TW200427683A - Improved process - Google Patents
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- TW200427683A TW200427683A TW093114789A TW93114789A TW200427683A TW 200427683 A TW200427683 A TW 200427683A TW 093114789 A TW093114789 A TW 093114789A TW 93114789 A TW93114789 A TW 93114789A TW 200427683 A TW200427683 A TW 200427683A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
Abstract
Description
200427683 ⑴ 玖、發明說明 【發明所屬之技術領域】 本發明係有關一種改良的製備特別結晶形式之依曲普 坦（el etr ip tan )半硫酸鹽之方法。 【先前技術】 依曲普坦，3 — {〔丨—甲基吡咯啶—2 — ( R ) 一基〕 甲基} 一 5 — （ 2 —苯磺醯基乙基）一 1 η _吲哚，及其製 法，經揭示於美國專利第5,6 09,95 1號之中。 依曲普坦半硫酸鹽具有下面式（I )之構造。 ch3200427683 ⑴ 玖, Description of the invention [Technical field to which the invention belongs] The present invention relates to an improved method for preparing el etr ip tan hemisulfate in a particularly crystalline form. [Prior art] Etripttan, 3 — {[丨 —methylpyrrolidine-2 — (R) -one] methyl} — 5 — (2-benzenesulfonylethyl) — 1 η_indole And its manufacturing method are disclosed in US Patent No. 5,6 09,95 1. Etraprotan hemisulfate has a structure of the following formula (I). ch3
:0.5H2S〇4 (Ο XX/u Η 以WO-A-9 6/06 842公開的國際專利申請第 PCT/EP 9 5 /0 1 9 1 4號揭示出依曲普坦半硫酸鹽的兩種結晶 形式。第一種經編號爲α -形式，其特徵在於具有1 8 5 °C 之熔點。此形式在下文中稱爲依曲普坦半硫酸鹽形式II。 第二種經編號爲—形式，其特徵爲具有！ 4 5 -] 4 7 °C之熔 點，且在下文稱爲依曲普坦半硫酸鹽形式ΙΠ。 以WO-A-99/0] 135公開的國際專利申請第 PCT/EP 9 8/04 1 7 6號述及一種製造依曲普坦半硫酸鹽形式 ΠI之方法。 以W Ο - A - 0 1 /2 3 3 7 7公開的國際專利申請第 PCT/EB 0 0/0 1 3 0 5揭示依曲普坦半硫酸鹽的另一種結晶形 •5- (2) (2)200427683 式。此種於下文中稱爲依曲普坦半硫酸鹽形式I的多形體 所具特徵在於其22 6 °C之DSC熔點及其他數據例如其粉末X 一射線繞射（PXRD )圖樣。此外也揭示數種製備依曲普 坦半硫酸鹽形式I的方法，包括從依曲普坦本身及從具有 混合多形態的依曲普坦半硫酸鹽（亦即，以至少部份爲一 或更多種其他多形態形式存在者）兩者進行者。於後者之 情況中，係將混合形態的半硫酸鹽在四氫呋喃（THF )、 乙醇、異丙醇或工業甲基化酒精（IMS )之中回流攪和， 再過濾，洗滌和乾燥而得依曲普坦半硫酸鹽形式I。 此等製備依曲普坦半硫酸鹽形式I的方法業經證明係 不令人滿意者，尤其是在大規模時’且不能可靠地產生形 式I多形體。例如，在使用THF作爲溶劑的情況中，所得 產物常雜含溶劑合/水合形式（特別是水合物）。此等非 合意形式都是以不可預測方式獲得。 要了解者，於一藥物分子的大規模製備中，必須建立 一種具有能可靠地製造含相同結晶形式’不含其他結晶形 式和溶劑合物之均勻產物的強烈意義之方法。 因此，有需要提供一種高產率且堅強的方法，其可在 大規模上可靠地進行以製備依曲普坦半硫酸鹽形式1。 【發明內容】 頃令人訝異地發現可以用可靠且高產率的方式製備依 曲普坦半硫酸鹽形式I。於該新穎方法中，係將任何其他 形式的依曲普坦半硫酸鹽（或多種形式的任何混合物）置 -6 - (3) (3)200427683 於-c, 一 c6烷基乙酸酯溶劑內加熱，再經由共沸蒸餾予以 濃縮後，回收產物。 c】一C6烷基乙酸酯爲式CH3C00R化合物，其中尺爲匕 - c 6烷基。較佳的溶劑爲乙酸乙酯和乙酸正丙酯。特別較 佳者爲乙酸乙酯。 所用溶劑相對於依曲普坦半硫酸鹽重量而定的體積對 成功性不具決定性。於使用乙酸乙酯作爲溶劑的情況中， 較佳者爲採用8至I 2升乙酸乙酯每仟克依曲普坦半硫酸鹽 之量。 不過，反應中的水含量對於方法的成功具關鍵性且必 須不超過3 %體積/體積。於半硫酸鹽起始物經水合的情 況中，必須計算且慮及所含結合水的量〔K a r 1 F i s c h ( K F )分析爲最方便的分析工具〕。於需要時，可將起始物乾 燥以減低其水含量。反應混合物的水含量較佳者爲從〇. 2 至2%體積/體積，最佳者爲從].3至2%體積/體積。 一般而言’對轉化較不具抗性，有低結晶度的依曲普 坦形式可以在有較低水含量的反應混合物中容易地轉化， 而較具抗性的批料則在有較高水含量的反應混合物中更方 便地轉化。 該加熱必須繼續到所含的全部半硫酸鹽都轉化成形式 1多形體爲止。此步驟典型地要花數小時，常爲從4至24小 時。轉化時間決定於所選溫度，較高的溫度導致較短的轉 化時間。較佳者爲在從60至8 (TC之下加熱該漿液。最佳者 。於選用乙酸乙酯作爲溶劑之時，係在回流下加熱漿液。 -7- (4) (4)200427683 也可以將反應混合物加壓以增加轉化速率。可以對採自反 應混合物的樣品實施差示掃描熱量測定法（D S C )作爲轉 化進展程度的相略指示。 當轉化完全時，需要時，必須將一部份溶劑經由共沸 蒸餾予以移除直到反應混合物的水含量降到低於]%體積 /體積爲止。此步驟對於避免以後產物在周溫下形成任何 溶劑合物而言係重要者。例如，在使用約1 0升乙酸乙酯每 仟克依曲普坦半硫酸鹽起始物之情況中，蒸餾掉所加體積 的從五分之一至五分之二常爲足夠者。 偶而地，若轉化呈緩慢時，可以有利地在轉化中而非 轉化後即進行共沸蒸餾。於此種情況中，反應混合物的水 含量應該減低到低於〇 · 3 %體積/體積，且須加入無水溶 劑並在回流下加熱反應一般後續時期。 產物可經由過濾予以回收。典型地，係將反應混合物 冷卻到2 0至2 5 °C，過濾，用溶劑洗（較佳者約1升每仟克 產物）及乾燥（較佳者在70 °C真空中），於某些情況中， 可以需要消除結塊。 依曲普坦半硫酸鹽形式I的平均產率爲9 4 %。 原則上，轉化所用起始物可爲非晶型依曲普坦半硫酸 鹽，任何單一多形態形式的依曲普坦半硫酸鹽，任一者的 任何水合/溶劑合形式或前述的任何混合物，包括內含形 式】本身的混合物。 下面列出已知的依曲普坦半硫酸鹽之多形態形式及鑑 定數據。多形態形式I 一 XI及兩種乙酸乙酯溶劑合物X 11和 (5) (5)200427683 XIII與乙酸正丙酯溶劑合物XIV皆爲已知者，此等溶劑合 物含有不同量的水。於將非晶態依曲普坦半硫酸鹽分別置 於乙酸乙酯或乙酸正丙酯內攪和時可輕易地觀察到溶劑合 物。當依曲普坦在乙腈中的溶液用稀硫酸處理時可觀察到 形式IV。 粉末X —射線繞射（PXRD )圖樣典型地係使用配置著 一自動樣品轉換器，0 — 0測角器，自動光束發散眼，第 二單色光器及一閃爍計數器的SIEMENS D 5 000粉末X 一射 線繞射儀予以測定的。樣品係經由將粉末塡載在矽晶圓架 上而準備分析。每一檢體都在用銅K 一 α 1 X -射線（波長 =1 .5 406 A )，以40 kV/ 40 mA操作X —射線管，照射之 下轉動。典型地係將測角器於2 °至4 0 °的2 0 —範圍內， 設定爲5秒計數每0 · 0 2 ^階之連續方式運轉之下實施該分 析。差示掃描熱量測定法（D S C )係使用配置著一自動樣 品轉換器的Perkin Elmer Diamond DSC儀器實施的。正確 地稱取約3毫克的每一樣品到一50微升鋁盤中並用穿孔蓋 皺封。以2 0 °C /分的速率於3 0 °C至2 5 0 °C範圍內在氮氣沖 滌下加熱樣品。形式Π I及更高級者所得D S C蒸譜都具有相 似的曲線型態’在局達〜]4 0 °C有脫水合或脫溶劑合及熔 化，然後爲一變成形成式Π的放熱型再結晶事件（尖峰在 約1 86t：)，接著爲變成形式I的第二放熱型再結晶事件（ 尖峰在約2 2 6 °C )。 200427683 形式i RXRD 參閱圖1 a 特性譜峰爲= 2- Θ ° 強度，％ 2- 0 ° 強度，％ 2- 0 ° 強度 7.34 1 8.9 20.649 34.2 27.773 18 9.234 27.4 21.256 49.6 2 8.139 16.9 10.23 7 25.6 21.894 2 1.5 28.759 10.3 11.315 26.5 22.162 37.3 2 9.2 62 11.9 12.35 1 42.7 22.613 43.9 2 9.74 8 13.7 12.7 7 7 6.3 23.027 27 3 0.643 8.7 16.79 1 100 23.452 22.6 3 1.472 15.4 17.478 38.9 24.849 13.6 3 2.423 8.9 17.928 3 7.2 25.169 38.6 33.089 10.2 18.65 1 2 1.4 25.738 26.8 33.889 1 6.4 18.92 14.5 26.899 23.2 34.804 10.6 19.43 25.3 DSC參閱圖1 b ( 2 2 6 1：，吸熱）。: 0.5H2S〇4 (〇 XX / u 的 International Patent Application No. PCT / EP 9 5/0 1 9 1 4 published as WO-A-9 6/06 842 discloses two It is a crystalline form. The first is numbered α-form, which is characterized by having a melting point of 18.5 ° C. This form is hereinafter referred to as etraprotan hemisulfate form II. The second number is-form , Which is characterized by having a melting point of! 4 5-] 4 7 ° C and is hereinafter referred to as Etripttan Hemisulfate Form II. International Patent Application No. PCT / published under WO-A-99 / 0] 135 EP 9 8/04 1 7 6 describes a method for the production of the form of ertriptan hemisulfate ΠI. International Patent Application No. PCT / EB 0 0 published as W 0-A-0 1/2 3 3 7 7 / 0 1 3 0 5 reveals another crystalline form of Etripttan Hemisulfate • Formula 5- (2) (2) 200427683. This polymorph is hereinafter referred to as Etripttan Hemisulfate Form I It is characterized by its DSC melting point of 22 6 ° C and other data such as its powder X-ray diffraction (PXRD) pattern. It also reveals several methods for preparing Etripttan Hemisulfate Form I, including from Equ Putan itself And both from a mixture of polymorphs of Etripttan Hemisulfate (ie, those that exist at least in part as one or more other polymorphs). In the latter case, the mixed forms The hemisulfate is stirred under reflux in tetrahydrofuran (THF), ethanol, isopropanol, or industrial methylated alcohol (IMS), and then filtered, washed, and dried to obtain etriptan hemisulfate form I. These preparations The method of Etripttan Hemisulfate Form I has proven to be unsatisfactory, especially at large scales and does not reliably produce Form I polymorphs. For example, in the case of using THF as a solvent, the resulting product Often mixed with solvated / hydrated forms (especially hydrates). These undesired forms are obtained in unpredictable ways. It is understood that in the large-scale preparation of a drug molecule, it is necessary to establish a method that can be reliably manufactured. A method with a strong meaning of a homogeneous product that contains the same crystalline form 'without other crystalline forms and solvates. Therefore, there is a need to provide a high yield and robust method which can be used in large scale It has been performed reliably to prepare Etripttan Hemisulfate Form 1. [Summary of the invention] It has surprisingly been found that Etripttan Hemisulfate Form I can be prepared in a reliable and high yield manner. In this novel method In this case, any other form of etraprotan hemisulfate (or any mixture of multiple forms) is placed in -6-(3) (3) 200427683 in -c, a c6 alkyl acetate solvent, and then After concentrating through azeotropic distillation, the product is recovered. C] A C6 alkyl acetate is a compound of the formula CH3C00R, where the ruler is C-6 alkyl. The preferred solvents are ethyl acetate and n-propyl acetate. Particularly preferred is ethyl acetate. The volume of solvent used relative to the weight of triptotan hemisulfate is not decisive for success. In the case where ethyl acetate is used as a solvent, it is preferable to use 8 to 12 liters of ethyl acetate per gram of itatriptan hemisulfate. However, the water content of the reaction is critical to the success of the method and must not exceed 3% volume / volume. In the case where the hemisulfate starting material is hydrated, the amount of bound water must be calculated and taken into account [K a r 1 F i s c h (K F) analysis is the most convenient analysis tool]. When needed, the starting material can be dried to reduce its water content. The water content of the reaction mixture is preferably from 0.2 to 2% volume / volume, and most preferably from]. 3 to 2% volume / volume. In general 'is less resistant to conversion, the form of etrotriptan with low crystallinity can be easily converted in reaction mixtures with lower water content, while more resistant batches have higher water content The content of the reaction mixture is more conveniently converted. This heating must continue until all the hemisulfate contained has been converted to Form 1 polymorph. This step typically takes several hours, often from 4 to 24 hours. The conversion time depends on the selected temperature, and higher temperatures result in shorter conversion times. Preferably, the slurry is heated from 60 to 8 ° C. The best. When ethyl acetate is selected as the solvent, the slurry is heated under reflux. -7- (4) (4) 200427683 is also possible The reaction mixture is pressurized to increase the conversion rate. Differential scanning calorimetry (DSC) can be performed on the sample taken from the reaction mixture as a similar indicator of the progress of the conversion. When the conversion is complete, a part must be taken when necessary The solvent is removed via azeotropic distillation until the water content of the reaction mixture drops below]% vol / vol. This step is important to avoid the formation of any solvates of the product at ambient temperature in the future. For example, in use In the case of about 10 liters of ethyl acetate per gram of etrotriptan hemisulfate starting material, it is often sufficient to distill off the added volume from one-fifth to two-fifths. Occasionally, if converted When it is slow, it may be advantageous to perform azeotropic distillation during the conversion instead of immediately after the conversion. In this case, the water content of the reaction mixture should be reduced to less than 0.3% volume / volume, and an anhydrous solvent must be added and Reflow The heating reaction is generally subsequent. The product can be recovered by filtration. Typically, the reaction mixture is cooled to 20 to 25 ° C, filtered, washed with a solvent (preferably about 1 liter per gram of product), and dried ( The best is in a vacuum of 70 ° C). In some cases, it may be necessary to eliminate agglomeration. The average yield of Etripttan Hemisulfate Form I is 94%. In principle, the starting materials used for the conversion may be It is an amorphous etroprotan hemisulfate, any single polymorphic form of etraprotan hemisulfate, any hydrated / solvated form of any one, or any mixture of the foregoing, including embedded forms] itself The following are the polymorphic forms and identification data of the known etraprotan hemisulfate. Polymorphic forms I-XI and two ethyl acetate solvates X 11 and (5) (5) 200427683 XIII and The n-propyl acetate solvates XIV are known, and these solvates contain different amounts of water. The amorphous etroprotan hemisulfate is stirred in ethyl acetate or n-propyl acetate, respectively. A solvate can be easily observed when it is. Form IV can be observed when the solution in acetonitrile is treated with dilute sulfuric acid. The powder X-ray diffraction (PXRD) pattern is typically configured with an automatic sample converter, 0-0 goniometer, automatic beam diverging eyes, section Two monochromators and a scintillation counter were used for the measurement of the SIEMENS D 5 000 powder X-ray diffractometer. The samples were prepared for analysis by loading the powder on a silicon wafer holder. Each specimen was made of copper K-α 1 X-ray (wavelength = 1.5 406 A), operating X-ray tube at 40 kV / 40 mA, rotating under irradiation. Typically, the goniometer is 2 ° to 40 ° 2 ° In the 0-range, the analysis is performed under a continuous mode operation with a 5 second count every 0 · 02 2 ^ steps. Differential scanning calorimetry (DSC) was performed using a Perkin Elmer Diamond DSC instrument equipped with an automatic sample converter. Approximately 3 mg of each sample was correctly weighed into a 50 microliter aluminum pan and crimped with a perforated cap. Heat the sample at a rate of 20 ° C / min from 30 ° C to 250 ° C under a nitrogen purge. DSC vapor spectra obtained from Form II I and higher have similar curve patterns. 'At the station ~] 40 ° C, there is dehydration or desolvation and melting, and then an exothermic recrystallization that becomes a formula II Event (spike at about 186 t :), followed by a second exothermic recrystallization event that turned into Form I (spike at about 2 2 6 ° C). 200427683 Form i RXRD Refer to Figure 1a The characteristic peak is = 2- Θ ° intensity,% 2- 0 ° intensity,% 2- 0 ° intensity 7.34 1 8.9 20.649 34.2 27.773 18 9.234 27.4 21.256 49.6 2 8.139 16.9 10.23 7 25.6 21.894 2 1.5 28.759 10.3 11.315 26.5 22.162 37.3 2 9.2 62 11.9 12.35 1 42.7 22.613 43.9 2 9.74 8 13.7 12.7 7 7 6.3 23.027 27 3 0.643 8.7 16.79 1 100 23.452 22.6 3 1.472 15.4 17.478 38.9 24.849 13.6 3 2.423 8.9 17.928 3 7.2 25.169 38.6 33.089 10.2 18.65 1 2 1.4 25.738 26.8 33.889 1 6.4 18.92 14.5 26.899 23.2 34.804 10.6 19.43 25.3 DSC Refer to Figure 1b (2 2 6 1: Endothermic).
- 1〇- 200427683 形式πRXRD 參閱圖2 特性譜峰爲： 2- 0。 強度，％ 2 - Θ ° 強度，％ 2- Θ ° 強度，％ 10.974 17 2 1.456 33。4 2 8.9 6 6 29.9 12.566 9.3 22.2 9 7 6 7 2 9。1 6 4 33.6 13.142 18.1 23.104 43.5 29.72 30.4 14.239 15.5 23.477 1 00 3 0.2 0 7 23 14.596 7.6 23.834 60.6 30.918 24.6 15.737 19.6 24.113 56.4 3 1.223 2 1.9 15.942 12.5 24.978 45.4 3 1.465 26.9 16.44 2 1.7 2 5.3 4 4 30.7 3 2.117 20.1 17.3 15 3 7.7 25.95 3 5.8 3 2.7 5 2 21.7 18.191 11.8 26.54 5 3 7.5 3 3.3 5 4 3 7.4 19.054 25.9 26.877 49 33.923 29 19.429 32.2 274.07 43.7 34.4 14 25.1 19.979 30.7 27.8 18 39.6 3 4.8 9 8 29.4 2 0.7 5 8 64.5 DSC ( 1 8 6 °C ，吸熱）。-1〇- 200427683 Form πRXRD Refer to Figure 2. The characteristic spectrum peaks are: 2- 0. Strength,% 2-Θ ° Strength,% 2- Θ ° Strength,% 10.974 17 2 1.456 33. 4 2 8.9 6 6 29.9 12.566 9.3 22.2 9 7 6 7 2 9. 1 6 4 33.6 13.142 18.1 23.104 43.5 29.72 30.4 14.239 15.5 23.477 1 00 3 0.2 0 7 23 14.596 7.6 23.834 60.6 30.918 24.6 15.737 19.6 24.113 56.4 3 1.223 2 1.9 15.942 12.5 24.978 45.4 3 1.465 26.9 16.44 2 1.7 2 5.3 4 4 30.7 3 2.117 20.1 17.3 15 3 7.7 25.95 3 5.8 3 2.7 5 2 21.7 18.191 11.8 26.54 5 3 7.5 3 3.3 5 4 3 7.4 19.054 25.9 26.877 49 33.923 29 19.429 32.2 274.07 43.7 34.4 14 25.1 19.979 30.7 27.8 18 39.6 3 4.8 9 8 29.4 2 0.7 5 8 64.5 DSC (1 8 6 ° C , Endothermic).
-11 - 200427683 形式πι RXRD 參閱圖3a-11-200427683 Form π RXRD see Figure 3a
特性譜峰爲： 2- 0。 強度，％ 2 - Θ ° 強度，％ 2- 0。 強度，％ 10.24 7.9 19.141 59.5 2 6.4 9 3 4 1 11.858 2 1.3 19.76 39.3 2 7.3 3 5 47 13.077 9.7 20.623 50.9 2 7.6 3 7 4 1.8 13.6 15.6 21.408 27.5 27.923 44.5 14.47 18.2 22.104 59.6 2 8.3 5 7 2 8.1 15.035 10.7 22.715 63 28.82 28.3 16.171 33.5 23.515 1 00 29.4 0 5 29.2 17.138 3 4.8 2 4.166 4 5.2 2 9.8 2 6 28.9 17.558 20.5 24.943 49.8 32.094 24.7 18.344 24.2 2 5.5 0 8 38.9 34.021 28.8 18.63 26.8 D S C 參閱圖 3 b ( 1 4 8 °C，1 8 7 °C，2 2 6 °C，全都是吸熱）。The characteristic spectrum peaks are: 2- 0. Strength,% 2-Θ ° Strength,% 2-0. Strength,% 10.24 7.9 19.141 59.5 2 6.4 9 3 4 1 11.858 2 1.3 19.76 39.3 2 7.3 3 5 47 13.077 9.7 20.623 50.9 2 7.6 3 7 4 1.8 13.6 15.6 21.408 27.5 27.923 44.5 14.47 18.2 22.104 59.6 2 8.3 5 7 2 8.1 15.035 10.7 22.715 63 28.82 28.3 16.171 33.5 23.515 1 00 29.4 0 5 29.2 17.138 3 4.8 2 4.166 4 5.2 2 9.8 2 6 28.9 17.558 20.5 24.943 49.8 32.094 24.7 18.344 24.2 2 5.5 0 8 38.9 34.021 28.8 18.63 26.8 DSC See Figure 3 b (1 4 8 ° C, 1 8 7 ° C, 2 2 6 ° C, all endothermic).
-12 - (9) (9) 2- 0 ° 強度，％ 2- Θ ° 強度，％ 2- Θ ° 強度 11.445 40.3 19.505 20.7 25.883 27 12.245 19.4 20.093 44.5 26.9 19 11.7 12.739 15.6 20.845 54.5 27.672 20.2 13.436 14.9 21.471 12.8 28.161 14.1 13.693 32.1 21.847 9.1 28.615 10.4 14.586 17.3 22.417 3 5.3 2 9.222 16 15.026 45.6 22.597 44.3 2 9.8 8 1 19 15.998 100 23.027 Ο Ο Γ J J . J 3 0.6 5 2 18.9 16.543 48.3 23.517 56.3 32.671 10.2 1 7。45 7 48.4 23.692 78.3 34 12.7 17.711 41.8 24.327 29.7 34.4 11.6 18.716 39.3 25.223 58.2 34.805 13.1 200427683-12-(9) (9) 2- 0 ° strength,% 2- Θ ° strength,% 2- Θ ° strength 11.445 40.3 19.505 20.7 25.883 27 12.245 19.4 20.093 44.5 26.9 19 11.7 12.739 15.6 20.845 54.5 27.672 20.2 13.436 14.9 21.471 12.8 28.161 14.1 13.693 32.1 21.847 9.1 28.615 10.4 14.586 17.3 22.417 3 5.3 2 9.222 16 15.026 45.6 22.597 44.3 2 9.8 8 1 19 15.998 100 23.027 Ο Ο Γ JJ. J 3 0.6 5 2 18.9 16.543 48.3 23.517 56.3 32.671 10.2 1 7.45 7 48.4 23.692 78.3 34 12.7 17.711 41.8 24.327 29.7 34.4 11.6 18.716 39.3 25.223 58.2 34.805 13.1 200427683
形式IV RXRD 參閱圖4 特性譜峰爲： -13- 200427683 形式v RXRD 參閱圖5a 特性譜峰爲： 2- Θ。 強度，％ 2- Θ ° 強度，％ 2 - 0 ° 強度，％ 10.556 24 18.572 50.9 25.958 3 1.7 11.943 57.6 19.046 26.7 26.168 29.7 12.418 ]2.3 19.53 1 00 26.685 29.4 13.032 16 19.837 64.8 26.801 3 1.4 13.611 19 2 0.3 8 6 32.1 2 7.445 32.9 14.008 9.2 2 0.9 72 49.6 28.122 32.5 14.609 66.2 2 1.47 1 34.1 2 8.4 8 5 22.2 14.908 Λ Ο Ο H J . 0 22.09 45.8 2 9.134 2 7 15.277 14.3 22.692 48.2 3 0.202 2 7.4 16.103 53.8 23.495 72.8 3 1.281 19.4 16.422 35.6 23.745 7 0.3 31.948 19.8 17.105 42.3 2 4.23 6 61.9 32.882 25.6 17.423 2 2.5 25.113 30.5 33.999 24.3 17.794 26.2 25.568 45.3 34.798 18.5 18.271 。 勹 J Z . J DSC 參閱圖 5b(153°C，1S9T：，227 °C，全都是吸熱）。See Figure 4 for Form IV RXRD. The characteristic peak is: -13- 200427683 See Figure 5a for Form v RXRD. The characteristic peak is: 2- Θ. Strength,% 2- Θ ° Strength,% 2-0 ° Strength,% 10.556 24 18.572 50.9 25.958 3 1.7 11.943 57.6 19.046 26.7 26.168 29.7 12.418] 2.3 19.53 1 00 26.685 29.4 13.032 16 19.837 64.8 26.801 3 1.4 13.611 19 2 0.3 8 6 32.1 2 7.445 32.9 14.008 9.2 2 0.9 72 49.6 28.122 32.5 14.609 66.2 2 1.47 1 34.1 2 8.4 8 5 22.2 14.908 Λ Ο Ο HJ. 0 22.09 45.8 2 9.134 2 7 15.277 14.3 22.692 48.2 3 0.202 2 7.4 16.103 53.8 23.495 72.8 3 1.281 19.4 16.422 35.6 23.745 7 0.3 31.948 19.8 17.105 42.3 2 4.23 6 61.9 32.882 25.6 17.423 2 2.5 25.113 30.5 33.999 24.3 17.794 26.2 25.568 45.3 34.798 18.5 18.271.勹 J Z. J DSC Refer to Figure 5b (153 ° C, 1S9T :, 227 ° C, all endothermic).
-14- (11) (11)200427683-14- (11) (11) 200427683
形式VI RXRD 參閱圖6a 特性譜峰爲： 2- Θ。 強度 ，％ 2- Θ ° 強度，％ 2 - θ ° 強度 //〇 10 495 6. 8 17.749 32 .5 26, .12 1 42 . 6 10 9 13 16 .4 18. 347 56 .8 26. ,422 30. 3 11 3 72 7. 9 18 • 99 6 1 26. .957 30. 4 11 88 1 3 9 7 19. 657 47 。3 28. .02 1 24. 1 12 . 3 73 10 .5 20. 1 52 43 .4 29. ,03 1 24. 7 1 2 · 65 8 2 1 , .5 20. 686 3 7 .7 29. ,397 20. 9 12. 943 3 9. .9 20. 957 34 .1 30. ,0 1 7 23 13 .58 20. .1 2 1.399 26 • 5 3 1 . .18 1 1 9 13. 94 8 13 . .4 22. 198 100 3 1 . 79 7 15. 9 14 • 49 19· ,4 22 • 99 5 6 .3 32. 302 1 6 . 4 14. 845 3 7 . Ί 23 . 〇 〇 η J J J 62 .7 32. 398 20. 6 15.368 20. 1 23 · 863 54 .8 32. 8 1 5 19. 3 15. 93 7 4 1 . 6 24. 119 55 .5 η η J J · 179 16. 3 16.399 52. 7 25.064 42 .5 3 4. 297 2 1. 3 17. 063 3 0· 5 25 .36 ο η J J • 8 34. 9 19 20. 3 DSC 參閱 圖6 b (1 4 9 °C : '1 8 6 °C ，2 2 6 〇C ，全 都是吸熱） 0 (12) 200427683See Figure 6a for Form VI RXRD. The characteristic peaks are: 2-Θ. Intensity,% 2- Θ ° Intensity,% 2-θ ° Intensity // 〇10 495 6. 8 17.749 32 .5 26, .12 1 42. 6 10 9 13 16 .4 18. 347 56 .8 26., 422 30. 3 11 3 72 7. 9 18 • 99 6 1 26.. 957 30. 4 11 88 1 3 9 7 19. 657 47. 3 28. .02 1 24. 1 12. 3 73 10 .5 20. 1 52 43 .4 29., 03 1 24. 7 1 2 · 65 8 2 1, .5 20. 686 3 7 .7 29. , 397 20. 9 12. 943 3 9. .9 20. 957 34 .1 30., 0 1 7 23 13 .58 20. .1 2 1.399 26 • 5 3 1. .18 1 1 9 13. 94 8 13. .4 22. 198 100 3 1. 79 7 15. 9 14 • 49 19 ·, 4 22 • 99 5 6 .3 32. 302 1 6. 4 14. 845 3 7. Ί 23. 〇〇η JJJ 62 .7 32. 398 20. 6 15.368 20. 1 23 · 863 54 .8 32. 8 1 5 19. 3 15. 93 7 4 1. 6 24. 119 55 .5 η η JJ · 179 16. 3 16.399 52. 7 25.064 42 .5 3 4. 297 2 1. 3 17. 063 3 0 · 5 25 .36 ο η JJ • 8 34. 9 19 20. 3 DSC Refer to Figure 6 b (1 4 9 ° C: ' 1 8 6 ° C, 2 2 6 0C, all endothermic) 0 (12) 200427683
形式VII RXRD 參閱圖7Form VII RXRD see Figure 7
特性譜峰爲： U ° 強度，％ 2- 0。 強度，％ 2 - θ z 強度，％ 10.67 3 1.5 17.178 50.8 23.532 96 1 0.964 27.2 17.507 45.2 24.2 3 7 97.4 12.029 59 18.145 63。2 24.838 69.1 13.337 7 6.2 18.591 7 7.5 25.583 47.1 13.629 3 1.2 1 8.863 52.1 26.759 55.7 13.978 26.7 19.543 38.6 27.93 43.5 14.683 29.2 19.803 36.5 28.458 42.2 15.222 38.7 20.7 7 50.2 32.323 25.8 15.682 3 8 21.489 68.6 33.743 27.2 16.338 6 6.5 22.2 7 7 1 00 34.363 28.8 16.583 5 1.6 22.7 56 94.8 DSC 參閱圖 6b(]49t：，186°C，226 °C，全都是吸熱）。The characteristic spectral peaks are: U ° intensity,% 2-0. Strength,% 2-θ z Strength,% 10.67 3 1.5 17.178 50.8 23.532 96 1 0.964 27.2 17.507 45.2 24.2 3 7 97.4 12.029 59 18.145 63. 2 24.838 69.1 13.337 7 6.2 18.591 7 7.5 25.583 47.1 13.629 3 1.2 1 8.863 52.1 26.759 55.7 13.978 26.7 19.543 38.6 27.93 43.5 14.683 29.2 19.803 36.5 28.458 42.2 15.222 38.7 20.7 7 50.2 32.323 25.8 15.682 3 8 21.489 68.6 33.743 27.2 16.338 6 6.5 22.2 7 7 1 00 34.363 28.8 16.583 5 1.6 22.7 56 94.8 DSC See Figure 6b () 49t: , 186 ° C, 226 ° C, all endothermic).
-16 - (13) 200427683-16-(13) 200427683
形式VIII RXRD 參閱圖8 特性譜峰爲： 2_ 0 c 強度，％ 2 - Θ ° 強度，％ 強度，％ 6.922 10.2 17.047 83.6 24.503 45.3 10.52 1 29.2 17.396 35.7 24.858 46.7 11.103 17.3 17.754 40.1 25.44 8 37.6 11.939 7 1.8 18.499 67.3 25.63 3 6.8 12.322 26.1 19.46 1 5 1.8 26.13 7 3 1.2 13.015 28.1 19.756 52 26.6 8 7 42.9 13.285 34.5 20.39 42.5 27.4 1 35.5 13.557 6 0.8 20.905 50.1 28.091 39.6 14.013 22.4 21.406 49.8 28.871 28 14.578 45.7 22.05 1 00 3 0.09 1 28.2 14.831 28.2 22.594 88.7 3 0.63 8 26.8 15.25 3 3.4 23.469 100 32.082 24.1 15.693 28.7 23.648 9 1.1 33.979 25.9 16.162 75.1 24.125 73.6 34.245 25.3Form VIII RXRD Refer to Figure 8. The characteristic peaks are: 2_ 0 c intensity,% 2-Θ ° intensity,% intensity,% 6.922 10.2 17.047 83.6 24.503 45.3 10.52 1 29.2 17.396 35.7 24.858 46.7 11.103 17.3 17.754 40.1 25.44 8 37.6 11.939 7 1.8 18.499 67.3 25.63 3 6.8 12.322 26.1 19.46 1 5 1.8 26.13 7 3 1.2 13.015 28.1 19.756 52 26.6 8 7 42.9 13.285 34.5 20.39 42.5 27.4 1 35.5 13.557 6 0.8 20.905 50.1 28.091 39.6 14.013 22.4 21.406 49.8 28.871 28 14.578 45.7 22.05 1 00 3 0.09 1 28.2 14.831 28.2 22.594 88.7 3 0.63 8 26.8 15.25 3 3.4 23.469 100 32.082 24.1 15.693 28.7 23.648 9 1.1 33.979 25.9 16.162 75.1 24.125 73.6 34.245 25.3
-17 - (14) 200427683-17-(14) 200427683
形式IX RXRD 參閱圖9Form IX RXRD see Figure 9
特性譜峰爲： 2- Θ ° 強度，％ 2- Θ ° 強度 ，％ 2- Θ ° 強度 ，％ 7.34 1 1 8.2 17.42 63 23 . 057 52. 5 9 24 28.7 17.962 5 5 23 . 408 65 . 3 10, .356 3 7.6 18.634 3 8. 5 23 . 739 5 1· 4 11 . .0 18 36.8 19.01 40.1 24. 092 46. 2 1 1 . ,3 16 3 8.1 19.369 46. 6 24. 9 16 48 12 . ,333 46.1 19.763 33. 2 25 . 192 49. 2 13 · 128 34 20.022 3 6. 1 25 · 74 1 53 . 7 Ϊ 5 . 199 26.6 20.702 77. 1 27. 024 48. 5 15.655 37.4 21.368 93 · 9 27. 8 12 45 . 9 16· 4 11 4 1.1 22.257 93. 9 2 8.3 04 34. 6 16. 798 1 00 22.649 78. 9 29 .48 3 1. 9The characteristic spectrum peaks are: 2- Θ ° intensity,% 2- Θ ° intensity,% 2- Θ ° intensity,% 7.34 1 1 8.2 17.42 63 23. 057 52. 5 9 24 28.7 17.962 5 5 23. 408 65. 3 10, .356 3 7.6 18.634 3 8. 5 23. 739 5 1 · 4 11.. 0 18 36.8 19.01 40.1 24. 092 46. 2 1 1., 3 16 3 8.1 19.369 46. 6 24. 9 16 48 12 ., 333 46.1 19.763 33. 2 25. 192 49. 2 13 · 128 34 20.022 3 6. 1 25 · 74 1 53. 7 Ϊ 5.. 199 26.6 20.702 77. 1 27. 024 48. 5 15.655 37.4 21.368 93 · 9 27. 8 12 45. 9 16 · 4 11 4 1.1 22.257 93. 9 2 8.3 04 34. 6 16. 798 1 00 22.649 78. 9 29 .48 3 1. 9
-18- (15) (15) 2- Θ ° 強度 ,% 2- Θ ° 強度 ?% 2- Θ c 強度 ，％ 7.086 59 9 17. 15 1 56. ,8 2 1 · 95 1 55. 6 8 · 1 88 25. .9 18. 028 52. .8 22. .3 82 5 1 . ,7 8. 729 23 . .7 18 .78 62, .5 22 · .986 40. ,8 11 .188 45 . .9 19. 0 62 73 , .4 23 · .9 12 48 . .Ί 12 .3 76 4 1 · ,1 19.9 67. .7 24. .375 4 1 ‘ ,9 13 .175 26. .8 20. 106 80. .9 26. .127 36. ,2 1 4 .188 59. ,8 20. 663 54. .5 27. .198 24, .8 14 .774 62 . .4 2 1 . 3 83 67, • 4 2 7 , .668 26 .5 16 .07 1 1 00 2 1. 645 56, ,1 28 .623 22 .8 1 6 .561 89, .8 200427683 形式χ RXRD 參閱圖1 0 特性譜峰爲： (16) (16)200427683-18- (15) (15) 2- Θ ° intensity,% 2- Θ ° intensity?% 2- Θ c intensity,% 7.086 59 9 17. 15 1 56., 8 2 1 · 95 1 55. 6 8 1 88 25. .9 18. 028 52. .8 22. .3 82 5 1., 7 8. 729 23. .7 18 .78 62, .5 22 · .986 40., 8 11 .188 45 . .9 19. 0 62 73, .4 23 · .9 12 48. .Ί 12 .3 76 4 1 ·, 1 19.9 67. .7 24. .375 4 1 ', 9 13 .175 26. .8 20. 106 80. .9 26. .127 36., 2 1 4 .188 59., 8 20. 663 54. .5 27. .198 24, .8 14 .774 62. .4 2 1. 3 83 67, • 4 2 7, .668 26 .5 16 .07 1 1 00 2 1. 645 56,, 1 28 .623 22 .8 1 6 .561 89, .8 200427683 Form χ RXRD See Figure 10 The peak is: (16) (16) 200427683
形式XI RXRD 參閱圖1 1 特性譜峰爲= 2 _ Θ ° 強度 ;% 2- Θ。 強度，％ 2 - Θ ° 強度 ，％ 5 . 67 1 12. 7 1 5 63 1 3 3 • 8 23.068 53 . 7 6 • 85 1 4 . 6 16.071 5 4 23 .35 47. 2 10, ,409 66. 4 16, ,678 3 7 24. 0 16 5 1· 6 11 , .884 1 00 17· .489 3 3 .9 25 . 054 29. 6 12 ‘ ‘346 26. 7 1 7_ ,869 22 .7 25 • 91 32. 8 12 .6 1 20 18. 4 1 1 45 .6 27. 43 7 20 13 . .026 36. 3 1 8. 883 22 .2 28 .6 1 17. 7 13 . 243 3 0· ϊ 19· 232 7 1 .1 3 1· 524 11. 6 14. 099 22. 2 19. 687 29 .2 32. 253 11. 1 ]4 . 43 1 4 1. 8 20. 647 67 • 9 34. 09 1 11· 1 1 4. 701 28. 4 22. 1 55 47 .1 (17) (17)200427683 形式XII ( EtOAc溶劑合物1 ) RXRD 參閱圖]2a 特性譜峰爲： 2- Θ ° 強度 ,% 2- θ ° 強度 ，％ 2- Θ c 強度，％ 5 · 50 2 1· 6 17 • 56 55. 1 23 .77 68 .4 Ί · 45 18. 7 18 • 12 6 1. 5 24 .22 72 .1 9· 47 11· 5 18 .50 53. 1 24 .76 7 1 • 3 10 .74 5 1· 4 1 8. 85 1 6 1. 1 25 • 12 46 • 8 11 • 2 1 68 . 6 18 • 98 70. 8 25 .82 25 .6 12. .14 6 1· 6 20 • 59 29. 8 26 .5 1 29 .8 13 , .3 1 68 . 6 20 .94 3 1 · 6 27 .02 39 .4 13 . .50 80. 3 2 1.44 78. 7 28 • 24 40 .5 14 . .23 47. 4 2 1 .86 43.] 29 .3 7 23 .5 15 . .55 100 22, .36 85 30 .85 2 1 • 4 1 6. 00 50. 9 22, ,84 46. 3 32.06 18 • 8 16. ,32 74. 9 23. • 54 50. 7 34 .59 1 8 16 7 1 7 1. 1 DSC 參閱 圖 1 2 b ( 1 4 6 cC ，1 8 6 〇C ， 226 °C ， 全都 是吸 熱） -21- (18) (18)200427683 形式XIII ( EtOAc溶劑合物2 ) RXRD 參閱圖1 3 特性譜峰爲： 2 - 0。 強度 2 - Θ。 強度，％ 2- 0。 強度，％ 4.76 17.1 17.50 44.1 24.5 1 η 〇 〇 J J . 3 5.52 26.4 18.10 52.3 24.77 57.8 7.45 20。2 18.43 45.4 25.11 29.7 10.79 69.2 18.80 47.9 25.87 20.7 11.22 79.7 19.01 59.6 26.32 19.0 12.21 52.8 20.55 30.3 2 6.89 30.6 13.26 59.6 20.96 23.7 2 7.30 2 1.5 13.55 74.5 2 1.43 65.0 28.27 24.3 14.26 50.1 21.85 34.7 29.36 15.1 15.09 17.9 22.33 5 8.4 30.85 12.1 15.54 1 00 22.76 33.9 3 1.39 10.5 16.01 46.2 23.43 28.1 3 1.96 11.0 16.32 67.7 23.76 5 6.8 34.08 9.9 16.72 54.3 24.19 53.5 34.59 10.5 -22 - (19)200427683 形式XIV ( η — Pr 0 Ac溶劑合物） RXRD 參閱圖1 4 特性譜峰爲： 2 - Θ ^ 強度 ，％ 2 - Θ ° 強度 ，％ 2- Θ ° 強度 ，％ 5 . 62 15 .5 16.64 53 , .3 23.94 32, .2 7 . 30 8 . 6 17.61 36, ,2 24 .30 63 , .6 7 . 52 1 1 .5 18.19 50. • 8 24 .86 55, ‘2 10. .85 48 • 9 18.66 3 8 , • 4 25 .85 19. .6 11 . ,23 46. ,5 18.97 68. .1 26 .50 2 1 . .0 12. >18 5 1 , ,6 20.55 23 . .1 27 .06 38, .1 13 , ,45 100 20.85 34, .6 28 .2 1 Ο 〇 D J . .1 14. ,25 3 5 , .2 2 1.56 73 . .5 29 .06 -1 η 1 J , .4 15 · 10 17· .4 2 1.99 28. .9 29 • 37 15 . .5 15 . ,53 67, 3 2 2.35 68 . .9 30 • 90 12, .1 15 . 82 54. • 6 22.86 39. .1 3 1 • 97 11 • 3 16· 39 48. ，8 23.56 44. .0 - 23- (20) (20)200427683 根據當時的相對濕度，形式111、V、V 11和X I會互變 〇 依曲普坦半硫酸鹽常係經由依曲普坦游離鹼與硫酸反 應而製備者°例如，W 0 - A - 0 1 / 2 3 3 7 7述及一種方法，包括 依曲普坦與濃硫酸在丙酮中的回流溶液形式或在四氫呋喃 中的冷卻溶液形式之反應。作爲本發明另一方面者，係發 展出一種新的製備依曲普坦半硫酸鹽之方法，該鹽可呈特 別適合放進一步處理成爲形式I多形體之形式。 於該新穎方法中’係用稀硫酸水溶液處理依曲普坦在 丙酮中的冷卻溶液，然後回收沈澱產。稀硫酸的使用，有 別於先前技藝方法中的濃硫酸之使用，係特別有利者，因 其可更容易且更安全地處置並可導致產生較低含量副產物 之更完全反應之故。 依曲普坦溶液在丙酮中的濃度較佳者爲從7.5至]5升 每仟克，最佳者爲約1 〇升每仟克且在添加稀硫酸之前，可 以有利地過濾該溶液。從約0.4 5至0.5 5莫耳當量的硫酸每 莫耳依曲普坦的使用可產生最優結果且該稀硫酸水溶液較 佳地含有約〇 · 2仟克/升的硫酸。該反應較佳者係在從- 5 °C至+ 5 °C的溫度下進行且較佳者爲逐漸添加硫酸（例如 ，於1至2小時之期間）。該產物可方便地經由粒化（較佳 者在從一 5 °C至+ 5 °C的溫度下，於約2小時之期間），過 濾，用另外的丙酮洗滌（較佳者兩份各約0.5升每仟克產 物）及乾燥（較佳者在約5 0 °C，真空中）予以回收。 此方法的產物在乾燥後，典型地爲具有變異的水和丙 -24- (21) (21)200427683 酮含量（以Karl Fischer分析，常爲約15至6%重量/重 量的水）之數種水纟’吸濕性形式的混合物。已觀察到者 有形式m、v、VI、^丨和幻一細節請參閱下面的實驗段 。於使用上述方法轉化成形式丨多形體之前，需要時要將 產物乾燥直到其水含量不超過6 % g纛/重量爲止。 【實施方式】 下面諸實施例係用以闡明本發明。粉末X 一射線繞射 (PXRD)係使用STOE STADI — P粉末X —射線繞射儀測定 的。每一檢體係在用銅K 一 α】X -射線（波長=；[.5 4 〇 6 A )照射之同時轉動。分析係用設定爲於4。至5 6。的2 Θ範 圍內以7秒計數每0 · 02 °階之透射方式運轉的測角器實施 的。只列出特譜峰’其相對強度示於括號之內。差示掃描 熱量測定分析（D S C )係使用M e 111 e 1· - Τ ο 1 e d 〇 D S C 8 2 2 e儀 器實施的。樣品係在3 〇 °C至3 0 0 °C範圍內以1 〇 t /分加熱 。紅外光（IR)分析係使用—Bruker-Optics Vector 22儀 器實施的。樣品係使用G ο 1 d e η - G a t e A T R技術製備。只列 出特性譜峰。 實施例1 將依曲普坦（100克，0.26莫耳）在丙酮（955毫升） 中的溶液過濾並另一份丙酮（4 5毫升）洗過濾器。將所得 透明黃色溶液冷卻到0 °C且在從一 5 °C至+ 5 °C的溫度下攪 拌加入稀硫酸水溶液（7 7克的]:5重量/重量之9 6 %濃硫 -25 - (22) (22)200427683 酸：水混合物，〇 . 1 2 6莫耳，0 · 4 8當量）。該添加係在1小 時期間進行。經由在〇°C下再攪彳半2小時將所得懸浮液造粒 。過濾回收沉澱物並用丙酮洗（2 X〗0毫升）。於置於周 溫下2小時之後，取出1 〇克雜含著水和丙酮（K _ F .水含量 ，8.22% ; GC丙酮含量〜1 .85% )的產物供檢驗所用。 DSC : 70 t吸熱，96 t：吸熱，131 °C吸熱，165 °C吸熱 ，2 2 4 °C吸熱 PXRD: 5.6(10) ，6.7 9(12) ，10.33(30)， ".83(74) ， 12.21 (24)， 13.15 (24) ， 13.57 (24) ,1 4.5 5 ( 24 ) ，：15.61 (2]) ，16.01 (72) ，：16.57(31 )，23.43 (100) IR: 3581 ， 3400— 2200， 1710， 1479， 1295， 1138， 1037 ， 688 ， 597 經指定爲形式III與一丙酮溶劑合物的混合物。 將剩餘量在5 0 °c強制空氣乾燥器內乾燥1 5小時得依曲 普坦半硫酸鹽（100.2克，95 % )爲蒼白色固體（K.F·水 含量，1.93% ; GC丙酮含量，<0·04%)。 D S C : I 2 5艽吸熱，1 3 2 °C吸熱，]7 2 °C吸熱，2 1 8 t吸 熱 PXRD : 5.67 ( 2 1 ) ，6.85 ( 8 ) ，7·83 ( 10 ) ，10·4 (10) ，：10.88(19) ，：Μ.3 7 (15) 5 11.89(41)， 12.61 ( 27 ) ^ 12.91 (51) ，1 3.6 3 ( 31 ) 5 1 4.8 5 ( 24 ) 5 1 5.8 9 ( 6 0 ) ，]6.39(37) ，：17.07(31) ，：17.65 (48 )，]8.2 9 ( 5 7 ) ^ 2 2.15 ( 1 0 0 ) -26- (23) 200427683 IR ： 3590，3400-2200，1480，1293，1139，1024 686 ， 598 經指定爲形式VI。 取一部份此材料（5 0 . 1克）在7 0 °C強制空氣乾燥器 再乾燥1 5小時而得5 0 . 1克蒼白色固體（K . F .水含量，2 . % ; GC丙酮含量，<0·01%) D S C : 1 1 9 °C 吸熱，1 2 5 t：吸熱，1 6 4 °C 吸熱，1 7 3 °C 熱，209 t吸熱，222 °C吸熱 PXRD： 5.67(21) ，6.85(8) ，7.83(10) ，1( (10) ，10.88(19) ，11.37(15) ，11.89(41) 12.61(2 7) ，：12.91 (51) ，13.6 3 (31) ，：14.85 (24 ^ 1 5.8 9 ( 6 0 ) ，1 6.3 9 ( 3 7 ) ，1 7.0 7 ( 31 ) ，1 7·6 5 ( )，18.2 9(57) ，22.15(100) IR ： 3590， 3400-2200， 1479， 1293， 1025， 686 598 經指定爲形式ΠΙ和形式VI之混合物。 實施例2 將依曲普坦（75克，196毫莫耳）在丙酮（715毫克 中的溶液過濾並用另一份丙酮（3 5毫升）洗過濾器。將 得透明黃色溶液冷卻到〇 °C且在從- 5 °C至+ 5 t的溫度 攪拌加入稀硫酸水溶液（58克的1 : 5重量/重量之96% 硫酸：水混合物，9 5毫莫耳，0.4 7當量）。該添加係在 分鐘期間進行。經由在〇 °C下再攪拌2小時將所得懸浮液 內 5 3 放 |.4 48 ) 所 下 濃 4 5 is -27 - (24) 200427683 粒。過濾回收沉澱物並用丙酮洗（2 x 3 5毫 強制空氣乾燥器內乾燥]6小時而得依曲普 80.9克，94%)爲蒼白色固體（K.F.水含量 丙酮含量，<〇·〇6%)。 D S C : 1 2 9 °C 吸熱，1 3 5 °C 吸熱，1 7 1 °C Θ 熱，2 2 1 °C吸熱 PXRI ： 5.71(19) ，7.91(6) ，10.91 (8) ， 11.89(31) ， 12.93(87) ， 13.65 (10) ，14.45(15) ，：14.85(23) ，1 15.91(51) ， 22.19 (100) IR ： 3590， 3400— 2200， 1480， 1293, 686 ， 598 經指定爲形式VI。 實施例3 將依曲普坦（100克，0.2 6莫耳）在丙画 中的溶液過濾並用另一份丙酮（4 5毫升）洗 得透明黃色溶液冷卻到〇 °C且在從- 5 t至Η 攪拌加入稀硫酸水溶液（7 7克的1 : 5重量/ 硫酸：水混合物，〇 .] 2 6莫耳，0.4 8當量）< 小時期間進行。經由在〇 t下再攪拌2小時將 粒。過濾回收沉澱物並用丙酮洗（2 X 5 0毫 強制空氣乾燥器內乾燥]5小時而得依曲普 1] ] · 5 克，9 6 %，9 9 . 8 4 % Η P L C 純度）爲蒼白 升）並於5 0 °C 坦半硫酸鹽（ ，1.43% ； GC δ熱，1 8 2 t放 (20 ) ^ 11.41 (13) ，13.87 5.37(16)， 1139， 1024， 同（ 955毫升） 過濾器。將所 - 5 °C的溫度下 重量之9 6 %濃 >該添加係在1 所得懸浮液造 升）並於5 (TC 坦半硫酸鹽（ 色固體（K.F. -28 - (25) (25)200427683 水含量，2.94%; GC丙酮含量，1.3%)。 D S C : 1 1 6 t：吸熱，1 2 0 °C 放熱，]5 0 °C 放熱，1 7 9 t 吸 熱，2 2 3 °C吸熱 PXRD ： 5.55 ( 52) ，6.85 (43) ，7.43 ( 25)， 10.47 (27) ，11.11 (22) ，11.91(73) ，13.55 (53) ，14.53 (25) ， 16.19 (94) ， 16.59 (26) ， 17.03(53 )，17.65(48) ， 18.43(54) ， 23.45(100) IR ： 3591， 3400— 2200， 1710， 1480， 1302， 1138， 1024， 687 ， 600 經指定爲形式VIII。 實施例4 將依韵普坦（2 0克，5 2.3毫莫耳）在丙酮（2 0 0毫升 )中的溶液過濾。將所得透明黃色溶液冷卻到〇 °C且在從 —5 °C至+ 5 °C的溫度下攪拌加入稀釋水溶液（1 5 . 1克的1 :5重量/重量之96%濃硫酸：水混合物，24.6毫莫耳， 〇 . 4 7當量）。該添加係在2小時期間進行。經由在0 °C下再 攪拌2小時將所得懸浮液造粒。過濾回收沉澱物並於5 (TC 強制空氣乾燥器內乾燥1 〇小時而得依曲普坦半硫酸鹽（ 22·]克，93%，99.89%HPLC純度）爲蒼白色固體（K.F· 水含量，5.0 4 % )。 PXRD ： 5.67(10) ，6.77( 10) ，10.24(]5)， 11.87(66) ， 13.07 (21) ， 13.57 (43) ， 14.49 (35) ，：16.07(91) ，：17.53(23) ，：18.27(23 ) ，23.43(100 -29- (26) (26)200427683 經指定爲形式111。 實施例5 將依曲普坦（20克，52.3毫莫耳）在丙酮（200毫升 )中的溶液過濾。將所得透明黃色溶液冷卻到〇。(：且在從 —5 °C至+ 5 °C的溫度下攪拌加入稀釋水溶液（1 8 . 5克的1 :5重量/重量之9 6 %濃硫酸：水混合物，3 〇 . 2毫莫耳， 0 · 5 8當量）。該添加係在2小時期間進行。經由在〇艽下再 攪拌2小時將所得懸浮液造粒。過濾回收沉澱物並於5 〇 強制空氣乾燥器內乾燥1 〇小時而得依曲普坦半硫酸鹽（ 】8.〇克，77%，99.8 9 %HPLC純度）爲蒼白色固體（K.F. 水含量，5 · 3 2 % )。 實施例6 將依曲普坦（66.3克，166毫莫耳）在丙酮（633毫升 )中的溶液過濾並用另一份丙酮（3 0毫升）洗過濾器。將 所得透明黃色溶液冷卻到〇 °C且在從—5 °C至+ 5 °C的溫度 下攪拌加入稀釋水溶液（1 5克的1 : 5重量/重量之9 6 %濃 硫酸：水混合物，8 3毫莫耳，0 · 5當量）。該添加係在5 5 分鐘期間進行。經由在〇°C下再攪拌3小時將所得懸浮液造 粒。在周溫下靜置整夜之後，過濾回收沉澱物。用丙酮洗 (2 X 3 3毫升）並於5 〇 t強制空氣乾燥器內乾燥7小時而得 依曲普坦半硫酸鹽（70·5克，94% )爲白色固體（K.F.水 -30- (27) (27)200427683 含量，2.6% ; GC丙酮含量，<0.01%)。 D S C : 1 2 1°C 吸熱，1 2 6 °C 吸熱，1 6 7 °C 吸熱 PXRD ： 5.6 7 ( 10) ， 67 7 ( 1 0 ) ， 10.24 ( 15)， 11.87(66) ，]3·07(21) ， 13.57(43) ， 14.49(35) ，16.07(91) ， 17.53(23) ， 18.27(23) ， 23.43(100 ) IR ： 3582， 3400— 2200， 1479， 1302， 1151， 1036， 687 ， 601 經指定爲形式ΠΙ。 取一份產物樣品（1 〇克）在7 0 °c進一步乾燥3小時而 得一白色固體（9.91克，K.F·水含量，1.99%)。 D S C. : 1 3 2 °C 吸熱，1 3 9 °C 放熱，1 7 5 °C.吸熱，1 8 5 t：吸 熱 PXRD ： 5.69 ( 3 0 ) ，6.8 (5) ，7.86 ( 10) ，10.89 (21) ，11.85 (59) ，12.57 ( 36) ，12·89 (69)， 15.89 (85) ^ 1 7.4 7 ( 62 ) ，：18.29 (81) ^ 1 8.9 5 ( 6 5 ) ，22.1 3 ( 1 00 ) IR ： 3589， 3400— 2200， 1480， 1304， 1149， 1037， 690 ， 620 經指定爲形式VI。 實施例7 將依曲普坦（]〇〇克，0.2 6毫莫耳）在丙酮（9 5 5毫升 )中的溶液過濾並用另一份丙酮（4 5毫升）洗過濾器。將 -31 - (28) 200427683 所得透明黃色溶液冷卻到〇 °C且在從- 5 °C至+ 5 下攪拌加入稀釋水溶液（7 7克的1 : 5重量/重量 硫酸：水混合物，〇 . 1 2 6毫莫耳，0.4 8當量）。 在5 5分鐘期間進行。經由在0 °C下再攪拌2小時將 液造粒。過濾回收沉澱物，用丙酮洗（2 X 5 0毫 5 〇 °C強制空氣乾燥器內乾燥1 4小時而得依曲普坦 (110.4 克，96%，99.86%HPLC純度）爲蒼白 K.F.水含量，3.04% ; GC丙酮含量，0.01% )。 D S C : 1 1 7 °C 吸熱，1 6 9 °C 吸熱，2 0 5 °C 吸熱 熱 PXID ： 5.6 5 ( 2 2 ) ，6(10) ，10.28(19 (15) ^ 1 1.8 9 ( 7 0 ) ，1 2.9 3 ( 3 0 ) ，1 3 . 5 7 14.55(44) ， 16.13 (91) ， 17.07(61) ，17. ，1 8.3 5 ( 6 3 ) ^ 2 3.4 7 ( 1 0 0 ) IR ： 3590， 3400— 2200， 1479， 1302， 1138 687 ， 589 經指定爲形式ΠΙ。 實施例8 將依曲普坦半硫酸鹽（實施例1的水合形式 )在乙酸乙酯（1 0 0毫升）和水（1毫升）的混合 浮液攪拌回流加熱1 6小時（總含水量〜].2 %體 )。經由共沸蒸餾移除一部分溶劑（40毫升，4( 並加入新鮮的無水乙酸乙酯（4 0毫升）。將懸浮 °C的溫度 之9 6 %濃 該添加係 所得懸浮 升）並於 半硫酸鹽 色固體（ ，2 22 cC 吸 )，1 0.49 (43 )， 53(35) ;，1025 ， VI ， 10克 物中之懸 積/體積 %體積） 液再回流 -32 - (29) (29)200427683 加熱6小時。於冷卻到周溫之後，過濾回收沉澱物，用乙 酸乙酯洗（1 0毫升）並於7 0 °C下乾燥7小時而得依曲普坦 半硫酸鹽形式I多形體（9.3 6克，94% )爲白色固體。 DSC ： 2 2 3 °C 吸熱 IR ； 3400-2200， 1480， 1302， 1133， 1006， 690, 603 實施例9 將依曲普坦半硫酸鹽（實施例2的水合產物，1 0克） 在乙酸乙酯（1 0 0毫升）和水（1 · 5毫升）的混合物中之懸 浮液攪拌回流加熱1 6小時（總含水量〜1 .65 %體積/體積 )。經由共沸蒸餾移除一部分溶劑（4 0毫升，4 0 %體積） 並加入新鮮的無水乙酸乙酯（40毫升）。將懸浮液再回流 加熱6小時。於冷卻到周溫（經3 0分鐘）之後，過濾回收 沉澱物，用乙酸乙酯洗（1 〇毫升）並於7 0 °C下乾燥3小時 而得依曲普坦半硫酸鹽形式I多形體（9.38克，94% )爲 蒼白色固體。 DSC: 2 2 3 °C 吸熱 IR ： 3400— 2200， ]480， 1302， 1133， 1006， 690, 603 實施例]〇 將依曲普坦半硫酸鹽（實施例3的水合形式¥111，]0 克）在含有1 . 7 %體積/體積水的乙酸乙酯（2 5毫升）混 -33- (30) 200427683 合物中之懸浮液攪拌回流加熱24小時（總含水量2 % /體積）。經由共沸蒸餾移除一部分溶劑（5毫升， 體積）。於冷卻到周溫之後，過濾回收沉澱物，用乙 酯洗（2 · 5毫升）並於7 0°C下乾燥4小時而得依曲普坦 酸鹽形式I多形體（2J2克，93%)爲白色固體。 DSC ： 2 2 2 〇C 吸熱 實施例1 1 將依曲普坦半硫酸鹽（實施例4的水合形式III產 5克）在含有0.45%體積/體積水的乙酸乙酯（50毫 混合物中之懸浮液回流加熱2 4小時（總含水量0.9 5 % /體積）。經由共沸蒸餾移除一部分溶劑（〗〇毫升， 體積）。於冷卻到周溫之後，過濾回收沉澱物，用乙 醋洗（5毫升）並於7 〇它下乾燥〗5小時而得依曲普坦 酸鹽形式I多形體（4.7克，93%，99.79%HPLC純度 白色固體。 D S C : 2 2 3 °C 吸熱 實施例1 2 將依曲普坦半硫酸鹽（實施例5的產物，5克）在 〇 . 4 5 %體積/體積水的乙酸乙酯（5 〇毫升）混合物中 浮液回流加熱2 4小時（總含水量]%體積/體積）。 共沸蒸餾移除一部分溶劑（]〇毫升，2 〇 %體積）。於 到周溫之後，過濾回收沉澱物，用乙酸乙酯洗（5毫 體積 20% 酸乙 半硫 物， 升） 體積 2 0 96 酸乙 半硫 ) 爲 含有 之懸 經由 冷卻 升） -34- (31) 200427683 並於7 crc下乾燥]5小時而得依曲普坦半硫酸鹽形式I多形 體（4.7克，93%，99.84%1^1^純度）爲白色固體。 DSC： 2 2 2 °C 吸熱 PXRD： 7.37(21) ，9.27 (25) ，]0·37 ( 43)， 11。35 ( 34) ，12.35 (35) ，16.81 (73) ，17.47 (54) ^ 1 7.9 3 ( 5 5 ) ，：18.67(34) ，19.43(25) ，21.39(100Form XI RXRD Refer to Figure 1 1 The characteristic peak is = 2 _ Θ ° intensity;% 2- Θ. Strength,% 2-Θ ° Strength,% 5.67 1 12. 7 1 5 63 1 3 3 • 8 23.068 53. 7 6 • 85 1 4. 6 16.071 5 4 23 .35 47. 2 10,, 409 66 4 16,, 678 3 7 24. 0 16 5 1 · 6 11, .884 1 00 17 · .489 3 3 .9 25. 054 29. 6 12 '' 346 26. 7 1 7_, 869 22 .7 25 • 91 32. 8 12 .6 1 20 18. 4 1 1 45 .6 27. 43 7 20 13. .026 36. 3 1 8. 883 22 .2 28 .6 1 17. 7 13. 243 3 0 · Ϊ 19 · 232 7 1 .1 3 1 · 524 11. 6 14. 099 22. 2 19. 687 29 .2 32. 253 11. 1] 4. 43 1 4 1. 8 20. 647 67 • 9 34 09 1 11 · 1 1 4. 701 28. 4 22. 1 55 47 .1 (17) (17) 200427683 Form XII (EtOAc solvate 1) RXRD (see figure) The characteristic peak of 2a is: 2- Θ ° Intensity,% 2- θ ° Intensity,% 2- Θ c Intensity,% 5 · 50 2 1 · 6 17 • 56 55. 1 23 .77 68 .4 • · 45 18. 7 18 • 12 6 1. 5 24 .22 72 .1 9 · 47 11 · 5 18 .50 53. 1 24 .76 7 1 • 3 10 .74 5 1 · 4 1 8. 85 1 6 1. 1 25 • 12 46 • 8 11 • 2 1 68. 6 18 • 98 70. 8 25 .82 25 .6 12. .14 6 1 · 6 20 • 59 29. 8 26 .5 1 29 .8 13, .3 1 68. 6 20 .94 3 1 · 6 27 .02 39 .4 13. .50 80. 3 2 1.44 78. 7 28 • 24 40 .5 14. .23 47. 4 2 1 .86 43.] 29 .3 7 23 .5 15. .55 100 22, .36 85 30 .85 2 1 • 4 1 6. 00 50. 9 22,, 84 46. 3 32.06 18 • 8 16., 32 74. 9 23. • 54 50. 7 34 .59 1 8 16 7 1 7 1. 1 DSC See Figure 1 2 b (1 4 6 cC, 1 8.6 ℃, 226 ° C, all endothermic) -21- (18) (18) 200427683 Form XIII (EtOAc solvent Compound 2) RXRD Refer to Figure 1 3 The characteristic peaks are: 2-0. Intensity 2-Θ. Intensity,% 2-0. Strength,% 4.76 17.1 17.50 44.1 24.5 1 η 〇〇JJ. 3 5.52 26.4 18.10 52.3 24.77 57.8 7.45 20. 2 18.43 45.4 25.11 29.7 10.79 69.2 18.80 47.9 25.87 20.7 11.22 79.7 19.01 59.6 26.32 19.0 12.21 52.8 20.55 30.3 2 6.89 30.6 13.26 59.6 20.96 23.7 2 7.30 2 1.5 13.55 74.5 2 1.43 65.0 28.27 24.3 14.26 50.1 21.85 34.7 29.36 15.1 15.09 17.9 22.33 5 8.4 30.85 12.1 15.54 1 00 22.76 33.9 3 1.39 10.5 16.01 46.2 23.43 28.1 3 1.96 11.0 16.32 67.7 23.76 5 6.8 34.08 9.9 16.72 54.3 24.19 53.5 34.59 10.5 -22-(19) 200427683 Form XIV (η — Pr 0 Ac solvate) RXRD See Figure 1 4 Characteristic peaks are: 2-Θ ^ intensity,% 2-Θ ° intensity,% 2- Θ ° Intensity,% 5.62 15 .5 16.64 53, .3 23.94 32, .2 7. 30 8. 6 17.61 36,, 2 24 .30 63, .6 7. 52 1 1 .5 18.19 50. • 8 24 .86 55, '2 10. .85 48 • 9 18.66 3 8, • 4 25 .85 19. .6 11., 23 46., 5 18.97 68. .1 26 .50 2 1. .0 12. > 18 5 1,, 6 20.55 23. .1 27 .06 38, .1 13,, 45 100 20.85 34, .6 28 .2 1 〇 〇D J. .1 14., 25 3 5, .2 2 1.56 73. .5 29 .06 -1 η 1 J, .4 15 · 10 17 · .4 2 1.99 28. .9 29 • 37 15. .5 15., 53 67, 3 2 2.35 68.. 9 30 • 90 12, .1 15. 82 54. • 6 22.86 39.. 1 3 1 • 97 11 • 3 16 · 39 48., 8 23.56 44.. 0-23- (20) (20) 200427683 Depending on the relative humidity at that time, forms 111, V, V 11 and XI will interconvert. Etratriptan hemisulfate is usually formed by reacting the free base of etriptan with sulfuric acid. Prepared by ° For example, W 0-A-0 1/2 3 3 7 7 describes a method that includes the reaction of Etripttan with concentrated sulfuric acid in the form of a reflux solution in acetone or in the form of a cooled solution in tetrahydrofuran. As a further aspect of the present invention, a new method for the preparation of etraprotan hemisulfate has been developed which can be in a form particularly suitable for further processing into form I polymorphs. In this novel method, a cooled solution of eztriptan in acetone is treated with a dilute sulfuric acid aqueous solution, and the precipitate is recovered. The use of dilute sulfuric acid, which is different from the use of concentrated sulfuric acid in the prior art methods, is particularly advantageous because it can be handled more easily and safely and can lead to a more complete reaction with lower levels of by-products. The concentration of the etraprotan solution in acetone is preferably from 7.5 to 5 liters per gram, and most preferably about 10 liters per gram and the solution may be advantageously filtered before adding dilute sulfuric acid. The use of from about 0.4 5 to 0.5 5 mole equivalents of sulfuric acid per mole of etotriptan yields optimal results and the dilute aqueous sulfuric acid solution preferably contains about 0.2 g / l of sulfuric acid. The reaction is preferably carried out at a temperature from -5 ° C to + 5 ° C and more preferably by adding sulfuric acid gradually (for example, during a period of 1 to 2 hours). The product can be conveniently granulated (preferably at a temperature from -5 ° C to + 5 ° C over a period of about 2 hours), filtered, and washed with additional acetone (preferably in two portions each) 0.5 liters of product per gram) and dried (preferably at about 50 ° C in vacuum) to be recovered. The product of this method after drying is typically a number of mutated water and propane-24- (21) (21) 200427683 ketone content (analyzed by Karl Fischer, often about 15 to 6% weight / weight water). A mixture of leeches' hygroscopic form. Observed persons have the form m, v, VI, ^ 丨 and magic one. Please refer to the experimental section below for details. Prior to conversion to polymorphs using the methods described above, the product is dried as needed until its water content does not exceed 6% g% / wt. [Embodiments] The following examples are provided to illustrate the present invention. Powder X-ray diffraction (PXRD) was measured using a STOE STADI-P powder X-ray diffractometer. Each inspection system was rotated while being irradiated with copper K-α] X-rays (wavelength =; [.5 4 〇 6 A). The analysis system is set to 4. To 5 6. It is implemented by a goniometer that operates in a transmission mode of 2 Θ every 7 seconds within a range of 2 Θ. Only the specific peaks are listed and their relative intensities are shown in parentheses. Differential scanning calorimetry analysis (D S C) was performed using a Me 111 1 1--To 1 e d 0 D S C 8 2 2 e instrument. The sample was heated at 10 t / min in the range of 30 ° C to 300 ° C. Infrared (IR) analysis was performed using a Bruker-Optics Vector 22 instrument. The samples were prepared using G ο 1 d e η-G a t e A T R technology. Only the characteristic peaks are listed. Example 1 A solution of Etraprotan (100 g, 0.26 mole) in acetone (955 ml) was filtered and the filter was washed with another portion of acetone (45 ml). The resulting transparent yellow solution was cooled to 0 ° C and stirred at a temperature of from 5 ° C to + 5 ° C. A dilute sulfuric acid aqueous solution (77 g): 5 weight / weight of 96% concentrated sulfur-25- (22) (22) 200427683 acid: water mixture, 0.1 2 mol, 0.48 equivalent). The addition was performed during an hour. The resulting suspension was granulated by stirring at 0 ° C for a further 2 hours. The precipitate was recovered by filtration and washed with acetone (2 X 0 ml). After being left at ambient temperature for 2 hours, 10 grams of the product containing water and acetone (K_F. Water content, 8.22%; GC acetone content ~ 1.85%) was taken out for inspection. DSC: 70 t heat absorption, 96 t: heat absorption, 131 ° C heat absorption, 165 ° C heat absorption, 2 2 4 ° C heat absorption PXRD: 5.6 (10), 6.7 9 (12), 10.33 (30), " .83 ( 74), 12.21 (24), 13.15 (24), 13.57 (24), 1 4.5 5 (24), 15.61 (2)), 16.01 (72), 16.57 (31), 23.43 (100) IR: 3581 , 3400-2200, 1710, 1479, 1295, 1138, 1037, 688, 597 are designated as a mixture of Form III and a monoacetone solvate. Dry the remaining amount in a forced air drier at 50 ° C for 15 hours to obtain etraprotan hemisulfate (100.2 g, 95%) as a pale solid (KF · water content, 1.93%; GC acetone content, & lt 0.04%). DSC: I 2 5 艽 endothermic, 1 3 2 ° C endothermic,] 7 2 ° C endothermic, 2 1 8 t endothermic PXRD: 5.67 (2 1), 6.85 (8), 7.83 (10), 10 · 4 (10) ,: 10.88 (19) ,: M.3 7 (15) 5 11.89 (41), 12.61 (27) ^ 12.91 (51), 1 3.6 3 (31) 5 1 4.8 5 (24) 5 1 5.8 9 (6 0),] 6.39 (37) ,: 17.07 (31) ,: 17.65 (48),] 8.2 9 (5 7) ^ 2 2.15 (1 0 0) -26- (23) 200427683 IR: 3590, 3400-2200, 1480, 1293, 1139, 1024 686, 598 are designated as Form VI. Take a portion of this material (50.1 grams) and dry it at 70 ° C for 15 hours in a forced air dryer to obtain 50.1 grams of pale solid (K.F. water content, 2.%; GC Acetone content, < 0.01%) DSC: 1 1 9 ° C endothermic, 1 2 5 t: endothermic, 16 4 ° C endothermic, 17 3 ° C endothermic, 209 t endothermic, 222 ° C endothermic PXRD: 5.67 (21), 6.85 (8), 7.83 (10), 1 ((10), 10.88 (19), 11.37 (15), 11.89 (41) 12.61 (2 7), 12.91 (51), 13.6 3 ( 31) ,: 14.85 (24 ^ 1 5.8 9 (60), 16.3 9 (37), 17.0 7 (31), 17.6 (5), 18.2 9 (57), 22.15 (100) IR : 3590, 3400-2200, 1479, 1293, 1025, 686 598 are designated as a mixture of Form II and Form VI. Example 2 Etratriptan (75 g, 196 mmol) in acetone (715 mg The solution was filtered and the filter was washed with another portion of acetone (35 ml). The resulting clear yellow solution was cooled to 0 ° C and stirred at a temperature from -5 ° C to +5 t. Dilute sulfuric acid aqueous solution (58 g of 1: 5 weight / weight 96% sulfuric acid: water mixture, 95 mmol, 0.4 7 equivalent). The addition is based on It is carried out during the bell period. After stirring at 0 ° C for another 2 hours, 5 3 of the obtained suspension is put into a concentration of .4 48). The concentration of 4 5 is -27-(24) 200427683 particles. The precipitate is recovered by filtration and washed with acetone ( 2 x 3 5m forced drying in a forced air dryer] for 6 hours to obtain 80.9 g of eztrope, 94%) is a pale white solid (KF water content, acetone content, < 0.006%). DSC: 1 2 9 ° C endothermic, 1 3 5 ° C endothermic, 1 7 1 ° C Θ endothermic, 2 2 1 ° C endothermic PXRI: 5.71 (19), 7.91 (6), 10.91 (8), 11.89 (31), 12.93 (87 ), 13.65 (10), 14.45 (15), 14.85 (23), 1 15.91 (51), 22.19 (100) IR: 3590, 3400-2200, 1480, 1293, 686, 598 are designated as Form VI. Implementation Example 3 A solution of etraprotan (100 g, 0.2 6 mol) in C painting was filtered and washed with another portion of acetone (4.5 ml) to obtain a clear yellow solution. The solution was cooled to 0 ° C and from -5 t to加入 Add dilute sulfuric acid aqueous solution (77 g of 1: 5 weight / sulfuric acid: water mixture, 0.26 mol, 0.4 8 eq.) ≪ The granules were granulated by stirring for an additional 2 hours at 0 t. The precipitate was recovered by filtration, and washed with acetone (2 x 50 millimeter forced air dryer) for 5 hours to get eztropu 1]] 5 grams, 96%, 99.8%, PLC purity) was pale Liters) and tanzanyl sulfate (50%, 1.43%; GC δ heat, 1 8 2 t) (20) ^ 11.41 (13), 13.87 5.37 (16), 1139, 1024, same (955ml) Filter. 96% by weight at a temperature of -5 ° C> The addition is made in 1 suspension of the obtained suspension) and the temperature is 5 (TC tan hemisulfate (colored solid (KF -28-(25 ) (25) 200427683 water content, 2.94%; GC acetone content, 1.3%). DSC: 1 1 6 t: endothermic, 1 2 0 ° C exothermic,] 5 0 ° C exothermic, 1 7 9 t endothermic, 2 2 Endothermic PXRD at 3 ° C: 5.55 (52), 6.85 (43), 7.43 (25), 10.47 (27), 11.11 (22), 11.91 (73), 13.55 (53), 14.53 (25), 16.19 (94) , 16.59 (26), 17.03 (53), 17.65 (48), 18.43 (54), 23.45 (100) IR: 3591, 3400-2200, 1710, 1480, 1302, 1138, 1024, 687, 600 are designated as the form VIII. Example 4 Evanbutan (20 g, 5 2.3 mmol) ) The solution in acetone (200 ml) was filtered. The resulting clear yellow solution was cooled to 0 ° C and a dilute aqueous solution (15.1 grams of 1: 5 weight / weight 96% concentrated sulfuric acid: water mixture, 24.6 mmoles, 0.47 equivalents). The addition was performed during 2 hours. The resulting suspension was stirred for another 2 hours at 0 ° C Granulation. The precipitate was recovered by filtration and dried in a 5 ° C forced air drier for 10 hours to obtain etraprotan hemisulfate (22 ·] g, 93%, 99.89% HPLC purity) as a pale solid (KF · Water content, 5.0 4%). PXRD: 5.67 (10), 6.77 (10), 10.24 (] 5), 11.87 (66), 13.07 (21), 13.57 (43), 14.49 (35), 16.07 ( 91), 17.53 (23), 18.27 (23), 23.43 (100 -29- (26) (26) 200427683) are designated as Form 111. Example 5 A solution of etraprotan (20 g, 52.3 mmol) in acetone (200 ml) was filtered. The resulting clear yellow solution was cooled to zero. (: And add the diluted aqueous solution (18. 5 g of 1: 5 weight / weight of 96% concentrated sulfuric acid: water mixture at a temperature of from -5 ° C to + 5 ° C, 3 0.2 mmol) Ear, 0.58 equivalent). The addition was carried out over a period of 2 hours. The resulting suspension was granulated by stirring for an additional 2 hours at 0 °. The precipitate was recovered by filtration and dried in a 50 ° forced air dryer for 1 °. The etraprotan hemisulfate (8.0 g, 77%, 99.98% HPLC purity) was obtained as a pale solid (KF water content, 5.32%) in Example 6. Example 6 Etrapultan (66.3 g, 166 mmol) was filtered in acetone (633 ml) and the filter was washed with another portion of acetone (30 ml). The resulting clear yellow solution was cooled to 0 ° C and at -5 ° C Add the diluted aqueous solution with stirring to a temperature of + 5 ° C (15 g of 1: 5 weight / weight of 96% concentrated sulfuric acid: water mixture, 8 3 mmol, 0.5 equivalent). The addition is at 5 This was carried out during a period of 5 minutes. The resulting suspension was granulated by stirring at 0 ° C. for another 3 hours. After standing at ambient temperature overnight, the precipitate was recovered by filtration. Wash with acetone (2 X 3 3 ml) and dry in a 50 t forced air dryer for 7 hours to obtain etraprotan hemisulfate (70 · 5 g, 94%) as a white solid (KF water -30- ( 27) (27) 200427683 content, 2.6%; GC acetone content, < 0.01%) DSC: 1 2 1 ° C endothermic, 1 2 6 ° C endothermic, 16 7 ° C endothermic PXRD: 5.6 7 (10) , 67 7 (1 0), 10.24 (15), 11.87 (66),] 3.07 (21), 13.57 (43), 14.49 (35), 16.07 (91), 17.53 (23), 18.27 (23) , 23.43 (100) IR: 3582, 3400-2200, 1479, 1302, 1151, 1036, 687, 601 are designated as Form II. A sample of the product (10 grams) is further dried at 70 ° C for 3 hours and A white solid (9.91 g, KF · water content, 1.99%) was obtained. DS C.: 1 2 2 ° C endothermic, 1 3 9 ° C exothermic, 17 5 ° C. Endothermic, 1 8 5 t: endothermic PXRD : 5.69 (30), 6.8 (5), 7.86 (10), 10.89 (21), 11.85 (59), 12.57 (36), 12.89 (69), 15.89 (85) ^ 1 7.4 7 (62) ,: 18.29 (81) ^ 1 8.9 5 (6 5), 22.1 3 (1 00) IR: 3589, 3400— 2200, 1480, 1304 , 1149, 1037, 690, 620 are designated as Form VI. Example 7 A solution of etraprotan (100 g, 0.26 mmol) in acetone (995 ml) was filtered and the filter was washed with another portion of acetone (45 ml). The resulting clear yellow solution of -31-(28) 200427683 was cooled to 0 ° C and a dilute aqueous solution (77 g of a 1: 5 weight / weight sulfuric acid: water mixture was added at -5 ° C to +5 with stirring. 1 2 6 millimoles, 0.4 8 equivalents). Performed over 5 5 minutes. The liquid was granulated by stirring at 0 ° C for another 2 hours. The precipitate was recovered by filtration, and washed with acetone (2 x 50 millimeters at 50 ° C for 14 hours in a forced air dryer to obtain etraprotan (110.4 g, 96%, 99.86% HPLC purity) as pale KF water content. , 3.04%; GC acetone content, 0.01%). DSC: 1 1 7 ° C endothermic, 1 6 9 ° C endothermic, 2 5 5 ° C endothermic PXID: 5.6 5 (2 2), 6 (10), 10.28 (19 (15) ^ 1 1.8 9 (7 0 ), 1 2.9 3 (3 0), 1 3. 5 7 14.55 (44), 16.13 (91), 17.07 (61), 17., 1 8.3 5 (6 3) ^ 2 3.4 7 (1 0 0) IR : 3590, 3400-2200, 1479, 1302, 1138 687, 589 are designated as Form II. Example 8 Etraprotan hemisulfate (hydrated form of Example 1) in ethyl acetate (100 ml) The mixed floating liquid with water (1 ml) was heated under reflux for 16 hours under stirring (total water content ~]. 2% body). A part of the solvent (40 ml, 4 (and fresh anhydrous ethyl acetate was added via azeotropic distillation) (40 ml). 96% of the suspension temperature will be concentrated at 96% of the concentration of the suspension obtained) and in a hemisulfate colored solid (2, 22 cC absorption), 1 0.49 (43), 53 (35); 1025, VI, Suspension / volume% by volume in 10 grams) The liquid was refluxed again -32-(29) (29) 200427683 Heated for 6 hours. After cooling to ambient temperature, the precipitate was recovered by filtration, and ethyl acetate was used. Wash (10 ml) and at 70 ° C After drying for 7 hours, the etraprotan hemisulfate Form I polymorph (9.36 g, 94%) is a white solid. DSC: 2 2 3 ° C endothermic IR; 3400-2200, 1480, 1302, 1133, 1006, 690, 603 Example 9 Suspension of etraprotan hemisulfate (hydrated product of Example 2, 10 g) in a mixture of ethyl acetate (100 ml) and water (1.5 ml) Stir at reflux for 16 hours (total water content ~ 1.65% volume / volume). Remove part of the solvent (40ml, 40% vol) by azeotropic distillation and add fresh anhydrous ethyl acetate (40ml) The suspension was heated at reflux for another 6 hours. After cooling to ambient temperature (over 30 minutes), the precipitate was recovered by filtration, washed with ethyl acetate (10 ml) and dried at 70 ° C for 3 hours to obtain Etripttan hemisulfate Form I polymorph (9.38 g, 94%) is a pale white solid. DSC: 2 2 3 ° C Endothermic IR: 3400-2200,] 480, 1302, 1133, 1006, 690, 603 Implementation Example] 〇 The etraprotan hemisulfate (hydrated form of Example 3 ¥ 111,] 0 g) containing 1.7% by volume / body Water in ethyl acetate (25 ml) was mixed -33- (30) 200 427 683 The compositions suspension was stirred heated under reflux for 24 hours (total moisture content of 2% / vol). A portion of the solvent was removed via azeotropic distillation (5 ml, volume). After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (2.5 ml) and dried at 70 ° C for 4 hours to obtain the etraprotan salt form I polymorph (2J2 g, 93% ) Is a white solid. DSC: 2 2 2 0C Endothermic Example 1 1 Etratriptan hemisulfate (5 g of the hydrated form III of Example 4) was added in ethyl acetate (50 mmol of 50 mmol mixture) The suspension was heated under reflux for 24 hours (total moisture content 0.95% / volume). Part of the solvent was removed via azeotropic distillation (0 ml, volume). After cooling to ambient temperature, the precipitate was recovered by filtration and washed with ethyl acetate. (5 ml) and dried at 70 ° C for 5 hours to obtain the etratriptan salt Form I polymorph (4.7 g, 93%, 99.79% HPLC purity white solid. DSC: 2 2 3 ° C Endothermic Example 1 2 Etraprotan hemisulfate (product of Example 5, 5 g) was heated at reflux in a mixture of 0.45% v / v water in ethyl acetate (50 ml) for 24 hours (total Water content]% vol / vol). A part of the solvent was removed by azeotropic distillation (0 ml, 20% vol). After reaching the ambient temperature, the precipitate was recovered by filtration and washed with ethyl acetate (5 mmol vol 20% acid). Ethylene sulfide, liters) Volume 2 0 96 Ethyl sulfide, containing liters suspended by cooling) -34- (31) 200427683 and drying at 7 crc] for 5 hours to obtain the etraprotan hemisulfate form I polymorph (4.7 g, 93%, 99.84% 1 ^ 1 ^ purity) as a white solid. DSC: 2 2 2 ° C Endothermic PXRD: 7.37 (21), 9.27 (25), 0.37 (43), 11.35 (34), 12.35 (35), 16.81 (73), 17.47 (54) ^ 1 7.9 3 (5 5): 18.67 (34), 19.43 (25), 21.39 (100
實施例1 3 將依曲普坦半硫酸鹽（實施例6的水合形式III和V產 物，2.5克）在乙酸乙酯（25毫升）混合物中之懸浮液回 流加熱4小時（總含水量0.2 6 %體積/體積）。於冷卻到 周溫之後，過濾回收沉澱物，用乙酸乙酯洗（5毫升）並 於7 0 °C下乾燥7小時而得依曲普坦半硫酸鹽形式I多形體（ 2.]克，85%)爲白色固體。Example 1 3 A suspension of etraprotan hemisulfate (products of hydrated forms III and V of Example 6, 2.5 g) in a mixture of ethyl acetate (25 ml) was heated under reflux for 4 hours (total water content 0.2 6 % Volume / volume). After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (5 ml) and dried at 70 ° C for 7 hours to obtain etraprotan hemisulfate form I polymorph (2) g, 85%) as a white solid.
DSC: 2 2 2 °C 吸熱 實施例1 4 將依曲普坦半硫酸鹽（實施例6的水合形式VI產物，5 克）在乙酸乙酯（25毫升）中之懸浮液回流加熱24小時（ 總含水量〇 . 2 %體積/體積）。於冷卻到周溫之後，過濾 回收沉澱物，用乙酸乙酯洗（5毫升）並於7 0 °C下乾燥7小 時而得依曲普坦半硫酸鹽形式I多形體（2 .2克，8 9 % )爲 白色固體。 -35- (32) (32)200427683 實施例1 5 將依曲普坦半硫酸鹽（實施例7的水合形式111產物， 2.5克）在含有0.3%體積/體積水的乙酸乙酯（25毫升） 混合物中之懸浮液回流加熱24小時（總含水量0.6 %體積 /體積）。經由共沸蒸餾移除一部分溶劑（5毫升，2 0 % 體積）。於冷卻到周溫之後，過濾回收沉澱物，用乙酸乙 酯洗（2.5毫升）並於70°C下乾燥4小時而得依曲普坦半硫 酸鹽形式I多形體（2.1克，88%)爲白色固體。 DSC ： 2 2 3 t 吸熱 實施例1 6 將依曲普坦半硫酸鹽（具有較高的水含量（〜9 % ) 和丙酮含量（〜6.4%) ，10克）在乙酸乙酯（10毫升） 和水（0.6毫升）的混合物中之懸浮液回流加熱1 6小時（ 總含水量約1 . 5 %體積/體積）。經由共沸蒸餾移除一部 分溶劑（40毫升，40%體積）。並添加新鮮無水乙酸乙酯 (4 0毫升）。將反應混合物再回流加熱6小時。於冷卻到 周溫（3 0分鐘期間）之後，過濾回收沉澱物，用乙酸乙酯 洗（〗〇毫升）並於7 0 °C下乾燥2.5小時而得依曲普坦半硫 酸鹽形式I多形體（8.2克，9 6 % )爲蒼白色固體。 DSC ： 2 2 3 °C 吸熱 實施例]7 -36- (33) (33)200427683 將依曲普坦半硫酸鹽（具有較高的水含量5 . 2 3 %和丙 酮含量低於50 ppm，] 0克）在乙酸乙酯（]0毫升）和水（ ]毫升）的混合物中之懸浮液回流加熱1 6小時（總含水量 約1 . 5 %體積/體積）。經由共沸蒸餾移除一部分溶劑（ 40毫升，40%體積）。並添加新鮮無水乙酸乙酯（40毫升 )。將反應混合物再回流加熱6小時。於冷卻到周溫（20 分鐘期間）之後，過濾回收沉澱物，用乙酸乙酯洗（1 〇毫 升）並於7 0 °c下乾燥3小時而得依曲普坦半硫酸鹽形式I多 形體（9.1克，96%)爲蒼白色固體。 DSC ： 222°C 吸熱 實施例1 8 將依曲普坦半硫酸鹽（主要爲水合形式V I，水含量 2.3 3 %，1 0克）在乙酸乙酯（1 0 0毫升）和水（1毫升）的 混合物中之懸浮液回流加熱1 6小時（總含水量約1 . 3 %體 積/體積）。經由共沸蒸餾移除一部分溶劑（40毫升，40 %體積）並添加新鮮無水乙酸乙酯（40毫升）。將反應混 合物再回流加熱6小時。於冷卻到周溫（2 0分鐘期間）之 後，過濾回收沉澱物，用乙酸乙酯洗（10毫升）並於7〇 °C 下乾燥而得依曲普坦半硫酸鹽形式I多形體（9克，92% ) 爲蒼白色固體。 DSC: 2 2 4 °C 吸熱 IR ： 3400— 2200， 1480， ]302， 1]33， ]006， 690， -37- 604DSC: 2 2 2 ° C Endothermic Example 1 4 A suspension of etraprotan hemisulfate (the hydrated form VI product of Example 6, 5 g) in ethyl acetate (25 ml) was heated at reflux for 24 hours ( Total water content 0.2% volume / volume). After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (5 ml) and dried at 70 ° C for 7 hours to obtain the etraprotan hemisulfate form I polymorph (2.2 g, 89%) was a white solid. -35- (32) (32) 200427683 Example 1 5 Etraprotan hemisulfate (the hydrated form 111 product of Example 7, 2.5 g) was added to ethyl acetate (25 ml of 0.3% v / v water). ) The suspension in the mixture was heated at reflux for 24 hours (total water content 0.6% v / v). A portion of the solvent was removed via azeotropic distillation (5 ml, 20% by volume). After cooling to ambient temperature, the precipitate was recovered by filtration, washed with ethyl acetate (2.5 ml) and dried at 70 ° C. for 4 hours to obtain the etraprotan hemisulfate form I polymorph (2.1 g, 88%). As a white solid. DSC: 2 2 3 t Endothermic Example 1 6 Etraprotan hemisulfate (with a higher water content (~ 9%) and acetone content (~ 6.4%), 10 g) in ethyl acetate (10 ml The suspension in a mixture of water and water (0.6 ml) was heated at reflux for 16 hours (total water content of about 1.5% v / v). A portion of the solvent was removed via azeotropic distillation (40 ml, 40% by volume). And fresh anhydrous ethyl acetate (40 ml) was added. The reaction mixture was heated at reflux for another 6 hours. After cooling to ambient temperature (for a period of 30 minutes), the precipitate was recovered by filtration, washed with ethyl acetate (0 ml) and dried at 70 ° C for 2.5 hours to obtain Etraprotan Hemisulfate Form I. The shape (8.2 g, 96%) was a pale white solid. DSC: 2 2 3 ° C Endothermic Example] 7 -36- (33) (33) 200427683 will be etriptan hemisulfate (has a higher water content of 5. 2% and an acetone content of less than 50 ppm, ] 0 g) A suspension in a mixture of ethyl acetate (] 0 ml) and water (] ml) was heated at reflux for 16 hours (total water content of about 1.5% vol / vol). A portion of the solvent was removed via azeotropic distillation (40 mL, 40% by volume). And fresh anhydrous ethyl acetate (40 ml) was added. The reaction mixture was heated at reflux for another 6 hours. After cooling to ambient temperature (for a period of 20 minutes), the precipitate was recovered by filtration, washed with ethyl acetate (10 ml) and dried at 70 ° C for 3 hours to obtain the etraprotan hemisulfate form I polymorph. (9.1 g, 96%) was a pale white solid. DSC: 222 ° C Endothermic Example 1 8 Etraprotan hemisulfate (mainly hydrated form VI, water content 2.33%, 10 g) in ethyl acetate (100 ml) and water (1 ml The suspension in the mixture was heated at reflux for 16 hours (total water content of about 1.3% volume / volume). A portion of the solvent (40 mL, 40% by volume) was removed via azeotropic distillation and fresh anhydrous ethyl acetate (40 mL) was added. The reaction mixture was heated at reflux for another 6 hours. After cooling to ambient temperature (for a period of 20 minutes), the precipitate was recovered by filtration, washed with ethyl acetate (10 ml) and dried at 70 ° C. to give the etraprotan hemisulfate form I polymorph (9 G, 92%) as a pale white solid. DSC: 2 2 4 ° C Endothermic IR: 3400—2200, 1480,] 302, 1] 33,] 006, 690, -37- 604
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| GBGB0312478.1A GB0312478D0 (en) | 2003-05-30 | 2003-05-30 | Improved process |
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| EP (1) | EP1633739A1 (en) |
| JP (1) | JP2006528968A (en) |
| AR (1) | AR044463A1 (en) |
| BR (1) | BRPI0410841A (en) |
| CA (1) | CA2527127A1 (en) |
| CL (1) | CL2004001132A1 (en) |
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| GB9417310D0 (en) * | 1994-08-27 | 1994-10-19 | Pfizer Ltd | Therapeutic agents |
| EA002174B1 (en) * | 1997-07-03 | 2002-02-28 | Пфайзер Инк. | Pharmaceutical compositions containing eletriptan hemisulphate and caffeine |
| GB9922963D0 (en) * | 1999-09-28 | 1999-12-01 | Pfizer Ltd | Polymorphic salt |
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2003
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| Publication number | Publication date |
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| GB0312478D0 (en) | 2003-07-09 |
| JP2006528968A (en) | 2006-12-28 |
| TWI290923B (en) | 2007-12-11 |
| AR044463A1 (en) | 2005-09-14 |
| EP1633739A1 (en) | 2006-03-15 |
| MXPA05012838A (en) | 2006-02-13 |
| WO2004106327A1 (en) | 2004-12-09 |
| CA2527127A1 (en) | 2004-12-09 |
| BRPI0410841A (en) | 2006-06-27 |
| CL2004001132A1 (en) | 2005-03-18 |
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