JPS58159449A - Manufacture of acebutorol - Google Patents
Manufacture of acebutorolInfo
- Publication number
- JPS58159449A JPS58159449A JP57221058A JP22105882A JPS58159449A JP S58159449 A JPS58159449 A JP S58159449A JP 57221058 A JP57221058 A JP 57221058A JP 22105882 A JP22105882 A JP 22105882A JP S58159449 A JPS58159449 A JP S58159449A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- butyramidophenoxy
- dioxalanyl
- isopropylamino
- formula
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 2
- 238000010306 acid treatment Methods 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 10
- 229960002122 acebutolol Drugs 0.000 description 7
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RKJXMIZQSQZBKO-UHFFFAOYSA-N 2-oxidodioxathiolan-2-ium Chemical compound [O-][O+]1OCCS1 RKJXMIZQSQZBKO-UHFFFAOYSA-N 0.000 description 1
- CFPKVTKDDGALCR-UHFFFAOYSA-N 4-(phenoxymethyl)-1,3,2-dioxathiolane 2-oxide Chemical class O1S(=O)OCC1COC1=CC=CC=C1 CFPKVTKDDGALCR-UHFFFAOYSA-N 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
- GOXBZODPPBKULK-UHFFFAOYSA-N C(C)(=O)C1=C(OCC2OS(OC2)=O)C=CC(=C1)NC(CCC)=O Chemical compound C(C)(=O)C1=C(OCC2OS(OC2)=O)C=CC(=C1)NC(CCC)=O GOXBZODPPBKULK-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229960003830 acebutolol hydrochloride Drugs 0.000 description 1
- KTUFKADDDORSSI-UHFFFAOYSA-N acebutolol hydrochloride Chemical compound Cl.CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 KTUFKADDDORSSI-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CMHWPQYLNODERU-UHFFFAOYSA-N butanamide phenol Chemical compound C1(=CC=CC=C1)O.C(CCC)(=O)N CMHWPQYLNODERU-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- FGWZEOPEZISTTR-UHFFFAOYSA-N n-(3-acetyl-4-hydroxyphenyl)butanamide Chemical group CCCC(=O)NC1=CC=C(O)C(C(C)=O)=C1 FGWZEOPEZISTTR-UHFFFAOYSA-N 0.000 description 1
- MFGKLROXINRXIU-UHFFFAOYSA-N n-[3-acetyl-4-(oxiran-2-ylmethoxy)phenyl]butanamide Chemical compound CC(=O)C1=CC(NC(=O)CCC)=CC=C1OCC1OC1 MFGKLROXINRXIU-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
本発明は式（１）
％式％
ルあるいはアセブトロールの製造法に関するものである
。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing formula (1) or acebutolol.
アセブトロールは衆知の医薬化合物である。Acebutolol is a well-known pharmaceutical compound.
英国特許第１．．２４７，３８４号には式（Ｉ Ｉ）で
示される３−（２−アセチル−４−ブチラミドフェノキ
シ）−１，２−プロピレンオキサイドをイソプロピルア
ミンと反応させアセブトロールを製造する方法が記載さ
れている。特開昭５７−２２４６号には式（Ｉ Ｉ Ｉ
）
で示される４−フェノキシメチル−１，３，２−ジオキ
サチオラン−２−オキシド誘導体とイソプロピルアミン
を反応させ、１−イソプロピルアミノ−５−（２−アリ
ルフェノキシ）−９１−イソプロピルアミノ−３−フェ
ノキシ−あるいはＩ−イソプロピルアミノ−５−（２−
アリロキシフェノキシ）−２−プロパツールを製造する
方法が記載されている。British Patent No. 1. ．． No. 247,384 describes a method for producing acebutolol by reacting 3-(2-acetyl-4-butyramidophenoxy)-1,2-propylene oxide represented by formula (II) with isopropylamine. . JP-A No. 57-2246 has the formula (I I I
) is reacted with isopropylamine and the 4-phenoxymethyl-1,3,2-dioxathiolane-2-oxide derivative represented by - or I-isopropylamino-5-(2-
A method for making aryloxyphenoxy)-2-propatol is described.
１−イソプロピルアミノ−３−アリールオキシ−２−プ
ロパツール製造の一般的方法が例えばＫｅｍｉｓｋＴｉ
、ｄｓｋｒ」ｆｔ、１９７６、ｎｏ、１０．４８および
Ｋｅｍｉａ −Ｋｅｍｉ 。A general method for producing 1-isopropylamino-3-aryloxy-2-propanol is, for example, KemiskTi.
, dskr”ft, 1976, no. 10.48 and Kemia-Kemi.
１０７ｇ、ｎｏ、５．１８６に貫己載されている。107g, no. 5.186.
アセブトロールの特殊な製法がまたフィンランド特許第
８０３２２６号、同８０３２２７号に記載されている。A special method for the preparation of acebutolol is also described in Finnish patents 803226 and 803227.
今回本発明者らにより式（■ｖ）
３−
〇
で示される４−［（２−（１−メチル−２，５−ジオキ
サラニル）−４−ブチラミドフェノキシ）メチル〕−１
，３，２−ジオキサチオラン−２−オキシドとイソプロ
ピルアミンを反応させ、得られた１−イソプロピルアミ
ノ−３−［２−（１−メチル−２，５−ジオキサラニル
）−４−ブチラミドフェノキシ〕−２−プロパツールを
鉱酸で処理してアセブトロールを製造し得ることが見い
だされた。This time, the present inventors developed 4-[(2-(1-methyl-2,5-dioxalanyl)-4-butyramidophenoxy)methyl]-1 represented by the formula (■v) 3-
, 3,2-dioxathiolane-2-oxide and isopropylamine were reacted to obtain 1-isopropylamino-3-[2-(1-methyl-2,5-dioxalanyl)-4-butyramidophenoxy]-2. - It has been found that propatool can be treated with mineral acids to produce acebutolol.
式（ＴＶ）の化合物は新規化合物である。このものは式
（Ｖ）
＝４−
キサラニル）−４−ブチラミドフェノキシ〕−１゜２−
プロパンジオールと塩化チオニルの反応で得られる。こ
の反応は不活性溶媒中、第３アミンの存在下常温または
低温で実施せられる。The compound of formula (TV) is a new compound. This product has the formula (V) =4-xalanyl)-4-butyramidophenoxy]-1゜2-
Obtained by the reaction of propanediol and thionyl chloride. This reaction is carried out in an inert solvent in the presence of a tertiary amine at room or low temperature.
式（Ｖ）で示される化合物も新規である。このものは２
−アセチル−４−ブチラミドフェノールをケタール化し
て２−（１−メチル−２，５−ジオキサラニル）−４−
ブチラミドフェノールとし、これを塩基触媒の存在下グ
リシドールと反応させて製造するのが好ましい。化合物
ＩＶとイソプロピルアミンの反応はそれらを適当な有機
溶媒、好ましくはアセトニトリル中加熱することにより
実施せられる。中間体１−イソプロピルアミノ−３−（
２−（１−メチル−２，５−ジオキサラニル）−４−ブ
チラミドフェノキシ〕−２−プロパツールの処理は好ま
しくはアセトン中塩酸により行なわれる。かくしてアセ
ブトロールは医薬目的に望ましい形の塩酸塩として容易
に得られる。英国特許第１，２４７，３８４号の方法で
の主たる問題点は望ましからざる副反応であった。特に
化合物ＴＩを対応するフエノールとエピクロルヒドリン
から作る際に、このフェノールが目的生成物ＩＩと反応
する問題があった。The compound represented by formula (V) is also new. This one is 2
-Acetyl-4-butyramidophenol is ketalized to 2-(1-methyl-2,5-dioxalanyl)-4-
Preferably, butyramide phenol is produced by reacting it with glycidol in the presence of a base catalyst. The reaction of compound IV with isopropylamine is carried out by heating them in a suitable organic solvent, preferably acetonitrile. Intermediate 1-isopropylamino-3-(
Treatment of 2-(1-methyl-2,5-dioxalanyl)-4-butyramidophenoxy]-2-propatol is preferably carried out with hydrochloric acid in acetone. Acebutolol is thus easily obtained as the hydrochloride salt, a form desirable for pharmaceutical purposes. The main problem with the process of GB 1,247,384 was undesirable side reactions. In particular, when compound TI was prepared from the corresponding phenol and epichlorohydrin, there was a problem that this phenol reacted with the target product II.
また化合物ＩＴとイソプロピルアミンの反応で容易に対
応する異性体１−プロパツールが生成する。Furthermore, the corresponding isomer 1-propatool is easily produced by the reaction of compound IT with isopropylamine.
従って該方法の全収率は比較的低く、また精製が必要な
ため非経済的である。特開昭５７−２２４６号の方法は
４− （（２−アセチル−４−ブチラミドフェノキシ）
メチル）−１，３，２−ジオキサチオラン−２−オキシ
ドが提案された方法で得られなり）ためアセブトロール
の製造には利用出来ない。Therefore, the overall yield of the process is relatively low and the purification required makes it uneconomical. The method of JP-A-57-2246 is 4-((2-acetyl-4-butyramidophenoxy)
methyl)-1,3,2-dioxathiolane-2-oxide cannot be obtained by the proposed method) and therefore cannot be used for the production of acebutolol.
本発明方法の収率は高く、また望ましからざる副生物の
生成は殆んど認められない。従って工業的方法として極
めて適している。The yield of the process according to the invention is high, and the formation of undesirable by-products is hardly observed. Therefore, it is extremely suitable as an industrial method.
以下実施例により本発明を説明する。The present invention will be explained below with reference to Examples.
実施例
ａ）３− ［２−（１−メチル−２，５−ジオキサラン
−２−イル）−４−ブチラミドフェノキシ１４，２−プ
ロパンジオール （Ｖ）
４．５ｇ（０，０６モル）のグリシドールを６０ｍ１の
１゜１．２−１−ＩＪクロルエチレンにとかした溶液を
、１３、３ｇ （０，０５モル）の２−（１−メチル−
２，５−ジオキサランル）−４−ブチラミドフェノール
と触媒量のナトリウムメトキシドを６０ｍ１の１．］、
］２−トリクロルエチレにとかし煮沸せる溶液にＮ２気
流下徐々に加えた。Ｎ２気流下に混液を２４時間還流し
た。溶媒を減圧下に留去し、１７．０ｇ（１００％）の
目的化合物を得た。Example a) 3-[2-(1-Methyl-2,5-dioxalan-2-yl)-4-butyramidophenoxy 14,2-propanediol (V) 4.5 g (0.06 mol) of glycidol of 2-(1-methyl-
2,5-Dioxalanyl)-4-butyramidophenol and a catalytic amount of sodium methoxide were added to 60 ml of 1. ],
] It was gradually added to the solution dissolved in 2-trichlorethylene and boiled under a stream of N2. The mixture was refluxed for 24 hours under a stream of N2. The solvent was distilled off under reduced pressure to obtain 17.0 g (100%) of the target compound.
１（’ −ＮＭＲ（ＣＤＣＩ ３ ）： δ ＝
０．９７（３）１し）、１．７０（２）１ｓｅｘｔ）。1('-NMR(CDCI3): δ=
0.97 (3) 1 sex), 1.70 (2) 1 sex).
１．７２（３１１ｓ）、２．３０（２１１し）、３．５
０−４．２０（１１１１ｍ）、６．９０（］Ｈｄ）、７
．５０−７．７２（２１＋ｍ）、９．１０（ＩＨｓ）ｂ
）４− （（２−（２−メチル−１，３−ジオキサラン
−２−イル）−４−ブチラミドフェノキシ）メチル〕−
１、，３，２−ジオキサチオラン−２−オキシド（ｍ４
．４ｍｌの塩化チオニルを６ｍｌのジクロルメタンにと
かした溶液を、１７ｇ（０，０６モル）の化合物Ｖ、６
．１ｇ（０，ｏ６モル）のトリエチルアミン、６０ｍ１
のジクロルメタンの溶液に０℃で加えた。混合物を０〜
５°Ｃで１５分間撹拌し、０． １Ｎ塩酸及び水で洗い
、Ｎａ ２ ＳＯ４で乾燥させた。溶液を減圧下蒸発乾
固させ、２０．７ｇ （９３％）の目的化合物を得た。1.72 (311s), 2.30 (211s), 3.5
0-4.20 (1111m), 6.90 (]Hd), 7
．． 50-7.72 (21+m), 9.10 (IHs)b
)4- ((2-(2-methyl-1,3-dioxalan-2-yl)-4-butyramidophenoxy)methyl]-
1,,3,2-dioxathiolane-2-oxide (m4
．． A solution of 4 ml of thionyl chloride in 6 ml of dichloromethane was added to 17 g (0.06 mol) of compound V, 6.
．． 1 g (0.06 mol) triethylamine, 60 ml
of dichloromethane at 0°C. Mixture from 0 to
Stir for 15 minutes at 5°C, Washed with 1N hydrochloric acid and water and dried over Na 2 SO 4 . The solution was evaporated to dryness under reduced pressure to obtain 20.7 g (93%) of the desired compound.
７−
Ｈ’ −ＮＭＲ： ０．９７（３Ｈｔ）、１．７０（
３Ｆｌｓ）、１．７５（２Ｈｓｅｘｔ）。7-H'-NMR: 0.97 (3Ht), 1.70 (
3Fls), 1.75 (2Hsext).
２．３０（２１１ｔ）、３．５５−４．８０（８１１ｍ
）、５．２０（ＩＨｑｕ）、６．８０（１）１ｄ）、７
．４０〜７．６５（１，１１ｇ）ｃ）１−イソプロピル
アミノ−５−（２−アセチル−４−ブチラミドフェノキ
シ）−２−プロパツール（Ｉ）１９．３ｇ（０，０５モ
／Ｌ／） （７）化合物ＩＶ及び３（ｈａｌ（７）イソ
プロピルアミンを１０抛１のアセトニトリルに加えた溶
液を２０時間加熱還流させた。溶媒を減圧下に留去し、
残渣にアセトンを加えた。混合物をろ過し、０．０４モ
ルの濃塩酸を加え、１６．４ｇ （８８％）のアセブト
ロール塩酸塩を得た。融点１４１〜１４３℃
８−2.30 (211t), 3.55-4.80 (811m
), 5.20 (IHqu), 6.80 (1) 1d), 7
．． 40-7.65 (1,11 g) c) 1-isopropylamino-5-(2-acetyl-4-butyramidophenoxy)-2-propatol (I) 19.3 g (0,05 mo/L/) (7) A solution of compounds IV and 3 (hal (7) isopropylamine in 10 parts of acetonitrile was heated to reflux for 20 hours. The solvent was distilled off under reduced pressure.
Acetone was added to the residue. The mixture was filtered and 0.04M concentrated hydrochloric acid was added to obtain 16.4g (88%) of acebutolol hydrochloride. Melting point 141-143℃ 8-
Claims (1)
サラニル）−４−ブチラミドフェノキシ）メチルクー１
．３．２−ジオキサチオラン−２−オキシドをイソプロ
ピルアミンと反応させ得られる】−イソプロピルアミノ
−３−［２−（］−］メチルー２，５−ジオキサラニル
−１−ブチラミドフェノキシ〕−２−プロパツールを鉱
酸で処理し、得られた塩を所望により遊離塩基に変換す
ることを特徴とする式４−ブチラミドフェノキシ）−２
−プロパツールまたはその塩の製造法。 （２）反応を有機溶媒中で実施する特許請求の範囲第１
項記載の方法。 （３）有機溶媒がアセト二１−リルである特許請求の範
囲第２項記載の方法。 （４）４− ［（２−（１−メチル−２，５−ジオキサ
ラニル）−４−ブチラミドフェノキシ）メチル］−１゜
３．２−ジオキ什チオランー２−オキシドがアセ１ヘン
中イソプロピルアミンと約２０時間還流される特許請求
の範囲第３項記載の方法。 （５）使用せられる鉱酸が塩酸である特許請求の範囲第
１項〜第４項のいづれかに記載の方法。 （６）１−イソプロピルアミノ−３−［２−（１−メチ
ル−２，５−ジオキサラニル）−４−ブチラミドフェノ
キシ〕−２−プロパツールの鉱酸処理がアセ１ヘン中で
実施せられる特許請求の範囲第１項〜第５項のいづれか
に記載の方法。 （７）１−イソプロピルアミノ−３−［２−（１−メチ
ル−２，５−ジオキサラニル）−４−プチラミドフエノ
キシ〕−２−プロパツール。[Scope of Claims] 4-[(2-(+-Methyl-2,5-dioxalanyl)-4-butyramidophenoxy)methylcous 1 represented by the formula (+)
．． 3. ]-isopropylamino-3-[2-(]-]methyl-2,5-dioxalanyl-1-butyramidophenoxy]-2-propatol obtained by reacting 2-dioxathiolane-2-oxide with isopropylamine Formula 4-butyramidophenoxy)-2, characterized in that it is treated with a mineral acid and the salt obtained is optionally converted into the free base.
- A method for producing propatool or its salt. (2) Claim 1 in which the reaction is carried out in an organic solvent
The method described in section. (3) The method according to claim 2, wherein the organic solvent is acetonyl-lyl. (4) 4-[(2-(1-methyl-2,5-dioxalanyl)-4-butyramidophenoxy)methyl]-1゜3.2-diokithiolane-2-oxide is reacted with isopropylamine in acetic acid. 4. The method of claim 3, wherein the method is refluxed for about 20 hours. (5) The method according to any one of claims 1 to 4, wherein the mineral acid used is hydrochloric acid. (6) A patent in which mineral acid treatment of 1-isopropylamino-3-[2-(1-methyl-2,5-dioxalanyl)-4-butyramidophenoxy]-2-propanol is carried out in acetic acid. A method according to any one of claims 1 to 5. (7) 1-isopropylamino-3-[2-(1-methyl-2,5-dioxalanyl)-4-butyramidophenoxy]-2-propatol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI814053 | 1981-12-17 | ||
| FI814053 | 1981-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS58159449A true JPS58159449A (en) | 1983-09-21 |
Family
ID=8514961
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57221057A Pending JPS58159446A (en) | 1981-12-17 | 1982-12-16 | Manufacture of methoprorol |
| JP57221058A Pending JPS58159449A (en) | 1981-12-17 | 1982-12-16 | Manufacture of acebutorol |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57221057A Pending JPS58159446A (en) | 1981-12-17 | 1982-12-16 | Manufacture of methoprorol |
Country Status (9)
| Country | Link |
|---|---|
| JP (2) | JPS58159446A (en) |
| KR (1) | KR840002768A (en) |
| CA (1) | CA1198125A (en) |
| DK (2) | DK541982A (en) |
| HU (1) | HU186649B (en) |
| NO (2) | NO824232L (en) |
| SE (2) | SE452612B (en) |
| SU (1) | SU1170968A3 (en) |
| YU (2) | YU275982A (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56152461A (en) * | 1980-04-30 | 1981-11-26 | Ota Seiyaku Kk | Preparation of indole derivative |
-
1982
- 1982-12-06 KR KR1019820005450A patent/KR840002768A/en unknown
- 1982-12-07 DK DK541982A patent/DK541982A/en not_active Application Discontinuation
- 1982-12-07 DK DK542082A patent/DK156567C/en not_active IP Right Cessation
- 1982-12-14 YU YU02759/82A patent/YU275982A/en unknown
- 1982-12-14 YU YU02758/82A patent/YU275882A/en unknown
- 1982-12-15 SU SU823523098A patent/SU1170968A3/en active
- 1982-12-16 JP JP57221057A patent/JPS58159446A/en active Pending
- 1982-12-16 SE SE8207199A patent/SE452612B/en not_active IP Right Cessation
- 1982-12-16 HU HU824069A patent/HU186649B/en not_active IP Right Cessation
- 1982-12-16 CA CA000417934A patent/CA1198125A/en not_active Expired
- 1982-12-16 JP JP57221058A patent/JPS58159449A/en active Pending
- 1982-12-16 SE SE8207198A patent/SE8207198L/en not_active Application Discontinuation
- 1982-12-16 NO NO824232A patent/NO824232L/en unknown
- 1982-12-16 NO NO824233A patent/NO155619C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SU1170968A3 (en) | 1985-07-30 |
| HU186649B (en) | 1985-08-28 |
| YU275982A (en) | 1985-03-20 |
| NO824232L (en) | 1983-06-20 |
| DK156567C (en) | 1990-03-05 |
| NO155619B (en) | 1987-01-19 |
| YU275882A (en) | 1985-03-20 |
| CA1198125A (en) | 1985-12-17 |
| NO824233L (en) | 1983-06-20 |
| SE8207199D0 (en) | 1982-12-16 |
| DK541982A (en) | 1983-06-18 |
| SE8207198L (en) | 1983-06-18 |
| DK156567B (en) | 1989-09-11 |
| DK542082A (en) | 1983-06-18 |
| NO155619C (en) | 1987-04-29 |
| SE452612B (en) | 1987-12-07 |
| SE8207199L (en) | 1983-06-18 |
| JPS58159446A (en) | 1983-09-21 |
| SE8207198D0 (en) | 1982-12-16 |
| KR840002768A (en) | 1984-07-16 |
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