TW390882B

TW390882B - Production of avermectin compounds

Info

Publication number: TW390882B
Application number: TW087111457A
Authority: TW
Inventors: Masanori Honda; Hiroshi Kadoi; Hiromasa Morita; Isao Nagakura
Original assignee: Pfizer
Priority date: 1998-07-13
Filing date: 1998-07-13
Publication date: 2000-05-21

Description

A7 B7 五、發明説明（i ) 技術範圍 (請先聞讀背面之注意事項再填寫本頁) 本發明係關於一種新穎且改良的方法供從式（ϊ Ϊ ) 之艾維美丁（ AVERMECTIN )B2化合物製備式（I)之艾維美丁化合物，式（I I )化合物爲一種發酵衍生的艾維美丁產物，此式（I )之艾維美丁化合物已知可作爲抗寄生物劑，此方法導致明顯地改進總產量。、技藝背'景根據先前技藝，已經揭示數種已知可作爲抗寄生物劑之化合物，包括在其中的艾維美丁化合物是揭示並申請專利於 Bishop Bernard Frank et al.之國際公告編號 W 0 9 4 / 1 5 9 4 4 及 Fisher, Michael H. et al.之歐洲公告編號 E P 〇 3 7 9 3 4 1 A 2 ,但是根據上述慣用方法，最終反應產物之產量並不永遠令人滿意，本發明之目的是在高 '產量下將式（I I )之艾維美丁化合物轉化成式（I )之艾維美丁化合物。發明槪述經濟部中央標準局見Η消費合作社印製本發明提供式（I )化合物之製法：A7 B7 V. Description of the invention (i) Technical scope (please read the notes on the back before filling out this page) This invention is about a novel and improved method for AVERMECTIN (从 Ϊ) The compound B2 is used to prepare an avimetine compound of formula (I). The compound of formula (II) is a fermentation-derived evimetine product. This evimetine compound of formula (I) is known as an antiparasitic agent. This method results in a marked improvement in overall yield. According to previous techniques, several compounds known to be useful as antiparasitic agents have been disclosed, including the evimetine compound, which is disclosed and patented in the International Bulletin No. W of Bishop Bernard Frank et al. 0 9 4/1 5 9 4 4 and European Publication No. EP of Fisher, Michael H. et al. EP 0 3 7 9 3 4 1 A 2, but according to the conventional method described above, the final reaction product yield is not always satisfactory The object of the present invention is to convert the avimetine compound of the formula (II) into the avimetine compound of the formula (I) at a high yield. Description of the invention Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, printed by the Consumer Cooperatives The present invention provides a method for preparing compounds of formula (I):

本紙張尺度適用中國國家標準(CNS ) A4im ( 210X297公釐）經濟部中央標準局I工消費合作社印製This paper size applies to China National Standard (CNS) A4im (210X297 mm) Printed by I Industrial Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

A7 _________ B7 五、發明説明（2 ) 其中R1爲Η或羥基亞胺基保護基；R2爲h、 Ci-4 焼基或c 1 - 4烷氧基；R 3爲C 1 - 8烷碁（較宜爲Cj - 4㈣基）、C2-8烯基（較宜爲c2-5烯基）或C3-8環烷基 (較宜爲環己基）；且R4爲H、鹵基、Ci-4烷基或Ci - 4烷氧基，此方法包括之步驟爲： (a)使式（I I )化合物與氧化劑反應而形成5 -氧化合物； (b) 使5 —氧化合物與式R 1 — 〇 _ N Η 2化合物反應其中 R1爲Η或羥基亞胺基保護基，形成5 _亞胺基化合物 (c) 使5 —亞胺基化合物與硫逐碳化劑反應而形成4 〃，2 3-雙硫逐羰基酯； (d) 使4 〃，2 3 —雙硫逐羰基酯與脫氧劑反應而形成4 " ，2 3 —二脫氧化合物；及 (e) 使4〃，23_二脫氧化合物與酸反應而形成式（I) 化合物。此方法還包括當R1爲Η時，在步驟（b )後加入鹵基 (讀先聞讀背面之注意事項再填寫本頁)A7 _________ B7 5. Description of the invention (2) where R1 is fluorene or hydroxyimino protecting group; R2 is h, Ci-4 fluorenyl or c 1-4 alkoxy; R 3 is C 1-8 alkoxy ( More preferably, Cj-4-), C2-8 alkenyl (more preferably c2-5 alkenyl) or C3-8 cycloalkyl (more preferably cyclohexyl); and R4 is H, halo, Ci-4 Alkyl or Ci-4 alkoxy, the method includes the steps of: (a) reacting a compound of formula (II) with an oxidant to form a 5-oxy compound; (b) reacting a 5-oxy compound with the formula R 1- _ N Η 2 compounds where R1 is fluorene or a hydroxyimino protecting group to form a 5- imimine compound (c) The 5-imide compound is reacted with sulfur as a carbonizing agent to form 4 ，, 2 3-bis Thiocarbonyl esters; (d) 44, 2 3 -dithiocarbonyl esters are reacted with a deoxidizing agent to form 4 ", 2 3-dideoxy compounds; and (e) 4〃, 23_dideoxy compounds Reacts with an acid to form a compound of formula (I). This method also includes adding a halogen group after step (b) when R1 is Η (read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） c 經满部中央標率^¾工消費合作社印裝 A7 B7 五、發明説明（3) 三苯基矽烷、第三丁基二甲基砂烷、鹵基三甲基矽烷、鹵基（鹵基甲基)矽烷、違基烯丙基二甲基矽烷、鹵基三乙基矽烷、鹵基三異丙基矽烷、鹵基（3 —氰基丙基）二甲基矽烷、鹵基二甲基辛基矽烷、鹵基三苄基矽烷、鹵基三己基矽烷等（較宜爲鹵基三苯基砂烷）、及三乙胺、三正丙胺、二異丙基乙基胺、咪唑、吡啶或4 一二甲胺基吡啶以保護羥基亞胺基，而且當R1爲烯丙基時，在步驟（e) 、之反應（視需要在去除保護處理後）可在鈀觸媒存在下進行，如先前所述，經由本發明此方法生產之最終產物爲抗寄生物劑之有用化合物。發明之詳細敘沭在本文中所稱的"Ci-8烷基〃係指含1至8個碳原子之直鏈或支鏈飽和基，包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、己基等。在本文中所稱的〃 c 2 - 8烯基〃係指含2至8個碳原子之直鏈或支鏈不飽和基，包括但不限於1-乙烯基、1 —丙烯基、2—丙烯基、1一丁烯基、2—丁烯基、2— 甲基—1 _丙烯基等。在本文中所稱的〃 C3-8環烷基〃係指含3至8個碳原子之碳環基，包括但不限於環丙基、環丁基、環戊基、環己基等。在本文中所稱的〃鹵基〃係指氟、氯、溴或碘。 (請先閱讀背面之注意事項再填寫本頁) 訂本紙張尺度適用中國國家標準（CNS ) A4规格（210Χ297公釐） ~ 經濟部中央標率局—工消費合作社印f A 7 ___________B7_ 五、發明説明（4 ) 在本文中所稱的〃烯丙基〃係指在2，3 -位置含一個碳-碳雙鍵之烷基或經取代之烷基，包括但不限於烯丙基、甲基烯丙基、巴豆基、氯烯丙基、肉桂基等。以下詳細地說明本發明之方法。在步驟（a)之反應中，式（I I)化合物This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) c. Central standard ^^ printed by Industrial Consumer Cooperatives A7 B7 V. Description of the invention (3) Triphenylsilane, third butyl di Methylsarane, halotrimethylsilane, halo (halomethyl) silane, arylallyldimethylsilane, halotriethylsilane, halotriisopropylsilane, halo ( 3-cyanopropyl) dimethylsilane, halodimethyloctylsilane, halotribenzylsilane, halotrihexylsilane, etc. (preferably halotriphenylsarane), and triethyl Amine, tri-n-propylamine, diisopropylethylamine, imidazole, pyridine or 4-dimethylaminopyridine to protect the hydroxyimino group, and when R1 is allyl, the reaction in step (e), ( After removing the protective treatment if necessary, it can be carried out in the presence of a palladium catalyst. As mentioned previously, the final product produced by this method of the present invention is a useful compound of an antiparasitic agent. Detailed description of the invention "Ci-8 alkyl" as used herein refers to a straight or branched chain saturated group containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, second butyl, third butyl, pentyl, hexyl, and the like. As used herein, 〃c 2-8 alkenyl〃 refers to a linear or branched unsaturated group containing 2 to 8 carbon atoms, including but not limited to 1-vinyl, 1-propenyl, 2-propenyl Group, 1-butenyl, 2-butenyl, 2-methyl-1-propenyl and the like. The "C3-8 cycloalkyl" referred to herein means a carbocyclic group containing 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. As used herein, halohalo refers to fluorine, chlorine, bromine or iodine. (Please read the notes on the back before filling in this page) The size of the paper used for this edition is Chinese National Standard (CNS) A4 (210 × 297 mm) ~ Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives' printing f A 7 ___________B7_ V. Invention Note (4) "Allyl" as referred to herein means an alkyl group or substituted alkyl group containing a carbon-carbon double bond at the 2,3-position, including but not limited to allyl, methyl Allyl, crotonyl, chloroallyl, cinnamyl and the like. The method of the present invention is explained in detail below. In the reaction of step (a), the compound of formula (I I)

與氧化劑反應而形成5-氧化合物，更確定地說，在此反應中，化合物（I I )在5 -位置之羥基經由氧化轉化成氧基，式（I I )化合物爲一種艾維美丁 B 2化合物其爲發酵衍生的艾維美丁產物，式（I I )化合物可經由艾維美丁產生的艾維密替力鏈霉菌（Streptomyces avermitilis )菌種例如 ATCC31267、31271 或 3 1 2 7 2之發酵而分離，如美國專利編號 5，089，480之揭示，得到式（I I)化合物之其他方法包括從艾維密替力鏈霉菌ATC C 5 3 5 6 8之發酵肉湯分離，如’Dutton et al.，Journalof Antibiotics,44,357- --------0¾------ίτ.------iL (請先聞讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標率（CNS ) A4規格（210X 297公釐） ~ 經濟部中央標準局貞工消費合作社印製 A7 B7 五、發明説明（5 ) 65(1 99 1)之揭示。合適氧化劑包括例如二氧化錳、過氧化鎳或二鉻酸吡啶，鑑於選擇性地氧化α -位置之雙鍵，以二氧化錳較佳 ,在步驟（a)使用之氧化劑可爲1至20 0當量，較宜爲1 0至7 0當量，相對於被處理之式（I I )化合物，步驟（a )之反應可在0至8 0°C之溫度下反應1 〇分鐘至10小時，此反應可在選自但不限於氯仿、二氯甲烷、苯、甲苯、二甲苯、四氫呋喃、二腭烷、二甲基甲醯胺、丙酮、乙腈、第三丁基甲基醚及其混合物之惰性溶劑中進行，以二氯甲烷較佳。在步驟（b)之反應中，所得的5 —氧基化合物與式 R1 - Ο — NH2化合物反應其中R1爲Η或羥基亞胺基保護基，形成5_亞胺基化合物，合適的羥基亞胺基保護基包括例如三苯基矽烷基、第三丁基二甲基矽烷基、四氫吡喃基、甲硫基甲基、烯丙基、甲基烯丙基、巴豆基、氯烯丙基、肉桂基或烯丙酯基（較宜爲三苯基矽烷基或烯丙基〔C Η 2 = C H C Η 2 -〕），在步驟（b )使用的亞胺化劑（R1 —。一 NH2)可爲0 . 5至50當量，較宜爲1 至10當量，相對於被處理之5_氧基化合物，步驟（b )之反應可在—1 0至8 0°C之溫度下反應5分鐘至2 0 小時，此反應可在選自但不限於氯仿、二氯甲烷、苯、甲苯、二甲苯、四氫呋喃、二腭烷、二甲基甲醯胺、甲醇、第三丁基甲基醚、乙腈、異丙醇、水及其混合物之惰性溶劑中進行，以甲醇、二噚烷及水之混合物較佳。本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 一裝· 訂經濟部中央樣率局員工消費合作社印掣 A7 B7 五、發明説明（6 ) 在步驟（c)之反應中，5 _亞胺基化合物與硫逐碳化劑反應而形成4〃，23-雙硫逐羰基酯，合適的硫逐 . ..... ............. ............ .................. .............. ... .... 碳化劑包括例如r5〇-c (S)—鹵基或R5s — C (S )—鹵基（鹵基較宜爲氯）其中RSgCi- 4烷基、苯基或诩基、視需要被選自C i - 4烷基、C i - 4烷氧基、鹵基取代之Ci-4烷基、鹵基取代之Ci-4烷氧基、硝基、羥基、胺基及鹵基之一或兩個取代基取代之苯基或萘基，以氯 &硫逐甲酸苯酯較佳，在步驟（c )使用的硫逐碳化劑可爲 1至2 0當量，較宜爲2至5當量，相對於被處理之5 — 亞胺基化合物，此反應可在0至13 0°C之溫度下反應5 分鐘至1 0小時，此反應可在選自但不限於氯仿、二氯甲烷、苯、甲苯、二甲苯、四氫呋喃、二噚烷、二甲基甲醯胺、乙腈、醋酸乙酯及其混合物之惰性溶劑中進行，以甲苯較佳。在步驟（d)之反應中，4〃，23—雙硫逐羰基酯與脫氧劑反應而形成4〃，23-二脫氧化合物，合適的基團脫氧劑包括例如三丁基氫化錫、參（三甲矽烷基）矽烷、三乙基矽烷、三丙基矽烷、苯基矽烷、二苯基矽烷、三苯基矽烷、二烷基亞磷酸鹽或次磷酸，較宜爲含基團引發劑之參（三甲矽烷基）矽烷，在步驟（d )使用的基團脫氧劑可爲1至1 〇當量，較宜爲2至4當量，相對於被處理之4〃，2 3 —雙硫逐羰基酯，此反應可在〇至 1 4 0 °C之溫度下反應5分鐘至1 5小時，此反應可在選自但不限於氯仿、二氯甲院、苯、甲苯、二甲苯、四氫口夫本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公嫠') (請先閲讀背面之注意事項再填寫本頁) 訂 -9 - 經濟部中央摞準局—工消費合作社印掣 A7 ___ _ B7 ^ --— --- —— —一 - _ 五、發明説明（7 ) 喃、二噚院、二甲基甲醯胺及其混合物之惰性溶劑中進行 ,以甲苯較佳。在步驟（e )之反應中，4〃，2 3 —二脫氧化合物與酸反應而形成式（I )化合物，合適的酸包括例如對甲苯磺酸、苯磺酸、HF、HC1、H2S〇4、113?〇4及 HC 1〇4，較宜爲對甲苯磺酸，在步驟（e )使用的酸可爲0 . 0 1至2 〇當量，較宜爲〇 . 5至5當量，相對於、被處理之4〃，2 3 —二脫氧化合物，此反應可在〇至 10 0°C之溫度下反應5分鐘至15小時，此反應可在選自但不限於氯仿、二氯甲烷、苯、甲苯、二甲苯、四氫呋喃、二-烷、二甲基甲醯胺、甲醇、乙醇、異丙醇、丁醇、丙酮、醋酸乙酯、水及其混合物之情性溶劑中進行，以甲醇較佳。而且在步驟（e )中，當保護烯丙基時，在鈀觸媒存在下進行去除保護反應，鈀觸媒爲當與烯丙基化合物反應時可很容易形成π-烯丙基絡合物之鈀化合物，更適當的鈀觸媒包括例如含一個配位基者例如肆（三苯膦）鈀（0 ) 、二氯雙（三苯膦）鈀（I I)、二氯雙（乙腈）鈀（I I)及二氯雙（三異丙氧基膦）鈀（I I)或二醋酸鈀（ I I )與三苯基臉或亞磷酸三乙酯之結合（參見Jiro Tsuji，〃 Transition Metalsin Organic Synthesis 〃，Kagakudojin, 1991 ),在一個使用甲酸作爲去除保護劑之慣用方法中，反應是在沸騰的二吗院中進行（Yamada，T. et al.，Tetrahedron Lett，27,2368(1 986)，但是在本發明之方法中，因爲本反應本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -------—〇裝— (請先閱讀背面之注意事項再填离本頁) 、1T- 經濟部中央標隼局員工消費合作社印製 A7 B7 五、發明説明（8 ) 系統之高反應速率，是在室溫下進行去除保護。常用量爲0 · 1至50莫耳％，較宜爲1至10莫耳 %在步騾（e )中被處理之4〃，2 3 —二脫氧化合物。去除保護反應是在適當的反應惰性溶劑中進行，適當的溶劑包括含羥基之溶劑，例如醇類如甲醇、乙醇及水；及非羥基溶劑，包括例如鹵基烷基化合物例如二氯甲烷及氯仿；酯類例如醋酸甲酯及醋酸乙酯；醚類例如乙醚及四 ;.氫呋喃；腈類例如乙腈及丙腈；酮類例如丙酮及甲基乙基酮；及芳族烴類例如苯及甲苯；及其混合物。去除保護反應可在實質上中性的情形下進行，因此，本發明方法可使用對酸性或鹼性情形過敏之起始物質及最終化合物進行合成。去除保護反應之情形可根據被處理化合物、去除保護劑、觸媒、使用溶劑等之種類而決定，一般而言，去除保It reacts with an oxidant to form a 5-oxy compound. More specifically, in this reaction, the hydroxyl group of the compound (II) at the 5-position is converted to an oxy group through oxidation. The compound of the formula (II) is an imimetine B 2 The compound is a fermented product of avermectin. The compound of formula (II) can be produced by avermectin through the fermentation of Streptomyces avermitilis strains such as ATCC31267, 31271 or 3 1 2 7 2 And isolation, as disclosed in U.S. Patent No. 5,089,480, other methods of obtaining compounds of formula (II) include isolation from fermented broth of Streptomyces avermitilis ATC C 5 3 5 6 8 such as' Dutton et al., Journal of Antibiotics, 44,357- -------- 0¾ ------ ίτ .------ iL (Please read the precautions on the back before filling this page) This paper is applicable to the standard China National Standards (CNS) A4 Specification (210X 297 mm) ~ Printed by A7 B7 of Zhengong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Disclosure of Invention Note (5) 65 (1 99 1). Suitable oxidants include, for example, manganese dioxide, nickel peroxide or pyridinium dichromate. In view of the selective oxidation of the double bond at the α-position, manganese dioxide is preferred. The oxidant used in step (a) may be from 1 to 200. The equivalent is preferably 10 to 70 equivalents. The reaction in step (a) can be performed at a temperature of 0 to 80 ° C for 10 minutes to 10 hours relative to the compound of formula (II) to be treated. Can be performed in an inert solvent selected from, but not limited to, chloroform, dichloromethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, acetone, acetonitrile, third butyl methyl ether, and mixtures thereof Of these, dichloromethane is preferred. In the reaction of step (b), the obtained 5-oxy compound is reacted with a compound of the formula R1-O-NH2 where R1 is a fluorene or a hydroxyimine protecting group to form a 5-imine compound, a suitable hydroxyimine Protecting groups include, for example, triphenylsilyl, third butyldimethylsilyl, tetrahydropyranyl, methylthiomethyl, allyl, methallyl, crotyl, chloroallyl , Cinnamyl or allyl ester (preferably triphenylsilyl or allyl [C Η 2 = CHC Η 2-]), the imidating agent (R1-. -NH2) used in step (b) ) Can be 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, relative to the treated 5-oxy compound, the reaction in step (b) can be reacted at a temperature of -10 to 80 ° C 5 Minutes to 20 hours, this reaction can be selected from but not limited to chloroform, dichloromethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, methanol, third butyl methyl ether, acetonitrile , Isopropanol, water and mixtures thereof in an inert solvent, preferably a mixture of methanol, dioxane and water. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page) One Pack · Order Printed by the Consumer Sample Cooperative of the Central Sample Rate Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Explanation (6) In the reaction of step (c), the 5-imino compound is reacted with the sulfurized carbonizing agent to form 4〃, 23-dithioated carbonyl ester, suitable sulfurized ... ....................................................... ..... ... .... Carbonizing agents include, for example, r50-c (S) -halo group or R5s-C (S) -halo group (halogen group is preferably chlorine), among which RSgCi-4 alkyl group , Phenyl or fluorenyl, optionally substituted with Ci-4 alkyl, Ci-4 alkoxy, halo-substituted Ci-4 alkyl, halo-substituted Ci-4 alkoxy, nitro Phenyl or naphthyl substituted with one or two substituents of hydroxyl, amine, amine and halo, preferably chlorine & phenyl thiothioate, the thiocarburizing agent used in step (c) may be 1 to 20 equivalents, preferably 2 to 5 equivalents, relative to the treated 5-imino compound, the reaction can be performed at a temperature of 0 to 13 0 ° C for 5 minutes to 10 hours This reaction can be performed in an inert solvent selected from, but not limited to, chloroform, dichloromethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, ethyl acetate, and mixtures thereof. Toluene is preferred. In the reaction of step (d), 4〃, 23-bisthiothiocarbonyl ester is reacted with a deoxidizing agent to form a 4〃, 23-dideoxy compound. Suitable group deoxidizing agents include, for example, tributyltin hydride, ginseng ( Trimethylsilyl) silane, triethylsilane, tripropylsilane, phenylsilane, diphenylsilane, triphenylsilane, dialkylphosphite, or hypophosphorous acid, more preferably a group-containing initiator (Trimethylsilyl) silane, the group deoxidizer used in step (d) may be 1 to 10 equivalents, more preferably 2 to 4 equivalents, relative to the treated 4〃, 2 3 -dithiothiocarbonyl ester This reaction can be performed at a temperature of 0 to 140 ° C for 5 minutes to 15 hours. This reaction can be selected from, but not limited to, chloroform, dichloromethane, benzene, toluene, xylene, and tetrahydrograft. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 Gong ') (Please read the notes on the back before filling out this page) Order -9-Central Bureau of Standards of the Ministry of Economic Affairs-Industrial and Consumer Cooperative Press A7 ___ _ _ B7 ^ --- -------- _ V. Description of the invention (7) Nan, Eryuan, Dimethylformate The amidine and its mixture are carried out in an inert solvent, preferably toluene. In the reaction of step (e), a 4 ，, 2 3 -dideoxy compound is reacted with an acid to form a compound of formula (I). Suitable acids include, for example, p-toluenesulfonic acid, benzenesulfonic acid, HF, HC1, H2S04. 113, 04, and HC 104, more preferably p-toluenesulfonic acid, and the acid used in step (e) may be 0.01 to 2 equivalents, more preferably 0.5 to 5 equivalents, relative to 4, treated 4〃, 2 3-dideoxy compounds, this reaction can be reacted at a temperature of 0 to 100 ° C for 5 minutes to 15 hours, this reaction can be selected from but not limited to chloroform, dichloromethane, benzene , Toluene, xylene, tetrahydrofuran, di-alkane, dimethylformamide, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, water and mixtures of solvents. good. Moreover, in step (e), when the allyl group is protected, a removal protection reaction is performed in the presence of a palladium catalyst. The palladium catalyst can easily form a π-allyl complex when reacted with an allyl compound. Palladium compounds, more suitable palladium catalysts include, for example, those containing a ligand such as tris (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (acetonitrile) palladium (II) and the combination of dichlorobis (triisopropoxyphosphine) palladium (II) or palladium (II) diacetate with triphenyl face or triethyl phosphite (see Jiro Tsuji, 〃 Transition Metals in Organic Synthesis 〃 , Kagakudojin, 1991), in a conventional method using formic acid as a protective agent, the reaction is carried out in a boiling Er Mo (Yamada, T. et al., Tetrahedron Lett, 27, 2368 (1 986), but In the method of the present invention, because of the reaction, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) --------- 〇Package-- (Please read the precautions on the back before filling in this paper Page), 1T- printed by A7 B7, employee consumer cooperative of Central Bureau of Standards, Ministry of Economic Affairs Description of the invention (8) The high reaction rate of the system is removal protection at room temperature. The commonly used amount is 0.1 · 50 to 50 mole%, preferably 1 to 10 mole% is processed in step (e). 4〃, 2 3-dideoxy compounds. The deprotection reaction is performed in a suitable reaction inert solvent, suitable solvents include hydroxyl-containing solvents, such as alcohols such as methanol, ethanol and water; and non-hydroxy solvents, including for example Haloalkyl compounds such as dichloromethane and chloroform; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl ethyl And ketones; and aromatic hydrocarbons such as benzene and toluene; and mixtures thereof. The removal protection reaction can be carried out in a substantially neutral condition, and therefore, the method of the present invention can use a starting material that is allergic to acidic or alkaline conditions and The final compound is synthesized. The situation of removing the protection reaction can be determined according to the type of compound to be treated, removal of protective agent, catalyst, use of solvent, etc. In general, removal of protection

護反應可在一 2 0°C至1 0 0°C且較宜爲1 〇°C至4 0°C 之溫度下進fr 1分鐘至1 8小時，較宜爲5分鐘至5小時〇式（I )化合物爲有用的抗寄生物劑，且因此可用於處理狗與貓的跳蚤及心絲蟲、貓的線蟲等。下列代表性實例說明本發明而不是用於限制本發明之範圍。實例本發明經由下列實例說明，但是必須知道本發明並不本紙張尺度適用中國國家標準（CNS ) A4規格（2丨ΟΧ^7公釐） (請先聞讀背面之注意事項再填寫本頁) 訂 -11 - 經濟部中央標隼局—工消費合作社印掣 Α7 Β7 五、發明説明（9 ) 限制在這些實例的特定細節中，負F A B質譜（FABMS ) 是在J E 0 L J M S - 7 0 0上記錄，紅外線吸收光譜（ * ....... ........... . + + + + 1 R )是用Shimadzu紅外光譜儀（FTIR-8200PC )測量， iH及1 3C — NMR光譜是用J EOLNMR光譜儀（ JNM— LA270)分別在 270MHz 及 6 7 · 5 Μ Η z下記錄，化學位移以百萬組份（<5 )相對於四甲基矽烷表示1 H — NMR及相對於CHC 13 (5) ,，表示 1 3 C — N M R。實例1 1— A . 5_氧基—25 —環己基艾維美丁 Β2 將5 —氧基一25 —環己基艾維美丁 B2 (2 . 00 克，2 . 18毫莫耳）溶解在二氯甲烷（20毫升）並加入活化的二氧化錳（8 . 0克），使混合物在室溫下攪拌 3 0分鐘並用補充過濾劑（3克）過濾，用二氯甲烷（ 2 0毫升）淸洗過濾餅塊，將二氯甲烷溶液合倂並在真空下濃縮，定量地得到標題化合物類似樹脂之黃色晶體（1 • 9 9克），標題化合物之NMR光譜（核磁共振光譜）與】.八£4(；.1?〇〇(1.(：1^111.,29,881(1981)中的5—氧基—艾維美丁 B 1 a及5 —氧基—艾維美丁 B 2 a之特徵訊號符合。 1 Η - N M R (5 6.60(s，lH，3 — Η)， 3.42 ( s ，2χ3Η，4，一 OCH3.4" - Ο C Η 3 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） --------ο裝— (請先閲讀背面之注意事項再填寫本頁)The protection reaction can be carried out at a temperature of 20 ° C to 100 ° C and more preferably 10 ° C to 40 ° C for 1 minute to 18 hours, more preferably 5 minutes to 5 hours. The (I) compound is a useful antiparasitic agent, and therefore can be used for treating fleas and heartworms in dogs and cats, nematodes in cats, and the like. The following representative examples illustrate the invention and are not intended to limit the scope of the invention. Examples The present invention is illustrated by the following examples, but it must be known that the present invention does not apply the Chinese National Standard (CNS) A4 specification (2 丨〇 × ^ 7 mm) to this paper size (please read the precautions on the back before filling out this page) -11-11-Central Bureau of Standards, Ministry of Economic Affairs—Industrial and Consumer Cooperative Cooperative Association A7 B7 V. Description of Invention (9) Limited to the specific details of these examples, negative FAB mass spectrometry (FABMS) is on JE 0 LJMS-7 0 0 Recorded that the infrared absorption spectrum (* ....... ............ + + + + 1 R) was measured with a Shimadzu infrared spectrometer (FTIR-8200PC), iH and 1 3C — NMR spectra were recorded with a J EOLNMR spectrometer (JNM-LA270) at 270 MHz and 67 · 5 Μ Η z, respectively. Chemical shifts are expressed in millions of components (< 5) relative to tetramethylsilane. 1 H — NMR and Relative to CHC 13 (5), it shows 1 3 C — NMR. Example 1 1—A. 5-oxy-25-cyclohexylavidomine B2 5-oxy-25-cyclohexylavidomine B2 (2.00 g, 2.18 mmol) was dissolved in Dichloromethane (20 ml) and activated manganese dioxide (8.0 g) was added, and the mixture was stirred at room temperature for 30 minutes and filtered with a supplementary filter (3 g), with dichloromethane (20 ml) Wash the filter cake, combine the dichloromethane solution and concentrate under vacuum to quantitatively obtain the title compound as a resin-like yellow crystal (1.99 g), and the title compound's NMR spectrum (nuclear magnetic resonance spectrum) and】. Eight £ 4 (;. 1? 〇〇 (1. (: 1 ^ 111., 29,881 (1981) 5-oxy-ivilmedine B 1 a and 5-oxy-ivilmedine B 2 The characteristic signal of a is in accordance with. 1 Η-NMR (5 6.60 (s, lH, 3 — Η), 3.42 (s, 2χ3Η, 4, -1 OCH3.4 "-〇 C Η 3 This paper standard applies to the Chinese National Standard (CNS ) Α4 size (210X297mm) -------- ο equipment— (Please read the precautions on the back before filling this page)

'IT 4 經濟部中央摞準局贵工消費合作社印裝 A7 B7 五、發明説明（10) IR (KBr，公分_1) 1720 ’ 1680，145 5 〇 1 一 B . 5 —（0 —三苯矽烷氣基亞胺基）—2 5-環己基艾維美丁 B 2 將5 一氧基—25—環己基艾維美丁 B2 (1 _ 92 克，2 . 10毫莫耳）溶解在甲醇（9 . 6毫升）及二口萼、烷（9 . 6毫升）之混合物中，加入羥基胺鹽酸鹽（ 4 5 1毫克，6 . 4 9毫莫耳）的水溶液（2 . 0毫升），經2 . 5小時後，加入羥基胺鹽酸鹽（5 0 0毫克）的水溶液（2毫升），經3 . 5小時後，加入羥基胺鹽酸鹽 (1 . 0克）的水溶液（3毫升），使混合物在室溫下攪拌5小時，加入水後用醋酸乙酯萃取，醋酸乙酯層用飽和鹽（N a C 1 )水溶液淸洗，經由硫酸鈉乾燥並過濾，過濾液在真空下濃縮，使殘留物溶解在二氯甲烷中，經由添加己烷將沈澱的白色固體過瀘，在真空下乾燥後得到5 -羥基亞胺基-2 5 —環己基艾維美丁 B 2 ( 1 . 9 0克， 9 7 %產量）。將此5 -羥基亞胺基—2 5 —環己基艾維美丁 B 2 ( 1.00克，1.08毫莫耳）溶解在四氫呋喃（5.0 毫升）並冷卻至3 — 5 °C，加入氯三苯基砂院（9 5 1毫克，3 . 23毫莫耳）及三乙胺（0 . 60毫升， 4 . 30毫莫耳），反應溶液溫熱至室溫並攪拌30分鐘，加入水後用醋酸乙酯萃取，使過濾液在真空下濃縮，在本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐） (請先閱讀背面之注意事項再填寫本頁)'IT 4 Printed by your work co-operative cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 B7 V. Description of invention (10) IR (KBr, cm_1) 1720' 1680, 145 5 〇1 B. 5 — (0 — triphenyl Silaneaminoimino) — 2 5-cyclohexylavidomine B 2 Dissolve 5 monooxy-25 —cyclohexylavidomine B2 (1 — 92 g, 2.10 mmol) in methanol (9.6 ml) and a mixture of hydrazone and alkanes (9.6 ml) was added with an aqueous solution (2.0 ml) of hydroxylamine hydrochloride (4.51 mg, 6.9 mmol). After 2.5 hours, an aqueous solution (2 ml) of hydroxylamine hydrochloride (500 mg) was added, and after 3.5 hours, an aqueous solution of hydroxylamine hydrochloride (1.0 g) was added (3 Ml), and the mixture was stirred at room temperature for 5 hours. After adding water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated salt (N a C 1) aqueous solution, dried over sodium sulfate, and filtered. It was concentrated under reduced pressure, the residue was dissolved in dichloromethane, and the precipitated white solid was filtered through addition of hexane. After drying under vacuum, 5-hydroxyimino-2 5 — US hexyl Jiai Wei Ding B 2 (1. 9 0 g, 97% of production). Dissolve this 5 -hydroxyimino-2 5 -cyclohexylavidomine B 2 (1.00 g, 1.08 mmol) in tetrahydrofuran (5.0 ml) and cool to 3-5 ° C. Add chlorotriphenyl Shayuan (95 1 mg, 3.23 mmol) and triethylamine (0.60 ml, 4.30 mmol). The reaction solution was warmed to room temperature and stirred for 30 minutes. Water was added and acetic acid was added. Ethyl acetate extraction, so that the filtrate is concentrated under vacuum, the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) is applied to the paper size (please read the precautions on the back before filling this page)

A7 B7 一 _ _______ 11 —1 ........ 五、發明説明（11 ) 矽膠上經由層析法純化殘留物（溶離溶液爲己烷一醋酸乙酯1 : i — 2 : 3 )，得到標題化合物類似淡白色樹脂之體晶克量產 % XU R Μ Ν I Η 5 8 4 ο 2 m m Η Η 族族芳芳 sA7 B7 1 _ _______ 11 —1 ........ V. Description of the invention (11) Purification of the residue by chromatography on silica gel (the dissolution solution is hexane-ethyl acetate 1: i — 2: 3) The yield of the title compound is similar to that of a pale white resin. Mass production% XU R Μ Ν I Η 5 8 4 ο 2 mm Η Η Family aromatic s

X 3 Η Η c 〇 Η C 〇 Μ Γν 7 8 IX -—! e /m s M B 「A F 負基羰逐硫基氧苯雙 ο I 5 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準历只工消費合作社印繁 -三苯矽烷氬某亞胺基）一 2 5 —環己基艾維美丁 B 2 將5 — (〇 —三苯矽烷氧基亞胺基）—2 5 -環己基艾維美丁 B2 (1 . 09克，0 . 918毫莫耳）溶解在甲苯（1 1毫升）並加入吡啶（3 . 3毫升，40 . 8毫莫耳），將溶液加熱至8 0 °C，逐滴加入氯硫逐甲酸苯酯 (0 . 6 3 5毫升，4 . 59毫莫耳），使反應混合物在 80°C下攪拌50分鐘後冷卻至3 — 5°C，加入0 . 2當量濃度氫氯酸水溶液（2 0毫升）後，用甲苯（1 0毫升 )萃取混合物，用甲苯（1 0毫升）萃取水層，將甲苯萃取異合倂並用飽和的碳酸氫鈉水溶液（2 0毫升）及飽和的鹽（N a C 1 )水溶液（2 0毫升）淸洗，經由硫酸鈉乾燥及過濾後，在真空下濃縮過濾液，在矽膠上經由層析法純化殘留物（溶離溶液爲己烷一醋酸乙酯7 : 2 )，得本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -14- 經濟部中央標準局只工消費合作社印製 A7 B7 五、發明説明（12) 到標題化合物類似淡白色樹脂之晶體（1 . 2 6克，9 4 %產量）。 1 Η - N M R <5 7.7 0- 7.61(111，611，芳族）， 7.48-7.24 (瓜’1511，芳族）， 7.15 — 7.07(m，4H，芳族）， 3.46(s，3H，-〇CH3)， 3 . 4 3 ( s，3 Η，一〇 C Η 3 )。 I R ( K B r，公分一 3480，2 9 31 ’ 17 16 〇負 FABMSm/el459 (M) -，1201 (M—P h 3 S i Η )—。 1-D . 47/ _ 去氧基一22 ，23 -二氤一5— 三苯矽烷氧基亞胺基）—2 5 -環己某艾維笔TB 1 將4" ，23 —雙（苯氧基硫逐羰基）=5 —（◦一三苯矽烷氧基亞胺基）_ 2 5 —環己基艾維美丁 B 2 ( 1 . 26克，0 . 862毫莫耳）溶解在甲苯（12 . 6 毫升），然後加入三丁基氫化錫（0 . 9 3毫升， 3 . 46毫莫耳）及偶氮雙異.丁羟（1 4 2毫克， 0 . 8 6 5毫莫耳），將溶液加熱至1 〇〇 °C ,攪拌5 5 分鐘後在真空下濃縮（3毫升），在矽膠上經由層析法純化如此所得的殘留物（溶離溶液爲己烷一醋酸乙酯4 : 1 一 5 : 2 )，得到標題化合物類似淡白色樹脂之晶體（本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂 -15- 經濟部中央標準局货工消費合作社印掣 A7 B7 五、發明説明（13) 748毫克，75%產量）。 1 Η - N M R 5 7.70-7.60(m，6H)， 7.48-7. 30 (m>.9H)， 5.99-5.91 (m，lH)， 5.85 — 5.69 (m，2H)， 5.50-5.33(m，2H)， 5.00(d，J = 8.8Hz，lH)， 4 . 8 8 ( s，1 H )， 4.81-4.62 (m，2H)， 4.00-3. 52(m，6H)， 3.50 — 3.42(m，lH)， 3 · 4 2 ( s > 3 H )， 3.36(s，3H)， 3.25(t，J=8.8Hz，lH)， 3.11_3.00(m，lH)， 2.58-2.46(m>lH)， 2.38-2.12(m>3H)， 2.08 — 1.90(m，4H)， 1.85 — 1.05(m，38H)， 0 · 9.0 — 0 . 70 (m.’ 4H)。 13C-NMR<5173.2，157.8，155 .6, 138·6，138. 2，135.8，135.0， 133. 3，132.7，130.0，127.6，本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ~ ' . 裝訂 -L. (請先閱讀背面之注意事項再填寫本頁) A7 B7 五、發明説明（14X 3 Η Η c 〇Η C 〇Μ Γν 7 8 IX -—! E / ms MB 「AF Negative Carbonylthiothiophene bis Iο 5 (Please read the precautions on the back before filling this page) Ministry of Economy Central Standard Calendar Industrial Consumers' Cooperatives-India-Triphenylsilane Ar Imine)-2 5 -Cyclohexyl Iveymetin B 2 5-(〇-Triphenylsilyloxyimine)-2 5- Cyclohexyl Ivermetin B2 (1.09 g, 0.918 mmol) was dissolved in toluene (11 ml) and pyridine (3.3 ml, 40.8 mmol) was added and the solution was heated to 8 At 0 ° C, phenyl chlorothiothioformate (0.63 5 ml, 4.59 mmol) was added dropwise. The reaction mixture was stirred at 80 ° C for 50 minutes and then cooled to 3-5 ° C. After 0.2 equivalent concentration hydrochloric acid aqueous solution (20 ml), the mixture was extracted with toluene (10 ml), and the aqueous layer was extracted with toluene (10 ml). The toluene was extracted with isocyanate and saturated aqueous sodium hydrogen carbonate solution was used. (20 ml) and saturated saline (N a C 1) aqueous solution (20 ml), rinsed, dried over sodium sulfate and filtered, and then concentrated the filtrate under vacuum, The residue was purified by chromatography on a gel (the dissolution solution was hexane-ethyl acetate 7: 2), and the paper size obtained was in accordance with Chinese National Standard (CNS) A4 (210X297 mm). -14- Central Bureau of Standards, Ministry of Economic Affairs A7 B7 printed by Gongying Cooperative Co., Ltd. 5. Description of the invention (12) The title compound is similar to a pale white resin crystal (1.26 g, 94% yield). 1 Η-NMR < 5 7.7 0- 7.61 (111 , 611, aromatic), 7.48-7.24 (melon'1511, aromatic), 7.15 — 7.07 (m, 4H, aromatic), 3.46 (s, 3H, -〇CH3), 3. 4 3 (s, 3 Η, 〇C Η 3). IR (KB r, cm 3480, 2 9 31 '17 16 〇 negative FABMSm / el459 (M)-, 1201 (M—P h 3 S i Η) —. 1-D 47 / _ deoxy-22,23-dioxan-5-triphenylsilyloxyimino) -2 5 -cyclohexyl avid pen TB 1 will be 4 ", 23-bis (phenoxysulfur Percarbonyl group) = 5 — (◦triphenylsilyloxyimino group) — 2 5 —cyclohexyl evimetine B 2 (1.26 g, 0.862 mmol) dissolved in toluene (12.6 Ml) and then tributyltin hydride (0.93 ml, 3.46 millimoles) and azobisisobutanol (142 mg, 0.865 millimoles), the solution was heated to 1000 ° C, stirred for 5 5 minutes and concentrated under vacuum (3 ml), the residue thus obtained was purified by chromatography on silica gel (the dissolution solution was hexane-ethyl acetate 4: 1 to 5: 2) to obtain the title compound as a pale white resin crystal (this paper scale Applicable to China National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Order -15- Printed by the Consumer Goods Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (13 ) 748 mg, 75% yield). 1 Η-NMR 5 7.70-7.60 (m, 6H), 7.48-7. 30 (m > .9H), 5.99-5.91 (m, lH), 5.85-5.69 (m, 2H), 5.50-5.33 (m, 2H), 5.00 (d, J = 8.8Hz, 1H), 4. 8 8 (s, 1 H), 4.81-4.62 (m, 2H), 4.00-3. 52 (m, 6H), 3.50 — 3.42 ( m, lH), 3 · 4 2 (s > 3 H), 3.36 (s, 3H), 3.25 (t, J = 8.8Hz, lH), 3.11_3.00 (m, lH), 2.58-2.46 ( m > lH), 2.38-2.12 (m > 3H), 2.08—1.90 (m, 4H), 1.85—1.05 (m, 38H), 0 · 9.0—0.70 (m. '4H). 13C-NMR < 5173.2, 157.8, 155.6, 138.6, 138.2, 135.8, 135.0, 133.3, 132.7, 130.0, 127.6, this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) ） ~ '. Binding-L. (Please read the precautions on the back before filling this page) A7 B7 V. Invention Description (14

經濟部中央摞準局员工消费合作社印聚己基艾維美丁B1單糖將4"—去氧基一 22 ’ 2 3—二氫一5 — (〇 —三苯矽烷氧基亞胺基）一 2 5 —環己基艾維美丁 B 1 ( 748毫克，〇. 647毫莫耳）溶解在甲醇（22. 5 毫升），加入對甲苯磺酸（246毫克，1 . 29毫莫耳 ),在室溫下攪拌60分鐘後，加入三乙胺（0 . 2毫升 )並在真空下濃縮，在矽膠上經由層析法純化濃縮後的殘留物（溶離溶液爲己烷-醋酸乙酯1 : 1 ),得到標題化本紙張尺度適用中國國家標準（CNS )八4規格（210X297公釐）經濟部中央標準而貞工消費合作社印家 A7 B7 五、發明説明（15) 合物類似無色樹脂之晶體9 0毫克，5 8%產量），標題化合物之N M R光譜（核磁共振光譜）與國際公告編號W 0 94 / 15944揭示之方法合成之22 ，23 — 二氫-5 —羥基亞胺基—2 5 —環己基艾維美丁 Β 1單糖特徵訊號吻合。 1 Η - N M R (5 8.10(s，1H，=N — OH)， ' 3.47(s，3H，4’-〇CH3)， 3 . 18 (t，J = 9 . 1Hz，ih，4’-H)。 IR(KBr，公分_1) 3450，2920，1715 o 實例2 2 — A . 5 —(〇一烯丙氧基亞胺基）一2 5 —環己維美丁 B 2 將實例1 — A製備之5 -氧基—2 5 —環己基艾維美丁 B 2 (9 9 3毫克，1 . 09毫莫耳）溶解在甲醇（ 7 . 0毫升）及二噚烷（7 . 〇毫升）之混合物中，然後加入0 —烯丙基羥基胺鹽酸鹽（597毫克，5 . 44毫莫耳）的水溶液，在室溫下攪.拌1 7小時後，加入水（ 2 0毫升），用醋酸乙酯（1 0 0毫升）萃取，醋酸乙酯層用飽和鹽（N a C 1 )水溶液淸洗，經由硫酸鎂乾燥並過濾，過濾液在真空下濃縮後得到標題化合物類似淡黃色樹脂之晶體（9 9 2毫克，9 4%產量）。本紙張尺度適用中國國瓣（CNS ) Μ規格（2數歸酱—18 _ (讀先聞讀背面之注意事項再填寫本頁) 、?τ 經濟部中央標準扃货工消費合作社印掣 A7 _____ J _ B7___ 五、發明説明（16) 1 Η - n M R (5 6.l〇-5.70(m，5H)， 5.45 — 5.20(m，4H)， 5.04-4.95 (m，.lH)， 4.80-4.65(m，4H)， 4 . 6 0 ( s，1 H )， 3 . 9 5 ( s，1 H )，、3.90 — 3.37(m，17H)， 3.25(t，J = 9.1Hz，lH)， 3.15(t，J = 9.1Hz，lH)， 2.60 — 2.20(m，6H)， 2.〇3-1.40(m，22H)， 1.34-1.15(m，12H)， 0.96-0.80 (m，4H)。 IR(KBr，公分-1) 3257，2931，1735 ，1 7 1 8 ° 負 FABMSm/e968(M-H)-。 2-B.5 — (〇_烯丙氧某亞胺基4〃 > ^ - mMinistry of Economic Affairs, Central Bureau of Quasi-Employees, Consumer Cooperatives, Polyhexyl Iveymetin B1 Monosaccharides 4 " -Deoxy- 22 '2 3-Dihydro- 5-(〇-Triphenylsilyloxyimino) 1 2 5 —Cyclohexyl Ivermetin B 1 (748 mg, 0.647 mmol) was dissolved in methanol (22.5 mL), and p-toluenesulfonic acid (246 mg, 1.29 mmol) was added. After stirring at room temperature for 60 minutes, triethylamine (0.2 ml) was added and concentrated under vacuum. The concentrated residue was purified by chromatography on silica gel (the dissolution solution was hexane-ethyl acetate 1: 1). ) To get the title. The paper size is applicable to Chinese National Standards (CNS) 8 4 specifications (210X297 mm) Central Standard of the Ministry of Economic Affairs and Zhengong Consumer Cooperative Press A7 B7 V. Description of the invention (15) Compounds are similar to colorless resin crystals 90 mg, 58% yield), NMR spectrum (nuclear magnetic resonance spectrum) of the title compound and the method disclosed in International Publication No. W 94/15944 22,23 —dihydro-5 —hydroxyimino-2 5 —The characteristic signals of cyclohexyl avimetidine B 1 monosaccharides are consistent. 1 Η-NMR (5 8.10 (s, 1H, = N — OH), '3.47 (s, 3H, 4'-〇CH3), 3. 18 (t, J = 9.1Hz, ih, 4'-H ). IR (KBr, cm_1) 3450, 2920, 1715 o Example 2 2 — A. 5 — (〇-allyloxyimino) 2 5 —Cyclohexavidin B 2 Example 1 — The 5-oxy-2,5-cyclohexylavidomine B 2 (9.33 mg, 1.09 mmol) prepared in A was dissolved in methanol (7.0 ml) and dioxane (7.0 ml). ), Then add 0-allylhydroxylamine hydrochloride (597 mg, 5.44 mmol) and stir at room temperature. After stirring for 17 hours, add water (20 ml) , Extracted with ethyl acetate (100 ml), the ethyl acetate layer was washed with a saturated salt (N a C 1) aqueous solution, dried over magnesium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound similar to pale yellow Resin crystals (9.22 mg, 94% yield). This paper size is applicable to China National Flap (CNS) M specifications (2 counts to sauce—18 _ (read the notes on the back and then fill out this page), ? τ Central Standard of the Ministry of Economy Zuosha A7 _____ J _ B7___ V. Description of the invention (16) 1 Η-n MR (5 6.l0-5.70 (m, 5H), 5.45 — 5.20 (m, 4H), 5.04-4.95 (m, .lH), 4.80-4.65 (m, 4H), 4.60 (s, 1H), 3.95 (s, 1H), 3.90-3.37 (m, 17H), 3.25 (t, J = 9.1Hz, lH), 3.15 (t, J = 9.1Hz, lH), 2.60 — 2.20 (m, 6H), 2.〇3-1.40 (m, 22H), 1.34-1.15 (m, 12H), 0.96 -0.80 (m, 4H). IR (KBr, cm-1) 3257, 2931, 1735, 1 7 1 8 ° Negative FABMSm / e968 (MH)-. 2-B.5 — (〇_Allyloxy Amine 4〃 > ^-m

(苯氧基硫逐羰基）一 2 5 _環己基艾維美丁 B 將5 — ( Ο —烯丙氧基亞胺基）—2 5 -環己基艾維美丁 B2 (992毫克，1 . 02毫莫耳）溶解在甲苯（ 1 0 . 7毫升）並加入吡陡（3 . 7毫升，4 5 . 7毫莫耳），將溶液加熱至7 0 t，逐滴加入氯硫逐甲酸苯酯（本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） m nn n ml m n tn n^— n、一OJ (請先閲讀背面之注意事項再填寫本頁) -19 - 經濟部中央標率而货工消費合作社印犁 A7 B7 五、發明説明（17 ) 0 . 64毫升，4 . 62毫莫耳），使反應混合物在80 —8 5°C下攪拌9 0分鐘後冷卻至室溫，用甲苯（1 〇毫升）淸洗沈積的黑色油，將甲苯合併並用醋酸乙酯（6 0 毫升）稀釋，醋酸乙酯溶液用水（20毫升）、1當量濃度氫氯酸水溶液（10毫升）及飽和的碳酸氫鈉水溶液（ 1 0毫升）淸洗，經由硫酸鎂乾燥及過濾後，在真空下濃縮過濾液，在矽膠上經由層析法純化殘留物（溶離溶液爲、己烷一醋酸乙酯6 0 : 1 6 )，得到標題化合物類似淡紅色樹脂之晶體（9 4 9毫克，7 5%產量）。 1 Η - N M R 5 7.50-7·05 (m，10Η，芳族）， 4.62(s，1H，6—H)， 3.48(s，3H，-OCH3)， 3.43(s，3H，-OCH3)。負 FABMSm/el241 (M) 一。 2 - C . 5 -(烯丙氧基亞胺基）—4〃 _去氧基—2 2 ，2 3—二氫—2 5—環己基艾維美丁 B1 將5_ (0 —烯丙氧基亞胺基）—4〃，23 —雙（苯氧基硫逐羰基）一 2 5 —環己基艾維美丁 B 2 ( 9 4 9 毫克，0.764毫莫耳）溶解在甲苯（25毫升），然後加入參（三甲矽烷基）矽烷（0 . 71毫升，2.36 毫莫耳）及偶氮雙異丁腈（125毫克，0.761毫莫耳），使溶液在8 0 — 1 0 0°C下攪拌5 0分鐘後在真空本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ---------r裝— (讀先聞讀背面之注意事項再填寫本頁)(Phenoxythiothiocarbonyl)-2 5 _cyclohexyl evimetine B 5-(0-allyloxyimino)-2 5 -cyclohexyl evimetine B2 (992 mg, 1. 02 millimoles) dissolved in toluene (10.7 milliliters) and pyridoxine (3.7 milliliters, 45.7 millimoles) was added, the solution was heated to 70 t, and chlorosulfuric acid and benzene were added dropwise. Ester (This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) m nn n ml mn tn n ^ — n, one OJ (please read the precautions on the back before filling this page)) -19-Ministry of Economy Central standard rate and goods and workers' cooperatives Yinli A7 B7 V. Description of the invention (17) 0.64 ml, 4.62 millimoles), the reaction mixture was stirred at 80-8 5 ° C for 90 minutes and then cooled to Rinse the deposited black oil with toluene (10 ml) at room temperature. Combine the toluene and dilute with ethyl acetate (60 ml). Ethyl acetate solution with water (20 ml), 1 equivalent strength hydrochloric acid aqueous solution (10 Ml) and a saturated aqueous solution of sodium bicarbonate (10 ml), dried over magnesium sulfate and filtered, and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (the dissolution solution was, hexane-ethyl acetate 60:16) to obtain the title compound as a pale red resin-like crystal (9 4 9 mg, 7 5% yield). 1 Η-N M R 5 7.50-7 · 05 (m, 10Η, aromatic), 4.62 (s, 1H, 6-H), 3.48 (s, 3H, -OCH3), 3.43 (s, 3H, -OCH3). Negative FABMSm / el241 (M) One. 2-C. 5-(allyloxyimino) -4〃 _deoxy-2 2, 2 3 -dihydro-2 5 -cyclohexyl evimetine B1 5_ (0 -allyloxy Imino) -4〃, 23-bis (phenoxythiothiocarbonyl)-25-cyclohexylavidomine B 2 (9 4 9 mg, 0.764 mmol) dissolved in toluene (25 ml) And then add ginseng (trimethylsilyl) silane (0.71 ml, 2.36 mmol) and azobisisobutyronitrile (125 mg, 0.761 mmol) to make the solution at 80 ° -10 ° C After stirring for 50 minutes, the Chinese paper standard (CNS) A4 (210X297 mm) is applied to the paper in vacuum. --------- r pack— (read the precautions on the back and fill in this page)

、1T A7 B7 五、發明説明（18) 下濃縮，在矽膠上經由層析法純化如此所得的殘留物（溶離溶液爲己烷-醋酸乙醋4 : 1 )，得到標題化合物類似淡黃色樹脂之晶體（3 5 6毫克，50%產量）。 1 Η - n M R <5 3.42(s，3H，4’—〇CH3)， 3 . 37 (s，3H，4’一〇CH3)，全部芳族之訊號消失。 .I R ( K B r，公分_1) 3481，2 9 2 9，2 8 5 4 ’1716，1450。經濟部中央標率而貨工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 13C- NMR5173.3，150.3，138.3, 135.0，134.0，132. 4，124. 8， 124. 5，121. 3，118. 4 ’117.7， 99. 2，97. 5，94. 9，81. 9，80. 3, 79.4，78.6，78·5，75.9，73.2, 72. 4，68. 7，67. 3，67.1，64. 5, 56. 6，55. 2，46. 4，41.0，39. 9, 3 9.2，38, 6，36. 9，36. 3，35. 7, 34. 6，34.1，31. 2，30.6，28.1， 26. 8，26. 6，24. 7，21. 4，20.1， 18. 3，17. 4，15. 2° 負 FABMSm/e937 (Μ)_。 2 — D . 5 —(〇一烯丙氧基亞胺基）一22 ，23 —二氫- 2 5 —環己某艾維美丁 B 1單糖本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經满部中央標準而货工消費合作杜印製 A7 B7 / 五、發明説明（19) 將5 —（烯丙氧基亞胺基）—4'_去氧基一 2 2， 2 3—二氫一 2 5—環己基艾維美丁 B 1 ( 3 5 6毫克，〇 . 3 79毫莫耳.）溶解在甲醇（12毫升），加入對甲苯磺酸（108毫克，0 · 568毫莫耳），在室溫下攪拌9 0分鐘後，加入飽和的碳酸氫鈉水溶液（1 2毫升），將沈積的白色固體過濾，用水淸洗，然後在矽膠上經由層析法純化（溶離溶液爲己烷一醋酸乙酯3 : 1 )，得到 ..標題化合物類似無色樹脂之晶體（2 1 8毫克，7 3 %產量）。 1 E - N M R δ 6.10 — 5.90(m，2H)， 5.82-5.68(m>2H)， 5.50 — 5.40(m，lH)， 5.35 — 5.18(m，2H)， 4 . 9 8 ( d，J = 7 . 0 H z，1 H )， 4.82(d，J = 2.9Hz，lH)， 4.80-4.62 (m，4H)， 4 . 6 0 ( s，1 H )， 4.00 — 3.80 (m，4H)， 3.72-3.50 (m，3H)， 3.47(s，3H，4’-〇CH3)， 3.39(t，J = 2.2Hz，lH)， 3.16(t，J = 9.2Hz，lH)， 3.06(d，J = 8.1Hz，lH)，本紙張尺度it财關家縣（CNS ) A4規格（210X297公釐) '"' -22- (請先閱讀背面之注意事項再填寫本頁), 1T A7 B7 V. Description of the invention (18), the residue thus obtained was purified by chromatography on silica gel (the dissolution solution was hexane-ethyl acetate 4: 1) to obtain the title compound similar to a pale yellow resin. Crystals (3 5 6 mg, 50% yield). 1 Η-n M R < 5 3.42 (s, 3H, 4 '-0CH3), 3. 37 (s, 3H, 4'-0CH3), all aromatic signals disappear. .I R (K B r, cm_1) 3481, 2 9 2 9, 2 8 5 4 ′ 1716, 1450. Printed by the Central Ministry of Economic Affairs and the Consumer Goods Cooperative (please read the precautions on the back before filling this page) 13C-NMR5173.3, 150.3, 138.3, 135.0, 134.0, 132. 4, 124. 8, 124. 5 , 121. 3, 118. 4 '117.7, 99.2, 97.5, 94.9, 81. 9, 80. 3, 79.4, 78.6, 78.5, 75.9, 73.2, 72. 4, 68. 7 , 67.3, 67.1, 64. 5, 56. 6, 55.2, 46.4, 41.0, 39. 9, 3 9.2, 38, 6, 36. 9, 36. 3, 35. 7, 34. 6, 34.1, 31.2, 30.6, 28.1, 26. 8, 26. 6, 24. 7, 21. 21. 20.1, 18. 3, 17. 4, 15. 2 ° negative FABMSm / e937 (Μ) _ . 2 — D. 5 — (〇-allyloxyimino)-22, 23-dihydro-2 5-cyclohexyl imimetine B 1 monosaccharide The paper size applies the Chinese National Standard (CNS) A4 Specifications (210X297 mm) A7 B7 printed with full cooperation of the central standard and cargo-consumer cooperation / V. Description of the invention (19) 5-(allyloxyimino)-4'_desoxy-1 2, 2 3-dihydro-2 5-cyclohexyl evimetine B 1 (356 mg, 0.379 mmol) was dissolved in methanol (12 ml), and p-toluenesulfonic acid (108 mg) was added. 0,568 mmol), and after stirring at room temperature for 90 minutes, a saturated aqueous sodium bicarbonate solution (12 ml) was added, and the deposited white solid was filtered, washed with water, and then chromatographed on silica gel. Purification (the dissolution solution was hexane-ethyl acetate 3: 1), and the title compound was obtained as a colorless resin crystal (218 mg, 73% yield). 1 E-NMR δ 6.10 — 5.90 (m, 2H), 5.82-5.68 (m > 2H), 5.50 — 5.40 (m, lH), 5.35 — 5.18 (m, 2H), 4. 9 8 (d, J = 7. 0 H z, 1 H), 4.82 (d, J = 2.9 Hz, 1 H), 4.80-4.62 (m, 4H), 4. 6 0 (s, 1 H), 4.00 — 3.80 (m, 4H) , 3.72-3.50 (m, 3H), 3.47 (s, 3H, 4'-〇CH3), 3.39 (t, J = 2.2Hz, lH), 3.16 (t, J = 9.2Hz, lH), 3.06 (d , J = 8.1Hz, lH), this paper size it Caiguanjia County (CNS) A4 specification (210X297 mm) '"' -22- (Please read the precautions on the back before filling this page)

經濟部中央標準局員工消費合作社印製 A7 ____ B7 五、發明説明（2〇 ) 2.62-2.45(m»2H) > 2.40-2.18(m，3H)， 2.03 — 1.09 (m，31H) ， 0.91-0.72 (m，4H)。負 FABMSm/e809(M)_。 2 — E . 22，23 —二氤-5-羥基亞胺基- 25 —環己基艾維美丁 B 1單糖將5— ( ◦—烯丙氧基亞胺基）—22，2 3—二氫一 2 5—環己基艾維美丁 B 1單糖（2 1 8毫克， 0 . 269毫莫耳）、肆（三苯膦）鈀（32毫克， 0 . 0 2 8毫莫耳）及苯亞磺酸（69毫克，0.485 毫莫耳）添加至氯仿（2 . 5毫升），反應混合物在室溫下攪拌1 . 5小時後，加入三苯膦（72毫克， 0 . 2 7 4毫莫耳），經2小時後加入肆（三苯膦）鈀（ 52毫克，0 . 045毫莫耳），攪拌5 . 5小時後，在矽膠上經由層析法純化反應溶液（溶離溶液爲己烷-醋酸乙酯2 : 1 — 1 : 1 ),得到標題化合物類似無色樹脂之晶體（175毫克，8 5%產量），標題化合物之NMR 光譜（核磁共振光譜）與國際公告編號WO 9 4/ 1 5 9 44揭示之方法合成之22，23 —二氫—5 —羥基亞胺基- 2 5 -環己基艾維美丁 B 1單糖特徵訊號吻合〇 1 Η - N M R 5 、本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） (諳先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ B7 V. Description of the invention (20) 2.62-2.45 (m »2H) > 2.40-2.18 (m, 3H), 2.03 — 1.09 (m, 31H), 0.91 -0.72 (m, 4H). Negative FABMSm / e809 (M) _. 2 — E. 22,23 —Difluoren-5-hydroxyimino — 25 —cyclohexyl evimetine B 1 monosaccharide will be 5 — (◦ —allyloxyimine) — 22, 2 3 — Dihydro-2 5—cyclohexyl evimetine B 1 monosaccharide (218 mg, 0.269 mmol), palladium (triphenylphosphine) palladium (32 mg, 0.028 mmol) And benzenesulfinic acid (69 mg, 0.485 mmol) were added to chloroform (2.5 ml). After the reaction mixture was stirred at room temperature for 1.5 hours, triphenylphosphine (72 mg, 0.27 4 Millimolar), after 2 hours, tris (triphenylphosphine) palladium (52 mg, 0.045 millimolar) was added, and after stirring for 5.5 hours, the reaction solution was purified by chromatography on silica gel (the dissolution solution was Hexane-ethyl acetate 2: 1-1: 1), the title compound is similar to a colorless resin crystal (175 mg, 8 5% yield), and the title compound has an NMR spectrum (nuclear magnetic resonance spectrum) and International Bulletin No. WO 9 4 / 1 5 9 44 The 22,23 —dihydro-5 —hydroxyimino group — 2 5 —cyclohexyl evimetine B 1 monosaccharide synthesized by the disclosed method agrees with the characteristic signal 〇 1 Η-NMR 5, the paper rule Applicable to China National Standard (CNS) Α4 specification (210X297 mm) (谙 Please read the precautions on the back before filling this page)

-23- A7 390882 B7 五、發明説明（21 ) 8 · 1 0 ( S，1 Η，= N - Ο Η )， 3.47(s，3H，4’-〇CH3)， 3.18(t，J = 9.1Hz，lH，4，— Η)。 IR(KBr ，公分―1) 3450，2920， 1715 ----------- (請先聞讀背面之注意事項再填寫本頁) 訂經濟部中央標準局員工消費合作社印製本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -24--23- A7 390882 B7 V. Description of the invention (21) 8 · 1 0 (S, 1 Η, = N-Ο Η), 3.47 (s, 3H, 4'-〇CH3), 3.18 (t, J = 9.1 Hz, lH, 4, — Η). IR (KBr, cm -1) 3450, 2920, 1715 ----------- (Please read the notes on the back before filling this page) Print the printed copy of the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Paper size applies to China National Standard (CNS) A4 (210X297 mm) -24-

Claims

390882 A8 B8 C8 D8 Patent Application Scope 1. A method for preparing a compound of formula (i):

Wherein, R 1 is fluorene or hydroxyimino protecting group; R 2 is fluorene, C 1-alkyl or C 1-4 alkoxy; R 3 is C 1-8 alkyl, C 2-8 alkenyl Or C3-8 cycloalkyl; and R4 is fluorene, halo, Coxy, the method includes the steps of: (a) making the compound of formula (II) a 1-4 alkyl group or a C 1-4 alkane central Printed by Standards Bureau Staff Consumer Cooperative

React with an oxidant to form a 5-oxo compound; (b) react the 5-oxo compound with a compound of formula R1- 0-NH2t where R.1 is a hydrazone or a hydroxyimino protecting group. To form a 5-imino compound (Please read the notes on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -25- 390882? 88 _ D8 6. Application for patent scope y (c) The reaction of 5 _ imine compounds with sulfur and carbonizing agent to form 4 〃, 2 3 -dithiocarbamate; (d) reacting 4 〃 '2 3 -dithiocarbamide with a deoxidizing agent to form a compound, 2 3 .-dideoxy compounds; and (e-) The 4 2 3 -dideoxy compound is reacted with an acid to form a compound of formula (I). 2. The method according to item 1 of the scope of patent application, which further comprises adding halotriphenylsilane, third butyldimethylsilane, and dentyltrimethylsilyl after step (b) when R1 is fluorene. Silyl, haloyl (halo-methyl) alkane, halo-propyl propyl. A :: base ... shayuan, .. halo: triethyl, keshayuan, halotriisopropyl Silane, halo (_ 3 -cyanopropionamidine) dimethylsilane, halodi .. methyloctyl, alkane, halotriphenyl, haloane or halotrihexylsilane, and triethyl Amine, tri-n-propylamine, diisopropyl S-based amine, imidazole, or pyridine to protect ... hydroxyimine, group. 3. Method τ according to item 1 of the scope of patent application, and its electricity when R 1 is allyl At the time, the response of step (e) can be avoided by the presence of catalysts. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 4. According to the scope of patent application The method according to item 1, wherein the oxidizing agent in step 乂 ..a.) Is manganese dioxide i nickel peroxide ^ two storms. Μ A. 5. The method according to item 4 of the scope of patent application, wherein the reaction of step (a) Yes At a temperature of 0 to 8 0 ° C of I. Lu 10 min to 10 "], when. 6. The method according to item 1 of the scope of patent application, wherein in step (b), the hydroxyimine-imine-group ... protecting group is triphenylsilyl group, and the third butyl dimethyl group is applicable to China. Standard (CNS) A4 specification (210X297 mm) -26- Α8 Β8 C8 D8 Β90882 6. Application for patent scope. Silyl, tetraoxopyranyl, methylthiomethyl, allyl, methallyl Group, crotonyl, chloroallyl, cinnamyl, or -propyl. (Please read the note f on the back before filling out this page) 7 · According to the method of item 6 of the scope of patent application, where step (b, ... ............. The reaction is HJS at a temperature of 5 to 80 ° C for 5 minutes to 20 hours. Β According to the method and steps of item 1 of the scope of patent application The _ (C) -sulfurized carbonizing agent is R 50-C. (S) -pyridyl or R.5 S-C (S) ........... Where alkyl, benzene, phenyl, or naphthyl, optionally substituted with ci "alkyl", C "-4alkane substituted with halo, selected from Cdi-4 alkyl, Ci-4 alkyloxy, halo Oxyhydrazone, nitro, hydroxyl, amine and halo ... groups have two meanings. Substitute n or naphthyl. 9. The method according to item 8 of the scope of patent application, wherein step (CI). Conversely, Ji is a reaction at a temperature of 0 to 130 ° C for 5 minutes to 10 hours γ 1 〇. The method of item 1, the group deoxidizing agent in step (d) is tributyltin hydride, ginseng (trimethylsilyl) silane, triethylsilane, tripropylsilane, phenylsilane, diphenylsilicon.荇 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,-,, 1 ;. 1. The method according to item 10 of the scope of patent application, wherein the reaction in step (d) is a reaction at a temperature of 0 to 140 ° C for 5 minutes to 15 hours. 1 2 .. According to the method in the first item of the scope of patent application, step (e)-the acid-is p-toluene acid, benzenesulfonic acid, HF, HC1, H2S〇4, Η 3 P〇4 or HC 104 . Applicable to Chinese national standard (CNS) A4 specification (210 × 297 mm) 3 Riding _2 S D8 6. Application scope of patent »1 3. According to the method of item No. 12 of the scope of patent application, the reaction of step (e) It is at a temperature of 0 to 100 ° C, and the reaction is performed for 5 minutes until the catalyst is touched in the palladium, which is the third law of the law. Please refer to it according to the root. Hours 4 hours. 1 5 I-I ο C palladium {palladium acid pin.} Acetic acid-hydroxydiphosphine ethyl or monomethyl C} Tris-IC IC Chlorine I Isodium C is, Palladium I Phosphorus I-based C Oxypalladium Propionate X Isophosphine Triphenyl C Tris double V Chlorobis ) Chlorine and (please read the precautions of back xenon before filling out this page) Order the paper size printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to apply the national standard (CNS) Α4 specification (210X297 mm) -28-