparation of Compound 02
210ml of methanol was charged into a 500ml reaction flask, and 30.5g of 7-fluoro-6-nitro-4-quinazolinamine was added with mechanical stirring. 9.3g of sodium hydroxide was added to the reaction solution in portions, and dissolved down with stirring. Stirring for 1-2 hours at 20-30 ℃, gradually precipitating red solids, continuously stirring for 10 hours to generate a large amount of solids, adding a dilute hydrochloric acid solution (the volume ratio of concentrated hydrochloric acid to water is 1: 49), adjusting the pH of the reaction system to 7-8, and reducing the viscosity of the reaction system. The reaction system was filtered, the filter cake was washed with water 2 times and rinsed once with methanol. Air-dried at 50 to 60 ℃ to a constant weight to give 143.0g of compound 02 as a yellow solid, with a yield of 84.0%. The purity was 99.62%.
Example 3 preparation of Compound 03
2.16L of tetrahydrofuran were placed in a 3L four-necked reaction flask, 108g of compound 02 were added with mechanical stirring, and 8.5g of ferric chloride and 27g of activated carbon were added in portions with continued stirring.
Raising the temperature to 55-65 ℃, starting to dropwise add 155.2g of hydrazine hydrate with the mass fraction of 80%, generating bubbles, paying attention to the dropwise adding speed, gradually increasing the bubbles, accelerating the reflux, controlling the temperature to be less than 65 ℃, and preventing the flushing of the material. After dripping, heating to reflux reaction for 3-4 h.
And (3) after the reaction is finished, performing thermal filtration, adding diatomite into a Buchner funnel for filtration assistance during filtration, leaching the filter cake for 2 times by using hot tetrahydrofuran, (after the filtration, immediately adding water into the filter cake for treatment, reacting hydrazine hydrate with carbon dioxide in the air to generate smoke after volatilization, safely disposing), standing the filtrate for layering, immediately discarding a water layer (incapable of standing for too long time and preventing solid from separating out), concentrating an organic layer under reduced pressure, pouring the remainder into 2L of purified water after most of tetrahydrofuran is concentrated, stirring for 20-30 min, filtering, and washing the filter cake for 1 time by using purified water. Vacuum drying at 50-60 deg.C to constant weight to obtain 96.2g of compound 03 as light green to off-white solid. The yield thereof was found to be 97.47%. The purity is 99.93%.
Example 4 preparation of Compound 03
3L of tetrahydrofuran were placed in a 5L four-necked reaction flask, 150g of compound 02 were added with mechanical stirring, and 11.8g of ferric chloride and 37.5g of activated carbon were added in portions with continued stirring.
And (3) heating to 55-65 ℃, starting to dropwise add 172.2g of hydrazine hydrate with the mass fraction of 80%, generating bubbles, paying attention to the dropwise adding speed, gradually increasing the bubbles, accelerating reflux, controlling the temperature to be less than 65 ℃, and preventing the flushing of the material. After dripping, heating to reflux reaction for 3-4 h.
And (3) after the reaction is finished, performing thermal filtration, adding diatomite into a Buchner funnel for filtration assistance during filtration, leaching the filter cake for 2 times by using hot tetrahydrofuran, (after the filtration, immediately adding water into the filter cake for treatment, reacting hydrazine hydrate with carbon dioxide in the air to generate smoke after volatilization, safely disposing), standing and layering the filtrate, immediately discarding a water layer (incapable of standing for too long time and preventing solid precipitation), concentrating an organic layer under reduced pressure, concentrating most of tetrahydrofuran, pouring the remainder into 2L of purified water, stirring for 20-30 min, filtering, washing the filter cake for 1 time by using purified water, and performing vacuum drying at 50-60 ℃ to constant weight to obtain 128.9g of the compound 03 in a light green to white-like solid state. The yield thereof was found to be 94%. The purity is 99.91%.
Example 5 preparation of Compound 04
380ml of N-methylpyrrolidone and 79.6g of compound 11 are added into a 2L three-necked flask and cooled to-5 ℃.
Controlling the temperature to be-5 ℃, and dropwise adding 44.3g of thionyl chloride (the temperature is increased violently during the dropwise adding of the thionyl chloride), wherein a large amount of solids exist in the bottle. After dripping, the mixture is stirred for 1 to 2 hours at the temperature of minus 5 to 5 ℃, and a large amount of solid still exists in the bottle.
95.0g of the compound 03 and 380ml of N-methylpyrrolidone are added dropwise to the reaction solution at-5 to 5 ℃. Stirring for 1-2 h after dripping, and clearing the solution in the bottle.
After the reaction, 2.85L of purified water was added dropwise (heat was released by dropping water, temperature was controlled to-5 ℃ C.), and 475ml of ethyl acetate was added. After the addition, the temperature is controlled to be-5 ℃, then 15% (w/w) of sodium hydroxide aqueous solution is dripped, the pH value of the reaction solution is adjusted to about 9, and a large amount of solid is separated out.
After the adjustment is finished, stirring for 30-60 min, measuring the pH value to be about 9, and filtering. The filter cake was washed 2 more times with purified water.
Drying the mixture in vacuum at 50-60 ℃ to constant weight. 128.0g of crude dacomitinib is obtained in the form of a pale yellow to off-white solid with a yield of 91.4%. The purity is 99.14%.
Example 6 preparation of Compound 04
380ml of N-methylpyrrolidone and 79.6g of compound 11 are added into a 2L three-necked flask and cooled to-5 ℃.
Controlling the temperature to be-5 ℃, and dripping 59.85g of thionyl chloride (the temperature is increased violently during the dripping of the thionyl chloride), so that the solid is insoluble and has a large amount of solids. After dripping, the mixture is stirred for 1 to 2 hours at the temperature of minus 5 to 5 ℃, and a large amount of solid still exists in the bottle.
To the above reaction solution was added dropwise a solution of 95.0g of Compound 03 and 380ml of N-methylpyrrolidone. Controlling the temperature to be-5 ℃, dropwise adding, stirring for 1-2 h after dropwise adding, and dissolving.
After the reaction, 2.85L of purified water was added dropwise (the temperature was controlled to-5 ℃ C. with heat release from water drop), and 475ml of ethyl acetate was added. Controlling the temperature to be-5 ℃, then dropwise adding 15% (w/w) of sodium hydroxide aqueous solution, adjusting the pH value of the reaction solution to about 9, and separating out a large amount of solids.
After the adjustment is finished, stirring for 30-60 min, measuring the pH value to be about 9, and filtering. The filter cake was washed 2 more times with purified water.
Drying the mixture in vacuum at 50-60 ℃ to constant weight. Crude pale yellow to off-white solid compound 04, 137.2g, yield 98% was obtained. The purity is 99.17%.
Example 7 preparation of dacomitinib
1.65L of ethanol and 44.0g of purified water were added to a 3L reaction flask, and 110.0g of crude dacomitinib was added. Heating until the mixture is refluxed and dissolved to be clear, then adding 5.5g of active carbon, and stirring for 20-30 min. Filtering while hot, transferring the filtrate into a reaction bottle, heating to 60-70 ℃, and then dropwise adding 66.0g of purified water. Stirring for 30min after dripping, cooling to 5 deg.C, and separating out solid. Naturally cooling to 10-20 ℃, and then preserving heat, stirring and crystallizing for 4-5 h. Filtration and washing of the filter cake once with 70% (w/w) ethanol. Vacuum drying at 50-60 deg.C to constant weight to obtain white powdery dacomitinib 95.0 g. The yield is 86.4%; the purity is 99.92%. The high resolution mass spectrum, 1H-NMR spectrum and HPLC spectrum of the product are shown in FIG. 1, FIG. 2 and FIG. 3.
Example 8 preparation of dacomitinib
1.95L of ethanol and 52.0g of purified water are added into a 3L reaction bottle, and 130.0g of crude dacomitinib is added. Heating until the mixture is refluxed and dissolved to be clear, then adding 6.5g of activated carbon, and stirring for 20-30 min. Filtering while hot, transferring to a reaction bottle, heating to 60-70 ℃, dripping 78.0g of purified water, stirring for 30min after dripping, cooling to 5 ℃ or so, separating out solids, naturally cooling to 10-20 ℃, and then keeping the temperature and stirring for crystallization for 4-5 h. Filtration and washing of the filter cake once with 70% (w/w) ethanol. Vacuum drying at 50-60 deg.C to constant weight to obtain Dacrotinib 105.3g as white powder. The yield is 80.8%; the purity is 99.96%. The HPLC profile of the product is shown in FIG. 4.
The present invention is not limited to the above-described embodiments, and various modifications and variations of the present invention are intended to be included within the scope of the claims and the equivalent technology of the present invention if they do not depart from the spirit and scope of the present invention.
Claims (10)
1. A preparation method of dacomitinib is characterized by comprising the following process steps:
s1, adding N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine and alkali into methanol, stirring, and reacting to obtain N- (3-chloro-4-fluorophenyl) -7-methoxy-6-nitroquinazolin-4-amine;
s2, adding a catalyst, activated carbon, a reducing agent and tetrahydrofuran into the N- (3-chloro-4-fluorophenyl) -7-methoxy-6-nitro quinazoline-4-amine, and heating and stirring until reflux reaction to obtain a reduction product N- (3-chloro-4-fluorophenyl) -7-methoxy-6-amino quinazoline-4-amine;
s3, stirring (2E) -4- (1-piperidyl) -2-butenoic acid hydrochloride and a solvent at a low temperature, dropwise adding an acylation reagent for acylation reaction, dropwise adding an N-methylpyrrolidone solution of a reduction product N- (3-chloro-4-fluorophenyl) -7-methoxy-6-aminoquinazoline-4-amine prepared in the step S2 after the acylation reaction is completed, controlling the low temperature, adjusting alkali at the low temperature after the dropwise adding is completed and the reaction is completed, and crystallizing to obtain a cotinib crude product;
s4, adding the product obtained in the step S3 into ethanol and purified water, heating and refluxing, adding activated carbon for decoloring, cooling and crystallizing to obtain the cotinib.
2. The method for preparing dacomitinib according to claim 1, characterized in that: the reaction in step S1 is performed under reflux.
3. The method for preparing dacomitinib according to claim 1, characterized in that: the alkali in the step S1 is sodium hydroxide.
4. The method for preparing dacomitinib according to claim 1, characterized in that: and in the step S2, the catalyst is ferric trichloride.
5. The method for preparing dacomitinib according to claim 1, characterized in that: the reducing agent in the step S2 is hydrazine hydrate.
6. The method for preparing dacomitinib according to claim 1, characterized in that: the reaction solvent in the step S3 is N-methylpyrrolidone.
7. The method for preparing dacomitinib according to claim 1, characterized in that: the acylating agent in the step S3 is one or more selected from thionyl chloride, phosphorus oxychloride and oxalyl chloride.
8. The method for preparing dacomitinib according to claim 7, characterized in that: the acylating agent is thionyl chloride.
9. The method for preparing dacomitinib according to claim 1, characterized in that: the step S3 further includes recrystallizing the crude dacomitinib product after the crude dacomitinib product is prepared.
10. The method for preparing dacomitinib according to claim 9, characterized in that: the solvent for recrystallization is ethanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008480A (en) * | 2016-05-19 | 2016-10-12 | 江西科技师范大学 | Quinazoline compound containing cinnamamide structure and preparation method and application thereof |
| CN106008372A (en) * | 2016-03-16 | 2016-10-12 | 江苏悦兴药业有限公司 | Preparation method and key intermediate of dacomitinib |
| CN112661707A (en) * | 2020-12-25 | 2021-04-16 | 扬子江药业集团有限公司 | Preparation method of dacomitinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106008372A (en) * | 2016-03-16 | 2016-10-12 | 江苏悦兴药业有限公司 | Preparation method and key intermediate of dacomitinib |
| CN106008480A (en) * | 2016-05-19 | 2016-10-12 | 江西科技师范大学 | Quinazoline compound containing cinnamamide structure and preparation method and application thereof |
| CN112661707A (en) * | 2020-12-25 | 2021-04-16 | 扬子江药业集团有限公司 | Preparation method of dacomitinib |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114380835A (en) * | 2022-01-06 | 2022-04-22 | 南京桦冠生物技术有限公司 | Preparation method of 7- (3, 4-dimethoxyphenyl) -2-pyrazolo [1,5-A ] pyrimidine carboxylic acid |
| CN114380835B (en) * | 2022-01-06 | 2022-12-27 | 南京桦冠生物技术有限公司 | Preparation method of 7- (3,4-dimethoxyphenyl) -2-pyrazole [1,5-A ] pyrimidine carboxylic acid |
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