TWI454470B - 硫苯並薁丙酸衍生物之製造法 - Google Patents
硫苯並薁丙酸衍生物之製造法 Download PDFInfo
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- TWI454470B TWI454470B TW099124859A TW99124859A TWI454470B TW I454470 B TWI454470 B TW I454470B TW 099124859 A TW099124859 A TW 099124859A TW 99124859 A TW99124859 A TW 99124859A TW I454470 B TWI454470 B TW I454470B
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- 238000004519 manufacturing process Methods 0.000 title claims description 36
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 title 1
- 150000005599 propionic acid derivatives Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 52
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 47
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 235000019260 propionic acid Nutrition 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
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- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 6
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
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- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
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- 235000006408 oxalic acid Nutrition 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本發明係有關一種硫苯並薁丙酸衍生物之製造法,該硫苯並薁丙酸衍生物可使用作為抗組織胺劑等之醫藥組成物的有效成分。
組織胺(histamine)係作為誘發過敏性反應之化學介質的代表者,成為過敏之原因的物質進入體內時,由肥大細胞(mast cell)或嗜鹼性球(basophil)等之細胞釋出。所釋出之組織胺與組織胺H1受體(H1受體)蛋白質結合,發揮血壓降低、血管透過性亢進、平滑肌收縮、血管擴張、腺體分泌的促進等之藥理作用,係與過敏性反應及發炎的顯現有關。如此,組織胺係與人類的各種疾病有關,藉由抑制該作用,即可預防或治癒過敏性疾病以及發炎現象。抑制組織胺的游離之藥劑及阻礙與受體結合之藥劑(抗組織胺藥)多有販售,係在支氣管氣喘、過敏性鼻炎、花粉症、蕁麻疹、異位性皮膚炎等疾病中使用。
然而,目前已知的抗組織胺藥係因基於中樞作用之鎮靜作用、出現睡意、暈眩、倦怠感等,或基於抗膽鹼作用(Anticholinorgic effects)之口渴、黏膜乾燥感、視調節障礙等不期望的副作用之顯現,即有在開車前禁止服用等之使用限制,而成為使用不易之原因。因此,如此問題的解決且具有優異效果之抗組織胺藥係病患及醫療的現場中所要尋求的。本發明者等發現出中樞性副作用少且具有強力的抗組織胺作用之硫苯並薁丙酸衍生物的優異合成法,遂而完成本發明。
有關9至10位間為雙鍵之具有硫苯並薁骨架的哌啶衍生物,係在專利文獻1中揭示一種硫苯並薁骨架的2位以甲基、醇、烷基酮取代且哌啶的1位以烷基取代之具有神經阻斷作用及中樞神經壓抑作用的化合物。另在專利文獻2中揭示一種同樣之硫苯並薁骨架的2位以甲基、氯取代且哌啶的1位以烷基酮取代之具有鎮靜作用、睡眠促進作用以及肌肉鬆弛作用的化合物。然而,至今對於能以本發明之製造法合成的硫苯並薁骨架之2位與丙酸鍵結的化合物之合成法尚無任何的報告。
[專利文獻1]日本特開昭49-69677號公報
[專利文獻2]日本特開昭50-18478號公報
由於選擇性地使丙酸之3位取代在硫苯並薁骨架上有合成上的困難,因而進行乙氧羰基乙烯基導入硫苯並薁骨架之2位的化合物[通式(I)之R2
為乙基]之合成。此時,由於事先已在哌啶環之1位[通式(I)之R1
]中導入乙氧羰基等的保護基,因此,以合成之化合物的脫保護為目的而進行一般所使用之溴化氫(HBr)乙酸處理。果然,明顯地在目的之脫保護的同時,硫苯並薁骨架之2位側鏈的乙烯基部分之雙鍵轉移到硫苯並薁骨架之7員環部分(9至10位間)。經由本轉移反應,即可開始製造硫苯並薁骨架之2位經丙酸取代的化合物之3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸[通式(II)中,R1
’及R2
’為氫]。該化合物之抗組織胺作用優異且具有低的腦內遷移性,因此在作為出現睡意等之中樞性的副作用少之抗組織胺劑等的醫藥組成物之有效成分,係適用性極高之物。
本發明之目的係提供一種可用為抗組織胺劑等的醫藥組成物之有效成分的硫苯並薁丙酸衍生物之製造法。
目前為止,9至10位間為雙鍵之硫苯並薁骨架的2位經丙酸取代的化合物之合成尚未出現。本發明之製造法係根據:硫苯並薁骨架的2位經導入羧乙烯基或乙氧羰基乙烯基等取代基的化合物[通式(I)]藉由溴化氫-乙酸等之處理,使側鏈取代基之乙烯部分的雙鍵轉移到硫苯並薁骨架之7員環部分(9至10位間)之所謂的新穎合成法者。經由本轉移反應,即可製造硫苯並薁骨架的2位經丙酸取代之化合物的硫苯並薁丙酸衍生物。
經合成之硫苯並薁丙酸衍生物具有優異之組織胺H1受體拮抗作用,並且,即使在對小鼠經口投與時之腦內受體結合試驗中亦呈現低的腦內遷移性,其結果可達到對出現睡意等之中樞性副作用的減輕效果。因此,可合成作為抗組織胺劑等之醫藥組成物的有效成分之具有所要特性的硫苯並薁丙酸衍生物之本發明的製造法,係應用性極高者。
本發明係有關一種下述通式(II)所示之化合物的製造法,其特徵係:使下述通式(I)所示之化合物在甲酸、乙酸或丙酸之溶媒中與溴化氫、氯化氫、三氟化硼、甲磺酸或亞硫醯氯反應,
[式中,R1
及R1
’各為相同或相異,表示氫或COOX,X表示烷基或可具有取代基之苄基或苯基;R2
及R2
’各為相同或相異,表示氫、烷基、二苯基甲基或可具有取代基之苄基或苯基]。
上述通式(I)及(II)中,「可具有取代基」中之取代基可列舉如:鹵素、烷基、烷氧基、硝基以及苯基等,該取代基可不止一個,可為複數個。
通式(I)及(II)中之烷基(包含上述取代基中之烷基)的較佳者係表示甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、第三戊基、己基、異己基等碳數1至6之直鏈狀或分支狀的烷基。
上述取代基中之鹵素係表示氟、氯、溴、碘等。並且,烷氧基之較佳者係表示甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基、正戊氧基、正己氧基等碳數1至6之直鏈狀或分支狀的烷氧基。
在上述反應中,係使通式(I)所示之3-(9,10-二氫-4H-1-硫苯並[f]薁-2-基)丙烯酸衍生物在乙酸、甲酸、丙酸等溶媒中,與同於該衍生物之量或以上之量的酸性試劑,例如氯化氫、溴化氫、碘化氫、三氟化硼、甲磺酸或亞硫醯氯,宜在室溫至溶媒沸點間之適當溫度使其作用。由該反應,經由對該衍生物的上述酸之作用,丙烯酸部分的雙鍵轉移到環內,即可製造3-(4H-1-硫苯並[f]薁-2-基)丙酸衍生物。反應時間可在數十分鐘至數小時內進行,例如在溴化氫-乙酸時,在90至100℃中以30分鐘、50至55℃中以3小時左右,雙鍵的轉移反應終告結束。
上述通式(I)之R1
為乙氧羰基等保護基時,上述雙鍵可在轉移反應之前以鹼處理去除。經酸處理時,會與保護基的去除同時引發雙鍵的轉移反應。由於保護基的去除反應比雙鍵的轉移反應較為費時,因此,為了同時進行兩反應,必須有比雙鍵的轉移反應所需的時間更長時間的反應。雙鍵的轉移反應後,可在通式(II)之R1
’上導入第三丁氧羰基(Boc基)(參照實施例7、實施例10)。藉由Boc基的導入而提高脂溶性,可容易地進行藉由有機溶媒等的精製。Boc基可依照一般的去除反應,藉由酸或鹼之處理而去除。
在作為醫藥等之有效成分使用時,則要求純度極高之精製物。因此,將本發明之製造方法所合成之3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸轉換為鹽即可提高純度。例如:可轉換成有機磺酸(甲磺酸、乙磺酸等烷基磺酸;對甲苯磺酸、苯磺酸、萘磺酸等芳香族磺酸;樟腦磺酸;三氟甲磺酸等)、三氟乙酸、氫溴酸、氫碘酸、過氯酸、鹽酸、硫酸、硝酸等之鹽。亦可進一步進行再結晶法而作成高純度者。在轉換為鹽中的溶媒以及再結晶法中的溶媒可適當地選擇。
上述通式(I)及通式(II)所示之化合物係包含該等之各種鹽,可列舉例如:與鹽酸、草酸、富馬酸、對甲苯磺酸、馬來酸、琥珀酸、乙酸、檸檬酸、酒石酸、碳酸、硝酸等之酸的加成鹽。並且,羧基之鹽亦包含鈉、鉀、鈣等之適當的鹼金屬以及鹼土金屬鹽。該等之鹽可依習知方法由游離之各化合物製造,或可相互轉換。
接著,列舉實施例以更具體地說明本發明,本發明並不受該等實施例所限定。
熔點係將試料放入玻璃毛細管並以YAMATO MP-21型熔點測定儀測定(並無進行溫度計的補正)。MS光譜係以POLARIS Q(Thermo Quest公司)測定。1
H-NMR係以Bruker ARX500型核磁共振裝置測定,化學位移值係以作為內部標準之添加的TMS(δ=0ppm)為基準並以ppm表示。矽膠管柱層析法係使用層析用矽膠BW-127ZH(富士Silysia化學)而進行。薄層層析法係使用Silica gel F254(Merck、No.5715),並以UV燈及5%磷鉬酸-乙醇顯色試劑檢測。
將市售之4-(9,10-二氫-1-硫苯並[f]薁-4-亞基)-1-甲基哌啶(200g)與三乙胺(30mL)之甲苯(1.5L)溶液加熱至60℃,在該溶液中徐緩地滴入氯甲酸乙酯(162mL)。在本反應中,要注意剛開始的激烈反應。結束滴入後,再進行1小時的加熱回流。放冷後,以飽和氯化銨水溶液進行清洗,將有機層通過矽膠短柱,以5%乙酸乙酯-甲苯溶液2L將生成物進行洗提。減壓下餾除溶媒,在殘渣中添加石油醚使之結晶化。再將結晶濾出並加以乾燥,得到215g之化合物1(90%)。
Mp. 110-113℃. MS(EI):m/z 353[M+].1
H-NMR(DMSO-d6
)δ:1.18(t,J=7.1 Hz,3H),2.13-2.16(m,1H),2.18-2.23(m,1H),2.43-2.46(m,2H),2.80-2.83(m,2H),3.03-3.12(m,1H),3.17-3.28(m,3H),3.57-3.62(m,1H),3.69-3.71(m,1H),4.04(q,J=7.1Hz,2H),6.79(d,J=5.2 Hz,1H),7.01-7.03(m,1H),7.17-7.21(m,2H),7.29-7.31(m,2H).
將1,2-二氯乙烷(20mL)與DMF(4.1mL)之混合物在冰浴中冷卻,在液溫為0至5℃之範圍內以0.5小時以上的時間滴入磷醯氯(3.5mL)。再將所得混合物在室溫攪拌混合1小時後,以1小時之時間滴入1,2-二氯乙烷(40mL)溶液。將反應混合物在50℃攪拌混合36小時後,再投入碳酸鉀(25g)水溶液(200mL)。將混合物在室溫攪拌混合1小時之後,分離有機層。將水層以二氯甲烷(50mL×3)萃取,再與之前的有機層一起以水(50mL)、飽和食鹽水(50mL)清洗後,於無水硫酸鈉上進行乾燥。將減壓下餾除溶媒而得的殘渣油狀物溶解於甲基第三丁醚(100mL)中。在該溶液中徐緩地添加正庚烷(400mL)時,因固體開始析出而靜置30分鐘。再添加正庚烷(400mL)後,於減壓下將溶媒濃縮至約200mL,然後,濾取結晶,再以正庚烷(30mL×2)清洗。將所得結晶在減壓下、60℃乾燥1小時,得到8.4g之化合物2(73%)。
Mp. 146-149 ℃. MS(EI):m/z 381[M+].1
H-NMR(DMSO-d6
)δ:1.18(t,J=7.1 Hz,3H),2.15-2.17(m,1H),2.26-2.29(m,1H),2.45-2.51(m,1H),2.81-2.91(m,2H),3.02-3.14(m,1H),3.16-3.43(m,3H),3.60-3.62(m,1H),3.72-3.75(m,1H),4.04(q,J=7.1 Hz,2H),7.06-7.07(m,1H),7.19-7.24(m,2H),7.32-7.34(m,1H),7.76(s,1H),9.82(s,1H).
在化合物2(100g)中加入吡啶(60mL)、哌啶(1mL)、丙二酸(32.4g)進行一整晚之加熱回流。放冷後,在2mol/L鹽酸(740mL)中添加反應混合物,將硬化之生成物充分地磨碎後,濾取結晶。將結晶以水(1L)清洗並在減壓下乾燥,得到111g之化合物3(100%)。
Mp. 228℃(dec.).1
H-NMR(DMSO-d6
)δ:1.18(t,J=7.0 Hz,3H),2.08-2.14(m,1H),2.43-2.48(m,1H),2.49-2.53(m,2H),2.81-2.83(m,2H),3.01-3.15(m,1H),3.22-3.29(m,3H),3.57-3.59(m,1H),3.70-3.72(m,1H),4.05(q,J=7.0 Hz,2H),6.00(d,J=15.7 Hz,1H),7.02-7.04(m,1H),7.17-7.23(m,3H),7.30-7.32(m,1H),7.65(d,J=15.7 Hz,1H).
將化合物3(42.4g)與氫氧化鉀(66g)添加在異丙醇(500mL)中,進行24小時之加熱回流。放冷後,溶媒於減壓下餾除至剩下一半之量,再於殘渣中添加水(500mL)。將混合物冰冷後,於2mol/L鹽酸中將pH值調整至7。濾取所析出之固體後,以充分量之水清洗,於減壓下、50℃中乾燥,得到35.8g之化合物4(85%)。
Mp. 269-272℃(dec.). MS(EI):m/z 351[M+
].1
H-NMR(DMSO-d6
+三氟乙酸(5%))δ:2.32-2.39(m,1H),2.45-2.50(m,1H),2.60-2.67(m,1H),2.70-2.76(m,1H).2.81-2.90(m,2H),2.92-3.00(m,1H),3.05-3.13(m,1H),3.18-3.25(m,1H),3.28-3.38(m,3H),6.02(d,J=15.7 Hz,1H),7.06-7.10(m,1H),7.18-7.26(m,2H),7.27(s,1H),7.32-7.36(m,1H),7.68(d,J=15.7 Hz,1H),8.68-8.84(br,2H).
(1)在化合物4(40g)與乙酸(800mL)之混合物中添加30%HBr乙酸溶液(80mL)後,在55℃至60℃攪拌混合3小時。放冷後,在溶媒於減壓下餾除而得之殘渣中添加1mol/L氫氧化鈉水溶液(400mL),由40℃加熱至50℃,再添加乙醇(200mL)使之溶解。由40℃至50℃之持續加熱中,適量地添加1mol/L鹽酸使pH值由7調整至8之後,於室溫攪拌混合16小時。於減壓下餾除乙醇後,濾取所析出之固體並以水(100mL×2)與乙醇(100mL×2)清洗。將所得固體在減壓下乾燥16小時,得到鍵結於噻吩環之丙烯酸的雙鍵轉移至7員環部分的化合物5之32g粗結晶(80%)。
(2)上述操作(1)係將化合物3進行鹼處理,並將去除乙氧羰基之化合物4進行HBr乙酸處理,使鍵結於噻吩環之丙烯酸的雙鍵轉移至7員環部分的化合物5之製造方法。另一種方法係將化合物3直接進行HBr乙酸處理,並在乙氧羰基之去除反應的同時進行雙鍵的轉移反應,即可製造化合物5。
(3)將上述操作(1)所得之化合物(5)的粗結晶添加在1.8mol/L氫氧化鈉水溶液(35mL)中並加熱回流而得到均勻溶液。以1.5小時以上徐緩地冷卻至室溫後,濾取所析出之固體並以1.8mol/L氫氧化鈉水溶液(5mL×2)與二氯甲烷(50mL×2)清洗。將所得之固體添加在水(100mL)中,加熱回流而得到大致幾乎均勻的溶液。於該溶液中在90至100℃添加1mol/L鹽酸使pH值調整為7至8。放冷至室溫後,濾取所生成之結晶並以水(5mL×2)與乙醇(5mL×2)清洗。將所得結晶添加於乙醇中之後加熱回流1小時。放冷後,濾取結晶再以乙醇(5mL×2)清洗。減壓下於50至60℃乾燥4小時,得到2.6g純度99.6%(經HPLC分析)之化合物5(回收率為52%)。
Mp. 254 ℃(dec.). MS(EI):m/z 351[M+].1
H-NMR(DMSo-d6
)δ1.92-1.99(m,1H),2.14-2.20(m,1H),2.22-2.28(m,1H),2.38-2.44(m,1H),2.49(t,J=7.2 Hz,2H),2.55-2.68(m,2H),2.83-2.94(m,2H),2.97(t,J=7.2 Hz,2H),6.70(s,1H),6.83(d,J=11.5 Hz,1H),6.89(d,J=11.5 Hz,1H),7.09-7.13(m,1H),7.26-7.32(m1H),7.36-7.40(m,2H).
將化合物3(45.1g)與氫氧化鉀(66g)添加在異丙醇(500mL)中,進行8小時之加熱回流。放冷後,在反應混合物中加入水(500mL)並加熱至60℃,然後滴入二-第三丁基二碳酸酯(24g)之異丙醇(500mL)溶液。攪拌混合4小時後,將反應溶液放冷至室溫,在減壓下餾除有機溶媒。在殘渣水溶液中添加檸檬酸使pH值調整為4至5,濾取所析出之固體並以水充分地清洗。減壓下於50℃乾燥24小時,得到44.9g之化合物6(99%)。
Mp. 186℃(dec.).1
H-NMR(DMSO-d6
)δ:1.40(s,9H),2.08-2.14(m,1H),2.21-2.32(m,1H),2.41-2.53(m,2H),2.79-2.83(m,2H),3.01-3.15(m,1H),3.21-3.29(m,3H),3.51-3.54(m,1H),3.64-3.67(m,1H),6.00(d,J=15.7 Hz,1H),7.02-7.04(m,1H),7.10-7.11(m,1H),7.16-7.23(m,2H),7.30-7.32(m,1H),7.52(d,J=15.7 Hz,1H).
(1)將化合物6(39.0g)溶解於乙酸(700mL)中,添加30%HBr乙酸溶液(162mL)後於室溫攪拌混合1小時。再於100℃攪拌混合1小時後,於減壓下餾除溶媒,得到含有Boc基經去除且鍵結於噻吩環之丙烯酸的雙鍵轉移至7員環部分的化合物5之HBr鹽的殘渣。
(2)在該殘渣中添加水(200mL)、異丙醇(400mL)、2mol/L氫氧化鈉水溶液(500mL)使之溶解,然後滴入二-第三丁基二碳酸酯(21.9g)之異丙醇(100mL)溶液。於室溫攪拌混合20小時後,於減壓下餾除有機溶媒,將水層以檸檬酸作成酸性。以二氯甲烷(100mL×3)萃取後,與有機層一起以水(100mL)與飽和食鹽水(100mL)清洗後,再以無水硫酸鈉乾燥。將減壓下經餾除溶媒而得的殘渣油狀物以矽膠管柱層析法(二氯甲烷:丙酮=19:1)精製,將所得油狀物以石油醚進行結晶化,得到22.5g之化合物7(60%)。
Mp. 172℃(dec.). MS(EI):m/z 451[M+].1
H-NMR(DMSO-d6
)δ:1.39(s,9H),1.88-1.95(m,1H),2.08-2.15(m,1H),2.19.2.26(m,1H),2.34-2.40(m,1H),2.55-2.61(m,2H),2.99(t,J=7.2 Hz,2H),3.06-3.22(m,2H),3.39-3.51(m,2H),6.73(s,1H),6.84(d,J=11.5 Hz,1H),6.90(d,J=11.5 Hz,1H),7.12-7.16(m,1H),7.27-7.32(m,1H),7.36-7.42(m,2H).
於甲酸(210mL)中添加化合物7(13.5mmol)並於室溫攪拌混合2小時。於減壓下餾除溶媒後,於殘渣中加入水,再度於減壓下餾除溶媒。在此操作重複3次後所析出之結晶中加入乙醇(100mL)並濾取,再以乙醇(50mL)清洗,得到9.71g之化合物5(92%)。
在氬氣環境下,於500mL圓底燒瓶中添加氫氧化鈉(礦油中60%;3,6g),以正己烷清洗。減壓下將正己烷去除後,於氬氣環境下添加無水THF(90mL)。在該混合物中於冰冷下以30分鐘滴入二乙基膦醯乙酸乙酯(18mL)之無水THF(30mL)溶液,再於室溫攪拌混合30分鐘。於室溫以1小時滴入化合物2(31.2g)之THF(200mL)溶液後,攪拌混合1小時。將反應混合物投入冰水(500mL)後,分離有機層,並將水層以乙酸乙酯(100mL×3)萃取。集合有機層並以水(100mL×2)與飽和食鹽水(50mL)清洗後,以無水硫酸鈉乾燥。將溶媒在減壓下餾除,再以石油醚使所得殘渣油狀物結晶化,得到29.7g之化合物8的白色結晶(81%)。
Mp. 90-93 ℃. MS(EI):m/z 451[M+].1
H-NMR(DMSO-d6
)δ:1.18(t,J=7.0 Hz,3H),1.22(t,J=7.1 Hz,3H),2.08-2.14(m,1H),2.43-2.48(m,1H),2.49-2.53(m,2H),2.81-2.83(m,2H),3.01-3.15(m,1H),3.22-3.29(m,3H),3.57-3.59(m,1H),3.70-3.72(m,1H),4.05(q,J=7.0 Hz,2H),4.16(q,J=7.1 Hz,2H),6.07(d,J=15.7 Hz,1H),7.01-7.04(m,1H),7.17-7.23(m,2H),7.28(s,1H),7.30-7.32(m,2H),7.71(d,J=15.7 Hz,1H).
(1)將化合物8(9.0g)、乙酸(200mL)與30%HBr乙酸溶液(19mL)之混合物加熱回流6小時。將減壓下經餾除溶媒而得的殘渣油狀物溶解於水(100mL),添加碳酸鉀(20g),得到乙氧羰基經去除且鍵結於噻吩環之丙烯酸的雙鍵轉移至7員環部分的3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸乙酯(化合物9)。
(2)不將化合物9單離而在室溫滴入二碳酸二第三丁酯(4.4g)之乙腈(100mL)溶液。於室溫攪拌混合20小時後,於水(100mL)中添加反應混合物,再以乙酸乙酯萃取。集合有機層並以水(100mL)與飽和食鹽水(50mL)清洗後,以無水硫酸鈉乾燥。將溶媒在減壓下餾除並使所得油狀物以矽膠管柱層析法(己烷:乙酸乙酯=9:1)精製,得到5.3g之化合物10的油狀物(55%)。
MS(EI):m/z 479[M+].1
H-NMR(DMSO-d6
)6:1.16(t,J=7.1 Hz,3H),1.39(s,9H),1.88-1.96(m,1H),2.08-2.15(m,1H),2.19-2.26(m,1H),2.33-2.40(m,1H),2.59.2.72(m,2H),3.03(t,J=7.2 Hz,2H),3.06-3.19(m,2H),3.39-3.51(m,2H),4.05(q,J=7.1 Hz,2H),6.73(s,1H),6.84(d,J=11.5 Hz,1H),6.90(d,J=11.5 Hz,1H),7.11-7.16(m,1H),7.27-7.33(m,1H),7.37-7.42(m,2H).
於室溫將2mol/L氫氧化鈉水溶液(11mL)加入化合物10(5.3g)之乙醇溶液中並攪拌混合20小時。減壓下餾除溶媒後,使殘渣溶於水(50mL)中,加入檸檬酸(10g)並以乙酸乙酯(50mL×3)萃取。集合有機層並以水(50mL)、飽和食鹽水(50mL)清洗後,以無水硫酸鈉乾燥。將溶媒餾除再以石油醚使所得殘渣油狀物結晶化,得到3.7g之化合物7(74%)。化合物7進行與實施例8之相同處理而得化合物5。
於4-(9,10-二氫-1-硫苯並[f]薁-4-亞基)-1-甲基哌啶(5.76g)之氯仿(50mL)溶液中在0℃滴入溴(1.0mL)。於室溫攪拌混合2小時後,加入飽和小蘇打水並分離有機層。將有機層以飽和食鹽水清洗並以無水硫酸鈉乾燥。將溶媒在減壓下餾除並將殘渣以矽膠管柱層析法(氯仿:甲醇=9:1)精製,得到5.6g之化合物11的白色結晶(91%)。
Mp. 141-142℃. MS(EI):m/z 375[M+
+2],373[M+
].1
H-NMR(DMSO-d6
)δ:1.90-2.79(m,13H),3.18-3.22(m,2H),6.85(s,1H),6.98-7.30(m,4H).
化合物11(21.0g)之甲苯(200mL)溶液中添加氯甲酸乙酯(32mL)後加熱回流6小時。放冷後,於飽和小蘇打水中添加混合物並分離有機層。將有機層以飽和食鹽水清洗再以無水硫酸鈉乾燥後,將溶媒在減壓下餾除並將殘渣以管柱層析法(己烷:乙酸乙酯=19:1)精製,得到15.0g之化合物12的油狀物(62%)。
MS(EI):m/z 433[M+
+2],431[M+
].1
H-NMR(DMSO-d6
)δ:1.17(t,J=7.1 Hz,3H),2.10-2.23(m,2H),2.38-2.48(m,2H),2.68-2.83(m,2H),2.92-3.26(m,4H),3.52-3.78(m,2H),4.04(q,J=7.1 Hz,2H),6.90(s,1H),7.02-7.13(m,1H),7.16-7.36(m,3H).
於室溫,於化合物1(50g)之氯仿(500mL)溶液中滴入溴(10.9mL),攪拌混合2小時。依序將反應混合物以硫代硫酸鈉水溶液(100mL)、飽和碳酸鉀水溶液(100mL)清洗,並將有機層以無水硫酸鈉乾燥。將溶媒在減壓下餾除並將殘渣以矽膠管柱層析法(己烷:乙酸乙酯=9:1)精製,得到67g之化合物12(100%)。[實施例15]4-[2-(2-乙氧羰基乙烯基)-9,10-二氫-1-硫苯並[f]薁-4-亞基]哌啶-1-羧酸乙酯(化合物8)之製造
在氬氣氣流下,於化合物12(8.80g)之DMF(50mL)溶液中加入丙烯酸乙酯(18.5mL)、三乙胺(24mL)、乙酸鈀(0.3g)以及三(鄰甲苯甲醯基)膦(2.0g),於80℃進行一整晚之攪拌混合。放冷後,將水加入反應混合物中並以乙酸乙酯萃取,有機層以飽和食鹽水清洗後,再以無水硫酸鈉乾燥。將溶媒在減壓下餾除並將殘渣以管柱層析法(己烷:乙酸乙酯=9:1)精製,得到6.1g之化合物8(79%)。
在化合物8(6.10g)之乙酸(50mL)溶液中添加30%HBr乙酸溶液(3.8mL)後,在120℃攪拌混合4小時,使反應物放冷至室溫。反應生成物經分析之結果,確認生成乙氧羰基經去除且鍵結於噻吩環之丙烯酸部分的雙鍵轉移至7員環部分的化合物9。接著,將減壓下餾除溶媒而得的殘渣溶於乙醇(50mL)中,再加入2mol/L氫氧化鈉水容易(14mL),於室溫攪拌混合3小時。餾除溶媒後,於殘渣中添加水,並將該水溶液以稀鹽酸將pH值調整至7,再以氯仿萃取,得到化合物5。
(1)使化合物5(4.0g;純度96.9%)分散在丙酮(120mL)中,並於室溫添加對甲苯磺酸1水合物(2.16g)。攪拌混合1小時後,濾取所析出之結晶,再以丙酮(20mL)清洗,得到4.5g之化合物5的純度99.1%之對甲苯磺酸鹽(收率75%)。
(2)將上述生成物1.0g加入水、異丙醇、環戊基甲基醚(3:37:60)之混合溶媒(13mL)中,進行加熱回流使完全溶解後,放冷至室溫後濾取所析出之結晶,再以之前的混合溶媒(5mL)中清洗,得到0.68g之純度99.8%的3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸對甲苯磺酸鹽(收率68%)。
(1)使化合物5(4.0g;純度96.9%)分散在丙酮(120mL)中,並於室溫添加苯磺酸1水合物(2.02g)。攪拌混合15小時後,濾取所析出之結晶,再以丙酮(20mL)清洗,得到2.7g之純度99.9%的化合物5之苯磺酸鹽(收率46%)。
(2)將純度99.6%之3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸苯磺酸鹽(1.0g)於丙酮(50mL)中加熱溶解後,放冷至室溫後並濾取所析出之結晶,得到0.30g之純度100%的3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸苯磺酸鹽(收率30%)。
使化合物5(0.5g;純度96.9%)分散在丙酮(10mL)中,並於室溫添加甲磺酸(0.14g)。攪拌混合40小時後,濾取所析出之結晶,再以丙酮(2mL)清洗,得到0.49g之純度98.7%的化合物5之甲磺酸鹽(收率77%)。
(1)使化合物5(0.5g;純度96.9%)分散在丙酮(10mL)中,並於室溫添加2mol/L鹽酸(0.9mL)。攪拌混合1小時後,濾取所析出之結晶,再以丙酮(2mL)清洗,得到0.39g之純度98.2%的化合物5之鹽酸鹽(收率71%)。
(2)將化合物5(4.0g;純度96.9%)溶解於甲酸(80mL)中,在冰冷下添加濃硫酸(1.13g)。攪拌混合1小時後,在減壓下餾除溶媒而得的殘渣中加入水(40mL)後,濾取所析出之結晶並以冷水(2mL)清洗,得到0.39g之純度97.4%的化合物5之硫酸鹽(收率76%)。
(3)使化合物5(0.5g;純度96.9%)分散在水(40mL)中,並於冰冷下添加70%硝酸(0.2mL)。攪拌混合1小時後,濾取所析出之結晶,再以水(2mL)清洗,得到0.39g之純度98.4%的化合物5之硝酸鹽(收率71%)。
使化合物5(2.85kg;純度99.8%)分散在從80℃加熱至90℃之水(37kg)中,攪拌混合30分鐘。加入2mol/L鹽酸(4.1kg),再於同溫度攪拌混合30分鐘使化合物5溶解。持續地維持溫度並濾除不溶物後,於濾液中添加2mol/L鹽酸(2.05kg)。將混合物由90℃冷卻至20℃後攪拌混合17小時。濾取所析出之結晶,再以水(2L×3)清洗後,以60℃至65℃進行48小時之乾燥,得到2.79kg之純度99.1%的化合物5之鹽酸鹽(收率88.7%)。
如依本發明之製造法,根據藉由將羧乙烯基或乙氧羰基乙烯基等取代基導入硫苯並薁骨架之2位的化合物[通式(I)]以溴化氫-乙酸等處理,使側鏈取代基之乙烯基部分的雙鍵轉移到硫苯並薁骨架之7員環部分(9至10位間)的新穎合成法,即可製造硫苯並薁骨架之2位經丙酸取代的化合物。依本發明之製造法所合成的3-(4-哌啶-4-亞基-4H-1-硫苯並[f]薁-2-基)丙酸(化合物5)等,具有優異之組織胺H1受體拮抗作用,並在對小鼠經口投與時之腦內受體結合試驗中亦呈現低的腦內遷移性,其結果可達到對出現睡意等之中樞性副作用的減輕效果。因此,可合成作為抗組織胺劑等之醫藥組成物的有效成分之具有所要特性的上述化合物之本發明的製造法,係應用性極高者。
Claims (7)
- 一種下述通式(II)所示之化合物的製造法,其特徵係:使下述通式(I)所示之化合物在選自甲酸、乙酸及丙酸所成群組之一種溶媒中與選自溴化氫、氯化氫、三氟化硼、甲磺酸及亞硫醯氯所成群組之一種酸性試劑進行反應,
- 如申請專利範圍第1項所述之製造法,其中,通式(II)所示之化合物係R1 ’及R2 ’均為氫之化合物。
- 如申請專利範圍第2項所述之製造法,其係使用通式 (I)之R1 及R2 均為氫之化合物。
- 一種申請專利範圍第1項之通式(II)之R1 ’及R2 ’均為氫之化合物的製造法,其係對於申請專利範圍第1項之通式(II)之R1 ’及/或R2 ’為氫以外之基的化合物,將該氫以外之基去除。
- 一種化合物的製造法,係將申請專利範圍第1項之通式(II)之R1 ’及R2 ’均為氫的化合物再轉換為鹽而得到純度更高之該化合物。
- 如申請專利範圍第5項所述之製造法,其中,鹽為有機磺酸鹽。
- 如申請專利範圍第5項所述之製造法,其中,鹽為鹽酸鹽。
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US4052412A (en) * | 1973-10-10 | 1977-10-04 | Sandoz Ltd. | Benzo cycloheptathiophene carboxylic acid derivatives |
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