CN104447713A - Preparation method of afatinib compound - Google Patents
Preparation method of afatinib compound Download PDFInfo
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- CN104447713A CN104447713A CN201410658194.4A CN201410658194A CN104447713A CN 104447713 A CN104447713 A CN 104447713A CN 201410658194 A CN201410658194 A CN 201410658194A CN 104447713 A CN104447713 A CN 104447713A
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- compound
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- buddhist nun
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- -1 afatinib compound Chemical class 0.000 title claims abstract description 10
- 229960001686 afatinib Drugs 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 85
- 238000000034 method Methods 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 47
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 30
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- PQBOTZNYFQWRHU-UHFFFAOYSA-N 1,2-dichlorobutane Chemical compound CCC(Cl)CCl PQBOTZNYFQWRHU-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 230000007774 longterm Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- 238000001035 drying Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 0 *c1ccccc1 Chemical compound *c1ccccc1 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- GJOGRUGECVQJBK-UHFFFAOYSA-N 2-diphenylphosphanylacetic acid Chemical compound C=1C=CC=CC=1P(CC(=O)O)C1=CC=CC=C1 GJOGRUGECVQJBK-UHFFFAOYSA-N 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 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
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GRWPTSXPZYCYOM-UHFFFAOYSA-N 2-(dimethylamino)acetaldehyde Chemical compound CN(C)CC=O GRWPTSXPZYCYOM-UHFFFAOYSA-N 0.000 description 1
- GOLSFPMYASLXJC-UHFFFAOYSA-N 2-(dimethylamino)ethyl acetate Chemical compound CN(C)CCOC(C)=O GOLSFPMYASLXJC-UHFFFAOYSA-N 0.000 description 1
- LYIIBVSRGJSHAV-UHFFFAOYSA-N 2-aminoacetaldehyde Chemical compound NCC=O LYIIBVSRGJSHAV-UHFFFAOYSA-N 0.000 description 1
- QDSFNOHWQKVVEB-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)morpholine Chemical compound CCOP(=O)(OCC)CN1CCOCC1 QDSFNOHWQKVVEB-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
- OHGXUYCQNQGNNJ-ISWWPPQXSA-N CC(C(C(/C(/C)=C\N)Nc1ccc(C)c(Cl)c1)C=C1NC(C(C2)([C@@H](CN(C)C)O)[O]2(C2=CC=CCC2)(c2ccccc2)O)=O)C=C1O[C@@H]1CC(CC2)C2CC1 Chemical compound CC(C(C(/C(/C)=C\N)Nc1ccc(C)c(Cl)c1)C=C1NC(C(C2)([C@@H](CN(C)C)O)[O]2(C2=CC=CCC2)(c2ccccc2)O)=O)C=C1O[C@@H]1CC(CC2)C2CC1 OHGXUYCQNQGNNJ-ISWWPPQXSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 229960002736 afatinib dimaleate Drugs 0.000 description 1
- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical compound 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 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940087158 gilotrif Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a novel preparation method of an afatinib compound. Raw materials and reagents used in the preparation method have the advantages of low cost, stable chemical property and convenience in long-term storage and the content of an impurity cis-isomer in the prepared afatinib compound is very low.
Description
Technical field
The present invention is medicinal chemistry art, relates to Ah method replaces Buddhist nun a kind of new preparation process for Buddhist nun's compound and toxilic acid Ah method particularly.
Background technology
Toxilic acid Ah method is a kind of tyrosine kinase inhibitor for Buddhist nun (Afatinib dimaleate).In July, 2013 ratifies listing by U.S. FDA, commodity are called GILOTRIF, be used for the treatment of EGF-R ELISA (EGFR) exons 19 lack or alternative Metastatic Nsclc (NSCLC) patient suddenlyd change of exon 21 (L858R) as first-line treatment medicine.
The Ah method that discloses in CN1481370A is for Buddhist nun's compound (embodiment 1 compound (10)).
Disclose in CN1867564A and a kind ofly prepare toxilic acid Ah method for the method for Buddhist nun, by N
4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the arylamide that 6-diamines obtains with the reaction of diethyl phosphonoacetic acid, there is Wittig-Horner-Emmons reaction with 2-aminoacetaldehyde (or its acetal) again and generate Ah method for Buddhist nun, and then with toxilic acid salify.This technique raw materials used dimethylamino acetaldehyde, dimethylamino acetal cost is higher and be easy to oxidative degradation, be difficult to long-time storage, be unfavorable for suitability for industrialized production, and this technique also needs to provide ar gas environment in process of production.This technique constructs trans double bond by Wittig-Horner-Emmons reaction simultaneously, due to stereoselective difference, still there is a small amount of cis-isomeride impurity in product.
Summary of the invention
The invention provides a kind of novel method of preparation Ah method for Buddhist nun's compound, and the toxilic acid Ah method that the Ah method obtained by the method obtains further for Buddhist nun replaces Buddhist nun, containing the pharmaceutical composition of described toxilic acid Ah method for Buddhist nun.Additionally provide and describedly prepare toxilic acid Ah method for the new intermediate compound used in Buddhist nun's compound novel method.
Preparation Ah method provided by the invention, for the novel method of Buddhist nun's compound, can realize by following scheme:
(1) formula VI compound and formula VII compound are obtained by reacting V compound,
(2) formula V compound and formula IV compound react and obtain formula III compound under n-Butyl Lithium exists,
(3) formula III compound passes through NaBH
4reduction acquisition formula II compound,
(4) formula II compound is by NaH reduction acquisition formula I,
In step of the present invention (1), reaction conditions is selected from following condition one or more: the reaction solvent of formula VI compound and formula VII compounds accepted way of doing sth V compound is preferably selected from methylene dichloride, 1, one or more in 2-ethylene dichloride, trichloromethane, 1,2-dichlorobutane; It is more preferably methylene dichloride.Temperature of reaction is preferably room temperature.Reaction times is preferably 1 ~ 20 hour.The mol ratio of formula VI compound and formula VII compound is preferably 1:(0.85 ~ 1.15).In the present invention, room temperature is 10 ~ 30 DEG C, is more preferably 15 ~ 25 DEG C.
In step of the present invention (2), reaction conditions is selected from following condition one or more: the reaction solvent of formula V compound and formula IV compounds compound of Formula III is preferably selected from tetrahydrofuran (THF) and/or 2-methyltetrahydrofuran; It is more preferably tetrahydrofuran (THF).Temperature of reaction is preferably room temperature.Reaction times is preferably 0.5 ~ 4 hour.The mol ratio of formula V compound and formula IV compound is preferably 1:(0.85 ~ 1.15).The mol ratio of formula V compound and n-Butyl Lithium is preferably 1:(0.8 ~ 1.2).
Reaction conditions is selected from following condition one or more in step of the present invention (3): the reaction solvent that formula III compound is reduced to formula II compound be preferably selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol one or more; Be more preferably methyl alcohol and/or ethanol.Temperature of reaction is preferably 55 ~ 75 DEG C.Reaction times is preferably 0.5 ~ 6 hour.Formula III compound and NaBH
4mol ratio be preferably 1:(1.5 ~ 0.5).
In step of the present invention (4), reaction conditions is selected from following condition one or more: the reaction solvent that formula II compound is reduced to formula I is preferably selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide; It is more preferably DMF.Temperature of reaction is preferably 10 ~ 30 DEG C.Reaction times is preferably 0.5 ~ 6 hour, is more preferably 1 ~ 6 hour.The mol ratio of formula II compound and NaH is preferably 1:(1.5 ~ 4), be more preferably 1:(2 ~ 3).
Present invention also offers described preparation Ah method and obtain new intermediate compound, formula II compound or its salt in Buddhist nun's novel method,
Present invention also offers described preparation Ah method and obtain new intermediate compound, formula III compound or its salt in Buddhist nun's novel method,
Present invention also offers described preparation Ah method and obtain new intermediate compound, formula V compound or its salt in Buddhist nun's novel method,
The Ah method prepared by the inventive method can also be prepared into pharmacy acceptable salt further for Buddhist nun, preferably makes 2-maleate, can be realized by the technical scheme recorded in prior art CN1867564A.Toxilic acid Ah method described in the present invention refers to the 2-maleate of Ah method for Buddhist nun for Buddhist nun.
Toxilic acid Ah method provided by the invention can also make pharmaceutical composition further for Buddhist nun; The dosage form of described composition can be oral solid formulation or parenteral formulations agent.In the present invention, described composition also comprises pharmaceutically acceptable carrier; Pharmaceutically acceptable carrier normally those of ordinary skill in the art specifically can be selected according to concrete form of medication.Available well known technology is as manufacture technics pharmaceutical compositions of the present invention such as conventional granulation, mixing, dissolving, formation capsule, freeze-drying.The present composition can be made the form for various route of administration, such as, oral administration, intravenously etc.Preferably, toxilic acid Ah method provided by the invention for Buddhist nun can conventionally in CN102056589A technical scheme make the pharmaceutical composition of solid dosage form.
Preparation Ah method provided by the invention is the obtainable chemicals raw material of commercialization for the (diphenylphosphino)acetic acid used in Buddhist nun's novel method and N, N-dimethylamino ethyl acetate, and cost is low, stable chemical nature, is convenient to prolonged storage.
Present invention process respectively walks easy and simple to handle, without the need to special gas preservation conditions such as argon gas, and reaction times mild condition, technique is smooth, is applicable to industry and amplifies.
Method provided by the invention is prepared toxilic acid Ah method and is replaced the total recovery of Buddhist nun to reach more than 60%, has the value of suitability for industrialized production.
Preparation Ah method provided by the invention replaces cis isomerism body burden in the salt (including but not limited to maleate) of Buddhist nun lower for the Ah method of Buddhist nun's novel method acquisition for Buddhist nun or Ah method, uses the result of routine HPLC methods detection for not detect.
Accompanying drawing explanation
The Ah method that Fig. 1 embodiment 5 obtains is for the MS collection of illustrative plates of Buddhist nun
The toxilic acid Ah method that Fig. 2 embodiment 5 obtains is for the HPLC collection of illustrative plates of Buddhist nun
The toxilic acid Ah method that Fig. 3 obtains according to the embodiment 1 ~ 3 of CN1867564A is for the HPLC collection of illustrative plates of Buddhist nun
The toxilic acid Ah method that Fig. 4 obtains according to the embodiment 1 ~ 3 of CN1867564A is for the LC-MS collection of illustrative plates of Buddhist nun
Embodiment
Mode below by embodiment further illustrates, but those skilled in the art understand, and following embodiment is not limiting the scope of the invention.
Prepared by embodiment 1 formula V compound
Phosphorus trichloride (0.5g) is slowly instilled (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL dichloromethane solution, controls temperature of reaction 0 DEG C.Drip complete 15 DEG C of stirring reactions and be cooled to 0 DEG C after 2 hours.Triethylamine (1.02g) and 4-[(the chloro-4-fluorophenyl of 3-)-amino]-6-amino-7-((S)-tetrahydrofuran (THF)-3-base oxygen base)-quinazoline (3.41g) are dissolved in 25mL1, above-mentioned solution is slowly instilled in 2-dichloroethane solution, drip and finish, 25 DEG C are reacted 2 hours.20mL purified water is added extracting and demixing by TLC monitoring after completion of the reaction, organic phase continues to use the washing of 20mL purified water, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume to oily matter, adds tetrahydrofuran (THF)/isopropyl ether (1:1) 40mL recrystallization and obtains off-white color solid (formula V compound).
Phosphorus trichloride (0.5g) is slowly instilled (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL chloroform soln, controls temperature of reaction 0 DEG C.Drip complete 25 DEG C of stirring reactions and be cooled to 0 DEG C after 1.5 hours.Triethylamine (1.02g) and 4-[(the chloro-4-fluorophenyl of 3-)-amino]-6-amino-7-((S)-tetrahydrofuran (THF)-3-base oxygen base)-quinazoline (3.41g) are dissolved in 25mL1, above-mentioned solution is slowly instilled in 2-dichlorobutane solution, drip and finish, 15 DEG C are reacted 8 hours.20mL purified water is added extracting and demixing by TLC monitoring after completion of the reaction, organic phase continues to use the washing of 20mL purified water, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume to oily matter, adds tetrahydrofuran (THF)/isopropyl ether (1:1) 40mL recrystallization and obtains off-white color solid (formula V compound).
Phosphorus trichloride (0.5g) is slowly instilled (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL dichloromethane solution, controls temperature of reaction 0 DEG C.Drip complete 20 DEG C of stirring reactions and be cooled to 0 DEG C after 2 hours.Triethylamine (1.02g) and 4-[(3-chloro-4-fluorophenyl)-amino]-6-amino-7-((S)-tetrahydrofuran (THF)-3-base oxygen base)-quinazoline (3.41g) are dissolved in 25mL chloroform soln and slowly instill above-mentioned solution, drip and finish, 10 DEG C are reacted 16 hours.20mL purified water is added extracting and demixing by TLC monitoring after completion of the reaction, organic phase continues to use the washing of 20mL purified water, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume to oily matter, adds tetrahydrofuran (THF)/isopropyl ether (1:1) 40mL recrystallization and obtains off-white color solid (formula V compound).
Prepared by embodiment 2 formula III compound
In being controlled by n-Butyl Lithium (1.5M, 6ml), at temperature 0 DEG C, slowly dropping type V compound (5g) is dissolved in 28mL dry tetrahydrofuran solution.Drip and finish, be cooled to-10 DEG C; Dimethylin ethyl acetate (1.05g) is instilled in above-mentioned solution, drip and finish, rise to stirring at room temperature 0.5 hour, TLC monitoring adds saturated ammonium chloride solution 12mL after completion of the reaction in reaction solution, saturated nacl aqueous solution 8mL, methylene dichloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure obtain oily matter, add tetrahydrofuran (THF)/isopropyl ether (1:2) 40mL recrystallization and obtain off-white color solid (formula III compound).
In being controlled by n-Butyl Lithium (1.5M, 6ml), at temperature 0 DEG C, slowly dropping type V compound (5g) is dissolved in 28mL dry 2-methyltetrahydrofuran solution.Drip and finish, be cooled to-10 DEG C; Dimethylin ethyl acetate (1.05g) is instilled in above-mentioned solution, drip and finish, rise to stirring at room temperature 4 hours, TLC monitoring adds saturated ammonium chloride solution 12mL after completion of the reaction in reaction solution, saturated nacl aqueous solution 8mL, methylene dichloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure obtain oily matter, add tetrahydrofuran (THF)/isopropyl ether (1:2) 40mL recrystallization and obtain off-white color solid (formula III compound).
In being controlled by n-Butyl Lithium (1.5M, 6ml), at temperature 0 DEG C, slowly dropping type V compound (5g) is dissolved in 28mL dry tetrahydrofuran solution.Drip and finish, be cooled to-10 DEG C; Dimethylin ethyl acetate (1.05g) is instilled in above-mentioned solution, drip and finish, rise to stirring at room temperature 2 hours, TLC monitoring adds saturated ammonium chloride solution 12mL after completion of the reaction in reaction solution, saturated nacl aqueous solution 8mL, methylene dichloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure obtain oily matter, add tetrahydrofuran (THF)/isopropyl ether (1:2) 40mL recrystallization and obtain off-white color solid (formula III compound).
Prepared by embodiment 3 formula II compound
Sodium borohydride (0.15g) is added formula III compound (5g) to be dissolved in the solution of 50mL methyl alcohol, 75 DEG C of heating were cooled to room temperature after 0.5 hour, add 50mL saturated ammonium chloride solution, underpressure distillation remove portion solvent, add 50mL saturated nacl aqueous solution, the layering of 80mL dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure, resistates adds methylene dichloride/normal heptane (1:3) 50mL stirring and crystallizing and obtains faint yellow solid (formula II compound).
Sodium borohydride (0.27g) is added formula III compound (5g) to be dissolved in the solution of 50mL Virahol, 65 DEG C of reflux were cooled to room temperature after 4 hours, add 50mL saturated ammonium chloride solution, underpressure distillation remove portion solvent, add 50mL saturated nacl aqueous solution, the layering of 80mL dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure, resistates adds methylene dichloride/normal heptane (1:3) 50mL stirring and crystallizing and obtains faint yellow solid (formula II compound).
Sodium borohydride (0.38g) is added formula III compound (5g) to be dissolved in the solution of 50mL n-propyl alcohol, 55 DEG C of heating were cooled to room temperature after 6 hours, add 50mL saturated ammonium chloride solution, underpressure distillation remove portion solvent, add 50mL saturated nacl aqueous solution, the layering of 80mL dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure, resistates adds methylene dichloride/normal heptane (1:3) 50mL stirring and crystallizing and obtains faint yellow solid (formula II compound).
Embodiment 4 formula I (Ah method is for Buddhist nun) preparation
By sodium hydride (80%, 0.42g) add the N of the drying of formula II compound (5g), in dinethylformamide 30mL solution, by reaction solution 10 DEG C of stirring reactions 6 hours, TLC monitoring adds purified water 85mL after completion of the reaction, saturated nacl aqueous solution 20mL, methylene dichloride 50mL extracts separatory, gained organic phase anhydrous magnesium sulfate drying, concentrating under reduced pressure, resistates adds ethyl acetate/methylcyclohexane (1:2) 60mL stirring and crystallizing and obtains white powdery solids (formula I).
By sodium hydride (80%, 0.42g) add the N of the drying of formula II compound (5g), in N-N,N-DIMETHYLACETAMIDE 30mL solution, by reaction solution 30 DEG C of stirring reactions 2 hours, TLC monitoring adds purified water 85mL after completion of the reaction, saturated nacl aqueous solution 20mL, methylene dichloride 50mL extracts separatory, gained organic phase anhydrous magnesium sulfate drying, concentrating under reduced pressure, resistates adds ethyl acetate/methylcyclohexane (1:2) 60mL stirring and crystallizing and obtains white powdery solids (formula I).
By sodium hydride (80%, 0.42g) add in the methyl-sulphoxide 30mL solution of the drying of formula II compound (5g), by reaction solution 20 DEG C of stirring reactions 4 hours, TLC monitoring adds purified water 85mL after completion of the reaction, saturated nacl aqueous solution 20mL, methylene dichloride 50mL extracts separatory, gained organic phase anhydrous magnesium sulfate drying, concentrating under reduced pressure, resistates adds ethyl acetate/methylcyclohexane (1:2) 60mL stirring and crystallizing and obtains white powdery solids (formula I).
Embodiment 5 toxilic acid Ah method is for the preparation of Buddhist nun
Phosphorus trichloride (4.94g, 0.036mol) slowly being instilled (diphenylphosphino)acetic acid (23.42g, 0.09mol) is dissolved in 250mL anhydrous methylene chloride solution, controls temperature of reaction 0 DEG C.Drip complete 20 DEG C of stirring reactions and be cooled to 0 DEG C after 1.5 hours.By triethylamine (10.12g, 0.1mol) with 4-[(the chloro-4-fluorophenyl of 3-)-amino]-6-amino-7-((S)-tetrahydrofuran (THF)-3-base oxygen base)-quinazoline (33.73g, 0.09mol) be dissolved in 250mL anhydrous methylene chloride solution and slowly instill above-mentioned solution, drip and finish, 20 DEG C are reacted 1.5 hours.200mL purified water is added extracting and demixing by TLC monitoring after completion of the reaction, organic phase continues with the washing of 200mL purified water, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume to oily matter, add tetrahydrofuran (THF)/isopropyl ether (1:1) 400mL recrystallization and obtain off-white color solid 52.75g, yield: 94.9%.
Walk product (52.75g, 0.085mol) on slowly instilling at n-Butyl Lithium (1.5M, 62.5ml) is controlled interior warm 0 DEG C to be dissolved in 280mL dry tetrahydrofuran solution.Drip and finish, be cooled to-10 DEG C; By dimethylin ethyl acetate (11.15g, 0.085mol) instill in above-mentioned solution, drip and finish, rise to stirring at room temperature 1 hour, TLC monitoring adds saturated ammonium chloride solution 120mL, saturated nacl aqueous solution 80mL after completion of the reaction in reaction solution, methylene dichloride 120mL extracting and demixing, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure obtain oily matter, add tetrahydrofuran (THF)/isopropyl ether (1:2) 420mL recrystallization and obtain off-white color solid 50.13g, yield: 83.4%.
By sodium borohydride (1.52g, 0.04mol) add step intermediate (50.13g, 0.071mol) be dissolved in the solution of 500mL dehydrated alcohol, reflux was cooled to room temperature after 1 hour, add 500mL saturated ammonium chloride solution, underpressure distillation remove portion solvent, add 500mL saturated nacl aqueous solution, the layering of 800mL dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure, resistates adds methylene dichloride/normal heptane (1:3) 500mL stirring and crystallizing and obtains faint yellow solid 46.05g, yield: 92.1%.
By sodium hydride (80%, 3.9g, 0.13mol) add step product (46.05g, the N of drying 0.065mol), in dinethylformamide 300mL solution, reaction solution stirring at room temperature is reacted 1 hour, TLC monitoring adds purified water 800mL after completion of the reaction, saturated nacl aqueous solution 200mL, methylene dichloride 500mL extracts separatory, gained organic phase anhydrous magnesium sulfate drying, concentrating under reduced pressure, resistates adds ethyl acetate/methylcyclohexane (1:2) 570mL stirring and crystallizing and obtains white powder Ah method for Buddhist nun 27.58g, yield: 87.3%.The MS detected result of white powder solid is [M+H]
+=486.2 (Fig. 1 is shown in by collection of illustrative plates), determination of moisture result is 0.8% (Karl_Fischer method, instrument KF870).
The Ah method upper step obtained adds in reaction flask for Buddhist nun (20g, 0.041mol), ethanol 280mL, is warming up to 70 DEG C, adds toxilic acid (9.7g, the 0.084mol) solution & stir being dissolved in 120mL ethanol.After crystallize out, mixture is cooled to 20 DEG C to stir 2 hours, then stirs at 0 DEG C and filter for 3 hours.Filter cake alcohol flushing and at 40 DEG C drying under reduced pressure obtain 27.7g toxilic acid Ah method for Buddhist nun, yield 94.1%.
Embodiment 6
For Buddhist nun, HPLC detection is carried out to the toxilic acid Ah method that embodiment 5 obtains; Fig. 2 is shown in by HPLC collection of illustrative plates.Carry out reference examples experiment according to embodiment 1 ~ 3 in CN1867564A, for Buddhist nun, HPLC detection is carried out to the toxilic acid Ah method obtained; Fig. 3 is shown in by HPLC collection of illustrative plates.
HPLC condition is:
Chromatographic column: octadecylsilane chemically bonded silica (Inertsil ODS-SP, 150mm × 4.6mm, 5 μm)
Moving phase: ammonium acetate buffer (get ammonium acetate 7.7g, the 1000ml that adds water makes dissolving, shakes up, and to obtain final product): acetonitrile (60:40)
Flow velocity: 1.0mL/min
Determined wavelength: 252nm
Column temperature: 30 DEG C
Sample size: 5 μ L
Result shows: in Fig. 3, Ah method is 10.663 minutes for the chromatographic peak retention time of Buddhist nun, and peak area percent is 99.496%; Retention time is that the chromatographic peak of 9.467 minutes represents cis-isomeride impurity, its peak area percent 0.318%; Retention time is the chromatographic peak of 1 ~ 2 minute is the chromatographic peak of toxilic acid.In Fig. 2, Ah method is 10.679 minutes for the chromatographic peak retention time of Buddhist nun, and peak area percent is 99.879%; Do not detect cis-isomeride impurity; Retention time is the chromatographic peak of 1 ~ 2 minute is the chromatographic peak of toxilic acid.
Carry out reference examples experiment according to embodiment 1 ~ 3 in CN1867564A, for Buddhist nun, LC-MS detection is carried out to the toxilic acid Ah method obtained; Fig. 4 is shown in by collection of illustrative plates.In Fig. 4, X-coordinate is retention time (min); Retention time is the peak of 7.060min is cis-isomeride impurity, and retention time is that the peak of 8.620min is for Ah method is for Buddhist nun.Also show the MS collection of illustrative plates of 7.301min place material in Fig. 4, is cis-isomeride impurity; Show the MS collection of illustrative plates of 9.312min place material, for Ah method is for Buddhist nun.
Claims (10)
1. Ah method shown in preparation formula I is for a method for Buddhist nun's compound, the steps include:
(1) formula VI compound and formula VII compound are obtained by reacting V compound,
(2) formula V compound and formula IV compound react and obtain formula III compound under n-Butyl Lithium exists,
(3) formula III compound passes through NaBH
4reduction acquisition formula II compound,
(4) formula II compound is by NaH reduction acquisition formula I,
2. method according to claim 1, it is characterized in that the reaction conditions of formula VI compound and formula VII compounds accepted way of doing sth V compound is selected from following condition one or more: reaction solvent is selected from methylene dichloride, 1, one or more in 2-ethylene dichloride, trichloromethane, 1,2-dichlorobutane; The mol ratio of formula VI compound and formula VII compound is 1:(0.85 ~ 1.15); Reaction times is 1 ~ 20 hour.
3. method according to claim 1, is characterized in that being selected from following condition one or more by the reaction conditions of formula V compound and formula IV compounds compound of Formula III: reaction solvent is tetrahydrofuran (THF) and/or 2-methyltetrahydrofuran; The mol ratio of formula V compound and formula IV compound is 1:(0.85 ~ 1.15); The mol ratio of formula V compound and n-Butyl Lithium is 1:(0.8 ~ 1.2); Reaction times is 0.5 ~ 4 hour.
4. method according to claim 1, is characterized in that the reaction conditions that formula III compound is reduced to formula II compound is selected from following condition one or more: reaction solvent be selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol one or more; Temperature of reaction is 55 ~ 75 DEG C; Formula III compound and NaBH
4mol ratio be 1:(1.5 ~ 0.5); Reaction times is 0.5 ~ 6 hour.
5. method according to claim 1, it is characterized in that the reaction conditions that formula II compound is reduced to formula I is selected from following condition one or more: reaction solvent is selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide; Temperature of reaction is 10 ~ 30 DEG C; The mol ratio of formula II compound and NaH is 1:(1.5 ~ 4); Reaction times is 0.5 ~ 6 hour.
6. the Ah method that the method according to any one of Claims 1 to 5 prepares is for Buddhist nun, and the toxilic acid Ah method obtained with toxilic acid salify is for Buddhist nun.
7. containing the pharmaceutical composition of the toxilic acid Ah method described in claim 6 for Buddhist nun.
8. formula II compound or its salt,
9. formula III compound or its salt,
10. formula V compound or its salt,
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| CN104892584A (en) * | 2015-05-27 | 2015-09-09 | 重庆泰濠制药有限公司 | Amorphous-state Afatinib dimaleate and preparation method and preparation of amorphous-state Afatinib dimaleate |
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