TWI660940B - 用於製備苯基二氫化茚光起始劑之製程 - Google Patents
用於製備苯基二氫化茚光起始劑之製程 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 3
- VNAFWALXWOAPCK-UHFFFAOYSA-N 1-phenyl-2,3-dihydro-1h-indene Chemical compound C1CC2=CC=CC=C2C1C1=CC=CC=C1 VNAFWALXWOAPCK-UHFFFAOYSA-N 0.000 title description 2
- 239000000539 dimer Substances 0.000 claims abstract description 35
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims abstract description 28
- -1 butyl fluorenyl Chemical group 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 55
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003377 acid catalyst Substances 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000003456 ion exchange resin Substances 0.000 claims description 3
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
- RZZPMLOMCCHDFQ-UHFFFAOYSA-N C(C(C)C)C1=C(C=2CC3=CC=CC=C3C2C=C1)Cl Chemical group C(C(C)C)C1=C(C=2CC3=CC=CC=C3C2C=C1)Cl RZZPMLOMCCHDFQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- 150000004820 halides Chemical class 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 238000005658 halogenation reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000026030 halogenation Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- NLSDESGMVSPARQ-UHFFFAOYSA-N 2-chloro-2-methyl-1-(4-propan-2-ylphenyl)propan-1-one Chemical compound CC(C)C1=CC=C(C(=O)C(C)(C)Cl)C=C1 NLSDESGMVSPARQ-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- XYLMUPLGERFSHI-UHFFFAOYSA-N alpha-Methylstyrene Chemical compound CC(=C)C1=CC=CC=C1 XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000013638 trimer Substances 0.000 description 2
- 238000005533 tritiation Methods 0.000 description 2
- PVPBBTJXIKFICP-UHFFFAOYSA-N (7-aminophenothiazin-3-ylidene)azanium;chloride Chemical compound [Cl-].C1=CC(=[NH2+])C=C2SC3=CC(N)=CC=C3N=C21 PVPBBTJXIKFICP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XWSSGICWOAGIQT-UHFFFAOYSA-N 2-chloro-1-[4-(2-chloropropan-2-yl)phenyl]-2-methylpropan-1-one Chemical compound ClC(C(=O)C1=CC=C(C=C1)C(C)(C)Cl)(C)C XWSSGICWOAGIQT-UHFFFAOYSA-N 0.000 description 1
- NWLQNWLHBBNMFJ-UHFFFAOYSA-N 2-chloro-1-[4-[6-(2-chloro-2-methylpropanoyl)-1,3,3-trimethyl-2h-inden-1-yl]phenyl]-2-methylpropan-1-one Chemical compound C1=CC(C(=O)C(C)(Cl)C)=CC=C1C1(C)C2=CC(C(=O)C(C)(C)Cl)=CC=C2C(C)(C)C1 NWLQNWLHBBNMFJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001908 cumenes Chemical class 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
- B01J31/08—Ion-exchange resins
- B01J31/10—Ion-exchange resins sulfonated
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
本發明係關於製造5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)的製程，製程包含用異丁醯基鹵化物於4-位置醯化異丙苯，然後芣基鹵化及二聚合(環化)所得產物。
Description
本發明係關於製造固體與純形態之苯基二氫茚光起始劑(5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚，二聚物異構物5)的位向異構物的製程。
相較於使用單體光起始劑，光聚合使用寡聚光起始劑有數個優點，例如較低光起始劑遷移性及光分解衍生較少揮發性化合物。該等特性就光起始劑的工業用途而言很重要，因為此可降低污染成品的風險。
在已知寡聚光起始劑中，此領域最賞識式A之α-甲基苯乙烯寡聚物的α-羥羰基衍生物，其中n係等於或大於0的數值。
該等光起始劑描述於美國專利案第4,987,159號，且主要由二聚物和三聚物異構物的混合物構成。在室溫下，二聚物與三聚物異構物混合物係高黏性產物，此產物通常需預熱以便於處理。
因而開發出粉末形態的α-甲基苯乙烯寡聚物的α-羥羰基衍生物固體混合物，現為光聚合壓克力系統的常用光起始劑。
上述光起始劑組成和合成描述於EP 1389177。
EP 1389177的α-甲基苯乙烯寡聚物的α-羥羰基衍生物固體混合物含有約90%-98%的兩種二聚物異構物：5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)和6-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物6)。
二聚物異構物5係下式V之化合物。
二聚物異構物6係下式VI之化合物。
EP 1389177的製程藉由使α-甲基苯乙烯寡聚物的α-羥羰基衍生物高黏性混合物控制結晶而提供該等固體混合物，合成則描述於如美國專利案第4,987,159號。
兩種二聚物異構物均可有效做為光起始劑，但在光聚合中，二聚物異構物5比二聚物異構物6更具反應性，此亦如描述於EP 1389177。
EP 1389177的控制結晶的優點在於提供富含二聚物異構物5的α-甲基苯乙烯寡聚物的α-羥羰基衍生物固體混合物。
製備二聚物異構物V與VI之結晶混合物的製程亦描述於EP 1620382。該製程使用1,1,3-三甲基-1-苯基二氫茚做為起始產物，且適於透過分離中間物而製備個別二聚物異構物V。
EP 1389177的製程和EP 1620382的製程皆藉由醯化α-甲基苯乙烯寡聚物或二聚物來製備α-甲基苯乙烯二聚物的α-羥羰基衍生物。由於醯化將在5-和6-位置進行，故一直會得到5-與6-二聚物混合物，製備富含或隔離形態的二聚物異構物5
暗指必須排出或分離使用較低反應性的二聚物異構物6。
因此，非常期望設計簡短、有效又無異構物6的二聚物異構物5合成方式，且亦得省去昂貴、不便的純化步驟，並提供固體與純形態的產物。
現已發現此目的可由包含用異丁醯基鹵化物於4-位置醯化異丙苯，然後芐基鹵化及二聚合(環化)所得產物的製程達成。
因此，本發明的主要目的為提供製備5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)的製程，包含下列步驟：
i. 依據下圖，用式Ia之化合物醯化異丙苯，其中X0係Cl或Br，X1係Cl或Br，以得式IIa之化合物，及鹵化式IIa之化合物，以得式IIIa之化合物，其中X1和X2個別為Cl或Br；或者用式Ib之化合物醯化異丙苯，其中X0係Cl或Br，以得式IIb之化合物，及鹵化式IIb之化合物，以得式IIIb之化合物，其中X1係Cl或Br；
ii. 依據下圖，用酸催化劑環化式IIIa或IIIb之化合物，以得式IV之化合物，其中X1係Cl或Br；
iii. 使式IV之化合物水解，以得式V之化合物(二聚物異構物5)。
用式Ia或Ib之化合物醯化異丙苯係夫里得-夸夫特(Friedel Craft)醯化反應。特定基材(異丙苯)致使醯化反應極具位置選擇性，並且提供幾乎完全對位取代的異丙苯衍生物(H-NMR測定選擇性為約98%)。
故式IIIa和IIIb之化合物很容易以幾個極高選擇性的步驟由異丙苯獲得。
式Ia和Ib之化合物可為市售醯基鹵化物。式Ia之化合物較佳為α-氯異丁醯基氯化物和α-溴異丁醯基溴化物；式Ib之化合物較佳為異丁醯基氯化物。
在步驟i中，異丙苯和醯基鹵化物較佳係在無溶劑下或溶於有機溶劑中混合及反應。在醯化條件下呈惰性的任何溶劑皆可使用。可用溶劑實例為二氯甲烷、氯苯、氯化乙烯、1,2-二氯苯、硝基甲烷、四氯乙烷；較佳溶劑為二氯甲烷和氯苯。
在步驟i中，每莫耳異丙苯使用1.50至1.10莫耳的醯基鹵化物，較佳為1.10至1.05。
步驟i的醯化反應通常係按每莫耳異丙苯加入1.5至0.1莫耳的路易士酸進行，例如AlCl3、FeCl3、TiCl4、BF3或SnCl4，較佳為
AlCl3，且較佳係在-20℃至+20℃下，更佳為-10℃至10℃。反應後處理(work-up)如此領域習知為用水使反應混合物水解及分離可能溶於溶劑的所得產物。
取得醯化反應的定量產率。
鹵化式IIa之化合物係芣基鹵化反應，此可依US 2007/0161814所述進行：利用太陽光燈或紫外光(UV)燈照射、或在存有催化量的過氧化二苯甲醯或2,2'-偶氮異丁醯腈(AIBN)下，使式IIa之化合物與N-溴琥珀醯亞胺反應，或在自由基條件(照射或存有催化量的過氧化二苯甲醯或AIBN)下，與硫醯氯、氯或溴或與叔丁基次氯酸鹽反應。鹵化可在和步驟i用於醯化一樣的鹵化溶劑(若有)或在另一相容溶劑中進行，例如二氯甲烷、氯苯、1,2-二氯苯或其他鹵化溶劑。
或者，當步驟i係用式Ib之化合物進行醯化時，可在一個步驟中，使用氯、溴或硫醯氯，同時於芣基和α-酮位置(烯醇鹵化)鹵化所得式IIb之化合物，此如EP 161463的階段(C)所述。
在步驟ii中，用酸催化劑環化(二聚合)式IIIa或IIIb之化合物，以得式IV之化合物，其中X1係Cl或Br。
酸催化劑可為無機或有機強酸，例如磺化膦酸或路易士酸。較佳酸催化劑為酸性黏土、具磺
基之酸性離子交換樹脂、C6-C18-芳基磺酸和三氟甲磺酸。更佳地，酸催化劑係具磺基之酸性離子交換樹脂或無機酸。反應可在40℃至140℃下，在溶劑中或無溶劑時進行。
在步驟iii中，使式IV之化合物水解。式IV之化合物可與鹼金屬醇氧化物反應，較佳為在甲醇中與甲醇鈉反應，及用酸性水溶液水解，以得式V之化合物(二聚物5)，此例如描述於EP 0 161463(階段(D)與階段(E))和US 4,987,159(實例4)；或者，可用鹼金屬氫氧化物使式IV之化合物直接水解，例如用NaOH 30重量%備於甲醇(此描述於WO 2004/099111(實例1.3))或用NaOH 30重量%備於水，以得式V之化合物。
藉由從甲苯、異丙醇、乙酸乙酯或其他溶劑結晶，可獲得固體與純形態的式V化合物，此例如描述於EP 1389177。
合成2-氯-1-(4-異丙基苯基)-2-甲基丙-1-酮(式IIa之化合物)
在氮中、5℃下攪拌備於二氯甲烷(250克)的異丙苯(20.0克、0.165莫耳)與α-氯異丁醯基氯化物(24.7克、0.173莫耳)溶液。在相同溫度下，在90分鐘內將氯化鋁(24.2克、0.182莫
耳)分批加至溶液。再攪拌1小時後，邊攪拌，邊把溶液倒入冰水中。用水洗滌有機相，在真空中蒸餾掉二氯甲烷，以得38.0克的澄清油。產率：定量。
H1NMR(CDCl3，δ ppm)：1.26(d,6H)、1.85(s,6H)、2.95(m,1H)、7.29(d,2H)、8.13(d,2H)。
合成2-氯-1-(4-(2-氯丙-2-基)苯基)-2-甲基丙-1-酮(式IIIa之化合物)
使2-氯-1-(4-異丙基苯基)-2-甲基丙-1-酮(10.0克、0.045莫耳)溶於氯苯(73克)，在室溫下攪拌，並利用氮去氧。接著在-10℃下冷卻溶液，及一次加入叔丁基次氯酸鹽(7.24克、0.067莫耳，依「Organic Syntheses,Coll.Vol.5,184(1973)」所述製備)，以得黃色溶液。用300瓦的Osram Ultra Vitalux燈照射攪拌溶液，直到溶液褪色且溫度上升至20℃。冷卻至室溫後，在真空中蒸餾掉溶劑，以得11克的澄清油。產率：定量。
H1NMR(CDCl3，δ ppm)：1.86(s,6H)、1.95(s,6H)、7.15(d,2H)、8.13(d,2H)。
合成5-(2-氯-2-甲基-1-側氧-丙-1-基)-3-(4-(2-氯-2-甲基-1-側氧-丙-1-基)苯基)-2,3-二氫-1,1,3-三甲基-1H-茚(式IV之化合物)
在存有1.50克催化劑Amberlyst 15下，以135℃加熱2-氯-1-(4-)2-氯丙-2-基)苯基)-2-甲基丙-1-酮(8.30克、0.032莫耳)並攪拌。經過5小時後，反應完成(TLC SiO2、甲苯)。冷卻後，使固體物質溶於二氯甲烷及濾掉催化劑。在真空中使溶劑蒸發後可得5.89克(產率為82.5%)的油，油靜置後將凝固。在甲苯中使樣品結晶而得白色固體，熔點為139℃-140℃。產率：定量。
H1NMR(CDCl3，δ ppm)：1.03(s,3H)、1.38(s,3H)、1.73(s,3H)、1.86(m,12H)、2.26(d,1H)、2.47(d,1H)、7.25(m,3H)、7.92(s,1H)、8.07(d,2H)、8.18(d,1H)。
合成5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5，式V之化合物)
使5-(2-氯-2-甲基-1-側氧-丙-1-基)-3-(4-(2-氯-2-甲基-1-側氧-丙-1-基)苯基)-2,3-二氫-1,1,3-三甲基-1H-茚(5.2克、
0.011莫耳)溶於二氯甲烷(30克)，及加入30%的NaOH水溶液(7.30克、0.055莫耳)。在存有四丁基溴化銨(0.10克)下，迴流加熱混合物。經過8小時後，反應完成(TLC SiO2、甲苯：乙酸乙酯=8：2)。用水洗滌有機相並用硫酸鈉乾燥，使溶劑蒸發後可得4.5克、如同油般的化合物I，油靜置後將凝固。在甲苯中使樣品結晶而得白色粉末，熔點為117℃-118℃。產率：幾乎定量。
H1NMR(CDCl3，δ ppm)：1.04(s,3H)、1.37(s,3H)、1.61(m,12H)、1.73(s,3H)、2.25(d,1H)、2.46(d,1H)、3.90-4.10(bs,2OH)、7.25(m,3H)、7.80(s,1H)、7.92(d,2H)、8.00(d,1H)。
Claims (10)
- 一種製備5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)的製程，該製程包含下列步驟：i.依據下圖，用一式Ia之化合物醯化異丙苯，其中X0係Cl或Br，X1係Cl或Br，以得一式IIa之化合物，並鹵化該式IIa之化合物，以得一式IIIa之化合物，其中X1和X2個別為Cl或Br；或者用一式Ib之化合物醯化異丙苯，其中X0係Cl或Br，以得一式IIb之化合物，並鹵化該式IIb之化合物，以得一式IIIb之化合物，其中X1係Cl或Br；ii.依據下圖，用一酸催化劑環化該式IIIa或IIIb之化合物，以得一式IV之化合物，其中X1係Cl或Br；iii.使該式IV之化合物水解，以得一式V之化合物(二聚物異構物5)。
- 如請求項1所述之製備二聚物異構物5的製程，其中該式Ia之化合物係α-氯異丁醯基氯化物或α-溴異丁醯基溴化物。
- 如請求項1所述之製備二聚物異構物5的製程，其中該式Ib之化合物係異丁醯基氯化物。
- 如請求項1所述之製備二聚物異構物5的製程，其中在步驟i中，就每莫耳異丙苯使用1.50至1.10莫耳的該式Ia或Ib之化合物和1.5至0.1莫耳的一路易士酸。
- 如請求項1所述之製備二聚物異構物5的製程，其中在步驟ii中，該酸催化劑係具磺基之一酸性離子交換樹脂或係一無機酸。
- 如請求項1所述之製備二聚物異構物5的製程，其中在步驟iii中，使該式IV之化合物與一鹼金屬醇氧化物反應水解，然後用一酸性水溶液水解。
- 如請求項6所述之製備二聚物異構物5的製程，其中該鹼金屬醇氧化物係甲醇鈉。
- 如請求項1所述之製備二聚物異構物5的製程，其中在步驟iii中，使該式IV之化合物與一鹼金屬氫氧化物反應水解。
- 如請求項8所述之製備二聚物異構物5的製程，其中該鹼金屬氫氧化物係於甲醇或於水中之30重量%的NaOH。
- 如請求項1至9中任一項所述之製備二聚物異構物5的製程，其中在完成步驟iii後，藉由結晶獲得固體且無異構物6之該式V之化合物。
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