CA2375841A1 - New bispidine compounds useful in the treatment of cardiac arrhythmias - Google Patents

Info

Publication number

CA2375841A1

CA2375841A1 CA002375841A CA2375841A CA2375841A1 CA 2375841 A1 CA2375841 A1 CA 2375841A1 CA 002375841 A CA002375841 A CA 002375841A CA 2375841 A CA2375841 A CA 2375841A CA 2375841 A1 CA2375841 A1 CA 2375841A1

Authority

CA

Canada

Prior art keywords

formula

compound

alkyl

compounds

diazabicyclo

Prior art date

1999-06-16

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

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 206010003119 arrhythmia Diseases 0.000 title claims abstract description 24
• 238000011282 treatment Methods 0.000 title claims abstract description 17
• PTPQJKANBKHDPM-UHFFFAOYSA-N 3,7-diazabicyclo[3.3.1]nonane Chemical class C1NCC2CNCC1C2 PTPQJKANBKHDPM-UHFFFAOYSA-N 0.000 title claims description 13
• 150000001875 compounds Chemical class 0.000 claims abstract description 419
• 230000006793 arrhythmia Effects 0.000 claims abstract description 15
• 238000011321 prophylaxis Methods 0.000 claims abstract description 7
• 230000001746 atrial effect Effects 0.000 claims abstract description 5
• 206010047281 Ventricular arrhythmia Diseases 0.000 claims abstract description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 97
• 238000006243 chemical reaction Methods 0.000 claims description 86
• 238000000034 method Methods 0.000 claims description 60
• -1 C1-4 Chemical group 0.000 claims description 49
• 125000002947 alkylene group Chemical group 0.000 claims description 36
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
• 125000001424 substituent group Chemical group 0.000 claims description 32
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
• 125000005843 halogen group Chemical group 0.000 claims description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
• 125000004122 cyclic group Chemical group 0.000 claims description 25
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 229910052799 carbon Inorganic materials 0.000 claims description 19
• 125000002015 acyclic group Chemical group 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 230000009467 reduction Effects 0.000 claims description 16
• 125000004432 carbon atom Chemical group C* 0.000 claims description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 9
• 239000003795 chemical substances by application Substances 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• 230000008569 process Effects 0.000 claims description 8
• 125000003107 substituted aryl group Chemical group 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 7
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
• VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 238000002360 preparation method Methods 0.000 claims description 6
• 229920006395 saturated elastomer Polymers 0.000 claims description 6
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
• 150000007524 organic acids Chemical class 0.000 claims description 5
• 229910052717 sulfur Chemical group 0.000 claims description 5
• 239000011593 sulfur Chemical group 0.000 claims description 5
• 230000029936 alkylation Effects 0.000 claims description 4
• 238000005804 alkylation reaction Methods 0.000 claims description 4
• 230000003647 oxidation Effects 0.000 claims description 4
• 238000007254 oxidation reaction Methods 0.000 claims description 4
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 238000010511 deprotection reaction Methods 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 239000004480 active ingredient Substances 0.000 claims description 2
• 239000002671 adjuvant Substances 0.000 claims description 2
• 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 230000002140 halogenating effect Effects 0.000 claims description 2
• 238000006467 substitution reaction Methods 0.000 claims description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 10
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 6
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• 102220024746 rs199473444 Human genes 0.000 claims 1
• 206010003130 Arrhythmia supraventricular Diseases 0.000 abstract description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 204
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 134
• 239000000203 mixture Substances 0.000 description 111
• 239000000243 solution Substances 0.000 description 83
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 40
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 39
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
• 238000010992 reflux Methods 0.000 description 31
• 239000012044 organic layer Substances 0.000 description 26
• 239000003960 organic solvent Substances 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 25
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 20
• 229960004592 isopropanol Drugs 0.000 description 19
• 125000003545 alkoxy group Chemical group 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
• 239000002904 solvent Substances 0.000 description 16
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 15
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
• 239000002585 base Substances 0.000 description 14
• 238000004440 column chromatography Methods 0.000 description 14
• 239000012043 crude product Substances 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 238000012360 testing method Methods 0.000 description 14
• 230000015572 biosynthetic process Effects 0.000 description 13
• 235000019439 ethyl acetate Nutrition 0.000 description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
• 239000000741 silica gel Substances 0.000 description 13
• 229910002027 silica gel Inorganic materials 0.000 description 13
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• 238000004587 chromatography analysis Methods 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• 238000001914 filtration Methods 0.000 description 11
• 238000003818 flash chromatography Methods 0.000 description 11
• 238000004128 high performance liquid chromatography Methods 0.000 description 11
• 238000003786 synthesis reaction Methods 0.000 description 11
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 125000006239 protecting group Chemical group 0.000 description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• KAAITWOSDOCHEH-UHFFFAOYSA-N 3-benzyl-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1C(C2)CNCC2CN1CC1=CC=CC=C1 KAAITWOSDOCHEH-UHFFFAOYSA-N 0.000 description 9
• 229910052739 hydrogen Inorganic materials 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
• 239000000047 product Substances 0.000 description 9
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
• 239000003054 catalyst Substances 0.000 description 8
• ZMJREUBTESMFEN-UHFFFAOYSA-N n-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide Chemical compound C1NCC2CN(C(=O)NCC)CC1C2 ZMJREUBTESMFEN-UHFFFAOYSA-N 0.000 description 8
• 239000002244 precipitate Substances 0.000 description 8
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 7
• 239000003638 chemical reducing agent Substances 0.000 description 7
• 238000002474 experimental method Methods 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• 238000000746 purification Methods 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 239000000725 suspension Substances 0.000 description 7
• DLQGGZNCJPLPQJ-UHFFFAOYSA-N 4-[3-(3,7-diazabicyclo[3.3.1]nonan-3-yl)-2-hydroxypropoxy]benzonitrile Chemical compound C1C(C2)CNCC2CN1CC(O)COC1=CC=C(C#N)C=C1 DLQGGZNCJPLPQJ-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• 239000003416 antiarrhythmic agent Substances 0.000 description 6
• 239000007864 aqueous solution Substances 0.000 description 6
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
• 239000012267 brine Substances 0.000 description 6
• 229940079593 drug Drugs 0.000 description 6
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• 125000005233 alkylalcohol group Chemical group 0.000 description 5
• 239000012298 atmosphere Substances 0.000 description 5
• CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
• 230000000747 cardiac effect Effects 0.000 description 5
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 5
• OQJBFFCUFALWQL-UHFFFAOYSA-N n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)N=NC(=O)N1CCCCC1 OQJBFFCUFALWQL-UHFFFAOYSA-N 0.000 description 5
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
• 239000011734 sodium Substances 0.000 description 5
• 239000012279 sodium borohydride Substances 0.000 description 5
• 229910000033 sodium borohydride Inorganic materials 0.000 description 5
• 239000000126 substance Substances 0.000 description 5
• IIEJAPGXLGSUOV-UHFFFAOYSA-N 1,2-diazabicyclo[3.3.1]nonane-3-carboxamide Chemical compound C1CCN2NC(C(=O)N)CC1C2 IIEJAPGXLGSUOV-UHFFFAOYSA-N 0.000 description 4
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
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• SMFFZOQLHYIRDA-UHFFFAOYSA-N 3,4-dimethoxyphenol Chemical compound COC1=CC=C(O)C=C1OC SMFFZOQLHYIRDA-UHFFFAOYSA-N 0.000 description 4
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• ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 4
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
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• ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 4
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• 239000010410 layer Substances 0.000 description 4
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• 150000003839 salts Chemical class 0.000 description 4
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• QUUXDQNJCQCLFO-UHFFFAOYSA-N 7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-n-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide Chemical compound C1N(C(=O)NCC)CC(C2)CC1CN2CCCC(C=1C=CC(=CC=1)C#N)OC1=CC=C(OC)C(OC)=C1 QUUXDQNJCQCLFO-UHFFFAOYSA-N 0.000 description 3
• TWDWATDUYGORKC-UHFFFAOYSA-N 7-benzyl-n-propan-2-yl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide Chemical compound C1N(C(=O)NC(C)C)CC(C2)CC1CN2CC1=CC=CC=C1 TWDWATDUYGORKC-UHFFFAOYSA-N 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
• 125000004429 atom Chemical group 0.000 description 3
• UFXKXBXIKWAQKP-UHFFFAOYSA-N bicyclo[3.3.1]nonane-3-carboxamide Chemical compound C1CCC2CC(C(=O)N)CC1C2 UFXKXBXIKWAQKP-UHFFFAOYSA-N 0.000 description 3
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
• 239000013078 crystal Substances 0.000 description 3
• 238000002425 crystallisation Methods 0.000 description 3
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 3
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