CN115784950B - Preparation method of ritalst intermediate - Google Patents
Preparation method of ritalst intermediate Download PDFInfo
- Publication number
- CN115784950B CN115784950B CN202211571885.1A CN202211571885A CN115784950B CN 115784950 B CN115784950 B CN 115784950B CN 202211571885 A CN202211571885 A CN 202211571885A CN 115784950 B CN115784950 B CN 115784950B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- solution
- preparation
- added
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 102
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- 229940125898 compound 5 Drugs 0.000 claims abstract description 46
- 229940125904 compound 1 Drugs 0.000 claims abstract description 40
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003960 organic solvent Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002738 chelating agent Substances 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 166
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 89
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 55
- 239000000243 solution Substances 0.000 claims description 51
- 239000007864 aqueous solution Substances 0.000 claims description 47
- 238000003756 stirring Methods 0.000 claims description 46
- 229940125782 compound 2 Drugs 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 238000001914 filtration Methods 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 32
- 229940126214 compound 3 Drugs 0.000 claims description 28
- 230000001105 regulatory effect Effects 0.000 claims description 27
- 239000008346 aqueous phase Substances 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 5
- KFDNQUWMBLVQNB-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].[Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KFDNQUWMBLVQNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- XFLNVMPCPRLYBE-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;tetrahydrate Chemical group O.O.O.O.[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O XFLNVMPCPRLYBE-UHFFFAOYSA-J 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- ZAWGLAXBGYSUHN-UHFFFAOYSA-M sodium;2-[bis(carboxymethyl)amino]acetate Chemical compound [Na+].OC(=O)CN(CC(O)=O)CC([O-])=O ZAWGLAXBGYSUHN-UHFFFAOYSA-M 0.000 claims description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 1
- 239000003446 ligand Substances 0.000 abstract description 16
- 239000010949 copper Substances 0.000 abstract description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 14
- 229910052802 copper Inorganic materials 0.000 abstract description 14
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 5
- 230000003113 alkalizing effect Effects 0.000 abstract description 2
- 230000020477 pH reduction Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 28
- 238000011084 recovery Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000012071 phase Substances 0.000 description 14
- 229960004641 rituximab Drugs 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 230000006837 decompression Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical group [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 5
- 206010013774 Dry eye Diseases 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- -1 o-methylthiobenzyl Chemical group 0.000 description 4
- 238000010979 pH adjustment Methods 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000208445 Sarcodes Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003163 gonadal steroid hormone Substances 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- GDMOHOYNMWWBAU-QMMMGPOBSA-N (2s)-2-amino-3-(3-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(Br)=C1 GDMOHOYNMWWBAU-QMMMGPOBSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- 206010052143 Ocular discomfort Diseases 0.000 description 1
- 208000023715 Ocular surface disease Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- 229920002125 Sokalan® Polymers 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940127284 new molecular entity Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical class [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 229940023106 xiidra Drugs 0.000 description 1
Classifications
-
- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a litaxetil intermediate compound 1, which adopts a specific copper ligand compound, a reaction organic solvent and sodium hydroxide to obtain a compound 4, acidifying the compound 4 in the specific organic solvent, adding a chelating agent, alkalizing to obtain a compound 5, recovering a catalyst compound 6 after acidification, and reacting the compound 5 with Boc anhydride to obtain a target compound 1. The method has high reaction stereoselectivity, low isomer and disubstituted impurity content, no need of purification, and can be directly used for the subsequent synthesis reaction of the ritodynamic.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a rituximab intermediate.
Background
Dry Eye (DED), also known as keratoconjunctivitis sicca, is a multifactorial tear and ocular surface disease that can lead to symptoms such as ocular discomfort, vision impairment, and tear film instability, with increased tear film permeability and ocular surface inflammation. DED has high incidence rate in women and the elderly, can have great influence on the life quality of patients, and can be even blinded seriously. The etiology of DED is complex, the pathogenesis is not clear, wherein inflammation is the most critical factor causing DED, and apoptosis, sex hormone level change and the like are also one of important factors. The conventional treatment scheme of DED at present is mainly based on artificial tear wetting, and in addition, schemes of inhibiting inflammation, sex hormone therapy and the like are included in the scheme of medicines for relieving DED symptoms, such as carbomer eye drops, sodium carboxymethyl cellulose eye drops, artificial tear preparations, cyclosporine A, androgen preparations and the like. Only 0.05% of cyclosporin a ophthalmic emulsions were previously approved by the us FDA as prescription drugs for DED clinical treatment, but the drugs have side effects that cause burning sensation after use, and many patients have stopped using them.
Lifitegast (Lifiteglast) is a new molecular entity designed and developed by US SARcode Bioscience for the treatment of dry eye, ireland pharmaceutical megaly in 2013 purchased SARcode Bioscience in dollars of 1.6 million and obtained the development and marketing rights of this company, bifidesstat. Litaset eye drops developed by Sharp company were approved by the United states FDA for the treatment of symptoms and signs of dry eye at day 7 and 11 of 2016 under the trade name Xiidra, which is the first FDA approved antagonist-type new drug for lymphocyte function-associated antigen (LFA-1) for the treatment of dry eye and is also the only prescribed eye drop in the United states market.
The structural formula of the ritalst is as follows:
wherein L-Boc-m-methylsulfonylalanine (Compound 1) Is a key intermediate for synthesizing the rituximab, and the preparation methods which have been reported are as follows.
The preparation methods reported in patent WO2014/18748A1 and WO2009/102876A1 take L-m-bromophenylalanine as a starting material, and L-Boc-m-methylsulfonyl alanine is obtained by substitution of sodium methylsulfinate through Boc protection. Although the method is short, a large amount of copper salt is used when the methanesulfonyl is introduced, so that pollution is caused, and the starting material L-m-bromophenyl alanine is expensive and is not easy to prepare. L-m-bromophenyl alanine is obtained by multi-step reaction of m-bromophenyl formaldehyde, wherein one step is asymmetric hydrogenation with noble metal, special hydrogenation equipment is needed, and the method is not suitable for industrial production.
Chinese patent zl201410826534.X at 2015.05.06 discloses a synthetic method for preparing OMLT, OMLT02 and OMLT03, which uses S-glycine schiff base Ni (II) complex [ Ni- (S) -BPB-Gly ] as starting material to synthesize target chiral amino acids, but the method still has the effect of isomer impurities and disubstituted impurities.
Smith, daniel J, 2011, published "Enhanced Stereose lectivity of aCu(II)Complex Chiral Auxiliary in the Synthesis of Fmoc-L-γ-carboxyglutamic Acid"(The Journal of Organic Chemistry,76(6),1513–1520),, which reports selective synthesis of Fmoc-L-gamma-carboxyglutamic acid by a series of chiral auxiliary of copper (Cu) or nickel (Ni) complexes, but the reaction aims at addition of an ethylenic bond, and the yield and the chiral selectivity are difficult to improve simultaneously.
The requirement on impurities of the rituximab serving as an eye drop for treating xerophthalmia is far higher than that of a common preparation, and the existing synthesis process of the rituximab intermediate has the defects of long route, complex reaction, low yield, low catalyst recovery rate and the like, so that the development of the process for preparing the rituximab intermediate with simple operation, economy, environmental protection and high yield and purity is a technical problem to be solved in the field. According to the scheme, the specific copper ligand compound is added in the process, and the high-purity high-chirality litaxetil intermediate can be obtained through specific reaction steps, so that the method can be directly used for synthesizing litaxetil without purification, and the catalyst is high in recovery rate, economical and environment-friendly.
Disclosure of Invention
The invention aims to provide a novel chiral center construction method of a litaxetil intermediate compound 1, which is simple to operate, high in yield and purity, high in catalyst recovery rate, economical and environment-friendly, and the obtained litaxetil intermediate can be used subsequently without purification.
Specifically, the preparation method of the litaxetil intermediate compound 1 comprises the steps of adopting a specific copper ligand compound, reacting an organic solvent with sodium hydroxide to obtain a compound 4, acidifying the compound 4 in the specific organic solvent, adding a chelating agent, alkalizing to obtain a compound 5, acidifying, recovering a catalyst compound 6, and reacting the compound 5 with Boc anhydride to obtain the target compound 1.
The beneficial effects of the invention are realized by the following technical scheme.
A process for the preparation of ritodynamic intermediate compound 1 comprising the following three steps:
A. Adding the compound 2 into an organic solvent, mixing with a sodium hydroxide solution, cooling, dropwise adding a solution of the compound 3 for reaction, adding ice water after the reaction is finished, preserving heat, filtering and drying to obtain a compound 4;
B. dissolving the compound 4 in an organic solvent I, adding hydrochloric acid, heating to react, adding a chelating agent after the reaction is finished, concentrating under reduced pressure, adding water and an organic solvent II, adding a sodium hydroxide solution, separating the solution, washing with water to obtain a compound 5 aqueous solution, combining the organic phases, dropwise adding hydrochloric acid at room temperature, stirring at room temperature after the dropwise adding is finished, filtering, and drying to obtain a compound 6;
C. the water solution of the compound 5 reacts with Boc anhydride, hydrochloric acid is added after the reaction is finished, and the mixture is stirred, filtered and dried to obtain a compound 1;
In the present invention, the copper ligand compound in step a is one of the important keys to achieve technical effects. The inventors found that when the substituent on the N atom of the pyrrolyl group in the copper ligand compound is o-methylthiobenzyl, the yield of compound 4 is lower, and when the substituent on the N atom of the pyrrolyl group in the copper ligand compound is benzyl, the reaction produces compound 4 while producing a small amount of dimer impurity. The above situation occurs because the substitution reaction of compound 3 is unfavorable because the steric hindrance is large when the substituent on the N atom of the pyrrolyl group is o-methylthiobenzyl, and because the steric hindrance is small when the substituent on the N atom of the pyrrolyl group is benzyl, di-substitution or poly-substitution reaction is likely to occur. Therefore, only with the specific copper ligand compound of the present invention, it is possible to sufficiently react with the compound 3 while avoiding the occurrence of di-or poly-substitution reaction.
In the invention, the type of the organic solvent, the mass-to-volume ratio (g/ml) of the compound 2 to the organic solvent, and the molar ratio of the compound 2 to the compound 3 in the step A are one of important keys for realizing the technical effect. Specifically, when the organic solvent is acetonitrile or acetone, the mass-volume ratio of the compound 2 to the solution is 1:3-7, the compound 2 can be fully dissolved in the organic solvent, so that subsequent reaction is facilitated, the generation of isomer impurities is reduced, and when the molar ratio of the compound 2 to the compound 3 is 1:1.05-1.20, the reaction is fully performed, and the occurrence of di-substitution and multi-substitution reaction is reduced. More specifically, in the preparation method of the compound 1, the organic solvent in the step A is acetone, the mass-volume ratio of the compound 2 to the solution is 1:5, and the molar ratio of the compound 2 to the compound 3 is 1:1.1.
In the present invention, the choice of the X substituent in compound 3 in step A is one of the keys to achieve the technical effect. Specifically, when X is F, cl or Br, the leaving of halogen ions and substitution reaction are facilitated. More specifically, in the preparation method of the compound 1, in the step A, X is Cl.
In the invention, the reaction pH condition, temperature and time in the step A are one of the keys for realizing the technical effect. The proper pH condition and temperature can further shorten the reaction time and improve the reaction efficiency while ensuring the yield and purity, and when the concentration of sodium hydroxide is 40-60%, the pH is regulated to 6.5-8.5, the temperature is 0-10 ℃ and the reaction is carried out for 2-4 hours, so that the yield and the purity of the reaction are better. Specifically, when the concentration of sodium hydroxide is 50%, the pH is regulated to 7.0-8.0, the temperature is 0-5 ℃, and the reaction is carried out for 3 hours, so that the yield and purity of the reaction can be optimal.
In the invention, the selection of hydrolysis reaction conditions in the step B is one of the keys for realizing technical effects. The proper solvent and proportion, pH condition and temperature can make the hydrolysis reaction more sufficient, and at the same time shorten the reaction time, when the mass volume ratio of the first organic solvent is methanol, ethanol, acetonitrile and tetrahydrofuran, and the mass volume ratio of the compound 4 to the first organic solvent is 1:2-5, the concentrated hydrochloric acid is used for slowly adjusting the pH to 1.5-3.0, the temperature is raised to 60-70 ℃, and when the reaction is carried out for 2-4 hours, the hydrolysis reaction is fully carried out, the yield and purity of the compound 5 are ensured, and the recovery rate of the removed compound 6 is improved. Specifically, when the first organic solvent is acetonitrile, the mass-volume ratio of the compound 4 to the first organic solvent is 1:3, the pH is slowly adjusted to 2.5 by using concentrated hydrochloric acid, the temperature is raised to 65 ℃, and the reaction is carried out for 3 hours, the hydrolysis reaction is carried out most fully at the moment, the yield and the purity of the reaction can reach the best, and the recovery of the subsequent compound 6 is facilitated.
In the present invention, the selection of the reaction conditions for recovering compound 6 in step B is one of the keys to achieve the technical effect. And proper chelating agent, organic solvent and pH condition ensure the yield of the compound 5 and improve the recovery rate of the compound 6. When the chelating agent is sodium ethylenediamine tetraacetate or sodium aminotriacetate, and the organic solvent is dichloromethane or chloroform, the dissolution degree of the compound 6 and the chelating agent is better, when the concentration of sodium hydroxide is 40-60%, the pH is adjusted to 9.0-10.0, the compound 5 can be fully dissolved in the water phase, the residue of the compound 6 in the water phase is reduced, after the water phase is extracted by dichloromethane or chloroform, the dichloromethane or chloroform is combined, and the pH is adjusted to 1.5-2.5 by concentrated hydrochloric acid, so that the compound 6 solid can be gradually separated out. Specifically, when the chelating agent is tetra sodium ethylenediamine tetraacetate tetrahydrate and the organic solvent is dichloromethane, the compound 5 and the chelating agent are best dissolved, when the concentration of sodium hydroxide is 50%, the pH is adjusted to 9.0-10.0, the compound 5 is more fully dissolved in the water phase, the residue of the compound 6 in the water phase is reduced, the use of water in a reaction system is reduced, after the water phase is extracted by dichloromethane, the dichloromethane is combined, the pH is adjusted to 1.5-2.5 by concentrated hydrochloric acid, the compound 6 solid can be fully separated out, and the yield of the compound 6 is improved.
In the present invention, the molar ratio of the chelating agent to the compound 4 has a certain influence on the reaction of the compound 6, and it is known to those skilled in the art that when the amount of the chelating agent is equal to or larger than the amount of the compound 4, the reaction is more complete, and therefore, the molar ratio of the tetrasodium ethylenediamine tetraacetate tetrahydrate to the compound 4 is 1:1 in terms of the extent of the reaction and economic efficiency.
In the present invention, in the step C, after obtaining an aqueous solution containing the compound 5, boc anhydride is added dropwise to the aqueous solution containing the compound 5 at room temperature, and after the completion of the addition, the reaction is carried out for 8 to 12 hours, preferably 10 hours, to obtain the objective compound 1. The molar ratio of Boc anhydride to compound 4 was 1.7:1, and the binding was sufficient. After the reaction is finished, dichloromethane is added, the liquid is separated by extraction, the water phase is washed by dichloromethane again, the temperature of the water phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% hydrochloric acid, the mixture is stirred for 1-2 hours, the compound 1 can be gradually separated out, and the purity of the obtained compound 1 can be further improved after the compound 1 is washed and dried by isopropyl ether.
A preferred process for the preparation of compound 1 of the present invention comprises the following three steps:
A. Adding the compound 2 into acetone, mixing with 50%wt sodium hydroxide solution until the pH value is 7.0-8.0, wherein the mass volume ratio of the compound 2 to the acetone is 1:5, the molar ratio of the compound 2 to the compound 3 is 1:1.1, cooling to 0-5 ℃, dropwise adding the solution of the compound 3 for reaction, continuing the reaction for 3 hours, adding ice water after the reaction is finished, preserving the heat at 0-5 ℃, and filtering and drying to obtain the compound 4;
B. adding the compound 4 into acetonitrile, adding concentrated hydrochloric acid into the mixture, adjusting the pH value of the mixture to 2.5, heating the mixture to 65 ℃ for reaction for 3 hours, adding the tetra-sodium ethylenediamine tetraacetic acid tetrahydrate into the mixture after the reaction is finished, wherein the molar ratio of the tetra-sodium ethylenediamine tetraacetic acid tetrahydrate to the compound 2 is 1:1, concentrating the mixture under reduced pressure, adding water and methylene dichloride into the mixture, adjusting the pH value of the mixture to 9-10 by using a 50%wt sodium hydroxide aqueous solution, separating the mixture, washing the aqueous phase by methylene dichloride again to obtain a compound 5 aqueous solution, merging the organic phases, dropwise adding the concentrated hydrochloric acid at room temperature to the pH value of 1.5-2.5, stirring the mixture at room temperature after the dropwise adding is finished, and filtering and drying the mixture to obtain a compound 6;
C. after obtaining an aqueous solution containing a compound 5, C. dropwise adding Boc anhydride into the aqueous solution containing the compound 5 at room temperature, wherein the molar ratio of Boc anhydride to the compound 4 is 1.7:1, reacting for 10 hours after the dropwise adding, adding dichloromethane after the reaction is finished, extracting and separating liquid, washing a water phase by the dichloromethane again, controlling the temperature of the water phase to 10-20 ℃, adjusting the pH value to 3-5 by 12% hydrochloric acid, stirring for 1-2 hours, filtering, washing a filter cake by isopropyl ether, and drying to obtain the compound 1.
The invention also provides an application of the compound 1 prepared by the preparation method in preparing the rituximab, wherein the compound 1 can be directly used for subsequent synthesis reaction of the rituximab without purification.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. The copper ligand compound is used for synthesizing the key intermediate of the rituxetat for the first time, has high reaction stereoselectivity and low isomer and disubstituted impurity content, does not need purification, and can be directly used for the subsequent synthesis reaction of the rituxetat.
2. The copper ligand compound can be recovered after the reaction, and the recovery rate is high, so that the resource loss is reduced, and the cost is further reduced.
3. The reaction condition is simple and easy to implement, and is suitable for industrialized amplified production.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein, and compound 2 can be prepared according to the method "Enhanced Stereoselectivity of a Cu(II)Complex Chiral Auxiliary in the Synthesis of Fmoc-L-γ-carboxyglutamic Acid".
In the present invention, boc represents t-butoxycarbonyl, EDTA.4Na.4H2 2 O represents tetrasodium ethylenediamine tetraacetate tetrahydrate, bnOH represents benzyl alcohol, EDCI represents 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, DCM represents dichloromethane, DMAP represents 4-dimethylaminopyridine, dioxane represents Dioxane, IPAc represents isopropyl acetate, SOCl 2 represents thionyl chloride, DMF represents N, N-dimethylformamide, and THF represents tetrahydrofuran.
Example 1
Preparation of Compound A4
At room temperature, 40mL of acetone and 10g of compound 2 are added into a 100mL three-neck flask, the mixture is stirred, 50%wt of sodium hydroxide aqueous solution is added, the pH is regulated to 7.0-8.0, after the addition is finished, the temperature is reduced to 0-5 ℃,10 mL of compound 3 (chlorine substituted, 4.26 g) of acetone solution is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 3 hours, 100mL of ice water is dropwise added after the reaction is finished, the mixture is kept at 0-5 ℃ for 1 hour, and the mixture is filtered and dried to obtain compound 4.9 g, wherein the yield is about 98.0% and the purity is 99.2%.
Preparation of Compound B5
To a 100mL single-neck flask, 12.9g of compound 4, 38.7mL of acetonitrile and concentrated hydrochloric acid are added at room temperature, the pH is adjusted to 2.5, the temperature is raised to 65 ℃ and after the reaction is carried out for 3 hours, the HPLC detection is completed, the temperature is reduced to room temperature, 8.5g of EDTA 4Na 4H 2 O is added, the acetonitrile is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is adjusted to 9-10 by 50% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained and is ready for the next reaction.
Recovery of compound 6:
Mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dripping, filtering, and drying to obtain off-white solid compound 6.22 g with yield of about 95.0% and purity of 99.9%.
Preparation of Compound C1
6.87G of Boc anhydride is slowly added dropwise into a flask containing a compound 5 water solution at room temperature, stirring is carried out for 10 hours after the dropwise addition is finished, 25mL of dichloromethane is added after the reaction is finished, stirring is carried out, the liquid is separated, the water phase is washed by 25mL of dichloromethane again, the temperature of the water phase is controlled to 10-20 ℃, 12% hydrochloric acid is used for adjusting the pH value to 3-5, solid precipitation is carried out, stirring is carried out for 1-2 hours, filtering is carried out, a filter cake is washed by isopropyl ether, and a white solid compound 1.29 g is obtained after vacuum drying at 50-60 ℃, the yield is 98.9%, and the purity is 99.5%.
Example 2
A. Preparation of Compound 4
At room temperature, adding 20mL of acetonitrile and 10g of compound 2 into a 100mL three-neck flask, stirring, adding 40%wt of sodium hydroxide aqueous solution, adjusting the pH to 6.5-7.0, cooling to 0-5 ℃ after the addition, slowly dropwise adding 10mL of acetonitrile solution of compound 3 (fluorine substituted, 3.74 g), continuing to react for 2 hours after the dropwise adding is finished, dropwise adding 100mL of ice water after the reaction is finished, preserving heat for 1 hour at 0-5 ℃, filtering, and drying to obtain compound 4.5 g, wherein the yield is about 95.0% and the purity is 99.0%.
B. Preparation of Compound 5
To a 100mL single-neck flask, 12.5g of compound 4, 25.0mL of methanol and concentrated hydrochloric acid are added at room temperature, the pH is adjusted to 1.5, the temperature is raised to 60 ℃, after the reaction is carried out for 2 hours, HPLC detection is completed, the temperature is reduced to room temperature, 4.7g of sodium aminotriacetate is added, the methanol is removed by decompression concentration, 10mL of water and 25mL of chloroform are added, the pH value is adjusted to 9-10 by 40% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by chloroform (25 mL of x 2) again, so that compound 5 aqueous solution is obtained and is used for the next reaction.
Recovery of compound 6:
Mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dripping, filtering, and drying to obtain off-white solid compound 6.82g with yield of 92.5% and purity of 99.8%.
C. preparation of Compound 1
6.66G of Boc anhydride is slowly added dropwise into a flask containing the aqueous solution of the compound 5 at room temperature, stirring is carried out for 8 hours after the dropwise addition, 25mL of dichloromethane is added after the reaction is finished, stirring is carried out, the liquid is separated, the aqueous phase is washed by 25mL of dichloromethane again, the temperature of the aqueous phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% of hydrochloric acid, solid precipitation is carried out, stirring is carried out for 1-2 hours, filtering is carried out, a filter cake is washed by isopropyl ether, and the white solid compound 1.99 g is obtained after vacuum drying at 50-60 ℃, the yield is 97.2%, and the purity is 99.3%.
Example 3
A. Preparation of Compound 4
30ML of acetone and 10g of compound 2 are added into a 100mL three-neck flask at room temperature, stirring is carried out, 60%wt of sodium hydroxide aqueous solution is added, the pH is regulated to 8.0-8.5, after the addition is finished, the temperature is reduced to 5-10 ℃,10 mL of compound 3 (bromine substituted, 5.70 g) of acetone solution is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 4 hours, 100mL of ice water is dropwise added after the reaction is finished, the temperature is kept at 0-5 ℃ for 1 hour, and the compound 4.8 g is obtained through filtration and drying, wherein the yield is about 97.5%, and the purity is 98.7%.
B. Preparation of Compound 5
12.8G of compound 4, 64.2mL of tetrahydrofuran are added into a 100mL single-neck flask at room temperature, concentrated hydrochloric acid is added, the pH is regulated to 3.0, the temperature is raised to 70 ℃, after the reaction is carried out for 4 hours, HPLC detection is completed, the temperature is reduced to room temperature, 8.4g of EDTA 4Na 4H 2 O is added, the tetrahydrofuran is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is regulated to 9-10 by 60% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained for later use in the next reaction.
Recovery of compound 6:
and combining the organic phases, slowly dropwise adding concentrated hydrochloric acid at room temperature, regulating the pH to 1.5-2.5, stirring overnight at room temperature after the dropwise adding is finished, filtering, and drying to obtain 6.10 g of off-white solid compound with the yield of about 93.8% and the purity of 99.9%.
C. preparation of Compound 1
6.84G of Boc anhydride is slowly added dropwise into a flask containing the aqueous solution of the compound 5 at room temperature, stirring is carried out for 12h after the dropwise addition, 25mL of dichloromethane is added after the reaction is completed, stirring is carried out, the liquid is separated, the aqueous phase is washed by 25mL of dichloromethane again, the temperature of the aqueous phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% of hydrochloric acid, solid precipitation is carried out, stirring is carried out for 1-2 h, filtering is carried out, the filter cake is washed by isopropyl ether, and the white solid compound 1.19 g is obtained after vacuum drying at 50-60 ℃, the yield is 97.8%, and the purity is 99.3%.
Example 4
A. Preparation of Compound 4
At room temperature, 40mL of acetone and 10g of compound 2 are added into a 100mL three-neck flask, stirring is carried out, 45%wt of sodium hydroxide aqueous solution is added, the pH is regulated to 6.5-7.0, after the addition is finished, the temperature is reduced to 0-5 ℃,10 mL of compound 3 (chlorine substituted, 4.14 g) of acetone solution is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 3 hours, 100mL of ice water is dropwise added after the reaction is finished, the temperature is kept at 0-5 ℃ for 1 hour, and the compound 4.8 g is obtained through filtration and drying, wherein the yield is about 97.0% and the purity is 99.1%.
B. Preparation of Compound 5
12.8G of compound 4, 51.1mL of ethanol and concentrated hydrochloric acid are added into a 100mL single-neck flask at room temperature, the pH is regulated to 2.0, the temperature is raised to 65 ℃, after the reaction is carried out for 3 hours, the HPLC detection is completed, the temperature is reduced to room temperature, 8.4g of EDTA 4Na 4H 2 O is added, the ethanol is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is regulated to 9-10 by 45% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained and is ready for the next reaction.
Recovery of compound 6:
And combining the organic phases, slowly dropwise adding concentrated hydrochloric acid at room temperature, regulating the pH to 1.5-2.5, stirring overnight at room temperature after the dropwise adding is finished, filtering, and drying to obtain 6.10 g of off-white solid compound with the yield of about 94.3% and the purity of 99.8%.
C. preparation of Compound 1
6.80G of Boc anhydride is slowly added dropwise into a flask containing a compound 5 aqueous solution at room temperature, stirring is carried out for 9h after the dropwise addition is finished, 25mL of dichloromethane is added after the reaction is finished, stirring is carried out, the liquid is separated, the aqueous phase is washed by 25mL of dichloromethane again, the temperature of the aqueous phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% of hydrochloric acid, solid precipitation is carried out, stirring is carried out for 1-2 h, filtering is carried out, a filter cake is washed by isopropyl ether, and a white solid compound 1.18 g is obtained after vacuum drying at 50-60 ℃, the yield is 98.1%, and the purity is 99.5%.
Example 5
A. Preparation of Compound 4
At room temperature, 40mL of acetone and 10g of compound 2 are added into a 100mL three-neck flask, stirring is carried out, 55%wt of sodium hydroxide aqueous solution is added, the pH is regulated to 8.0-8.5, after the addition is finished, the temperature is reduced to 5-10 ℃,10 mL of compound 3 (chlorine substituted, 4.22 g) of acetone solution is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 3 hours, 100mL of ice water is dropwise added after the reaction is finished, the temperature is kept at 0-5 ℃ for 1 hour, and the compound 4.7 g is obtained after filtering and drying, wherein the yield is about 96.5% and the purity is 99.0%.
B. Preparation of Compound 5
To a 100mL single-neck flask, 12.7g of compound 4, 38.2mL of acetonitrile and concentrated hydrochloric acid are added at room temperature, the pH is adjusted to 2.5, the temperature is raised to 70 ℃, after the reaction is carried out for 3 hours, the HPLC detection is completed, the temperature is reduced to room temperature, 8.3g of EDTA 4Na 4H 2 O is added, the acetonitrile is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is adjusted to 9-10 by 55% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained and is ready for the next reaction.
Recovery of compound 6:
Mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dripping, filtering, and drying to obtain off-white solid compound 6.08 g with yield of about 94.6% and purity of 99.9%.
C. preparation of Compound 1
6.77G of Boc anhydride is slowly added dropwise into a flask containing an aqueous solution of the compound 5 at room temperature, stirring is carried out for 11h after the dropwise addition, 25mL of dichloromethane is added after the reaction is finished, stirring is carried out, the separated solution is separated, the aqueous phase is washed by 25mL of dichloromethane again, the temperature of the aqueous phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% of hydrochloric acid, solid precipitation is carried out, stirring is carried out for 1-2 h, filtering is carried out, a filter cake is washed by isopropyl ether, and the white solid compound 1.15 g is obtained after vacuum drying at 50-60 ℃, the yield is 98.2%, and the purity is 99.3%.
Comparative examples 1 to 6
Preparation of Compound 4
Referring to the method of example 1, comparative examples 1 to 6, compound 2 was replaced with the same type of copper ligand or nickel ligand compound, compound 2 analog, yield, purity as shown in table 1, compound 2 analog, isomer and disubstituted structure as shown in table 2.
Table 1 compound 2 analog, yield, purity table
Table 2 table of compound 2 analogues, isomers and disubstituted structures
As can be seen from the data in table 2, the copper ligand catalyst of the present invention used in the preparation method of example 1 had higher purity and yield of the compound 4, whereas the preparation method of comparative example 2 had lower steric hindrance with the R substituent being H, and thus, although the yield of the compound 4 was higher, the content of the isomer and disubstituted impurity compounds was also relatively higher, and the preparation methods of comparative examples 5 and 6 had higher steric hindrance with the R substituent being SMe, and thus, although the stereoselectivity was better, the yield of the compound was relatively lower. Meanwhile, under the same conditions, the copper ligand compound has certain advantages in purity and yield compared with the nickel ligand compound for the reaction of the invention.
Comparative example 7
A. Preparation of Compound 4
70ML of acetone and 10g of compound 2 are added into a 100mL three-neck flask at room temperature, stirring is carried out, 50%wt of sodium hydroxide aqueous solution is added, the pH is adjusted to 9.0-9.5, after the addition is finished, the temperature is reduced to 0-5 ℃,10 mL of compound 3 (chlorine substituted, 5.03 g) of acetone solution is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 3 hours, 100mL of ice water is dropwise added after the reaction is finished, the temperature is kept at 0-5 ℃ for 1 hour, and the obtained product is filtered and dried to obtain compound 4.12.1 g, wherein the yield is about 92.0% and the purity is 97.5%.
B. Preparation of Compound 5
To a 100mL single-neck flask, 12.1g of compound 4, 72.7mL of dichloromethane are added, concentrated hydrochloric acid is added, the pH is adjusted to 1.0, the temperature is raised to 75 ℃, after the reaction is carried out for 3 hours, HPLC detection is completed, the temperature is reduced to room temperature, 7.9g of EDTA 4Na 4H 2 O is added, the dichloromethane is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is adjusted to 11-12 by 50% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained and is ready for the next reaction.
Recovery of compound 6:
Mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 3.0-3.5, stirring overnight at room temperature after dripping, filtering, and drying to obtain off-white solid compound 6.78 g with yield of about 81.0% and purity of 96.7%.
C. preparation of Compound 1
6.45G of Boc anhydride is slowly added dropwise into a flask containing an aqueous solution of the compound 5 at room temperature, stirring is carried out for 13h after the dropwise addition, 25mL of dichloromethane is added after the reaction is completed, stirring is carried out, the liquid is separated, the aqueous phase is washed by 25mL of dichloromethane again, the temperature of the aqueous phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% of hydrochloric acid, solid precipitation is carried out, stirring is carried out for 1-2 h, filtering is carried out, a filter cake is washed by isopropyl ether, and the white solid compound 1.15 g is obtained after vacuum drying at 50-60 ℃, the yield is 86.2%, and the purity is 97.5%.
Comparative example 8
A. Preparation of Compound 4
10ML of acetone and 10g of compound 2 are added into a 100mL three-neck flask at room temperature, stirring is carried out, 30%wt of sodium hydroxide aqueous solution is added, the pH is regulated to 7.0-8.0, after the addition is finished, the temperature is reduced to 5-10 ℃,10 mL of compound 3 (chlorine substituted, 3.87 g) of acetone solution is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 3 hours, 100mL of ice water is dropwise added after the reaction is finished, the temperature is kept at 0-5 ℃ for 1 hour, the filtration and the drying are carried out, and the compound 4.9 g is obtained, the yield is about 75.2%, and the purity is 99.1%.
B. Preparation of Compound 5
9.9G of compound 4, 14.9mL of acetonitrile and concentrated hydrochloric acid are added into a 100mL single-neck flask at room temperature, the pH is regulated to 3.5, the temperature is raised to 55 ℃, after the reaction is carried out for 5 hours, the HPLC detection is completed, the temperature is reduced to room temperature, 6.5g of EDTA 4Na 4H 2 O is added, the acetonitrile is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is regulated to 8-9 by 30% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained and is ready for the next reaction.
Recovery of compound 6:
Mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dripping, filtering, and drying to obtain off-white solid compound 6.49 g with yield of 77.0% and purity of 95.2%.
C. preparation of Compound 1
Slowly dropwise adding 5.27g of Boc anhydride into a flask containing a compound 5 water solution at room temperature, stirring for 14h after the dropwise adding is finished, adding 25mL of dichloromethane after the reaction is finished, stirring, separating the solution, washing the water phase by 25mL of dichloromethane again, controlling the temperature of the water phase to 10-20 ℃, regulating the pH value to 3-5 by 12% of hydrochloric acid, separating out solids, stirring for 1-2 h, filtering, washing a filter cake by isopropyl ether, and vacuum drying at 50-60 ℃ to obtain white solid compound 1.39 g, wherein the yield is 69.4% and the purity is 92.5%.
Comparative example 9
A. Preparation of Compound 4
40ML of N, N-dimethylformamide and 10g of compound 2 are added into a 100mL three-neck flask at room temperature, the mixture is stirred, 50% wt of sodium hydroxide aqueous solution is added, the pH is adjusted to 7.0-8.0, after the addition is finished, the temperature is reduced to 0-5 ℃,10 mL of N, N-dimethylformamide solution of compound 3 (substituted by chlorine, 4.26 g) is slowly added dropwise, after the dropwise addition is finished, the reaction is continued for 3 hours, 100mL of ice water is dropwise added after the reaction is finished, the temperature is kept at 0-5 ℃ for 1 hour, and the mixture is filtered and dried to obtain 12.5g of compound 4, wherein the yield is about 95.0% and the purity is 98.6%.
B. Preparation of Compound 5
To a 100mL single-neck flask, 12.5g of compound 4, 37.5mL of acetonitrile and concentrated hydrochloric acid are added at room temperature, the pH is adjusted to 2.5, the temperature is raised to 65 ℃ and after the reaction is carried out for 3 hours, the HPLC detection is completed, the temperature is reduced to room temperature, 8.2g of EDTA 4Na 4H 2 O is added, the acetonitrile is removed by decompression concentration, 10mL of water and 25mL of dichloromethane are added, the pH value is adjusted to 9-10 by 50% wt of sodium hydroxide aqueous solution, the solution is separated, and the aqueous phase is washed by dichloromethane (25 mL of x 2) again, so that a compound 5 aqueous solution is obtained and is ready for the next reaction.
Recovery of compound 6:
Mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dripping, filtering, and drying to obtain off-white solid compound 6.97g with yield of about 94.5% and purity of 99.8%.
C. preparation of Compound 1
6.66G of Boc anhydride is slowly added dropwise into a flask containing the aqueous solution of the compound 5 at room temperature, stirring is carried out for 10 hours after the dropwise addition, 25mL of dichloromethane is added after the reaction is finished, stirring is carried out, the liquid is separated, the aqueous phase is washed by 25mL of dichloromethane again, the temperature of the aqueous phase is controlled to 10-20 ℃, the pH value is regulated to 3-5 by 12% of hydrochloric acid, solid precipitation is carried out, stirring is carried out for 1-2 hours, filtering is carried out, a filter cake is washed by isopropyl ether, and the white solid compound 1.68 g is obtained after vacuum drying at 50-60 ℃, the yield is 92.2%, and the purity is 99.2%.
It can be seen from examples 1 to 5 and comparative examples 7 to 9 that the selection of the reaction conditions has a large influence on the purity and yield of the compound 1 and the recovery rate of the compound 6. In comparative example 7, too much solvent was added in step a, too much compound 3 was added, pH was adjusted to be too basic, resulting in that part of compound 3 impurities were contained in compound 4, purity was lowered, yield was lowered, methylene chloride was used as a reaction solvent in step B, too much solvent was added, pH was adjusted to be too acidic, the progress of hydrolysis reaction was not favored, subsequent pH adjustment was more than 10, the purity of compound 5 was affected, and pH adjustment in the organic phase was 3.0 to 3.5, the precipitation of compound 6 was not favored, resulting in a lowered recovery rate of compound 6. In comparative example 8, the amount of the solvent added in step a was too small, the reaction did not proceed sufficiently, the yield of compound 4 was lowered, the amount of the reaction solvent added in step B was insufficient, the pH adjustment was too low to facilitate the hydrolysis reaction, the subsequent pH adjustment was less than 9, the compound 5 could not be dissolved sufficiently in the aqueous phase, the yield of the subsequent compound 1 was lowered, part of the compound 6 remained in the aqueous phase to facilitate the precipitation of the compound 6, and the recovery rate of the compound 6 was lowered. In comparative example 9, nucleophilic substitution reaction was performed using amide solution in step a, but for this reaction, the stereoselectivity was still inferior to that of acetone and acetonitrile. While all parameters of examples 1 to 5 fall within the scope of the present invention, the appropriate metal ligand compound, reaction solvent and reaction conditions are selected, so that the yield and purity of the rituximab intermediate compound 1 are ensured, the recovery rate of compound 6 is high, the purity is high, the loss is reduced, and the economic benefit is increased. In particular, the technical parameters of example 1, the yield and purity of compound 1 and the recovery of compound 6 are optimized at the same time.
EXAMPLE 6 preparation of Litaset
A. preparation of Compound 3-1
To a flask containing 10.0g of compound 1 prepared in example 1, 100mL of methylene chloride, 4.7g of benzyl alcohol and 0.36g of DMAP were added, cooled to 0-5℃and stirred for 30 minutes, 5.56g of EDCI was added, after completion of the TLC detection reaction, 50mL of sodium hydrogencarbonate solution was added to quench, and the solution was separated, and the organic phase was washed with 50mL of citric acid solution and 50mL of saturated brine in this order to give an organic phase of compound 2-1, which was directly used for the next reaction. The temperature of the organic phase is controlled to 10-15 ℃, 10mL of 4M HCl dioxane solution is added, after the reaction is finished, the mixture is concentrated, and the mixture is recrystallized through a dimethylformamide/dichloromethane system to obtain 3-1.5 g of compound, the yield is 97.4%, and the purity is 99.2%.
B. Preparation of Compound 6-1
To a flask containing 14.2g of Compound 4-1, 100mL of isopropyl acetate, 5.2g of thionyl chloride, the temperature was controlled to be not more than 20℃and stirring was carried out for 2 hours, concentrating, 100mL of tetrahydrofuran was added, 10.5g of Compound 3-1 was added dropwise 6g of diisopropylethylamine, after the completion of which water was added, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated, 30mL of a dioxane solution of 4M HCl was added, stirring was carried out at room temperature overnight, filtration was carried out, and vacuum drying was carried out to obtain Compound 6-1.3 g, yield 96.0% and purity 99.3%.
C. Preparation of Compound 8-1
Into a flask containing 4.7g of Compound 7-1, 100mL of tetrahydrofuran, 5.2g of thionyl chloride and a catalytic amount of DMF (0.3 mL) were added, stirred overnight, concentrated, 100mL of dichloromethane and 16.3g of Compound 6-1 were added, 6.0g of diisopropylethylamine was added dropwise, and after completion of the reaction at 0-5℃an aqueous solution was added, and concentrated to give Compound 8-118.2g in 94.6% yield and 98.5% purity.
D. Preparation of Litaset
To a flask containing 18.2g of Compound 8-1 were added 100mL of methanol, 10mL of tetrahydrofuran, 10mL of formic acid and 2.0g of 10% palladium on charcoal, and the mixture was stirred overnight under nitrogen protection, filtered, concentrated, slurried with butanone, filtered and dried to give 15.1g of rituximab in a yield of 95.1% and a purity of 99.6%.
EXAMPLE 7 preparation of Compound 2
2.73G of compound 6 recovered from the preparation of example 1 was dissolved in 30mL of methanol at room temperature, and 2.50g of glycine and 3.32g of copper sulfate pentahydrate were added. After 2.61g of potassium hydroxide was dissolved in 10mL of methanol, it was added to the above mixture. The mixture system was stirred at room temperature for 1h, 30ml of 10% citric acid solution was added, extracted with dichloromethane (3 x 50 ml), concentrated in fractions, and eluted with a gradient of dichloromethane-acetone in an automatic flash chromatography system on silica gel to give a solid which was then rinsed with acetone solution and dried to give 2.1g of solid compound in 60.1% yield.
From examples 6 and 7, it can be seen that the intermediate compound 1 of the rituximab prepared by the invention can be directly used for the subsequent preparation of the rituximab, and the prepared rituximab has good yield and purity and is beneficial to the preparation of the subsequent preparation. The obtained compound 6 can be recovered, and the copper ligand compound can be prepared again, so that the method is economical and environment-friendly.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.
Claims (11)
1. A process for the preparation of a ritodynamic intermediate compound 1, comprising the steps of:
A. Adding the compound 2 into an organic solvent, mixing with a sodium hydroxide solution, cooling, adding the compound 3 for reaction, adding ice water after the reaction is finished, preserving heat, filtering and drying to obtain a compound 4;
B. Dissolving the compound 4 in an organic solvent I, adding hydrochloric acid, heating to react, adding a chelating agent after the reaction is finished, concentrating under reduced pressure, adding water and an organic solvent II, adding a sodium hydroxide solution, separating the solution, washing with water to obtain a compound 5 aqueous solution, mixing the organic phases, adding hydrochloric acid at room temperature, stirring at room temperature after the addition is finished, filtering, and drying to obtain a compound 6;
C. the water solution of the compound 5 reacts with Boc anhydride, hydrochloric acid is added after the reaction is finished, and the mixture is stirred, filtered and dried to obtain a compound 1;
and X is F, cl or Br.
2. The process for the preparation of the ritodlast intermediate compound 1 according to claim 1, wherein in step a, X is Cl.
3. The preparation method of the litaxetil intermediate compound 1 according to claim 1, wherein in the step a, the compound 3 is a compound 3-acetonitrile solution or a compound 3-acetone solution, the mass-volume ratio of the compound 2 to the solution is 1:3-7, the molar ratio of the compound 2 to the compound 3 is 1:1.05-1.20, and a sodium hydroxide aqueous solution with the mass concentration of 40-60% is added to adjust the pH to 6.5-8.5.
4. The process for preparing a litaxetil intermediate compound 1 according to claim 3, wherein in the step a, the compound 3 is a compound 3-acetone solution, the mass-to-volume ratio of the compound 2 to the solution is 1:5, the molar ratio of the compound 2 to the compound 3 is 1:1.1, and a 50% by mass aqueous solution of sodium hydroxide is added to adjust the pH to 7.0-8.0.
5. The preparation method of the litaxetil intermediate compound 1 according to claim 1, wherein in the step A, the temperature is reduced to 0-10 ℃, and the solution of the compound 3 is dropwise added for reaction for 2-4 hours.
6. The process for preparing a litaxetil intermediate compound 1 according to claim 5, wherein in the step a, the solution of the compound 3 is added dropwise at a temperature of 0 to 5 ℃ for a reaction time of 3 hours.
7. The preparation method of the litaxetil intermediate compound 1 according to claim 1, wherein in the step B, the organic solvent I is one or more of methanol, ethanol, acetonitrile and tetrahydrofuran, the mass-volume ratio of the compound 4 to the organic solvent I is 1:2-5, the pH is regulated to 1.5-3.0 by concentrated hydrochloric acid, the temperature is raised to 60-70 ℃, the reaction time is 2-4h, the chelating agent is sodium ethylenediamine tetraacetate or sodium aminotriacetate, the organic solvent II is dichloromethane or chloroform, the pH is regulated to 9.0-10.0 by adding a sodium hydroxide aqueous solution with the mass concentration of 40-60%, and the pH is regulated to 1.5-2.5 by dropwise adding concentrated hydrochloric acid at room temperature after the organic phases are combined.
8. The preparation method of the ritodynamic t intermediate compound 1 of claim 7, wherein in the step B, the first organic solvent is acetonitrile, the mass-volume ratio of the compound 4 to the first organic solvent is 1:3, the concentrated hydrochloric acid is used for adjusting the pH to 2.5, the temperature is raised to 65 ℃, the reaction time is 3 hours, the chelating agent is tetra sodium ethylenediamine tetraacetate tetrahydrate, the second organic solvent is dichloromethane, and the aqueous solution of sodium hydroxide with the mass concentration of 50% is added for adjusting the pH to 9.0-10.0.
9. The process for the preparation of the ritodlast intermediate compound 1 according to claim 1, wherein in step C the reaction time is 8-12h.
10. The process for the preparation of the ritodlast intermediate compound 1 according to claim 1, characterized in that in step C the reaction time is 10h.
11. A process for the preparation of ritodynamic intermediate compound 1 comprising the following three steps:
A. Adding the compound 2 into acetone, mixing with 50%wt sodium hydroxide solution until the pH value is 7.0-8.0, wherein the mass volume ratio of the compound 2 to the acetone is 1:5, the molar ratio of the compound 2 to the compound 3 is 1:1.1, cooling to 0-5 ℃, dropwise adding the solution of the compound 3 for reaction, continuing to react for 3 hours after the dropwise adding is finished, adding ice water after the reaction is finished, preserving heat at 0-5 ℃, filtering and drying to obtain the compound 4;
B. Adding the compound 4 into acetonitrile, adding concentrated hydrochloric acid into the mixture, adjusting the pH value of the mixture to 2.5, heating the mixture to 65 ℃ for reaction for 3 hours, adding the tetra-sodium ethylenediamine tetraacetic acid tetrahydrate into the mixture after the reaction is finished, wherein the molar ratio of the tetra-sodium ethylenediamine tetraacetic acid tetrahydrate to the compound 4 is 1:1, concentrating the mixture under reduced pressure, adding water and methylene dichloride, adjusting the pH value of the mixture to 9-10 by using a 50% wt sodium hydroxide aqueous solution, separating the solution, washing the aqueous phase by the methylene dichloride again to obtain a compound 5 aqueous solution, merging the organic phases, dropwise adding the concentrated hydrochloric acid to the pH value of the mixture to 1.5-2.5 at room temperature, stirring the mixture at room temperature after the dropwise adding is finished, and filtering and drying the mixture to obtain a compound 6;
C. After obtaining an aqueous solution containing a compound 5, dropwise adding Boc anhydride into the aqueous solution containing the compound 5 at room temperature, wherein the molar ratio of Boc anhydride to the compound 4 is 1.7:1, reacting for 10 hours after the dropwise adding, adding dichloromethane after the reaction is finished, extracting and separating liquid, washing an aqueous phase by the dichloromethane again, controlling the temperature of the aqueous phase to 10-20 ℃, regulating the pH value to 3-5 by 12% hydrochloric acid, stirring for 1-2 hours, filtering, washing a filter cake by isopropyl ether, and drying to obtain the compound 1
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211571885.1A CN115784950B (en) | 2022-12-08 | 2022-12-08 | Preparation method of ritalst intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211571885.1A CN115784950B (en) | 2022-12-08 | 2022-12-08 | Preparation method of ritalst intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115784950A CN115784950A (en) | 2023-03-14 |
| CN115784950B true CN115784950B (en) | 2024-06-28 |
Family
ID=85419039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211571885.1A Active CN115784950B (en) | 2022-12-08 | 2022-12-08 | Preparation method of ritalst intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115784950B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104797574A (en) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | LFA-1 inhibitor and polymorph thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080287687A1 (en) * | 2006-11-03 | 2008-11-20 | Ajinomoto Co. Inc | Production method of diphenylalanine-Ni (II) complex |
| CN101759601B (en) * | 2010-01-13 | 2013-07-24 | 北京欧凯纳斯科技有限公司 | Method for preparing chiral alpha-unnatural amino acid by transition metal complex |
| CN101817773A (en) * | 2010-01-25 | 2010-09-01 | 北京欧凯纳斯科技有限公司 | Preparation method of chiral alpha-non-natural amino acid |
| CN105384660B (en) * | 2014-09-02 | 2018-10-16 | 广东东阳光药业有限公司 | A kind of preparation method of a-amino acid |
| CN104592309B (en) * | 2014-12-23 | 2017-08-08 | 广东东阳光药业有限公司 | A kind of preparation method of chiral amino acid |
-
2022
- 2022-12-08 CN CN202211571885.1A patent/CN115784950B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104797574A (en) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | LFA-1 inhibitor and polymorph thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115784950A (en) | 2023-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10934257B2 (en) | Method for preparing pimavanserin and tartrate thereof by using triphosgene | |
| WO2017202365A1 (en) | Preparation method for trifluoromethyl-substituted pyran derivative | |
| CN114315534A (en) | Preparation method of dapagliflozin intermediate | |
| CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
| CN115784950B (en) | Preparation method of ritalst intermediate | |
| CN110015978B (en) | Synthesis method of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine | |
| CN111961114A (en) | Argatroban intermediate and preparation method and application thereof | |
| CN111100118A (en) | Ritasate impurity and preparation method thereof | |
| CN115894664A (en) | Synthesis method of semaglutide side chain | |
| CN105745191A (en) | Method for preparing silodosin and intermediate thereof | |
| CN111285914B (en) | Preparation method of obeticholic acid | |
| CN110734393B (en) | Preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride | |
| CN109942462B (en) | Synthesis process of bambuterol hydrochloride | |
| CN113956198A (en) | Impurity of roxasistat, preparation method and application thereof | |
| CN114539288B (en) | Preparation method of everolimus | |
| CN111440154B (en) | Synthetic method of tegaserod dimer impurity | |
| CN115785057B (en) | Preparation method of ticagrelor intermediate compound and salt thereof | |
| CN113651762B (en) | Preparation method of 1-methyl-1H-1, 2, 4-triazole-3-methyl formate | |
| CN112778180B (en) | Vitamin D 2 Is prepared by the preparation method of (2) | |
| CN111875666B (en) | Method for synthesizing Edwarden sweet | |
| CN113683574B (en) | Method for synthesizing 1-methyl-1H-1, 2, 4-triazole-3-methyl formate | |
| WO2023000517A1 (en) | Method for preparing paeoniflorin-6-o'-benzene sulfonate | |
| CN107129437A (en) | The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application | |
| CN101289417A (en) | Process for preparing D-3-thioacetyl-2-methylpropionyl-L-proline | |
| CN113493488A (en) | Synthetic method of taltirelin |
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 | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhang Zhenfeng Inventor after: Yuan Shuai Inventor after: Luo Tongyou Inventor after: Ning Zuochao Inventor after: Deng Jun Inventor after: Tan Zhenyou Inventor before: Zhang Zhenfeng Inventor before: Yuan Shuai Inventor before: Luo Tongyou Inventor before: Ning Zuochao Inventor before: Deng Jun Inventor before: Tan Zhenyou |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant |