CN104725333A - Preparation method of novel azacycloheptane derivative - Google Patents
Preparation method of novel azacycloheptane derivative Download PDFInfo
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- CN104725333A CN104725333A CN201310715025.5A CN201310715025A CN104725333A CN 104725333 A CN104725333 A CN 104725333A CN 201310715025 A CN201310715025 A CN 201310715025A CN 104725333 A CN104725333 A CN 104725333A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical class C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 claims abstract description 6
- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- -1 nitrogenous organic bases Chemical class 0.000 claims description 4
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 claims description 3
- 238000005915 ammonolysis reaction Methods 0.000 claims description 3
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 6
- 150000001875 compounds Chemical class 0.000 claims 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 4
- 239000011707 mineral Substances 0.000 claims 4
- 150000007524 organic acids Chemical class 0.000 claims 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 230000032050 esterification Effects 0.000 claims 2
- 238000005886 esterification reaction Methods 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000012320 chlorinating reagent Substances 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 125000002346 iodo group Chemical group I* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229960000817 bazedoxifene Drugs 0.000 abstract description 2
- 239000003446 ligand Substances 0.000 abstract 3
- 150000003839 salts Chemical class 0.000 abstract 3
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- OMZAMQFQZMUNTP-UHFFFAOYSA-N acetic acid;1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound CC(O)=O.C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 OMZAMQFQZMUNTP-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229960003713 bazedoxifene acetate Drugs 0.000 description 5
- 229940051250 hexylene glycol Drugs 0.000 description 5
- SVTBMSDMJJWYQN-UHFFFAOYSA-N hexylene glycol Natural products CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- GCGYREODZIZPLJ-UHFFFAOYSA-N azepan-1-ium;chloride Chemical compound Cl.C1CCCNCC1 GCGYREODZIZPLJ-UHFFFAOYSA-N 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- ZQDSOUPBYJIPNM-UHFFFAOYSA-N 1-(2-chloroethyl)azepane;hydrochloride Chemical compound [Cl-].ClCC[NH+]1CCCCCC1 ZQDSOUPBYJIPNM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940038615 duavee Drugs 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/067—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents attached to the same carbon chain, which is not interrupted by carbocyclic rings
Landscapes
- 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 provides a preparation method of 1-(2-haloethyl)azacycloheptane base ligand and its acid salt. The preparation method is suitable for industrial production. The preparation method is characterized in that 1,6-hexanediol as an initial raw material undergoes three-step reactions to produce the 1-(2-haloethyl)azacycloheptane base ligand and its acid salt. The 1-(2-haloethyl)azacycloheptane base ligand and its acid salt are key intermediates for bazedoxifene synthesis. The preparation method has the advantages of cheap raw material, operation simpleness, mild conditions, simple after-treatment and high yield and is a preparation route suitable for industrialization.
Description
Technical field
The invention belongs to technical field of medicine synthesis, particularly, the present invention relates to the synthesis for the treatment of postmenopausal osteoporosis medicine bazedoxifene acetate key intermediate.
Background technology
Bazedoxifene acetate, English Bazedoxifene Acetate by name, its structural formula is:
Bazedoxifene acetate is developed by Wyeth at first, after transfer Pfizer, be third generation selective estrogen receptor modulators, be mainly used in treat postmenopausal osteoporosis.In April, 2009, commodity were called Conbriza in Italy and Spain's listing, and within 2010, in Japan's listing, commodity are called Viviant, and in October, 2013, commodity were called Duavee in U.S.'s approval listing.
At present, the preparation WAY 140424 of report Measures compare simple possible have following two kinds:
From route map, two kinds of methods all need to use the intermediate of intermediate " 1-(2-chloroethyl) azepan hydrochloride " this key.This intermediate domestic supply producer is fewer and all can not suitability for industrialized production, expensive.The synthetic method of current report is mainly raw material and 1,2-ethylene dichloride generation electrophilic substitution reaction with azepan, is shown below:
The raw material azepan that the method uses is inherently expensive and toxicity is very large, and another kind of raw material 1,2-ethylene dichloride is the kind solvent that toxicity is larger, and it has two reaction site, the improper product being easy to generation two chlorine and all occurring to replace of reaction controlling is not desirable industrialized route in this way.
The exploitation of my company a kind of newly prepare 1-(2-chloroethyl) method of azepan hydrochloride, not only raw materials used low price, and simple to operate, yield is high, whole process does not use the king-sized raw material of toxicity, and the three wastes are few, can not cause too large pressure to environmental protection, it is the industrialized route of a green, environmental protection, greatly can reduce the synthesis cost of bazedoxifene acetate, be conducive to the production domesticization of this medicine, have marketable value and social value.
Summary of the invention
The invention provides a kind of is that 1-(2-chloroethyl prepared by raw material with 1,6-hexylene glycol) method of azepan hydrochloride, not only solve the problem that existing technological process material toxicity is large, cost is high, impurity is many, and good product quality, yield is high.
Technical scheme
1-(2-chloroethyl) preparation method's altogether three-step reaction of azepan hydrochloride:
The first step with 1,6-hexylene glycol and Tosyl chloride be raw material, organic bases as acid binding agent, in methylene dichloride, be obtained by reacting 1,6-bis-tosic acid hexylene glycol ester.
Second step reaction is that raw material generation sulphonate ammonolysis reaction obtains 2-(azepan with 1,6-bis-tosic acid hexylene glycol ester and thanomin)-1-ethanol.
3rd step 2-(azepan)-1-ethanol generation halogenating reaction obtains 1-(2-chloroethyl) azepan hydrochloride or 1-(2-bromotrifluoromethane) azepan hydrobromate
Specific embodiment
The preparation of embodiment one: 1,6-bis-tosic acid hexylene glycol ester
Take 1.77 gram of 1,6-hexylene glycol (15.0mmol) to mix with 30ml anhydrous pyridine, stir and be cooled to 0 DEG C, add 8.58 grams of Tosyl chlorides (45.0mmol).Finish, react 3 hours under room temperature, add 3ml shrend to go out reaction, continue stirring 30 minutes, add methylene dichloride, be added dropwise to 1M hydrochloric acid under stirring and adjust PH=6-7, stir stratification after 30 minutes, dichloromethane layer priority water and saturated brine washing, then dry (anhydrous sodium sulphate), filter, decompression steams methylene dichloride, residue first through column chromatography purification (methylene dichloride/n-hexane/acetone=48:50:2), then obtains 5.12 gram of 1,6-bis-tosic acid hexylene glycol ester (80%) through recrystallization process (methylene dichloride/normal hexane).Mp:77-79 DEG C,
1h NMR (500MHz, CDCl
3) δ 1.25-1.27 (m, 4H), 1.57-1.60 (m, 4H), 2.45 (s; 6H), 3.97 (t, J=6.3Hz, 4H), 7.34 (d; J=8.4Hz, 4H), 7.77 (d, J=8.4Hz, 4H); 13C NMR (125MHz, CDCl3) δ 21.60,21.75,28.26,70.08,127.96,130.00,133.01,144.96; HRMS (ESI) m/z calculated value C20H26O6S2Na [M+Na]
+449.1064; Measured value 449.1068.
Embodiment two: 2-(azepan) preparation of-1-ethanol
A certain amount of 1,6-bis-tosic acid hexylene glycol ester mixes with excessive thanomin and toluene, be heated with stirring to 120 DEG C, react 2 hours, reaction is finished, decompression steams excessive thanomin, methylene dichloride is added, then priority water and saturated brine washing, dry (anhydrous magnesium sulfate), filtration, distillation removing methylene dichloride in residue, residue obtains oily matter 2-(azepan through column chromatography purification (n-hexane/ethyl acetate=98:2))-1-ethanol, yield 90%.
Bp：97℃（14mmHg）
Embodiment three: 1-(2-chloroethyl) preparation of azepan hydrochloride
A certain amount of 2-(azepan)-1-ethanol mixes with methylene dichloride, add the sulfur oxychloride of 5 molar equivalents and the DMF of catalytic amount, be heated with stirring to backflow, react 2 hours, cooling is filtered, filter cake washed with dichloromethane, recrystallisation from isopropanol, vacuum-drying obtains 1-(2-chloroethyl) azepan hydrochloride, yield 85%.Mp:208-209℃。
Claims (5)
1. a 1-(2-haloethyl) azepan alkali body and hydrochlorate thereof
The preparation method of (formula I), is characterized in that with 1,6-hexylene glycol for starting raw material, obtains the compound as formula I through esterification, sulphonate ammonolysis reaction, halogenating reaction.
Wherein X represents halogen atom, as: Cl, Br, I; Y representative can ionize out H
+mineral acid and organic acid, mineral acid is as HCl, HBr, H
2sO
4deng; Organic acid is as HAc, TsOH etc.
2. as claimed in claim 1, esterification is by 1,6-hexylene glycol and SULPHURYL CHLORIDE (RSO
2cl) under acid binding agent exists, reaction generates the intermediate 1 as shown in formula II.
Wherein R represent methyl, ethyl, trifluoromethyl etc. be less than three carbon alkyl or containing the group of phenyl ring, as phenyl, p-methylphenyl etc., preferred p-methylphenyl.Acid binding agent is nitrogenous organic bases, as: triethylamine, pyridine etc.
3. as claimed in claim 1, intermediate 1 and thanomin generation sulphonate ammonolysis reaction obtain the intermediate 2 as shown in formula III.
。
4. as claimed in claim 1, intermediate 2 obtains the compound as shown in formula I through halogenating reaction, and this compound can be alkaline matter, also can be inorganic acid salt or the organic acid salt of alkali body, for the preparation of WAY 140424.
The chlorinating agent that chlorination uses has: PCl
3, PCl
5, SOCl
2, CH
3siCl, HCl etc., preferred SOCl
2; The brominated reagent that bromo-reaction uses has: PBr
3, HBr, Br
2deng, preferred PBr
3; The iodo reagent that iodide reaction uses has: I
2, KI etc., preferred KI.
5. the Y representative as claimed in claim 4, in formula I compound can ionize out H
+mineral acid or organic acid, wherein mineral acid has: hydrochloric acid, Hydrogen bromide, sulfuric acid etc., preferred hydrochloric acid; Organic acid has: HAc, TsOH, CF
3cOOH etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310715025.5A CN104725333A (en) | 2013-12-20 | 2013-12-20 | Preparation method of novel azacycloheptane derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310715025.5A CN104725333A (en) | 2013-12-20 | 2013-12-20 | Preparation method of novel azacycloheptane derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104725333A true CN104725333A (en) | 2015-06-24 |
Family
ID=53449814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310715025.5A Pending CN104725333A (en) | 2013-12-20 | 2013-12-20 | Preparation method of novel azacycloheptane derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104725333A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180540A (en) * | 2018-09-20 | 2019-01-11 | 武汉海斯普林科技发展有限公司 | A kind of preparation method and application of highly branched chain dicarboxylic acids ammonium salt |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101784551A (en) * | 2007-06-15 | 2010-07-21 | 万有制药株式会社 | Dicycloaniline Derivatives |
| WO2013090921A1 (en) * | 2011-12-16 | 2013-06-20 | Olema Pharmaceuticals, Inc. | Novel benzopyran compounds, compositions and uses thereof |
-
2013
- 2013-12-20 CN CN201310715025.5A patent/CN104725333A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101784551A (en) * | 2007-06-15 | 2010-07-21 | 万有制药株式会社 | Dicycloaniline Derivatives |
| WO2013090921A1 (en) * | 2011-12-16 | 2013-06-20 | Olema Pharmaceuticals, Inc. | Novel benzopyran compounds, compositions and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| JIANQUAN FAN 等: "Polymer Micelle with pH-Triggered Hydrophobic−Hydrophilic Transition and De-Cross-Linking Process in the Core and Its Application for Targeted Anticancer Drug Delivery", 《BIOMACROMOLECULES》 * |
| XIAOKE GU 等: "Synthesis and biological evaluation of novel bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potent P-glycoprotein inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180540A (en) * | 2018-09-20 | 2019-01-11 | 武汉海斯普林科技发展有限公司 | A kind of preparation method and application of highly branched chain dicarboxylic acids ammonium salt |
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