TW200412946A - Synthesis of pyrrolidine derivatives and their salts - Google Patents

Synthesis of pyrrolidine derivatives and their salts Download PDF

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TW200412946A
TW200412946A TW092133491A TW92133491A TW200412946A TW 200412946 A TW200412946 A TW 200412946A TW 092133491 A TW092133491 A TW 092133491A TW 92133491 A TW92133491 A TW 92133491A TW 200412946 A TW200412946 A TW 200412946A
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compound
solvate
formula
sulfate
salt
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Yasuyuki Kawanishi
Masaaki Uenaka
Ide Yataka
Shoji Shinomoto
Takayuki Okuno
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Shionogi & Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical

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Abstract

The present invention relates to compounds represented by the following formula (I): their p-toluenesulfonate salts, sulfate salts, hydrochlorides, or their solvates, or their crystals, and the preparation thereof.

Description

200412946 玖、發明說明 【發明所屬之技術領域】 本發明係關於對CPL2有抑制活性之吡咯啶化合物之鹽， 其結晶，或其製造方法，及中間體。 【先前技術】 磷脂酶2(PL2)爲將磷脂質2位酯鍵結水解之酶的總稱，與 活體膜磷脂質的新陳代謝有關，且作爲類前列腺素 (Prostnoid)等脂質傳達物質（Meditor)産生之花生四烯酸 (rchidonic cid)進階之啓始酵素發揮機能。目前，已知哺乳動物 存在各種PL2，依其部位，分子量，基質特異性等，可分類 爲分泌型PL2(sPL2)，C2 +非依存型PL2(iPL2)，細胞質型 PL2(cPL2)等群。 具有cPL2抑制活性之在2位側鏈有噻唑啶二酮之吡咯啶 衍生物化合物記載於專利文獻1、2及3與非專利文獻1及 2中。但所有文獻中皆無記載如下式（I)化合物之鹽及其結晶200412946 (ii) Description of the invention [Technical field to which the invention belongs] The present invention relates to a salt of a pyrrolidine compound having an inhibitory activity against CPL2, a crystal thereof, a method for producing the same, and an intermediate. [Prior art] Phospholipase 2 (PL2) is a general term for enzymes that hydrolyze ester linkages at the 2-position of phospholipids. It is related to the metabolism of phospholipids in living membranes, and is produced as lipid-transmitting substances (Meditor) such as prostnoid The advanced starting enzyme of rhodonic cid functions. At present, various PL2s are known to exist in mammals, and can be classified into secreted PL2 (sPL2), C2 + + non-dependent PL2 (iPL2), cytoplasmic PL2 (cPL2), etc., depending on their location, molecular weight, and substrate specificity. A pyrrolidine derivative compound having a thiazolidinedione at the 2-position side chain having cPL2 inhibitory activity is described in Patent Documents 1, 2 and 3 and Non-Patent Documents 1 and 2. However, there is no record in all documents of the salt of the compound of formula (I) and its crystal

(1) ’且使用其鹽之精製方法亦無δ3載。再者，具可作爲醫藥使 用純度之式（I)化合物的工業製造方法亦無記載。 (專利文獻1 ) 國際公開第97/05 1 3 5號小冊 (專利文獻2) 200412946 國際公開第98/3 37 97號小冊 (專利文獻3) 國際公開第0 1 /303 87號小冊 (非專利文獻1) J.Med.Chem.2000，43(6)，p. 1042- 1 1044 (非專利文獻2)(1) ', and there is no δ3 load in the purification method using its salt. Furthermore, there is no description of an industrial production method having a compound of the formula (I) which can be used as a medicine for purity. (Patent Document 1) International Publication No. 97/05 1 3 5 (Patent Document 2) 200412946 International Publication No. 98/3 37 Booklet 97 (Patent Document 3) International Publication No. 0 1/303 87 (Non-Patent Document 1) J. Med. Chem. 2000, 43 (6), p. 1042- 1 1044 (Non-Patent Document 2)

Biochimic et Biophysic ct 200 1，1 5 1 3ρ. 1 60-166 【發明內容】 爲提供具有CPL2抑制活性且結晶性低之吡咯啶化合物作 爲醫藥，對於具作爲醫藥使用純度之該化合物的工業製造方 法有迫切需要。 本發明者鑑於以上理由，特意進行檢討的結果，硏究出爲 提供高純度吡咯啶化合物所使用之鹽及其結晶，或其製造方 法。將非結晶之吡略啶化合物以鹽結晶形式予以精製，再附 加脫鹽反應而得具可作爲醫藥使用程度之純度的該化合物。 本發明係有關1)式（I):Biochimic et Biophysic ct 200 1,1 5 1 3ρ. 1 60-166 [Summary of the Invention] In order to provide a pyrrolidine compound having CPL2 inhibitory activity and low crystallinity as medicine, an industrial manufacturing method for the compound having purity as a medicine There is an urgent need. In view of the above reasons, the present inventors have deliberately conducted a review and found out a salt and a crystal used for providing a high-purity pyrrolidine compound, or a method for producing the same. The non-crystalline pyrrolidine compound is purified in the form of a salt crystal, followed by a desalting reaction to obtain the compound having a purity that can be used as a medicine. The invention relates to 1) Formula (I):

化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其溶劑合 物。 詳言之，係有關以下2)〜27)。 2)如1)記載之鹽，或其溶劑合物，其爲甲苯磺酸鹽。 3 )如1)記載之鹽，或其溶劑合物，其爲硫酸鹽。 200412946 4)如式U)化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其 溶劑合物之結晶：The p-toluenesulfonate, sulfate, hydrochloride, or solvate of the compound. Specifically, it is related to the following 2) to 27). 2) The salt according to 1), or a solvate thereof, which is a tosylate salt. 3) The salt according to 1), or a solvate thereof, which is a sulfate. 200412946 4) Crystals of p-toluenesulfonate, sulfate, hydrochloride, or solvate of a compound of formula U):

5) 如4)記載之結晶，其爲甲苯磺酸鹽或其溶劑合物之結晶。 6) 如5)記載之結晶，其粉末x線繞射峯中，面間隔（d)爲6.34 、12.04、19·06、23.78、24.76、2 5 · 4 4、及 2 5 · 7 6 (單位:Α) 之主峯。 7) 如4)記載之結晶，其爲硫酸鹽或其溶劑合物之結晶。 8) 如7 )記載之結晶，其粉末X線繞射峯中，面間隔（d)爲1 4 . 〇 4 、16.22、19.60、22.02、及 22.28(單位：）之主峯。 9) 一種製備式（I)化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽 、或其溶劑合物、或其結晶之方法，係將式（I)化合物：5) The crystal according to 4), which is a crystal of a tosylate salt or a solvate thereof. 6) For the crystal as described in 5), among the powder x-ray diffraction peaks, the interplanar spacing (d) is 6.34, 12.04, 19.06, 23.78, 24.76, 2 5 · 4 4, and 2 5 · 7 6 (units) : Α) the main peak. 7) The crystal according to 4), which is a crystal of a sulfate or a solvate thereof. 8) The crystal as described in 7), among the powder X-ray diffraction peaks, the interplanar spacing (d) is the main peak of 14.04, 16.22, 19.60, 22.02, and 22.28 (unit :). 9) A method for preparing p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof, or a crystal thereof of a compound of formula (I):

或其溶劑合物，與對-甲苯磺酸、硫酸、或鹽酸反應。 10) 如9)記載之方法，係爲對-甲苯磺酸鹽、硫酸鹽、鹽酸臨 、或其溶劑合物結晶之製造方法。 11) 如10)記載之方法，係爲對-甲苯磺酸鹽或其溶劑合物結 晶之製造方法。 12) 如1〇)記載之方法，係爲硫酸鹽或其溶劑合物結晶之製造 方法。 200412946 1 3)—種製備式（I)化合物或其溶劑合物之方法，係式（I):Or a solvate thereof, reacted with p-toluenesulfonic acid, sulfuric acid, or hydrochloric acid. 10) The method according to 9) is a method for producing a crystal of p-toluenesulfonate, sulfate, hydrochloric acid, or a solvate thereof. 11) The method according to 10) is a method for crystallizing p-toluenesulfonate or a solvate thereof. 12) The method according to 10) is a method for producing a crystal of sulfate or a solvate thereof. 200412946 1 3) —A method for preparing a compound of formula (I) or a solvate thereof, which is a formula (I):

化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其溶劑合物 ，進行結晶之脫鹽處理。 14) 如13)記載之製造方法，係將式⑴化合物之對-甲苯磺酸 鹽或其溶劑合物’進行結晶之脫鹽處理。 15) 如13)記載之製造方法，係將式（1)化合物之硫酸鹽或其溶 劑合物，進行結晶之脫鹽處理。 16) —種製備式（I)化合物或其溶劑合物之方法，係與對-甲苯 磺酸，硫酸，或鹽酸反應，而得式（I):The p-toluenesulfonate, sulfate, hydrochloride, or solvate of the compound is desalted by crystallization. 14) The production method according to 13), which is a desalting treatment of crystallizing the p-toluenesulfonic acid salt of the compound of the formula (I) or a solvate thereof. 15) The production method according to 13), which comprises subjecting the sulfate of a compound of formula (1) or a solvate thereof to a desalting treatment for crystallization. 16) A method for preparing a compound of formula (I) or a solvate thereof, which is reacted with p-toluenesulfonic acid, sulfuric acid, or hydrochloric acid to obtain formula (I):

化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其溶劑合物 結晶之工程，並將所得對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、 或其溶劑合物之結晶，進行脫鹽反應之工程。 1 7 )如1 6)記載之製造方法’係與甲苯磺酸反應，而得式（j) 化合物之對-甲苯磺酸鹽或其溶劑合物結晶之工程，及將所 得甲苯磺酸鹽或其溶劑合物之結晶，進行脫鹽反應之工程。 1 8)如1 6)記載之製造方法，係與硫酸反應，而得式（〗）化合物 之硫酸鹽或其溶劑合物結晶之工程，及將所得硫酸鹽或其溶 劑合物之結晶，進行脫鹽反應之工程。 -9- 200412946 19)一種如下式（II):A process of crystallizing p-toluenesulfonate, sulfate, hydrochloride, or a solvate of the compound, and crystallizing the obtained p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof, Engineering for desalination reaction. 17) The production method according to 16) is a process of crystallizing p-toluenesulfonate of a compound of formula (j) or a solvate thereof by reacting with toluenesulfonic acid, and crystallizing the obtained tosylate or The solvate crystals are subjected to a process of desalting reaction. 18) The production method according to 16), which is a process of reacting with sulfuric acid to crystallize the sulfate or solvate of the compound of formula (), and crystallizing the obtained sulfate or its solvate to Engineering of desalination reaction. -9- 200412946 19) A formula (II):

化合物，其溶劑合物，或其鹽。 20) 如19)記載之鹽，其爲鹽酸鹽。 21) —種製備含式（I):A compound, a solvate thereof, or a salt thereof. 20) The salt according to 19), which is a hydrochloride salt. 21) — a preparation containing formula (I):

化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其溶劑合物 、或其結晶之方法，係將式（II):The method of the compound's p-toluenesulfonate, sulfate, hydrochloride, or its solvate, or its crystal, is the formula (II):

化合物，其溶劑合物，或其鹽，與式（III):A compound, a solvate thereof, or a salt thereof, and formula (III):

XX

(HI) (式中，X爲鹵素或羥基） 化合物，其溶劑合物，或其鹽反應，可得式（I)(HI) (wherein X is a halogen or a hydroxyl group) A compound, a solvate thereof, or a salt thereof is reacted to obtain formula (I)

-10- 200412946 化合物’或其彳谷劑合物之工程；及將所得化合物或其溶劑合 物與對-甲苯磺酸，硫酸，或鹽酸反應之工程。 22)如21)記載之方法，其爲對-甲苯磺酸鹽、硫酸鹽、鹽酸 鹽、或其溶劑合物結晶之製造方法。 2 3 )如2 2)記載之方法，其爲對-甲苯磺酸鹽或其溶劑合物結 晶之製造方法。 24) 如22)記載之方法，其爲硫酸鹽或其溶劑合物結晶之製造 方法。 25) —種如下式（IV):-10- 200412946 Project of compound 'or its cereals; and project of reacting the obtained compound or its solvate with p-toluenesulfonic acid, sulfuric acid, or hydrochloric acid. 22) The method according to 21), which is a method for producing crystals of p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof. 2 3) The method according to 2 2), which is a method for crystallizing p-toluenesulfonate or a solvate thereof. 24) The method according to 22), which is a method for producing a crystal of sulfate or a solvate thereof. 25)-the following formula (IV):

之化合物，其溶劑合物，或其鹽。 26) 如25)記載之鹽，其爲式（IV)化合物之對-甲苯磺酸鹽， 草酸鹽，或甲酸鹽。 27) 如26)記載之鹽，其爲甲苯磺酸鹽。 式（I) ’式（II)及式（IV)化合物可含有光學異構物及消旋體 之光學異構物混合物。 本說明書中，「溶劑合物」爲如有機溶劑之溶劑合物，包 含水合物等。形成水合物時，可配以任意數目之水分子。 本說明書中使用化合物之鹽爲無機酸（鹽酸，氫溴酸，磷 酸，硫酸’硝酸等），及有機酸（乙酸，草酸，檸檬酸，順丁 烯二酸，反丁烯二酸，苯磺酸，對-甲苯磺酸，甲磺酸，甲 酸等）之鹽，或鹼金屬（鋰，鈉，鉀等），鹼土金屬（鎂，鈣等） ，銨，有機鹼及胺基酸之鹽。此鹽可依習用方法而形成。 200412946 本說明書中，式（i)化合物之鹽，及其溶劑合物之鹽Compounds, solvates, or salts thereof. 26) The salt according to 25), which is a p-toluenesulfonate, an oxalate, or a formate of a compound of the formula (IV). 27) The salt according to 26), which is a tosylate salt. The compounds of formula (I) 'and formula (II) and formula (IV) may contain a mixture of optical isomers and optical isomers. In this specification, a "solvate" is a solvate such as an organic solvent, including a hydrate, and the like. When forming a hydrate, any number of water molecules can be added. The salts of the compounds used in this specification are inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, etc.) and organic acids (acetic acid, oxalic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid Salts of acids, p-toluenesulfonic acid, methanesulfonic acid, formic acid, etc., or salts of alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases and amino acids. This salt can be formed according to conventional methods. 200412946 In this specification, salts of compounds of formula (i), and salts of solvates thereof

宜爲無機酸鹽或有機酸鹽。無機酸鹽宜爲硫酸鹽及鹽酸鹽 ’有機酸鹽宜爲對-甲苯磺酸鹽。特宜爲硫酸鹽或對-甲苯磺 酸鹽。 可得對-甲苯磺酸鹽、硫酸鹽、及鹽酸鹽結晶。該結晶之 不純物含量低而所得純度高。尤其爲對-甲苯磺酸鹽及硫酸 鹽結晶之場合，可得不純物含有量非常低，且純度爲高之結 晶。因此’將式（I)化合物，轉爲上述鹽，尤其對-甲苯磺酸 鹽或硫酸鹽’結晶化後，予以脫鹽反應來對該化合物進行精 製。依上述方法精製，則可作爲醫藥使用純度之式⑴化合物 可工業製造。 本說明書中，式（II)化合物，其溶劑合物，其鹽，或其結Preferably it is an inorganic acid salt or an organic acid salt. The inorganic acid salt is preferably a sulfate and the hydrochloride. The organic acid salt is preferably a p-toluenesulfonate. Particularly preferred is sulfate or p-toluenesulfonate. Crystals of p-toluenesulfonate, sulfate, and hydrochloride are obtained. The crystal has a low impurity content and a high purity is obtained. In particular, when crystals of p-toluenesulfonate and sulfate are crystallized, crystals having a very low impurity content and a high purity can be obtained. Therefore, 'the compound of formula (I) is converted into the above-mentioned salt, especially p-toluenesulfonate or sulfate', and then the compound is purified by desalting reaction. Purified according to the above method, the compound of formula (I) can be used in medicine for purity and can be industrially manufactured. In the present specification, a compound of formula (II), a solvate thereof, a salt thereof, or a compound thereof

爲製造式（I)化合物之較佳中間體。特宜爲上述化合物之鹽酸 鹽0 本說明書中，式（IV)化合物，其溶劑合物，其鹽，或其結 200412946It is a preferred intermediate for the production of compounds of formula (I). Particularly preferred is the hydrochloride salt of the above compound. In this specification, the compound of formula (IV), its solvate, its salt, or its compound 200412946

爲製造式（i)化合物之較佳中間體。特宜爲上述化合物，及上 述化合物之早酸鹽’對-甲苯磺酸鹽，或甲酸鹽爲有高利用 價値之中間體。最宜爲上述化合物或上述化合物之對-甲苯 磺酸鹽。 本說明書中，下式化合物，其溶劑合物，其鹽，或其結晶It is a preferred intermediate for the production of compounds of formula (i). Particularly preferred are the above-mentioned compounds, and the early salt of the above-mentioned compound, p-toluenesulfonate, or the formate is an intermediate having a high valency. Most preferred is the above-mentioned compound or a p-toluenesulfonic acid salt of the above-mentioned compound. In this specification, a compound of the following formula, a solvate thereof, a salt thereof, or a crystal thereof

MsO -^^C0NH2 九N、nMsO-^^ C0NH2 Nine, n

Boc (式中，Ms爲甲磺醯基，Boc爲第三丁氧羰基） 爲製造式（I)化合物之較佳中間體。 本說明書中，下式化合物，其溶劑合物，其鹽，或其結晶 /^CONH,Boc (in the formula, Ms is methanesulfonyl and Boc is a third butoxycarbonyl group) is a preferred intermediate for the production of a compound of formula (I). In this specification, a compound of the following formula, a solvate thereof, a salt thereof, or a crystal thereof

Boc (式中，Boc之定義如上） 爲製造式（I)化合物之較佳中間體。 本說明書中，脫鹽反應係將式（I)化合物之鹽，例如無機酸 鹽或有機酸鹽，與式（I)化合物進行轉換反應。具體而言，係 將化合物（I)之鹽以鹼性水溶液處理來進行。 【實施方式】 1工程 -13- 以下爲將式（i)化合物引導爲鹽之工程。Boc (wherein Boc is as defined above) is a preferred intermediate for the production of compounds of formula (I). In this specification, a desalting reaction is a conversion reaction of a salt of a compound of formula (I), such as an inorganic acid salt or an organic acid salt, with a compound of formula (I). Specifically, the salt of the compound (I) is treated with an alkaline aqueous solution. [Embodiment] 1 Project -13- The following is a project for guiding a compound of formula (i) into a salt.

200412946 (式中，Ts爲對-甲苯磺醯基。） 鹽（I)之製備 將化合物（I)溶在溶劑，加入對-甲苯磺酸溶液，攪拌並過 濾後，可得鹽（I)。 對-甲苯磺酸鹽之反應溶劑（結晶溶劑）爲乙酸乙酯，甲醇， 丙酮，乙醇，四氫呋喃，乙腈，丁酮，二氯甲烷，乙醚，或 其混合溶液等。宜爲乙酸乙酯及甲醇之混合溶劑。 又，對-甲苯磺酸之溶液爲乙酸乙酯，丙酮，四氫呋喃， 乙腈，丁酮，二氯甲烷，乙醚等溶液。宜爲乙酸乙酯溶液。 反應溫度爲ot：〜50°c，宜爲5°c〜35t：。 反應時間爲0.5小時〜5 · 0小時，宜爲〇 . 5小時〜3 · 5小時 〇 相同地，加入硫酸，鹽酸，硝酸，草酸，甲磺酸，或甲酸 等，各可得硫酸鹽，鹽酸鹽，硝酸鹽，草酸鹽，甲磺酸鹽’ 或甲酸鹽。特宜爲硫酸鹽及鹽酸鹽。 硫酸鹽之反應溶劑爲甲醇，結晶溶劑宜爲丁酮。 鹽酸鹽之結晶溶劑宜爲丙酮。 2工程 以下爲脫鹽反應之工程。 -14- 200412946200412946 (In the formula, Ts is p-toluenesulfonyl.) Preparation of salt (I) Compound (I) is dissolved in a solvent, p-toluenesulfonic acid solution is added, and the salt (I) is obtained after stirring and filtering. The reaction solvent (crystallization solvent) of p-toluenesulfonate is ethyl acetate, methanol, acetone, ethanol, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dichloromethane, ether, or a mixed solution thereof. A mixed solvent of ethyl acetate and methanol is preferred. The solution of p-toluenesulfonic acid is a solution such as ethyl acetate, acetone, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dichloromethane, diethyl ether and the like. Preferably it is an ethyl acetate solution. The reaction temperature is ot: ~ 50 ° c, preferably 5 ° c ~ 35t :. The reaction time is 0.5 hours to 5.0 hours, preferably 0.5 hours to 3.5 hours. Similarly, sulfuric acid, hydrochloric acid, nitric acid, oxalic acid, methanesulfonic acid, or formic acid, etc. are added, and sulfates and salts can be obtained each. Acid salt, nitrate, oxalate, mesylate 'or formate. Especially suitable are sulfate and hydrochloride. The reaction solvent of the sulfate is methanol, and the crystallization solvent is preferably methyl ethyl ketone. The crystalline solvent of the hydrochloride is preferably acetone. 2 Project The following is the project of desalination reaction. -14- 200412946

(式中，Ts之定義如上） 本工程爲將對-甲苯磺酸鹽（I)進行脫鹽反應，而得化合物 (I)之工程。 在鹽（I)中加入溶劑後，加入鹼性水溶液，攪拌，可得化合 物（I)。 溶劑可爲乙酸乙酯，甲醇，乙醇，丙酮，乙腈，二甲亞礪 等溶劑，宜爲乙酸乙酯。 鹼性水溶液爲碳酸氫鈉水溶液，碳酸鈉水溶液，氫氧化鈉 水溶液’氫氧化鉀水溶液等，宜爲碳酸氫鈉水溶液。 反應溫度爲0 °c〜5 0 °c，宜爲0 °C〜3 5 °c。 反應時間爲5分〜3.0小時，宜爲10分〜1.5小時。化合 物（I)依上述方法可得固體。 依此脫鹽反應，可將硫酸鹽、鹽酸鹽等鹽引導爲化合物（1) 〇 式⑴化合物可依WOO 1 /303 87記載之方法合成，亦可依以 下所示方法合成。 3工程(In the formula, the definition of Ts is as above.) This project is a project to obtain a compound (I) by desalting a p-toluenesulfonate (I). After adding a solvent to the salt (I), an alkaline aqueous solution is added and stirred to obtain the compound (I). The solvent may be ethyl acetate, methanol, ethanol, acetone, acetonitrile, dimethylarene, etc., and is preferably ethyl acetate. The alkaline aqueous solution is an aqueous solution of sodium bicarbonate, an aqueous solution of sodium carbonate, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, etc., and is preferably an aqueous solution of sodium bicarbonate. The reaction temperature is from 0 ° C to 50 ° C, preferably from 0 ° C to 3 5 ° C. The reaction time is 5 minutes to 3.0 hours, preferably 10 minutes to 1.5 hours. Compound (I) can be obtained as a solid by the above-mentioned method. According to this desalting reaction, salts such as sulfate and hydrochloride can be guided to the compound (1). The compound of formula (I) can be synthesized according to the method described in WO 1/303 87, or can be synthesized according to the method shown below. 3 works

-15- 200412946 (式中’ Boc之定義如上） 本工程爲將1位保護基之Boc基進行脫保護之工程。 將化合物（8)在溶劑中溶解，加入酸（含路易士酸），攪拌， 可得化合物（IV)。 溶劑可爲乙酸乙酯，甲醇，乙醇，異丙醇，二氯甲烷，二 曙烷’水等。宜爲乙酸乙酯及甲醇之混合溶劑。 酸（含路易士酸）可爲鹽酸，三氟乙酸，乙酸，對-甲苯磺酸 ，氯化鋁，矽膠等。宜爲鹽酸。鹽酸宜加入乙酸乙酯溶液。 反應溫度爲0°C〜50°C，宜爲5°C〜45°C。 反應時間爲1.0小時〜5.0小時，宜爲1.0小時〜4.0小時 4工程-15- 200412946 (where ‘Boc’ is defined as above) This project is a project to deprotect a Boc group with a protecting group. The compound (8) is dissolved in a solvent, an acid (including Lewis acid) is added, and the mixture is stirred to obtain the compound (IV). The solvent may be ethyl acetate, methanol, ethanol, isopropanol, dichloromethane, dioxane 'water, and the like. A mixed solvent of ethyl acetate and methanol is preferred. The acid (including Lewis acid) may be hydrochloric acid, trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, aluminum chloride, silicone, etc. Preferably it is hydrochloric acid. Hydrochloric acid is preferably added to an ethyl acetate solution. The reaction temperature is 0 ° C ~ 50 ° C, preferably 5 ° C ~ 45 ° C. The reaction time is 1.0 hours to 5.0 hours, preferably 1.0 hours to 4.0 hours. 4 works

(式中，Boc之定義如上，p-TsOH爲對-甲苯磺酸） 本工程爲製備化合物（IV)之對-甲苯磺酸鹽之工程。 將化合物（IV)在溶劑中溶解，加入對-甲苯磺酸，攪拌後 ，濾集結晶，可得鹽（IVb)。 溶劑可爲乙酸乙酯，乙酸丁酯，甲醇，乙醇，丙醇，丁酮 ，丙酮，四氫呋喃，乙腈，二氯甲烷，氯仿，乙醚，或其混 合溶液等。宜爲乙酸丁酯及乙酸乙酯之混合溶劑。 對·甲苯磺酸必要時也可以含對-甲苯磺酸之乙酸乙酯，甲 醇，乙醇，丙醇，丁酮，乙酸丁酯等之溶液加入。宜以乙酸 -16- 200412946 乙酯之溶液加入。 與草酸，甲酸，鹽酸，硫酸，硝酸等酸反應，可得對應化 合物（iv)之草酸鹽，甲酸鹽，鹽酸鹽、硫酸鹽、硝酸鹽。宜 草酸鹽，甲酸鹽。 欲得草酸鹽時，宜使用乙酸乙酯及正丙醇之混合液。又， 加入草酸鹽時，宜以乙酸乙酯及正丙醇之混合液加入。 欲得甲酸鹽時，溶劑宜爲丁酮。 反應溫度爲0°C〜50°C，宜爲5°c〜45°c。 反應時間爲1 · 0小時〜5.0小時，宜爲1.5小時〜4.5小時 5工程(In the formula, Boc is defined as above, p-TsOH is p-toluenesulfonic acid.) This project is a process for preparing p-toluenesulfonic acid salt of compound (IV). The compound (IV) is dissolved in a solvent, p-toluenesulfonic acid is added, and after stirring, the crystals are collected by filtration to obtain a salt (IVb). The solvent may be ethyl acetate, butyl acetate, methanol, ethanol, propanol, methyl ethyl ketone, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, ether, or a mixed solution thereof. It is preferably a mixed solvent of butyl acetate and ethyl acetate. If necessary, p-toluenesulfonic acid may be added as a solution containing p-toluenesulfonic acid in ethyl acetate, methanol, ethanol, propanol, methyl ethyl ketone, butyl acetate, and the like. It should be added as a solution of -16- 200412946 ethyl acetate. By reacting with oxalic acid, formic acid, hydrochloric acid, sulfuric acid, nitric acid and other acids, the oxalate, formate, hydrochloride, sulfate, and nitrate of the corresponding compound (iv) can be obtained. Should be oxalate, formate. To obtain oxalate, a mixed solution of ethyl acetate and n-propanol should be used. When adding oxalate, it is suitable to add it as a mixed solution of ethyl acetate and n-propanol. When formate is to be obtained, the solvent is methyl ethyl ketone. The reaction temperature is 0 ° C ~ 50 ° C, preferably 5 ° c ~ 45 ° c. The reaction time is 1.0 hours to 5.0 hours, preferably 1.5 hours to 4.5 hours. 5 works

(式中，Boc及p-TsOH之定義如上） 本工程將1位N-Boc基之脫保護與鹽之生成反應以1工程 來進行。 在化合物（8)溶液中加入對-甲苯磺酸一水合物。反應後， 加入結晶化之溶劑，攪拌結晶化後，可得目的鹽（IVb)。 溶解化合物（8)之溶劑可爲乙酸乙酯，乙酸丁酯，甲醇，丙 酮，乙醇，四氫呋喃，乙腈，丁酮，二氯甲烷，乙醚，或其 混合溶液等。宜爲乙酸乙酯。 反應溫度爲〇°C〜50°C，宜爲3〇t〜45°C。 -17- 200412946 反應時間爲1.0小時〜5.0小時，宜爲2.0小時〜4.0小時 〇 所加入結晶化溶劑可爲乙酸丁酯，乙醚，氯仿，二氯甲烷 等。宜爲乙酸乙酯及乙酸丁酯之混合溶劑。 結晶化溫度爲- l〇°C〜45°c，宜爲- 5°c〜45°c。 結晶化時間爲1 · 〇小時〜5.0小時，宜爲2.0小時〜4.0小 時。 6工程(In the formula, the definitions of Boc and p-TsOH are as above.) In this project, the reaction of deprotection of N-Boc group at one position and the formation of salt is performed in one process. To the solution of compound (8) was added p-toluenesulfonic acid monohydrate. After the reaction, a crystallization solvent is added, and after stirring and crystallization, the objective salt (IVb) can be obtained. The solvent in which the compound (8) is dissolved may be ethyl acetate, butyl acetate, methanol, acetone, ethanol, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dichloromethane, ether, or a mixed solution thereof. Preferably it is ethyl acetate. The reaction temperature is 0 ° C ~ 50 ° C, preferably 30t ~ 45 ° C. -17- 200412946 The reaction time is 1.0 hour to 5.0 hours, preferably 2.0 hours to 4.0 hours. The crystallization solvent added may be butyl acetate, ether, chloroform, dichloromethane, and the like. A mixed solvent of ethyl acetate and butyl acetate is preferred. The crystallization temperature is -10 ° C ~ 45 ° c, preferably -5 ° c ~ 45 ° c. The crystallization time is from 1.0 hour to 5.0 hours, and preferably from 2.0 hours to 4.0 hours. 6 works

本工程爲在1位引入已取代苄醯基之工程。 將對應1位側鏈之羧酸（V)在溶劑中溶解，加入少量之二 甲基甲醯胺及鹵化劑，攪拌後，可得對應1位側鏈之醯鹵化 物。 用以合成醯鹵化物之溶劑可爲乙腈，二氯甲烷，四氫呋喃 等，宜爲乙腈。 鹵化劑爲亞磺醯氯，氧氯化磷，草醯氯，五氯化磷等。宜 爲亞磺醯氯。 反應溫度爲0 °C〜5 0 °c，宜爲1 0 °c〜3 0 °c。 反應時間爲0 · 5小時〜3 · 5小時，宜爲1 · 〇小時〜3.0小時 將含化合物（IV)之溶劑中，加入鹼及上述醯鹵化物之溶液 200412946 ，攪拌後，可得化合物（v i)。 醯鹵化物及化合物（IV)之反應溶劑可爲四氫呋喃，乙膳， 苯’二氯甲烷，氯仿，二噚烷等。宜爲四氫呋喃。 鹼可爲三乙胺，三丁胺，吡啶，N-甲嗎啉等。宜爲三乙胺 〇 反應溫度爲-10°C〜50°c，宜爲（TC〜35°c。 反應時間爲5小時〜24小時，宜爲1 〇小時〜2〇小時。 7工程This project is a project to introduce a substituted benzamidine group at the 1 position. The carboxylic acid (V) corresponding to the side chain at the 1-position is dissolved in a solvent, and a small amount of dimethylformamide and a halogenating agent are added. After stirring, a hafnium halide corresponding to the side chain at the 1-position can be obtained. The solvent used for synthesizing the hafnium halide may be acetonitrile, dichloromethane, tetrahydrofuran, etc., preferably acetonitrile. Halogenating agents are sulfenyl chloride, phosphorus oxychloride, grasshopper chlorine, and phosphorus pentachloride. Should be sulfenyl chloride. The reaction temperature is 0 ° C ~ 50 ° C, preferably 10 ° C ~ 30 ° C. The reaction time is from 0.5 hours to 3.5 hours, preferably from 1.0 hours to 3.0 hours. The solvent containing the compound (IV) is added with a solution of the base and the above hafnium halide 200412946. After stirring, the compound ( vi). The reaction solvents of the sulfonium halide and the compound (IV) may be tetrahydrofuran, ethyl acetate, benzene 'dichloromethane, chloroform, dioxane and the like. Tetrahydrofuran is preferred. The base may be triethylamine, tributylamine, pyridine, N-methylmorpholine and the like. It is preferably triethylamine 〇 The reaction temperature is -10 ° C ~ 50 ° c, preferably (TC ~ 35 ° c. The reaction time is 5 hours ~ 24 hours, preferably 10 hours ~ 20 hours. 7 projects

本工程爲將2位側鏈醯胺基轉爲氰基之工程。 將化合物（VI)在溶劑中溶解，加入鹼及脫水劑之溶液，攪 拌後，可得化合物（VII)。 溶劑可爲四氫呋喃，二氯甲烷，氯仿，二噚烷，二甲亞礪 ，二甲基甲醯胺，乙腈等。宜爲四氫呋喃。 鹼可爲三乙胺，吡啶，N-甲嗎啉等。宜爲三乙胺。 脫水劑可爲三氯乙醯氯，氧氯化磷，草醯氯，三氟乙酐， 亞磺醯氯等。宜爲三氯乙醯氯。 反應溫度爲-1 0 °C〜1 0 0 °C，宜爲-5 °C〜1 5 °C。 反應時間爲0.5小時〜5.0小時，宜爲0.5小時〜2 · 0小時 200412946This project is a project to convert the amine group at the 2-position side chain to a cyano group. The compound (VI) is dissolved in a solvent, a solution of an alkali and a dehydrating agent is added, and the compound (VII) is obtained after stirring. The solvent may be tetrahydrofuran, dichloromethane, chloroform, dioxane, dimethylarylene, dimethylformamide, acetonitrile, and the like. Tetrahydrofuran is preferred. The base may be triethylamine, pyridine, N-methylmorpholine and the like. Should be triethylamine. The dehydrating agent can be trichloroacetammonium chloride, phosphorus oxychloride, chloramphenicol, trifluoroacetic anhydride, sulfenyl chloride, and the like. Should be trichloroacetamidine. The reaction temperature is -10 ° C to 100 ° C, preferably -5 ° C to 15 ° C. The reaction time is 0.5 hours to 5.0 hours, preferably 0.5 hours to 2.0 hours.

m 本工程爲將2位側鏈氰基還原成胺基之工程。 將含化合物（VII)之溶液，加入氨水及觸媒，加入水後， 濾除觸媒，可得化合物（II)。 含化合物（II)及氨水之溶液爲乙醇，甲醇，異丙醇，水， 四氫呋喃，乙酸乙酯等溶液，宜爲乙醇溶液。 觸媒可爲阮來鎳（註冊商標），鈀-碳，氧化鉑，氫氧化絶_ 碳等。宜爲阮來鎳（註冊商標）。 反應溫度爲OC〜50C ’宜爲5°C〜40°C。 反應時間爲1.0小時〜1 0小時，宜爲2.0小時〜7 · 0小時 〇 再將化合物（II)在溶劑中溶解，與鹽酸反應，可得鹽酸鹽 (II)。 所得鹽酸鹽（II)之溶劑可爲乙酸乙酯，甲醇，丙酮，乙醇 ，四氫呋喃，乙腈，丁酮，二氯甲烷，乙醚等。宜爲乙酸乙 酯。 與硫酸，乙酸，硝酸，對-甲苯磺酸，草酸，甲酸，檸檬 酸等酸反應，可得對應化合物（II)之硫酸鹽，乙酸鹽，硝酸 鹽，對-甲苯磺酸鹽，草酸鹽，甲酸鹽，檸檬酸鹽等鹽。 9工程 -20·m This project is a project to reduce the cyano group at the 2-position side chain to an amine group. The solution containing the compound (VII) is added with ammonia water and a catalyst. After adding water, the catalyst is filtered off to obtain the compound (II). The solution containing the compound (II) and ammonia water is a solution of ethanol, methanol, isopropanol, water, tetrahydrofuran, ethyl acetate, etc., preferably an ethanol solution. The catalyst can be Ruanlai Nickel (registered trademark), palladium-carbon, platinum oxide, carbon hydroxide, etc. Should be Ruan Lai Nickel (registered trademark). The reaction temperature is OC ~ 50C ', preferably 5 ° C ~ 40 ° C. The reaction time is 1.0 hour to 10 hours, preferably 2.0 hours to 7.0 hours. The compound (II) is dissolved in a solvent and reacted with hydrochloric acid to obtain the hydrochloride (II). The solvent of the obtained hydrochloride (II) may be ethyl acetate, methanol, acetone, ethanol, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dichloromethane, diethyl ether and the like. Preferably it is ethyl acetate. By reacting with sulfuric acid, acetic acid, nitric acid, p-toluenesulfonic acid, oxalic acid, formic acid, citric acid and other acids, sulfate, acetate, nitrate, p-toluenesulfonic acid, and oxalate of the corresponding compound (II) can be obtained , Formate, citrate and other salts. 9 Engineering -20 ·

200412946 (式中，x爲鹵素或羥基） 本工程爲在化合物（II)或其鹽之2位引入側鏈之工程。 將化合物（II)或其鹽在溶劑中溶解，加入鹼後，加入2位 側鏈之酸或醯鹵化物（III)，攪拌後，可得化合物（I)。 出發物質宜爲化合物（II)之鹽。特宜爲鹽酸鹽。 化合物（III)宜爲醯鹵化物。特宜爲醯氯。 溶劑可爲乙腈，四氫呋喃，苯，二氯甲烷，氯仿，二噚烷 等。宜爲乙腈。 鹼可爲三丁胺，三乙胺，吡啶等。宜爲三丁胺。 反應溫度爲- 20T：〜30°c，宜爲- 20°c〜5°c。 反應時間爲0.5小時〜5.0小時，宜爲2.0小時〜4.0小時 〇 4工程之出發原料化合物（8)可由如下第1工程〜第7工程 來合成。 第1工程200412946 (wherein x is a halogen or a hydroxyl group) This project is a project of introducing a side chain at the 2-position of compound (II) or a salt thereof. The compound (II) or a salt thereof is dissolved in a solvent, and after adding a base, an acid or a hafnium halide (III) of a side chain at the 2-position is added, and the compound (I) is obtained after stirring. The starting material is preferably a salt of compound (II). Particularly preferred is the hydrochloride. Compound (III) is preferably a hafnium halide. Especially suitable for thorium chloride. The solvent may be acetonitrile, tetrahydrofuran, benzene, methylene chloride, chloroform, dioxane and the like. Should be acetonitrile. The base may be tributylamine, triethylamine, pyridine and the like. Should be tributylamine. The reaction temperature is -20T: ~ 30 ° c, preferably -20 ° c ~ 5 ° c. The reaction time is 0.5 hours to 5.0 hours, preferably 2.0 hours to 4.0 hours. The starting compound (8) from the 4th process can be synthesized from the first process to the 7th process as follows. The first project

(式中’ Boc之疋義如上） 此工程爲將吡咯啶基之1位以Boc保護之工程。 將反-4-羥基L-脯胺酸（1)在溶劑中，於鹼存在下，加入Boc 200412946 化劑來反應而得化合物（2)。 溶劑可爲甲醇，丁醇，二曙烷等。宜爲甲醇。 鹼可爲氫氧化鈉，氫氧化鉀，碳酸鈉，碳酸鉀等鹼性水溶 液’且爲氣氧化納水溶液。(In the formula, the meaning of Boc is as above.) This project is a project in which 1-position of pyrrolidinyl is protected by Boc. The compound (2) is obtained by reacting trans-4-hydroxy L-proline (1) in a solvent in the presence of a base and adding a Boc 200412946 chemist. The solvent may be methanol, butanol, dioxane and the like. Methanol is preferred. The alkali may be an alkaline aqueous solution 'such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, and it may be a sodium hydroxide aqueous solution.

Boc化劑可爲二碳酸二第三丁酯，第三丁氧羰基疊氮， 桌二丁氧系氧亞胺）-2 -苯乙腈等。宜爲二碳酸二第三丁酯。 B 〇c化劑必要時，可使用四氫呋喃，二卩等烷之溶劑，宜爲四 氫呋喃溶液。 反應溫度爲- 5.0°C〜35°C，宜爲0°C〜35。(：。 反應時間爲1 · 0小時〜1 0小時，宜爲3 · 0小時〜5 · 〇小時 第2工程The Bocating agent may be di-tert-butyl dicarbonate, tert-butoxycarbonyl azide, bis-dioxy-oxyimine) -2 -phenylacetonitrile, and the like. Preferably it is di-tert-butyl dicarbonate. If necessary, a solvent such as tetrahydrofuran, dioxane and the like may be used as the B ocating agent, preferably a tetrahydrofuran solution. The reaction temperature is -5.0 ° C ~ 35 ° C, preferably 0 ° C ~ 35. (:. The reaction time is from 1.0 hours to 10 hours, preferably from 3.0 hours to 5 hours. The second process

(式中，Boc及Ms之定義如上） 本工程爲將4位羥基予以甲磺醯化之工程。 將化合物（2)在溶劑中，依次加入鹼，甲磺醯化劑，攪拌 後，可得化合物（3)。 溶劑可爲乙酸乙酯，二氯甲烷，四氫呋喃等。宜爲乙酸乙 酯。 鹼可爲三乙胺，吡啶，N-甲嗎啉，三丁胺等。宜爲三乙胺 甲磺醯化劑可爲甲磺醯氯，甲磺酐等。宜爲甲磺醯氯。 反應溫度爲- 20°C〜25°C，宜爲-15°C〜0°C。 -22- 200412946 反應時間爲〇. 5小時〜1 〇小時，宜爲1 · 0小時〜5 ·0小時 第3工程(In the formula, the definitions of Boc and Ms are as above.) This project is a project in which the 4-position hydroxyl group is methylsulfonated. The compound (2) is added to the solvent, a base, a methanesulfonating agent are sequentially added, and the compound (3) is obtained after stirring. The solvent may be ethyl acetate, dichloromethane, tetrahydrofuran and the like. Preferably it is ethyl acetate. The base may be triethylamine, pyridine, N-methylmorpholine, tributylamine, and the like. It is preferably triethylamine. The methanesulfonating agent may be methanesulfonyl chloride, methanesulfonic anhydride and the like. Should be mesylate. The reaction temperature is -20 ° C ~ 25 ° C, preferably -15 ° C ~ 0 ° C. -22- 200412946 The reaction time is from 0.5 hours to 10 hours, preferably from 1.0 hours to 5.0 hours

(式中’ Boc及Ms之定義如上） 此工程爲將2位羧酸與4位甲磺醯基環化來內酯化之工程 〇 將含化合物（3)之溶液，加入溶劑及鹼，攪拌後，可得化 合物（4)。 溶劑可爲乙酸乙酯，二甲基甲醯胺，四氫呋喃等。宜爲乙 酸乙酯，二甲基甲醯胺。 鹼可爲無水碳酸鈉，無水碳酸鉀，碳酸鈉，碳酸鉀等。特 宜爲無水碳酸鈉。 反應溫度爲50°C〜100°C，宜爲75°C〜9(TC。 反應時間爲〇 · 5小時〜3 · 0小時，宜爲〇 . 5小時〜1 · 5小時 〇 第4工程(In the formula, the definition of Boc and Ms is as above.) This project is a process of lactonizing the carboxylic acid at the 2-position and the mesylate at the 4-position by lactonization. 0. The solution containing the compound (3) is added with a solvent and a base and stirred Then, compound (4) can be obtained. The solvent may be ethyl acetate, dimethylformamide, tetrahydrofuran and the like. Preferred are ethyl acetate and dimethylformamide. The alkali may be anhydrous sodium carbonate, anhydrous potassium carbonate, sodium carbonate, potassium carbonate and the like. Particularly preferred is anhydrous sodium carbonate. The reaction temperature is from 50 ° C to 100 ° C, preferably from 75 ° C to 9 ° C. The reaction time is from 0.5 to 3 hours, preferably from 0.5 to 1.5 hours. Project 4

(式中，Boc之定義如上） 將化合物（4)開環而合成化合物（5)之工程。 將化合物（4)在溶劑中，加入氨水，攪拌後，可得化合物（5) 200412946 溶劑可爲乙酸乙酯，異丙醇，四氫呋喃等。宜爲乙酸乙酯 反應溫度爲-2 0 °C〜2 5。(：，宜爲-1 〇 °C〜2 5 °C。 反應時間爲20分〜5.0小時，宜爲20分〜2.5小時。 第5工程 _aCONH2 5 6 (式中，Boc及Ms之定義如上）(In the formula, the definition of Boc is as above.) The process of compound (4) ring-opening to synthesize compound (5). Compound (4) is added to a solvent, ammonia water is added, and after stirring, compound (5) 200412946 can be obtained. The solvent can be ethyl acetate, isopropanol, tetrahydrofuran and the like. It is preferably ethyl acetate. The reaction temperature is -20 ° C ~ 25. (:, Preferably -10 ° C to 25 ° C. The reaction time is 20 minutes to 5.0 hours, preferably 20 minutes to 2.5 hours. 5th project_aCONH2 5 6 (where Boc and Ms are as defined above) )

本工程爲令4位羥基予以甲磺醯化之工程。 將化合物（5)於溶劑中，加入鹼及甲磺醯化劑，攪拌後 可得化合物（6)。 溶劑可爲四氫呋喃，乙酸乙酯等。宜爲四氫呋喃。 鹼可爲二異丙胺，三乙胺，N-甲嗎啉等。宜爲二異丙胺。 甲磺醯化劑可爲甲磺醯氯，甲磺酐等。宜爲甲磺醯氯。 反應溫度爲-2 0 °C〜1 5 °C，宜爲-1 〇 °C〜5 °C。 反應時間爲0 · 5小時〜5小時，宜爲1小時〜3小時。This project is a process to make the 4-position hydroxyl group mesylate. Compound (5) is added to a solvent, a base and a mesylate are added, and the compound (6) is obtained after stirring. The solvent may be tetrahydrofuran, ethyl acetate and the like. Tetrahydrofuran is preferred. The base may be diisopropylamine, triethylamine, N-methylmorpholine and the like. Should be diisopropylamine. Methanesulfonating agents may be methanesulfonyl chloride, methanesulfonic anhydride and the like. Should be mesylate. The reaction temperature is -2 0 ° C to 15 ° C, preferably -1 0 ° C to 5 ° C. The reaction time is from 0.5 hours to 5 hours, preferably from 1 hour to 3 hours.

第6工程The sixth project

(式中，Boc及Ms之定義如上） 本工程爲令4位側鏈轉爲異丁胺基之工程。 將化合物（6)與異丁胺反應，可得化合物（7)。 溶劑可爲水，二甲亞颯，氯仿，乙腈，甲醇，二甲基甲醯 胺等溶劑。特宜爲水。 -24- 200412946 反應溫度爲50°C〜100°C，宜爲6(TC〜90°C。 反應時間爲5.0小時〜15小時，宜爲8.0小時〜12小時。 第7工程(In the formula, Boc and Ms are as defined above.) This project is a project to convert the 4-position side chain into an isobutylamine group. Compound (6) is reacted with isobutylamine to obtain compound (7). The solvent may be a solvent such as water, dimethylformamide, chloroform, acetonitrile, methanol, dimethylformamide and the like. Especially suitable for water. -24- 200412946 The reaction temperature is 50 ° C ~ 100 ° C, preferably 6 ° C ~ 90 ° C. The reaction time is 5.0 hours ~ 15 hours, preferably 8.0 hours ~ 12 hours. The seventh project

(式中，Boc之定義如上） 本工程爲令4位側鏈中引入苄胺基之工程。 將化合物（7)在溶劑中，與2-苯基-苄基鹵及鹼反應，可得 化合物（8)。 溶劑可爲乙腈，二甲基甲醯胺，二甲亞楓，四氫呋喃，乙 醇，丙醇，異丙醇，甲苯等。宜爲乙腈。 2-苯基-苄基鹵爲2-苯基-苄基氯，2-苯基-苄基溴等。宜爲 2-苯基-苄溴。 鹼可爲碳酸鈉，碳酸氫鈉，碳酸鉀等。宜爲碳酸鈉。 反應溫度爲20°C〜60°C，宜爲40°C〜50°C。 反應時間爲5 · 0小時〜24小時，宜爲7.0小時〜1 0小時。 化合物（1)〜（8)，（VI)，（VII)可包含光學異構物及消旋體 之光學異構物混合物。 實施例 本發明可由以下實施例詳加説明，但本發明並不限於此。 化合物（I)，（I)，（II)，及（IV)可由以下反應流程來合成。参 考例1〜1 5及實施例1〜1 3詳述各工程。 實施例中，使用以下之縮寫。 -25- 200412946(In the formula, the definition of Boc is as above.) This project is a project to introduce a benzylamine group into the 4-position side chain. Compound (7) is reacted with 2-phenyl-benzyl halide and a base in a solvent to obtain compound (8). The solvent may be acetonitrile, dimethylformamide, dimethylformene, tetrahydrofuran, ethanol, propanol, isopropanol, toluene, and the like. Should be acetonitrile. The 2-phenyl-benzyl halide is 2-phenyl-benzyl chloride, 2-phenyl-benzyl bromide, and the like. Preferably it is 2-phenyl-benzyl bromide. The base may be sodium carbonate, sodium bicarbonate, potassium carbonate and the like. Should be sodium carbonate. The reaction temperature is 20 ° C ~ 60 ° C, preferably 40 ° C ~ 50 ° C. The reaction time is 5.0 hours to 24 hours, preferably 7.0 hours to 10 hours. Compounds (1) to (8), (VI), (VII) may include a mixture of optical isomers and optical isomers. Examples The present invention will be described in detail by the following examples, but the present invention is not limited thereto. Compounds (I), (I), (II), and (IV) can be synthesized by the following reaction schemes. Reference examples 1 to 15 and examples 1 to 13 describe each process in detail. In the examples, the following abbreviations are used. -25- 200412946

Boc :第三丁氧羰基 Ms :甲磺醯基 Ts :對-甲苯磺醯基Boc: tert-butoxycarbonyl Ms: mesylsulfonyl Ts: p-toluenesulfonyl

- 26- 200412946 吡 200412946 4位側鏈之合成 Ο-26- 200412946 Pyramid 200412946 Synthesis of 4-side chain 〇

12 13 14 15 2位側鏈之合成 Η12 13 14 15 Synthesis of 2 side chain Η

Ο 16Ο 16

1818

HO,HO,

19 兄一— ο (ΜΙΑ) 1位側鏈之合成19 一一 — ο (ΜΙΑ) Synthesis of side chain at position 1

參考例1Reference example 1

羥體（2)之合成 將含反-4-羥基L-脯胺酸（l) 1000g(7.63mol)之甲醇3.6L懸 浮液，於5〜8°C下加入含氫氧化鈉3 17.8g(96%，7.63mol) 之水1.5L。於3〜9°C及1小時20分內滴加含二碳酸二第三 -28- 200412946 丁酯1831g(8.39mol)之四氫呋喃150mL溶液，於室溫下攪拌 3小時。將反應液減壓濃縮，所得殘留液3.44kg以乙酸乙酯 洗淨（2次），將有機層以水萃取。合倂水層，以濃鹽酸調至 ρΗ2·0，加入食鹽，以乙酸乙酯萃取3次。將有機層以飽和 食鹽水洗浄後減壓濃縮。在所得殘留液中加入乙酸乙酯，減 壓濃縮，反覆進行3次（水分至基質之1%以下），可得羥體（2) 之乙酸乙酯溶液3.5 0kg。此溶液可用於下一工程。 参考例2 HO〇Synthesis of Hydroxyl Form (2) A 3.6 L suspension of methanol containing 1000 g (7.63 mol) of trans-4-hydroxy L-proline (l) was added to 17.8 g of sodium hydroxide 3 at 5 to 8 ° C ( 96%, 7.63 mol) of water 1.5L. A 150 mL solution of tetrahydrofuran containing 1831 g (8.39 mol) of butyl dicarbonate -28- 200412946 was added dropwise at 3 to 9 ° C and 1 hour and 20 minutes, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, 3.44 kg of the obtained residual solution was washed with ethyl acetate (twice), and the organic layer was extracted with water. The aqueous layer was combined, adjusted to pH 2 · 0 with concentrated hydrochloric acid, common salt was added, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. Ethyl acetate was added to the obtained residual solution, concentrated under reduced pressure, and repeated 3 times (moisture to less than 1% of the matrix) to obtain 3.50 kg of an ethyl acetate solution of the hydroxyl body (2). This solution can be used in the next project. Reference example 2 HO〇

22

BocBoc

甲磺醯體（3)之合成 將含羥體（2)之乙酸乙酯溶液3.50kg (7.63m〇l)，加入乙酸 乙酯15.7L，再於-3〜-7°C下加入三乙胺2551 mL(d0.726， 18.3mol)。於-5〜- 9°C下及1小時55分間滴加甲磺醯氯 1299mL(dl.48，16.8mol)，於-5 〜- 8°C 下攪拌 1 小時 30 分。 加入含無水碳酸鈉1617g(15.3m〇l)之水4.5L溶液，於15〜 24°C下攪拌2小時20分。將反應液以濃鹽酸調至ρΗ2·0， 分層。將水層以乙酸乙酯萃取，將有機層以飽和食鹽水洗（2 次）後減壓濃縮。在所得殘留液中加入乙酸乙酯’減壓濃縮（ 水分至基質之1%以下），可得甲磺醯體（3)之乙酸乙酯溶液 3 · 5 0 k g 〇此溶液可用於下一工程。 参考例3 -29- 200412946Synthesis of methanesulfonate body (3): 3.50 kg (7.63 ml) of ethyl acetate solution containing hydroxyl body (2), 15.7 L of ethyl acetate was added, and then triethyl was added at -3 to -7 ° C. Amine 2551 mL (d0.726, 18.3mol). At -5 to -9 ° C and 1 hour 55 minutes, 1299 mL of mesylate chloride (dl.48, 16.8 mol) was added dropwise, and the mixture was stirred at -5 to -8 ° C for 1 hour and 30 minutes. A 4.5 L solution of 1617 g (15.3 ml) of anhydrous sodium carbonate was added, and the mixture was stirred at 15 to 24 ° C for 2 hours and 20 minutes. The reaction solution was adjusted to pH 2 · 0 with concentrated hydrochloric acid, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine (twice), and then concentrated under reduced pressure. Ethyl acetate was added to the obtained residual solution and concentrated under reduced pressure (moisture to less than 1% of the matrix) to obtain an ethyl acetate solution of methylsulfonate (3) 3.50 kg. This solution can be used in the next project . Reference example 3 -29- 200412946

內酯體（4)之合成 將含甲磺醯體（3)之乙酸乙酯溶液3.50kg(相當7.63mol)加 入乙酸乙酯1.0L，二甲基甲醯胺4.7L及無水碳酸鈉 9 7 0g( 9.15 mol)，於80〜86 °C下攪拌1小時18分。將反應液 冷却後加入含乙酸524mL(d1.049，9.15mo1)之冰水14.lkg ，以乙酸乙酯萃取2次。以乙酸乙酯萃取（2次）’將有機層 以水洗浄（3次）後減壓濃縮，可得含內酯體（4)之乙酸乙酯溶 液5.06kg。此溶液可用於下一工程。 参考例4Synthesis of lactone body (4) 3.50 kg (equivalent to 7.63 mol) of ethyl acetate solution containing methanesulfonium body (3) was added to 1.0 L of ethyl acetate, 4.7 L of dimethylformamide and anhydrous sodium carbonate 9 7 0g (9.15 mol), and stirred at 80 ~ 86 ° C for 1 hour and 18 minutes. After the reaction solution was cooled, 14.1 kg of ice water containing 524 mL of acetic acid (d1.049, 9.15 mo1) was added, and extracted twice with ethyl acetate. Extraction with ethyl acetate (twice) ', the organic layer was washed with water (three times), and then concentrated under reduced pressure to obtain 5.06 kg of an ethyl acetate solution containing a lactone (4). This solution can be used in the next project. Reference example 4

醯胺體（5)之合成 將含內酯體（4)之乙酸乙酯溶液5.06kg(相當7· 63mol)，加 入乙酸乙酯3.51^，於10〜17°〇及32分內滴加28%氨水 650mL(d0.995，10.6mol)，於 16 〜20 〇C 下攪拌 1 小時 20 分 。將反應液減壓濃縮，在所得殘留液中加入乙酸乙酯，再減 壓濃縮。將所得結晶性殘渣以乙酸乙酯/甲苯（1/1)洗浄，可 得含醯胺體（5)l442g(4工程總產率82.1%)之無色結品（熔點 164 〜166〇C ) 〇 C10H18N2O4 分析値：C，52.16; Η，7.88; N，12.17。 200412946 實測値：C，52.13; Η，7.87; N，12.31; H20，0.31。Synthesis of amide body (5) 5.06 kg (equivalent to 7.63 mol) of ethyl acetate solution containing lactone body (4), 3.51 ^ of ethyl acetate was added, and 28 was added dropwise within 10 to 17 ° and 32 minutes. 650mL of ammonia water (d0.995, 10.6mol), and stirred at 16 ~ 20 ° C for 1 hour and 20 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the solution was concentrated under reduced pressure. The obtained crystalline residue was washed with ethyl acetate / toluene (1/1) to obtain a colorless product (melting point: 164 ~ 166 ° C) containing 1,442 g (4 project total yield of 82.1%) of amidine (5). C10H18N2O4 analysis 値: C, 52.16; Η, 7.88; N, 12.17. 200412946 Found 値: C, 52.13; Η, 7.87; N, 12.31; H20, 0.31.

[a ]d-3· li〇.4〇， [ α ] 3 5 5 ]9·8±_0·6。，（MeOH，cl.004，25〇C 参考例5[a] d-3 · li0.4.0, [α] 3 5 5] 9 · 8 ± _0 · 6. , (MeOH, cl.004, 25 ° C Reference Example 5

甲磺醯體（6)之合成Synthesis of Mesylate (6)

將含醯胺體（5) 1 300g(5.65mol)之四氫呋喃15.6L懸浮液中 ，於-3 〜- 3.5°C 下加入二異丙胺 959mL(d0.715，6.78mol)， 再於-5〜2°C及45分內滴加甲磺醯氯481mL(dl.48,6.21mol) ，於1〜-2°C下攪拌1小時。反應液中加入imol/LHCl 1.2L 之冰水8.8kg及食鹽（l.9kg)，以乙酸乙酯萃取3次。將有機 層以飽和食鹽水洗浄（2次）後減壓濃縮。將所得殘渣自乙酸 乙酯/甲苯結晶化，可得甲磺醯體（6) 1 670g，（產率95.9%)之 無色結晶（熔點1 1 2〜1 1 4。(3 )。Add 1 300 g (5.65 mol) of tetrahydrofuran suspension containing ammonium (5) to 959 mL (d0.715, 6.78 mol) of diisopropylamine at -3 to -3.5 ° C, and then -5 to 481 mL (dl.48, 6.21 mol) of methanesulfonyl chloride was added dropwise at 2 ° C and 45 minutes, and stirred at 1 ~ -2 ° C for 1 hour. To the reaction solution, 8.8 kg of ice water and 1.2 L of imol / L HCl and common salt (1.9 kg) were added, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine (twice), and then concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate / toluene to obtain 1 670 g of mesylate carbohydrate (6) (yield 95.9%) as colorless crystals (melting point 1 12 to 1 1 4) (3).

Cl 1H20N2O6SCl 1H20N2O6S

分析値：C，42.85; Η，6.54; N，9.08; S，10.40。 實測値·· C，42.65; Η，6·45; Ν，9.22; S，10.34; Η20， 0.3 1。 [a ]D-24.9 九 〇.7°(MeOH，cl.000，2 5 °C )， 参考例6Analysis 値: C, 42.85; Η, 6.54; N, 9.08; S, 10.40. Measured 値 ·· C, 42.65; Η, 6.45; Ν, 9.22; S, 10.34; Η20, 0.3 1. [a] D-24.9 Nine 0.7 ° (MeOH, cl.000, 25 ° C), reference example 6

齡 6 -31- 200412946 異丁胺體（7)之合成 將甲磺醯體（6)1500g(4.87mol)溶在異丁胺 2417mL(d0.7 36 ，24.3 mol)及水4 95 mL，攪拌回流10小時30分。將反應液 減壓濃縮，所得油狀殘渣中加入乙酸乙酯，減壓濃縮，重覆 進行2次。將所得油狀殘渣中加入乙酸乙酯，冰水及20 %碳 酸鈉水溶液，萃取。將水層以乙酸乙酯萃取，有機層以10% 食鹽水洗浄後減壓濃縮。將所得油狀殘渣溶在乙腈，再減壓 濃縮，可得異丁胺體（7)1.50kg之油狀物。 参考例7Age 6 -31- 200412946 Synthesis of isobutylamine body (7) Dissolve 1500 g (4.87 mol) of methanesulfonium body (6) in 2417 mL (d0.7 36, 24.3 mol) of isobutylamine and 4 95 mL of water, stir Reflux for 10 hours and 30 minutes. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained oily residue, and the mixture was concentrated under reduced pressure. This was repeated twice. The obtained oily residue was added with ethyl acetate, ice water and 20% aqueous sodium carbonate solution, and extracted. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with 10% brine, and then concentrated under reduced pressure. The obtained oily residue was dissolved in acetonitrile and then concentrated under reduced pressure to obtain 1.50 kg of an isobutylamine body (7) as an oily substance. Reference example 7

苄胺體（8)之合成 將含異丁胺體1.56kg(4.83mol)之乙腈9L溶液，加入2-苯基-苄基溴1260g(校正純度1202g; leq)及碳酸鈉 77 4g(1.5eq)，於45〜46°C下攪拌8.5小時。靜置一夜放置後 ，以濾紙過濾，減壓濃縮，可得含目的物（8)之油狀殘渣 2.50kg(理論量 2183g)。 参考例8 (以下至参考例1〇爲有關4位側鏈2-苯基-苄基溴（15)之合成Synthesis of benzylamine (8) 9L of acetonitrile containing 1.56kg (4.83mol) of isobutylamine was added to 1260g of 2-phenyl-benzyl bromide (corrected purity 1202g; leq) and 77 4g of sodium carbonate (1.5eq ), And stirred at 45 ~ 46 ° C for 8.5 hours. After leaving it to stand overnight, it was filtered through filter paper and concentrated under reduced pressure to obtain 2.50 kg (theoretical amount 2183 g) of an oily residue containing the object (8). Reference Example 8 (The following to Reference Example 10 are for the synthesis of 2-phenyl-benzyl bromide (15) at the 4-position side chain

200412946 2-苯基苄酸（13)之合成 將9-·藉酮（ 1 2)(1000g，5.5 5m〇l)於室溫攪拌下加入甲苯 (7L)，加入氫氧化鉀（i245g，22.20mol)並加熱至80°C〜90 °C。約2小時後，於50°C下冷却加入水（4L)，再加入甲苯 (500mL)，水（3L)來萃取，分層。在有機層加1〇%氫氧化鉀 水溶液（3 L)，水層加甲苯（3L)來萃取，將前者之水層及後者 之有機層合倂，萃取並合倂水層。在水層（pH= 14.6 8)加入濃 鹽酸（1.7 L)使pH = 7.00後，加入乙酸乙酯（7 L)，濃鹽酸 (67 0mL)，使ρΗ = 0·98後萃取。有機層以水（4L)洗浄（3次） ，將水層及洗浄水層以乙酸乙酯28(3 L)反萃取。合倂有機層 ，於硫酸鎂下乾燥後，減壓濃縮。殘渣中加入己烷（3 L)，於 5 0°C下15分，冷卻攪拌1小時。濾集結晶，以冷己烷（1L) 洗浄，在室溫乾燥，可得2_苯基苄酸（13)(1040.3g，94.6%) 〇 参考例9200412946 Synthesis of 2-phenylbenzoic acid (13) 9- · borone (1 2) (1000 g, 5.5 5mol) was added at room temperature with toluene (7L), and potassium hydroxide (i245g, 22.20mol) was added. ) And heated to 80 ° C ~ 90 ° C. After about 2 hours, add water (4L) at 50 ° C, add toluene (500mL), and water (3L) to extract and separate the layers. 10% potassium hydroxide aqueous solution (3 L) was added to the organic layer, and toluene (3 L) was added to the aqueous layer to extract. The former aqueous layer and the latter organic layer were combined, and the aqueous layer was extracted and combined. Concentrated hydrochloric acid (1.7 L) was added to the aqueous layer (pH = 14.6 8) to make pH = 7.00, then ethyl acetate (7 L) and concentrated hydrochloric acid (67 0 mL) were added to make ρΗ = 0.98 and extracted. The organic layer was washed with water (4 L) (three times), and the aqueous layer and the washed water layer were back-extracted with ethyl acetate 28 (3 L). The organic layer was combined, dried over magnesium sulfate, and concentrated under reduced pressure. Hexane (3 L) was added to the residue, and the mixture was stirred at 50 ° C for 15 minutes, and then cooled and stirred for 1 hour. The crystals were collected by filtration, washed with cold hexane (1 L), and dried at room temperature to obtain 2-phenylbenzoic acid (13) (1040.3 g, 94.6%). Reference Example 9

2 -苯基苄醇（I4)之合成 200412946 將2-苯基苄酸（ 1 3)( 1040g，5.25mol)中於-15°C攬拌下加入 四氫呋喃（5.2L)，於5t：下滴加三乙胺（87 8mL，6.30mol)， 氯碳酸乙酯（602mL，6.30mL)。約30分後，過濾所生成之三 乙胺鹽酸鹽，將濾液於-1 5 t下冷却。於此溶液中，於5 °C下 將含硼氫化鈉（397g，10.50mol)，冷水（2L)之懸浮液分4次 滴加。約40分後，在濃鹽酸（8 80mL)，冰水（3.5L)中緩慢地 加入反應液，加入乙酸乙酯（1 1L)，濃鹽酸（280mL)使pH = 0.75 並萃取。將有機層以水（5L ; 2次），5%碳酸氫鈉水溶液（l〇L ;3次），水（5L ; 2次）洗浄，將水層及洗浄水層以乙酸乙酯 (3L)反萃取。將合倂有機層於硫酸鈉乾燥後，減壓濃縮，可 得 2-苯基苄醇（ 14)(895g，92.5%)。 参考例1 0Synthesis of 2-phenylbenzyl alcohol (I4) 200412946 Add tetrahydrofuran (5.2L) to 2-phenylbenzyl acid (1 3) (1040g, 5.25mol) at -15 ° C with stirring, and drop at 5t: Add triethylamine (87 8 mL, 6.30 mol), ethyl chlorocarbonate (602 mL, 6.30 mL). After about 30 minutes, the triethylamine hydrochloride formed was filtered, and the filtrate was cooled at -15 t. In this solution, a suspension containing sodium borohydride (397 g, 10.50 mol) and cold water (2 L) was added dropwise 4 times at 5 ° C. After about 40 minutes, the reaction solution was slowly added to concentrated hydrochloric acid (8 80 mL), ice water (3.5 L), ethyl acetate (1 1 L), and concentrated hydrochloric acid (280 mL) were added to pH = 0.75 and extracted. The organic layer was washed with water (5L; 2 times), 5% aqueous sodium bicarbonate solution (10L; 3 times), water (5L; 2 times), and the aqueous layer and the washed water layer were washed with ethyl acetate (3L). Back extraction. The combined organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to obtain 2-phenylbenzyl alcohol (14) (895 g, 92.5%). Reference example 1 0

2-苯基苄基溴（15)之合成 將47%氫溴酸（3.041^，27.3 6111〇1)溶液中，於25°〇〜40°〇 下滴加含2-苯基苄醇（ 1 4)(995g，5.40mol)之乙腈（1L)。加溫 至5(TC以反應2小時。於室溫下冷却，加入乙酸乙酯（i〇l) ，氯化鈉（500g)以萃取。將有機層以水（5L ; 3次）洗浄，將 水層及洗浄水層以乙酸乙酯（5 L)反萃取。將合倂有機層於硫 酸鈉乾燥後，減壓濃縮，可得2-苯基苄基溴（ 1 5)( 1 244.5g， 93.3%)。 lHNMR(COC\3) ： (5 4.45(s，2H)，7.23-7.54(m，9H) -34- 200412946 参考例11 (以下至参考例1 3，與2位側鏈合成有關。）Synthesis of 2-phenylbenzyl bromide (15) In a solution of 47% hydrobromic acid (3.041 ^, 27.3 6111〇1), 2-phenylbenzyl alcohol (1 4) (995 g, 5.40 mol) of acetonitrile (1 L). Warm to 5 (TC to react for 2 hours. Cool at room temperature, add ethyl acetate (101), sodium chloride (500 g) to extract. The organic layer is washed with water (5 L; 3 times), and The water layer and the washed water layer were back-extracted with ethyl acetate (5 L). The combined organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to obtain 2-phenylbenzyl bromide (1 5) (1 244.5 g, 93.3%). LHNMR (COC \ 3): (5 4.45 (s, 2H), 7.23-7.54 (m, 9H) -34- 200412946 Reference Example 11 (the following to Reference Example 13 are related to the 2-position side chain synthesis) .)

OHCOHC

16 CHgCCDOH), IRA, Py16 CHgCCDOH), IRA, Py

3-(4-甲醯苯基）-丙烯酸（17)之合成Synthesis of 3- (4-formamylphenyl) -acrylic acid (17)

在2L之4頸三角瓶中，加入對酞醛（16)75.00 (0.559 mol) ，丙二酸64.00g(0.615mol)，異丙醇375mL，滴加吡啶 4 5.211^(0.5 59111〇1)後，於90°(：下攪拌4小時。滴加甲苯75 011^ 後，於90°C下攪拌0.5小時，於水冷却下攪拌0.5小時，再 於冰冷却下攬拌1.5小時。濾集結晶，以冰冷却甲苯600mL 洗浄後乾燥，可得無色結晶79.48ga(毛產率80.6%，由HPLC 所得定量値爲3-(4-甲醯苯基）-丙烯酸（17)68%，3-[4-(2-羰乙 烯基）苯基]-丙烯酸（18)10 %)。 参考例12In a 2L 4 neck triangle flask, add terephthalaldehyde (16) 75.00 (0.559 mol), malonic acid 64.00 g (0.615 mol), isopropyl alcohol 375 mL, and add pyridine 4 5.211 ^ (0.5 59111〇1) dropwise. , And stirred at 90 ° for 4 hours. After adding 75 011 ^ of toluene dropwise, stirred at 90 ° C for 0.5 hours, stirred for 0.5 hours under water cooling, and stirred for 1.5 hours under ice cooling. The crystals were collected by filtration, and 600mL toluene was cooled in ice, washed and dried to obtain colorless crystals 79.48ga (gross yield 80.6%, quantified by HPLC: 3- (4-methylphenyl) -acrylic acid (17) 68%, 3- [4- (2-carbonylvinyl) phenyl] -acrylic acid (18) 10%). Reference Example 12

3-[4-(2，4-二氧亞噻唑啶-5-基甲基）-苯基]-丙烯酸（III) 在2L之4頸三角瓶中，將上述合成之3-(4-甲醯苯基丙 烯酸（17)與3-[4-(2-羰乙烯基）苯基]-丙烯酸（18)之混合結晶 79.20g及噻唑啶二酮72，04(0.615mol)，加入異丙醇750mL ，滴加哌啶55.4mL(0.5 59mol)，於90°C下攪拌6小時。於 約60°C下滴加鹽酸水（濃鹽酸61.2g在水375mL之稀釋溶液 -35- 200412946 )後，於水冷却下攪拌1小時，靜置過夜。次日濾集結晶， 以50%異丙醇水375mL及異丙醇375mL洗浄後乾燥，可得 淡頁色結晶1 2 9.0 5 g。 在2L之4頸三角瓶中，將上述所得結晶129.05g，加入水 1.03L及氫氧化鉀65.76g(1.17mol)，於60°C下攪拌1小時。 以濾紙濾除不溶物後，將濾液在7(TC下攪拌，以濃鹽酸中 和後，於水冷却下攪拌1小時。濾集結晶，以50%甲醇水 375mL及甲醇375mL洗浄後，風乾，可得黄色結晶l〇9.66g 〇 在2L之4頸三角瓶中，將上述所得結晶109.66g，加入水 650mL及二甲基甲醯胺650mL，於7(TC下。以濃鹽酸調至 pH = 2，於水冷却下攪拌1小時。濾集結晶，以50%二甲基 甲醯胺水520mL及甲醇520mL洗浄後，風乾，可得淡黃色 結晶（III)91.28g。（〇.332mol，產率 73.8%，自對酞 2 工程 總產率5 9 · 5 %) 3-[4-(2，4-二氧亞噻唑啶-5-基甲基）-苯基]_丙烯酸（19) 熔點 300°C <。 iHNMR(d6_DMSO, 300MHz): 6.64(lH，d，J=16.2Hz)，7.62(lH ，d，J=16.2Hz)，7·63(2Η，d，J = 8.1Hz)，7·82(2Η，d，J = 8.1Hz) ，7·83(1Η，d，J=16.2Hz)。 C13H9NO4S (H2〇)o.i 分析値：C，56·35; Η，3·35; N，5.06; S，11.57; H2〇， 0.65。 實測値：C，5 6.26 ; H，3.29 ; N，5.07 ; S，11·42 ; H20， 0.65 〇 -36- 2004129463- [4- (2,4-dioxothiazolidine-5-ylmethyl) -phenyl] -acrylic acid (III) In a 4-necked flask of 2L, the above synthesized 3- (4-methyl结晶 79.20 g of mixed crystals of phenylphenylacrylic acid (17) and 3- [4- (2-carbonylvinyl) phenyl] -acrylic acid (18) and thiazolidinedione 72,04 (0.615mol), add isopropanol 750mL, 55.4mL (0.559mol) of piperidine was added dropwise, and stirred at 90 ° C for 6 hours. Hydrochloric acid water (61.2g of concentrated hydrochloric acid in 375mL of diluted solution of water-35-200412946) was added dropwise at about 60 ° C. Stir under water cooling for 1 hour and let stand overnight. The crystals were collected by filtration the next day, washed with 375 mL of 50% isopropanol water and 375 mL of isopropanol, and then dried to obtain light-colored crystals 1 2 9.0 5 g. In 2 L In a 4-neck flask, add 129.05 g of the crystal obtained above, add 1.03 L of water and 65.76 g (1.17 mol) of potassium hydroxide, and stir at 60 ° C for 1 hour. After removing insoluble matter with filter paper, place the filtrate at 7 ( Stir at TC, neutralize with concentrated hydrochloric acid, and stir under water cooling for 1 hour. Collect the crystals by filtration, wash with 375mL of 50% methanol water and 375mL of methanol, and air dry to obtain 109.66g of yellow crystals. 4 in 2L In the neck flask, the crystal 1 obtained above is obtained. 09.66 g, add 650 mL of water and 650 mL of dimethylformamide, at 7 ° C. Adjust to pH = 2 with concentrated hydrochloric acid, and stir under water cooling for 1 hour. Filter the crystals to 50% dimethylformamidine After washing with 520mL of amine water and 520mL of methanol and air-drying, 91.28g of pale yellow crystals (III) were obtained. (0.332mol, yield 73.8%, total yield from paraphthalein 2 project 5 9 · 5%) 3- [4 -(2,4-dioxothiazolidine-5-ylmethyl) -phenyl] -acrylic acid (19) Melting point 300 ° C <. iHNMR (d6_DMSO, 300MHz): 6.64 (lH, d, J = 16.2 Hz), 7.62 (lH, d, J = 16.2Hz), 7.63 (2Η, d, J = 8.1Hz), 7.82 (2Η, d, J = 8.1Hz), 7.83 (1Η, d , J = 16.2Hz). C13H9NO4S (H2〇) oi analysis 値: C, 56 · 35; Η, 3.35; N, 5.06; S, 11.57; H2〇, 0.65. Measured 値: C, 5 6.26; H , 3.29; N, 5.07; S, 11.42; H20, 0.65 〇-36- 200412946

参考例1 3 3 - [4-(2，4-二氧亞噻唑啶-5-基甲基）-苯基卜丙烯醯氯（III)Reference Example 1 3 3-[4- (2,4-Dioxothiazolidin-5-ylmethyl) -phenylpropenyl chloride (III)

將化合物（III)(55g，0.2mol)溶在乙腈（1.1L)溶液，加入二 甲基甲醯胺（7.7 41111，0.0169)，草醯氯（34.91111，〇.4111〇1)，於 70〜72 °C下攪拌2小時30分。冷却至室溫後，濾集結晶， 以乙腈（0.5L)洗浄。可得乾燥目的物（111)(55.5g，94.5%)。 ^NMRCda-DMSO) ： (5 6 · 6 4 (1 Η，d，J = 1 5 · 9 Η z)，7 · 5 5 - 7 · 9 0 (5 Η ，m)，12·69(1Η，s)。 参考例14 (参考例14及参考例15爲有關1位側鏈爲2-(1，3-二氟苄 醯基）苄酸（V)之合成。）Compound (III) (55 g, 0.2 mol) was dissolved in a solution of acetonitrile (1.1 L), and dimethylformamide (7.7 41111, 0.0169) and chlorpyrazine (34.91111, 0.411〇1) were added at 70 ~ Stir at 72 ° C for 2 hours and 30 minutes. After cooling to room temperature, the crystals were collected by filtration and washed with acetonitrile (0.5 L). The target product (111) (55.5 g, 94.5%) was obtained in dry form. ^ NMRCda-DMSO): (5 6 · 6 4 (1 Η, d, J = 1 5 · 9 Η z), 7 · 5 5-7 · 9 0 (5 Η, m), 12.69 (1Η, s). Reference Example 14 (Reference Example 14 and Reference Example 15 relate to the synthesis of 2- (1,3-difluorobenzyl) benzyl acid (V) at the 1-position side chain.)

(V)(V)

备Prepare

21 ° 2221 ° 22

Friedel-Crfts 法 在lCl3(720g，5·40πιο1)中，於室溫攪拌下加入1，3-二氯 苯（22)(7951111^，8.1〇111〇1)，於約5分內加入酞酐（21)(40(^， 2.70mol)。將反應液在7CTC〜73t下加熱攪拌約5小時30 分以進行反應。反應終了後，於約1 5分內及6 0 °C〜7 0 °C下 滴加乙酸乙酯（720mL)。此後之後處理與同規模之別批合倂 進行。將反應液使用乙酸乙酯（6L)，冰水（2L)於冰水（9L)中 乘熱時加入，分層。將有機層以lmol/L鹽酸（6L; 2次），水 -37- 200412946 (5 L· ; 3次）洗浄，將水層及洗浄水層以乙酸乙酯（3 L)反萃取 。將合倂有機層於硫酸鈉下乾燥後，減壓濃縮。殘渣中加入 甲苯（2.8 3 L)，於6 0 °C下1 5分，於室溫下冷却後在5 °C靜置 過夜。濾集結晶，以冷甲苯（1 L)洗浄，於室溫乾燥，可得 2-(1，3-二氟苄醯基）苄酸（V)(1117.1g，78.9%)。再將濾液減 壓濃縮，以同樣方法可得第二結晶（V)(97.2g，6·9%)(合計產 量1214.3g，合計產率85.8%)。Friedel-Crfts method In lCl3 (720g, 5.40πιο1), 1,3-dichlorobenzene (22) (7951111 ^, 8.10111〇1) was added under stirring at room temperature, and phthalic anhydride was added in about 5 minutes. (21) (40 (^, 2.70 mol). The reaction solution is heated and stirred at 7CTC ~ 73t for about 5 hours and 30 minutes to perform the reaction. After the reaction is completed, within about 15 minutes and 60 ° C ~ 70 ° Ethyl acetate (720 mL) was added dropwise at C. Thereafter, the subsequent treatment was carried out in a batch of the same scale. The reaction solution was ethyl acetate (6 L), and ice water (2 L) was heated in ice water (9 L). Add and separate layers. Wash the organic layer with 1 mol / L hydrochloric acid (6 L; 2 times), water-37- 200412946 (5 L ·; 3 times), and wash the water layer and the washed water layer with ethyl acetate (3 L) Back extraction. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. Toluene (2.8 3 L) was added to the residue, and the mixture was cooled at room temperature for 15 minutes at 60 ° C. The crystals were collected by filtration, washed with cold toluene (1 L), and dried at room temperature to obtain 2- (1,3-difluorobenzylfluorenyl) benzoic acid (V) (1117.1 g, 78.9%). The filtrate was concentrated under reduced pressure to obtain a second crystal (V) (97.2 g) in the same manner. 6 · 9%) (total yield 1214.3g, total yield 85.8%).

熔點 129-13TCMelting point

Ci4HgF2〇3 分析値：C，64.13 ; Η，3.08 ; F，14.49。 實測値：1-XL。C，64.20; Η，2.96; F，14.22。2XL。C， 64.10 ; Η，3.06 ; F，13.99。Analysis of Ci4HgF203: ，: C, 64.13; Η, 3.08; F, 14.49. Found 値: 1-XL. C, 64.20; Η, 2.96; F, 14.22. 2XL. C, 64.10; Hf, 3.06; F, 13.99.

格任亞法 將含鎂（731mg，30mmol)之四氫呋喃（20ml)溶液，於50°C 以下滴加含2，4-二氟溴苯（24)(5.81g，30mmol)之四氫呋喃 (25ml)溶液，可得格任亞試劑（25)。將此溶液中，於-60°C下 加入酞酐（21)(3.56g，24mmol)，回溫至- 20°C後攪拌2小時 。反應液注至稀鹽酸（5 0ml)，以乙酸乙酯（5 0m 1x2)萃取。將 有機層水洗，乾燥後減壓濃縮。 所得粗生成物中可含有副生成物如原料（2 1)由來之酞酸 -38- 200412946 (26)，其可由以下方法純化。將濃縮殘渣溶在乙酸乙酯，以 飽和碳酸氫鈉水溶液萃取。此碳酸氫鈉水溶液中加入2N鹽 酸使pH爲4.5，以乙酸乙酯萃取。水層中再加入2N鹽酸使 pH爲4.5，以乙酸乙酯萃取。重覆此操作2次。合倂有機層 後，於硫酸鎂下乾燥後濃縮。將濃縮殘渣自甲苯再結晶，得 白色結晶之目的物（V)(4.66g，74%)。 此工程爲關於在鎂及溶劑中加入2，4-二氟溴苯溶液以製 備格任亞試劑（25)之工程，將所得格任亞試劑與酞酐反應， 得未精製之2-(1,3-二氟苄醯基）苄酸（V)，將所得粗生成物調 整pH來將2-(1，3-二氟苄醯基）苄酸（V)精製，而製造2-(1,3-二氟苄醯基）苄酸（V)之方法。 前述Friedel-Crfts法中，原料之1，3-二氟溴苯必需使用 3當量程度，該方法對應之格任亞試劑，需使用超出必要之 過剩酞酸爲佳。例如，對應酞酸1當量格任亞試劑之比例， 宜爲2當量〜0.5當量，特宜爲1.5當量〜0.7當量。 自粗生成物除去酞酸（26)之精製工程中pH檢討結果，目 的物（2 3)與副產物（26)，於pH約爲未至5時分離。特宜於 pH爲4.5以下時可有效分離。 製備格任亞試劑之溶劑及格任亞試劑與酞酸反應中所用 溶劑可爲四氫呋喃，乙醚，二丁醚，四氫呋喃-甲苯混合溶 劑等。宜爲四氫呋喃。 製備格任亞試劑之反應溫度爲〇°C〜55t。宜爲l〇°C〜50 〇C。 製備格任亞試劑之反應時間爲0.2小時〜4小時，宜爲〇.5 小時〜2小時。 -39- 200412946 與酞酐之反應溫度爲-7〇°C〜35°C，宜爲_65°C〜5°C。 與酞酐之反應時間爲〇. 5小時〜1 〇小時’宜爲1小時 小時。 實施例1Grignard's solution of magnesium (731mg, 30mmol) in tetrahydrofuran (20ml) was added dropwise below 50 ° C to a solution of 2,4-difluorobromobenzene (24) (5.81g, 30mmol) in tetrahydrofuran (25ml). Degrenia reagent (25). To this solution, phthalic anhydride (21) (3.56 g, 24 mmol) was added at -60 ° C, and the temperature was raised to -20 ° C, followed by stirring for 2 hours. The reaction solution was poured into dilute hydrochloric acid (50 ml), and extracted with ethyl acetate (50 m 1x2). The organic layer was washed with water, dried, and then concentrated under reduced pressure. The obtained crude product may contain by-products such as phthalic acid -38- 200412946 (26) derived from raw material (21), which can be purified by the following method. The concentrated residue was dissolved in ethyl acetate and extracted with a saturated aqueous sodium hydrogen carbonate solution. 2N hydrochloric acid was added to this aqueous sodium bicarbonate solution to adjust the pH to 4.5, and the mixture was extracted with ethyl acetate. To the aqueous layer was further added 2N hydrochloric acid to make the pH 4.5, and the mixture was extracted with ethyl acetate. Repeat this operation 2 times. The organic layer was combined, dried over magnesium sulfate, and concentrated. The concentrated residue was recrystallized from toluene to obtain the object (V) (4.66 g, 74%) as white crystals. This project is about adding 2,4-difluorobromobenzene solution in magnesium and solvent to prepare the Grignard reagent (25). The obtained Grignard reagent is reacted with phthalic anhydride to obtain unrefined 2- (1 2,3-difluorobenzylfluorenyl) benzoic acid (V), and the obtained crude product was adjusted to pH to purify 2- (1,3-difluorobenzylfluorenyl) benzoic acid (V) to produce 2- (1 , 3-Difluorobenzylfluorenyl) benzoic acid (V). In the aforementioned Friedel-Crfts method, 1,3-difluorobromobenzene as a raw material must be used in an amount of about 3 equivalents, and the corresponding qualitative reagent used in this method needs to use excess phthalic acid more than necessary. For example, the ratio of the equivalent of 1 equivalent of phthalic acid to Grenia reagent is preferably 2 to 0.5 equivalents, and particularly preferably 1.5 to 0.7 equivalents. As a result of the pH review in the purification process for removing phthalic acid (26) from the crude product, the target product (23) and the by-product (26) were separated at a pH of about 5 or less. It is especially suitable for effective separation when the pH is below 4.5. The solvent for preparing the Grignard reagent and the solvent used in the reaction between the Grignard reagent and phthalic acid may be tetrahydrofuran, diethyl ether, dibutyl ether, a tetrahydrofuran-toluene mixed solvent, and the like. Tetrahydrofuran is preferred. The reaction temperature for preparing the Grignard reagent was 0 ° C ~ 55t. It should be 10 ° C ~ 50 ° C. The reaction time for preparing the Grignard reagent is 0.2 hours to 4 hours, and preferably 0.5 hours to 2 hours. -39- 200412946 The reaction temperature with phthalic anhydride is -7 ° C ~ 35 ° C, preferably _65 ° C ~ 5 ° C. The reaction time with phthalic anhydride is from 0.5 hours to 10 hours', preferably 1 hour and hours. Example 1

卜NH體（IV)之合成 將含苄胺體（8)2.47kg(4.77mol)之乙酸乙酯4.3L及甲醇 1. 1L溶液中，於1 1〜19°C下滴加4mol/L鹽酸/乙酸乙酯溶 液5.96L(5eq)。於25〜28°C下攪拌1小時25分後，加入冰 水以分層。水層以乙酸乙酯4· 3L洗浄，乙酸乙酯層以水4· 3L 萃取。水層中加入冰，在1 5〜1 9°C滴加4N氫氧化鈉水溶液 (6L)而調整至pH9.5，以乙酸乙酯7.5L，4.3L依次萃取。將 乙酸乙酯層以10%食鹽水7.5Lx2依次洗浄後減壓濃縮，得 目的物（IV)之油狀殘渣1.52kg(90.6%，理論量1 677g)。 實施例2Synthesis of NH body (IV) 4ml / L hydrochloric acid was added dropwise at 1.1 to 19 ° C in a solution of 4.3L of ethyl acetate and 1.1L of methanol containing 2.47kg (4.77mol) of benzylamine (8). / Ethyl acetate solution 5.96 L (5 eq). After stirring at 25 to 28 ° C for 1 hour and 25 minutes, ice water was added to separate the layers. The aqueous layer was washed with 4 · 3L of ethyl acetate, and the ethyl acetate layer was extracted with 4 · 3L of water. Ice was added to the aqueous layer, and a 4N sodium hydroxide aqueous solution (6L) was added dropwise at 15 to 19 ° C to adjust the pH to 9.5, followed by extraction with 7.5L of ethyl acetate and 4.3L of sequentially. The ethyl acetate layer was sequentially washed with 7.5 Lx2 of 10% saline, and then concentrated under reduced pressure to obtain 1.52 kg (90.6%, theoretical amount of 1 677) of an oily residue of the target compound (IV). Example 2

1-NH草酸鹽（IV)之合成 將化合物（IV)15g溶在乙酸乙酯25M1及正丙醇105mL溶 液，於40°C下加入草酸4·61g(2·2eq)/乙酸乙酯5mL，正丙 -40- 200412946 醇15mL之混液。於40 °C下攪拌2小時後，於室溫下攪拌2 小時，於冰浴冷卻下攪拌1.5小時以結晶化。濾集結晶，冷 却並清洗以乙酸乙酯：正丙醇=8 : 2溶液50mL，減壓乾燥 可得白色草酸鹽（IV) 14· lg(74.2%)。 C22H29N3O · 2.0C2H2O4 · 〇.2H2〇 分析値：C，64.76; Η，7.11; N，9.44; H2〇，0.81。 實測値：C，64.7 8 ; Η，7.12 ; Ν，9.59 ; Η20，0.69。 實施例3Synthesis of 1-NH oxalate (IV) 15 g of compound (IV) was dissolved in 25 M 1 of ethyl acetate and 105 mL of n-propanol, and 4.61 g (2.2 eq) of oxalic acid / 5 mL of ethyl acetate were added at 40 ° C. , 15 mL of n-propyl-40-200412946 alcohol. After stirring at 40 ° C for 2 hours, it was stirred at room temperature for 2 hours, and then stirred for 1.5 hours under ice-cooling to crystallize. The crystals were collected by filtration, cooled and washed with 50 mL of a solution of ethyl acetate: n-propanol = 8: 2, and dried under reduced pressure to obtain white oxalate (IV) 14 · lg (74.2%). C22H29N3O. 2.0C2H2O4. 0.2H2O Analysis 値: C, 64.76; Η, 7.11; N, 9.44; H2O, 0.81. Measured 値: C, 64.7 8; Η, 7.12; N, 9.59; Η20, 0.69. Example 3

1-ΝΗ對-甲苯磺酸鹽（IVb)之合成 將化合物（IV) 1457g溶在乙酸正丁酯19.28L及乙酸乙酯 5.86L，於40°C下加入對-甲苯磺酸一水合物1 392g(1.6eq)/ 乙酸乙酯7L溶液。於40 〇c下攪拌2小時後，於室溫下攪拌 1小時以結晶化。濾集結晶，依次清洗以乙酸正丁酯/乙酸乙 酯=2/1及乙酸正丁酯/乙酸乙酯=5n 3 2L，加溫減壓乾燥， 得白色對-甲苯磺酸鹽（”乜）22388(自6爲69%)。Synthesis of 1-ΝΗ p-toluenesulfonate (IVb) 1457 g of compound (IV) was dissolved in n-butyl acetate 19.28L and ethyl acetate 5.86L, and p-toluenesulfonic acid monohydrate 1 was added at 40 ° C. 392 g (1.6 eq) / ethyl acetate 7L solution. After stirring at 40 ° C for 2 hours, it was stirred at room temperature for 1 hour to crystallize. The crystals were collected by filtration, and washed sequentially with n-butyl acetate / ethyl acetate = 2/1 and n-butyl acetate / ethyl acetate = 5n 3 2L, and dried under heating and reduced pressure to obtain white p-toluenesulfonate ("乜22388 (69% from 6).

C22H29N3O · 2.0C2H2O4 · O.lHoO 分析値：C’ 61.97; Η，6.53; N，6.02; s，9.19; H2〇，0.26 ο 貫測値：C，61.43; Η，6.49; Ν，6.10; S，9.38; Η2〇，〇·19 ο 實施例4 -41- 200412946C22H29N3O · 2.0C2H2O4 · O.lHoO Analysis 値: C '61.97; Η, 6.53; N, 6.02; s, 9.19; H2O, 0.26 ο Continuous measurement 値: C, 61.43; Η, 6.49; Ν, 6.10; S, 9.38; Η20, 〇19. Ο Example 4 -41- 200412946

l-NH甲酸鹽（IVc)之合成 將含化合物（IV)1.6g之丁酮2lmL溶液中，加入9S%甲酸 0.3 6mL(2.0eq)，於室溫下攪拌2小時後，濾集結晶，清洗以 冷丁酮12mL，減壓乾燥，可得白色甲酸鹽（IVc)1.2g(59.2%) 實施例5Synthesis of l-NH formate (IVc) To a 2 mL solution of 1.6 g of methyl ethyl ketone containing compound (IV) was added 0.3 6 mL (2.0 eq) of 9S% formic acid. After stirring at room temperature for 2 hours, the crystals were collected by filtration. 12 mL of cold methyl ethyl ketone was washed and dried under reduced pressure to obtain 1.2 g (59.2%) of white formate (IVc). Example 5

^NH對-甲苯磺酸鹽（IVb)之直接法 將含化合物（8)234 1 g之乙酸乙酯13.4L溶液中，加入對-甲苯磺酸一水合物22 6 6(2.5 eq)。於40°C下攪拌3小時後， 加入乙酸正丁酯20.1L，於40°C後於室溫，再於冰冷却下攪 拌以結晶化。濾集結晶，依次清洗以乙酸正丁酯/乙酸乙酯 = 2/1 3.35L及乙酸正丁酯/乙酸乙酯=5/13.35L，加溫減壓乾 燥，可得白色對-甲苯磺酸鹽（IVb)2135g(63.7%)。 實施例6 -42- 200412946^ Direct method of NH-p-toluenesulfonic acid (IVb) p-toluenesulfonic acid monohydrate 22 6 6 (2.5 eq) was added to a 13.4 L solution of 1 g of ethyl acetate containing compound (8) 234. After stirring at 40 ° C for 3 hours, 20.1 L of n-butyl acetate was added, and after stirring at 40 ° C at room temperature, it was stirred under ice cooling to crystallize. The crystals were collected by filtration, and washed sequentially with n-butyl acetate / ethyl acetate = 2/1 3.35L and n-butyl acetate / ethyl acetate = 5 / 13.35L, and dried under heating and reduced pressure to obtain white p-toluenesulfonic acid. Salt (IVb) 2135 g (63.7%). Example 6 -42- 200412946

1·醯體（VI)之合成 將含Μ立側鏈羧酸（v)(320g，1.22mol)之乙腈（2.56L)溶液 ，於室溫下加入二甲基甲醯胺（3ml)，亞磺醯氯（l〇7ml， 1.4 64 mol)，於同下攪拌2小時。減壓濃縮可得油狀物質385 g 。將化合物（IV)(自由體，440g，1.25mol)之四氫呋喃（2.4L) 溶液，於1 〇 °C下加入三乙胺（5 1 0 ml，3 · 6 6 mο 1 )，含上述油狀 物質之四氫呋喃（2L)溶液。於3〜下攪拌0.5小時後，於 室溫下攪拌17.5小時。注至稀鹽酸（5L)中，以乙酸乙酯（3L X2)萃取。將有機層以5%碳酸鈉水溶液（3Lx2)，水（3Lx2)， 食鹽水（3L)洗浄。蒸除溶劑，可得目的物質（vi)(740g，99%) 實施例7 φ1. Synthesis of carcass (VI) A solution of acetonitrile (2.56L) containing M vertical side chain carboxylic acid (v) (320 g, 1.22 mol) was added with dimethylformamide (3 ml) at room temperature. Sulfonium chloride (107 ml, 1.4 64 mol) was stirred for 2 hours. Concentration under reduced pressure gave 385 g of an oily substance. A solution of compound (IV) (free body, 440 g, 1.25 mol) in tetrahydrofuran (2.4 L) was added at 10 ° C. triethylamine (5 10 ml, 3.66 mο 1), containing the above oil Tetrahydrofuran (2L) solution of the substance. After stirring at 3 to 0.5 hours, it was stirred at room temperature for 17.5 hours. Pour into dilute hydrochloric acid (5L) and extract with ethyl acetate (3L X2). The organic layer was washed with a 5% sodium carbonate aqueous solution (3Lx2), water (3Lx2), and brine (3L). The solvent was distilled off to obtain the target substance (vi) (740 g, 99%). Example 7 φ

2-腈體（VII)之合成Synthesis of 2-nitrile (VII)

將含化合物（VI)(280g，0.432mol)之四氫呋喃（1.12L)溶液 ，於10 °C下加入三乙胺（180ml，1.296 mol)，三氯乙醯氯 (7 2.4ml，0.648)之四氫呋喃（280ml)溶液。於2〜1(TC下攪 -43- 200412946 拌1小時後，注至稀鹽酸（1.5L)中，以乙酸乙酯（iLx2)萃取 。將有機層以5%碳酸鈉水溶液（1Lx2)，水（1Lx2)，食鹽水（1L) 洗浄。蒸除溶劑，可得目的物質（VII)(262g，98%)。 實施例8A solution of compound (VI) (280 g, 0.432 mol) in tetrahydrofuran (1.12 L) was added at 10 ° C with triethylamine (180 ml, 1.296 mol) and trichloroacetamidine chloride (7 2.4 ml, 0.648) in tetrahydrofuran. (280ml) solution. Stir at 2 ~ 1 (TC-43- 200412946 for 1 hour), pour it into dilute hydrochloric acid (1.5L), and extract with ethyl acetate (iLx2). The organic layer is 5% sodium carbonate aqueous solution (1Lx2), water (1Lx2), washed with brine (1L). The solvent was distilled off to obtain the target substance (VII) (262g, 98%). Example 8

2-胺甲基體（II)之合成 將含化合物（VII)(188g，O.3mol)之乙醇（300ml)溶液，加 入4mol/L氨水之乙醇（300ml，1 ·2ιηο1)溶液，阮來鎳（商標名 )(3 7 6ml)，於室溫6小時加入水。濾除觸媒，以乙酸乙酯 (900ml)洗浄。將乙酸乙酯溶液以水（600mlx2)，食鹽水 (300ml)洗浄。各水層以乙酸乙酯（300ml)萃取。合倂乙酸乙 酯層，於硫酸鈉下乾燥後，加入4mol/L鹽酸之乙酸乙酯 (240ml)，於室溫下攪拌16小時。濾集結晶，以乙酸乙酯 (5 00ml)洗浄。減壓乾燥，可得目的物（11)(1 20g，61%)。 實施例9Synthesis of 2-Amine Methyl Form (II) A solution of compound (VII) (188 g, O.3 mol) in ethanol (300 ml) was added to a solution of 4 mol / L ammonia water in ethanol (300 ml, 1.2 ml), and Ruanlai Nickel (trademark Name) (36, 6 ml), and water was added at room temperature for 6 hours. The catalyst was filtered off and washed with ethyl acetate (900 ml). The ethyl acetate solution was washed with water (600 ml x 2) and brine (300 ml). Each aqueous layer was extracted with ethyl acetate (300 ml). The ethyl acetate layer was dried over sodium sulfate, 4 mol / L hydrochloric acid in ethyl acetate (240 ml) was added, and the mixture was stirred at room temperature for 16 hours. The crystals were collected by filtration and washed with ethyl acetate (500 ml). It was dried under reduced pressure to obtain the target substance (11) (120g, 61%). Example 9

化合物⑴之合成 將含化合物（II)(l〇g，15.3mol)之乙腈（200mlL)溶液，於3 °C下加入三丁胺（12.7ml)。再於-1 1〜-14°C下加入2-位側鏈 -44- 200412946 之醯氯（III)(4.49g，15.3mol)，於同溫下攪拌3.5小時，注 至水（150ml)，以乙酸乙酯（150m卜100ml)萃取。將各有機層 以1111〇1/1鹽酸（15〇1111)，5%碳酸鈉水溶液（15〇1111)，水（11^ 2)，食鹽水（150ml)洗浄。蒸除溶劑，可得目的物質（17.5 g) 。合倂各批（共60g)，溶在乙醇：丙酮（9 : l)(300ml)溶液， 於室溫下滴加5%食鹽水，於同溫下攪拌2小時後過濾。以 水（200mlx3)洗浄後乾燥，得化合物（1)(5 3.35g，88.95 %)。 C49H44F2N4O5S · 0.5H2〇Synthesis of compound VII A solution of compound (II) (10 g, 15.3 mol) in acetonitrile (200 ml L) was added with tributylamine (12.7 ml) at 3 ° C. Then add chloro (III) (4.49g, 15.3mol) of 2-position side chain -44- 200412946 at 1-1 to -14 ° C, stir for 3.5 hours at the same temperature, and pour water (150ml). It was extracted with ethyl acetate (150 ml, 100 ml). Each organic layer was washed with 11110/1/1 hydrochloric acid (1501011), 5% aqueous sodium carbonate solution (1501111), water (11 ^ 2), and brine (150 ml). The solvent was distilled off to obtain the target substance (17.5 g). Combine each batch (60g in total), dissolve in a solution of ethanol: acetone (9: 1) (300ml), dropwise add 5% saline at room temperature, stir at the same temperature for 2 hours, and filter. It was washed with water (200 ml x 3) and then dried to obtain compound (1) (5.33 g, 88.95%). C49H44F2N4O5S0.5H2〇

分析値：c，69.40 ; Η ’ 6.53 ; F，4.48 ; N，6.61 ; S，3·78 ;H20，0.26。 實測値·· C，69·45 ; Η，5·35 ; F，4.47 ; N，6.64 ; S，3.85 ;Η20，1·83。 Ν<0·1，Cl<0.1%， ^NMRiCDCh) : 5 〇.72(d，3Η，J = 6.3Hz)，0.78(d，3Η，Analysis 値: c, 69.40; Η '6.53; F, 4.48; N, 6.61; S, 3.78; H20, 0.26. Measured 値 · C, 69 · 45; Η, 5.35; F, 4.47; N, 6.64; S, 3.85; Η20, 1.83. N < 0.1, Cl < 0.1%, ^ NMRiCDCh): 5 0.72 (d, 3Η, J = 6.3Hz), 0.78 (d, 3Η,

】 = 6·6Ηζ)，1.47- 1.56(m，1H)，1.68- 1.7 5 (m，1H)，1.94-2.17(m ，4 H)，2 · 9 5 - 3.0 1 (m，1 H)，3 · 1 3 - 3 . 1 9 (m，1 H)，3 · 3 9 - 3 · 7 1 (m ，5H)，4.41-4.57(m，1H)，6.52(d，1H，J=15.9Hz)，6.84-7.00(m ，2H)，7.12-7.75(m，21H)。 實旋例1 〇] = 6 · 6Ηζ), 1.47- 1.56 (m, 1H), 1.68- 1.7 5 (m, 1H), 1.94-2.17 (m, 4 H), 2 · 9 5-3.0 1 (m, 1 H), 3 · 1 3-3. 1 9 (m, 1 H), 3 · 3 9-3 · 7 1 (m, 5H), 4.41-4.57 (m, 1H), 6.52 (d, 1H, J = 15.9Hz ), 6.84-7.00 (m, 2H), 7.12-7.75 (m, 21H). Practical example 1 〇

對-甲苯磺酸鹽（I)之製備 將化合物（1)(8.96g)溶在乙酸乙酯（25.2mi)及甲醇（8.4ml) -45- 200412946 ，加入含對-甲苯磺酸（1.9g，l.Oeq)之乙酸乙酯（5.2ml)溶液 ，於室溫下攪拌3小時。濾集結晶，以乙酸乙酯（50ml)洗浄 。減壓乾燥，得對-甲苯磺酸鹽（I)(9.〇7g，88.1%)。 C56H52F2 N408S2-1 ·6Η20 3·65 ; Ν，5·39 ; S，6. 17 分析値：c，64.67; Η，5.35; F， ο 實測値：C，64·73 ; Η，5.43 ; F， ;Η20，1 ·95，Ash < 〇· 1 〇 實施例11Preparation of p-toluenesulfonate (I) Compound (1) (8.96g) was dissolved in ethyl acetate (25.2mi) and methanol (8.4ml) -45- 200412946, and p-toluenesulfonic acid (1.9g) was added. 1.0 eq) of ethyl acetate (5.2 ml), and stirred at room temperature for 3 hours. The crystals were collected by filtration and washed with ethyl acetate (50 ml). Drying under reduced pressure gave p-toluenesulfonate (I) (9.07 g, 88.1%). C56H52F2 N408S2-1 · 6Η20 3.65; Ν, 5.39; S, 6. 17 Analysis 値: c, 64.67; Η, 5.35; F, ο Measured 値: C, 64 · 73; Η, 5.43; F, Η20,1.95, Ash < 〇 · 1〇 Example 11

Cfa) 3·46 ; Ν ， 5.34 ; S ， 5·92Cfa) 3.46; N, 5.34; S, 5.92

0) 對-甲苯磺酸鹽（ι)之脫鹽處理 將對-甲苯磺酸鹽（1)(9.07 g)懸浮在乙酸（90ml)，加入5% 重碳酸鈉水（90ml)，於室溫下攪拌17分。分層後將水層以 乙酸乙酯（32ml)萃取。各乙酸乙酯層以食鹽水（3 2mlx2)洗浄 。於硫酸鈉下乾燥後，減壓濃縮可得化合物（I)殘渣（7.88g) 實施例1 20) Desalting treatment of p-toluenesulfonate (ι) Suspend p-toluenesulfonate (1) (9.07 g) in acetic acid (90ml), add 5% sodium bicarbonate water (90ml), and place at room temperature Stir for 17 minutes. After the layers were separated, the aqueous layer was extracted with ethyl acetate (32 ml). Each ethyl acetate layer was washed with brine (32 ml x 2). After drying over sodium sulfate, concentration under reduced pressure gave the residue of compound (I) (7.88g). Example 1 2

硫酸鹽（lb)之製備 -46- 200412946 將化合物（1)1.4§(1.66〇1111〇1)溶在甲醇（25.21111)後，加入硫 ★ 酸（4 4 · 2 // 1，〇 . 5 e q)，置於室溫下1小時，蒸除甲醇。將部 · 份殘渣200mg溶在丁酮（〇.8ml)，於5。(：下攪拌。濾集結晶 後，可得57mg硫酸鹽（lb)。 將部份殘渣200mg溶在丙酮（〇.6ml)，加入少量乙醚，於 5°C下攪拌。濾集結晶後，得60mg硫酸鹽（lb)。 C49H44F2O5S · H2SO4 分析値：C，62.80 ; Η，4.95 ; F，4.06 ; N，5.98 ; S，6.84 〇 實測値：C，62.34; Η，5.08; F，3.97; Ν，6.08; S，6.72 實施例13Preparation of sulfate (lb) -46- 200412946 After dissolving compound (1) 1.4§ (1.66〇1111〇1) in methanol (25.21111), add sulfur ★ acid (4 4 · 2 // 1, 0.5 eq ), Left at room temperature for 1 hour, and distilled off methanol. Dissolve 200 mg of the residue in methyl ethyl ketone (0.8 ml) in 5. (: Stir down. After filtering and crystallizing, 57 mg of sulfate (lb) can be obtained. 200 mg of a portion of the residue is dissolved in acetone (0.6 ml), a small amount of ether is added, and the mixture is stirred at 5 ° C. After filtering and crystallizing, 60mg sulfate (lb). C49H44F2O5S · H2SO4 analysis 値: C, 62.80; Η, 4.95; F, 4.06; N, 5.98; S, 6.84. Measured 値: C, 62.34; Η, 5.08; F, 3.97; Ν, 6.08; S, 6.72 Example 13

鹽酸鹽（I)之製備 φ 於氯氣下，將化合物（I)(20.0g，0.024mol)溶在丙酮（200mL) 及水（8mL)之混合溶液，於22〜25 °C及3分內加入濃鹽酸 (3.03 mL，〇.〇3 6mol)。加入種晶後，將反應液置於室溫下20 小時。將混液過濾，分離所生成之沈澱物。以丙酮洗浄，減 壓乾燥，得目的物鹽（Ic)(19.8g，產率95%)之結晶。Preparation of hydrochloride (I) φ Under chlorine, dissolve compound (I) (20.0g, 0.024mol) in a mixed solution of acetone (200mL) and water (8mL), at 22 ~ 25 ° C and within 3 minutes Concentrated hydrochloric acid (3.03 mL, 0.03 6 mol) was added. After seed crystals were added, the reaction solution was left at room temperature for 20 hours. The mixture was filtered and the resulting precipitate was separated. After washing with acetone and drying under reduced pressure, crystals of the target salt (Ic) (19.8 g, yield 95%) were obtained.

Det(UV): 350nm，峯面積 ％ = 96.1% [a ]24d-93.7：l1 .3〇， （c 1 ·0 1 1，DMSO)， IR(Nujol) ·· 3352，1 736，1 699，1 653，1606，789cm·1 » -47- 200412946 Η N M R (d 6 - D M S Ο) · 5 0 · 6 0 - 0.9 0 (6 Η，m)，1 · 4 〇 - 3 5 Ο (m)， 3·60-4·50(4Η，m)，6.60-6·80(1Η，m)，7.10-8.00(21Η，m) ’ 8·35-8·55(1Η ’ m) ’ 9·50-10·20(1Η，m)，12.65(1Η，s)， C49H44F2N4O5S · HC1 分析値：C，67.23 ; Η，5.18 ; C1，4·〇5 ; F，4.34 ; Ν，6.40 ;S，3 · 6 6。 實測値· C’ 66.55; Η’ 5.32; Cl，4.14; F, 4.03; Ν，6 37 ;S ， 3·69 。 産業上利用可能性 使用具有c P L 2抑制活性之卩比咯π定化合物鹽及結晶，作爲 有醫藥使用純度之該化合物的工業製造方法。 【圖式簡單說明】 第1圖爲貫施例1 0所得化合物（I)之結晶粉末X線測定結 果。 第2圖爲實施例1 2所得化合物（lb)之結晶粉末X線測定結 果。Det (UV): 350nm, peak area% = 96.1% [a] 24d-93.7: 11.30, (c 1 · 0 1 1, DMSO), IR (Nujol) · 3352, 1 736, 1 699, 1 653, 1606, 789 cm · 1 »-47- 200412946 Η NMR (d 6-DMS Ο) · 50 0 · 6 0-0.9 0 (6 Η, m), 1 · 4 〇-3 5 Ο (m), 3.60-4 · 50 (4Η, m), 6.60-6 · 80 (1Η, m), 7.10-8.00 (21Η, m) '8.35-8 · 55 (1Η'm)' 9 · 50- 10 · 20 (1Η, m), 12.65 (1Η, s), C49H44F2N4O5S · HC1 analysis: C, 67.23; Η, 5.18; C1, 4.05; F, 4.34; Ν, 6.40; S, 3 · 6 6. Measured 値 · C ’66.55; Η’ 5.32; Cl, 4.14; F, 4.03; Ν, 6 37; S, 3.69. INDUSTRIAL APPLICABILITY The salt and crystal of a pyridine compound compound having c P L 2 inhibitory activity is used as an industrial production method of the compound having a medical purity. [Brief description of the figure] Fig. 1 shows the results of X-ray measurement of the crystalline powder of the compound (I) obtained in Example 10. Fig. 2 is an X-ray measurement result of the crystalline powder of the compound (lb) obtained in Example 12.

-48--48-

Claims (1)

200412946 拾、申請專利範圍 1. 一種如下式（I)化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽 、或其溶劑合物’200412946 Scope of patent application 1. A p-toluenesulfonate, sulfate, hydrochloride, or solvate of the compound of formula (I) 2 ·如申請專利範圍第1項之鹽或其溶劑合物，其爲對-甲苯磺 酸鹽。 3 ·如申請專利範圍第1項之鹽或其溶劑合物’其爲硫酸鹽。 4· 一種如式（I)之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其溶 劑合物之結晶，2. The salt or solvate thereof according to item 1 of the scope of patent application, which is p-toluenesulfonate. 3. If the salt or solvate thereof of item 1 of the scope of patent application 'is a sulfate. 4. A crystal of p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof according to formula (I), -49- 200412946 間隔（d)爲 14·04、16.22、19.60、22.02、及 22.28(單位： 人）之主峯。 9· 一種製備式（I)化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽 、或其溶劑合物、或其結晶之方法，係將式（1)化合物或其 溶劑合物-49- 200412946 The interval (d) is the main peak of 14.04, 16.22, 19.60, 22.02, and 22.28 (unit: person). 9. · A method for preparing p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof, or a crystal thereof, of a compound of formula (I), which comprises compound (1) or a solvate thereof ’與對-甲苯磺酸、硫酸、或鹽酸反應。 10·如申請專利範圍第9項之方法，係爲對_甲苯磺酸鹽、硫酸 鹽、鹽酸鹽、或其溶劑合物結晶之製造方法。 •如申tiR專利範圍第1 〇項之方法，係爲對-甲苯磺酸鹽或其 溶劑合物結晶之製造方法。 12·如申請專利範圍第1〇項之方法，係爲硫酸鹽或其溶劑合 物結晶之製造方法。 13·—種製備式（I)化合物或其溶劑合物之方法，係將式（1):'Reacts with p-toluenesulfonic acid, sulfuric acid, or hydrochloric acid. 10. The method according to item 9 of the scope of patent application is a method for producing a crystal of p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof. • The method as claimed in item 10 of the tiR patent scope is a method for producing crystals of p-toluenesulfonate or its solvate. 12. The method according to item 10 of the scope of patent application is a method for producing a crystal of sulfate or a solvent compound thereof. 13 · —A method for preparing a compound of formula (I) or a solvate thereof, which is based on formula (1): 化合物之對-甲苯磺酸鹽、； 物，進彳了結晶之脫鹽處理。 、硫酸鹽、鹽酸鹽、或其溶劑合 14·如申請專利範圍第 項之製造方法，係將式（I)化合物之 封-甲苯磺酸鹽或其溶劑合物，進行結晶之脫鹽處理。 1 5 .如申請專利範圍第1 3 項之製造方法，係將式（I)化合物之 200412946 硫酸鹽或其溶劑合物，進行結晶之脫鹽處理。 16.—種製備式（I)化合物或其溶劑合物之方法，係與對·甲苯 石貝酸’硫酸’或鹽酸反應，而得式（I)化合物之對-甲苯擴 酸鹽、硫酸鹽、鹽酸鹽、或其溶劑合物結晶之工程The p-toluenesulfonate of the compound is desalted by crystallization. 14. Sulfate, hydrochloride, or its solvate 14. The manufacturing method according to the scope of application for a patent, is a desalting treatment of crystallization of the compound of formula (I) -toluenesulfonate or its solvate. 15. The manufacturing method according to item 13 of the scope of patent application, is a desalting treatment of crystallization of 200412946 sulfate or a solvate of a compound of formula (I). 16.—A method for preparing a compound of formula (I) or a solvate thereof, which is reacted with p-toluenebeylic acid 'sulfuric acid' or hydrochloric acid to obtain p-toluene salt and sulfate of a compound of formula (I) Of water, hydrochloride, or its solvate ，並將所得對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽、或其溶劑 合物之結晶，進行脫鹽反應之工程。 Φ 1 7 .如申請專利範圍第1 6項之製造方法，係與甲苯磺酸反應 ，而得式（I)化合物之對-甲苯磺酸鹽或其溶劑合物結晶之 工程，及將所得甲苯磺酸鹽或其溶劑合物之結晶，進行脫 鹽反應之工程。 1 8 ·如申請專利範圍第1 6項之製造方法，係與硫酸反應，而 得式（I)化合物之硫酸鹽或其溶劑合物結晶之工程，及將所 得硫酸鹽或其溶劑合物之結晶，進行脫鹽反應之工程。 1 9 · 一種如下式（II)化合物、其溶劑合物、或其鹽， 馨And, the obtained p-toluenesulfonate, sulfate, hydrochloride, or its solvate crystal is subjected to a process of desalting reaction. Φ 1 7. The manufacturing method according to item 16 of the scope of patent application is a process of crystallizing p-toluenesulfonate or a solvate of the compound of formula (I) by reacting with toluenesulfonic acid, and crystallizing the obtained toluene The process of crystallization of sulfonate or its solvate for desalting reaction. 18 · The manufacturing method according to item 16 of the scope of patent application, which is a process of reacting with sulfuric acid to crystallize the sulfate or solvate of the compound of formula (I), and crystallizing the obtained sulfate or its solvate Crystallization, the process of desalination reaction. 1 9 · A compound of the following formula (II), a solvate thereof, or a salt thereof, 2 0 .如申請專利範圍第1 9項之鹽，其爲鹽酸鹽。 2 1 ·—種製備式（I)化合物之對-甲苯磺酸鹽、硫酸鹽、鹽酸鹽 、或其溶劑合物、或其結晶之方法， -51- 20041294620. The salt of item 19 in the scope of patent application is the hydrochloride. 2 1-Method for preparing p-toluenesulfonate, sulfate, hydrochloride, or solvate thereof, or crystal thereof of compound of formula (I), -51- 200412946 ，與式（III)化合物，其溶劑合物，或其鹽反應：, With a compound of formula (III), a solvate thereof, or a salt thereof: (式中，X爲鹵素或羥基） ，得式（I)化合物，或其溶劑合物之工程(Wherein X is a halogen or a hydroxyl group) to obtain a compound of formula (I), or a solvate thereof ;及將所得化合物或其溶劑合物與對-甲苯磺酸，硫酸’ 或鹽酸反應之工程。 22. 如申請專利範圍第2 1項之製造方法，其爲對-甲苯磺酸鹽 、硫酸鹽、鹽酸鹽、或其溶劑合物結晶之製造方法。 23. 如申請專利範圍第22項之製造方法，其爲對-甲苯擴酸鹽 或其溶劑合物結晶之製造方法。 2 4 如申請專利範圍第22項之製造方法，其爲硫酸鹽或其溶 劑合物結晶之製造方法。 25 一種如下式（IV)之化合物、其溶劑合物、或其鹽， -52- 200412946And a process for reacting the obtained compound or a solvate thereof with p-toluenesulfonic acid, sulfuric acid 'or hydrochloric acid. 22. The manufacturing method according to item 21 of the scope of patent application, which is a manufacturing method of crystals of p-toluenesulfonate, sulfate, hydrochloride, or a solvate thereof. 23. The manufacturing method according to item 22 of the scope of patent application, which is a manufacturing method of crystals of p-toluene salt or a solvate thereof. 2 4 The manufacturing method according to item 22 of the scope of patent application, which is a manufacturing method of sulfate or a solvate crystal. 25 A compound of the following formula (IV), a solvate thereof, or a salt thereof, -52- 200412946 m 26.如申請專利範圍第25項之鹽，其爲式（IV)化合物之對-甲 苯磺酸鹽，草酸鹽，或甲酸鹽。 27 .如申請專利範圍第26項之鹽，其爲甲苯磺酸鹽。m 26. The salt according to item 25 of the scope of patent application, which is a p-toluenesulfonic acid salt, an oxalate salt, or a formate salt of a compound of formula (IV). 27. The salt according to item 26 of the scope of patent application, which is tosylate. -53--53-
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