CN101400637A - Process for producing adamantyl (mono-or poly-) acetic acid and process for producing adamantyl (mono-or poly-) ethanol using the same - Google Patents
Process for producing adamantyl (mono-or poly-) acetic acid and process for producing adamantyl (mono-or poly-) ethanol using the same Download PDFInfo
- Publication number
- CN101400637A CN101400637A CNA2007800088171A CN200780008817A CN101400637A CN 101400637 A CN101400637 A CN 101400637A CN A2007800088171 A CNA2007800088171 A CN A2007800088171A CN 200780008817 A CN200780008817 A CN 200780008817A CN 101400637 A CN101400637 A CN 101400637A
- Authority
- CN
- China
- Prior art keywords
- adamantyl
- quality
- acetate
- general formula
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 title claims abstract description 97
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 238000000034 method Methods 0.000 title claims abstract description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 114
- -1 adamantane compound Chemical class 0.000 claims abstract description 90
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 230000002829 reductive effect Effects 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 40
- 239000002253 acid Substances 0.000 claims description 33
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 26
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 claims description 19
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 claims description 18
- 230000001476 alcoholic effect Effects 0.000 claims description 13
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 13
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000012545 processing Methods 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract description 43
- 239000012535 impurity Substances 0.000 abstract description 10
- 230000009467 reduction Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 58
- 238000004817 gas chromatography Methods 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 35
- ZYLRDAOEBRPIGT-UHFFFAOYSA-N 1-adamantyl acetate Chemical compound C1C(C2)CC3CC2CC1(OC(=O)C)C3 ZYLRDAOEBRPIGT-UHFFFAOYSA-N 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 30
- 229910000085 borane Inorganic materials 0.000 description 29
- 235000006408 oxalic acid Nutrition 0.000 description 29
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 229910015900 BF3 Inorganic materials 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- YALBLVPSPRKDJI-UHFFFAOYSA-N 1-(1-adamantyl)ethanol Chemical compound C1C(C2)CC3CC2CC1(C(O)C)C3 YALBLVPSPRKDJI-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- BLQURGBJSSSGAU-UHFFFAOYSA-N 2-(1-adamantyl)acetaldehyde Chemical compound C1C(C2)CC3CC2CC1(CC=O)C3 BLQURGBJSSSGAU-UHFFFAOYSA-N 0.000 description 2
- CUDPMMJZLBMJTR-UHFFFAOYSA-N 2-(1-adamantyloxy)-2-oxoacetic acid Chemical compound C1C(C2)CC3CC2CC1(OC(=O)C(=O)O)C3 CUDPMMJZLBMJTR-UHFFFAOYSA-N 0.000 description 2
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylphenylamine Natural products CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000032696 parturition Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- WJURWIRFCBARRW-UHFFFAOYSA-N (3,5-dimethyl-1-adamantyl) acetate Chemical compound C1C(C2)CC3(C)CC2(C)CC1(OC(=O)C)C3 WJURWIRFCBARRW-UHFFFAOYSA-N 0.000 description 1
- VRNVXCKIMHTRPA-UHFFFAOYSA-N 1-(3,5-dimethyl-1-adamantyl)ethanol Chemical compound C1C(C2)CC3(C)CC2(C)CC1(C(O)C)C3 VRNVXCKIMHTRPA-UHFFFAOYSA-N 0.000 description 1
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical class CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- VFIJBTVGUHVPPW-UHFFFAOYSA-N [Br].C=C Chemical compound [Br].C=C VFIJBTVGUHVPPW-UHFFFAOYSA-N 0.000 description 1
- VFSMYOPZIYBHBZ-UHFFFAOYSA-N [Br].CC1(CC(C(=O)O)=CC=C1)C(=O)O Chemical compound [Br].CC1(CC(C(=O)O)=CC=C1)C(=O)O VFSMYOPZIYBHBZ-UHFFFAOYSA-N 0.000 description 1
- BWMILNOZFDXUOR-UHFFFAOYSA-N [Cl].CC1(CC(C(=O)O)=CC=C1)C(=O)O Chemical compound [Cl].CC1(CC(C(=O)O)=CC=C1)C(=O)O BWMILNOZFDXUOR-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001312 dry etching Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- JDVIRCVIXCMTPU-UHFFFAOYSA-N ethanamine;trifluoroborane Chemical compound CCN.FB(F)F JDVIRCVIXCMTPU-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012770 industrial material Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920002120 photoresistant polymer Polymers 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000012070 reactive reagent Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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Abstract
The present invention provides a process for producing substituted or unsubstituted adamantyl (mono-or poly-) acetic acid in high yield with significantly reduced production of impurities; a process for producing substituted or unsubstituted adamantyl (mono-or poly-) ethanol by reducing the adamantyl (mono-or poly-) acetate. The method comprises the following steps: a method for producing an adamantyl (mono-or poly-) acetic acid represented by the general formula (2) by dropping sulfuric acid having a concentration of 80 to 97% by mass into a mixture of an adamantane compound represented by the general formula (1) and a vinylidene halide while maintaining the mixture at a temperature of 0 to 15 ℃ to react the adamantane compound and the vinylidene halide, and then contacting the resulting reaction solution with water; and a method for producing an adamantyl (mono-or poly-) ethanol represented by the general formula (3) by subjecting the adamantyl (mono-or poly-) acetate to a reduction treatment. Wherein R represents an alkyl group or the like, X represents a hydroxyl group or a halogen atom, and m and n represent specific integers.
Description
Technical field
The present invention relates to obtain to replace or do not have (one or many) acetate and the replacement of replacement adamantyl or do not have replacement adamantyl (one or many) alcoholic acid preparation method with high yield and high purity.
Background technology
Known diamantane has the structure that four cyclohexane rings condense into cage type, is symmetry height, stable compound, and its derivative shows specific function, so the raw material of useful as drug raw material or high functionality Industrial materials etc.For example, owing to have optical characteristics or thermotolerance etc., therefore once attempted being used for (for example with reference to patent documentations 1 and 2) such as optic disc base board, fiber optics or lens.
Also attempt utilizing its acid-sensitive, dry etching patience, ultraviolet perviousness etc., diamantane ester class is used (for example with reference to patent documentation 3) as photoresists with resin raw material.
Discovered in recent years, have in the said derivative from replacing or not having the medicine that replaces adamantyl alcoholic acid structure and can be made into as the effective TNF-α of Parmaceutical for treating disease of autoimmunization system and generate inhibitory substance, as the replacement of raw material or do not have the adamantyl of replacement alcoholic acid importance and increase (for example with reference to patent documentation 4) day by day.
In the past,, demand (for example with reference to patent documentation 5) was also arranged, therefore its preparation method had been carried out various researchs replacing or not having the adamantyl of replacement ethanol as the raw material of part medicine.
Replace or do not have in the adamantyl of the replacement ethanol, normally synthetic earlier 1-adamantyl acetate of known 1-adamantyl alcoholic acid preparation method or 1-adamantyl acetaldehyde are then with they reductive methods.
The preparation method of the 1-adamantyl acetate of report has: in the presence of boron trifluoride, and the method (for example with reference to patent documentation 6) that 1-bromine diamantane and vinylidene chloride are reacted in the vitriol oil.
The 1-adamantyl alcoholic acid preparation method of report also has: in the presence of boron trifluoride, 1-adamantanol and diethyl malonate are reacted in normal hexane, synthetic 1-adamantyl diethyl malonate, then it is decomposed with alkali, the 1-adamantyl acetate that obtains is used the method (for example with reference to patent documentation 7) of lithium aluminium hydride reduction.
These methods are all used boron trifluoride, need special equipment for handling fluorine-containing waste liquid, and the high problem of cost is arranged.
In addition, the preparation method of 1-adamantyl acetaldehyde has: use acetylene to replace the method (for example with reference to non-patent literature 1) of above-mentioned vinylidene chloride.But acetylene is dangerous high high pressure gas, during use special equipment must be arranged, and this is conventional industrialization method for making hardly.
In addition, the reduction of 1-adamantyl acetate is to use lithium aluminum hydride as reductive agent, perhaps must carry out shortening with the high pressure about 20MPa.But the thermal value of lithium aluminum hydride when reaction is big, therefore is difficult to the expansion scale, produces the problem of aluminium waste liquid in addition.Must use special high-pressure reaction vessel in the shortening, aforesaid method is all unfavorable aspect cost.
Also has report: as the preparation method of 1-adamantyl acetate, be in the presence of the hexanaphthene and the trimethyl carbinol, diamantane and vinylidene chloride are reacted, obtain the method (for example with reference to patent documentation 8) of 1-adamantyl acetate in sulfuric acid.
The problem of the maximum of conventional art is to have impurity to generate in preparation process.Aforesaid method has all used boron trifluoride or the contour reactive reagent of acetylene, therefore, not only generates target adamantyl acetate (a substituted acetic acid compound), the also secondary impurity-adamantyl oxalic acid (two substituted acetic acid compounds) of giving birth to.Therefore, if gained adamantyl acetate directly is reduced to alkylol cpd, then generate the di-alcohol compound.The reactivity of this di-alcohol compound approaches an alcohol cpd, and therefore, variety of issue takes place the impurity as being very difficult to remove at former medicine preparatory phase easily.In addition, even attempt carrying out purifying before reduction, common two substituted acetic acid compounds are lower to the solvability of organic solvent than a substituted acetic acid compound, therefore are difficult to separate by partial crystallization.Therefore,, must adopt the whole bag of tricks purifying repeatedly, the problem of the yield first mate reduction of target compound alkylol cpd is arranged for this reason in order to obtain can be used as the high purity product of medicine material.
Even the same problem of preparation with 1-adamantyl acetate also takes place in the preparation of adamantyl polyacetic acid.That is, not only generate target adamantyl polyacetic acid, the also secondary substituted acetic acid compound of impurity-(m+1) of giving birth to.Here, m is 2～4 integer.
Patent documentation 1: Japanese kokai publication hei 6-305044 communique
Patent documentation 2: Japanese kokai publication hei 9-302077 communique
Patent documentation 3: Japanese kokai publication hei 4-39665 communique
Patent documentation 4: TOHKEMY 2002-53555 communique
Patent documentation 5: No. 3534084 specification sheetss of United States Patent (USP)
Patent documentation 6: No. 1149291 specification sheetss of English Patent
Patent documentation 7: No. 1168781 specification sheetss of English Patent
Patent documentation 8: Japanese Patent Publication 48-28904 communique
Non-patent literature 1:Bott.K, Liebigs Ann.Chem.1972,766,51～57
Summary of the invention
Invent problem to be solved
The object of the present invention is to provide the generation of impurity is significantly reduced, and prepare the method that replaces or do not have replacement adamantyl (one or many) acetate with high yield; And use operation and reaction control to be easy to reductive agent, above-mentioned adamantyl (one or many) acetate is reduced processings, thereby prepare replacement or do not have replacement adamantyl (one or many) alcoholic acid method.
Solve the method for problem
The inventor etc. have carried out deep research, found that: with specific adamantane compound as raw material, itself and vinylidene halide are reacted, contact with water again, can replace or do not have replacement adamantyl (one or many) acetate with high yield and prepared in high purity thus, by this adamantyl (one or many) acetate being reduced the method for handling, can prepare replacement or not have replacement adamantyl (one or many) ethanol with high yield and high purity high-level efficiency.The present invention is based on above-mentioned cognition finishes.
That is, the invention provides the preparation method and adamantyl (one or many) the alcoholic acid preparation method of following adamantyl (one or many) acetate.
1. the preparation method of adamantyl (one or many) acetate, this adamantyl (one or many) acetate is represented by general formula (2):
(in the formula, R represents that the alkyl of carbonatoms 1～8 or 2 R form together=O, and n represents 0～15 integer, and m represents 1～4 integer, n+m ≦ 16),
This preparation method is characterised in that: when using adamantane compound and vinylidene halide to prepare adamantyl (one or many) acetate, the limit remains on 0～15 ℃ with the temperature of the mixture of adamantane compound shown in the general formula (1) and vinylidene halide, the limit drips concentration in this mixture be the sulfuric acid of 80～97% quality, after making the reaction of adamantane compound and vinylidene halide, the gained reaction solution is contacted with water
(in the formula, R, n and m are same as described above, and X represents hydroxyl or halogen atom, n+m ≦ 16).
2. the preparation method of above-mentioned 1 adamantyl (one or many) acetate, wherein the sulfuric acid concentration of Di Jiaing is 85～93% quality.
3. the preparation method of above-mentioned 1 adamantyl (one or many) acetate, the adamantane compound shown in its formula of (1) is 1-adamantanol, 1-bromine diamantane, 1,3-diamantane glycol or 1,3-dibromodiamantane.
4. the preparation method of adamantyl (one or many) acetate, this adamantyl (one or many) acetate is represented by general formula (2):
(in the formula, R, n and m are same as described above),
This preparation method is characterised in that: when using adamantane compound and vinylidene halide to prepare adamantyl (one or many) acetate, under 0～15 ℃ of temperature, adamantane compound shown in the general formula (1) to be suspended in the sulfuric acid that concentration is 70～90% quality, is dripped vinylidene halide in this suspension, make it under 0～15 ℃ of temperature, to react, when this reaction is stagnated, append sulfuric acid, making vitriolic concentration is 80～95% quality, further after the reaction, the gained reaction solution is contacted with water
(in the formula, R, X, n and m are same as described above).
5. the preparation method of above-mentioned 4 adamantyl (one or many) acetate, the adamantane compound shown in its formula of (1) is 1-adamantanol, 1-bromine diamantane, 1,3-diamantane glycol or 1,3-dibromodiamantane.
6. adamantyl (one or many) alcoholic acid preparation method, this adamantyl (one or many) ethanol is represented by general formula (3):
(in the formula, R, n and m are same as described above),
This preparation method is characterised in that: adamantyl (the one or many) acetate that is obtained by each method in above-mentioned 1～5 is reduced processing.
The invention effect
According to the present invention, the generation that can obtain impurity significantly reduces and obtains to replace or do not have with high yield adamantyl (the one or many) acetate of replacement; By this adamantyl (one or many) acetate being reduced processing, can obtain not contain in fact highly purified replacement adamantyl (the one or many) ethanol of target (one or many) ethanol many alcohol cpds in addition with high yield.
The best mode that carries out an invention
The preparation method of adamantyl of the present invention (one or many) acetate has two kinds, preparation method I wherein is: the limit remains on 0～15 ℃ with the temperature of the mixture of adamantane compound shown in the following general formula (1) and vinylidene halide, the limit drips concentration in this mixture be the sulfuric acid of 80～97% quality, after making the reaction of adamantane compound and vinylidene halide, the gained reaction solution is contacted with water, prepare the method for the adamantyl shown in the following general formula (2) (one or many) acetate.
In above-mentioned general formula (1) and (2), R represents that the alkyl of carbonatoms 1～8 or 2 R form together=O.N represents 0～15 integer, and m represents 1～4 integer, n+m ≦ 16.The alkyl of the carbonatoms 1～8 shown in the R can be straight chain shape, a catenate arbitrary form, and object lesson has: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, various amyl group, various hexyl, various heptyl or various octyl groups etc.
X is hydroxyl or halogen atom, and halogen atom for example has chlorine atom, bromine atoms and iodine atom.Preferred n is 0～2 situation, is preferably 0 situation especially.When n was a plurality of, R can be identical or different.
In the adamantane compound shown in the above-mentioned general formula (1), the compound of m=1 for example has: 1-adamantanol, 1-chlorine diamantane, 1-bromine diamantane, 3,5-dimethyl-1-chlorine diamantane, 3,5-dimethyl-1-bromine diamantane, 3-methyl isophthalic acid-chlorine diamantane and 3-methyl isophthalic acid-bromine diamantane etc.Preferred 1-adamantanol and 1-bromine diamantane.In the adamantane compound shown in the above-mentioned general formula (1), the compound of m=2～4 for example has: 1, and 3-diamantane glycol, 1,3-dichloro diamantane, 1,3-dibromodiamantane, 1,3,5-diamantane triol, 1,3,5-trichlorine diamantane and 1,3,5-tribromo diamantane etc., preferred 1,3-diamantane two is pure and mild 1,3-bromine diamantane.
Adamantyl one acetate in adamantyl shown in the above-mentioned general formula (2) (the one or many) acetate for example has: 1-adamantyl acetate, 3-methyl isophthalic acid-adamantyl acetate and 3,5-dimethyl-1-adamantyl acetate etc., preferred 1-adamantyl acetate.Adamantyl polyacetic acid in adamantyl shown in the above-mentioned general formula (2) (the one or many) acetate for example has: 1,3-adamantyl oxalic acid, 5-methyl isophthalic acid, 3-adamantyl oxalic acid, 1,3,5-adamantyl nitrilotriacetic and 1,3,5,7-adamantyl tetraacethyl etc., preferred 1,3-adamantyl oxalic acid.
The vinylidene halide that uses among the present invention for example has vinylidene chloride and inclined to one side bromine ethene etc., preferred vinylidene chloride.
Above-mentioned vitriolic concentration is generally the scope of 80～97% quality.As long as in this scope, when then target product was 1-adamantyl acetate, the growing amount of impurity such as adamantyl oxalic acid was few; In addition, when target product was the adamantyl polyacetic acid, (m+1) growing amount of substituted acetic acid compound impurity such as (m are 2～4 integer) was few, and reaction conversion ratio improves.Vitriolic concentration is preferably 85～92% quality.Sulfuric acid uses with the scope of 3～20 times of moles usually with respect to the adamantane compound shown in the general formula (1).As long as in this scope, then can obtain preferred speed of response, can suppress the rising of by-product concentration.The vitriolic usage quantity is preferably the scope of 5～15 times of moles.
Above-mentioned vinylidene halide uses with the scope of 2～20 times of moles usually with respect to the adamantane compound shown in the general formula (1).As long as in this scope, then can obtain high reaction conversion ratio, can suppress the rising of target product (one or many) acetate by-product concentrations such as diamantane polyacetic acid in addition.The usage quantity of vinylidene halide is preferably the scope of 5～15 times of moles.
Temperature of reaction as mentioned above, 0～15 ℃ scope.As long as in this scope, then the yield of speed of response and target product can not reduce.Temperature of reaction is preferably 0～10 ℃ scope.
During reaction, need not to use especially solvent, but also can use.Solvent for example has: hydro carbons such as normal hexane, heptane, hexanaphthene, halogenated hydrocarbons such as methylene dichloride, chloroform, ethers such as diethyl ether, tetrahydrofuran (THF), glycol dimethyl ether He diox etc.
Vitriolic drips the mixture limit dropping that adamantane compound shown in the general formula (1) and vinylidene halide are stirred in preferred limit.Reaction times normally dripped the beginning back 1～5 hour from sulfuric acid.
The method that the reaction solution that adamantane compound shown in the general formula (1) and vinylidene halide reaction are obtained contacts with water, can be that water is added in the reaction solution, the method that makes it to react, also can be that reaction solution is added in the water, any methods such as the method that makes it to react can be selected according to technology.Water uses in the scope of 2～10 mass parts usually for the adamantane compound shown in the 1 mass parts general formula (1).As long as in this scope, then can roughly generate the adamantyl shown in the general formula (2) (one or many) acetate quantitatively.The usage quantity of water is 2～100 mass parts with respect to the adamantane compound shown in the 1 mass parts general formula (1) preferably.
When above-mentioned reaction solution is mixed with water, preferably slowly add the opposing party to a side wherein.The reaction of above-mentioned reaction solution and water is carried out after the disappearance by the adamantane compound shown in the gas-chromatography affirmation general formula (1) normally to the reaction solution sampling.
Temperature of reaction is generally-10 ℃ to 30 ℃ scope.As long as in this scope, then yield and selection rate aspect are preferred.Temperature of reaction is preferably-5 to 20 ℃ scope, more preferably 0～15 ℃ scope.Reaction times was generally about 1～5 hour.
The method of separating the adamantyl shown in the general formula (2) (one or many) acetate in the reaction solution by above-mentioned gained is not particularly limited, and can be following method.For example, after reaction finishes, the reaction solution of gained is extracted with inert solvent, then this extraction liquid is handled with alkaline aqueous solutions such as sodium hydroxide, be extracted into water one side, then water is made strongly-acid with acidic aqueous solutions such as hydrochloric acid, crystal is separated out.The crystal that leaching is separated out washs, and can obtain the crude product of the adamantyl shown in the general formula (2) (one or many) acetate.Inert solvent for example has: ethyl acetate, toluene, chloroform, ethylene dichloride, methylene dichloride, diethyl ether, normal hexane and heptane etc., they can be used alone or as a mixture.
The purification process of the adamantyl shown in the general formula (2) (one or many) acetate for example has: distillation, partial crystallization, post separation etc., can select according to the proterties of product and the kind of impurity, when the adamantyl (one or many) shown in the general formula (2) when acetate is solid, the preferred partial crystallization of industrialized purification process.Method for crystallization is not particularly limited, following method is for example arranged: about 40～50 ℃, crude product is dissolved in the minimum single or mixed solvent, is cooled near the method 0 ℃; Or add the solvent of minimum processable, and make the crude product dissolving, slowly add the solvent of low-solubility then, make method that crystal separates out etc.
The partial crystallization solvent can use various, but preferably water, acetonitrile, methyl alcohol, ethanol, ethyl acetate, normal hexane, heptane, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) etc. is used alone or as a mixture.The partial crystallization temperature can be selected optimal conditions according to the solubleness of adamantyl (the one or many) acetate shown in the general formula (2) in solvent.
The crude product of the adamantyl shown in the general formula (2) (one or many) acetate need not purifying can reduce processing, also can make it reaction behind purifying.
The preparation method II of adamantyl of the present invention (one or many) acetate is: under 0～15 ℃ of temperature, adamantane compound shown in the above-mentioned general formula (1) is suspended in the sulfuric acid that concentration is 70～90% quality, in this suspension, drip vinylidene halide, make it under 0～15 ℃ of temperature, to react, when this reaction is stagnated, append sulfuric acid, making vitriolic concentration is 80～95% quality, further after the reaction, the gained reaction solution is contacted, the method for adamantyl (the one or many) acetate shown in the preparation general formula (2) with water.
The temperature of reaction that contains the sulfuric acid suspension of the adamantane compound shown in the general formula (1) and vinylidene halide as mentioned above, 0～15 ℃ scope.As long as in this scope, then the yield of speed of response and target product can not reduce.Temperature of reaction is preferably 0～10 ℃ scope.Reaction times normally began to drip behind the vinylidene halide 1～5 hour.It is low when reaction begins owing to sulfuric acid concentration, therefore reaction stops, but be 0～15 ℃, preferred 0～10 ℃ state by keeping temperature of reaction afterwards, adding the vitriol oil, making sulfuric acid concentration is 80～95% quality, preferred 85～92% quality, then can suppress the generation of target product adamantyl (one or many) acetate impurity such as adamantyl polyacetic acid in addition.
The method of the reaction solution that obtains about the reaction that makes adamantane compound shown in the general formula (1) and vinylidene halide and water contact, separate the method for the adamantyl shown in the general formula (2) (one or many) acetate etc., same with above-mentioned preparation method I.
Among the present invention, the adamantyl shown in the following general formula (3) (one or many) ethanol can prepare by being reduced to handle by the preparation method I of above-mentioned adamantyl (one or many) acetate or adamantyl (one or many) acetate that II obtains,
(in the formula, R, m and n are same as described above).
The reductive agent that uses during above-mentioned reduction is handled can use common reductive agent.For example have: lithium aluminum hydride (LiAlH
4), sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, LiAlH (O-R)
3(R is an alkyl), diboron hexahydride, borine/tetrahydrofuran (THF) (THF) complex compound, borine/1, two (uncle's butylthio) the ethane complex compounds of 2-, borine/TERTIARY BUTYL AMINE complex compound, borine/N, N-diethylbenzene amine complex, borine/dimethylamine complex compound, borine/methyl-sulfide complex compound, borine/morpholine complex compound, borine/pyridine complex, borine/triethylamine complex compound, borine/Trimethylamine 99 complex compound, borine/triphenyl phosphine complex compound etc.
Never discharging the angle of aluminium waste liquid considers, preferred sodium borohydride, lithium borohydride, lithium borohydride, diboron hexahydride, borine/tetrahydrofuran complex, borine/1, two (uncle's butylthio) the ethane complex compounds of 2-, borine/TERTIARY BUTYL AMINE complex compound, borine/N, N-diethylbenzene amine complex, borine/dimethylamine complex compound, borine/methyl-sulfide complex compound, borine/morpholine complex compound, borine/pyridine complex, borine/triethylamine complex compound, borine/Trimethylamine 99 complex compound, borine/triphenyl phosphine complex compound etc., more preferably borine/tetrahydrofuran complex, borine/TERTIARY BUTYL AMINE complex compound, borine/dimethylamine complex compound, borine/pyridine complex, borine/triethylamine complex compound, borine/triphenyl phosphine complex compound.
Reductive agent is with respect to adamantyl (the one or many) acetate shown in the general formula (2), uses with the scope of the scope of 1～10 times of mole, preferred 1～5 times of mole usually.
Above-mentioned reductive agent can use with Lewis acid.Lewis acid for example has: boron trifluoride, boron trifluoride/diethyl ether complex compound, boron trifluoride/piperidines complex compound, boron trifluoride/butyl ethyl ether complexes, boron trifluoride/methyl alcohol complex compound, boron trifluoride monoethylamine, aluminum chloride, titanium chloride (IV) etc.These Lewis acids use with the scope of the scope of 1～10 times of mole, preferred 1～5 times of mole usually with respect to adamantyl (the one or many) acetate shown in the general formula (2).
When preparation adamantyl (one or many) ethanol, solvent can use conventional organic solvent.For example have: hydro carbons such as normal hexane and heptane, aromatic hydrocarbons such as benzene, toluene and dimethylbenzene, ether series solvents such as diethyl ether, tetrahydrofuran (THF), glycol dimethyl ether and diglyme, non-protonic solvents such as dimethyl sulfoxide (DMSO), hexamethyl phosphoric triamide, dimethyl formamide and tetramethylene sulfone etc.Be preferably tetrahydrofuran (THF), normal hexane, heptane, glycol dimethyl ether, diglyme.The usage quantity of organic solvent is generally the scope of 3～20 mass parts with respect to adamantyl (the one or many) acetate shown in the 1 mass parts general formula (2), is preferably the scope of 5～10 mass parts.
Temperature of reaction is generally 0～50 ℃ scope.As long as in this scope, then can obtain target product with the yield that is fit to.Temperature of reaction is preferably 0～40 ℃ scope, more preferably 0～30 ℃ scope.
Reaction pressure can adopt the scope of absolute pressure 0.01～10MPa usually.As long as in this scope, then need not special pressure-resistant apparatus, comparatively economical.Reaction pressure is preferably normal pressure～1MPa.Reaction times is generally 1～5 hour scope.
Be not particularly limited from the gained reaction solution, separating the adamantyl shown in the general formula (3) (one or many) alcoholic acid method, can exemplify following method.For example, after reaction finishes, the gained reaction solution is mixed with water and stir, extract with inert solvent then, then with this extraction liquid with solution washings such as saturated aqueous common salts, make it dry with siccative such as anhydrous magnesium sulfates, heat up in a steamer then and desolvate, can obtain the adamantyl shown in the general formula (3) (one or many) alcoholic acid crude product.Inert solvent for example has: ethyl acetate, toluene, chloroform, ethylene dichloride, methylene dichloride, diethyl ether, tetrahydrofuran (THF), normal hexane and heptane etc., they can be used alone or as a mixture.
The purification process of this crude product for example has distillation, partial crystallization, post separation etc., can select according to the proterties of product and the kind of impurity, and the adamantyl shown in the general formula (3) (one or many) is when ethanol is solid, and preferred partial crystallization is as industrialized purification process.
Method for crystallization is not particularly limited, for example can about 40～50 ℃, crude product is dissolved in the minimum single or mixed solvent, be cooled near 0 ℃, make the method for its partial crystallization; Or add minimum processable solvent, and make the crude product dissolving, slowly add the solvent of low-solubility then, make the method for crystal partial crystallization; Can be again to be dissolved in the solvent of processable, heat up in a steamer, make method that crystal separates out etc. by solvent heating or decompression are placed.These methods can be used in combination as required.
The partial crystallization solvent can use various, but preferably water, acetonitrile, methyl alcohol, ethanol, ethyl acetate, normal hexane and heptane etc., they can be used alone or as a mixture.
The partial crystallization temperature can be selected optimal conditions to the solubleness of solvent according to adamantyl (the one or many) ethanol shown in the general formula (3).
In adamantyl shown in the above-mentioned general formula (3) (the one or many) ethanol, adamantyl one ethanol for example has: 1-adamantyl ethanol, 3-methyl isophthalic acid-adamantyl ethanol and 3,5-dimethyl-1-adamantyl ethanol etc., preferred 1-adamantyl ethanol.In addition, the many ethanol of adamantyl in the adamantyl shown in the above-mentioned general formula (3) (the one or many) ethanol for example have: 1, and 3-adamantyl di-alcohol, 5-methyl isophthalic acid, 3-adamantyl di-alcohol, 5,7-dimethyl-1,3-adamantyl di-alcohol, 1,3,5-adamantyl three ethanol and 1,3,5,7-adamantyl tetraethoxide etc., preferred 1,3-adamantyl di-alcohol.
Embodiment
Then, further describe the present invention, but the present invention is not subjected to any qualification of these examples by embodiment.
Measure its purity by the product that following examples obtain by gas-chromatography (GC).GC analyzes the GC-14A that is to use Shimadzu Seisakusho Ltd. to make, and analysis condition is as follows.
Capillary column [J﹠amp; The DB-1 that W company makes: coating-forming agent (dimethyl polysiloxane); Thickness: 0.25 μ m], internal diameter: 0.25mm, length: 30m, intensification condition: be warming up to 250 ℃, under this temperature, kept injection temperature 25 minutes by 100 ℃ with 10 ℃/minute: 250 ℃, detector: FID, detector temperature: 250 ℃, carrier gas: He (1.0kg/cm
2), carrier gas flux: 1.1mL/ minute, make-up gas: N
2, make-up gas flow: 50mL/ minute, splitting ratio: 100:1
Embodiment 1 (synthesizing of 1-adamantyl acetate)
Add 9.75g (64mmol) 1-adamantanol and 52.5g (540mmol) vinylidene chloride in the three-necked flask of the internal volume 300mL that possesses stirrer, thermometer, the limit is stirred the limit with stirrer and is cooled to about 10 ℃.The 7.5g water and the 83.0g96% quality vitriol oil (adding up to 50.1mL, 88% quality sulfuric acid) are joined in the dropping funnel, and the limit keeps 8～10 ℃ of limits to drip in above-mentioned three-necked flask with 65 minutes.After dripping end, the limit keeps 10 ℃ of limits to stir 3 hours.Reaction solution is slowly injected the 150mL frozen water, stirred 30 minutes.After reaction finishes, reaction solution with 100mL toluene extraction three times, is handled toluene layer with 5% quality aqueous sodium hydroxide solution, be extracted into the water layer side.This aqueous sodium hydroxide solution is made strongly-acid with 35% quality hydrochloric acid, and the crystal that leaching is separated out is washed.Make its drying under reduced pressure to constant, obtain 1-adamantyl acetate (yield 85.2% quality, GC purity 98.3%, the GC purity of 50 percent .02% of adamantyl oxalic acid).
Embodiment 2 (synthesizing of 1-adamantyl acetate)
In embodiment 1, use 10.2g water, the 78.8g96% quality vitriol oil (adding up to 50mL, 85% quality sulfuric acid) to replace 7.5g water, the 83.0g96% quality vitriol oil (adding up to 50.1mL, 88% quality sulfuric acid), in addition react similarly to Example 1.As a result, obtain 1-adamantyl acetate with yield 79.8% quality, GC purity 98.8%, adamantyl oxalic acid GC purity of 50 percent .03%.
Embodiment 3 (synthesizing of 1-adamantyl acetate)
In embodiment 1, use 3.22g water, the 92g96% quality vitriol oil (adding up to 50mL, 93% quality sulfuric acid) to replace 7.5g water, the 83.0g96% quality vitriol oil (adding up to 50.1mL, 88% quality sulfuric acid), in addition react similarly to Example 1.As a result, obtain 1-adamantyl acetate with yield 85.3% quality, GC purity 96.1%, adamantyl oxalic acid GC purity of 50 percent .08%.
Embodiment 4 (synthesizing of 1-adamantyl acetate)
Among the embodiment 1, use 13.77g (64mmol) 1-bromine diamantane to replace 9.75g (64mmol) 1-adamantanol, in addition react similarly to Example 1.As a result, obtain 1-adamantyl acetate with yield 84.6% quality, GC purity 97.6%, adamantyl oxalic acid GC purity of 50 percent .05%.
Embodiment 5 (synthesizing of 1-adamantyl acetate)
In embodiment 1, use 12.3g water, the 78.2g96% quality vitriol oil (adding up to 50mL, 83% quality sulfuric acid) to replace 7.5g water, the 83.0g96% quality vitriol oil (adding up to 50.1mL, 88% quality sulfuric acid), in addition react similarly to Example 1.As a result, obtain 1-adamantyl acetate with yield 35.1% quality, GC purity 99.1%, adamantyl oxalic acid GC purity of 50 percent .01%.
Embodiment 6 (synthesizing of 1-adamantyl acetate)
In embodiment 1, use the 90g96% quality vitriol oil (50mL) to replace 7.5g water, the 83.0g96% quality vitriol oil (adding up to 50.1mL, 88% quality sulfuric acid), in addition react similarly to Example 1.As a result, obtain 1-adamantyl acetate with yield 66.6% quality, GC purity 86.4%, adamantyl oxalic acid GC purity 2.05%.
Embodiment 7 (synthesizing of 1-adamantyl acetate)
Add the 14.5g water and 72.6g 96% vitriol oil (80% quality sulfuric acid) in the three-necked flask of the internal volume 500mL that possesses stirrer, thermometer, the limit is stirred the limit with stirrer and is cooled to about 10 ℃.Repeatedly add 9.75g (64mmol) 1-adamantanol while stirring on a small quantity.52.5g (540mmol) vinylidene chloride is joined in the dropping funnel, keep 10 ℃, be added drop-wise in the above-mentioned three-necked flask with 90 minutes.After dripping end, the limit kept 10 ℃ of limit stir abouts 3 hours.Afterwards, the limit keeps 8～12 ℃ of limits with dripping 145g 96% quality sulfuric acid (sulfuric acid concentration that drips in the three-necked flask before the sulfuric acid is 80% quality, is 90% quality but make the sulfuric acid concentration in the three-necked flask by dropping sulfuric acid) in 15 minutes.After dripping end, the limit keeps 10 ℃ of limits to stir 3 hours.Reaction solution slowly is injected in the cold water (5 ℃) of 150mL, stirred 30 minutes.Then, reaction solution slowly is injected in the frozen water of 150mL, stirred 30 minutes.After reaction finishes,, handle toluene layer, be extracted into the water layer side with 5% quality aqueous sodium hydroxide solution with 100mL toluene extraction 3 times.Making aqueous sodium hydroxide solution with 35% quality hydrochloric acid is strongly-acid, and the crystal that leaching is separated out is washed.Make its drying under reduced pressure to constant.Obtain 1-adamantyl acetate (yield 84.9% quality, GC purity 98.5%, adamantyl oxalic acid GC purity of 50 percent .03%).
Embodiment 8 (synthesizing of 1-adamantyl acetate)
Among the embodiment 7, use 21.6g water, the 68.4g 96% quality vitriol oil (73% quality sulfuric acid) to replace using 14.5g water, 72.6g 96% vitriol oil (80% sulfuric acid), drip the 69.2g 96% quality vitriol oil and replace dripping 145g96% quality sulfuric acid, in addition react (sulfuric acid concentration that drips in the sulfuric acid three-necked flask before is 73% quality, is 83% quality but make the sulfuric acid concentration in the three-necked flask by dropping sulfuric acid) similarly to Example 7.As a result, obtain 1-adamantyl acetate with yield 39.8% quality, GC purity 98.7%, adamantyl oxalic acid GC purity of 50 percent .02%.
Embodiment 9 (synthesizing of 1-adamantyl acetate)
Among the embodiment 7, use 9.4g water, the 80.4g 96% quality vitriol oil (86% quality sulfuric acid) to replace using 14.5g water, 72.6g 96% vitriol oil (80% sulfuric acid), drip the 290g 96% quality vitriol oil and replace dripping 145g 96% quality sulfuric acid, in addition react (sulfuric acid concentration that drips in the sulfuric acid three-necked flask before is 86% quality, is 93% quality but make the sulfuric acid concentration in the three-necked flask by dropping sulfuric acid) similarly to Example 7.As a result, obtain 1-adamantyl acetate with yield 52.4% quality, GC purity 85.5%, adamantyl oxalic acid GC purity 2.11%.
Embodiment 10 (1-adamantyl alcoholic acid is synthetic)
The 1-adamantyl acetate, the 10g tetrahydrofuran (THF) (THF) that add 1g embodiment 1 gained in the three-necked flask of the internal volume 50mL that possesses stirrer, thermometer, the limit is stirred the limit with stirrer and is cooled to about 5 ℃.4.2g borine/THF complex compound (1%mol)-THF solution is joined in the dropping funnel, was added drop-wise in the above-mentioned three-necked flask with 10 minutes.After dripping end, the limit keeps 10 ℃ of limits to stir 3 hours.Reaction solution slowly is injected in the 20mL frozen water, stirred 30 minutes.Use the 50mL ethyl acetate extraction then 3 times, with saturated common salt water washing ethyl acetate layer.With anhydrous magnesium sulfate ethyl acetate layer is dewatered, heat up in a steamer by vaporizer then and desolvate, obtain crude product.To wherein adding 5g water/methyl alcohol=10/90 (% volume ratio) mixed solution, under 0 ℃, leave standstill, make its crystallization.With the crystal cold water washing, make its drying under reduced pressure to constant then, obtain 1-adamantyl ethanol (yield 90.1% quality, GC purity 99.3%).Adamantyl di-alcohol content is detecting below the lower limit.
Embodiment 11 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 1, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, in addition reacts similarly to Example 1.As a result, obtain 1,3-adamantyl oxalic acid with yield 77.5% quality, GC purity 97.6%, adamantyl nitrilotriacetic GC purity of 50 percent .01%.
Embodiment 12 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 1, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, uses 10.2g water, the 78.8g 96% quality vitriol oil (adding up to 50mL, 85% quality sulfuric acid), in addition reacts similarly to Example 1.As a result, obtain 1,3-adamantyl oxalic acid with yield 72.3% quality, GC purity 97.6%, adamantyl nitrilotriacetic GC purity of 50 percent .02%.
Embodiment 13 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 1, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, uses 3.22g water, the 92g 96% quality vitriol oil (adding up to 50mL, 93% quality sulfuric acid), in addition reacts similarly to Example 1.As a result, obtain 1,3-adamantyl oxalic acid with yield 77.0% quality, GC purity 95.7%, adamantyl nitrilotriacetic GC purity of 50 percent .10%.Embodiment 14 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 1, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, uses 12.3g water, the 78.2g 96% quality vitriol oil (adding up to 50mL, 83% quality sulfuric acid), in addition reacts similarly to Example 1.As a result, obtain 1 with yield 31.2% quality, GC purity 98.3%, 3-adamantyl oxalic acid.The adamantyl nitrilotriacetic does not detect.
Embodiment 15 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 1, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, directly uses the 90g 96% quality vitriol oil (50mL), in addition reacts similarly to Example 1.As a result, obtain 1,3-adamantyl oxalic acid with yield 54.8% quality, GC purity 83.0%, adamantyl nitrilotriacetic GC purity 1.78%.
Embodiment 16 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 7, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, in addition reacts similarly to Example 7.As a result, obtain 1,3-adamantyl oxalic acid with yield 77.4% quality, GC purity 98.0%, adamantyl nitrilotriacetic GC purity of 50 percent .04%.
Embodiment 17 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 8, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, in addition react (sulfuric acid concentration that drips in the sulfuric acid three-necked flask before is 73% quality, is 83% quality but make the sulfuric acid concentration in the three-necked flask by dropping sulfuric acid) similarly to Example 8.As a result, obtain 1,3-adamantyl oxalic acid with yield 30.5% quality, GC purity 98.2%, adamantyl nitrilotriacetic GC purity of 50 percent .03%.
Embodiment 18 (1,3-adamantyl oxalic acid synthetic)
Among the embodiment 9, use 5.39g (32mmol) 1,3-diamantane glycol replaces the 1-adamantanol, in addition react (sulfuric acid concentration that drips in the sulfuric acid three-necked flask before is 86% quality, is 93% quality but make the sulfuric acid concentration in the three-necked flask by dropping sulfuric acid) similarly to Example 9.As a result, obtain 1,3-adamantyl oxalic acid with yield 49.2% quality, GC purity 82.2%, adamantyl nitrilotriacetic GC purity 1.94%.
Embodiment 19 (1,3-adamantyl di-alcohol synthetic)
Among the embodiment 10, use 2g (8mmol) 1,3-adamantyl oxalic acid replaces 1-adamantyl acetate, in addition reacts similarly to Example 10.As a result, obtain 1 with yield 91.2% quality, GC purity 99.4%, 3-adamantyl di-alcohol.
Above summary sheet is shown in the table 1.
Industrial applicability
By implementing specific step with adamantane compound and vinylidene halide as raw material, can the high efficiency preparation as agricultural chemicals, medicine material, particularly effectively have TNF-α as the treating autoimmune diseases medicine and generate inhibiting medicine material-replace or do not have replacement adamantyl (one or many) ethanol.
Claims (6)
1. the preparation method of adamantyl one or polyacetic acid, this adamantyl one or polyacetic acid are represented by general formula (2):
In the formula, R represents that the alkyl of carbonatoms 1～8 or 2 R form together=O, n
The integer of expression 0～15, m represents 1～4 integer, n+m ≦ 16,
This preparation method is characterised in that: when using adamantane compound and vinylidene halide to prepare adamantyl one or polyacetic acid, the limit remains on 0～15 ℃ with the temperature of the mixture of adamantane compound shown in the general formula (1) and vinylidene halide, the limit drips concentration in this mixture be the sulfuric acid of 80～97% quality, after making the reaction of adamantane compound and vinylidene halide, the gained reaction solution is contacted with water
In the formula, R, n, m are same as described above, and X represents hydroxyl or halogen atom, n+m ≦ 16.
2. the adamantyl one of claim 1 or the preparation method of polyacetic acid, wherein the sulfuric acid concentration of Di Jiaing is 85～93% quality.
3. the adamantyl one of claim 1 or the preparation method of polyacetic acid, the adamantane compound shown in its formula of (1) is 1-adamantanol, 1-bromine diamantane, 1,3-diamantane glycol or 1,3-dibromodiamantane.
4. the preparation method of adamantyl one or polyacetic acid, this adamantyl one or polyacetic acid are represented by general formula (2):
In the formula, R represents that the alkyl of carbonatoms 1～8 or 2 R form together=O, n
The integer of expression 0～15, m represents 1～4 integer, n+m ≦ 16,
This preparation method is characterised in that: when using adamantane compound and vinylidene halide to prepare adamantyl one or polyacetic acid, under 0～15 ℃ of temperature, adamantane compound shown in the general formula (1) is suspended in the sulfuric acid that concentration is 70～90% quality, in this suspension, drips vinylidene halide, make it under 0～15 ℃ of temperature, to react, when this reaction is stagnated, append sulfuric acid, making vitriolic concentration is 80～95% quality, further after the reaction, the gained reaction solution is contacted with water
In the formula, R, n, m are same as described above, and X represents hydroxyl or halogen atom, n+m ≦ 16.
5. the adamantyl one of claim 4 or the preparation method of polyacetic acid, the adamantane compound shown in its formula of (1) is 1-adamantanol, 1-bromine diamantane, 1,3-diamantane glycol or 1,3-dibromodiamantane.
6. adamantyl one or many alcoholic acid preparation method, this adamantyl one or many ethanol are represented by general formula (3):
In the formula, R represents that the alkyl of carbonatoms 1～8 or 2 R form together=O, n
The integer of expression 0～15, m represents 1～4 integer, n+m ≦ 16,
This preparation method is characterised in that: the adamantyl one that obtained by each method in the claim 1～5 or polyacetic acid are reduced processing.
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| CN (1) | CN101400637A (en) |
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| CN106397119A (en) * | 2016-04-11 | 2017-02-15 | 上海博康精细化工有限公司 | Preparation method for 1,3-adamantane diethanol |
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| JP2009256306A (en) * | 2008-03-18 | 2009-11-05 | Daicel Chem Ind Ltd | Adamantane derivative having polymerizable unsaturated group, and method for producing the same |
| JP2009292784A (en) * | 2008-06-06 | 2009-12-17 | Idemitsu Kosan Co Ltd | Adamantyl alkane polyol, adamantyl alkane (meth)acrylate, their production method, resin composition comprising the same di(meth)acrylate and optical electronic part material |
| JP6102547B2 (en) * | 2013-06-18 | 2017-03-29 | 三菱瓦斯化学株式会社 | Novel ethyladamantanediol compound and method for producing the same |
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| GB1168781A (en) * | 1965-08-03 | 1969-10-29 | Lilly Industries Ltd | Cyclic Organic Compounds |
| EP0053621B1 (en) * | 1980-06-11 | 1984-07-25 | Battelle Memorial Institute | Unsaturated esters of adamantane containing diols and thermo-resistant cross-linked polymers therefrom |
| CS246816B1 (en) * | 1985-06-03 | 1986-11-13 | Josef Janku | The 4,9-diamantanbisacetic acid and the method of its preparation |
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| CN106397119A (en) * | 2016-04-11 | 2017-02-15 | 上海博康精细化工有限公司 | Preparation method for 1,3-adamantane diethanol |
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