CN116514833A - 一种氘代物及其合成方法和医药用途 - Google Patents
一种氘代物及其合成方法和医药用途 Download PDFInfo
- Publication number
- CN116514833A CN116514833A CN202310480947.6A CN202310480947A CN116514833A CN 116514833 A CN116514833 A CN 116514833A CN 202310480947 A CN202310480947 A CN 202310480947A CN 116514833 A CN116514833 A CN 116514833A
- Authority
- CN
- China
- Prior art keywords
- compound
- deuterated
- formula
- solvent
- reaction
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 102100029392 Secretory phospholipase A2 receptor Human genes 0.000 claims abstract description 4
- 101710122046 Secretory phospholipase A2 receptor Proteins 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 239000007858 starting material Substances 0.000 claims description 22
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 239000000543 intermediate Substances 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000443 aerosol Substances 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- -1 deuterated sodium methoxyborohydride Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 208000023504 respiratory system disease Diseases 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- ZPOROQKDAPEMOL-UHFFFAOYSA-N 1h-pyrrol-3-ol Chemical compound OC=1C=CNC=1 ZPOROQKDAPEMOL-UHFFFAOYSA-N 0.000 claims description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 239000004480 active ingredient Substances 0.000 claims description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 4
- 230000027939 micturition Effects 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
- 238000007670 refining Methods 0.000 claims description 4
- 230000002485 urinary effect Effects 0.000 claims description 4
- 208000014001 urinary system disease Diseases 0.000 claims description 4
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 3
- 229960004373 acetylcholine Drugs 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000003862 glucocorticoid Substances 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229920002866 paraformaldehyde Polymers 0.000 claims description 3
- 230000000241 respiratory effect Effects 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 229940037128 systemic glucocorticoids Drugs 0.000 claims description 3
- 238000005809 transesterification reaction Methods 0.000 claims description 3
- 238000009423 ventilation Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 2
- 206010066091 Bronchial Hyperreactivity Diseases 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- 206010063057 Cystitis noninfective Diseases 0.000 claims description 2
- 102000000543 Histamine Receptors Human genes 0.000 claims description 2
- 108010002059 Histamine Receptors Proteins 0.000 claims description 2
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 2
- 102100040460 P2X purinoceptor 3 Human genes 0.000 claims description 2
- 101710189970 P2X purinoceptor 3 Proteins 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 102000004136 Vasopressin Receptors Human genes 0.000 claims description 2
- 108090000643 Vasopressin Receptors Proteins 0.000 claims description 2
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical class [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 2
- 230000000172 allergic effect Effects 0.000 claims description 2
- 208000010668 atopic eczema Diseases 0.000 claims description 2
- 230000036427 bronchial hyperreactivity Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 201000003139 chronic cystitis Diseases 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- 201000003146 cystitis Diseases 0.000 claims description 2
- 208000007784 diverticulitis Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 206010013990 dysuria Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 230000001272 neurogenic effect Effects 0.000 claims description 2
- 208000020629 overactive bladder Diseases 0.000 claims description 2
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 201000004240 prostatic hypertrophy Diseases 0.000 claims description 2
- 239000000018 receptor agonist Substances 0.000 claims description 2
- 229940044601 receptor agonist Drugs 0.000 claims description 2
- 239000002464 receptor antagonist Substances 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 206010039083 rhinitis Diseases 0.000 claims description 2
- 239000012354 sodium borodeuteride Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 230000001148 spastic effect Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 206010005063 Bladder pain Diseases 0.000 claims 1
- 150000002617 leukotrienes Chemical class 0.000 claims 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims 1
- 239000007939 sustained release tablet Substances 0.000 claims 1
- 230000002503 metabolic effect Effects 0.000 abstract description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 abstract description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 abstract description 2
- 229960001231 choline Drugs 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000001078 anti-cholinergic effect Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004896 high resolution mass spectrometry Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 210000002460 smooth muscle Anatomy 0.000 description 3
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 3
- KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000017927 CHRM1 Human genes 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- 101150073075 Chrm1 gene Proteins 0.000 description 2
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 2
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 2
- 102000034337 acetylcholine receptors Human genes 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 230000000916 dilatatory effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000614 adrenergic beta-2 receptor agonist Substances 0.000 description 1
- 229940124627 adrenergic β2 receptor agonist Drugs 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000002590 anti-leukotriene effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 238000009924 canning Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- BKBMACKZOSMMGT-UHFFFAOYSA-N methanol;toluene Chemical compound OC.CC1=CC=CC=C1 BKBMACKZOSMMGT-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000000192 parasympathetic ganglia Anatomy 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940098458 powder spray Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000005090 tracheal smooth muscle Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Otolaryngology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种氘代物及其合成方法和医药用途，所述氘代化合物的结构如式II所示，本发明在式II季铵碱部位进行氘代提高了化合物的代谢稳定性。其次本发明提供了式II化合物的方法，该方法简洁高效，氘代率高，纯度高，适合快速制备获得高质量的式II化合物。本发明还提供了式II化合物及其制剂的医药领域实际用途，可有效治疗以胆碱M型受体为靶点疾病。
Description
技术领域
本发明属于药物化学领域，具体涉及一种氘代物及其合成方法和医药用途。
背景技术
慢性阻塞性肺病(chronic obstructive pulmonary disease,COPD)是一类常见和多发的进行性呼吸系统疾病，包括慢性支气管炎、哮喘、支气管扩张、囊性纤维化等，其患病率和致死率均居高不下，是全球第三大死因(《全球卫生评估》，WHO，2020)。COPD以持续气道炎症为特征，存在炎症和炎症介质的级联反应，患者常因肺部病变或肺内气道狭窄，导致呼气和吸气时气流受限，出现呼吸困难症状。COPD的药物治疗包括使用糖皮质激素和抗白三烯类等抗炎类药物以及使用抗胆碱能药物和肾上腺β2受体激动剂等扩张支气管药物为主，必要时需采用药物双联或三联疗法治疗。
抗胆碱能药物是近年来研发进展较快的COPD治疗药物。毒蕈碱型乙酰胆碱受体(MuscarinicAcetylcholine Receptor，mAChR)是广泛分布于中枢神经和外周副交感神经的重要神经递质感受器，可以分为M1-M5五种受体亚型。其中分布于支气管平滑肌的M3亚型是COPD治疗药物的主要作用靶点，M3型是介导支气管和气管平滑肌收缩的主要乙酰胆碱受体亚型，参与黏液分泌和血管平滑肌细胞血管扩张。抗胆碱能药物通过阻断平滑肌上的M3型受体，舒张气道平滑肌、抑制黏液分泌，从而实现全面控制症状。M1受体主要分布于连接呼吸道的副交感神经节，抑制M1型受体可通过切断中枢神经传导同样实现舒张支气管平滑肌的作用。M2型受体在胆碱能神经末梢中节前定位的受体充当自身感受器，介导反馈抑制乙酰胆碱从神经释放，拮抗胆碱神经激动效应。理想的COPD抗胆碱能药物应拮抗M1型和M3型受体，对M2型受体的亲和力较小。
一种高选择性的M3型胆碱能受体抑制剂，结构式如式I所示，其季铵碱部位存在代谢稳定性的问题，会影响药物的吸收及作用时间。
发明内容
本发明为了克服现有技术存在的不足，提出了一种氘代化合物的制备方法及其医药用途，以快速高效的方式实现氘代物的制备合成并且将其应用于医药领域。
为解决上述技术问题，本发明采用的技术方案是：
一种氘代化合物，其结构如式II所示：
在一些实施方案中，所述的氘代化合物选自如下化合物
另一方面，本发明提供了式II化合物的制备路线：
包括如下步骤：
S1、氘代甲基化反应：溶解3-羟基吡咯于溶剂A中，加入氘代甲醛或氘代多聚甲醛以及氘代负氢还原剂，搅拌反应，直至反应完成；
S2、酯交换反应：以溶剂B溶解d3-起始物料2，加入碱A，升温，加入起始物料1的溶剂B溶液，加热反应；
S3、溴甲基化反应：d3-中间体溶解在溶剂C中，于低温条件下向反应液中通入足量溴甲烷气体，于反应结束后停止通气，室温继续搅拌，析出式II化合物粗品；
S4、精制：S3中所得式II化合物粗品经活性炭脱色和溶剂D重结晶后得式II化合物成品。
在一些实施方案中，所述S1中溶剂A选自四氢呋喃、二氧六环、甲醇、乙醇、1-丙醇、2-丙醇和异丙醇中的一种或多种。
在一些实施方案中，所述S1中氘代负氢还原剂选自但是不限于氘代甲酸、氘代硼氢化钠、氘代甲氧基硼氢化钠、氘代腈基硼氢化钠或氘代四氢铝锂中任意一种。
在一些实施方案中，所述S1中的反应温度为-20～110℃。
在一些实施方案中，所述S1中3-羟基吡咯与氘代负氢还原剂的摩尔比为0.77:1～1.2。
在一些实施方案中，所述S2中溶剂B选自苯、甲苯、二甲苯和N，N二甲基甲酰胺中任意一种，优选为甲苯或苯。
在一些实施方案中，所述S2中碱A选自氢化钠、金属钠、碳酸铯、碳酸钠、碳酸钾以及碳酸锂中任意一种，优选为碳酸铯。
在一些实施方案中，所述S2中d3-起始物料2和起始物料1摩尔比为0.8～1.2:1。
在一些实施方案中，所述S2中d3-起始物料2和碱A摩尔比为1:1～2。
在一些实施方案中，所述S2中溶剂和起始物料2体积比为20～72：1，优选比例25～36：1。
在一些实施方案中，所述S2中反应时间为1～8h，反应温度为50～150℃，优选地，反应时间为1～4h，反应温度为100～120℃。
在一些实施方案中，所述S2反应完成后，还包括重结晶过程，以醚类溶剂溶解S2中所得d3-中间体粗品，所述醚类溶剂为乙醚、异丙醚和甲基叔丁基醚中任意一种，优选为异丙醚和甲基叔丁基醚。
在一些实施方案中，所述S3中溶剂C选自但不限于丙酮、二氯甲烷、乙酸乙酯、乙腈、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、甲醇、乙醇、2-丙醇、1-丙醇、异丙醇中任意一种，优选为二氯甲烷或乙酸乙酯。
在一些实施方案中，所述S3中反应温度为-20～20℃，优选为-10～10℃。
在一些实施方案中，所述S3中反应时间为0.5～4个小时，优选1～1.5个小时。
在一些实施方案中，所述S4中溶剂D为甲醇、乙醇、1-丙醇、2-丙醇、异丙醇、水、乙腈、四氢呋喃、二氧六环、丙酮和二氯甲烷中一种或两种的组合，优选为乙醇。
在一些实施方案中，所述S4中活性炭与式II化合物粗品的质量比为0.05～0.3:1，优选比例为0.1～0.15：1。
采用本发明的制备方法制得的式II化合物，纯度不小于98.0％，氘代率不小于98.0％。
本发明所述式II～式Ⅵ化合物或其药学上可接受的盐、溶剂化物或水合物用于制备预防或者治疗以乙酰胆碱M型受体为靶点疾病药物的用途。
优选地，所述疾病选自呼吸系统、泌尿系统或肠胃道疾病。
优选地，所述呼吸系统疾病包括慢性阻塞性肺疾病、支气管炎、支气管反应过度、咳嗽、鼻炎或哮喘。所述泌尿系统疾病包括膀胱过度活动症、前列腺肥大、排尿困难、尿频、尿急、尿失禁、慢性膀胱炎、神经源性或不稳定性膀胱炎或膀胱痉挛。所述肠胃道疾病包括过敏性肠道综合症、憩室炎、痉挛性结肠炎或消化性溃疡病。
本发明的式II～式Ⅵ化合物或其药学上可接受的盐、溶剂化物或水合物可以单独给药，或与其他具有可以有效治疗此类疾病的药物联用，如与M受体抑制剂肾上腺素β受体激动剂、糖皮质激素类、组胺受体抑制剂、磷酸二酯酶4(PDE4)抑制剂、血管加压素受体激动剂、嘌呤P2X3受体抑制剂和/或白三烯D4(LTD4)受体拮抗剂同时、独立或序贯联合给药，用于预防和治疗呼吸系统疾病。
本发明还提供了一种用于制备预防或治疗所述的呼吸系统、泌尿系统或肠胃道疾病药物的组合物，所述组合物中含有治疗有效量的本发明的式II～式Ⅵ化合物或其药学上可接受的盐、溶剂化物或水合物作为活性成份和药学上可接受的载体。所述药物组合物可以是吸入气雾剂、吸入粉雾剂、普通片剂、缓释片剂、控释片剂、胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂。
包含式II化合物的吸入气雾剂，包括式II化合物500mg，氮气或HFC-134A蒸汽。
包含式II化合物的片剂，包括式II化合物1g，23g乳糖、5.7g微晶纤维素和0.3g轻质二氧化硅和0.3g硬脂酸镁。
本发明的有益效果：本发明提供了式II化合物，在季铵碱部位进行氘代提高了化合物的代谢稳定性；其次本发明提供一种通过化学合成法合成式II化合物的方法，所用原料、试剂和溶剂均可通过市售获得，合成路线简洁高效，氘代率高，产品稳定，适合快速制备获得高质量的式II化合物，最后本发明还提供了式II化合物作为胆碱M型受体抑制剂及其制剂用于医药领域的实际用途。
附图说明
图1是使用本发明实施例1方法制备的d3-起始物料2的1H-NMR图谱；
图2是使用本发明实施例1方法制备的d3-起始物料2的13C-NMR图谱；
图3是使用本发明实施例1方法制备的d3-起始物料2的HR-MS图谱；
图4是使用本发明实施例2方法制备的d3-中间体的1H-NMR图谱；
图5是使用本发明实施例2方法制备的d3-中间体的13C-NMR图谱；
图6是使用本发明实施例3方法制备的d3-式II化合物的1H-NMR图谱；
图7是使用本发明实施例3方法制备的d3-式II化合物的13C-NMR图谱；
图8是使用本发明实施例3方法制备的d3-式II化合物的HR-MS图谱；
图9是使用本发明实施例3方法制备的d3-式II化合物的HPLC图谱。
具体实施方式
下面的实施例可以使本专业的本领域技术人员更全面地理解本发明，但并不因此将本发明限制在所述的实施例范围之中。
一种式II化合物氘代物路线具体如下：
包括如下步骤：
S1、氘代甲基化反应：以3-羟基吡咯烷为原料与氘代甲醛、氘代负氢还原剂发生还原胺化反应，生成d3-起始物料2；
S2、酯交换反应：以氘代起始物料2和2,2-二噻吩基乙醇酸甲酯作为起始物料于碱性条件下生成d3-中间体；
S3、溴甲基化反应：S2中所得d3-中间体通过与溴甲烷反应生成d3-式II化合物粗品；
S4、精制：S2中所得d3-式II化合物粗品经脱色和重结晶后得d3-式II化合物成品。
采用本发明的制备方法制的的化合物，化学结构通过1HNMR、13CNMR和MS确证。核磁共振测试条件为Agilent 400MR超导脉冲傅里叶变换核磁共振波谱仪；溶剂使用DMSO-d6；基准参考为DMSO-d6(1H谱、13C谱)。MS条件为仪器Thermo Vanquish-Q Exactive液质联用仪；色谱柱为Agilent ZORBAX SB-C18；检测波长210、254nm。化合物纯度分析方法使用反相HPLC法，条件为色谱柱Agilent ZORBAX Eclipse Plus或效能相当的色谱柱)流动相为0.02mol/L庚烷磺酸钠溶液(用磷酸调节pH值至3.5)-甲醇(51：49)；检测波长：237nm。手性异构体拆分条件为色谱柱用涂有纤维素-三(3,5-二氯苯基氨基甲酸酯)的硅胶为填充剂，流动相：0.02mol/L庚烷磺酸钠溶液(含0.5％氨水，用磷酸调节pH值至3.0)-甲醇(65：35)。本发明所述氘代率系指化合物D3氘代率，使用FT-MS法测定。
以下结合实施例对于本申请的制备过程作进一步说明。
实施例1d3-起始物料2的合成制备
将3-羟基吡咯烷(1000mg,5.74mmol)和无水THF(20mL)混合于50mL圆底烧瓶中，加入氘代多聚甲醛(364mg,105.8mmol)和氘代甲酸(710mg,7.39mmol)，N2保护下，升温至回流使固体完全溶解，继续反应3小时。反应结束后，加入3NNaOH溶液调节反应液pH为10左右，使用二氯甲烷/甲醇(v/v＝10:1,60mL)分三次萃取，合并有机相，加入无水硫酸钠干燥。挥去溶剂，经50℃真空干燥，得到淡黄色油状液体604mg(收率：51％)。1HNMR(400MHz,DMSO-d6)δ4.12(ddt,J＝7.5,6.3,3.6Hz,1H),2.55(dd,J＝9.5,6.2Hz,1H),2.49-2.39(m,1H),2.27(td,J＝8.3,5.6Hz,1H),2.18(dd,J＝9.5,3.8Hz,1H),1.93(dtd,J＝12.9,7.8,6.4Hz,1H),1.46(dddd,J＝13.2,7.9,5.6,3.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ70.50,65.31,55.13,35.64.HR-MS cal.m/z:105.1062[Μ+H]+,found m/z:105.1071[Μ+H]+.d3-起始物料2氘代率D3为99.2％。图谱见附图1～3。
实施例2d3-中间体的合成制备
称取600mg d3-起始物料2，加入12ml甲苯，室温下搅拌溶清，加入碳酸铯(1877mg,)粉末，升温至微回流。滴加起始物料1(1465mg)的甲苯溶液，滴毕共计15分钟，滴毕回流反应1小时，同时分馏出甲醇-甲苯混合液。TLC(PE:EA＝3:1)监测反应，冰水降温至20℃以下，抽滤，加水洗后浓缩有机相，浓缩完毕，加入5mL叔丁基甲基醚，升温使固体完全溶解，降温至0～10℃搅拌1小时。过滤用2mL冰冻甲基叔丁基醚洗涤，40℃鼓风1小时，得到淡黄色粉末617mg(收率：32.8％，HPLC纯度：96.8％)。1H NMR(400MHz,DMSO-d6)δ7.43(d,J＝4.9Hz,2H),7.28(s,1H),7.05(dd,J＝7.8,3.6Hz,2H),6.94(dd,J＝5.2,3.4Hz,2H),5.13(m,1H),2.66-2.53(m,2H),2.46(p,J＝2.0Hz,1H),2.28-2.08(m,2H),1.65(m,1H).13C NMR(101MHz,DMSO-d6)δ171.39,147.85,127.12,126.54,125.88,77.05,76.76,54.80,32.37.m/z:327.1[Μ+H]+.图谱见附图4～5。
实施例3d3-式II化合物粗品的合成制备
将d3-中间体(600mg)加入二氯甲烷(15mL)中，搅拌溶清，降温至-5～5℃，缓缓通入足量溴甲烷气体，TLC(MeOH:CH2Cl2＝1:10)监测反应，中间体几乎消失时撤去冷却，0.5小时后停止通气，保温继续搅拌30小时后，室温搅拌1小时，过滤。滤饼用5mL冷的二氯甲烷洗涤后，滤饼40℃鼓风干燥2小时，得到粗品淡黄色粉末约760mg。
实施例4d3-式II化合物的精制
粗品用热的95％乙醇(10mL)溶解，升温至回流，加入150mg活性炭，继续搅拌30分钟。抽滤，滤液升温至完全溶解，降温至0～5℃析出产品，抽滤，烘干，得到白色粉末694mg(收率89.6％，HPLC纯度：98.4％)。1H NMR(400MHz,DMSO-d6)δ7.51(dd,J＝5.1,1.3Hz,2H),7.14(dd,J＝9.1,3.6,1.3Hz,2H),7.00(dd,J＝5.1,3.6Hz,2H),5.50(d,J＝8.1Hz,1H),3.95-3.86(m,1H),3.77-3.64(m,2H),3.63-3.52(m,1H),3.19(m,2H),3.03(m,2H),2.73(m,1H),2.22-2.07(m,1H).13C NMR(101MHz,DMSO-d6)δ170.93,147.23,147.21,127.28,126.83,126.34,126.28,76.83,74.43,69.56,64.41,53.11,52.40,30.31.HR-MS cal.m/z:341.1061[Μ+H]+,found m/z:341.1067[Μ+H]+.d3-起始物料2氘代率D3为98.6％(本发明所述氘代率系指化合物D3氘代率，使用FT-MS法测定。)。图谱见附图6～9。
实施例4式II化合物气雾剂的制备
药用组合物的制备：吸入气雾剂
将式II化合物500mg溶于22g乙醇中，制备活性成分的浓缩液。将该浓缩液加入到合适的罐装设备中，将活性成分浓缩液分装到气雾剂容器中，向所述容器顶端空间冲入氮气或HFC-134A蒸汽(所冲入成分不得含有超过1ppm氧)，用阀密封。将115Ghfc-134A抛射器加压充入所述密封的容器中。
实施例5式II化合物片剂的制备
将式II化合物1g与23g乳糖和5.7g微晶纤维素用混合机混合。用滚轴压紧机将所得混合物压制成型，获得薄片状压制物料。用锤式粉碎机将所述薄片状压制物料研磨成粉，使所得粉状物料通过20目筛过筛。将一份0.3g轻质二氧化硅和0.3g硬脂酸镁加入到已过筛的物料中，并混合。所得混合物用制片机压制成片。
实施例6式II化合物消旋体的手性拆分
色谱柱：以表面键合有纤维素-三(3,5-二氯苯基氨基甲酸酯)的硅胶为固定相色谱柱(CHIRALPAK IC手性色谱柱或效能相当的色谱柱)
流动相：0.02mol/L庚烷磺酸钠溶液(含0.5％三乙胺，用磷酸调节pH值至3.5)-甲醇(70：30)
流速：1.0ml/min
柱温：30℃
检测波长：237nm
进样体积：10μL
供试品溶液：取本品约10mg，精密称定，置20ml量瓶中，加流动相溶解并稀释至刻度，摇匀，即得。
异构体对照溶液：精密量取供试品溶液1ml，置100ml量瓶中，用流动相稀释至刻度，摇匀，即得，异构体对照来源于市售。
拆分：将供试品溶液注入色谱仪，根据峰形收集组分，可得四种构型的化合物。
本发明的技术范围不仅仅局限于上述说明中的内容，本领域技术人员可以在不脱离本发明技术思想的前提下，对上述实施例进行多种变形和修改，而这些变形和修改均应当属于本发明的保护范围内。
Claims (10)
1.一种氘代化合物，其结构如式II所示：
2.根据权利要求1所述的氘代化合物，其特征在于，所述氘代化合物选自如下化合物
3.权利要求1所述的式II化合物的制备方法，
包括如下步骤：
S1、氘代甲基化反应：溶解3-羟基吡咯于溶剂A中，加入氘代甲醛或氘代多聚甲醛以及氘代负氢还原剂，搅拌反应，直至反应完成；
S2、酯交换反应：以溶剂B溶解d3-起始物料2，加入碱A，升温，加入起始物料1的溶剂B溶液，加热反应；
S3、溴甲基化反应：d3-中间体溶解在溶剂C中，于低温条件下向反应液中通入足量溴甲烷气体，于反应结束后停止通气，室温继续搅拌，析出式II化合物粗品；
S4、精制：S3中所得式II化合物粗品经活性炭脱色和溶剂D重结晶后得式II化合物成品。
4.根据权利要求3所述的氘代化合物的制备方法，其特征在于，所述S1中溶剂A选自四氢呋喃、二氧六环、甲醇、乙醇、1-丙醇、2-丙醇和异丙醇中的一种或多种；优选地，所述氘代负氢还原剂选自氘代甲酸、氘代硼氢化钠、氘代甲氧基硼氢化钠、氘代腈基硼氢化钠或氘代四氢铝锂中任意一种；优选地，所述S1中的反应温度为-20～110℃；优选地，所述S1中3-羟基吡咯与氘代负氢还原剂的摩尔比为0.77:1～1.2。
5.根据权利要求3所述的氘代化合物的制备方法，其特征在于，所述S2中溶剂B选自苯、甲苯、二甲苯和N，N二甲基甲酰胺中任意一种，优选为甲苯或苯；优选地，所述S2中碱A选自氢化钠、金属钠、碳酸铯、碳酸钠、碳酸钾以及碳酸锂中任意一种，优选为碳酸铯；优选地，所述S2中d3-起始物料2和起始物料1摩尔比为0.8～1.2:1；优选地，所述S2中d3-起始物料2和碱A摩尔比为1:1～2；优选地，所述S2中溶剂和起始物料2体积比为20～72：1，优选比例25～36：1；优选地，所述S2中反应时间为1～8h，反应温度为50～150℃，优选地，反应时间为1～4h，反应温度为100～120℃；优选地，所述S2反应完成后，还包括重结晶过程，以醚类溶剂溶解S2中所得d3-中间体粗品，所述醚类溶剂为乙醚、异丙醚和甲基叔丁基醚中任意一种，优选为异丙醚和甲基叔丁基醚。
6.根据权利要求3所述的氘代化合物的制备方法，其特征在于，所述S3中溶剂C选自丙酮、二氯甲烷、乙酸乙酯、乙腈、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、甲醇、乙醇、2-丙醇、1-丙醇、异丙醇中任意一种，优选为二氯甲烷或乙酸乙酯；优选地，所述S3中反应温度为-20～20℃，优选为-10～10℃；优选地，所述S3中反应时间为0.5～4个小时，优选1～1.5个小时。
7.根据权利要求3所述的氘代化合物的制备方法，其特征在于，所述S4中溶剂D为甲醇、乙醇、1-丙醇、2-丙醇、异丙醇、水、乙腈、四氢呋喃、二氧六环、丙酮和二氯甲烷中一种或两种的组合，优选为乙醇；优选地，所述S4中活性炭与式II化合物粗品的质量比为0.05～0.3:1，优选比例为0.1～0.15：1。
8.权利要求1-2所述的化合物或其药学上可接受的盐、溶剂化物或水合物用于制备预防或者治疗以乙酰胆碱M型受体为靶点疾病药物的用途；优选地，所述疾病选自呼吸系统、泌尿系统或肠胃道疾病；所述呼吸系统疾病包括慢性阻塞性肺疾病、支气管炎、支气管反应过度、咳嗽、鼻炎或哮喘；所述泌尿系统疾病包括膀胱过度活动症、前列腺肥大、排尿困难、尿频、尿急、尿失禁、慢性膀胱炎、神经源性或不稳定性膀胱炎或膀胱痉挛；所述肠胃道疾病包括过敏性肠道综合症、憩室炎、痉挛性结肠炎或消化性溃疡病。
9.权利要求1-2所述的化合物或其药学上可接受的盐、溶剂化物或水合物与其他药物组合用于制备治疗呼吸系统、泌尿系统或肠胃道疾病药物的用途，所述其他药物选自肾上腺素β受体激动剂、糖皮质激素类、组胺受体抑制剂、磷酸二酯酶4抑制剂、血管加压素受体激动剂、嘌呤P2X3受体抑制剂或白三烯D4受体拮抗剂。
10.一种药物组合物，所述药物组合物中含有治疗有效量的式II～式Ⅵ化合物或其药学上可接受的盐、溶剂化物或水合物作为活性成份和药学上可接受的载体，所述药物组合物选自吸入气雾剂、吸入粉雾剂、普通片剂、缓释片剂、控释片剂、胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂；优选地，所述药物组合物选自吸入气雾剂，包括式II化合物500mg，氮气或HFC-134A蒸汽；优选地，所述药物组合物选自片剂，包括式II化合物1g，23g乳糖、5.7g微晶纤维素和0.3g轻质二氧化硅和0.3g硬脂酸镁。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310480947.6A CN116514833A (zh) | 2023-04-28 | 2023-04-28 | 一种氘代物及其合成方法和医药用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310480947.6A CN116514833A (zh) | 2023-04-28 | 2023-04-28 | 一种氘代物及其合成方法和医药用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116514833A true CN116514833A (zh) | 2023-08-01 |
Family
ID=87397128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310480947.6A Pending CN116514833A (zh) | 2023-04-28 | 2023-04-28 | 一种氘代物及其合成方法和医药用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116514833A (zh) |
-
2023
- 2023-04-28 CN CN202310480947.6A patent/CN116514833A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102482673B1 (ko) | 방향족 아세틸렌 또는 방향족 에틸렌계 화합물, 그의 중간체, 제조 방법, 약물 조성물 및 용도 | |
| CA3076150C (en) | Selective p2x3 modulators | |
| US6780891B2 (en) | Tramadol analogs and uses thereof | |
| JP2005501034A (ja) | モルホリン架橋のピラゾロピリジン誘導体 | |
| CN104781272A (zh) | 奥贝胆酸的制备、用途和固体形式 | |
| MXPA06012664A (es) | Antagonistas del receptor crth2. | |
| US6350758B1 (en) | Tropane derivatives and method for their synthesis | |
| Teng et al. | Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory agents | |
| JP2009538359A (ja) | 置換カルボン酸化合物の製造および利用 | |
| EP0581167A1 (en) | Novel arylglycinamide derivatives and preparative processes therefor and their use for treatment of dysuria | |
| JP5852269B2 (ja) | Ｍｏｇａｔ−２阻害剤として有用な新規モルホリニル誘導体 | |
| KR20210034082A (ko) | 2,6-디아미노 피리딘 화합물 | |
| WO2009087285A1 (fr) | 5,6-diaryles pyridines substitues en position 2 et 3, leur preparation et leur application en therapeutique | |
| TW200918506A (en) | Indane-amine derivatives, their preparation and use as medicaments | |
| JP7395762B2 (ja) | Ｊａｋキナーゼ関連疾患の治療のための薬物の調製におけるｊａｋ阻害剤の使用 | |
| FR2593818A1 (fr) | Derives d'acylaminomethyl-3 imidazo(1,2-a)pyridine, leur preparation et leur application en therapeutique | |
| JPS5980668A (ja) | Ｎ−アリル化オキサゾリジン−２−オンの光学活性な誘導体、該誘導体の製法及び該誘導体による薬剤 | |
| CN116514833A (zh) | 一种氘代物及其合成方法和医药用途 | |
| MX2007009007A (es) | Derivados de acido aminobutanoico que inhiben carnitina palmitoil transferasa. | |
| EP1648895A1 (en) | Metabolite of xanthine phosphodiesterase 5 inhibitor and derivatives thereof useful for treatment of erectile dysfunction | |
| EP1140855A1 (en) | Tetrahydroindazole derivatives as ligands for gaba-a alpha 5 receptors | |
| CN111320606B (zh) | 苯联吡唑并环类衍生物及其在抗肿瘤药物中的应用 | |
| US4287211A (en) | Derivatives of phenylethylamines, processes for their preparation and related pharmaceutical compositions | |
| NO140186B (no) | Analogifremgangsmaate ved fremstilling av terapeutisk aktive, nye 2-(2-pyridyl)-3-(p-klorfenyl)-propylaminer | |
| CN110446713B (zh) | 一种吡唑嘧啶衍生物及其用途和药物组合物 |
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 |