CN117430548A - 一种urat1抑制剂中间体的制备方法 - Google Patents
一种urat1抑制剂中间体的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940083914 URAT1 inhibitor Drugs 0.000 title claims abstract description 11
- ASUMVAPLXCRBMA-UHFFFAOYSA-N (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydro-1,4-benzoxazin-4-yl)methanone Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2OCC1 ASUMVAPLXCRBMA-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 238000012544 monitoring process Methods 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 70
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
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- 238000006722 reduction reaction Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 239000001119 stannous chloride Substances 0.000 claims description 5
- 235000011150 stannous chloride Nutrition 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-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
- 239000002904 solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 3
- 229940087646 methanolamine Drugs 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 238000010979 pH adjustment Methods 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- FHXASJKBBLIBAQ-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)naphthalene Chemical compound C1=CC=C2C(CBr)=CC=C(Br)C2=C1 FHXASJKBBLIBAQ-UHFFFAOYSA-N 0.000 abstract description 12
- 150000003839 salts Chemical class 0.000 abstract description 8
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000004537 pulping Methods 0.000 abstract description 5
- -1 3 - [ (4-bromonaphthalen-1-yl) methyl]2, 3-diaminopyridine Chemical compound 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000706 filtrate Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 238000005070 sampling Methods 0.000 description 10
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 9
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 229940116269 uric acid Drugs 0.000 description 9
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- 229940125782 compound 2 Drugs 0.000 description 7
- 238000010907 mechanical stirring Methods 0.000 description 7
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- 239000000543 intermediate Substances 0.000 description 5
- MEKKCDZXQANIPF-UHFFFAOYSA-N (2-aminopyridin-1-ium-3-yl)azanium;dichloride Chemical compound Cl.Cl.NC1=CC=CN=C1N MEKKCDZXQANIPF-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- GZBKVUGZEAJYHH-UHFFFAOYSA-N 2-nitropyridin-3-amine Chemical compound NC1=CC=CN=C1[N+]([O-])=O GZBKVUGZEAJYHH-UHFFFAOYSA-N 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 2
- AVHPSHRBXHDYIR-UHFFFAOYSA-N 1-bromo-4-(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=C(Br)C2=C1 AVHPSHRBXHDYIR-UHFFFAOYSA-N 0.000 description 1
- QBPDSKPWYWIHGA-UHFFFAOYSA-N 3-hydroxy-2-nitropyridine Chemical compound OC1=CC=CN=C1[N+]([O-])=O QBPDSKPWYWIHGA-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 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
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明属于药物合成领域,具体涉及一种URAT1抑制剂中间体的制备方法。其方法以2,3‑二氨基吡啶(盐)与1‑溴‑4‑溴甲基萘为原料,搅拌,HPLC监测,过滤,打浆,干燥,即得。本发明只需一步反应就可合成产物N3‑[(4‑溴萘‑1‑基)甲基]‑2,3‑二氨基吡啶(盐),成本低,简便高效,产物收率在65%‑98%,纯度在86‑98%,适合工业化大规模生产。
Description
技术领域
本发明属于药物合成领域,具体涉及一种URAT1抑制剂中间体的制备方法。
背景技术
目前治疗痛风的药物主要有两类:一类是抑制尿酸生成的黄嘌呤氧化酶抑制剂,另一类是促进尿酸排泄的URAT1抑制剂。从靶点安全性或产品临床试验药效出发,URAT1抑制剂成为目前该领域新药开发唯一突破点,尿酸转运体1(Uratetransporter 1,URAT1)是重要尿酸转运体,尿酸在近端肾小管的重吸收大部分依靠URAT1完成,URAT1不受膜电压和细胞内外pH值的影响,抑制URAT1就会抑制肾脏中尿酸的重吸收、增加尿液中尿酸的排泄,进而达到降低血尿酸和控制痛风发作的目的。相较于别嘌醇和非布司他等黄嘌呤氧化酶抑制剂,URAT1抑制剂的作用机制更加合理,因为只有10%患者存在尿酸生成过多,其余90%患者均有不同程度的肾脏排泄不足。
URAT1抑制剂的关键中间体所含结构如式1化合物所示,该中间体的制备方法由CN114478522A所公开,及Journal of Medicinal Chemistry 2020,63,19,10829-1085所报道,该路线总共5步,总收率为21.7%(以2-硝基3-羟基吡啶计),该法步骤多,周期长,成本高。因此为了满足未来临床需求,迫切需要研发一种更简单、更高效的URAT1抑制剂中间体的合成方法。
为了避免吡啶2-位氨基烷基化异构体的生成,本发明最初尝试的思路是使用2-硝基-3-氨基吡啶作为起始物料,后续可以把硝基还原为氨基,但是经实验后发现,该原料的3-位氨基活性较低,反应需要加热至50-70℃才能进行,而在该温度下另一原料1-溴-4-溴甲基萘稳定性较差,从而导致反应液中主峰纯度较差,经过详细的研究和对比,最终选择2,3-二氨基吡啶及其盐作为起始物料。
发明内容
为实现上述目的,本发明采用的技术方案如下:
一种URAT1抑制剂中间体的制备方法,包括如下反应:
具体过程为将式2化合物与式3化合物按摩尔比1:1-1:1.2反应,即得。
优选地,所述式2化合物的Y取代基选自硝基和氨基中的任意一种,所述式2化合物的含酸分子数n为0-3,所述式3化合物的苄位取代基Z选自F、Cl、Br、I和O中的任意一种。
优选地,所述Y取代基为硝基时,反应后还进行还原,冷却,调pH。
优选地,所述还原的温度为50-60℃,还原的时间为3-5h,所述还原时加入氯化亚锡,所述氯化亚锡的浓度为4-6mol/L,所述冷却的温度为0-5℃,所述pH为7-9。
优选地,所述式1化合物的含酸根X选自卤基、硫酸根、硫酸氢根、磺酸根、磷酸根、甲酸根、乙酸根及C3-C18羧酸衍生物中的一种或多种,所述式1化合物的含酸分子数m为0-3。
优选地,所述反应时加入有机溶剂,所述有机溶剂选自二氯甲烷、氯仿、四氢呋喃、乙腈、乙酸乙酯、醋酸异丙酯、甲醇、乙醇、异丙醇、丁醇、N,N-二甲基甲酰胺、二甲基亚砜、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的一种或多种,更优选地,所述有机溶剂选自四氢呋喃、乙腈、乙酸乙酯、甲醇和乙醇中的一种或多种。
优选地,所述反应后加入缚酸剂,所述缚酸剂选自N-甲基咪唑、N-甲基吗啉、三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、碳酸钠、碳酸钾和碳酸铯中的一种或多种。
优选地,所述加入缚酸剂后还进行加水淬灭,萃取,干燥,过滤,浓缩,洗脱,结晶,所述萃取的溶剂为甲基叔丁基醚,所述洗脱时的洗脱剂为体积比为80-120:1的石油醚和乙酸乙酯的混合物。
优选地,所述反应时进行搅拌,所述搅拌的时间为5-20h,搅拌的温度为20-55℃,所述反应后还进行HPLC或TLC监测,过滤,打浆,干燥。
优选地,所述TLC监测的展开剂包括体积比为150-250:5:1-3的二氯甲烷、甲醇和三乙胺的混合物,所述HPLC监测时需取样并用针式过滤器过滤,直至滤液中式2化合物或式1化合物含量<0.5%,所述HPLC监测的条件包括色谱柱的型号为IC,流动相包括正己烷、乙醇和二乙胺,所述正己烷、乙醇和二乙胺的体积比为100-900:100-900:0.1-10。
更优选地,TLC监测的展开剂为体积比为40:1:0.4的二氯甲烷、甲醇和三乙胺的混合物,正己烷:乙醇:二乙胺的体积比为880:120:2。
优选地,所述打浆的溶剂选自甲醇、水、四氢呋喃和乙酸乙酯中的一种或多种,所述干燥的温度为40-60℃,干燥的时间为12-18h,更优选地,干燥的温度为50℃,干燥的时间为16h。
相比现有技术,本发明有益效果:
本发明仅需一步反应,即可得N3-[(4-溴萘-1-基)甲基]-2,3-二氨基吡啶(盐),收率大、纯度高。
本发明的制备方法简单高效,成本低,适于大规模工业化生产。
附图说明
图1为原料2,3-二氨基吡啶的HPLC图谱;
图2为原料1-溴-4-溴甲基萘的HPLC图谱;
图3为产物N3-[(4-溴萘-1-基)亚甲基]-2,3-二氨基吡啶(盐)的HPLC图谱;
图4为产物N3-[(4-溴萘-1-基)亚甲基]-2,3-二氨基吡啶(盐)的1H NMR图谱。
值得注意的是,说明书附图不清晰之处不影响本领域技术人员对本发明技术方案的理解。
具体实施方式
值得说明的是,本发明中使用的原料均为普通市售产品。
实施例1
在3L反应釜中投入甲醇1.10L,2,3-二氨基吡啶(110g,1.00mol,1.0eq),1-溴-4-溴甲基萘(300g,1.0mol,1.0eq),开启机械搅拌,控温20℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液混合,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末(339g,纯度86%)。粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为280g,纯度98%,收率65%,其中,本实施例中的原料2,3-二氨基吡啶的HPLC图谱如图1所示,原料1-溴-4-溴甲基萘的HPLC图谱如图2所示,产物N3-[(4-溴萘-1-基)亚甲基]-2,3-二氨基吡啶(盐)的HPLC图谱如图3所示,产物N3-[(4-溴萘-1-基)亚甲基]-2,3-二氨基吡啶(盐)的1H NMR图谱如图4所示。
1H NMR(600MHz,DMSO-d6)δ8.25-8.20(q,J=8.4Hz,2H),7.86-7.84(d,J=7.2Hz,1H),7.74-7.68(m,2H),7.41-7.41(d,J=8.2Hz,1H),7.30-7.41(d,Ja=4.8Hz,Jb=0.6Hz1H),6.55-6.53(dd,Ja=7.8Hz,Jb=4.8Hz 1H),5.54(s,2H),5.44-5.43(t,1H),4.73-4.72(d,J=7.2Hz,2H).MS(ESI)m/z:327.9,329.9计算值:C16H14BrN3,327.04,329.04。
实施例2
在3L反应釜中投入甲醇1.10L,2,3-二氨基吡啶(110g,1.00mol,1.0eq),1-溴-4-溴甲基萘(360g,1.2mol,1.2eq),开启机械搅拌,控温25℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液混合,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为900:900:10,原料式1化合物<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末,粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为401g,纯度86%,收率98%。
实施例3
在3L反应釜中投入甲醇1.10L,2,3-二氨基吡啶盐酸盐(1HCl)(147g,1.00mol,1.0eq),1-溴-4-溴甲基萘(360g,1.2mol,1.2eq),开启机械搅拌,控温20℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液混合,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末,粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为438g,纯度97%,收率98%。
实施例4
在3L反应釜中投入甲醇1.10L,2,3-二氨基吡啶二盐酸盐(2HCl)(183g,1.00mol,1.0eq),1-溴-4-溴甲基萘(360g,1.2mol,1.2eq),开启机械搅拌,控温25℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液混合,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末,粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为438g,纯度98%,收率98%。
实施例5
在3L反应釜中投入四氢呋喃1.10L,2,3-二氨基吡啶(110g,1.00mol,1.0eq),1-溴-4-氯甲基萘(255g,1.0mol,1.0eq),开启机械搅拌,控温20℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液混合,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末(339g,纯度86%)。粗品经甲醇(1.10L)打浆,于50℃干燥16h。即得式1化合物,其质量为289g,纯度98%,收率80%。
实施例6
在3L反应釜中投入N-甲基吡咯烷酮1.10L,2-硝基-3-氨基吡啶(139g,1.00mol,1.0eq),1-溴-4-溴甲基萘(300g,1.0mol,1.0eq),碳酸钾(138g,1.0mol,1.0eq),开启机械搅拌,控温55℃,搅拌7h。取样,TLC监测。反应完成后加水淬灭,甲基叔丁基醚萃取,硫酸钠干燥,过滤,浓缩,柱层析洗脱,洗脱剂为体积比为100的石油醚和乙酸乙酯的混合溶剂,结晶,得黄色固体。加N-甲基吡咯烷酮溶液和氯化亚锡(945g,5.00mol,5.0eq),控温55℃,反应4h,冷却至0℃,氢氧化钠水溶液调至pH=8,大量无机盐析出,加四氢呋喃和乙酸乙酯打浆,过滤,得到产物粗品。粗品经水(1.10L)打浆,于50℃干燥16h,即得纯品式1化合物,其质量为290g,纯度98%,收率65%。
对比例1
在3L反应釜中投入水1.10L,2,3-二氨基吡啶二盐酸盐(2HCl)(183g,1.00mol,1.0eq),1-溴-4-溴甲基萘(360g,1.2mol,1.2eq),开启机械搅拌,控温25℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液混合,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末,粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为290g,纯度55%,收率65%。
对比例2
在3L反应釜中投入甲醇1.10L,2,3-二氨基吡啶二盐酸盐(2HCl)(183g,1.00mol,1.0eq),1-溴-4-溴甲基萘(360g,1.2mol,1.2eq),开启机械搅拌,控温60℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末,粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为246g,纯度85%,收率55%。
对比例3
在3L反应釜中投入甲醇2.20L,2,3-二氨基吡啶二盐酸盐(2HCl)(183g,1.00mol,1.0eq),1-溴-4-溴甲基萘(360g,1.2mol,1.2eq),开启机械搅拌,控温25℃,搅拌18h。取样,针式过滤器过滤后,取滤液,与10%(v/v)N-甲基吡咯烷酮的甲醇溶液,HPLC监测反应,色谱柱型号为IC,流动相为正己烷、乙醇和二乙胺,正己烷、乙醇和二乙胺的体积比为880:120:2,化合物2<0.5%。将反应液过滤,得到产物粗品,为褐色固体粉末,粗品经甲醇(1.10L)打浆,于50℃干燥16h,即得式1化合物,其质量为80g,纯度50%,收率20%。
最后应当说明的是,以上内容仅用以说明本发明的技术方案,而非对本发明保护范围的限制,本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换,均不脱离本发明技术方案的实质和范围。
Claims (10)
1.一种URAT1抑制剂中间体的制备方法,其特征在于,包括如下反应:
将式2化合物与式3化合物按摩尔比1:1-1:1.2反应,即得。
2.根据权利要求1所述的制备方法,其特征在于,所述式2化合物的Y取代基选自硝基和氨基中的任意一种,所述式2化合物的含酸分子数n为0-3,所述式3化合物的苄位取代基Z选自F、Cl、Br、I和O中的任意一种。
3.根据权利要求2所述的制备方法,其特征在于,所述Y取代基为硝基时,反应后还进行还原,冷却,调pH。
4.根据权利要求3所述的制备方法,其特征在于,所述还原的温度为50-60℃,还原的时间为3-5h,所述还原时加入氯化亚锡,所述氯化亚锡的浓度为4-6mol/L,所述冷却的温度为0-5℃,所述pH为7-9。
5.根据权利要求1所述的制备方法,其特征在于,所述式1化合物的含酸根X选自卤基、硫酸根、硫酸氢根、磺酸根、磷酸根、甲酸根、乙酸根及C3-C18羧酸衍生物中的一种或多种,所述式1化合物的含酸分子数m为0-3。
6.根据权利要求1所述的制备方法,其特征在于,所述反应时加入有机溶剂,所述有机溶剂选自二氯甲烷、氯仿、四氢呋喃、乙腈、乙酸乙酯、醋酸异丙酯、甲醇、乙醇、异丙醇、丁醇、N,N-二甲基甲酰胺、二甲基亚砜、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的一种或多种。
7.根据权利要求1所述的制备方法,其特征在于,所述反应后加入缚酸剂,所述缚酸剂选自N-甲基咪唑、N-甲基吗啉、三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、碳酸钠、碳酸钾和碳酸铯中的一种或多种。
8.根据权利要求7所述的制备方法,其特征在于,所述加入缚酸剂后还进行加水淬灭,萃取,干燥,过滤,浓缩,洗脱,结晶,所述萃取的溶剂为甲基叔丁基醚,所述洗脱时的洗脱剂包括体积比为80-120:1的石油醚和乙酸乙酯的混合物。
9.根据权利要求1-8任一项所述的制备方法,其特征在于,所述反应时进行搅拌,所述搅拌的时间为5-20h,搅拌的温度为20-55℃,所述反应后还进行HPLC或TLC监测,过滤,打浆,干燥。
10.根据权利要求9所述的制备方法,其特征在于,所述HPLC监测的条件包括色谱柱的型号为IC,流动相包括正己烷、乙醇和二乙胺,所述正己烷、乙醇和二乙胺的体积比为100-900:100-900:0.1-10,所述TLC监测的展开剂为体积比为150-250:5:1-3的二氯甲烷、甲醇和三乙胺的混合物,所述打浆的溶剂选自甲醇、水、四氢呋喃和乙酸乙酯中的一种或多种,所述干燥的温度为40-60℃,干燥的时间为12-18h。
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