JP2000128835A - Production of nicotinamide derivative and intermediate - Google Patents
Production of nicotinamide derivative and intermediateInfo
- Publication number
- JP2000128835A JP2000128835A JP11298121A JP29812199A JP2000128835A JP 2000128835 A JP2000128835 A JP 2000128835A JP 11298121 A JP11298121 A JP 11298121A JP 29812199 A JP29812199 A JP 29812199A JP 2000128835 A JP2000128835 A JP 2000128835A
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- formula
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- methyl
- reacting
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、ニコチンアミド誘
導体の製造方法及び中間体に関する。TECHNICAL FIELD The present invention relates to a method for producing a nicotinamide derivative and an intermediate.
【０００２】[0002]
【従来の技術】本発明に従って製造されるニコチンアミ
ド誘導体は、米国特許第４，８６１，８９１号（出願日
１９８８年８月３１日、発明の名称“Ａｎｔｉｄｅｐｒ
ｅｓｓａｎｔ−Ｎ−ｓｕｂｓｔｉｔｕｔｅｄ Ｎｉｃｏ
ｔｉｎａｍｉｄｅ Ｃｏｍｐｏｕｎｄｓ”）、及びＰＣ
Ｔ出願第ＰＣＴ／ＩＢ９８００３１５号（出願日１９９
８年３月１０日、発明の名称“Ｎｉｃｏｔｉｎａｍｉｄ
ｅ Ｄｅｒｉｖａｔｉｖｅｓ”）に開示されている。上
記の米国特許及びＰＣＴ国際出願は、いずれも参照によ
り全内容を本発明に取り込まれる。BACKGROUND OF THE INVENTION Nicotinamide derivatives prepared according to the present invention are disclosed in U.S. Pat. No. 4,861,891 (filed Aug. 31, 1988, entitled "Antideprt").
essant-N-substituted Nico
tinamide Compounds "), and PC
T Application No. PCT / IB9800315 (filing date 199)
On March 10, 2008, the title of the invention, "Nicotinamid"
e Derivatives "). All of the above U.S. patents and PCT international applications are incorporated herein by reference in their entirety.
【０００３】[0003]
【発明が解決しようとする課題】本発明の化合物及び方
法は、カルシウム非依存性ホスホジエステラーゼの選択
的阻害薬で、抗うつ薬として有用なＮ−置換ニコチンア
ミド誘導体の製造に有用である。このようなニコチンア
ミド誘導体は、ホスホジエステラーゼ４型（ＰＤＥ４）
及び腫瘍壊死因子（ＴＮＦ）産生の選択的阻害薬であ
る。The compounds and methods of the present invention are useful for the preparation of N-substituted nicotinamide derivatives which are selective inhibitors of calcium-independent phosphodiesterase and are useful as antidepressants. Such nicotinamide derivatives are phosphodiesterase type 4 (PDE4)
And a selective inhibitor of tumor necrosis factor (TNF) production.
【０００４】[0004]
【課題を解決するための手段】本発明は、式：SUMMARY OF THE INVENTION The present invention provides a compound of the formula:
【０００５】[0005]
【化８】 Embedded image
【０００６】の化合物をアルコール溶媒中で塩基と反応
させることを含む、式：Reacting a compound of the formula with a base in an alcoholic solvent,
【０００７】[0007]
【化９】 Embedded image
【０００８】の化合物の製造方法に関する。本発明の更
なる態様において、式：The present invention relates to a method for producing the compound of the present invention. In a further embodiment of the present invention, the formula:
【０００９】[0009]
【化１０】 Embedded image
【００１０】の化合物［式中、Ｒは（Ｃ1−Ｃ6）アルキ
ル］を不活性溶媒中でアルキルグリニャール反応物と反
応させることにより、式IVの化合物を製造する。本発明
の更なる態様において、式：A compound of formula IV is prepared by reacting a compound of the formula wherein R is (C 1 -C 6 ) alkyl with an alkyl Grignard reactant in an inert solvent. In a further embodiment of the present invention, the formula:
【００１１】[0011]
【化１１】 Embedded image
【００１２】の化合物［式中、Ｒは（Ｃ1−Ｃ6）アルキ
ル］を、塩素化溶媒中でアミン塩基の存在下、無水トリ
フルオロ酢酸と反応させることにより、式IIIの化合物
を製造する。A compound of formula III is prepared by reacting a compound of the formula wherein R is (C 1 -C 6 ) alkyl with trifluoroacetic anhydride in a chlorinated solvent in the presence of an amine base. .
【００１３】本発明の更なる態様において、式：In a further embodiment of the present invention, the formula:
【００１４】[0014]
【化１２】 Embedded image
【００１５】の化合物を、酸性媒体中でアルコールと反
応させることによりエステルを形成させて、式IIの化合
物を製造する。化合物Ｉを製造するプロセスにおいて、
好ましくは過剰のグリニャール試薬を使用する。適切な
グリニャール試薬の例は、塩化メチルマグネシウム、臭
化メチルマグネシウム、及びヨウ化メチルマグネシウム
である。グリニャール試薬は、好ましくは塩化メチルマ
グネシウムである。溶媒は、反応条件下で不活性で、好
ましくはテトラヒドロフランである。塩基は、メチルア
ルコール溶媒中のカーボネート、好ましくは炭酸カリウ
ムである。エステル化試薬は、無水酢酸及びアミン、好
ましくはジクロロエチレン中の無水トリフルオロ酢酸及
びトリメチルアミンである。エステル形成基は、塩酸中
のメチルアルコールである。 また、本発明は、式：The compound of formula II is prepared by reacting the compound of formula II with an alcohol in an acidic medium to form an ester. In a process for producing Compound I,
Preferably, an excess of Grignard reagent is used. Examples of suitable Grignard reagents are methyl magnesium chloride, methyl magnesium bromide, and methyl magnesium iodide. The Grignard reagent is preferably methylmagnesium chloride. The solvent is inert under the reaction conditions and is preferably tetrahydrofuran. The base is a carbonate in a methyl alcohol solvent, preferably potassium carbonate. Esterifying reagents are acetic anhydride and amines, preferably trifluoroacetic anhydride and trimethylamine in dichloroethylene. The ester forming group is methyl alcohol in hydrochloric acid. The present invention also provides a compound of the formula:
【００１６】[0016]
【化１３】 Embedded image
【００１７】の新規化合物［式中、Ｒは（Ｃ1−Ｃ6）ア
ルキル］にも関する。また、本発明は、式：The present invention also relates to novel compounds of the formula wherein R is (C 1 -C 6 ) alkyl. The present invention also provides a compound of the formula:
【００１８】[0018]
【化１４】 Embedded image
【００１９】の新規化合物にも関する。これらの新規化
合物は、カルシウム非依存性ホスホジエステラーゼの選
択的阻害薬として有用なＮ−置換ニコチンアミド誘導体
の中間体、並びにホスホジエステラーゼ４型（ＰＤＥ
４）及び腫瘍壊死因子（ＴＮＦ）産生の選択的阻害薬と
して有用なニコチンアミド誘導体の中間体の製造に使用
される。The present invention also relates to a novel compound. These novel compounds are intermediates of N-substituted nicotinamide derivatives useful as selective inhibitors of calcium-independent phosphodiesterase, as well as phosphodiesterase type 4 (PDE
4) and for the production of intermediates of nicotinamide derivatives useful as selective inhibitors of tumor necrosis factor (TNF) production.
【００２０】[0020]
【発明の実施の形態】新規合成方法を以下の反応スキー
ム１に示す。BEST MODE FOR CARRYING OUT THE INVENTION The novel synthesis method is shown in the following reaction scheme 1.
【００２１】[0021]
【化１５】 Embedded image
【００２２】アミノメチル安息香酸の化合物Ｉを酸性媒
体中でアルコールで処理し、その酸官能性基を変換して
エステル化合物IIにする。アセトアミド基を用いて化合
物IIの遊離アミンを保護し、トリフルオロアセトアミド
エステル化合物IIIを得る。トリフルオロアセトアミド
エステル化合物IIIを不活性溶媒中でメチルグリニャー
ルで処理し、所望の第三級アルコール化合物IVを得る。
アセトアミド化合物IVをアルコール溶媒中でカーボネー
ト塩基と反応させて、トリフルオロアセトアミドを脱保
護し、所望のアミノアルコール化合物Ｖを得る。Compound I of aminomethylbenzoic acid is treated with an alcohol in an acidic medium and its acid functionality is converted to ester compound II. The free amine of compound II is protected with an acetamido group to give trifluoroacetamido ester compound III. Treatment of the trifluoroacetamide ester compound III with methyl Grignard in an inert solvent gives the desired tertiary alcohol compound IV.
Acetamide compound IV is reacted with a carbonate base in an alcohol solvent to deprotect trifluoroacetamide to give the desired amino alcohol compound V.
【００２３】化合物Vの以前の合成方法は、４−シアノ
安息香酸メチルエステルにメチルグリニャールを選択的
に付加する方法に頼っていた（ＰＣＴ／ＩＢ９８００３
１５）。このメチルグリニャール添加は、複合反応混合
物を生ずるため、クロマトグラフィー精製が必要とな
る。本発明のプロセスは、めんどうな精製の必要なく、
多量の所望のアミノアルコールを製造する。Previous methods of synthesizing compound V relied on the selective addition of methyl Grignard to 4-cyanobenzoic acid methyl ester (PCT / IB98003).
15). This addition of methyl Grignard results in a complex reaction mixture and requires chromatographic purification. The process of the present invention does not require troublesome purification,
Produce large quantities of the desired amino alcohol.
【００２４】化合物Ｖは、米国特許第４，８６１，８９
１号に開示されている２−アリールオキシ−ニコチン酸
化合物とともに中間体として使用して、ホスホジエステ
ラーゼ４型（ＰＤＥ４）及び腫瘍壊死因子（ＴＮＦ）産
生の選択的阻害薬のニコチンアミド誘導体を形成するこ
とができる。Compound V is disclosed in US Pat. No. 4,861,89.
Use as intermediates with the 2-aryloxy-nicotinic acid compounds disclosed in No. 1 to form nicotinamide derivatives of phosphodiesterase type 4 (PDE4) and selective inhibitors of tumor necrosis factor (TNF) production Can be.
【００２５】これらの有用なＰＤＥ４及びＴＮＦの阻害
薬は、各種の投与形態で投与できる。炎症性疾患の治癒
的又は予防的処置としてヒトに投与する場合、式Ｉの化
合物又はその製薬学的に許容しうる塩（活性化合物）の
経口投与量は、一般的に平均的成人患者（７０ｋｇ）に
対し、１回に又は分割して１日０．１〜１０００ｍｇの
範囲である。活性化合物は、１回で又は分割して投与で
きる。個別の錠剤又はカプセルは、一般的に、適切な製
薬学的に許容しうる賦形剤又は担体中に０．１〜１００
ｍｇの活性化合物を含まなければならない。静脈内投与
量は、通常、必要に応じて１回量当たり０．１〜１０ｍ
ｇの範囲内である。鼻腔内又は吸入投与の場合、投与量
は、一般的に０．１〜１％（ｗ／ｖ）溶液として製剤さ
れる。実際的には、医師が個々の患者に最も適切な実際
の投与量を決定するが、これは特定の患者の年齢、体
重、及び応答性によって変動する。上記の投与量は平均
的症例の典型的投与量であって、当然ながら、それより
高用量又は低用量が効果的である個別例も存在しうる
が、それらの投与量もすべて本発明の範囲内に含まれ
る。[0025] These useful inhibitors of PDE4 and TNF can be administered in various dosage forms. When administered to humans as a curative or prophylactic treatment of an inflammatory disease, the oral dosage of a compound of Formula I or a pharmaceutically acceptable salt thereof (active compound) will generally be that of an average adult patient (70 kg). ) Is 0.1 to 1000 mg per day, once or divided. The active compounds can be administered in single or divided doses. Individual tablets or capsules are generally prepared from 0.1 to 100 in a suitable pharmaceutically acceptable excipient or carrier.
It must contain mg of active compound. The intravenous dose is usually 0.1 to 10 m per dose as needed.
g. For intranasal or inhaled administration, dosages are generally formulated as 0.1-1% (w / v) solutions. In practice, the physician will decide the actual dosage which will be most suitable for an individual patient but will vary with the age, weight and responsiveness of the particular patient. The above dosages are typical of the average case and, of course, there may be individual cases where higher or lower doses are effective, but all such dosages are within the scope of the present invention. Contained within.
【００２６】ヒトに使用する場合、本発明の活性化合物
は単独でも投与できるが、一般的には、意図する投与経
路及び標準の製薬学的実施基準に従って選ばれた製薬学
的希釈剤又は担体との混合物として投与される。例え
ば、経口的には、デンプンや乳糖のような賦形剤を含有
する錠剤の形態で、又は単独もしくは賦形剤との混合物
のカプセルで、又は香味剤や着色剤を含有するエリキシ
ルもしくは懸濁液の形態で投与できる。非経口的に、例
えば静脈内、筋肉内又は皮下に注入することもできる。
非経口投与の場合、無菌水溶液の形態で最もよく用いら
れる。これには、溶液を等張性にするための別の物質、
例えば十分な塩又はブドウ糖が含まれてもよい。For use in humans, the active compounds of the present invention can be administered alone, but will generally be combined with a pharmaceutical diluent or carrier selected according to the intended route of administration and standard pharmaceutical practice. Is administered as a mixture. For example, orally, in the form of tablets containing excipients such as starch and lactose, or in capsules alone or in mixtures with excipients, or elixirs or suspensions containing flavoring or coloring agents It can be administered in liquid form. It can also be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
For parenteral administration, they are most often used in the form of a sterile aqueous solution. This includes another substance to make the solution isotonic,
For example, enough salt or glucose may be included.
【００２７】また、当該活性化合物は、皮膚の炎症状態
を処置する場合には局所的に投与することもできる。こ
れは、標準の製薬学的実施基準に従って、クリーム、ゼ
リー、ゲル、ペースト、及び軟膏の手段で行うことがで
きる。The active compounds can also be administered topically when treating inflammatory conditions of the skin. This can be done by means of creams, jellies, gels, pastes, and ointments according to standard pharmaceutical practice.
【００２８】当該治療化合物は、ヒト以外の哺乳動物に
投与してもよい。哺乳動物に投与する用量は、動物腫及
び処置される疾患又は障害によって異なる。当該治療化
合物は、動物に、カプセル、ボーラス、錠剤、又は水薬
の形態で投与できる。当該治療化合物は、動物に、注射
又は移植片として投与することもできる。これらの製剤
は、標準の獣医学的実施基準に従って従来の方法で製造
される。あるいは、当該治療化合物は、動物飼料ととも
に投与してもよい。この目的のために、濃縮飼料添加物
又はプレミックスを製造し、通常の動物飼料と混合す
る。The therapeutic compound may be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal tumor and the disease or disorder being treated. The therapeutic compound can be administered to the animal in the form of a capsule, bolus, tablet, or drench. The therapeutic compound can also be administered to the animal as an injection or implant. These formulations are prepared in a conventional manner according to standard veterinary practices. Alternatively, the therapeutic compounds may be administered with animal feed. For this purpose, concentrated feed additives or premixes are prepared and mixed with normal animal feed.
【００２９】本発明を以下の実施例によって説明する
が、本発明は実施例の詳細には制限されない。The present invention will be described by the following examples, but the present invention is not limited to the details of the examples.
【００３０】[0030]
【実施例】実施例Ｉ ４−［（２，２，２−トリフルオロ−アセチルアミノ）
−メチル］−安息香酸メチルエステル Ｎ2導入口、機械式攪拌器、及び添加漏斗を備えた１０
０ｍｌの三つ口フラスコに、５０ｍＬのＣＨ2Ｃｌ2中の
４−アミノメチル−安息香酸メチルエステルヒドロクロ
リド（５．００グラム、２４．８ミリモル）を装入し
た。トリエチルアミン（７．３ｍｌ、５２．１ミリモ
ル）をシリンジ経由で添加し、反応混合物をアセトン／
氷浴中で０℃に冷却した。無水トリフルオロ酢酸（３．
７ｍＬ、２６．０ミリモル）を添加漏斗に入れ、３０分
かけて反応に一滴ずつ添加した。発熱が起こり、３．１
℃になった。無水トリフルオロ酢酸の添加後、氷浴を取
り除き、反応の完了がＨＰＬＣによって示された［ウォ
ーターズ・シンメトリー（Ｗａｔｅｒｓ Ｓｙｍｍｅｔ
ｒｙ） Ｃ−８、 ＣＨ3ＣＮ：緩衝液 ５０：５０ｐ
Ｈ＝３、１ｍＬ／分、２５４及び２０５ｎｍ］。反応を
５０ｍＬのＨ2Ｏで分配し、次いで層を分離した。水層
は、２×５０ｍＬのＣＨ2Ｃｌ2で抽出した。有機層は合
わせて１×１００ｍＬの食塩水で洗い、乾燥（Ｎａ2Ｓ
Ｏ4）、ろ過、及び濃縮して白色固体を得た（５．４３
グラム、８４％）。 １Ｈ ＮＭＲ（ＣＤＣｌ3、４００ＭＨｚ）ｄ８．０１
（２Ｈ、ｂｒ ｄ、ＣＨ）、７．２８（２Ｈ、ｂｒ
ｄ、ＣＨ）、４．５８（２Ｈ、ｂｒ ｄ、ＣＨ2）、
３．９０（３Ｈ、ｓ、ＣＨ3）；１３Ｃ ＮＭＲ（ＣＤ
Ｃｌ3、１００ＭＨｚ）ｄ１６６．５、１４０．８、１
３０．３、１３０．１、１２７．７、５２．２、４３．
４；ＩＲ（ＫＢｒ、ｃｍ-1）３２９０、１７２３、１７
０２、１５５９、１４３８；元素分析理論値：Ｃ５０．
５８ Ｈ３．８６ Ｎ５．３６ Ｆ２１．８２ 実測
値：ｍ．ｐ．７０．６〜７４．４℃。実施例II ２，２，２−トリフルオロ−Ｎ−［４−（１−ヒドロキ
シ−１−メチル−エチル）ベンジル］−アセトアミド 火炎乾燥した、Ｎ2導入口、機械式攪拌器、及び添加漏
斗を備えた２００ｍｌの三つ口フラスコに、１３５ｍＬ
のＴＨＦ中の４−［（２，２，２−トリフルオロ−アセ
チルアミノ）−メチル］−安息香酸メチルエステル
（３．３７グラム、１２．９ミリモル）を装入した。こ
れを、アセトン／氷浴中で０℃に冷却した。塩化メチル
マグネシウム（ＴＨＦ中の３Ｍ溶液２１．５ｍＬ、６
４．５ミリモル）を添加漏斗に入れ、１５分かけて一滴
ずつ反応に導入した。反応は７．４℃に発熱した。グリ
ニャール試薬添加後、反応を室温まで上昇させた。反応
をＨＰＬＣでモニターし（ウォーターズ・シンメトリー
Ｃ−８、 ＣＨ3ＣＮ：緩衝液５０：５０ ｐＨ＝
３、１ｍＬ／分、２５４及び２０５ｎｍ）、３．５時間
後に完了した。次に、反応を１３０ｍＬのＨ2Ｏ中のＮ
Ｈ4Ｃｌ（３．４５グラム、６４．５ミリモル）で緩や
かに反応を停止した。水層を２×２５０ｍＬのＥｔＯＡ
ｃで抽出した。合わせた有機層は、１×５００ｍＬの食
塩水で洗い、乾燥（Ｎａ2ＳＯ4）、ろ過、及び濃縮して
蒼白色油状物とした（３．１１グラム、９２．６％）。 １Ｈ ＮＭＲ（ＣＤＣｌ3、４００ＭＨｚ）δ７．５０
（２Ｈ、ｂｒ ｄ、ＣＨ）、７．２７（２Ｈ、ｂｒ
ｄ、ＣＨ）、４．５０（２Ｈ、ｂｒ ｄ、ＣＨ2）、
１．５７（３Ｈ、ｓ、ＣＨ3）；１３Ｃ ＮＭＲ（ＣＤ
Ｃｌ3、１００ＭＨｚ）ｄ１４９．４、１３４．１、１
２７．９、１２５．２、１１２．４、７２．４、４３．
６、３１．８；ＩＲ（原液、ｃｍ-1）３３００、３０９
２、２９７７、１７０７、１５５８、１２１８；元素分
析理論値：Ｃ５５．１７ Ｈ５．４０ Ｆ２１．８２
Ｎ５．３６。実施例III ２−（４−アミノメチル−フェニル）−プロパン−２−
オール 攪拌棒を備えた１００ｍＬ一口フラスコに、３１ｍＬの
ＭｅＯＨ中の２，２，２−トリフルオロ−Ｎ−［４−
（１−ヒドロキシ−１−メチル−エチル）ベンジル］−
アセトアミド（３．１１グラム、１１．９ミリモル）を
装入した。これに、９．６ｍＬのＨ2Ｏ中のＫ2ＣＯ
3（４．１１グラム、２９．７５ミリモル）を加えた。
反応は、室温で攪拌させた。反応をＨＰＬＣでモニター
し（ウォーターズ・シンメトリー Ｃ−８、 ＣＨ3Ｃ
Ｎ：緩衝液 ５０：５０ ｐＨ＝３、１ｍＬ／分、２５
４及び２０５ｎｍ）、２４時間後に完了した。反応は、
１５０ｍＬのＣＨＣｌ3及び１５０ｍＬの食塩水を添加
することにより、後処理した。層を分離し、水層を３×
１５０ｍＬの１０％ＭｅＯＨ／ＣＨ2Ｃｌ2で抽出した。
当該層を乾燥（Ｎａ2ＳＯ4）、ろ過、及び濃縮し、ろう
状の黄色固体を得た（１．１８グラム、６０％）。実施例IV ４−（１−ヒドロキシ−１−メチル−エチル）ベンジル
−アンモニウム；ベンゾエート 攪拌棒を備えた２５ｍＬの丸底フラスコに、２．７ｍＬ
のイソプロピルアルコール中の２−（４−アミノメチル
−フェニル）−プロパン−２−オール（１８４ｍｇ、
１．１２ミリモル）を装入した。安息香酸（１３６ｍ
ｇ、１．１２ミリモル）を加え、反応を室温で攪拌させ
た。直ちに固体が析出し始めた。１時間後、混合物をろ
過し、固体を追加のイソプロピルアルコールで洗った。
白色固体（１４１ｍｇ、４４％収率）を単離した。ろ液
は、室温で一晩攪拌させた。第二の生成物（３２ｍｇ、
１０％収率）を単離した。EXAMPLES Example I 4-[(2,2,2-trifluoro-acetylamino)
- methyl] - benzoic acid methyl ester N 2 inlet, mechanical stirrer, and an addition funnel 10
Three-necked flask 0 ml, CH 2 Cl 2 solution of 4-aminomethyl 50 mL - was charged with methyl benzoate ester hydrochloride (5.00 grams, 24.8 mmol). Triethylamine (7.3 ml, 52.1 mmol) was added via syringe and the reaction mixture was acetone /
Cooled to 0 ° C. in an ice bath. Trifluoroacetic anhydride (3.
(7 mL, 26.0 mmol) was added to the addition funnel and added dropwise to the reaction over 30 minutes. Fever occurs 3.1
° C. After the addition of trifluoroacetic anhydride, the ice bath was removed and the completion of the reaction was indicated by HPLC [Waters Symmet.
ry) C-8, CH 3 CN: buffer 50: 50p
H = 3, 1 mL / min, 254 and 205 nm]. The reaction was partitioned with H 2 O in 50 mL, then the layers were separated. The aqueous layer was extracted with 2 × 50 mL of CH 2 Cl 2 . The combined organic layers were washed with 1 × 100 mL of saline and dried (Na 2 S
O 4 ), filtered and concentrated to give a white solid (5.43).
G, 84%). 1H NMR (CDCl 3 , 400 MHz) d8.01
(2H, br d, CH), 7.28 (2H, br
d, CH), 4.58 (2H, br d, CH 2 ),
3.90 (3H, s, CH 3 ); 13C NMR (CD
Cl 3 , 100 MHz) d166.5, 140.8, 1
30.3, 130.1, 127.7, 52.2, 43.
4: IR (KBr, cm -1 ) 3290, 1723, 17
02, 1559, 1438; theoretical value of elemental analysis: C50.
58 H3.86 N5.36 F21.82 Found: m.p. p. 70.6-74.4 ° C. Example II 2,2,2-trifluoro-N- [4- (1-hydroxy
Shi-1-methyl - ethyl) benzyl] - was acetamide flame dried, N 2 inlet, three-necked flask mechanical stirrer, and an addition funnel 200 ml, 135 mL
Of 4-[(2,2,2-trifluoro-acetylamino) -methyl] -benzoic acid methyl ester (3.37 grams, 12.9 mmol) in THF. This was cooled to 0 ° C. in an acetone / ice bath. Methyl magnesium chloride (21.5 mL of a 3M solution in THF, 6
(4.5 mmol) was placed in an addition funnel and introduced dropwise into the reaction over 15 minutes. The reaction exothermed to 7.4 ° C. After addition of the Grignard reagent, the reaction was allowed to warm to room temperature. The reaction was monitored by HPLC (Waters Symmetry C-8, CH 3 CN: buffer 50:50 pH =
3, 1 mL / min, 254 and 205 nm) after 3.5 h. Next, the reaction was run with N in 130 mL of H 2 O.
The reaction was quenched slowly with H 4 Cl (3.45 grams, 64.5 mmol). The aqueous layer was washed with 2 x 250 mL of EtOA
Extracted with c. The combined organic layers were washed with 1 × 500 mL of brine, dried (Na 2 SO 4 ), filtered, and concentrated to a pale oil (3.11 grams, 92.6%). 1H NMR (CDCl 3 , 400 MHz) δ7.50
(2H, br d, CH), 7.27 (2H, br d, CH)
d, CH), 4.50 (2H, br d, CH 2 ),
1.57 (3H, s, CH 3 ); 13C NMR (CD
Cl 3 , 100 MHz) d149.4, 134.1, 1
27.9, 125.2, 112.4, 72.4, 43.
6, 31.8; IR (stock solution, cm -1 ) 3300, 309
2,2977,1707,1558,1218; Theoretical value of elemental analysis: C55.17 H5.40 F21.82
N5.36. Example III 2- (4-aminomethyl-phenyl) -propane-2-
In a 100 mL one-necked flask equipped with an all stirring bar, add 2,2,2-trifluoro-N- [4-
(1-hydroxy-1-methyl-ethyl) benzyl]-
Acetamide (3.11 grams, 11.9 mmol) was charged. This was followed by the addition of K 2 CO in 9.6 mL of H 2 O.
3 (4.11 grams, 29.75 mmol) was added.
The reaction was allowed to stir at room temperature. The reaction was monitored by HPLC (Waters Symmetry C-8, CH 3 C
N: buffer 50:50 pH = 3, 1 mL / min, 25
4 and 205 nm), which was complete after 24 hours. The reaction is
Work-up was performed by adding 150 mL of CHCl 3 and 150 mL of brine. Separate the layers and filter the aqueous layer 3 ×
Extracted with 150 mL of 10% MeOH / CH 2 Cl 2 .
The layer was dried (Na 2 SO 4 ), filtered, and concentrated to give a waxy yellow solid (1.18 grams, 60%). Example IV 4- (1-hydroxy-1-methyl-ethyl) benzyl
-Ammonium; 2.7 mL in a 25 mL round bottom flask equipped with a benzoate stir bar
2- (4-aminomethyl-phenyl) -propan-2-ol (184 mg,
1.12 mmol). Benzoic acid (136m
g, 1.12 mmol) was added and the reaction was allowed to stir at room temperature. Immediately a solid began to precipitate. After 1 hour, the mixture was filtered and the solid was washed with additional isopropyl alcohol.
A white solid (141 mg, 44% yield) was isolated. The filtrate was allowed to stir at room temperature overnight. The second product (32 mg,
10% yield).
Claims (15)
させることを含む、式： 【化２】 の化合物の製造方法。1. The formula: embedded image Reacting a compound of the formula with a carbonate base in an alcoholic solvent, comprising reacting a compound of formula: A method for producing a compound of the formula:
求項１に記載の方法。2. The method according to claim 1, wherein the carbonate is potassium carbonate.
１に記載の方法。3. The method according to claim 1, wherein the solvent is methyl alcohol.
活性溶媒中でメチルグリニャール試薬と反応させること
によって製造される、請求項１に記載の方法。4. The compound of formula IV has the formula: [Wherein, R is (C 1 -C 6) alkyl] compounds are prepared by reacting a methyl Grignard reagent in a reaction inert solvent, A method according to claim 1.
いられる、請求項４に記載の方法。5. The method of claim 4, wherein more than about 5 equivalents of a Grignard reagent is used.
ウムである、請求項４に記載の方法。6. The method according to claim 4, wherein the Grignard reagent is methylmagnesium chloride.
項４に記載の方法。7. The method according to claim 4, wherein the solvent is tetrahydrofuran.
溶媒中で無水酢酸及びアミン塩基と反応させることによ
って製造される、請求項４に記載の方法。8. The compound of formula III having the formula: Compounds wherein, R represents (C 1 -C 6) alkyl] are prepared by reacting acetic anhydride and an amine base in a chlorinated solvent, A method according to claim 4.
る、請求項８に記載の方法。9. The method according to claim 8, wherein the acetic anhydride is trifluoroacetic anhydride.
求項８に記載の方法。10. The method according to claim 8, wherein the amine is triethylamine.
項８に記載の方法。11. The method according to claim 8, wherein the solvent is dichloroethylene.
ル基を形成させることによって製造される、請求項８に
記載の方法。12. The compound of formula II having the formula I: 9. A process according to claim 8, wherein the compound is prepared by reacting a compound of the formula with an alcohol in an acidic medium to form an ester group.
ルコールである、請求項１２に記載の方法。13. The method according to claim 12, wherein the ester forming group is methyl alcohol in hydrochloric acid.
式： 【化６】 の化合物。14. R is (C 1 -C 6 ) alkyl.
Formula: Compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10512098P | 1998-10-21 | 1998-10-21 | |
| US60/105120 | 1998-10-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2000128835A true JP2000128835A (en) | 2000-05-09 |
Family
ID=22304138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11298121A Pending JP2000128835A (en) | 1998-10-21 | 1999-10-20 | Production of nicotinamide derivative and intermediate |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JP2000128835A (en) |
| KR (1) | KR20000029190A (en) |
| AR (1) | AR020919A1 (en) |
| AU (1) | AU5595399A (en) |
| BR (1) | BR9904696A (en) |
| CA (1) | CA2286646A1 (en) |
| HU (1) | HU9903736D0 (en) |
| IL (1) | IL132405A0 (en) |
| PL (1) | PL336111A1 (en) |
| ZA (1) | ZA996624B (en) |
-
1999
- 1999-10-14 IL IL13240599A patent/IL132405A0/en unknown
- 1999-10-19 AU AU55953/99A patent/AU5595399A/en not_active Abandoned
- 1999-10-19 CA CA002286646A patent/CA2286646A1/en not_active Abandoned
- 1999-10-20 BR BR9904696-2A patent/BR9904696A/en not_active Application Discontinuation
- 1999-10-20 PL PL99336111A patent/PL336111A1/en not_active Application Discontinuation
- 1999-10-20 JP JP11298121A patent/JP2000128835A/en active Pending
- 1999-10-20 AR ARP990105300A patent/AR020919A1/en unknown
- 1999-10-20 ZA ZA9906624A patent/ZA996624B/en unknown
- 1999-10-20 HU HU9903736A patent/HU9903736D0/en unknown
- 1999-10-20 KR KR1019990045464A patent/KR20000029190A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2286646A1 (en) | 2000-04-21 |
| AR020919A1 (en) | 2002-06-05 |
| AU5595399A (en) | 2000-05-04 |
| BR9904696A (en) | 2000-08-08 |
| ZA996624B (en) | 2001-04-20 |
| HU9903736D0 (en) | 1999-12-28 |
| IL132405A0 (en) | 2001-03-19 |
| PL336111A1 (en) | 2000-04-25 |
| KR20000029190A (en) | 2000-05-25 |
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