TW520359B

TW520359B - Practical syntheses of chiral trans-3,4-disubstituted piperidines and the intermediates

Info

Publication number: TW520359B
Application number: TW89111422A
Authority: TW
Inventors: Li-Tai Liou; Shiang-Ling Huang; Bau-Chuen Hung; Sz-Feng Chen
Original assignee: Dev Center Biotechnology
Priority date: 2000-06-12
Filing date: 2000-06-12
Publication date: 2003-02-11

Abstract

A new method for the preparation of chiral 4-substituted 2-piperidinones, trans-3,4-disubstituted 2-piperidinones, and trans-3,4-disubstituted piperidines is invented. Chiral paroxetine can be obtained from a chiral trans-3,4-disubstituted piperidine intermediate in high purity and good selectivity.

Description

520359520359

五、發明說明6 經濟部智慧財產局員工消費合作社印製發明背免本發明係關於一種製備對掌性反式-Μ-二取代六氫峨啥之^万^且特別是利用對掌性胺作為對掌性輔助劑，以氣備對掌性帕西；;丁。走L重技藝之播诫帕西汀（paroxetine)為一種反式_3,4_二取代六氨峨咬衍生物之類型，其為有效選擇性5_羥色胺再攝取抑制劑，且已被廣泛地使用’作為抗抑發症藥物與抗巴金生症(Parkn—藥物：V. Description of the invention 6 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economics The present invention relates to a method for the preparation of palm-trans-M-di-substituted hexahydroethanoate, especially the use of palm amines. As a palm adjuvant, Qi prepared for palm parsi; Ding. Take the heavy arts to teach that paroxetine is a type of trans_3,4_disubstituted hexaammonium bite derivative, which is an effective selective 5-hydroxytryptamine reuptake inhibitor and has been widely used Use 'as an anti-suppressive drug and anti-Parkinson's disease (Parkn-drug:

反式_3,4-二取代對反式-(-)-(3 S，4R)帕西汀掌性六氫p比矣鹽酸鹽反式七)-(3S，4R)帕西汀為具藥理學上活性之對掌異構物其通常係由相應之對掌性先質合成而得。目前用於製造此等對掌性先質之製程，係涉及非對映異構物鹽之選擇性再結晶作用1b，e，外消旋酯之生物催化動力學解析lf，及、、萃性輔助劑輔助之不對稱Michael加成2。一般而+ . 、力又向&，成功地解析一種外消旋化合物之要求條件，係為其非對映異構物鹽必須呈良好結晶形式。但是，據報告有也外一 π嘀旋反式_ 3,4-六氫吡啶衍生物，由於非結晶性鹽而不能被解析ig。亦 -4- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------訂----：-----線 C請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 520359 五、發明說明〒 /旋帕西汀與六氫吡啶類似物之一些非對映異損虞，、非結晶性。於過去數年來，雖然數種對掌性3_或 4_取代I六氫❹衍生物，已經由化學或酵素方法，對掌異構物純度製成2 - 5，扣p° ..^ . 仁已發現在非固體產物之純化上 Η’會阻滯其在大規模製程巾及在工業上之應用。料係列示於本專利説明書末，且以其全文併於取近，已在又獻上發表少數特定對掌性3·、4·取代及3 1 2代1六氫峨淀酮之不對稱合成2,3。但是，用於製備對旱十，4、取代2_六氫吡啶酮與六氫吡啶衍生物之一般合成万法，仍然極有限2,3。由於對掌性2六氫峨錢已被認爲疋用以合成其相應對掌性六氫吡啶之有用先質，故本發明對於發展-種製備此等化合物之合宜方法有興趣。此處， 1·發月係提供對|性4_取代以及3,4_二取代六氫峨淀嗣之非對映異構選擇性合成，其係使用市購可得之對掌性胺類，包=對掌性一級胺類或對掌性胺基酸衍生物，譬如⑻_ Ψ基卞胺’作爲對掌性輔助劑，並於數種對掌性反式-3,4- 二取代之六氫吡啶衍生物，譬如帕西汀之製備上，應用此方法。 ^3摘述因此，本發明之一項目的係爲提供一種自相應3_取代戊一 fe肝及對革性胺，作爲用以合成對掌性二取代二氫㈣酮之中間物，以製備對掌性4取代2/六|^咬社新顆方法。 ___-5- 本紙張尺度適用中國國家標準（CNS)A4規格χ挪公爱）--Trans_3,4-disubstituted p-trans-(-)-(3 S, 4R) paxetine palmitic hexahydrop ratio hydrazone hydrochloride trans seven)-(3S, 4R) paxetine is The pharmacologically active isomers are usually synthesized from the corresponding opposite precursors. The current process used to make these homophobic precursors involves the selective recrystallization of diastereomeric salts 1b, e, the biocatalytic kinetic analysis of racemic esters, lf, and, extractability Adjuvant assisted asymmetric Michael addition 2. In general, +., Force and & successfully resolve the requirements of a racemic compound because its diastereomeric salt must be in a good crystalline form. However, it has been reported that a π-trans-trans-3,4-hexahydropyridine derivative cannot be resolved due to an amorphous salt. Also -4- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------------------- Order ----:- ---- Line C, please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520359 V. Description of the invention Different damage, non-crystalline. In the past few years, although several palladium 3_ or 4_ substituted I hexahydrofluorene derivatives have been made by chemical or enzymatic methods, the purity of palladium isomers is 2-5, deduction p ° .. ^. Ren has found that purification of non-solid products will hinder its application in large-scale process towels and industry. The material series are shown at the end of this patent specification, and the full text is close to it. A few specific symmetric 3 ·, 4 · substitutions and 3 1 2 generation 1 hexahydroelidenes have been published. Synthesis of 2,3. However, the general synthesis method for the preparation of paraoxan 4,4, substituted 2-hexahydropyridone and hexahydropyridine derivatives is still extremely limited 2,3. Since palmitic 2Hydrogenene has been considered as a useful precursor for the synthesis of its corresponding palmitic hexahydropyridine, the present invention is interested in developing a suitable method for preparing such compounds. Here, 1 · fayue series provides diastereoselective synthesis of the enantioselective 4_ substitution and 3,4_ disubstituted hexahydroeodonium, which uses commercially available para-amino amines, Includes: Para palmitic primary amines or para palmitic amino acid derivatives, such as ⑻ Ψ fluorenyl ammonium amine 'as a paraliming adjuvant, and several para-trans-3,4-disubstituted six Hydropyridine derivatives, such as paroxetine, are prepared using this method. ^ 3 Abstract Therefore, one of the items of the present invention is to provide a 3_ substituted pentane-fe liver and p-lemonamine as an intermediate for synthesizing p-palladium di-substituted dihydrofluorenone to prepare Palm 4 replaces 2 / Six | ^ Bite new method. ___- 5- This paper size applies to China National Standard (CNS) A4 specifications (Norway Love)-

520359520359

五、發明說明經濟部智慧財產局員工消費合作社印製本發明之另一項目的係爲提供一種使用市購可得之對掌性胺作爲對掌性輔助劑，以進行對掌性4-取代以及3,4_二. 取代2-六氫吡啶酮之非對映異構選擇性合成，其可用於大規模製程上。本發明之又另一項目的係爲提供一種經由在4-取代2•六氫p比淀_之α碳處進行酿化作用，以產生反式二取代 2-六氫吡啶酮，接著爲此產物之還原作用，以製備反式· 3,4_二取代六氫ρ比咬之方法。本發明之另一項目的係爲提供一種自對掌性4_芳基取代之2-六氫吡啶酮，經由四個步驟，製備對掌性帕西汀之合 Jl方法·在α凌處之酿化作用，以產生對掌性反式冬二取代2-六氫吡啶酮，還原以形成純反式3,4_二取代六氫吡是此胺基醇之轉化成芳基醚，及對掌性輔助劑之氫解作用，以獲得對掌性帕西汀。本發明之此等及其他目的、優點及特徵，在參考所撰窝之本專利説明書及随文所附之圖後，將更充分明白與瞭解。發明詳沭本發明係關於一種自3-取代之戊二酸酐與對掌性胺，譬如（SH-苯基乙胺，經由四個步驟，製備對掌性4_取代2_六氫吡啶酮之新穎方法。3-芳基戊二酸酐與對掌性胺之非對映異構選擇性醯胺化作用，會獲得對掌性半醯胺。醯胺之官能基轉換作用，接著爲環化作用，提供對掌性芳基取代12-六氫吡啶酮。根據本發明，一種製備對掌性‘取代 2-六氫吡啶酮之方法，係包括： (請先閱讀背面之注意事項再填寫本頁) --------訂----^-----線】 -6 - 520359 Α7 Β7 經濟部智慧財產局員工消費合作社印製五、發明說明< ) ⑴使下式3-取代之戊二酸肝 R1 〇，/、〇^^〇，、中R爲芳基、烷基或任何其他基團，與作爲對掌性輔助劑之式（I)對掌性胺反應 NH2V. Description of the Invention Another item of the invention printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is to provide a palm-like auxiliary using a commercially available palm-like amine as a palm-like 4-substitution. And 3,4_bis. Diastereoselective synthesis of substituted 2-hexahydropyridones, which can be used in large-scale processes. Still another item of the present invention is to provide a method for producing trans-disubstituted 2-hexahydropyridone by carrying out the fermentation at the α-carbon of 4-substituted 2 • hexahydro p ratio lake. The reduction of the product is a method for preparing trans · 3,4-disubstituted hexahydrogen ρ specific bite. Another item of the present invention is to provide a self-palladium 4-aryl substituted 2-hexahydropyridone, through four steps, to prepare a palmitridin combination J1 method. Fermentation to produce palm-trans-trans-disubstituted 2-hexahydropyridone, reduction to form pure trans 3,4-di-substituted hexahydropyridine is the conversion of this amino alcohol to an aryl ether, and Hydrolysis of palm adjuvant to obtain palm paroxetine. These and other objects, advantages, and features of the present invention will be more fully understood and understood after reference to the written patent specification and accompanying drawings accompanying this article. Detailed description of the invention The present invention relates to a 3-substituted glutaric anhydride and a palmitic amine, such as (SH-phenylethylamine). Novel method. Diastereoselective amidation of 3-arylglutaric anhydride and p-palmylamine will give p-palm hemiamine. Functional conversion of p-amine and subsequent cyclization Provides palmaryl-substituted 12-hexahydropyridone. According to the present invention, a method for preparing palmar-substituted 2-hexahydropyridone includes: (Please read the precautions on the back before filling this page ) -------- Order ---- ^ ----- line] -6-520359 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention <) Use the following formula 3 -Substituted glutaric acid R1 〇, /, 〇 ^^ 〇, where R is aryl, alkyl or any other group, react with palmitic amine of formula (I) as a palmitic adjuvant NH2

Ar^^R 獲得半醯胺之混合物，其中&表示芳族基團，而R表示烷基； (2) 使該半醯胺之酸基還原成一級醇； (3) 使該一級醇_化’而得自化物；及 ⑷以鹼使該南化物環化，產生對掌性2_六氫吡啶酮。在本發明製程之步骤⑴中使用之對掌性胺，可爲對掌性二胺類或對掌性胺基酸衍生物。較佳情況是，對掌性胺之芳族基團爲苯基’而對掌性胺之烷基爲甲基。更佳情況是，於本發明中使用之對掌性輔助劑爲卜苯基乙胺，特別是（SH-苯基乙胺。此對掌性胺可以足夠與3_芳基戊二酸肝反應I量添加，且較佳係以化學計量添加。任何習用反應條件均可用於本發明。取代基R可被芳基、燒基或任何其他基團取代，嬖如燒氧基㈣、胺基陶、氟基⑺、氣基(α)、漠基⑽、碘基 -------------------------------^ (請先閱讀背面之注意事項再填寫本頁)Ar ^^ R to obtain a mixture of hemiamines, where & represents an aromatic group and R represents an alkyl group; (2) reducing the acid group of the hemiamine to a primary alcohol; (3) making the primary alcohol _ From the compound; and hydration of the compound with a base to produce a 2-hexahydropyridone. The palmitic amine used in step (i) of the process of the present invention may be a palmitic diamine or a palmitic amino acid derivative. Preferably, the aromatic group of the para-amine is phenyl 'and the alkyl group of the para-amine is methyl. More preferably, the palmitic adjuvant used in the present invention is p-phenylethylamine, especially (SH-phenylethylamine. This palmitic amine can sufficiently react with 3-arylglutaric acid liver I is added in an amount, and is preferably added in a stoichiometric amount. Any conventional reaction conditions can be used in the present invention. The substituent R may be substituted with an aryl group, an alkyl group or any other group, such as an alkyloxy group, an amino group , Fluorinated fluorene, gas-based (α), molybdenum, iodo ------------------------------- ^ ( (Please read the notes on the back before filling out this page)

520359 A7 B7 五、發明說明f (D。取代基R1較佳於4位置上經取代，且係爲Μ夂& 於本發明製程步驟（3)中之自化，較佳爲㈣，因此於步驟（3)中形成之產物係爲漠化物。 ^性4·取代之2_六^相，係爲用以合成對掌性# 二取代2_六氫ρ比咬酮及並★處、* 啊夂其相應q峨哫之重要中間物。在此四個步驟以自3-取代戊-醴醉盥# 产戊一 I酐與對掌性胺製備對掌性4- 取代2- 7T氲P比淀_之後，於一、碳處'^醯化作用，會產生對莩性反式-3,4-二取代2-六氫p比症酮。在、〆，、在此内醯胺還原後，2- 穴虱吡哫酮可平順地轉化成對掌異構上純之代六氫吡啶。 ^ ? ^ 因此，本發明係提供一種製備對掌性反式部· 訂氫ρ比咬酮之方法，其包括： /、 (1)使下式3-取代之戊二酸奸 R1 線 &輔助其中R1爲芳基、烷基或任何其他基團，與作爲對掌,丨經| 劑之式（I)對掌性胺反應 j520359 A7 B7 V. Description of the invention f (D. The substituent R1 is preferably substituted at the 4 position, and is M 夂 & The self-chemical in step (3) of the process of the present invention, preferably ㈣, so The product formed in step (3) is a desert. ^ Nature 4 · Substituted 2_hexa ^ phase, which is used to synthesize the opposite palmity # disubstituted 2_hexahydroρ than ketone ketone and * ★, * Ah, its corresponding important intermediate of Emei. In this four steps, the production of p-palladium I-anhydride from 3-substituted pentamidine and p-amylamine is used to prepare p-palladium 4-substituted 2- 7T 氲 P. After the precipitation, the reaction at the carbon and carbon sites will produce the anti-trans-3,4-disubstituted 2-hexahydrop-pyridone. At this time, the hydrazone is reduced. After that, 2-pyridoxone can be smoothly converted into para palmar isomerically pure hexahydropyridine. ^? ^ Therefore, the present invention provides a method for preparing para palmar trans-derivatives. A method comprising: (1) making a 3-substituted glutaric acid R1 of the following formula & an auxiliary wherein R1 is an aryl group, an alkyl group or any other group, and acting as a counterpart, via the agent Formula (I) reaction to palm amine j

Ar^R S|獲得半酿胺之混合物’其中义表示芳族基團，費丨基；％小現合，作社印製 -8· 本紙張尺度適用中國國家標準（CNS)A4規格⑵〇 x 297公爱 52〇359 A7 B7 五、發明說明^ (2) 使該半醯胺之酸基還原成一級醇； (請先閱讀背面之注意事項再填寫本頁) (3) 使該一級醇卣化，而得自化物； (4) 以鹼使該卣化物環化，產生對掌性2_六氫响咬綱·及 (5) 使該2_六氫吡啶酮之泛碳醯基化，而得對掌性反式3 * ~取代2-六氫p比淀酮。再者，値得注意的是，在本申請案製程中之大部份化合物係爲固體，並可容易地藉由簡易再結晶作用進行2化: 此外’所有試劑幾乎均爲無毒性，且爲環境上良性的。於另一方面，本發明係提供一種製備下式對掌性反式_ 3,4-二取代-六氫吡啶之方法 R1 .R2 、N， R3 其中R1爲芳基、烷基或任何其他基團，R2爲烷基或任何基團取代之燒基，及R3爲氫、垸基或任何基團取代之统基，該方法包括：經濟部智慧財產局員工消費合作社印製 (1)使下式3-取代之戊二酸肝 R1 〇人〇人〇其中R1爲芳基、烷基或任何其他基團，與作爲對掌性輔助劑之式（I)對掌性胺反應 -9 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 520359Ar ^ RS | A mixture of semi-fermented amines is obtained, in which the meaning represents an aromatic group, Fei group;% small spot combination, printed by the company -8 · This paper size applies to China National Standard (CNS) A4 specifications⑵〇x 297 Gongai 52〇359 A7 B7 V. Description of the invention ^ (2) Reduce the acid group of the hemiamine to a primary alcohol; (Please read the precautions on the back before filling this page) (3) Make the primary alcohol 卣(4) cyclize the hydrazone with a base to produce a 2-hydroxyhexahydropyridine; and (5) ubicarbonate the hexahydropyridone, Instead, the palmar trans 3 * ~ substituted 2-hexahydrop-pyridone. Furthermore, it should be noted that most of the compounds in the process of this application are solid and can be easily converted by simple recrystallization: In addition, 'all reagents are almost non-toxic and are Environmentally benign. In another aspect, the present invention provides a method for preparing a para-trans-3,4-disubstituted-hexahydropyridine of the formula R1. R2, N, R3 where R1 is an aryl group, an alkyl group, or any other group Group, R2 is an alkyl group or any radical substituted group, and R3 is a hydrogen, fluorenyl group or any radical substituted group, the method includes: printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (1) Formula 3-Substituted glutaric acid liver R1 〇 person 〇 person 〇 where R1 is an aryl group, an alkyl group or any other group, and reacts with a palmitic amine of formula (I) as a palmitic adjuvant. Paper size applies to China National Standard (CNS) A4 (210 X 297 public love) 520359

五、發明說明I )V. Invention Description I)

獲知半酿胺之混合物，其中知表示芳族基團，而r表示烷基； (2) 使該半醯胯之酸基還原成一級醇； (3) 使該一級醇.化，而得鹵化物； (4) 以鹼使該鹵化物環化，產生對掌性2_六氫吡咬酮； (5) 使2-六氫吡啶酮之α碳醯基化，而得對掌性反式_3,4_二取代2-六氫峨咬酮；及 ⑹使對苳性反式_3,‘二取代孓六氫吡啶酮之酯與醯胺基還原，形成反式-3，4-二取代六氫吡啶。本發明亦提供一種製備對掌性帕西汀之方法，其包括： (1)使下式3-芳基戊二酸酐 (*請先閱讀背面之注意事項再填寫本頁) I裝----- 訂----------線一經濟部智慧財產局員工消費合作社印製〇入〇人〇其中R1爲芳基，與作爲對掌1 性輔助劑之式①對掌性胺反應It is known that a mixture of semi-fermented amines, in which it is known that it represents an aromatic group, and r represents an alkyl group; (2) the acid group of the hemiphosphonium is reduced to a primary alcohol; (3) the primary alcohol is converted into a halogenation (4) cyclize the halide with a base to produce p-hexahydropyridone; (5) acylate the 2-carbon-pyridone to form an alpha carbohydrazone to give a palmate trans _3,4_ di-substituted 2-hexahydrometaphenone; and ⑹ reduce the para-trans 3, 'di-substituted hexahydropyridone ester and the amine group to form trans-3,4- Disubstituted hexahydropyridine. The present invention also provides a method for preparing palmitine paxetine, which comprises: (1) making 3-arylglutaric anhydride of the following formula (* Please read the precautions on the back before filling this page) -Order ---------- Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 〇 0〇〇 Among them, R1 is an aryl group, and it is used as an assistant agent for palmity ① palmity Amine reaction

R 獲得半醯胺之屍合物’其中Ar表示芳族基團，基； ’ -10- 本紙張尺度顧㈣目m^g)A4 (210 x 297 520359 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明？) (2) 使該半醯胺之酸基還原成一級醇； (3) 使該一級醇齒化’而得闺化物； (4) 以鹼使該函化物環化，產生對掌性厶六氫吡啶酮； (5) 使2-六氫吡啶酮之“碳醯基化，而得對掌性反式_3,4_二取代2- 鼠17比^^§)^; ⑹使對掌性反式·3,4-二取代2-六氫吡啶酮之酯與醯胺基還原’ &供反式-3,4_二取代六氫p比嗓；及 ⑺使反式-3,4-二取代六氫吡啶之羥基轉化成芳基醚，然後藉由氫解作用移除對掌性輔助劑，獲得對掌性帕西汀鹽酸鹽。上述用以製備對掌性帕西汀之本發明方法之步驟⑺，可以下列三個步驟取代： ⑺使反式，3,4_一取代穴氫吡哫結晶，並使此化合物之羥基轉化成續酸醋，接著以芝麻醇及燒氧化却處理，以提供自由態胺； ⑻使此自由態胺轉化成鹽❹，並藉再結晶作用純化鹽酸鹽；及 (9)藉由氫解作用移除對掌性輔助劑，冑得性帕西鹽酸鹽。如上述，於本發明步驟⑴中使用之對掌性胺，可爲對手性一級胺類或對掌性胺基酸衍灯王物此對掌性胺可以足夠與3-芳基戊二酸奸反庥$蚕夫應 < 量泰加，且較佳係以化學計量加0 根據本發明，較佳製程且；^,、牧住I程具體實施例又合成程序，係描此汀掌添 --------^----------^ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺㈣财關^73ns)A4 -11 - 520359 A7 五、發明說明{0 ) 頑對掌性2-六氫吡啶酮10。質子_光譜顯示孓六氫吡啶酮仞爲純非對映異構物（>99% de)，無任何其他非對映異構物存在。以過量鹼，譬如鋰二異丙基胺（LDA)、鋰六甲基二矽烷 (LiHMDS)及氫化鈉（NaH)，以及氯甲酸甲酯，在譬如四氫呋南（THF)與***之溶劑中處理，於2_六氫吡啶酮ι〇之“碳處進行醯化作用，以令人滿意之產率與非對映異構選擇性，獲得新穎酯11。質子NMR光譜顯示僅獲得一種化合物，其係被指定爲反式立體異構物。此新穎化合物11之單晶X—射 ’、泉刀析確涊其（4S，3R)絕對組態，因此確認酸7a之立體化學。以氫化鋰鋁，使2-六氫吡啶酮n之酯與醯胺基還原，提供新穎胺基醇12，其中R表示氫。化合物^爲黏稠油，且於靜置時極慢地固化。但是，化合物12在管柱層析後易於〜曰日化。化合物12中之無基轉化成新穎甲燒續酸酯，接著以芝麻醇及烷氧化鉀處理，提供新穎自由態胺14a。此新穎自由態胺14a之純化，可經由14a轉化成新穎鹽酸鹽14b 而達成。於14b中之芊基之氫解作用，形成帕西汀鹽酸鹽 15 ’爲黏稠團塊，依據文獻程序，藉再結晶使其純化lc。 (請先閱讀背面之注意事項再填寫本頁) ^----I----^ . 經濟部智慧財產局員工消費合作社印製 -13- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 520359 A7 B7 五、發明說明Γ 圖式1 4-F-C6H4R Obtained the corpse of hemiamidamine, where Ar represents an aromatic group, a radical; -10- This paper is scaled to Gu㈣me m ^ g) A4 (210 x 297 520359 A7 B7 Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Printing 5. Description of the invention?) (2) The acid group of the hemiamine is reduced to a primary alcohol; (3) The primary alcohol is dentified to obtain a compound; (4) The compound is cyclized with a base (5) The "carbohydrazone" of 2-hexahydropyridone is obtained, and the palm trans-3,4_disubstituted 2-rat 17 ratio is obtained ^^ § ); 对 reduction of palmitic trans · 3,4-disubstituted 2-hexahydropyridone esters and sulfonylamino groups' & for trans-3,4_disubstituted hexahydropyridine; and ⑺Convert the hydroxyl group of trans-3,4-disubstituted hexahydropyridine to an aryl ether, and then remove the palmar adjuvant by hydrogenolysis to obtain palmaroxetine hydrochloride. Step 方法 of the method of the present invention for the preparation of palmaroxetine can be replaced by the following three steps: ⑺ crystallize trans, 3,4_-substituted anhydropyrazine, and convert the hydroxyl group of this compound into a continuous acid vinegar , And then sesame alcohol and burning oxidation To provide a free amine; ⑻ convert the free amine to a salt, and purify the hydrochloride by recrystallization; and (9) remove the palm-like adjuvant by hydrogenolysis to obtain a sex amine West hydrochloride. As mentioned above, the palmitic amine used in step 本 of the present invention may be a chiral primary amine or a palmitic amino acid derivative. The palmitic amine may be sufficiently The glutaric acid is the best solution for the amount of taiga, and is preferably a stoichiometry plus 0. According to the present invention, the preferred process is: Describing this Tingzhang Tim -------- ^ ---------- ^ (Please read the precautions on the back before filling this page) This paper rule ㈣Fortune Pass ^ 73ns) A4 -11 -520359 A7 V. Description of the invention {0) Stubborn palmitic 2-hexahydropyridone 10. The proton spectrum shows that hexahydropyridone is a pure diastereomer (> 99% de) without any Other diastereomers exist. Excess bases, such as lithium diisopropylamine (LDA), lithium hexamethyldisilanes (LiHMDS) and sodium hydride (NaH), and methyl chloroformate, such as tetrahydro Furan (THF) Solvent such as ether in the treatment, acting acylated 'carbon of the pyridone ι〇 2_ hexahydro to a satisfactory yield of the non-enantioselective obtain novel ester 11. Proton NMR spectroscopy showed that only one compound was obtained, which was designated as the trans stereoisomer. The single crystal X-ray of this novel compound 11 and spring knife analysis confirmed its absolute configuration of (4S, 3R), so the stereochemistry of acid 7a was confirmed. Reduction of the ester of 2-hexahydropyridone n with amidinoyl group with lithium aluminum hydride provides a novel amino alcohol 12, where R represents hydrogen. Compound ^ is a viscous oil and solidifies very slowly when left standing. However, compound 12 is easy to be chemically modified after column chromatography. The radical-free compound in compound 12 is converted into a novel methylsalcatelic acid ester, which is then treated with sesitol and potassium alkoxide to provide a novel free-state amine 14a. Purification of this novel free-state amine 14a can be achieved by converting 14a into novel hydrochloride 14b. Hydrogenolysis of the fluorenyl group in 14b formed parstine hydrochloride 15 'as a viscous mass, which was purified by recrystallization according to literature procedures. (Please read the notes on the back before filling out this page) ^ ---- I ---- ^. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -13- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 520359 A7 B7 V. Description of the invention Γ Scheme 1 4-F-C6H4

-CC^R 1 R = H 2 R = CH3-CC ^ R 1 R = H 2 R = CH3

RO2C CO2R 3 R = CH3 4R = H 4-F-CeK4RO2C CO2R 3 R = CH3 4R = H 4-F-CeK4

HO2C CO2H 5 4-F-C6H4HO2C CO2H 5 4-F-C6H4

(e)(e)

CH3 ihL·CH3 ihL ·

Nj/ \ph HNj / \ ph H

〇CH3 Ph^ ^CH3 Ph’\cH3 (請先閱讀背面之注意事項再填寫本頁) 7a R1 = 4-F-C6H4i R2 = H 8 X = OH 7b R1 = H, R2 = 4-F- C6H4 9 X =巳r 10 11 G), (k) 4-F-C6H4 4-F-C6H4 4-F-i 06Η4 〇〇CH3 Ph ^ ^ CH3 Ph '\ cH3 (Please read the notes on the back before filling this page) 7a R1 = 4-F-C6H4i R2 = H 8 X = OH 7b R1 = H, R2 = 4-F- C6H4 9 X = 巳 r 10 11 G), (k) 4-F-C6H4 4-F-C6H4 4-Fi 06Η4 〇

-〇 -裝--------訂----------線一、〇R (I) 〇、〇 (m〉-〇 -install -------- order ---------- line one, 〇R (I) 〇, 〇 (m>

經濟部智慧財產局員工消費合作社印製 12R = H 13 R = 02SCH3 14a自由態胺 14b HC丨鹽 15aR = H, HC丨鹽 15b R = H，順丁烯二酸鹽請注意圖式1之中間化合物7a，7b，8, 9, 10, 11，12, 13, 14a及14b 係爲新穎的。任何適當試劑與反應條件均可用於本發明之製程中。於圖式1所示各步驟中使用之試劑與條件，均爲 -14- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 520359 五、發明說明严Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 12R = H 13 R = 02SCH3 14a Free state amine 14b HC 丨 Salt 15aR = H, HC 丨 Salt 15b R = H, please refer to the middle of Figure 1 Compounds 7a, 7b, 8, 9, 10, 11, 12, 13, 14a and 14b are novel. Any appropriate reagents and reaction conditions can be used in the process of the present invention. The reagents and conditions used in each step shown in Figure 1 are -14- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 520359 V. Strict description of the invention

較佳具體實施例，且例如係爲：（a)甲醇H 二醇；回流20小時，7°%產率；(㈣氫氧化：，= 小時，（C)痕鹽酸，回流2〇小時，7〇%產机氯化乙醯，回流20小時，9〇0/產聿步驟）；（d) R、吁90/〇產率，·㈨（S)-甲基苄胺、二Γ 胺、甲苯，_78°C，1〇小時，蚨尨、人、 —乙川』呼，然後於1：溫下1〇小時，率；（f)三乙胺、氯甲酸昱丁醋气 ° 丁敗，、J酉曰四風呋喃，·78 - 0〇C，20 ,j、時；然後’硼氫化納、水’㈣。c，2()小時，8g% 三溴化磷，濃氫濞酸，O^C，4 δ ^ χ 穴70 /。產率；（h)氫化鈉，四氫咬喃，回流則、時，85%產率；㈣二異丙胺甲酸甲醋、四氫吱H10小時，78%產率；隐鍵銘、四氫吱喃，回流72小時，62%產率；⑻氯化甲燒磺醯、二氯甲烷，室溫20小時；①①芝麻醇、㉟、丙醇，回流36小時；⑻鹽酸，65%產率；（m)H2，5%pd_c，甲醇，96 %產率。下述實例係以説明方式提出。此等實例並非意欲在任何方面限制本發明之範圍，且不應如此解釋。實例實例1 : (3S)-3-(4-氟苯基)_5_酮基-5-(lS)_(l-苯基乙胺基）戊酸（7a) 將5.0克酐6在100毫升甲苯中，逐滴添加至5 25毫升（S)-甲基芊胺在200毫升甲苯中之_78°C溶液内。添加完成後，逐滴添加3.5毫升三乙胺。將混合物自此溫度攪拌至室溫過夜。於甲苯蒸發後，將混合物與50毫升1 N鹽酸一起搅拌，然後以熱醋酸乙酯萃取。合併有機層，以鹽水洗滌，以硫 15 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）訂線經濟部智慧財產局員工消費合作社印製 520359 Α7 Β7 五、發明說明p ) 酸鍰脱水乾燥，並蒸發至乾涸。使粗產物再結晶，在第一 (請先閱讀背面之注意事項再填寫本頁) 份收取產物中供給標題化合物，爲無色固體（7〇0/。產率，9〇_ 95% de):溶點 i95.(M95.5°C ; [a]25D=-78 8 (cl〇 CH3〇BQ ; ijj NMR (200 MHz, CDC13 ) ci 7.30-7.00 (m, 7H)? 6.95 (t? J=8.7 Hz, 2H), 5.60 (m? 1H)，4·94 ( J=6.9 Hz，3H) ; 1 3 C NMR (125 MHz，CDC13 /CD3 OD) J 176·8, 173.6, 164.3, 145.8, 140.8, 131.6, 131.0, 129.7, 128.6, 117.8, 51.1，45.3, 43.0, 41.1，23.9·對A preferred embodiment is, for example: (a) methanol H diol; reflux for 20 hours, 7 °% yield; (hydrazone hydroxide :, = hour, (C) trace hydrochloric acid, reflux for 20 hours, 7 〇% production of acetamidine chloride, refluxing for 20 hours, 9000 / amidine production step); (d) R, 90 / y yield, ㈨ (S) -methylbenzylamine, di-amine, toluene , _78 ° C, 10 hours, 蚨尨, person,-Eichuan ", and then at 1: temperature for 10 hours, the rate; (f) triethylamine, chloroformic acid, butyric acid, chlorobenzene, J酉 said four wind furan, · 78-0 ° C, 20, j, h; then 'sodium borohydride, water' ㈣. c, 2 () hours, 8 g% phosphorus tribromide, concentrated hydrofluoric acid, O ^ C, 4 δ ^ acupoint 70 /. Yield; (h) Sodium hydride, tetrahydrofuran, and 85% yield at reflux; ㈣ diisopropylamine formic acid, tetrahydrofuran for 10 hours, 78% yield; Hidden bond, tetrahydrofuran Ran, reflux for 72 hours, 62% yield; ⑻methanesulfonium chloride, dichloromethane, room temperature for 20 hours; ①① sesame alcohol, osmium, propanol, reflux for 36 hours; ⑻ hydrochloric acid, 65% yield; ( m) H2, 5% pd_c, methanol, 96% yield. The following examples are presented by way of illustration. These examples are not intended to limit the scope of the invention in any way, and should not be interpreted as such. EXAMPLES Example 1: (3S) -3- (4-fluorophenyl) -5_keto-5- (lS) _ (l-phenylethylamino) valeric acid (7a) 5.0 g of anhydride 6 in 100 ml Toluene was added dropwise to a -78 ° C solution of 525 ml (S) -methylamidamine in 200 ml toluene. After the addition was complete, 3.5 ml of triethylamine was added dropwise. The mixture was stirred from this temperature to room temperature overnight. After the toluene had evaporated, the mixture was stirred with 50 ml of 1 N hydrochloric acid and then extracted with hot ethyl acetate. Combine the organic layers, wash with brine, and use 15 sulfur paper sizes. Applicable to China National Standards (CNS) A4 specifications (210 X 297 mm). Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs. Printed by the Consumer Consumption Cooperative of 520359 Α7 Β7 V. Description of invention p ) The acid solution is dried and evaporated to dryness. The crude product was recrystallized, and the title compound was supplied in the first (please read the precautions on the back before filling this page) portion of the collected product as a colorless solid (700 /. Yield, 90-95% de): Melting point i95. (M95.5 ° C; (a) 25D = -78 8 (cl〇CH3〇BQ; ijj NMR (200 MHz, CDC13) ci 7.30-7.00 (m, 7H)? 6.95 (t? J = 8.7 Hz, 2H), 5.60 (m? 1H), 4.94 (J = 6.9 Hz, 3H); 1 3 C NMR (125 MHz, CDC13 / CD3 OD) J 176 · 8, 173.6, 164.3, 145.8, 140.8 , 131.6, 131.0, 129.7, 128.6, 117.8, 51.1, 45.3, 43.0, 41.1, 23.9

CbH^oFnO3之分析計算値·· c，6929; H，6 u ; N，425 實測値 :C，69.07 ; H，6.09 ; N，3.83。使母液濃縮，並使固體自醋酸乙酉曰與己垸再結晶，而得第二份收取產物，其含有％與几之混合物’並使其在滚酸中水解，以回收二酸5。實例2 : (3R)-3-(4-氟苯基）_5-義基戊酸（1S)+苯基乙基醯胺⑻ 經濟部智慧財產局員工消費合作社印製將3笔升二乙胺，於室溫下，添加至5克化合物7a在2〇〇宅升四氫吱喃中之溶液内。將此溶液在室溫下攪拌6〇分鐘 ’然後移至-78 C乾冰丙酮浴中。於此溶液中逐滴添加2 $毫升氯甲酸異丁酯。將此懸浮液自_78。(：攪拌至室溫過夜。使混合物經過矽藻土與矽膠墊過濾，並以少量四氫吱喃洗滌。於此位在冰浴内之溶液中，添加2.0克硼氫化鈉，接著逐滴添加10毫升水。二氧化碳氣體激烈地釋出。將反應混合物攪拌2-4小時，並經過矽藻土墊過濾。在蒸發溶劑後，將水層以醋酸乙酯萃取數次。合併有機層，以鹽水洗務，以硫酸鎂脱水乾燥，及濃縮。固體自醋酸乙酯與己燒再結晶 ’形成^越化合物，爲無色固體（SO%產率，95%和）：溶點 Ο ί -16- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 520359 A7 ___B7_ 五、發明說明ϋ4 ) 170.0-170.5 °C ； [ ^]25D=.86.4(cl.0?CH3OH) ； 1H NMR (200 MHz， (請先閱讀背面之注意事項再填寫本頁) CDC13) d 7.40-7.10 (m，7H)，6.98 (t，J=8.7 Hz，2H)，5.51 (br d，J=7.7 Hz，1Π)， 5·00 (五重峰，J=7.4 Hz，1H)，3.60-3.50 (m5 2H)，3.33 (m，1H)，2.55 (d4 J=6.6, 14.2 Hz? 1H)? 2.38 (dd, J=8.6, 14.2 Hz, 1H)? 1.95-1.75 (m? 2H)? 1.27 (d? J=6.9 Hz，3H) ; 1 3 C NMR (125 MHz，CDC13) d 170.6, 161.6, 142.9, 139.6, 128.9, 128·6, 127·4, 126·1，115·4, 60.1，48.6, 44.0, 38.9, 38.4, 21.3。對C19H22FN-〇2之分析計算値·· C，72J6 ; H，7.03 ; N，4.44.實測値：C，72.35 ;H，6.83 ; N，4·33. 實例3 : (3S)_5_溴基·3_(4_氟苯基）戊酸（is)-i·苯基乙基酿胺⑼ 經濟部智慧財產局員工消費合作社印製在4.5克醇8於250毫升無水***中之溶液内，位於冰浴中，逐滴添加1.7毫升三溴化磷。於冰浴中攪拌3天後，將0.5 毫升濃氫溴酸加入此混合物中。將所形成之溶液於室溫下連續攪拌過夜，並添加100毫升冰，使反應淬滅。收集白色固體，溶於醋酸乙酯中，以飽和碳酸氫鈉溶液及飽和鹽水洗滌。使有機層經過矽膠墊過濾。蒸發溶劑後，使粗製固體自醋酸乙酯與己烷再結晶，形成3.8克標題化合物，爲白色固體（72% 產率，>95% de) ··熔點 156.5-157.5°C ; [a]25D = -38.2 (c 1.05 CH3 OH) ； 1H NMR (200 MHz, CDC13 ) ά 7.40-7.10 (m? 7H)? 6.99 (m，2H)，5.52 (br d，J=7.6 Hz，1H)，4.98 (m，IK), 3·35-3·20 (m，2H)，3.05 (m，lH)，2.51(dd5J=6.3，14.0Hz，m)，2.37(dd，J=8.7，14.0Hz，lH)，2.25- 2.05 (m? 2H)? 1.25 (d, J=6.9 Hz, 3H) ； 13 C NMR (125 MHz, CDC13 ) ά 169.7, 161.8, 142·8，137·7, 129.1，128.6, 127.4, 126.1，115.7, 48.6, 44.0, 40.6, 38.7， 30.9,21·3.對 C19H21BrFNO 之分析計算値：c，60.33 ; H，5.60 ; -17- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公爱) ^ 520359 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明{5 N，3·70·實測値：c5 60.57 ; H，5.54 ; Ν，3·82· 實例4 : (4R)-[4_(4_氟苯基）_1><1!§><1-苯基乙基）】六氫吡啶：酮⑼）將〇.7克氫化鈉（8〇〇/。分散液）在10毫升無水四氫呋喃中之 w浮液’於主溫下，添加至3·5克化合物9在4〇毫升無水四氫呋喃中之溶液内。將混合物在65-75°C下加熱過夜。於冷 :至室溫後，在冰浴中，以1〇毫升料，使反應混合物慢慢洋滅。在蒸發所有溶劑後，將殘留物以醋酸乙酯稀釋，然後以鹽水洗滌。收集有機層，並經過矽膠墊過濾。移除溶劑後，使粗製固體自醋酸乙酯與己烷再結晶，形成2•六氫吹淀嗣1〇，爲無色結晶（87%產率，〉99% de):熔點163 5_ 164.0Ό a^]25D=-108.4 (c 1.0, CHC13)； 1HNMR (200 MHz? CDC13) ^ 7.36-7.25 (m，5H)，7.13(m，2H)，7.00(m，2H)，6.18(q，J=7.08Hz，lH)，3.16-2·87 (m，2H)，2·87-2·69 (m，2H)，2·55 (dd，J=10.1，17.4 Hz，1H)，2.05-1.78 (m? 2H)? 1.51 (d, J=7.1 Hz? 3H) ; 1 3 C NMR (125 MHz, CDC13 ) ά 168.7, 161.6, 140.0, 139.3, 128.5, 128.0, 127.6, 127.4, 115.5, 49.8, 40.3, 39.6, 37.5, 3 0·3，15·1.對 C19H2〇FNO 之分析計算値：C，76.74; Η，6·78; Ν，4.71· 實測値：C，76·93 ; Η, 6·82 ; Ν，4.30. 實例5 : (3S，4R)-[4-(4-氟苯基）-3-甲氧羰基小(1S)-(1-苯基乙基）]六氫吡啶-2_嗣（11a) 將經一丙基胺在J哀己燒中之19.5毫升1.5 Μ溶液，逐滴添加至2克内醯胺10在50毫升四氫呋喃中，於-78°C下之經攪拌溶液内。1小時後，逐滴添加0.8毫升氯甲酸甲酯。將所 -18 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------訂----------線‘ C請先間讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 520359 A7 B7 五、發明說明t6 ) 形成之溶液於-78°C下攪拌4小時，然後在此溫度下，以氯化按水溶液，使其淬滅。使混合物濃縮以蒸發四氫嗅喃，’ 並以醋酸乙酯萃取水層。將合併之有機層以鹽水洗滌，以硫酸鎂脱水乾燥，過濾及濃縮，形成黃色黏稠油，其在靜置時極慢地固化。自醋酸乙酯與己烷再結晶，獲得1.85克 (78% )標題化合物，爲白色針狀結晶：熔點73.5-74.5T ; [ α ]25D=-181.2(cl.0?CHCl3) ； 1HNMR (500 MHz, CDC13) ά 7.45-7.30 (m，5HX 7.20-7.16 (m5 2H)，7.06-7.00 (m，2H)，6·17 (q5 J=7.03 Hz，lH)，3.70 (s? 3H)? 3.64 (d, J=10.2 Hz, 3H)? 3.39 (td, J=3.5? 10.7 Hz? 1H)? 3.17 (dt? J=4.9? 12·6 Hz，1H)，2·88 (m，1H)，2.05 (m，1H)，1·96 (m，1H)，1.57 (d，J=7.0 Hz，3H) ;13 C NMR (125 MHz，CDC13 ) d 170.6, 165.4, 161.9, 139.4, 137.4, 128.6, 128.3, 127.5, 115.7, 56.6, 52.3, 50.4, 41.4, 40.5, 29.4, 15.0·對 C21H24FN03 之分析計算値：C，70·57 ; H，6.77 ; N，3.92.實測値：C，70.97 ; H，6.17 ; N，4.01· 實例6 : (3S，4RH4_(4·氟苯基）-3-樂甲基小(is)-(lj基乙基）】六氫吡啶（12) 將5·6克酯11，在氮大氣下，逐滴添加至6克氫化鋰鋁於 150毫升四氫呋喃中之懸浮液内。使混合物回流三天，然後，於冰浴中，以10毫升水、6毫升15%氫氧化鈉溶液及 25毫升水處理。在過濾沉澱物之後，將有機溶液以鹽水洗滌，以硫酸鎂脱水乾燥，過濾，及在眞空中濃縮，形成3.2 克（62% )粗產物，爲淡黃色固體。自醋酸乙酯與己烷再結晶，獲得標題化合物，爲白色薄片：熔點13〇.(M31.(TC ; [ a] 25D=-17.4(cl.0，CHCl3) ; 1HNMR (200 MHz, CDC13) d 7.40-7.10 (m? -19- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------·裝--------訂----------線Φ (請先閱讀背面之注意事項再填寫本頁) 520359 A7 B7 五、發明說明Γ ) (請先閱讀背面之注意事項再填寫本頁) 7Η)，7.05-6.90 (m，2Η)，3·51 (q，J=6.78 Ηζ，1Η)，3.45-3.34 (m，2H)，3.23 (m， 1H)，2.89 (m，1H)，2.20 (m，1H)，2.05-1.80 (m，4H)，1.80-1.65 (m，2H)，1.44 (d，J=6.8 Hz，3H) ； 1 3 C NMR (125 MHz，CDC13) d 161.4, 143.2, 1403, 128.8, 128.2, 127,8, 127.0, 115.3, 65.1，63·9, 54.7, 50.6, 44.4, 34.6, 19.6.對 C2〇H24FNO 之分析計算値：C，76.65 ; H，7·72 ; N，4.47.實測値 :C，76.86 ; H，7.77 ; N，4.58. 實例7 : (3S，4R)-[3-(苯弁[1，3】二氧伍圜烯_5-基氧基甲基）冬(4_氟苯基）小 (1S)-(1-苯基乙基）]-六氫TT比咬鹽酸鹽（14b) 於冰浴中，將1·65毫升三乙胺與〇·86毫升氣化甲烷磺醯，逐滴添加至2克醇12在60毫升二氣甲烷中之溶液内。將混合物在此溫度下揽掉3小時，並以30毫升飽和碳酸氫鈉，使其淬滅。水溶液以二氯甲烷萃取。合併之有機層以鹽水洗綠，以硫酸鎂脱水乾燥及濃縮，以供給曱烷磺酸g旨13，爲黃色黏調油。經濟部智慧財產局員工消費合作社印製將3克芝麻醇在30毫升丙醇中之溶液，添加至〇28克鈉在 20毫升丙醇中之溶液内。溫和回流3〇分鐘後，添加甲烷磺酸醋13在50毫升丙醇中之溶液。使混合物回流15天，冷卻至室溫，然後以30毫升冰水，使其淬滅。蒸發丙醇後，將水溶液以***萃取。合併之有機層以1 N氫氧化鈉溶液、鹽水洗務，以硫酸鎂脱水乾燥，過濾及濃縮，形成自由態胺14a，爲紅褐色黏稠油。將此自由態胺以5〇亳升甲醇稀釋’並以0.5¾升濃鹽酸處理。將所形成之溶液靜置數天，沉殿出黃色固體。收集固體，自甲醇與醋酸乙酯再結晶， ____ -20- 規格（210 X 297公釐）本紙張尺度適用中國國家標準（CNS)a^ 520359 A7. _____ B7 五、發明說明严) (請先閱讀背面之注意事項再填寫本頁) 形成1.92克鹽酸鹽，爲白色針狀物。熔點>25〇°C (分解）；〇] 2 5D=-87.4(cl.O，CH3OH) ; 1HNMR (500 MHz, CDC13) d 7.65-7.60 (m? 2H)，7.55-7.45 (m，3H)，7.30-7.20 (m，2H)，6·97 (t，J=8.7 Hz，2H)，6.66 (d， J=8.5 Hz，1 Hz)，6·34 (4 J=2.5 Hz，1 Hz)，6.14 (dd，J=2.5, 8·5 Hz，1H)，5.92 (s， 2H)，4.23 (五重峰，J=6.0 Hz，1H)，3.86 (m，1H)，3.64 (dd，J=2.3, 9.6 Hz，1H)， 3.49 (d4 J=3.9, 9.6 Hz, 1H)，3.32 (m，1H)，2.9-2.8 (m，3H)，2.57 (m，1Π)， 2.02 (d, J=6.9 Hz, 3H), 1.9 (m, 1H) ; 13 C NMR (125 MHz, CDC13 ) d 161.8, 153.7, 148.2, 142.0, 136.9, 133.9, 123.0, 129.4, 129.2, 115.7, 107.9, 105.5， 101.2, 97.9, 67.6, 67.5, 54.6, 49.5, 41.2, 39.3, 29.9, 17.5.對 C27H29C1FN〇3 之分析計算値：C，09.00，· H，6·22 ; N，2·98·實測値：C，69.36 ; Η, 6.22 ； N, 3.07. 實例8 : 帕西汀鹽酸鹽或（3S，4R)-[3-(苯并[1，3】二氧伍圜烯-5-基氧基甲基）-4-(4-氟苯基）】六氫吡啶鹽酸鹽（工5) 經濟部智慧財產局員工消費合作社印製將1.6克化合物14b與20毫克10% Pd-C在140毫升無水甲醇中之懸浮液，於室溫及1大氣壓氫氣下，攪拌48小時。使所形成之懸浮液經過矽藻土過濾，以甲醇洗滌，及在眞空中濃縮。獲得粗製帕西汀鹽酸鹽，爲紅色黏稠團塊。自甲醇-***-己烷再結晶，達成純化，形成〇·85克（68% )帕西汀鹽酸鹽，爲粉紅色結晶：熔點123-124°C (文獻1 c 129-13TC ); [α]2 5 D =-88.6 (c 1.0, CH3 〇H) ; 1H NMR (500 MHz，CDC13) J 7.35-7.25 (m, 2H)5 7.05 (t? J=8.5 Hz, 2H)? 6.68 (d3 J=8.4 Hz, 1H)5 6.40 (d, J=2.3 Hz? 1H)? 6.18 (dd，J=2.3, 8.5 Hz，1 Hz)，5.95 (s，2H)，3.83 (d，J=10.3 Hz，1H)，3.75 (d，J =12.4 Hz，1H)，3·68 (d，J=9.5 Hz，1H)，3.24 (m，1H)，3.12 (m，1H)，2.97 (td，J= -21- 本紙張尺度適用中國國家標準（CNS)A4規格(210 X 297公釐）經濟部智慧財產局員工消費合作社印製 520359 A7 B7 五、發明說明（19 ) 3.3, 12.9 Hz, 1H), 2.75 (m, 1H), 2.50 (m9 1H)? 2.01 (d, J=13.1 Hz, 1H) ； 13 C NMR(125MHz, CDC13) d 161.9, 153.7, 148.2, 142.0, 137.1，128.9, 115.8, 107.9, 105.6, 101.2, 97.9, 67.5, 46.8, 44.5, 41.7, 39.4, 30.1· 雖然本發明已針對某些較佳範例與具體實施例加以説明，但並非意欲將本發明之範圍限制於其中，而是僅被隨文所附之申請專利範圍所限制。參考資料與註釋 1 (a) Christensen，J. A*; Squires，K F.美國專利 3912743, 1975. (b) Christensen，J. A·; Squires，R F.美國專利 4007196, 1977. (c) Bames， R. D.; Wood-Kaczmar, M. W.; Richardson, J. E.; Lynch, I R.; Buxton, P. C·; Curzons，A D·歐洲專利 0223403, 1987· (d) Borrett，G· T.美國專利 4861893, 1989. (e) Faruk^ E. A; Martin，K 丁·美國專利 4902801，1990. (f) Zepp，C. ML; Gao, Υ·; Heefiier，D. L.美國專利 5258517, 1993. (g) Kozikowski, A. P.; Araldi, G. L.; Boja, X; Meil, W. M.; Johnson, K. M.; Flippen-Anderson, J. L.; George, C.; Saiah? E. J. Med Chem. 1998, 41，1962. 2 Amat M.; Hidalgo, X; Bosch, J. Tetrahedron · Asymmetry, 1996, 7? 1591. 3 (a) Herdeis, C.; Kaschinski, C.; Karla, R.? Lotter, H. Tetrahedron: Asymmetry, 1996, 73 867. (b) Weber, K.; Gmeiner, P. Synlett, 1998, 885. (c) Matsuo, J·，Kobayashi，S·; Koga，K. Tetrahedron Lett· 1996, 7, 9723. 4 (a) Wirz，B·; Walther，Tetrahedron:Asymmetry，1992, 3, 1049. (b) Altenbach, Blanda, G. Tetrahedron:Asymmetry 1998, 9, 1519. 5 (a) Meyers, A. I.; Natale, N. R.; Aettlaufer, D. G.; Rafii, S.; Clardy, I Tetrahedron Lett. 1981, 22, 5123. (b) Meyers, A. I; Natale, N. R. _ -22- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂----------線一 520359 A7 B7 五、發明說明(2° )Analytical calculation of CbH ^ oFnO3 値 · c, 6929; H, 6 u; N, 425 Measured 値: C, 69.07; H, 6.09; N, 3.83. The mother liquor was concentrated, and the solid was recrystallized from ethyl acetate and hexane, to obtain a second recovered product containing a mixture of% and several percent 'and hydrolyzed in a rolling acid to recover the diacid 5. Example 2: (3R) -3- (4-fluorophenyl) _ 5-isopropylvaleric acid (1S) + phenylethylphosphonium amine ⑻ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 3 liters of diethylamine, At room temperature, was added to a solution of 5 g of compound 7a in 200 liters of tetrahydrofuran. This solution was stirred at room temperature for 60 minutes' and then transferred to a -78 C dry ice acetone bath. To this solution was added dropwise 2 $ mL of isobutyl chloroformate. Place this suspension from _78. (: Stir to room temperature overnight. Filter the mixture through a pad of diatomaceous earth and silica gel, and wash with a small amount of tetrahydrofuran. At this place in the ice bath, add 2.0 grams of sodium borohydride, then dropwise. 10 ml of water. Carbon dioxide gas is violently released. The reaction mixture is stirred for 2-4 hours and filtered through a pad of diatomaceous earth. After evaporation of the solvent, the aqueous layer is extracted several times with ethyl acetate. The organic layers are combined and brine Washing, dehydration drying with magnesium sulfate, and concentration. The solid was recrystallized from ethyl acetate and hexane to form a compound, which is a colorless solid (SO% yield, 95% and): melting point Ο ί -16- Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 520359 A7 ___B7_ V. Description of invention ϋ4) 170.0-170.5 ° C; [^] 25D = .86.4 (cl.0? CH3OH); 1H NMR (200 MHz, (Please read the notes on the back before filling this page) CDC13) d 7.40-7.10 (m, 7H), 6.98 (t, J = 8.7 Hz, 2H), 5.51 (br d, J = 7.7 Hz , 1Π), 5.00 (quintet, J = 7.4 Hz, 1H), 3.60-3.50 (m5 2H), 3.33 (m, 1H), 2.55 (d4 J = 6.6, 14.2 Hz? 1H)? 2.38 (dd, J = 8.6, 14.2 Hz, 1H)? 1.95-1.75 (m? 2H)? 1.27 (d? J = 6.9 Hz, 3H); 1 3 C NMR (125 MHz, CDC13) d 170.6, 161.6, 142.9, 139.6, 128.9, 128 · 6, 127 · 4, 126 · 1, 115 · 4, 60.1, 48.6, 44.0, 38.9, 38.4, 21.3. Analytical calculations for C19H22FN-〇2: C, 72J6; H, 7.03; N, 4.44. Found: C, 72.35; H, 6.83; N, 4.33. Example 3: (3S) _5-bromo · 3_ (4_Fluorophenyl) valeric acid (is) -i · Phenethyl ethyl amine ⑼ Printed in a solution of 4.5 g of alcohol 8 in 250 ml of anhydrous ether in the Intellectual Property Bureau of the Ministry of Economic Affairs, located in In an ice bath, 1.7 ml of phosphorus tribromide was added dropwise. After stirring for 3 days in an ice bath, 0.5 ml of concentrated hydrobromic acid was added to the mixture. The resulting solution was continuously stirred overnight at room temperature, and 100 ml of ice was added to quench the reaction. The white solid was collected, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate solution and saturated saline. The organic layer was filtered through a silicone pad. After evaporation of the solvent, the crude solid was recrystallized from ethyl acetate and hexane to form 3.8 g of the title compound as a white solid (72% yield, > 95% de). Melting point 156.5-157.5 ° C; [a] 25D = -38.2 (c 1.05 CH3 OH); 1H NMR (200 MHz, CDC13); 7.40-7.10 (m? 7H)? 6.99 (m, 2H), 5.52 (br d, J = 7.6 Hz, 1H), 4.98 (m, IK), 3.35-3 · 20 (m, 2H), 3.05 (m, lH), 2.51 (dd5J = 6.3, 14.0Hz, m), 2.37 (dd, J = 8.7, 14.0Hz, lH ), 2.25-2.05 (m? 2H)? 1.25 (d, J = 6.9 Hz, 3H); 13 C NMR (125 MHz, CDC13) ά 169.7, 161.8, 142.8, 137.7, 129.1, 128.6, 127.4 , 126.1, 115.7, 48.6, 44.0, 40.6, 38.7, 30.9, 21 · 3. Analysis and calculation of C19H21BrFNO 値: c, 60.33; H, 5.60; -17- This paper standard applies to China National Standard (CNS) A4 specifications ( 210 χ 297 public love) ^ 520359 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention {5 N, 3.70 · Measured 値: c5 60.57; H, 5.54; Ν, 3.82. Example 4 : (4R)-[4_ (4_fluorophenyl) _1 > < 1! § > < 1-phenylethyl)] hexahydropyridine: ketone ⑼) 0.7 g of hydrogen Sodium (8〇〇 / dispersion) w floating solution in 10 ml of dry tetrahydrofuran 'at the primary temperature, added to a solution of 3.5 g of compound 3 in 9 ml of anhydrous 4〇 of tetrahydrofuran. The mixture was heated at 65-75 ° C overnight. After cooling: to room temperature, the reaction mixture was slowly quenched with 10 ml of material in an ice bath. After all solvents were evaporated, the residue was diluted with ethyl acetate and then washed with brine. The organic layer was collected and filtered through a silicone pad. After removing the solvent, the crude solid was recrystallized from ethyl acetate and hexane to form 2 • hexahydropyridine 嗣 10 as colorless crystals (87% yield,> 99% de): melting point 163 5_ 164.0Ό a ^] 25D = -108.4 (c 1.0, CHC13); 1HNMR (200 MHz? CDC13) ^ 7.36-7.25 (m, 5H), 7.13 (m, 2H), 7.00 (m, 2H), 6.18 (q, J = 7.08Hz, lH), 3.16-2 · 87 (m, 2H), 2.87-2 · 69 (m, 2H), 2.55 (dd, J = 10.1, 17.4 Hz, 1H), 2.05-1.78 ( m? 2H)? 1.51 (d, J = 7.1 Hz? 3H); 1 3 C NMR (125 MHz, CDC13) 168.7, 161.6, 140.0, 139.3, 128.5, 128.0, 127.6, 127.4, 115.5, 49.8, 40.3, 39.6, 37.5, 3 0 · 3, 15 · 1. Analysis and calculation of C19H20FNO 値: C, 76.74; Η, 6.78; Ν, 4.71 · Measured 値: C, 76 · 93; Η, 6.82 Ν, 4.30. Example 5: (3S, 4R)-[4- (4-fluorophenyl) -3-methoxycarbonyl small (1S)-(1-phenylethyl)] hexahydropyridine-2_嗣 (11a) Add 19.5 ml of 1.5 M solution of monopropylamine in J. hexane, dropwise to 2 g of lactam 10 in 50 ml of tetrahydrofuran, and stir the solution at -78 ° C. . After 1 hour, 0.8 ml of methyl chloroformate was added dropwise.所所 -18-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------ Installation -------- Order ---- ------ Line 'C Please read the notes on the back before filling in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520359 A7 B7 V. Description of the invention t6) The solution formed at -78 ° C Stir for 4 hours, then quench at this temperature with chlorinated aqueous solution. The mixture was concentrated to evaporate tetrahydromethane, 'and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to form a yellow viscous oil, which solidified very slowly upon standing. Recrystallized from ethyl acetate and hexane to obtain 1.85 g (78%) of the title compound as white needle crystals: melting point 73.5-74.5T; [α] 25D = -181.2 (cl.0? CHCl3); 1HNMR (500 MHz, CDC13) ά 7.45-7.30 (m, 5HX 7.20-7.16 (m5 2H), 7.06-7.00 (m, 2H), 6.17 (q5 J = 7.03 Hz, lH), 3.70 (s? 3H)? 3.64 (d, J = 10.2 Hz, 3H)? 3.39 (td, J = 3.5? 10.7 Hz? 1H)? 3.17 (dt? J = 4.9? 12 · 6 Hz, 1H), 2.88 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.57 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDC13) d 170.6, 165.4, 161.9, 139.4, 137.4, 128.6, 128.3, 127.5, 115.7, 56.6, 52.3, 50.4, 41.4, 40.5, 29.4, 15.0 · Analysis and calculation of C21H24FN03 値: C, 70 · 57; H, 6.77; N, 3.92. Measured 値: C, 70.97; H, 6.17; N, 4.01 · Example 6: (3S, 4RH4- (4 · fluorophenyl) -3-lemethyl small (is)-(ljylethyl)] hexahydropyridine (12) 5. 6 g of ester 11. Under a nitrogen atmosphere, add dropwise to a suspension of 6 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture is refluxed for three days. Then, in an ice bath, 10 ml of water and 6 ml of 15% hydroxide are added. Sodium solution Treated with 25 ml of water. After filtering the precipitate, the organic solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated in the air to form 3.2 g (62%) of a crude product as a pale yellow solid. From ethyl acetate The ester was recrystallized from hexane to obtain the title compound as a white flake: melting point 130.0 (M31. (TC; [a] 25D = -17.4 (cl.0, CHCl3); 1HNMR (200 MHz, CDC13) d 7.40- 7.10 (m? -19- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ Installation -------- Order- --------- Line Φ (Please read the notes on the back before filling this page) 520359 A7 B7 V. Description of the invention Γ) (Please read the notes on the back before filling this page) 7Η), 7.05 -6.90 (m, 2Η), 3.51 (q, J = 6.78 Ηζ, 1Η), 3.45-3.34 (m, 2H), 3.23 (m, 1H), 2.89 (m, 1H), 2.20 (m, 1H ), 2.05-1.80 (m, 4H), 1.80-1.65 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H); 1 3 C NMR (125 MHz, CDC13) d 161.4, 143.2, 1403, 128.8 , 128.2, 127,8, 127.0, 115.3, 65.1, 63.9, 54.7, 50.6, 44.4, 34.6, 19.6. Analysis and calculation of C20H24FNONO: C , 76.65; H, 7.72; N, 4.47. Measured radon: C, 76.86; H, 7.77; N, 4.58. Example 7: (3S, 4R)-[3- (benzenehydrazone [1,3] dioxy Vinoline_5-yloxymethyl) winter (4-fluorophenyl) small (1S)-(1-phenylethyl)]-hexahydroTT than bite hydrochloride (14b) in an ice bath 1.65 ml of triethylamine and 0.86 ml of gasified methanesulfonium were added dropwise to a solution of 2 g of alcohol 12 in 60 ml of digas methane. The mixture was stirred at this temperature for 3 hours and quenched with 30 ml of saturated sodium bicarbonate. The aqueous solution was extracted with dichloromethane. The combined organic layers were washed green with brine, dried over magnesium sulfate, and concentrated to provide phanane sulfonic acid g13 as a yellow viscous oil. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. A solution of 3 g of sesamol in 30 ml of propanol was added to a solution of 028 g of sodium in 20 ml of propanol. After 30 minutes of gentle reflux, a solution of methanesulfonic acid 13 in 50 ml of propanol was added. The mixture was refluxed for 15 days, cooled to room temperature, and then quenched with 30 ml of ice water. After the propanol was evaporated, the aqueous solution was extracted with ether. The combined organic layers were washed with 1 N sodium hydroxide solution, brine, dried over magnesium sulfate, filtered and concentrated to form the free amine 14a as a reddish brown viscous oil. This free state amine was diluted with 50 liters of methanol 'and treated with 0.5¾ liters of concentrated hydrochloric acid. The resulting solution was allowed to stand for several days, and a yellow solid appeared in Shen Dian. Collect solids, recrystallize from methanol and ethyl acetate, ____ -20- Specifications (210 X 297 mm) This paper size applies Chinese National Standard (CNS) a ^ 520359 A7. _____ B7 V. Strict description of the invention) (please first Read the notes on the reverse side and fill out this page again.) 1.92 g of hydrochloride is formed as white needles. Melting point> 25 ° C (decomposition); 〇] 2 5D = -87.4 (cl.O, CH3OH); 1HNMR (500 MHz, CDC13) d 7.65-7.60 (m? 2H), 7.55-7.45 (m, 3H) ), 7.30-7.20 (m, 2H), 6.97 (t, J = 8.7 Hz, 2H), 6.66 (d, J = 8.5 Hz, 1 Hz), 6.34 (4 J = 2.5 Hz, 1 Hz ), 6.14 (dd, J = 2.5, 8.5 Hz, 1H), 5.92 (s, 2H), 4.23 (quintet, J = 6.0 Hz, 1H), 3.86 (m, 1H), 3.64 (dd, J = 2.3, 9.6 Hz, 1H), 3.49 (d4 J = 3.9, 9.6 Hz, 1H), 3.32 (m, 1H), 2.9-2.8 (m, 3H), 2.57 (m, 1Π), 2.02 (d, J = 6.9 Hz, 3H), 1.9 (m, 1H); 13 C NMR (125 MHz, CDC13) d 161.8, 153.7, 148.2, 142.0, 136.9, 133.9, 123.0, 129.4, 129.2, 115.7, 107.9, 105.5, 101.2 , 97.9, 67.6, 67.5, 54.6, 49.5, 41.2, 39.3, 29.9, 17.5. Analysis and calculation of C27H29C1FN〇3: C, 09.00, · H, 6.22; N, 2.98 · Measured: C, 69.36; pyrene, 6.22; N, 3.07. Example 8: Parsetin hydrochloride or (3S, 4R)-[3- (benzo [1,3] dioxolene-5-yloxymethyl ) -4- (4-fluorophenyl)] hexahydropyridine hydrochloride (Industrial 5) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1. A suspension of 6 g of compound 14b and 20 mg of 10% Pd-C in 140 ml of anhydrous methanol was stirred at room temperature under 1 atmosphere of hydrogen for 48 hours. The resulting suspension was filtered through celite, washed with methanol, and concentrated in vacuo. Crude paracetin hydrochloride was obtained as a red sticky mass. Recrystallized from methanol-ether-hexane to achieve purification, forming 0.85 g (68%) of paxetine hydrochloride as pink crystals: melting point 123-124 ° C (Reference 1 c 129-13TC); [ α) 2 5 D = -88.6 (c 1.0, CH3 〇H); 1H NMR (500 MHz, CDC13) J 7.35-7.25 (m, 2H) 5 7.05 (t? J = 8.5 Hz, 2H)? 6.68 (d3 J = 8.4 Hz, 1H) 5 6.40 (d, J = 2.3 Hz? 1H)? 6.18 (dd, J = 2.3, 8.5 Hz, 1 Hz), 5.95 (s, 2H), 3.83 (d, J = 10.3 Hz , 1H), 3.75 (d, J = 12.4 Hz, 1H), 3.68 (d, J = 9.5 Hz, 1H), 3.24 (m, 1H), 3.12 (m, 1H), 2.97 (td, J = -21- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520359 A7 B7 V. Description of the invention (19) 3.3, 12.9 Hz, 1H), 2.75 (m, 1H), 2.50 (m9 1H)? 2.01 (d, J = 13.1 Hz, 1H); 13 C NMR (125MHz, CDC13) d 161.9, 153.7, 148.2, 142.0, 137.1, 128.9, 115.8, 107.9, 105.6, 101.2, 97.9, 67.5, 46.8, 44.5, 41.7, 39.4, 30.1 · Although the present invention has been described with reference to certain preferred examples and specific embodiments, it is not intended to limit the scope of the invention Wherein, but is appended with the text of the patent is only limited by the scope. References and Notes 1 (a) Christensen, J. A *; Squires, K F. US Patent 3912743, 1975. (b) Christensen, J. A .; Squires, R F. US Patent 4007196, 1977. (c) Bames, RD; Wood-Kaczmar, MW; Richardson, JE; Lynch, I R .; Buxton, P.C .; Curzons, AD · European Patent 0234403, 1987 · (d) Borrett, G · T. US Patent 4861893, 1989. (e) Faruk ^ E. A; Martin, K. D. US Patent 4902801, 1990. (f) Zepp, C. ML; Gao, J .; Heefiier, DL US Patent 5285517, 1993. (g) Kozikowski, AP; Araldi, GL; Boja, X; Meil, WM; Johnson, KM; Flippen-Anderson, JL; George, C .; Saiah? EJ Med Chem. 1998, 41, 1962. 2 Amat M .; Hidalgo, X; Bosch, J. TetrahedronAsymmetry, 1996, 7? 1591. 3 (a) Herdeis, C .; Kaschinski, C .; Karla, R.? Lotter, H. Tetrahedron: Asymmetry, 1996, 73 867. (b) Weber , K .; Gmeiner, P. Synlett, 1998, 885. (c) Matsuo, J., Kobayashi, S .; Koga, K. Tetrahedron Lett. 1996, 7, 9723. 4 (a) Wirz, B .; Walther , Tetrahedron: Asymmetry, 1992, 3, 1049. (b) Alten bach, Blanda, G. Tetrahedron: Asymmetry 1998, 9, 1519. 5 (a) Meyers, AI; Natale, NR; Aettlaufer, DG; Rafii, S .; Clardy, I Tetrahedron Lett. 1981, 22, 5123. (b ) Meyers, A. I; Natale, NR -22 ------- Line one 520359 A7 B7 V. Description of the invention (2 °)

Heterocycles 1982, 18, 13. (c) Akiba, K.; Iseki, Υ.; Wada, Μ. Tetrahedron Lett· 1982, 23, 429. (d) Mangeney，Ρ·; Gosmini，Κ; Raussou, S.; Commercon, M.; Alexakis, A. J. Org. Chem. 1994, 59, 1877. 6 Cason, J. Organic Syntheses Collective Vol.4? 1963, 630. 7 Theisen, P. D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 142. 8 Fieser, L. F.; Martin, E. L. Organic Syntheses Collective Vol.2, 1943? 560. 9 Karanewsky, D.; Malley, M.; Gougoutas, J. Z. J. Org. Chem. 1991, 56, 3744. 10 Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, I Tetrahedron Lett. 1991, 32, 923. (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -23 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）Heterocycles 1982, 18. Commercon, M .; Alexakis, AJ Org. Chem. 1994, 59, 1877. 6 Cason, J. Organic Syntheses Collective Vol. 4? 1963, 630. 7 Theisen, PD; Heathcock, CHJ Org. Chem. 1993, 58, 142.8 Fieser, LF; Martin, EL Organic Syntheses Collective Vol. 2, 1943? 560. 9 Karanewsky, D .; Malley, M .; Gougoutas, JZJ Org. Chem. 1991, 56, 3744. 10 Rodriguez, M. ; Llinares, M .; Doulut, S .; Heitz, A .; Martinez, I Tetrahedron Lett. 1991, 32, 923. (Please read the notes on the back before filling out this page) -23-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims

520359 % 咬_之方法，其包 A8 B8520359% Way to bite, including A8 B8

第89111422號專利申請案一請專利範圍修正本(91毛又月)g88 、申請專利範圍一種製備對掌性4-取代2·六氫吡括： (1)使下式3-取代之戊二酸酐 R1Patent Application No. 89114422 First, I am requesting a revised range of patents (91 gross and monthly) g88, and a range of patent applications for the preparation of 4-palladium 2-hexahydropyrazine: (1) Make the following formula 3-substituted glutaric acid Anhydride R1

其中為苯基或㈣烷基’其视需要由由素所取代，與作為對掌性輔助劑之式①對掌性胺反應 NH2 Ο) Ar^^R 而R表示Ci - 獲得半醯胺之混合物，其中Ar表示苯基，坑基； (2) 使該半酿胺之酸基還原成一級醇； (3) 使該一級醇齒化，而得卣化物；及 (4) 以鹼使該卣化物環化，產生對掌性厶六氫吡啶酮。 2.根據申請專利範圍第丨項之方法，其中對掌性胺為對掌性一級胺類或對掌性胺基酸衍生物。 3·根據申請專利範圍第1項之方法，其中對掌性胺之烷基為甲基。 4.根據申請專利範圍第丨項之方涂，其中對掌性胺為甲基苄胺。 5·根據申請專利範圍第}項之方法，其中對掌性胺為⑶_ 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公爱） )20359Among them is phenyl or fluorenyl ', which is optionally substituted by a prime, and reacts with palladium amine of formula NH2 NH 2) Ar ^^ R and R represents Ci-which is obtained from hemiamine A mixture in which Ar represents a phenyl group and a pit group; (2) reducing the acid group of the semi-fermented amine to a primary alcohol; (3) toothing the primary alcohol to obtain a halide; and (4) using a base to make the The hydrazone is cyclized to produce palmitate hexahydropyridone. 2. The method according to item 1 of the scope of patent application, wherein the palmitic amine is a palmitic primary amine or a palmitic amino acid derivative. 3. The method according to item 1 of the application, wherein the alkyl group of the p-amine is methyl. 4. The coating according to item 丨 of the patent application scope, wherein the palm amine is methylbenzylamine. 5. The method according to item} in the scope of patent application, where palm amine is ⑶_ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 public love) 20359

申请專利範圍甲基苄胺。 6·根據申請專利範圍第1項之方法，其中Ri為4-F-C6H4。 7· 一種製備對掌性反式-3,4-二取代厶六氫吡啶酮之方法，其包括： (1)使下式3-取代之戊二酸酐 R1 其中Ri為表基或Ci - C6挺基’其视需要由卣素所取代，與作為對掌性輔助劑之式（I)對掌性胺反應Scope of patent application Methyl benzylamine. 6. The method according to item 1 of the scope of patent application, wherein Ri is 4-F-C6H4. 7. · A method for preparing para-trans--3,4-disubstituted fluorene hexahydropyridone, comprising: (1) making 3-substituted glutaric anhydride R1 of the following formula wherein Ri is epitope or Ci-C6 Tingyi ', which is optionally substituted by halogen, reacts with palmitic amine of formula (I) as a palmitic adjuvant

(I) 獲得半醯胺之混合物，其中Ar表示苯基，而R表示Cl-C6烷基； (2) 使該半醯胺之酸基還原成一級醇； (3) 使該一級醇齒化，而得齒化物； (4) 以驗使該鹵化物環化，產生對掌性2·六氫吡啶酮；及 (5) 使2-六氫吡啶酮之α碳醯基化，而得對掌性反式_ 3,4-二取代2-六氫吡啶酮。、 8·根據申請專利範園第7項之方法，其中對掌性胺為對掌性一級胺類或對掌性胺基酸衍生物。 -2- 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇X 297公酱) 520359 A8 B8 C8 ____________ D8 六、申請專利範圍 9·根據申請專利範圍第7項之方法，其中對掌性胺之烷基為甲基。 10·根據申請專利範圍第7項之方法，其中對掌性胺為甲基苄胺。 11·根據申請專利範圍第7項之方法，其中對掌性胺為⑸_ 甲基芊胺。 12.根據申請專利範圍第7項之方法，其中Ri為4-F_c6仏。 13· —種製備下式之反式·3,4-二取代六氫吡啶之方法， R1(I) A mixture of hemiamines is obtained, where Ar represents a phenyl group and R represents a Cl-C6 alkyl group; (2) the acid group of the hemiamine is reduced to a primary alcohol; (3) the primary alcohol is toothed (4) cyclize the halide to produce p-palladium 2. hexahydropyridone; and (5) acylate the 2-carboxhydropyridone α carbohydrazone to obtain Palm trans_ 3,4-disubstituted 2-hexahydropyridone. 8. The method according to item 7 of the patent application park, wherein the palmitic amine is a palmitic primary amine or a palmitic amino acid derivative. -2- This paper size applies to China National Standard (CNS) A4 specification (21〇X 297 male sauce) 520359 A8 B8 C8 ____________ D8 VI. Application scope of patent 9. According to the method of the scope of patent application No. 7, among which the applicability The alkyl group of the amine is methyl. 10. The method according to item 7 of the scope of patent application, wherein the palm amine is methylbenzylamine. 11. The method according to item 7 of the scope of patent application, wherein the palmitic amine is ammonium methylamine. 12. The method according to item 7 of the scope of patent application, wherein Ri is 4-F_c6 仏. 13 · —A method for preparing trans · 3,4-disubstituted hexahydropyridine of the formula, R1

R3*R3 *

其中R為本基或Ci_C6燒基’ R2為燒基、c〇OR，( R，為 Η 或 Ci - Cg 坑基）或 CH^OR" ( R” 為 Η、Q2SCH3 或，及 R3 為氩、q - C6 烷基或（CH2) n〇R"，（ r”《為 Η、^ q 烷基或芳香環，n=l-6)，該方法包括： ⑴使下式3-取代之戊二酸酐 R1 Λ 其中R1為苯基SCi-C：6烷基，與作為對掌性辅助劑之式 (I)對掌性胺反應 -3- 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 520359 六 A8 B8 C8 _ D8 、申請專利祀圍Where R is a radical or Ci_C6 alkyl, R2 is alkyl, coor, (R, is Η or Ci-Cg pit) or CH ^ OR " (R "is Η, Q2SCH3 or, and R3 is argon, q-C6 alkyl or (CH2) n〇R ", (r "" is Η, ^ q alkyl or aromatic ring, n = 1-6), the method includes: ⑴ making the following formula 3-substituted pentane Anhydride R1 Λ, where R1 is phenyl SCi-C: 6 alkyl, and reacts with palmitic amine of formula (I) as a palmitic adjuvant. -3- This paper applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 520 359 Six A8 B8 C8 _ D8

(I) 獲得半酿胺之混合物，其中Ar表示麥基，而R表示cK C6烷基； (2) 使該半醯胺之酸基還原成一級醇； (3) 使該一級醇_化，而得卣化物； (4) 以鹼使該鹵化物環化，產生對掌性2-六氫吡啶_ ; (5) 使2-六氫吡啶酮之α碳醯基化，而得對掌性反式_ 3,4·二取代2-六氫说淀酮；及〆 (6) 使對掌性3,4-二取代2-六氫ρ比淀酮之g旨與酿胺基還原，形成反式-3,4-二取代六氫π比遠。 14· 一種製備對掌性帕西汀之方法，其包括： (1)使下式3-芳基戊二酸酐 R1(I) obtaining a mixture of semi-fermented amines, wherein Ar represents a cyclyl group, and R represents a cK C6 alkyl group; (2) reduction of the acid group of the hemiamidine to a primary alcohol; (3) the primary alcohol, (4) cyclize the halide with a base to produce para-hexahydropyridine_; (5) acetylate the 2-carbohydroxanthone to obtain palmity Trans_ 3,4 · disubstituted 2-hexahydrohydroxanthone; and) (6) reducing the g of the palato 3,4-disubstituted 2-hexahydroρ-pyridone with the amino group to form The ratio of trans-3,4-disubstituted hexahydrogen is far. 14. A method for preparing paclitaxel, which comprises: (1) making 3-arylglutaric anhydride R1 of the following formula

其中R1為苯基，與作為對掌性輔助劑之式（I)對掌性胺反應Where R1 is a phenyl group and reacts with a palmitic amine of formula (I) as a palmitic adjuvant

(I) 獲得半醯胺之混合物，其中Ar表示苯基，而R表示Cr -4- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） ^>20359 A8 B8(I) Obtaining a mixture of hemiamines, where Ar represents phenyl and R represents Cr -4- The paper size applies to China National Standard (CNS) A4 (210X297 mm) ^ > 20359 A8 B8

C8 D8 '申請專利範園燒基； (2) 使該半醯胺之酸基還原成一級醇； (3) 使該一級醇_化，而得卣化物； (4) 以驗使該鹵化物環化，產生對掌性2-六氫P比淀_ ; (5) 使2-六氫吡啶酮之α碳醯基化，而得對掌性反式_ 3，“二取代2-六氫吡啶酮； ⑹使對掌性反式·3,4-二取代2-六氫吡啶酮之酯與醯胺基還原，提供反式-3,4-二取代六氩吡啶；及 ⑺使反式·3,4-二取代六氫吡啶之羥基轉化成芳基謎，然後藉由氫解移除對掌性辅助劑，獲得對掌性帕西知鹽酸鹽。 Κ根據申請專利範圍第1 4項之方法，其包括： (1)使下式3-芳基戊二酸酐C8 D8 'Fanyuan base for patent application; (2) reducing the acid group of hemiamine to a primary alcohol; (3) hydrating the primary alcohol to obtain a halide; (4) verifying the halide Cyclization to produce palmitic 2-hexahydro P ratio _; (5) The α-carbohydrazone of 2-hexahydropyridone is obtained to obtain palmitic trans-3, "disubstituted 2-hexahydro Pyridone; ⑹ reducing para palmar trans · 3,4-disubstituted 2-hexahydropyridone ester and fluorenylamine group to provide trans-3,4-disubstituted hexaargyridine; and 反 trans · The hydroxyl group of 3,4-disubstituted hexahydropyridine is converted into an aryl mystery, and the palmarity adjuvant is removed by hydrogenolysis to obtain palmarthic hydrochloride. According to the scope of application patent No. 1 4 The method of item, comprising: (1) making 3-arylglutaric anhydride of formula

其中R1為苯基，與作為對掌性輔助劑之式（1)對掌性胺Where R1 is phenyl, and para-amine as formula (1)

獲得半醯胺之混合物，其中Μ表示苯基，而汉表示^ C6烷基；不1 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱) 520359 A8 B8 C8 ___ D8 、申請專利範圍 (2) 使該半醯胺之酸基還原成一級醇； (3) 使該一級醇由化，而得鹵化物； ⑷以鹼使該鹵化物環化，產生對掌性2_六氫晚淀_ ; (5)使2·六氫说淀酮之α碳醯基化，而得對掌性反式_ 3,4-二取代2-六氫吡啶酮； ⑹使對掌性反式-3,4-二取代2-六氫p比咬_之g旨與醯胺基▲原’提供反式-3,4-二取代六氨ρ比淀； ⑺使反式_3,4_二取代六氯p比症結晶，並使此化合物之羥基轉化成磺酸酯，接著以芝麻醇及烷氧化珅處理，提供自由態胺； - (8) 使該自由態胺轉化成鹽酸鹽，及藉再結晶作用純化該鹽酸鹽；及 (9) 藉由氫解移除對掌性輔助劑，獲得對掌性帕西汀鹽酸鹽。 16· —種下式7a之(3S)-3-(4-氟苯基>5-酮基-5-(lS)-(l-苯基乙胺基）戊酸，Obtain a mixture of hemiamine, where M represents phenyl, and Han represents ^ C6 alkyl; not 1 paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 public love) 520359 A8 B8 C8 ___ D8, patent application Range (2) The acid group of the hemiamine is reduced to a primary alcohol; (3) The primary alcohol is converted to obtain a halide; ⑷ The base is used to cyclize the halide to produce a palmar 2_hexahydro Late Lake_; (5) The α-carbohydrazone of 2.hexahydrohydroxidone was obtained to give the palmate trans_ 3,4-disubstituted 2-hexahydropyridone; -3,4-disubstituted 2-hexahydro p ratio bite _ g and amine amino group ▲ proton 'to provide trans-3,4-disubstituted hexaamine p ratio; ⑺ make trans _3,4_ Disubstituted hexachloropyridine crystal, and converted the hydroxyl group of this compound into sulfonate, and then treated with sesanol and alkoxide to provide the free amine;-(8) convert the free amine to the hydrochloride And purifying the hydrochloride by recrystallization; and (9) removing the palmarity adjuvant by hydrogenolysis to obtain palmaroxetine hydrochloride. 16. · (3S) -3- (4-fluorophenyl) of the formula 7a below: 5-keto-5- (lS)-(l-phenylethylamino) valeric acid,

其中R1表示4-F-C6H4，且R2表示、Η。 17· —種下式7b之（3S)-3-(4·氟苯基）-5-_基-5-(lS)-(l-苯基乙胺基）戊酸， -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 520359 8 8 8 8 A B c D 申請專利範圍 R2, Η〇2〇Where R1 represents 4-F-C6H4, and R2 represents Η. 17 · — (3S) -3- (4 · fluorophenyl) -5-_yl-5- (lS)-(l-phenylethylamino) valeric acid of formula 7b, -6- this paper Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) 520359 8 8 8 8 AB c D Patent application scope R2, Η〇2〇

、N/ \ph Η 7b 其中R1表示Η，且R2表示4-F-C6H4 18. —種（3R)-3-(4·氟苯基）_5·羥基戊酸（1S)_1_苯基乙基醯胺。 19· 一種（3S)-5_溴基-3-(4-氟苯基）戊酸（1S)_1_苯基乙基醯胺。 20. —種（4R)-[4-(4-氟苯基）-l-(lS)-(l-苯基乙基)]六氫吡啶-2-酮。 21· —種（3S，4R)_[4-(4_氟苯基）·3-甲氧羰基-1-(1SM1-苯基乙基）]六氫外1：淀-2-酮。 22· —種（3S，4R)-[4-(4·氟苯基）-3_羥甲基-l-ClSMl-苯基乙基）]六氫叶匕症。 23. —種下式13之甲烷磺酸酯， • 4-F-CgH4, N / \ ph Η 7b where R1 represents Η and R2 represents 4-F-C6H4 18. — (3R) -3- (4 · fluorophenyl) _5 · hydroxyvaleric acid (1S) _1_phenylethyl Methylamine. 19. A type of (3S) -5-bromo-3- (4-fluorophenyl) pentanoic acid (1S) _1-phenylethylamidamine. 20.-(4R)-[4- (4-fluorophenyl) -l- (lS)-(l-phenylethyl)] hexahydropyridin-2-one. 21 · —Species (3S, 4R) _ [4- (4-fluorophenyl) · 3-methoxycarbonyl-1- (1SM1-phenylethyl)] hexahydroexogen 1: Yodo-2-one. 22 · —Species (3S, 4R)-[4- (4 · fluorophenyl) -3_hydroxymethyl-l-ClSMl-phenylethyl)] hexahydro leaf dagger. 23. —Methanesulfonate of formula 13, • 4-F-CgH4

、OR N〆 .I Ph^^CHa 13 其中R表示02SCH3。 24. —種下式14a之自由態胺 4-F-c6H4 14a Ph’ 'Chb 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 520359 8 8 8 8 ABCD 、申請專利範圍 25. —種（3S，4R)-[3-(苯并[1，3]二氧伍圜婦-5-基氧基甲基）·4-(4-氟苯基）-l-(lS)-(l-苯基乙基）]-六氫吡啶鹽酸鹽。 -8- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）OR N〆.I Ph ^^ CHa 13 where R represents 02SCH3. 24. —A free form amine of formula 14a 4-F-c6H4 14a Ph '' Chb This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 520359 8 8 8 8 ABCD, scope of patent application 25. —Species (3S, 4R)-[3- (benzo [1,3] dioxo-5-yloxymethyl) · 4- (4-fluorophenyl) -l- (lS )-(l-phenylethyl)]-hexahydropyridine hydrochloride. -8- This paper size applies to China National Standard (CNS) A4 (210X297 mm)