TW389754B

TW389754B - Process for preparing aryl-piperidine carbinols

Info

Publication number: TW389754B
Application number: TW83102170A
Authority: TW
Inventors: Sidney Edward Callander
Original assignee: Smithkline Beecham Plc
Priority date: 1994-03-14
Filing date: 1994-03-14
Publication date: 2000-05-11

Description

經濟部中央標準局貝工消费合作杜印製Printed by Shellfish Consumer Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs

FF

-4 - A7 _B7__ 五、發明说明（丨）本發明係有關一棰製備芳基一六氫吡啶甲酵類之新穎方法。美國專利4 , G fl 7，1 9 6號揭示某些化合物，其係被掲示為具抗抑鬱活性。製備上文所提及化合物之中間體為式（A )化合物：-4-A7 _B7__ 5. Explanation of the invention (丨) The present invention relates to a novel method for preparing aryl-hexahydropyridylcarboxamidines. U.S. Patent No. 4, G fl 7, 196 discloses certain compounds which have been shown to have antidepressant activity. The intermediates for the preparation of the compounds mentioned above are compounds of formula (A):

R 其中R1表氫，三氟（Ci _4 )烷基•烷基或烷炔基’ 及X表氫，具1-4個碳原子之烷基，烷氧基，三氫烷基’ 羥基，鹵素，甲硫基，或芳烷氧基。式（A)化合物揭示為具藥理活性而使得其為有效的抗抑鬱劑。式（A )之一特殊化合物己被發現為特別有效的抗抑鬱劑。此化合物己知為派洛斯丁（ P a r ο X e t i n e )且具下列结構式：本纸浪尺度適用t困國家標準（CNS ) Α4规格（210Χ297公着） ---!------·裝-------訂------線 (請先閱讀背面之注意事項再4寫本頁) A7 _ _B7___ 五、發明说明（2 ) 美國專利4,902,801號揭示式（B)化合物之製備：R wherein R1 represents hydrogen, trifluoro (Ci_4) alkyl • alkyl or alkynyl 'and X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trihydroalkyl' hydroxyl, halogen , Methylthio, or aralkyloxy. The compound of formula (A) is disclosed as having pharmacological activity making it an effective antidepressant. A special compound of formula (A) has been found to be a particularly effective antidepressant. This compound is known as Parosetin (P ar ο X etine) and has the following structural formula: The paper scale is applicable to the national standard (CNS) A4 specification (210 × 297) ---! ------ · Install ------- Order ------ line (please read the precautions on the back before writing this page) A7 _ _B7___ V. Description of the invention (2) US Patent No. 4,902,801 Revealed (B) Preparation of compounds:

At Λ. ch2oh V J (B)At Λ. Ch2oh V J (B)

II

R 其中Ar表一芳基或經取代芳基及R表氫’烷基或芳烷基； Μ遷原式（C )而得：R wherein Ar represents an aryl group or a substituted aryl group and R represents a hydrogen 'alkyl group or an aralkyl group; Μ is derived from the original formula (C) to obtain:

ArAr

其中Ar及R如式（B)所定義，及R 為烷基。此方法被揭示為適合於製備派洛斯丁之式（Β)前趨化合物。經濟部中央揉準局貝工消費合作社印氧 (請先閱讀背面之注^項再螇寫本頁) 於美國專利4，9 G 2 , 8 (Π號僅特別揭示實施此方法之遷原劑為氫化鋁鋰或氫化鋁。該等遷原劑昂貴，難Μ控剌且 ft随大量放熱而使得當大量實施反應時會產生製程控制上的問題。令人騖訝地，本發明Μ二硼烷作為遷原劑而克服或滅輕上述問題。其亦獲得較佳產率且更為經濟。據上所述，本發明提供一製備式（I)化合物之方法：本紙》尺度適用t國國家標準（CNS ) Α4規格（210Χ297公釐） A7 B7 五、發明説明（>)Wherein Ar and R are as defined in formula (B), and R is an alkyl group. This method has been revealed to be suitable for the preparation of the precursor compound of formula (B). Printed oxygen by the Central Bureau of the Ministry of Economic Affairs of the Shellfish Consumer Cooperative (please read the note ^ on the back before writing this page) in U.S. Patent No. 4, 9 G 2, 8 (No. Π only reveals the original agent for implementing this method Lithium aluminum hydride or aluminum hydride. These migration agents are expensive, difficult to control, and ft with a large amount of exothermic heat will cause problems in process control when a large number of reactions are carried out. Surprisingly, the present invention has diboron Alkane is used as a migration agent to overcome or eliminate the above problems. It also obtains better yields and is more economical. According to the above, the present invention provides a method for preparing compounds of formula (I): This paper is applicable to countries in t Standard (CNS) A4 specification (210 × 297 mm) A7 B7 V. Description of the invention (>)

FF

R3 其中R3為氫，Ci _6烷基或Ci _6烷芳基，藉由使用二硼烷將式（II)化合物還原：R3 wherein R3 is hydrogen, Ci-6 alkyl or Ci-6 alkylaryl, and the compound of formula (II) is reduced by using diborane:

F (請先閱讀背面之注意事項再填寫本頁)F (Please read the notes on the back before filling this page)

r3 經濟部中夬橾準局貝工消費合作杜印装其中R3如相關式（I)所定義及R4為Cid烷基。較佳R 3為甲基。較佳R 4為乙基或甲基或乙基/甲基混合物。反應適合賁施於惰性溶劑如四氫呋喃或二甲氧基乙烷 (D Μ E )中。二硼烷適合於遷原溫度如-1 G至2 (TC，較佳於0至5 °C下Κ三氟化硼***絡合物對氫硼化納於式（11)化合物存在下之加成反應而產生。或者，為安全及控制之理由，更佳為於遷原溫度如-1 0至2 (TC，較佳於0至5 C下二硼烷本紙張尺度適用中國國家揉準（CNS ) Α4规格（210Χ297公釐）經濟部中央橾準局貝工消费合作社印装 A7 B7 五、發明説明（4) K氯化氫氣體（其可適宜地溶解於惰性溶劑如DMF中）對氫硼化納於式（II)化合物存在下之加成反應而產生。三氟化砸合***或氣化氫氣體之加成反應一旦完成’ 將反應適宜地溫熱至室溫或較高溫度例如20至6 Ot：，更佳為 2 0 至 4 Ot：。然後可Μ將反應混合物加至無機酸如氯化氫水溶液+ 或將無機酸如氛化氫水溶液加至反應混合物中终止或淬$ 反應。然後過濾掉任何所得固體及式（I)化合物產物可蒸餾掉反應溶劑而單離。以適合之溶劑取代，由此產物可為沈澱型式，例如甲苯，及於濃縮產物溶液後可適宜地加人沈澱溶劑如正庚烷以沈澱產物。本發明亦提供一製備派洛斯丁或其藥學上可接塩之方法，特別是塩酸塩半水合物，其包括形成如上述式（Π化合物及随後使用習知之技術特別是揭示於美國專利4,903， 801及4,721，723號中者將其轉變成派洛斯丁或其藥學上可接塩。下列實施例說明本發明。實施例1 (土）-反式- 4-(4氟苯基）-3-羥甲基-Ν-甲基-六氫吡啶輸入 * (士）反式-3-乙氧基/甲氧基羰基-4-(4氟苯基）- N -甲基-六塞批陡-2,6-二酮 15.3克含量 93.7% 本紙張尺度適用申a國家揉準（CNS ) A4規格（2丨0X297公釐） —：------ri------IT-----線 (請先《讀背面之注意事項弄4寫本肓) A7 B7_ 五、發明説明（$ ) 氫砸化納 6 . 3克三氟化硼***絡合物 18毫升四氫呋喃（THF) 75毫升甲苯 2 0 0牽升 3N HC1 40 毫升庚烷 70毫升 4 0%氫氧化納水溶液 2 5毫升方法-下列方法論被實施r3 DuPont Packing Co., Ltd., Shellfish Consumer Cooperative of the Ministry of Economic Affairs, where R3 is as defined in related formula (I) and R4 is a Cid alkyl group. Preferably, R 3 is methyl. Preferably R 4 is ethyl or methyl or an ethyl / methyl mixture. The reaction is suitably carried out in an inert solvent such as tetrahydrofuran or dimethoxyethane (DME). Diborane is suitable for exogenous temperatures such as -1 G to 2 (TC, preferably 0 to 5 ° C). The addition of borohydride boron trifluoride ether complex to sodium borohydride in the presence of a compound of formula (11) Reaction. Or, for reasons of safety and control, it is more preferable to relocate to a temperature such as -10 to 2 (TC, preferably 0 to 5 C). CNS) A4 specification (210 × 297 mm) Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed A7 B7 V. Description of the invention (4) K hydrogen chloride gas (which can be suitably dissolved in an inert solvent such as DMF) It is generated by the addition reaction in the presence of the compound of formula (II). Once the addition reaction of trifluoride with ether or hydrogen gas is completed, the reaction is suitably warmed to room temperature or a higher temperature such as 20 to 6 Ot :, more preferably 20 to 4 Ot: The reaction mixture can then be added to an inorganic acid such as an aqueous hydrogen chloride solution + or an inorganic acid such as an aqueous hydrogenated aqueous solution can be added to the reaction mixture to stop or quench the reaction. Then filtered Any solids obtained and the product of the compound of formula (I) can be isolated by distilling off the reaction solvent. The suitable solvent is substituted, so that the product can be in the form of Shendian, such as toluene, and after concentrating the product solution, a precipitation solvent such as n-heptane can be suitably added to precipitate the product. The present invention also provides a method for preparing pirostatin or its pharmacy. An accessible method, in particular an osmium osmium hemihydrate, includes the formation of a compound of formula (II) and subsequent use of conventional techniques, particularly disclosed in U.S. Patent Nos. 4,903,801 and 4,721,723 to convert it to Pyrostine or pharmaceutically acceptable. The following examples illustrate the present invention. Example 1 (Earth) -trans- (4-fluorophenyl) -3-hydroxymethyl-N-methyl-hexahydro Pyridine input * (±) trans-3-ethoxy / methoxycarbonyl-4- (4fluorophenyl) -N-methyl-hexasepide-2,6-dione 15.3 g content 93.7% This paper size applies to the national standard (CNS) A4 (2 丨 0X297 mm) of the Shena standard: -------- ri ------ IT ----- line (please read the " Notes for writing 4) A7 B7_ V. Description of the invention ($) Hydrogenated sodium 6.3 g boron trifluoride ether complex 18 ml tetrahydrofuran (THF) 75 ml toluene 2 0 0 draft 3N H C1 40 ml heptane 70 ml 40% aqueous sodium hydroxide solution 2 5 ml Method-The following methodology is implemented

1) 將6 . 3克氫硼化納加至50毫升THF 2) 冷却溶液至0 - 5 3) 將15.3克（±)反式-3-乙氧基/甲氧基羰基- 4-(4氟苯基）-Ν-甲基-六氫吡啶-2,6,-二酮 1溶解於2 5毫升 T H F中。在約5分鐘時間期間加至氫化砸溶液且保持溫度於0 - 5 t’1) Add 6.3 g of sodium borohydride to 50 ml of THF 2) Cool the solution to 0-5 3) Add 15.3 g (±) of trans-3-ethoxy / methoxycarbonyl-4- (4 Fluorophenyl) -N-methyl-hexahydropyridine-2,6, -dione 1 was dissolved in 25 ml of THF. Add to the hydrogenated solution over a period of about 5 minutes and keep the temperature at 0-5 t ’

4) 在約15分鐘期間慢慢將18毫升***絡合物加至溶液中且保持溫度於〇 - 5 °C4) Slowly add 18 ml of ether complex to the solution over about 15 minutes and keep the temperature at 0-5 ° C

5) 約於1小時期間將溫度升至2 0 °C 經濟部中夹橾準局貝工消費合作杜印裂 (請先閲讀背面之注意事項再填寫本頁) 6) 溫熱溶疲至3 5 - 4 0 °C 2小時 7) 冷却溶疲至0 - 5 υ5) Raise the temperature to 20 ° C in about 1 hour. The printed materials will be printed at the Ministry of Economic Affairs. Please read the notes on the back before filling out this page. 6) Warm heat to 3 5-4 0 ° C 2 hours 7) Cooling to 0-5 υ

8) 將溶液慢慢反加至40毫升3Ν HC1中，讓溶液之溫度升至2 Q - 2 5 °C 9) 冷却溶液至5 °C及過濾掉硼酸固體 1 0 )用2 0毫升水清洗濾液 -8 - 本紙張尺度適用t國國家標準（CNS ) A4現格（210X297公釐）經濟部中央橾率局貝工消費合作杜印製挪 754_^_ 五、發明説明（6)8) Slowly add the solution to 40 ml of 3N HC1, let the temperature of the solution rise to 2 Q-2 5 ° C 9) Cool the solution to 5 ° C and filter out the boric acid solids 10) Wash with 20 ml of water Filtrate-8-This paper size is applicable to National Standards (CNS) A4 (210X297 mm). Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumption Cooperation Du Yinhao 754 _ ^ _ V. Description of the Invention (6)

1 1)將溶液迴流於6 5 t：以收集T H F 12) 讓溶液溫度升至100¾ 13) 將5 G毫升水/7 5毫升甲苯加至入K冷却溶液至60TC 1 4 )分雛較低水層 15) 將另外之50毫升水加至甲苯中保持溫度於6〇υ 16) 分離且收集水相部份 17) 將75橐升甲笨加至水相部份。使pH至12-12.5及分離各層 18) 將另外之50毫升甲苯加至水相中且分離之 1 9 )合併甲苯相且蒸發至約2 0克 20)加入50毫升庚烷，冷却至5 ΊΟ及過濾 2 1 )用20毫升庚烷清洗濾液 22)乾燥於真空烤箱4QC過夜。單離重量9.6克含量 9 7% 產率 85% Μ使用高效液體層析儀完成分析。 *根據美國專利4 , 9 0 2 , 8 Q 1號摘錄之方法製備。簧施例2 (士）-反式- 4- (4氟苯基）-3-羥甲基-Ν-甲基-六氫吡啶之合成輸入 * (+,-) -反式-3-乙氧基/甲氧基羰基- 4- (4氟苯 -9- 本紙張尺度適用中國國家棣準（CNS ) Α4規格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁) -裝_1 1) reflux the solution at 6 5 t: to collect THF 12) let the solution temperature rise to 100¾ 13) add 5 G ml of water / 7 5 ml of toluene to the K cooling solution to 60TC 1 4) divide the lower water Layer 15) Add another 50 ml of water to toluene and keep the temperature at 60 ° 16) Separate and collect the aqueous phase portion 17) Add 75 liters of methylbenzene to the aqueous phase portion. Adjust the pH to 12-12.5 and separate the layers 18) Add another 50 ml of toluene to the water phase and separate 19) Combine the toluene phases and evaporate to about 20 g 20) Add 50 ml of heptane and cool to 5 ° O And filter 2 1) wash the filtrate with 20 ml heptane 22) dry in a vacuum oven 4QC overnight. Isolation weight: 9.6 g. Content: 9 7%. Yield: 85%. * Prepared according to the method extracted from U.S. Patent No. 4,902,8 Q1. Example 2 (±) -trans-4- (4-fluorophenyl) -3-hydroxymethyl-N-methyl-hexahydropyridine synthesis input * (+,-)-trans-3-ethyl Oxy / methoxycarbonyl-4- (4-fluorobenzene-9-) This paper is sized for China National Standard (CNS) A4 (210 × 297 mm) (Please read the precautions on the back before filling this page)-Packing _

、1T A7 389754 ___B7_ 五、發明説明（1) 基）-N-甲基-六氫吡啶-15. 3克氫硼化納-8 . 0克氯化Μ氣體-6. 5克. 二甲氧基乙烷（DME) -150毫升甲苯-50毫升 3 Ν氛化氫溶液-6 0毫升庚烷-2Q笔升 40%氫氧化鈉水溶液-25奄升方法-下列方法論被實施1T A7 389754 ___B7_ V. Description of the invention (1) group) -N-methyl-hexahydropyridine-15.3 g of sodium borohydride-8. 0 g of M chloride gas-6. 5 g. Dimethoxy Ethane (DME)-150 ml toluene-50 ml 3 N hydrogenated hydrogen solution-60 ml heptane-2Q pen liter 40% sodium hydroxide aqueous solution-25 liter method-the following methodology is implemented

1 將氫硼化納（8.0克）加至DME(75毫升）中Q 2 冷却溶液至0 - 5 °C。 3 將15.3克（±)-反式-3-乙氧基/甲氧基羰基ΜΗ’-氟苯基）-N-甲基-六氫砒啶（15.3克）溶解於 D M F ( 2 5毫升）中且加至氫硼化納泥漿中保持溫度於〇-5·〇。 4 將氯化氫氣體（6. 5克）溶解於DMF (50毫升）。 5將氯化氫/ DMF溶液加至氫硼化納泥漿中保持溫度於0 - 5 °C。在其階段，反應為掩蓋氮及釋放出氫。 6 於0 - 5 °C授拌混合物3 0分鐘。 7 溫熱混合物至35-4GC且攪拌2小時。 8 冷却反應混合物至〇 - 5 °C。 9加入3 Ν氳氯酸溶液（6 0毫升）淬想反應且保持溫度於2 (TC以下。 -10- 本纸張Λ度適用中國國家揉率（CNS ) Α4規格（210X297公釐） * 裝------訂-----線 (請先《讀背面之注意事項再填寫本頁) 經濟部中央揉率局負工消费合作社印製 389754 A7 _B7_ 五、發明説明（X ) 10將水（50毫升）加至反應混合物中且保持溫度於20 以下。 11蒸餾此溶疲高至9〇υ及收集濕DMF溶液（約15 0毫升）。 12加入甲苯（50毫升）且讓溫度降至801。 13分離各層。 1 4冷却水相至5 0 - 5 5 °C及加入庚烷（2 0毫升）。 15加入氫氧化納溶液至溶液使pH至11. 0-11.5同時保持溫度於5 Q - 5 5 1C 。 1 6在至少3 0分鐘間冷卻混合物至5 - 1 0 t。 1 7過濾掉產物。 18用水（2X2D毫升）清洗產物。 1 3產物乾燥於約4 0 °C。典型單離重量9 . 1克典型純度 9D-95% 典型產率 7 8 - 8 0 % 本根據美國專利4,9 0 2,8 0 1號摘錄之方法製備。 ---------1 Ί------ΐτ-----.^ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央橾準局貝工消費合作社印袈本纸張尺度逍用中國國家檁準（CNS ) A4規格（210X297公釐）1 Add sodium borohydride (8.0 g) to the Q 2 cooling solution in DME (75 ml) to 0-5 ° C. 3 Dissolve 15.3 g (±) -trans-3-ethoxy / methoxycarbonyl M ''-fluorophenyl) -N-methyl-hexahydropyridine (15.3 g) in DMF (2.5 ml) Add to the sodium borohydride slurry and keep the temperature at 0-5 · 〇. 4 Dissolve hydrogen chloride gas (6.5 g) in DMF (50 ml). 5 Add the hydrogen chloride / DMF solution to the sodium borohydride slurry to maintain the temperature at 0-5 ° C. At this stage, the reaction is to mask nitrogen and release hydrogen. 6 Incubate the mixture at 0-5 ° C for 30 minutes. 7 Warm the mixture to 35-4GC and stir for 2 hours. 8 Cool the reaction mixture to 0-5 ° C. 9 Add 3 Ν 氲 chloric acid solution (60 ml) to quench the reaction and keep the temperature below 2 (TC. -10- The paper Λ degree applies to the Chinese national kneading rate (CNS) Α4 size (210X297 mm) * pack ------ Order ----- line (please read "Notes on the back side and fill out this page first") Printed by the Central Government Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 389754 A7 _B7_ V. Description of Invention (X) 10 Water (50 ml) was added to the reaction mixture and the temperature was kept below 20. 11 Distill this solution to 90 ° and collect the wet DMF solution (about 150 ml). 12 Add toluene (50 ml) and let the temperature Reduce to 801. 13 Separate the layers. 1 4 Cool the water phase to 50-5 5 ° C and add heptane (20 ml). 15 Add sodium hydroxide solution to the solution to bring the pH to 11. 0-11.5 while maintaining the temperature At 5 Q-5 5 1C. 16 Cool the mixture to 5-10 t for at least 30 minutes. 17 Filter off the product. 18 Wash the product with water (2X2D ml). 1 3 The product is dried at about 40 ° C. The typical single weight is 9.1 grams, the typical purity is 9D-95%, and the typical yield is 7 8-80%. This is prepared according to the method extracted from US Patent No. 4,9 0,2 0 0. ---- ----- 1 Ί ------ ΐτ -----. ^ (Please read the notes on the back before filling out this page) Printed paper size of the Central Laboratories Bureau of the Ministry of Economic Affairs Free use of China National Standards (CNS) A4 specifications (210X297 mm)

Claims

丨…输年?用//3 ;補1 389754 Ag η 丨〇 ?88 公告本 D8 — 六、申請專利範圍 1 · 一種製備式（I )f化合物之方法： Μ 請委貝明示本丨 ... Lost year // 3; Supplement 1 389754 Ag η 丨〇～ 88 Announcement D8 — VI. Application scope 1 · A method for preparing the compound of formula (I) f: Μ Please submit a copy

正後是否變更原内 % 經濟部中央標準員工消費合作社印製Is it changed after printing? Printed by the former Central Labor Standards Cooperative of the Ministry of Economic Affairs

r3 其中R3為氫，Ci _s烷基或Ci 烷芳基，藉由使用二硼烷將式（11)化合物遷原： Fr3 where R3 is hydrogen, Ci_s alkyl or Ci alkaryl, and the compound of formula (11) is relocated by using diborane: F

R3 , 其中R 3如相關式（I)所定義及R 4為C i 烷基。 2 ·根據申請專利範圍第1項之方法，其中R 3為甲基〇 3 ·根據申請專利範圍第1項之方法，其中R 4乙基或甲基。 4 ·根據申請專利範圍第1項之方法，其中反應實施於四氫呋喃或二甲氧基乙烷。 5 ·根據申請專利範圍第1項之方法·其中二硼烷之生成係K三氟化硼***絡合物對氫硼化納於式（11)化合物本纸張尺度適用中國國家標準（CNS )六衫見格（210X297公釐）丨…输年?用//3 ;補1 389754 Ag η 丨〇 ?88 公告本 D8 — 六、申請專利範圍 1 · 一種製備式（I )f化合物之方法： Μ 請委貝明示本R3, wherein R3 is as defined in the related formula (I) and R4 is C i alkyl. 2 · The method according to item 1 of the scope of patent application, wherein R 3 is methyl 03 · The method according to item 1 of the scope of patent application, wherein R 4 is ethyl or methyl. 4. The method according to item 1 of the scope of patent application, wherein the reaction is carried out in tetrahydrofuran or dimethoxyethane. 5 · Method according to item 1 of the scope of patent application · Among them, the formation of diborane is K boron trifluoride ether complex. Sodium borohydride is used for the compound of formula (11). The paper size applies Chinese National Standard (CNS) Six shirts (210X297 mm) 丨 ... Lost year use // 3; Supplement 1 389754 Ag η 丨〇? 88 Bulletin D8 — VI. Application for patent scope 1 · A method for preparing a compound of formula (I) f: Μ asked Weibei to express this

R3 , 其中R 3如相關式（I)所定義及R 4為C i 烷基。 2 ·根據申請專利範圍第1項之方法，其中R 3為甲基〇 3 ·根據申請專利範圍第1項之方法，其中R 4乙基或甲基。 4 ·根據申請專利範圍第1項之方法，其中反應實施於四氫呋喃或二甲氧基乙烷。 5 ·根據申請專利範圍第1項之方法·其中二硼烷之生成係K三氟化硼***絡合物對氫硼化納於式（11)化合物本纸張尺度適用中國國家標準（CNS )六衫見格（210X297公釐） A8 B8 C8 D8 383754 々、申請專利範圍存在下加成反應。 _· 6 ·根據申請專利範圍第1項之方法，其中二硼烷之生成係Μ氛化氫氣體對氫硼化納於式（II)化合物存在下加成反懕。 7·根據申譆專利範圍第1項之方法，將所得式（I) 化合物縳變成派洛斯丁（paroxetine)或其藥學上可接塩。 8 ·根據申請專利範圍第7項之方法，其中藥學上可接塩為塩酸塩半水合物。；--7------.裝------，ιτ------J C (請先Η讀背面之注意事項再填寫本頁) 經濟部中央標準局負工消費合作社印製尺 I張 -纸本準標家一國 j國 -中用 I適 |釐公 7 9 2R3, wherein R3 is as defined in the related formula (I) and R4 is C i alkyl. 2 · The method according to item 1 of the scope of patent application, wherein R 3 is methyl 03 · The method according to item 1 of the scope of patent application, wherein R 4 is ethyl or methyl. 4. The method according to item 1 of the scope of patent application, wherein the reaction is carried out in tetrahydrofuran or dimethoxyethane. 5 · Method according to item 1 of the scope of patent application · Among them, the formation of diborane is K boron trifluoride ether complex. Sodium borohydride is used for the compound of formula (11). The paper size applies Chinese National Standard (CNS) Six shirts (210X297 mm) A8 B8 C8 D8 383754 々 Addition reaction in the presence of patent application scope. _ · 6 · The method according to item 1 of the scope of patent application, wherein the generation system of the diborane is a hydrogenated hydrogen gas that reacts with sodium borohydride in the presence of a compound of formula (II). 7. According to the method of item 1 of the Shen He patent scope, the obtained compound of formula (I) is bound to paroxetine or pharmaceutically acceptable. 8. The method according to item 7 of the scope of patent application, wherein the pharmaceutically acceptable compound is osmic acid osmium hemihydrate. ;-7 ------. Install ------, ιτ ------ JC (please read the precautions on the back before filling out this page) Central Laboratories of Ministry of Economic Affairs, Consumer Cooperatives Printed ruler I-paper quasi-standard home country j country-China use I suitable | centimeter 7 9 2