JPH0616603A - Production of catecholamine derivative hydrochloride - Google Patents
Production of catecholamine derivative hydrochlorideInfo
- Publication number
- JPH0616603A JPH0616603A JP3222027A JP22202791A JPH0616603A JP H0616603 A JPH0616603 A JP H0616603A JP 3222027 A JP3222027 A JP 3222027A JP 22202791 A JP22202791 A JP 22202791A JP H0616603 A JPH0616603 A JP H0616603A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- alkali metal
- hydrochloride
- carbon atoms
- derivative hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 150000003943 catecholamines Chemical class 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- -1 cesium Chemical class 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 9
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 6
- 150000001340 alkali metals Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 abstract description 5
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 abstract description 5
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 4
- 229930195729 fatty acid Natural products 0.000 abstract description 4
- 239000000194 fatty acid Substances 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 238000013019 agitation Methods 0.000 abstract 1
- 238000007664 blowing Methods 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 238000011109 contamination Methods 0.000 abstract 1
- 150000004665 fatty acids Chemical class 0.000 abstract 1
- 150000002739 metals Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical group C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229910001485 alkali metal perchlorate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WKDKOOITVYKILI-UHFFFAOYSA-M caesium perchlorate Chemical compound [Cs+].[O-]Cl(=O)(=O)=O WKDKOOITVYKILI-UHFFFAOYSA-M 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- VKFAUCPBMAGVRG-UHFFFAOYSA-N dipivefrin hydrochloride Chemical compound [Cl-].C[NH2+]CC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 VKFAUCPBMAGVRG-UHFFFAOYSA-N 0.000 description 1
- AXZAYXJCENRGIM-UHFFFAOYSA-J dipotassium;tetrabromoplatinum(2-) Chemical compound [K+].[K+].[Br-].[Br-].[Br-].[Br-].[Pt+2] AXZAYXJCENRGIM-UHFFFAOYSA-J 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960003072 epinephrine hydrochloride Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910001487 potassium perchlorate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、交感神経興奮作用を有
し、眼内圧の低下、気管支拡張剤として使用される塩酸
エピネフリン等のカテコラミン誘導体塩酸塩の製造方法
に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a catecholamine derivative hydrochloride such as epinephrine hydrochloride, which has a sympathomimetic activity, reduces intraocular pressure and is used as a bronchodilator.
【０００２】[0002]
【従来の技術・発明が解決しようとする課題】従来よ
り、エピネフリン（アドレナリン）等のカテコラミン誘
導体の遊離塩基は不安定であるため、通常塩酸塩として
製造されており、その方法としては（ａ）遊離塩基を化
学量論量の塩酸で処理する一般的方法、（ｂ）アンモニ
アを作用させ、抽出後、塩化水素で飽和させる方法（特
公昭６１−４７８２０号公報）、（ｃ）塩化セシウムを
作用させる方法（特公昭６１−４７８２０号公報）等が
知られている。2. Description of the Related Art Conventionally, the free base of catecholamine derivatives such as epinephrine (adrenaline) is unstable, so that it is usually produced as a hydrochloride salt. A general method of treating the free base with a stoichiometric amount of hydrochloric acid, (b) a method of acting with ammonia, followed by extraction and saturating with hydrogen chloride (Japanese Patent Publication No. 61-47820), and (c) cesium chloride. A method (Japanese Patent Publication No. 61-47820) and the like are known.
【０００３】しかしながら、これらの方法は以下の点で
工業的に好ましい方法とは言えない。即ち、（ａ）法で
は遊離塩基が不安定であることから、最終生成物が変色
し、また塩酸塩とする段階で収率、純度の低下を招く。
（ｂ）法は収率が５０％以下であり、遊離塩基の不安定
性から変動しやすい。（ｃ）法では収率は比較的高い
が、用いるセシウムの価格が高く経済的とはいえない。
また最終生成物に微量のセシウム金属が残留するという
問題が指摘される。本発明における目的化合物が時に医
薬の分野で使用されることからも、見逃してはならない
問題点である。以上のような問題点を有することから、
収率よくしかも安全性に問題のない工業的に有利な方法
の開発が当業界では期待されているが、未だ有用な方法
は見い出されていない。However, these methods are not industrially preferable in the following points. That is, in the method (a), since the free base is unstable, the final product is discolored, and the yield and the purity are lowered at the stage of forming the hydrochloride.
The method (b) has a yield of 50% or less and is liable to change due to instability of the free base. Although the yield is relatively high in the method (c), the price of cesium used is high and it is not economical.
It is also pointed out that a trace amount of cesium metal remains in the final product. This is a problem that should not be overlooked because the object compound of the present invention is sometimes used in the field of medicine. Since it has the above problems,
Although it is expected in the art to develop an industrially advantageous method in which the yield is high and the safety is not a problem, a useful method has not yet been found.
【０００４】[0004]
【課題を解決するための手段】本発明者らは前記課題を
解決するため鋭意検討した結果、本発明に至った。即
ち、本発明の要旨は、式（１）Means for Solving the Problems The inventors of the present invention have made extensive studies to solve the above problems, and as a result, have reached the present invention. That is, the gist of the present invention resides in the formula (1)
【化３】 （式中、Ｒ1 およびＲ2 はそれぞれ独立に炭素数１〜２
２のアルカノイル基であり、Ｒ3 は炭素数１〜５の直鎖
又は分枝鎖のアルキル基である）で表される化合物に、 ＱＣＯＯ- Ｍ+ （式中、Ｑは炭素数１〜４のアルキル基であり、Ｍはア
ルカリ金属である）で表される化合物を反応させ、生成
する過塩素酸アルカリ金属塩を除去し、次いで塩化水素
で処理することを特徴とする式（２）[Chemical 3] (In the formula, R 1 and R 2 each independently have 1 to 2 carbon atoms.
2 is an alkanoyl group and R 3 is a linear or branched alkyl group having 1 to 5 carbon atoms, and a compound represented by QCOO - M + (in the formula, Q is 1 to 4 carbon atoms). Of the formula (2), wherein the compound represented by the formula (2) is reacted with a compound represented by the formula (2)
【化４】 （式中、Ｒ1 、Ｒ2 およびＲ3 は前記と同意義である）
で表されるカテコラミン誘導体塩酸塩の製造方法に関す
る。[Chemical 4] (In the formula, R 1 , R 2 and R 3 have the same meanings as described above.)
The present invention relates to a method for producing a catecholamine derivative hydrochloride represented by
【０００５】Ｒ1 およびＲ2 で表される炭素数１〜２２
のアルカノイル基としては、ホルミル、アセチル、プロ
ピオニル、ブチリル、イソブチリル、バレリル、イソバ
レリル、２−メチルブタノイル、ピバリル、３−メチル
ペンタノイル、３，３−ジメチルブタノイル、２，２−
ジメチルペンタノイル、ドコサノイル、７，７−ジメチ
ルオクタノイル等が挙げられ、直鎖でも分岐鎖のいずれ
でもよい。Ｒ3 で表される炭素数１〜５のアルキル基と
しては直鎖でも分岐鎖のいずれでもよく、例えばメチ
ル、エチル、プロピル、イソプロピル、ｎ−ブチル、ｓ
ｅｃ−ブチル、ｔ−ブチル、ペンチル、ネオペンチル等
が挙げられる。Ｑで表される炭素数１〜４のアルキル基
としてはメチル、エチル、プロピル、イソプロピル、ｎ
−ブチル、ｓｅｃ−ブチル、ｔ−ブチルが挙げられる。
Ｍで表されるアルカリ金属としてはリチウム、ナトリウ
ム、カリウム等が挙げられ、好ましくはカリウムであ
る。1 to 22 carbon atoms represented by R 1 and R 2
As the alkanoyl group of, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-
Examples thereof include dimethylpentanoyl, docosanoyl, and 7,7-dimethyloctanoyl, which may be linear or branched. The alkyl group having 1 to 5 carbon atoms represented by R 3 may be linear or branched, and examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl and s.
Examples include ec-butyl, t-butyl, pentyl, neopentyl and the like. The alkyl group having 1 to 4 carbon atoms represented by Q includes methyl, ethyl, propyl, isopropyl, n
-Butyl, sec-butyl, t-butyl.
Examples of the alkali metal represented by M include lithium, sodium, potassium and the like, and potassium is preferable.
【０００６】本発明の方法はまず式（１）の化合物を極
性のある有機溶媒に溶解し、該化合物とＱＣＯＯ- Ｍ+
で表される脂肪酸アルカリ金属塩とを反応させる。ここ
で、極性のある有機溶媒としては特に限定されるもので
はなく例えば、メタノール、エタノール、イソプロパノ
ール等あるいはこれらの混合物が例示される。脂肪酸ア
ルカリ金属塩の使用量は式（１）の化合物に対して１．
０〜５．０倍モル、好ましくは１．０〜１．３倍モルで
ある。脂肪酸アルカリ金属塩の使用量が１．０倍モルよ
りも少ないと反応は完結しない。５．０倍モルよりも多
いと未反応として残り経済的でない。反応温度は通常０
〜８０℃、好ましくは１５〜３０℃の温度で、１〜２時
間程度で終了する。次いで、生成する過塩素酸アルカリ
金属塩をろ過により除去した後、塩化水素を過剰量吹き
込み、０〜５℃で１〜３時間攪拌させて式（２）の化合
物を生成させる。得られる目的化合物の単離精製は、例
えば抽出、濾過、クロマトグラフィー等の公知の方法で
適宜行われる。In the method of the present invention, the compound of formula (1) is first dissolved in a polar organic solvent, and the compound and QCOO - M + are dissolved.
Is reacted with a fatty acid alkali metal salt represented by Here, the polar organic solvent is not particularly limited, and examples thereof include methanol, ethanol, isopropanol and the like, or a mixture thereof. The amount of the fatty acid alkali metal salt used is 1 with respect to the compound of the formula (1).
It is 0 to 5.0 times mol, preferably 1.0 to 1.3 times mol. The reaction is not completed when the amount of the fatty acid alkali metal salt used is less than 1.0 times the molar amount. If it is more than 5.0 times mol, it remains unreacted and is not economical. Reaction temperature is usually 0
The temperature is -80 ° C, preferably 15-30 ° C, and is completed in about 1 to 2 hours. Next, after removing the generated alkali metal perchlorate by filtration, an excess amount of hydrogen chloride is blown in, and the mixture is stirred at 0 to 5 ° C. for 1 to 3 hours to form the compound of formula (2). Isolation and purification of the obtained target compound are appropriately carried out by known methods such as extraction, filtration, chromatography and the like.
【０００７】[0007]
【実施例】以下、実施例および参考例により本発明をさ
らに詳しく説明するが、本発明はこれらの実施例等に何
ら限定されるものではない。 実施例１ ｄ，ｌ−ｍ，ｐ−ジピバリルエピネフリン塩酸塩の製造 １４．９ｇ（０．０３３モル）のｄ，ｌ−ｍ，ｐ−ジピ
バリルエピネフリン過塩素酸塩をメタノールに溶解し、
これに３．９ｇ（０．０４０モル、１．２当量）の酢酸
カリウムのメタノール溶液を室温で攪拌しながら滴下し
た。１．５時間攪拌した後、過塩素酸カリウムを濾過し
て除き、濾液に１．５当量の塩化水素を吹き込み、０℃
で２時間攪拌した。減圧下でメタノールを除去して無定
形固体を得た。残留物を酢酸エチルから再結晶して１
１．１ｇ（０．０２９モル）のｄ，ｌ−ｍ，ｐ−ジピバ
リルエピネフリン塩酸塩を得た（収率８７％、融点１６
０〜１６１℃）。ＩＲスペクトルおよびＮＭＲスペクト
ルは標準品のそれと完全に一致した。EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples. Example 1 Preparation of d, l-m, p-dipivalyl epinephrine hydrochloride 14.9 g (0.033 mol) of d, l-m, p-dipivalyl epinephrine perchlorate was dissolved in methanol. ,
To this was added 3.9 g (0.040 mol, 1.2 eq) of a solution of potassium acetate in methanol at room temperature with stirring. After stirring for 1.5 hours, potassium perchlorate was removed by filtration, 1.5 equivalent of hydrogen chloride was blown into the filtrate, and the mixture was cooled to 0 ° C.
And stirred for 2 hours. Methanol was removed under reduced pressure to give an amorphous solid. Recrystallize the residue from ethyl acetate to 1
1.1 g (0.029 mol) of d, lm-p-dipivalyl epinephrine hydrochloride was obtained (yield 87%, melting point 16).
0-161 ° C). The IR spectrum and the NMR spectrum were in perfect agreement with those of the standard product.
【０００８】参考例１ ３７．９ｇ（０．０８４モル）のｄ，ｌ−ｍ，ｐ−ジピ
バリルエピネフリン過塩素酸塩を温水に溶解し、窒素気
流下、０℃で１．０当量のアンモニア（２５％水溶液）
を攪拌しながら滴下した。溶液を酢酸エチルで抽出し、
無水硫酸マグネシウムで乾燥した。濾過後、濾液に１．
５当量の塩化水素を吹き込み、０℃で３時間攪拌した。
減圧下で溶媒を除去し、残留物を酢酸エチルから再結晶
して１１．９ｇ（０．０３１モル）のｄ，ｌ−ｍ，ｐ−
ジピバリルエピネフリン塩酸塩を得た（収率３７％、融
点１６０〜１６１℃）。Reference Example 1 37.9 g (0.084 mol) of d, lm, p-dipivalyl epinephrine perchlorate was dissolved in warm water, and 1.0 equivalent of it was added at 0 ° C under a nitrogen stream. Ammonia (25% aqueous solution)
Was added dropwise with stirring. Extract the solution with ethyl acetate,
It was dried over anhydrous magnesium sulfate. After filtration, 1.
5 equivalents of hydrogen chloride was blown in, and the mixture was stirred at 0 ° C for 3 hours.
The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate to give 11.9 g (0.031 mol) of d, lm, p-.
Dipivalyl epinephrine hydrochloride was obtained (yield 37%, melting point 160-161 ° C).
【０００９】参考例２ １６．０ｇ（０．０３５モル）のｄ，ｌ−ｍ，ｐ−ジピ
バリルエピネフリン過塩素酸塩をメタノールに溶解し、
０℃で攪拌しながら６．０ｇ（０．０３５モル、１．０
当量）のセシウムクロライドのメタノール溶液を滴下し
た。０℃で２時間攪拌した後、濾過してセシウムパーク
ロレイトを除き、減圧下でメタノールを除去した。酢酸
エチルから再結晶させて１１．７ｇ（０．０３０モル）
のｄ，ｌ−ｍ，ｐ−ジピバリルエピネフリン塩酸塩を得
た（収率８５％、融点１５８〜１５９℃）。残留セシウ
ムを原子吸光光度法により検査したところ生成物全体の
０．６８％であった。Reference Example 2 16.0 g (0.035 mol) of d, lm-p-dipivalyl epinephrine perchlorate was dissolved in methanol,
6.0 g (0.035 mol, 1.0 with stirring at 0 ° C)
An equivalent amount of a cesium chloride solution in methanol was added dropwise. After stirring at 0 ° C. for 2 hours, cesium perchlorate was removed by filtration, and methanol was removed under reduced pressure. Recrystallized from ethyl acetate, 11.7 g (0.030 mol)
To obtain d, lm, p-dipivalyl epinephrine hydrochloride (yield 85%, melting point 158-159 [deg.] C.). The residual cesium was examined by atomic absorption spectrometry and found to be 0.68% of the whole product.
【００１０】[0010]
【発明の効果】本発明の方法によればカテコラミン誘導
体塩酸塩を過塩素酸塩から、収率よく、しかもセシウム
のような金属を混在させることがなく、容易に得ること
ができるので、安全性が高くかつ工業的に有利である。Industrial Applicability According to the method of the present invention, the catecholamine derivative hydrochloride can be easily obtained from the perchlorate with a high yield and without mixing a metal such as cesium. Is high and industrially advantageous.
Claims (1)
２のアルカノイル基であり、Ｒ3 は炭素数１〜５の直鎖
又は分枝鎖のアルキル基である）で表される化合物に、 ＱＣＯＯ- Ｍ+ （式中、Ｑは炭素数１〜４のアルキル基であり、Ｍはア
ルカリ金属である）で表される化合物を反応させ、生成
する過塩素酸アルカリ金属塩を除去し、次いで塩化水素
で処理することを特徴とする式（２） 【化２】 （式中、Ｒ1 、Ｒ2 およびＲ3 は前記と同意義である）
で表されるカテコラミン誘導体塩酸塩の製造方法。1. Formula (1): (In the formula, R 1 and R 2 each independently have 1 to 2 carbon atoms.
2 is an alkanoyl group and R 3 is a linear or branched alkyl group having 1 to 5 carbon atoms, and a compound represented by QCOO - M + (in the formula, Q is 1 to 4 carbon atoms). Which is an alkyl group of M and M is an alkali metal), the resulting alkali metal salt of perchloric acid is removed, and then treated with hydrogen chloride. Chemical 2] (In the formula, R 1 , R 2 and R 3 have the same meanings as described above.)
A method for producing a catecholamine derivative hydrochloride represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3222027A JP2802456B2 (en) | 1991-08-06 | 1991-08-06 | Method for producing catecholamine derivative hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3222027A JP2802456B2 (en) | 1991-08-06 | 1991-08-06 | Method for producing catecholamine derivative hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0616603A true JPH0616603A (en) | 1994-01-25 |
| JP2802456B2 JP2802456B2 (en) | 1998-09-24 |
Family
ID=16775948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3222027A Expired - Fee Related JP2802456B2 (en) | 1991-08-06 | 1991-08-06 | Method for producing catecholamine derivative hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2802456B2 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4035405A (en) | 1976-07-09 | 1977-07-12 | Interx Research Corporation | Novel synthesis for preparing the hydrochloride salt of selected catecholamine derivatives |
-
1991
- 1991-08-06 JP JP3222027A patent/JP2802456B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2802456B2 (en) | 1998-09-24 |
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