CN102146075B - Preparation method of quinazoline compound - Google Patents
Preparation method of quinazoline compound Download PDFInfo
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- CN102146075B CN102146075B CN201010108505.1A CN201010108505A CN102146075B CN 102146075 B CN102146075 B CN 102146075B CN 201010108505 A CN201010108505 A CN 201010108505A CN 102146075 B CN102146075 B CN 102146075B
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- -1 quinazoline compound Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 8
- 150000003839 salts Chemical class 0.000 abstract description 7
- 230000003247 decreasing effect Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229960001320 lapatinib ditosylate Drugs 0.000 description 15
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 229950004288 tosilate Drugs 0.000 description 9
- 239000011737 fluorine Substances 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000013517 stratification Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical class NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- BBBYHBIWEUJCFT-UHFFFAOYSA-N n-ethylmethanesulfonamide;hydrochloride Chemical compound Cl.CCNS(C)(=O)=O BBBYHBIWEUJCFT-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- KVSLPQXJQYNHIK-UHFFFAOYSA-N c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O Chemical class c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O KVSLPQXJQYNHIK-UHFFFAOYSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Abstract
The invention provides a method for preparing a quinazoline compound, in the method, the compound in a form of salt is directly used as a raw material, the reaction step is shortened, the number of used agents is decreased and the cost is lowered.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, particularly, relate to a kind of quinazoline compound, i.e. the preparation method of lapatinibditosylate.
Background technology
A kind of quinazoline compound, be specially, US Patent No. 6713485 (title: heterocyclic compound (Heterocyclic compounds), patentee: Smithkline Beecham Corp (SmithKline Beecham Corporation), publication date: on March 30th, 2004) a kind of medicinal compound that can be used for human body of report, name is called lapatinibditosylate, and structure is suc as formula shown in (I):
Its English Lapatinib by name; chemistry is by name: the chloro-4-[(3-fluorophenyl of N-[3-) methoxyl group] phenyl]-6-[5[[[2-(methylsulfonyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine (N-[3-Chloro-4-[(3-fluorophenyl) methoxy] phenyl]-6-[5[[[2-(methylsulfonyl) ethyl] amino] methyl]-2-furanyl]-4-quinazolinamine); cas number is 231277-92-2, molecular formula: C29H26ClFN4O4S.
It is a kind of PTS, and its tosilate monohydrate is in Nikkei united States food and drug administration (FDA) approval listing March 13 in 2007.This medicine is a kind of kinase inhibitor, mainly by multipath, deprives the needed bio signal of growth of tumour cell and brings into play antitumor action.It can be combined with another kind of anticarcinogen capecitabine (capectabine) and uses treatment to shift HER2 positive breast cancer late period.Than this high molecular weight protein monoclonal antibody of Herceptin (trastuzumab), lapatinibditosylate is a kind of micromolecular compound, can enter the function that stops some albumen in cell, can treat the inoperative mammary cancer of Herceptin with it.
The method of preparing lapatinibditosylate has description in patent US6713485, it is to use as shown in the formula (1) compound (5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde) and formula (2) compound (methylsulfonyl ethamine) to do raw material, first generate western Buddhist alkali, then going back under the condition of original reagent sodium triacetoxy borohydride existence, reduction C=N key makes target product.Concrete route is as follows:
Wherein compound (1) and compound (2) are all monomeric compounds.Their synthetic method is as described below:
1. the synthetic route of compound (1) is:
Note: R1 wherein, R2 represents alkyl
Sloughing after aldehyde radical protecting group with acid (example hydrochloric acid), obtain hydrochloride compound (II); Then add alkali (as sodium hydroxide, sodium carbonate or salt of wormwood etc.) and carry out neutralization reaction, obtain compound (1).
2. the synthetic route of compound (2) is:
In by acid (as tosic acid) deaminize protecting group (tertbutyloxycarbonyl), obtain compound (III); Then add alkali neutralization compound (III) and obtain monomeric compound (2).
Another piece of US Patent No. 7157466 (title: quinazoline ditosylate salt compounds (Quinazoline ditosylate salt compounds), patentee: Smithkline Beecham Corp (SmithKline Beecham (Cork) Limited), publication date: the preparation method who on January 2nd, 2007) has announced again a kind of lapatinibditosylate, the difference of itself and previous method is, the compound of one of raw material (1) is changed into the form (as shown in the formula compound shown in (4)) of its tosilate, and compound (4) is to obtain by hydrochloric acid 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde (being described formula (II) compound) conversion, process is more loaded down with trivial details.Concrete route is as follows:
Wherein, THF represents tetrahydrofuran (THF), and IPA represents Virahol.
Patent WO2008024439 (date of publication: the route of on February 28th, 2008) announcing is as follows:
In this route, monomeric compound (1) and methylsulfonyl ethamine monomer generate western Buddhist alkali, are also with sodium triacetoxy borohydride reduction, also will protect amido with Boc, and main purpose should be to guarantee that amido is NH rather than ND; The de-Boc of last hydrochloric acid, and use tosic acid salify, process is also comparatively loaded down with trivial details.
Can draw thus, prior art is for the preparation of quinazoline compound lapatinibditosylate, being all to use monomeric compound (1) (or its tosic acid salt compound (4)) and monomeric compound (2) as raw material, is all that the compound of salt form reacts and do not use raw material; Monomer (or its tosilate) also needs first with the compound of other salt form, to change, and makes undoubtedly reactions steps increase by a step, and cost is increased, and causes yield to reduce.And methylsulfonyl ethamine monomer itself is liquid, even free, also be inconvenient to process, if but form salt, easily processing is a lot.And in existing method, reductive agent is all with sodium triacetoxy borohydride, not only expensive, and atom utilization is quite low, yield is not high yet.
Summary of the invention
Object of the present invention is exactly for the problems referred to above and deficiency, provides a kind of preparation method of quinazoline compound, more properly, a kind of method of preparing lapatinibditosylate is provided, and the method is directly used the compound of salt form to do raw material, and reactions steps shortens, agents useful for same reduces, cost.
To achieve these goals, the technical solution used in the present invention is as follows:
A preparation method for quinazoline compound, is characterized in that, reaction scheme is as follows:
Wherein, HX is mineral acid or organic acid; Mineral acid can be haloid acid or sulfuric acid etc.; Organic acid can be tosic acid, fumaric acid, tartrate or acetic acid etc.; Preferred hydrochloric acid, acetic acid.
HY is hydrochloric acid or tosic acid (TsOH) etc.; Preferred tosic acid.
The present invention uses 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde hydrochlorate (compound (II)) and methylsulfonyl ethamine hydrochlorate (compound (III)) to do raw material, and reaction obtains quinazoline compound lapatinibditosylate (compound (I)).
Further, in reaction process, compound (II) directly reacts with compound (III) and generates western Buddhist alkali, i.e. compound (3) shown in following structure:
Western Buddhist alkali reduces with metal borohydride, obtains described lapatinibditosylate (Compound I).
Further, described metal borohydride can be selected from: sodium borohydride (NaBH
4) or POTASSIUM BOROHYDRIDE (KBH
4).
Further, can in reaction process, add Lewis acid, improve reducing power, make reduction effect better, use metal borohydride and lewis acidic combination, can be selected from: NaBH
4/ LiBr, NaBH
4/ LiCl, KBH
4/ LiBr, NaBH
4/ CH
3cOOH or NaBH
4/ I
2deng; NaBH most preferably
4/ LiBr.
Further, in reaction process, the solvent using is ether solvent, preferably tetrahydrofuran (THF) (THF).
Further, temperature of reaction is controlled at 10～70 ℃, preferably 20～30 ℃.
Beneficial effect of the present invention is as follows:
(1) processing condition are reasonable, directly with the reaction of salt form compound, generate western Buddhist alkali, need not as method described in patent US7157466, adjust especially compound (II) is tosilate, also without patent US6713485, announce route and like that compound (II) is dissociated into monomer with compound (III), this point just reduces single step reaction process than two kinds of methods of patent.
(2) reducing activity that utilizes Lewis acid to improve sodium borohydride replaces sodium triacetoxy borohydride to reduce, and not only with low cost, Atom economy is high.And the stability of sodium borohydride itself is also good more than sodium triacetoxy borohydride, does not resemble sodium triacetoxy borohydride and be easy in storage process because the moisture in ingress of air decomposes rotten.And methylsulfonyl ethamine directly participates in reaction with salt, rather than free alkali, also easier than patented method.
In sum, the present invention directly uses the compound of salt form to do raw material, has shortened reactions steps, and agents useful for same reduces; And replace expensive sodium triacetoxy borohydride with sodium borohydride, and make material used cheap and easy to get, cost, Atom economy is high, has avoided sodium triacetoxy borohydride to store the inconvenience of transportation, has larger suitability for industrialized production advantage.
Embodiment
The preparation of embodiment 1 lapatinibditosylate
In four-hole bottle, drop into 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde hydrochloride (10g), methylsulfonyl ethamine tosilate (9g), THF (200ml), acetic acid (5g), diisopropylethylamine (10g), 20～25 ℃ of insulation 30min.Then slowly add NaBH
4(1.8g), LiBr (0.1g), controls temperature at 20～30 ℃ of reaction 10h.Reaction finishes, and adds water 10ml, is cooled to 20～30 ℃ and splashes into sodium hydroxide solution stopped reaction, stirring at room.Stratification, extraction, merges organic phase, and washing, and evaporated under reduced pressure THF, obtains lapatinibditosylate (10g, yield 87.8%, content 99.1%).
The preparation of embodiment 2 lapatinibditosylates
In four-hole bottle, drop into 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde hydrochloride (10g), methylsulfonyl ethylamine hydrochloride (4.2g), THF (200ml), acetic acid (5g), diisopropylethylamine (10g), 30～35 ℃ of insulation 30min.Then slowly add NaBH
4(1.8g), LiBr (0.1g) is warming up to 50 ℃ of reaction 10h.Reaction finishes, and adds water 10ml, is cooled to 20～30 ℃ and splashes into sodium hydroxide solution stopped reaction, stirring at room.Stratification, extraction, merges organic phase, and washing, and evaporated under reduced pressure THF, obtains lapatinibditosylate (9.5g, yield 83.5%, content 99.2%).
The preparation of embodiment 3 lapatinibditosylates
In four-hole bottle, drop into 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde hydrochloride (10g), methylsulfonyl ethamine tosilate (9g), THF (200ml), acetic acid (5g), diisopropylethylamine (10g), 20～25 ℃ of insulation 30min.Then slowly add NaBH
4(1.8g), control temperature at 20～30 ℃ of reaction 10h.Reaction finishes, and adds water 10ml, is cooled to 20～30 ℃ and splashes into sodium hydroxide solution stopped reaction, stirring at room.Stratification, extraction, merges organic phase, and washing, and evaporated under reduced pressure THF, obtains lapatinibditosylate (7.5g, yield 65.9%, content 79.5%).
The preparation of embodiment 4 lapatinibditosylates
With 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-the quinolyl)-2 furan carboxyaldehyde acetate of equimolar amount, substitute 5-(4-(4-(3-fluorine benzyloxy)-3-chlorobenzene is amino)-6-quinolyl)-2 furan carboxyaldehyde hydrochloride, working method is with embodiment 1, obtain lapatinibditosylate (8.5g, yield 81.2%, content 85.2%).
The preparation of embodiment 5 lapatinibditosylates
With the methylsulfonyl ethylamine hydrochloride of equimolar amount, substitute methylsulfonyl ethamine tosilate, working method, with embodiment 1, obtains lapatinibditosylate (8g, yield 78.5%, content 89.2%).
The preparation of methylsulfonyl ethamine tosilate (compound III)
The preparation of embodiment 6 first mercaptoethylamines (compound 7)
In 500ml four-hole bottle, drop into 40g chloroethylamine hydrochloride, 160g sodium methyl mercaptide, 70 ℃ of stirring reaction 1h, cooling.Product need not be separated, is directly used in next step reaction.
The preparation of embodiment 7 first mercaptoethylamine-Boc (compound 8)
In the reaction solution of last embodiment, drip (Boc) 2O (75g), after dripping off, have a large amount of oily matter to generate.Continue the about 2h of insulation reaction.After reaction finishes, stratification, gets upper strata organic layer.Lower aqueous layer extraction, merges organic layer, making beating, and phase-splitting, gets upper strata organic layer, subtracts steaming, obtains faint yellow oily matter, about 61.3g, two step yields are 93.8%.
The preparation of embodiment 8 methylsulfonyl ethamine-BOC (compound 9)
20g first mercaptoethylamine-BOC is put in the four-hole bottle of 250ml, be cooled to 20 ℃.Drip 40g Peracetic Acid, drip off at room temperature insulation 12h.Drip aqueous solution of sodium bisulfite, survey starch potassium iodide paper and do not develop the color.Temperature control drips 25% aqueous sodium hydroxide solution at 10～20 ℃, adjusts PH=8-9.Be cooled to 0-5 ℃ of insulated and stirred, suction filtration, drip washing is washed till PH=7-8, suction filtration, filter cake vacuum drying, obtains the about 10.5g of product, and yield is 90.9%.
The preparation of embodiment 9 methylsulfonyl ethamine-BOC (compound 9)
20g first mercaptoethylamine-BOC is put in the four-hole bottle of 250ml, be cooled to 20 ℃.Add 40g Glacial acetic acid, the 2g vitriol oil, then drips 60g hydrogen peroxide, drips off at room temperature insulation 12h.Drip aqueous solution of sodium bisulfite, survey starch potassium iodide paper and do not develop the color.Temperature control drips 25% aqueous sodium hydroxide solution at 10～20 ℃, adjusts PH=8-9.Be cooled to 0-5 ℃ of insulated and stirred, suction filtration, drip washing is washed till PH=7-8, suction filtration, filter cake vacuum drying, obtains the about 10.2g of product, and yield is 87.4%.
The preparation of embodiment 10 methylsulfonyl ethamine tosilate (compound III)
40ml dehydrated alcohol is put in the four-hole bottle of 100ml, and dropped into 10g methylsulfonyl ethamine-Boc, then drop into 8.5g tosic acid, reflux 1h, is cooled to room temperature.Suction filtration, after filter cake drip washing, in 40 ℃ of oven dry.Obtain the about 12.0g of product, yield is 95%.
Claims (4)
1. suc as formula a preparation method for the quinazoline compound shown in (I), comprise the phosphate compounds direct reaction of using suc as formula shown in (II) and formula (III), generate western Buddhist alkali formula (3) compound,
Through sodium borohydride or potassium borohydride reduction, prepare again:
Wherein, HX is mineral acid or organic acid; Mineral acid is selected from haloid acid or sulfuric acid; Organic acid is selected from tosic acid, fumaric acid, tartrate or acetic acid; HY is selected from hydrochloric acid or tosic acid.
2. preparation method according to claim 1, is characterized in that, adds Lewis acid in reaction.
3. preparation method according to claim 1 and 2, is characterized in that, adds sodium borohydride or POTASSIUM BOROHYDRIDE and lewis acidic combination in reaction.
4. preparation method according to claim 3, is characterized in that, described sodium borohydride or POTASSIUM BOROHYDRIDE and lewis acidic being combined as: NaBH
4/ LiBr, NaBH
4/ LiCl, KBH
4/ LiBr, NaBH
4/ CH
3cOOH or NaBH
4/ I
2.
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| CN1882576A (en) * | 2003-09-16 | 2006-12-20 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives |
| CN101083995A (en) * | 2004-12-17 | 2007-12-05 | 史密丝克莱恩比彻姆（科克）有限公司 | Cancer treatment method |
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| CN1882576A (en) * | 2003-09-16 | 2006-12-20 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives |
| CN101083995A (en) * | 2004-12-17 | 2007-12-05 | 史密丝克莱恩比彻姆（科克）有限公司 | Cancer treatment method |
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| Title |
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| 冯光熙等.金属硼氢化物MBH4.《无机化学丛书第一卷，希有气体 氢 碱金属》.科学出版社,1984,(第一版),第253-254页. * |
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Commission number: 4W103510 Conclusion of examination: Claim No. 201010108505.1 of the invention No. 1 is invalid and the patent is maintained on the basis of claim 2-4. Decision date of declaring invalidation: 20150922 Decision number of declaring invalidation: 26971 Denomination of invention: Preparation method of quinazoline compound Granted publication date: 20140402 Patentee: ZHEJIANG JIUZHOU PHARMACEUTICAL Co.,Ltd. |