JP2005508964A - 組織−選択性エストロゲンの生成のための価値ある中間生成物としての酸素−置換されたベンゾシクロへプテンの合成 - Google Patents
組織−選択性エストロゲンの生成のための価値ある中間生成物としての酸素−置換されたベンゾシクロへプテンの合成 Download PDFInfo
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- JP2005508964A JP2005508964A JP2003536202A JP2003536202A JP2005508964A JP 2005508964 A JP2005508964 A JP 2005508964A JP 2003536202 A JP2003536202 A JP 2003536202A JP 2003536202 A JP2003536202 A JP 2003536202A JP 2005508964 A JP2005508964 A JP 2005508964A
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- 239000013067 intermediate product Substances 0.000 title claims abstract description 6
- -1 oxygen-substituted benzocycloheptenes Chemical class 0.000 title claims description 7
- 229940011871 estrogen Drugs 0.000 title claims description 4
- 239000000262 estrogen Substances 0.000 title claims description 4
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- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
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- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
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- 239000002253 acid Substances 0.000 claims description 6
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- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
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- 229910052763 palladium Inorganic materials 0.000 claims description 4
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- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- XHYAQFCRAQUBTD-HWKANZROSA-N (e)-3-(3-methoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(\C=C\C=O)=C1 XHYAQFCRAQUBTD-HWKANZROSA-N 0.000 claims description 2
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- 238000011097 chromatography purification Methods 0.000 abstract description 4
- HEOQXHNKRXRCTO-UHFFFAOYSA-N 6,7,8,9-tetrahydro-5h-benzo[7]annulene Chemical compound C1CCCCC2=CC=CC=C21 HEOQXHNKRXRCTO-UHFFFAOYSA-N 0.000 abstract description 2
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 27
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
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- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
- 0 CCc(cc1)ccc1C(c1ccc(*)cc1CCC1)=C1c1ccc(*)cc1 Chemical compound CCc(cc1)ccc1C(c1ccc(*)cc1CCC1)=C1c1ccc(*)cc1 0.000 description 3
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PHHNNDKXQVKJEP-UHFFFAOYSA-N 1-bromo-5-chloropentane Chemical compound ClCCCCCBr PHHNNDKXQVKJEP-UHFFFAOYSA-N 0.000 description 2
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- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 2
- 206010067572 Oestrogenic effect Diseases 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
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- VZAWCLCJGSBATP-UHFFFAOYSA-N 1-cycloundecyl-1,2-diazacycloundecane Chemical compound C1CCCCCCCCCC1N1NCCCCCCCCC1 VZAWCLCJGSBATP-UHFFFAOYSA-N 0.000 description 1
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- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- MCSAZHIQYXNCOP-UHFFFAOYSA-N 5-(3-methoxyphenyl)-2-phenylpentanoic acid Chemical compound COC1=CC=CC(CCCC(C(O)=O)C=2C=CC=CC=2)=C1 MCSAZHIQYXNCOP-UHFFFAOYSA-N 0.000 description 1
- SKXOKTTZRSZDGO-UHFFFAOYSA-N 5-[4-(5-chloropentoxy)phenyl]-2-methoxy-6-phenyl-8,9-dihydro-7h-benzo[7]annulene Chemical compound C=1C(OC)=CC=C(C=2C=3C=CC(OCCCCCCl)=CC=3)C=1CCCC=2C1=CC=CC=C1 SKXOKTTZRSZDGO-UHFFFAOYSA-N 0.000 description 1
- CHTQRHGGWOTXHR-UHFFFAOYSA-N 5-[4-(5-chloropentoxy)phenyl]-6-phenyl-8,9-dihydro-7h-benzo[7]annulen-2-ol Chemical compound C=1C(O)=CC=C(C=2C=3C=CC(OCCCCCCl)=CC=3)C=1CCCC=2C1=CC=CC=C1 CHTQRHGGWOTXHR-UHFFFAOYSA-N 0.000 description 1
- HNOYFMBCFNHLIE-UHFFFAOYSA-N 5-[4-[5-(4,4,5,5,5-pentafluoropentylsulfanyl)pentoxy]phenyl]-6-phenyl-8,9-dihydro-7h-benzo[7]annulen-2-ol Chemical compound C=1C(O)=CC=C(C=2C=3C=CC(OCCCCCSCCCC(F)(F)C(F)(F)F)=CC=3)C=1CCCC=2C1=CC=CC=C1 HNOYFMBCFNHLIE-UHFFFAOYSA-N 0.000 description 1
- YDMKKJVVAGMKRL-UHFFFAOYSA-N 5-[4-[5-(4,4,5,5,5-pentafluoropentylsulfinyl)pentoxy]phenyl]-6-phenyl-8,9-dihydro-7h-benzo[7]annulen-2-ol Chemical compound C=1C(O)=CC=C(C=2C=3C=CC(OCCCCCS(=O)CCCC(F)(F)C(F)(F)F)=CC=3)C=1CCCC=2C1=CC=CC=C1 YDMKKJVVAGMKRL-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
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- 206010028980 Neoplasm Diseases 0.000 description 1
- MGNLRTXJTWHBFV-UHFFFAOYSA-N OB(O)O.Br.Br.Br Chemical compound OB(O)O.Br.Br.Br MGNLRTXJTWHBFV-UHFFFAOYSA-N 0.000 description 1
- FTDSHODXIQZEJK-PFKGSKDKSA-N OC(/C(/c1ccccc1)=C\C=C\c1cc(O)ccc1)=O Chemical compound OC(/C(/c1ccccc1)=C\C=C\c1cc(O)ccc1)=O FTDSHODXIQZEJK-PFKGSKDKSA-N 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001491 aromatic compounds Chemical group 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- OVYCPCXSJXTCLB-UHFFFAOYSA-N o-(4,4,5,5,5-pentafluoropentyl) ethanethioate Chemical compound CC(=S)OCCCC(F)(F)C(F)(F)F OVYCPCXSJXTCLB-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 150000008379 phenol ethers Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- OSCBARYHPZZEIS-UHFFFAOYSA-N phenoxyboronic acid Chemical class OB(O)OC1=CC=CC=C1 OSCBARYHPZZEIS-UHFFFAOYSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 238000004904 shortening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
【化1】
Description
一般式Aの化合物(WO00/03979号)は、強い抗エストロゲン作用を有する化合物を提供する。この場合、それらは、選択性エストロゲンであり、その作用は組織−選択性態様で存在する。エストロゲン作用は特に、骨に対して存在する。この種類の化合物の利点は、エストロゲン作用又はわずかなエストロゲン作用でさえ子宮及び肝臓に生じないことである。
そのような作用のプロフィールを有する化合物は、選択性エストロゲン受容体モジュレーター(SERM)として示される。この種類の化合物の最も著名な代表物は、閉経後オステオポローシスの予防及び処理のための薬剤として可能であるラロキシフェンである。
一般的に、それらは大用量化合物であるので、多量の活性成分の供給が必要である。従って、この種類の物質の単純且つ経済的な合成についての所望が特に、明白である。
本発明の目的は、式Cの化合物(WO00/03979号における例9)のより効果的な生成方法を入手することである。
標的化合物Cを形成するための反応は、WO00/03979号(例8及び9を参照のこと)において、下記のように記載される:
従って、産業規模の生成は、WO00/03979号に開示される一般式Aの化合物、及び特に例9(本明細書において、C)の化合物の組織−選択性エストロゲンの生成のためのより短く且つより効果的な合成順序の開発を必要とする。
単純化された実施(いくつかのワン−ポット工程)に基づけば、わずか8の中間段階が、Cの生成において分離される。
下記表は、新規工程及び従来技術の工程の比較を示す。
さらに、本発明の方法は、使用される本発明の一般式Iの中間段階により、R2により置換される追加の芳香族化合物の導入を可能にする:
Xは、Cl又はBrを表し、
Arは、任意には3個までの置換基により置換され得る、芳香族又は複素芳香族基をあらわす。
Xは、Cl又はBrを表し、
Arは、任意には3個までの置換基により置換され得る、芳香族又は複素芳香族基をあらわす]
により表される化合物の調製により達成される。
一般式Iのそれらの中間段階の生成後、反応は、WO00/03979号に記載されるように、一般式Aの最終生成物を形成するために続けられる得る。
で表される化合物のメチルエーテルの、三臭化硼素及び2,6−ジメチルピリジンから成る試薬(1:1〜1:1.5の比での)による選択的分解により得られる。使用される試薬の量は、1〜6当量(三臭化硼酸及び分解される芳香族メチルエーテルに対して)である。
反応は、非プロトン性溶媒、例えばジクロロメタン、クロロホルム、1,2−ジクロロメタン、好ましくはジクロロメタンにおいて、−30℃〜50℃、好ましくは10〜30℃の温度で行われる。
芳香族メチルエーテルの分解のためへのBBr3の基本的な使用は、当業者に知られている(Synthetic Communications, 9(5), 407-410 (1979))。ルチダイン(lutidine)の添加を伴わないで、分解は、任意の態様で行われる(すべての芳香族エーテルは分解される)。2,6−ルチダインとの組合せのみが、驚くべき選択性を生む。
Rは、過弗素化された直鎖のC1−C8アルキル基、好ましくはCF3, C4F9, C8F17を表す]
で表される化合物から、一般式IV:
で表されるフェニル硼酸との反応により、当業者に知られているパラジウム触媒されたSuzukiカップリングの方法(J. Org. Chem. 1999, 64,6797-6803/Chem. Rev. 1995,95, 2457-2483/Pure Appl. Chem. 1991,63, 419-422/Synlett 1990,221-223/JOC 1993,58, 2201-2208)に従って生成される。
このためには、市販のPd触媒、例えばPd(PPh3)4又はPd(Cl2)(PPh3)2が使用され得る(追加の触媒については、例えばChemicals for Research, Metals, Inorganics and Organometallics in STREM-Katalog No. 18, 1999-2001を参照のこと)。
で表されるケトンから、当業者に知られているエノールトリフレートの生成方法(J. Amer. Chem. Soc. ; EN ; 96 ; 1974 ; 1100-1110/Chem. Ber. ; GE ; 110 ; 1977 ; 199-207/Tetrahedron Lett. ; EN ; 23 ; 1 ; 1982 ; 117-120/Synthesis ; EN ; 1 ; 1981 ; 29-30/Tetrahedron Lett. ; EN ; 40 ; 29 ; 1999 ; 5337-5340)に従って、下記一般式VI:
R−SO2Nu (VI)
[式中、Rは、一般式III に示される意味を有し、そして
Nuは、脱離基、例えばF, Cl, I又はR−SO3を表す]
で表される試薬との反応により得られる。0℃でのTHF中、ノナフルオロブチルスルホニルフルオリドとDBUとの組合せが特に好都合であることがわかっている。このようにして得られるノナフレートは、驚くべきことには、安定性があり、そして所望には、固体形で単離され得る。しかしながら、一般的には、粗生成物溶液はさらに反応せしめられる。一般式VIの化合物は市販されている(Aldrich, Fluorochem, etc.)。
Halは、ハロゲン原子、例えばCl, Br, Iを表す]
で表される化合物から、当業者に知られているハロ−芳香族化合物からのフェニル硼酸の生成方法(Houben Weyl,"Methoden der organi- schen Chemie, Bd 13/3a, S. 637 ff. (1982), Georg Thieme Verlag Stuttgart, New York)に従って生成され得る。
ハロゲン金属交換のためにn−ブチルリチウムを使用することが好都合であることがわかっている。次に、リチウム化合物がB(OMe)3と反応せしめられ、そして所望するフェニル硼酸誘導体を形成するために酸により加水分解される。
しかしながら、特に、技術的実行及び拡大においては、それは、一般式Vの化合物が、下記一般式VIII:
で表される化合物から、当業者に知られているフリーデル・クラフツの閉環工程に従って行われ得る場合、非常に好都合であることがわかっている(Chem. Rev. 70, 553 (1970))。
80〜120℃の範囲の温度でのポリリン酸の使用が、特に好ましいものとして言及され得る。前記ポリリン酸は、購入され得るか、又は新しく調製され得る。
で表される化合物との続くKnoevenagel反応(Organic Reactions, Vol. 15 (1967), pp. 204 ff.)において、単離を伴わないで反応せしめられるシングル−ポット反応において得られる。
Knoevenagel反応に関しては、好ましくは無水酢酸及びトリエチルアミンが塩基として使用される。反応温度は、60℃〜還流温度である。
好ましい基Lとして、下記例が言及され得る:
-C2H4-,-C3H6-, CH2-CH (CH3)-CH2,-C4H8-,-C5H10-,-C6H12-,-C7H14-, -C8H16-。
−C4H10基が特に好ましい。
塩素原子は好ましくは、Xを表す。
本発明の次の例により説明される。
例1a. (2Z, 4E)−5−(3−メトキシフェニル)−2−フェニルペンタジエン−2,4−ジエノン酸
20%水酸化カリウム水溶液310mlを、水3750ml中、750g(5.5モル)の3−メトキシベンズアルデヒドに添加する。次に、30分間にわたって水450mlに溶解されたアセトアルデヒド160mlを滴下し、内部温度が30℃を超えないようにする。次に、この工程を7度、反復する(最初に、20%水性KOH310ml、次にアセトアルデヒド160ml/水450ml/30分)。
748.80g(5.5モル)のフェニル酢酸、1000mlの無水酢酸及び1470mlのトリエチルアミンを、前記残渣(オレンジ色の油状物)に添加し、そして100℃まで、4時間、加熱する。
収量:1094g(71%の理論値)の淡黄色固形物。
1000g(3.567モル)の例1aの標記化合物を、BLのテトラヒドロフランに溶解し、そして75gのパラジウム触媒(10%Pd/C)を添加する。それを室温で水素化する(2バール)。
触媒を濾過し、それを500mlのテトラヒドロフランにより再洗浄し、そしてその溶液を真空下で乾燥状態に蒸発する。
収量:1015g(100%の理論値)の無色の粘性油状物。
5.6kgの115%ポリリン酸を、560g(1.97モル)の例1bの標記化合物に添加し、そしてそれを95℃に3時間、加熱する。
それを50℃に冷却し、そしてまだ暖かいその溶液を、9Lの氷水中に注ぐ。次に、5000mlメチル−tert−ブチルエーテルを添加し、そして10分間、強く攪拌する。有機相を分離し、そして水相を、1500mlのメチル−tert−ブチルエーテルにより再び洗浄する。
組合された有機相を、400mlの水により、次に、1200mlの5%水酸化ナトリウム水溶液により1度洗浄する。有機相を分離し、そして280gの活性炭と共に混合する。それを2時間、還流する。活性炭を濾過し、少々のメチル−tert−ブチルエーテルにより再洗浄し、そして濾液を真空下で乾燥状態に蒸発する。
収量:456.5g(87%の理論値)の無色の油状物、これは静置される場合、結晶化する。
1000g(5.78モル)の4−ブロモフェノール、1125.7g(6.069モル)の1−ブロモ−5−クロロペンタン及び1118.3g(8.092モル)の炭酸カリウムを、4000mlのジメチルホルムアミドに添加し、そして60℃で5時間、攪拌する。
それを20℃に冷却し、そして3500mlのトリエンを添加する。沈殿された塩を濾過する。塩を、それぞれ3500mlのトルエンにより3度、再洗浄する。
DMF/トルエン濾液を、4000mlの水と共に混合し、そして5分間、吸収沈殿せしめる。トルエン相を分離し、そして水性相を、3000mlのトルエンにより1度、再洗浄する。
残渣を、9Lのテトラヒドロフランに溶解し、そして−65℃(内部温度)に冷却する。次に、2860mlのn−ブチルリチウム溶液(ヘキサン中、1.6モル)をゆっくり滴下し、温度を−60℃を越えないようにする。それを−65℃でさらに30分間、攪拌する。
次に、1291gの硼酸トリメチルエステルを滴下、そして−65℃でさらに2時間、攪拌する。次に、それを−20℃に加熱する。
有機相を組合し、そして1Lの2Nの水酸化ナトリウム溶液により吸収沈殿せしめる(30分)。水相を分離し(生成物)、そして300mlのメチル−tert−ブチルエーテルにより2度、洗浄する。水相を、6Nの塩酸を添加することによってpHを1に設定し、次に6000mlのメチル−tert−ブチルエーテルを添加し、そしてそれを室温で2時間、攪拌する。
収量:1219.5g(87%の理論値)のばら色の固形物。
81.67g (306.64mモル)の例1cの標準化合物を、400mlのテトラヒドロフラン/メチル−tert−ブチルエーテルに溶解し、そしてその溶液を3℃に冷却する。56.02gのジアザビシクロウンデカンDBU(367.97mモル)を添加し、それにより、温度を3℃で維持する。それを、40mlのTHFによりすすぐ。次に、111.46gのペルフルオロブタン−1−スルホン酸フルオリド(367.97mモル)をそれに添加し(3℃で)、40.96mlのメチル−tert−ブチルエーテルによりすすぎ、それにより、温度は、添加の間、8℃を越えないようにすべきである。次に、それを3℃で12時間、攪拌し、そしてそれを5分間、攪拌する。有機相を分離し、そして約500mlの体積まで、真空下での蒸発により濃縮する。次にこのようにして得られる粗ノナフレート溶液を、次の段階に使用する。
収量:112.4g(82%の理論値)の無色の結晶性固形物。
127.51g(508.93mモル)の三臭硼素を、室温で650mlのジクロロメタンに溶解する。320mlのジクロロメタン中、57.26g(534.37mモル)の2,6−ジメチルピリジンから成る溶液を、0℃でゆっくり添加する(温度は0℃で維持されることが好ましい)。それを0℃に冷却する。それを20℃に加熱し、そして次に、65.00g (145.4mモル)の例1cの標記化合物(300mlのジクロロメタンに溶解される)から成る溶液を滴下し、そしてこの場合、内部温度は20℃で超えるべきではない。それを20℃でさらに4時間、攪拌する。溶液を0℃に冷却し、そして10mlの水及び65mlのテトラヒドロフランから成る混合物を、激しく攪拌しながら、注意して滴下する。
収量:51.6g(82%の理論値)の無色の結晶性粉末。
100g(230.9mモル)の例1fの標記化合物及び132.1g(881.1mモル)のヨウ化ナトリウムを、1000mlのメチルエチルケトン(MEK)において16時間、還流する。次に、約650mlの溶媒を減圧下で蒸留し、そしてそれを、1500mlの水と共に混合する。それを室温で15分間、攪拌し、沈積した沈殿物を濾過し、そしてそれを、240mlの例エタノール/160mlの水から成る混合液により洗浄する。まだ幾分湿った沈殿物を、1200mlのテトラヒドロプランに溶解する。通常圧力で、400mlのテトラヒドロフランを蒸留し、そして400mlのメタノールを添加する。
2種の溶液を組合した後、それを室温で1時間以上、攪拌する。
収量:124.1g(91%の理論値)の無色の細やかな結晶性粉末。
100g(169.3mモル)の例1gの標的化合物を、800mlのアセトン/500mlのメタノールに溶解する。次に、175mlの水を注意して添加する。次に、36.20 (169.3 m モル)の過ヨウ化ナトリウムを添加して、そしてそれを室温で16時間、攪拌する。
収量:99.6g(97%の理論値)の無色の結晶性粉末。
下記においては、他の例の収率及び元素分析が示される。それらは、例1下に記載される方法に類似して生成され得る。
Claims (26)
- 下記一般式II:
Xは、Cl又はBrを表し、
Arは、任意には3個までの置換基により置換され得る、芳香族又は複素芳香族基をあらわす]
で表される化合物の生成方法であって、下記一般式III :
Rは、過弗素化された直鎖のC1−C8アルキル基、好ましくはCF3, C4F9, C8F17を表す]
で表される化合物を、下記一般式IV:
Xは、Cl又はBrを表す]
で表される化合物と、パラジウム触媒(Suzukiカップリング)下で反応せしめることを特徴とする方法。 - 下記一般式III :
Rは、過弗素化された直鎖のC1−C8アルキル基、好ましくはCF3, C4F9, C8F17を表す]
で表されている化合物の生成方法であって、下記一般式V:
で表される化合物を、下記一般式VI:
R−SO2Nu (VI)
[式中、Rは、過弗素化された直鎖のC1−C8アルキル基、好ましくはCF3, C4F9, C8F17を表し、
Nuは、脱離基、例えばF, Cl, I又はR−RO3を表す]
で表される化合物と、非プロトン性溶媒中、有機又は無機塩基の使用を伴って、反応せしめることを特徴とする方法。 - Arが、フェニル基、ピリジル基又はチオフェン基を表す請求項7記載の方法。
- Arが、フェニル基、ピリジル基又はチオフェン基を表す請求項13記載の化合物。
- 下記一般式A:
で表される化合物の生成方法であって、
請求項6に従って、一般式IXの化合物を生成せしめ、
後者を請求項5に従って水素化し、そして一般式VIIIの化合物を得、
後者を請求項4に従って、ポリリン酸により環化し、そして一般式Vの化合物を得、
後者を請求項3に従って、一般式VIの化合物と反応せしめ、そして一般式III の化合物を得、
後者を請求項2に従って、一般式IVの化合物と反応せしめ、そして一般式IIの化合物を得、
請求項1に従って、一般式IIの化合物におけるメチルエーテルを分解し、そして一般式I又は一般式XIの化合物を得、そして次に、問題の一般式I又は一般式XIの化合物を、一般式Aの化合物(WO00/03979号における式Iに対応する)を形成するために、WO00/03979号に記載される方法に類似して、さらに処理することを特徴する方法。 - 一般式Aの組織−選択性エストロゲンの生成のための中間生成物としての請求項9〜14のいずれか1項記載の化合物の使用。
- 使用されるパラジウム−触媒複合体が、その複合体にPd(O)又はPd(II)のいずれかを含む請求項2記載の方法。
- 芳香族メチルエーテルの適度な及び選択的分解のためへの三臭化硼素及び2,6−ジメチルピリジンから成る試薬の使用。
- 芳香族メチルエーテルの適度な及び選択的分解、それによる出発化合物に存在する高級芳香族エーテルの獲得のためへの三臭化硼素及び2,6−ジメチルピリジンの使用。
- 三臭化硼素及び2,6−ジメチルピリジンからなる試薬。
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DE10151095A DE10151095A1 (de) | 2001-10-12 | 2001-10-12 | Synthese von Sauerstoff-substituierten Benzocycloheptenen als wertvolle Zwischenprodukte für die Herstellung gewebeselektiver Estrogene |
US33068101P | 2001-10-29 | 2001-10-29 | |
PCT/EP2002/011485 WO2003033461A1 (de) | 2001-10-12 | 2002-10-14 | Synthese von sauerstoff-substituierten benzocycloheptenen als wertvolle zwischenprodukte für die herstellung gewebeselektiver estrogene |
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EP2048126A1 (de) * | 2007-10-11 | 2009-04-15 | Bayer Schering Pharma AG | Benzocycloheptanderivate als selektiv wirksame Estrogene |
WO2011092127A1 (en) | 2010-01-26 | 2011-08-04 | Bayer Schering Pharma Aktiengesellschaft | 14,17-bridged estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring |
US8684695B2 (en) | 2011-01-04 | 2014-04-01 | General Electric Company | Damper coverplate and sealing arrangement for turbine bucket shank |
US8827642B2 (en) | 2011-01-31 | 2014-09-09 | General Electric Company | Flexible seal for turbine engine |
DE102011087987A1 (de) | 2011-12-08 | 2013-06-13 | Bayer Intellectual Property Gmbh | 6,7-Dihydro-5H-benzo[7]annulen-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln |
WO2015028409A1 (de) * | 2013-08-27 | 2015-03-05 | Bayer Pharma Aktiengesellschaft | 6,7-dihydro-5h-benzo[7]annulen-derivate, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln |
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US4617373A (en) | 1985-02-15 | 1986-10-14 | Eastman Kodak Company | Condensation polymers and products therefrom |
DE19833786A1 (de) * | 1998-07-18 | 2000-01-20 | Schering Ag | Benzocycloheptene, Verfahren zu ihrer Herstellung, pharmazeutische Präparate, die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln |
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RU2310643C2 (ru) | 2007-11-20 |
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