JPH0768244B2 - Process and intermediates for preparing azabicyclo[2,2,2octan-3-imines] - Google Patents
Process and intermediates for preparing azabicyclo[2,2,2octan-3-imines]Info
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- JPH0768244B2 JPH0768244B2 JP4-502391A JP50239192A JPH0768244B2 JP H0768244 B2 JPH0768244 B2 JP H0768244B2 JP 50239192 A JP50239192 A JP 50239192A JP H0768244 B2 JPH0768244 B2 JP H0768244B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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Description
【発明の詳細な説明】
発明の背景
本発明は、サブスタンスＰ拮抗性を有する置換２−ジフ
ェニルメチル−Ｎ−フェニルメチル−１−アザビシクロ
［2,2,2］オクタン−３−アミン化合物類（“最終化合
物”）の製造の中間体であるアザビシクロ［2,2,2］オ
クタン−３−イミン類を製造するための方法と中間体に
関する。本発明はまた、アザビシクロ［2,2,2］オクタ
ン−３−イミン類の製造のフェニルメチレンイミン中間
体と、それらの製造方法とに関する。本発明はさらに、
アザビシクロ［2,2,2］オクタン−３−イミン類から最
終化合物のシス化合物の製造方法と、シス化合物のラセ
ミ混合物の分割方法とに関する。BACKGROUND OF THE INVENTION The present invention relates to processes and intermediates for preparing azabicyclo[2,2,2]octan-3-imines, which are intermediates in the preparation of substituted 2-diphenylmethyl-N-phenylmethyl-1-azabicyclo[2,2,2]octan-3-amine compounds ("final compounds") having substance P antagonistic properties. The present invention also relates to phenylmethyleneimine intermediates in the preparation of azabicyclo[2,2,2]octan-3-imines and methods for their preparation. The present invention further relates to
The present invention relates to a method for producing the final cis compound from azabicyclo[2,2,2]octan-3-imines, and a method for resolving a racemic mixture of the cis compound.
最終化合物、それらの製造方法、及びそれらのサブスタ
ンスＰ拮抗能力は国際出願公開公報第WO90/05729号に開
示されている。これらの化合物は過剰なサブスタンスＰ
によって惹起される疾患の治療に有効である。サブスタ
ンスＰはタキキニン系ペプチドに属する、天然に産生す
るウンデカペプチドであり、タキキニン系ペプチドは平
滑筋組織に対するそれらの迅速な刺激作用のためにこの
ように呼ばれる。さらに詳しくは、サブスタンスＰは哺
乳動物において産生される（本来、腸から単離される）
薬理学的活性な神経ペプチドであり、特徴的なアミノ酸
配列を有する。多くの疾患の病態生理学にサブスタンス
Ｐとその他のタキキニンが広範囲に関係していることは
当該技術分野において詳細に実証されている。このよう
な疾患の例は精神病、偏頭痛、リウマチ性関節炎及び潰
痕性大腸炎である。The final compounds, their methods of preparation, and their substance P antagonizing abilities are disclosed in International Application Publication No. WO 90/05729. These compounds inhibit excess substance P.
Substance P is a naturally occurring undecapeptide that belongs to the tachykinin family of peptides, so named because of their rapid stimulatory action on smooth muscle tissue. More specifically, substance P is produced in mammals (originally isolated from the intestine).
It is a pharmacologically active neuropeptide with a characteristic amino acid sequence. The widespread involvement of substance P and other tachykinins in the pathophysiology of many diseases is well documented in the art. Examples of such diseases are psychosis, migraine, rheumatoid arthritis, and cicatricial colitis.
発明の概要
本発明は式：
［式中、R1とR2は下記で定義する通りである］
で示される化合物と、
式：
［式中、R3は下記で定義する通りであり、ＡはMgCl、Mg
Br又はリチウムである］
で示される化合物とを反応させることによる、式：
［式中、R1とR2及びR3は独立的に水素、又はフッ素、塩
素、臭素、トリフルオロメチル、炭素数１〜３のアルキ
ル及び炭素数１〜３のアルコキシから成る群から選択さ
れる１個もしくは２個の置換基である］
で示される化合物の製造方法に関する。SUMMARY OF THE INVENTION The present invention relates to a compound of formula: wherein R1 and R2 are as defined below; and a compound of the formula: wherein R3 is as defined below, A is MgCl, Mg
Br or lithium] to give a compound of the formula: wherein R1 , R2 , and R3 are independently hydrogen or one or two substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms.
この方法の特定の実施態様では、R1はオルト置換基、例
えばｏ−メトキシ又はｏ−ハロ、例えばｏ−クロロであ
り、R2とR3はそれぞれ水素である。他の特定の実施態様
では、R1は１個のアルコキシ、例えばｏ−メトキシと１
個のハロ、例えば５−ハロであるか、又はR1は２個のア
ルコキシ、例えば2,5−ジメトキシである。In certain embodiments of this method, R1 is an ortho substituent, such as o-methoxy or o-halo, such as o-chloro, and R2 and R3 are each hydrogen. In other particular embodiments, R1 is one alkoxy, such as o-methoxy, and one alkoxy.
or R 1 is two alkoxy, such as 2,5-dimethoxy.
本発明はまた、式：
［式中、R2は式Ｉに関連して上記で定義する通りであ
る］
で示される化合物と、
式：
［式中、R1は式Ｉに関連して上記で定義する通りであ
る］
で示される化合物とを反応させることによる、
式：
［式中、R1とR2は独立的に水素、又はフッ素、塩素、臭
素、トリフルオロメチル、炭素数１〜３のアルキル及び
炭素数１〜３のアルコキシから成る群から選択される１
個もしくは２個の置換基である］
で示される化合物の製造方法に関する。この方法の特定
の実施態様では、R1はオルト置換基、例えばｏ−メトキ
シ又はｏ−ハロ、例えばｏ−クロロであり、R2とR3はそ
れぞれ水素である。The present invention also provides a compound of formula: wherein R2 is as defined above in relation to formula I; and a compound of formula: wherein R1 is as defined above in relation to formula I, by reacting a compound of formula: wherein R 1 and R 2 are independently hydrogen or one selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms.
In certain embodiments of this method, R1 is an ortho substituent, such as o-methoxy or o-halo, such as o-chloro, and R2 and R3 are each hydrogen.
本発明はまた、式IV化合物と式Ｖ化合物とを反応させる
ことによって製造される式II化合物と、式III化合物と
を反応させることによる式Ｉ化合物の総合製造方法にも
関する。このような方法の特定の実施態様では、R1はオ
ルト置換基、例えばｏ−メトキシ又はｏ−ハロ、例えば
ｏ−クロロであり、R2とR3はそれぞれ水素である。他の
実施態様では、R1は１個のアルコキシ、例えばｏ−メト
キシと１個のハロとによる２置換基であるか、又はR1は
２個のアルコキシ、例えば2,5−ジメトキシによる２置
換基である。The present invention also relates to an overall process for preparing a compound of Formula I by reacting a compound of Formula II, which is prepared by reacting a compound of Formula IV with a compound of Formula V, with a compound of Formula III. In certain embodiments of such a process, R1 is an ortho-substituent, such as o-methoxy or o-halo, such as o-chloro, and R2 and R3 are each hydrogen. In other embodiments, R1 is disubstituted with one alkoxy, such as o-methoxy, and one halo, or R1 is disubstituted with two alkoxy, such as 2,5-dimethoxy.
本発明はさらに、式：
で示される化合物をトリアセトキシホウ水素化ナトリウ
ムと酢酸とによって還元することによる、式：
［式中、R1、R2及びR3は独立的に水素、又はフッ素、塩
素、臭素、トリフルオロメチル、炭素数１〜３のアルキ
ル又は炭素数１〜３のアルコキシから成る群から選択さ
れる１個もしくは２個の置換基である］
で示されるシス化合物のラセミ混合物の製造方法に関す
る。この方法の特定の実施態様では、R1はオルト置換
基、例えばｏ−メトキシ又はｏ−ハロ、例えばｏ−クロ
ロであり、
R2とR3はそれぞれ水素である。もう一つの実施態様で
は、R1は１個のアルコキシ、例えばｏ−メトキシと１個
のハロとによる２置換基であるか、又はR1は２個のアル
コキシによる２置換基であり、例えばR1は2,5−ジメト
キシである。The present invention further provides a compound of formula: with sodium triacetoxyborohydride and acetic acid to give a compound of the formula: wherein R1 , R2 , and R3 are independently hydrogen or one or two substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, alkyl of 1 to 3 carbon atoms, or alkoxy of 1 to 3 carbon atoms. In a particular embodiment of this method, R1 is an ortho-substituent, such as o-methoxy or o-halo, such as o-chloro, and R2 and R3 are each hydrogen. In another embodiment, R1 is disubstituted with one alkoxy, such as o-methoxy, and one halo, or R1 is disubstituted with two alkoxy, such as 2,5-dimethoxy.
本発明はさらに、式：
で示されるcis−化合物のラセミ混合物を（−）マンデ
ル酸と反応させ、式VI化合物の（−）マンデル酸塩を精
製し、（−）マンデル酸塩を強塩基で処理し、式VIIの
（−）化合物を回収することによる前記ラセミ化合物の
分割方法に関する。The present invention further provides a compound of formula: with (-) mandelic acid, purifying the (-) mandelate salt of the compound of formula VI, treating the (-) mandelate salt with a strong base, and recovering the (-) compound of formula VII.
本発明はさらに、式：
［式中、R1とR2は独立的に水素、又はフッ素、塩素、臭
素、トリフルオロメチル、炭素数１〜３のアルキル又は
炭素数１〜３のアルコキシから成る群から選択される１
個もしくは２個の置換基である］
で示される化合物に関する。The present invention further provides a compound of formula: wherein R 1 and R 2 are independently hydrogen or one selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms.
wherein the substituents are one or two.
この化合物の特定の実施態様では、R1はオルト置換基、
例えばｏ−メトキシ又はｏ−ハロ、例えばｏ−クロロで
あり、R2とR3はそれぞれ水素である。もう一つの実施態
様では、R1は１個のアルコキシ、例えばｏ−メトキシと
１個のハロとによる２置換基であるか、又はR1は２個の
アルコキシによる２置換基であり、例えばR1は2,5−ジ
メトキシである。In certain embodiments of this compound, R 1 is an ortho substituent,
For example, o-methoxy or o-halo, such as o-chloro, and R and R are each hydrogen. In another embodiment, R is disubstituted with one alkoxy, such as o-methoxy, and one halo, or R is disubstituted with two alkoxy, for example, R is 2,5-dimethoxy.
発明の詳細な説明
式II化合物と式III化合物との反応は、式IIIのグリニャ
ール試薬を溶解させることができる反応に不活性な溶剤
中で実施される。適当な溶剤は例えばジ（C1−C6）アル
キルエーテル又は環状エーテル例えばテトラヒドロフラ
ンもしくはジオキサンのようなエーテルである。他の適
当な溶剤はトルエン、ジメトキシーエタン及びグリムで
ある。これらの溶剤の混合物も同様に使用可能である。
反応温度は一般に約０℃から室温までの範囲である。反
応速度を高めるためには、約50℃以上の高い反応温度も
使用可能である。DETAILED DESCRIPTION OF THE INVENTION The reaction of a compound of formula II with a compound of formula III is carried out in a reaction-inert solvent capable of dissolving the Grignard reagent of formula III. Suitable solvents are, for example, di( C1 - C6 ) alkyl ethers or cyclic ethers such as tetrahydrofuran or dioxane. Other suitable solvents are toluene, dimethoxyethane and glyme. Mixtures of these solvents can also be used.
The reaction temperature generally ranges from about 0° C. to room temperature. To increase the reaction rate, a higher reaction temperature of about 50° C. or higher can also be used.
式IV化合物と式Ｖ化合物との反応は、例えば芳香族炭化
水素（例えばトルエン、キシレン又はベンゼン）のよう
な、反応に不活性な溶剤中で実施される。この反応は一
般に室温から反応に不活性な溶剤の還流温度までの範囲
内の温度において実施される。この反応中には、一般に
酸触媒が存在する。このような触媒の例は例えば樟脳ス
ルホン酸及びｐ−トルエンスルホン酸のようなスルホン
酸である。The reaction of the compound of formula IV with the compound of formula V is carried out in a reaction-inert solvent, such as an aromatic hydrocarbon (e.g., toluene, xylene, or benzene). The reaction is generally carried out at a temperature ranging from room temperature to the reflux temperature of the reaction-inert solvent. An acid catalyst is generally present during the reaction. Examples of such catalysts are sulfonic acids, such as camphorsulfonic acid and p-toluenesulfonic acid.
式Ｉ化合物のトリアセトキシホウ水素化ナトリウムと酢
酸とによる還元は、一般に約５〜約50℃、通常は約20〜
約25℃、例えば室温において実施される。The reduction of a compound of formula I with sodium triacetoxyborohydride and acetic acid is generally carried out at temperatures between about 5°C and about 50°C, usually between about 20°C and about 50°C.
It is carried out at about 25°C, for example at room temperature.
式VII化合物と（−）マンデル酸との反応は一般に酢酸
エチル中で実施される。この後の精製は一般に、酢酸エ
チル中で還流温度において（−）マンデル酸塩をスラリ
ー化することによって実施される。この精製された塩を
強塩基で処理して、式VIIの（−）化合物を回収する。
この処理は一般にpH10〜12において実施される。強塩基
の例は例えばアルカリ金属水酸化物（例えば水酸化カリ
ウム）のような強無機塩基と、例えば炭酸カリウムのよ
うなアルカリ金属炭酸塩である。The reaction of the formula VII compound with (-) mandelic acid is typically carried out in ethyl acetate. Subsequent purification is typically accomplished by slurrying the (-) mandelic acid salt in ethyl acetate at reflux. The purified salt is treated with a strong base to recover the (-) compound of formula VII.
This treatment is generally carried out at a pH of 10 to 12. Examples of strong bases are strong inorganic bases such as alkali metal hydroxides (e.g. potassium hydroxide) and alkali metal carbonates such as potassium carbonate.
本発明の最終化合物は、上記国際出願公開公報第WO90/0
5729号にさらに詳細に説明されるように、約5.0mg/日〜
約1500mg/日の範囲内の用量で、経口経路、非経口経路
又は局所経路のいずれかで投与されることができる。The final compound of the present invention is disclosed in the above-mentioned International Patent Application Publication No. WO90/0
As described in more detail in US Pat. No. 5,729, approximately 5.0 mg/day to
It can be administered either orally, parenterally or topically in a dosage range of about 1500 mg/day.
サブスタンスＰアンタゴニストとしての本発明の最終化
合物の活性は、ウシ尾組織のサブスタンスの受容体部位
におけるサブスタンスＰの結合を阻害するそれらの能力
によって、オートラジオグラフィーによってタキキニン
受容体を可視化するために放射性リガンドを用いて評価
される。ここに述べるキヌクリジン化合物類のサブスタ
ンスＰアンタゴニスト活性はJournal of Biological
Chemistry,258巻,5158頁（1983）に報告される、M.A.
Cascieri等が述べる標準分析方法を用いて評価される。
この方法は本質的に、前記単離ウシ組織のサブスタンス
Ｐ受容体部位における放射性標識サブスタンスＰリガン
ド量を50％減ずるために必要な個々の化合物濃度を測定
し、それによって各供試化合物の特徴的IC50を得ること
を含む。The activity of the final compounds of the present invention as substance P antagonists is assessed by their ability to inhibit the binding of substance P at its receptor site in bovine tail tissue using a radioligand to visualize tachykinin receptors by autoradiography. The substance P antagonist activity of the quinuclidine compounds described herein has been reported in the Journal of Biological
Chemistry, Vol. 258, p. 5158 (1983), MA
It is assessed using standard analytical methods described by Cascieri et al.
The method essentially involves determining the concentration of each compound required to reduce by 50% the amount of radiolabeled substance P ligand at substance P receptor sites in the isolated bovine tissue, thereby obtaining a characteristic IC50 for each test compound.
下記実施例によって、本発明を説明する。The following examples illustrate the invention.
実施例１
A.N−［（２−メトキシフェニル）メチル］−２−フェ
ニルメチレン−１−アザビシクロ［2,2,2］−オクタン
−３−イミン
メカニカルスターラー、温度計、冷却管、Dean Stark
トラップを備えた12L三つ口丸底フラスコ（3nrbf）に、
トルエン5.9L、２−フェニルメチレン−１−アザビシク
ロ［2,2,2］オクタン−３−イミン791.8g（3.7モル）、
２−メトキシベンジルアミン764g（5.6モル、1.5当
量）、及び（＋）樟脳スルホン酸8.8g（0.0039モル）を
装入した。この溶液を還流するまで（116℃）加熱し、4
2時間還流させた。DeanStarkトラップには全体で75mlの
水が回収され、反応が進行していることを示した。標題
生成物を含む溶液を室温に冷却した。Example 1 AN-[(2-methoxyphenyl)methyl]-2-phenylmethylene-1-azabicyclo[2,2,2]-octan-3-imine Mechanical stirrer, thermometer, condenser, Dean Stark
In a 12 L three-neck round-bottom flask (3nrbf) equipped with a trap,
5.9 L of toluene, 791.8 g (3.7 mol) of 2-phenylmethylene-1-azabicyclo[2,2,2]octan-3-imine,
764 g (5.6 mol, 1.5 equivalents) of 2-methoxybenzylamine and 8.8 g (0.0039 mol) of (+) camphorsulfonic acid were charged. The solution was heated to reflux (116° C.) and 4
The mixture was refluxed for 2 hours. A total of 75 ml of water was collected in the Dean-Stark trap, indicating that the reaction was proceeding. The solution containing the title product was cooled to room temperature.
単離した場合に、下位NMRデータが得られた:1H NMR（C
DCl3）:8.05（d,2H）,7.40−6.80（m,9H）,4.80（s,2
H）,3.80（s,3H）,3.25−2.95（m,5H）,1.90−1.70（m,
4H）。Upon isolation, low-level NMR data was obtained: 1 H NMR (C
DCl 3 ):8.05(d,2H),7.40−6.80(m,9H),4.80(s,2
H),3.80(s,3H),3.25−2.95(m,5H),1.90−1.70(m,
4H).
B.2−（ジフェニルメチル）−Ｎ−［（２−メトキシフ
ェニル）メチル］−１−アザビシクロ［2,2,2］−オク
タン−３−イミン
５℃の3Mフェニルマグネシウムブロミド／ジエチルエー
テル溶液1.8L（5.6モル,1.5当量）を含む22L3nrbfに、
この実施例のパートＡで得られた溶液を装入した。この
トルエン溶液は、温度を10℃未満に維持しながら、1.5
時間にわたって加えた。トルエン溶液の約半分を加えた
後に、黄褐色スラリーが得られた。反応を室温に加温し
ながら12〜18時間撹拌した。黄褐色スラリーを５℃に冷
却し、6.1Lの水によって徐々に反応を停止させた。停止
した反応にCelite500g量を加え、これを30℃に加温し、
30℃において30分間撹拌した。このスラリーをCeliteに
通して濾過し、トルエンによって洗浄した。層を分離
し、水層をトルエン1Lによって洗浄し、有機層を一緒に
し、硫酸マグネシウム500gによって30分間乾燥させた。
このスラリーを濾過し、濾液を濃厚な油性固体になるま
で真空蒸発させた。この濃厚な油性固体にイソプロパノ
ール（4.5L）を加え、得られたスラリーを５℃に冷却
し、この温度において１時間顆粒化させた。固体を濾別
し、冷イソプロパノール0.5Lで洗浄し、50℃において真
空蒸発させて、標題化合物494.9g（２工程にわたって3
0.5％）を得た。融点:154−158℃。1H NMR（CDCl3）:
7.45−6.70（m,14H）,4.65（d,1H）,4.45（q,2H）,4.25
（d,2H）,3.80（s,3H）,3.15−3.00（m,3H）,2.70−2.3
5（m,2H）,1.85−1.65（m,4H）。B. 2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2,2,2]-octan-3-imine In a 22 L 3nrbf containing 1.8 L (5.6 mol, 1.5 equivalents) of a 3 M phenylmagnesium bromide/diethyl ether solution at 5° C.
The solution from Part A of this example was charged. The toluene solution was heated to 1.5° C. while maintaining the temperature below 10° C.
The toluene solution was added over a period of 12 hours. After approximately half of the toluene solution had been added, a tan slurry resulted. The reaction was stirred for 12-18 hours while warming to room temperature. The tan slurry was cooled to 5°C and slowly quenched with 6.1 L of water. A 500 g portion of Celite was added to the quenched reaction, which was warmed to 30°C.
Stirred for 30 minutes at 30° C. The slurry was filtered through Celite and washed with toluene. The layers were separated, the aqueous layer was washed with 1 L of toluene, and the organic layers were combined and dried over 500 g of magnesium sulfate for 30 minutes.
The slurry was filtered and the filtrate evaporated under vacuum to a thick oily solid. Isopropanol (4.5 L) was added to the thick oily solid and the resulting slurry was cooled to 5°C and granulated at this temperature for 1 hour. The solid was filtered off, washed with 0.5 L of cold isopropanol and evaporated under vacuum at 50°C to give 494.9 g of the title compound (3% over two steps).
0.5%). Melting point: 154-158°C. 1H NMR ( CDCl3 ):
7.45−6.70 (m, 14H), 4.65 (d, 1H), 4.45 (q, 2H), 4.25
(d,2H),3.80(s,3H),3.15−3.00(m,3H),2.70−2.3
5 (m, 2H), 1.85−1.65 (m, 4H).
実施例２
２−ジフェニルメチル−Ｎ−［（２−メトキシフェニ
ル）メチル］−１−アザビシクロ［2,2,2］オクタン−
３−アミン
22L3nrbfに、酢酸10.3Lを装入した後に、トリアセトキ
シホウ水素化ナトリウム531.1g（2.5モル）を15分間に
わたって加えた。この溶液に実施例1Bの標題化合物411.
5g（1.0モル）を20分間にわたって加えた。この添加中
に温度は25℃から30℃に上昇した。反応を周囲温度にお
いて4.5時間攪拌し、次に濃厚な油状物に成るまで濃縮
した。この油状物を塩化メチレン3.1Lと水6.3Lとに分配
した。この混合物のpHを50％水酸化ナトリウム645mlに
よって4.2から8.4に調節した。層を分離し、水層を塩化
メチレン1.4Lによって洗浄し、有機層を一緒にし、硫酸
マグネシウム500gによって30分間乾燥させた。このスラ
リーを濾過し、濾液を油状物になるまで真空蒸発させ
た。この油状物をイソプロパノール3.3Lで希釈すると、
白色固体の濃厚な沈殿が生じた。このスラリーを真空下
で35℃に加熱して、残留塩化メチレンを除去し、５℃に
冷却し、30分間顆粒化させた。白色固体を濾過によって
単離させ、冷イソプロパノールで洗浄し、45℃において
真空乾燥させて、標題化合物（ラセミ混合物）356gを8
6.1％収率で得た。融点は133−135℃であった。Example 2 2-diphenylmethyl-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2,2,2]octane-
To the 3-amine 22L3nrbf was charged 10.3 L of acetic acid, followed by the addition of 531.1 g (2.5 mol) of sodium triacetoxyborohydride over 15 minutes. To this solution was added the title compound 411 of Example 1B.
5 g (1.0 mol) of HCl was added over 20 minutes. The temperature rose from 25°C to 30°C during the addition. The reaction was stirred at ambient temperature for 4.5 hours and then concentrated to a thick oil. The oil was partitioned between 3.1 L of methylene chloride and 6.3 L of water. The pH of the mixture was adjusted from 4.2 to 8.4 with 645 mL of 50% sodium hydroxide. The layers were separated, the aqueous layer was washed with 1.4 L of methylene chloride, and the organic layers were combined and dried with 500 g of magnesium sulfate for 30 minutes. The slurry was filtered, and the filtrate was evaporated under vacuum to an oil. The oil was diluted with 3.3 L of isopropanol, which gave
A thick precipitate of white solid formed. The slurry was heated to 35°C under vacuum to remove residual methylene chloride, cooled to 5°C, and granulated for 30 minutes. The white solid was isolated by filtration, washed with cold isopropanol, and dried under vacuum at 45°C to give 356g of the title compound (racemic mixture), in an amount of 8.5g.
The yield was 6.1% and the melting point was 133-135°C.
実施例３
（−）−２−ジフェニルメチル−Ｎ−［（２−メトキシ
フェニル）メチル］−１−アザビシクロ［2,2,2］オク
タン−３−アミン
メカニカルスターラーと温度計とを装備した22L3nrbf
に、実施例２の標題化合物345g（0.84モル）と酢酸エチ
ル10.4Lとを装入した。反応を25℃において10分間攪拌
すると、濁りを帯びた溶液が生じた。この溶液に（−）
マンデル酸127.2g（0.84モル）を装入し、20−25℃にお
いて約４分間攪拌した後に、白色スラリーが生じた。こ
の反応混合物をこの温度において２時間攪拌してから、
白色固体を濾過によって単離させ、酢酸エチルによって
洗浄し、風乾させて、マンデル酸塩386g（81.8％）を得
た。この収率は理論収量が236gである目的ジアステレオ
マー塩の31.8％過剰を表す。Example 3 (-)-2-diphenylmethyl-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine A 22L3nrbf flask equipped with a mechanical stirrer and thermometer was used.
To the flask was charged 345 g (0.84 mol) of the title compound of Example 2 and 10.4 L of ethyl acetate. The reaction was stirred at 25°C for 10 minutes, resulting in a cloudy solution.
127.2 g (0.84 moles) of mandelic acid was charged and after stirring for about 4 minutes at 20-25°C, a white slurry was formed. The reaction mixture was stirred at this temperature for 2 hours, then
The white solid was isolated by filtration, washed with ethyl acetate, and air-dried to give 386 g (81.8%) of the mandelate salt, which represents a 31.8% excess of the desired diastereomeric salt for a theoretical yield of 236 g.
この塩を下記方法によって精製した。不純なマンデル酸
塩（386g）を還流酢酸エチル7.7L中で45分間スラリー化
し、１時間にわたって20−25℃に冷却し、濾過し、酢酸
エチル約1Lで洗浄した。溶媒で湿ったケーキを還流酢酸
エチル5.5L中で45分間スラリー化し、１時間にわたって
20−25℃に冷却し、濾過し、酢酸エチル約1Lで洗浄し
た。溶媒で湿ったケーキを還流酢酸エチル4.0L中で45分
間スラリー化し、１時間にわたって20−25℃に冷却し、
濾過し、酢酸エチル約1Lで洗浄し、風乾させて、目的ジ
アステテレオマー塩199.6g（84.6％収率）を得た。この
マンデル酸塩の比施光度（specific rotation）は
［α］Ｄ＝−51.5゜（CH2Cl2,c＝0.55）であり、融点は
196−198℃であった。This salt was purified by the following method: The impure mandelate salt (386 g) was slurried in 7.7 L of refluxing ethyl acetate for 45 minutes, cooled to 20-25°C over 1 hour, filtered, and washed with approximately 1 L of ethyl acetate. The solvent wet cake was slurried in 5.5 L of refluxing ethyl acetate for 45 minutes and cooled to 20-25°C over 1 hour.
Cool to 20-25°C, filter, and wash with approximately 1 L of ethyl acetate. Slurry the solvent wet cake in 4.0 L of refluxing ethyl acetate for 45 minutes, cool to 20-25°C over 1 hour, and
Filtration, washing with approximately 1 L of ethyl acetate, and air drying gave 199.6 g (84.6% yield) of the desired diastereomeric salt. The specific rotation of this mandelate salt was [α] D = −51.5° (CH 2 Cl 2 , c = 0.55), and the melting point was
The temperature was 196-198°C.
12L3nrbfにメカニカルスターラー、温度計、pH計を装備
した。このヘラスコに、精製マンデル酸塩198.6g（0.35
モル）、水3.97L及び塩化メチレン3.4Lを装入した。こ
の二相混合物のpHは5.2であり、これを50％水酸化ナト
リウム44mlによってpH13−14に調節した。水酸化ナトリ
ウム添加中の温度は18℃であった。層を分離し、水層を
塩化メチレン1.7Lによって洗浄した。有機層を一緒に
し、水2Lによって逆洗し、硫酸マグネシウムによって乾
燥させ、濾過した。濾液を大気中で約0.5Lに濃縮し、イ
ソプロパノール約0.5Lによって0.5L量及び60℃温度にな
るように置換した。さらにイソプロパノール0.5Lを加
え、反応を1.5時間かけて20−25℃に冷却させた。この
冷却期間中に、白色スラリーが発現し、これを濾過によ
って単離させ、イソプロパノールによって洗浄し、真空
乾燥させて、ラセミ出発物質345gから可能な172.5gか
ら、目的鏡像異性体である標題化合物115.5g（67.0％収
率）を得た。この物質の比施光度は［α］Ｄ＝−22.2゜
（CH2Cl2,c＝0.50）であり、融点は155−157℃であっ
た。A 12L 3NRBF was equipped with a mechanical stirrer, a thermometer, and a pH meter. 198.6 g (0.35
A mixture of 3.97 L of water and 3.4 L of methylene chloride was charged. The pH of the biphasic mixture was 5.2 and was adjusted to pH 13-14 with 44 mL of 50% sodium hydroxide. The temperature during the sodium hydroxide addition was 18°C. The layers were separated and the aqueous layer was washed with 1.7 L of methylene chloride. The organic layers were combined, backwashed with 2 L of water, dried with magnesium sulfate, and filtered. The filtrate was concentrated atmospherically to approximately 0.5 L and purged with approximately 0.5 L of isopropanol to a volume of 0.5 L and a temperature of 60°C. An additional 0.5 L of isopropanol was added, and the reaction was allowed to cool to 20-25°C over 1.5 hours. During this cooling period, a white slurry developed, which was isolated by filtration, washed with isopropanol, and dried under vacuum to give 115.5 g (67.0% yield) of the desired enantiomer, the title compound, from 172.5 g possible from 345 g of racemic starting material. The specific rotation of this material was [α] D = −22.2° ( CH2Cl2 , c = 0.50), and the melting point was 155–157°C.
実施例４
メカニカルスターラー、温度計、添加ロート及びスチー
ムバスを装備した5L3nrbfに、実施例３の標題化合物12
3.3g（0.30モル）とアセトン3.1Lとを装入した。このス
ラリーを溶解のために30℃に加熱してから、再び24℃に
冷却した。アセトン252mlに溶解したメタンスルホン酸5
8.6g（0.60モル）の溶液を５分間で加えた。この反応は
24℃から32℃に温度上昇し、濃厚な白色スラリーになっ
た、これを周囲温度において２時間攪拌した。反応を大
気中で300−400mlのスラリー量及び60℃の温度に成るま
で濃縮した。このスラリーに、固体物質を溶解するメタ
ノール750mlを加えた。この溶液を濾過によって“小粒
（speck）含まず”にし、150−200ml量になるまで大気
中で濃縮した。濾過済みイソプロパノール500ml量を加
え、反応を150−200mlになるまで真空濃縮した。さらに
濾過済みイソプロパノール500ml量を加え、反応を最終
量の500ml及び温度45℃に成るまで真空濃縮した。反応
を冷却すると、結晶化が生じた。このスラリーを周囲温
度に冷却しながら1.5時間攪拌し、次に５℃において45
分間攪拌した。生成物を濾過によって単離し、ケーキを
濾過済み冷イソプロパノール200mlによって２回洗浄し
た。45℃において12時間真空乾燥した後に、実施例３の
標題生成物のメタンスルホン酸塩170.7g（94.4％）が得
られた。融点は244.5〜246℃であり、比施光度は［α］
Ｄ＝−25.8゜（CH3OH,c＝1.1）であった。Example 4 In a 5 L 3NRBF equipped with a mechanical stirrer, thermometer, addition funnel, and steam bath, the title compound 12 from Example 3 was added.
3.3 g (0.30 mol) of methanesulfonic acid dissolved in 252 ml of acetone was charged. The slurry was heated to 30°C to dissolve, and then cooled back to 24°C.
8.6 g (0.60 mol) of the solution was added over a 5 minute period.
The temperature rose from 24°C to 32°C, resulting in a thick white slurry, which was stirred at ambient temperature for 2 hours. The reaction was concentrated atmospherically to a slurry volume of 300-400 mL and a temperature of 60°C. To this slurry was added 750 mL of methanol, which dissolved the solid material. The solution was made "speck-free" by filtration and concentrated atmospherically to a volume of 150-200 mL. A 500 mL portion of filtered isopropanol was added and the reaction was concentrated under vacuum to 150-200 mL. An additional 500 mL portion of filtered isopropanol was added and the reaction was concentrated under vacuum to a final volume of 500 mL and a temperature of 45°C. Crystallization occurred upon cooling the reaction. The slurry was stirred for 1.5 hours while cooling to ambient temperature, then stirred at 5°C for 45°C.
The mixture was stirred for 1 minute. The product was isolated by filtration, and the cake was washed twice with 200 ml of cold filtered isopropanol. After drying in vacuo at 45°C for 12 hours, 170.7 g (94.4%) of the methanesulfonate salt of the title product of Example 3 was obtained. The melting point was 244.5-246°C, and the specific rotation was [α]
D = -25.8° (CH 3 OH, c = 1.1).
Claims (5)
Br又はリチウムである］ で示される化合物とを反応させることによる、式： ［式中、R1、R2及びR3は独立的に水素、又はフッ素、塩
素、臭素、トリフルオロメチル、炭素数１〜３のアルキ
ル及び炭素数１〜３のアルコキシから成る群から選択さ
れる１個もしくは２個の置換基である］ で示される化合物の製造方法。[Claim 1] Formula: wherein R1 and R2 are as defined below; and a compound of the formula: wherein R3 is as defined below, A is MgCl, Mg
Br or lithium] to give a compound of the formula: [wherein R1 , R2 and R3 are independently hydrogen or one or two substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, alkyl having 1 to 3 carbon atoms and alkoxy having 1 to 3 carbon atoms].
ぞれ水素である請求項１記載の方法。2. The method of claim 1, wherein R 1 is an ortho-substituent and R 2 and R 3 are each hydrogen.
請求項１又は２に記載の方法。3. The compound of formula II defined in claim 1, wherein the compound has the formula: wherein R2 is as defined in claim 1, 3. The method according to claim 1 or 2, wherein R 1 is as defined in claim 1, and the compound is produced by reacting the compound represented by the formula:
素、トリフルオロメチル、炭素数１〜３のアルキル又は
炭素数１〜３のアルコキシから成る群から選択される１
個もしくは２個の置換基である］ で示される化合物。[Claim 4] Formula: wherein R 1 and R 2 are independently hydrogen or one selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms.
The compound of the formula: wherein R is a substituted or unsubstituted group;
る請求項４記載の化合物。5. The compound according to claim 4, wherein R 1 is an ortho-substituent and R 2 is hydrogen.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/637,102 US5138060A (en) | 1991-01-03 | 1991-01-03 | Process and intermediates for preparing azabicyclo(2.2.2)octan-3-imines |
| US637102 | 1991-01-03 | ||
| PCT/US1991/009186 WO1992012152A1 (en) | 1991-01-03 | 1991-12-18 | Process and intermediates for preparing azabicyclo[2.2.2]octan-3-imines |
Related Child Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6322355A Division JP2703193B2 (en) | 1991-01-03 | 1994-12-26 | Method for resolving a racemic mixture of cis compounds of 2-diphenylmethyl-N-[(2-methoxyphenyl) methyl] -1-azabicyclo [2,2,2] octane-3-amine |
| JP6322350A Division JP2845425B2 (en) | 1991-01-03 | 1994-12-26 | Method for producing intermediate for producing azabicyclo [2,2,2] octane-3-imines |
| JP6322353A Division JP2583026B2 (en) | 1991-01-03 | 1994-12-26 | Method for producing cis compound of 2-diphenylmethyl-N-phenylmethyl-1-azabicyclo [2,2,2] octane-3-amine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05508867A JPH05508867A (en) | 1993-12-09 |
| JPH0768244B2 true JPH0768244B2 (en) | 1995-07-26 |
Family
ID=24554545
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|---|---|---|---|
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| JP4-502391A Expired - Lifetime JPH0768244B2 (en) | 1991-01-03 | 1991-12-18 | Process and intermediates for preparing azabicyclo[2,2,2octan-3-imines] |
| JP6322353A Expired - Fee Related JP2583026B2 (en) | 1991-01-03 | 1994-12-26 | Method for producing cis compound of 2-diphenylmethyl-N-phenylmethyl-1-azabicyclo [2,2,2] octane-3-amine compound |
| JP6322350A Expired - Fee Related JP2845425B2 (en) | 1991-01-03 | 1994-12-26 | Method for producing intermediate for producing azabicyclo [2,2,2] octane-3-imines |
| JP6322355A Expired - Fee Related JP2703193B2 (en) | 1991-01-03 | 1994-12-26 | Method for resolving a racemic mixture of cis compounds of 2-diphenylmethyl-N-[(2-methoxyphenyl) methyl] -1-azabicyclo [2,2,2] octane-3-amine |
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| JP6322350A Expired - Fee Related JP2845425B2 (en) | 1991-01-03 | 1994-12-26 | Method for producing intermediate for producing azabicyclo [2,2,2] octane-3-imines |
| JP6322355A Expired - Fee Related JP2703193B2 (en) | 1991-01-03 | 1994-12-26 | Method for resolving a racemic mixture of cis compounds of 2-diphenylmethyl-N-[(2-methoxyphenyl) methyl] -1-azabicyclo [2,2,2] octane-3-amine |
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| AT (1) | ATE115580T1 (en) |
| AU (1) | AU653380B2 (en) |
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| DE (1) | DE69106003T2 (en) |
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| US5364943A (en) * | 1991-11-27 | 1994-11-15 | Pfizer Inc. | Preparation of substituted piperidines |
| UA39168C2 (en) * | 1991-06-20 | 2001-06-15 | Пфайзер, Інк. | FLUORALCOXYPHENYL DERIVATIVES OF PIPERIDINE OR QINUCLIDINE, WHICH ARE ANTAGONISTS OF SUBSTANCE P AND PHARMACEUTICAL COMPOSITION BASED ON THEM |
| FI942187L (en) * | 1991-11-12 | 1994-05-11 | Pfizer | Acyclic ethylenediamine derivatives as substance P receptor antagonists |
| ES2164657T3 (en) * | 1992-05-18 | 2002-03-01 | Pfizer | AZA-BICYCLE DERIVATIVES BRIDGED AS ANTAGONISTS OF THE SUBSTANCE P. |
| US5637699A (en) * | 1992-06-29 | 1997-06-10 | Merck & Co., Inc. | Process for preparing morpholine tachykinin receptor antagonists |
| US5719147A (en) * | 1992-06-29 | 1998-02-17 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| US6048859A (en) | 1992-06-29 | 2000-04-11 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| AU4396193A (en) * | 1992-08-04 | 1994-03-03 | Pfizer Inc. | 3-benzylamino-2-phenyl-piperidine derivatives as substance p receptor antagonists |
| US5387595A (en) * | 1992-08-26 | 1995-02-07 | Merck & Co., Inc. | Alicyclic compounds as tachykinin receptor antagonists |
| US5518628A (en) * | 1993-11-08 | 1996-05-21 | Shipley Company Inc. | Purification process |
| TW385308B (en) * | 1994-03-04 | 2000-03-21 | Merck & Co Inc | Prodrugs of morpholine tachykinin receptor antagonists |
| US6861526B2 (en) | 2002-10-16 | 2005-03-01 | Pfizer Inc. | Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine |
| US20050136487A1 (en) * | 2003-10-27 | 2005-06-23 | Meyer Donald W. | Transmissible spongiform encephalopathy detection in cervids, sheep and goats |
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| US3560510A (en) * | 1969-03-05 | 1971-02-02 | Aldrich Chem Co Inc | 2-benzhydrylquinuclidines |
| US3993652A (en) * | 1973-07-09 | 1976-11-23 | Air Products And Chemicals, Inc. | Cyclic quaternary hydroxyalkyl phenoxide catalysts for isocyanate reactions |
| US4203990A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal 2-substituted quinuclidines |
| FR2529548A1 (en) * | 1982-07-02 | 1984-01-06 | Delalande Sa | NOVEL DERIVATIVES OF AMINO-3 QUINUCLIDINE, THEIR PROCESS AND THEIR THERAPEUTIC APPLICATION |
| JPS59110656A (en) * | 1982-12-15 | 1984-06-26 | Hiroyuki Nohira | Optical resolution of 1-phenyl-2-(p-tolyl)ethylamine |
| DE3604591A1 (en) * | 1986-02-14 | 1987-08-20 | Degussa | METHOD FOR PRODUCING CHIRAL GLYCINE DERIVATIVES |
| JPS6354342A (en) * | 1986-08-26 | 1988-03-08 | Daicel Chem Ind Ltd | Optical resolution of (+-)-alpha-ethylbenzylamine |
| JPS63145256A (en) * | 1986-12-09 | 1988-06-17 | Nippon Kayaku Co Ltd | Production of optically active homophenylalanine and intermediate therefor |
| MX18467A (en) * | 1988-11-23 | 1993-07-01 | Pfizer | THERAPEUTIC AGENTS OF QUINUCLIDINES |
| FI935134L (en) * | 1991-05-22 | 1993-11-19 | Pfizer | SUBSTITUERADE 3-AMINOQUINUCLIDINER |
-
1991
- 1991-01-03 US US07/637,102 patent/US5138060A/en not_active Expired - Lifetime
- 1991-12-18 HU HU9301931A patent/HU9301931D0/en unknown
- 1991-12-18 CA CA002098989A patent/CA2098989C/en not_active Expired - Fee Related
- 1991-12-18 CA CA002158130A patent/CA2158130C/en not_active Expired - Fee Related
- 1991-12-18 WO PCT/US1991/009186 patent/WO1992012152A1/en not_active Ceased
- 1991-12-18 EP EP92901603A patent/EP0565558B1/en not_active Expired - Lifetime
- 1991-12-18 AU AU91298/91A patent/AU653380B2/en not_active Expired - Fee Related
- 1991-12-18 JP JP4502391A patent/JPH0768244B1/ja active Pending
- 1991-12-18 ES ES92901603T patent/ES2065161T3/en not_active Expired - Lifetime
- 1991-12-18 KR KR1019930702007A patent/KR970001157B1/en not_active Expired - Lifetime
- 1991-12-18 AT AT92901603T patent/ATE115580T1/en not_active IP Right Cessation
- 1991-12-18 DK DK92901603.8T patent/DK0565558T3/en active
- 1991-12-18 FI FI933065A patent/FI933065L/en not_active Application Discontinuation
- 1991-12-18 DE DE69106003T patent/DE69106003T2/en not_active Expired - Fee Related
- 1991-12-18 JP JP4-502391A patent/JPH0768244B2/en not_active Expired - Lifetime
- 1991-12-23 NZ NZ241161A patent/NZ241161A/en unknown
- 1991-12-27 IL IL100541A patent/IL100541A0/en unknown
-
1992
- 1992-01-02 MX MX9200003A patent/MX9200003A/en unknown
- 1992-01-02 ZA ZA928A patent/ZA928B/en unknown
- 1992-01-02 PT PT99970A patent/PT99970B/en not_active IP Right Cessation
- 1992-01-02 IE IE920001A patent/IE65005B1/en not_active IP Right Cessation
-
1993
- 1993-07-02 NO NO93932431A patent/NO932431L/en unknown
-
1994
- 1994-12-26 JP JP6322353A patent/JP2583026B2/en not_active Expired - Fee Related
- 1994-12-26 JP JP6322350A patent/JP2845425B2/en not_active Expired - Fee Related
- 1994-12-26 JP JP6322355A patent/JP2703193B2/en not_active Expired - Fee Related
-
1995
- 1995-02-08 GR GR950400264T patent/GR3015021T3/en unknown
-
2000
- 2000-05-10 FI FI20001109A patent/FI20001109L/en not_active Application Discontinuation
- 2000-05-10 FI FI20001108A patent/FI20001108L/en not_active Application Discontinuation
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