CA2960473A1 - Procedes de preparation de tadalafil et d'intermediaires associes - Google Patents

Procedes de preparation de tadalafil et d'intermediaires associes Download PDF

Info

Publication number: CA2960473A1
Authority: CA; Canada
Prior art keywords: formula; compound; salt; cis; isomer
Prior art date: 2017-03-10
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA2960473A

Other languages

English (en)

Inventor

Prabhudas Bodhuri

Alfredo Paul Ceccarelli

Gamimi Weeratunga

Boris Gorin

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Apotex Inc

Original Assignee

Apotex Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2017-03-10

Filing date

2017-03-10

Publication date

2018-09-10

2017-03-10 Application filed by Apotex Inc filed Critical Apotex Inc

2017-03-10 Priority to CA2960473A priority Critical patent/CA2960473A1/fr

2018-09-10 Publication of CA2960473A1 publication Critical patent/CA2960473A1/fr

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 99
230000008569 process Effects 0.000 title claims abstract description 88
IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract description 48
229960000835 tadalafil Drugs 0.000 title claims abstract description 36
238000002360 preparation method Methods 0.000 title claims abstract description 28
239000000543 intermediate Substances 0.000 title description 9
150000001875 compounds Chemical class 0.000 claims abstract description 138
150000007522 mineralic acids Chemical class 0.000 claims abstract description 31
150000003839 salts Chemical class 0.000 claims description 53
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
239000000203 mixture Substances 0.000 claims description 22
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 20
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 17
239000003795 chemical substances by application Substances 0.000 claims description 17
230000003213 activating effect Effects 0.000 claims description 15
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
239000002253 acid Substances 0.000 claims description 13
238000005886 esterification reaction Methods 0.000 claims description 13
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
230000032050 esterification Effects 0.000 claims description 11
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 11
229910000041 hydrogen chloride Inorganic materials 0.000 claims description 11
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
239000003960 organic solvent Substances 0.000 claims description 10
DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical group NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 9
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
239000011260 aqueous acid Substances 0.000 claims description 8
238000010438 heat treatment Methods 0.000 claims description 8
-1 hydrogen halides Chemical class 0.000 claims description 8
VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 7
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
229910017604 nitric acid Inorganic materials 0.000 claims description 4
JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
239000001257 hydrogen Substances 0.000 claims description 3
229910052739 hydrogen Inorganic materials 0.000 claims description 3
230000006872 improvement Effects 0.000 abstract description 3
238000006243 chemical reaction Methods 0.000 description 40
SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 28
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
239000002904 solvent Substances 0.000 description 19
QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 17
239000007787 solid Substances 0.000 description 16
239000000243 solution Substances 0.000 description 16
238000009833 condensation Methods 0.000 description 13
230000005494 condensation Effects 0.000 description 13
238000006317 isomerization reaction Methods 0.000 description 13
239000011541 reaction mixture Substances 0.000 description 13
229940081310 piperonal Drugs 0.000 description 12
239000000047 product Substances 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
230000035484 reaction time Effects 0.000 description 10
239000000725 suspension Substances 0.000 description 10
JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 9
125000004432 carbon atom Chemical group C* 0.000 description 9
238000010992 reflux Methods 0.000 description 9
238000003756 stirring Methods 0.000 description 9
238000005160 1H NMR spectroscopy Methods 0.000 description 8
150000001408 amides Chemical class 0.000 description 8
239000007822 coupling agent Substances 0.000 description 8
238000013459 approach Methods 0.000 description 7
230000000052 comparative effect Effects 0.000 description 7
239000012535 impurity Substances 0.000 description 7
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
125000003158 alcohol group Chemical group 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 5
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
239000006227 byproduct Substances 0.000 description 5
239000012071 phase Substances 0.000 description 5
238000010626 work up procedure Methods 0.000 description 5
ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 4
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
238000006482 condensation reaction Methods 0.000 description 4
238000001914 filtration Methods 0.000 description 4
KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 4
229930182827 D-tryptophan Natural products 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
230000001476 alcoholic effect Effects 0.000 description 3
125000000217 alkyl group Chemical group 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000008367 deionised water Substances 0.000 description 3
229910021641 deionized water Inorganic materials 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
239000012065 filter cake Substances 0.000 description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
238000002955 isolation Methods 0.000 description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
150000004702 methyl esters Chemical class 0.000 description 3
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
230000009467 reduction Effects 0.000 description 3
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
238000005481 NMR spectroscopy Methods 0.000 description 2
QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
150000001298 alcohols Chemical class 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
239000002585 base Substances 0.000 description 2
230000008878 coupling Effects 0.000 description 2
238000010168 coupling process Methods 0.000 description 2
238000005859 coupling reaction Methods 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
150000002170 ethers Chemical class 0.000 description 2
NIDZUMSLERGAON-UHFFFAOYSA-N ethyl 2-(methylamino)acetate;hydron;chloride Chemical compound Cl.CCOC(=O)CNC NIDZUMSLERGAON-UHFFFAOYSA-N 0.000 description 2
239000012458 free base Substances 0.000 description 2
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
229910052751 metal Inorganic materials 0.000 description 2
239000002184 metal Substances 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
KCUNTYMNJVXYKZ-SNVBAGLBSA-N methyl (2r)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-SNVBAGLBSA-N 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
239000012044 organic layer Substances 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
239000002994 raw material Substances 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
229930195734 saturated hydrocarbon Natural products 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000002002 slurry Substances 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
FFCZQVKVWGGQFB-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
208000010228 Erectile Dysfunction Diseases 0.000 description 1
102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
239000008186 active pharmaceutical agent Substances 0.000 description 1
150000001263 acyl chlorides Chemical class 0.000 description 1
230000004075 alteration Effects 0.000 description 1
150000008064 anhydrides Chemical class 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
125000002843 carboxylic acid group Chemical group 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
229940117229 cialis Drugs 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
238000010961 commercial manufacture process Methods 0.000 description 1
238000001816 cooling Methods 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
238000006345 epimerization reaction Methods 0.000 description 1
BTKSUULMJNNXHG-UHFFFAOYSA-N ethyl 2-(methylamino)acetate Chemical compound CCOC(=O)CNC BTKSUULMJNNXHG-UHFFFAOYSA-N 0.000 description 1
230000001747 exhibiting effect Effects 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
239000007789 gas Substances 0.000 description 1
229940029575 guanosine Drugs 0.000 description 1
231100001261 hazardous Toxicity 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
125000001183 hydrocarbyl group Chemical group 0.000 description 1
229910000039 hydrogen halide Inorganic materials 0.000 description 1
239000012433 hydrogen halide Substances 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
201000001881 impotence Diseases 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
235000015110 jellies Nutrition 0.000 description 1
239000008274 jelly Substances 0.000 description 1
239000007788 liquid Substances 0.000 description 1
238000012423 maintenance Methods 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
230000011987 methylation Effects 0.000 description 1
238000007069 methylation reaction Methods 0.000 description 1
238000012544 monitoring process Methods 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
238000005191 phase separation Methods 0.000 description 1
238000000746 purification Methods 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
238000011084 recovery Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
150000003462 sulfoxides Chemical class 0.000 description 1
239000001117 sulphuric acid Substances 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
238000012360 testing method Methods 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
238000012795 verification Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA2960473A 2017-03-10 2017-03-10 Procedes de preparation de tadalafil et d'intermediaires associes Abandoned CA2960473A1 (fr)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
CA2960473A CA2960473A1 (fr)	2017-03-10	2017-03-10	Procedes de preparation de tadalafil et d'intermediaires associes

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
CA2960473A CA2960473A1 (fr)	2017-03-10	2017-03-10	Procedes de preparation de tadalafil et d'intermediaires associes

Publications (1)

Publication Number	Publication Date
CA2960473A1 true CA2960473A1 (fr)	2018-09-10

Family

ID=63518935

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2960473A Abandoned CA2960473A1 (fr)	2017-03-10	2017-03-10	Procedes de preparation de tadalafil et d'intermediaires associes

Country Status (1)

Country	Link
CA (1)	CA2960473A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN111253399A (zh) *	2020-03-30	2020-06-09	苏州弘森药业股份有限公司	一种他达拉非原料药的生产工艺
CN113214251A (zh) *	2021-04-30	2021-08-06	湖北丽益医药科技有限公司	一种他达拉非中间体杂质的制备方法
CN115184531A (zh) *	2021-04-07	2022-10-14	浙江康恩贝制药股份有限公司	一种同时测定他达拉非中3种杂质含量的方法
CN117143070A (zh) *	2023-09-07	2023-12-01	玉溪健坤生物药业有限公司	一种胡椒醛的制备方法

2017
- 2017-03-10 CA CA2960473A patent/CA2960473A1/fr not_active Abandoned

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN111253399A (zh) *	2020-03-30	2020-06-09	苏州弘森药业股份有限公司	一种他达拉非原料药的生产工艺
CN115184531A (zh) *	2021-04-07	2022-10-14	浙江康恩贝制药股份有限公司	一种同时测定他达拉非中3种杂质含量的方法
CN115184531B (zh) *	2021-04-07	2024-06-11	浙江康恩贝制药股份有限公司	一种同时测定他达拉非中3种杂质含量的方法
CN113214251A (zh) *	2021-04-30	2021-08-06	湖北丽益医药科技有限公司	一种他达拉非中间体杂质的制备方法
CN113214251B (zh) *	2021-04-30	2024-06-11	湖北丽益医药科技有限公司	一种他达拉非中间体杂质的制备方法
CN117143070A (zh) *	2023-09-07	2023-12-01	玉溪健坤生物药业有限公司	一种胡椒醛的制备方法

Legal Events

Date	Code	Title	Description
2020-05-06	FZDE	Dead	Effective date: 20200311

Publication	Publication Date	Title
JP6574474B2 (ja)	2019-09-11	キラルジペプチジルペプチダーゼ−ｉｖ阻害剤の製造方法
US20080275237A1 (en)	2008-11-06	Method for Obtaining Pure Tetrahydrocannabinol
CN105473544B (zh)	2017-10-31	3‑(5‑取代的氧‑2,4‑二硝基‑苯基)‑2‑氧‑丙酸酯的化合物，方法及其应用
WO2016125191A2 (fr)	2016-08-11	Procédés de préparation de bromhydrate de vortioxétine
RU2621725C2 (ru)	2017-06-07	Способ получения 1-([1,3]диоксолан-4-илметил)-1н-пиразол-3-иламина
CA2373077A1 (fr)	2000-11-16	Sels d'intermediaires de 2,2-dimethyl-1,3-dioxane et leur procede de preparation
CN104837817B (zh)	2017-03-22	制备3‑氨基‑哌啶化合物的合成路线
WO2014064712A2 (fr)	2014-05-01	Procédé amélioré pour la préparation de fulvestrant
WO2019115000A1 (fr)	2019-06-20	Procédé de préparation de rucaparib et nouveaux intermédiaires de synthèse
KR20180116371A (ko)	2018-10-24	4-알콕시-3-히드록시피콜린산의 제조 방법
CN115417816B (zh)	2024-01-26	一种3,6-二溴-1-氯-异喹啉的制备方法
JP2009114166A (ja)	2009-05-28	ジベンゾオキセピン化合物の製造方法
CN104072495A (zh)	2014-10-01	天然产物生物碱Aaptamine的制备方法
RU2620379C2 (ru)	2017-05-25	СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ 2-ФЕНИЛ[1,2,4]ТРИАЗОЛО[1,5-а]ПИРИДИНА
CN111808040A (zh)	2020-10-23	多构型2-氧代噁唑烷-4-羧酸类化合物的合成方法
CN117603094B (zh)	2026-05-05	一种氨基保护的2-氨基甲基烯酸衍生物的合成方法
CN108129357B (zh)	2021-12-21	阿拉莫林中间体的制备方法
US6426417B1 (en)	2002-07-30	Processes and intermediates useful to make antifolates
Moskalenko et al.	2009	Synthesis of N-arylmethyl-3-azabicyclo [3.3. 1] nonan-9-ones.
CN118084767B (zh)	2025-06-17	一种外型-6-氟甲基-3-氮杂双环[3,1,0]己烷盐酸盐及其衍生物的合成方法
CN113816955B (zh)	2022-08-26	一种ret激酶抑制剂中间体及其制备方法
CN110015996B (zh)	2020-07-28	一种合成2′-螺环基取代三元碳环核苷的方法
CN108358780B (zh)	2022-04-19	合成高非对映选择性的α-酰氧化环酮类化合物的方法
JP2935515B2 (ja)	1999-08-16	１―アザビシクロ［ｍ，ｎ，０］アルカン誘導体及びその塩並びにこれらの製法
CN104955803B (zh)	2017-11-28	通过硝基‑四氢吡啶前体制备3‑氨基‑哌啶化合物