JP2015533373A - オスペミフェンの製造方法 - Google Patents
オスペミフェンの製造方法 Download PDFInfo
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- JP2015533373A JP2015533373A JP2015537313A JP2015537313A JP2015533373A JP 2015533373 A JP2015533373 A JP 2015533373A JP 2015537313 A JP2015537313 A JP 2015537313A JP 2015537313 A JP2015537313 A JP 2015537313A JP 2015533373 A JP2015533373 A JP 2015533373A
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- trimethylphenyl
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- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 238000000034 method Methods 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 24
- -1 phenylmagnesium halide Chemical class 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 150000004795 grignard reagents Chemical class 0.000 claims description 9
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 8
- 125000002524 organometallic group Chemical group 0.000 claims description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 238000006894 reductive elimination reaction Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical group [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 claims description 2
- LUMKNAVTFCDUIE-VHXPQNKSSA-N ospemifene Chemical compound C1=CC(OCCO)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 LUMKNAVTFCDUIE-VHXPQNKSSA-N 0.000 abstract description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229960003969 ospemifene Drugs 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 229920000137 polyphosphoric acid Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000007142 ring opening reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 0 *C(OCCOc(cc1)ccc1C(c1ccccc1)=C(CCCl)c1ccccc1)=O Chemical compound *C(OCCOc(cc1)ccc1C(c1ccccc1)=C(CCCl)c1ccccc1)=O 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- XOFORMIUCZSDQQ-UHFFFAOYSA-N 2-phenoxyethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCOC1=CC=CC=C1 XOFORMIUCZSDQQ-UHFFFAOYSA-N 0.000 description 1
- JRAPAWFDOQVLLC-DQRAZIAOSA-N 4-[(z)-4-hydroxy-1,2-diphenylbut-1-enyl]phenol Chemical compound C=1C=CC=CC=1C(/CCO)=C(C=1C=CC(O)=CC=1)/C1=CC=CC=C1 JRAPAWFDOQVLLC-DQRAZIAOSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 229940122880 Estrogen receptor agonist Drugs 0.000 description 1
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-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
- 210000003905 vulva Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
- C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
- C07C69/28—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with dihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/753—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of polycyclic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- 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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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
(a)式(III)
の化合物を、フェニルマグネシウムハロゲン化物と反応させ、式(IV)
の化合物を生成すること、および
(b)式(IV)の化合物を塩酸で処理し、式(V)
の化合物を生成すること、および
(c)式(V)(式中、Rは上述のとおりである)の化合物のエステル結合を切断し、式(I)の化合物を得ること
を含む方法を提供する。
の化合物は、フェニルマグネシウムハロゲン化物と反応し、式(IV)
の化合物を生成する。
の化合物を、2−フェニル酢酸と反応させることにより適切に製造することができる。通常、反応は、ポリリン酸(PPA)などのブレンステッドの酸によって触媒される。したがって、温めたPPAに式(VI)の化合物および2−フェニル酢酸が添加される。約3時間攪拌した後、水が加えられ、混合物はさらに約2時間室温で撹拌される。式(II)の沈殿した化合物は、ろ過、洗浄、そして乾燥され、所望により、ヘキサン/イソプロパノール(1:1)などの適切な溶媒から再結晶される。
2−フェノキシエタノール(50g、0.362mol)を、ジクロロメタン(500ml)に溶解し、溶液を0〜5℃に冷却した。トリエチルアミン(101ml、0.724mol)を冷却した溶液に加え、温度を5℃より低く維持しながら塩化ピバロイル(53.5ml、0.434mol)を加えた。添加後、混合物を5℃で30分間撹拌し、室温で12時間攪拌した。反応を1M HCl溶液(300ml)の添加によりクエンチし、しっかりと攪拌した。相を分離し、有機相を飽和NaHCO3溶液(2×150ml)、水(1×100ml)およびブライン(1×100ml)で洗浄した。乾燥(Na2SO4)およびろ過後、溶媒を蒸発させ、表題の化合物(76.78g、0.345mol、95%)を黄色の油状物として得た。
1H-NMR (400 MHz, DMSO-d6) δ(ppm): 7.31-7.27(2H, m, ArH), 6.96-6.93(3H, m, ArH), 4.34(2H, m, CH2CH2OPiv), 4.19(2H, m, ArOCH2CH2), 1.13(9H, s, 3×Me). 13C-NMR (100 MHz, DMSO-d6) δ(ppm): 177.7, 158.7, 130.1, 121.1, 114.9, 66.1, 62.9, 38.5, 27.6.
ポリリン酸(PPA)(250g)を反応容器に入れ、機械的に攪拌しながら50℃(浴温)に温めた。2−フェニル酢酸(30.6g、0.225mol)をPPAに加え、その後2−フェノキシエチルピバル酸エステル(50g、0.225mol)を加えた。3時間後、TLCおよびHPLCが完全な変換を示し、水(1000ml)を加えた。混合物を室温で2時間攪拌した。沈殿した生成物をろ過し、水(300ml)で洗浄した。真空下で乾燥後、粗生成物(65g)をヘキサン/i−PrOH 1:1で再結晶し、表題の化合物を淡黄色の固体として得た(51.49g、0.151mol、67%)。
1H-NMR (400 MHz, DMSO-d6) δ(ppm): 8.02(2H, d, J=9.2Hz, ArH), 7.32-7.22(5H, m, ArH), 7.07(2H, d, J=8.8Hz, ArH), 4.37(2H, m, CH2CH2OPiv), 4.31(2H, s, ArCH2CO), 4.3(2H, m, ArOCH2CH2), 1.12(9H, s, 3×Me). 13C-NMR (100 MHz, DMSO-d6) δ(ppm): 196.4, 177.7, 162.6, 135.8, 131.2, 129.9, 129.8, 128.7, 126.8, 114.8, 66.5, 62.7, 44.8, 38.6, 27.2.
2−(4−(2−フェニルアセチル)フェノキシ)エチルピバル酸エステル(15g、44.1mmol)を窒素を吹き込んだトルエン(150ml)に溶解し、窒素雰囲気下で10分間、室温で撹拌した。硫酸水素テトラブチルアンモニウム(1.496g、4.41mmol)触媒を撹拌した溶液に加え、その後、50%NaOH溶液(60ml、1137mmol)を加えた。二相系を10分間しっかり撹拌した。1−ブロモ−2−クロロエタン(9.17ml、110mmol)をトルエン(35ml)に溶解し、撹拌反応混合物に滴下した。12時間後、出発原料が消費され、水(100ml)を添加した。相を分離し、水層をトルエン(50ml)で抽出した。合わせたトルエン相を水(100ml)およびブライン(100ml)で洗浄した。乾燥(Na2SO4)およびろ過後、トルエンを真空下で除去した。表題の粗化合物(15.39g、42mmol、95%)を、15%のO−アルキル化副生成物の混じった粘性の茶色の油状物として得た。
1H-NMR (400 MHz, CDCl3) δ(ppm): 7.80(2H, d, J=9.2Hz, ArH), 7.26-7.16(5H, m, ArH), 6.77(2H, d, J=8.8Hz, ArH), 4.37(2H, t, J=4.8Hz, CH2CH2OPiv), 4.15(2H, t, J=5.0Hz, ArOCH2CH2), 1.60(2H, AB-系, J=4.4Hz, CH2CH2), 1.32(2H, AB-系, J=4.4Hz, CH2CH2), 1.17(9H, s, 3×Me). 13C-NMR (100 MHz, CDCl3) δ(ppm): 198.6, 178.9, 162.1, 141.7, 132.3, 130.2, 129.1, 127.9, 126.8, 114.2, 67.0, 62.8, 39.2, 35.0, 27.5, 16.1.
粗2−(4−(1−フェニルシクロプロパンカルボニル)フェノキシ)エチルピバル酸エステル(15.3g、41.8mmol)を、窒素雰囲気下で撹拌しながらテトラヒドロフラン(THF)(200ml)に溶解した。塩化フェニルマグネシウムの1M THF溶液(35.5ml、71mmol)を、溶液に室温で滴下した。添加後、反応を60℃まで温め、この温度で2時間保持した。反応を飽和NH4Cl溶液(300ml)の添加によりクエンチした。5%HCl溶液でpHを4に調整し、THF相を分離した。水相をジクロロメタン(2×75ml)で抽出し、THF相と合わせ、水(100ml)およびブライン(100ml)で洗浄した。乾燥(Na2SO4)およびろ過後、溶媒を蒸発させ、粗シクロプロピルカルビノール中間体(21g)を開環工程に直接送った。粗シクロプロピルカルビノール中間体を、ジクロロメタン(DCM)(150ml)に溶解し、30%HCl溶液(120ml)で処理した。60分後、脱水および開環が完了し、反応混合物を飽和NaHCO3溶液(350)mlに注いだ。相を分離し、DCM相を水(100ml)およびブライン(100ml)で洗浄した。乾燥(Na2SO4)およびろ過後、溶媒を蒸発させた。残渣を沸騰メタノールに溶解し、40℃まで冷却し、結晶化させた。室温で攪拌(12時間)後、沈殿した表題の化合物をろ過し、冷MeOHで洗浄した。表題の化合物を、白色固体として得た(5.4g、11.7mmol、二工程を通じて28%)。
1H-NMR (400 MHz, CDCl3) δ(ppm): 7.39-7.13(6H, m, ArH), 6.79(2H, d, J=8.8Hz, ArH), 6.56(2H, d, J=8.8Hz, ArH), 4.31(2H, t, J=4.4Hz, CH2CH2OPiv), 4.04(2H, t, J=4.8Hz, ArOCH2CH2), 3.41(2H, t, J=7.6Hz, ClCH2CH2), 2.92(2H, t, J=7.6Hz, ClCH2CH2), 1.17(9H, s, 3×Me). 13C-NMR (100 MHz, CDCl3) δ(ppm): 178.5, 156.8, 142.8, 141.6, 140.9, 135.3, 135.2, 131.7, 129.5, 129.4, 128.4, 128.2, 127.0, 126.6, 113.6, 65.7, 62.7, 42.8, 38.7, 38.6, 27.1.
(Z)−2−(4−(4−クロロ−1,2−ジフェニルブト−1−エン−1−イル)フェノキシ)エチルピバル酸エステル(1g、2.16mmol)をTHF(8ml)に溶解し、その後MeOH(1ml)および水(1ml)を添加した。水酸化ナトリウム(0.1g、2.5mmol)を一度に加え、反応を室温で12時間攪拌した。反応完了後、混合物を水(20ml)およびEtOAc(20ml)との間に分配した。有機相を水(20ml)およびブライン(20ml)で洗浄し、乾燥(Na2SO4)し、ろ過し、そして濃縮した。残渣をi−PrOHから結晶化し、オスペミフェン(0.29g、35%)を白色固体として得た。
1H-NMR (400 MHz, CDCl3) δ(ppm): 7.37(2H, t, J=8Hz, ArH), 7.29(3H, t, J=7.2Hz, ArH), 7.20(2H, t, J=7.6Hz, ArH), 7.16-7.13(3H, m, ArH), 6.80(2H, d, J=8.8Hz, ArH), 6.57(2H, d, J=8.8Hz, ArH), 3.94(2H, t, J=4.4Hz, ArOCH2CH2OH), 3.87(2H, m, ArOCH2CH2OH), 3.42(2H, t, J=7.2Hz, ClCH2CH2), 2.92(2H, t, J=7.2Hz, ClCH2CH2), 1.95(1H, t, J=6.4Hz, OH). 13C-NMR (100 MHz, CDCl3) δ(ppm):157.2, 143.2, 142.1, 141.3, 2 x 135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.
(Z)−2−(4−(4−クロロ−1,2−ジフェニルブト−1−エン−1−イル)フェノキシ)エチルピバル酸エステル(3.5g、7.56mmol)をトルエン(35ml)に溶解し、窒素雰囲気下、室温で5分間撹拌した。水素化リチウムアルミニウム溶液(THF中1M)(7.56ml、7.56mmol)を反応に滴下し、混合物を室温で30分間撹拌した。HPLCが完了を示した後、反応を飽和NH4Cl溶液(75ml)の添加によりクエンチした。さらにトルエン(30ml)を加え、相を分離した。有機相を水(50ml)、ブライン(50ml)で洗浄し、乾燥(Na2SO4)し、ろ過し、そして真空下で濃縮した。残渣を90%MeOHから結晶化し、オスペミフェン(1.75g、61%)を白色固体として得た。
Claims (28)
- フェニルマグネシウムハロゲン化物が塩化フェニルマグネシウムである請求項1記載の方法。
- 式(V)の化合物が結晶化により単離される請求項1または2記載の方法。
- 式(V)の化合物が低級アルコールから結晶化される請求項3記載の方法。
- 式(V)の化合物がメタノールまたはエタノールからなる溶媒から結晶化される請求項4記載の方法。
- 工程(c)における式(V)の化合物のエステル結合の切断が、塩基触媒加水分解または還元的切断を用いて行われる請求項1〜5のいずれか1項に記載の方法。
- 還元的切断が、水素化リチウムアルミニウムの存在下で行われる請求項6記載の方法。
- 生成された式(I)の化合物が結晶化により単離される請求項1〜7のいずれか1項に記載の方法。
- 式(I)の化合物が、C1-5アルコールから、またはC1-5アルコールおよび水の混合物から結晶化される請求項8記載の方法。
- Rがt−ブチル、アダマンチルまたは2,4,6−トリメチルフェニルである請求項1〜9のいずれか1項に記載の方法。
- Rがt−ブチルである請求項10記載の方法。
- X1がハロゲンであり、かつX2がハロゲンである請求項12記載の方法。
- X1がBrであり、かつX2がClである請求項13記載の方法。
- Rがt−ブチル、アダマンチルまたは2,4,6−トリメチルフェニルである請求項12〜14のいずれか1項に記載の方法。
- Rがt−ブチルである請求項15記載の方法。
- 反応が、相間移動触媒の存在下で行われる請求項12〜16のいずれか1項に記載の方法。
- 相間移動触媒が硫酸水素テトラブチルアンモニウム(TBAHS)である請求項15記載の方法。
- Rがt−ブチル、アダマンチルまたは2,4,6−トリメチルフェニルである請求項19記載の方法。
- Rがt−ブチルである請求項20記載の方法。
- Rがt−ブチル、アダマンチルまたは2,4,6−トリメチルフェニルである請求項2記載の方法。
- Rがt−ブチルである請求項23記載の方法。
- Rがt−ブチルである請求項25記載の化合物。
- Rがt−ブチルである請求項27記載の化合物。
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US9975832B2 (en) | 2014-12-29 | 2018-05-22 | Olon S.P.A. | Process for the preparation of ospemifene and fispemifene |
US10138190B2 (en) | 2015-01-09 | 2018-11-27 | Glenmark Pharmaceuticals Limited | Process for preparation of ospemifene |
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