CN106749169B - Chiral preparation method of Ertiprotafib - Google Patents
Chiral preparation method of Ertiprotafib Download PDFInfo
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- CN106749169B CN106749169B CN201610975726.6A CN201610975726A CN106749169B CN 106749169 B CN106749169 B CN 106749169B CN 201610975726 A CN201610975726 A CN 201610975726A CN 106749169 B CN106749169 B CN 106749169B
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- FONCZICQWCUXEB-RUZDIDTESA-N (2r)-2-[4-(9-bromo-2,3-dimethylbenzo[f][1]benzothiol-4-yl)-2,6-dimethylphenoxy]-3-phenylpropanoic acid Chemical compound C([C@@H](OC1=C(C)C=C(C=C1C)C=1C2=CC=CC=C2C(Br)=C2SC(=C(C2=1)C)C)C(O)=O)C1=CC=CC=C1 FONCZICQWCUXEB-RUZDIDTESA-N 0.000 title claims abstract description 14
- 229950001310 ertiprotafib Drugs 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
- 229940126214 compound 3 Drugs 0.000 claims abstract description 50
- 229940125782 compound 2 Drugs 0.000 claims abstract description 42
- 229940125904 compound 1 Drugs 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000012467 final product Substances 0.000 claims abstract description 9
- 238000001308 synthesis method Methods 0.000 claims abstract description 7
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 117
- 239000000243 solution Substances 0.000 claims description 97
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- -1 azo compound Chemical class 0.000 claims description 37
- 239000003208 petroleum Substances 0.000 claims description 35
- 239000003480 eluent Substances 0.000 claims description 33
- 238000010898 silica gel chromatography Methods 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 26
- 239000011259 mixed solution Substances 0.000 claims description 26
- 238000005406 washing Methods 0.000 claims description 25
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 230000000171 quenching effect Effects 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000012071 phase Substances 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 239000000047 product Substances 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 238000007865 diluting Methods 0.000 description 11
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- 239000012074 organic phase Substances 0.000 description 11
- 230000035484 reaction time Effects 0.000 description 11
- 238000009423 ventilation Methods 0.000 description 11
- QXHLMWWPSWWKOK-UHFFFAOYSA-N 2,3-dimethylnaphthalen-1-ol Chemical compound C1=CC=C2C(O)=C(C)C(C)=CC2=C1 QXHLMWWPSWWKOK-UHFFFAOYSA-N 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- CDMFKOGXDUTORS-UHFFFAOYSA-N methyl 2-hydroxy-2-phenylpropanoate Chemical compound COC(=O)C(C)(O)C1=CC=CC=C1 CDMFKOGXDUTORS-UHFFFAOYSA-N 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 4
- 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 4
- 102000002072 Non-Receptor Type 1 Protein Tyrosine Phosphatase Human genes 0.000 description 4
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 102000003746 Insulin Receptor Human genes 0.000 description 3
- 108010001127 Insulin Receptor Proteins 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
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- 229940079593 drug Drugs 0.000 description 3
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229940100607 GPR119 agonist Drugs 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- 102100021854 Inhibitor of nuclear factor kappa-B kinase subunit beta Human genes 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011697 diabetes animal model Methods 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical group O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 229940126731 protein tyrosine phosphatase inhibitor Drugs 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/74—Naphthothiophenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthesis method of Ertiprotafib shown in a formula (4), which specifically comprises the following steps: carrying out Mitsnobu reaction on the compound 1 shown in the formula (1) and L-methyl phenyl lactate to obtain a compound 2 shown in the formula (2); then carrying out bromination reaction on the compound 2 shown in the formula (2) to obtain a compound shown in a formula (3)Compound 3 of (1); the compound 3 represented by the formula (3) is hydrolyzed under alkaline conditions to obtain the final product Ertiprostafib represented by the formula (4). The invention has simple route, simple and convenient operation, high stereoselectivity and good chemical selectivity, is green and environment-friendly, and provides a new method and thought for the preparation and production of the medicine.
Description
(I) technical field
The invention particularly relates to a preparation method of an antidiabetic drug Ertiprotafib, which has a structural formula as follows:
(II) background of the invention
Diabetes Mellitus (DM) is a chronic disease caused by insulin deficiency or insulin function defect, and the development of diabetes drugs is always a hot focus of pharmaceutical industry attention. At present, new target drugs for diabetes treatment are: GKA agonists, PTP-1B inhibitors, GPR-40 agonists, GPR119 agonists and the like. Wherein PTP-1B inhibitors were the hot targets of development at the end of the last century. Protein Tyrosine Phosphatase 1B (PTP-1B) is a non-transmembrane Protein Tyrosine phosphohydrolase, is located in the cytoplasmic endoplasmic reticulum, maintains the balance of Tyrosine Protein phosphorylation together with Protein Tyrosine Kinase (PTK), and is involved in cell signal transduction. PTP-1B is a key negative regulatory protein in an insulin signal transduction pathway, and a PTP-1B inhibitor influences phosphorylation of an insulin receptor (IRS-1) by blocking tyrosine phosphorylation of the Insulin Receptor (IR) stimulated by insulin, so that insulin-like and insulin are sensitized, blood sugar is reduced, and meanwhile, leptin signals can be enhanced, fat metabolism level is increased, and weight is reduced.
Ertiprafib [ chemical name: (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid; CAS: 251303-04-5; PTP-112, which is a protein tyrosine phosphatase inhibitor (PTP-1B), has the efficacy of Ertiprotafib in regulating blood sugar and insulin levels in diabetes animal model tests, and the drug is developed in phase II clinical tests at present. The therapeutic effect of Ertiprotafib on non-insulin dependent diabetes mellitus has great potential, and the Ertiprotafib can promote the control of the blood sugar level of the organism and reduce the fat level through various mechanisms. In addition, Ertiprotafib is also a potent IKK-beta inhibitor with an IC (50) value of up to 400nM.
Few synthetic documents of Ertiprotafib are reported, and only the synthetic route is reported in the current U.S. Pat. No. 4, 6251936, 1, and the synthetic thought is as follows: protecting phenolic hydroxyl in a structure by using a compound 1 through acetylation reaction to obtain a compound A, selectively brominating at low temperature to obtain a compound B, removing an acetyl protecting group by using alkaline hydrolysis to obtain a compound C, carrying out Mitsnobu reaction on the compound C and L-methyl phenyl lactate to obtain a compound 3 with reversed configuration, and finally hydrolyzing methyl ester into carboxylic acid under alkaline conditions to obtain a final product Ertiprostafib. The specific synthetic route is as follows:
the route has the defects of harsh bromination reaction conditions of the compound A, more byproducts, low yield, poor selectivity and the like, and nuclear magnetic results show that the reaction mainly generates the byproduct B1 and the unreacted compound A; and the polarities of the compound A, the compound B and the by-product B1 are very close, so that the separation and purification are difficult. This brings great trouble to the purification of the final product, and requires repeated column chromatography for many times to obtain a qualified sample, and the total yield of the reaction is very low. The route needs two steps of reaction of acetylation protection and hydrolysis deprotection, and has complex steps and long production period.
Disclosure of the invention
The invention aims to provide a new synthesis method aiming at the existing synthesis route of Ertiprotafib, so as to solve the problems of complex reaction steps, poor chemical selectivity, complex operation, difficult product purification, low yield and the like in the prior art.
In order to achieve the purpose, the invention adopts the following technical route:
a synthetic method of Ertiprotafib shown in formula (4) comprises the following steps:
a, carrying out Mitsnobu reaction on a compound 1 shown in a formula (1) and L-methyl phenyl lactate to obtain a compound 2 shown in a formula (2);
b, carrying out bromination reaction on the compound 2 shown in the formula (2) to obtain a compound 3 shown in a formula (3);
c hydrolyzing the compound 3 represented by the formula (3) under an alkaline condition to obtain a final product Ertiprostafib represented by the formula (4).
Further, the synthesis method of the ertipratafib (5) shown in the formula (5) of the invention specifically comprises the following steps:
a, dissolving a compound 1 shown in a formula (1), L-methyl phenyl lactate and triphenylphosphine in an organic solvent A, slowly dropwise adding an azo compound, heating a reaction solution to 80-85 ℃, refluxing for 1-5 h, cooling to room temperature, reacting for 1-3 d to obtain a reaction solution A, and carrying out aftertreatment on the reaction solution A to obtain a compound 2 shown in a formula (2); the azo compound is diethyl azodicarboxylate or diisopropyl azodicarboxylate; the mass ratio of the compound 1 shown in the formula (1), L-methyl phenyl lactate, triphenylphosphine and an azo compound is 1: 1.0-1.5: 1.0-1.5: 1.0 to 1.5;
b, dissolving the compound 2 shown in the formula (2) obtained in the step a and a brominating reagent in an organic solvent B, reacting for 20-60 minutes at-10 to-78 ℃ under the catalysis of anhydrous ferric trichloride to obtain a reaction liquid B, and carrying out post-treatment on the reaction liquid B to obtain a compound 3 shown in the formula (3); the brominating reagent is liquid bromine, N-bromosuccinimide (NBS) or dibromohydantoin; the mass ratio of the compound 2 shown in the formula (2) to the brominating reagent and the anhydrous ferric trichloride is 1: 1.0-1.5: 0.03 to 0.07;
c, dissolving the compound 3 shown in the formula (3) obtained in the step b in an organic solvent C, reacting for 2-6 h at room temperature under the action of an alkaline substance to obtain a reaction liquid C, and carrying out aftertreatment on the reaction liquid C to obtain a final product Ertiprostafib shown in the formula (4); the amount ratio of the compound 3 represented by the formula (3) to the base is 1: 1-3.
Further, it is preferable that the ratio of the amounts of the compound 1 represented by the formula (1), L-methyl phenyllactate, triphenylphosphine and an azo compound in step a is 1:1.2:1.2: 1.2.
Further, the organic solvent A in the step a is: benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or dichloromethane; further, the volume usage amount of the organic solvent A is 10-15 mL/g based on the mass of the compound 1 represented by the formula (1).
Still further, the post-treatment method of the reaction solution A in the step a comprises the following steps: after the reaction is finished, concentrating under reduced pressure to remove the solvent, dissolving the concentrate in a mixed solvent (the volume ratio of petroleum ether to ethyl acetate is 0:1), filtering under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography to obtain the compound 2 shown in the formula (2).
Further, it is preferable that the mass ratio of the compound 2 represented by the formula (2) in the step b to the brominating agent is 1: 1.1.
Further, the organic solvent B in the step B is: dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, or acetonitrile; further, the volume usage amount of the organic solvent B is 15-30 mL/g based on the mass of the compound 2 represented by the formula (2).
Furthermore, the post-treatment method of the reaction solution B in the step B comprises the following steps: after the reaction is finished, adding a 5% sodium bisulfite solution into the reaction solution B at 0-10 ℃ for quenching, extracting with ethyl acetate, washing the extract with water and saturated saline solution in sequence, drying, concentrating under reduced pressure, and performing column chromatography separation (the volume ratio of an eluent is petroleum ether: ethyl acetate is 25:1) to obtain a compound 3 shown in the formula (3).
Further, in step c, the alkaline substance is: potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or lithium hydride.
Furthermore, the initial final concentration of the alkaline substance in the step c is 1-4 mol/L, preferably 2 mol/L.
Further, in the step C, the organic solvent C is one or a mixture of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, n-propanol or isopropanol; further, the volume usage amount of the organic solvent C is 10-13.3 mL/g based on the mass of the compound 3 shown in the formula (3).
Furthermore, the post-treatment method of the reaction solution C in the step C comprises the following steps: after the reaction is finished, acidifying the reaction solution C by 2.0mol/L hydrochloric acid, adjusting the pH value to 1-3, extracting by ethyl acetate, taking an extract, washing the extract by saturated saline solution, drying, concentrating, and purifying by silica gel column chromatography, wherein the petroleum ether: and (3) taking a mixed solution with the volume of ethyl acetate being 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution to obtain the final product Ertiprostafib.
In the present invention, the terms "reaction solution a", "reaction solution B" and "reaction solution C" have no special meaning, and are labeled "a", "B" and "C" only for distinguishing the reaction solutions mentioned in the different reaction steps; the terms "organic solvent a", "organic solvent B", "organic solvent C" have no special meaning, and the labels "a", "B" and "C" are used only to distinguish the organic solvents mentioned in the different reaction steps.
The invention has the following beneficial effects:
the method has simple route, avoids two-step reaction of introducing acetyl protecting group and removing protecting group in literature, has simple and convenient operation, better chemical selectivity, higher yield, easier separation and purification of products, lower production cost and larger practical application value and social and economic benefits.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by the following examples, without restricting its scope.
Example 1: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
3.65g of Compound 1(11.0mmol), 2.4g L-methyl phenyllactate (13.2mmol) and 3.5g Ph3P (13.2mmol) in 37mL benzene, N22.3g (13.2mmol) of DEAD are added dropwise with protection; refluxing and reacting at 80 ℃ for 2h, and cooling to room temperature; stirring and reacting for 3 days at room temperature; concentration of the reaction solutionVacuum filtering, concentrating the filtrate, and purifying by silica gel column chromatography (eluent volume ratio is 20:1 for petroleum ether and ethyl acetate); yield 2.1g of compound 2: 40 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 2: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
2.41g of Compound 1(7.2mmol), 1.30g L-methyl phenyllactate (7.2mmol) and 1.89g Ph3P (7.2mmol) in 30mL of xylene, N2DIAD 1.46g (7.2mmol) was added dropwise with protection; refluxing and reacting at 80 ℃ for 5h, and cooling to room temperature; stirring and reacting for 3 days at room temperature; concentrating the reaction solution, performing suction filtration under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography (the volume ratio of an eluent is 20: 1: petroleum ether: ethyl acetate); yield 1.24g of compound 2: 36 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 3: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
2.02g of Compound 1(6.1mmol), 1.64g L-phenyllactic acid methyl ester (9.1mmol) and 2.39g Ph3P (9.1mmol) in 27mL of toluene, N2DEAD 1.58g (9.1mmol) was added dropwise with protection; refluxing and reacting at 85 ℃ for 1h, and cooling to room temperature; stirring and reacting for 3 days at room temperature; concentrating the reaction solution, performing suction filtration under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography (the volume ratio of an eluent is 20: 1: petroleum ether: ethyl acetate); 0.87g of pure compound 2 was obtained, yield: 30 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 4: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
2.01g of Compound 1(6.1mmol), 1.64g L-phenyllactic acid methyl ester (9.1mmol) and 2.39g Ph3P (9.1mmol) in 20mL tetrahydrofuran, N2DIAD 1.84g (9.1mmol) was added dropwise with protection; refluxing and reacting at 85 ℃ for 2h, and cooling to room temperature; stirring and reacting for 1 day at room temperature; concentrating the reaction solution, performing suction filtration under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography (the volume ratio of an eluent is 20: 1: petroleum ether: ethyl acetate); 1.02g of Compound 2 were obtained, yield: 35 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 5: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
2.01g of Compound 1(6.1mmol), 1.64g L-phenyllactic acid methyl ester (9.1mmol) and 2.39g Ph3P (9.1mmol) in 20mL 2-methyltetrahydrofuran, N2DIAD 1.84g (9.1mmol) was added dropwise with protection; refluxing and reacting at 85 ℃ for 2h, and cooling to room temperature; stirring and reacting for 1 day at room temperature; concentrating the reaction solution, performing suction filtration under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography (the volume ratio of an eluent is 20: 1: petroleum ether: ethyl acetate); 1.13g of compound 2 are obtained, yield: 39 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 6: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
2.01g of Compound 1(6.1mmol), 1.64g L-phenyllactic acid methyl ester (9.1mmol) and 2.39g Ph3P (9.1mmol) in 20mL of dichloromethane, N2DIAD 1.84g (9.1mmol) was added dropwise with protection; refluxing at 85 deg.CReacting for 2 hours, and cooling to room temperature; stirring and reacting for 1 day at room temperature; concentrating the reaction solution, performing suction filtration under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography (the volume ratio of an eluent is 20: 1: petroleum ether: ethyl acetate); 0.87g of compound 2 was obtained, yield: 30 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 7: preparation of methyl (R) -2- (4- (2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 2)
2.01g of Compound 1(6.1mmol), 1.64g L-phenyllactic acid methyl ester (9.1mmol) and 2.39g Ph3P (9.1mmol) was dissolved in 20mL of 1, 4-dioxane, N2DIAD 1.84g (9.1mmol) was added dropwise with protection; refluxing and reacting at 85 ℃ for 2h, and cooling to room temperature; stirring and reacting for 1 day at room temperature; concentrating the reaction solution, performing suction filtration under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography (the volume ratio of an eluent is 20: 1: petroleum ether: ethyl acetate); 0.91g of compound 2 is obtained, yield: 31 percent.1H NMR(500MHz,CDCl3),δ(ppm)＝8.28(s,1H),7.88(d,J＝8.2Hz,1H,),7.53-7.59(m,1H),7.41-7.44(m,5H),7.00(dd,J＝3.4Hz,7.8Hz,2H),4.80(t,J＝7Hz,1H),3.68(s,1H),2.44(s,1H),2.34(s,1H),2.19(s,1H),1.62(s,1H).
Example 8: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.4g of Compound 2(3.0mmol) are dissolved in 30mL of dichloromethane, 15mg of anhydrous FeCl are added3(0.09mmol)，N2Cooling to-78 deg.C under protection; 0.54g of Br previously frozen2(3.3mmol) is dissolved in 10mL of dichloromethane, and slowly dropped into a reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); the reaction is quenched by adding saturated sodium bisulfite solution at 0 ℃; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; saturated sodium bisulfite solution, saturatedWashing with NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 1.02g of pure compound 3, yield: 61 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 9: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.4g of Compound 2(3.0mmol) are dissolved in 30mL of dichloromethane, 25mg of anhydrous FeCl are added3(0.15mmol)，N2Cooling to-78 deg.C under protection; 0.54g of Br previously frozen2(3.3mmol) is dissolved in 10mL of carbon tetrachloride and slowly dropped into a reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 1.10g of pure compound 3, yield: 65 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 10: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of chloroform, and 24mg of anhydrous ferric chloride (0.147mmol), N2Cooling to-78 deg.C under protection; 0.38g of Br previously frozen2(2.1mmol) is dissolved in 10mL of chloroform, and the solution is slowly dropped into a reaction system to ensure good ventilation; (the dropping time is 5min,reaction time 20min, TLC detection, developing agent: PE: EA 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 0.66g of pure compound 3, yield: 56 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 11: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) are dissolved in 20mL of 1, 2-dichloroethane, 17mg of anhydrous FeCl are added3(0.1mmol)，N2Cooling to-78 deg.C under protection; 0.45g of Br previously frozen2(2.5mmol) is dissolved in 10mL of 1, 2-dichloroethane, and is slowly dropped into the reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio of petroleum ether to ethyl acetate 25:1) to obtain 0.61g of pure compound 3, yield: 52 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 12: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of dichloromethane, 17mg of anhydrous FeCl are added3(0.1mmol)，N2Cooling to-78 deg.C under protection; 0.57g of Br previously frozen2(3.15mmol) is dissolved in 10mL of dichloromethane, and slowly dropped into a reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 0.56g of pure compound 3, yield: 48 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 13: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of dichloromethane, 17mg of anhydrous FeCl are added3(0.1mmol)，N2Cooling to-78 deg.C under protection; dissolving 0.56g of NBS (3.15mmol) in 10mL of dichloromethane, and slowly dropping into the reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio of petroleum ether to ethyl acetate 25:1) to obtain 0.52g of pure compound 3, yield: 44 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 14: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of acetonitrile and 17mg of anhydrous FeCl are added3(0.1mmol)，N2Cooling to-78 deg.C under protection; dissolving 0.56g of NBS (3.15mmol) in 10mL of acetonitrile, and slowly dropping the solution into the reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 10 ℃ to quench; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 0.44g of pure compound 3, yield: 38 percent.1H NMR(500MHz,DMSO-d6)δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 15: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of chloroform, 17mg of anhydrous FeCl is added3(0.1mmol)，N2Cooling to-78 deg.C under protection; dissolving 0.56g of NBS (3.15mmol) in 10mL of chloroform, and slowly dropping the solution into the reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying and concentratingThe product was purified by silica gel column chromatography (eluent volume ratio petroleum ether: ethyl acetate 25:1) to give 0.50g of pure compound 3, yield: 42 percent.1H NMR(500MHz,DMSO-d6),δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 16: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of chloroform, 17mg of anhydrous FeCl is added3(0.1mmol)，N2Cooling to-78 deg.C under protection; dissolving 0.9g of dibromohydantoin (3.15mmol) in 10mL of chloroform, and slowly dripping into a reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 0.54g of pure compound 3, yield: and 47 percent.1H NMR(500MHz,DMSO-d6),δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574.
Example 17: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of dichloromethane, 17mg of anhydrous FeCl are added3(0.1mmol)，N2Cooling to-10 deg.C under protection; dissolving 0.56g of NBS (3.15mmol) in 10mL of dichloromethane, and slowly dropping into the reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 20min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); reaction in 0Adding saturated sodium bisulfite solution at the temperature of lower degree centigrade for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 0.48g of pure compound 3, yield: 41.4 percent.1H NMR(500MHz,DMSO-d6),δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574。
Example 18: preparation of methyl (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionate (Compound 3)
1.0g of Compound 2(2.1mmol) is dissolved in 20mL of dichloromethane, 17mg of anhydrous FeCl are added3(0.1mmol)，N2Cooling to-78 deg.C under protection; dissolving 0.56g of NBS (3.15mmol) in 10mL of dichloromethane, and slowly dropping into the reaction system to ensure good ventilation; (dropping time is 5min, reaction time is 60min, TLC detection is carried out, and a developing agent PE: EA is 25: 1); adding saturated sodium bisulfite solution at 0 ℃ for quenching; slowly heating to room temperature, and properly communicating with the atmosphere by paying attention to the change of the air pressure in the bottle; diluting the reaction solution by adding 30mL of water; separating liquid, extracting the water phase with EA, and combining the organic phases; washing with saturated sodium bisulfite solution and saturated NaCl solution; drying, concentrating, purifying the product by silica gel column chromatography (eluent volume ratio is petroleum ether: ethyl acetate 25:1) to obtain 0.44g of pure compound 3, yield: 37.9 percent.1H NMR(500MHz,DMSO-d6),δ8.18(d,1H),7.64(ddd,1H),7.53-7.43(m,2H),7.38-7.24(m,5H),7.00(s,2H),4.80(t,1H),3.58(s,3H),3.31(m,2H),2.42(s,3H),2.24(s,3H),2.19(s,3H),1.55(s,3H)；MS(EI):[M+]572,[M+2]+574。
Example 19: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
3.1g of Compound 3(5.5mmol) are dissolved in 30mL of THF and 10mL of MeOH, slowly adding KOH (4mol/L, 3.5mL, 5min) dropwise at room temperature, and stirring for reaction for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying by silica gel column chromatography, and purifying with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 2.7g, yield: 90.3 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 20: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
2.4g of Compound 3(4.3mmol) are dissolved in 24mL of THF and 8mL of MeOH, and K is slowly added dropwise at room temperature2CO3(1mol/L, 9mL, 5min), stirring and reacting for 2 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.98g, yield: 85 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 21: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolve 2.0g of Compound 3(3.6mmol) in 20mL THF and 7mL MeOH, slowly add NaOH (1mol/L, 4mL, 5min) dropwise at room temperature, stir for 6 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.52g, yield: 78 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 22: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
2.0g of Compound 3(3.6mmol) are dissolved in 20mL of THF and 7mL of MeOH, and Na is slowly added dropwise at room temperature2CO3(1mol/L, 11mL, 5min), stirring and reacting for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.42g, yield: 75 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 23: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolving 2.0g of compound 3(3.6mmol) in 30mL of dichloromethane, slowly dropwise adding NaOH (2mol/L, 5.5mL, 5min) at room temperature, and stirring for reaction for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.55g, yield: 80 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 24: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolving 2.0g of compound 3(3.6mmol) in 30mL of methanol, slowly dropwise adding NaOH (2mol/L, 5.5mL, 5min) at room temperature, and stirring for reacting for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.50g, yield: 77%;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 25: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolving 2.0g of compound 3(3.6mmol) in 20mL of 1, 4-dioxane and 10mL of MeOH, slowly adding NaOH (2mol/L, 5.5mL, 5min) dropwise at room temperature, and stirring for reacting for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.52g, yield: 78 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 26: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolving 2.0g of compound 3(3.6mmol) in 30mL of isopropanol, slowly dropwise adding NaOH (1mol/L, 11mL, 5min) at room temperature, and stirring for reacting for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.52g, yield: 78 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 27: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolving 2.0g of compound 3(3.6mmol) in 30mL of ethanol, slowly dropwise adding NaOH (1mol/L, 11mL, 5min) at room temperature, and stirring for reacting for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying the product by silica gel column chromatography with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 1.52g, yield: 78 percent.1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
Example 28: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolving 2.4g of compound 3(4.3mmol) in 24mL of 2-methyltetrahydrofuran and 8mL of n-propanol, slowly adding KOH (1mol/L, 9mL, 5min) dropwise at room temperature, and stirring for reacting for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, and purifying by silica gel column chromatography (with petroleum ether and ethyl acetate in volume)3:1 of mixed solution is used as eluent, and acetic acid with the volume of 1 percent of the mixed solution is added; yield and yield 2.0g, yield: 86 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560。
example 29: preparation of (R) -2- (4- (9-bromo-2, 3-dimethylnaphthol [2,3-b ] thiophen-4-yl) -2, 6-dimethylphenoxy) -3-phenylpropionic acid (Ertiprostafib)
Dissolve 2.4g of Compound 3(4.3mmol) in 24mL THF and 8mL MeOH, slowly add LiOH (1mol/L, 9mL, 5min) dropwise at room temperature, stir for 4 h; adding 4mol/L hydrochloric acid to adjust the pH value to 1-2, and adding 50mL of water to dilute the reaction solution; separating, extracting the water phase with EA for 3 times, mixing the oil phases, and washing with saturated NaCl solution for 2 times; drying, concentrating, purifying by silica gel column chromatography, and purifying with petroleum ether: taking a mixed solution with the volume of ethyl acetate of 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution; yield and yield 2.05g, yield: 88 percent;1H NMR(500MHz,DMSO-d6)δ12.90(br s,1H),8.17(d,1H),7.63(ddd,1H),7.50-7.43(m,2H),7.36-7.23(m,5H),6.97(s,2H),4.71(t,1H),3.25(d,2H),2.41(s,3H),2.24(s,3H),2.21(s,3H),1.54(s,3H)；13C NMR(500MHz,CDCl3)δ175.9,153.9,140.0,137.2,136.1,135.6,134.4,133.2,131.8,130.1,129.8,129.5,128.9,128.6,128.3,127.2,126.0,125.4,124.8,114.3,81.3,60.5,39.0,21.0,17.2,14.2；MS(EI):[M]+558,[M+2]+560.
Claims (10)
1. a synthetic method of Ertiprotafib shown in formula (4) is characterized by comprising the following steps:
a, carrying out Mitsnobu reaction on a compound 1 shown in a formula (1) and L-methyl phenyl lactate to obtain a compound 2 shown in a formula (2);
b, carrying out bromination reaction on the compound 2 shown in the formula (2) to obtain a compound 3 shown in a formula (3);
c hydrolyzing the compound 3 represented by the formula (3) under an alkaline condition to obtain a final product Ertiprostafib represented by the formula (4).
2. The method of synthesis according to claim 1, characterized in that it is carried out as follows:
a, dissolving a compound 1 shown in a formula (1), L-methyl phenyl lactate and triphenylphosphine in an organic solvent A, slowly dropwise adding an azo compound, heating a reaction solution to 80-85 ℃, refluxing for 1-5 h, cooling to room temperature, reacting for 1-3 d to obtain a reaction solution A, and carrying out aftertreatment on the reaction solution A to obtain a compound 2 shown in a formula (2); the azo compound is diethyl azodicarboxylate or diisopropyl azodicarboxylate; the mass ratio of the compound 1 shown in the formula (1), L-methyl phenyl lactate, triphenylphosphine and an azo compound is 1: 1.0-1.5;
b, dissolving the compound 2 shown in the formula (2) obtained in the step a and a brominating reagent in an organic solvent B, reacting for 20-60 minutes at-10 to-78 ℃ under the catalysis of anhydrous ferric trichloride to obtain a reaction liquid B, and carrying out post-treatment on the reaction liquid B to obtain a compound 3 shown in the formula (3); the brominating reagent is liquid bromine, N-bromosuccinimide (NBS) or dibromohydantoin; the mass ratio of the compound 2 shown in the formula (2) to the brominating reagent and the anhydrous ferric trichloride is 1: 1.0-1.5: 0.03 to 0.07;
c, dissolving the compound 3 shown in the formula (3) obtained in the step b in an organic solvent C, reacting for 2-6 h at room temperature under the action of an alkaline substance to obtain a reaction liquid C, and carrying out aftertreatment on the reaction liquid C to obtain a final product Ertiprostafib shown in the formula (4); the ratio of the amount of the compound 3 represented by the formula (3) to the amount of the basic substance is 1:1 to 3.
3. The method of claim 2, wherein the organic solvent a in step a is: benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or dichloromethane; the volume dosage of the organic solvent A is 10-15 mL/g based on the mass of the compound 1 shown in the formula (1).
4. The synthesis method according to claim 2, wherein the post-treatment method of the reaction solution A in the step a is as follows: after the reaction is finished, concentrating under reduced pressure to remove the solvent, dissolving the concentrate in a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 20:1, filtering under reduced pressure, concentrating the filtrate, and purifying by silica gel column chromatography to obtain the compound 2 shown in the formula (2).
5. The method of claim 2, wherein the organic solvent B in step B is: dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, or acetonitrile; the volume dosage of the organic solvent B is 15-30 mL/g based on the mass of the compound 2 shown in the formula (2).
6. The synthesis method according to claim 2, wherein the post-treatment method of the reaction solution B in the step B is as follows: after the reaction is finished, adding a 5% sodium bisulfite solution into the reaction solution B at 0-10 ℃ for quenching, extracting by ethyl acetate, washing the extract by water and saturated saline solution in sequence, drying, concentrating under reduced pressure, and then separating by column chromatography, wherein the volume ratio of an eluent is petroleum ether: ethyl acetate 25:1 gave compound 3 represented by formula (3).
7. The method of claim 2, wherein in step c the basic material is: potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or lithium hydroxide.
8. The method according to claim 2, wherein the initial final concentration of the basic substance in step c is 1-4 mol/L.
9. The synthesis method according to claim 2, wherein the organic solvent C in step C is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, n-propanol and isopropanol; the volume dosage of the organic solvent C is 10-13.3 mL/g based on the mass of the compound 3 shown in the formula (3).
10. The synthesis method according to claim 2, wherein the post-treatment method of the reaction solution C in the step C is as follows: after the reaction is finished, acidifying the reaction solution C by using 4.0mol/L hydrochloric acid, adjusting the pH value to 1-3, extracting by using ethyl acetate, taking an extract, washing the extract by using saturated saline solution, drying, concentrating, and purifying by using a silica gel column chromatography, wherein the petroleum ether: and (3) taking a mixed solution with the volume of ethyl acetate being 3:1 as an eluent, and then adding acetic acid with the volume of 1% of the mixed solution to obtain a final product Ertiprostafib shown in the formula (4).
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