JPH0527617B2 - - Google Patents
Info
- Publication number
- JPH0527617B2 JPH0527617B2 JP5263984A JP5263984A JPH0527617B2 JP H0527617 B2 JPH0527617 B2 JP H0527617B2 JP 5263984 A JP5263984 A JP 5263984A JP 5263984 A JP5263984 A JP 5263984A JP H0527617 B2 JPH0527617 B2 JP H0527617B2
- Authority
- JP
- Japan
- Prior art keywords
- dipivaloyloxyphenyl
- propanone
- methylamino
- reaction
- 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 - Lifetime
Links
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 10
- HNWIHBDMOYWCGX-UHFFFAOYSA-N 1-(3,4-dihydroxyphenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(O)C(O)=C1 HNWIHBDMOYWCGX-UHFFFAOYSA-N 0.000 claims description 8
- GEEFADHMLIWOIR-UHFFFAOYSA-N [2-(2,2-dimethylpropanoyloxy)-4-[2-(2-phenylethylamino)propanoyl]phenyl] 2,2-dimethylpropanoate Chemical compound C=1C=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=CC=1C(=O)C(C)NCCC1=CC=CC=C1 GEEFADHMLIWOIR-UHFFFAOYSA-N 0.000 claims description 5
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 5
- VZALFOUHLFJALS-UHFFFAOYSA-N [2-(2,2-dimethylpropanoyloxy)-4-propanoylphenyl] 2,2-dimethylpropanoate Chemical compound CCC(=O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 VZALFOUHLFJALS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 5
- -1 pivalic acid halide Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- XUUUALINSBFRTN-UHFFFAOYSA-N [2-(2,2-dimethylpropanoyloxy)-4-[1-hydroxy-2-(methylamino)propyl]phenyl] 2,2-dimethylpropanoate Chemical compound CNC(C)C(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 XUUUALINSBFRTN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- ZHYJAYBTJJKTDI-UHFFFAOYSA-N [4-(2-bromopropanoyl)-2-(2,2-dimethylpropanoyloxy)phenyl] 2,2-dimethylpropanoate Chemical compound CC(Br)C(=O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 ZHYJAYBTJJKTDI-UHFFFAOYSA-N 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- NIRQIFAAAYJDGZ-UHFFFAOYSA-N 1-(3,4-dihydroxyphenyl)-2-(methylamino)propan-1-one Chemical compound CNC(C)C(=O)C1=CC=C(O)C(O)=C1 NIRQIFAAAYJDGZ-UHFFFAOYSA-N 0.000 description 1
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- PXWASTUQOKUFKY-UHFFFAOYSA-N 2-(methylamino)propan-1-ol Chemical class CNC(C)CO PXWASTUQOKUFKY-UHFFFAOYSA-N 0.000 description 1
- ZDLYDAGNAVKVBZ-UHFFFAOYSA-N 2-(methylamino)propan-1-ol;hydrochloride Chemical compound Cl.CNC(C)CO ZDLYDAGNAVKVBZ-UHFFFAOYSA-N 0.000 description 1
- BJRXZMCJFCAZDL-UHFFFAOYSA-N 2-bromopropanal Chemical compound CC(Br)C=O BJRXZMCJFCAZDL-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- BALXUFOVQVENIU-UHFFFAOYSA-N hydron;2-(methylamino)-1-phenylpropan-1-ol;chloride Chemical compound Cl.CNC(C)C(O)C1=CC=CC=C1 BALXUFOVQVENIU-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
Description
【発明の詳細な説明】
本発明は１−（３，４−ジピバロイルオキシフ
エニル）−２−メチルアミノ−１−プロパノール
の製造に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the production of 1-(3,4-dipivaloyloxyphenyl)-2-methylamino-1-propanol.
１−（３，４−ジピバロイルオキシフエニル）−
２−メチルアミノ−１−プロパノール〔Ｄ〕は眼
内圧低下剤として有用な化合物で、その製造法と
しては１−（３，４−ジヒドロキシフエニル）−２
−ブルモ−１−プロパノン〔Ａ〕にメチルアミン
を作用させて１−（３，４−ジヒドロキシフエニ
ル）−２−メチルアミノ−１−プロパノン〔Ｂ〕
とし、次いでピバロイルクロリドを作用させる
か、前記化合物〔Ａ〕にピバロイルクロリドを作
用させて１−（３，４−ジピバロイルオキシフエ
ニル）−２−ブロモ−１−プロパノン〔Ｃ〕とし、
次いでメチルアミンを作用させる方法が提案され
ている（特許出願公表昭58−50044号）。 1-(3,4-dipivaloyloxyphenyl)-
2-Methylamino-1-propanol [D] is a compound useful as an intraocular pressure-lowering agent, and its production method involves 1-(3,4-dihydroxyphenyl)-2
-Brumo-1-propanone [A] is reacted with methylamine to produce 1-(3,4-dihydroxyphenyl)-2-methylamino-1-propanone [B]
and then reacting with pivaloyl chloride or reacting the compound [A] with pivaloyl chloride to obtain 1-(3,4-dipivaloyloxyphenyl)-2-bromo-1-propanone [ C] and
Next, a method of using methylamine has been proposed (Patent Application Publication No. 58-50044).
しかしながら、これらの方法によれば目的物の
収率が悪く、満足できる結果を与えない。その原
因は明らかではないが、おそらく副反応の生起や
立体障碍などによると思われる。 However, these methods have poor yields of the target product and do not give satisfactory results. Although the cause is not clear, it is probably due to the occurrence of side reactions or steric hindrance.
本発明者らは化合物〔Ｄ〕を工業的規模で収率
良く生産しうる方法を探究した結果、本発明の方
法を確立するに至つた。 The present inventors investigated a method capable of producing compound [D] on an industrial scale with good yield, and as a result, established the method of the present invention.
本発明は、１−（３，４−ジヒドロキシフエニ
ル）−１−プロパノン〔〕をピバリン酸でアシ
ル化して１−（３，４−ジピバロイルオキシフエ
ニル）−１−プロパノン〔〕を生成させ、続い
てこれにハロゲンを作用させて１−（３，４−ジ
ピバロイルオキシフエニル）−２−ハロ−プロパ
ノン〔Ｃ〕を生成させ、これにＮ−ベンジルメチ
ルアミンを作用させて１−（３，４−ジピバロイ
ルオキシフエニル）−２−ベンジルメチルアミノ
−１−プロパノン〔〕を得、次いでこれを接触
還元して１−（３，４−ジピバロイルオキシフエ
ニル）−２−メチルアミノ−１−プロパノール
〔Ｄ〕を得ることを特徴とする２−メチルアミノ
−１−プロパノール誘導体の製造法。 The present invention produces 1-(3,4-dipivaloyloxyphenyl)-1-propanone[] by acylating 1-(3,4-dihydroxyphenyl)-1-propanone[] with pivalic acid. This is then treated with halogen to produce 1-(3,4-dipivaloyloxyphenyl)-2-halo-propanone [C], which is then treated with N-benzylmethylamine. to obtain 1-(3,4-dipivaloyloxyphenyl)-2-benzylmethylamino-1-propanone [ ], which was then catalytically reduced to 1-(3,4-dipivaloyloxyphenyl)-2-benzylmethylamino-1-propanone [ ]. 1. A method for producing a 2-methylamino-1-propanol derivative, which comprises obtaining phenyl)-2-methylamino-1-propanol [D].
本発明の製造法における反応は次式で示されう
る。 The reaction in the production method of the present invention can be represented by the following formula.
（式中、Pivは（CH3）3CO基、Ｘはハロゲンを表
わす）
ピバリン酸はカルボキシル基における反応性誘
導体、たとえば、ピバリン酸クロリドのようなピ
バリン酸ハライド、ピバリン酸無水物などの形で
反応に用いられるが、所望によりピバリン酸を脱
水条件下に用いてもよい。酸ハライドの形で用い
る場合は脱酸剤、たとえばピリジン、ジメチルア
ミノピリジンなどの存在下に反応を行うのがよ
く、これらは溶媒と兼用してもよい。 (In the formula, Piv represents a (CH 3 ) 3 CO group, and X represents a halogen.) Pivalic acid is a reactive derivative at the carboxyl group, for example, in the form of pivalic acid halide such as pivalic acid chloride, pivalic acid anhydride, etc. Although used in the reaction, pivalic acid may be used under dehydrated conditions if desired. When used in the form of an acid halide, the reaction is preferably carried out in the presence of a deoxidizing agent such as pyridine or dimethylaminopyridine, which may also be used as a solvent.
１−（３，４−ジヒドロキシフエニル）−１−プ
ロパノン〔〕をピバリン酸でアシル化すること
により、１−（３，４−ジピバロイルオキシフエ
ニル）−１−プロパノン〔〕が生成する。化合
物〔〕は水に難溶、有機溶媒に可溶なので、反
応混合物から中性有機溶媒、たとえば酢酸エチル
のような酢酸エステルで抽出して、油状の粗製物
として得ることができ、これを精製することなく
次の工程の反応原料とすることができる。 By acylating 1-(3,4-dihydroxyphenyl)-1-propanone[] with pivalic acid, 1-(3,4-dipivaloyloxyphenyl)-1-propanone[] is produced. do. Since the compound [] is sparingly soluble in water and soluble in organic solvents, it can be extracted from the reaction mixture with a neutral organic solvent, such as an acetate ester such as ethyl acetate, to obtain an oily crude product, which is purified. It can be used as a reaction raw material for the next step without further treatment.
次いで化合物〔〕をハロゲン化してプロピオ
ニル基の２位のメチレン基に１個のクロルやブロ
ムのようなハロゲン原子を導入する。 Next, the compound [] is halogenated to introduce one halogen atom such as chloro or brome into the methylene group at the 2-position of the propionyl group.
ハロゲン化は非反応性有機溶媒、たとえばクロ
ロホルム中で化合物〔〕に塩素や臭素を作用さ
せることにより行われる。反応により１−（３，
４−ジピバロイルオキシフエニル）−２−ハロ−
１−プロパノン〔Ｃ〕が生成する。反応混合物を
水洗し、溶媒を留去すれば油状の粗製物として化
合物〔Ｃ〕が得られ、これを精製することなく次
の工程の反応に用いることができる。 Halogenation is carried out by reacting the compound with chlorine or bromine in a non-reactive organic solvent such as chloroform. The reaction causes 1-(3,
4-dipivaloyloxyphenyl)-2-halo-
1-propanone [C] is produced. The reaction mixture is washed with water and the solvent is distilled off to obtain compound [C] as an oily crude product, which can be used in the next reaction without purification.
かくして生成した化合物〔Ｃ〕にＮ−ベンジル
メチルアミンを作用させる。反応はベンゼンのよ
うな非反応性有機溶媒中、脱酸剤の存在下に有利
に進行する。脱酸剤としてはピリジンなども用い
うるが、Ｎ−ベンジルメチルアミンを過剰に用い
て過剰分を脱酸剤としてもよい。反応が進むと脱
酸剤はハロゲン化水素の塩となり析出する。 The thus produced compound [C] is treated with N-benzylmethylamine. The reaction advantageously proceeds in a non-reactive organic solvent such as benzene and in the presence of a deoxidizing agent. Pyridine or the like may be used as the deoxidizing agent, but N-benzylmethylamine may be used in excess and the excess amount may be used as the deoxidizing agent. As the reaction progresses, the deoxidizing agent turns into a hydrogen halide salt and precipitates.
この反応によつて得られる１−（３，４−ジピ
バロイルオキシフエニル）−２−ベンジルメチル
アミノ−１−プロパノン〔〕は遊離塩基の形で
固体であるが、これに塩酸のような酸を作用させ
て酸塩の結晶を得ることもできる。 1-(3,4-dipivaloyloxyphenyl)-2-benzylmethylamino-1-propanone [] obtained by this reaction is a solid in the form of a free base. It is also possible to obtain acid salt crystals by reacting with an acid.
次いで、化合物〔〕を還元してベンジル基を
離脱させると共にカルボニル基を第２級アルコー
ルに変換する。 Next, the compound [] is reduced to remove the benzyl group and convert the carbonyl group to a secondary alcohol.
還元は接触還元の形式で容易に行われる。触媒
としては酸化白金、パラジウムなどが好んで用い
られる。 Reduction is easily carried out in the form of catalytic reduction. As the catalyst, platinum oxide, palladium, etc. are preferably used.
還元により、１−（３，４−ジピバロイルオキ
シフエニル）−２−メチルアミノ−１−プロパノ
ール〔Ｄ〕が得られる。 The reduction yields 1-(3,4-dipivaloyloxyphenyl)-2-methylamino-1-propanol [D].
化合物〔〕を、たとえば塩酸塩の形で還元し
て化合物〔Ｄ〕の塩酸塩を得ることもできる。 The hydrochloride of compound [D] can also be obtained by reducing the compound [] in the form of a hydrochloride, for example.
以上の各工程の収率は約70−90％に達しきわめ
て良好であり、反応剤も入手し易く、また操作も
容易である。したがつて、本発明は１−（３，４
−ジピバロイルオキシフエニル）−２−メチルア
ミノ−１−プロパノールを工業的に製造する場合
にきわめて適している。 The yield of each of the above steps is extremely good, reaching about 70-90%, and the reactants are easily available and the operations are easy. Therefore, the present invention provides 1-(3,4
-dipivaloyloxyphenyl)-2-methylamino-1-propanol is extremely suitable for industrial production.
実施例 １
１−（３，４−ジピバロイルオキシフエニル）−
１−プロパノンの製造
１−（３，４−ジヒドロキシフエニル）−１−プ
ロパノン10ｇをピリジン50mlに溶解し、氷冷撹拌
下にピバロイルクロリド15.24ｇを加え、室温で
約１時間撹拌した。その反応液に氷水および塩酸
を加えて酸性としたのち、酢酸エチルで抽出す
る。有機層（酢酸エチル抽出液）を５％炭酸ナト
リウム水溶液で洗浄し、無水硫酸ナトリウムで乾
燥後減圧下で溶媒を留去して微黄色油状の１−
（３，４−ジピバロイルオキシフエニル）−１−プ
ロパノン19.0ｇを得た。本品は精製することなく
次の反応に用いた。Example 1 1-(3,4-dipivaloyloxyphenyl)-
Production of 1-propanone 10 g of 1-(3,4-dihydroxyphenyl)-1-propanone was dissolved in 50 ml of pyridine, 15.24 g of pivaloyl chloride was added while stirring under ice cooling, and the mixture was stirred at room temperature for about 1 hour. The reaction solution was made acidic by adding ice water and hydrochloric acid, and then extracted with ethyl acetate. The organic layer (ethyl acetate extract) was washed with a 5% aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a slightly yellow oily 1-
19.0 g of (3,4-dipivaloyloxyphenyl)-1-propanone was obtained. This product was used in the next reaction without purification.
実施例 ２
１−（３，４−ジピバロイルオキシフエニル）−
２−ブロモ−プロパノンの製造
１−（３，４−ジピバロイルオキシフエニル）−
１−プロパノン19.0ｇをクロロフオルム150mlに
溶解する。この溶液を50℃に加温、撹拌しつゝ、
これに臭素9.5ｇをクロロフオルム50mlに溶解し
た液を少しずつ滴下した。滴下終了後、臭素色が
消失したら直ちに冷却し、５％炭酸ナトリウム水
溶液および水で洗浄後、塩化カルシウムで乾燥
し、減圧下で溶媒を留去して、微黄色油状の１−
（３，４−ジピバロイルオキシフエニル）−２−ブ
ロモ−１−プロパノン21.6ｇを得た。Example 2 1-(3,4-dipivaloyloxyphenyl)-
Production of 2-bromo-propanone 1-(3,4-dipivaloyloxyphenyl)-
Dissolve 19.0 g of 1-propanone in 150 ml of chloroform. While heating this solution to 50℃ and stirring,
A solution prepared by dissolving 9.5 g of bromine in 50 ml of chloroform was added dropwise little by little to this. After the dropwise addition, when the bromine color disappears, it is immediately cooled, washed with a 5% aqueous sodium carbonate solution and water, dried over calcium chloride, and the solvent is distilled off under reduced pressure to obtain a slightly yellow oily 1-
21.6 g of (3,4-dipivaloyloxyphenyl)-2-bromo-1-propanone was obtained.
本品は精製することなく次の反応に用いた。 This product was used in the next reaction without purification.
実施例 ３
１−（３，４−ジピバロイルオキシフエニル）−
２−ベンジルメチルアミノ−１−プロパノンの
製造
１−（３，４−ジピバロイルオキシフエニル）−
２−ブロモ−１−プロパノン8.5ｇをベンゼン50
mlに溶解する。この液を、Ｎ−ベンジルメチルア
ミン5.0ｇをベンゼン100mlに溶解した液に、室温
で撹拌下に滴下した。滴下終了後、室温で約２時
間撹拌し、さらに室温で一夜放置するとＮ−ベン
ジルメチルアミンの臭化水素塩が析出した。この
結晶を濾別し、濾液を減圧下に留去して黄色固体
の１−（３，４−ジピバロイルオキシフエニル）−
２−ベンジルメチルアミノ−１−プロパノン7.6
ｇを得た。これをエーテルに溶解し、塩酸ガスを
通じて白色粉末の１−（３，４−ジピバロイルオ
キシフエニル）−２−ベンジルメチルアミノ−１
−プロパノン塩酸塩7.2ｇを得た。この塩酸塩の
一部をアセトン−ｎ−ヘキサンより再結晶して無
色プリズム晶（m.p.195°−197℃）を得た。Example 3 1-(3,4-dipivaloyloxyphenyl)-
Production of 2-benzylmethylamino-1-propanone 1-(3,4-dipivaloyloxyphenyl)-
8.5 g of 2-bromo-1-propanone and 50 g of benzene
Dissolve in ml. This solution was added dropwise to a solution of 5.0 g of N-benzylmethylamine dissolved in 100 ml of benzene at room temperature while stirring. After completion of the dropwise addition, the mixture was stirred at room temperature for about 2 hours, and then left at room temperature overnight to precipitate the hydrobromide salt of N-benzylmethylamine. The crystals were separated by filtration, and the filtrate was distilled off under reduced pressure to form a yellow solid, 1-(3,4-dipivaloyloxyphenyl)-
2-benzylmethylamino-1-propanone 7.6
I got g. This was dissolved in ether and passed through hydrochloric acid gas to form a white powder of 1-(3,4-dipivaloyloxyphenyl)-2-benzylmethylamino-1.
- 7.2 g of propanone hydrochloride were obtained. A part of this hydrochloride was recrystallized from acetone-n-hexane to obtain colorless prism crystals (mp 195°-197°C).
元素分析：C27H35NO5・HCl
計算値 Ｃ、66.12；Ｈ、7.35；Ｎ、2.82
実験値 Ｃ、66.16；Ｈ、7.39；Ｎ、2.88
IRνKBr naxcm-1 1765（CO）
実施例 ４
１−（３，４−ジピバロイルオキシフエニル）−
２−メチルアミノ−１−プロパノール塩酸塩の
製造
１−（３，４−ジピバロイルオキシフエニル）−
２−ベンジルメチルアミノ−１−プロパノン塩酸
塩6.0ｇをエタノール100mlに溶解し、酸化白金
0.2ｇを加え、室温で水素気流中接触還元を行う。
約５時間で計算量の水素を吸収する。酸化白金を
濾別したのち、減圧下で溶媒を留去し、少量のエ
ーテルを加えて溶解し、ｎ−ヘキサンを加えて結
晶化し、白色粉末の１−（３，４−ジピバロイル
オキシフエニル）−２−メチルアミノ−１−プロ
パノール塩酸塩4.4ｇを得た。この塩酸塩の一部
をアセトン−ｎ−ヘキサンより再結晶して無色プ
リズム晶（m.p.191°−193℃）を得た。Elemental analysis: C 27 H 35 NO 5・HCl Calculated value C, 66.12; H, 7.35; N, 2.82 Experimental value C, 66.16; H, 7.39; N, 2.88 IRν KBr nax cm -1 1765 (CO) Example 4 1-(3,4-dipivaloyloxyphenyl)-
Production of 2-methylamino-1-propanol hydrochloride 1-(3,4-dipivaloyloxyphenyl)-
Dissolve 6.0 g of 2-benzylmethylamino-1-propanone hydrochloride in 100 ml of ethanol, and dissolve platinum oxide.
Add 0.2 g and perform catalytic reduction in a hydrogen stream at room temperature.
The calculated amount of hydrogen is absorbed in about 5 hours. After filtering off the platinum oxide, the solvent was distilled off under reduced pressure, a small amount of ether was added to dissolve it, and n-hexane was added to crystallize it to give 1-(3,4-dipivaloyloxy) as a white powder. 4.4 g of (phenyl)-2-methylamino-1-propanol hydrochloride was obtained. A part of this hydrochloride was recrystallized from acetone-n-hexane to obtain colorless prism crystals (mp 191°-193°C).
元素分析：C20H35NO5・HCl 計算値 Ｃ、59.8；Ｈ、7.96；Ｎ、3.48 実験値 Ｃ、59.80；Ｈ、8.06；Ｎ、3.48 IRνKBr naxcm-1 1768（CO）Elemental analysis: C 20 H 35 NO 5・HCl Calculated value C, 59.8; H, 7.96; N, 3.48 Experimental value C, 59.80; H, 8.06; N, 3.48 IRν KBr nax cm -1 1768 (CO)
Claims (1)
プロパノンをピバリン酸でアシル化して１−（３，
４−ジピバロイルオキシフエニル）−１−プロパ
ノンを生成させ、続いてこれにハロゲンを作用さ
せて１−（３，４−ジピバロイルオキシフエニル）
−２−ハロープロパノンを生成せ、これにＮ−ベ
ンジルメチルアミンを作用させて１−（３，４−
ジピバロイルオキシフエニル）−２−ベンジルメ
チルアミノ−１−プロパノンを得、次いでこれを
接触還元して１−（３，４−ジピバロイルオキシ
フエニル）−２−メチルアミノ−１−プロパノー
ルを得ることを特徴とする２−メチルアミノ−１
−プロパノール誘導体の製造法。 ２ 中間に生成する１−（３，４−ジピバロイル
オキシフエニル）−１−プロパノンおよび１−
（３，４−ジピバロイルオキシフエニル）−２−ブ
ロモープロパノンを精製することなく次工程の反
応に用いる特許請求の範囲第１項記載の製造法。[Claims] 1 1-(3,4-dihydroxyphenyl)-1-
Propanone is acylated with pivalic acid to produce 1-(3,
4-dipivaloyloxyphenyl)-1-propanone is produced, and then a halogen is reacted on this to produce 1-(3,4-dipivaloyloxyphenyl).
1-(3,4-
dipivaloyloxyphenyl)-2-benzylmethylamino-1-propanone, which was then catalytically reduced to 1-(3,4-dipivaloyloxyphenyl)-2-methylamino-1 - 2-methylamino-1, characterized in that it yields propanol
- A method for producing a propanol derivative. 2 1-(3,4-dipivaloyloxyphenyl)-1-propanone and 1-
The manufacturing method according to claim 1, wherein (3,4-dipivaloyloxyphenyl)-2-bromopropanone is used in the next step reaction without being purified.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5263984A JPS60197644A (en) | 1984-03-19 | 1984-03-19 | Preparation of 2-methylamino-1-propanol derivative and its intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5263984A JPS60197644A (en) | 1984-03-19 | 1984-03-19 | Preparation of 2-methylamino-1-propanol derivative and its intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60197644A JPS60197644A (en) | 1985-10-07 |
| JPH0527617B2 true JPH0527617B2 (en) | 1993-04-21 |
Family
ID=12920400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5263984A Granted JPS60197644A (en) | 1984-03-19 | 1984-03-19 | Preparation of 2-methylamino-1-propanol derivative and its intermediate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60197644A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07306061A (en) * | 1994-05-13 | 1995-11-21 | West Japan Railway Co | Data recorder and synchronous recording system |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153485B (en) * | 2011-02-21 | 2013-06-19 | 天津科洛医药科技有限公司 | Method for preparing dipivefrine |
-
1984
- 1984-03-19 JP JP5263984A patent/JPS60197644A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07306061A (en) * | 1994-05-13 | 1995-11-21 | West Japan Railway Co | Data recorder and synchronous recording system |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60197644A (en) | 1985-10-07 |
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