WO2023223335A1 - Procédé de préparation de (1s)-2-chloro-1-(3,4-difluorophényl)éthanol - Google Patents
Procédé de préparation de (1s)-2-chloro-1-(3,4-difluorophényl)éthanol Download PDFInfo
- Publication number
- WO2023223335A1 WO2023223335A1 PCT/IN2023/050078 IN2023050078W WO2023223335A1 WO 2023223335 A1 WO2023223335 A1 WO 2023223335A1 IN 2023050078 W IN2023050078 W IN 2023050078W WO 2023223335 A1 WO2023223335 A1 WO 2023223335A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- charged
- difluorophenyl
- enzyme
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 24
- RYOLLNVCYSUXCP-MRVPVSSYSA-N (1s)-2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClC[C@@H](O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-MRVPVSSYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 102000004190 Enzymes Human genes 0.000 claims abstract description 17
- 108090000790 Enzymes Proteins 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- VMEDAWUIKFAFJQ-UHFFFAOYSA-N 2-chloro-1-(3,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C=C1F VMEDAWUIKFAFJQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000872 buffer Substances 0.000 claims abstract description 3
- XJLXINKUBYWONI-NNYOXOHSSA-O NADP(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-O 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000007853 buffer solution Substances 0.000 claims description 14
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 claims description 14
- 229960002528 ticagrelor Drugs 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- 229960004418 trolamine Drugs 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QVUBIQNXHRPJKK-IMTBSYHQSA-N (1r,2s)-2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound N[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-IMTBSYHQSA-N 0.000 description 5
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- UNJRFWWCCAHSRB-MRVPVSSYSA-N (2s)-2-(3,4-difluorophenyl)oxirane Chemical compound C1=C(F)C(F)=CC=C1[C@@H]1OC1 UNJRFWWCCAHSRB-MRVPVSSYSA-N 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CSLVZAGSOJLXCT-NKWVEPMBSA-N (1r,2r)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 CSLVZAGSOJLXCT-NKWVEPMBSA-N 0.000 description 1
- -1 (lR,2R)-2-(3,4-difluorophenyl)-N-hydroxycyclopropanecarboxamide Chemical compound 0.000 description 1
- JBWIJKZPCPUWBR-HTRCEHHLSA-N 1,2-difluoro-4-[(1r,2r)-2-methylcyclopropyl]benzene Chemical compound C[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 JBWIJKZPCPUWBR-HTRCEHHLSA-N 0.000 description 1
- OEKWJQXRCDYSHL-UHFFFAOYSA-N 3-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol Chemical compound C=12N=NN(C3C(C(O)C(OCCO)C3)O)C2=NC(SCCC)=NC=1NC1CC1C1=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 241001468191 Lactobacillus kefiri Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000922 anti-bactericidal effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000002894 chemical waste Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 238000010949 in-process test method Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical group B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- Compound of Formula (I) prepared by the above disclosed steps.
- Compound of Formula (III) is formed from compound of Formula (I) in the presence of toluene and sodium hydroxide.
- Compound of Formula (IV) is formed from compound of Formula (III) in the presence of trimethyl phosphonoacetate (TMPA) and sodium tert-butoxide.
- TMPA trimethyl phosphonoacetate
- Compound of Formula (V) is formed from compound of Formula (IV) in the presence of methanol and sodium hydroxide.
- Compound of Formula (VI) is formed from compound of Formula (V) in the presence of thionyl chloride, hydroxylamine hydrochloride and toluene.
- the wet solid was purified by stirring in water (1000 ml) at 25-30°C for 1 hour. The slurry was filtered and washed with water (500 ml). The wet solid was dried under vacuum at 45-50°C for 8-9 hours to yield Ticagrelor (Formula IX) (Dry weight: 128 gm; 94% yield)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
L'invention concerne un procédé de préparation d'un composé de formule (I) par réaction de 2-chloro-1-(3,4-difluorophényl)éthanone de formule (II) dans un tampon et en présence d'une enzyme CDX-023 et d'une co-enzyme NADP.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202221027963 | 2022-05-16 | ||
| IN202221027963 | 2022-05-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023223335A1 true WO2023223335A1 (fr) | 2023-11-23 |
Family
ID=88834784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2023/050078 WO2023223335A1 (fr) | 2022-05-16 | 2023-01-24 | Procédé de préparation de (1s)-2-chloro-1-(3,4-difluorophényl)éthanol |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2023223335A1 (fr) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008018823A1 (fr) * | 2006-08-05 | 2008-02-14 | Astrazeneca Ab | Procédé de préparation de cyclopropylamines optiquement actives |
| WO2016003070A1 (fr) * | 2014-06-30 | 2016-01-07 | Samsung Electronics Co., Ltd. | Méthode de mesure de vitesse de débit sanguin mise en oeuvre par un appareil d'imagerie médicale et appareil d'imagerie médicale associé |
| CN109423484A (zh) * | 2017-09-04 | 2019-03-05 | 尚科生物医药（上海）有限公司 | 一种酮还原酶及其在制备（s）-2-氯-1-（3,4-二氟苯基）乙醇上的应用 |
-
2023
- 2023-01-24 WO PCT/IN2023/050078 patent/WO2023223335A1/fr unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008018823A1 (fr) * | 2006-08-05 | 2008-02-14 | Astrazeneca Ab | Procédé de préparation de cyclopropylamines optiquement actives |
| WO2016003070A1 (fr) * | 2014-06-30 | 2016-01-07 | Samsung Electronics Co., Ltd. | Méthode de mesure de vitesse de débit sanguin mise en oeuvre par un appareil d'imagerie médicale et appareil d'imagerie médicale associé |
| CN109423484A (zh) * | 2017-09-04 | 2019-03-05 | 尚科生物医药（上海）有限公司 | 一种酮还原酶及其在制备（s）-2-氯-1-（3,4-二氟苯基）乙醇上的应用 |
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