TW201309665A - 脂肪酸衍生物製備方法 - Google Patents
脂肪酸衍生物製備方法 Download PDFInfo
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- TW201309665A TW201309665A TW101123403A TW101123403A TW201309665A TW 201309665 A TW201309665 A TW 201309665A TW 101123403 A TW101123403 A TW 101123403A TW 101123403 A TW101123403 A TW 101123403A TW 201309665 A TW201309665 A TW 201309665A
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- Prior art keywords
- group
- azaadamantane
- derivative
- oxyl
- ether
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 15
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 8
- 239000000194 fatty acid Substances 0.000 title claims abstract description 8
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 8
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- BCJCJALHNXSXKE-UHFFFAOYSA-N azado Chemical group C1C(C2)CC3CC1N([O])C2C3 BCJCJALHNXSXKE-UHFFFAOYSA-N 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000002430 hydrocarbons Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- ORWXHNXGXZJPKA-UHFFFAOYSA-N C1C(C2)CC3CC2N(O)C1(C)C3 Chemical group C1C(C2)CC3CC2N(O)C1(C)C3 ORWXHNXGXZJPKA-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- SFXINVPZIZMFHM-UHFFFAOYSA-N azadol(r) Chemical group C1C(C2)CC3CC1N(O)C2C3 SFXINVPZIZMFHM-UHFFFAOYSA-N 0.000 claims description 2
- BZDWENUBDLILHM-UHFFFAOYSA-N dehydroadamantane Chemical compound C1C(C2)CC3CC2=CC1C3 BZDWENUBDLILHM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- -1 for example Chemical group 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000007254 oxidation reaction Methods 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 7
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 7
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- 239000000543 intermediate Substances 0.000 description 6
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 6
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- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
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- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 3
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- 125000005907 alkyl ester group Chemical group 0.000 description 3
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- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
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- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
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- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
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- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- NKJOXAZJBOMXID-UHFFFAOYSA-N 1,1'-Oxybisoctane Chemical compound CCCCCCCCOCCCCCCCC NKJOXAZJBOMXID-UHFFFAOYSA-N 0.000 description 1
- PUBSWBHFVCUPOF-UHFFFAOYSA-N 1-(1-cyclopropylethoxy)ethylcyclopropane Chemical compound C1CC1C(C)OC(C)C1CC1 PUBSWBHFVCUPOF-UHFFFAOYSA-N 0.000 description 1
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- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LTSWUFKUZPPYEG-UHFFFAOYSA-N 1-decoxydecane Chemical compound CCCCCCCCCCOCCCCCCCCCC LTSWUFKUZPPYEG-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 1
- DEBGMRXCXCOKTA-UHFFFAOYSA-N 1-methoxy-1-(1-methoxyethoxy)ethane Chemical compound COC(C)OC(C)OC DEBGMRXCXCOKTA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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Abstract
本發明之目的為提供製備脂肪酸衍生物的新方法,此方法可以很容易地在相對溫和的條件下進行。
Description
本發明係關於製備脂肪酸衍生物的新方法,該脂肪酸衍生物係用於作為藥物或藥物的合成中間體。
脂肪酸衍生物係存在人類和其他哺乳動物的組織和器官中之有機羧酸,並具有多種生物活性。在自然界中發現的一些脂肪酸衍生物,包含彼等有如式(A)所示之前列腺酸(prostanoic acid)骨架作為一般結構:
在製備脂肪酸衍生物,如具有上述前列腺酸骨架之前列腺素(prostaglandin)衍生物,羥基的氧化是重要反應步驟之一。已知許多氧化羥基的方法。
傳統合成前列腺素衍生物使用斯文(Swern)氧化反應,需要可在極低反應溫度(-70至-40℃)操作之特殊製造設備。此外,當脂肪酸衍生物於分子中具有羧基時,由於副反應,不欲之副產物可能成為主要產物(參見例如,US2006-0036108A,尤其是比較例1,此文獻納入本文參考)。為了避免此問題,在斯文氧化反應前保護羧基,與氧
化後保護基之去保護係必需的,其結果,這些額外的步驟使製造過程變得長和冗餘。
此外,斯文氧化反應共產生的二甲硫醚有強烈惡臭味,因此需要如排氣洗滌器、活性碳吸附塔與類似設備以避免臭味。
使用重金屬試劑(例如,鉻酸)之傳統的氧化方法,可用於含有羧基化合物之氧化。然而,大多重金屬具有毒性,且視情況不適合用於藥物的工業製造方法。
戴斯-馬丁(Dess-Martin)氧化也可用以氧化含有羧基化合物,然而,已有報告此氧化劑之熱敏感度與撞擊敏感度(Chem.Eng.News,July 16,3,1990,此文件納入本文參考)。此外,此氧化劑不易以工業原料而從市場取得。因此,戴斯-馬丁氧化不適用於工業製造。
TEMPO氧化亦用於羥基之氧化。此反應可在相對溫和的條件下容易進行,且因而不需使用如超低溫反應器和排氣洗滌器之設備。已知可以高純度與高產率製造產物之方法(US 2006-0036108A,此文件納入本文參考)。然而,在相關技藝中已知TEMPO氧化有些問題。例如TEMPO之氧化型,亦即,TEMPO之活化型,結構上不穩定,因此,該反應需要相對大量之催化劑。此外,當龐大的基質以TEMPO氧化,難以達到足夠的反應性。為了促進該反應,每1莫耳當量羥基通常對該反應添加1.0至2.0莫耳當量之鹵化鹽,例如溴化鈉、溴化鉀、溴化四丁基銨或氯化四丁基銨。然而這些鹵化鹽可能導致例如溴化類似物之副產物的產
生。
根據上述討論情況,仍需要可壓制副產物產生之氧化羥基之工業應用方法。
本發明之目的為提供製備脂肪酸衍生物的新方法,此方法可以很容易地在相對溫和的條件下進行。
本發明者已深入研究與發現,在氮雜金剛烷-N-氧基(azaadamantane-N-oxyl)衍生物存在下,藉由始用共氧化劑氧化合成中間體,可有效率地產生脂肪酸衍生物。根據本發明之方法,藉由使用易取得之低成本共氧化劑,不需特殊裝置,可合成欲得的脂肪酸衍生物,且可壓制不欲得的副產物。
根據本發明提供以式(I)表示之脂肪酸衍生物之製造方法:
其中,X1係、或,其中R1係羥基之保護基;Y1係、或,其中R2係羥基之保護基;
Z1係,其中R3和R4係氫原子、鹵素原子、低級烷基或低級烷氧基時;當R3和R4係低級烷氧基時,R3和R4可互相連結形成環結構;限制條件為X1和Y1至少一個係;A係-CH3、-CH2OH、-COCH2OH、-COOH或該等之官能衍生物;B係單鍵、-CH2-、-CH2-CH2-、-CH=CH-或-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;Ra係二價飽和或不飽和之低級-中級脂肪族烴基,該烴基係未經取代或經鹵素原子、低級烷基、低級烷氧基、側氧基、芳基或雜環基取代,限制條件為該脂肪族烴基的一個或多個碳原子可視需要經氧、氮或硫原子置換;以及Rb係氫原子;飽和或不飽和之低級-中級脂肪族烴基,該烴基係未經取代或經鹵素、側氧基、羥基、低級烷氧基、低級烷醯氧基、環(低級)烷基、環(低級)烷基氧基、芳基、芳基氧基、雜環或雜環氧基取代;環(低級)烷基;環(低級)烷基氧基;芳基;芳基氧基;雜環;或雜環氧基,該方法包括在氮雜金剛烷-N-氧基衍生物的存在下以共氧化劑與式(II)化合物反應之步驟:式(II)
其中,X1與X2相同,除了當X1係時,X2係或;Y1與Y2相同,除了當Y1係時,Y2係或;Z1與Z2相同;限制條件為X2和Y2至少一個係;以及,A、B、Ra和Rb與上述相同。
在上述Ra和Rb之定義,該詞「不飽和」係定義為Ra和Rb旨在主鏈與/或側鏈碳原子間,包含至少一個或多個單獨、分別或連續存在之雙鍵與/或參鍵。根據慣用命名,在二連續位置間之不飽和鍵係以該二位置中較低數字表示,在二不連續位置間之不飽和鍵係表示該兩者位置。
該詞「低級-中級脂肪族烴」意指具有1個至14個碳原子之直鏈或支鏈烴,其中該側鏈較佳具有1個至3個碳原子。Ra較佳具有1個至10個碳原子,更佳具有6個至10個碳原子,以及Rb較佳具有1個至10個碳原子,更佳具有1個至8個碳原子。
該詞「鹵素」包含氟、氯、溴和碘原子。
該詞「低級」除非另有定義,意指具有1個至6個碳原子之基團。
該詞「低級烷基」意指具有1個至6個碳原子之直鏈或支鏈型飽和烴基,例如:甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基和己基。
該詞「低級烷氧基」意指低級烷基-O-,其中低級烷基如上述。
該詞「低級烷醯氧基」意指以式RCO-O-所表示之基,其中RCO-係藉由氧化如上述低級烷基形成之醯基,例如,乙醯基。
該詞「低級環烷基」意指如上述包含3個或更多個碳原子之低級烷基之環化所形成之基,例如,環丙基、環丁基、環戊基和環己基。
該詞「環(低級)烷基氧基」意指以式環烷基-O-所表示之基,其中環烷基如上述。
該詞「芳基」包含可經取代之芳香烴環(較佳為多環基),例如,苯基、甲苯基和二甲苯基。此例之取代基實例包含鹵素、及經鹵素取代之低級烷基,其中鹵素原子和低級烷基如上述。
該詞「芳基氧基」意指以式ArO-所表示之基,其中Ar如上述之芳基。
該詞「雜環」包含單環至三環,較佳為單環雜環基,該單環雜環基為5員至14員,較佳為5員至10員,具有視需要經取代之碳原子以及選自氮、氧和硫原子之1至4
個(較佳為1至3個)1種或2種雜原子。該雜環基之實例包含呋喃基、噻吩基、吡咯基、唑基、異唑基、噻唑基、異噻唑基、咪唑基、吡唑基、呋呫基、哌喃基、吡啶基、噠嗪基、嘧啶基、吡基、2-吡咯啉基、吡咯啶基、2-咪唑啉基、咪唑啶基、2-吡唑啉基、吡唑啶基、N-六氫吡啶基、哌基、N-嗎啉基、吲哚基、苯并噻吩基、喹啉基、異喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、啡啶基、苯并咪唑基、苯并咪唑啉基、苯并噻唑基、啡噻基。此例之取代基實例包含鹵素及經鹵素取代之低級烷基,其中鹵素原子和低級烷基如上述。
該詞「雜環氧基」意指以式HcO-所表示之基,其中Hc如上述之雜環基。
A之該詞「官能衍生物」包含鹽、較佳為藥學上可接受之鹽、醚、酯和醯胺。
「藥學上可接受之鹽」之合適實例包含通用的非毒性鹽、含無機鹼之鹽,例如,鹼金屬鹽(鈉鹽、鉀鹽及類似者);鹼土金屬鹽(鈣鹽、鎂鹽及類似者);銨鹽;含有機鹼之鹽,例如,胺鹽(諸如,甲基胺鹽、二甲基胺鹽、環己基胺鹽、苯甲基胺鹽、哌啶鹽、乙二胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、參(羥基甲基胺)乙烷鹽、單甲基-單乙醇胺鹽、賴胺酸鹽、普卡因鹽和咖啡因鹽);鹼性胺基酸鹽(諸如,L-精胺酸鹽和賴胺酸鹽);四烷基銨鹽及類似者。這些鹽,例如,可自按照傳統方式相應的酸和鹼或鹽交換而製造。
醚之實例包含烷基醚,例如,低級烷基醚,諸如,甲基醚、乙基醚、丙基醚、異丙基醚、丁基醚、異丁基醚、第三丁基醚、戊基醚和1-環丙基乙基醚;及中級或高級烷基醚,諸如,辛基醚、二乙基己基醚、月桂基醚和十六基醚;不飽和醚,諸如,油醇醚和次亞麻醇醚;低級烯基醚,諸如,乙烯基醚、烯丙基醚;低級炔基醚,諸如,乙炔基醚和丙炔基醚;羥基(低級)烷基醚,諸如,羥基乙基醚和羥基異丙基醚;低級烷氧基(低級)烷基醚,諸如,甲氧基甲基醚和1-甲氧基乙基醚;視需要經取代之芳基醚,諸如,苯基醚、甲苯磺醯基醚、第三丁基苯基醚、柳醯基醚、3,4-二-甲氧基苯基醚和苯甲醯胺基苯基醚;以及芳基(低級)烷基醚,諸如,苯甲基醚、三苯甲基醚和二苯甲基醚。
酯之實例包含脂肪族酯,例如,低級烷基酯,諸如,甲基酯、乙基酯、丙基酯、異丙基酯、丁基酯、異丁基酯、第三丁基酯、戊基酯和1-環丙基乙基酯;低級烯基酯,諸如,乙烯基酯和烯丙基酯;低級炔基酯,諸如,乙炔基酯和丙炔基酯;羥基(低級)烷基酯,諸如,羥基乙基酯;及低級烷氧基(低級)烷基酯,諸如,甲氧基甲基酯和1-甲氧基乙基酯,以及例如,視需要經取代之芳基酯,諸如,苯基酯、甲苯磺醯基酯、第三丁基苯基酯、柳醯基酯、3,4-二甲氧基苯基酯和苯甲醯胺基苯基酯;以及芳基(低級)烷基酯,諸如,苯甲基酯、三苯甲基酯和二苯甲基酯。
A之醯胺係以式-CONR’R"所表示之基,其中R’和R"獨立表示氫原子、低級烷基、芳基、烷基磺醯基或芳基磺
醯基、低級烯基或低級炔基。醯胺之實例包含單低級烷基醯胺或二低級烷基醯胺,諸如,甲基醯胺、乙基醯胺和二甲基醯胺;芳基醯胺,諸如,醯苯胺和鄰甲苯胺;以及烷基磺醯基醯胺或芳基磺醯基醯胺,諸如,甲基磺醯基醯胺、乙基磺醯基醯胺和甲苯基磺醯基醯胺。
A之較佳實例包含-COOH、藥學上可接受之鹽、酯和醯胺。
B較佳係-CH2-CH2-,提供所謂的13,14-二氫型衍生物結構。
Ra較佳係具有1個至10個碳原子之烴基,更佳係具有6個至10個碳原子。烴基之一個或多個碳原子可視需要經氧、氮和硫原子置換。
Ra之實例包含,例如以下族群:-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-O-CH2-、-CH2-CH=CH-CH2-O-CH2-、-CH2-C≡C-CH2-O-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
Rb較佳係氫原子或經鹵素原子(例如,氟)取代之含1個至10個碳原子之烴,更佳係含1個至8個碳原子之烴。
於說明書和申請專利範圍之該詞「羥基之保護基」,意指採用避免羥基氧化之官能基。本發明之保護基可為能如是作用之任意基。保護基之實例可包含甲基、甲氧基甲基、乙基、1-乙氧基乙基、苯甲基、經取代之苯甲基、烯丙基、四哌喃基、第三丁基二甲基矽基、三乙基矽基、三異丙基矽基、二苯基甲基矽基、甲醯基、乙醯基、經取代之乙醯基、苯甲醯基、經取代之苯甲醯基、甲基氧基羰基、苯甲基氧基羰基、第三丁基氧基羰基和烯丙基氧基羰基。
可應用於本發明之氮雜金剛烷-N-氧基衍生物之實例包含(但不侷限於)2-氮雜金剛烷-N-氧基(AZADO)和1-甲基-2-氮雜金剛烷-N-氧基(1-Me-AZADO)。該氮雜金剛烷-N-氧基衍生物亦包含於反應系統中藉由使用共氧化劑而產生如從2-氮雜金剛烷-N-氧基(AZADO)、1-甲基-2-氮雜金剛烷-N-氧基(1-Me-AZADO)或類似者獲得之活性氧化物種為相似化學物種之化學物質。其實例包含(但不侷限於)2-羥
基-2-氮雜金剛烷(AZADOL[Nissan Chemical Industries,Ltd.之註冊商標])、2-羥基-1-甲基-2-氮雜金剛烷(1-Me-AzADOL)及類似者。
對於每1莫耳之欲氧化的起始化合物或式(II)化合物,氮雜金剛烷-N-氧基衍生物於反應中之用量約為0.0005至1.0莫耳,較佳為約0.001至0.1莫耳。
用於本發明之共氧化劑如下述方案所示為可轉換(i)氮雜金剛烷-N-氧基衍生物成為其活性氧化物種者;(ii)於基質氧化時產生之氮雜金剛烷衍生物(例如,2-羥基-2-氮雜金剛烷)之還原型,成為活性氧化物種者。共氧化劑之實例可包含次含鹵酸諸如次氯酸或其鹽、含鹵酸諸如溴酸或其鹽、含多價碘之化合物,諸如乙酸碘苯、過氧化物諸如3-氯苯甲酸、經N-鹵素取代之丁二醯亞胺,諸如,N-氯丁二醯亞胺。
共氧化劑(例如,次氯化鈉)之催化循環和反應
對於欲氧化之每1莫耳當量羥基,共氧化劑於反應中之用量可為1.0至3莫耳當量,較佳為1.1至2莫耳當量
以及更佳為1.1至1.5莫耳當量。
該反應可在有機溶劑、水溶劑、其混合物或由有機溶劑和水溶劑所組成之二相溶劑系統中進行。
用於本發明之有機溶劑實例可為芳香羥溶劑(如,甲苯)、脂肪族烴溶劑(如,己烷)、含鹵素溶劑(如,二氯甲烷)、酮(如,丙酮)、酯(如,乙酸乙酯)。
該水溶劑可包含pH調節劑(如,碳酸氫鈉)、pH緩衝劑(如,磷酸二氫鉀和磷酸二氫鈉)。
根據本發明,為了促進反應,鹵化鹽(例如,溴化鈉、溴化鉀、溴化四丁基銨和氯化四丁基銨)可加至該反應。
對於欲氧化之每1莫耳當量羥基之鹵化鹽添加量不侷限且可為約0.05至0.5莫耳當量。相較之下,當使用TEMPO(四甲基哌啶-1-氧基)取代氮雜金剛烷-N-氧基衍生物,對於欲氧化之每1莫耳當量羥基需要1.0至2.0莫耳當量之TEMPO。
根據本發明,該反應可於-10℃至50℃(更佳為約0℃至-20℃)溫度進行。
本發明將藉以下實施例更詳細說明。不以這些實施例限制本發明。
將醇化合物(1)0.200g(0.34mmol)溶於乙酸乙酯(1.4ml),並加入AZADO(1mg/ml於乙酸乙酯0.3ml,0.0017mmol)於其中。該混合物冰浴冷卻至0℃。加入3%碳酸氫鈉水溶液1.91ml(0.68mmol)與溴化鉀4.1mg(0.034mmol)於其中。然後,滴加1.9M次氯酸鈉水溶液0.22ml(0.41mmol)至該反應中,並於0℃攪拌該混合物1小時。然後加入飽和硫代硫酸鈉水溶液至該反應混合物中,並以乙酸乙酯萃取該混合物三次。該萃取物以稀鹽酸、飽和碳酸氫鈉水溶液、飽和食鹽水清洗,以無水硫酸鎂乾燥,過濾並減壓濃縮。該殘留物以矽膠急速層析法(管柱:BW-300SP 60g;乙酸乙酯:己烷=1:5)獲得無色油狀化合物(2)。產率0.1929g(96.8%)。
1H-NMR(400MHz於CDCl3,TMS=0ppm)δ:0.05(3H,s),0.08(3H,s),0.85-0.90(12H,m),1.23(6H,d,J=6.3Hz),1.21-1.91(28H,m),2.15(1H,dd,J=6.1,18.0Hz),2.24(2H,t,J=7.6Hz),2.56(1H,m),3.89-3.95(4H,m),4.03(1H,m),5.00(1H,septet,J=6.3Hz)
將醇化合物(1)0.200g(0.34mmol)溶於乙酸乙酯(1.4ml),並加入AZADO(1mg/ml於乙酸乙酯0.3ml,0.0017mmol)
於其中。該混合物冰浴冷卻至0℃。加入3%碳酸氫鈉水溶液1.91ml(0.68mmol)與溴化鉀4.1mg(0.034mmol)於其中。然後,滴加約1.9M次氯酸鈉水溶液0.22ml(0.41mmol)至該反應中,並於0℃攪拌該混合物8小時。如實施例1之類似方法處理與純化該反應混合物,獲得無色油狀化合物(2)。產率0.1903g(95.5%)。
1H-NMR(400MHz於CDCl3,TMS=0ppm)δ:0.05(3H,s),0.08(3H,s),0.85-0.90(12H,m),1.23(6H,d,J=6.3Hz),1.28-1.91(28H,m),2.15(1H,dd,J=6.1,18.0Hz),2.24(2H,t,J=7.7Hz),2.56(1H,m),3.89-3.97(4H,m),4.04(1H,m),5.00(1H,septet,J=6.3Hz)
將醇化合物(1)0.200g(0.34mmol)溶於乙酸乙酯(1.4ml),並加入1-Me-AZADO(1mg/ml於乙酸乙酯0.3ml,0.0017 mmol)於其中。該混合物冰浴冷卻至0℃。加入3%碳酸氫鈉水溶液1.91ml(0.68mmol)與溴化鉀4.1mg(0.034 mmol)於其中。然後,滴加約1.9M次氯酸鈉水溶液0.22ml(0.41 mmol)至該反應中,並於0℃攪拌該混合物2小時。如實施例1之類似方法處理與純化該反應混合物,獲得無色油狀化合物(2)。產率0.1866g(93.6%)。
1H-NMR(400MHz in CDCl3,TMS=0ppm)δ:0.05(3H,s),0.08(3H,s),0.84-0.90(12H,m),1.23(6H,d,J=6.3Hz),1.20-1.91(28H,m),2.15(1H,dd,J=6.1,18.0Hz),2.24(2H,t,J=7.6Hz),2.56(1H,m),3.89-3.97(4H,m),4.04(1H,m),5.00(1H,septet,J=6.3Hz)
將醇化合物(3)0.200g(0.34mmol)溶於乙酸乙酯(1.4ml),並加入AZADO(1mg/ml於乙酸乙酯0.3ml,0.0017mmol)於其中。該混合物冰浴冷卻至0℃。加入3%碳酸氫鈉水溶液1.91ml(0.68mmol)與溴化鉀4.1mg(0.034mmol)於其中。然後,滴加約1.9M次氯酸鈉水溶液0.22ml(0.41mmol)至該反應中,並於0℃攪拌該混合物1小時。如實施例1之類似方法處理與純化該反應混合物,獲得無色油狀化合物(4)。產率0.1914g(96.0%)。
1H-NMR(400MHz in CDCl3,TMS=0ppm)δ:0.04(3H,s),0.06(3H,s),0.85-0.89(12H,m),1.23(6H,d,J=6.3Hz),1.22-1.82(27H,m),2.04-2.08(1H,m),2.25-2.28(4H,m),3.92(4H,m),4.38-4.39(1H,m),5.01(1H,septet,J=6.2Hz)
將醇化合物(5)0.200g(0.37mmol)溶於甲苯(1.4ml),並加入AZADO(1mg/ml於甲苯0.3ml,0.0018mmol)於其中。該混合物冰浴冷卻至0℃。加入3%碳酸氫鈉水溶液2.91ml(0.74mmol)與溴化鉀4.4mg(0.037mmol)於其中。然後,滴加約1.9M次氯酸鈉水溶液0.23ml(0.44mmol)至該反應中,並於0℃攪拌該混合物1小時。然後加入飽和硫代硫酸鈉水溶液與稀鹽酸至該反應混合物中,並以乙酸乙酯萃取該混合物三次。該萃取物以水,再以飽和食鹽水清洗,然後以無水硫酸鎂乾燥,過濾並減壓濃縮。該殘留物以矽膠急速層析法(管柱:FL60D含水量15%;60g,乙酸乙酯:己烷=1:2)獲得無色油狀化合物(2)。產率0.1825g(91.6%)。
1H-NMR(400MHz in CDCl3,TMS=0ppm)δ:0.05(3H,s),0.08(3H,s),0.85-0.90(12H,m),1.24-1.91(29H,m),2.16(1H,dd,J=6.1,18.1Hz),2.33(2H,t,J=7.6Hz),2.54-2.60(1H,m),3.92-3.96(4H,m),4.01-4.06(1H,m)
Claims (6)
- 一種製造式(I)表示之脂肪酸衍生物之方法:
- 如申請專利範圍第1項所述之方法,其中A係-COOH或其官能衍生物。
- 如申請專利範圍第1項所述之方法,其中該氮雜金剛烷-N-氧基衍生物係2-氮雜金剛烷-N-氧基。
- 如申請專利範圍第1項所述之方法,其中該氮雜金剛烷-N-氧基衍生物係1-甲基-2-氮雜金剛烷-N-氧基。
- 如申請專利範圍第1項所述之方法,其中該氮雜金剛烷-N-氧基衍生物係2-羥基-2-氮雜金剛烷。
- 如申請專利範圍第1項所述之方法,其中該氮雜金剛烷-N-氧基衍生物係2-羥基-1-甲基-2-氮雜金剛烷。
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