CN110372598A - 一种合成氘代酰胺及氘代磺酰胺的新方法 - Google Patents
一种合成氘代酰胺及氘代磺酰胺的新方法 Download PDFInfo
- Publication number
- CN110372598A CN110372598A CN201910295994.7A CN201910295994A CN110372598A CN 110372598 A CN110372598 A CN 110372598A CN 201910295994 A CN201910295994 A CN 201910295994A CN 110372598 A CN110372598 A CN 110372598A
- Authority
- CN
- China
- Prior art keywords
- synthetic method
- deuterated
- substituted
- hydroxide
- solvent
- Prior art date
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 150000001408 amides Chemical class 0.000 title abstract description 11
- 229940124530 sulfonamide Drugs 0.000 title abstract description 8
- 150000003456 sulfonamides Chemical class 0.000 title abstract description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 44
- -1 amides compounds Chemical class 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000001412 amines Chemical class 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- 238000010189 synthetic method Methods 0.000 claims description 33
- 239000002585 base Substances 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Natural products C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- IVORCBKUUYGUOL-UHFFFAOYSA-N 1-ethynyl-2,4-dimethoxybenzene Chemical compound COC1=CC=C(C#C)C(OC)=C1 IVORCBKUUYGUOL-UHFFFAOYSA-N 0.000 claims description 2
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- VQWFNAGFNGABOH-UHFFFAOYSA-K chromium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[Cr+3] VQWFNAGFNGABOH-UHFFFAOYSA-K 0.000 claims description 2
- AEJIMXVJZFYIHN-UHFFFAOYSA-N copper;dihydrate Chemical compound O.O.[Cu] AEJIMXVJZFYIHN-UHFFFAOYSA-N 0.000 claims description 2
- 235000014413 iron hydroxide Nutrition 0.000 claims description 2
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 claims description 2
- 229910021514 lead(II) hydroxide Inorganic materials 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 claims description 2
- 229910021511 zinc hydroxide Inorganic materials 0.000 claims description 2
- 229940007718 zinc hydroxide Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 2
- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 claims 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910000428 cobalt oxide Inorganic materials 0.000 claims 1
- BFDHFSHZJLFAMC-UHFFFAOYSA-L nickel(ii) hydroxide Chemical compound [OH-].[OH-].[Ni+2] BFDHFSHZJLFAMC-UHFFFAOYSA-L 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 23
- 239000003814 drug Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 150000008065 acid anhydrides Chemical class 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical class [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 238000000605 extraction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical class CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000012263 liquid product Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102100032187 Androgen receptor Human genes 0.000 description 3
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 108010080146 androgen receptors Proteins 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 3
- 229960004671 enzalutamide Drugs 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- MKJIEFSOBYUXJB-VFJJUKLQSA-N (3r,11br)-3-(2-methylpropyl)-9,10-bis(trideuteriomethoxy)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one Chemical compound C1CN2C[C@@H](CC(C)C)C(=O)C[C@@H]2C2=C1C=C(OC([2H])([2H])[2H])C(OC([2H])([2H])[2H])=C2 MKJIEFSOBYUXJB-VFJJUKLQSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- WVXNSAVVKYZVOE-UHFFFAOYSA-N DCC-2036 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=C4C=CC=NC4=CC=3)=CC=2)=C1 WVXNSAVVKYZVOE-UHFFFAOYSA-N 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003005 anticarcinogenic agent Substances 0.000 description 2
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 description 2
- 229960003005 axitinib Drugs 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 229950005031 deutetrabenazine Drugs 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229950007043 rebastinib Drugs 0.000 description 2
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 2
- 229960004836 regorafenib Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
- 229960003708 sumatriptan Drugs 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- NAGFMACWWJYORB-UHFFFAOYSA-N 2-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1F NAGFMACWWJYORB-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- 102000035038 5-HT1 receptors Human genes 0.000 description 1
- 108091005478 5-HT1 receptors Proteins 0.000 description 1
- FSAIWKIFEKPXMV-UHFFFAOYSA-N C(=C)OC(=O)N1N=CC2=CC=CC=C12 Chemical compound C(=C)OC(=O)N1N=CC2=CC=CC=C12 FSAIWKIFEKPXMV-UHFFFAOYSA-N 0.000 description 1
- 229910021503 Cobalt(II) hydroxide Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-VVKOMZTBSA-N Dideuterium Chemical compound [2H][2H] UFHFLCQGNIYNRP-VVKOMZTBSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- RSPBQSYWXAROOO-UHFFFAOYSA-N N-methylhexanamide Chemical compound CCCCCC(=O)NC RSPBQSYWXAROOO-UHFFFAOYSA-N 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 description 1
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229950007511 apalutamide Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- ASKVAEGIVYSGNY-UHFFFAOYSA-L cobalt(ii) hydroxide Chemical compound [OH-].[OH-].[Co+2] ASKVAEGIVYSGNY-UHFFFAOYSA-L 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RWGJVMFILBWTGJ-UHFFFAOYSA-N n-methyl-3-phenylpropanamide Chemical compound CNC(=O)CCC1=CC=CC=C1 RWGJVMFILBWTGJ-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种合成氘代酰胺及氘代磺酰胺的新方法,步骤如下:(1)将化合物M、DMAP、R3‑X加入到溶剂中,反应完全后得化合物N;(2)将化合物N、R4‑NH‑R5或其盐、碱加入到溶剂中,反应完全后,纯化得化合物Ⅰ。该方法反应条件温和,路线短,仅需两步即可得到,可以应用于已有方法不能适用的原料,提高合成效率,可以适用于很多酰胺类化合物,具有较强的普适性,为制备氘代胺的酰胺及磺酰胺类化合物提供了一种新的选择。
Description
技术领域
本发明涉及一种合成氘代酰胺及氘代磺酰胺的新方法。
背景技术
氘代药物是目前新药研发的一个热点研究领域。氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近,氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定,使得氘代药物在代谢反应过程中,C-D键更不容易断裂,其半衰期可能会延长,代谢产物可能会减少,从而达到更好的药代动力学。目前已经有一个氘代药物AUSTEDO(deutetrabenazine)被批准上市,另有若干个氘代药物在临床阶段。因此开发氘代化合物的新的合成方法有重要的意义。
Enzalutamide是一种雄激素受体androgen-receptor(AR)拮抗剂,适用于抗肿瘤药多西他赛治疗后的***癌患者,Enzalutamide是被证实可延长患者生命的治疗该疾病的最新方法。Apalutamide(ARN-509)是一种选择性的、竞争性androgen receptor抑制剂,对***癌的治疗有效。Sorafenib是一种新型多靶向性的***的口服药物,其首要开发目标为,用于治疗对标准疗法没有响应或不能耐受之胃肠道基质肿瘤和转移性肾细胞,能选择性地靶向某些蛋白的受体,后者被认为在肿瘤生长过程中起着一种分子开关样的作用。Regorafenib是一种多靶点抑制剂,靶作用于VEGFR1/2/3,PDGFRβ,Kit,RET和Raf-1。Rebastinib是一种Bcr-Abl抑制剂抑制剂。Axitinib可用于其它***治疗无效的晚期肾癌。Sumatriptan是5-HT1受体激动剂。
上述药物都是酰胺或磺酰胺类药物,其氘代化合物在药物研究中有许多重要的用途,例如,化合物1,2,3已经进入了临床或临床前开发阶段。如何利用上述药物温和高效地制备得到其氘代药物,具有重要的意义,它们不但可以用作未被氘代药物的替代药物,也可以用作药物代谢研究的同位素标准品。
发明内容
为了解决上述问题,本发明提供了一种合成氘代酰胺及氘代磺酰胺的新方法。
本发明提供了一种合成氘代胺的方法,步骤如下:
式中,
L选自羰基、磺基;
R1选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基;
R2选自取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
R3选自-CO-R6、-SO2R7;X为一个离去基团;
其中,R6、R7各自独立地选自烷氧基、烷基、取代的烷基、芳基;
R4、R5各自独立地选自H、氘代的取代或未取代的烷基、氘代的环烷基、氘代的杂环基、氘代的芳基、氘代的杂芳基,且R4、R5不同时为氢;
(1)将化合物M、DMAP、R3-X加入到溶剂中,反应完全后得化合物N;
(2)将化合物N、R4-NH-R5或其盐、碱加入到溶剂中,反应完全后,纯化得化合物Ⅰ。
进一步地,
R3选自-CO-R6、-SO2R7;X选自-OR3、Cl、Br;
其中,R6、R7各自独立地选自叔丁氧基、异丙氧基、苄氧基、甲基、三氟甲基、苯基、甲苯基。
进一步地,
R3选自-CO-R6、-SO2R7;
其中,R6选自叔丁氧基、异丙氧基、苄氧基;R7选自甲基、三氟甲基、苯基、甲苯基。
进一步地,
R3选自-CO-R6;X为-OR3;
其中,R6选自叔丁氧基。
进一步地,
R4、R5各自独立地选自H、氘代的烷基,且R4、R5不同时为氢。
进一步地,
R4、R5各自独立地选自H、氘代的甲基,且R4、R5不同时为氢。
进一步地,
R2选自取代或未取代的C1~C6烷基。
进一步地,
R2选自C1~C4烷基。
进一步地,
R2选自甲基。
进一步地,R1选自下述结构之一:
进一步地,化合物Ⅰ选自下述结构之一:
进一步地,步骤(1)中,所述溶剂为极性溶剂或非极性溶剂。
进一步地,所述极性溶剂选自二氯甲烷、二氯乙烷、甲酰胺、三氟乙酸、DMSO、乙腈、DMF、六甲基磷酰胺、甲醇、乙醇、乙酸、异丙醇、吡啶、四甲基乙二胺、丙酮、三乙胺、正丁醇、二氧六环、四氢呋喃、甲酸甲酯、三丁胺、甲乙酮、乙酸乙酯、氯仿、三辛胺、碳酸二甲酯、***、异丙醚、正丁醚、三氯乙烯、二苯醚。
进一步地,所述极性溶剂选自二氯甲烷。
进一步地,所述非极性溶剂选自苯、甲苯、四氯化碳、二硫化碳、环己烷、己烷。
进一步地,步骤(1)中,所述化合物M、DMAP、R3-X的摩尔比为1:1~3:1~10,优选为1:2~3:1.5~2。
进一步地,步骤(1)中,所述化合物M与溶剂的投料比为1:2~20mmol/mL;优选为1:2~15mmol/mL,更优选为1:5.5~10mmol/mL。
进一步地,步骤(1)中,所述反应温度为10~60℃。
进一步地,所述反应温度为20~30℃,优选为25℃。
进一步地,步骤(1)中,所述反应时间为10~120h,优选为10~16h,更优选为10~14h,进一步优选为12h。
进一步地,步骤(2)中,所述溶剂为极性溶剂或非极性溶剂。
进一步地,所述极性溶剂选自二氯甲烷、二氯乙烷、甲酰胺、三氟乙酸、DMSO、乙腈、DMF、六甲基磷酰胺、甲醇、乙醇、乙酸、异丙醇、吡啶、四甲基乙二胺、丙酮、三乙胺、正丁醇、二氧六环、四氢呋喃、甲酸甲酯、三丁胺、甲乙酮、乙酸乙酯、氯仿、三辛胺、碳酸二甲酯、***、异丙醚、正丁醚、三氯乙烯、二苯醚。
进一步地,所述极性溶剂选自乙腈。
进一步地,所述非极性溶剂选自苯、甲苯、四氯化碳、二硫化碳、环己烷、己烷。
进一步地,步骤(2)中,所述化合物N与溶剂的投料比为1:1~25mmol/mL,优选为1:1~20mmol/mL,更优选为1:2.5~15mmol/mL。
进一步地,步骤(2)中,所述碱为有机碱或无机碱。
进一步地,所述有机碱选自DBU、甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠、三乙胺、三乙烯二胺、DBN、DMAP、吡啶、N-甲基吗啉、四甲基乙二胺、TMG、正丁基锂、LDA。
进一步地,所述有机碱选自DBU。
进一步地,所述无机碱选自氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、氢氧化铜、氢氧化铁、氢氧化铅、氢氧化钴、氢氧化铬、氢氧化锆、氢氧化镍、氢氧化铵、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾。
进一步地,步骤(2)中,所述化合物N、R4-NH-R5或其盐、碱的摩尔比为1:1~4:1~5,优选为1:1~4:1~4.5。
进一步地,所述化合物N、R4-NH-R5或其盐、碱的摩尔比为1:3:4。
进一步地,步骤(2)中,所述反应温度为10~100℃,优选为20~30℃,更优选为25℃。
进一步地,步骤(2)中,所述反应时间为10~120h,优选为10~14h,更优选为12h。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名***命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本发明中所述化合物的结构均是指能够稳定存在的结构。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
“氘”是指氢(H)的同位素,也被称为重氢,元素符号一般为D或2H。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基,例如,甲基-CH3,乙基-CH3CH2等。
“取代或未取代的C1-4烷基”是指C1-4烷基可以是被取代的,也可以没有取代基的。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。含有至少一个选自N、O或S的环杂原子,其余环原子是C,另外具有完全共轭的π电子***。例如呋喃基、吡咯基、喹啉基、噻吩基、吡啶基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、噻吩并吡啶基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
“环烷基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“C3-8环烷基”指碳原子数为3~8的环烷基。
“杂环基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环,且携带至少一个选自O、S或取代的氮原子的环烷基,其余环原子为碳,例如,“C3-8杂环基”指碳原子数和杂原子数共为3~8的杂环基。杂环基可以是非取代的,也可以被一个或多个取代基取代。
化合物1为氘代的抗***癌药物Enzalutamide,化合物2为氘代的抗***癌药Apalutamide,化合物3为氘代的抗癌药Sorafenib,化合物4为氘代的抗癌药Regorafenib,化合物5为Rebastinib,化合物6为氘代的Axitinib。化合物7为氘代的治疗偏头痛的药物Sumatriptan。
DMAP:4-二甲氨基吡啶。
Boc2O:Boc酸酐,结构式为
DCM:二氯甲烷。
DBU:1,8-二氮杂二环十一碳-7-烯,结构式为
本发明所述“室温”为“25±5℃”。
本发明所述“过夜”为“12±1h”。
本发明提供了一种合成氘代酰胺及氘代磺酰胺的新方法,该方法反应条件温和,路线短,仅需两步即可得到,可以应用于已有方法不能适用的原料,提高合成效率,可以适用于很多酰胺类化合物,具有较强的普适性,为制备氘代胺的酰胺及磺酰胺类化合物提供了一种新的选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1、化合物1的合成
(1)叔丁基(4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧-2-硫代咪唑啉-1-基)-2-氟苯基)(甲基)甲酰胺(1-2)
(4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧-2-硫代咪唑啉-1-基)-2-氟-N-甲基苯甲酰胺(1-1,400mg,0.85mmol),DMAP(210mg,1.7mmol)加入到5mL的二氯甲烷中,再滴加Boc酸酐(280mg,1.3mmol)。室温搅拌过夜。加入DCM和0.1mol/L稀HCl(50mL:50mL),萃取,有机层用饱和食盐水洗涤2次,干燥,旋干,过硅胶柱纯化,得到白色固体叔丁基(4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧-2-硫代咪唑啉-1-基)-2-氟苯基)(甲基)甲酰胺(1-2,450mg,0.80mmol)白色固体。收率92.3%。
MS(ESI)m/e 465.1(M-100+1)+。
(2)(4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧-2-硫代咪唑啉-1-基)-2-氟-N-氘代甲基苯甲酰胺(1)
叔丁基(4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧-2-硫代咪唑啉-1-基)-2-氟苯基)(甲基)甲酰胺(1-2,50mg,0.09mmol),氘代甲胺盐酸盐(19mg,0.27mmol)加入到0.25mL的乙腈中。有白色不溶物,再加入DBU(54mg,0.36mmol),固体溶解。室温搅拌过夜,点板,显示原料点消失。加入二氯甲烷和0.1mol/L稀HCl(30mL:30mL),萃取,有机层用饱和食盐水洗涤2次,干燥,旋干,Pre-TLC纯化,得到白色固体(4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧-2-硫代咪唑啉-1-基)-2-氟-N-氘代甲基苯甲酰胺(1,38mg,0.09mmol)。收率92.8%。
MS(ESI)m/e 468.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ8.52–8.38(m,2H),8.31(d,J=1.5Hz,1H),8.10(dd,J=8.3,1.7Hz,1H),7.80(t,J=8.1Hz,1H),7.45(dd,J=10.7,1.7Hz,1H),7.35(dd,J=8.2,1.8Hz,1H),1.55(s,6H)。
实施例2、化合物2的合成
(1)4-(7-(6-氰基-5-(三氟甲基)吡啶-3-基)-8-氧-6-巯基-5,7-二氮杂螺[3.4]辛烷-5-基)-2-氟-N-Boc-甲基苯甲酰胺(2-2)
4-(7-(6-氰基-5-(三氟甲基)吡啶-3-基)-8-氧-6-巯基-5,7-二氮杂螺[3.4]辛烷-5-基)-2-氟-N-甲基苯甲酰胺(2-1,500.0mg,1.05mmol),DMAP(384.0mg,3.15mmol)加入到10mL的二氯甲烷中,再滴加Boc酸酐(458.0mg,2.10mmol)。室温搅拌过夜。加入DCM和0.1N稀HCl(50mL:50mL),萃取,有机层用饱和食盐水洗涤2次,干燥,旋干,过硅胶柱纯化,得到白色固体4-(7-(6-氰基-5-(三氟甲基)吡啶-3-基)-8-氧-6-巯基-5,7-二氮杂螺[3.4]辛烷-5-基)-2-氟-N-Boc-甲基苯甲酰胺(2-2,450.0mg,0.80mmol)白色固体。收率82.6%。
MS(ESI)m/e478.0(M-100+1)+。
(2)4-(7-(6-氰基-5-(三氟甲基)吡啶-3-基)-8-氧-6-巯基-5,7-二氮杂螺[3.4]辛烷-5-基)-2-氟-N-氘代甲基苯甲酰胺(2)
将4-(7-(6-氰基-5-(三氟甲基)吡啶-3-基)-8-氧-6-巯基-5,7-二氮杂螺[3.4]辛烷-5-基)-2-氟-N-Boc-甲基苯甲酰胺(2-2,200.0mg,0.35mmol)溶于5mL乙腈,加入氘代甲胺盐酸盐(75.0mg,1.06mmol),有固体不溶,加入DBU(215.6mg,1.42mmol)后溶清。室温反应过夜。加入二氯甲烷和0.1N稀HCl(30mL:30mL),萃取,有机层用饱和食盐水洗涤2次,干燥,旋干,Pre-TLC纯化,得到白色固体4-(7-(6-氰基-5-(三氟甲基)吡啶-3-基)-8-氧-6-巯基-5,7-二氮杂螺[3.4]辛烷-5-基)-2-氟-N-氘代甲基苯甲酰胺(2,130.0mg,0.27mmol)。收率76.2%。
MS(ESI)m/e 481.0(M+H)+。
1H NMR(400MHz,CDCl3)δ9.09(d,J=2.1Hz,1H),8.43–8.27(m,2H),7.28(d,J=1.9Hz,1H),7.17(dd,J=11.5,1.8Hz,1H),6.71(d,J=11.6Hz,1H),2.77–2.69(m,3H),2.57(dt,J=12.7,10.2Hz,2H),2.32–2.22(m,1H)。
实施例3、化合物3的合成
(1)将阿西替尼(3-1,193mg,0.5mmol,1.0eq)溶于二氯甲烷(10ml),搅拌下加入DMAP(183mg,1.5mmol),加入Boc酸酐(327mg,1.5mmol),室温反应16小时,TLC检测直至反应完全,反应体系用0.1N盐酸水溶液洗涤直至把DMAP洗干净,有机层分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,薄层柱层析纯化(PE/EA=2:1),得到白色固体产品(E)-叔丁基6-((2-((叔丁氧基羰基)(甲基)氨甲酰)苯基)硫基)-3-(2-(吡啶-2-基)乙烯基-1H-吲唑-1-羧酸酯(3-2)收率为81.9%。
1H NMR(400MHz,CDCl3)δ8.65(d,J=4.0Hz,1H),8.02(s,1H),7.93(t,J=10.6Hz,2H),7.77(d,J=15.6Hz,2H),7.51(d,J=6.5Hz,1H),7.46–7.41(m,1H),7.39–7.32(m,3H),7.28(dd,J=8.5,1.5Hz,2H),3.26(s,3H),1.62(s,9H),1.22(s,9H)。
(2)将上一步产品(E)-叔丁基6-((2-((叔丁氧基羰基)(甲基)氨甲酰)苯基)硫基)-3-(2-(吡啶-2-基)乙烯基-1H-吲唑-1-羧酸酯(3-2,117.2mg,0.2mmol)溶于5ml乙腈中,加入氘代甲胺盐酸盐(56mg,0.8mmol),加入DBU(136mg,0.9mmol),室温反应过夜。TLC检测,反应完全,水洗,乙酸乙酯萃取,有机层用0.1N盐酸水溶液洗涤,再分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,得淡黄色固体产品(E)-N-氘代甲基-2-(3-(2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫代酰胺)(3)75mg,收率96.4%。
MS(ESI)m/e 390(M+H)+。
1H NMR(400MHz,DMSO-d6)δ13.36(s,1H),8.61(d,J=3.8Hz,1H),8.42–8.35(m,1H),8.22(d,J=8.5Hz,1H),7.95(d,J=16.4Hz,1H),7.81(td,J=7.7,1.8Hz,1H),7.67(d,J=7.8Hz,1H),7.63–7.54(m,2H),7.49(dd,J=7.3,1.7Hz,1H),7.33–7.25(m,3H),7.19(dd,J=8.5,1.1Hz,1H),7.03(dd,J=7.7,1.1Hz,1H)。
实施例4、化合物4的合成
(1)将N-甲基苯甲酰胺(4-1,135mg,1mmol)溶于二氯甲烷(5ml),搅拌下加入DMAP(244mg,2mmol),加入Boc酸酐(436mg,2mmol),室温反应16小时,TLC检测直至反应完全,反应体系用0.1N盐酸水溶液洗涤直至把DMAP洗干净,有机层分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,薄层柱层析纯化(PE/EA=2:1),得到白色固体产品(4-2)220mg,收率:93.6%。
MS(ESI)m/e 180.1([M–56+H]+)。
(2)将上一步产品(4-2,118mg,0.5mmol)溶于2ml乙腈中,加入氘代甲胺盐酸盐(105mg,1.5mmol),加入DBU(304mg,2mmol.),25℃搅拌反应过夜,冷却至室温,TLC检测,反应完全,水洗,乙酸乙酯萃取,有机层用0.1N盐酸水溶液洗涤,再分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,得白色固体产品(4)57mg,收率82.6%。
MS(ESI)m/e 139.1([M+H]+)。
1H NMR(400MHz,CDCl3)δ7.76(m,2H),7.47(dd,J=8.5,6.1Hz,1H),7.40(t,J=7.4Hz,2H),6.37(s,1H)。
实施例5、化合物5的合成
(1)将5-1(153mg,1mmol)溶于二氯甲烷(5ml),搅拌下加入DMAP(244mg,2mmol),加入Boc酸酐(436mg,2mmol),室温反应16小时,TLC检测直至反应完全,反应体系用0.1N盐酸水溶液洗涤直至把DMAP洗干净,有机层分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,薄层柱层析纯化(PE/EA=2:1),得到白色固体产品(5-2)200mg,收率:93.6%。
MS(ESI)m/e 198.2([M–56+H]+)。
(2)将上一步产品(5-2,118mg,0.5mmol)溶于2ml乙腈中,加入氘代甲胺盐酸盐(105mg,1.5mmol),加入DBU(304mg,2mmol),25℃搅拌反应过夜,冷却至室温,TLC检测,反应完全,水洗,乙酸乙酯萃取,有机层用0.1N盐酸水溶液洗涤,再分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,得白色固体产品(5)57mg,收率82.6%。
MS(ESI)m/e 157.3([M+H]+)。
1H NMR(400MHz,CDCl3)δ7.77(dd,J=8.7,5.3Hz,2H),7.11(t,J=8.6Hz,2H),6.12(s,1H)。
实施例6、化合物6的合成
(1)将N-甲基环己甲酰胺(6-1,141mg,1mmol)溶于二氯甲烷(5ml),搅拌下加入DMAP(244mg,2mmol),加入Boc酸酐(436mg,2mmol),室温反应16小时,TLC检测直至反应完全,反应体系用0.1N盐酸水溶液洗涤直至把DMAP洗干净,有机层分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,薄层柱层析纯化(PE/EA=2:1),得到白色液体产品(6-2)202mg,收率:83.8%。
MS(ESI)m/e 186.1([M–56+H]+)。
(2)将上一步产品(6-2,120mg,0.5mmol)溶于2ml乙腈中,加入氘代甲胺盐酸盐(105mg,1.5mmol),加入DBU(304mg,2mmol),室温反应过夜。TLC检测,反应完全,水洗,乙酸乙酯萃取,有机层用0.1N盐酸水溶液洗涤,再分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,得白色液体产品(6)62mg,收率86.1%。
MS(ESI)m/e 145.1([M+H]+)。
1H NMR(400MHz,CDCl3)δ5.6(s,1H),2.05(tt,J=9.2,5.9Hz,1H),1.75(m,4H),1.41(m,2H),1.25(m,4H)。
实施例7、化合物7的合成
(1)将N-甲基-3-苯基丙酰胺(7-1,163mg,1mmol)溶于二氯甲烷(5ml),搅拌下加入DMAP(244mg,2mmol),加入Boc酸酐(436mg,2mmol),室温反应16小时,TLC检测直至反应完全,反应体系用0.1N盐酸水溶液洗涤直至把DMAP洗干净,有机层分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,薄层柱层析纯化(PE/EA=2:1),得到白色固体产品(7-2)214mg,收率:81.4%。
MS(ESI)m/e 208.1([M–56+H]+)。
(2)将上一步产品(7-2,131mg,0.5mmol)溶于2ml乙腈中,加入氘代甲胺盐酸盐(105mg,1.5mmol),加入DBU(304mg,2mmol),室温反应过夜。TLC检测,反应完全,水洗,乙酸乙酯萃取,有机层用0.1N盐酸水溶液洗涤,再分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,得白色固体产品(7)73mg,收率88.1%。
MS(ESI)m/e 167.1([M+H]+)。
1H NMR(400MHz,CDCl3)δ7.3(m,2H),7.19(t,J=6.2Hz,3H),5.57(s,1H),2.96(t,J=7.8Hz,2H),2.46(t,J=7.8Hz,2H)。
实施例8、化合物8的合成
(1)将N-甲基己酰胺(8-1,129mg,1mmol)溶于二氯甲烷(5ml),搅拌下加入DMAP(244mg,2mmol),加入Boc酸酐(436mg,2mmol),室温反应16小时,TLC检测直至反应完全,反应体系用0.1N盐酸水溶液洗涤直至把DMAP洗干净,有机层分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,薄层柱层析纯化(PE/EA=2:1),得到白色液体产品(8-2)199mg,收率:86.9%。
MS(ESI)m/e 174.1([M–56+H]+)。
(2)将上一步产品(8-2,115mg,0.5mmol)溶于2ml乙腈中,加入氘代甲胺盐酸盐(105mg,1.5mmol.),加入DBU(304mg,2.5mmol),室温反应过夜。TLC检测,反应完全,水洗,乙酸乙酯萃取,有机层用0.1N盐酸水溶液洗涤,再分别用饱和NaHCO3水溶液、NaCl水溶液洗涤,无水Na2SO4干燥,旋干,得白色液体产品(8)56mg,收率84.8%。
1H NMR(400MHz,CDCl3)δ6.16(s,1H),2.12(t,J=7.7Hz,2H),1.58(m,2H),1.23(dd,J=8.6,4.9Hz,4H),0.82(t,J=6.8Hz,3H)。
MS(ESI)m/e 133.1([M+H]+)。
综上,本发明提供了一种合成氘代酰胺及氘代磺酰胺的新方法,该方法反应条件温和,路线短,仅需两步即可得到,可以应用于已有方法不能适用的原料,提高合成效率,可以适用于很多酰胺类化合物,具有较强的普适性,为制备氘代胺的酰胺及磺酰胺类化合物提供了一种新的选择。
Claims (33)
1.一种合成氘代胺的方法,其特征在于:步骤如下:
式中,
L选自羰基、磺基;
R1选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基;
R2选自取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
R3选自-CO-R6、-SO2R7;X为一个离去基团;
其中,R6、R7各自独立地选自烷氧基、烷基、取代的烷基、芳基;
R4、R5各自独立地选自H、氘代的取代或未取代的烷基、氘代的环烷基、氘代的杂环基、氘代的芳基、氘代的杂芳基,且R4、R5不同时为氢;
(1)将化合物M、DMAP、R3-X加入到溶剂中,反应完全后得化合物N;
(2)将化合物N、R4-NH-R5或其盐、碱加入到溶剂中,反应完全后,纯化得化合物Ⅰ。
2.根据权利要求1所述的合成方法,其特征在于:
R3选自-CO-R6、-SO2R7;X选自-OR3、Cl、Br;
其中,R6、R7各自独立地选自叔丁氧基、异丙氧基、苄氧基、甲基、三氟甲基、苯基、甲苯基。
3.根据权利要求2所述的合成方法,其特征在于:
R3选自-CO-R6、-SO2R7;
其中,R6选自叔丁氧基、异丙氧基、苄氧基;R7选自甲基、三氟甲基、苯基、甲苯基。
4.根据权利要求3所述的合成方法,其特征在于:
R3选自-CO-R6;X为-OR3;
其中,R6选自叔丁氧基。
5.根据权利要求1所述的合成方法,其特征在于:
R4、R5各自独立地选自H、氘代的烷基,且R4、R5不同时为氢。
6.根据权利要求5所述的合成方法,其特征在于:
R4、R5各自独立地选自H、氘代的甲基,且R4、R5不同时为氢。
7.根据权利要求1所述的合成方法,其特征在于:
R2选自取代或未取代的C1~C6烷基。
8.根据权利要求7所述的合成方法,其特征在于:
R2选自C1~C4烷基。
9.根据权利要求8所述的合成方法,其特征在于:
R2选自甲基。
10.根据权利要求1所述的合成方法,其特征在于:R1选自下述结构之一:
11.根据权利要求1所述的合成方法,其特征在于:化合物Ⅰ选自下述结构之一:
12.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述溶剂为极性溶剂或非极性溶剂。
13.根据权利要求12所述的合成方法,其特征在于:所述极性溶剂选自二氯甲烷、二氯乙烷、甲酰胺、三氟乙酸、DMSO、乙腈、DMF、六甲基磷酰胺、甲醇、乙醇、乙酸、异丙醇、吡啶、四甲基乙二胺、丙酮、三乙胺、正丁醇、二氧六环、四氢呋喃、甲酸甲酯、三丁胺、甲乙酮、乙酸乙酯、氯仿、三辛胺、碳酸二甲酯、***、异丙醚、正丁醚、三氯乙烯、二苯醚。
14.根据权利要求13所述的合成方法,其特征在于:所述极性溶剂选自二氯甲烷。
15.根据权利要求12所述的合成方法,其特征在于:所述非极性溶剂选自苯、甲苯、四氯化碳、二硫化碳、环己烷、己烷。
16.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述化合物M、DMAP、R3-X的摩尔比为1:1~3:1~10,优选为1:2~3:1.5~2。
17.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述化合物M与溶剂的投料比为1:2~20mmol/mL;优选为1:2~15mmol/mL,更优选为1:5.5~10mmol/mL。
18.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述反应温度为10~60℃。
19.根据权利要求18所述的合成方法,其特征在于:所述反应温度为20~30℃,优选为25℃。
20.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述反应时间为10~120h,优选为10~16h,更优选为10~14h,进一步优选为12h。
21.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述溶剂为极性溶剂或非极性溶剂。
22.根据权利要求21所述的合成方法,其特征在于:所述极性溶剂选自二氯甲烷、二氯乙烷、甲酰胺、三氟乙酸、DMSO、乙腈、DMF、六甲基磷酰胺、甲醇、乙醇、乙酸、异丙醇、吡啶、四甲基乙二胺、丙酮、三乙胺、正丁醇、二氧六环、四氢呋喃、甲酸甲酯、三丁胺、甲乙酮、乙酸乙酯、氯仿、三辛胺、碳酸二甲酯、***、异丙醚、正丁醚、三氯乙烯、二苯醚。
23.根据权利要求22所述的合成方法,其特征在于:所述极性溶剂选自乙腈。
24.根据权利要求21所述的合成方法,其特征在于:所述非极性溶剂选自苯、甲苯、四氯化碳、二硫化碳、环己烷、己烷。
25.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述化合物N与溶剂的投料比为1:1~25mmol/mL,优选为1:1~20mmol/mL,更优选为1:2.5~15mmol/mL。
26.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述碱为有机碱或无机碱。
27.根据权利要求26所述的合成方法,其特征在于:所述有机碱选自DBU、甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠、三乙胺、三乙烯二胺、DBN、DMAP、吡啶、N-甲基吗啉、四甲基乙二胺、TMG、正丁基锂、LDA。
28.根据权利要求27所述的合成方法,其特征在于:所述有机碱选自DBU。
29.根据权利要求26所述的合成方法,其特征在于:所述无机碱选自氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、氢氧化铜、氢氧化铁、氢氧化铅、氢氧化钴、氢氧化铬、氢氧化锆、氢氧化镍、氢氧化铵、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾。
30.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述化合物N、R4-NH-R5或其盐、碱的摩尔比为1:1~4:1~5,优选为1:1~4:1~4.5。
31.根据权利要求30所述的合成方法,其特征在于:所述化合物N、R4-NH-R5或其盐、碱的摩尔比为1:3:4。
32.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述反应温度为10~100℃,优选为20~30℃,更优选为25℃。
33.根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述反应时间为10~120h,优选为10~14h,更优选为12h。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018103321341 | 2018-04-13 | ||
CN201810332134 | 2018-04-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110372598A true CN110372598A (zh) | 2019-10-25 |
Family
ID=68163089
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910295994.7A Pending CN110372598A (zh) | 2018-04-13 | 2019-04-12 | 一种合成氘代酰胺及氘代磺酰胺的新方法 |
Country Status (7)
Country | Link |
---|---|
US (1) | US11753392B2 (zh) |
EP (1) | EP3778538A4 (zh) |
JP (1) | JP2021521190A (zh) |
KR (1) | KR102482289B1 (zh) |
CN (1) | CN110372598A (zh) |
CA (1) | CA3096963A1 (zh) |
WO (1) | WO2019196945A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112194633A (zh) * | 2020-11-06 | 2021-01-08 | 杭州新拜思生物医药有限公司 | 一种合成阿帕鲁胺及其中间体的方法及中间体 |
WO2021037198A1 (zh) * | 2019-08-30 | 2021-03-04 | 润佳(苏州)医药科技有限公司 | 氘代化合物及其在治疗癌症方面的应用 |
CN112442011A (zh) * | 2019-08-30 | 2021-03-05 | 润佳(苏州)医药科技有限公司 | 一种前药化合物及其在治疗癌症方面的应用 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4021912A4 (en) * | 2019-08-30 | 2023-08-23 | Risen (Suzhou) Pharma Tech Co., Ltd. | TYROSINE KINAS INHIBITOR PRODRUGS FOR THE TREATMENT OF CANCER |
CN112679348B (zh) * | 2020-12-27 | 2023-09-05 | 河南师范大学 | 一种3-芳甲酰基茚酮-2-甲酸酯类化合物的合成方法 |
CN115896823A (zh) * | 2022-03-29 | 2023-04-04 | 天津大学 | D2O为氘源电催化腈制备α,β-氘代胺类药物及药物前体的方法 |
CN114634471B (zh) * | 2022-04-14 | 2023-05-19 | 河南师范大学 | 一种合成γ-羟基-γ-全氟甲基环外双键丁内酯类化合物的方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090062347A1 (en) * | 2007-08-29 | 2009-03-05 | Protia, Llc | Deuterium-enriched axitinib |
CN103159680A (zh) * | 2011-12-14 | 2013-06-19 | 爱美尼迪药物有限公司 | 咪唑二酮类化合物及其用途 |
CN104211683A (zh) * | 2013-05-29 | 2014-12-17 | 成都海创药业有限公司 | 咪唑二酮类化合物及其用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070041933A1 (en) * | 2005-08-10 | 2007-02-22 | Simanek Eric E | Functionally Diverse Macromolecules and Their Synthesis |
US8212047B2 (en) * | 2007-09-20 | 2012-07-03 | Exxonmobil Chemical Patents Inc. | Methods for preparation of pyridylamines |
US9505667B2 (en) * | 2014-11-06 | 2016-11-29 | E I Du Pont De Nemours And Company | Method for preparing deuterated aromatic compounds |
-
2019
- 2019-04-12 CA CA3096963A patent/CA3096963A1/en active Pending
- 2019-04-12 KR KR1020207029303A patent/KR102482289B1/ko active IP Right Grant
- 2019-04-12 US US17/047,380 patent/US11753392B2/en active Active
- 2019-04-12 JP JP2020555814A patent/JP2021521190A/ja active Pending
- 2019-04-12 EP EP19785608.1A patent/EP3778538A4/en active Pending
- 2019-04-12 CN CN201910295994.7A patent/CN110372598A/zh active Pending
- 2019-04-12 WO PCT/CN2019/082555 patent/WO2019196945A1/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090062347A1 (en) * | 2007-08-29 | 2009-03-05 | Protia, Llc | Deuterium-enriched axitinib |
CN103159680A (zh) * | 2011-12-14 | 2013-06-19 | 爱美尼迪药物有限公司 | 咪唑二酮类化合物及其用途 |
CN104211683A (zh) * | 2013-05-29 | 2014-12-17 | 成都海创药业有限公司 | 咪唑二酮类化合物及其用途 |
Non-Patent Citations (1)
Title |
---|
YONGMEI LIU,ET AL.: "Metal-Free Transamidation of Secondary Amides via Selective N-C Cleavage under Mild Conditions", 《 ORG. LETT.》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021037198A1 (zh) * | 2019-08-30 | 2021-03-04 | 润佳(苏州)医药科技有限公司 | 氘代化合物及其在治疗癌症方面的应用 |
CN112442011A (zh) * | 2019-08-30 | 2021-03-05 | 润佳(苏州)医药科技有限公司 | 一种前药化合物及其在治疗癌症方面的应用 |
CN112442011B (zh) * | 2019-08-30 | 2023-11-14 | 润佳(苏州)医药科技有限公司 | 一种前药化合物及其在治疗癌症方面的应用 |
CN112194633A (zh) * | 2020-11-06 | 2021-01-08 | 杭州新拜思生物医药有限公司 | 一种合成阿帕鲁胺及其中间体的方法及中间体 |
Also Published As
Publication number | Publication date |
---|---|
KR102482289B1 (ko) | 2022-12-27 |
WO2019196945A1 (zh) | 2019-10-17 |
CA3096963A1 (en) | 2019-10-17 |
EP3778538A1 (en) | 2021-02-17 |
JP2021521190A (ja) | 2021-08-26 |
US11753392B2 (en) | 2023-09-12 |
KR20200130418A (ko) | 2020-11-18 |
US20210115009A1 (en) | 2021-04-22 |
EP3778538A4 (en) | 2022-03-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110372598A (zh) | 一种合成氘代酰胺及氘代磺酰胺的新方法 | |
TWI787018B (zh) | 轉染過程重排之抑制劑 | |
CN112638917B (zh) | 作为激酶抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法 | |
TWI795362B (zh) | 拮抗藥與免疫核查點阻礙藥而成之組合 | |
JP7097358B2 (ja) | アルファvインテグリン阻害剤としての3-置換プロピオン酸 | |
CA3133753A1 (en) | Novel small molecule inhibitors of tead transcription factors | |
JP2022518591A (ja) | 複素環式化合物であるベンゾピリドンおよびその使用 | |
JP2022543767A (ja) | 四環式化合物、その調製と使用の方法 | |
JP2021500330A (ja) | Pad阻害剤としてのイミダゾ−ピリジン化合物 | |
WO2022028346A1 (zh) | 一种芳香类化合物及其在抗肿瘤药物中的应用 | |
CN103124730A (zh) | 杂环炔苯类化合物及其药用组合物和应用 | |
CN104341425A (zh) | 氘代乙炔衍生物、其药物组合物及应用 | |
ES2837018T3 (es) | Ligandos del receptor D3 de dopamina de 6,7,8,9-tetrahidro-5H-pirido[2,3-d]azepina | |
CN104926788A (zh) | 取代哌啶类衍生物、含其的药物组合物及其在抗肿瘤中的应用 | |
CN113527293B (zh) | Kras g12c突变蛋白抑制剂及其药物组合物、制备方法和用途 | |
WO2015049629A1 (en) | Imidazoquinoline compounds as bromodomain inhibitors | |
CN114685460A (zh) | Kras g12c抑制剂及其在医药上的应用 | |
CA3182595A1 (en) | Immunosuppressant, and preparation method therefor and use thereof | |
CN115991706A (zh) | Pim激酶抑制剂 | |
JP2021513549A (ja) | インドール−2、3−ジオキシゲナーゼ阻害剤としてのスピロ化合物 | |
CN110066277A (zh) | 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 | |
CN107793371B (zh) | 一类溴结构域识别蛋白抑制剂及其制备方法和用途 | |
CN112601745B (zh) | 一种氮杂芳基酰胺衍生物及其制备方法和应用 | |
TWI676625B (zh) | 磺醯胺類衍生物、其製備方法及其在醫藥上的用途 | |
CN107903208B (zh) | 一类联芳吡啶类去泛素化酶抑制剂、其制备方法及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information | ||
CB02 | Change of applicant information |
Address after: No.2 and No.3, floor 4, building 1, Rongyao building, No.5 Keyuan South Road, high tech Zone, Chengdu, Sichuan 610000 Applicant after: Haichuang Pharmaceutical Co.,Ltd. Address before: No.1, floor 4, building a, Rongyao building, No.5 Keyuan South Road, high tech Zone, Chengdu, Sichuan 610000 Applicant before: HINOVA PHARMACEUTICALS Inc. |
|
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191025 |