TW420670B

TW420670B - Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them

Info

Publication number: TW420670B
Application number: TW83103428A
Authority: TW
Inventors: Robert A Holton; Ki-Byung Chai; Hossain Nadizadeh
Original assignee: Univ Florida State
Priority date: 1992-11-13
Filing date: 1994-04-18
Publication date: 2001-02-01

Abstract

A taxane derivative having the formula wherein X1 is hydroxy; X2 is hydrogen; X3 is hydrogen; X4 is -CH=C(CH3)2; X5 is -COO(C1-6 alkyl), -COOCH2CH=CH2, -COOCH2TMS or -COOCH2Ph; R1 is hydroxy; R2 is -OCOPh; R4a is -OAc; R7 is hydrogen, hydroxy or -OAc; R9 is hydrogen or oxo together with R9a; R9a is hydrogen, hydroxy or oxo together with R9; R10 is hydrogen or oxo together with R10a; R10a is hydrogen, hydroxy, -OAc or oxo together with R10; and R14 is hydrogen.

Description

42Π6Τ0 at B7 五、發明説明（1 ) 發明背暑本發明偽針對具有為抗白血病及抗睡瘺麵之用途之新穎紫杉烷。秸烯之紫杉烷族（其中紫杉酵為一成員）*已於生物學及化學技藝界吸引相當之«注。紫杉醇為具有廣效之抗白血病及抑制β»活性之有希Μ之癌化學抬療繭》紫杉酵具有2’R, 3’S姐®及下列结構式： 0 Ac42Π6T0 at B7 V. Description of the invention (1) Invention of the summer heat The present invention is directed to a novel taxane having an anti-leukemia and anti-sleep fistula surface. The taxane family of straws (including taxanes as a member) * has attracted considerable attention in the fields of biology and chemical technology. Paclitaxel has a broad-spectrum anti-leukemia and inhibits β »activity of the cancerous cocoon that raises cancer cells." Taxase has 2’R, 3’Sister® and the following structural formula: 0 Ac

{請先閡讀背面之注意ί項再填寫本頁J 訂經，濟部中央樣準局員工消费合作社印製式中Ac為乙醢基。由於此有希望之活性，紫杉酵目前正於法鼸及美國進行明床試驗》 Colin等人於美國専利第4,814,470號中報告·具下面结構式（2)之紫杉酵衍生物具有顯著高於紫杉酵（1)之活性。本紙張尺度適用中國國家梯準（CNS)A4規格（210〆297公釐）一 4- 83.110,000 420670 at B7五、發明説明（2 ){Please read the note on the back first and then fill in the J-Book on this page. In the printed form of the Employee Consumer Cooperative of the Central Bureau of Procurement of the Ministry of Economic Affairs, Ac is Ethyl. Due to this promising activity, taxanes are currently undergoing open-bed tests in French and Americans. Colin et al. Reported in US Patent No. 4,814,470 that the taxane derivatives with the following structural formula (2) have significantly higher levels. In the activity of yew yeast (1). This paper size applies to China National Standard (CNS) A4 (210〆297 mm) 1 4- 83.110,000 420670 at B7 V. Description of the invention (2)

<讀先聞讀背面之注意事項再填寫本頁) 經濟部中央樣準局貝工消费合作社中製 Ιί，表fi蜱乙，基及R”及R，"中之一表羥華而S二者表第三丁氣獷肢基及彼等之立體異構形式*及其混合物。式（2) 中R”為羥基，R*’，為具2’R、3’S姐態之第三丁氧镞胺基之化合物通常稱為紫杉忒（taxotere)。雖然紫杉酵及紫杉忒為有希Μ之化學療劑*但彼等並非 / 普遍有效的，於是|仍有對另外之化學療劑之須要。發明g要因此於本發明之目的中，為提供有價值之抗白血病及抗臛庙劑之新類紫杉烷衍生物。因此簡言之，本發明悌針對具有包含烷基取代基之C13 支备之紫杉烷衍生物。於較佳之具《貢施例中*紫杉烷衍生物具三環或四環之中心且相當於下式：本紙張尺度逍用中8國家揉準（CNS>A4规格（ 210X297公釐）一5- 81110,000 4206*70 五、發明説明（）< Read the notes on the back and fill in this page before filling in this page) Central Samples Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative Co., Ltd., I, table fi tick B, base and R "and R," one of the table is huahuaer S both represent the third isobutyryl group and their stereoisomeric forms * and mixtures thereof. In the formula (2), R "is a hydroxyl group, and R * 'is the third one having 2'R and 3'S sister states. Butoxyamido-based compounds are commonly referred to as taxotere. Although yew yeast and yew yeast are chemotherapeutic agents with a certain MH *, they are not / universally effective, so there is still a need for another chemotherapeutic agent. SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a novel taxane derivative of valuable anti-leukemia and anti-templar agents. Briefly, therefore, the present invention is directed to taxane derivatives having a C13 support comprising an alkyl substituent. In a better example, the "taxane derivative in the Gong Shi example has a three- or four-ring center and is equivalent to the following formula: This paper size is easy to use in 8 countries (CNS > A4 size (210X297 mm)) 5- 81110,000 4206 * 70 5. Description of the invention ()

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央搮準局貝工消费合作社印製式中 .______ X:為-0Xe 、 -sx7 、或-ΝΧβΧβ ; Χ2為氫、烷基、烯基：炔基、芳基、或雜芳碁； X 3 為 9 ; Χ4為丁烯基；〆 ΧΒ為-COX1〇、-COOXi。、-C0S)ilo、-CONXeX1〇、或 -S 0 2 X 1 1 ! χβ為氬、烷基、烯基、炔基、芳基、雜芳基、羥基保護基或增加紫杉烷衍生物之水溶解度之官能基； χ7為垸基、烯基、炔基、芳基、锥芳基、或蠔基保護基 # ! » χβ為《、烷基、烯基、炔基、芳基、雜芳基或蜾雜取代之烷基、烯基、炔基、芳基或雄芳基： χβ為胺基保護基； χ1〇為烷基、烯基、炔基、芳基、雜芳基或經雜取代之訂 6丨· ίν 本紙張尺度逍用中國國家#準（CNS ) Α4规格（2丨0X297公嫠）一6 — 83.3.10,000 A7 B7五、發明説明（4 ) 420670 經濟部+央揉率局貝工消费合作社印装烷基、烯基、炔基、芳基或》芳基； Xu為烷基、烯基、炔*、芳基、雜芳基、-OXu或 -ΗΧβΧι* ； χ1Λ為氬、烷*、烯基、炔基、芳基、或雜芳基； Ri為氢、理基、經保護羥基或與«一起形成碳酸醋： 112為氳、羥基、-0C0RS1或輿R2e —起形成氧基； R2•為氳或輿一起形成氧基·， R«為氩、與1U·-起形成氧基、環氧乙烷或亞甲基，或輿Re_及彼等所連接之碩原子一起形成氧雜環丁烷環； R4„為氫、烷基、烯基、炔基、芳基、雜芳基、氰基、羥基、-OCOR3〇或與IU—起形成氣基、環氣乙烷或亞甲基 t (U為氡或與rb· —起形成氧基： Ret•為氳、羥基、埋保護羥基、雜氧基、與R8 —起形成 / 氧基|或與R 4及彼等所連接之碳原子一起形成氧轅環丁烷環： Re為氫、烷基、烯基、炔基、芳基、或雜芳基、羥基、經保護羥綦、或與IU· —起形成氧基； Rea為氩、烷基、烯基、炔基、芳基、或雄芳基、羥基、运保餿羥基或興IU —起形成氧基； b為氫或與R7e —起形成氧基； R7·為氫、由素、經保護羥基、-0R2* 、或與—起肜成氧基； IU為氬或與R»· —起形成氧基； (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度逋用中®國家樣牟（CNS > A4規格（210X297公釐）一 7 - 83. 3.10,000 420670 a? _B7 五、發明説明（5)(Please read the notes on the back before filling out this page) In the printed format of the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. ______ X: -0Xe, -sx7, or -Νχβχβ; χ2 is hydrogen, alkyl, olefin Group: alkynyl, aryl, or heteroarylfluorene; X3 is 9; X4 is butenyl; XYB is -COX10, -COOXi. , -C0S) ilo, -CONXeX1〇, or -S 0 2 X 1 1! Χβ is argon, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl protecting group or adding taxane derivatives Functional group with water solubility; χ7 is fluorenyl, alkenyl, alkynyl, aryl, cone aryl, or oyster protecting group #! »Χβ is", alkyl, alkenyl, alkynyl, aryl, heteroaryl Or heterosubstituted alkyl, alkenyl, alkynyl, aryl, and androstyl: χβ is an amino protecting group; χ10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted Order 6 丨 · ίν The size of this paper is free to use China National Standards (CNS) Α4 Specification (2 丨 0X297) 嫠 6 — 83.3.10,000 A7 B7 V. Description of the Invention (4) 420670 Ministry of Economic Affairs + Central Government Bureau Baker ’s Consumer Cooperative printed alkyl, alkenyl, alkynyl, aryl or aryl groups; Xu is alkyl, alkenyl, alkyne *, aryl, heteroaryl, -OXu or -Ηχβχι *; χ1Λ is argon , Alkane *, alkenyl, alkynyl, aryl, or heteroaryl; Ri is hydrogen, aryl, protected hydroxy or together with «to form carbonate vinegar: 112 is fluorene, hydroxy, -0C0RS1 or R2e together oxygen ; R2 • is 氲 or 氲 together to form an oxy ·, R «is argon, and form 1U ·-to form an oxy, ethylene oxide, or methylene group, or ReRe_ and their attached master atoms are formed together An oxetane ring; R4 „is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR3O or together with IU to form a gas group, a cyclogas ethane or Methylene t (U is fluorene or forms an oxy group with rb ·: Ret • is fluorene, a hydroxyl group, a buried protective hydroxy group, a heterooxy group, and R8 form a / oxy group | or with R 4 and their The connected carbon atoms together form an oxocyclobutane ring: Re is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxyl, protected hydroxyamidine, or forms an oxy group with IU · ; Rea is argon, alkyl, alkenyl, alkynyl, aryl, or andraryl, hydroxyl, hydrazone, or Xing IU — forming an oxygen group; b is hydrogen or forming an oxygen group with R7e — R7 · It is hydrogen, sulfonium, protected hydroxyl, -0R2 *, or forms oxygen with —; IU is argon or forms oxygen with R »·; (Please read the precautions on the back before filling this page) Paper size 逋In countries like Mu ® (CNS >? A4 size (210X297 mm) a 7 - 83. 3.10,000 420670 a _B7 V. invention is described in (5)

Re-為氫、羥基、經保護羥基、醯氧基、或與Re—起形成氣基： IU 〇為氫或與R ^ —起形成氧基； I。•為氫、-OCORu 、羥基、或煙保護羥基或與iU。一起形成氧基； R14為氫、烷基、烯基、炔基、芳基、雜芳基、羥基、經保饑羥基或與。一起形成磺酸醅：Re- is hydrogen, hydroxy, protected hydroxy, fluorenyloxy, or forms an amino group with Re-: IU 0 is hydrogen or forms an oxygen group with R ^; I. • Protects hydroxyl or iU from hydrogen, -OCORu, hydroxyl, or smoke. Together, it forms an oxy group; R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy, hydroxyl-protective, or hydroxy. Together form sulfonium sulfonate:

Riu為氪、烷基、烯基、炔基、芳基、或雄芳基： R2e為Μ、醢基、羥基保護基或蝤加紫杉烷衍生物之溶解度之官能基；及. R2e、R3〇及R31分別為氫、烷基、烯基、炔基、單環芳基或單環箱芳基；然而限制條件為該紫杉烷衍生物不具下式： (請先閲讀背面之注意事項再填寫本頁)Riu is fluorene, alkyl, alkenyl, alkynyl, aryl, or androstyl: R2e is a functional group of the solubility of M, fluorenyl, hydroxy protecting group or fluorene plus taxane derivative; and R2e, R3. And R31 are hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic box aryl; however, the limitation is that the taxane derivative does not have the following formula: (Please read the precautions on the back before filling (This page)

經濟部中央摞準局—工消费合作社印製式中 1^為丁烯基* R3為笨基》Printed by the Central Bureau of Standards of the Ministry of Economic Affairs and the Industrial and Consumer Cooperatives. 1 ^ is butenyl * R3 is stupid "

Ti為氬、羥基保嫌基、或-COT2，本纸張尺度逍用中國國家搞準(CNS ) Α4ί?| ( 210 X 297公釐）一 8 - 83.3.10,000 420670 A7 B7 五、發明説明（6 ) <請先閲讀背面之注意事項再填寫本頁) T2為Η 、Ci-Ce烷基、C2-Ce烯基、c2-ce炔基或單環芳基，Ti is argon, hydroxyl-protective group, or -COT2. The size of this paper is Chinese National Standard (CNS) Α4ί? | (210 X 297 mm) 8-83.3.10,000 420670 A7 B7 V. Description of the invention ( 6) < Please read the notes on the back before filling this page) T2 is Η, Ci-Ce alkyl, C2-Ce alkenyl, c2-ce alkynyl or monocyclic aryl,

Ac為乙醢基*及玨工及E2分別壤自氫及羥基保諼基。本發明之其他目的及特»部分已_然且部分於下文中指出。 »住旦《窗掄俐夕连钿逋明當本文使用” Ar”意即芳基；” Ph”意即笨基：”Ac"籯即乙釀基；"St”意即乙基；"R”意即烷基除非S有定義； "Bu”意即丁基；”Pr”意即丙基；"TES"意即三乙矽烷基； ”TMS”意即三甲矽烷基；”TPAP”意即過釕酸四丙銨；經濟部4*夬橾率局貝工消費合作杜印製 ” DMAP"意即對二甲胺基吡啶："DMF"意即二甲基甲«胺； "LDA”意即二異丙胺基化鋰；”LHMDS"意即六甲二矽ft氮化鋰："LAH"意即氩化鋁鋰；”Red-Al”意即氬化雙（2-甲氧乙氧基）鋁納；"AIBH”意即偶氰-(雙）-異丁臃； "10-DAB”蕙即10-脫乙醣基漿果赤檄素III ; FAR意即 2-氣-1,1,2-三氟三乙胺；經保護之羥基意职-0R其中R 為羥基保艚基；’’癍基保護基”包括但不限於半硫嫌醛如 1-乙氧乙基及甲氧甲基、硫_或硫磺馥_ ; ”胺保護基”包括ή不限於胺甲酸酯*例如2,2,2-三氛乙基胺甲酸酯或第三丁基胺甲酸磨；及”羥基保_基”包括但不限於醚如甲基、第三丁基、笮基、對甲氧苄基、對硝苄基、烯丙基、三笨甲基、甲氧甲基、2-甲氧丙基、甲氧乙氧甲基、乙氧乙基、四氩呋喃基、四氫哌喃基、四氳嘍喃基及三烷矽烷基 83.3.10,000 本紙張尺度逍用中國®家梯率（-CNS ) Α4规格（210X297公釐> 一 9 一 Λ20 6T〇 Α7 Β7五、發明説明（7 ) 經濟部中央梯準局貝工消費合作社印裂鰱如三甲矽烷基醱、三乙矽烷基醚、二甲芳矽烷基醚、三異丙矽焼基醚及第三丁基二甲矽烷基醚；sg如苯醣基、乙醮基、苯乙醣基、甲醣基、單_、二一及三由乙醯基如氣乙醢基、二氯乙醢基、三氯乙醢基、三氟乙醣基；及碳酸顦包括但不限於具1至6思碳原子之碳酸烷基_如甲基、乙基、正丙基、異丙基、正丁基、第三丁基；異丁基及正戊基；具1至6思《原子及Μ—或多俚鹵素原子取代之碾酸烷基_如2,2,2-三氛乙氧甲基及2,2,2-三氣乙基；具2 至6届破原子之碳酸烯基酯如乙烯基及烯丙基；具3至6 偁碾原子之碳酸瑁烷基酯如瓖丙基、環丁基、瑁戊基及環己基；及碳酸笨釀或苄賄視情況於環上Μ—或多烷氧基或硝基取代。其他羥基、技基及肢保護基可於”有楣合成中之保護基"（T.W. Greene, John liiley and Sons, 1981 )中找到。本文所述之烷基，或為單獨或具本文所定義之各種取代基，較好為於主鏈中含1至6倨碳原子及高壤15俚碳原子之低碳烷基。彼等可為經取代、直鏈、支鍵或瑁狀，且包括甲基、乙基、丙基、異丙基、丁基、己基、環丙基、環戊基、環己基之類。未文所述之烯基，或為單獨或具本文所定義之各種取代基·較佳地為於主鐽中含2至6儷碳原子及高達15儷碳原子之低碳烯基。彼等可為經取代、直鍵或支《 ·並包括乙烯基、丙烯基、異丙烯基、丁烯基、異丁烯基、己烯基之類。 (請先聞讀背面之注意事項再填寫本頁) 本紙張尺度追用中國國家標準（CNS>A4規格（210X297公釐）一 10 — 83,3,10,000 420670 a? B7 五、發明説明（8 ) 本文所述之炔基，或為軍獨或具本文所定義之各種取代基·較佳地為於主鏈中含2至6 β碳原子且高達15俚碳原子之低碳炔基。彼等可為經取代、直鍵或支鍵，並包括乙炔基、丙炔基、丁炔基、舆丁炔基、己炔基之類。本文所述之芳基部分，或為單獨或具各種取代基*含6 至15儸碳原子且包括笨基。取代基包括烷醢氧基、經保護羥基、鹵素、烷基、芳基、烯基、醣基、釀氧基、硝基、胺基、醢胺基等。苯基為較佳之芳基。本文所述之雜芳基部分，或為單獨或具各種取代基，含 5至15個原子且包括呋嘲基、_吩基、吡啶基之類。取代基包括烷氧基、經保護羥基、鹵索、烷基、芳基、烯基、醣基、酶氧基、硝基、胺基及β胺基。本文所述之«氧基包含烷基、烯基、炔基、芳基或雜芳基。本文所述之經取代烷基、烯基、炔基、芳基及雜芳基及部分|可為烷基、烯基、炔基、芳基、雑芳基及/或可含氮、氧、硫、由素•且包括例如低碳烷氧基如甲氧基、乙氧基、丁氧基、鹵素如氛基、或氟基、磚基、胺基及_基 Ο 經濟部中央揉準局貝工消费合作社印製 i據本發明已發琨相當於结構式3之化合物，顯示活體外顯著之性質•且為有價值之抗白血病及抗膻癯劑。彼等之生物活性已於活體外澜定，使用根據！>arn ess等人， 1. Cell. Biology. 91 : 479-487 (1981)之方法及人類癌畑瞄糸之微管蛋白瀏定，且可輿由紫杉酵及紫杉忒所顯現者 81110,000 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度逋用中國國家標準（CNS)A4洗格（210X297公釐）一11 一 420670 ； a? Β7 五、發明説明（9) 相比較〇於本發明之一具體賁豳例中，紫杉烷之瓖狀核之取代基 (除了 C13取代基Μ外）相當於存在於嫌果赤徽素III或 10-DAB上之取代基。亦即· 及R14•為氬，ίί1〇為氳· Ri〇e為羥基或乙醯氧基· R»及IU- —起形成氧基。R7為氩，R7為羥基，Re為氧· RBe及IU及彼等所連接之碳肜成氧雜環丁烷環，R4e為乙醸氧基· R2為氫，R2_為苯雄氧基*及“為羥基。於其他具賵實腌例中，紫杉烷具與紫杉酵或紫杉忒有MC13支鍵不同之结構及至少一倨其他之取代基。例如.R14可為羥基· ίϊ2可為羥基或-〇C〇R31 .其中R31為氫、烷基或選自下列之基 zAc is ethenyl *, and masonry and E2 are self-hydrogen and hydroxyphosphoryl groups, respectively. Other objects and features of the present invention are partially identified and partly indicated below. »Zhu Dan's" Chang Li Li Xi Lian Ming Ming "When this article uses" Ar "means aryl;" Ph "means stupid:" Ac " 籯 means ethyl alcohol; " St "means ethyl; & quot "R" means alkyl unless S is defined; " Bu "means butyl;" Pr "means propyl; " TES " means triethylsilyl;" TMS "means trimethylsilyl;" TPAP "means tetrapropylammonium perruthenate; printed by the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. DMAP " means p-dimethylaminopyridine: " DMF " means dimethylmethyl« amine "&Quot; LDA" means lithium diisopropylamide; "LHMDS" means hexalithic silicon ft lithium nitride: " LAH " means lithium aluminum hydride; "Red-Al" means argon double (2 -Methoxyethoxy) aluminum sodium; " AIBH "means dicyano- (bis) -isobutylamidine; " 10-DAB": 10-deacetylated berry erythrodin III; FAR means 2-Gas-1,1,2-trifluorotriethylamine; protected hydroxy group -0R where R is a hydroxy fluorenyl group; "fluorenyl protecting group" includes but is not limited to hemithioanal such as 1- Ethoxyethyl and methoxymethyl, sulphur or sulphur hydrazone_; "Including" is not limited to carbamates * such as 2,2,2-trifluoroethyl carbamate or tertiary butyl carbamate; and "Hydroxyphenyl" includes but is not limited to ethers such as methyl , Tertiary butyl, fluorenyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trimethyl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxy Ethyl, Tetrahydrofuranyl, Tetrahydropiperanyl, Tetrahexyl, and Trialkylsilyl 83.3.10,000 This paper size is not used in China® Home Slope (-CNS) Α4 size (210X297 mm > a 9 一 Λ20 6T〇Α7 B7 V. Description of the invention (7) Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, such as trimethylsilyl, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl Fluorenyl ether and tertiary butyldimethylsilyl ether; sg such as phenylglycosyl, ethylfluorenyl, phenethylosyl, methylosyl, mono-, di-, and tri-methyl ethoxy Dichloroethenyl, trichloroethenyl, trifluoroethylglycosyl; and europium carbonate include, but are not limited to, alkyl carbonates having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl Base, n-butyl, Butyl; isobutyl and n-pentyl; 1 to 6 "atom and M-or polyfluorinated halogen atom substituted carboxylic acid alkyl _ such as 2,2,2-trifluoroethoxymethyl and 2,2 , 2-trifluoroethyl; alkenyl carbonates with 2 to 6 atomic breaks such as vinyl and allyl; fluorinated alkyls with 3 to 6 fluorene atoms such as propyl, cyclobutyl, Pentamyl and cyclohexyl; and carbonate or benzyl carbonate optionally substituted by M- or polyalkoxy or nitro on the ring. Other hydroxyl, technical and limb protecting groups can be found in "Protective Groups in Organic Synthesis" (TW Greene, John liiley and Sons, 1981). The alkyl groups described herein may be alone or have the meanings defined herein. The various substituents are preferably low-carbon alkyl groups containing 1 to 6 倨 carbon atoms and 15 俚 high carbon atoms in the main chain. They may be substituted, linear, branched, or fluorene-like, and include Methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like. Alkenyl not mentioned above, or alone or with various substitutions as defined herein. Is preferably a lower alkenyl group containing 2 to 6 carbon atoms and up to 15 carbon atoms in the main group. They may be substituted, straight-bonded or branched, and include vinyl, propenyl, Isopropenyl, butenyl, isobutenyl, hexenyl, etc. (Please read the precautions on the back before filling out this page) This paper follows the Chinese national standard (CNS > A4 specification (210X297 mm)) 10 — 83,3,10,000 420670 a? B7 V. Description of the invention (8) The alkynyl group described in this article is either military or unique. The various substituents defined are preferably low-carbon alkynyl groups containing 2 to 6 β carbon atoms and up to 15 俚 carbon atoms in the main chain. They may be substituted, straight or branched, and include ethynyl , Propynyl, butynyl, butynyl, hexynyl and the like. The aryl moieties described herein may be alone or have various substituents * containing 6 to 15 carbon atoms and including a benzyl group. Substitutions Groups include alkoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, glycosyl, alkoxy, nitro, amino, amido, etc. Phenyl is the preferred aryl. The heteroaryl moiety mentioned above may be alone or have various substituents, containing 5 to 15 atoms and including furyl, pheno, pyridyl and the like. Substituents include alkoxy, protected hydroxyl, halo , Alkyl, aryl, alkenyl, glycosyl, enzyme oxy, nitro, amine, and beta amine. As used herein, "oxy" includes alkyl, alkenyl, alkynyl, aryl, or heteroaryl. The substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein may be alkyl, alkenyl, alkynyl, aryl, fluorenyl, and / or Nitrogen, Oxygen, Sulfur, Benzene and includes, for example, lower alkoxy groups such as methoxy, ethoxy, butoxy, halogens such as fluoro, fluoro, brick, amine, and radical Printed by the Central Government Bureau of Shellfish Consumer Cooperatives According to the present invention, compounds equivalent to structural formula 3 have been developed, showing significant properties in vitro • and are valuable anti-leukemias and anti-tidal agents. Their biological activity It has been determined in vitro and used according to the method of > arn ess et al., 1. Cell. Biology. 91: 479-487 (1981) and the tubulin of human cancer cells. Yew Yeast and Yew Mandarin 81110,000 (Please read the notes on the back before filling out this page) This paper uses Chinese National Standard (CNS) A4 Washing (210X297 mm)-11-420670; a? B7 V. Description of the invention (9) In comparison, in one specific example of the present invention, the substituents (except the C13 substituent M) of the tadpole-shaped nucleus of taxane are equivalent to those present in erythromycin III. Or a substituent on 10-DAB. That is, · and R14 · are argon, ίί10 is 氲, Ri〇e is hydroxyl or ethoxy, and R »and IU- together form an oxy group. R7 is argon, R7 is hydroxy, Re is oxygen. RBe and IU and the carbocyclic oxetane ring to which they are attached, R4e is ethoxyl, R2 is hydrogen, and R2_ is phenylandrostyl * And "is a hydroxyl group. In other examples of solid pickles, taxanes have a structure different from the MC13 branch of taxane or taxane, and have at least one other substituent. For example, R14 may be a hydroxyl group. 2 It may be hydroxy or -0COR31. Wherein R31 is hydrogen, alkyl or a group selected from the group consisting of z

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局男工消费合作社印製且Z為烷基、羥基、烷氧基、鹵素或三氟甲基〇ΐ{ββ可為氫及1?«可為氬或羥基，可為氫及可為乙醮氧基或其他ώ氧基或鹵素，或R10及1?10«可各為《或一起肜成氧基〇有MC13支《，於較佳具體霣施例中·又1為-0[1 , “為氬* χ3為氬，χ4為丁烯基，又15為-(：(^1〇或-(：0(^1〇，及 χ1〇為烷基、烯基、炔基、芳基、呋哺基、瘙吩基或其他本紙張尺度逋用中國國家揉準（CNS>A4規格（ 210X297公釐）一 12 — 83.3.10,000 420670 A7 B7 五、發明説明（11 锥芳基，即紫杉烷例中* X4為異丁烯喃基、噻吩基、烷三一、異一、或正基、環己基、烯丙 2-甲氧Z*基、戊基 -HH„Pr、-HHPh 、具通式3之紫杉四現之核及C-13金 C-13上具爲一鼸胺结構式：具；TR, 3’S姐態。於待別較佳具體實_ 基，叉6為-(：(^1〇或-(：0(^1。及Xi。為呋基取代之呋哺基或嘻吩基、吡啶基、第一丁基、乙基、異一或正一丙基、環丙 *、巴豆基、1,3-二乙氣-2-丙基、、新戊基、PhCH2〇- 、-NPhz 、或-NHEt 。烷可藉由/9 一内醢胺與具紫杉烷三環或鼷氣化物取代基之酵鹽反應肜成於基齙取代基而製得。冷一内β胺具下列(Please read the precautions on the back before filling this page) Printed by the Men ’s Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and Z is alkyl, hydroxyl, alkoxy, halogen or trifluoromethyl 〇 {(ββ may be hydrogen and 1? «Can be argon or hydroxyl, can be hydrogen and can be ethoxyl or other free oxygen or halogen, or R10 and 1 ~ 10« can each be "or together to form oxygen. There are MC13 branches", In a preferred embodiment, 1 is -0 [1, "is argon * χ3 is argon, χ4 is butenyl, and 15 is-(: (^ 1〇 or-(: 0 (^ 1〇 , And χ10 is an alkyl, alkenyl, alkynyl, aryl, furanyl, phenenyl, or other paper standard, using the Chinese national standard (CNS > A4 specification (210X297 mm)-12-83.3. 10,000 420670 A7 B7 V. Description of the invention (11 Cone aryl group, that is, in the case of taxane * X4 is isobutenyl, thienyl, alkanetrione, isoone, or n-, cyclohexyl, allyl 2-methoxy Z * Base, pentyl-HH „Pr, -HHPh, yew core with general formula 3 and C-13 gold C-13 with monoamine structure formula: with; TR, 3'S sister state. To be better and more concrete, the fork 6 is-(: (^ 1〇 -(: 0 (^ 1. And Xi. Are furyl-substituted furanyl or oxopentyl, pyridyl, first butyl, ethyl, iso- or n-propyl, cyclopropyl *, crotonyl, 1,3-Diethyl-2-propyl,, neopentyl, PhCH2〇-, -NPhz, or -NHEt. Alkanes can be obtained via / 9-endoamine and a taxane tricyclic or tritium gas. Substituted fermented salt is prepared by reacting with the substituent of the base. The β amine in the cold one has the following

X 5\ (請先聞讀背面之注意事項再填寫本頁) 訂X 5 \ (Please read the notes on the back before filling this page) Order

XX

V 經濟部中夹棋準局貝工消奢合作社印裝式中Xi-XB如上述。卢一内醮胺可自易得之物霣*如下面_示A及B中之說明痴備·· 本紙張尺度逋用中國國家標準（CNS)A4規格（2UXX297公嫠）一 13_ 83.1.10,000 4 2 0 6 7 0 A7 B7 五、發明説明（π)V The Xi-XB in the printed form of the Beige Consumers Luxury Cooperatives of the Chinese Vice President of the Ministry of Economy. Lu Yiliamine can be easily obtained. * As shown below_indicated in A and B. This paper size uses the Chinese National Standard (CNS) A4 specification (2UXX297). 13_ 83.1.10,000 4 2 0 6 7 0 A7 B7 V. Description of the invention (π)

圓示A 經濟部中央揉準局員工消費合作社印製Yuanshi A Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

χ 3 Χ2 —Ί——.—.----产------訂------r (請先閔讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家樣率（CNS ) A4規格（2丨0X297公釐）一14一 83· 3.10,000 420670 經濟部中夹揉準局貝Μ消費合作社印m 五、發明説明（1) 試爾：（a)三乙胺，CH2CU，25t!，18小時；（b) 4當最之硝酸鈽铵，CH3CN，-101C，10分；（c) KOH ，THF ， H20，01C . 30分，或吡咯啶•吡啶* 25t!，3小時，（d) TESC1 ，吡啶，25t；，30分或2-甲氧丙烯甲苯磺酸 (cat.)，THF，Ot： * 2 小時；（e)正丁基鋰* THF ，-78 X： · 30分；及醢氛或«甲酸_(XfC0X1〇) : (f>二興丙胺基化鋰，THF· -78t至-50 υ ; U)六甲二矽疊氰化鋰，THF· 至 0 *C ; (h)THF* -78C 至 25¾ * 12小時》起始物質易於得到。於示A中·《 —乙醢氣基乙釀» 係自乙酵酸且於三«Κ存在下製備，其與自醛友對甲氧基苯胺製榭之亞胺起《嫌合作用，得卜對甲氧笨基-3-釀氧 -4-芳基一氮四園-2-酮。對甲氧苯基可經由从硝酸钸銨氣化而容易地除去•而_氧基可於精於此道者所热悉之禰準條件下水解得3-羥-4-芳基一氮四園-2-酮。於B示B / 中· α —三乙矽烷氧基乙酸乙曲易於自乙酵酸製備。於圔示Α及Β中，Xi較好為-0Χβ及Χβ為羥基保護基。保護基為2-甲氧丙基（"Μ0ΡΜ)、1-乙氧乙基（"ΕΕ")為佳· 但各種其他之標準保_基如三乙矽烷基或其他三烷基（或芳基）矽烷基可使用。如上所提，另外之羥基保_基及其合i可於"有欐合成中之保__"(T.W. Greene, John Vi ley & Sons, 1981)中找到。濟旋之/9 —内醢胺可在保護前，藉由對應之2-甲氧-2-(三氟甲基）笨基乙酸酯之重結晶離析成純對掌異構物。然而，下文所述之反齷（其中將0 —醢胺基酯支鐽連接）具 JI. 1 1^1 ^ n f' (請先閲讀背面之注意事項再填寫本頁) 訂 V. 本紙張尺度適用中國Η家橾準（CNS)A4说格（210X297公釐）一 15 — 83. 3.10,000 420670 A7 B7 五、發明説明（13) 有高度非對箪異構選擇性之好處，因此允許使用支鍵前駆賵之消旋混合物。具三環或四瑁紫杉烷核及C-13金靨氧化物或氧化銨取代基之醇Μ具下列结構式：χ 3 Χ2 —Ί ——.—.---- Production ------ Order ------ r (Please read the precautions on the back before filling out this page) This paper size applies to Chinese national samples Rate (CNS) A4 specification (2 丨 0X297 mm)-14-83 · 3.10,000 420670 Printed by the Ministry of Economic Affairs, the Bureau of Consumers, Cooperative Consumer Cooperatives, and m. 5. Description of the invention (1) Trial: (a) Sanyi Amine, CH2CU, 25t !, 18 hours; (b) 4 when the ammonium ammonium nitrate, CH3CN, -101C, 10 minutes; (c) KOH, THF, H20, 01C. 30 minutes, or pyrrolidine • pyridine * 25t !, 3 hours, (d) TESC1, pyridine, 25t ;, 30 minutes or 2-methoxypropylene toluenesulfonic acid (cat.), THF, Ot: * 2 hours; (e) n-butyllithium * THF,- 78 X: · 30 minutes; and the atmosphere or «formic acid_ (XfC0X1〇): (f > lithium dipropylpropylamine, THF · -78t to -50 υ; U) lithium hexamethyldisilazide, THF · To 0 * C; (h) THF * -78C to 25¾ * 12 hours "The starting material is readily available. In “A”, “—Ethyl carbamoyl ethyl alcohol” is prepared from acetic acid and in the presence of three «κ. It is used in conjunction with the imine produced from aldol p-methoxyaniline. Bu p-methoxybenzyl-3-vinyl-4-aryl-tetrazol-2-one. P-methoxyphenyl group can be easily removed by gasification from ammonium nitrate. And _oxy group can be hydrolyzed to 3-hydroxy-4-aryl-tetrazolium under standard conditions known to those skilled in the art. Orn-2-one. B is shown in B / Medium. Α-Triethoxysilylacetic acid is easily prepared from acetic acid. In the formulae A and B, Xi is preferably -0 × β and Xβ is a hydroxyl protecting group. The protecting group is preferably 2-methoxypropyl (" MIMO) and 1-ethoxyethyl (" ΕΕ "), but various other standard protecting groups such as triethylsilyl or other trialkyl (or Aryl) silane groups can be used. As mentioned above, other hydroxyl groups and their combinations can be found in " Polymers in Ammonia Synthesis " (T.W. Greene, John Viley & Sons, 1981). Ji Xuanzhi / 9-Linolide can be isolated into pure para palmar isomers by recrystallization of the corresponding 2-methoxy-2- (trifluoromethyl) benzyl acetate before protection. However, the reverse method described below (where the 0-amido branch is linked) has JI. 1 1 ^ 1 ^ nf '(Please read the precautions on the back before filling this page) Order V. This paper size Applicable to China National Standards (CNS) A4 (210X297 mm)-15-83. 3.10,000 420670 A7 B7 V. Description of the invention (13) Has the advantage of high non-isomeric heterogeneous selectivity, so it is allowed to use Racemic mixture of branched fronts. The alcohol M having a tricyclic or tetrafluorene taxane core and a C-13 arsine oxide or ammonium oxide substituent has the following structural formula:

式中IU-R14••如前所定義及Η包括按或為金鹰視情況選自 / ΙΑ族、ΙΙΑ族及過度金屬且較佳為Li、Hg、Na、Κ或Ti。最佳地•酵鹽具四環紫杉烷核且相當於下面結構式： (請先閲讀背面之注意事項再填寫本頁) 經濟部中央揉準局貝工消費合作社印装 MOlllllIn the formula, IU-R14 is defined as above and Η includes or is selected from Group IA, Group IA and transition metal, and is preferably Li, Hg, Na, K or Ti, as appropriate. Optimally • Fermented salt has a tetracyclic taxane core and is equivalent to the following structural formula: (Please read the precautions on the back before filling out this page) Printed by the Central Labor Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, MOlllll

R. 式中 H、R2、R·*·、R7、1ί·7β、Re、Re·、Ri〇及如前所本紙張尺度逍用中國國家揉準（CNS)A4规格（ 210X297公釐）一 16 — 81110,000 ' 42067^ A7 B7 五、發明説明（14 定義。酵鹽可《由具紫杉wac-l 3理·基之酵與有櫬金羼化合物於迪宜溶靖中反應而製備。最佳地，酵為經保護之漿果赤徹素III ·尤其是7-0-三乙矽烷基漿果赤徽素丨‘11(其可如 Greene,笠人於JACS 1 10 : 5917 (1988)中所述或由其他途徑製得）或7,10-雙-0-三乙矽烷基漿果赤黴素ΪΙΙ 。根據Greene等人之報告，將10-脫乙_基漿果赤黴素 III依下列反應晒示轉化成7-0-三乙砂烷基-10-脫乙釀基漿果赤靄素III :R. In the formula, H, R2, R · * ·, R7, 1ί · 7β, Re, Re ·, Ri〇 and the paper size used in the previous Chinese National Standard (CNS) A4 (210X297 mm) 16 — 81110,000 '42067 ^ A7 B7 V. Description of the invention (14 Definitions. Fermentation salts can be prepared by reacting yeast with yew wac-l 3 physyl radical and gold compound with hydrazone in Diyi solution. Optimally, the leaven is the protected berry chelatin III · especially 7-0-triethylsilyl berry erythromycin 丨 '11 (which can be used as Greene, Tadpole JACS 1 10: 5917 (1988) As described in or prepared by other means) or 7,10-bis-0-triethylsilyl berry gibberellin III. According to the report of Greene et al., 10-deethyl-baccatin III was prepared as follows The reaction shows that it is converted into 7-0-triethylsalyl-10-deethylated berry erythrodin III:

OHOH

1 . /CCjH533S i Cl v c5h5n 2. CH3COCI , CsH5N (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局爲工消費合作社印«.1. / CCjH533S i Cl v c5h5n 2. CH3COCI, CsH5N (Please read the notes on the back before filling out this page) The Central Standards Bureau of the Ministry of Economic Affairs printed for the Industrial and Consumer Cooperatives «.

OROR

於據報告小心地使最a之條件下，將ίο-脫乙b碁漿果本紙張尺度逍用中困蔺家揉準（CNS ) A4規格（210X297公嫠）一 1 7 — 81 3.10,000 420670、 A7 •V B7 五、發明説明（1' 赤徽素III與20當量之（C2He)3SiCl於於50«升吡啶/ ¾莫耳10-脫乙釀基漿下反應•於鈍化後W 84-86X產率得7-三醮基漿果赤徽素111(43)為反應產物。況K5當量之CH3C0C1及25«升吡啶/ 、酋大氣下乙釀化48小時，K 86X產率漿果赤謙素III(4b), Greene等人*於 5918 (1988)。 7-經保護之菜果赤徽素III(4b)與有 LHHDS於溶劑如四氳味(THF)中，如示反應形成金靥酵邇13-0-鋰-7-0-三乙 III ： 23TC、籌大氣下，果赤徽素III存在乙矽烷* -10-脫乙反蘼產物可再祺情奄莫耳4a，於0 t：得7-0-三乙矽烷基 JACS 110. 5917至櫬金靄化合物如下面反應_示中所矽烷基漿果赤黴素 (請先閲讀背面之注意1P項再填寫本页> -----訂 LHMOS + 經濟部中央標準局属工消费合作杜印裂Under the conditions that are reported to be carefully adjusted to the maximum a, the paper size of οο-deacetylate is reduced, and it is difficult to use the standard paper (CNS) A4 size (210X297) 嫠 1 7 — 81 3.10,000 420670 , A7 • V B7 V. Description of the invention (1 'erythromycin III and 20 equivalents of (C2He) 3SiCl reacted under 50 «liter pyridine / ¾ Mor 10-deacetylated base pulp • After passivation W 84- The yield of 86-yield 7-trisyl berry erythromycin 111 (43) is the reaction product. In addition, K5 equivalents of CH3C0C1 and 25 «liter pyridine / acetic fermentation for 48 hours in the atmosphere, K 86X yield of erythromycin III (4b), Greene et al. * In 5918 (1988). 7-Protected vegetables and fruits erythromycin III (4b) and LHHDS in a solvent such as tetramethylene scent (THF), as shown in the figure to form a gold ferment.迩 13-0-lithium-7-0-triethyl III: At 23TC, the presence of ethoxysilane in erythromycin III * -10-deethylation reaction product can be reunited with Moore 4a, at 0 t : Get 7-0-triethylsilyl JACS 110. 5917 to the gold compound as shown below _ shown in the silyl berry gibberellin (please read the note 1P on the back before filling this page > --- --Order LHMOS + Central Standards Bureau of the Ministry of Economy Consumer cooperatives and India split

THF ^'. 本纸張尺度逍用中國國家揉準（CNS>A4規格（ 210X297公釐）一18- 83. 3.10*000 420670 at B7 五、發明説明（16 ) onTHF ^ '. The size of this paper is in accordance with China's national standard (CNS > A4 size (210X297mm)-18- 83. 3.10 * 000 420670 at B7 V. Description of the invention (16)

ococ6h5ococ6h5

如下面反應臞示中所示，13-0-鋰- 7-0-三乙矽烷基漿果赤雒素III與/3 —内醢胺（其中Χα較好為-0Χβ (Χβ為羥基保譲基）及）ίζ-ΧΒ如前所定義）反»，得其中C-7及 cy羥基經保護之中間钧。保護基再於不干播醯鍵或紫杉烷取代基之溢和條件下水解 AcO (請先閲讀背面之注意事項再填寫本頁) 經濟部中央樣準局貝工消费合作社印策As shown in the reaction scheme below, 13-0-lithium-7-0-triethylsilyl berry erythrophin III and / 3-lactamamine (wherein Xα is preferably -0Xβ (Xβ is a hydroxyprotective group) ) And) Γζ-χΒ as previously defined) anti », in which the C-7 and cy hydroxyl groups are protected. The protecting group is hydrolyzed under the conditions of non-drying bond or taxane substitution (please read the notes on the back before filling this page).

鑄之轉化成薄81及最後合成紫杉烷衍生物可於同一反應本紙張尺度適用中®H家揉率（CNS)A4规格（210X297公董）一 19— 813.10,000 420670 A7 B7五、發明説明（17 ) 經濟部中央標準局員工消费合作社印裝容器中發生。較佳地，於其中形成酵鹽後，將3 —内釀胺加至反應容器。本發明之式3化合物有用於抑制動物（包括人類）之腫钃生長，且較好K含有效之抗膻β量之本發明化合物與路第上可接受之栽劑或稀釋劑混合之》蕖组合物形式投蕖。本文之抗腫癎姐合物可Κ逋合所須之用途例如口服、腸外或局部投蕖之任何逋宜形式姐成。睹外給藥之霣例為肌肉内、靜赈内、腹旗内、直腸及皮下給藥。稀釋劑或«劑成分不應會《少抗膣期化合物之療效者。供口服之遘宜覿型包括錠劑、分敗用散劑、頼粒劑、膠囊鯆、懸浮液、辘漿阐及醮劑》供錠瘌之檐性稀释Β(及載劑包括例如碳酸鈣、碳酸納、乳糖及滑石。錠劑亦可含粒化劑及崩敗爾如教粉及薄酸•黏合爾如«粉、明膠及金合歡膠，及獮滑劑如硬脂酸鎂、硬脂$及滑石。淀劑可為未烴塗佈或可«已知技術加Μ塗佈；例如延緩崩敗及吸收。可用於膠囊_之憤性稀釋劑及載劑包括例如碳酸鈣、磷酸鈣及陶土。想浮液、糖漿_及酏鵡可含習用之賦形劑•例如甲基孅維素、黄蕾謬、糠酸納：潤湄劑如弗磷脂及聚硬脂酸氧乙二酵及防腐_例如對羥基苯酸乙釀。 ik宜腸外給藥之劑型包括溶液、懸浮液、分敢液、乳疲之類。彼等亦可製埴成可在臨用前溶解或懸浮於滅菌注射用媒霣中之滅菌固體组合物之形式。彼等可含技藝中已知之想浮或分散劑。式（3)化合物之水溶解度可賴修飾C2’及/或C7取代基 (請先閎讀背面之注意事項再填寫本頁) 本紙張尺度逍用中國國家揉準（CNS ) A4現格（210X297公釐）_ 2 0 — 83.3.10,000 420670 A7 B7五、發明説明（18) 而增進。例如，若為-〇Rze，及义0與（128分別為S或-COGCOR 1其中 G為伸乙基、伸丙基、-CH = CH- ' 1 , 2-環己烷或1,2-伸苯基· R1= 0H贓、NR2R3 、 OR3 、 SR3 、 OCH2CONR4Rs 、 OH R2=氫、甲基 R3= (CHz)„MReR7 ； (CHa)„N® ReR7RaX® n = 1 至 3 R4=S、含1至4個碳之低碳烷基 f = S、含1至4偁碳原子之低碳烷基、苄基、羥乙基、（:H2C〇2H 、二甲胺乙基 ReR7=含1至2俚碳之低碳烷基、苄基或與 NReR7之氮原子一起形成下列之環Conversion of cast to thin 81 and the final synthetic taxane derivative can be used in the same reaction. This paper size is applicable. H family kneading rate (CNS) A4 specification (210X297). 19- 813.10,000 420670 A7 B7 V. Invention Note (17) Occurred in printed containers of consumer cooperatives of employees of the Central Standards Bureau of the Ministry of Economic Affairs. Preferably, after the fermented salt is formed therein, 3-lactam is added to the reaction vessel. The compound of the formula 3 of the present invention is useful for inhibiting the growth of swelling in animals (including humans), and it is preferred that the compound of the present invention containing an effective anti- 膻 β amount is mixed with an acceptable vehicle or diluent on the road. The composition is cast. The antitumor compounds described herein can be formulated in any suitable form such as for oral, parenteral or topical administration. Examples of external administration include intramuscular, intramuscular, intraventricular, rectal and subcutaneous administration. Diluents or ingredients should not be less effective than those with anti-diarrheal compounds. Suitable tablets for oral administration include tablets, powders, granules, capsules, suspensions, syrups, and tinctures. "Emulsion dilutions for tablets (and carriers such as calcium carbonate, Sodium carbonate, lactose, and talc. Lozenges can also contain granulating agents and disintegrating powders such as edible powder and thin acids. Binders such as «powder, gelatin, and acacia gum, and slip agents such as magnesium stearate, stearin $ And talc. The precipitant can be unhydrocarbon coated or can be coated with known techniques plus M; for example, to delay collapse and absorption. Inactive diluents and carriers that can be used in capsules include, for example, calcium carbonate, calcium phosphate and Clay. Think of floating liquids, syrups, and crocodile can contain customary excipients such as methyl sulvin, Huang Leimu, sodium furoate: emollients such as phospholipids and polystearate Preservatives_ such as ethyl p-hydroxybenzoate. Ik Formulations suitable for parenteral administration include solutions, suspensions, split liquids, milk fatigue and the like. They can also be prepared and dissolved or suspended in sterilization before use. The form of a sterilized solid composition in a vehicle for injection. They may contain a floating or dispersing agent known in the art. The compound of formula (3) Water solubility depends on the modification of C2 'and / or C7 substituents (please read the precautions on the back before filling out this page) This paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) _ 2 0 — 83.3.10,000 420670 A7 B7 V. Description of the invention (18). For example, if it is -〇Rze, and meanings 0 and (128 are S or -COGCOR 1 where G is ethylene, propyl,- CH = CH- '1, 2-cyclohexane or 1,2-phenylene · R1 = 0H, NR2R3, OR3, SR3, OCH2CONR4Rs, OH R2 = hydrogen, methyl R3 = (CHz) MRER7; ( CHa) N® ReR7RaX® n = 1 to 3 R4 = S, lower alkyl with 1 to 4 carbons f = S, lower alkyl with 1 to 4 carbon atoms, benzyl, hydroxyethyl , (: H2C〇2H, dimethylaminoethyl ReR7 = lower alkyl group containing 1 to 2 carbon atoms, benzyl group or together with the nitrogen atom of NReR7 to form the following ring

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局貝工消費合作衽印裝 ΐίβ=含1或2個碳之低碳烷基、苄基 X® = 鹵化物 «= NH3、（H0C21U)3N、N(CH3)3、CHaN(C2[U0H)2、 NH2(CH2)eHH2 、N-甲基胺基葡糖、Na0H、K0H 則水溶解度增加。本紙張尺度逍用中國國家捸準（CNS ) A4規格（210X297公釐）—2 1 — 81 3.10,000 420670 A7 B7 五、發明说明（19) 化合物中乂1或）^為-COGCOR1者之製備記逑於Haugwitz美 Η專利4,942,184 ，將其併入本文供#考。替代地，當XiM-OXe及Χβ為具式-COCX=CHX或 -C0X-CHX-CHX-SO20-M (其中）{為氫、烷基或芳基及Μ為氫、联金屬或如Kingston等人於美國專利第5,059,699中所述之銨-(aiaonio)基（併人本文供參考））之基時•則溶解度可增加。具替代之C9鬭基取代基之紫杉烷可拜選擇性埋原得對應之C9/3—羥基衍生物而製懺。«原繭較好為翻氫化物，且最佳地為《氫化四丁基銨（Bu4NBH4)或三乙醮氧基_〇|氫化物。如反應匾示1中之說明•漿果赤徽素III與Bu4NBfU於二氛甲烷中之反應得9-脫氧基-9/3-羥基漿果赤徽素111 5 。C7羥基Μ例如三乙矽烷基保護基保護後竈宜之支鍵可如本文之他處所述連接於7-經保謅-9冷-羥基衍生物6 。留下之保護基之除去因此得具C13支》之9冷-羥基-脱氧基紫杉酵或其他9/S -羥基四環紫杉烷。 (請先闉讀背面之注意事項再填寫本頁) r 趄濟部中央標準局貝工消费合作杜印«- 本紙張尺度逋用中國國家揉準（CNS ) A4规格（210X297公釐）一 2 2 — 83. 3.10,000 420670 A7 B7 五、發明説明（20 )(Please read the precautions on the back before filling out this page.) Shellfish Consumer Cooperation of the Central Bureau of Standards of the Ministry of Economy (printed) β β = lower alkyl with 1 or 2 carbons, benzyl X® = halide «= NH3, (H0C21U) 3N, N (CH3) 3, CHaN (C2 [U0H) 2, NH2 (CH2) eHH2, N-methylaminoglucose, Na0H, K0H, the water solubility increases. This paper uses Chinese National Standards (CNS) A4 (210X297 mm) — 2 1 — 81 3.10,000 420670 A7 B7 V. Description of the invention (19) Compounds with 1 or ^^-COGCOR1 It is described in Haugwitz US Patent 4,942,184, which is incorporated herein by reference. Alternatively, when XiM-OXe and Xβ have the formula -COCX = CHX or -C0X-CHX-CHX-SO20-M (where) {is hydrogen, alkyl or aryl and M is hydrogen, bimetal or such as Kingston, etc. When the base of the ammonium- (aiaonio) group described in U.S. Patent No. 5,059,699 (and herein incorporated by reference) is used, the solubility can be increased. Taxanes with alternative C9 fluorenyl substituents can be prepared by selectively burying the corresponding C9 / 3-hydroxy derivatives. «The original cocoon is preferably a hydride, and most preferably« tetrabutylammonium hydride (Bu4NBH4) or triethylhexyloxy_〇 | hydride. As described in the reaction plaque 1 • The reaction of berry erythromycin III and Bu4NBfU in dichloromethane gives 9-deoxy-9 / 3-hydroxyberry erythromycin 111 5. A C7 hydroxy M, such as a triethylsilyl protecting group, may protect a branch of the rear bond, as described elsewhere herein, and may be attached to the 7-Cyto-9 cold-hydroxy derivative 6. Removal of the remaining protecting groups therefore results in a C13 branch of 9 cold-hydroxy-deoxytaxane or other 9 / S-hydroxytetracycline. (Please read the notes on the reverse side before filling out this page) r The Ministry of Economic Affairs, Central Bureau of Standards, Consumer Product Cooperation Du Yin «-This paper size uses China National Standards (CNS) A4 (210X297 mm)-2 2 — 83. 3.10,000 420670 A7 B7 V. Description of the invention (20)

OAC HOUOAC HOU

Βυ,,ΝΒΗ,Βυ ,, ΝΒΗ,

TESCt et3nTESCt et3n

6 (請先閲讀背面之注意事項再填寫本頁) 疒經濟部中夬梯率局一®：工消费合作社印製替代地，7-經保護-9/3 -羥基衍生物6之C13羥基可如反應鬮示2中之說明以三甲矽烷基或其他保護基保護，其坷k對於C7羥基保護基選擇性地除去，使能進一步遘擇性的搡作紫杉烷之各種取代基。例如· 7,13-經保護-9召-理基衍生物7與KH之反應，引起乙酸醅基自CIO移至C9及理基自C9移至C10 ·因此得10-脫乙釀基衍生物8。10-脫乙醣基衍生物8之C10羥基以三乙矽烷基保護得衍生物9 本纸張尺度逍用中國國家揉牟（CNS ) A4规格（210X297公釐）一 23 — 83.3.10,000 420670 A7 B76 (Please read the notes on the back before filling out this page) 夬 Middle of the Ministry of Economic Affairs 夬 Elevation Bureau 1®: Printed by the Industrial and Consumer Cooperatives instead, 7-protected-9 / 3 -C13 hydroxy derivatives of hydroxy derivatives 6 As described in Reaction Scheme 2, it is protected with trimethylsilyl or other protecting groups, and its 坷 k is selectively removed from the C7 hydroxyl protecting group, enabling further selective use as various substituents of taxane. For example, · The reaction of 7,13-protected-9-yl-derivative 7 with KH caused the acetic acid acetonyl group to move from CIO to C9 and the aryl group from C9 to C10. Therefore, a 10-deacetylated derivative was obtained 8.10-Deacetylated Derivatives 8 The C10 hydroxyl group of 8 is protected with triethylsilyl to obtain a derivative 9 This paper is scaled to the Chinese National Standard (CNS) A4 (210X297 mm)-23 — 83.3.10,000 420670 A7 B7

五、發明説明（U °CU羥基保護*自衍生物9之适揮性除去得衍生物10, 於其上可如上述連接邊宜之支鍵。反_ B尕2 0AC HQmV. Description of the invention (U ° CU hydroxyl protection * Derivative 10 is removed from the compatibility of derivative 9 on which the branch bond can be connected as described above. Anti_ B 尕 2 0AC HQm

OTES PhOTES Ph

QAC ores TMSOM 1) TMSCI , et3NQAC ores TMSOM 1) TMSCI, et3N

TMS0h_.« (請先聞讀背面之注意事項再填寫本頁)TMS0h_. «(Please read the notes on the back before filling out this page)

£ "Γ£ " Γ

ores T£5c Iores T £ 5c I

經濟部中夾揉準局貝工消費合作社印製 oresPrinted by the Shellfish Consumer Cooperative of the Central Bureau of Economic Affairs

1 0 如反應_示3中所示*可箱氧化10-脫乙鶸基衍生物8 提供10-氧基衍生物11。其後可理擇性地除去C13羥基保本紙浪尺度逋用中國國家揉準（CNS>A4規格（ 210X297公釐} 一 24- 813.10,000 反鹿B示31 0 As shown in Reaction_Scheme 3 * 10-deacetylamidine derivative 8 can be box-oxidized 8 to provide a 10-oxy derivative 11. After that, the C13 hydroxy-protected paper can be reasonably removed, and the size of the paper should be corrected according to the Chinese national standard (CNS > A4 (210X297 mm)-24- 813.10,000.

420 6 70 A7 _^_B7 五、發明説明（22) 護基，接著如上述連接支鐽，得具C-1 3支鍵之9-乙醢氧棊 -10-氧基-紫杉酵或其他9-乙醢氧基-ίο-氧基四瓚紫杉烷。替代地，藉堪原劑如二碘化釤堪原10-氧基衍生物n, 可選擇性地除去C9乙酸酷基，得9-脫氧基- ίο-叙基衍生物 12，自其可選擇性地除去π 3羥基保護基，接著如上述埋接支鍵’得具C13支鏈之9-脫氧基-10-氧基-紫杉酵或其他9-脱氧基-10-氧基四環紫杉烷。 (諳先聞讀背面之注意事項再填寫本頁)420 6 70 A7 _ ^ _ B7 V. Description of the invention (22) Protective base, and then connecting the branch as described above, to obtain 9-acetoxyoxo-10-oxy-taxane or other with C-1 3 branch bond 9-Ethyloxy-Lio-tetrahydrotaxane. Alternatively, C9 acetate can be selectively removed by using a kanogen agent such as diiodinated kankan 10-oxy derivative n to obtain 9-deoxy-L-syl derivative 12, which can be selected from it. Remove the π 3 hydroxyl protecting group, and then embed the branched bond as described above to obtain 9-deoxy-10-oxy-taxane with C13 branch or other 9-deoxy-10-oxy tetracyclic violet Taxane. (谙 First read the notes on the back before filling out this page)

00

0TES 經濟部中央標準局員工消費合作社印裝0TES Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

TUSOHTUSOH

反應國示4說明其中10-DAB被堪原之反應得五元醇13。五元酵13之C7及CIO羥基可再K三乙矽焼基或另外之保護本纸張尺度逋用t囲困家揉準（CNS)A4規格（210x297公釐）一 25 一 83.3.10,000 420670 A7 B7 五、發明説明（23 ) 基遘擇性地保護，得三元酵14，於其上可如上述連接C13 支鍵•或替代地，於進一步修鎳四環之取代基後為之。反K 示.iThe reaction state 4 shows that 10-DAB is reacted by kangen to obtain pentanol 13. The C7 and CIO hydroxyl groups of the five-membered yeast 13 can be protected with triethylsilyl or other paper sizes. Use the standard (CNS) A4 (210x297 mm)-25-83.3.10,000 420670 A7 B7 V. Description of the invention (23) The base is selectively protected to obtain the ternary yeast 14 on which the C13 branch can be connected as described above or, alternatively, after further repairing the substituent of the nickel tetracyclic ring. Inverse K.i

CH，CICH, CI

OHOH

0TES0TES

14 {請先閲讀背面之注項再填寫本頁) 經濟部中央揉準局—工消费合作社印装具除了乙酸酷外之C9及/或CIO釀氧基取代基之紫杉烷，可用10-DAB為起始物霣如反應臞示5中之說明製備。 10-DAB與三乙矽烷基氯於吡啶中之反應，得7-經保護之 10-DAB 15 。7-綬保護-10-DAB 15之C10羥基取代基可再林财HB家辟（CNS ) A嫩Μ 210X29則η - 26 - 83. 3.10,00014 {Please read the note on the back before filling in this page) The Central Government Bureau of the Ministry of Economic Affairs, Industrial and Consumer Cooperative Cooperatives, printed with taxanes other than acetic acid, C9 and / or CIO oxo substituents, 10-DAB can be used Prepared as starting material as described in Reaction Scheme 5. The reaction of 10-DAB with triethylsilyl chloride in pyridine gives 7-protected 10-DAB 15. 7- 绶 Protection-10-DAB 15's C10 hydroxyl substituent can be replaced Lin Cai HB Jiapi (CNS) A tender M 210X29 n-26-83. 3.10,000

s 420670 A7 _B7五、發明説明（2M K任何檷準纗化_容易地釀化，得具新的CIO醯氧基取代基之衍生物16。衍生物16之C9嗣基取代基之選擇性埋原得 9/?-羥基衍生物17，於其上可連接C13支鍵。替代地. C10及C9基可如上面反懕示2中所述引起移ife。反囊_式5s 420670 A7 _B7 V. Description of the invention (2M K any quasi-fluorinated _ easily brewed to obtain a derivative 16 with a new CIO alkoxy substituent. Selective burying of the C9 fluorenyl substituent of derivative 16 The 9 /?-Hydroxy derivative 17 was originally obtained, to which a C13 branch can be connected. Alternatively, the C10 and C9 groups can cause ife shift as described in the reverse example 2 above.

薄化朝I (請先閲讀背面之注^項再填寫本頁)Thinning towards I (Please read the note ^ on the back before filling this page)

-'A 經濟部中央搮率局貝工消費合作杜印装-'A Central Government Bureau of the Ministry of Economic Affairs

! / 16 ί 具替代之C2及/或C4酯之紫杉烷可用漿果赤徽素III及 10-DAB為起始物質製備。漿果赤徽素III及10-DAB之C2及本紙張尺度適用中as家梯準（CNS > A4规格（21.0X297公釐）_ 2 7 — ~ 83.3.10,000! / 16 ί Taxanes with alternative C2 and / or C4 esters can be prepared with berry erythromycin III and 10-DAB as starting materials. Berry erythromycin III and 10-DAB C2 and this paper size are applicable in China (CNS > A4 size (21.0X297 mm) _ 2 7 — ~ 83.3.10,000

VV

42067U A7 B7五、發明说明（25 ) /或C4酗可用遒原劑如LHA或Red-Al堪擇性地堪原成對應之酵*且其後新酯可用檷準醯化劑如酐及«氮併用胺如吡啶、三乙胺、DM AP或二異丙基乙胺加Μ取代。替代地* C2及/或C4酵可藉*宜碱如LDA接著釀化劑如醢氛之處理，烴由形成對應之酵馥而轉化成新的C2及/或C4酯。具不闻取代基於C2及/或C4之漿果赤撇素及ΊΟ-DAB可如反應圈示6-10所述製備。為簡化說明，10-DAB用為起始物霣。然而•應了解的是，用相同系列之反應（除了對C10 羥基之保謅外）藉由簡軍地Μ漿果赤黴素III代替 10-DAB為起始物寅，可製造漿果赤撇素III衍生物或類似物ΰ具不同取代基於C2及/或C4之漿果赤徽素III及 10-DAB類似物之9-脫氧基衍生物則可箱由堪原瑄些類似物之C9醑基取代基並進行上述之其他反應而製備。於反應圔示6中•經保護之10-DAB 3Κ氫化鋁鋰轉化成 / 三元酵18。三元酵18再用CUC0 (於吡啶中）接著Μ親核性試爾（例如格利雅試劑或烷基鋰試爾）轉化成對應之 C4酯。 t請先閲讀背面之法意事項再填寫本頁) 、ΤΓ .rv 經濟部中央橾準局負工消费合作社印製本紙張尺度適用中國國家揉準（CNS)A4规格（210X297公釐）一 28 — 813.10,000 420670 A7 B7 五、發明説明（2642067U A7 B7 V. Description of the invention (25) / or C4 can be used as a protozoan, such as LHA or Red-Al, optionally, and the corresponding new ester can be used as a quasi-hydraulic agent such as anhydride and « The nitrogen is substituted with an amine such as pyridine, triethylamine, DM AP or diisopropylethylamine plus M. Alternatively, * C2 and / or C4 enzymes can be treated with a suitable alkali such as LDA followed by a brewing agent such as scent, and the hydrocarbons are converted into new C2 and / or C4 esters by forming corresponding enzymes. Substitute C2 and / or C4-based berry chelatins and O-DAB can be prepared as described in Reaction Circles 6-10. For simplicity, 10-DAB is used as the starting material 物. However, it should be understood that the same series of reactions (except for the protection of the C10 hydroxyl group) can be made by replacing the 10-DAB as the starting material with Jianjundi berry gibberellin III. Derivatives or analogs with different substitutions of 9-deoxy derivatives based on C2 and / or C4 berry erythromycin III and 10-DAB analogs can be substituted by C9 fluorenyl substituents of some analogs And prepared by carrying out the other reactions described above. In Reaction Example 6 • Protected 10-DAB 3K lithium aluminum hydride is converted to / ternary enzyme 18. Ternary enzyme 18 is then converted to the corresponding C4 ester using CUC0 (in pyridine) followed by M nucleophilic test (such as Grignard reagent or alkyllithium test). (Please read the French and Italian matters on the back before filling in this page). ΤΓ.rv Printed by the Central Consumers ’Bureau of the Ministry of Economic Affairs and Consumer Cooperatives. This paper is printed in accordance with China National Standards (CNS) A4 (210X297 mm) 28 — 813.10,000 420670 A7 B7 V. Description of the invention (26

18LS ores18LS ores

LAH 3 TMSOhiuLAH 3 TMSOhiu

(請先閲讀背面之注意事項再填寫本頁) ores TMSQl(Please read the notes on the back before filling this page) ores TMSQl

TMSOjriiTMSOjrii

2 Q 1 9 經濟部中央橾準局員工消费合作社印装兰元醇18KLDA脫去質子接著遘擇性地引入醢《得C4酷。例如當用乙醣氣畤，如反應匾示7中所述將三元酵18轉化成1,2二元酵4 。三元酵18亦可容易地轉化成1,2磺酸醣19。碳酸_19於有效之欏準條件下乙釀化*如反雇鼷示S中所述得磺酸醮本纸張尺度適用中國國家梂準（CNS ) A4规格（210X297公釐）_ 2 9 — 813.10,000 4、2 Ο 6 7 ϋ Α7 Β7 五、發明説明（ 21;烷基鋰或格利雅試劑加至碳酸酷19，如反應圈示6中所述，得具自由態羥基於C4之C2_。反醣IB示7 0TE5 TMSQliiii2 Q 1 9 Printed by the Consumer Cooperatives of the Central Bureau of quasi-Ministry of the Ministry of Economic Affairs, 18KLDA delaminated protons, and then selectively introduced "C4 Cool". For example, when using diose, ternary yeast 18 is converted into 1, 2 binary yeast 4 as described in Reaction Plaque 7. The ternary yeast 18 can also be easily converted into 1,2 sulfonate 19. Carbonic acid _19 is brewed under the effective standard conditions * The sulfonic acid is obtained as described in the counter-employment instructions S. The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) _ 2 9 — 813.10,000 4, 2 0 6 7 ϋ Α7 B7 V. Description of the invention (21; alkyl lithium or Grignard reagent is added to carbon dioxide 19, as described in reaction circle 6, there can be C2_ Anti-sugar IB showed 7 0TE5 TMSQliiii

LDA R3〇COC I 18 OTES TMSOl !iLDA R3〇COC I 18 OTES TMSOl! I

(請先閲讀背面之注意事項再填寫本1) jg HI Η 7κ 8 OTES TWSOmil(Please read the notes on the back before filling in this 1) jg HI Η 7κ 8 OTES TWSOmil

ci2co 吡啶 18ci2co pyridine 18

OTESOTES

ac2o 經濟部中央揉率局員工消費合作社印製ac2o Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

OMAPOMAP

OTESOTES

2 1 本紙張尺度適用中S國家榇準（CNS)A4规格（210X297公釐）一 30 — 83, 3.10,000 420670 五、發明説明（28 ) 如反®國示9中所述，其他之C4取代基之提供可_碩酸 _ 19輿醣镢及三级胺反應得破酸賄22*其再與烷基鋰或格利雅試劑反應得具新取代基於C2之ΊΟ-DAB衍生物。 B tR 9 ores2 1 This paper size is applicable to China National Standards (CNS) A4 (210X297 mm)-30 — 83, 3.10,000 420670 5. Description of the invention (28) As described in Anti-National Standard 9 and other C4 The supply of substituents can be _serum_19 and glycerol and tertiary amines to react to break the acid bridging 22 *, and then react with alkyl lithium or Grignard reagents to have a newly substituted C2 based Ί-DAB derivative. B tR 9 ores

(請先W讀背面之注意事項再填寫本頁) 訂· 疒經濟部中央標準局貝工消费合作社印裂 2 3 2 2 替代地，漿果赤撇素III可用為起始物質且如反懕圓示 10中所示反應。於C7及C13加以保護後，漿果赤徽素III 从1^11堪原產生1,2,4,10四元酵24。四元薄24用（：12(：0及本紙張尺度適用中國國家揉準（CNS ) A4規格（210X297公釐）一 3 1 — 83. 3.10,000 420670 A7 _B7 五、發明説明（29) 吡啶轉化成碳酸》25_再將其以醣氯及吡啶將CIO醢化產生碳酸酯26 (如所示）或Μ乙酸酐及吡I®豔化（未示出）。碳酸酯26於有效之檷準條件下之乙醣化•得碾酸酯27, 再將其與烷基鋰反應得具新取代基於C2及C10之漿果赤徽素III衍生物。 at 元 1〇 (請先閲讀背面之注意事項再填寫本頁}(Please read the precautions on the back before filling out this page.) 疒印 Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives 2 3 2 2 Alternatively, berry chelatin III can be used as a starting material and as anti-round The reaction shown in Figure 10 is shown. After being protected by C7 and C13, berry erythromycin III produces 1, 2, 4, 10 quaternary yeast 24 from 1 ^ 11 kanyuan. For quaternary thin 24 (: 12 (: 0 and this paper size applies to Chinese National Standards (CNS) A4 specifications (210X297 mm)-3 1-83. 3.10,000 420670 A7 _B7 V. Description of the invention (29) Pyridine Transformed to Carbonic Acid> 25_ and then CIO with sugar chloride and pyridine to produce carbonate 26 (as shown) or M acetic anhydride and pyridine I® (not shown). Carbonate 26 is effective Ethyl saccharification under quasi-conditions. • Ester 27 was obtained, and then it was reacted with lithium alkyl to newly replace C2 and C10-based berry erythromatin III derivatives. At Yuan 10 (Please read the precautions on the back first) Fill out this page again}

-B 經濟部中央揉率局貝工消費合作社印裝 0H TMSOirn-B Printed by the shelling consumer cooperative of the Central Rubbing Bureau of the Ministry of Economic Affairs 0H TMSOirn

25 r29cocI 吡啶 QH TMSOiill25 r29cocI pyridine QH TMSOiill

L AH 83.3.10t〇〇〇本紙張尺度適用中國國家標準（CNS)A4规格（ 210X297公釐）一32 一 420670 A7 B7 五、發明説明（ 30 TMSOmtL AH 83.3.10t〇〇〇 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm)-32-420670 A7 B7 V. Description of the invention (30 TMSOmt

Ac2〇 dmap 丁 MSOlilAc2〇 dmap D MSOlil

(請先聞讀背面之注意事項再填寫本頁) 經濟部中央樣準局I工消费合作社印製漿果赤徽素III之10-脘乙鐮氧基衍生物及10-DAB之 10·脫氧基衍生物可藉漿果赤徽素III或10-DAB (或其衍生& )與二碘化釤反應而製備。具C10游離基之四瓖紫杉烷與二碘化釤間之反懕可於0 t下、溶劑如四氳呋喃中進行。有利地，二碘化釤遘擇性地除去C10游離基；四環之核上之C13支鍵及其他取代基保持不受干播。其後，C9酮基取代基可如本文他處所述堪原得對應之9-脫氣基-9/3- 本紙張尺度遑用中國钃家搮準（CNS)A4規格（ 210X297公釐）一33 — 83.3.10,000 420670 μ B7 五、發明説明（）羥基-10-脫乙醸氧基或10-脫氧基衍生物。C7二氬及其他C71SS取代之紫杉烷可如反應麵示11、12及 12a中所述製脔。反鏖示11 鲤濟部中央標準局貝工消費合作社印裝(Please read the precautions on the reverse side before filling out this page) The 10-Acethyloxybenzyl Derivatives of Berberin III and 10-DAB 10 · Deoxy are printed by the Central Bureau of Standards, Ministry of Economic Affairs, I Industrial Consumer Cooperatives Derivatives can be prepared by reacting berry erythromycin III or 10-DAB (or its derivative &) with europium diiodide. The reaction between tetramethylene taxane having a C10 radical and diiodide can be carried out in a solvent such as tetramethylenefuran at 0 t. Advantageously, the diiodide selectively removes the C10 radical; the C13 branch bond and other substituents on the nucleus of the tetracyclic ring remain free from dry seeding. Thereafter, the C9 keto substituent may be as described elsewhere in this document. The corresponding 9-degassing group-9 / 3- This paper size uses China National Standard (CNS) A4 (210X297 mm) A 33 — 83.3.10,000 420670 μ B7 V. Description of the invention () Hydroxy-10-deacetylamyloxy or 10-deoxy derivative. C7 diargon and other C71SS-substituted taxanes can be prepared as described in Reaction Surfaces 11, 12, and 12a. Counter-indication 11 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards

〇 (請先閎讀背面之注意事項再填寫本頁) 訂本紙張尺度逋用中國國家揉準（CNS ) A4规格（210X297公釐）一34-〇 (Please read the precautions on the reverse side before filling out this page) The size of this paper is in Chinese National Standard (CNS) A4 (210X297 mm)-34-

Si 3.10,000 經濟部中央標準局貞工消費合作社印装Si 3.10,000 Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

420 67 0、 A7 B7 五、發明説明（32) 反醣麵沄1 ?. 本紙張尺度遑用中菌®家橾率（CNS ) ( 210X297公釐> 一 3 5 _ 83.3.10,000 (請先聞讀背面之注意事項再填寫本頁)420 67 0, A7 B7 V. Description of the invention (32) Anti-sugar noodles 1?. The medium scale used in this paper scale: Household bacteria rate (CNS) (210X297 mm > 1 3 5 _ 83.3.10,000 (please first (Read the notes on the back and fill out this page)

Α7 Β7 五、發明説明（33 ) 反 Βϋ IH 录 1 2 a TMSQiimΑ7 Β7 V. Description of the invention (33) Anti-Bϋ IH Record 1 2 a TMSQiim

,α χ4 χ2 χ! c 1) THF * · (請先閱讀背面之注意事項再填寫本頁) --••, α χ4 χ2 χ! c 1) THF * · (Please read the precautions on the back before filling this page)-••

X. XX. X

/2〕Hf=,吡啶，CH3CN ，OH/ 2] Hf =, pyridine, CH3CN, OH

經濟部中央標隼局5工消费合作社印製 ,如反應圖不12中所示，獎果赤級素Πι可藉FAR於室溫、THF溶疲中處理而轉化成7-氟漿果赤課素ΙΠ 。具自由態C7羥基之其他漿果赤两素衍生物類似地反應。替代地 ,7-氰漿果赤激素[π之製胬，藉由以甲爾醣氛及三乙胺於含遇虽鹽酸三乙胺之二氣甲垸溶孩處理漿果赤徽素m 而得。具q截氧基取代基之紫杉烷可如反應颸示12a中所述製辑，將7, 13-纆保護之ίο-氧基·衍生物丨丨藉埋擇性地除去本紙張尺度逋用中萄國家樣準（CNS ) A4规格（210X297公釐） 83. 3.10,000 -36 420670 at B7 五、發明説明（34 ) C13保護基並Μ金靨如經置捵而轉化成其對應之C13酵» 。酵鹽再輿/3 —内釀胺成其它支鐽前驪«反應。鼸後C7保護基之水解引起C7羥基取代基移至CIO，CIO氧基取代基移至C9，及C9SI氧基取代基移至C7。廣泛之各種三瑁紫杉烷為天然產，且纆由類似於本文所述之那些操作，可將《當支鍵連接於此等坊霣之C13氧。替代地•如反應騮示13中所示· 7-0-三乙矽烷基麋果赤黴索III可纆由四氟__三甲絆於二«甲烷涫液中之作用，轉化成三環紫杉烷。產物二元酵再與四乙酸鉛反應得對應 ^ C4K 〇；反廳_录t3Printed by the 5th Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, as shown in the reaction diagram No. 12, the reward erythroline can be converted into 7-fluoroberry erythroline by FAR at room temperature and THF solution. IΠ. Other berry erythrobin derivatives with free C7 hydroxyl groups react similarly. Alternatively, 7-cyanoberry erythromatin [π] is obtained by dissolving berry erythromycin m with methylol and triethylamine in digas formamidine containing triethylamine hydrochloride. Taxanes with q-oxyl substituents can be prepared as described in Reaction Scheme 12a, and 7, 13- 纆 protected ο-oxy · derivatives can be selectively removed by paper size. Using China National Standard (CNS) A4 (210X297 mm) 83. 3.10,000 -36 420670 at B7 V. Description of the invention (34) C13 protection group and M gold will be converted into their corresponding ones if placed. C13 leaven ». Yeast salt again / 3-the reaction of the endogenous amines to other branches. Subsequent hydrolysis of the C7 protecting group caused the C7 hydroxyl substituent to move to CIO, the CIO oxygen substituent to C9, and the C9SI oxygen substituent to C7. A wide variety of tristaxanes are naturally produced and can be manipulated in a manner similar to those described herein, and can be linked to the C13 oxygen of these compounds. Alternatively • As shown in Reaction Example 13 • 7-0-Triethylsilyl elm gibberellin III can be converted into tricyclic purple by the action of tetrafluoro-trimethyl ether in methane solution. Taxane. The product binary enzyme reacts with lead tetraacetate to obtain the corresponding ^ C4K 〇

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央揉準局員工消費合作杜印製(Please read the notes on the back before filling out this page) Printed by the Central Government Bureau of the Ministry of Economy

本纸張尺度逍用中S國家揉準（CNS ) A4洗格（210X297公釐）一 37 — 83.3.10,000 420B70 at B7五、發明説明（35) 最近已於紫杉針狀葉之抽提物中發現羥基化之紫杉烷（ 14-羥基-10-脘乙釀基漿果赤徽素III) (01EJL P36-37 Αρ「Π 12, .1993)。具上述各種C2、C4等官能基之此羥基化之紫杉烷衍生物亦可拜使用此羥基化之紫杉燒製備。此外，C14羥基與ΊΟ-DAB之C1羥基一起可如CiiUL中所述轉化成1,2-磺醭_ •或其可轉化成各種醮或如本文他處中所述有闞C2、C4、C9及CIO取代基之其他官能基。下面賁例用來更完全地說明本發明。奮例1The standard of this paper is SCN Standard (CNS) A4 Washing (210X297mm)-37-83.3.10,000 420B70 at B7 V. Description of the Invention (35) The extract has recently been extracted from the needle-shaped leaves of Yew It was found that hydroxylated taxane (14-hydroxy-10- 脘 ethyl ethyl berry erythromycin III) (01EJL P36-37 Αρ 「Π 12,. 1993）. There are various functional groups such as C2 and C4 mentioned above. The hydroxylated taxane derivative can also be prepared by using this hydroxylated taxane. In addition, the C14 hydroxyl group, together with the C1 hydroxyl group of ΊΟ-DAB, can be converted into 1,2-sulfohydrazone as described in CiiUL. It can be converted into various amidines or other functional groups with C2, C4, C9 and CIO substituents as described elsewhere herein. The following examples are provided to more fully illustrate the present invention. Example 1

<請先聞讀背面之注意事項再填寫本頁) 經濟部中央標隼局貝工消费合作社印装 (29-4) 3’-脫苯基_3夂（2-甲-卜丙烯基）紫杉酵之製備於7-三乙矽烷基漿果赤徽素III (120«克· 0. 171毫其耳）於1.2奄升THF中之溶液，於-45 TC下滴加0.104奄升1.63Μ n&uLi溶液（於己烷中）。於-45 下0.5小時後，將順-1-笨醢-3-三乙矽烷氧基-4-(2-甲-卜丙烯基）一氬四國-2-酮（ 295毫克· 0.8 85毫莫耳）於1.2笔升 THF中之溶液滴加至混合物。溶液瀣至〇t，並於加1¾ 本紙張尺度逍用中國國家揉準（CNS ) A4規格（210X 297公釐）一3 8 — 83. 3.10,000 420670 A7 B7 五、發明説明（36 ) ' 升10X AcOH溶液（於THF中）Μ前，维持於該ffl度1小時。混合物於鉋和HaHCOs水溶液及60/40乙酸乙_/己烷之間分S。蒸發有機靥得殘留物•其藉由矽腰過濾纯化得 179毫克含（2’R,3_S)-2,7-(雙）三乙矽烷基-3’-脫苯基 -3^(2-甲-卜丙烯基 > 紫杉酵及少量（21, 31)異構物之混合物。於179奄克<0.171奄萁耳）之得自前面反應之混合物於11笔升乙騎及0. 55奄升吡啶中之溶液，於0 1C下加1.7 亳升48% HF水溶液。混合物於0 1C下攪拌3小時•再於 251C下13小時，並於HaHC〇3鉋和水溶液及乙酸S®間分配。乙酸乙酸溶液蒸發得140奄克物霣，其藉快速曆析法纯化得109.0奄克（78Χ)3^脫苯基-3*-(2-甲-1-丙烯基）紫杉酵•其自甲酵/水中重结晶。 i.P. 143-144t：： ία ]ΖΒΝβ-61.0° (c 0.0065, CHC13)< Please read the notes on the back before filling in this page) (29-4) 3'-dephenylated_3 夂 (2-methyl-propenyl) Yew yeast was prepared from a solution of 7-triethylsilyl berry erythromycin III (120 «g · 0.171 mil) in 1.2 liters of THF, and 0.104 liters of 1.63M was added dropwise at -45 TC. n & uLi solution (in hexane). After 0.5 hours at -45, the cis-1-benzyl-3-triethylsilyloxy-4- (2-methyl-propenyl) -argon tetrakone-2-one (295 mg · 0.8 85 mmol Mol) was added dropwise to the mixture in 1.2 liters of THF. Solution 瀣 to 0t, and add 1¾ of this paper size to the Chinese National Standard (CNS) A4 specification (210X 297 mm)-3 8 — 83. 3.10,000 420670 A7 B7 V. Description of the invention (36) Before liters of 10X AcOH solution (in THF) were maintained, the temperature was maintained at this level for 1 hour. The mixture was partitioned between a planer and an aqueous solution of HaHCOs and 60/40 ethyl acetate / hexane. The organic residue was evaporated to obtain a residue. It was purified by silica gel filtration to obtain 179 mg containing (2'R, 3_S) -2,7- (bis) triethylsilyl-3'-dephenyl-3 ^ (2- A-propenyl > A mixture of yew yeast and a small amount of (21, 31) isomers. At 179 g (< 0.171 奄萁), the mixture obtained from the previous reaction was added in 11 liters of ethyl acetate and 0. 55 liters of the solution in pyridine, add 1.7 liters of a 48% aqueous HF solution at 0 1C. The mixture was stirred at 0 1C for 3 hours • 13 hours at 251C and partitioned between HaHC03 and aqueous solution and acetic acid S®. The acetic acid solution was evaporated to give 140 g of mash, which was purified by rapid calendar analysis to obtain 109.0 g of (78 ×) 3 ^ dephenyl-3 *-(2-methyl-1-propenyl) taxus. Formazan / recrystallized in water. i.P. 143-144t: ία] ZΒΝβ-61.0 ° (c 0.0065, CHC13)

O HMR (CDC13, 300 MHz) 58.11(d, J=7.1 Hz, 2H, 位苯甲酸酷）· 7.69(d, J = 8.3 Hz, 2H,鄰位苯醯胺>, 7.64-7.36 (，δΗ·芳族 >,6.45(d, J = 8.2 Hz. 1H, HH)f 6.29(s, 1H, H10), 6.20 (dd, J=7.7, 7.7 Hz, 經濟部中央標準局員工消费合作社印策 (請先閲讀背面之注意事項再填寫本頁) 1H. H13), 5.68 (d. J=7.1 Hz, 1H, H2/3 ), 5.46(b, 1H,乙烯基）.5.27(ddd, J = 8,8, 8.8, 3.3 Hz, 1H, H3'), 4.96(d. J=7.7 Hz, 1H, H5), 4.40(·, 1H, H7), 4.36 (i, 1H, H2f). 4.32 (d, J = 7.8 Hz, 1H, H20a ), 4.22(d, J = 7.8 He, 1H, H20 /3 ), 3.82 (d, J = 7.1 Hz, 本紙張尺度適用中國國家揉準（CNS ) A4规格（210X297公釐）一 3 9 — 83.3.10,000 420670 A7 B7 五、發明説明（37 ) 1H, H3). 3.63 (d, J = 6.6 Hz, 1H, 2ΌΗ), 2.54 (·, 1H, Η6α), 2.48 (d, J = 3.9 Hz, 1H, 70H), 2.42 (, 2H, H14), 2.39 is, 3H, 4Ac), 2.23 (s, 3H, lOAc). 2.16 (br s, 3H, Hel8), 1.89 (. 1H, H6>3 ), 1.88(s, 3H, Mel9), 1.80 (s, 4H, Me 噻吩基 +10H), 1.24(s, 3H, Mel7>, l，14(s. 3H, Kel6>。實例2O HMR (CDC13, 300 MHz) 58.11 (d, J = 7.1 Hz, 2H, benzoic acid) · 7.69 (d, J = 8.3 Hz, 2H, orthobenzidine >, 7.64-7.36 (, δΗ Aromatic >, 6.45 (d, J = 8.2 Hz. 1H, HH) f 6.29 (s, 1H, H10), 6.20 (dd, J = 7.7, 7.7 Hz, policy of employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) 1H. H13), 5.68 (d. J = 7.1 Hz, 1H, H2 / 3), 5.46 (b, 1H, vinyl). 5.27 (ddd, J = 8,8, 8.8, 3.3 Hz, 1H, H3 '), 4.96 (d. J = 7.7 Hz, 1H, H5), 4.40 (·, 1H, H7), 4.36 (i, 1H, H2f). 4.32 (d , J = 7.8 Hz, 1H, H20a), 4.22 (d, J = 7.8 He, 1H, H20 / 3), 3.82 (d, J = 7.1 Hz, this paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) 3 9 — 83.3.10,000 420670 A7 B7 V. Description of the invention (37) 1H, H3). 3.63 (d, J = 6.6 Hz, 1H, 2ΌΗ), 2.54 (·, 1H, Η6α), 2.48 (d, J = 3.9 Hz, 1H, 70H), 2.42 (, 2H, H14), 2.39 is, 3H, 4Ac), 2.23 (s, 3H, lOAc). 2.16 (br s, 3H, Hel8), 1.89 ( 1H, H6 > 3), 1.88 (s, 3H, Mel9), 1.80 (s, 4H, Me thienyl + 10H), 1.24 (s, 3H, Mel7 >, 1, 14 (s. 3H, Kel6 >. Example 2

OACOAC

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央揉牟局員工消費合作杜印氧 (51-3) 3脫苯基-3’-異丁烯基-H-脫苯®基-N-(第三丁氧羰基）紫杉酵之製備於7-三乙矽烷基漿果赤徽素Ιίί ( 30.0奄克，0,043罨莫耳）於0.5奄升THF中之溶液，於-45 TC下滴加0.047 毫升 1.0Μ (TMS)2NLi 溶获（於 THF 中）。於-45 下 0.5 小時後•滴加顒-1-(第三丁氧羰基）-3-(2-甲氧-2-丙氣基 )-4-異丁烯基一氮四匾-2-酮（44.2奄克，0. 13奄莫耳）於0.4奄升THF中之溶液至混合物。溶液溫至0 C ·並維本纸張尺度適用中國國家揉準（CNS ) A4洗格（210X297公釐）一 4 0 83. 3.10,000 420670 a? _ B7五、發明説明（38 ) 經濟部中央揉準局貝工消費合作杜印簟持於該溢下1小時•再加1奄升之10S AcDH溶液（於THF 中）》混合物於鉋和HaHC03水溶液及60/40乙酸乙醮/己烷間分配。蒸發有拥曆得殘留物，其藉由矽鏐遇濾純化· 得40.3蠹克含（2'11,3’5)-2'-(2-甲氧-2-丙氧基>-3’-脫苯基-3’-興丁烯基-7-三乙矽烷基-H-脫笨«[基-H-(第三丁氧蒙基）紫杉醇及少量（2'S, 3Ίί)異構物之混合物。於40.3毫克（ 0.038 «莫耳）自前面反應所得混合物於 2毫升乙腾及0·1 «升吡啶中之溶液，於0 下加0.3奄升48Χ HF水溶硖。琨合物於0 下攢拌3小時，再於25t 下13小時*並於飽和HaHC03水溶液及乙酸乙醸間分S。Μ 發乙_乙_溶液得34.2«克物霣，其鷓快速靥析法纯化得 22.4¾克（72Χ)3’_脫苯基-3·-異丁烯基-Η-脫苯醯基 -Η-(第三丁氧羰基）紫杉酵•其自甲酵/水中重结晶。 B.p. 147-149t：； [a ]aBHa-65.2e (c 0.0023, CHCU) 0 XH NHR (CDCU, 300 MHz) 5 8.11(d, J=7.1 Hz, 2H, m 位苯甲酸酯），7.61U, 1H,對位苯甲酸酯），7.48 U, 2H,間位苯甲酸酯），6.45(s, 1H, KH), 6.30 Cd, J=8.3 Hz, 1H, H10), 6.18 (dd. J=7.7, 7.7 Hz, 1H, 5 . H13), 5.68 (d, J = 7.1 Hz, 1H, H2/3 ), 5.31(«, 1H, 乙烯基），5.01(ddd. J = 8.8, 8.8, 3.3 Hz, 1H, Η3Ί, 4.95(d, J=7.7 Hz, 1H. H5), 4.76(i. 1H, H7), 4.43 (, 1H, H2'), 4.32 (d. J=7.8 Hz, 1H, H20a), 4.19(d, J = 7.8 H2, 1H, H20j8), 3.81 (d, J = 7.1 Hz, -------；----妒-------訂------線 (請先閲讀背面之注意事項再填寫本頁) 本纸張尺度遒用中國H家揉準（CNS ) A4規格（210X 297公釐）一41 一 83.3.10,000 420670 A、7 B7_五、發明説明（39 ) 1H. H3), 3.74 (d, J=6.6 Hz. 1H, 2ΌΗ), 2.54 (, 1H, H6a), 2.48 (d, J=3.9 Hz, 1H, 70H), 2.44 (a, 2H, H14), 2.39 (s, 3H, 4Ac), 2.26(s, 3H, Me 乙烯基 ),2.25(s, 3H, Me 乙烯基），2.23 (s, 3H, i〇Ac). 1.98 (br s, 3H, Mel8), 1.86 (a, 1H. H6^S), 1.76(s, 3H, Mel9), 1,43 (s, 9H· 3Me 第三丁氧基）， 1.25(s, 3H， Mel7), 1.14(s, 3H. Mel6)。奮拥3(Please read the notes on the back before filling in this page.) Consumer cooperation of the Central Ministry of Economic Affairs of the Ministry of Economic Affairs, Du Indiax (51-3) 3 Dephenyl-3'-isobutenyl-H-dephenyl®-N- (Third butoxycarbonyl) Yew fermented solution of 7-triethylsilyl berry erythromycin Ιί (30.0 g, 0,043 mol) in 0.5 liter THF solution, dropwise added at -45 TC 0.047 ml of 1.0M (TMS) 2NLi was dissolved (in THF). After 0.5 hours at -45 • 颙 -1- (Third-butoxycarbonyl) -3- (2-methoxy-2-propanyl) -4-isobutenyl-tetrazol-2-one ( 44.2 g, 0.13 mol) in 0.4 liter THF to the mixture. Solution temperature to 0 C. And the paper size is suitable for Chinese National Standard (CNS) A4 Washing (210X297 mm)-4 0 83. 3.10,000 420670 a? _ B7 V. Description of Invention (38) Ministry of Economic Affairs The Central Government Bureau of Zhuhai Bureau ’s consumerism cooperation, Du Yin, held at the overflow for 1 hour. • Add 1 liter of 10S AcDH solution (in THF). ”Mixture in planer and HaHC03 aqueous solution and 60/40 ethyl acetate / hexane. Allocation. There is a rich residue after evaporation, which is purified by filtration with silica gel to obtain 40.3 g of (2'11,3'5) -2 '-(2-methoxy-2-propoxy) > -3 '-Dephenyl-3'-oxetenyl-7-triethylsilyl-H-debenzation «[yl-H- (tertiary butoxymenthyl) paclitaxel and small amount (2'S, 3Ίί) isomers A mixture of 40.3 mg (0.038 «mol) of the mixture obtained in the previous reaction in 2 ml of acetone and 0.1 liter liter of pyridine, 0.3 liters of 48X HF water was added at 0 to dissolve the sulfonium. Stir for 3 hours, and then at 25t for 13 hours * and partition S in a saturated aqueous solution of HaHC03 and ethyl acetate to obtain 34.2 «g 霣, which was purified by rapid decantation to 22.4¾ Gram (72 ×) 3'_dephenyl-3 · -isobutenyl-fluorene-dephenylfluorenyl-fluorene- (third butoxycarbonyl) taxane • It is recrystallized from formazan / water. Bp 147-149t :; [A] aBHa-65.2e (c 0.0023, CHCU) 0 XH NHR (CDCU, 300 MHz) 5 8.11 (d, J = 7.1 Hz, 2H, m-position benzoate), 7.61U, 1H, right Benzoate), 7.48 U, 2H, meta-benzoate), 6.45 (s, 1H, KH), 6.30 Cd, J = 8.3 Hz, 1H, H10), 6.18 (dd. J = 7.7, 7.7 H z, 1H, 5. H13), 5.68 (d, J = 7.1 Hz, 1H, H2 / 3), 5.31 («, 1H, vinyl), 5.01 (ddd. J = 8.8, 8.8, 3.3 Hz, 1H, Η3Ί, 4.95 (d, J = 7.7 Hz, 1H. H5), 4.76 (i. 1H, H7), 4.43 (, 1H, H2 '), 4.32 (d. J = 7.8 Hz, 1H, H20a), 4.19 ( d, J = 7.8 H2, 1H, H20j8), 3.81 (d, J = 7.1 Hz, -------; ---- Je Please read the notes on the back before filling this page.) This paper size is based on Chinese standard (CNS) A4 size (210X 297 mm)-41-83.3.10,000 420670 A, 7 B7_V. Description of the invention (39) 1H. H3), 3.74 (d, J = 6.6 Hz. 1H, 2ΌΗ), 2.54 (, 1H, H6a), 2.48 (d, J = 3.9 Hz, 1H, 70H), 2.44 (a, 2H, H14), 2.39 (s, 3H, 4Ac), 2.26 (s, 3H, Me vinyl), 2.25 (s, 3H, Me vinyl), 2.23 (s, 3H, i〇Ac). 1.98 (br s, 3H, Mel8), 1.86 (a, 1H. H6 ^ S), 1.76 (s, 3H, Mel9), 1,43 (s, 9H · 3Me third butoxy), 1.25 (s, 3H, Mel7), 1.14 (s, 3H. Mel6). Endeavour 3

In— ml m^i If i n - , 手i (請先閲讀背面之注意事項再填寫本頁)In— ml m ^ i If i n-, hand i (Please read the precautions on the back before filling in this page)

訂經濟部中央標準局員工消费合作杜印策 (54-1) N-脫苯蠤基-N-(正丁氧捩基）-3夂脫苯基-3'-異丁烯基紫杉酵之製備於7-三乙矽烷綦漿果赤撤素III ( 70.0奄克> 0.086奄 Γ 舆耳）於0.7奄升THF中之溶液•於-45 1C下滴加0.10¾ 升1.0K UN(SiHe3)2之溶液（於己烷中）。於-45 t：下 0.5小時後，滴加頭-1-(正丁氧羰基）-3-(2-甲氧-2-丙氧基）-4-異丁烯基一氮四園-2- _ (94.2奄克，0,214奄莫耳）於0.5奄升THF中之溶液至混合物。溶液溫至0 t · 本纸張尺度適用中國Η家揉準（CNS)A4规格（210X297公釐）一 42 — 83.3.10,000 420670 A7 B7 五、發明説明（4Q ) 並鰌持於該湛下1小時•再加1.0亳升10X AcOH溶液（於 THF中}。混合物於鉋和“|{(：03水溶液及60/40乙酸乙酯 /己烷間分配。蒸發有櫬曆得殘留物•其賴由矽謬過籌鈍化•得82.8奄克含（2’R, 3’S)-2’-(2-甲氧-2-丙氧基 )-7-三乙矽烷基-H-脫笨釀基-H-(正丁氧羰基）-3'-脫苯基-3’-異丁烯基紫杉©及少1(2'S, 3'R)異構物之混合物 Ο 於82.8¾克（ 0.083奄莫耳）得自前面反應之混合物於 6.0 «升乙«及0.3奄升吡啶中之溶液，於0 C下加0.7 奄升48X HF水溶液。琨合物於0 1C下攪拌3小時，再於 25 υ下13小時，並於飽和NaHC03水溶液及乙酸乙賄間分配。蒸發乙酸乙酯溶液得67.7«克物質•其藉快速雇析法鈍化*得53.2奄克（77!«)}<-脫苯醯基-1^(正丁氧羧基）-3’·* 脫苯基-3’-異丁烯基紫杉酵，其自甲酵/水中重结晶。 .P. 132-134t：； [a ]2Bm.-64.0° (c 0.0023, CHCU) oConsumption cooperation between employees of the Central Standards Bureau of the Ministry of Economic Affairs Du Yince (54-1) Preparation of N-dephenylfluorenyl-N- (n-butoxyfluorenyl) -3 fluorenated dephenyl-3'-isobutenyl taxane A solution of 7-triethylsilyl berry erythropoline III (70.0 g > 0.086 g) in 0.7 liters of THF • 0.10 ¾ 1.0 K UN (SiHe3) 2 was added dropwise at -45 1C Solution (in hexane). At -45 t: After 0.5 hour, add the head -1- (n-butoxycarbonyl) -3- (2-methoxy-2-propoxy) -4-isobutenyl-tetrazol-2- _ (94.2 μg, 0,214 μmol) in 0.5 μl of THF to the mixture. The temperature of the solution is 0 t. The paper size is applicable to the standard of China National Standard (CNS) A4 (210X297 mm) 42-83.3.10,000 420670 A7 B7. 5. Description of the invention (4Q). Hours • Add 1.0 liters of 10X AcOH solution (in THF). The mixture was partitioned between a planer and "| {(: 03 aqueous solution and 60/40 ethyl acetate / hexane. The residue was evaporated after evaporation. Its its Passivation by Si-Muc • 82.8 g containing (2'R, 3'S) -2 '-(2-methoxy-2-propoxy) -7-triethylsilyl-H-destabilizing group- H- (n-Butoxycarbonyl) -3'-dephenyl-3'-isobutenyl Taxol © and a mixture of less 1 (2'S, 3'R) isomers 0 82.8¾ g (0.083 mol) A solution of the mixture obtained in the previous reaction in 6.0 liters of acetic acid and 0.3 liters of pyridine, 0.7 liters of 48X HF aqueous solution was added at 0 C. The admixture was stirred at 0 1 C for 3 hours, and then at 25 υ 13 Hours, and partitioned between saturated NaHC03 aqueous solution and ethyl acetate. Evaporation of the ethyl acetate solution yielded 67.7 «g of substance • Passivated by rapid employment analysis * to obtain 53.2 奄 g (77!«)} &Lt; -dephenylfluorenyl -1 ^ (n-butoxycarboxyl) -3 '· * dephenyl-3'-iso Butenyl taxane, recrystallized from formazan / water. P. 132-134t:; [a] 2Bm.-64.0 ° (c 0.0023, CHCU) o

HMR (CDCU, 300 MHz) 3 8.11(d. J = 7.2 Hz, 2H,鄰位苯甲酸醅），7.61U, 1H,對位苯甲酸酯），7,48 (· 2H,間位苯甲酸酯）.6.30(s, 1H, H10), 6.21 (dd, J=7.5, 7.5 Hz, 1H. H13), 5.67 (d, J=7.2 Hz, 1H, H2yS ), 5.33(·, 1H,興丁烯基之烯），4.97(d. J = H 1H, Η5)Γ 4.91 (d, J=8.2 Hz, 1H, HH), 4.78(ddd, J=8.7, 8.7, 2,7 Ηε, 1H, H3'), 4.43(·, 1H, H2'), 4.31 (d, J=7.8 Hz, 1H, H20a), 4.25(m, 1H. H7), 本紙浪尺度逍用中S國家揉準（CNS > A4规格（210X 297公釐> _ 4 3 — (請先s讀背面之注項再填寫本頁) 、Tr- 線經濟部令央標準局負工消费合作社印製 83.3.10,000 A206T0五、發明説明（41 ) A7 B7HMR (CDCU, 300 MHz) 3 8.11 (d. J = 7.2 Hz, 2H, ortho-benzoate), 7.61U, 1H, para-benzoate), 7,48 (· 2H, meta-benzoate Esters). 6.30 (s, 1H, H10), 6.21 (dd, J = 7.5, 7.5 Hz, 1H. H13), 5.67 (d, J = 7.2 Hz, 1H, H2yS), 5.33 (·, 1H, Xing Butenylene), 4.97 (d. J = H 1H, Η5) Γ 4.91 (d, J = 8.2 Hz, 1H, HH), 4.78 (ddd, J = 8.7, 8.7, 2,7 Ηε, 1H, H3 '), 4.43 (·, 1H, H2'), 4.31 (d, J = 7.8 Hz, 1H, H20a), 4.25 (m, 1H. H7), the standard of this paper is easy to use in S countries (CNS > A4 specification (210X 297mm > _ 4 3 — (please read the note on the back before filling this page), Tr-line Ministry of Economic Affairs, the Central Standards Bureau, Off-line Consumer Cooperative, printed 83.3.10,000 A206T0 Invention description (41) A7 B7

4.16 (d, J = 7.8 Hz, 1H. H20^), 3.96 (q, J = 6.6 Hz, 2H,正丁氧基），3.81 (d, J=7.2 Hz, 1H, H3), 3.34 (d, J = 6.6 Hz, 1H. 2ΌΗ), 2.54 1H, H6 a ) , 2.50 (d, J=3.9 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.33 (a, 2H, H14), 2.26 (s, 3H, lOAc), 2.24 (br s, 3H, Hel8). 1.89(s. 3H, Kel9), 1.87 (·, 1H, H6/3), 1.77(s, 3H· Me 異丁烯基），1.75U, 1H. 10H), l,68(s, 3H· Me 異丁烯基），1.5β(·, 2H,正丁氧基）， 1.32(«, 2H,正丁氧基），1.26(s, 3H, Mel7), 1.15 (s, 3H, Hel6), 0.85U, J = 6,6 Hz. 3H,正丁氡基之 Me) 0SLJLA (請先閲讀背面之注意^項再填寫本頁) 經濟部中央標準局負工消費合作社印製 (54-2)4.16 (d, J = 7.8 Hz, 1H. H20 ^), 3.96 (q, J = 6.6 Hz, 2H, n-butoxy), 3.81 (d, J = 7.2 Hz, 1H, H3), 3.34 (d, J = 6.6 Hz, 1H. 2ΌΗ), 2.54 1H, H6 a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.33 (a, 2H, H14), 2.26 (s, 3H, lOAc), 2.24 (br s, 3H, Hel8). 1.89 (s. 3H, Kel9), 1.87 (·, 1H, H6 / 3), 1.77 (s, 3H · Me isobutenyl), 1.75 U, 1H. 10H), 1,68 (s, 3H · Me isobutenyl), 1.5β (·, 2H, n-butoxy), 1.32 («, 2H, n-butoxy), 1.26 (s, 3H , Mel7), 1.15 (s, 3H, Hel6), 0.85U, J = 6,6 Hz. 3H, n-butyridyl's Me) 0SLJLA (Please read the note on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by Off-Work Consumer Cooperatives (54-2)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X29?公釐）一 44 — 83· 3* 10,000 42HR70 A7 B7 五、發明説明p ) 娌濟部中夬棣準局貝工消費合作社印装 3夂脫苯基-3·-異丁烯基-η-脫笨鼸基-N_(異丁氧羰基 > 紫杉酵之製備於7-三乙矽烷基漿果赤徽素III ( 40.0¾克· 0.042奄莫耳）於0.5毫升THP中之溶液*於-45 TC下滴加0.05« 升1.0M LiN(SiMe*)2於己烷中之溶液。於-45它下0.5小時後* »加顒-1-(異丁氣漩基）-3-(2-甲氧-2-丙氧基 )-4_異丁烯基一氟四醐-2-麵（43.0毫克，0.13¾莫耳）於〇.5奄升THP中之溶液至混合物。將溶液潙至0它並維持於該溫1小時•再加0.5毫升10X AcOH溶液（於THF中 )°混合物於飽和HaHC03溶液及60/40乙酸乙_/己烷間分S。蒸發有禳靥得殘留物*其藉矽膠《濾纯化•得 31.2奄克含（2’13’3)-2’-(2-甲氧-2-丙氧基）-7-三乙矽垸基-3’-脫苯基-3’-異丁烯基-N-脫苯鼸基-H-(異丁氧羰基）紫杉酵及少量（2’S, 3’R)異構物。於31.2奄克（0.030奄萁耳）得自前面反應之混合物於 2.0奄升乙聃及0.12毫升吡啶中之溶联，於0 1C下加 0.25毫升48X Η卩水溶液。混合物於0 υ下攒拌3小時，再於25t下13小時，並於飽和HaHC〇3及乙酸乙_間分配。蒸發乙酸乙®溶液得27.7毫克物質，其藉快速層析法純化得 20Λ毫克（83Χ)3·-脫苯基-3’-異丁烯基-H-脫苯醣基 (異丁氧羰基）紫杉酵，其自甲酵/水中重结基。 *.P. 147-1 48 t ： [ α ]2Β«β-58.2° (c 0.0016, CHC1S) O lH HHR (CDCU. 300 MHz) 5 8.11(d, J = 7.2 Hz, 2H, 99 (請先閲讀背面之注意事項再填寫本頁) 訂本纸張尺度逋用中國國家揉準（CNS ) A4规格U10X297公釐）一 45 — 83.110,000 420670 A7 B7 五、發明説明（43 ) 位笨甲酸K : 丨，7 .6 1 (, 1H, 對位苯甲酸 m ). 7.50 (*, 2H, 間位苯i 甲酸 m ), e .30 (s, 1H H10) , 6 .22 (dd, J = 7. 5, 7.5 Hz, 1H , H13), 5,65 (d ,J = 7.2 Hz , 1H, H2 β ), 5.31 ( ,1H, 異丁烯基之烯 ), 4.95 (d, J = 7.8 1Η, H5) .4. 91 (d, J = 8.2 Hz, 1H » NH) ,4, 76 (ddd, J = 8 · 7, 8.7, ,2. 7 Hz, 1H, H3 *). 4. 41 (, 1H, H2 '), 4.33(d, J = 7.8 Hz, 1H ,H20 a ), 4 . 25 (, 1H, H7), 4.16 Kd. J=7.S Hz, 1H ,H20/9 ), 3 . 81 (d, J=7. 2 Hz, 1H, H3) ,3. 71 (dd, J = 10. 2. 6.6 H z , 1H, 異丁基）， 3.60 (dd, J = 10.2, δ.6 Hz, 1H.異丁基），2.31(d, J = 6.6 Hz, 1H, 2ΌΗ), 2.55 (η, 1H, H6a), 2.50 (d, J=3.9 Hz, 1H, 70H), 2.37(s, 3H, 4Ac), 2.31 (a, 2H, H14), 2.26 (s, 3H, lOftc), 2.23(br s, 3H, Mel8), 1.89 (s, 3H, Mel9), 1.87(m, 1H, H6/3), 1.77 (s , 3H , He 異丁烯基）， 1 . 75 (s, 1H, 10H). 1.66 (s, 3H , Me 異丁烯基）， 1 .25 (s, 3H , Mel7), 1.15(s, 3H, Mel6), 0.76(d, J=7.2 Hz, 3H,異丁基之 Me), 0.70(d, J=6.6 Hz, 3H 異丁基之 Me)。窖锎 (請先閲讀背面之注意事項再填寫本頁) 訂經濟部中央標準局貝工消費合作社印裝本紙張尺度逍用中國固家揉準（CNS ) A4規格（210X297公* ) — 46 — 83.3.10,000 4206T〇;五、發明説明（ A7 B7This paper size applies to China National Standard (CNS) A4 specification (210X29? Mm) 1 44 — 83 · 3 * 10,000 42HR70 A7 B7 V. Description of the invention p) Printed by Shellfisher Consumer Cooperatives, China ’s Procurement Bureau, Ministry of Economic Affairs 3夂 Dephenyl-3 · -isobutenyl-η-debenzylidene-N_ (isobutoxycarbonyl) yew yeast is prepared in 7-triethylsilyl berry erythromycin III (40.0¾g · 0.042 奄Mol) solution in 0.5 ml THP * 0.05 «liter of 1.0M LiN (SiMe *) 2 in hexane was added dropwise at -45 TC. After 0.5 hours at -45 * * add 颙 -1 -(Isobutyryl) -3- (2-methoxy-2-propoxy) -4_isobutenyl monofluorotetramidine-2-plane (43.0 mg, 0.13¾ mole) at 0.5 Liter of THP solution to the mixture. Stir the solution to 0 and maintain it at this temperature for 1 hour. Add 0.5 ml of 10X AcOH solution (in THF) ° mixture in saturated HaHC03 solution and 60/40 ethyl acetate / hexane. Partition S. Residue obtained by evaporation * It is purified by silica gel "filtration purification to obtain 31.2 g of (2'13'3) -2 '-(2-methoxy-2-propoxy) -7- Triethylsilyl-3'-dephenyl-3'-isobutenyl-N-dephenylfluorenyl-H- (isobutoxycarbonyl ) Yew yeast and a small amount of (2'S, 3'R) isomers. Dissolve in 31.2 奄萁 g (0.030 奄萁 ear) of the previous reaction mixture in 2.0 奄 L acetam and 0.12ml pyridine. Add 0.25 ml of 48X Η 卩 aqueous solution at 1C. Mix the mixture at 0 υ for 3 hours, then at 25t for 13 hours, and partition between saturated HaHC03 and ethyl acetate. Evaporate the ethyl acetate solution to obtain 27.7 mg of substance. It was purified by flash chromatography to obtain 20Λmg (83 ×) 3 · -dephenyl-3'-isobutenyl-H-dephenylosyl (isobutoxycarbonyl) taxane, which was restructured from formazan / water * .P. 147-1 48 t: [α] 2Β «β-58.2 ° (c 0.0016, CHC1S) O lH HHR (CDCU. 300 MHz) 5 8.11 (d, J = 7.2 Hz, 2H, 99 ( Please read the notes on the back before filling in this page) The size of the paper used for this edition (CNS) A4 size U10X297 mm) 45 — 83.110,000 420670 A7 B7 5. Description of the invention (43) Formic acid K: 丨, 7. 6 1 (, 1H, para-benzoic acid m). 7.50 (*, 2H, meta-benzoic acid m), e. 30 (s, 1H H10), 6.22 (dd, J = 7. 5, 7.5 Hz, 1H, H13), 5,65 (d, J = 7.2 Hz, 1H, H2 β), 5.31 (, 1H, isobutenylene), 4.95 (d, J = 7.8 1Η, H5). 4. 91 (d, J = 8.2 Hz, 1H »NH), 4, 76 (ddd , J = 8.7, 8.7,, 2. 7 Hz, 1H, H3 *). 4. 41 (, 1H, H2 '), 4.33 (d, J = 7.8 Hz, 1H, H20 a), 4. 25 (, 1H, H7), 4.16 Kd. J = 7.S Hz, 1H, H20 / 9), 3. 81 (d, J = 7. 2 Hz, 1H, H3), 3. 71 (dd, J = 10. 2. 6.6 H z, 1H, isobutyl), 3.60 (dd, J = 10.2, δ. 6 Hz, 1H. Isobutyl), 2.31 (d, J = 6.6 Hz, 1H, 2ΌΗ), 2.55 (η, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.31 (a, 2H, H14), 2.26 (s, 3H, lOftc), 2.23 (br s, 3H, Mel8), 1.89 (s, 3H, Mel9), 1.87 (m, 1H, H6 / 3), 1.77 (s, 3H, He isobutenyl), 1. 75 (s, 1H, 10H) 1.66 (s, 3H, Me isobutenyl), 1.25 (s, 3H, Mel7), 1.15 (s, 3H, Mel6), 0.76 (d, J = 7.2 Hz, 3H, isobutyl of Me), 0.70 (d, J = 6.6 Hz, 3H isobutyl of Me). Cellar (please read the precautions on the reverse side and fill in this page) Order the paper size of the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative Co., Ltd. Print this paper size and use China Gujia Standard (CNS) A4 size (210X297 male *) — 46 — 83.3.10,000 4206T〇; V. Description of the invention (A7 B7

經濟部中央樣準局貝工消费合作社印裝 (54-3) 3’-脫笨基-3·-異丁烯基-Η-脫笨醢基-H-(乙氧猓基）紫杉醻之製備於7-三乙矽烷基槳果赤撇素III ( 100.0奄克· 0. 142 毫莫耳 > 於1.0 «升THF中之溶液，於-45 下滴加 0.16« 升 1·〇Μ UN(SiMes)a溶液（於己烷中）。於-45 t：下0.5小時後，癱.坡累.-1-(乙氧羰基）-3-(2·-2、，（2'甲氧 -2-丙氧基）-4-異丁烯基·一氮四醒-2-鹂（155藿克，〇.4 3«其耳）於1.0 «升THF中之溶液至混合物。混合物灌至0 t並維持於該溫1小時•再加1.0毫升l〇X AcOH溶液（於THF中 > 。痗合物於飽和KaHC〇3*溶液及60/40乙酸乙酯/己烷間分配。蒸發有櫬層得殘留物，其箱由矽腰 ΝΙ»純化，得112.2奄克含（2’11,3飞）-2’-(2-甲氣-2-丙氧基）-3'-脫苯基-3·-異丁烯基-7-三乙矽烷基-N-脫苯醣基-N-(乙氧羰基）紫杉酵及少董（2’S, 3*R)異構物之混合物。於112.2奄克（0.109奄奠耳）之得自前面反患之混合物於7.0奄升乙騁及0.4奄升吡啶中之溶液*於0 Ό下加 0.9毫升48 X HF水溶液。混合物於〇 <〇下攢拌3小時•再於25TD下13小畤，並於飽和HaHC〇3水溶液及乙酸乙酯間分配。蒸發乙酸乙酷溶液*得98.7奄克物質，其鶫快速曆析 (請先閲讀背面之注意事項再填寫本頁) -¾ 本纸浪尺皮逋Λ中國國家標準（CNS ) A4规格（210X297公釐）一 47 — 83.3.10,000 經濟部中央標準局員工消費合作社印装 4gr>6TQ_^_五、發明説明（45 ) 法純化，得81.4^克（93!1；)3'-脫苯基-3’-異丁烯基-找-脫笨麵基-N-(乙氧羰基）紫杉酵，其自甲酵/水中重结晶 Ο -P. 137-140 t：； t a ]aBM--56.2° (c 0.0023, CHCU) O NKR (CDCla, 300 MHz) 58.11(d, J=7.2 Ηε, 2H,鄰位苯甲酸凿），7.61U, 1H,對位笨甲_酯）.7,50 (酿， 2H,間位苯甲 _Κ). 6.30 (s, 1H, H10)· 6,19 (dd, J-7.5, 7.5 Hz, 1H, H13), 5.65 (d. J=7.2 Hz, 1H, H2/3 ), 5·31(·, 1H,異丁烯基之烯），4.98(d、，J = 7,8, 1H, H5), 4.90 (d, J=8.2 Hz, 1H, NH), 4.75(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.45(a, 1H, H2'), 4.31{d, J = 7.8 Hz, 1H, H20a), 4.25 («, 1H. H7), 4.16(d. J = 7.8 Hz, 1H, H20y3), 3.93 (q, J=7.2 Hz, 2H,乙基），3.81(d, J = 7.2 Hz, 1H. H3), 3,34 (d, J = 6.6 Hz, 1H, 2ΌΗ), 2.54 (1, 1H, H6a), 2.50 (d, J=3.9 Hz, 1H, ?0H), 2.36(s, 3H, 4Ac), 2.33 (n, 2H, H14), 2.26 (s, 3H, lOAc), 2.24(br s, 3H, Hel8), 1.89 (s, 3H. Mel9), 1.87(π, 1H, H6/3), (請先閲讀背面之注意事項再填寫本頁) 1·78 (S, 3H, Me 異丁烯基），1 .73 (s, 1H, 10H), l,68(s, 3H, Me 異丁烯基），1 * 26 (s， 3H， Kel7)， 1，15 (s , 3H, Me 16), 1. 08 (t, J = 7.2 Hz, 3H，乙基之Me> 窗捆ft 本紙張尺度逋用中國國家揉半（CNS > A4規捧（21QX297公釐）一48 — 83.110,000 420670 at B7五、發明説明（46 )Preparation of (54-3) 3'-debenzyl-3 · -isobutenyl-fluorene-debenzyl-H- (ethoxyfluorenyl) taxane tincture printed by the Shell Sample Consumer Cooperative of the Ministry of Economic Affairs To a solution of 7-triethylsilyl phytochelatin III (100.0 g · 0.142 mmol) in 1.0 «liter THF, 0.16« liter 1.0 mM UN ( SiMes) a solution (in hexane). At -45 t: After 0.5 hours, paralysis. Polie.-1- (ethoxycarbonyl) -3- (2 · -2 ,, (2'methoxy- 2-propoxy) -4-isobutenyl-nitroazatetra-2-oxine (155 g, 0.4 3 «its ear) in 1.0 liter THF to the mixture. The mixture was poured to 0 t and Maintained at this temperature for 1 hour • Add 1.0 ml of 10X AcOH solution (in THF>). The hydrazone was partitioned between saturated KaHC03 * solution and 60/40 ethyl acetate / hexane. A layer was evaporated The residue was obtained, and the box was purified from silicon waist Ν »to obtain 112.2 g of (2'11,3 fly) containing 2 '-(2-methyl-2-propoxy) -3'-dephenyl- A mixture of 3 · -isobutenyl-7-triethylsilyl-N-dephenylosyl-N- (ethoxycarbonyl) taxan and isomer (2'S, 3 * R) isomers. 112.2 g (0.10 9 mol) of the mixture from the previous reaction in 7.0 liters of acetic acid and 0.4 liters of pyridine solution * 0.9 liters of 48 X HF aqueous solution was added at 0 混合物. The mixture was mixed with 0 < 〇 3 Hour • 13 hours at 25TD, and partition between saturated HaHC03 aqueous solution and ethyl acetate. Ethyl acetate solution * is evaporated to obtain 98.7 g of substance, which is quickly analyzed (please read the precautions on the back before (Fill in this page) -¾ This paper lang ruler 逋 Λ Chinese National Standard (CNS) A4 specification (210X297 mm) 47-83.3.10,000 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4gr > 6TQ _ ^ _ V. Invention Explanation (45) Purification, 81.4 ^ g (93! 1;) 3'-dephenyl-3'-isobutenyl-m-benzylidene-N- (ethoxycarbonyl) taxane was obtained. Formazan / recrystallization in water 〇 -P. 137-140 t: ta) aBM--56.2 ° (c 0.0023, CHCU) O NKR (CDCla, 300 MHz) 58.11 (d, J = 7.2 Ηε, 2H, ortho Benzoic acid chisel), 7.61U, 1H, para-benzyl ester). 7,50 (brew, 2H, meta-benzyl_K). 6.30 (s, 1H, H10) · 6,19 (dd, J -7.5, 7.5 Hz, 1H, H13), 5.65 (d. J = 7.2 Hz, 1H, H2 / 3), 5.31 ( ·, 1H, isobutenylene), 4.98 (d ,, J = 7,8, 1H, H5), 4.90 (d, J = 8.2 Hz, 1H, NH), 4.75 (ddd, J = 8.7, 8.7, 2.7 Hz, 1H, H3 '), 4.45 (a, 1H, H2'), 4.31 (d, J = 7.8 Hz, 1H, H20a), 4.25 («, 1H. H7), 4.16 (d. J = 7.8 Hz , 1H, H20y3), 3.93 (q, J = 7.2 Hz, 2H, ethyl), 3.81 (d, J = 7.2 Hz, 1H. H3), 3,34 (d, J = 6.6 Hz, 1H, 2ΌΗ) , 2.54 (1, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H,? 0H), 2.36 (s, 3H, 4Ac), 2.33 (n, 2H, H14), 2.26 (s, 3H, lOAc ), 2.24 (br s, 3H, Hel8), 1.89 (s, 3H. Mel9), 1.87 (π, 1H, H6 / 3), (Please read the precautions on the back before filling this page) 1.78 (S , 3H, Me isobutenyl), 1.73 (s, 1H, 10H), 1,68 (s, 3H, Me isobutenyl), 1 * 26 (s, 3H, Kel7), 1,15 (s, 3H , Me 16), 1. 08 (t, J = 7.2 Hz, 3H, Me of Me > window bundle ft This paper size is half-sized in China (CNS > A4 gauge (21QX297 mm)-48 — 83.110,000 420670 at B7 V. Description of the invention (46)

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央橾準局舅工消費合作社印製 (58-3) .3乂-联苯基-3'•異丁烯基-Μ-脫苯醯基-N-(斩戊氧紫基 > 紫杉酵之製備於7-三乙矽烷基漿果赤徽素III (50.0奄克· 0.071毫莫耳）於0.7 «升THF中之溶液•於-45 t：下滴加〇.〇8毫升1.0H LiN(SiMe3)2瘠液（於己烷中）。於-45 υ下0.5 / 小時後，滴加顬-1-(新戊氧嫌*)-3-(2_甲氧-2-丙氧基卜4-異丁烯基一第四Η -2-酮（68.9罨克，0.21¾莫耳）於1.0奄升THF中之溶液至琨合钧。溶液溫至0 1C並雄持於該溢1小時•再加1.0毫升10X AcOH溶液（於THF中）。琨合物於鉋和1(8{1(：〇3水溶液及60/40乙酸乙酯/己烷之間会配。蒸發有機庸得殘留物，其藉由矽膠過濾純化，得 δ5·1毫克含（2’R,3'S卜2'-(2-甲氧-2-丙氧基）-3’-脫笨基 -3·-異丁烯基-7-三乙矽烷基-N-脫笨_基-M-(新戊氧羰基）紫杉酵及少量（2*S, 3'R)興構物之混合物。於65.1奄克（ 0.057考奠耳）之得自前面反應之混合物訂 f 本紙張尺度逍用中國國家梯準（CNS ) A4规格（210 X 297公釐）一4 9 - 83.3.10,000(Please read the precautions on the back before filling out this page) Printed by the Central Consumers 'Bureau of the Ministry of Economic Affairs and Industrial Cooperatives (58-3) .3 乂 -biphenyl-3' • isobutenyl-M-dephenylfluorenyl -N- (Cyclopentyl violet group) Preparation of Yew Yeast in 7-Triethylsilyl Berberin III (50.0 g · 0.071 mmol) Solution in 0.7 «L THF • at -45 t: 0.08 ml of 1.0H LiN (SiMe3) 2 barren solution (in hexane) was added dropwise. After 0.5 / hour at -45 υ, 顬 -1- (neopentylamine *)-was added dropwise. A solution of 3- (2-methoxy-2-propoxyb 4-isobutenyl-fourth fluoren-2-one (68.9 g, 0.21 ¾ mole) in 1.0 liter of THF to hydrazone. Solution Warm to 0 1C and hold the overflow for 1 hour. • Add 1.0 ml of 10X AcOH solution (in THF). Mix the mixture on a planer and 1 (8 {1 (: 0 3 aqueous solution and 60/40 ethyl acetate / Hexanes will be mixed. The organic residue is evaporated and purified by silica gel filtration to give δ5.1 · mg containing (2'R, 3'S and 2 '-(2-methoxy-2-propoxy)- 3'-debenzyl-3 · -isobutenyl-7-triethylsilyl-N-debenzyl-M- (neopentyloxycarbonyl) taxus and a small amount (2 * S, 3'R) Of structure Mixture. The mixture obtained from the previous reaction at 65.1 g (0.057 Comor). F The paper size is in accordance with China National Standards (CNS) A4 (210 X 297 mm)-4 9-83.3.10,000.

7 7 A B 420ΘΤ0 五、發明説明（47) (請先閎讀背面之注意事項再填寫本頁) 於δ.0笔升乙臍及0.3奄升吡啶中之痗液’於0 ^^加〇·7奄升48Χ HF水溶液。混合物於〇 "C下攪拌3小時，再於25¾下13小時，並於铯和HaHCOa水溶液及乙酸乙酯間分配。蒸發乙酸乙酯溶液得58.2奄克物霣，其藉快速層析法鈍化，得31.2奄克（65!〇3’-脫苯基-3*-(異丁烯基） -H-脫苯醣基-H-(新戊氧羰基）紫杉酵•其自甲酵/水中重结晶。 ».P. 147-149T：； [ a ]z6h--58.5° (c 0.0019, CHCU) Ο IKMIi (CDCU, 300 MHz) 3 8.15(d, J=7.2 Hz, 2H,鄴位笨甲酸醣）· 7.61U, 1H,對位苯甲酸釀），7.50 (, 2H,間位苯甲酸》). 6.30 (s, 1H, H10>, 6.22 (dd, J=7.5, 7.5 Hz, 1H, H13), 5.68 (d. J=7.2 Hz, 1H, H2/S 5.32(1, 1H,異丁烯基之烯.），4.98(d, J = 7.8, / 1H, H5), 4.89 (d, J=8.2 Hz. 1H, NH), 4.76(ddd, 經濟部中央標準局貞工消費合作社印装 J = 8.7, δ.7, 2.7 Hz, 1H, H3’），4.43U, 1H, H2，）， 4.29(d, J=7.8 Hz, 1H, H20a), 4.25 (*. 1H, H7), 4.16(d, J = 7.8 Hz, 1H· H20j9>，3.76(s, 2H，新戊氧基 ),3.81(d. J=7.2 Hz, 1H, H3), 3.34 (d, J=6.6 Hz, 1H,!2'0H), 2.55 (n, 1H, H6a), 2.50 (d, J=3.9 Hz, 1H, 70H)· 2.33(s, 3H, 4Ac), 2.30 (謙，2H. H14), 2.26 (s, 3H, lOAc), 2-24(br s, 3H, Hel8), 1.89 (s, 3Hf Mel9), 1.87(., 1H, H6/3), 1.77(s, 3H, Me 異丁烯基），1.75(s, 1H, 10H), 1.68U, 3H, Ke 興丁烯 83.3.10,000 度適用中0國家樣準(CNS ) A4規格（210X297公釐）一50- 420670 A7 B7 _ 五、發明说明（48) 基），l,26(s, 3H，Hel7), 1.20(s, 9H,新戊氧基之 Me7 7 AB 420ΘΤ0 V. Description of the invention (47) (Please read the precautions on the back before filling this page) Add δ.0 liters of umbilical cord and 0.3 liters of pyridine to the solution at 0 ^^. 7 liters of 48 × HF aqueous solution. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 13 hours, and partitioned between cesium and aqueous HaHCOa solution and ethyl acetate. Evaporation of the ethyl acetate solution gave 58.2 g of gadolinium, which was passivated by flash chromatography to give 31.2 g of (65.03′-dephenyl-3 *-(isobutenyl) -H-dephenylyl- H- (Neopentyloxycarbonyl) Yew Yeast • Its self-formase / water recrystallization. ».P. 147-149T:; [a] z6h--58.5 ° (c 0.0019, CHCU) 〇 IKMIi (CDCU, 300 MHz) 3 8.15 (d, J = 7.2 Hz, 2H, tartaric acid) · 7.61U, 1H, para-benzoic acid), 7.50 (, 2H, meta-benzoic acid)) 6.30 (s, 1H , H10 >, 6.22 (dd, J = 7.5, 7.5 Hz, 1H, H13), 5.68 (d. J = 7.2 Hz, 1H, H2 / S 5.32 (1, 1H, isobutenylene.), 4.98 (d , J = 7.8, / 1H, H5), 4.89 (d, J = 8.2 Hz. 1H, NH), 4.76 (ddd, printed by Zhengong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs J = 8.7, δ.7, 2.7 Hz , 1H, H3 '), 4.43U, 1H, H2,), 4.29 (d, J = 7.8 Hz, 1H, H20a), 4.25 (*. 1H, H7), 4.16 (d, J = 7.8 Hz, 1H · H20j9 >, 3.76 (s, 2H, neopentyloxy), 3.81 (d. J = 7.2 Hz, 1H, H3), 3.34 (d, J = 6.6 Hz, 1H ,! 2'0H), 2.55 (n, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H) · 2.33 (s, 3H, 4Ac), 2.30 (Qian, 2H. H14), 2.26 (s, 3H, lOAc), 2-24 ( br s, 3H, Hel8), 1.89 (s, 3Hf Mel9), 1.87 (., 1H, H6 / 3), 1.77 (s, 3H, Me isobutenyl), 1.75 (s, 1H, 10H), 1.68U, 3H, Ke Xingbutene 83.3.10,000 degrees applicable to China 0 National Standards (CNS) A4 specifications (210X297 mm)-50- 420670 A7 B7 _ V. Description of the invention (48) basis, l, 26 (s, 3H, Hel7) , 1.20 (s, 9H, neopentyloxy of Me

(58-4) (請先閲讀背面之注意事項再填寫本頁> 經濟部中夬樣华局員工消费合作社印装 3’-脫笨基-3’-興丁烯基-Η-脫苯醢基-Η-(異丙氧捩基）紫杉酵之製餚 t 於？-三乙矽烷基漿果赤黴素III (50.0¾克，0.071奄莫耳）於0.7毫升THF中之溶液•於-45 Ό下滴加0.08¾ 升1.0H UM(SiMe3>2溶液（於己烷中）。於-45 t：下0.5 小時後•滴加順-1Μ異丙氧期基）-3-(2-甲氧-2-丙氧基 )-4-異丁烯基一氟四圏-2-鬵（56.3¾克，0·22毫莫耳）於Γ.0毫升THF中之溶液至混合物。溶液溫至〇 c並保持於該濩1小時，再加1，0毫升10Χ AcOH溶液（於THF中）。混合物於鉋和MaHC〇3水溶液及60/40乙酸乙_ /己烷阳分配。蒸發有機蘑得殘留物，其經由矽謬過濾纯化得 63,4毫克含（21,3 1)-2，-(2-甲氧-2-丙氧基）-3，-脫苯基本紙張尺度遑用中國國家樣準（CNS ) A4规格（210X297公釐> -5 1 — 83.3.10,000 A7 420670 __B7_ 五、發明説明（49 ) -3·-異丁烯基-7-三乙矽烷基-N-脫苯酾基-N-(異丙氧羰基）紫杉酵及少S(2’S, 3’R)異構物之混合物。於63.4奄克（ 0.057 «莫耳）之得自前面反«之混合物於5.5毫升乙臍及0.3奄升吡啶中之溶液•於0 t下加 0.66«升48» HF水溶液。混合物於0 υ下攪拌3小時*再於25TC下13小時*並於飽和KaHC03A溶液及乙酸乙酯間分配。蒸發乙酸乙酯溶液得49.2¾克物質，其藕快速履析法銪化，得38.2毫克（82!〇3’-脫苯基-3'-異丁烯基-1?-税苯醻基(異丙氧羰基）紫杉酵，其自甲酵/水中里结晶〇 > m.p, 145-147^ ； [α ]2ΒΗ--5δ.3α (c 0.0019, CHCU) o HMR (CDCU, 300 MHz) 5 8.12(d, J = 7.2 Hz, 2H. W 位笨甲酸酯>· 7.61U. 1H,對位笨甲酸醱），7.50 (画， t 2H.間位苯甲酸酶），6.30 (s, 1H, H10), 6.20 (dd, J=7.5, 7.5 Hz, 1H, H13). 5.65 (d. J=7.2 Hz, 1H, H2yS ), 5.31(·, 1H,異丁烯基之烯），4.96(d, J = 7.8· 1H. H5), 4,90(d, J=8.2 Hz, 1H. HH), 4.77(ddd, J=8.7. 8.7, 2.7 Hz. 1H, Η3·), 4.69(·, 1H,異丙氧基 ),：4.43(·, 1H, H2'), 4.31(d, J=7.8 Hz. 1H, H20a ),4.24 {, 1H, H7), 4.15(d, J=7.8 Hz, 1H, H20/3 ),3.81(d, J=7.2 Hz, 1H， H3), 3.33(d, J=6.6 Hz, 1H, 2ΌΗ), 2.54 (, 1H, H6 a ) , 2.50 (d. J=3.9 Hz, 1H, 70H), 2.34(s, 3H, 4Ac) , 2.30 (ι. 2H, H14). 本紙張尺度適用t國國家揉準（CNS > A4说格（21f)X297公釐）一52 - 83.3-!〇.〇〇〇 <請先閲讀背面之注意事項再填寫本頁) 、vs 經濟部中央棣準局貝工消费合作社印製(58-4) (Please read the notes on the back before filling out this page> Printed on the 3'-debenzyl-3'-hexbutenyl-fluorene-debenzene Preparation of hydrazone-fluorene- (isopropoxyfluorenyl) yew fermentation in Yu-triethylsilyl berry gibberellin III (50.0¾ g, 0.071 mol) in 0.7 ml THF • 0.08¾ liters of 1.0H UM (SiMe3 > 2 solution (in hexane) was added dropwise at -45 Ό. After -45 t: 0.5 hour later · cis-1M isopropoxy group was added dropwise -3- (2 -Methoxy-2-propoxy) -4-isobutenyl monofluorotetrafluorene-2-fluorene (56.3¾ g, 0.22 mmol) in Γ.0 ml of THF to the mixture. The solution was warmed to 〇c and kept at this temperature for 1 hour, and then add 1.0 ml of 10X AcOH solution (in THF). The mixture was partitioned into a planer and an aqueous solution of MaHC03 and 60/40 ethyl acetate / hexane. The organic mushrooms were evaporated to obtain Residue, which was purified by silica filtration to obtain 63,4 mg containing (21,3 1) -2,-(2-methoxy-2-propoxy) -3, -dephenyl This paper is in Chinese standard Sample standard (CNS) A4 specification (210X297mm > -5 1 — 83.3.10,000 A7 420670 __B7_ V. Stated (49) -3 · -isobutenyl-7-triethylsilyl-N-dephenylfluorenyl-N- (isopropoxycarbonyl) taxane and S (2'S, 3'R) isomers A mixture of 63.4 g (0.057 «mol) of the mixture obtained from the previous reaction in 5.5 ml of ethyl umbilical and 0.3 ml of pyridine • Add 0.66« 48 of HF aqueous solution at 0 t. The mixture is in Stir at 0 υ for 3 hours * and then at 25TC for 13 hours * and partition between saturated KaHC03A solution and ethyl acetate. Evaporate the ethyl acetate solution to obtain 49.2¾ g of the substance, which is triturated by rapid analysis to obtain 38.2 mg ( 82! 〇3'-dephenyl-3'-isobutenyl-1? -Hydrophenylphenyl (isopropoxycarbonyl) taxane, which crystallizes from formazan / water 〇 > mp, 145-147 ^ ; [Α] 2BΗ--5δ.3α (c 0.0019, CHCU) o HMR (CDCU, 300 MHz) 5 8.12 (d, J = 7.2 Hz, 2H. W-position stearic acid esters > · 7.61U. 1H, Para-benzyl formate), 7.50 (paint, t 2H. Meta-benzoate), 6.30 (s, 1H, H10), 6.20 (dd, J = 7.5, 7.5 Hz, 1H, H13). 5.65 (d. J = 7.2 Hz, 1H, H2yS), 5.31 (·, 1H, isobutenylene), 4.96 (d, J = 7.8.1H. H5), 4,90 (d, J = 8.2 Hz, 1H. HH), 4.77 (ddd, J = 8.7. 8.7, 2.7 Hz. 1H, Η3 ·), 4.69 (·, 1H, isopropoxy), 4.43 (·, 1H, H2 '), 4.31 (d, J = 7.8 Hz. 1H, H20a), 4.24 (, 1H, H7), 4.15 (d, J = 7.8 Hz, 1H, H20 / 3), 3.81 (d, J = 7.2 Hz, 1H, H3), 3.33 (d , J = 6.6 Hz, 1H, 2ΌΗ), 2.54 (, 1H, H6 a), 2.50 (d. J = 3.9 Hz, 1H, 70H), 2.34 (s, 3H, 4Ac), 2.30 (ι. 2H, H14 ). This paper size is applicable to countries and countries (CNS > A4 format (21f) X297 mm) 52-83.3-! 〇.〇〇〇 < Please read the precautions on the back before filling this page) Vs. Printed by Shellfish Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

42067U A7 B7__五、發明説明（5〇 ) 2.24 (s, 3H, lOAc), 2.21(br s. 3H, Mel8), 1.88 (s, 3H, Hel9), 1.87(i, 1H. H6/? ) , 1 .77 (s, 3H, Me 異丁烯基）.1.75(s, 1H, 10H), 1.66(s, 3H· Me 異丁稀基}, 1.25(s, 3H, Mel7), 1.16(s. 3H, Mel6). l.U(d, J=6.6 Hz, 3H,異丙氧基之 Me). 1.12(d, J = 6.6 H2, 3H,異丙氧基之Me)。富相ί 842067U A7 B7__ V. Description of the invention (50) 2.24 (s, 3H, 10Ac), 2.21 (br s. 3H, Mel8), 1.88 (s, 3H, Hel9), 1.87 (i, 1H. H6 /?) , 1.77 (s, 3H, Me isobutenyl). 1.75 (s, 1H, 10H), 1.66 (s, 3H · Me isobutenyl), 1.25 (s, 3H, Mel7), 1.16 (s. 3H , Mel6). LU (d, J = 6.6 Hz, 3H, Me of isopropoxy). 1.12 (d, J = 6.6 H2, 3H, Me of isopropoxy). Rich phase 8

(請先閲读背面之注意事項存填寫本育) \ 經濟部t夹搮窣局貝工消費合作社印装 (59-1) 3’-脫笨基-3'-異丁烯基脫苯酶基- Η-(烯丙氧羰基）紫杉酵之製備於7-三乙矽烷基漿果赤微素111 (50.0¾克，0.071¾ 莫耸）於0.7聚升THF中之溶液，於-45 TC下滴加0.08毫升1.0«1^1<(5丨1^3)2溶液（於己烷中）。於-451[：下〇.5 小時後，滴加順-1-(烯丙氧捩基）-3-(2-甲氧-2-丙氧基 )-4-興丁烯基一氪四匾-2-爾U5.4奄克，0.22奄莫耳）於1.0奄升THF中之溶液至混合物。溶寐溫至〇 υ並雎持本紙張尺度適用中國困家揉率（CNS ) Α4规格（21.0X297公釐）一5 3 — 83.3.10,000 經濟部+央揉準局貝工消费合作杜印装 420670 A7 A7 __B7____五、發明説明（51 ) 於該溫1小時，再加1.0奄升10¾ AcOH溶液（於THF中）。混合物於鉋和HaHC〇3水溶获及60/40乙酸乙醮/己烷間分配。蒸發有檝曆得殘留物•其藉矽腰過濾鈍化，得 64.4毫克含（21,3’5)-2'-(2-甲氧-2-丙氧基）-3*-脫苯基 -3'-異丁烯基-7-三乙矽烷基-H-脫苯醣基-H-(烯丙氣捩基）紫杉酵及少嫌（2’S, 3· 10異構物之混合物。於64.4«克（ 0.058奄萁耳）之得自前面反應混合物於 6.0亳升乙明及0.28毫升吡啶中之溶液，於0 t下加0.7 毫升48X HF水溶液。混合物維持於0 t下3小時，再於 2 5T：下13小時，並於飽和HaHC〇3水溶液及乙酸S酷間分配。蒸發乙酸乙_溶液得53.2¾克物質，其藉快速曆析法纯化得33.3¾克（71X)3’_脫笨基-3’-異丁烯基-N-脫苯醯基-H-(烯丙氧羰基 > 紫杉酵*其自甲酵/水中重结晶。 .P. 137-139t：； [ a ]2eMa-59. 1° (c 0.0022, CHCls) 0 1 NMR (CDC 13, 300 MHz) 5 8.U(d, J = 7,2 Hz, 2H,邮位苯甲酸酯>,7.60(·, 1H,對位笨甲酸酯），7·50 (, 2Η,間位苯甲酸酯 >，6.29 (s, 1Η, Η10), 6.21 (dd, J = 7.5, 7.5 Hz, 1H, H13), 5·78(·, 1H.烯丙基）， 5.07 (d· J=7.2 Hz, 1H, H2/3 )，5·33(·, 1H,異丁烯基之烯），5.14(_, 2H,烯丙基 >,4.97(d, J = 7.8, 1Η· H5), 4.91(d, J=8.2 Hz, 1H, HH), 4.78(ddd. J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.43(», 1H, H2,), 4.31(d, J=7.8 Hz, 1H, H20a), 4.25 (a, 1H, H7), 4.18(d, (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度遑用中薄困家櫟準（CNS ) A4規格（210X297公釐）-54 — 83.110,000 4 匕 U ti / U 第S 3 1 0 3 4 2 S號專利申謫累中文說明書修正頁（39年元月Y Β7(Please read the precautions on the back and fill in this education first) \ Printed by the Ministry of Economic Affairs of the Tiapan Bureau Shellfish Consumer Cooperative (59-1) 3'-debenzyl-3'-isobutenyl dephenylase group- Preparation of hydrazone- (allyloxycarbonyl) taxane in 7-triethylsilyl berry erythropoulin 111 (50.0¾ g, 0.071¾ mol) solution in 0.7 liter THF, dripping at -45 TC Add 0.08 ml of a 1.0 «1 ^ 1 < (551 ^ 3) 2 solution (in hexane). At -451 [: 0.5 hours later, cis-1- (allyloxyfluorenyl) -3- (2-methoxy-2-propoxy) -4-oxetenyl-tetramethylene was added dropwise. Plaque-2-E U5.4 g, 0.22 mol) in 1.0 liter of THF to the mixture. Dissolve the temperature to 〇υ and support the standard of this paper. Applicable to China ’s poor households (CNS) Α4 size (21.0X297 mm)-5 3 — 83.3.10,000 Ministry of Economic Affairs + Central Kindergarten Bureau, shellfish consumer cooperation Du printed equipment 420670 A7 A7 __B7____ V. Description of the invention (51) At this temperature for 1 hour, add 1.0 liter of 10¾ AcOH solution (in THF). The mixture was water-soluble in a planer and HaHC03 and partitioned between 60/40 ethyl acetate / hexane. Residues after evaporation • It was passivated by silicon waist filtration to obtain 64.4 mg containing (21,3'5) -2 '-(2-methoxy-2-propoxy) -3 * -dephenyl- 3'-Isobutenyl-7-triethylsilyl-H-dephenylosyl-H- (allyl fluorenyl) taxane and a mixture of isomers (2'S, 3 · 10 isomers. In 64.4 « G (0.058 奄萁) of the solution obtained from the previous reaction mixture in 6.0 liters of acetam and 0.28 ml of pyridine, 0.7 ml of 48X HF aqueous solution was added at 0 t. The mixture was maintained at 0 t for 3 hours, and then at 2 5T: 13 hours, and partitioned between saturated HaHC03 aqueous solution and acetic acid S. Ethyl acetate solution was evaporated to obtain 53.2¾ grams of substance, which was purified by rapid calendar analysis to obtain 33.3¾ grams (71X) 3'_ Tuben -3'-isobutenyl-N-dephenylfluorenyl-H- (allyloxycarbonyl) Taxol * It is recrystallized from formazan / water. .P. 137-139t:; [a] 2eMa- 59. 1 ° (c 0.0022, CHCls) 0 1 NMR (CDC 13, 300 MHz) 5 8.U (d, J = 7,2 Hz, 2H, postal benzoate>, 7.60 (·, 1H , Para-paraben), 7.50 (, 2Η, meta-benzoate), 6.29 (s, 1Η, Η10), 6.21 (dd, J = 7.5, 7.5 Hz, 1H, H13), 5 · 78 (·, 1H. Allyl), 5.07 (d · J = 7.2 Hz, 1H, H2 / 3), 5.33 (·, 1H, isobutenylene), 5.14 (_, 2H, ene Propyl >, 4.97 (d, J = 7.8, 1ΗH5), 4.91 (d, J = 8.2 Hz, 1H, HH), 4.78 (ddd. J = 8.7, 8.7, 2.7 Hz, 1H, H3 ') , 4.43 (», 1H, H2,), 4.31 (d, J = 7.8 Hz, 1H, H20a), 4.25 (a, 1H, H7), 4.18 (d, (Please read the precautions on the back before filling this page ) This paper uses the medium and thin oak (CNS) standard A4 (210X297 mm)-54 — 83.110,000 4 U Uti / U No. S 3 1 0 3 4 2 S patent application, tired Chinese manual Revised Page (Year 39Y Β7

五、發明説明（52 ) J 二 7·8 Hz, 1Η, Η20/3)，4.0S(d，J = 6.6 Hz, 2Η，烯丙基 ),3.79(d, J=7.2 Hz, 1H, H3), 3.34(d, J=6.6 H2, 1H, 2ΌΗ), 2.55 (1, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.36(s, 3H, 4Ac), 2.33 (ίο , 2H, H14), 2.26 (s, 3H, lOAc), 2.24(br s, 3H, Mel8), 1.88 (s, 3H, Hel9), 1.85(ηι, 1H, H6^), 1.72(s, 3H, Me 異丁烯基），1.69(s, 1H，10H), l，61(s, 3H, He 異丁烯基），l‘25(s, 3H, Mel7), 1.15(s, 3H, Mel6)。蜜俐9V. Description of the invention (52) J 2 7.8 Hz, 1Η, Η20 / 3), 4.0S (d, J = 6.6 Hz, 2Η, allyl), 3.79 (d, J = 7.2 Hz, 1H, H3 ), 3.34 (d, J = 6.6 H2, 1H, 2ΌΗ), 2.55 (1, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.33 ( ίο, 2H, H14), 2.26 (s, 3H, lOAc), 2.24 (br s, 3H, Mel8), 1.88 (s, 3H, Hel9), 1.85 (ηι, 1H, H6 ^), 1.72 (s, 3H , Me isobutenyl), 1.69 (s, 1H, 10H), l, 61 (s, 3H, He isobutenyl), l'25 (s, 3H, Mel7), 1.15 (s, 3H, Mel6). Honey 9

PhPh

OAcOAc

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 (5 9 - 2) 3’-脫苯基-3'-異丁烯基-N-脫窄醢基-N-(苄氧羰基）紫杉酵之製備於7 -三乙矽烷基漿果赤徽素III (50.0毫克，0.071毫莫耳）於0.7毫升THF中之溶液，於-4t下滴加0.08毫升 1.0M LiN(SiMe3)2溶液（於己烷中）。於-4t下0·5小時後，滴加順-1-(笨醯氧羰基）-3-(2 -甲氧-2-丙氧基）-4 -異丁烯基一氮四團-2-酮（53毫克，0.21毫莫耳）於0.5毫升THF中之溶液至混合物。溶液溫至0 並維持於該溫1 55 本紙張尺度適用中國國家搮準（CNS ) A4規格（210X297公釐） 420670 A7 B7五、發明説明（53) 經濟部t夬搮準局員工消费合作社印装小時，再加1 · 0毫升10X AcOH溶获（於THP中）。混合物於飽和HaHC〇3水溶液及60/40乙酸乙酷/己烷間分g。蒸發有櫬雇得殘留物，其藉由矽臞«濾純化，得60. 4毫克之含（2 1,3'$)-2'-(2-甲氧-2-丙氧基）-3’-脫苯基-3’胃異丁烯基-7-三乙矽烷基-Η-脫苯醮基-Ν-(苯釀氧羰基）紫杉酵及少悬（2’S_ 3D異構物之混合物。於60.4«克（ 0.053毫莫耳）之得自前面反應之混合物於5·0瑾升乙騎及0.3亳升吡啶中之溶液，於〇 t;下加 0. 65¾升48X HF水溶液。混合物於0幻下攒拌3小時，再於25t：下13小時，並於飽和HaHC03水溶液及乙酸乙_間分配。蒸發乙酸乙酯溶液得48.2毫克物質，其箱快速餍析法純化，得34.1¾克（74X)3’-脫苯基-3，-異丁烯基-H-脫苯醯基-N-(苯醯氧羰基）紫杉酵，其自甲酵/水中重结晶 0 1. P. 148-149t：； [α ]25ν«-53.2.0° (c 0.0026，CHC 1 3)。 NMR (CDCU, 300 MHz) 38.15(d, J = 7.2 Hz, 2H,鄰位苯甲酸酯）· 7.61(·· 1H,對位笨甲酸酯）· 7,48 (, 2H,間位苯甲酸 _), 7.22-7.20 (·, 3H,苄基）， 7.1:0-7.05(m, 2Η.苄基），6,29 U, 1H, Η10), 6.21 idd, J=7.5, 7.5 Hz, 1H, H13), 5.63(d, J=7.2 Hz, 1H，H2b), 5.33U, 1H,異丁烯基之烯），5.06(d, J = 12.3 Hz, 1H.苄基），4.97(d, J = 7.8, 1H, H5>, 4.91(d, J=8.2 Hz, 1H, MH), 4.85(d, J=12.3 Hz, 1H, (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中固國家揉準（CNS ) A4規格（210X297公羞）一 5 6 - 83.3.10,000 42〇670A、發明説明 A7 B7 (54 ) ^ ), 4.76(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4·4δ(·, 1H, H2'), 4.30Cd, J=7.8 Hz, 1H, H20a), τ· 4.25 (*, 1H, H7), 4.16(d, J=7.8 Hz, 1H, H20/S), 3.8l(d, J=7.2 Hz, 1H, H3), 3.34(d, J=6.6 Hz, 1H, 2ΌΗ), 2.55 (·, 1H, H6a), 2.49 (d, J = 3.9 Hz, 1H 7〇H), 2.36(s, 3H, 4Ac), 2.32 (a, 2H, H14), 2.27 (s, 3H. IOAc), 2.24(br s, 3H, Mel8), 1.90 (s, 3H Mel9), 1.86U, 1H, H6/3), 1.77(s, 3H, Me 異丁烯基 ).1.75(s, 1H, 10H), 1.67<s, 3H, Me 異丁烯基）， l27(s, 3H, Hel7) , 1.16(s, 3H, Hel6)。 ' 富拥10(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (5 9-2) 3'-dephenyl-3'-isobutenyl-N-de-n-pyridyl-N -(Benzyloxycarbonyl) Taxane Preparation A solution of 7-triethylsilyl berry erythromycin III (50.0 mg, 0.071 mmol) in 0.7 ml of THF, 0.08 ml of 1.0 M was added dropwise at -4 t LiN (SiMe3) 2 solution (in hexane). After 0.5 hours at -4t, cis-1- (benzyloxycarbonyl) -3- (2-methoxy-2-propoxy) -4 -isobutenyl-tetrazol-2-one was added dropwise. (53 mg, 0.21 mmol) in 0.5 ml of THF to the mixture. Solution temperature to 0 and maintained at this temperature 1 55 This paper size is applicable to China National Standards (CNS) A4 specifications (210X297 mm) 420670 A7 B7 V. Description of invention (53) Printed by the Consumers ’Cooperatives of the Ministry of Economic Affairs t 夬搮 Standards Bureau After loading, add 1.0 ml of 10X AcOH (dissolved in THP). The mixture was partitioned between a saturated aqueous solution of HaHC03 and 60/40 ethyl acetate / hexane. The residue was evaporated and purified by filtration through silica gel to obtain 60.4 mg of (2 1,3 '$)-2'-(2-methoxy-2-propoxy) -3 Mixture of '-dephenyl-3' gastric isobutenyl-7-triethylsilyl-fluorene-dephenylfluorenyl-N- (benzyloxycarbonyl) taxane and oligo (2'S_ 3D isomers) . 65¾ liters of 48X HF aqueous solution at 60.4 «g (0.053 millimoles) of the mixture obtained from the previous reaction in 5.0 liters of acetone and 0.3 liters of pyridine. Mix at room temperature for 3 hours, then at 25t: for 13 hours, and partition between saturated aqueous solution of HaHC03 and ethyl acetate. Evaporate the ethyl acetate solution to obtain 48.2 mg of substance, which is purified by rapid decantation in a box to obtain 34.1¾ G (74X) 3'-dephenyl-3, -isobutenyl-H-dephenylfluorenyl-N- (phenyloxocarbonyl) taxane, which is recrystallized from formazan / water 0 1. P. 148 -149t:; [α] 25ν «-53.2.0 ° (c 0.0026, CHC 1 3). NMR (CDCU, 300 MHz) 38.15 (d, J = 7.2 Hz, 2H, ortho-benzoate) · 7.61 (·· 1H, para-paraben) · 7,48 (, 2H, meta-benzoic acid), 7.22-7.20 (·, 3H, benzyl), 7.1: 0-7.0 5 (m, 2Η.benzyl), 6,29 U, 1H, Η10), 6.21 idd, J = 7.5, 7.5 Hz, 1H, H13), 5.63 (d, J = 7.2 Hz, 1H, H2b), 5.33 U, 1H, isobutenylene), 5.06 (d, J = 12.3 Hz, 1H. Benzyl), 4.97 (d, J = 7.8, 1H, H5 >, 4.91 (d, J = 8.2 Hz, 1H, MH ), 4.85 (d, J = 12.3 Hz, 1H, (Please read the precautions on the back before filling in this page) This paper size is applicable to China Solid State Standards (CNS) A4 size (210X297), 5 6-83.3 .10,000 42〇670A, Invention Description A7 B7 (54) ^), 4.76 (ddd, J = 8.7, 8.7, 2.7 Hz, 1H, H3 '), 4.4δ (·, 1H, H2'), 4.30Cd, J = 7.8 Hz, 1H, H20a), τ · 4.25 (*, 1H, H7), 4.16 (d, J = 7.8 Hz, 1H, H20 / S), 3.8l (d, J = 7.2 Hz, 1H, H3 ), 3.34 (d, J = 6.6 Hz, 1H, 2ΌΗ), 2.55 (·, 1H, H6a), 2.49 (d, J = 3.9 Hz, 1H 7〇H), 2.36 (s, 3H, 4Ac), 2.32 (a, 2H, H14), 2.27 (s, 3H. IOAc), 2.24 (br s, 3H, Mel8), 1.90 (s, 3H Mel9), 1.86U, 1H, H6 / 3), 1.77 (s, 3H , Me isobutenyl). 1.75 (s, 1H, 10H), 1.67 < s, 3H, Me isobutenyl), l27 (s, 3H, Hel7), 1.16 (s, 3H, Hel6). '' Rich 10

TWSTWS

〇Ac〇Ac

(請先閲讀背面之注意事項再填寫本頁) 經濟部令央橾準局貝工消費合作杜印氧 (60-3) 3’-脫苯基-3’-異丁烯基-N-脫笨醃基-H-(三甲矽烷甲氧歎 *)紫杉酵之製備菸7-三乙矽烷基漿果赤撇素III ( 50.0¾克· 0_ 71«莫耳）於0.7毫升THF中之溶液•於-45 t：下滴加0.08¾升 1.〇»1^{<(511^3)2溶液（於己烷中）。於-45<0下〇.5小時後，滴加顚-1-(三甲矽烷甲氧琺基）-3-(2-甲氧-2-丙氧基）-4-(異丁烯基）一氮四釀-2-酮（77.0奄克· 本紙張尺度逋用中國國家標率（CNS ) A4规格（210X297公釐）-57 — 83.3.10,000 420670 A7 B7五、發明説明（5今經濟部中央榡準局貝工消費合作社印裝 0.22毫其耳 > 於〇·?毫升THP中之溶液至混合物中。溶液湛至0 並雉持於該溫1小時•再加1.0奄升10Χ AcOH溶液（於THF中）。混合物於飽和HaHC〇3A溶液及60/40乙酸乙_/己烷之間分配。蒸發有櫬雇得殘留物*其藉由矽膠邊瀘純化，得58.4毫克含（2'11,31)-2*-(2-甲氧-琴-丙氧基）-3’-脫苯基- 3’-異丁烯基-7-三乙矽烷基-K-脫苯醯基-N-(三甲矽烷甲氧羰基）紫杉酵及少*t(2*S, 3*R)異構物之混合物。於5δ.4奄克（0.51¾莫耳）得自前面反應之混合物於 5,0奄升乙觭及0.30毫升吡啶中之溶液•於0亡下加 0,60¾升48X HF水溶液。据合物於0 t；下攪拌3小時•再於25 TC下13小時*並於HaHC〇3水溶液及乙酸乙酯間分配。蒸發乙酸乙酯溶液得51.2«克物質，其藉快速層析法纯化，得31.1¾克（7U)3·-脫苯基-3*-異丁烯基-H-脫苯》 / 基-N-(三甲矽烷甲氧羰基）紫杉酵•其自甲酵/水中重结晶。 a.p. 149-151^ ； [α ]2ΒΜ.-58.0β (c 0.0018, CHCU) O lH HMR (CDCla, 300 MHz) 58.11(d, J=7.2 Hz, 2H, 位餐甲酸_), 7.61(·, 1H,對位苯甲酸酷），7.48 (a, 2H,間位苯甲酸酷），e.30(s, 1H, H10), 6.21 (dd, J=7.5, 7.5 Hz, 1H. H13), 5.67(d, J=7.2 Hz, 1H. H2 泠），5.33(·, 1H,異丁烯基之烯），4.97(d, J = 7,8, 1H, H5), 4.88(d, J=8.2 Hz, 1H, HH). 4.76(ddd. I：— ^^--M----/-----—訂------貧» . -- {請先閲讀背面之注^^項再填寫本頁) 本紙張尺度逋用中國國家揉準（CNS ) A4規格（210X297公釐）一58 — 83.3.10,000 A2〇67〇 A7 B7 五、發明説明（56 ) J=8.7, 8.7， 2.7 Hz, 1H, Η3·>, 4.41(·, 1H, H2，）， 4.28(d, J=7.a Hz, 1H, H20a), 4.25 (», 1H, H7). 4.16(d. J = 7.8 Hz, 1H, H20jS), 3.76(d, J = 7.2 Ηε, 1H. H3), 3.68(d, J = 14.1 Hz, 1H, Cib TMS), 3.5 1 (d, J=14.1 Hz, 1H, ClLzTHS). 3.41(d, J=6.6 Hz, 1H, 2ΌΗ), 2.55 (*, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.29(s, 3H, 4Ac), 2.25 («, 2H, H14), 2.21 (s, 3H, lOAc), 2.24(br s, 3H, Hel8), 1.89 is, 3H, Mel9)t 1.87(·, 1H, H6/S), 1.77(s, 3H, Me異丁烯基 ........)，1.75 (s, 1H, 10H) , 1.68(s, 3H, Me 異丁烯基）， 1.18(s, 3H, Hel7). 1.15(s, 3H, Hel6), -0.04(s, 9H, Me3Si-)。 g fflm (請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page) Ministry of Economic Affairs, Central Bureau of quasi-bureau, Shellfish consumer cooperation, Du Indian oxygen (60-3) 3'-dephenyl-3'-isobutenyl-N-debenzine -H- (Trimethylsilylmethoxylanth *) Preparation of Yew Yeast 7-Triethylsilyl Berberine III (50.0¾g · 0_ 71 «Mole) Solution in 0.7ml THF • 于- 45 t: 0.08 ¾ liter of 1.0. 1 ^ {< (511 ^ 3) 2 solution (in hexane) was added dropwise. After 0.5 hours at -45 < 0, fluorene-1- (trimethylsilylmethenamin) -3- (2-methoxy-2-propoxy) -4- (isobutenyl) -nitrogen was added dropwise. Sisang-2-one (77.0 奄 g · This paper size uses Chinese National Standard (CNS) A4 specifications (210X297mm) -57 — 83.3.10,000 420670 A7 B7 The Zhuhai Bureau Shellfish Cooperative Co., Ltd. printed a solution of 0.22 mils > in 0.1 ml of THP into the mixture. The solution reached 0 and held at that temperature for 1 hour. THF). The mixture was partitioned between saturated HaHC03A solution and 60/40 ethyl acetate / hexane. The residue was evaporated and purified by silica gel to obtain 58.4 mg containing (2'11, 31) -2 *-(2-methoxy-qin-propoxy) -3'-dephenyl-3'-isobutenyl-7-triethylsilyl-K-dephenylfluorenyl-N- (trimethyl A mixture of silane methoxycarbonyl) taxane and less * t (2 * S, 3 * R) isomers. At 5δ.4 g (0.51¾ mole) from the previous reaction mixture at 5,0 于Solution in liters of acetamidine and 0.30 ml of pyridine • Add 0,60 ¾ liters of 48X HF aqueous solution at 0 ° C. The mixture was stirred for 3 hours at 0 t; then 13 hours at 25 TC * and partitioned between HaHC0 aqueous solution and ethyl acetate. The ethyl acetate solution was evaporated to give 51.2 «g of material, which was purified by flash chromatography, 31.1¾ g (7U) of 3 · -dephenyl-3 * -isobutenyl-H-dephenyl "/ yl-N- (trimethylsilylmethoxycarbonyl) taxane was obtained. It was recrystallized from formazan / water. ap 149-151 ^; [α] 2BM.-58.0β (c 0.0018, CHCU) OlH HMR (CDCla, 300 MHz) 58.11 (d, J = 7.2 Hz, 2H, p-formic acid_), 7.61 (·, 1H, para-benzoic acid), 7.48 (a, 2H, meta-benzoic acid), e.30 (s, 1H, H10), 6.21 (dd, J = 7.5, 7.5 Hz, 1H. H13), 5.67 (d, J = 7.2 Hz, 1H. H2), 5.33 (·, 1H, isobutenylene), 4.97 (d, J = 7,8, 1H, H5), 4.88 (d, J = 8.2 Hz, 1H, HH). 4.76 (ddd. I: — ^^-M ---- / -----— Subscription ------ Poor ».-{Please read the note ^^ item on the back first (Fill in this page again) The paper size is in Chinese National Standard (CNS) A4 size (210X297 mm) 58-83.3.10,000 A2 067〇A7 B7 V. Description of the invention (56) J = 8.7, 8.7, 2.7 Hz, 1H, Η3 · >, 4.41 (·, 1H, H2,), 4.2 8 (d, J = 7.a Hz, 1H, H20a), 4.25 (», 1H, H7). 4.16 (d. J = 7.8 Hz, 1H, H20jS), 3.76 (d, J = 7.2 Ηε, 1H. H3), 3.68 (d, J = 14.1 Hz, 1H, Cib TMS), 3.5 1 (d, J = 14.1 Hz, 1H, ClLzTHS). 3.41 (d, J = 6.6 Hz, 1H, 2ΌΗ), 2.55 (* , 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.29 (s, 3H, 4Ac), 2.25 («, 2H, H14), 2.21 (s, 3H, lOAc), 2.24 (br s, 3H, Hel8), 1.89 is, 3H, Mel9) t 1.87 (·, 1H, H6 / S), 1.77 (s, 3H, Me isobutenyl ...), 1.75 (s, 1H , 10H), 1.68 (s, 3H, Me isobutenyl), 1.18 (s, 3H, Hel7). 1.15 (s, 3H, Hel6), -0.04 (s, 9H, Me3Si-). g fflm (Please read the notes on the back before filling this page)

,1T, 1T

經濟部中央標準局員工消費合作社印製 (70-4 )Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (70-4)

碑- 本紙張尺度逋用中國國家揉準（CNS ) A4規| ( 210X2^公釐）一 59 — 81 3.10,000 420670 at __B7五、發明説明（S7 ) 經濟部卡夬標準局負工消費合作社印策脫苯基-3'-(興丁烯基）-N-脫笨酿基(第三丁氧獷基）-9-脫氧基-9)3-羥基-10-脫乙醢基紫杉酵之製偁於7,10-(雙卜0-三乙矽烷基-9-脫氧基-9/8-羥基 -10-脘乙»基漿果赤撇素（III) ( 70.0¾克· 〇.〇9«莫耳 )於1.0毫升邝卩中之溶液•於-45 t下滴加0.10¾升 0. 98M UH(SiMe3) 2溶液（於己烷中）。於-45 υ下0.5小時後，滴加__1-(第三丁氧羰基）-3-(2-甲氧異丙氧基 )-4-(興丁烯基）-一氰四醒-2-醑（84.5¾克，〇,27奄萁耳）於1·0奄升THP中之溶液至琨合物中。溶液溫至0 並維持於該组1小時*再加1 *升10X AcOH溶液（於THF 中）。混合物於飽和NaHC〇3水溶液及60/40乙酸乙酯/己烷間分配。蒸發有櫬曆得殘留物，其藉由矽應遇濾纯化. 得88,3毫克含（2，卩，3,3)-2，，7，10-(叁）-0-三乙矽烷基 -3’-脫笨基-3'-(異丁烯基）-H-脫苯醸基-N-(第三丁氣羰基）-9-脫氧基-9点-羥基-10-脫乙醢基紫杉酵及少量 (2 'S, 3'R)異構物之混合物。於88.3¾克（0.080奄莫耳）得自前面反應之混合物於 13.5¾升乙臃及0.55«升吡啶中之溶液•於0 TC下加 1, 扑奄升48X HF水溶液。混合物於0 t：下攪拌3小時*再於25Τ；下13小時，並於餹和NaHC〇3水溶液及乙酸乙酯間分 E。蒸發乙酸乙酷溶液得67.2¾克物質，其藉快速簷析法鈍化得52.7奄克（82!〇3'-脫笨基-3'-縝丁烯基)-»1-脫苯釀基-H-(第三丁氧羰基）-9-脫氧基-9点-羥基-10-脫乙釀 (請先閲讀背面之注意事項再填寫本育) 本紙張尺度逋用中國國家標率（CNS ) A4規格（210X 297公釐> -6 0 — 83. 3.10,000 420670 A7 B7五、發明説明（58 )基紫杉酵，其自甲酵/水中重结昼。 B.P. 138-140t：； [α ] ΖΒ(.·-55.20 (c 0.0026, CHCU) 0 1 HMR (MeOH, 300 MHz) d8.11(d, J=7‘l Hz, 2H,鄰位笨甲酸_), 7_61U, 1H,對位苯甲酸酷），7.48 (a, 2H,間位苯甲酸酯），6.13U, 1H, H13), 6,12(1, 1H, H2), 5,21(br s.， 1H_ H3’）， 5.02(d, J=5.3 Hz, 1H, H10). 4.93(d, J=8.1 Hz, 1H, H5), 4.85(d, J=9.1 Hz, 1H, NH), 4.84(d, J = 8.5 Hz, 1H, MezC = CL~), 4.50(br s, 1H, H2')t 4.50 (d, _J = 5.. 5. Hz , 1H\ H9), 4.22(d, J=8.1 Hz, 1H. H20a), 4.18(d, J=8.1 Ηε, 1H, H20/3), 3.89(dd, J=9.4, 7.5 Hz, 1H, H7), 3.12(d, J=5.5 Hz, H3), 2.45(ι, 1H, H6a), 2.31(a. 1H, H14a), 2.29(s, 3H* 4Ac), 2.18 (b, 1H, H14^ ),1.85(ddd, J=15.1, 9.4, 1.2 Hz, H6^), 1.81 (s, 3H, Mel6), 1.76(s. 3H, Mel8), 1.72 (s, 6H, 2Me 來自異丁烯基），l,61(s，3H, Mel9), 1.39(s, 9H，3Me 第三丁氧基），1.26(s, 3H, Mel7)。 g俐1 2 (請先閲讀背面之注意事項再填寫本頁)Stele-This paper size uses the Chinese National Standard (CNS) A4 Regulation | (210X2 ^ mm) 1 59 — 81 3.10,000 420670 at __B7 V. Description of the Invention (S7) Card Work Standard Bureau, Ministry of Economic Affairs, Consumer Cooperative Imazadephenyl-3 '-(xetenyl) -N-destyryl (third butoxyfluorenyl) -9-deoxy-9) 3-hydroxy-10-deethylfluorenyl taxane Fermented by 7,10- (bisbu 0-triethylsilyl-9-deoxy-9 / 8-hydroxy-10-ethylethyl} berry chelatin (III) (70.0¾ g. 〇. 〇9 «Mole) solution in 1.0 ml of mash. · Add 0.10 ¾ liter of 0.98 UH (SiMe3) 2 solution (in hexane) dropwise at -45 t. After 0.5 hour at -45 υ, dropwise add __1- (Third-butoxycarbonyl) -3- (2-methoxyisopropoxy) -4- (oxetenyl) -monocyanotetrazine-2- 醑 (84.5¾g, 〇, 27 奄萁 Ear) in 1.0 liters of THP solution to the mixture. The solution was warmed to 0 and maintained in this group for 1 hour * plus 1 * liters of 10X AcOH solution (in THF). The mixture was saturated with NaHC. Partitioned between 3 aqueous solution and 60/40 ethyl acetate / hexane. The residue was evaporated and purified by silica gel filtration. 88,3 mg containing (2, 卩, 3,3) -2,, 7,10- (Tri) -0-triethylsilyl-3'-debenzyl-3 '-(isobutenyl) -H-dephenylfluorenyl-N- (third Butanyl carbonyl) -9-deoxy-9-hydroxy- 10-deacetylated yew yeast and a small amount of (2 'S, 3'R) isomers. At 88.3¾ g (0.080 mol) ) Solution obtained from the previous reaction mixture in 13.5¾ liters of acetamidine and 0.55 «liters of pyridine • Add 1 at 0 TC and pour liters of 48X HF aqueous solution. Stir the mixture at 0 t: 3 hours * then at 25T; In the next 13 hours, E was partitioned between hydrazone and NaHC03 aqueous solution and ethyl acetate. Ethyl acetate solution was evaporated to obtain 67.2¾ grams of material, which was passivated by rapid eaves analysis to obtain 52.7 grams (82! 03'-desulfurization). Benthyl-3'-fluorenyl butenyl)-»1-debenzoyl-H- (third butoxycarbonyl) -9-deoxy-9-dot-hydroxy-10-deethylated (please read the back first) Note: Please fill in this education again.) This paper uses China National Standards (CNS) A4 size (210X 297 mm > -6 0 — 83. 3.10,000 420670 A7 B7. 5. Description of the invention (58) Cedar leaven, which re-days from forma leaven / water. BP 138-140t:; [α] ZΒ (. · -55.20 (c 0.0026, CHCU) 0 1 HMR ( MeOH, 300 MHz) d8.11 (d, J = 7'l Hz, 2H, o-benzoic acid_), 7_61U, 1H, para-benzoic acid), 7.48 (a, 2H, meta-benzoate ), 6.13U, 1H, H13), 6,12 (1, 1H, H2), 5,21 (br s., 1H_ H3 '), 5.02 (d, J = 5.3 Hz, 1H, H10). 4.93 ( d, J = 8.1 Hz, 1H, H5), 4.85 (d, J = 9.1 Hz, 1H, NH), 4.84 (d, J = 8.5 Hz, 1H, MezC = CL ~), 4.50 (br s, 1H, H2 ') t 4.50 (d, _J = 5 .. 5. Hz, 1H \ H9), 4.22 (d, J = 8.1 Hz, 1H. H20a), 4.18 (d, J = 8.1 Ηε, 1H, H20 / 3 ), 3.89 (dd, J = 9.4, 7.5 Hz, 1H, H7), 3.12 (d, J = 5.5 Hz, H3), 2.45 (ι, 1H, H6a), 2.31 (a. 1H, H14a), 2.29 ( s, 3H * 4Ac), 2.18 (b, 1H, H14 ^), 1.85 (ddd, J = 15.1, 9.4, 1.2 Hz, H6 ^), 1.81 (s, 3H, Mel6), 1.76 (s. 3H, Mel8 ), 1.72 (s, 6H, 2Me from isobutenyl), 1,61 (s, 3H, Mel9), 1.39 (s, 9H, 3Me third butoxy), 1.26 (s, 3H, Mel7). g 莉 1 2 (Please read the notes on the back before filling in this page)

-tT 經濟部中央標準局員工消費合作社印裝 (68-4)-tT Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy (68-4)

本紙3L尺度逋用中國國家揲準（CNS ) A4说格（210X297公釐）一δ 1 — m ιο,οοο ^ (V A7 B7五 '發明说明（59 ) 經濟部中夬標準局—工消费合作社印製 3'-脍笨基-3’-(異丁烯基）-N-脫苯醣基-Η-(第三丁氧羰基 )-10-脱乙醢氧基紫杉酵之製備於7-0-三乙矽烷基-10-脫乙醣氧基漿果赤徽素（III)( 50.0«克· 0.077毫奠耳）於0.8奄升THF中之溶液*於 -45 ΐ：下滴加0.09毫升0.98Μ UH(SiMe3)2溶液（於己烷中 )。於-45 t下0.5小時後，滴加順-1-第三丁氧羰基 -3-(2-甲氧異丙氧基）-4-(異丁烯基）一氮四圈-2-瞩（ 58,0«克》0.193毫莫耳）於0.7躉升THF中之溶液至混合物中。溶液溫至0 並維持於該溫1小時*亩加1毫升 10X AcOH溶液（於THP中）。混合物於鉋和NaHC〇3水溶液與6 0/40乙酸乙酗/己烷間分fi。蒸發有機靥得殘留物· 其箱由矽謬遇濂纯化，得62.7奄克含 <2'R,3'S)-2',0-(2-甲氣異丙基）-770-三乙矽烷基-3’-脫苯基-3〜（異丁烯基卜Η-脫笨«基-H-(第三丁氧羰基 )-10-脫乙醯氧基紫杉酵及少量（2’$, 3’R)異構物之混合物0 於62.7奄克（ 0.059毫舆耳）得自前面反應之混合物於 3.5 *升乙騎及0.16毫升吡啶中之溶液•於〇 t：下加 0.55毫升48X HP水瘠液。混合物於0 t：下攪拌3小時，再於25X：下13小時，並於餹和MaHC〇3水溶液及乙酸乙_簡分配。蒸發乙酸乙鹿溶液得51. 5«克物霣，其藉快速雇析法鈍化》得43.0亳克（95S!)3’-脫苯基-3’-(異丁烯基） -H-脫笨醢基-H-(第三丁氣羰基）-10-脫乙鐮氧基紫杉酵 (请先聞讀背面之注意事項再填寫本頁) 訂銘_ 本紙張又度逋用中國國家揲率（CNS ) A4规格（210 X 297公釐）一 δ 2 - 83. 3.10,000 經濟部中央標準局員工消費合作社印製 420670 A7 B7五、發明説明（6〇 ) •其自甲酵/水中重结晶。 a.p. 153 -155TC ； [ α ]2ΒΝβ-56.3° (c 0.003, CHC13)° 1 HMR (CDCU, 300 MHz) <5 8.10(d, J=7.3 Hz，2H,鄰位苯甲酸醮），7.60U，1H,對位苯甲酸酯），7.47 (», 2H,間位笨甲酸醅），6.15(td, J = 8.5, 1.3 Hz, 1H, H13)f 5.69(d, J=6.9 Hz, 1H, H2), 5.32(d, J=9.2 Hz, 1H, HH). 4.93(dd, J=9.6, 1.8 Hz, 1H, H5), 4.82(d, J = 8.7 Hz, 1H, MezC = CIL-). 4.76(td, J = 8.7, 2.7 Hz, 1H, H3T), 4.37(d. J=8.7 Hz, 1H. H20a), 4.22(d, J = 8.7 Hz, 1H, Η20^8), 4.18(d, J = 2.7 HZ, 1H, H2'), 4.03(d, J=7.3 Hz, 1H, H7), 3.82(d, J = 15.2 Hz, 1H, HlOa), 3.47(b, 1H, 2ΌΗ), 3.41(d, J=6.6 Hz, 1H, H3)( 2.60(·, 1H, H6a). 2.39(a, 1H, HIOjS), 2.37(s, 3H· 4Ac), 2.18 ,(s, 1H, 70H), 2.08(1, 1H, H14a), 1.78(·, 1H, H14^3), 1.76(s, 3H, Mel8), l,74(s, 6H, 2Me 來自異丁烯基），1.63U, 1H, H6/3), 1.36(s, 9H, 3Me 第三丁氧基），1.26(s, 3Ht Hel7), 1.18(s, 3H, Hel9), 1.15(s, 3H, Hel6) ° 當俐Ί :¾ (請先聞讀背面之注意事項再填寫本頁)This paper is in 3L scale, using China National Standards (CNS) A4 format (210X297 mm)-δ 1 — m ιο, οοο ^ (V A7 B7 Five 'invention description (59) Ministry of Economic Affairs, China Standards Bureau-Industrial Consumer Cooperatives Printing 3'-Heptylbenzyl-3 '-(isobutenyl) -N-dephenylosyl-fluorene- (third butoxycarbonyl) -10-deacetylamyloxytaxase Preparation at 7-0 -Triethylsilyl-10-deacetyloxy berry erythromycin (III) (50.0 «g · 0.077 mil) in 0.8 liters of THF * at -45 ΐ: 0.09 ml 0.98 dropwise Μ UH (SiMe3) 2 solution (in hexane). After 0.5 hour at -45 t, cis-1-thirdbutoxycarbonyl-3- (2-methoxyisopropoxy) -4- (Isobutenyl) four circles of nitrogen-2-condensation (58.0 «g» 0.193 mmol) in 0.7 liters of THF into the mixture. The solution temperature was maintained at 0 and maintained at this temperature for 1 hour. 1 ml of 10X AcOH solution (in THP). The mixture was planed and NaHC03 aqueous solution was separated with 6 0/40 ethyl acetate / hexane fi. The organic residue was evaporated and the box was purified by silica gel. 62.7 g of < 2'R, 3'S) -2 ', 0- (2-methyl isopropyl) -770-triethylsilyl-3'- Phenyl-3 ~ (isobutenylbutyrate-debenzyl-H- (third-butoxycarbonyl) -10-deacetylamylide taxane and a small amount of (2 '$, 3'R) isomers Mixture 0 in 62.7 g (0.059 mmol) of the mixture obtained from the previous reaction in 3.5 * liters of acetone and 0.16 ml of pyridine. • Add 0.55 ml of 48X HP saline solution to the bottom. Mixture at 0 t: stirred for 3 hours, then at 25X: for 13 hours, and partitioned between tritium and aqueous solution of MaHC0 and ethyl acetate. Ethyl acetate solution was evaporated to obtain 51.5 gram of gadolinium, which is based on the rapid employment analysis method. "Passivation" gives 43.0 g (95S!) Of 3'-dephenyl-3 '-(isobutenyl) -H-debenzylidene-H- (third butane carbonyl) -10-deethinyloxy violet Shan Ye (please read the precautions on the reverse side before filling out this page) Binding _ This paper uses China National Standard (CNS) A4 size (210 X 297 mm)-δ 2-83. 3.10,000 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 420670 A7 B7 V. Description of the invention (60) • It is recrystallized from formazan / water. Ap 153 -155TC; [α] 2BNβ-56.3 ° (c 0.003, CHC13) ° 1 HMR (CDCU, 300 MHz ) < 5 8.10 (d, J = 7.3 Hz, 2H, ortho-benzoate), 7.60U, 1H, para-benzoate), 7.47 (», 2H, ortho-benzoate), 6.15 ( td, J = 8.5, 1.3 Hz, 1H, H13) f 5.69 (d, J = 6.9 Hz, 1H, H2), 5.32 (d, J = 9.2 Hz, 1H, HH). 4.93 (dd, J = 9.6, 1.8 Hz, 1H, H5), 4.82 (d, J = 8.7 Hz, 1H, MezC = CIL-). 4.76 (td, J = 8.7, 2.7 Hz, 1H, H3T), 4.37 (d. J = 8.7 Hz, 1H. H20a), 4.22 (d, J = 8.7 Hz, 1H, Η20 ^ 8), 4.18 (d, J = 2.7 HZ, 1H, H2 '), 4.03 (d, J = 7.3 Hz, 1H, H7), 3.82 (d, J = 15.2 Hz, 1H, HlOa), 3.47 (b, 1H, 2ΌΗ), 3.41 (d, J = 6.6 Hz, 1H, H3) (2.60 (·, 1H, H6a). 2.39 (a, 1H, HIOjS), 2.37 (s, 3H · 4Ac), 2.18, (s, 1H, 70H), 2.08 (1, 1H, H14a), 1.78 (·, 1H, H14 ^ 3), 1.76 (s, 3H, Mel8), l, 74 (s, 6H, 2Me from isobutenyl), 1.63U, 1H, H6 / 3), 1.36 (s, 9H, 3Me third butoxy), 1.26 (s, 3Ht Hel7), 1.18 (s, 3H, Hel9), 1.15 (s, 3H, Hel6) ° Dang LiΊ: ¾ (Please read the precautions on the back before filling this page)

V1T 本紙張尺度逋用中國國家橾準{ CNS ) A4規格< 210X297公釐）一8 3 - 83.3.10,000 420670 A7 B7 五、發明説明（61 tau〇V1T This paper uses China National Standards {CNS) A4 specification < 210X297 mm) 8 3-83.3.10,000 420670 A7 B7 V. Description of the invention (61 tau.

經濟部中夬樣準局貝工消費合作社印裝 (74-4) 3·-脫苯基-3’-(異丁烯基）-n-脫苯醸基- N-(第三丁氧羧基卜9-脫氧基M0-脫乙醢氧基-10•麵基-紫杉酵於7-0-三乙矽烷基-9-脫氣基-ίο-脫乙醢氧基_10-钃基漿果赤黴素111(30.0奄克，〇,〇47毫莫耳）於0,5 «升 THP宁之溶液，於-45 X；下滴加0.〇5奄升0.98H LiH(SiMea)2溶液（於己烷中）。於-45 t：下0.5小時後* 滴加顚-卜第三丁氧羰基-3-(2-甲氣異丙氧基）-4-<異丁烯基）一氮四钃-2-酮（44.1奄克· 〇·ΐ41奄莫耳）於〇,5 奄升THF中之溶液至混合物中。溶液溫至〇 t：並維持於該溫1小時，再加10X AcOH於THF中之溶液。混合物於飽和 NaHC〇3水溶获及60/40乙酸乙酯/己烷間分配。蒸發有機雇得殘留物，其賴由矽嫌過濾纯化，得40.8¾克含 (2’R，3’S)-2'-0-(2-甲氧舆丙基）-7-0-三乙矽烷基-3，-脱苯基- 3·-(異丁烯基卜N-脘苯釀基-H-(第三丁氧羰基脫氧基-10-脫乙酿氧基- ίο-酮基紫杉酵及小董（2, S， 3’R)異構物之混合物。於40.8奄克（0,043奄莫耳）得自前面反應之混合物於 4奄升乙腈及0.2毫升吡啶中之溶液，於0 X：下加〇.5毫升48S HF水溶液。混合物於〇勺下攪拌3小時，再於25t 本紙張尺度逋用中®國家棣準（CNS ) A4規格（210X297公釐> -8 4 - 83.3,10,000 (請先閲讀背面之注意事項再填寫本頁) 420670 μ__ B7五、發明説明（62 ) 經濟部中夬標隼局貝工消費合作社印製下13小時，並於飽和MaHCOs水溶液及乙酸乙酯間分S。蒸發乙酸乙酯溶液得34.4毫克物霣，其箱快速層析法鈍化，得23.0奪克（70SO3'-脫笨基y-(異丁烯基）-N-脫笨 «(基-N-(第三丁氧羰基卜9-脫氧基-10-脫乙醣氧基-10-酮基紫杉鹛·其自甲酵/水中重结晶。 • .P. 149-153*0 ; [ot ]2sM„-56.3。（e 0.0025 · C HC U ) Ο JH HHR (CDCU, 300 MHz) 5 8.12(d, J^7.2 Hz, 2H. m 位苯甲酸酯），7·64(·. 1H,對位笨甲酸酯），7.51 (, 2H,間位苯甲酸醏），6.12(t, J = 7.5 Hz, 1H, H13), 5.95(df J=6.2 Ηε, 1H, H2), 5.30(d, J=8.9 Hz, 1H, HH), 4.94(d, J=8.2 Hz, 1H, H5). 4.88(d, J=8.9 Hz, 1H, He2C = CiL-). 4.79(td, J=8.9, 2.4 Hz, 1H, H3*), 4.34(d, J=8.2 Hz, 1H, Η20σ), 4.27(dd, J=5.5, 2.7 Hz, 1H. H2'), 4.19(d. J = 8.2 Hz, 1H, H20/9), 3.73(«, 1H, H7), 3.67(br s, 1H, 2ΌΗ), 3.13(d, J=5,l Hz, 1H, H3), 3.12(d, J = 15.7 Hz, 1H, H9a), 2.90(d, J = 15.7 Hz, 1H. H9^), 2.55(., Ifl, H6a), 2.47(», 1H, H14jS), 2.32(s, 3H, 4Ac) , 2.28 (i, lH,:H14a), 2.04(br s, 1H, 7 OH), 1.88(s, 1H, 1 OH), 1,82(b, 1H, H6^3), 1.79(s, 3H, Mel8), 1.76U, 6H. 2Me 來自異丁烯基），1.57(s, 3H, 1.47(s, 3H· Mel9>, 1.40(s, 9H, 3Me 第三丁氧基）， 1.30(s, 3H, Mel7)。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度逋用中國國家搮準（CNS ) A4规格(210X297公釐）一 8 5 — 83.3.10,000 4 2 0 6 7 0 A7 B7(74-4) 3 · -Dephenyl-3 '-(isobutenyl) -n-Dephenylfluorenyl-N- (Third-Butoxy Carboxyl Alcohol 9) -DeoxyM0-deacetylamyloxy-10 • face group-yew yeast in 7-0-triethylsilyl-9-degassing group-ίο-deacetylamyloxy_10-fluorenyl berry gibberella Element 111 (30.0 μg, 0.047 mmol) at 0,5 liters of THP Ning solution at -45 X; 0.05 liters of 0.98H LiH (SiMea) 2 solution (in In hexane). After 0.5 hours at -45 t: 顚 -Bu third butoxycarbonyl-3- (2-methylisopropoxy) -4- < isobutenyl) -azatetrafluorene A solution of 2--2-one (44.1 g ···· 41 · mol) in 0.5 · L of THF was added to the mixture. The solution was warmed to 0 t: and maintained at this temperature for 1 hour, and then a solution of 10X AcOH in THF was added. The mixture was dissolved in saturated NaHC03 water and partitioned between 60/40 ethyl acetate / hexane. The organic residue was evaporated and purified by silica filtration to obtain 40.8¾ g of (2'R, 3'S) -2'-0- (2-methoxypropyl) -7-0-triethylsilane. -3, -dephenyl- 3 ·-(isobutenyl-B-N-benzyl alcohol-H- (third butoxycarbonyl deoxy-10-deethyl alcohol-oxo-ketotaxane and A mixture of Xiao Dong's (2, S, 3'R) isomers. A solution of 40.8 g (0,043 mol) of the previously reacted mixture in 4 liters of acetonitrile and 0.2 ml of pyridine at 0 X: Add 0.5ml of 48S HF aqueous solution. Stir the mixture for 3 hours under 0 spoon, and then use it in a 25t paper standard. National Standard (CNS) A4 (210X297 mm > -8 4-83.3,10,000 (Please read the precautions on the back before filling in this page) 420670 μ__ B7 V. Description of the invention (62) Printed by the Ministry of Economic Affairs, Standard Bureau, Shellfish Consumer Cooperative for 13 hours, and in saturated MaHCOs aqueous solution and ethyl acetate. It is divided into S. The ethyl acetate solution is evaporated to obtain 34.4 mg of hydrazone, which is passivated by box flash chromatography to obtain 23.0 g (70SO3'-debenzyl y- (isobutenyl) -N-debenzation «(group-N- (Third butoxycarbonyl group 9-dehydro --10-deacetyloxy-10-ketotaxane · Its recrystallization from formazan / water. • .P. 149-153 * 0; [ot] 2sM „-56.3. (E 0.0025 · C HC U) 〇 JH HHR (CDCU, 300 MHz) 5 8.12 (d, J ^ 7.2 Hz, 2H. M benzoate), 7.64 (·. 1H, para-paraben), 7.51 ( , 2H, m-benzoate), 6.12 (t, J = 7.5 Hz, 1H, H13), 5.95 (df J = 6.2 Ηε, 1H, H2), 5.30 (d, J = 8.9 Hz, 1H, HH) , 4.94 (d, J = 8.2 Hz, 1H, H5). 4.88 (d, J = 8.9 Hz, 1H, He2C = CiL-). 4.79 (td, J = 8.9, 2.4 Hz, 1H, H3 *), 4.34 (d, J = 8.2 Hz, 1H, Η20σ), 4.27 (dd, J = 5.5, 2.7 Hz, 1H. H2 '), 4.19 (d. J = 8.2 Hz, 1H, H20 / 9), 3.73 («, 1H, H7), 3.67 (br s, 1H, 2ΌΗ), 3.13 (d, J = 5, l Hz, 1H, H3), 3.12 (d, J = 15.7 Hz, 1H, H9a), 2.90 (d, J = 15.7 Hz, 1H. H9 ^), 2.55 (., Ifl, H6a), 2.47 (», 1H, H14jS), 2.32 (s, 3H, 4Ac), 2.28 (i, lH,: H14a), 2.04 (br s, 1H, 7 OH), 1.88 (s, 1H, 1 OH), 1,82 (b, 1H, H6 ^ 3), 1.79 (s, 3H, Mel8), 1.76U, 6H. 2Me from isobutenyl) , 1.57 (s, 3H, 1.47 (s, 3H · Mel9 >), 1.40 (s, 9H, 3Me tert-butoxy), 1.30 (s, 3H, Mel7). (Please read the precautions on the back before filling in this page) This paper uses the Chinese National Standard (CNS) A4 size (210X297 mm) 1 8 5 — 83.3.10,000 4 2 0 6 7 0 A7 B7

五、發明説明（63 ) 奩拥1 AV. Description of the Invention (63) Embrace 1 A

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央搮牟局員工消费合作社印袋 (70-1)……… ......' 3’-脫苯基-3’-(異丁烯基）-«-脫苯醯基-«-(第三丁氧期基 )-7-0-乙醢基-10-脫乙醯基紫杉酵之製備於7-三乙矽烷基-9-脫氧綦-9/8 -乙釀氧基-10-說乙醢氧基~1〇-鹬基漿果赤徽素（111)(33.0毫克，〇.〇47亳萁耳） f 於〇·5奄升THF中之溶液，於-45 X：下滴加0.05奄升 0.98Μ UN (SiMe3) ζ溶液（於己烷中 > 。於-45 t：下0.5小時，滴加順-卜第三丁氧羰基-3-(2-甲氧異丙氧基>-4-異丁烯基一氮四園-2-酮（44.1奄克，0,141奄莫耳）於 0.5毫升THF中之溶液至混合物。溶液醞至ο υ並雎持於該i，再加10Χ AcOH於THF中之溶液。混合物於飽和 Ha HC0 3水溶液及60/40乙酸& 己烷間分配。蒸發有機靥得殘留物•其藉由矽繆遇》純化得41.9«克含 (2· R，3’S)-2’-0-(2-甲氧異丙基）-7-0-三乙矽烷基-3，-脫苯基-3'-(異丁烯*)-H-脫苯醸基-H-(第三丁氧镟基本紙張尺度逋用中國國家揉率（CNS > M規格（21&X297公釐）8 6 — · 83.3.10,000 420670 經濟部中央標準局貝工消费合作社印製 A7 B7_______五、發明説明（64 ) )-9-脫氧基-9/J -乙醣氧基-10-联乙醯氧基基紫杉酵及小最（2*S, 3’1〇異構物之混合物。於41.9«克（ 0.045亳莫耳）得自前面反應之混合物於 3.5毫升乙臃及0.15毫升吡啶中之溶液，於〇 t：下加0.5 奄升48X HP水溶液。混合物於〇 υ下播伴3小時，再於 251：下13小時*並於鉋和MaHCO3水溶液及乙酸乙酯間分配。蒸發乙酸乙醆溶液得32.4¾克物霣，其與1.0克矽膠於 5奄升二《甲烷中、於室湛下播拌48小時。有檐層賴由砂鏐«»純化得26.2亳克（70)1〇3^脫苯基-3\(異丁烯基 > -N-脫苯鼸基-N-(第三丁氧_基）-7-0-乙醣基-10-脫乙黼基絷杉酵。 ffl.P. 1 136-139¾ ； [α ]25μa-60.2° (c 0.0025, CHC13)。 NMR (CDCI3· 300 MHz) 38.10(d, J=7.3 Hz, 2H,鄰 t 位苯甲酸凿），7·61(·, 1H,對位笨甲酸醏），7.48 U, 2H.間位苯甲酸酯），6_16(td. J=8_7, 1.8 Ηζ· 1H. Η13), 5.68(d, J=6.9 Hz, 1H, H2), 5.48(dd, J=10.5, 7.3 Hz. 1H, H7), 5.33(d, J=1.8 Hz, 1H, H10), 5.32(d, J=9.2 Hz. 1H, NH), 4.94(dd, J=9.6, 1.8 Hz； 1H, H5), 4.80(d, J=8.7 Hz, 1H, He2C=Cl-), 4.75(td, J=8.7, 2.7 Hz, 1H, H3'), 4.33(d, J=8.7 Hz, 1H, H20a), 4.23(d, J=2.7 Hz, 1H, H2'), 4.22(d, J = 8.7 Hz. 1H, H20/3), 4.01(d, J = 6.9 Ηε, 1H, H3), 3.98(d, J=1.8 Hz, 1H, 10OH), 3.68(b, 1H, (請先阅讀背面之注意事項再填寫本頁) 本紙張ΛΑ適用+國國家揉率（CNS ) ( 210X297公釐）_ 6 7 — 83.3.10,000 42〇6了〇五、發明説明（65〉 2OH), 2·54(·, 1Η. Η6 a ), 2.37(s, SH, 4Ac) * 2.35 (i, 1H, H14a). 2.01(b, 1H, H14/3)., 1.99(s, 3H, ?Ac), 1.98(br s. 3H, Hel8), 1.93(a, 1H, H6^). 1.85(s, 3H, 1.77(s, 6H, 2Me 得自 S 丁稀基 h 1.61(s, 1H, 70H), 1.37(s. 9H, 3Me 第三丁氣基）， 1.23(s. 3H, Mel7). 1.10(s. 3H. Mel6)。(Please read the precautions on the back before filling out this page) Printed bags (70-1) of the Consumer Cooperatives of the Central Ministry of Economic Affairs of the Ministry of Economic Affairs ......... '3'-Dephenyl-3'-( (Isobutylenyl)-«-Dephenylfluorenyl-«-(Third Butoxy Group) -7-0-Ethyl-10-Deacetylated Taxane Preparation in 7-Triethylsilyl-9 -Deoxyfluorene-9 / 8 -Ethyloxy-10-oxyacetoxy ~ 10-fluorenyl berry erythromycin (111) (33.0 mg, 0.047 亳萁) f in 0.5 To a solution in THF, add -0.05 X 0.98M UN (SiMe3) ζ solution (in hexanes) at -45 X: dropwise, add cis-bu third at -45 t: 0.5 hours at -45 t: A solution of butoxycarbonyl-3- (2-methoxyisopropoxy > -4-isobutenyl monoazatetra-2-one (44.1 g, 0,141 mol) in 0.5 ml of THF was added to the mixture. The solution was boiled to ο υ and held at i, and then a solution of 10 × AcOH in THF was added. The mixture was partitioned between saturated Ha HC0 3 aqueous solution and 60/40 acetic acid & hexane. The organic residue was evaporated to obtain a residue. Purified from Simuyu "to obtain 41.9« g containing (2 · R, 3'S) -2'-0- (2-methoxyisopropyl) -7-0-triethylsilyl-3,- Phenyl-3 '-(isobutylene *)-H-dephenylfluorenyl-H- (Third butoxy) Basic paper size (Chinese national kneading rate (CNS > M specification (21 & X297 mm) 8 6 — · 83.3.10,000 420670 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7_______ V. Description of the Invention (64)) -9-Deoxy-9 / J -Ethyloxy-10-biethoxyl A mixture of yew yeast and micro- (2 * S, 3'10 isomers. A solution of 41.9 «g (0.045 mol) obtained from the previous reaction in 3.5 ml of acetam and 0.15 ml of pyridine Add 0.5 liters of 48X HP aqueous solution at 0 t: The mixture was sown for 3 hours at υυ, and then 13 hours at 251: and partitioned between planer and aqueous MaHCO3 solution and ethyl acetate. Evaporate the ethyl acetate solution 32.4¾ grams of mash was obtained, which was sown with 1.0 gram of silicone in 5 liters of 2 "methane and simmered in Yuzhan for 48 hours. The eaves layer was purified by sand« »to obtain 26.2 gram (70) 103 ^ Dephenyl-3 \ (isobutenyl) -N-dephenylfluorenyl-N- (third butoxy-yl) -7-0-ethylglycosyl-10-deacetylfluorenolase.ffl .P. 1 136-139¾; [α] 25μa-60.2 ° (c 0.0025, CHC13 ). NMR (CDCI3 · 300 MHz) 38.10 (d, J = 7.3 Hz, 2H, o-t-benzoic acid chisel), 7.61 (·, 1H, p-benzoic acid), 7.48 U, 2H. Meta Benzoate), 6_16 (td. J = 8_7, 1.8 Ηζ · 1H. Η13), 5.68 (d, J = 6.9 Hz, 1H, H2), 5.48 (dd, J = 10.5, 7.3 Hz. 1H, H7 ), 5.33 (d, J = 1.8 Hz, 1H, H10), 5.32 (d, J = 9.2 Hz. 1H, NH), 4.94 (dd, J = 9.6, 1.8 Hz; 1H, H5), 4.80 (d, J = 8.7 Hz, 1H, He2C = Cl-), 4.75 (td, J = 8.7, 2.7 Hz, 1H, H3 '), 4.33 (d, J = 8.7 Hz, 1H, H20a), 4.23 (d, J = 2.7 Hz, 1H, H2 '), 4.22 (d, J = 8.7 Hz. 1H, H20 / 3), 4.01 (d, J = 6.9 Ηε, 1H, H3), 3.98 (d, J = 1.8 Hz, 1H, 10OH), 3.68 (b, 1H, (Please read the precautions on the back before filling this page) This paper ΛΑ is applicable + country kneading rate (CNS) (210X297 mm) _ 6 7 — 83.3.10,000 42〇6 〇 5. Description of the invention (65> 2OH), 2.54 (·, 1Η. Η6 a), 2.37 (s, SH, 4Ac) * 2.35 (i, 1H, H14a). 2.01 (b, 1H, H14 / 3 )., 1.99 (s, 3H,? Ac), 1.98 (br s. 3H, Hel8), 1.93 (a, 1H, H6 ^). 1.85 (s, 3H, 1.77 (s, 6H, 2Me from S Ding Dilute base h 1.61 (s, 1H, 70H), 1.37 (s. 9H, 3Me third butane group), 1.23 (s. 3H, Mel7). 1.10 (s. 3H. Mel6).

(請先閱讀背面之注意事項再填寫本頁) 經濟部_央標牟局員>工消費合作杜印製 3·-脫苯基-3*-(異丁烯基）-N-脫苯酿基-NM第三丁氧羰基 • ·, )-7-脫羥基紫杉酵於7-脫羥基漿果赤微素（III) (38.7亳克· 0,063毫莫耳 )於0.8奄升THF中之溶液•於-45 下滴加〇.〇8事升 0.98>11^>1(3丨》(63)2溶液（於己烷中）。於-4510下0,5小時後，滴加顧-1-第三丁氧羰基-3-(2-甲氧異丙氧基 )“-(異丁烯基）一氮四園-2-嗣（59.0奄克* 0,19¾莫耳 )於0.8奄升THF中之溶液至混合物中。溶液S至0 υ並維持於該溫1小時•再加1奄升10Χ AcOH溶液（於THF中 )。混合钧於鉋和NaHC03水溶硖及60/40乙酸乙酯/己掠間分配。蒸發有機層得残留物·其藉由矽應遢濾純化*得本紙張尺度遑用中國國家標率（CNS ) A4规格（210X 297公釐）一 6 8 — 83. 3.10,000 420670 at _B7五、發明説明（6今經濟部中央標準局負工消費合作社印簟 43.4奄克含（2’1?,31>-2’-0-(2-甲氧異丙基卜3’-脫苯基 -3’-(興丁烯基）-N-脫苯釀基-H-(第三丁氧羰基）-7-脫理基紫杉酵及小量（2’Sf 3·Ιί)異構物之混合物。於43.4奄克（ 0.049奄奠耳）得自前面反應之混合物於 3,5笔升乙騎及0.15¾升吡啶中之溶液*於0 t：下加0.5 毫升48X HF水溶液。混合物於0 t：下攪拌3小時*再於 251C下13小時，並於胞和HaHCG3水溶液及乙酸乙酯間分配。蒸發乙酸乙_溶液得40.2毫克物霣*其藉快速層析法纯化得34· 1奄克U6X)3脫苯基-3 ·-(異丁烯基> -H-晩苯»基-N-(第三丁氧搛基）-7-脫羥基紫杉酵•其自甲酵/ 水中重结晶。 a.p. 142-I44t：； [ a ] ZBHa-53.3 ° (c 0.0024. CHCU) Ο lH HMR (CDCU, 300 MHz) 5 8.13(d, J = 7.3 Hz, 2H,鄰 t 位笨甲酸醮），7.60U, 1H,對位笨甲酸醏），7.47 (b. 2H,間位笨甲酸酯），6.41(s, 1H, H10>. 6.20(dd. J=9.0, 0.9 Hz, 1H, H13), 5.67(d, J=7.2 Hz, 1H, H2), 5.39id, J=6.9 Hz, 1H, HH). 5.32(d, J-9.0 Hz, 1H, H3'), 4.93(dd, J = 8.7, 2.1 Hz, 1H, H5), 4.81(d, J = 8.7 Hz, 1H, He2C = CH_-), 4.61(d, J = 3.3 Hz, 1H, H2'), 4.30(d, J=8.1 Hz, 1H, H20a), 4.17Cd, J = 8.1 Hz, 1H, H20 /3 ), 3.75 (d, J-6.6 Hz, 1H, H3), 3.41(m, 1H, 2ΌΗ), 2.36(s, 3H, 4Ac), 2.33 (b, 1H. H14a), 2.30(«, 1H, H14^5), 2.26(*, (請先閲讀背面之注意事項再填寫本頁) 本紙浪尺度速用中國國家樣隼（CNSJA4规格（21QX297公釐）一 69 — 813.10,000 420670_ B77 _ 五、發明说明（67) 1H, Η6α), 2.08(·, 1Η, Η7α), 1.94(«, 1Η, Η6/3), 1.85(br s, 3Η. Mel8>, l,73(s, 6Η· 2He 得異丁嫌基 ).1.70U, 3H, Mel9). 1.66(s, 1H, 1 〇H), 1.53U, 1H, H7/9), 1.41(s, 9H, 3He 第三丁氧基），1.25(s, 3H, Hel6). 1.15(s, 3H. Hel7) 〇 gLfil 丄fi· <請先閲讀背面之注項再填寫本頁) 基笨脫 1 3 基理脱基羰氧丁三第 /L - Η I _ 備基製醢/之苯酵脫杉 Η-紫 )-基基氧烯醢丁zi 異脫(Please read the notes on the back before filling out this page) Ministry of Economic Affairs _ Member of the Central Standards Bureau > Industrial and consumer cooperation Du printed 3 · -dephenyl-3 *-(isobutenyl) -N-dephenylated brewing group- NM tert-butoxycarbonyl • ·,) -7-dehydroxytaxtaxel in 7-dehydroxy berry erythromycin (III) (38.7 g · 0,063 mmol) solution in 0.8 liter THF • -45 was added dropwise at 0.08 and 0.98 > 11 ^ > 1 (3 丨) (63) 2 solution (in hexane). After 0.5 hours at -4510, Gu-1 was added dropwise. -Third-butoxycarbonyl-3- (2-methoxyisopropoxy) "-(isobutenyl) azine-2-en (59.0 嗣 g * 0,19¾mol) in 0.8 奄 L of THF Solution to the mixture. Solution S to 0 υ and maintain at this temperature for 1 hour • Add 1 liter of 10X AcOH solution (in THF). Mix the planer and NaHC03 water-soluble 硖 and 60/40 ethyl acetate / hexane Partitioning between sweeps. Residues evaporated from the organic layer. It is purified by silica gel filtration. * This paper size is based on China National Standards (CNS) A4 specifications (210X 297 mm)-6 8 — 83. 3.10,000. 420670 at _B7 V. Description of the invention (6 Today's work of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, Seal 4 3.4 g containing (2'1?, 31 > -2'-0- (2-methoxyisopropylbubble 3'-dephenyl-3 '-(oxetenyl) -N-dephenylene) -H- (Third-butoxycarbonyl) -7-resyl taxane and a small amount (2'Sf 3.1) of the isomers. Obtained from the previous reaction at 43.4 g (0.049 mol). A solution of the mixture in 3,5 liters of ethyl acetate and 0.15 ¾ liters of pyridine * was added at 0 t: 0.5 ml of 48X HF aqueous solution. The mixture was stirred at 0 t: for 3 hours * and then at 251C for 13 hours, and It was partitioned between aqueous solution of HaHCG3 and ethyl acetate. Ethyl acetate solution was evaporated to give 40.2 mg of the compound 霣 * which was purified by flash chromatography to obtain 34.1 奄 g U6X) 3 dephenyl-3 ·-(isobutenyl)> -H-pyrene »yl-N- (tertiary butoxyfluorenyl) -7-dehydroxytaxol • Its autoformase / recrystallization in water. Ap 142-I44t:; [a] ZBHa-53.3 ° ( c 0.0024. CHCU) Ο lH HMR (CDCU, 300 MHz) 5 8.13 (d, J = 7.3 Hz, 2H, t t-position benzoate), 7.60U, 1H, p-formate benzoate), 7.47 (b. 2H, meta meta-formate), 6.41 (s, 1H, H10 >. 6.20 (dd. J = 9.0, 0.9 Hz, 1H, H13), 5.67 (d, J = 7.2 Hz, 1H, H2), 5.39 id, J = 6.9 Hz, 1H, HH). 5.32 (d, J-9.0 Hz, 1H, H3 '), 4.93 (dd, J = 8.7, 2.1 Hz, 1H, H5), 4.81 (d, J = 8.7 Hz, 1H, He2C = CH_-), 4.61 (d, J = 3.3 Hz, 1H, H2 '), 4.30 (d, J = 8.1 Hz, 1H, H20a), 4.17Cd, J = 8.1 Hz, 1H, H20 / 3), 3.75 (d, J-6.6 Hz, 1H, H3), 3.41 (m, 1H, 2ΌΗ), 2.36 (s, 3H, 4Ac), 2.33 (b, 1H. H14a), 2.30 («, 1H, H14 ^ 5) , 2.26 (*, (Please read the precautions on the back before filling in this page) This paper is a fast-moving Chinese national sample (CNSJA4 specification (21QX297 mm) 1 69 — 813.10,000 420670_ B77 _ V. Description of the invention (67 ) 1H, Η6α), 2.08 (·, 1Η, Η7α), 1.94 («, 1Η, Η6 / 3), 1.85 (br s, 3Η. Mel8 >, l, 73 (s, 6Η · 2He is isobutanyl ) .1.70U, 3H, Mel9). 1.66 (s, 1H, 1〇H), 1.53U, 1H, H7 / 9), 1.41 (s, 9H, 3He third butoxy), 1.25 (s, 3H , Hel6). 1.15 (s, 3H. Hel7) 〇gLfil 丄 fi · < Please read the note on the back before filling out this page) Gemben 1 3 Glyphoxycarbonyloxanthine / L-Η I _ Preparation of hydrazone / benzoylated cedar-violet) -isopropyloxetidine

經濟部中央標隼局貝工消費合作社印製於7-脫羥基-10-脫乙《氧基漿果赤徽素（HI) (28.7奄克，0.051邂舆耳）於0.7奄升THF中之溶液，於-45 t下滴加0.0Θ毫升0.98Η LiH(SiKe3)2溶液（於己烷中）。於 -45 t：下〇.5小時後，滴加順-卜第三丁氧戡基-3-(2-甲氧Μ丙氧基）-4-(異丁烯基）一氮四圈-2-醑（47,3毫克， 0.15毫萁耳）於0.7奪升THF中之溶液滴加至混合物。溶液溫至〇 t笼維持於該潘1小時，再加1奄升101 AcOH於 THF中之溶液。混合物於飽和HaHC03水溶联及60/40乙酸乙酯/己烷間分S。蒸發有檐靥得殘留物•其藉由矽應遘本紙張尺度逋用國家揉準（CNS > A4規格（210X297公釐> 一 7 0 - W.3.10,000 420670 五、發明説明（68) 經濟部中夬襟隼局負工消費合作社印製濾《化得40.3¾克含（2 ·ϋ，3’S) -2(2-甲氧異丙綦 )-3’-腴苯荃-3’-(異丁烯基卜Μ-脫苯醯基-Ν-(第三丁氧羰基）-7-脫羥基-10-脫乙鼸氧基紫杉酵及小曇（2*S. 3’R)異構物之混合物。於40.3毫克（0.04δ *莫耳）得自前面反應之混合物於 3,2奄升乙臃及0.15毫升吡啶中之溶液，於0 t下加 0.47奄升48X HF水溶液。琨合物於0艺下攪拌3小時，再於25勺下13小時，並於跑和NaHC03水溶液及乙酸乙醣間分配。蒸發乙酸乙醏溶液得35.2奄克物霣，其藉快速層析法纯化得24.0毫克（70Χ)3·-銳苯基-3·-(異丁烯'基脫苯》基-H-(第三丁氧羧基）-7-脫羥基-10-脫乙醣氧基紫杉酵*其自甲酵/水中重结晶。通.P. 122-125TC : [ot ]2%«-64.3。 (c 0.0025, CHC13) Ο lH HMR (CDCU. 300 MHz) 5 8.12(d, J = 7.1 Hz. 2H, B 位苯甲酸酯）.7.60U, 1H,對位苯甲酸醏），7·48 (b. 2Η,間位苯甲酸酯），6.11(td, J=8.U 1.8 Hz, 1Η, H13), 5.68(d, J=6.9 Hz. 1H, H2), 5.23(d, J=9.9 Hz, 1H, HH). 5.12(d, J=9.9 Hz, 1H, H3f), 4.96(dd, J=9；l, 2.7 Hz. 1H, H5), 4.80(d, J=8.7 Hz, 1H, Me2C = ClL-), 4.58(dd, J=5.7, 2.1 Hz, 1H, H2'), 4.30(d, J=8.1, 1H, Η20σ), 4.19(d, J=8.1 Hz, 1H, H20^), 3.97(d, J=6.9 Hz, H3), 3.83(d, J=16.5, 1H, HlOct), 3.33(b, 1H, H10/3), 3.30(·, 1H. (請先閲讀背面之注意事項再填寫本頁) 訂本紙張犬度逋用中國國家揉準（CNS ) A4规格（210X297公釐）_ 71 — 813.10,000 琴4:2 專利$請案中文說明害诤正頁（85年12月！泸1207 五、發明説明（ 69 經濟部中央棣準局员工消費合作社印製 2ΌΗ). 2.39(·, lfl, H14a), 2.35(s, 3H, 4Ac), 2.26(«, 1H, H14/S). 2.19(a, 1H. Η6α), 2.10(b. 1H, Η7α), l,95(a, 1H, H6^3), 1.73(s, 3H, Hel8), 1.69(s, 6H, 2Me 得自異丁烯基）.l,63(s, 3H. Mel9), 1.44(a, 1H, H7^), 1.39(br 1H, 1 OH), 1.35(s, 9H, 3Me 第三丁氣基），1.25(s. 3H, Mel6), 1.15(s, 3H, Mel7)。 g M 1 7 將實例卜 16 之紫杉烷 29-4、51-3、54-1、54-2、54-3、 58-3、58-4、59~1' 59-2' 60-3、7 0-4' 68-4' 7 4·* 4 ' 70-1、71-2及72-1活Η外評估其對人類结腸癌细胞 KCT-116之细胞毒性活性。於HCT11S人類结臈癌细胞中细胞毒性之評估係賴由ΧΤΤ(氫氧化2,3-雙（2-甲氧-4-¾-5-磺笨基）-5-|：(苯胺基）羰基]-2H-四钱）測定（ScUdiero等人，"使用人類及其他腫瘤细胞系，評估可溶性四銼/甲腾對培餐物中佃胞生長及藥物敏感度之測定"♦ C-a.tice.r_, Le^L. 48:4827-4833, 1983)。將细胞 Κ 400 细胞 / 孔覆蓋於96孔之嫌fi培養板，24小時後加槩物並以系列稀釋〇细胞於371C下培育72小時，於其時加四矬染料、XTT 。於活细由中之脫氫_堪茉TTT形成於450 η·吸光者•其可以分光光度計定量，吸光度愈大則活细胞數愈多。结果Κ IC6〇表示•其為抑剌细胞增殖（亦即於450 ηη之吸光度） Μ未®處理之對照姐细胞之50：«所須之槩物濃度）。所有化合物具少於0.1微克/毫升之1C 指示彼等於. 網跑毒性上具活性： ' (請先¾讀背面之注意事項再填寫本頁)Printed in 7-dehydroxy-10-deethyl "oxyberry erythromycin (HI) (28.7 g, 0.051 mil) in 0.7 liters of THF Add 0.0Θ ml of 0.98Η LiH (SiKe3) 2 solution (in hexane) dropwise at -45 t. At -45 t: After 0.5 hour, add cis-Bu third butoxyfluorenyl-3- (2-methoxyMpropoxy) -4- (isobutenyl) -nitrogen four circles-2- A solution of tritium (47,3 mg, 0.15 mJ) in 0.7 liters of THF was added dropwise to the mixture. The temperature of the solution was maintained at 0 ° C. for one hour in the pan, and 1 ml of a solution of 101 AcOH in THF was added. The mixture was dissolved in saturated HaHC03 in water and 60/40 ethyl acetate / hexane separated in S. Evaporation of the eaves to obtain residue • It is based on silicon paper and paper size, and it is used in the country (CNS > A4 size (210X297 mm > 1 7 0-W.3.10,000 420670) 5. Description of the invention (68 ) Printed by the Consumers ’Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People ’s Republic of China. -(Isobutenyl M-dephenylfluorenyl-N- (third butoxycarbonyl) -7-dehydroxy-10-deacetylfluorenyl taxane and berberine (2 * S. 3'R) iso A mixture of structures. A solution of 40.3 mg (0.04 δ * mol) of the previously reacted mixture in 3,2 liters of acetone and 0.15 ml of pyridine was added at 0.40 liters of a 48X HF aqueous solution at 0 t. The mixture was stirred at 0 ° C for 3 hours, and then at 25 scoops for 13 hours, and then partitioned between running and NaHC03 aqueous solution and ethyl acetate. Evaporation of the ethyl acetate solution gave 35.2 g of gallium, which was purified by flash chromatography. 24.0 mg (70 ×) of 3 · -rapyphenyl-3 ·-(isobutylene'-based dephenyl) yl-H- (third butoxycarboxyl) -7-dehydroxy-10-deacetylose taxane * It is recrystallized from formazan / water. T.P. 122-125TC: [ot] 2% « -64.3. (C 0.0025, CHC13) Ο lH HMR (CDCU. 300 MHz) 5 8.12 (d, J = 7.1 Hz. 2H, B-benzoate). 7.60U, 1H, p-paraben benzoate), 7.48 (b. 2Η, meta-benzoate), 6.11 (td, J = 8.U 1.8 Hz, 1Η, H13), 5.68 (d, J = 6.9 Hz. 1H, H2), 5.23 (d , J = 9.9 Hz, 1H, HH). 5.12 (d, J = 9.9 Hz, 1H, H3f), 4.96 (dd, J = 9; l, 2.7 Hz. 1H, H5), 4.80 (d, J = 8.7 Hz, 1H, Me2C = ClL-), 4.58 (dd, J = 5.7, 2.1 Hz, 1H, H2 '), 4.30 (d, J = 8.1, 1H, Η20σ), 4.19 (d, J = 8.1 Hz, 1H , H20 ^), 3.97 (d, J = 6.9 Hz, H3), 3.83 (d, J = 16.5, 1H, HlOct), 3.33 (b, 1H, H10 / 3), 3.30 (·, 1H. (Please first Read the notes on the back and fill in this page again.) The printed paper can only be used in the Chinese National Standard (CNS) A4 size (210X297 mm) _ 71 — 813.10,000 Qin 4: 2 Patent $ Please file in Chinese. Page (December 85!泸 1207 V. Description of the invention (69 printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 2) 2.39 (·, lfl, H14a), 2.35 (s, 3H, 4Ac), 2.26 («, 1H, H14 / S) 2.19 (a, 1H. Η6α), 2.10 (b. 1H, Η7α), l, 95 (a, 1H, H6 ^ 3), 1.73 (s, 3H, Hel8), 1.69 (s, 6H, 2Me derived from Isobutenyl). 1,63 (s, 3H. Mel9), 1.44 (a, 1H, H7 ^), 1.39 (br 1H, 1 OH), 1.35 (s, 9H, 3Me third butane group), 1.25 ( s. 3H, Mel6), 1.15 (s, 3H, Mel7). g M 1 7 The taxane 29-4, 51-3, 54-1, 54-2, 54-3, 58-3, 58-4, 59 ~ 1 '59-2' 60- 3, 7 0-4 '68-4' 7 4 · * 4 '70-1, 71-2, and 72-1 were evaluated in vitro for their cytotoxic activity against human colon cancer cell KCT-116. The evaluation of cytotoxicity in HCT11S human scab cancer cells is based on XT (hydroxide 2,3-bis (2-methoxy-4-¾-5-sulfobenzyl) -5- |: (aniline) carbonyl ] -2H-Four Money) Assay (ScUdiero et al., "Using human and other tumor cell lines to evaluate the determination of soluble tetra-file / methyl Teng on cell growth and drug sensitivity in cultures" ♦ Ca.tice .r_, Le ^ L. 48: 4827-4833, 1983). Cells K 400 cells / well were covered in a 96-well suspected fi culture plate. After 24 hours, mash was added and serially diluted. Cells were incubated at 371C for 72 hours, at which time tetrafluorene dye and XTT were added. The dehydrogenation of Yu-Hui-Kan-Kam TTT is formed at 450 η · absorber. It can be quantified by a spectrophotometer. The larger the absorbance, the larger the number of living cells. Results K IC60 indicates that it is a suppressor of cell proliferation (i.e., absorbance at 450 ηη) 50 of untreated control sister cell 50: «required concentration of callus]. All compounds have a 1C of less than 0.1 μg / ml, which indicates that they are equal to each other. The net running is active on toxicity: '(Please read the precautions on the back before filling this page)

本纸張尺度適用中國國家橾準（CNS ) A4规格（2丨0X297公釐）一 72 — 83.3.10,000This paper size applies to China National Standard (CNS) A4 (2 丨 0X297mm) 1 72 — 83.3.10,000

Claims

420670 第831〇3428號專利申請案 S5.泛中文補充説明書(85年12月）附表C C3'丁烯基之藥理數坡 IC5〇(微克/毫升） IC5〇(微克/毫升）説明書實例a HCT-1161 HCT-116/VM462 1 0.001 0.026 2 0.014 3 0.001 0.027 4 0.002 0.037 5 0.003 0.077 6 0.002 0.084 7 0.001 <0.018 8 0.002 0.059 9 0.008 0.227 10 0,009 0.164 11 0.004 0.330 12 0.003 13 0.0001 14 0.004 0.035 15 0.004 16 0.003 紫杉酚 0.004 0.536 紫杉萜 0.007 0.246 1·抑制人類結腸癌細胞HCT-116之細胞增生至50%未處理細胞增生所需藥物濃度(微克/毫升）’其係用説明書之實例17程序來決定。 2·抑制人類結腸癌細胞HCT-116/VM46之細胞增生至50%未處理細胞增生所需藥物濃度(微克/毫升）。 CCKVl57G.D〇d 4凑兑箱3】2&專利串中文申讅專利範圍修年C8 89. 8. 03 年；4 。申請專利範圍 1.—種具下式之紫杉烷衍生物： ^ 4 ^ Τ 0 Η X, X.420670 Patent Application No. 831〇3428 S5. Pan Chinese Supplementary Specification (December 1985) Schedule C C3 'Butenyl Pharmacological Number Slope IC50 (μg / ml) IC50 (μg / ml) Specification Example a HCT-1161 HCT-116 / VM462 1 0.001 0.026 2 0.014 3 0.001 0.027 4 0.002 0.037 5 0.003 0.077 6 0.002 0.084 7 0.001 < 0.018 8 0.002 0.059 9 0.008 0.227 10 0,009 0.164 11 0.004 0.330 12 0.003 13 0.0001 14 0.004 0.035 15 0.004 16 0.003 Paclitaxel 0.004 0.536 Paclitaxel 0.007 0.246 1. Inhibition of the proliferation of human colon cancer cell HCT-116 to 50% of untreated cell proliferation (micrograms / ml) 'its instruction manual Example 17 procedure to decide. 2. Inhibit the proliferation of human colon cancer cell HCT-116 / VM46 to 50% of untreated cells. The concentration of drug (micrograms / ml) required for proliferation. CCKVl57G.D〇d 4 redemption box 3] 2 & patent string Chinese patent application scope revision year C8 89. 8. 2003; 4. Scope of patent application 1.—A taxane derivative with the following formula: ^ 4 ^ Τ0 Η X, X.

經濟部中央橾隼局負.工消费合作社印装式中父^為羥基； χ2為氩； X 3為氩； χ4為-CH = C (CH3) 2 ; χ5 為-COtHCi-e 垸基）' -COOCH2CH=CCH2、 -COOCfUS或-COOCHzPh ; “為羥基； 1?2為- OCOPh; 1?4β為-OAc ; R7為氫、羥基或-QAc ; 尺9為氬或與Ree —起形成氧基； Re«為氳、羥基或與Re -起形成氧基； R i 〇為恒：或與R X 〇 a —起形成氧基； R1〇e為簋、羥基、-OAc或與R1〇—起形成氧基 R 1 4 為 S。及 ----------上______丁 * 、vs (請先閲讀背面之注意事項再填寫本f ) 本紙張尺度速用taa家揉準（CNS ) A4规格（210XW7公釐） 420670 Λ8 BS C8 D8 申請專利範圍 2. 根據申請專利範圍第1項之紫杉烷衍生物，其中乂5為 -COO(Ci -β烷基）。 3. —種具下式之紫杉烷衍生物： 15、The Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China. The father of the industrial and consumer cooperatives is hydroxyl group; χ2 is argon; X 3 is argon; χ4 is -CH = C (CH3) 2; χ5 is -COtHCi-e hydrazone) ' -COOCH2CH = CCH2, -COOCfUS or -COOCHzPh; "is a hydroxyl group; 1? 2 is -OCOPh; 1? 4β is -OAc; R7 is hydrogen, hydroxyl or -QAc; Rule 9 is argon or forms an oxygen group with Ree Re «is fluorene, hydroxy, or forms an oxy group with Re-; R i 〇 is constant: or forms an oxy group with RX 〇a; R10e is 簋, hydroxy, -OAc, or forms with R10 Oxygen R 1 4 is S. And ---------- on ______ 丁 *, vs (please read the precautions on the back before filling in this f) The paper size is quick to use CNS) A4 specification (210XW7 mm) 420670 Λ8 BS C8 D8 Patent application scope 2. According to the taxane derivative of the first patent application scope, where 乂 5 is -COO (Ci -β alkyl). 3. — A taxane derivative with the formula:

(請先閲讀背面之注意^項再填寫本頁) A 經濟部t央揉準局消費合作社印製式中乂^為徑基； χ2為氫；為氫； 5U 為-C H = C (C Η 3) 2 ; 又5為-COPh ; ^為羥基； R2為-OCOPh ; l?4a 為 _0Ac ; 為S、羥基或~0Ac ; Re為氫或與起形成氧基； R9e為氬、羥基、或輿I?a —起形成氧基； R1〇為氫或與R1〇« —起形成氧基； Ri〇e為氫、羥基、-OAc、或與R1〇—起形成氧基訂 % 本纸張尺度遢用t國國家#準（CMS ) A4規路（2iOX297公釐） 4206T0 ------------、申請專利範圍 A8 B8 C8 D8 6. r14為氫。 —種具细胞春性之《藥姐合物，其含根據申譆專利範圍第1項之紫杉烷衍生物及藥理上可接受之載劑或稀釋劑。根據申謫專利範圃第1項之紫杉烷衍生物*其中“為，coo-第三丁基、-coo-異丁基、-coo-正丁基、 •coo-乙基、-coo-異丙基、-coo-正丙基、-coo-烯丙基、-C00-戊基、-C00-新戊基或-C00-CH2Ph。 ~種具细胞毒性之S藥組合物·其含根據申請專利範騮第3項之紫杉烷衍生物及藥理上可接受之載劑或稀釋劑。 (請先聞讀背*之注意事項再填寫本I) Γ 經濟部t央梂準局負工消费合作杜印製 3 本紙浪尺度邃用中《國家榣準（CNS ) A4规格（210X297公釐） 4 匕 U ti / U 第S 3 1 0 3 4 2 S號專利申謫累中文說明書修正頁（39年元月Y Β7(Please read the note on the back ^ before filling this page) A In the printed format of the Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs, 乂 ^ is the diameter base; χ2 is hydrogen; is hydrogen; 5U is -CH = C (C Η 3) 2; and 5 are -COPh; ^ is a hydroxyl group; R2 is -OCOPh; l? 4a is _0Ac; is S, a hydroxyl group or ~ 0Ac; Re is hydrogen or forms an oxygen group; R9e is argon, a hydroxyl group, Or I? A — form an oxygen group; R1〇 is hydrogen or form an oxygen group with R1〇 «; RiOe is hydrogen, hydroxyl, -OAc, or form an oxygen group with R10 —% Zhang Jixiang uses the national standard #CMS (CMS) A4 (2iOX297 mm) 4206T0 ------------, the scope of patent application A8 B8 C8 D8 6. r14 is hydrogen. —A kind of pharmacological compound with cellular resilience, which contains the taxane derivative according to item 1 of Shen He patent scope and a pharmacologically acceptable carrier or diluent. According to the taxane derivative of item 1 of the patent application of the patent * wherein "is coo-third butyl, -coo-isobutyl, -coo-n-butyl, coo-ethyl, -coo- Isopropyl, -coo-n-propyl, -coo-allyl, -C00-pentyl, -C00-neopentyl or -C00-CH2Ph. ~ S drug composition with cytotoxicity · Based on The taxane derivative and the pharmacologically acceptable carrier or diluent of item 3 of the patent application (please read the notes of the back * before filling in this I) Consumption cooperation Du printed 3 This paper is in use in the national standard (CNS) A4 (210X297 mm) 4 U U ti / U No. S 3 1 0 3 4 2 S Patent application revised Chinese manual revision page (January 39 Y Β7

五、發明説明（52 ) J 二 7·8 Hz, 1Η, Η20/3)，4.0S(d，J = 6.6 Hz, 2Η，烯丙基 ),3.79(d, J=7.2 Hz, 1H, H3), 3.34(d, J=6.6 H2, 1H, 2ΌΗ), 2.55 (1, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.36(s, 3H, 4Ac), 2.33 (ίο , 2H, H14), 2.26 (s, 3H, lOAc), 2.24(br s, 3H, Mel8), 1.88 (s, 3H, Hel9), 1.85(ηι, 1H, H6^), 1.72(s, 3H, Me 異丁烯基），1.69(s, 1H，10H), l，61(s, 3H, He 異丁烯基），l‘25(s, 3H, Mel7), 1.15(s, 3H, Mel6)。蜜俐9 PhV. Description of the invention (52) J 2 7.8 Hz, 1Η, Η20 / 3), 4.0S (d, J = 6.6 Hz, 2Η, allyl), 3.79 (d, J = 7.2 Hz, 1H, H3 ), 3.34 (d, J = 6.6 H2, 1H, 2ΌΗ), 2.55 (1, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.33 ( ίο, 2H, H14), 2.26 (s, 3H, lOAc), 2.24 (br s, 3H, Mel8), 1.88 (s, 3H, Hel9), 1.85 (ηι, 1H, H6 ^), 1.72 (s, 3H , Me isobutenyl), 1.69 (s, 1H, 10H), l, 61 (s, 3H, He isobutenyl), l'25 (s, 3H, Mel7), 1.15 (s, 3H, Mel6). Honey Li 9 Ph

OAcOAc

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 (5 9 - 2) 3’-脫苯基-3'-異丁烯基-N-脫窄醢基-N-(苄氧羰基）紫杉酵之製備於7 -三乙矽烷基漿果赤徽素III (50.0毫克，0.071毫莫耳）於0.7毫升THF中之溶液，於-4t下滴加0.08毫升 1.0M LiN(SiMe3)2溶液（於己烷中）。於-4t下0·5小時後，滴加順-1-(笨醯氧羰基）-3-(2 -甲氧-2-丙氧基）-4 -異丁烯基一氮四團-2-酮（53毫克，0.21毫莫耳）於0.5毫升THF中之溶液至混合物。溶液溫至0 並維持於該溫1 55 本紙張尺度適用中國國家搮準（CNS ) A4規格（210X297公釐） 4凑兑箱3】2&專利串中文申讅專利範圍修年C8 89. 8. 03 年；4 。申請專利範圍 1.—種具下式之紫杉烷衍生物： ^ 4 ^ Τ 0 Η X, X.(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (5 9-2) 3'-dephenyl-3'-isobutenyl-N-de-n-pyridyl-N -(Benzyloxycarbonyl) Taxane Preparation A solution of 7-triethylsilyl berry erythromycin III (50.0 mg, 0.071 mmol) in 0.7 ml of THF, 0.08 ml of 1.0 M was added dropwise at -4 t LiN (SiMe3) 2 solution (in hexane). After 0.5 hours at -4t, cis-1- (benzyloxycarbonyl) -3- (2-methoxy-2-propoxy) -4 -isobutenyl-tetrazol-2-one was added dropwise. (53 mg, 0.21 mmol) in 0.5 ml of THF to the mixture. Solution temperature to 0 and maintained at this temperature 1 55 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 4 Coupon 3] 2 & patent string Chinese application patent scope revision year C8 89. 8 03; 4 Scope of patent application 1.—A taxane derivative with the following formula: ^ 4 ^ Τ0 Η X, X.

經濟部中央橾隼局負.工消费合作社印装式中父^為羥基； χ2為氩； X 3為氩； χ4為-CH = C (CH3) 2 ; χ5 為-COtHCi-e 垸基）' -COOCH2CH=CCH2、 -COOCfUS或-COOCHzPh ; “為羥基； 1?2為- OCOPh; 1?4β為-OAc ; R7為氫、羥基或-QAc ; 尺9為氬或與Ree —起形成氧基； Re«為氳、羥基或與Re -起形成氧基； R i 〇為恒：或與R X 〇 a —起形成氧基； R1〇e為簋、羥基、-OAc或與R1〇—起形成氧基 R 1 4 為 S。及 ----------上______丁 * 、vs (請先閲讀背面之注意事項再填寫本f ) 本紙張尺度速用taa家揉準（CNS ) A4规格（210XW7公釐）The Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China. The father of the industrial and consumer cooperatives is hydroxyl group; χ2 is argon; X 3 is argon; χ4 is -CH = C (CH3) 2; χ5 is -COtHCi-e hydrazone) ' -COOCH2CH = CCH2, -COOCfUS or -COOCHzPh; "is a hydroxyl group; 1? 2 is -OCOPh; 1? 4β is -OAc; R7 is hydrogen, hydroxyl or -QAc; Rule 9 is argon or forms an oxygen group with Ree Re «is fluorene, hydroxy, or forms an oxy group with Re-; R i 〇 is constant: or forms an oxy group with RX 〇a; R10e is 簋, hydroxy, -OAc, or forms with R10 Oxygen R 1 4 is S. And ---------- on ______ 丁 *, vs (please read the precautions on the back before filling in this f) The paper size is quick to use CNS) A4 specification (210XW7 mm)