JPS6228777B2 - - Google Patents
Info
- Publication number
- JPS6228777B2 JPS6228777B2 JP12630179A JP12630179A JPS6228777B2 JP S6228777 B2 JPS6228777 B2 JP S6228777B2 JP 12630179 A JP12630179 A JP 12630179A JP 12630179 A JP12630179 A JP 12630179A JP S6228777 B2 JPS6228777 B2 JP S6228777B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- sodium borohydride
- methoxyethyl
- phenoxy
- propanol
- 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.)
- Expired
Links
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 14
- 239000012279 sodium borohydride Substances 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 4
- OFRYBPCSEMMZHR-UHFFFAOYSA-N alpha-Hydroxymetoprolol Chemical compound COCC(O)C1=CC=C(OCC(O)CNC(C)C)C=C1 OFRYBPCSEMMZHR-UHFFFAOYSA-N 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 229960002237 metoprolol Drugs 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- -1 keto compound Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UJUKHOATWVVDER-UHFFFAOYSA-N 1-amino-1-phenoxypropan-1-ol Chemical compound CCC(N)(O)OC1=CC=CC=C1 UJUKHOATWVVDER-UHFFFAOYSA-N 0.000 description 1
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- HYMIUVGTKKAYNU-UHFFFAOYSA-N 2-methoxy-1-[4-(oxiran-2-ylmethoxy)phenyl]ethanol Chemical compound C1=CC(C(O)COC)=CC=C1OCC1OC1 HYMIUVGTKKAYNU-UHFFFAOYSA-N 0.000 description 1
- YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Substances OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical class C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003152 propanolamines Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は式：
を有する１−イソプロピルアミノ−３−〔４−（２
−メトキシエチル）フエノキシ〕−２−プロパノ
ール〔メトプロロール（metoprolol）〕またはそ
の塩の新規な製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula: 1-isopropylamino-3-[4-(2
-methoxyethyl)phenoxy]-2-propanol [metoprolol] or a salt thereof.
メトプロロールは、いわゆるβ−アドレナリン
作動性遮断剤（β−adrenergic blocking
agent）である。殆んどのβ−アドレナリン作動
性遮断剤は心臓のβ−受容体を遮断するのみなら
ず、血管と肺のβ−受容体をも遮断するという問
題点を有する。これに対して、メトプロロールは
心臓に対して特異的であり、そのため心臓の治療
のために重要な薬剤である。 Metoprolol is a so-called β-adrenergic blocking agent.
agent). Most β-adrenergic blocking agents have the problem of not only blocking β-receptors in the heart, but also blocking β-receptors in the blood vessels and lungs. In contrast, metoprolol is specific for the heart and is therefore an important drug for cardiac treatment.
メトプロロールの製法としては、たとえばスウ
エーデン特許第354851号明細書に記載されてお
り、該明細書には12種類の製法が示されている。
それらの方法はすべてプロパノール側鎖の生成に
関するものであるという点で共通している。 A method for producing metoprolol is described, for example, in Swedish Patent No. 354,851, which discloses 12 different production methods.
What these methods have in common is that they all involve the production of propanol side chains.
本発明の方法は、式（）：
を有するプロパノールアミン誘導体が水素化ホウ
素ナトリウムでメトプロロールに還元される点に
特徴を有する。アミン誘導体（）は公知の化合
物である（Acta Pharmacol.et Toxicol.、1975、
36、suppl.V、15）。 The method of the present invention is based on the formula (): It is characterized in that the propanolamine derivative having the formula is reduced to metoprolol with sodium borohydride. Amine derivatives () are known compounds (Acta Pharmacol.et Toxicol., 1975,
36 , suppl.V, 15).
特願昭54−39236号は、式（）：
を有する相当するケト化合物を、トリフルオロ酢
酸、メタンスルホン酸またはｐ−トルエンスルホ
ン酸を酸として用いた強い酸雰囲気下で水素化ホ
ウ素ナトリウムによつてメトプロロールに還元す
る方法に関する。 Patent Application No. 1983-39236 is based on the formula (): A process for reducing the corresponding keto compound having the formula to metoprolol with sodium borohydride in a strong acid atmosphere using trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid as acid.
しかるに出発物質として前記アルコール中間体
（）を用いるときは、より一層すぐれた利点を
有するという驚くべき事実が見出された。 However, it has been surprisingly discovered that when the alcohol intermediate (2) is used as a starting material, there are even more advantages.
しかして本発明は、１−イソプロピルアミノ−
３−〔４−（１−ヒドロキシ−２−メトキシエチ
ル）フエノキシ〕−２−プロパノールを、約０℃
の温度でトリフルオロ酢酸、メタンスルホン酸ま
たはｐ−トルエンスルホン酸を含有する不活性溶
剤中で水素化ホウ素ナトリウムによつて還元し、
１−イソプロピルアミノ−３−〔４−（２−メトキ
シエチル）フエノキシ〕−２−プロパノールをう
ることを特徴とするものである。 However, the present invention provides 1-isopropylamino-
3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-2-propanol at about 0°C.
reduction with sodium borohydride in an inert solvent containing trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid at a temperature of
It is characterized by obtaining 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol.
G.W.Gribble、R.M.Leese、Synthesis1977、
172によつて、ケト基（〓Ｃ＝０）およびアルコ
ール基（〓CH−OH）がトリフルオロ酢酸中で
水素化ホウ素ナトリウムによつてメチレン基に還
元されることが知られている。かかる還元はベン
ズヒドロール誘導体を用いたときにのみうまく進
行し、α−メチル−ベンジルアルコールなどを用
いたときはうまく進行しない。先行技術と比較し
て、置換されたα−メトキシメチル−ベンジルア
ルコールである中間体（）が相当する条件下で
高収率で還元されるということは驚くべきことで
ある。メタンスルホン酸およびｐ−トルエンスル
ホン酸は、従来水素化ホウ素ナトリウム還元にお
ける試薬として用いられていなかつたものであ
る。 GWGribble, RM Leese, Synthesis1977,
172, it is known that a keto group (〓C=0) and an alcohol group (〓CH-OH) are reduced to a methylene group by sodium borohydride in trifluoroacetic acid. Such reduction proceeds successfully only when benzhydrol derivatives are used, but not when α-methyl-benzyl alcohol and the like are used. It is surprising that, compared to the prior art, the substituted α-methoxymethyl-benzyl alcohol intermediate () is reduced in high yield under corresponding conditions. Methanesulfonic acid and p-toluenesulfonic acid have not previously been used as reagents in sodium borohydride reduction.
しかして本発明の方法は、フエノキシプロパノ
ールアミン（）の有するフエニル基の４−置換
体中のアルコール基〓CH−OHが強い酸雰囲気
下で水素化ホウ素ナトリウムによつてカルボケー
シヨン（carbocation）（）を経てメチレン基に
還元されることを特徴とするものである。酸試薬
としてはトリフルオロ酢酸、メタンスルホン酸ま
たはｐ−トルエンスルホン酸が用いられる。 Therefore, in the method of the present invention, the alcohol group (CH-OH) in the 4-substituted phenyl group of phenoxypropanolamine () is carbocationed with sodium borohydride in a strong acid atmosphere. )() and is reduced to a methylene group. Trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid is used as the acid reagent.
本発明における反応過程はつぎの反応式で示さ
れる。 The reaction process in the present invention is shown by the following reaction formula.
かくしてえられる最終生成物は、さらに常法に
よつて塩酸塩などの酸付加塩に変化させてもよ
い。 The final product thus obtained may be further converted into an acid addition salt such as a hydrochloride by a conventional method.
本発明の方法はケト化合物（）の水素化ホウ
素ナトリウムによる還元に比してつぎの利点を有
する。 The method of the present invention has the following advantages over the reduction of keto compounds () with sodium borohydride.
収率が著しく高い。 The yield is extremely high.
最終段階における水素化ホウ素ナトリウムお
よび酸の使用量が少ない。 Lower amounts of sodium borohydride and acid are used in the final stage.
叙上の理由によつて経済上の有利さが明らか
に改善される。 The economic advantages are clearly improved for the reasons given above.
出発物質（）は、たとえば４−ヒドロキシ−
ω−メトキシ−アセトフエノンをエタノール溶液
中で少量の水素化ホウ素ナトリウムによつて相当
するアルコール（）に還元するなどして生成さ
れ、該アルコール（）は単離されない。このも
のはナトリウムメトキシドおよびエピクロルヒド
リンと反応せられ、１−クロロ−３−〔４−（１−
ヒドロキシ−２−メトキシエチル）フエノキシ〕
−２−プロパノール（ａ）および１・２−エポ
キシ−３−〔４−（１−ヒドロキシ−２−メトキシ
エチル）フエノキシ〕−プロパン（ｂ）の混合
物が定量的な収率でえられる。この混合物は常法
によつてイソプロピルアミンと反応し、１−イソ
プロピルアミノ−３−〔４−（１−ヒドロキシ−２
−メトキシエチル）−フエノキシ〕−２−プロパノ
ール（）が78％の収率でえられる。この化合物
（）は油状物としてえられ、徐々に結晶化する
（融点65〜67℃）。 The starting material () is, for example, 4-hydroxy-
It is produced, for example, by reducing ω-methoxy-acetophenone to the corresponding alcohol ( ) with a small amount of sodium borohydride in an ethanol solution, which alcohol ( ) is not isolated. This was reacted with sodium methoxide and epichlorohydrin and 1-chloro-3-[4-(1-
Hydroxy-2-methoxyethyl) phenoxy]
A mixture of -2-propanol (a) and 1,2-epoxy-3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-propane (b) is obtained in quantitative yield. This mixture was reacted with isopropylamine in a conventional manner to obtain 1-isopropylamino-3-[4-(1-hydroxy-2-
-methoxyethyl)-phenoxy]-2-propanol () is obtained with a yield of 78%. The compound () is obtained as an oil and gradually crystallizes (melting point 65-67°C).
化合物（）の水素化ホウ素ナトリウムによる
還元は、メチレンクロライドなどの適宜な不活性
溶剤で希釈されたトリフルオロ酢酸中またはメク
ンスルホン酸もしくはｐ−トルエンスルホン酸が
加えられた不活性溶剤中において約０℃の温度で
行なわれる。 Reduction of compound () with sodium borohydride is carried out at about 0° C. in trifluoroacetic acid diluted with a suitable inert solvent such as methylene chloride or in an inert solvent to which mecnesulfonic acid or p-toluenesulfonic acid has been added. It is carried out at a temperature of
つぎに実施例をあげて本発明の方法を説明す
る。 Next, the method of the present invention will be explained with reference to Examples.
実施例 １
１−イソプロピルアミノ−３−〔４−（１−ヒド
ロキシ−２−メトキシエチル）フエノキシ〕−２
−プロパノール（）26.5ｇ、メチレンクロライ
ド100mlおよび水素化ホウ素ナトリウム5.0ｇを反
応フラスコに入れ、約０℃に冷却した。混合物中
にトリフルオロ酢酸50mlを滴下して混合物を０℃
で２時間撹拌し、ついで温度を室温にまで上昇さ
せた。水300mlを加え、PHを水酸化ナトリウムで
10以上に調整した。メチレンクロライド層を分離
し、水で洗浄して蒸発乾固した。残留物をヘプタ
ンから再結晶してメトプロロール塩基23.2ｇ
（95.3％）をえた（融点44〜45℃）。Example 1 1-isopropylamino-3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-2
-26.5 g of propanol (), 100 ml of methylene chloride and 5.0 g of sodium borohydride were placed in a reaction flask and cooled to about 0°C. Add 50ml of trifluoroacetic acid dropwise into the mixture and bring the mixture to 0°C.
Stirred for 2 hours at room temperature and then allowed the temperature to rise to room temperature. Add 300ml of water and check the pH with sodium hydroxide.
Adjusted to 10 or higher. The methylene chloride layer was separated, washed with water and evaporated to dryness. The residue was recrystallized from heptane to give 23.2 g of metoprolol base.
(95.3%) (melting point 44-45°C).
このものを塩酸塩に変化させたとき、82〜83℃
の融点を有する生成物がえられた。 When this substance is converted into hydrochloride, 82-83℃
A product was obtained with a melting point of .
実施例 ２
出発物質（）26.5ｇ、メチレンクロライド
100mlおよび水素化ホウ素ナトリウム6.0ｇを０℃
に冷却した。ついでメタンスルホン酸50.0ｇを少
しずつ加えたほかは実施例１と同様にしてメトプ
ロロール塩基22.1ｇ（90.3％）をえた（融点41〜
42℃）。Example 2 Starting material (26.5 g), methylene chloride
100ml and 6.0g of sodium borohydride at 0℃
It was cooled to Next, 22.1 g (90.3%) of metoprolol base was obtained in the same manner as in Example 1, except that 50.0 g of methanesulfonic acid was added little by little (melting point 41~
42℃).
実施例 ３
出発物質（）26.3ｇ、メチレンクロライド
200ml、水素化ホウ素ナトリウム10.0ｇおよびｐ
−トルエンスルホン酸70.0ｇを実施例１と同様に
して操作し、メトプロロール18.5ｇ（79.5％）を
えた（融点42〜43℃）。Example 3 Starting material (26.3 g), methylene chloride
200ml, sodium borohydride 10.0g and p
- 70.0 g of toluenesulfonic acid was worked up as in Example 1 to obtain 18.5 g (79.5%) of metoprolol (melting point 42-43 DEG C.).
Claims (1)
ドロキシ−２−メトキシエチル）フエノキシ〕−
２−プロパノールを、約０℃の温度でトリフルオ
ロ酢酸、メタンスルホン酸またはｐ−トルエンス
ルホン酸を含有する不活性溶剤中で水素化ホウ素
ナトリウムによつて還元し、１−イソプロピルア
ミノ−３−〔４−（２−メトキシエチル）フエノキ
シ〕−２−プロパノールをうることを特徴とする
式： を有する１−イソプロピルアミノ−３−〔４−（２
−メトキシエチル）フエノキシ〕−２−プロパノ
ールまたはその塩の製法。 ２ 塩が酸付加塩である特許請求の範囲第１項記
載の方法。[Claims] 1 1-isopropylamino-3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-
2-Propanol is reduced by sodium borohydride in an inert solvent containing trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid at a temperature of about 0°C to give 1-isopropylamino-3-[ Formula characterized by obtaining 4-(2-methoxyethyl)phenoxy]-2-propanol: 1-isopropylamino-3-[4-(2
-Methoxyethyl)phenoxy]-2-propanol or a salt thereof. 2. The method according to claim 1, wherein the salt is an acid addition salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12630179A JPS5651438A (en) | 1979-09-29 | 1979-09-29 | Manufacture of 11isopropylaminoo33*44*22 methoxyethyl*phenoxy**22propanol or its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12630179A JPS5651438A (en) | 1979-09-29 | 1979-09-29 | Manufacture of 11isopropylaminoo33*44*22 methoxyethyl*phenoxy**22propanol or its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5651438A JPS5651438A (en) | 1981-05-09 |
| JPS6228777B2 true JPS6228777B2 (en) | 1987-06-23 |
Family
ID=14931807
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12630179A Granted JPS5651438A (en) | 1979-09-29 | 1979-09-29 | Manufacture of 11isopropylaminoo33*44*22 methoxyethyl*phenoxy**22propanol or its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5651438A (en) |
-
1979
- 1979-09-29 JP JP12630179A patent/JPS5651438A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5651438A (en) | 1981-05-09 |
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