CN112062785B - Preparation method of ozagrel and intermediate thereof - Google Patents
Preparation method of ozagrel and intermediate thereof Download PDFInfo
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- CN112062785B CN112062785B CN201910501725.1A CN201910501725A CN112062785B CN 112062785 B CN112062785 B CN 112062785B CN 201910501725 A CN201910501725 A CN 201910501725A CN 112062785 B CN112062785 B CN 112062785B
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- SHZKQBHERIJWAO-AATRIKPKSA-N ozagrel Chemical compound C1=CC(/C=C/C(=O)O)=CC=C1CN1C=NC=C1 SHZKQBHERIJWAO-AATRIKPKSA-N 0.000 title abstract description 32
- 229950003837 ozagrel Drugs 0.000 title abstract description 32
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 154
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 38
- 239000007810 chemical reaction solvent Substances 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- QWMFKVNJIYNWII-UHFFFAOYSA-N 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine Chemical compound CC1=CC=C(C)N1C1=CC=C(Br)C=N1 QWMFKVNJIYNWII-UHFFFAOYSA-N 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- FQGLEMDXDTZJMJ-UHFFFAOYSA-N 3-cyano-4-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=CC=C(C(O)=O)C=C1C#N FQGLEMDXDTZJMJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 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 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 claims description 2
- AAQNGTNRWPXMPB-UHFFFAOYSA-N dipotassium;dioxido(dioxo)tungsten Chemical compound [K+].[K+].[O-][W]([O-])(=O)=O AAQNGTNRWPXMPB-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- PEHWWVVZOODHQY-UHFFFAOYSA-N tert-butyl-(2-chloroethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCl PEHWWVVZOODHQY-UHFFFAOYSA-N 0.000 claims description 2
- CAAUZMMMFDVBFD-UHFFFAOYSA-N tert-butyl-(2-iodoethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCI CAAUZMMMFDVBFD-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 9
- -1 sulfenamide compound Chemical class 0.000 abstract description 6
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 abstract description 4
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- BOSBAKAXZNVXMR-UGSOOPFHSA-N n-[(1s)-4-cyano-2,3-dihydro-1h-inden-1-yl]-2-methylpropane-2-sulfinamide Chemical compound C1=CC=C(C#N)C2=C1[C@@H](N[S@@](=O)C(C)(C)C)CC2 BOSBAKAXZNVXMR-UGSOOPFHSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- XRVDGNKRPOAQTN-FQEVSTJZSA-N 5-[3-[(1s)-1-(2-hydroxyethylamino)-2,3-dihydro-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)NCCO)=NO1 XRVDGNKRPOAQTN-FQEVSTJZSA-N 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 1
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical group OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 229950008141 ozanimod Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of ozagrel and an intermediate thereof, belonging to the field of pharmaceutical chemistry. The preparation method comprises the following steps: oxidizing a sulfenamide substrate to obtain a sulfenamide compound, and then carrying out substitution and other reactions to obtain ozagrel. The method of the invention does not need sodium hydrogen reagent with high risk, has high yield, and the obtained ozagrel intermediate has high purity, convenient operation and good safety, and is suitable for industrial amplification.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of ozagrel and an intermediate thereof.
Background
Ozagrel, english name: ozanimod, also known as 5- [3- [ (1S) -2, 3-dihydro-1- [ (2-hydroxyethyl) amino ] -1H-inden-4-yl ] -1,2, 4-oxadiazol-5-yl ] -2- (1-methylethoxy) -benzonitrile, has the structure shown in formula (I), and ozamad is a novel oral, selective sphingosine 1 phosphate receptor (S1P 1R) modulator developed by the Stokes institute (Scripps Research Institute) for use in the treatment of autoimmune diseases, such as Multiple Sclerosis (MS), crohn' S disease (CD), and the like.
Patent application WO2009151529 discloses a method for obtaining ozagrel by taking 4-nitrile-1-indene-ketone as a raw material, adding hydroxylamine after borohydride reduction, further carrying out cyclization reaction with carboxylic acid, then carrying out substitution reaction with 2-hydroxyethylamine and the like; the method is an achiral synthetic route, and the obtained intermediates or products are all racemized compounds, and further chiral resolution is needed to obtain ozagrel.
After this, there are subsequent literature modifications to this route, as in patent application WO2011060392, which discloses three routes for the synthesis of ozagrel, one of which is based on WO2009151529, the chiral reduction being carried out with a chiral Ru reagent such as RuCl (p-isopropyltoluene) [ (R, R) -Ts-DPEN ] instead of sodium borohydride, and others substantially in accordance with the route WO 2009151529; the method uses an expensive transition metal catalyst, which is not beneficial to industrial production. The other route is to take 4-bromo-1-indene-ketone as a raw material, carry out substitution, then carry out induction control by utilizing the chirality of sulfenamide, obtain chiral amino after hydrolysis and removal of sulfenamide protecting group, then carry out substitution reaction on the amino, then carry out addition reaction, cyclization reaction, deprotect the protecting group and then carry out substitution to obtain ozagrel; the reaction route has multiple steps, long product period and high production cost, and the first step also uses a highly toxic reagent zinc cyanide, so that the zinc cyanide has great harm to human bodies. Another approach is to use sodium hydride, which is a dangerous protecting group on chiral amine groups, which is prone to explosion during industrial scale-up and difficult to replace with other alkaline reagents, which limits the possibility of mass production. WO2018215807 discloses a method, wherein sulfenamide is used as a chiral induction reagent, and ozagrel is obtained through substitution reaction, addition, cyclization and deprotection; sodium hydride which is also dangerous and used in the first step of reaction has the same factors which are unfavorable for industrial production.
Therefore, research on the preparation method of ozagrel is still needed to obtain the method which is safe and simple to operate, easy to implement, low in cost, high in yield, high in purity and environment-friendly.
Disclosure of Invention
The invention aims to solve the problems and provide a preparation method of ozagrel and an intermediate thereof, which has low production cost and good safety and is suitable for industrial production.
In one aspect, the present invention provides an intermediate compound (B) having a structure represented by formula (B):
in another aspect, the present invention also provides a process for preparing compound (B), comprising: the compound (A) is subjected to oxidation reaction at a certain reaction temperature in the presence of an oxidant and a catalyst in a reaction solvent, and is subjected to post-treatment to prepare a compound (B)
The reaction for producing the compound (B) according to the present invention may be carried out in one reaction solvent or in a mixed solvent of a plurality of reaction solvents. In some embodiments, the reaction solvent is selected from at least one of DMF, DMA, DMSO, NMP and THF. In some embodiments, the reaction solvent is DMF, which facilitates reaction progress and operation, and facilitates impurity control.
In some embodiments, the reaction temperature of the oxidation reaction described above is from 40 ℃ to 60 ℃. In some embodiments, the reaction temperature of the oxidation reaction described above is 45 ℃ to 50 ℃.
The oxidant is at least one selected from hydrogen peroxide, TEMPO and IBX. In some embodiments, the oxidizing agent is hydrogen peroxide.
The catalyst is at least one selected from sodium tungstate dihydrate and potassium tungstate. In some embodiments, the catalyst is sodium tungstate dihydrate.
In some embodiments, the molar ratio of compound (a) to oxidant is from 1:3.0 to 1:5.0; or the molar ratio is 1:3.5-1:4.5.
In some embodiments, the molar ratio of compound (a) to catalyst is from 1:0.2 to 1:0.4.
In some embodiments, the oxidation reaction has a reaction time of 3h to 7h; or the oxidation reaction time is 4-6 h.
The post-treatment comprises the following steps: stopping the reaction, adding ethyl acetate and water into the reaction system, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (B); the compound (B) is optionally purified or the like.
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: in a reaction solvent, the compound (A) reacts at 40-60 ℃ in the presence of an oxidant and a catalyst, and after the reaction is finished, the compound (B) is prepared through post-treatment.
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: stirring the compound (A) and the catalyst in a reaction solvent at room temperature; then reacting at 40-60 ℃ in the presence of an oxidant; after the reaction, the compound (B) is obtained through post-treatment.
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: in a reaction solvent, the compound (A) reacts at 40-60 ℃ in the presence of an oxidant and a catalyst, ethyl acetate and water are added after the reaction is finished, extraction is carried out, an organic phase is collected, and the organic phase is concentrated under reduced pressure, so that the compound (B) is prepared.
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: stirring the compound (A) and the catalyst in a reaction solvent at room temperature; then reacting at 40-60 ℃ in the presence of an oxidant; after the reaction, ethyl acetate and water were added, extraction was performed, and an organic phase was collected and concentrated under reduced pressure to obtain compound (B).
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: in DMF, the compound (A) and sodium tungstate dihydrate are stirred at room temperature, then H is added 2 O 2 And (3) carrying out a reaction at 40-60 ℃, and after the reaction is finished, carrying out post-treatment to obtain the compound (B).
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: in DMF, the compound (A) and sodium tungstate dihydrate are stirred at room temperature, then H is added 2 O 2 And (3) carrying out a reaction at 40-60 ℃, adding ethyl acetate and water after the reaction is finished, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain the compound (B).
In some embodiments, a method of preparing an ozagrel intermediate compound (B) comprises: in DMF, the compound (A) and sodium tungstate dihydrate were stirred at room temperature, and then H was added dropwise 2 O 2 Reacting at 40-60 deg.c, adding ethyl acetate and water, extracting and collecting organic matterConcentrating the organic phase under reduced pressure to obtain compound (B); wherein, the compounds (A) and H 2 O 2 The molar ratio of the compound (A) to the sodium tungstate dihydrate is 1:3.0-1:5.0, and the molar ratio of the compound (A) to the sodium tungstate dihydrate is 1:0.2-1:0.4.
The reaction may be terminated by monitoring the end point of the reaction by High Performance Liquid Chromatography (HPLC), and the reaction is terminated when the HPLC purity of the compound a is 0.5% or less, and the reaction time is usually 10 hours or less.
The reaction is carried out by oxidizing compound (A), namely (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-indene-1-yl) -2-methylpropane-2-sulfinamide, to obtain compound (B), namely (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-indene-1-yl) -2-methylpropane-2-sulfonamide, which has mild reaction condition and easy operation, yield is near 100%, and compound (B) is more stable than compound (A), is very suitable for being used as reaction intermediate, and is convenient for quality control.
In another aspect, the present invention also provides a process for preparing compound (C), comprising: in a reaction solvent, under the existence of an alkaline reagent and at a certain temperature, reacting the compound (B) with (2-halogenated ethoxy) -tert-butyldimethylsilane shown in a formula (01), and carrying out post-treatment to obtain a compound (C), wherein X is halogen, selected from chlorine, bromine and iodine,
in the method for producing the compound (C) of the present invention, the reaction may be carried out in one reaction solvent or in a mixed solvent of a plurality of reaction solvents. In some embodiments, the reaction solvent is selected from at least one of DMF, DMA, DMSO, NMP and THF. In some embodiments, the reaction solvent is DMF, which facilitates reaction progress and operation, and facilitates impurity control.
In some embodiments, in the above method for producing compound (C), the reaction temperature of the reaction is 20 ℃ to 40 ℃.
The alkaline reagent is at least one selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide and NaHMDS. In some embodiments, the alkaline reagent is cesium carbonate, which facilitates the reaction and the acquisition of high quality products.
The (2-halogenated ethoxy) -tertiary butyl dimethyl silane is at least one selected from (2-chloroethoxy) -tertiary butyl dimethyl silane, (2-bromoethoxy) -tertiary butyl dimethyl silane and (2-iodoethoxy) -tertiary butyl dimethyl silane.
In some embodiments, the molar ratio of compound (B) to (2-haloethoxy) -tert-butyldimethylsilane is from 1:1 to 1:3; or the molar ratio is 1:1.5-1:2.5.
In some embodiments, the molar ratio of compound (B) to alkaline agent may be 1:2.0 to 1:4.0. In some embodiments, the molar ratio of compound (B) to alkaline agent is from 1:2.5 to 1:3.5, facilitating the reaction.
In some embodiments, the reaction time of the reaction is from 10h to 20h; or the reaction time is 12h-18h.
In some embodiments, in the method of preparing compound (C), the post-treatment comprises: and stopping the reaction, adding dichloromethane and saturated saline into the reaction system, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (C).
In some embodiments, in the method of preparing compound (C), the post-treatment comprises: stopping the reaction, adding ethyl acetate and water, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (C).
In some embodiments, a method of preparing an ozagrel intermediate compound (C) comprises: reacting the compound (B) with (2-haloethoxy) -tert-butyldimethylsilane in the presence of an alkaline agent in a reaction solvent at 20-40 ℃; after the reaction, ethyl acetate and water were added, extraction was performed, and an organic phase was collected and concentrated under reduced pressure to obtain compound (C).
In some embodiments, a method of preparing an ozagrel intermediate compound (C) comprises: reacting the compound (B) with (2-haloethoxy) -tert-butyldimethylsilane in the presence of an alkaline agent in a reaction solvent at 20-40 ℃; after the completion of the reaction, methylene chloride and saturated brine were added, extraction was performed, and an organic phase was collected and concentrated under reduced pressure to obtain compound (C).
In some embodiments, a method of preparing an ozagrel intermediate compound (C) comprises: in DMF, the compound (B) is represented by cesium carbonate (C S2 CO 3 ) Reacting with (2-bromoethoxy) -tert-butyldimethylsilane at 20-40 ℃ in the presence of a catalyst; after the completion of the reaction, methylene chloride and saturated brine were added, extraction was performed, and an organic phase was collected and concentrated under reduced pressure to obtain compound (C).
In some embodiments, a method of preparing an ozagrel intermediate compound (C) comprises: in DMF, the compound (B) is represented by cesium carbonate (C S2 CO 3 ) Reacting with (2-bromoethoxy) -tert-butyldimethylsilane at 20-40 ℃ in the presence of a catalyst; after the reaction is finished, adding ethyl acetate and water, extracting, collecting an organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (C); wherein the compound (B) is mixed with cesium carbonate (C) S2 CO 3 ) The molar ratio of the compound (B) to the (2-bromoethoxy) -tert-butyldimethylsilane is 1:1-1:3.
In the method for producing the compound (C), the post-treatment comprises: adding water into the reaction system, and extracting by taking dichloromethane, ethyl acetate or toluene as an organic phase; according to the separation condition, an appropriate amount of saturated saline is optionally added to make the separation more obvious, and an organic phase is collected; the organic phase was concentrated under reduced pressure to give compound (C).
In the method for producing the compound (C) of the present invention, the end of the reaction can be monitored by High Performance Liquid Chromatography (HPLC), and the reaction is terminated when the HPLC purity of the compound (B) is 0.5% or less, and the reaction time is usually 20 hours or less.
In the preparation method of the compound (C), the compound (B), namely (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-indene-1-yl) -2-methylpropane-2-sulfonamide, is subjected to substitution reaction with (2-halogenated ethoxy) -tert-butyldimethylsilane in the presence of an alkaline reagent to obtain the compound (C), namely (S) -N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -N- (4-cyano-2, 3-dihydro-1H-indene-1-yl) -2-methylpropane-2-sulfonamide.
The present invention also provides a process for producing compound (F), which comprises: adding the compound (C) to hydroxylamine hydrochloride to obtain a compound (D); the compound (D) is cyclized with 3-cyano-4-isopropoxy benzoic acid to obtain a compound (E); hydrolyzing the compound (E) under an acidic condition to remove a protecting group to obtain ozagrel; the reaction route is as follows:
in some embodiments, a method of preparing compound (F) comprises: in a reaction solvent, in the presence of an alkaline reagent, reacting the compound (B) with (2-halogenated ethoxy) -tert-butyldimethylsilane shown in a formula (01) under a certain temperature condition, and performing post-treatment to obtain a compound (C); adding the compound (C) to hydroxylamine hydrochloride to obtain a compound (D); the compound (D) is cyclized with 3-cyano-4-isopropoxy benzoic acid to obtain a compound (E); hydrolyzing the compound (E) under an acidic condition to remove a protecting group to obtain ozagrel; the reaction route is as follows:
in some embodiments, a method of preparing compound (F) comprises: in a reaction solvent, in the presence of an alkaline reagent, reacting the compound (B) with (2-halogenated ethoxy) -tert-butyldimethylsilane shown in a formula (01) under a certain temperature condition, and performing post-treatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride under the condition of adding a base such as triethylamine to obtain a compound (D); the compound (D) and 3-cyano-4-isopropoxy benzoic acid are cyclized under the condition of adding HOBT and EDCI.HCl to obtain a compound (E); and (3) hydrolyzing the compound (E) under the action of hydrochloric acid to remove the protecting group to obtain ozagrel.
In the above-mentioned method for producing the compound (F), the compound (B) can be produced by the above-mentioned method for producing the compound (B).
In some embodiments, a method of preparing compound (F) comprises: cesium carbonate (C) in DMF S2 CO 3 ) In the presence of the compound (B), reacting with (2-halogenated ethoxy) -tert-butyldimethylsilane shown in a formula (01) at 20-40 ℃ and carrying out post-treatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride under the condition of adding a base such as triethylamine to obtain a compound (D); the compound (D) and 3-cyano-4-isopropoxy benzoic acid are cyclized under the condition of adding HOBT and EDCI.HCl to obtain a compound (E); and (3) hydrolyzing the compound (E) under the action of hydrochloric acid to remove the protecting group to obtain ozagrel.
In some embodiments, a method of preparing compound (F) comprises: in DMF, the compound (A) and sodium tungstate dihydrate are stirred at room temperature, then H is added 2 O 2 Carrying out reaction at 40-60 ℃, and after the reaction is finished, carrying out post-treatment to obtain a compound (B); cesium carbonate (C) in DMF S2 CO 3 ) In the presence of the compound (B), reacting with (2-halogenated ethoxy) -tert-butyldimethylsilane shown in a formula (01) at 20-40 ℃ and carrying out post-treatment to obtain a compound (C); adding the compound (C) and hydroxylamine hydrochloride under the condition of adding triethylamine to obtain a compound (D); the compound (D) and 3-cyano-4-isopropoxy benzoic acid are cyclized under the condition of adding HOBT and EDCI.HCl to obtain a compound (E); and (3) hydrolyzing the compound (E) under the action of hydrochloric acid to remove the protecting group to obtain ozagrel.
According to the intermediate and the preparation method thereof, the sulfonamide protecting group of the intermediate compound (B) is more stable, so that substitution reaction further occurs, a sodium hydrogen reagent with high risk is not needed, the adopted condition is mild, the obtained intermediate is more stable, the operation is convenient, the safety is good, the reaction time is short, the energy consumption is low, the control is convenient, the production cost is reduced, and the large-scale industrial production is facilitated.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound a" and "compound represented by formula a" mean the same compound.
Detailed Description
In order to better understand the technical solution of the present invention, the following further discloses some non-limiting examples, which are further described in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the present invention, mmol means millimoles, h means hours, g means grams, and ml means milliliters.
In the present invention, DMF means N, N-dimethylformamide, DMA means N, N-dimethylacetamide, DMSO means dimethylsulfoxide, NMP means N-methylpyrrolidone, THF means tetrahydrofuran, DCM means dichloromethane.
In the present invention, TEMPO represents 2, 6-tetramethylpiperidine-nitroxide, IBX represents 2-iodoxybenzoic acid.
In the present invention, naHMDS represents sodium bis (trimethylsilyl) amide.
In the present invention, room temperature means an ambient temperature, generally 20℃to 40℃or 20℃to 30 ℃.
In the present invention, TEA represents triethylamine, HOBT represents 1-hydroxybenzotriazole, and EDCI.HCl represents carbodiimide hydrochloride.
EXAMPLE 1 preparation of Compound (B)
To a reaction flask containing the compound (A) (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide (55 mg) were added 26mg of sodium tungstate dihydrate and 2mL of DMF, and after stirring at room temperature for 30min, 95mg of 30% H was added dropwise to the flask 2 O 2 The solution was dropped for 2 min. After the dripping is finished, heating to 45 ℃, continuously stirring for 5 hours, and finishing the reaction; then, 5mL of ethyl acetate and 10mL of water were added to the reaction system, and the mixture was stirred at room temperature for extraction. After 25min, the mixture was allowed to stand and separated to collect an organic phase. Extracting the water phase with ethyl acetate twice (6 mL/time), collecting the organic phases, combining, concentrating the organic phases under reduced pressure at 45-50 ℃ to obtain a compound (B), namely (S) -N- (4-cyano-2, 3-dihydro-1H-indene-1-yl) -2-methylpropane-2-sulfonamide, 64mg; yield 100%, detection: purity 91%, LC-MS: M/z (ESI): 279.3 (M+H) +.
EXAMPLE 2 preparation of Compound (B)
In a single vial was added compound (A) (S) -N- ((S) -4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfinamide (11 g), sodium tungstate dihydrate 4.15g,55mL DMF, 30% H was added dropwise 2 O 2 (19.0 g) heating the solution to 50 ℃ and stirring, and ending the reaction; then Na is added into the reaction system 2 SO 3 (21.12 g,4 eq) in water (100 mL), 150mL ethyl acetate and 100mL water were added, stirred for 30min, the organic phases were separated, the organic phases were collected, the organic phases were combined and distilled under reduced pressure at 45℃to give compound (B), namely (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropan-2-sulfonamide, 11.2g.
EXAMPLE 3 preparation of Compound (C)
To a reaction flask containing the compound (B) obtained in example 1, i.e., (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide, 147mg of CS was charged 2 CO 3 And 2mL DMF, stirring at room temperature, after 25min, 108mg (2-bromoethoxy) -tert-butyldimethylsilane at room temperature for 15h, the reaction being completed; adding 10mL of water into the reaction system, stirring at room temperature, stirring for about 1h, observing that the turbid system is not solid and is similar to emulsion, then adding 5mL of dichloromethane into the turbid system, stirring at room temperature for extraction, stirring for 25min, standing, finding emulsification, adding 2mL of saturated saline, obviously layering, collecting an organic phase, extracting the aqueous phase with dichloromethane twice (6 mL/time), collecting the organic phases, combining, and concentrating the organic phase at 30-40 ℃ under reduced pressure to obtain a compound (C) of 99mg; yield 100%, detection: the purity was 89%.
EXAMPLE 4 preparation of Compound (C)
In a single flask, the compound (B) obtained in example 2, namely (S) -N- (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-methylpropane-2-sulfonamide (1.8 g), 10mL of DMF and cesium carbonate (6.32 g) were added, stirring was turned on, and the reaction was completed at room temperature; 50mL of water was added, extraction was performed three times (30 mL/time) with ethyl acetate, the ethyl acetate layers were combined, and concentrated under reduced pressure to give 2.8g of compound (C); yield 99%, detection: purity 91%, LC-MS: M/z (ESI): 475.3 (M+K) +;
1 H NMR(400MHz,DMSO)δ7.76(d,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),3.88(t,J＝5.7Hz,1H),3.74(t,J＝6.1Hz,6H),3.46(s,2H),1.39(s,9H),0.76(s,9H),-0.13(s,6H)。
EXAMPLE 5 preparation of ozagrel hydrochloride
Hydroxylamine hydrochloride (8.38 g,3 eq), TEA (12.2 g,3 eq), absolute ethanol (100 mL) were put into a flask, stirred at 40 ℃ for clarification, and compound (C) (17.55 g,1 eq) was added under stirring, and the reaction was continued under stirring for 4 hours, and the reaction was completed; the system was cooled to room temperature, concentrated under reduced pressure at 45℃to remove ethanol, 100mL of water was added, extracted twice with ethyl acetate (150 mL. Times.2), the organic phase was collected, concentrated under reduced pressure to give 7.0g of compound (D) in total, and detection was made: the purity is 95%.
3-cyano-4-isopropoxybenzoic acid (1.51 g), HOBT (1.29 g), EDCI. HCl (1.83 g), DMA (12 mL), TEA (1.6 mL) and a DMA (8 mL) solution of compound (D) (3.49 g) are added into a flask, stirred for 30min at 25 ℃, and then heated to 80 ℃ for reaction for 24h under heat preservation after stirring, and the reaction is finished; cooling to 30 ℃, adding 60mL of water, extracting twice with DCM (50 ml×2), separating the liquid, collecting the organic phase, washing the organic phase with aqueous sodium bicarbonate (0.6 g) solution (40 mL), collecting the organic phase, removing the solvent under reduced pressure to give 6.0g of compound (E) in total, detecting: the purity was 70%.
Compound (E) (2.0 g), DCM (10 mL) and hydrochloric acid were added to the flask under stirring at 25 ℃ and stirring for 16h, and after the reaction was completed, compound (F), namely ozagrel hydrochloride, 0.4g was obtained by recrystallization and purification with 10mL of ethanol, and detection: the purity is 95%.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (10)
1. A process for producing compound (C) which comprises reacting compound (B) with (2-haloethoxy) -t-butyldimethylsilane of formula (01) in a reaction solvent in the presence of an alkaline agent at a temperature and subjecting the resulting product to post-treatment to give compound (C) represented by the following formula:
wherein,,
the alkaline reagent is at least one selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide and sodium bis (trimethylsilyl) amide;
the (2-halogenated ethoxy) -tertiary butyl dimethyl silane is at least one selected from (2-chloroethoxy) -tertiary butyl dimethyl silane, (2-bromoethoxy) -tertiary butyl dimethyl silane and (2-iodoethoxy) -tertiary butyl dimethyl silane.
2. The process of claim 1, wherein the molar ratio of compound (B) to (2-haloethoxy) -tert-butyldimethylsilane is from 1:1 to 1:3, or the molar ratio of compound (B) to alkaline agent is from 1:2.0 to 1:4.0.
3. The method of claim 1, wherein the reaction solvent is selected from at least one of DMF, DMA, DMSO, NMP and THF.
4. The method of claim 1, wherein the temperature is 20 ℃ -40 ℃.
5. A process for preparing compound (F), which comprises preparing compound (C) according to the process of claim 1, and adding hydroxylamine hydrochloride to compound (D); the compound (D) is cyclized with 3-cyano-4-isopropoxy benzoic acid to obtain a compound (E); hydrolyzing the compound (E) under an acidic condition to obtain a compound (F); the reaction formula is shown as follows:
6. the method of claim 1 or 2, further comprising the step of adding an oxidant and a catalyst to the compound (A) in a reaction solvent, performing an oxidation reaction at a certain reaction temperature, and performing post-treatment to obtain a compound (B) with the following formula:
wherein,,
the oxidant is at least one selected from hydrogen peroxide, 2, 6-tetramethyl piperidine-nitrogen oxide or 2-iodic acid;
the catalyst is at least one selected from sodium tungstate dihydrate or potassium tungstate.
7. The process of claim 6, wherein the molar ratio of compound (a) to oxidant is from 1:3.0 to 1:5.0, or the molar ratio of compound (a) to catalyst is from 1:0.2 to 1:0.4.
8. The process of claim 6, wherein the reaction temperature is 40 ℃ to 60 ℃.
9. The method according to claim 6, wherein the reaction time of the oxidation reaction is 3h to 7h.
10. A compound having the structure shown in formula (B) or formula (C):
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| WO2009151529A1 (en) * | 2008-05-14 | 2009-12-17 | The Scripps Research Institute | Novel modulators of sphingosine phosphate receptors |
| WO2011060392A1 (en) * | 2009-11-13 | 2011-05-19 | Receptos, Inc. | Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
| CN105130922A (en) * | 2009-11-13 | 2015-12-09 | 瑞塞普托斯公司 | Selective heterocyclic sphingosine 1 phosphate receptor modulators |
| WO2018215807A1 (en) * | 2017-05-22 | 2018-11-29 | Egis Gyógyszergyár Zrt. | Process for the production of ozanimod |
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| WO2009151529A1 (en) * | 2008-05-14 | 2009-12-17 | The Scripps Research Institute | Novel modulators of sphingosine phosphate receptors |
| WO2011060392A1 (en) * | 2009-11-13 | 2011-05-19 | Receptos, Inc. | Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
| CN105130922A (en) * | 2009-11-13 | 2015-12-09 | 瑞塞普托斯公司 | Selective heterocyclic sphingosine 1 phosphate receptor modulators |
| WO2018215807A1 (en) * | 2017-05-22 | 2018-11-29 | Egis Gyógyszergyár Zrt. | Process for the production of ozanimod |
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