CN107629039A - The preparation method and intermediate of deuterated acrylamide - Google Patents
The preparation method and intermediate of deuterated acrylamide Download PDFInfo
- Publication number
- CN107629039A CN107629039A CN201710949642.XA CN201710949642A CN107629039A CN 107629039 A CN107629039 A CN 107629039A CN 201710949642 A CN201710949642 A CN 201710949642A CN 107629039 A CN107629039 A CN 107629039A
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- China
- Prior art keywords
- compound
- deuterated
- organic solvent
- preparation
- acrylamide
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- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000003926 acrylamides Chemical class 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 15
- -1 haloacetyl chloride Chemical compound 0.000 claims abstract description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920006324 polyoxymethylene Polymers 0.000 claims abstract description 6
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001243 acetic acids Chemical class 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 5
- 239000007821 HATU Substances 0.000 claims description 5
- 229910052805 deuterium Inorganic materials 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 2
- HRJWXGFOMWZQLS-UHFFFAOYSA-N C(C)(=O)OO.[P].C(C)OOOCC Chemical compound C(C)(=O)OO.[P].C(C)OOOCC HRJWXGFOMWZQLS-UHFFFAOYSA-N 0.000 claims 1
- IYBLWEKTKNTGMF-UHFFFAOYSA-N C(C)(=O)O.[P].C(C)OOOCC Chemical compound C(C)(=O)O.[P].C(C)OOOCC IYBLWEKTKNTGMF-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229940125890 compound Ia Drugs 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 229910019891 RuCl3 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- BTIBIPZUOGKHFX-UHFFFAOYSA-N [P].C(C)OOOCC Chemical compound [P].C(C)OOOCC BTIBIPZUOGKHFX-UHFFFAOYSA-N 0.000 description 2
- 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000011981 lindlar catalyst Substances 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 2
- 229960003278 osimertinib Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 125000000394 phosphonato group Chemical group [O-]P([O-])(*)=O 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229940107700 pyruvic acid Drugs 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- OJASMMNWWIJWFK-KUSCCAPHSA-N (3r)-1-[[4-[[(3r)-3-(diethylcarbamoyl)piperidin-1-yl]methyl]phenyl]methyl]-n,n-diethylpiperidine-3-carboxamide;dihydrobromide Chemical compound Br.Br.C1[C@H](C(=O)N(CC)CC)CCCN1CC(C=C1)=CC=C1CN1C[C@H](C(=O)N(CC)CC)CCC1 OJASMMNWWIJWFK-KUSCCAPHSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- QKDCLUARMDUUKN-XMMPIXPASA-N 6-ethyl-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-[(3r)-1-prop-2-enoylpyrrolidin-3-yl]oxypyrazine-2-carboxamide Chemical compound N1=C(O[C@H]2CN(CC2)C(=O)C=C)C(CC)=NC(C(N)=O)=C1NC(C=C1)=CC=C1N(CC1)CCC1N1CCN(C)CC1 QKDCLUARMDUUKN-XMMPIXPASA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- MBTIGPJJQBDYNK-UHFFFAOYSA-N C(C#C)(=O)O.[Na] Chemical class C(C#C)(=O)O.[Na] MBTIGPJJQBDYNK-UHFFFAOYSA-N 0.000 description 1
- CMAXFEJXQVZZRP-UHFFFAOYSA-N C(C)(=O)O.[P].[O] Chemical compound C(C)(=O)O.[P].[O] CMAXFEJXQVZZRP-UHFFFAOYSA-N 0.000 description 1
- 0 CN(C)CCN(C)c(cc1OC)c(*C(C=C(*)[U])=O)cc1Nc1nc(-c2c[n](C)c3ccccc23)ccn1 Chemical compound CN(C)CCN(C)c(cc1OC)c(*C(C=C(*)[U])=O)cc1Nc1nc(-c2c[n](C)c3ccccc23)ccn1 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002118 epoxides Chemical class 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
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- JYIUNVOCEFIUIU-GHMZBOCLSA-N n-[(3r,4r)-4-fluoro-1-[6-[(3-methoxy-1-methylpyrazol-4-yl)amino]-9-methylpurin-2-yl]pyrrolidin-3-yl]prop-2-enamide Chemical compound COC1=NN(C)C=C1NC1=NC(N2C[C@H]([C@H](F)C2)NC(=O)C=C)=NC2=C1N=CN2C JYIUNVOCEFIUIU-GHMZBOCLSA-N 0.000 description 1
- 229950009708 naquotinib Drugs 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The invention discloses a kind of preparation method and intermediate of deuterated acrylamide, belongs to organic synthesis field.The structure of the deuterated acrylamide is shown in formula I.The preparation method includes the step of route shown below：Compound a 1 reacts to obtain compound a 2 in the presence of a base with diethoxy oxygen phosphorus acetic acid, and compound a 2 reacts to obtain compound I with two deuterated polyformaldehyde or two deuterated formaldehyde in the presence of a base.Compound a 2 can also react to obtain compound a 3 by compound a 1 and halogenated acetic acids or haloacetyl chloride, and gained Haloacetamide reacts to obtain with triethyl phosphite again.The method for preparing compound of formula I has the advantages that high income, purity are high, and process repeatability is good.
Description
Technical field
The present invention relates to the preparation method of deuterated acrylamide and intermediate, belongs to organic synthesis field.
Background technology
Deuterated compound is in the important purposes of many of drug research.They are not only used as not by deuterated medicine
Alternative medicine, it is also used as the isotopic standard product of drug metabolism study.Acrylic acid derivative has many use in terms of medicine
On the way, for example irreversible selective EGFR inhibition from mutation agent AZD9291 of the third generation and other EGFR suppressions containing acrylic amide
Preparation (such as DY3002, WZ4002, CI-1033, CO-1688, EGF816, ASP8273, PF-06747775 etc.).AZD9291 is
Through being approved by the fda in the United States for treating lung cancer.The purposes of deuterated acrylic acid and its derivative in terms of industry and medicine is more and more
It is more.But the synthetic method of deuterated acrylic acid and its derivative is seldom reported.United States Patent (USP) (US Pat.4874890) discloses
Using RuCl3Catalyst, deuterium or heavy water directly substitute the method for hydrogen in double bond to prepare deuterated acrylic compounds.Chemical combination
Activity order deuterated thing A is (a)=(b)>(c).But in RuCl3In the presence of, deuterated reaction reaches 45%.It is caused
Mixture does not have Practical significance in most instances.
Yang discloses the preparation of tri- deuterated acrylic acid of 2,3,3- in United States Patent (USP) (US Pat.8829238).With propine
Sour II is raw material, is exchanged into deuterated propiolic acid sodium III with heavy water in the presence of a base, then under deuterium, is urged with Lindlar catalyst
Change deuterate and obtain the required deuterated PAA IV of product 2,3,3- tri-.But when quality and the reaction of Lindlar catalyst
Between can all influence the purity of product.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the present invention to provide the preparation method of the deuterated acrylamide of Formulas I structure, realize
Produce deuterated acrylamide to high yield, high-purity.
Wherein,
R is selected from substitution or unsubstituted alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；Substituent be selected from halogen,
Hydroxyl, optionally by alkyl-substituted amino, amino acid group, amino-acid ester group, alkyl, alkoxy, alkylthio group, cycloalkyl,
Cycloalkyloxy, cycloalkylthio, heterocyclic radical, aryl, aryloxy group, arylthio, heteroaryl, nitro, cyano group ,-N3, sulfonyl, sulfuric acid
Foundation, phosphono, phosphoric acid foundation, phosphonato；
Alkyl in the alkyl, alkoxy, alkylthio group is each independently the C of straight or branched1~C20Alkyl, it is optional
Ground is the C of straight or branched1~C16Alkyl, it is optionally the C of straight or branched1~C10Alkyl, it is optionally straight or branched
C1~C6Alkyl, it is optionally the C of straight or branched1~C4Alkyl；
Cycloalkyl in the cycloalkyl, cycloalkyloxy, cycloalkylthio is each independently C3~C20Monocyclic or polynaphthene
Base, it is optionally C3~C15Monocyclic or multi-ring alkyl, is optionally C3~C10Monocyclic or multi-ring alkyl, is optionally C3~C7It is single
Ring or multi-ring alkyl；
The heterocyclic radical is 1-3 carbon atom in the cycloalkyl by selected from one or more of O, S, N hetero atom
The group of replacement；
Aryl in the aryl, aryloxy group, arylthio is each independently C6~C18Monocyclic or polyaromatic, alternatively
For C6~C14Monocyclic or polyaromatic, is optionally C6~C10Monocyclic or polyaromatic；
The heteroaryl is to be selected from heteroatomic 5~20 unit monocycle of N, O, S or polyheteroaromatic containing 1~3, alternatively
For 5~15 unit monocycles or polyheteroaromatic, 5~10 unit monocycles or polyheteroaromatic are optionally；
The halogen is selected from：F、Cl、Br、I；
Preferably, the alkyl can be optionally by halogen, hydroxyl ,-N (R1)(R2)、C1-5Alkoxy, C3-6Cycloalkanes
Epoxide, phenoxy group, C1-5Alkylthio group, C3-5Cycloalkylthio, thiophenyl, nitro, cyano group ,-N3In one or more
Substitution；
Preferably, the cycloalkyl, heterocyclic radical, aryl, heteroaryl can be optionally by halogen, C1-5Alkyl, hydroxyl ,-N
(R1)(R2)、C1-5Alkoxy, C3-6Cycloalkyloxy, C1-5Alkylthio group, C3-5Cycloalkylthio, phenoxy group, thiophenyl, nitre
Base, cyano group ,-N3, sulfonyl, sulphate groups, phosphono, phosphoric acid foundation, one or more kinds of substitutions in phosphonato；
R1、R2It is each independently hydrogen, alkyl；
Preferentially, R is the group shown in i：
Wherein, each R3It independently is alkyl, preferably C1-C3Alkyl, the alkyl are optionally deuterated；
Preferably, R is the group shown in i-1：
Preferably, above-mentioned compound of formula I, it is characterised in that the compound of formula I is following formula: compound Ia：
Researcher's experiment of the present invention compares the several method of following preparation compound of formula I：
Wherein, R is as described above.
Method one：
Compound 1 and pyruvic acid or acetone acyl chloride reaction generation compound 2, in the presence of alkali or catalyst in heavy water
Deuterium is exchanged to obtain compound 3, then generates compound 4 with sodium borohydride reduction, and compound 4 is handled with sulfonic acid chloride in the presence of a base
Obtain compound I.But deuterated product 3 is unstable, it is difficult to is stablized and high deuterated target product.
Method two：
Pyruvic acid 5 is deuterated in heavy water in the presence of a base to obtain compound 6, is changed with sodium borohydride reduction compound 6
Compound 7, then be dehydrated with concentrated hydrochloric acid to obtain compound 8, the latter and R-NH2Reaction generation compound I.It is deuterated in this synthetic route
The molecule of acrylic acid 8 is small, it is difficult to isolated and purified, so, this synthetic route is not readily used for preparing on a large scale.
Method three：
Compound a -1 generates compound a -2 in the presence of condensing agent with diethoxy oxygen phosphorus acetic acidreaction；Compound a -2
React to obtain compound I with two deuterated polyformaldehyde or two deuterated formaldehyde in the presence of a base.Compound a -2 can also pass through compound
A-1 and halogenated acetic acids or haloacetyl chloride react to obtain compound a -3, gained Haloacetamide a-3 again with phosphorous triethylenetetraminehexaacetic acid
Ester reaction is made.
Found in experiment, compound a -1 generates compound a -2 in the presence of condensing agent with diethoxy oxygen phosphorus acetic acidreaction
It is an exothermic reaction, adds 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU) condensation
During agent, controlling reaction temperature preferentially selects 0-25 DEG C at 0-50 DEG C, otherwise will increase side reaction.Decline yield, purification difficult.
Compound a -2 reacts to obtain compound I with two deuterated polyformaldehyde or two deuterated formaldehyde in the presence of a base, is made with KOH
It is more preferable to add the product quality of LiCl reaction gained and yield while alkali.Experiment finds the alkaline extremely important of reaction solution,
Preferentially, pH controls are in 10-12, pH<When 10, the alkalescence of reaction solution is not enough to deprotonation and triggers Wittig to react.But such as
Too big (the pH of fruit alkalescence>12) other side reactions such as amide hydrolysis can, then be caused.
Compound a -1 reacts to obtain compound a -3 in the presence of HATU with halogenated acetic acids, and this condensation reaction is also that heat release is anti-
Should, it may be preferable that controlling reaction temperature is at less than 25 degree Celsius, to improve reaction yield.
Compound a -1 reacts generation compound a -3 with haloacetyl chloride in the presence of a base, it is preferable that alkali used is selected from such as
The organic bases such as pyridine, triethylamine；Preferentially, reaction temperature control is at less than 25 degree Celsius.
Compound a -3 in the presence of a base with triethyl phosphite react generation compound a -2 ((J.Org.Chem.1996,
), 61,7202) alkali is selected from organic base；Preferably, selected from such as pyridine, triethylamine etc.；In the reaction, it is optionally added organic
Solvent；Preferably, the organic solvent is selected from aprotic solvents；Preferably, the organic solvent is selected from：THF,CH2Cl2,
DMF etc..
The present invention also provides the useful intermediates as shown in formula a-2I and a-3I：
The method provided by the invention for preparing compound of formula I has that yield is high, and up to more than 30%, purity is high, up to 95% with
On, the advantages that process repeatability is good, it is adapted to industrialized production.
Embodiment
The embodiment of the present invention is described in detail below.It is it should be appreciated that described herein specific
Being given for example only property of embodiment the present invention will be described, be not intended to limit the invention.
The compound Ia of embodiment 1. synthesis
Synthetic route is as follows：
1st, a-2I is prepared from diethoxy oxygen phosphorus acetic acid：By a-1I (5g, 0.011mol), diethoxy oxygen phosphorus acetic acid
(2.35g, 0.012mol) and DIPEA (1.68g, 0.013mol), is dissolved in tetrahydrofuran (25mL), slowly adds
Enter HATU (4.94g, 0.013mol), after having added, 25 DEG C are continued stirring 5 hours.Reaction solution is poured into water (50mL), and uses second
Acetoacetic ester (50mL x 2) extracts, and merges organic phase.Organic phase washed with water (50mL x 4) and semi-saturation saline solution (50mL x
4) wash, anhydrous sodium sulfate drying, be concentrated to give faint yellow solid a-2I (5g, yield 71.5%), without purifying, be directly used in
The next step.M.p:113‐116℃.LCMS[M+1]+:624.4。
1HNMR(400MHz,CDCl3):δ 1.26 (t, J=7.2Hz, 6H), 2.65 (s, 3H), 2.83 (s, 6H), 3.89 (s,
3H), 3.91 (s, 3H), 4.11 (q, J=7.2Hz, 4H), 7.02 (s, 1H), 7.18 (d, J=7.2Hz, 1H), 7.22-7.28
(m, 2H), 7.54 (d, J=7.2Hz, 1H), 8.00 (br, 1H), 8.29-8.32 (m, 2H), 8.53 (s, 1H), 8.72 (s, 1H),
8.97(br,1H),9.54(s,1H)。
2nd, prepare compound Ia:By a-2I (200mg, 0.32mmol), deuterated polyformaldehyde (10mg, 0.33mmol), chlorination
Lithium (20mg, 0.48mmol), potassium hydroxide (89mg, 1.6mmol) are dissolved in THF/H2In O (2mL/2mL) solution, pH controls exist
10-12, it is stirred overnight at room temperature (16h).Water (20mL) is added into reaction solution, is extracted with ethyl acetate (20mL), and use successively
Water (20mL), saline solution (20mL x 2) washing.Organic phase anhydrous sodium sulfate drying, it is concentrated to give crude product (150mg), post layer
Analyse (eluent:Dichloromethane:Methanol=20:1) faint yellow solid Ia (110mg, yield 68%) is separated to obtain.HPLC purity：
99.8%, M.p:100‐103℃.LCMS[M+1]+:502.5。1HNMR(400MHz,CDCl3):δ2.28(s,8H),2.71(s,
3H), 2.91 (br, 2H), 3.89 (s, 3H), 4.00 (s, 3H), 6.79 (br, 1H), 7.20 (d, J=5.2Hz, 1H), 7.24-
7.30 (m, 2H), 7.39-7.41 (m, 1H), 7.72 (s, 1H), 8.06 (dd, J=6.8Hz, J=1.6Hz, 1H), 8.38 (d, J
=5.6Hz, 1H), 9.10 (s, 1H), 9.85 (s, 1H), 10.14 (br, 1H).
Embodiment 2 is from halide prepare compound a-2I：
Route A
Route B
Route A is prepared from iodo acetic acid：The method for preparing a-2I with diethoxy oxygen phosphorus acetic acid, two are replaced with iodo acetic acid
Ethyoxyl oxygen phosphorus acetic acid obtains compound a -3I.LCMS[M+1]+:614。
It is prepared by route B Iodoactyl chloride：By compound a -1I (445mg, 1.0mmol) and triethylamine (303mg,
3.0mmol) it is dissolved in CH2Cl2(10mL).Iodoactyl chloride (204.4mg, 1.0mmol) is slowly added at 0 DEG C by syringe, added
2h is stirred at room temperature in compound of reaction after complete.Water (10mL) is added, mixture is extracted with EtOAc (10mL x 3), Na2SO4It is dry
It is dry, boil off solvent and obtain product a-3I, the next step is directly used in without purifying.
Gained a-3I and Et3N (303mg, 3.0mmol) is dissolved in CH2Cl2(10mL), triethoxy phosphine is added at 0 DEG C
(249mg,1.5mmol).24h is stirred at room temperature in reaction solution.Water (10mL) is added, mixture is extracted with EtOAc (10mL x3),
Organic phase Na2SO4Dry, boil off solvent, residue is through the silica gel column chromatography (CH of 0-5% methanol2Cl2) purifying obtain chemical combination
Thing a-2I.LCMS[M+1]+:624。
Comparative example 1
The synthetic route of bis- deuterated acrylic acid of 3,3- is as follows：
The chosen property of ethylene glycol (9) is protected to obtain compound 10.With usual method oxidized compound 10 generate aldehyde 11 after with
The two deuterated Wittig reagent reactings generation deuterated propylene 12 of 3,3- bis-.Compound 12 through Deprotection rear oxidation compound 13,
Obtain the deuterated acrylic acid 8 of 3,3- bis-.Compound 8 reacts to obtain the corresponding deuterated acrylamide I of 3,3- bis- with appropriate precursor amine.
But reaction scheme is oversize, compound 11 is easily excessively oxidated into acid, and total recovery is very low, usually 3-10%.
Comparative example 2
The synthetic route of bis- deuterated acrylic acid of 3,3- is as follows：
Malonate 14 reacts generation compound 15 with deuterated formaldehyde in the presence of alkali, then through hydrolysis generation deuterated third
Olefin(e) acid 8.The performance level of hydroxymethylation is difficult to control, and causes product 8 to be mixed with by-product acetic acid, it is difficult to pure
Change.Reaction repeatability is bad.
In summary, the present invention has high income, purity height, technique by the intermediate a-2I methods for preparing compound of formula I
Favorable repeatability etc. is a little.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
Claims (5)
1. the preparation method of deuterated acrylamide, it is characterised in that realize by the following method：
(1) in organic solvent, compound a -1 is given birth in the presence of condensing agent with diethoxy oxygen phosphorus peracetic acid temperature in 0-50 DEG C of reaction
Into compound a -2, the condensing agent selects dicyclohexylcarbodiimide (DCC) class or 2- (7- aoxidizes BTA)-N, N, N',
N'- tetramethylurea hexafluorophosphoric acid esters (HATU)；The organic solvent is selected from aprotic solvents；
(2) in organic solvent or/and water, compound a -2 in the presence of a base, adds LiCl, deuterated with two deuterated polyformaldehyde or two
Formaldehyde reacts to obtain compound I；The alkali is selected from：Potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide；The organic solvent choosing
From aprotic solvents or alcohol；R is the group shown in i：
Each R3It independently is C1-C3Alkyl, the alkyl are substituted by deuterium.
2. the preparation method of deuterated acrylamide, it is characterised in that realize by the following method：
(1) in organic solvent, compound a -1 reacts to obtain compound a -3 in the presence of condensing agent with halogenated acetic acids；The condensation
Dicyclohexylcarbodiimide (DCC) class or 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids are selected in agent
Ester (HATU)；The organic solvent is selected from aprotic solvents；
Or in organic solvent, compound a -1 reacts generation compound a -3 with haloacetyl chloride in the presence of an organic base, described
Organic solvent is selected from aprotic solvents；
(2) in organic solvent, compound a -3 reacts generation compound a -2 with triethyl phosphite in the presence of an organic base, described
Organic solvent is selected from aprotic solvents；
(3) in organic solvent or/and water, compound a -2 in the presence of a base, adds LiCl, deuterated with two deuterated polyformaldehyde or two
Formaldehyde reacts to obtain compound I；The alkali is selected from：Potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide；The organic solvent choosing
From aprotic solvents or alcohol；
R is the group shown in i：
Each R3It independently is C1-C3Alkyl, the alkyl are substituted by deuterium.
3. the preparation method of deuterated acrylamide as claimed in claim 1 or 2, it is characterised in that
R is the group shown in formula i-1：
4. the preparation method of deuterated acrylamide as claimed in claim 1 or 2, it is characterised in that prepared deuterated acryloyl
Amine selects following compound：
5. the intermediate in the preparation method of deuterated acrylamide as described in one of claim 1-4, it is characterised in that knot
Structure is as follows：
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