CN107879964A - Preparation method of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine - Google Patents
Preparation method of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine Download PDFInfo
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- CN107879964A CN107879964A CN201610863106.3A CN201610863106A CN107879964A CN 107879964 A CN107879964 A CN 107879964A CN 201610863106 A CN201610863106 A CN 201610863106A CN 107879964 A CN107879964 A CN 107879964A
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- sodium
- methylamine
- fluorophenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 title abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000005576 amination reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 17
- 229940125782 compound 2 Drugs 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 4
- 239000003513 alkali Substances 0.000 claims 4
- 239000012312 sodium hydride Substances 0.000 claims 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000012973 diazabicyclooctane Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000012280 lithium aluminium hydride Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- 229940090181 propyl acetate Drugs 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims 1
- 235000019345 sodium thiosulphate Nutrition 0.000 claims 1
- 210000002700 urine Anatomy 0.000 claims 1
- -1 urine Element Chemical compound 0.000 claims 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 1
- RZQWBHXXTLMXJR-UHFFFAOYSA-N 3-(3-methoxypropoxy)benzenesulfonyl chloride Chemical compound COCCCOC1=CC=CC(S(Cl)(=O)=O)=C1 RZQWBHXXTLMXJR-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000006268 reductive amination reaction Methods 0.000 abstract 1
- 230000006103 sulfonylation Effects 0.000 abstract 1
- 238000005694 sulfonylation reaction Methods 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 206010011224 Cough Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940126409 proton pump inhibitor Drugs 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101710127489 Chlorophyll a-b binding protein of LHCII type 1 Proteins 0.000 description 1
- 101710184917 Chlorophyll a-b binding protein of LHCII type I, chloroplastic Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine on the basis of the prior art, wherein 3- (3-methoxy propoxy) benzenesulfonyl chloride is subjected to reaction steps of sulfonylation amination, reductive amination and the like to obtain 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine. The preparation method has short reaction period, avoids highly toxic reagents and simplifies the treatment operation. Is a preparation method for obtaining 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine in a large scale with high efficiency and low cost.
Description
Technical field
The present invention relates to new chemical entities 1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles
Cough up -3- bases) preparation methods of-N- methyl amines.
Background technology
Since 1988, the proton pump inhibitor using Omeprazole as representative is digested by gastric acid secretion inhibiting with treating
Property ulcer, reflux esophagitis and Zollinger-Eillison syndrome etc. are widely applied clinically.Long-term clinical practice is found, existing
There is proton pump inhibitor to also have limitation in terms of pharmacokinetics, pharmacodynamics.Such as：Influence of the administration time to drug effect；Night
Acid, which is broken through, to work slowly；It is unstable under acid condition（Need to be configured to Enteral formulationses）；To the dependence of CYP450 enzymes（Cause individual difference
It is different notable）Deng.
The competitive sour retarding agent of potassium（Potassium-Competitive Acid Blockers, P-CABs）By directly,
Reversible process competitively suppresses the K+ in H+/K+-ATP enzymes and acted.Compared with traditional proton pump inhibitor, P-
The characteristics of CABs has lipophilicity, alkalescent, dissociation constant high and stablized at low ph conditions.Under sour environment, P-CABs
Combined with ionized form with H+/K+-ATP enzymes, prevent H+ transports and acid from being secreted into gastral cavity, it is rapid to raise pH value in stomach.It is dynamic
Thing is tested and clinical research shows：P-CABs possesses action rapidly, with regard to that can reach maximum hospital benefit in 1 hour；Blood medicine is dense
Degree is linearly related with qf oral administration dosage, is easier the advantage for reaching optimal acid suppression effect.
Compound 1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases)-N- first
Base amine（CN2015094255）Higher H+/K+-ATP enzyme inhibition activities are shown in vitro, in the rat hydrochloric acid in gastric juice point of histamine induction
Secrete and preferable drug effect is shown in model；In addition, in sub- anxious poison research, 1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies)
Benzene sulfonyl chloride) -1H- pyrroles -3- bases)-N- methyl amines show excellent security.Further to be studied compound, need
1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases are prepared on a large scale)-N- methyl
Amine.This research discloses a kind of 1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases) -
The preparation method of N- methyl amines, the preparation method have the advantages of post processing is simple, and gained compound purity is high.
The content of the invention
The invention provides a kind of new chemical entities 1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyls
Chlorine) -1H- pyrroles -3- bases)-N- methyl amines preparation method.Reaction scheme as follows, step（1）、（2）Reaction and after
Processing is simple, products obtained therefrom HPLC purity>95%.
The technical solution adopted in the present invention is as follows：
It is a kind of that 1- (5- (the 2- fluorine as shown in compound 3 is prepared as 3- (3- methoxy propoxies) benzene sulfonyl chloride as shown in compound 1
Phenyl) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases) and-N- methyl amines preparation method；
Preparation method includes following step：
（1）Under protic or non-proton organic solvent, at -40 DEG C -50 DEG C, alkaline environment, compound 1 and compound 1-1
Reaction obtains compound 2 in tetrahydrofuran solvent；
（2）Under organic solvent, at -20 DEG C -50 DEG C, under reducing agent existence condition, compound 2 is generating chemical combination through reduction amination
Thing 3；
Preparation method as described above, the step（1）Alkalescence condition be organic base or inorganic base, preferably NaH, the reaction time
Less than 0.5h, process for purification is that alcohols stirring separates out solid, obtains the compound 2 of high-purity, HPLC purity>98%.
Preparation method as described above, the step（2）Reaction dissolvent be protic or non-proton organic solvent, it is excellent
Select methanol, the preferred sodium triacetoxy borohydride of reducing agent.
Brief description of the drawings
Fig. 1：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles obtained by the embodiment of the present invention
Cough up -3- bases) the HPLC spectrograms of-N- methyl amines.
Fig. 2：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles obtained by the embodiment of the present invention
Cough up -3- bases) mass spectrograms of-N- methyl amines.
Fig. 3：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles obtained by the embodiment of the present invention
Cough up -3- bases) the nucleus magnetic hydrogen spectrum figures of-N- methyl amines.
Embodiment
The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.
Embodiment 1：5- (2- fluorophenyls) -1- ((3- (3- methoxypropoxies) benzenesulfonyl) -1H- pyrroles's -3- formaldehyde（Change
Compound 2）Preparation
In 10L reaction bulbs, 60%NaH (300g, 7.62mol) is added to 1-1（480g, 2.54mol）THF (200ml)
In solution, -30 DEG C of 25 min of stirring, compound 1 (800g, 3.06mol) is added dropwise, stirs 10 min. reaction solutions at -30 DEG C and falls
Enter in 5L frozen water and be extracted with ethyl acetate（2.5Lx3）Merge organic relevant dry, concentration, addition 1.5 ethanol stirring 1h, take out
Filter, it is dried in vacuo to obtain faint yellow solid 700g（Yield 66%）.
Embodiment 2：5- (2- fluorophenyls) -1- ((3- (3- methoxypropoxies) benzenesulfonyl) -1H- pyrroles's -3- formaldehyde（Change
Compound 2）Preparation
In 2L reaction bulbs, compound 1-1 (95g, 0.5mol) is dissolved in DMF (1000ml), adds sodium tert-butoxide（96g,
1mol）, 25 min are stirred, compound 1 (158g, 0.6mol) is added dropwise, stirring 1 hour reaction solution at 25 DEG C is cooled to room temperature,
Filter, be concentrated under reduced pressure into dry, column chromatography obtains faint yellow solid 80g（Yield 38.2%）.
Embodiment 3：5- (2- fluorophenyls) -1- ((3- (3- methoxypropoxies) benzenesulfonyl) -1H- pyrroles's -3- formaldehyde（Change
Compound 2）Preparation
In 2L reaction bulbs, compound 1-1 (95g, 0.5mol) is dissolved in acetonitrile (1000ml), adds N, N- diisopropyl
Ethamine（97g, 0.75mol）, the min of stirring at normal temperature 20, compound 1 (158g, 0.6mol), stirring at normal temperature reactions in 1 hour is added dropwise
It is concentrated under reduced pressure into dry after liquid cooling, column chromatography obtains faint yellow solid 68g（Yield 32.4%）.
Embodiment 4：5- (2- fluorophenyls) -1- ((3- (3- methoxypropoxies) benzenesulfonyl) -1H- pyrroles's -3- formaldehyde（Change
Compound 2）Preparation
In 2L reaction bulbs, compound 1-1 (95g, 0.5mol) is dissolved in dichloromethane (1000ml), adds triethylamine
（100g, 1mol）, the min of stirring at normal temperature 20, compound 1 (158g, 0.6mol), stirring at normal temperature reaction solutions cooling in 1 hour is added dropwise
After be concentrated under reduced pressure into dry, column chromatography obtains faint yellow solid 75g（Yield 35.8%）.
Embodiment 5：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases)-N-
Methyl amine（Compound 3）Preparation
In 10L reaction bulbs, by 4（700 g, 1.68mol）, 33% methylamine methanol solution（630g, 6.71mol）It is dissolved in 3.5L first
In alcohol, stirring at normal temperature 0.5h.0 DEG C is cooled to, adds sodium triacetoxy borohydride (882g, 4.20 mol), stirring at normal temperature
2h.Add 7L water quenchings to go out, be extracted with ethyl acetate three times（7Lx3）Extraction.Merge organic phase, be concentrated under reduced pressure into dry, addition 12L water
Dissolving, ethyl acetate wash four times（2.5L+1.5L+1.5L+1L）, aqueous phase 2NNaOH tune PH to 9, dichloromethane extraction is three times
（2.5Lx3）, merge organic phase, wash four times（2.5Lx4）, anhydrous sodium sulfate drying is concentrated under reduced pressure into dry, obtains faint yellow oily
Thing 640g（Yield 88.2%）.
MS（+1）：433
1HNMR：δ (ppm, DMSO), 12.37 (s, H, COOH), 6.99-7.71 (m, 11H, Ar-H), 4.60 (t, 2H,
CH2), 4.60 (t, 2H ,-OCH2), 4.20 (t, 2H ,-OCH2), 1.39 (q, 3H ,-CH3), 1.51 (q, 3H ,-CH3)。
Embodiment 6：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases)-N-
Methyl amine（Compound 3）Preparation
In 2L reaction bulbs, by compound 2（208g, 0.5mol）, 33% methylamine methanol solution（188g, 2mol）, glacial acetic acid
（36g, 0.6mol）It is dissolved in 1L methanol, stirring at normal temperature 0.5h.Sodium triacetoxy borohydride (265g, 1.25mol) is added,
Stirring at normal temperature 2h.Add 2L water quenchings to go out, be extracted with ethyl acetate three times（2Lx3）Extraction.Merge organic phase, be concentrated under reduced pressure into dry, add
Enter the dissolving of 3L water, ethyl acetate washs four times（1L+0.8L+0.5L+0.3L）, aqueous phase 2NNaOH tune PH to 9, dichloromethane extraction
Take three times（1Lx3）, merge organic phase, wash four times（1Lx4）, anhydrous sodium sulfate drying is concentrated under reduced pressure into dry, obtains faint yellow oil
Shape thing 150g（Yield 69.6%）.
Embodiment 7：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases)-N-
Methyl amine（Compound 3）Preparation
In 2L reaction bulbs, by compound 2（208g, 0.5mol）, 33% methylamine methanol solution（188g, 2mol）It is dissolved in 1L methanol
In, stirring at normal temperature 0.5h.Sodium borohydride (57g, 1.5mol), stirring at normal temperature 2h are added at 0 DEG C.Add 2L water quenchings to go out, use acetic acid
Ethyl ester extracts three times（2Lx3）Extraction.Merge organic phase, be concentrated under reduced pressure into dry, addition 3L water dissolvings, ethyl acetate washing four times
（1L+0.8L+0.5L+0.3L）, aqueous phase 2NNaOH tune PH to 9, dichloromethane extraction is three times（1Lx3）, merge organic phase, water
Wash four times（1Lx4）, anhydrous sodium sulfate drying is concentrated under reduced pressure into dry, obtains pale yellow oil 165g（Yield 76.5%）.
Embodiment 8：1- (5- (2- fluorophenyls) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases)-N-
Methyl amine（Compound 3）Preparation
In 2L reaction bulbs, by compound 2（208g, 0.5mol）, 33% methylamine methanol solution（188g, 2mol）It is dissolved in 1L dichloros
In methane, stirring at normal temperature 0.5h.Add sodium triacetoxy borohydride (265g, 1.25mol), stirring at normal temperature 2h.Add 2L water
It is quenched, liquid separation, organic phase is concentrated under reduced pressure into dry, addition 3L water dissolvings, ethyl acetate washing four times（1L+0.8L+0.5L+
0.3L）, aqueous phase 2NNaOH tune PH to 9, dichloromethane extraction is three times（1Lx3）, merge organic phase, wash four times（1Lx4）, nothing
Aqueous sodium persulfate is dried, and is concentrated under reduced pressure into dry, obtains pale yellow oil 138g（Yield 64%）.
Claims (10)
1. a kind of prepare the 1- (5- (2- as shown in compound 3 as 3- (3- methoxy propoxies) benzene sulfonyl chloride as shown in compound 1
Fluorophenyl) -1-3- (3- methoxypropoxies) benzene sulfonyl chloride) -1H- pyrroles -3- bases) and-N- methyl amines preparation method,
Characterized in that, preparation method includes following step：
（1）Under protic or non-proton organic solvent, at -40 DEG C -50 DEG C, alkaline environment, compound 1 and compound 1-1
Reaction obtains compound 2 in tetrahydrofuran solvent；
（2）Under organic solvent, at -20 DEG C -50 DEG C, under reducing agent existence condition, compound 2 is generating chemical combination through reduction amination
Thing 3；
。
2. preparation method as claimed in claim 1, it is characterised in that the step（1）In alkali used be organic base or nothing
Machine alkali.
3. such as the preparation method of claim 1 or 2, it is characterised in that step（1）In alkali used include triethylamine, N, N- bis- is different
Propylethylamine, triethylene diamine（DABCO）, the carbon -7- alkene (DBU) of 1,8- diazabicylo 11, pyridine, ethylenediamine, methylamine, urine
Element, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide.
4. the preparation method as described in claims 1 to 3 is any, it is characterised in that step（1）In alkali used include sodium hydride.
5. preparation method as claimed in claim 1, it is characterised in that：Step（2）Reaction dissolvent include protic it is organic molten
Agent and non-proton organic solvent.
6. the preparation method as described in claim 1 or 5, it is characterised in that：StepReaction dissolvent include methanol, ethanol,
Propyl alcohol, n-butanol, methyl acetate, ethyl acetate, propyl acetate, dichloromethane, chloroform, ether, isopropyl ether, tetrahydrochysene furan
Mutter, acetone, N, dinethylformamide, toluene, acetonitrile and its mixture.
7. the preparation method as described in claim 1 or 5 or 6, it is characterised in that：StepReaction dissolvent include methanol.
8. method as claimed in claim 1, it is characterised in that：StepReducing agent include sodium borohydride, potassium borohydride, three second
Triacetoxyborohydride, Lithium Aluminium Hydride, sodium thiosulfate, hydrogen, natrium nitrosum, hydrazine hydrate.
9. the preparation method as described in claim 1 or 8, it is characterised in that：StepReducing agent include triacetoxy borohydride
Sodium hydride.
10. the preparation method as described in claim 1-9 is any, it is characterised in that：At a temperature of -30 DEG C ± 5 DEG C, sodium hydride carries
For alkaline environment, compound 1 and compound 1-1 reacts in tetrahydrofuran solvent obtains compound 2, and compound 2 is in methyl alcohol
Compound 3 is generated by sodium triacetoxy borohydride reduction amination with methylamine.
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| WO2023280288A1 (en) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | Pyrrole sulfonyl derivative, and preparation method therefor and application thereof |
| CN115594623A (en) * | 2021-07-09 | 2023-01-13 | 天地恒一制药股份有限公司（Cn） | A pyrrolesulfonyl derivative, its preparation method and application |
| WO2024188316A1 (en) * | 2023-03-15 | 2024-09-19 | 江苏柯菲平医药股份有限公司 | Pyrrolesulfonic acid compound salt form, and preparation method therefor and use thereof |
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