TWI499594B - 磷酸酯之合成方法 - Google Patents
磷酸酯之合成方法 Download PDFInfo
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- TWI499594B TWI499594B TW099137980A TW99137980A TWI499594B TW I499594 B TWI499594 B TW I499594B TW 099137980 A TW099137980 A TW 099137980A TW 99137980 A TW99137980 A TW 99137980A TW I499594 B TWI499594 B TW I499594B
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- 238000003786 synthesis reaction Methods 0.000 title description 17
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- 229950004354 phosphorylcholine Drugs 0.000 description 1
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 1
- 125000001189 phytyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])([H])[C@@](C([H])([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@](C([H])([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係關於一種製備磷酸酯之方法,且係關於選定的化合物。
合成結構單元順式-甘油基-3-磷酸膽鹼(GPC)係合成對映體型純磷脂之重要前驅物:
順式-甘油基-3-磷酸膽鹼因此,GPC係(例如)合成醫藥上有關之脂質及類脂之重要中間物。另外,該物質已被用作治療阿茲海默氏病(Alzheimer's)患者之藥物,因為GPC對被破壞之神經組織明顯具有恢復正常化效用。已知GPC之總合成法。WO 2007/145476描述一種藉助磷酸膽鹼氯化物與R-(+)-縮水甘油之反應製備GPC之方法。EP 0486100 A1揭示一種製備GPC的方法,其中首先使亞異丙基甘油與2-氯-2-氧雜-3,3,2-二氧磷雜環戊烷反應。所得產物與三甲胺之反應及水解形成GPC。
儘管存在該等習知合成方法,但GPC通常係自大豆/雞蛋卵磷脂中大批量獲得。自天然來源分離係明顯比習知之全部合成變體廉價。
因此,本發明之目的係提供另一種製備磷酸酯之合成方法。
因此,本發明係關於一種製備式I化合物之方法,
其中R1、R2、R3各相互獨立地代表:a)式II之雜芳族化合物:
其中(-X-Y-)代表:
‧-CH-CH-CH-,
‧-Z-CH-CH-,
‧-CH-Z-CH-,
‧-CH-CH-Z-,
‧-CH-Z-,
‧-Z-CH-或
‧-Z-Z-,
其中Z在各情況下係相互獨立地選自O、S、N、NH之群,以提供芳族系統;b)-OR4,其中R4代表具有1至20個C原子之直鏈或分支鏈烷基;具有2至20個C原子及一或多個雙鍵之直鏈或分支鏈烯基;具有2至20個C原子及一或多個三鍵之直鏈或分支鏈炔基;具有3至24個C原子之飽和、部份或完全不飽和環烷基,其可經具有1至6個C原子之烷基取代,其中R4可經諸如-OR1
、-NR1 2
、-CN、-C(O)NR1 2
、-COOR1
、-C(=O)R1
、-SO2
NR1 2
或芳族基團(其視需要具有習知保護基且其中一或多個C原子可經雜原子置換)之取代基取代;其中R1
代表H、C1
-至C6
-烷基、C3
-至C7
-環烷基、未經取代或經取代之苯基;c)-O-
,該方法之特徵為:在第一步驟中,使磷醯氯與含N雜芳族化合物反應,且在隨後之步驟中,該等雜芳族化合物係視需要至少部份經具有OH官能基之化合物取代。
以其中式I化合物係選自式Ia、Ib、Ic、Id及Ie之方法較佳:
其中R5與R6各自且與R4相互獨立地代表具有1至20個C原子之直鏈或分支鏈烷基;具有2至20個C原子及一或多個雙鍵之直鏈或分支鏈烯基;具有2至20個C原子及一或多個三鍵之直鏈或分支鏈炔基;具有3至24個C原子之飽和、部份或完全不飽和環烷基,其可經具有1至6個C原子之烷基取代;其中R5與R6可經諸如-OR1
、-NR1 2
、-CN、-C(O)NR1 2
、-COOR1
、-C(=O)R1
、-SO2
NR1 2
或芳族基團(其視需要具有習知保護基且其中一或多個C原子可經雜原子置換)之取代基取代,其中R1
代表H、C1
-至C6
-烷基、C3
-至C7
-環烷基、未經取代或經取代之苯基,且其中基團X、Y及R4具有如上所述之定義。
具有1至20個C原子之直鏈或分支鏈烷基係,例如,甲基、乙基、異丙基、丙基、丁基、第二丁基或第三丁基;此外還有戊基;1-、2-、或3-甲基丁基;1,1-、1,2-或2,2-二甲基丙基;1-乙基-丙基、己基、庚基、1-乙基戊基、辛基、1-乙基己基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基或二十烷基。
具有2至20個C原子之直鏈或分支鏈烯基(另外,其中可存在複數個雙鍵)係,例如,烯丙基、2-或3-丁烯基、異丁烯基、第二丁烯基;此外係4-戊烯基、異戊烯基、己烯基、庚烯基、辛烯基、-C9
H17
、-C10
H19
至-C20
H39
;較佳係烯丙基、2-或3-丁烯基、異丁烯基、第二丁烯基;更佳係4-戊烯基、異戊烯基或己烯基。
具有2至20個C原子之直鏈或分支鏈炔基(另外,其中可存在複數個三鍵)係,例如,乙炔基、1-或2-丙炔基、2-或3-丁炔基,此外係4-戊炔基、3-戊炔基、己炔基、庚炔基、辛炔基、-C9
H15
、-C10
H17
至-C20
H37
,較佳為乙炔基、1-或2-丙炔基、2-或3-丁炔基、4-戊炔基、3-戊炔基或己炔基。
因此,具有3至24個C原子之飽和或部份或完全不飽和環烷基係環丙基、環丁基、環戊基、環己基、環庚基、環戊烯基、環己烯基、苯基、環庚烯基,其各可經C1
至C6
烷基取代。
就本發明而言,完全不飽和取代基亦意指芳族取代基。
其實例係苯甲基、苯基、苯乙基、苯丙基、苯丁基、苯戊基或苯己基。
基團R4、R5及R6較佳係相互獨立地選自包括烴基(其可視需要經一或多個OH官能基取代)、糖基、胺基酸基團或核酸基團之群。
基團R4、R5及R6特佳係相互獨立地選自:
在本發明方法之第一步驟中,使磷醯氯與含N雜芳族化合物反應。該等雜芳族化合物可選自(例如)包括以下之群:
本發明方法之第一步驟中的反應較佳係在非質子溶劑中進行。
以選自包括乙腈、乙酸乙酯、二噁烷、四氫呋喃、四甲基矽烷、二甲基甲醯胺、二甲亞碸、丙酮、乙醚、甲基第三丁基醚、環己烷、二甲基乙醯胺、環丁碸、N-甲基吡咯啶酮或二氯甲烷之群的溶劑特別佳。
該溶劑極佳為四氫呋喃。
進一步較佳係在含N鹼(例如氨、一級、二級或三級胺)的存在下實施本發明方法之第一步驟中之反應。
該鹼特別佳係選自三級烷胺。
該含氮鹼極佳係二異丙基乙胺(Hnig鹼)或三乙胺。
該含氮鹼特別佳係三乙胺。
在室溫或冷卻下實施該所述方法之第一步驟中的反應。
較佳在T>0℃下實施該反應。特別佳在10與0℃之間實施該反應。
在本發明方法之隨後步驟中,該等雜芳族基團可經具有OH官能基之化合物部份或完全取代。
該等具有OH官能基之化合物較佳為生物分子或生物分子衍生物。
以選自包括一元醇、二元醇、三元醇、四元醇、糖、多元醇、含有OH之胺基酸或含有OH之核酸之群之化合物特別佳。
以甘油或膽鹼衍生物(特定而言,膽鹼對甲苯磺酸鹽或亞異丙基甘油)極特別佳。
可在室溫或降溫下實施與該含有OH之化合物之反應。
較佳在T<0℃下,特別佳在T<-25℃下實施該反應。
此外,本發明方法可包括最終合成步驟,其中藉由在pH7下水解基團,製備化合物Id。
上述個別步驟之各產物可分別呈中間物單離出。或者,可依同爐合成法實施該合成。以藉由同爐合成法製備式I化合物之方法較佳。
以如上所述之方法特別佳,其特徵為:該含N芳族化合物係,且化合物係在第一步驟中製得。
以特徵為式I化合物係順式-甘油基-3-磷酸膽鹼之方法特別佳。
因此,本發明方法可製備順式-甘油基-3-磷酸膽鹼。此係闡述於流程圖1中:
該合成法之起點係在三乙胺之存在下使磷醯氯(III)與三唑(IV)反應,以提供磷酸化試劑(V),其選擇性地與對掌性合成結構單元(VI)原位反應,以提供單酯(VII)。隨後添加膽鹼對甲苯磺酸鹽(VIII),並形成加成物(IX),隨後以三個簡單步驟將其轉化為所需之最終產物GPC(X)。
可分別單離該合成法中之中間物,或者,可依同爐合成法實施該反應步驟。
此處之優點為:反應劑(V)係非常溫和的磷酸化試劑。若直接使用POCl3
,則獲得多種降解產物。該對掌性合成結構單元(VI)之酸敏性極高且不適合與POCl3
直接反應。
因此,本發明亦係關於一種式化合物(試劑V)作為磷酸化試劑之用途。
另外,本文所述之合成法可在所有步驟中實現約70%至90%以上之產率。
另一優勢在於:可獲得高純度結晶GPC。
此外,本發明係關於一種如上所述之式I化合物,其特徵為該化合物係選自:
根據本發明之化合物可藉由本發明方法製備且適合作為(例如)合成醫藥活性化合物之重要中間物。
可藉由本發明方法製備之其他化合物係(例如)式(1)至(5)化合物:
膽固醇磷酸膽鹼(1)係文獻(Gotoh等人,Chemistry & Biodiversity 2006,3,198-209)中已知之化合物。該親兩性物質(1)對脂質體之形成動力學有明顯的強烈影響。
式(2)至(5)化合物可作為合成多種化合物之重要起始物質且因此同樣係本發明之標的物。
式(2)化合物藉助(例如)由Sharpless提出之「點擊化學」打開末端炔之特定官能化作用。
式(3)之正交保護絲胺酸衍生物可例如,藉由特定官能化作用,直接轉化成新穎脂質或類脂。
式(4)化合物可提供脂質之構象受限型類環戊烷之類似物。在該化合物(4)轉化成(例如)二元醇衍生物之後,由此預期可製備多種新穎脂質化合物。
該不飽和植基衍生物(5)同樣可作為多種新穎醚脂質之結構單元。
以下操作實例意欲解釋本發明但不具有限制性。可在整個申請專利範圍內相應地實施本發明。自該實例開始,亦可獲得可能之變體。因此,該實例中所描述之反應的特徵及條件亦可應用於未詳細描述之其他反應,但其仍在該等申請專利範圍之保護範圍以內。
批料:
25.83 g亞異丙基甘油
29.94 g磷醯氯
59.31 g三乙胺+10 g
40.5 g三唑+2 g
500 ml THF(無水)
53.79 g膽鹼對甲苯磺酸鹽
50 ml水
300 ml 70%甲醇/水
50 ml of 0.1 N HCl
900 g of高純度Amberlite混合床離子交換劑(Roth)
400 ml乙醇(無水)
1 g(NH4
)2
MoO4
20 mg Ce(IV)SO4
10% H2
SO4
首先,在氬氣下將含於400 ml THF中之40.5 g(0.564 mol)三唑引入2 L玻璃儀器中,添加59.31 g(0.564 mol)三乙胺,並在5至10℃下將該混合物攪拌30分鐘。隨後以10分鐘時間,逐滴添加含於50 ml THF(無水)中之29.94 g(0.194 mol)磷醯氯。添加期間之溫度不應高過10℃。隨後在10℃下進一步攪拌該懸浮液2 h。過濾掉沉澱結晶,將該濾出液冷卻至-10℃,且隨後以1 h時間逐滴添加溶於50 ml THF中之25.83 g(0.195 mol)亞異丙基甘油。在添加期間該溫度保持在0℃以下。隨後在0℃至10℃下,將該混合物進一步攪拌5 h。隨後,以10分鐘時間引入53.79 g經研磨及乾燥的膽鹼對甲苯磺酸鹽,並在室溫下將該懸浮液進一步攪拌24 h。添加50 ml H2
O以後,將該批料在室溫下進一步攪拌5 h並在4℃下靜置過夜。過濾掉沉澱物,並在真空中將該溶液濃縮至20%。添加300 ml之70%甲醇/水,並利用0.1 N HCl將pH調節至2。隨後攪拌該溶液過夜。然後藉由混合床離子交換劑(3×300 g)處理該溶液,並藉由薄層層析法(Merck矽膠60F254
)(洗脫液70%甲醇/水,Rf
值GPC=0.25)監測該純化過程。將噴顯劑(NH4
)2
MoO4
(1 g)及Ce(IV)SO4
(20 mg)溶於20 ml 10% H2
SO4
中。在已噴霧分析板後,將其等加熱至150至200℃。藉此,磷化合物係染成藍色。在藉由離子交換劑處理之後,在旋轉蒸發器中蒸發該混合物,直至形成澄清黏性油。於50℃下,在旋轉蒸發器中利用乙醇重複蒸發,首先形成晶漿,其在油泵真空中乾燥後完全結晶。產量:22 g(45%)可分散之高吸濕性無色結晶(流程圖1中之X)。
I H-及 31 P-NMR光譜
:Bruker Avance 500(DRX)分光儀(1
H共振頻率500 MHz);除非另有指示,否則溶劑為CDCl3
;參照物:1
H-NMR:三甲基矽烷作為內標物,31
P-NMR:含於D2
O中之磷酸作為外標物。
含於DMSO中之該產物甘油磷酸膽鹼(X)之1
H-NMR:5.60 ppms,4.93 ppm s,4.05 ppm s,3.65-3.71 ppm m,3.47-3.53 ppm m,3.13 ppm s。
表1顯示經選擇作為實例之化合物(其已經由以上方法製備)之特徵性31
P-NMR信號:
首先,在氬氣下將含於0.2 L氯仿(無水)中之3.2 g(0.038 mol)三唑引入1 L玻璃儀器中,添加6 g(0.038 mol)二異丙基乙胺,並在室溫下將該混合物攪拌20分鐘。將該混合物冷卻至0℃,隨後以30分鐘時間,逐滴添加1.98 g(0.013 mol)磷醯氯(含於10 ml氯仿中)。隨後在0℃下進一步攪拌該懸浮液0.5 h且然後冷卻至-40℃。添加0.5 g二甲基胺基吡啶及1.66 g(0.013 mol)二異丙基乙胺。隨後在劇烈攪拌下,於-40℃下一次性添加3.7 g(0.129 mol)固體形式之膽鹼對甲苯磺酸鹽。
隨後進一步攪拌該懸浮液2 h。2 h以後,在-40℃下,以10分鐘時間引入5.0 g(0.0129 mol)膽固醇。隨後在-40℃下進一步攪拌該混合物1 h。隨後添加200 ml H2
O,並將該混合物升溫至室溫。添加0.5 L甲基第三丁基醚以實現相分離。廢棄該有機相,並藉由另外以氯仿搖晃3次來清洗該水相。隨後將0.2 kg混合床離子交換劑添加至該水溶液中,然後在室溫下攪拌2 h。
在藉由離子交換劑處理之後,過濾該混合物,並藉由70%甲醇/水進一步清洗該離子交換劑2次。在旋轉蒸發器中蒸發該等合併的溶液,形成白色固體。產物為4.6 g(64%)呈可分散微晶產物之膽固醇磷酸膽鹼(1)。
該產物之1
H-NMR(500 MHz,CDCl3
):δ(ppm)=5.14(s,br,1H),4.05(s,(br),1H),3.70(m,1H),3.39(m,2H),3.05(s,9H),2.0(m,2H),1.80(m,3H),1.50-0.85(m 27H),0.75(d,j=7 Hz,3H),0.69(d,j=6 Hz,6H),0.50(s,3H)。
實例3:2-(三甲基銨基)乙基十一碳-10-炔基磷酸酯之合成
類似於實例2所描述之步驟產生3.8 g 2-(三甲基銨基)乙基十一碳-10-炔基磷酸酯(2)之非晶形粉末。產率:71%。
該產物之1
H-NMR(500 MHz,CDCl3
):δ(ppm)=4.29(s,br,2H),3.90(m,2H),3.68(m,2H),3.24(s,9H),2.35(s,1H),2.22(m,2H),1.65(m,2H),1.53(m,2H),1.45-1.3(m,10H)。
類似於實例2所描述之步驟產生3.8 g2-(第三丁氧羰基胺基)-3-甲氧基-3-側氧基丙基2-(三甲基銨基)乙基磷酸酯(3)之無色油。產率:81%。
產物之1
H-NMR(500 MHz,CDCl3
)δ(ppm)=4.49(s,br,1H),4.28(m,3H),4.15(m,1H),3.67(m,2H),3.36(s,9H),3.36(s,3H),3.23(s,9H),1.46(s,9H)。
類似於實例2所描述之步驟產生2.6 g2-(三甲基銨基)乙基磷酸環戊-3-烯基酯(4)之無色油。產率:61%。
該產物之1
H-NMR(500 MHz,CDCl3
)δ(ppm)=5.75(s,2H),4.91(s,1H),4.21(m,2H),3.89(m,2H),3.21(s,9H),2.65(m,2H),2.45(m,2H)。
類似於實例2中所描述之步驟產生1.8 g植基磷酸膽鹼(5)之非晶形粉末。產率:52%。
該產物之1
H-NMR(500 MHz,CDCl3
)δ(ppm)=5.35(m,1H),4.40(m,2H),4.31(m,2H),3.81(m,2H),3.59(m,2H),3.31(s,9H),1.6(s,3H),1.6-0.9(m,18H),0.82(m,12H)。
Claims (14)
- 一種製備式Id化合物之方法,
- 如請求項1之方法,其特徵為:該第一步驟中的反應係在較佳選自包括乙腈、乙酸乙酯、二噁烷、四氫呋喃、四甲基矽烷、二甲基甲醯胺、二甲亞碸、丙酮、乙醚、甲基第三丁基醚、環己烷、二甲基乙醯胺、環丁碸、N-甲基吡咯啶酮及二氯甲烷之群之非質子溶劑中進行。
- 如請求項1之方法,其特徵為:該第一步驟中的反應係在較佳選自三級烷胺之含N鹼的存在下進行。
- 如請求項1之方法,其特徵為:該第一步驟中的反應係在室溫或冷卻下進行。
- 如請求項4之方法,其中該第一步驟中的反應係在T>0℃下進行。
- 如請求項1之方法,其特徵為:該等具有OH官能基之化合物係生物分子或生物分子衍生物。
- 如請求項6之方法,其中該等具有OH官能基之化合物係選自一元醇、二元醇、三元醇、四元醇、糖、多元醇、含有OH之胺基酸或含有OH之核酸。
- 如請求項1之方法,其特徵為:與該含有OH之化合物之反應係在室溫或降溫下進行。
- 如請求項8之方法,其中該含有OH之化合物之反應係在在T<0℃下進行。
- 如請求項9之方法,其中該含有OH之化合物之反應係在在T<-25℃下進行。
- 如請求項1之方法,其特徵為:該含N芳族化合物係,且化合物係在該第一步驟中製得。
- 如請求項1之方法,其特徵為:式Id化合物為順式-甘油基-3-磷酸膽鹼。
- 一種化合物,其係選自:
- 一種化合物,其係選自式(2)、(3)、(4)或(5)之化合物:
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JPS6156191A (ja) | 1984-08-27 | 1986-03-20 | Toagosei Chem Ind Co Ltd | リン酸トリエステル化合物の製造法 |
US6140496A (en) | 1990-10-09 | 2000-10-31 | Benner; Steven Albert | Precursors for deoxyribonucleotides containing non-standard nucleosides |
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Title |
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Kraszewski and Stawinski, "Phosphoryl tris-Triazole-a New Phosphorylating Reagent", Tetrahedron Letters, 1980, Vol.21, pages 2935-2936. * |
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US8940907B2 (en) | 2015-01-27 |
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