CN117897387A - Preparation method of GLP-1 receptor agonist intermediate - Google Patents
Preparation method of GLP-1 receptor agonist intermediate Download PDFInfo
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- CN117897387A CN117897387A CN202280058903.8A CN202280058903A CN117897387A CN 117897387 A CN117897387 A CN 117897387A CN 202280058903 A CN202280058903 A CN 202280058903A CN 117897387 A CN117897387 A CN 117897387A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 title description 3
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title description 3
- UMGLSEOSXMZRSC-LYVYPOQBSA-N (2S)-3-[(2S)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[[(1S)-1-phenylpropyl]amino]propanoic acid Chemical compound CC[C@H](N[C@@H](Cc1ccc2O[C@H](COc2c1)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(O)=O)c1ccccc1 UMGLSEOSXMZRSC-LYVYPOQBSA-N 0.000 claims abstract description 6
- BLHFLTNYYBCRMJ-DGGPYNQQSA-N (Z)-3-[(2S)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-hydroxyprop-2-enoic acid Chemical compound O/C(\C(O)=O)=C\C(C=C1)=CC(OC2)=C1O[C@H]2C(C=C1)=CC=C1OCC(C=C1)=CC(Cl)=C1Cl BLHFLTNYYBCRMJ-DGGPYNQQSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 229940125782 compound 2 Drugs 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 20
- 229940125904 compound 1 Drugs 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910052700 potassium Chemical group 0.000 claims description 2
- 239000011591 potassium Chemical group 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000011734 sodium Chemical group 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000007867 post-reaction treatment Methods 0.000 claims 4
- ZULTYUIALNTCSA-UHFFFAOYSA-N zinc hydride Chemical compound [ZnH2] ZULTYUIALNTCSA-UHFFFAOYSA-N 0.000 claims 1
- 229910000051 zinc hydride Inorganic materials 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 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 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- -1 3, 4-dichlorobenzyloxy Chemical group 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- BAZMYXGARXYAEQ-UHFFFAOYSA-N alpha-ethyl valeric acid Chemical compound CCCC(CC)C(O)=O BAZMYXGARXYAEQ-UHFFFAOYSA-N 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The preparation method of the (S, Z) -3- (2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-hydroxy acrylic acid and the preparation method of the (S) -3- ((S) -2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (((S) -1-phenylpropyl) amino) propionic acid have the advantages of low cost, high yield and controllable quality, and are more suitable for industrial production.
Description
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an intermediate (S, Z) -3- (2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-hydroxy acrylic acid and (S) -3- ((S) -2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (((S) -1-phenylpropyl) amino) propionic acid of a GLP-1 receptor agonist.
(S) -2- (3S, 8S) -3- (4- (3, 4-dichlorobenzyloxy) phenyl-7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1, 4)]-dioxino [2,3-g]Isoquinoline-8-carboxamido) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionic acid dihydrochloride (Compound I), a non-peptide small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, of formula C 50 H 49 Cl 4 N 3 O 6 The molecular weight is 929.76, and the chemical structural formula is as follows:
the invention patent CN102378574B discloses a method for preparing a compound I free base by taking 4-hydroxyacetophenone as a raw material and performing 14 steps of reactions such as nucleophilic substitution, bromination, asymmetric reduction, condensation, hydrolysis and the like. Wherein, the free base of the compound I is prepared from the compound A, and the free base is subjected to catalytic hydrogenation and multiple deprotection processes, so that the reaction step is longer.
Disclosure of Invention
In order to simplify the prior art, the invention uses the intermediate 3 to replace the intermediate compound A, and then the compound 3 is subjected to 5 steps of reactions such as hydrolysis, reduction, condensation and the like to prepare the free base I. Wherein the preparation of compound 2 from compound 3 requires a hydrolysis process, in the literature (US 6211235B 1; j.am. Chem. Soc.2018,140,32,10263) a strong acid hydrolysis is used for hydrolysis reactions containing both amide and ester structures. Since the ether bond in the compound 3 can be hydrolyzed under the acidic condition, the application of the method to the preparation of the compound 2 can lead to the chiral configuration inversion of the generated compound 2, thereby affecting the product quality. Therefore, there is a need to develop a process route for preparing compound 2 with good yield and controllable quality.
Further optimizing the process, using intermediate 3 to replace intermediate compound A, and carrying out 5 steps of hydrolysis, reduction, condensation and the like on compound 3 to obtain the free base of compound I. The new route of compound (S, S, S) -1 (compound 1) has 3 chiral centers, compound 1 is prepared by ammonification reduction reaction, two chiral centers are introduced, 8 diastereomers theoretically exist, and 3 isomer impurities (S, R, S) -1, (R, S, S) -1, (S, S, R) -1 are mainly existed in the actual process development process. The isomer content is mainly influenced by the chiral purity of the initial raw material and the reduction reaction, wherein the compound 1 is firstly reacted with S-phenylpropylamine to generate imine, and then the compound 1 is asymmetrically synthesized under the action of a reducing agent, and the main side reaction impurities are (R, S, S) -1 introduced by the asymmetric reduction reaction due to the reaction selectivity. The formation of impurity (R, S) -1 is mainly affected by the reducing agent, and when a single boron reducing agent (e.g., sodium borohydride) is used, the product is racemic. Asymmetric synthesis is achieved by increasing steric hindrance of the reducing agent, but when the volume of the reducing agent is too large, the reaction conversion rate is low, and the yield is affected. The problem to be solved is to increase the conversion rate of the reaction without affecting the chiral purity, so as to obtain compound 1 with high yield and purity.
The invention provides an economic and effective preparation method of a novel intermediate (S, Z) -3- (2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-hydroxy acrylic acid (compound 2) of a compound I, which has the advantages of low cost, high yield and controllable quality and is more suitable for industrial production.
The invention provides a method for preparing (S, Z) -3- (2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-hydroxyacrylic acid (compound 2), which comprises the following steps:
a-1) hydrolyzing the ester group of the compound 3 under the action of an aqueous inorganic base solution;
a-2) sequentially adding an organic acid and an inorganic acid aqueous solution to hydrolyze the amide to obtain the compound 2.
In one embodiment, the inorganic base used in step a-1) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; sodium hydroxide is preferred.
In one embodiment, in said step a-2), the aqueous solution of organic acid, mineral acid is added in portions.
In one embodiment, the organic acid used in step a-2) is selected from oxalic acid, citric acid, malic acid, succinic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid or propionic acid; acetic acid is preferred.
In one embodiment, the mineral acid used in step a-2) is selected from hydrochloric acid or sulfuric acid.
In one embodiment, in said step a-2), the organic acid is added first, followed by two separate additions of aqueous mineral acid.
In one embodiment, in said step a-2), the concentration of the mineral acid is selected from 2 to 8mol/L.
In one embodiment, the reaction temperature of step a-2) is 50 to 100 ℃.
In one embodiment, after the reaction of step a-1) and step a-2) is completed, post-treatment of the reaction is performed, wherein the post-treatment comprises cooling the reaction liquid, transferring the reaction liquid into water, stirring for crystallization, and filtering to obtain a crude product of the compound 2.
In one embodiment, the crude product can be further beaten by an organic solvent in the post-treatment, the beating temperature is controlled, and the pure product of the compound 2 is obtained after filtration.
In one embodiment, the temperature of the crystallization in the post-treatment is 0 to 40 ℃.
In one embodiment, the organic solvent used in the post-treatment is selected from dichloromethane, chloroform, ethyl acetate, methanol, 1, 2-dichloroethane, preferably dichloromethane.
In one embodiment, the beating temperature in the post-treatment is selected from 0 to 40 ℃, preferably 10 to 20 ℃.
The beneficial effects of this technical scheme are: the traditional one-step acid hydrolysis method is replaced by the step-by-step hydrolysis method, so that the occurrence of side reaction is effectively reduced, the occurrence rate of chiral inversion is reduced, the chiral isomer content is reduced from 9% to 0.9%, the product quality is obviously improved, and the purification pressure of the subsequent reaction is reduced.
The invention also provides a preparation method of the novel intermediate (S) -3- ((S) -2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (((S) -1-phenylpropyl) amino) propionic acid (compound 1) of the compound I, and the method has the advantages of low cost, high yield and controllable quality, and is more suitable for industrial production.
The present invention further provides a process for preparing (S) -3- ((S) -2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (((S) -1-phenylpropyl) amino) propionic acid (compound 1), comprising the steps of:
b-1) reacting the compound 2 with S-phenylpropylamine under the action of organic base to generate an imine intermediate;
b-2) the imine intermediate is subjected to reduction reaction under the action of a reducing agent and LiCl to obtain the compound 1.
In one embodiment, the organic base in step b-1) is selected from isopropylamine, triethylamine, N-methylmorpholine, piperazine, N-diisopropylethylamine.
In one embodiment, the reaction temperature in step b-1) is from 5 to 45℃and preferably from 15 to 35 ℃.
In one embodiment, the molar ratio of compound 2 to S-phenylpropylamine and organic base in step b-1) is 1:1.1:1.1 to 1:4:6.
In one embodiment, the reaction solvent in step b-1) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane.
In one embodiment, the reducing agent in step b-2) is MBH (RCOO) 3 And zinc borohydride.
In one embodiment, compound 2, MBH (RCOO) in step b-2) is described 3 The feeding ratio of the zinc borohydride to the zinc borohydride is 1:1.1:0.1-1:6:0.6.
In one embodiment, the MBH (RCOO) 3 Wherein M is selected from lithium, sodium and potassium; r is saturated alkyl of C6-C10.
In one embodiment, the reaction solvent in step b-2) is selected from toluene, xylene, chlorobenzene.
In one embodiment, the reaction temperature in step b-2) is from 0 to 40 ℃.
In one embodiment, after the reaction of the step b-1) and the step b-2) is completed, carrying out post-treatment, wherein the post-treatment comprises adding methanol for quenching reaction, adding DMF for distillation to remove a low boiling point reaction solvent, then dropwise adding an alcohol solvent, crystallizing, filtering and drying to obtain a compound 1; wherein the alcohol solvent is selected from methanol, ethanol, isopropanol and n-propanol.
The beneficial effects of this technical scheme are: the reducing agent component is added, and lithium chloride is added to promote the reaction, so that the reaction conversion rate is improved from 80% to 95%, the yield is improved from 70% to 85%, the isomer content is not improved, and the product quality is ensured while the yield is improved.
Brief description of the drawings
FIG. 1-HPLC spectra of isomers of Compound 1 obtained by the preparation methods described in examples 1 to 3
The present invention will be described in further detail with reference to specific examples.
The experimental methods in the examples, for which specific conditions are not specified, are generally conventional conditions or conditions recommended by the manufacturer of the raw materials or goods; reagents of unspecified origin are typically conventional reagents commercially available or may be prepared from known reagents by conventional methods.
Example 1: preparation of Compound 3
To the reaction flask were added compound 4 (83.1 g,0.2 mol), compound 5 (75.9 g,0.3 mol), toluene (300 g) and DMAP (48.9 g,0.4 mol), and the reaction was stirred at 20℃for 16 hours. TLC monitored the spot without compound 4. After the completion of the reaction, a 5% aqueous ammonium chloride solution (820 g) was added. The aqueous layer was separated, the organic layer was washed with saturated brine, the organic phase was concentrated, methanol/water (500 g/500 g) was added to the concentrate, stirred for crystallization, filtered, and dried to give 95.2g of Compound 3 in 88% yield. 1 H NMR(500MHz,d 6 -DMSO)δ9.54(s,1H),7.72(d,J＝1.5Hz,1H),7.66(d,J＝8.5Hz,1H),7.46-7.41(m,3H),7.29(d,J＝2Hz,1H),7.18(d,J＝1.5Hz,1H),7.14(s,1H),7.07(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,1H),5.24-5.33(m,1H),5.15(s,2H),4.42-4.40(m,1H),4.01(s,5H),4.17–4.10(m,3H),2.00(s,3H),1.23(t,J＝7.0Hz,3H).
Example 2: preparation of Compound 2
Into a reaction flask were charged compound 3 (150 g,0.28 mol), dioxane (750 g), stirred at 60℃until the system was completely dissolved, then 45% sodium hydroxide solution (NaOH 22.12g, H) was added dropwise 2 O27 mL). After the completion of the dropping, the mixture was stirred for 1.5 hours under heat preservation. After the reaction of the raw materials was completed, acetic acid (420 g) was added dropwise at 60℃under heat preservation. After the addition, the temperature was raised to 80℃and concentrated hydrochloric acid (HCl 277.08g, H was added 2 O249 mL). After the addition was completed, the reaction was stirred at 80℃for 3 hours. Then concentrated hydrochloric acid (HCl 277.08g, H) 2 O249 mL) and the reaction was continued for 8 hours after the addition was completed. After completion of the reaction, the temperature was lowered to room temperature, and then the reaction solution was transferred to a reaction flask containing 1500g of water. After the transfer was completed, the mixture was stirred at 15℃for 2 hours and then filtered. The filter cake was slurried with methylene chloride at 15℃for 2 hours, filtered and dried in vacuo to give 113.6g of Compound 2 in 86% yield and 98.46% purity. 1 H NMR(500MHz,d 6 -DMSO)δ13.11(s,1H),9.06(s,1H),7.72(d,J＝1.5Hz,1H),7.65(d,J＝8.5Hz,4H),7.47-7.41(m,4H),7.25(dd,J＝3.5,2.0Hz,2H),7.06(d,J＝9.0Hz,2H),6.92(d,J＝8.5Hz,1H),6.37(s,1H),5.18(d,J＝2.0Hz,1H),5.14(s,2H),4.39–4.37(m,1H),4.11–4.07(m,1H).
Example 3: preparation of Compound 1 (for purity detection)
To the reaction flask were added compound 2 (23.6 g,0.05 mol), toluene (142 g), kept at a temperature below 25℃and isopropylamine (5.9 g,0.1 mol) and (S) -phenylpropylamine (10.8 g,0.08 mol) in this order, followed by stirring. Sodium borohydride (3.7 g,0.1 mol) and 2-ethyl valeric acid (19.5 g,0.15 mol) were mixed in solution to form a reducing agent, which was added to the reaction system at 15-20 ℃. After the completion of the reaction, it was concentrated under reduced pressure. The residue was dissolved in hot DMSO. After cooling the solution, precipitation in methanol, filtration, washing and drying gave compound 1 (20.2 g, yield 70%), the content of isomer (R, S, S) -1 introduced from compound 2 was 0.9%.
Example 4: comparative example of preparation of Compound 2 (preparation of Compound 2 by one-step acid hydrolysis)
To the reaction flask, compound 3 (54.2 g,0.1 mol) and dioxane (542 g) were added and dissolved with stirring, 6mol/L hydrochloric acid (220.0 g,1.2 mol) was added, and the mixture was heated to 85℃to react for 18 hours. TLC monitored the spot without compound 3. After the reaction, cooling, adding water (542 g), stirring for crystallization, and filtering to obtain a wet product. The wet product was slurried with methylene chloride (300 g), filtered and dried to give compound 2 (40.1 g) in 85% yield and 89.9% purity.
Since the isomer detection method of compound 2 was unstable, the chiral purity of compound 2 was evaluated with the content of the specific isomer (R, S) -1 of compound 1.
Chiral evaluation: compound 1 was prepared according to the preparation method of example 3, and the content of isomer (R, S) -1 introduced from compound 2 was 8% by liquid phase detection.
The comparison experiment shows that the fractional hydrolysis method can obviously reduce the content of isomer impurities, thereby improving the product quality.
Example 5: preparation of Compound 1
Preparation of the reducing agent: adding NaBH into a reaction flask 4 (2.4 g), dioxane (36 g), xylene (28.8 g), and stirring at 15 ℃ under controlled temperature; isooctanoic acid (27.42 g) was added dropwise, and the mixture was stirred at a constant temperature after the completion of the dropwise addition. A THF solution (8 mL) of zinc borohydride was added and stirring was continued for 3-4h at constant temperature for further use.
To the reaction flask, compound 2 (10 g) and dioxane (44.5 g) were added, the solution was stirred at 20℃and triethylamine (6.6 g) was added dropwise and stirred uniformly, followed by S-phenylpropylamine (8 g). After the dripping, continuing to stir and react at the temperature of 20 ℃ until the raw materials are completely reacted, then adding dimethylbenzene (90 g), and stirring and dissolving the solution.LiCl (0.2 g) was added and the temperature was reduced to 0 ℃. And (3) dripping the prepared reducing agent, and reacting at 20 ℃ after the dripping is finished. After the reaction is finished, dropwise adding methanol for quenching, adding DMF for evaporating a low boiling point reaction solvent, dropwise adding methanol, stirring for crystallization, filtering, and vacuum drying to obtain 10.64g of compound 1, wherein the yield is: 85%, purity 99%, chiral purity: 95%. 1 H NMR(500MHz,d 6 -DMSO)δ7.53(s,1H),7.49-7.41(m,4H),7.32(d,J＝8.5Hz,2H),7.27-7.24(m,1H),7.21(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H), 6.82(d,J＝8.0Hz,1H),6.50(s,1H),6.43(d,J＝8.0Hz,1H),5.03(s,2H),4.99(d,J＝8.0Hz,1H),4.29(d,J＝2.0Hz,1H),4.27-4.16(m,1H),3.96-3.92(m,1H),3.83-3.83(m,1H),3.00-2.96(m,2H),2.24-2.17(m,1H),2.06-1.99(m,1H),0.81(t,J＝7.0Hz,3H).
Example 6: comparative example of preparation of Compound 1 (preparation of Compound 1 without Zinc borohydride and lithium chloride)
Preparation of the reducing agent: adding NaBH into a reaction flask 4 (2.4 g), dioxane (36 g), xylene (28.8 g), and stirring at 15 ℃ under controlled temperature; isooctanoic acid (27.42 g) is added dropwise, and the mixture is stirred at a constant temperature after the dripping is finished for later use.
To the reaction flask, compound 2 (10 g) and dioxane (44.5 g) were added, the solution was stirred at 20℃and triethylamine (6.6 g) was added dropwise and stirred uniformly, followed by S-phenylpropylamine (8 g). After the dripping, continuing to stir and react at the temperature of 20 ℃ until the raw materials are completely reacted, then adding dimethylbenzene (90 g), and stirring and dissolving the solution. Cooling to 0 ℃, dripping the prepared reducing agent, and reacting at 20 ℃ after the addition is finished. After the reaction is finished, dropwise adding methanol for quenching, adding DMF for evaporating a low boiling point reaction solvent, dropwise adding methanol, stirring for crystallization, filtering, and drying in vacuum to obtain 8.76g of compound 1, wherein the yield is: 70%, purity 98.5%, chiral purity: 95%.
The above embodiments are only for understanding the method and core idea of the present invention, and do not limit the scope of the present invention. It will be apparent to those skilled in the art that any possible variations or substitutions can be made without departing from the spirit of the invention.
Claims (8)
- A process for preparing (S) -3- ((S) -2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (((S) -1-phenylpropyl) amino) propionic acid comprising the steps of:a-1) hydrolyzing the ester group of the compound 3 under the action of an aqueous inorganic base solution;a-2) sequentially adding an organic acid and an inorganic acid aqueous solution to hydrolyze the amide to obtain (S, Z) -3- (2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-hydroxyacrylic acid (compound 2);b-1) reacting the compound 2 with S-phenylpropylamine under the action of organic base to generate an imine intermediate;b-2) the imine intermediate is subjected to reduction reaction under the action of a reducing agent and LiCl to obtain (S) -3- ((S) -2- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (((S) -1-phenylpropyl) amino) propionic acid (compound 1).
- The process according to claim 1, wherein the inorganic base used in step a-1) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.
- The method of claim 1 or 2, wherein:the organic acid in step a-2) is selected from oxalic acid, citric acid, malic acid, succinic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid or propionic acid, preferably acetic acid;and/or the inorganic acid in step a-2) is selected from hydrochloric acid or sulfuric acid;and/or, in the step a-2), firstly adding organic acid, and then adding inorganic acid aqueous solution twice;and/or, the reaction temperature of the step a-2) is 50-100 ℃;and/or the concentration of the inorganic acid in the step a-2) is selected from 2 to 8mol/L.
- A method according to any one of claims 1 to 3, wherein:after the step a-1) and the step a-2) are completed, carrying out post-reaction treatment, wherein the post-reaction treatment comprises cooling of a reaction liquid, transferring the reaction liquid into water, stirring and crystallizing, and filtering to obtain a crude product of the compound 2;and/or, the crystallization temperature in the post-treatment is 0-40 ℃;and/or the organic solvent used in the post-treatment is selected from dichloromethane, chloroform, ethyl acetate, methanol, 1, 2-dichloroethane, preferably dichloromethane;and/or the beating temperature in the post-treatment is selected from 0 to 40 ℃, preferably 10 to 20 ℃.
- The method of any one of claims 1 to 4, wherein:the organic base in the step b-1) is selected from isopropylamine, triethylamine, N-methylmorpholine, piperazine and N, N-diisopropylethylamine;and/or the reaction temperature in step b-1) is 5 to 45 ℃, preferably 15 to 35 ℃;and/or, the feeding mole ratio of the compound 2 to the S-phenylpropylamine to the organic base in the step b-1) is 1:1.1:1.1-1:4:6;and/or the reaction solvent in the step b-1) is selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane.
- The method of any one of claims 1 to 5, wherein:the reducing agent in the step b-2) is MBH (RCOO) 3 A composition with zinc borohydride;and/or, in said step b-2), compound 2, MBH (RCOO) 3 With boronThe feeding ratio of the zinc hydride is 1:1.1:0.1-1:6:0.6;and/or, the MBH (RCOO) 3 Wherein M is selected from lithium, sodium and potassium; r is C 6～10 Saturated alkyl groups of (a);and/or the reaction solvent in the step b-2) is selected from toluene, xylene and chlorobenzene;and/or the reaction temperature in the step b-2) is 0-40 ℃.
- The method according to any one of claims 1 to 6, wherein after completion of steps b-1) and b-2), a post-reaction treatment is performed, wherein the post-reaction treatment comprises quenching reaction by adding methanol, then adding DMF, distilling off a low boiling point reaction solvent, then dropwise adding an alcohol solvent, crystallizing, filtering and drying to obtain a compound 1; wherein the alcohol solvent is selected from methanol, ethanol, isopropanol and n-propanol.
- Use of a process according to any one of claims 1 to 7 for the preparation of the compound (S) -2- (3S, 8S) -3- (4- (3, 4-dichlorobenzyloxy) phenyl-7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] -dioxino [2,3-g ] isoquinoline-8-carboxamido) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionic acid dihydrochloride of formula I.
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