WO2022190047A1 - Process for consecutive continuous-flow reductions in the synthesis of medicinally relevant piperazine derivatives using a tubular reactor with alternating diameter - Google Patents
Process for consecutive continuous-flow reductions in the synthesis of medicinally relevant piperazine derivatives using a tubular reactor with alternating diameter Download PDFInfo
- Publication number
- WO2022190047A1 WO2022190047A1 PCT/IB2022/052191 IB2022052191W WO2022190047A1 WO 2022190047 A1 WO2022190047 A1 WO 2022190047A1 IB 2022052191 W IB2022052191 W IB 2022052191W WO 2022190047 A1 WO2022190047 A1 WO 2022190047A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- reactor
- formula
- compound
- flow
- fluid conveyance
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 39
- 230000009467 reduction Effects 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 19
- 150000004885 piperazines Chemical class 0.000 title claims description 20
- 238000003786 synthesis reaction Methods 0.000 title description 11
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 150000002148 esters Chemical class 0.000 claims abstract description 26
- 238000006722 reduction reaction Methods 0.000 claims abstract description 26
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 84
- 239000012530 fluid Substances 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 17
- 238000010791 quenching Methods 0.000 claims description 14
- 230000000171 quenching effect Effects 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 125000002723 alicyclic group Chemical group 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims 6
- 238000007872 degassing Methods 0.000 claims 1
- KPWSJANDNDDRMB-QAQDUYKDSA-N cariprazine Chemical compound C1C[C@@H](NC(=O)N(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 KPWSJANDNDDRMB-QAQDUYKDSA-N 0.000 abstract description 12
- 229960005123 cariprazine Drugs 0.000 abstract description 11
- 239000000543 intermediate Substances 0.000 abstract description 10
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000000561 anti-psychotic effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 34
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 13
- 239000012043 crude product Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 9
- 239000002245 particle Substances 0.000 description 8
- 239000004810 polytetrafluoroethylene Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000002699 waste material Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 238000005111 flow chemistry technique Methods 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000006664 bond formation reaction Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000005112 continuous flow technique Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- -1 methanesulfonyl ester Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229920002530 polyetherether ketone Polymers 0.000 description 3
- 239000010453 quartz Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000010936 titanium Substances 0.000 description 3
- 229910052719 titanium Inorganic materials 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Natural products NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000004696 Poly ether ether ketone Substances 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- JUPQTSLXMOCDHR-UHFFFAOYSA-N benzene-1,4-diol;bis(4-fluorophenyl)methanone Chemical compound OC1=CC=C(O)C=C1.C1=CC(F)=CC=C1C(=O)C1=CC=C(F)C=C1 JUPQTSLXMOCDHR-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- LDQCWGIXZGDJNL-IYARVYRRSA-N chembl3085821 Chemical compound C1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 LDQCWGIXZGDJNL-IYARVYRRSA-N 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 239000012045 crude solution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BKBMACKZOSMMGT-UHFFFAOYSA-N methanol;toluene Chemical compound OC.CC1=CC=CC=C1 BKBMACKZOSMMGT-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- KZEDPVFJLQLDIZ-UHFFFAOYSA-N (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1.C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZEDPVFJLQLDIZ-UHFFFAOYSA-N 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- UDQMXYJSNNCRAS-UHFFFAOYSA-N 2,3-dichlorophenylpiperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1Cl UDQMXYJSNNCRAS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- 229910003827 NRaRb Inorganic materials 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- NQZFAUXPNWSLBI-UHFFFAOYSA-N carbon monoxide;ruthenium Chemical compound [Ru].[Ru].[Ru].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] NQZFAUXPNWSLBI-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QCAWEPFNJXQPAN-UHFFFAOYSA-N methoxyfenozide Chemical compound COC1=CC=CC(C(=O)NN(C(=O)C=2C=C(C)C=C(C)C=2)C(C)(C)C)=C1C QCAWEPFNJXQPAN-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000011172 small scale experimental method Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 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
- C07D295/12—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 singly or doubly bound nitrogen atoms
- C07D295/135—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J10/00—Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles, or apparatus specially adapted therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/2415—Tubular reactors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00164—Controlling or regulating processes controlling the flow
Definitions
- the present invention relates to a novel alternating diameter flow reactor for continuous- flow reactions, a system for continuous-flow reactions comprising said alternating diameter flow reactor, a method for the formation of the C-N bond carried out in said system and a process for the preparation of the antipsychotic drug cariprazine described by the chemical stmcture (I) and its intermediates, and as well as other related 1 -arylpiperazine active pharmaceutical ingredients conducted in two continuous-flow reactors of said system comprising the consecutive steps of a first step being selective ester reduction carried out in said alternating diameter flow reactor and a second step being reductive amination carried out by continuous-flow catalytic hydrogenation.
- Cariprazine (3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-l -yl)ethyl)cyclohexyl)- 1,1-dimethylurea) of formula (I) is an active pharmaceutical ingredient (API) used for the treatment of schizophrenia and bipolar I disorder.
- This API belongs to the broader class of 1- arylpiperazines, which display affinities to aminergic receptors of the central nervous system, making them useful therapies in neuropsychiatric disorders.
- the intermediate of formula (XI) is used in the -alkylation of the piperazine derivative of formula (VII) to provide the desired product of formula (XII), which can be converted to cariprazine of formula (I), via subsequent deprotection and acylation.
- the drawback of this procedure is that it requires multiple steps (i.e. activation as methanesulfonyl ester) and stochiometric amounts of bases (i.e. TEA and K 2 CO 3 ).
- the ester intermediate of formula (IX) is reduced to an aldehyde of formula (XIII), by utilizing diisobutylaluminum hydride (DIBAL-H) in toluene at cryogenic temperatures.
- DIBAL-H diisobutylaluminum hydride
- This intermediate is reacted with the piperazine derivative of formula (VII), using NaBH(OAc) 3 to give the product of formula (XII).
- the drawback of this route is that the reduction must be carried out at a temperature below -70°C, and the aldehyde is produced with moderate yield.
- the hazardous DIBAL-H poses technological problems, when handled in traditional batch reactors.
- Amide formation is also suitable for the key C-N bond formation, according to patent application no. WO 2018/007986 Al.
- a carboxylic acid of formula (XIV) is coupled with the piperazine derivative of formula (VII), via various methods to give the amide of formula (XV).
- Reaction with in situ formed borane gives the borane adduct of formula (XVI), which can be decomposed thermally or under acidic conditions to give cariprazine of formula (I).
- the multiple steps of these process are not ideal for continuous-flow realization.
- Our aim was to provide a scalable continuous-flow process for the preparation of the key intermediate of formula (XII) utilizing the aldehyde of formula (XIII) under safer and more efficient reaction conditions.
- DIBAL-H In the continuous-flow synthesis of aldehydes from esters, the use of DIBAL-H has been widely reported by Ducry and Roberge ( Org . Process Res. Dev., Vol. 12, No. 2, 163 - 167 (2008)), Webb and Jamison (Org. Lett., Vol. 14, No. 2, 568 - 571 (2012)), Yoshida, et al. ( Eur . J. Org. Chem., Vol. 2014, No. 27, 6010 - 6016 (2014)) and Fukuyama, et al. (Org. Process Res. Dev., Vol. 20, No. 2, 503 - 509 (2016)).
- Reductive aminations also proved their utility in flow chemistry, especially when catalytic hydrogenation is used, which is well-suited to continuous transformations, since it is typically free from side-products and the removal of excess hydrogen is fairly simple. These methods were reviewed by Cossar, et al. (Org. Biomol. Chem., Vol. 13, No. 26. 7119 - 7130 (2015)). Application of reductive amination in a continuous-flow hydrogenation equipment for API production has been reported by Suveges, et al. (Eur. J. Org. Chem., Vol. 2017, No. 44, 6511 - 6517 (2017)) and Bana, et al. (React. Chem. Eng., Vol. 4, No. 4, 652 - 657 (2019)).
- This invention provides a process for the synthesis of cariprazine and other related 1- arylpiperazine active pharmaceutical ingredients, by the formation of the C-N bond using a consecutive reduction method conducted in continuous -flow reactors.
- the process consists of a selective ester reduction, followed by a reductive amination.
- the first step is conducted in an alternating diameter flow reactor, which provides higher conversions and better selectivity compared to a similar volume, constant diameter tubular flow reactor.
- hydrogenation using 5% Pt/C catalyst in toluene:methanol (5:1) solvent mixture provides a highly selective transformation.
- Figure 1 The schematic figure of the two-step consecutive continuous -flow system
- Figure 2 Schematic cross-section view of the alternating diameter reactor
- the present invention is based on a consecutive reduction method for the formation of the C-N bond, consisting of a selective ester reduction, followed by a reductive amination. Both steps are preferably conducted in continuous -flow reactors.
- alicyclic group denotes mono-, bi- or spirocyclic, saturated or unsaturated hydrocarbon groups comprising 3 to 10 carbon atoms, preferably monocyclic saturated hydrocarbon groups comprising 4 to 7 carbon atoms. Examples include cyclobutane, cyclopentane, or cyclohexane etc..
- hetero-bicyclic group denotes a bicyclic condensed, spiro or bridged saturated, unsaturated, or bicyclic aromatic ring cycle containing 1, 2, or 3 heteroatoms selected from O, S or N comprising 7 to 14 ring atoms.
- the hetero-bicyclic aromatic ring is a cyclic aromatic group comprising 9 to 11 ring atoms, containing a single 5- to 6-membered ring and contains 1 or 2 heteroatoms selected from O or N in which group at least one ring is aromatic.
- Examples include indoline, indole, indazole, azaindole, azaindazole, benzofuran, benzothiazole, tetrahydroquinoline, dihydroquinoline, (iso)quinoline, or (iso)chromene etc.
- substituted denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.
- substituent are -NHC(O)OR 4 , -NHC(O)NR a R b or oxo group, wherein R a and R b is each independently hydrogen, alkyl, akenyl, aryl, cycloalkyl, aroyl, or R a and R b form a heterocyclic ring with the adjacent nitrogen atom.
- substituted denotes that a specified group bears one or more substituents.
- any atom of the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents.
- substituents independently chosen from the group of possible substituents.
- one or more means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.
- One substituent on one given atom of the relevant group is preferred.
- step 2 the resulting aldehyde of general formula (XVII) is reacted with a piperazine derivative of general formula (III), wherein R 3 represents (hetero)aryl or phenyl groups, optionally substituted with one or two halogen atoms (such as chlorine) or trifluoromethyl groups.
- R 1 represents substituted alicyclic or hetero-bicyclic groups;
- R 3 represents (hetero)aryl or phenyl groups, optionally substituted with one or two halogen atoms or trifluoromethyl groups.
- step 1 the ester derivative of general formula (II) and the reducing agent (preferably DIBAL-H) are pumped by separate pumps (PI and P2, from injector loops), and the streams are mixed in a T-element before entering the reactor (Rl). Then, the reaction mixture arrives at another T-shaped mixer, where a toluene-methanol mixture is introduced form pump P3 for quenching the reaction in a separate reactor (R2).
- the reactors, both T-mixers and pre-cooling loops for each stream are submerged into a cooling bath.
- the reaction is conducted at low temperatures between -78°C and 0°C, preferably -40°C. Residence times in R1 are shorter than 60 seconds.
- Reactor R1 is an alternating diameter flow reactor for continuous-flow reactions, which comprises a means for fluid conveyance, a means for mixing a fluid inside the means for fluid conveyance and means for fitting at both ends of the means for fluid conveyance.
- any part of the alternating diameter flow reactor is made of a material suitable for continuous-flow reactions.
- the means for fluid conveyance is a tubular section or hollow cylinder, usually but not necessarily of circular cross-section allowing to convey substances which can flow, such as a pipe or a tube, having a length, a constant outside diameter and a constant internal diameter and a wall thickness.
- the length and the constant inside diameter of the means for fluid conveyance provides a sufficient volume for carrying out continuous-flow reaction in it.
- the fluid can be any liquid, preferably the liquid being in the form of a solution, such as a solution comprising any reagent or reaction mixture, for example a solution of compounds of formula (II).
- the means for mixing a fluid comprises at least two means for reducing the internal diameter of the means for fluid conveyance and at least one segment between the at least two means for reducing the internal diameter inside the means for fluid conveyance.
- the at least two means that allows for reducing the internal diameter inside the means for fluid conveyance such as a means or a pair of means facing each other that protrude out from the inner wall of the means for fluid conveyance or a means or a pair of means facing each other partially obstructing the flow of the fluid inside the means for fluid conveyance, to provide frequent cross-section changes resulting in the said at least one segment through the longitudinal axis of the means for fluid conveyance to such an extent that allows for the fluid to flow substantially laminar in its direction when passing through each location at which the at least two means for reducing the internal diameter is present, whilst providing turbulent flow characteristics to the fluid at each location of the at least one segment.
- the internal diameter at each location of the at least two means for reducing the internal diameter inside the means for fluid conveyance is preferably at most the half of the internal diameter of the means for fluid conveyance at each location of the at least one segment.
- the internal diameter at each location of the at least two means for reducing the internal diameter inside the means for fluid conveyance is thus reduced compared to that of the means for fluid conveyance without such means.
- the at least two means for reducing the internal diameter inside the means for fluid conveyance allowing for repeated reduced diameter of the means for fluid conveyance separated by the at least one segment has a sufficient length that provides a sufficient volume at the location of the at least one segment through the longitudinal axis of the means for fluid conveyance that allows for mixing a fluid inside that segment.
- Each change in the internal diameter of the means for fluid conveyance effectuated at each corresponding location by alternating the at least two means for reducing the internal diameter inside the means for fluid conveyance and the at least one segment contributes to the mixing of the fluid
- the means for fluid conveyance having a length that at least 10 times the length at which location one of the at least two means for reducing the internal diameter inside the means for fluid conveyance reduces the diameter inside the means for fluid conveyance that provides said sufficient volume for mixing.
- the means for fitting allows for connecting the alternating diameter reactor via the means for fluid conveyance to other parts of a flow system and provides fluid-tight fitting that prevents any leakages, such as such as an elbow, tee, a flexible element which may be formed or bent into custom configurations, or a further means for fluid conveyance having suitable outer diameter allowing for tightly fitting inside the corresponding end of the means for fluid conveyance.
- reactor R1 is an alternating diameter flow reactor that consists of repeating constrictions of shorter length inside a larger diameter tubing, separated by unconstricted sections.
- the internal diameter at the constrictions is smaller than the half of the internal diameter of the unconstricted sections.
- This miniature device is ideal for small scale experiments with residence times inside the sub-minute range. It can be constructed using commercially available microfluidic tubing, by tightly fitting pieces of suitable outer diameter tubing inside the larger diameter tubing ( Figure 2).
- this device causes low pressure drop, which is beneficial in complex continuous -flow systems.
- this device provides higher conversions and better selectivity compared to a similar volume constant diameter tubular flow reactor (Figure 3, reactor A) and a similar volume packed-bed flow reactor (Figure 3, reactor B), operated with comparable settings. This proves that the alternating diameter reactor ensures efficient mixing.
- the product of general formula (XVII) can either be collected or directed to the next step through a suitable connecting device (CD).
- a suitable connecting device CD
- This can be an in-line extraction device, or manual at-line extraction.
- Rochelle salt potassium sodium tartrate
- the crude mixture containing the product of general formula (XVII) can be transferred to step 2.
- step 2 the aldehyde of general formula (XVII) is transferred by a pump (P4) into a continuous-flow hydrogenation reactor (R3), where it is reacted with a piperazine derivative of general formula (III) under reductive amination conditions, using hydrogen gas and a heterogeneous catalyst.
- the piperazine derivative of general formula (III) can be preferably added to the quenching solution in step 1, which is transferred by P3, thus it is already present in the crude mixture before entering R3.
- the mixture containing the product of general formula (IV) is then collected in a vessel (CV), where excess hydrogen is degassed.
- the catalyst bed is heated to 30 - 100°C.
- the reactor is pressurized to 10 - 50 bar, to prevent vaporization of the solvent beyond its boiling point.
- an ester derivative of general formula (VI) and DIBAL-H are used in the continuous-flow step 1, wherein R 2 represents branched or straight chain alkyl groups comprising one to six carbon atoms; R 4 represents branched or straight chain alkyl groups comprising one to six carbon atoms, or benzyl group, or benzyl group substituted with alkyl, alkoxy or nitro groups as part of a carbamate protecting group.
- the piperazine derivative of formula (VII) is added in the continuous-flow step 2, to obtain protected derivatives of general formula (V), which are key intermediates of the antipsychotic drug cariprazine.
- an ester derivative of general formula (VIII) and DIBAL-H are used in the continuous-flow step 1, wherein R 2 represents branched or straight chain alkyl groups comprising one to six carbon atoms.
- the piperazine derivative of formula (VII) is added in the continuous-flow step 2, to obtain cariprazine of formula (I).
- the reactions proceed rapidly at the optimized conditions, however to the efficient mixing possible in flow reactors, especially in the alternating diameter flow reactor. Thus, this can be regarded as a more effective, “intensified” process.
- the reactions use minimal excess of reagents at the optimized conditions, and generate minimal amounts of by-products and impurities, which reduces waste and leads to high purity products.
- the reactions are conducted in the same solvent, and the crude solutions of each steps can be further processed in the next step with minimal work-up. This also contributes to waste minimali ation.
- the continuous-flow system has a small spatial footprint, and it is energetically economical, due to the small heated or cooled reactor volumes.
- the small reactor volumes also lead to enhanced safety.
- the continuous-flow devices are closed systems, which prevent environmental damage and exposure of the workers, as well as contamination of the product.
- the continuou -flow hydrogenation has additional safety benefits: the pressurized hydrogen and the catalyst are contained in a small sealed volume, consequently handling of the explosive gas and the pyrophoric catalyst are avoided.
- Solvents and chemicals were purchased from commercial vendors. Toluene is dried over 4 A molecular sieves for one day. DIBAL-H (1.0 M in toluene) and 2,3- dichlorophenylpiperazine were purchased from Sigma-Aldrich. Ethyl 2-(trans-A-((tert- butoxycarbonyl)amino)cyclohexyl)acetate is synthesized according to previously reported procedures. 5% Pt/C CatCart ® (30 mm) was purchased from ThalesNano (Budapest, Hungary). 1 H NMR spectra are measured on a Bruker Avance III HDX 400 MHz spectrometer equipped with 5 mm CryoProbe Prodigy; DMSO-d 6 is used as solvent.
- a larger diameter PTFE tube (1.6 mm i.d., 10 cm length each, Tube 1) is used.
- 10 identical pieces of PEEK tubes (0.5 mm i.d., 1.6 mm o.d., 5 mm length each, Tube 2) are placed inside Tube 1 at equal distances (5 mm) from each other, according to Figure 2.
- two different, alternating sections with different diameters are established in a reactor, 10 of each, giving a total volume of 111 ⁇ l.
- three of such units are connected by two tubes (PTFE tubing, 0.8 mm i.d, 7 cm length each), thus the net volume is 397.3 ⁇ l.
- a system is constructed, consisting of two Asia Syringe Pumps (P1 and P2; Syrris, Royston, United Kingdom) both having two separate flow channels, two of which are connected to two Asia Reagent Injectors (Syrris, Royston, United Kingdom, 5 ml (loop 1), 1 ml (loop 2), respectively), the third channel is used directly.
- the two channels of the injectors are connected to a T-adaptor (Diba Omnifit ® PTFE T-adaptor, 1.5 mm i.d), preceded by pre-cooling loops (0.5 ml), which is followed by an alternating diameter flow reactor (R1; 3 units of 10 cm long, 397.3 ⁇ l net volume).
- the output of the reactor and P3 are connected to a T-adaptor, followed by a second reactor (R2; PTFE tubing, 0.8 mm i.d., 1.6 mm o.d., 0.9 ml), after which the reaction mixture is collected.
- the system is washed with methanol, followed by toluene and finally anhydrous toluene.
- the reactors, pre-cooling loops and T-adaptors are cooled down to -40°C using a thermostated isopropanol bath. Washing with anhydrous toluene is upheld until steady temperature is reached. Other parts are kept at ambient temperature.
- Anhydrous toluene is transferred on both channels of the pumps with a flow rate of 1.25 ml/min (P1) and 187.5 ⁇ l/min (P2), respectively.
- Loop 1 is filled with the solution of the ester (IX; 0.05 M in anhydrous toluene; 0.25 mmol), while loop 2 is filled with the solution of DIBAL-H (1 M in anhydrous toluene; 0.75 mmol; 3 eq.).
- the flow rate of P3 is set at 1.25 ml/min, and the 2:1 mixture of toluene :MeOH is streamed on it.
- the reaction is controlled using the Asia Manager computer program, which is responsible for switching the injector valves at appropriate times.
- reaction mixture is collected in a flask containing saturated potassium sodium tartrate solution (10 ml). After collection, the system is washed with toluene, followed by methanol.
- the crude product is purified by column chromatography on silica gel (cyclohexane:EtOAc 4:1) to obtain pure trans-2-( 1 -(4-(N-tert- butoxycarbonyl)amino)cyclohexyl)acetaldehyde as white crystals.
- the spectroscopical data was consistent with the literature.
- the continuous-flow reactor system described in Example 2 is modified by substituting the reactor (Rl) with a constant diameter flow reactor (PTFE tubing, 0.8 mm i.d., 1.6 mm o.d., 0.02 - 0.2 ml), according to Figure 3, reactor A.
- reactor A The following parameters are systematically varied: temperature, reactor volume and residence time.
- the crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/( total area substrate area)) are given in Table 2.
- Comparative example 2 Using a packed -bed flow reactor filled with quartz particles in the continuous-flow selective ester reduction The continuous-flow reactor system described in Example 2 is modified by substituting the reactor (R1) with a packed-bed reactor filled with quartz particles (30x 4 mm i.d. CatCart ® , purchased from ThalesNano, Budapest, Hungary), according to Figure 3, reactor B. Approximate dead volume was determined as follows: total volume - volume of the particles. The following parameters are systematically varied: temperature, reactor volume and residence time. The crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/(total area - substrate area)) are given in Table 3. Pressure drop on the packed-bed was determined to be 3-5 bar in each case.
- Example 2 The continuous-flow reactor system described in Example 2 is modified by substituting the reactor (R1) with a packed-bed reactor filled with titanium particles (30x4 mm i.d. CatCart ® , purchased from ThalesNano, Budapest, Hungary), according to Figure 3, reactor B. Approximate dead volume was determined as follows: total volume - volume of the particles. The following parameters are systematically varied: temperature, reactor volume and residence time. The crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/(total area - substrate area)) are given in Table 4. Pressure drop on the packed-bed was determined to be 3-5 bar in each case.
- a 5% Pt/C CatCart ® (30 mm) is loaded into the H-Cube ® (R3; ThalesNano, Budapest, Hungary) continuous-flow hydrogenation reactor, and the system is washed with methanol, followed by a 5 : 1 mixture of toluene:MeOH. Reaction parameters are set to 80°C temperature, 0.5 ml/min flow rate and full 3 ⁇ 4 mode at ambient pressure. Washing with this mixture is upheld until steady state is reached.
- the crude product is purified by column chromatography on silica gel (EtOAc) to obtain pure trans-N-tert-butoxycarbonyl-4- ⁇ 2-[4-(2.3-dichlorophcnyl)-pipcrazin- 1 -yl]ethyl ⁇ - cyclohexylamine (XII) as white crystals.
- EtOAc silica gel
- Example 4 Using the continuous-flow hydrogenation reactor described in Example 4, the following parameters are systematically varied: temperature and catalyst.
- the cmde product is analyzed by LCMS. Conversion (product area/(product area + substrate area)), selectivity (product area/( total area - substrate area)) and amount of dehalogenated derivatives (sum of the area of mono-chlorinated and not chlorinated phenyl derivatives)/total area) are given in Table 5.
- Table 5 Reductive amination with different catalysts at various temperatures.
- Module 1 A system ( Figure 1) is constructed, consisting of two Asia Syringe Pumps (Syrris, Royston, United Kingdom) both having two separate flow channels, three of which are connected to two Asia Reagent Injectors (Syrris, Royston, United Kingdom, 5 ml (loop 1), 1 ml (loop 2) and 5 ml (loop 3) volume, respectively).
- the first two channels of the injectors are connected to a T-adaptor (Diba Omnifit ® PTFE T-adaptor, 1.5 mm i.d.), preceded by pre cooling loops (0.5 ml), which is followed by an alternating diameter flow reactor (R1; 3 units of 10 cm long, 397.3 m ⁇ net volume).
- the output of the reactor and the third channel are connected to a T-adaptor, followed by a second reactor (R2; PTFE tubing, 0.8 mm i.d., 1.6 mm o.d., 0.9 ml), after which the reaction mixture is collected.
- the system is washed with methanol, followed by toluene and finally anhydrous toluene.
- the reactors, pre-cooling loops and T-adaptors are cooled down to -40°C using a thermostated isopropanol bath. Washing with anhydrous toluene is upheld until steady temperature is reached. Other parts are kept at ambient temperature.
- Module 2 A 5% Pt/C CatCart ® (30 mm) is loaded into the H-Cube ® (R3; ThalesNano, Budapest, Hungary) continuous-flow hydrogenation reactor, and the system is washed with methanol, followed by a 5:1 mixture of toluene:MeOH. Reaction parameters are set to 80°C temperature, 0.5 ml/min flow rate and full H 2 mode at ambient pressure. Washing with this mixture is upheld until steady state is reached. In Module 1 anhydrous toluene is transferred on the first two channels with a flow rate of 1.25 ml/min (P1) and 187.5 m ⁇ /min (P2), respectively.
- Loop 1 is filled with the solution of the ester (IX; 0.05 M in anhydrous toluene; 0.25 mmol)
- loop 2 is filled with the solution of DIBAL-H (1 M in anhydrous toluene; 0.75 mmol; 3 eq.)
- Loop 3 is filled with the solution of the piperazine derivative (VII; 0.05 M in toluene: MeOH 2:1; 0.25 mmol; 1 eq.) and the respective pump is transferring the 2:1 mixture of toluene:MeOH at 1.25 ml/min (P3).
- the reaction is controlled using the Asia Manager computer program, which is responsible for switching the injector valves at appropriate times. The dead volume is discarded to the waste, until the reaction mixture appeared at the output of Module 1. Then, the reaction mixture is collected in a separatory funnel containing saturated potassium sodium tartrate solution (10 ml). The phases are shaken and carefully separated. The organic phase is extracted with further portions of saturated potassium sodium tartrate solution (2x10
- the organic phase is directed into Module 2, where the solution is transferred by an AZURA ® P4.1S (P4; KNAUER, Berlin, Germany) HPLC pump at a flow rate (2.7 ml/min), matching that of the exiting stream from Module 1.
- the dead volume is discarded to the waste, until the reaction mixture appeared at the output.
- the product mixture is collected into a vessel (CV), until the starting solution is consumed.
- the system is shut-down and washed with methanol.
- the crude product is purified by column chromatography on silica gel (EtOAc) to obtain pure trans-N-tert-butoxycarbonyl-4- ⁇ 2-[4-(2.3-dichlorophcnyl)-pipcrazin- 1 -yl]ethyl ⁇ - cyclohexylamine (XII) as white crystals (49% yield).
- EtOAc silica gel
- the crude product is recrystallized from acetonitrile (15 V/m), the product is given with 51% yield.
- the spectroscopical data was consistent with the literature.
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Abstract
The present invention relates to a novel alternating diameter flow reactor for continuous - flow reactions, a system for continuous-flow reactions (as shown in Figure 1) comprising said alternating diameter flow reactor, a method for the formation of the C-N bond carried out in said system and a process for the preparation of the antipsychotic drug cariprazine described by the chemical structure (I) and its intermediates, and as well as other related 1-arylpiperazine active pharmaceutical ingredients conducted in two continuous-flow reactors of said system comprising the consecutive steps of a first step being selective ester reduction carried out in said alternating diameter flow reactor and a second step being reductive amination carried out by continuous-flow catalytic hydrogenation.
Description
PROCESS FOR CONSECUTIVE CONTINUOUS-FLOW REDUCTIONS IN THE SYNTHESIS OF MEDICINALLY RELEVANT PIPERAZINE DERIVATIVES USING A TUBULAR REACTOR WITH ALTERNATING DIAMETER
Field of the invention
The present invention relates to a novel alternating diameter flow reactor for continuous- flow reactions, a system for continuous-flow reactions comprising said alternating diameter flow reactor, a method for the formation of the C-N bond carried out in said system and a process for the preparation of the antipsychotic drug cariprazine described by the chemical stmcture (I) and its intermediates, and as well as other related 1 -arylpiperazine active pharmaceutical ingredients conducted in two continuous-flow reactors of said system comprising the consecutive steps of a first step being selective ester reduction carried out in said alternating diameter flow reactor and a second step being reductive amination carried out by continuous-flow catalytic hydrogenation.
Background of the invention
Cariprazine (3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-l -yl)ethyl)cyclohexyl)- 1,1-dimethylurea) of formula (I) is an active pharmaceutical ingredient (API) used for the treatment of schizophrenia and bipolar I disorder. This API belongs to the broader class of 1- arylpiperazines, which display affinities to aminergic receptors of the central nervous system, making them useful therapies in neuropsychiatric disorders.
Known approaches to the key C-N bond formation in the synthesis of cariprazine
Formation of the C-N bond between the piperazine moiety and the cyclohexylethyl linker is the key step of the synthesis of cariprazine of formula (I). There are different notable sequences of chemical steps for realizing this transformation.
The first approach detailed in patent application no. WO 2010/070369 A1 describes the reduction of the ester type intermediate of formula (IX) to the corresponding alcohol of formula (X) using sodium borohydride and aluminium chloride, which in turn is transformed to its methanesulfonyl ester of formula (XI).
Next, the intermediate of formula (XI) is used in the -alkylation of the piperazine derivative of formula (VII) to provide the desired product of formula (XII), which can be converted to cariprazine of formula (I), via subsequent deprotection and acylation. The drawback of this procedure is that it requires multiple steps (i.e. activation as methanesulfonyl ester) and stochiometric amounts of bases (i.e. TEA and K2CO3).
Alternatively, as described in patent application no. WO 2005/012266 A1 and by Shonberg, et al. ( J . Med. Chem., Vol. 56, No. 22, 9199-9221 (2013)), the ester intermediate of formula (IX) is reduced to an aldehyde of formula (XIII), by utilizing diisobutylaluminum hydride (DIBAL-H) in toluene at cryogenic temperatures. This intermediate is reacted with the piperazine derivative of formula (VII), using NaBH(OAc)3 to give the product of formula (XII). The drawback of this route is that the reduction must be carried out at a temperature below -70°C, and the aldehyde is produced with moderate yield. Also, the hazardous DIBAL-H poses technological problems, when handled in traditional batch reactors.
Another method is described in patent application no. WO 2015/056164 Al, which utilizes the alcohol of formula (X). Its reaction with the piperazine derivative of formula (VII) is conducted in the presence of Ru3(CO)12 and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) in boiling toluene, to yield the alkylated product of formula
(XII). Although this method provides a shorter route, the high price of the precious metal catalyst and the phosphine ligand makes this method unfavorable at large scale.
Amide formation is also suitable for the key C-N bond formation, according to patent application no. WO 2018/007986 Al. A carboxylic acid of formula (XIV) is coupled with the piperazine derivative of formula (VII), via various methods to give the amide of formula (XV). Reaction with in situ formed borane gives the borane adduct of formula (XVI), which can be decomposed thermally or under acidic conditions to give cariprazine of formula (I). The multiple steps of these process are not ideal for continuous-flow realization.
Our aim was to provide a scalable continuous-flow process for the preparation of the key intermediate of formula (XII) utilizing the aldehyde of formula (XIII) under safer and more efficient reaction conditions.
Continuous-flow methods in the production of active pharmaceutical ingredients The utilization of continuous technologies in the production of APIs has become possible since the beginning of the 2010’s, as the technological progress and miniaturization of continuous-flow reactors and related tools (often referred to as microreactor technology) enabled the execution of organic chemical reactions (flow chemistry) in these devices, in a safe and efficient manner. The most advanced implementations of flow chemistry are modular continuous-flow reactor systems, in which coupling two or more chemical steps can be accomplished with minimal intermediate work-up. These systems contribute to the overall safety of the process (by reduction of the exposure of workers, and environmental hazards), and minimalization of waste. The continuous nature of the process ensures a stable product quality and prevents drug shortages. The comprehensive summary of this field is given in the reviews
by Gutmann, et al. (Angew. Chem. Int. Ed. Engl., Vol. 54, No. 23, 6688 - 6728 (2015)) and Gerardy, et al. (Eur J. Org. Chem., Vol. 2018, No. 20-21, 2301 - 2351 (2018)).
Reductions in continuous -flow reactors
Continuous-flow reactors are useful tools for performing reductions, recent achievements in this field are summarized by Riley and Neyt ( Synthesis , Vol. 50, No. 14, 2707 - 2720 (2018)).
In the continuous-flow synthesis of aldehydes from esters, the use of DIBAL-H has been widely reported by Ducry and Roberge ( Org . Process Res. Dev., Vol. 12, No. 2, 163 - 167 (2008)), Webb and Jamison (Org. Lett., Vol. 14, No. 2, 568 - 571 (2012)), Yoshida, et al. ( Eur . J. Org. Chem., Vol. 2014, No. 27, 6010 - 6016 (2014)) and Fukuyama, et al. (Org. Process Res. Dev., Vol. 20, No. 2, 503 - 509 (2016)). Other related reducing agents were also used, such as diisobutyI - ter t-buIoxyaIuminum hydride (LDBBA), as described by Munoz, et al. (Eur. J. Org. Chem., Vol. 2012, No. 2, 260 - 263 (2012)). Notably, when handling hazardous hydride based reducing agents, continuous-flow processing has several advantages in terms of safety, compared to convetional batch processing. Efficient mixing was crucial in all of these flow procedures. This is usually achieved by using high flow rates (which is difficult to match in downstream units) or introducing special mixing elements (which lead to high pressure drop). Neither of these approaches is suitable for multi-step continuous-flow processing, which is evidenced by the lack of multi-step flow systems involving reduction by DIBAL-H and related reagents.
Reductive aminations also proved their utility in flow chemistry, especially when catalytic hydrogenation is used, which is well-suited to continuous transformations, since it is typically free from side-products and the removal of excess hydrogen is fairly simple. These methods were reviewed by Cossar, et al. (Org. Biomol. Chem., Vol. 13, No. 26. 7119 - 7130 (2015)). Application of reductive amination in a continuous-flow hydrogenation equipment for API production has been reported by Suveges, et al. (Eur. J. Org. Chem., Vol. 2017, No. 44, 6511 - 6517 (2017)) and Bana, et al. (React. Chem. Eng., Vol. 4, No. 4, 652 - 657 (2019)).
Although both ester reduction and reductive aminations have been successfully employed under continuous-flow conditions, these two transformations have not been used in a consecutive continuous-flow reaction sequence before. This kind of operation would help
exploit the advantages of continuous processing in the C-N bond formation towards the preparation of medicinally relevant piperazine derivatives .
Brief description of the invention
This invention provides a process for the synthesis of cariprazine and other related 1- arylpiperazine active pharmaceutical ingredients, by the formation of the C-N bond using a consecutive reduction method conducted in continuous -flow reactors. The process consists of a selective ester reduction, followed by a reductive amination.
The first step is conducted in an alternating diameter flow reactor, which provides higher conversions and better selectivity compared to a similar volume, constant diameter tubular flow reactor. In the second step, hydrogenation using 5% Pt/C catalyst in toluene:methanol (5:1) solvent mixture provides a highly selective transformation.
Brief description of the figures
Figure 1: The schematic figure of the two-step consecutive continuous -flow system
Figure 2: Schematic cross-section view of the alternating diameter reactor
Figure 3. Continuous-flow setup for conducting step 1 using a constant diameter tubular flow reactor (reactor A) or packed-bed flow reactor (reactor B)
Detailed description of the invention
The present invention is based on a consecutive reduction method for the formation of the C-N bond, consisting of a selective ester reduction, followed by a reductive amination. Both steps are preferably conducted in continuous -flow reactors.
In step 1, an ester derivative of general formula (II) is selectively reduced to an aldehyde of general formula (XVII), wherein n = 0 or 1, L represents a -(CH2)m - linker, in which m = 1,
2, or 3; R1 represents substituted alicyclic or hetero-bicyclic groups; R2 represents branched or straight chain alkyl groups comprising one to six carbon atoms.
The term “alicyclic group” denotes mono-, bi- or spirocyclic, saturated or unsaturated hydrocarbon groups comprising 3 to 10 carbon atoms, preferably monocyclic saturated hydrocarbon groups comprising 4 to 7 carbon atoms. Examples include cyclobutane, cyclopentane, or cyclohexane etc..
The term “hetero-bicyclic group” denotes a bicyclic condensed, spiro or bridged saturated, unsaturated, or bicyclic aromatic ring cycle containing 1, 2, or 3 heteroatoms selected from O, S or N comprising 7 to 14 ring atoms. Preferably the hetero-bicyclic aromatic ring is a cyclic aromatic group comprising 9 to 11 ring atoms, containing a single 5- to 6-membered ring and contains 1 or 2 heteroatoms selected from O or N in which group at least one ring is aromatic. Examples include indoline, indole, indazole, azaindole, azaindazole, benzofuran, benzothiazole, tetrahydroquinoline, dihydroquinoline, (iso)quinoline, or (iso)chromene etc.
The term “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. Examples of substituent are -NHC(O)OR4, -NHC(O)NRaRb or oxo group, wherein Ra and Rb is each independently hydrogen, alkyl, akenyl, aryl, cycloalkyl, aroyl, or Ra and Rb form a heterocyclic ring with the adjacent nitrogen atom.
The term “substituted” denotes that a specified group bears one or more substituents.
Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same.
The term “unsubstituted” means that the specified group bears no substituents.
The term “optionally substituted” means that any atom of the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. One substituent on one given atom of the relevant group is preferred.
In step 2, the resulting aldehyde of general formula (XVII) is reacted with a piperazine derivative of general formula (III), wherein R3 represents (hetero)aryl or phenyl groups, optionally substituted with one or two halogen atoms (such as chlorine) or trifluoromethyl groups. Reductive amination conditions are applied, leading to formation of the product of general formula (IV), wherein n = 0 or 1, L represents a -(CH2)m- linker, in which in = 1. 2, or 3; R1 represents substituted alicyclic or hetero-bicyclic groups; R3 represents (hetero)aryl or phenyl groups, optionally substituted with one or two halogen atoms or trifluoromethyl groups.
Both steps are conducted in a way that is implemented in continuous -flow reactors, and they exploit several advantages of the flow methodology. Furthermore, using these steps, a consecutive continuous-flow system (Figure 1) can be constructed, in which the crude product solution of the first step can be utilized in the second step after a simple in-line or at-line work up.
Description of the continuous-flow steps
Step 1
In step 1, the ester derivative of general formula (II) and the reducing agent (preferably DIBAL-H) are pumped by separate pumps (PI and P2, from injector loops), and the streams are mixed in a T-element before entering the reactor (Rl). Then, the reaction mixture arrives at another T-shaped mixer, where a toluene-methanol mixture is introduced form pump P3 for quenching the reaction in a separate reactor (R2). The reactors, both T-mixers and pre-cooling loops for each stream are submerged into a cooling bath.
The reaction is conducted at low temperatures between -78°C and 0°C, preferably -40°C. Residence times in R1 are shorter than 60 seconds.
Reactor R1 is an alternating diameter flow reactor for continuous-flow reactions, which comprises a means for fluid conveyance, a means for mixing a fluid inside the means for fluid conveyance and means for fitting at both ends of the means for fluid conveyance.
Any part of the alternating diameter flow reactor is made of a material suitable for continuous-flow reactions.
The means for fluid conveyance is a tubular section or hollow cylinder, usually but not necessarily of circular cross-section allowing to convey substances which can flow, such as a pipe or a tube, having a length, a constant outside diameter and a constant internal diameter and
a wall thickness. The length and the constant inside diameter of the means for fluid conveyance provides a sufficient volume for carrying out continuous-flow reaction in it.
The fluid can be any liquid, preferably the liquid being in the form of a solution, such as a solution comprising any reagent or reaction mixture, for example a solution of compounds of formula (II).
The means for mixing a fluid comprises at least two means for reducing the internal diameter of the means for fluid conveyance and at least one segment between the at least two means for reducing the internal diameter inside the means for fluid conveyance.
The at least two means that allows for reducing the internal diameter inside the means for fluid conveyance, such as a means or a pair of means facing each other that protrude out from the inner wall of the means for fluid conveyance or a means or a pair of means facing each other partially obstructing the flow of the fluid inside the means for fluid conveyance, to provide frequent cross-section changes resulting in the said at least one segment through the longitudinal axis of the means for fluid conveyance to such an extent that allows for the fluid to flow substantially laminar in its direction when passing through each location at which the at least two means for reducing the internal diameter is present, whilst providing turbulent flow characteristics to the fluid at each location of the at least one segment.
The internal diameter at each location of the at least two means for reducing the internal diameter inside the means for fluid conveyance is preferably at most the half of the internal diameter of the means for fluid conveyance at each location of the at least one segment.
The internal diameter at each location of the at least two means for reducing the internal diameter inside the means for fluid conveyance is thus reduced compared to that of the means for fluid conveyance without such means. The at least two means for reducing the internal diameter inside the means for fluid conveyance allowing for repeated reduced diameter of the means for fluid conveyance separated by the at least one segment has a sufficient length that provides a sufficient volume at the location of the at least one segment through the longitudinal axis of the means for fluid conveyance that allows for mixing a fluid inside that segment. Each change in the internal diameter of the means for fluid conveyance effectuated at each corresponding location by alternating the at least two means for reducing the internal diameter inside the means for fluid conveyance and the at least one segment contributes to the mixing of the fluid
The means for fluid conveyance having a length that at least 10 times the length at which location one of the at least two means for reducing the internal diameter inside the means for fluid conveyance reduces the diameter inside the means for fluid conveyance that provides said sufficient volume for mixing.
The means for fitting allows for connecting the alternating diameter reactor via the means for fluid conveyance to other parts of a flow system and provides fluid-tight fitting that prevents any leakages, such as such as an elbow, tee, a flexible element which may be formed or bent into custom configurations, or a further means for fluid conveyance having suitable outer diameter allowing for tightly fitting inside the corresponding end of the means for fluid conveyance.
In an embodiment of the invention, reactor R1 is an alternating diameter flow reactor that consists of repeating constrictions of shorter length inside a larger diameter tubing, separated by unconstricted sections. The internal diameter at the constrictions is smaller than the half of the internal diameter of the unconstricted sections. Owing to the frequent cross- section change, segments with turbulent flow characteristics appear, behaving like a series of mixing elements in the entire length of the reactor. This miniature device is ideal for small scale experiments with residence times inside the sub-minute range. It can be constructed using commercially available microfluidic tubing, by tightly fitting pieces of suitable outer diameter tubing inside the larger diameter tubing (Figure 2).
Surprisingly, this device causes low pressure drop, which is beneficial in complex continuous -flow systems. We have found that this device provides higher conversions and better selectivity compared to a similar volume constant diameter tubular flow reactor (Figure 3, reactor A) and a similar volume packed-bed flow reactor (Figure 3, reactor B), operated with comparable settings. This proves that the alternating diameter reactor ensures efficient mixing.
Using short residence times, the product of general formula (XVII) is formed with high conversion and selectivity. Surprisingly, we have found that lower residence times lead to higher conversion.
The product of general formula (XVII) can either be collected or directed to the next step through a suitable connecting device (CD). This can be an in-line extraction device, or manual at-line extraction. We have found that extraction of the crude mixture by saturated solution of Rochelle salt (potassium sodium tartrate) effectively removes the aluminum salts
from the crude solution. After extraction, the crude mixture containing the product of general formula (XVII) can be transferred to step 2.
Step2
In step 2, the aldehyde of general formula (XVII) is transferred by a pump (P4) into a continuous-flow hydrogenation reactor (R3), where it is reacted with a piperazine derivative of general formula (III) under reductive amination conditions, using hydrogen gas and a heterogeneous catalyst. For ease of operation, the piperazine derivative of general formula (III) can be preferably added to the quenching solution in step 1, which is transferred by P3, thus it is already present in the crude mixture before entering R3. The mixture containing the product of general formula (IV) is then collected in a vessel (CV), where excess hydrogen is degassed.
The catalyst bed is heated to 30 - 100°C. Optionally, the reactor is pressurized to 10 - 50 bar, to prevent vaporization of the solvent beyond its boiling point.
In case of the reductive amination between an aldehyde of general formula (XVII) and the piperazine derivative of formula (VII), dehydrohalogenation of the aromatic ring is the main liability, leading to impurities in the crude product, and troublesome purification. Surprisingly, we have found that using an apolar solvent, such as toluene, or a solvent mixture of toluene: methanol (5:1) can suppress the formation of dehydrohalogenated product, when the commonly used 10% Pd/C catalyst is applied to the reaction. Unexpectedly, when using solvent mixture of toluene methanol (5:1) together with 5% Pt/C catalyst the reaction is highly selective. No dehydrohalogenated products were observed in this latter case.
Synthesis of cariprazine and its intermediates using the consecutive continuous-flow reduction
In a specific embodiment of the invention, an ester derivative of general formula (VI) and DIBAL-H are used in the continuous-flow step 1, wherein R2 represents branched or straight chain alkyl groups comprising one to six carbon atoms; R4 represents branched or straight chain alkyl groups comprising one to six carbon atoms, or benzyl group, or benzyl group substituted with alkyl, alkoxy or nitro groups as part of a carbamate protecting group. The piperazine derivative of formula (VII) is added in the continuous-flow step 2, to obtain protected derivatives of general formula (V), which are key intermediates of the antipsychotic drug cariprazine.
In another specific embodiment of the invention, an ester derivative of general formula (VIII) and DIBAL-H are used in the continuous-flow step 1, wherein R2 represents branched or straight chain alkyl groups comprising one to six carbon atoms. The piperazine derivative of formula (VII) is added in the continuous-flow step 2, to obtain cariprazine of formula (I).
Advantages of conducting the process in continuous-flow reactors
The continuous-flow realization of the process of the present invention has multiple advantages, which are summarized in the following.
The reactions proceed rapidly at the optimized conditions, thankfully to the efficient mixing possible in flow reactors, especially in the alternating diameter flow reactor. Thus, this can be regarded as a more effective, “intensified” process. The reactions use minimal excess of reagents at the optimized conditions, and generate minimal amounts of by-products and impurities, which reduces waste and leads to high purity products. The reactions are conducted in the same solvent, and the crude solutions of each steps can be further processed in the next step with minimal work-up. This also contributes to waste minimali ation.
The continuous-flow system has a small spatial footprint, and it is energetically economical, due to the small heated or cooled reactor volumes. The small reactor volumes also lead to enhanced safety. The continuous-flow devices are closed systems, which prevent environmental damage and exposure of the workers, as well as contamination of the product. The continuou -flow hydrogenation has additional safety benefits: the pressurized hydrogen
and the catalyst are contained in a small sealed volume, consequently handling of the explosive gas and the pyrophoric catalyst are avoided.
Better product quality can be obtained, as the continuous-flow system warrants higher level of control over reaction parameters such as reaction temperature, residence time and stoichiometry compared to batch processes. The continuous production warrants a steady, uniformly high quality of the product, and also helps preventing drug shortages. The process has the potential for industrial production, due to facile scale-up using known strategies, such as longer operating time, numbering-up, and enlargement of the flow channels.
Examples
Solvents and chemicals were purchased from commercial vendors. Toluene is dried over 4 A molecular sieves for one day. DIBAL-H (1.0 M in toluene) and 2,3- dichlorophenylpiperazine were purchased from Sigma-Aldrich. Ethyl 2-(trans-A-((tert- butoxycarbonyl)amino)cyclohexyl)acetate is synthesized according to previously reported procedures. 5% Pt/C CatCart® (30 mm) was purchased from ThalesNano (Budapest, Hungary). 1 H NMR spectra are measured on a Bruker Avance III HDX 400 MHz spectrometer equipped with 5 mm CryoProbe Prodigy; DMSO-d6 is used as solvent.
Example 1: Construction of the alternating diameter reactor
For a single reactor, a larger diameter PTFE tube (1.6 mm i.d., 10 cm length each, Tube 1) is used. 10 identical pieces of PEEK tubes (0.5 mm i.d., 1.6 mm o.d., 5 mm length each, Tube 2) are placed inside Tube 1 at equal distances (5 mm) from each other, according to Figure 2. Hence, two different, alternating sections with different diameters are established in a reactor, 10 of each, giving a total volume of 111 μl. In a larger volume reactor, three of such units are connected by two tubes (PTFE tubing, 0.8 mm i.d, 7 cm length each), thus the net volume is 397.3 μl.
Example 2:
Synthesis of trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde by continuous-flow selective ester reduction
A system is constructed, consisting of two Asia Syringe Pumps (P1 and P2; Syrris, Royston, United Kingdom) both having two separate flow channels, two of which are connected to two Asia Reagent Injectors (Syrris, Royston, United Kingdom, 5 ml (loop 1), 1 ml (loop 2), respectively), the third channel is used directly. The two channels of the injectors are connected to a T-adaptor (Diba Omnifit® PTFE T-adaptor, 1.5 mm i.d), preceded by pre-cooling loops (0.5 ml), which is followed by an alternating diameter flow reactor (R1; 3 units of 10 cm long, 397.3 μl net volume). The output of the reactor and P3 are connected to a T-adaptor, followed by a second reactor (R2; PTFE tubing, 0.8 mm i.d., 1.6 mm o.d., 0.9 ml), after which the reaction mixture is collected.
The system is washed with methanol, followed by toluene and finally anhydrous toluene. The reactors, pre-cooling loops and T-adaptors are cooled down to -40°C using a thermostated isopropanol bath. Washing with anhydrous toluene is upheld until steady temperature is reached. Other parts are kept at ambient temperature.
Anhydrous toluene is transferred on both channels of the pumps with a flow rate of 1.25 ml/min (P1) and 187.5 μl/min (P2), respectively. Loop 1 is filled with the solution of the ester (IX; 0.05 M in anhydrous toluene; 0.25 mmol), while loop 2 is filled with the solution of DIBAL-H (1 M in anhydrous toluene; 0.75 mmol; 3 eq.). The flow rate of P3 is set at 1.25 ml/min, and the 2:1 mixture of toluene :MeOH is streamed on it. The reaction is controlled using the Asia Manager computer program, which is responsible for switching the injector valves at appropriate times. The dead volume is discarded to the waste, until the reaction mixture appears at the output. Then, the reaction mixture is collected in a flask containing saturated potassium sodium tartrate solution (10 ml). After collection, the system is washed with toluene, followed by methanol.
The crude product is purified by column chromatography on silica gel (cyclohexane:EtOAc 4:1) to obtain pure trans-2-( 1 -(4-(N-tert- butoxycarbonyl)amino)cyclohexyl)acetaldehyde as white crystals. The spectroscopical data was consistent with the literature.
1 HNMR (400 MHz, DMSO) d 0.91 - 1.05 (m, 2H), 1.08 —1.22 (m, 2H), 1.37 (s, 9H), 1.61 - 1.81 (m, 5H), 2.28 (dd, J = 6.5, 1.9 Hz, 2H), 3.05 - 3.21 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 9.64 (t, J= 2.0 Hz, 1H).
Example 3:
Effect of reaction parameters in the continuous-flow selective ester reduction
Using the continuous -flow reactor system described in Example 2, the following parameters are systematically varied: equivalents of DIBAL-H, reactor volume and residence time. The crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/(total area - substrate area)) are given in Table 1. Pressure drop on this reactor was negligible in each case.
Table 1. Reduction using DIBAL-H in the alternating diameter reactor.
Comparative example 1:
Using a constant diameter tubular flow reactor in the continuous-flow selective ester reduction
The continuous-flow reactor system described in Example 2 is modified by substituting the reactor (Rl) with a constant diameter flow reactor (PTFE tubing, 0.8 mm i.d., 1.6 mm o.d., 0.02 - 0.2 ml), according to Figure 3, reactor A. The following parameters are systematically varied: temperature, reactor volume and residence time. The crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/( total area substrate area)) are given in Table 2.
Comparative example 2: Using a packed -bed flow reactor filled with quartz particles in the continuous-flow selective ester reduction
The continuous-flow reactor system described in Example 2 is modified by substituting the reactor (R1) with a packed-bed reactor filled with quartz particles (30x 4 mm i.d. CatCart®, purchased from ThalesNano, Budapest, Hungary), according to Figure 3, reactor B. Approximate dead volume was determined as follows: total volume - volume of the particles. The following parameters are systematically varied: temperature, reactor volume and residence time. The crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/(total area - substrate area)) are given in Table 3. Pressure drop on the packed-bed was determined to be 3-5 bar in each case.
Comparative example 3:
Using a packed-bed flow reactor filled with titanium particles in the continuous-flow selective ester reduction
The continuous-flow reactor system described in Example 2 is modified by substituting the reactor (R1) with a packed-bed reactor filled with titanium particles (30x4 mm i.d. CatCart®, purchased from ThalesNano, Budapest, Hungary), according to Figure 3, reactor B. Approximate dead volume was determined as follows: total volume - volume of the particles. The following parameters are systematically varied: temperature, reactor volume and residence time. The crude product is analyzed by GCMS. Conversion (product area/(product area + substrate area)) and selectivity (product area/(total area - substrate area)) are given in Table 4. Pressure drop on the packed-bed was determined to be 3-5 bar in each case.
Synthesis of trans-N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazin-l- yl]ethyl}-cyclohexylamine by continuous-flow reductive amination
A 5% Pt/C CatCart® (30 mm) is loaded into the H-Cube® (R3; ThalesNano, Budapest, Hungary) continuous-flow hydrogenation reactor, and the system is washed with methanol, followed by a 5 : 1 mixture of toluene:MeOH. Reaction parameters are set to 80°C temperature, 0.5 ml/min flow rate and full ¾ mode at ambient pressure. Washing with this mixture is upheld until steady state is reached.
The solution of 24.1 mg (0.1 mmol) of the aldehyde (XIII) and 23.1 mg (0.1 mmol) of the piperazine derivative (VII) in 2 ml of 5:1 mixture of toluene:MeOH is transferred by an AZURA® P4.1S (KNAUER, Berlin, Germany) HPLC pump (P4) at 0.5 ml/min flow rate into the reactor. The dead volume is discarded to the waste, until the reaction mixture appeared at the output. Then, the product mixture is collected, until the starting solution is consumed. The system is shut-down and washed with methanol.
The crude product is purified by column chromatography on silica gel (EtOAc) to obtain pure trans-N-tert-butoxycarbonyl-4-{ 2-[4-(2.3-dichlorophcnyl)-pipcrazin- 1 -yl]ethyl }- cyclohexylamine (XII) as white crystals. The spectroscopical data was consistent with the literature.
1H NMR (400 MHz, DMSO) δ 0.86 - 0.99 (m, 2H), 1.05 - 1.17 (m, 2H), 1.22 - 1.26 (m, 1H), 1.30 - 1.35 (m, 2H), 1.37 (s, 9H), 1.67 - 1.79 (m, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.49 - 2.51 (m, 4H), 2.92 - 3.02 (m, 4H), 3.09 - 3.21 (m, 1H), 6.66 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 6.3, 3.2 Hz, 1H), 7.27 - 7.32 (m, 2H).
Example 5:
Effect of reaction parameters in the continuous-flow reductive amination
Using the continuous-flow hydrogenation reactor described in Example 4, the following parameters are systematically varied: temperature and catalyst. The cmde product is analyzed by LCMS. Conversion (product area/(product area + substrate area)), selectivity (product area/( total area - substrate area)) and amount of dehalogenated derivatives (sum of the area of mono-chlorinated and not chlorinated phenyl derivatives)/total area) are given in Table 5.
Table 5. Reductive amination with different catalysts at various temperatures.
Example 6:
Synthesis of trans-N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazin-l- yl]ethyl}-cyclohexylamine by continuous-flow consecutive reductions
Module 1: A system (Figure 1) is constructed, consisting of two Asia Syringe Pumps (Syrris, Royston, United Kingdom) both having two separate flow channels, three of which are connected to two Asia Reagent Injectors (Syrris, Royston, United Kingdom, 5 ml (loop 1), 1 ml (loop 2) and 5 ml (loop 3) volume, respectively). The first two channels of the injectors are connected to a T-adaptor (Diba Omnifit® PTFE T-adaptor, 1.5 mm i.d.), preceded by pre cooling loops (0.5 ml), which is followed by an alternating diameter flow reactor (R1; 3 units of 10 cm long, 397.3 mΐ net volume). The output of the reactor and the third channel are connected to a T-adaptor, followed by a second reactor (R2; PTFE tubing, 0.8 mm i.d., 1.6 mm o.d., 0.9 ml), after which the reaction mixture is collected. The system is washed with methanol, followed by toluene and finally anhydrous toluene. The reactors, pre-cooling loops and T-adaptors are cooled down to -40°C using a thermostated isopropanol bath. Washing with anhydrous toluene is upheld until steady temperature is reached. Other parts are kept at ambient temperature.
Module 2: A 5% Pt/C CatCart® (30 mm) is loaded into the H-Cube® (R3; ThalesNano, Budapest, Hungary) continuous-flow hydrogenation reactor, and the system is washed with methanol, followed by a 5:1 mixture of toluene:MeOH. Reaction parameters are set to 80°C temperature, 0.5 ml/min flow rate and full H2 mode at ambient pressure. Washing with this mixture is upheld until steady state is reached.
In Module 1 anhydrous toluene is transferred on the first two channels with a flow rate of 1.25 ml/min (P1) and 187.5 mΐ/min (P2), respectively. Loop 1 is filled with the solution of the ester (IX; 0.05 M in anhydrous toluene; 0.25 mmol), loop 2 is filled with the solution of DIBAL-H (1 M in anhydrous toluene; 0.75 mmol; 3 eq.). Loop 3 is filled with the solution of the piperazine derivative (VII; 0.05 M in toluene: MeOH 2:1; 0.25 mmol; 1 eq.) and the respective pump is transferring the 2:1 mixture of toluene:MeOH at 1.25 ml/min (P3). The reaction is controlled using the Asia Manager computer program, which is responsible for switching the injector valves at appropriate times. The dead volume is discarded to the waste, until the reaction mixture appeared at the output of Module 1. Then, the reaction mixture is collected in a separatory funnel containing saturated potassium sodium tartrate solution (10 ml). The phases are shaken and carefully separated. The organic phase is extracted with further portions of saturated potassium sodium tartrate solution (2x10 ml).
The organic phase is directed into Module 2, where the solution is transferred by an AZURA® P4.1S (P4; KNAUER, Berlin, Germany) HPLC pump at a flow rate (2.7 ml/min), matching that of the exiting stream from Module 1. The dead volume is discarded to the waste, until the reaction mixture appeared at the output. Then, the product mixture is collected into a vessel (CV), until the starting solution is consumed. The system is shut-down and washed with methanol.
The crude product is purified by column chromatography on silica gel (EtOAc) to obtain pure trans-N-tert-butoxycarbonyl-4-{ 2-[4-(2.3-dichlorophcnyl)-pipcrazin- 1 -yl]ethyl }- cyclohexylamine (XII) as white crystals (49% yield). Alternatively, the crude product is recrystallized from acetonitrile (15 V/m), the product is given with 51% yield. The spectroscopical data was consistent with the literature.
1H NMR (400 MHz, DMSO) δ 0.86 - 0.99 (m, 2H), 1.05 - 1.17 (m, 2H), 1.22 - 1.26 (m, 1H), 1.30 - 1.35 (m, 2H), 1.37 (s, 9H), 1.67 - 1.79 (m, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.49 - 2.51 (m, 4H), 2.92 - 3.02 (m, 4H), 3.09 - 3.21 (m, 1H), 6.66 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 6.3, 3.2 Hz, 1H), 7.27 - 7.32 (m, 2H).
List of abbreviations
DIBAL-H diisobutylaluminum hydride
DMSO dimethyl sulfoxide
EtOAc ethyl acetate PEEK poly(ether ether ketone)
Pd/C palladium on carbon catalyst
Pt/C platinum on carbon catalyst
PTFE poly(tetrafluoroethylene) tBuOH tert-butanol TEA triethylamine
THF tetrahydrofuran
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Claims
1. A process for the preparation of a compound of formula (IV) comprising step 1) selective ester reduction of a compound of formula (II) carried out in the alternating diameter flow reactor according to any one of claim 8 to 10 in the presence of a reducing agent to give a compound of formula (XVII) step 2) reductive animation between a compound of formula (III) and a compound of formula (XVII) carried out by continuous-flow catalytic hydrogenation to give the compound of formula
(IV), wherein n is 0 or 1; L is a -(CH2)m- linker, in which m is 1, 2, or 3; R1 represents a substituted alicyclic or hetero-bicyclic group; and R2 represents a branched or straight chain alkyl group comprising one to six carbon atoms.
2. The process according to claim 1, wherein the reducing agent is DIBAL-H and step 1 is carried out in toluene, at a temperature between -100°C and 0°C.
3. The process according to any one of claims 1 or 2, wherein step 2 is carried out in the presence of 5% Pt/C as catalyst and hydrogen gas, at pressure up to 50 bar in a solvent mixture of toluene and methanol, at a temperature between 40°C and 100°C.
4. The process according to any one of claims 1 or 2, wherein the compound of formula (IV) is a compound of formula (V)
wherein R4 represents branched or straight chain alkyl groups comprising one to six carbon atoms, or benzyl group, or benzyl group substituted with alkyl, alkoxy or nitro groups as part of a carbamate protecting group.
5. The process according to any one of claim 1 to 4, wherein the compound of formula (II) is a compound of formula (VI), and the compound of formula (III) is a compound of formula (VII)
wherein R2 represents a branched or straight chain alkyl group comprising one to six carbon atoms and R4 represents branched or straight chain alkyl groups comprising one to six carbon atoms, or benzyl group, or benzyl group substituted with alkyl, alkoxy or nitro groups as part of a carbamate protecting group.
8. An alternating diameter flow reactor (Rl) for continuous-flow reactions comprising
(1) a means for fluid conveyance (1) having a length, a constant outside diameter, a constant internal diameter and a wall thickness,
(ii) means for fitting at both ends of the means for fluid conveyance (1) and
(iii) a means for mixing a fluid inside the means for fluid conveyance comprising
(iv) at least two means for reducing the internal diameter of the means for fluid conveyance
(2) having a length arranged inside the means for fluid conveyance and arranged such that
- reducing the internal diameter through the longitudinal axis of the means for fluid conveyance at each corresponding location and
- forming at least one segment inside the means for fluid conveyance; and
(v) at least one segment between the at least two means for reducing the internal diameter inside the means for fluid conveyance having a sufficient volume for mixing.
9. The alternating diameter flow reactor according to claim 8, wherein the means for fluid conveyance (1) is a tube.
10. The alternating diameter flow reactor according to any one of claims 8 or 9, wherein the at least two means for reducing the internal diameter of the means for fluid conveyance (2) are means partially obstructing the flow of the fluid inside the means for fluid conveyance.
11. The alternating diameter flow reactor according to any one of claims 8 to 10, wherein the at least two means for reducing the internal diameter of the means for fluid conveyance (2) are microfluidic tubings.
12. The alternating diameter flow reactor according to any one of claim 8 to 11, wherein the sufficient volume for mixing is provided by the length of the means for fluid conveyance (1) being at least 10 times the length at which location one of the at least two means reducing the internal diameter inside the means for fluid conveyance (2) reduces the diameter inside the means for fluid conveyance.
13. The alternating diameter flow reactor according to any one of claims 8 to 12, wherein the internal diameter at each corresponding location of the at least two means for reducing the internal diameter inside the means for fluid conveyance is at most half of the internal diameter of the means for fluid conveyance at each location of the at least one segment.
14. A system for continuous-flow reactions comprising a) a first unit comprising
- a cooling bath,
- a first reactor (R1) being the alternating diameter flow reactor according to any one of claims 8 to 13,
- a separate reactor (R2) for quenching a reaction mixture,
- a T-piece for mixing streams from pumps (P1 and P2) before the streams reaching the first reactor (R1) and
- an additional T-piece for introducing an additional stream from a pump (P3) and for transferring into the second reactor (R2), b) separate pumps (PI, P2 and P3) for transferring solutions to the first unit from corresponding separate containers and/or corresponding separate injector loops connected after the pumps,
c.) a connecting device (CD) for subjecting a reaction mixture quenched in the separate reactor (R2) working-up to obtain a crude mixture, d.) a pump (P4) for transferring the crude mixture to a second unit being a continuous-flow hydrogenation device (R3), e.) a vessel (CV) for collecting a product solution.
15. The system according to claim 14 wherein the connecting device (CD) is an in-line extraction device, or a manual at-line extraction.
16. The system according to any one of claims 14 or 15 for the process according to any one of claims 1 to 7 comprising
- a first pump (P1) for transferring the compound of formula (II),
- a second pump (P2) for transferring a solution of the reducing agent, and
- a third pump (P3) for transferring a quenching solution and optionally the compound of formula (III).
17. A method for the formation of C-N bond in the system according to any one of claims 14 to 16 comprising
- providing separate containers and/or loops, and separate corresponding pumps for the solution of an ester derivative, a reducing agent, a piperazine derivative and a quenching solution,
- providing a first unit comprising, in a cooling bath, a first reactor being the alternating diameter flow reactor according to any one of claims 8 to 13, a separate reactor for quenching a reaction mixture, a T-piece for mixing streams before the streams reaching the first reactor and an additional T-piece for introducing an additional stream from a pump and for transferring into the separate reactor,
- providing a suitable connecting device,
- providing a second unit being a continuous-flow hydrogenation device,
- providing a vessel for collecting the product solution,
- pumping of an ester derivative directed to a first reactor,
- pumping of a reducing agent directed to a first reactor,
- mixing the streams of the ester derivative and the reducing agent in the T-piece before reaching the first reactor,
- introducing the resulting stream of mixture to the first reactor,
- selectively reducing the ester derivative to an aldehyde derivative at a suitable temperature in the first reactor,
- pumping of the quenching solution directed to the separate reactor for quenching,
- mixing the streams of the reaction mixture of the ester derivative and the reducing agent with the quenching solution in the additional T-piece after the first reactor,
- quenching the thus obtained mixture in the separate reactor for quenching to obtain a crude mixture,
- extracting the crude mixture and directing to the second reactor via the suitable connecting device,
- pumping of the extracted aldehyde derivative to the second reactor,
- pumping of the piperazine derivative to the second reactor,
- reacting the extracted aldehyde derivative with the piperazine derivative in reductive amination conditions in the second reactor,
- collecting the product of the reaction carried out in the second reactor in the vessel and degassing excess hydrogen.
18. The method according to claim 17 wherein
- a common container and/or loop and corresponding pump is provided for the solution of the piperazine derivative and the quenching solution,
- pumping of the piperazine derivative and the quenching solution directed to the separate reactor for quenching is carried out simultaneously.
19. The method according to any one of claims 17 or 18 wherein
- the ester derivative is a compound of formula (II),
- the reducing agent is DIBAL-H,
- the piperazine derivative is a compound of formula (III),
- and the product is a compound of formula (IV).
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