CN113121512A - Preparation method of quinazolinyl butene amide compound - Google Patents
Preparation method of quinazolinyl butene amide compound Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- -1 quinazolinyl butene amide compound Chemical class 0.000 title description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 37
- 230000008569 process Effects 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 16
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 45
- 150000007529 inorganic bases Chemical class 0.000 claims description 14
- 150000007530 organic bases Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 63
- 239000003814 drug Substances 0.000 abstract description 48
- 229940079593 drug Drugs 0.000 abstract description 28
- 239000003513 alkali Substances 0.000 abstract description 19
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000006731 degradation reaction Methods 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015556 catabolic process Effects 0.000 abstract description 10
- CPSVKXXJPUSWJM-UHFFFAOYSA-N N-quinazolin-2-ylbut-2-enamide Chemical class O=C(C=CC)NC1=NC2=CC=CC=C2C=N1 CPSVKXXJPUSWJM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 229960001686 afatinib Drugs 0.000 description 34
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000012458 free base Substances 0.000 description 16
- 239000002994 raw material Substances 0.000 description 16
- 238000003860 storage Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000012043 crude product Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
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- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical class OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 USNRYVNRPYXCSP-JUGPPOIOSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 7
- 239000011976 maleic acid Substances 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- QKXMWBLNSPNBEY-UHFFFAOYSA-N 4,4-diethoxy-n,n-dimethylbutan-1-amine Chemical compound CCOC(OCC)CCCN(C)C QKXMWBLNSPNBEY-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- ULXXDDBFHOBEHA-UHFFFAOYSA-N N-[4-(3-chloro-4-fluoroanilino)-7-(3-oxolanyloxy)-6-quinazolinyl]-4-(dimethylamino)-2-butenamide Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)C=CCN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 238000012421 spiking Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229940071104 xylenesulfonate Drugs 0.000 description 2
- QLXWBTQQAUJBDU-UHFFFAOYSA-N 4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-7-ethoxy-6-(2-hydroxy-5-oxopyrrolidin-1-yl)quinoline-3-carbonitrile Chemical compound C=12C=C(N3C(CCC3O)=O)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 QLXWBTQQAUJBDU-UHFFFAOYSA-N 0.000 description 1
- QWPUJXPJUSIOGB-UHFFFAOYSA-N 4-quinolin-2-ylbutan-1-amine Chemical class C1=CC=CC2=NC(CCCCN)=CC=C21 QWPUJXPJUSIOGB-UHFFFAOYSA-N 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- XCDDTZYLRHAYKR-UHFFFAOYSA-N C1=CC=C2C(=C1)C=NC(=N2)CCCCN Chemical class C1=CC=C2C(=C1)C=NC(=N2)CCCCN XCDDTZYLRHAYKR-UHFFFAOYSA-N 0.000 description 1
- 240000000774 Cunila origanoides Species 0.000 description 1
- 235000018274 Cunila origanoides Nutrition 0.000 description 1
- 235000014866 Dictamnus albus Nutrition 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010959 commercial synthesis reaction Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- 238000009509 drug development Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940087158 gilotrif Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of quinazolinyl butenamide compounds, which effectively reduces the generation of impurities in a synthesis process by selecting a proper mixed alkali system and using a mixture of 1, 5-diaza-bicyclo [4.3.0] non-5-ene and potassium hydroxide, avoids the additional generation of degradation impurities in the process of storing medicines and realizes the accurate control of the generation and degradation of the impurities.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of quinazoline-based butenamide antitumor small molecule derivatives or pharmaceutically acceptable salts thereof.
Background
The butene amide pharmacophore can generate Michael addition reaction with the sulfydryl of target cysteine in vivo, so that the medicine and the target are combined covalently and irreversibly. In general, covalent drugs have higher target affinity and activity. Such structures are widely applied to the design of small-molecule antitumor drugs, such as afatinib of formula (1) developed by briger invalim, germany, naproxtinib of formula (2) developed by shenzhen haiwang pharmaceutical limited, and lenatinib of formula (3) developed by pyroxen and Puma jointly.
Afatinib is an oral small molecule tyrosine kinase irreversible inhibitor with a crotonamide pharmacophore. The dimaleate salt of this compound, afatinib maleate, was marketed by FDA approval in the united states on 7/12/2013 under the trade name of gitarel (Gilotrif).
According to the Boringer-Invehringer publication (WO2005037824), the commercial synthesis route of afatinib maleate is shown in the following figure, wherein compound (1), i.e., afatinib free base, is prepared by a Wittig-Horner-Emmons reaction of a compound of formula (4) with a compound of formula (5) under the action of lithium chloride and a base. However, the ability to remove impurities in the salt formation step in which the compound (1) is directly salified with maleic acid in ethanol to obtain the crude drug is poor. Therefore, the preparation process of the compound (1) is a key step directly related to the final quality of the medicine, and particularly, the related substances and stability need to meet the requirements of chemical bulk drugs.
In the above patent documents, the reaction is carried out using a suitable organic or inorganic base (e.g., 1, 5-diaza-bicyclo [4.3.0] non-5-ene (DBU), sodium hydroxide or potassium hydroxide), and specifically, potassium hydroxide or DBU is preferably used. However, even if the HPLC purity of afatinib obtained by the above reaction reaches 99.4F 1%, the content of important related substances cannot meet the requirement of chemical raw material drugs, and people have to develop a new purification process to refine and purify the synthesized product (e.g. the purification methods disclosed in chinese patent documents CN105669658A, CN104402872A, and CN 108467389A).
Impurities D and P in the afatinib bulk drug are specific impurities with the highest quality risk in the life cycle of the drug. Impurity D is a by-product inherent to the Horner-Wadsworth-Emmons reaction for the synthesis of compound (1) afatinib from compound (4), and is among the impurities produced in the process of WO2005037824 in the largest amount. Meanwhile, the double bond configuration of afatinib can be promoted to turn over by illumination, so that impurity D is formed.
The impurity P is generated by intermolecular cyclization reaction of afatinib or afatinib maleate, the afatinib or afatinib maleate can be degraded into the impurity P in the self storage process, and the degradation process can be obviously promoted by heating and alkali independently. The impurity P is generated in the process, and is continuously increased in the subsequent salt formation, bulk drug storage, preparation process and preparation storage, so that the impurity P becomes the impurity with the largest content in the life cycle of the medicine.
According to Haiwang pharmaceutical publications CN105777656B and CN105777655B, Naphtinib synthesis references Boringer Yinheim reported the synthesis of Afatinib. 2017 to 2018, Heiwang medicine naproxen dittany xylene sulfonate obtains Chinese and American pharmaceutical clinical trial batches.
Similar to afatinib, naproxtinib and naproxtinib xylene sulfonate prepared from the compound (6) can be greatly degraded to obtain the intermolecular cyclization impurity A of naproxtinib in the stages of bulk drug storage, preparation process and preparation storage. In subsequent prescription studies, researchers must add additional chemical stabilizers to the prescription to slow down the formation of impurity a (CN 106389435B). There is no disclosure of the isomeric impurity compound (7).
In addition to the two quinazolinylbutylamide compounds described above, the quinolinylbutylamide derivative, lenatinib, can also be prepared from the active phospholipid intermediate (8). Similarly, during the production and storage of pharmaceuticals, crotonamide pharmacophore cyclized impurities WAY-188954(Drug Development and Industrial Pharmacy,2012,38,307) are generated. There is no disclosure of isomeric impurities.
In conclusion, the butenamide antitumor small molecular derivative drug can generate double-bond isomeric impurities and/or butenamide pharmacophore cyclization impurities in production and storage. For example, known specific impurities D and P are two impurities with the greatest quality risk in free form of afatinib maleate, bulk drugs and preparations, and the existing synthesis method cannot obtain the bulk drugs meeting the requirements, and needs to additionally develop a purification process, resulting in reduced yield, increased pollution, increased cost and the like. According to the concept of three steps of avoiding, controlling and removing the drug impurities advocated by the ICH, a new preparation process suitable for industrial production needs to be developed, the generation of related substances is controlled from the source, the additional generation of degraded impurities in the drug storage process is avoided, and particularly the generation and degradation of the two impurities of the butenamide antitumor small-molecule drug are accurately controlled.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of an impurity-controllable quinazolinyl crotonamide compound or a pharmaceutically acceptable salt thereof.
The technical scheme of the invention is as follows:
a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof,
comprises the following synthetic steps:
using organic compoundsA mixed system of a base and an inorganic base, and reacting the obtained compound of the general formula (II) with an aldehyde represented by the formula (5) to prepare the compound of the general formula (I), wherein R1Alkyl of C1-6 ═ linear or branchedPreferably ethyl orR2And R3Identical or different, represents a linear or branched C1-6 alkyl group,
the organic alkali in the mixed system of the organic alkali and the inorganic alkali is DBU, and the inorganic alkali is selected from one or more of lithium hydroxide, sodium hydroxide or potassium hydroxide.
Preferably, the mixture system of the organic base and the inorganic base is a mixture of DBU and potassium hydroxide.
In the preparation method, the mixed alkali system is used for neutralizing hydrochloric acid in the chemical environment for preparing the compound (5) and is also used for removing alpha-hydrogen of amide of the compound in the general formula (II) to promote reaction. Thus, the total amount of mixed base and the amount of formula (II) are directly related to the amount of acid contained in compound (5).
In the preparation method, the molar ratio of the compound in the general formula (II) to the aldehyde in the formula (5) is 1:1 to 1:5, and more preferably 1:2 to 1: 3. And the acid in the chemical environment for preparing and storing the compound (5) is 2 times the molar amount of the compound (5). Therefore, the amount of the actual mixed base used in the preparation method is properly broadened to be in a molar ratio of 1:1 to 1:12, preferably 1:6 to 1:8, to the compound of the general formula (II).
In the preparation method of the invention, the ratio of the organic base and the inorganic base in the mixed base has a direct relation to control the generation of double bond isomeric impurities and/or butene amide cyclization impurities. Preferably, the molar ratio of organic base to inorganic base is from 1:1 to 1:130, more preferably from 1:3 to 1: 70.
The invention has the advantages that:
in the prior art (WO2005037824), potassium hydroxide or DBU, which is a single organic base or inorganic base system, is used for reacting a compound of a general formula (II) with a compound of a formula (5) to synthesize a quinazolinyl butene amide drug (such as afatinib), however, in the process research of the present invention, researchers find that the use of potassium hydroxide alone can cause significant increase of double bond isomeric impurities (such as afatinib impurity D) in the reaction, and although a large amount of potassium hydroxide can be removed in the subsequent treatment, the problem that the single impurity exceeds the standard still exists in the free refined bulk drug and the finished bulk drug. When the DBU is used independently, although the generation of double bond isomeric impurities in the reaction is obviously reduced, DBU in free alkali is obviously remained, DBU is difficult to completely remove in the process, and the remained DBU can cause the cyclocompound impurities (such as afatinib impurity P) of the crotonamide to obviously increase in the subsequent refining process and the storage process of the product. In the synthesis process, a potassium hydroxide-DBU mixed alkali system is selected, a proper amount of DBU is accurately used, the generation of double bond isomeric impurities is effectively controlled, the DBU is stably removed to be below the quality control limit of 0.1% in the subsequent refining and salifying process of preparing a finished product of a raw material medicine, the use amount of the DBU is accurately controlled, the residual risk (100ppm level is reduced to 1ppm level or is not detected) is greatly reduced, the increase of the butenamide cyclization impurities in the subsequent heating salifying process is controlled, the additional generation of degradation impurities in the pharmaceutical preparation process and the storage process of preparation products is effectively avoided, and the accurate control of the generation and degradation of the double bond isomeric impurities and the butenamide cyclization impurities is realized.
Drawings
Figure 1 example 1 HPLC profile of crude afatinib free base.
Figure 2 example 4 HPLC profile of crude afatinib free base.
FIG. 3 HPLC chart of crude naproxen tinib free base of example 8.
FIG. 4 HPLC chart of example 9 crude naproxen free base.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the scope of protection of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
The compounds (4) and (6) in the embodiment of the invention are synthesized according to the method disclosed in the WO2005037824 patent, and the purity is more than 98%. The compound (8) is synthesized according to the method disclosed in the CN103588755A patent, and the purity is more than 95%.
The method for analyzing related substances of the quinazolinyl crotonamide medicaments is optimized according to the registration standard of afatinib imported medicaments, and comprises the following steps of: octadecylsilane chemically bonded silica as filler (ODS-3(4.0 mm. times.100 mm, 3 μm) or column chromatography with equivalent potency), phosphate buffer (3.0 g disodium hydrogen phosphate dihydrate, 850mL water for dissolution, 4mL triethylamine, pH 6.6 adjusted with phosphoric acid, 900mL water) and acetonitrile (90:10) as mobile phase A; phosphate buffer (1.2 g of disodium hydrogen phosphate dihydrate was dissolved in 350mL of water, 4mL of triethylamine was added, pH was adjusted to 6.6 with phosphoric acid, and 400mL of water) -acetonitrile (40:60) was used as mobile phase B. The column temperature was 26 ℃, the flow rate was 0.8mL/min, and the detection wavelength was 245 nm.
The DBU analysis method is optimized according to the patent publication CN109725097A, and the detection limit is 0.05 mu g/mL (8ppm) and the quantification limit is 0.019 mu g/mL (3ppm) by adopting high performance liquid chromatography for detection.
The afatinib original research reference preparation used in the invention is purchased from a medicine sold in the Chinese market by Boringer-Yihn company, the trade name is Gettari, the batch number is 802858, and the production date is 2018, 3 months and 19 days.
The accelerated stability research method of the bulk drugs or related preparations of the invention is according to the guiding principle of 9001 raw material drug and preparation stability test of the general rules of the four ministry of the national formulary 2015. Accelerated test conditions were 40 ℃ 2 ℃ and RH 75% + -5%.
The amounts of alkali charged and the composition of the alkali used in examples 1 to 5 of the present invention are shown in Table 1.
TABLE 1 relating to the alkali dosage and constitution of examples 1-5
Example 1
Concentrated hydrochloric acid containing 16.5g (452.0mmol) of hydrogen chloride was added to 38mL of water, followed by dropwise addition of 36.4g (226.0mmol) of dimethylaminoethylaldehyde diethyl acetal (CAS No. 3616-56-6) at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
At the same time, 32.4g (578.6mmol) of potassium hydroxide were dissolved in 200mL of water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 50g (90.4mmol) of compound (4) and 3.8g (90.4mmol) of lithium chloride were added to 200mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. Stirring the mixture at-5 ℃ for 1-2 hours, adding 130mL of water to a reaction system, keeping the system at 0-5 ℃ for crystallization, performing suction filtration, washing the obtained solid with water, and drying to obtain a crude product 47.0g with water content of 6.5%. And recrystallizing the crude product by using a mixed solvent of butyl acetate and methylcyclohexane, and drying the solid to obtain 31.2g of a refined afatinib free base product with the yield of 71%.
Referring to the preparation method of WO2005037824, afatinib free alkali is dissolved in ethanol at 70 ℃, stirred with 2.05 equivalents of maleic acid to form salt, cooled and separated out, and dried to obtain a finished product of the raw material medicine.
The crude free base, the refined free base and the finished product of the raw material medicine obtained in the example are respectively subjected to HPLC inspection, and the results are shown in example 1 of Table 2. The HPLC chromatogram is shown in FIG. 1, in which the integration of the peak areas of impurities D and P is shown below:
related substances | Retention time (min) | Relative peak area (%) |
Impurity P | 17.143 | 0.145% |
Impurity D | 27.947 | 1.733% |
Afatinib | 32.952 | 97.396% |
Example 2
Concentrated hydrochloric acid containing 16.5g (452.0mmol) of hydrogen chloride was added to 38mL of water, followed by dropwise addition of 36.4g (226.0mmol) of dimethylaminoethylaldehyde diethyl acetal (CAS No. 3616-56-6) at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
Simultaneously 71.9g (578.6mmol) DBU were dissolved in 200mL water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 50g (90.4mmol) of the compound represented by the formula (4) and 3.8g (90.4mmol) of lithium chloride were added to 200mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. After the mixture is stirred for 1-2 hours at the temperature of-5 ℃, the reaction is stopped, the reaction solution is layered, 130mL of saturated saline solution is respectively added into an organic layer for washing, 130mL of water is added for crystallization, the system is always kept at the temperature of 0-5 ℃, the filtration is carried out, the obtained solid is washed by water and dried, and the crude product of 48.1g and the water content of 6.1 percent are obtained. And recrystallizing the crude product by using a mixed solvent of butyl acetate and methylcyclohexane, and drying the solid to obtain a refined product of afatinib free base, wherein the refined product is 32.9g, and the yield is 75%.
Referring to the preparation method of WO2005037824, afatinib free alkali is dissolved in ethanol at 70 ℃, stirred with 2.05 equivalents of maleic acid to form salt, cooled and separated out, and dried to obtain a finished product of the raw material medicine.
The crude free base, the refined free base and the finished product of the raw material medicine obtained in the example are respectively subjected to HPLC (high performance liquid chromatography) inspection, and the results are shown in example 2 of Table 2.
Example 3
Concentrated hydrochloric acid containing 16.5g (452.0mmol) of hydrogen chloride was added to 38mL of water, followed by dropwise addition of 36.4g (226.0mmol) of dimethylaminoethylaldehyde diethyl acetal (CAS No. 3616-56-6) at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
Simultaneously 25.4g (452.0mmol) of potassium hydroxide and 15.7g (126.6mmol) of DBU were dissolved in 200mL of water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 50g (90.4mmol) of the compound represented by the formula (4) and 3.8g (90.4mmol) of lithium chloride were added to 200mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. Stirring the mixture at-5 ℃ for 1-2 hours, adding 130mL of water to a reaction system, keeping the system at 0-5 ℃ for crystallization, performing suction filtration, washing the obtained solid with water, and drying to obtain a crude product 49.5g and a water content of 6.6%. And recrystallizing the crude product by using a mixed solvent of butyl acetate and methylcyclohexane, and drying the solid to obtain 33.3g of a refined afatinib free base product with the yield of 76%.
Referring to the preparation method of WO2005037824, afatinib free alkali is dissolved in ethanol at 70 ℃, stirred with 2.05 equivalents of maleic acid to form salt, cooled and separated out, and dried to obtain a finished product of the raw material medicine.
The crude free base, the refined free base and the finished product of the raw material medicine obtained in the example are respectively subjected to HPLC inspection, and the results are shown in example 3 of Table 2.
Example 4
Concentrated hydrochloric acid containing 16.5g (452.0mmol) of hydrogen chloride was added to 38mL of water, followed by dropwise addition of 36.4g (226.0mmol) of dimethylaminoethylaldehyde diethyl acetal (CAS No. 3616-56-6) at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
31.9g (569.5mmol) of potassium hydroxide and 1.4g (9.0mmol) of DBU were simultaneously dissolved in 200mL of water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 50g (90.4mmol) of the compound represented by the formula (4) and 3.8g (90.4mmol) of lithium chloride were added to 200mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. Stirring the mixture at-5 ℃ for 1-2 hours, adding 130mL of water to a reaction system, keeping the system at 0-5 ℃ for crystallization, performing suction filtration, washing the obtained solid with water, and drying to obtain a crude product 47.6g with water content of 6.9%. And recrystallizing the crude product by using a mixed solvent of butyl acetate and methylcyclohexane, and drying the solid to obtain a refined product of afatinib free base, wherein the refined product is 34.3g, and the yield is 78%.
Referring to the preparation method of WO2005037824, afatinib free alkali is dissolved in ethanol at 70 ℃, stirred with 2.05 equivalents of maleic acid to form salt, cooled and separated out, and dried to obtain a finished product of the raw material medicine.
The crude free base, the refined free base and the finished product of the raw material medicine obtained in the example are respectively subjected to HPLC inspection, and the results are shown in example 4 of Table 2. The HPLC chromatogram is shown in FIG. 2. The integration results of the peak areas of the impurities D and P are shown below:
related substances | Retention time (min) | Relative peak area (%) |
Impurity P | 17.145 | 0.074% |
Impurity D | 27.998 | 1.065% |
Afatinib | 32.932 | 98.326% |
Because the impurity removing capacity of the step of salifying afatinib free base and maleic acid is weak, the specific impurity D, P and other related substances are effectively controlled to be the most critical step in the production link in the synthesis and refining processes of the maleic acid free base.
TABLE 2 HPLC detection indexes and results of the products of the examples
As is clear from table 2 and fig. 1 and 2, in the synthesis of afatinib, the generation of impurity D was stably reduced by using the mixed base system (examples 3 and 4). In particular, in example 4, only 0.1 equivalent of organic base (a mixed system of 6.3 equivalents of potassium hydroxide and 0.1 equivalent of DBU) was added, and compared with example 1(6.4 equivalents of potassium hydroxide), impurity D in the reaction was directly reduced by 42%, and with the existing post-treatment, impurity D could be stably removed to below the quality control limit of 0.15%, and a qualified free body refined product and a raw material drug were obtained.
The use amount of DBU is reduced by using a mixed alkali system, so that the cost is reduced (the price of DBU is higher than that of KOH), the environment is protected (KOH is relatively more environment-friendly than DBU), and the residual risk is low (DBU has good fat solubility and water solubility and is easy to remain). Compared with example 2(6.4 equivalent DBU), the DBU used in example 4 is reduced by 98%, and the impurity residue of DBU is reduced from 100ppm level to 1ppm level or even not detected. More importantly, the impurity DBU residue can obviously promote the degradation of afatinib into the impurity P in the subsequent salt forming process, the storage period (2 years) of the raw material medicine, the preparation process and the storage period (3 years) of the preparation (see examples 6 and 7 for specific experiments).
Example 5
Concentrated hydrochloric acid containing 16.5g (452.0mmol) of hydrogen chloride was added to 38mL of water, followed by dropwise addition of 36.4g (226.0mmol) of dimethylaminoethylaldehyde diethyl acetal (CAS No. 3616-56-6) at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
Simultaneously 25.4g (574.0mmol) of potassium hydroxide and 0.69g (4.5mmol) of DBU were dissolved in 200mL of water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 50g (90.4mmol) of the compound represented by the formula (4) and 3.8g (90.4mmol) of lithium chloride were added to 200mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. Stirring the mixture at-5 ℃ for 1-2 hours, adding 130mL of water to a reaction system, keeping the system at 0-5 ℃ for crystallization, performing suction filtration, washing the obtained solid with water, and drying to obtain a crude product 48.1g with water content of 6.1%.
The crude free base obtained in this example was subjected to HPLC analysis and the results are given in example 5 of Table 3.
TABLE 3 HPLC DETECTION INDICATORS AND RESULTS FOR AFFINITY FREE BASE CRUDE PRODUCTS OF EXAMPLES 3-5
As can be seen from the comparison of the results, the DBU usage ratio is too low (example 5) compared to examples 3 and 4, and although the risk of remaining DBU is reduced by 30%, the impurity D is increased by 41% in the crude reaction product, which fails to achieve the objective of balanced control of the impurity D, DBU and the impurity P in afatinib synthesis by using the mixed base system.
Example 6 accelerated stability testing of a commercially available Primary research reference formulation
According to the relevant data such as drug import registration method, the retention period of the raw material drug is 2 years, and the retention period of the preparation is 3 years. The product standard of impurity P in the preparation is less than 1.5%, and the shelf life is less than 3.0%.
By utilizing purchased original reagents sold in the market, accelerated test conditions are set to 40 ℃ plus or minus 2 ℃ and RH75 percent plus or minus 5 percent according to the guiding principle of 9001 preparation stability test of the general rules of the four ministry of the State of China pharmacopoeia 2015 edition. According to the analysis of the data of 0-6 month accelerated stability experiment of the original preparation, the degraded impurity D hardly increases (within 0.1%) under the protection of lightproof external package, and the degraded impurity P is the only, the largest content and the continuously increasing related substance (Table 4). Therefore, the impurity P is the most critical quality attribute related to the storage stability of the product (including bulk drugs and preparations).
TABLE 4 degradation stability related test results for original developer impurity P
Example 7 impurity P stability and DBU spiking test
The finished drug substance prepared in example 4, afatinib maleate, was divided into 6 groups of about 5g each. And according to the weight of each group of samples, 0, 1000, 500, 100, 50 and 10ppm of DBU is respectively weighed, dissolved in 10mL of ethanol and respectively added into each group of afatinib maleate to form suspension mixed liquor. The mixture was distilled at 40 ℃ under reduced pressure to remove ethanol to constant weight. Each group of samples set accelerated test conditions of 40 ℃ plus or minus 2 ℃ and RH75 percent plus or minus 5 percent according to the guiding principle of 9001 raw material drug stability test in the four-part general rule of Chinese pharmacopoeia 2015 edition. The degradation of impurity P for each set of samples is shown in table 5.
The finished product of afatinib maleate DBU of the bulk drug prepared in example 4 is not detected (detection limit is 3.0ppm), and the impurity P in the sample increases from 0.06% to 0.59% initially under the test condition of drug stability accelerated by 6 months specified in pharmacopoeia (table 5, sequence 1).
0.1%, 0.05%, 0.01%, 0.005% and 0.001% of DBU was added to the above-mentioned group of drug substances in order to simulate the effect of DBU residue on the results of standard drug stability accelerated tests (Table 5, sequences 2-6). The results show that 0.1%, 0.05%, 0.01%, 0.005% of DBU can severely promote the degradation of afatinib maleate to impurity P (Table 5, sequences 2-5). The DBU effect was not significant when spiked at 0.001% (table 5, sequence 6). Therefore, controlling the DBU impurity residue is of great significance in controlling the generation of the impurity P.
Compared with an independent alkali system of the original grinding process, the mixed alkali system with potassium hydroxide as a main component and DBU as an auxiliary component is used, DBU is brought into play to remarkably inhibit generation of impurities D with the maximum content in the synthesis process, DBU impurity residue in the raw material medicine can be accurately controlled (lower than the detection limit of 3ppm), and further the increase of impurities P with the maximum quality risk in the subsequent salt forming process, the storage period of the raw material medicine, the preparation process and the storage period of the preparation is controlled.
TABLE 5 stability of impurity P and DBU spiking research test results
aNot detected.
Example 8
Concentrated hydrochloric acid containing 2.0g (55.0mmol) of hydrogen chloride was added to 4mL of water, and then 4.4g (27.5mmol) of dimethylaminoethylacetaldehyde diethyl acetal (CAS No. 3616-56-6) was added dropwise at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
Simultaneously 3.9g (70.4mmol) of potassium hydroxide are dissolved in 20mL of water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 5.6g (11.0mmol) of compound (6) and 0.47g (11.0mmol) of lithium chloride were added to 20mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. Stirring the mixture at-5 ℃ for 1-2 hours, adding 15mL of water to a reaction system, keeping the system at 0-5 ℃ for crystallization, performing suction filtration, washing the obtained solid with water, and drying to obtain a crude product of 4.70g and the water content of 6.9%. The crude free base obtained in this example was subjected to HPLC analysis, the results are shown in example 8 of Table 6, and the HPLC chromatogram is shown in FIG. 3.
Example 9
Concentrated hydrochloric acid containing 2.0g (55.0mmol) of hydrogen chloride was added to 4mL of water, and then 4.4g (27.5mmol) of dimethylaminoethylacetaldehyde diethyl acetal (CAS No. 3616-56-6) was added dropwise at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
3.88g (69.3mmol) of potassium hydroxide and 0.17g (1.1mmol) of DBU are simultaneously dissolved in 20mL of water and cooled to-5 ℃. This solution is referred to as solution C.
At the same time, 5.6g (11.0mmol) of compound (6) and 0.47g (11.0mmol) of lithium chloride were added to 20mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. Stirring the mixture at-5 ℃ for 1-2 hours, adding 15mL of water to a reaction system, keeping the system at 0-5 ℃ for crystallization, performing suction filtration, washing the obtained solid with water, and drying to obtain a crude product of 4.56g and the water content of 6.8%. The crude free base obtained in this example was subjected to HPLC analysis, the results are shown in example 9 of Table 6, and the HPLC chromatogram is shown in FIG. 4.
TABLE 6 HPLC TEST INDICATIONS AND RESULTS FOR PURPENINONINE FREE BASE PRODUCTS OF EXAMPLES 8-9
aAs is clear from table 6 and fig. 3 and 4, the use of the mixed base system can reduce the generation of the largest impurity of naproxtinib.
Example 10
Concentrated hydrochloric acid containing 2.5g (68.90mmol) of hydrogen chloride was added to 5mL of water, and then 5.55g (34.45mmol) of dimethylaminoethylaldehyde diethyl acetal (CAS No. 3616-56-6) was added dropwise at 30 ℃ over 20 minutes. The reaction solution was stirred at a temperature of 30 to 40 ℃ for 8 hours to obtain a compound (5) solution, which was cooled to 0 to 5 ℃ and kept under argon. This solution is referred to as solution B.
4.87g (86.81mmol) of potassium hydroxide and 0.21g (1.4mmol) of DBU are simultaneously dissolved in 20mL of water and cooled to-5 ℃. This solution is referred to as solution C.
Simultaneously, 8.6g (13.78mmol) of compound (8) and 0.58g (13.78mmol) of lithium chloride were added to 25mL of tetrahydrofuran, and cooled to-7 ℃ for further use. This solution is referred to as solution a.
Dropwise adding the cooled solution C into the solution A within 10 minutes under the condition of keeping stirring and at the temperature of-7 ℃; then, the solution B is slowly added into the mixed solution in a dropwise manner. The mixture was stirred at-5 ℃ for 1-2 hours. TLC examination of the reaction solution obtained in this example showed that the reaction was unsuccessful.
From the embodiments 8 to 10, in the synthesis of quinazolinyl butenamide antitumor small molecule drugs (such as afatinib and the like), the invention uses a mixed base system with potassium hydroxide as the main component and DBU as the auxiliary component, and compared with an independent base system in the original research process, the invention realizes the precise control of the generation and degradation of double bond isomeric impurities (such as afatinib impurity D), DBU and butenamide cyclization impurities (such as afatinib impurity P). However, the synthesis method can not be applied to the synthesis of other butenamide drugs (such as quinolyl butenamide derivative neratinib) for a long time.
Claims (9)
1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof,
reacting the obtained compound of the general formula (II) with an aldehyde represented by the formula (5) using a mixed system of an organic base and an inorganic base to prepare a compound of the formula (I), wherein R1Represents a linear or branched C1-6 alkyl group orR2And R3Identical or different, represents a linear or branched C1-6 alkyl group,
the method is characterized in that the organic base in the mixed system of the organic base and the inorganic base is 1, 5-diaza-bicyclo [4.3.0] non-5-ene, and the inorganic base is one or more selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
3. The method according to claim 1, wherein the mixture of organic and inorganic bases is a mixture of 1, 5-diaza-bicyclo [4.3.0] non-5-ene and potassium hydroxide.
4. The method of claim 2, wherein the organic base and the inorganic base are present in a molar ratio of 1:1 to 130.
5. The process according to claim 3, wherein the molar ratio of the organic base to the inorganic base is 1:3 to 70.
6. The process according to claim 1, wherein the molar ratio of the compound of formula (II) to the aldehyde of formula (5) is from 1:1 to 5.
7. The process according to claim 6, wherein the molar ratio of the compound of formula (II) to the aldehyde of formula (5) is from 1:2 to 3.
8. The process according to claim 1, wherein the molar ratio of the total amount of organic and inorganic bases used to the compound of formula (II) is from 1:1 to 12.
9. The process according to claim 8, wherein the molar ratio of the total amount of organic and inorganic bases used to the compound of formula (II) is from 1:6 to 8.
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