JPH029571B2 - - Google Patents
Info
- Publication number
- JPH029571B2 JPH029571B2 JP341882A JP341882A JPH029571B2 JP H029571 B2 JPH029571 B2 JP H029571B2 JP 341882 A JP341882 A JP 341882A JP 341882 A JP341882 A JP 341882A JP H029571 B2 JPH029571 B2 JP H029571B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- dimethylamino
- ethoxy
- reaction
- carvacrol
- 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
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- HHTWOMMSBMNRKP-UHFFFAOYSA-N carvacrol Natural products CC(=C)C1=CC=C(C)C(O)=C1 HHTWOMMSBMNRKP-UHFFFAOYSA-N 0.000 claims description 9
- RECUKUPTGUEGMW-UHFFFAOYSA-N carvacrol Chemical compound CC(C)C1=CC=C(C)C(O)=C1 RECUKUPTGUEGMW-UHFFFAOYSA-N 0.000 claims description 9
- 235000007746 carvacrol Nutrition 0.000 claims description 9
- WYXXLXHHWYNKJF-UHFFFAOYSA-N isocarvacrol Natural products CC(C)C1=CC=C(O)C(C)=C1 WYXXLXHHWYNKJF-UHFFFAOYSA-N 0.000 claims description 9
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910000085 borane Inorganic materials 0.000 claims description 4
- 150000001638 boron Chemical class 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 150000002989 phenols Chemical class 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 [ethoxy]carvacrol Chemical compound 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000005844 Thymol Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960000790 thymol Drugs 0.000 description 2
- QRJHNAFUAUKRTC-UHFFFAOYSA-N 2-(4-bromo-2-methyl-5-propan-2-ylphenoxy)-N,N-dimethylethanamine Chemical compound CC(C)C1=CC(OCCN(C)C)=C(C)C=C1Br QRJHNAFUAUKRTC-UHFFFAOYSA-N 0.000 description 1
- YQVCMSSJMLGWAM-UHFFFAOYSA-N 5-methyl-4-nitroso-2-propan-2-ylphenol Chemical compound CC(C)C1=CC(N=O)=C(C)C=C1O YQVCMSSJMLGWAM-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- VRYMTAVOXVTQEF-UHFFFAOYSA-N acetic acid [4-[2-(dimethylamino)ethoxy]-2-methyl-5-propan-2-ylphenyl] ester Chemical compound CC(C)C1=CC(OC(C)=O)=C(C)C=C1OCCN(C)C VRYMTAVOXVTQEF-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000007822 carvacrol derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- ITLLFVIOXCEGQS-UHFFFAOYSA-L potassium sodium hydroxy-oxido-oxo-sulfanylidene-lambda6-sulfane iodide Chemical compound S(=S)(=O)([O-])O.[Na+].[I-].[K+] ITLLFVIOXCEGQS-UHFFFAOYSA-L 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002214 sympathoinhibitory effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 229960003818 thymoxamine hydrochloride Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は下記式（）
を有する５―〔２―ジメチルアミノ）エトキシ〕
カルバクロールの製法に関する。
本発明は下記式（）
（上式中Ｘは塩素、臭素、またはヨウ素を表わ
す）で示される５―〔２―（ジメチルアミノ）エ
トキシ〕―２―ハロ―ｐ―シメンにマグネシウム
を作用させて、一般式
（式中Ｘは前記と同じ）で示されるグリニヤール
化合物となし、このグリニヤール化合物を、ボラ
ン（水素化ホウ素）と作用させることによつて、
式（）
（上式中ｍは０〜２、ｎは１〜３の整数を表わ
し、ｍ＋ｎ＝３の関数を有する）で示されるホウ
素誘導体に変換し、次いで過酸化水素で酸化する
ことを特徴とする５―〔２―（ジメチルアミノ）
エトキシ〕カルバクロール（式（））の製法に
関する。
５―〔２―（ジメチルアミノ）エトキシ〕カル
バクロール（式（））は交換神経抑制作用を有
し、（Arzneim.―Forsch.，17，305（1967）参
照）、さらに循環器系用医薬品として英国薬局方
（British Pharmacopoeia，p455，1980）にも収
載されている下記式（）
で示される塩酸チモキサミンを合成するための中
間体としても有用な化合物である。
５―〔２―ジメチルアミノ）エトキシ〕カルバ
クロール（式（））を製する方法については、
ドイツ特許第905738号、英国特許第745070号、あ
るいはA.Buza et al.，Bull.Soc.Chim.France，
1959，839にすでに報告されている。しかしこれ
らの各文献に記載されている方法は、いずれもチ
モールから６―ニトロソチモールを経由して、７
工程を要して５―〔２―（ジメチルアミノ）エト
キシ〕カルバクロール（式（））に導びくもの
である。この方法は、合成の工程数が多く、かつ
第７工程で、ジアゾニウム塩の分解によつてフエ
ノール誘導体（式（））に変換する反応で、安
定性に欠ける目的物（式（））の著しい着色
（暗褐色）を伴なうため、高純度の目的物（式
（））を得ることができないので工業的な製法と
しては、有利な方法ではない。
本発明者らはチモールから２工程で得られる５
―〔２―ジメチルアミノ）エトキシ〕―２―ハロ
―ｐ―シメン（式（））を出発原料とし、グリ
ニヤール化合物（式（））を経由する簡便な５
―〔２―（ジメチルアミノ）エトキシ〕カルバク
ロール（式（））の製造方法を見出した。
すなわち、５―〔２―（ジメチルアミノ）エト
キシ〕―２―ハロ―ｐ―シメン（式（））を無
水テトラヒドロフラン中で、当量のマグネシウム
と反応せしめ、対応するグリニヤール化合物（式
（））を製造する。この反応液を、ボランのテト
ラヒドロフラン溶液に低温において添加し、ホウ
素誘導体（式（））を製する。このホウ素誘導
体を含む反応液に、続いて過酸化水素を当量もし
くはわずかに過剰の量で加えることによつて、水
酸化アルカリに可溶の、５―〔２―ジメチルアミ
ノ）エトキシ〕カルバクロール（式（））が高
収率で得られる。
この際、アルカリに不溶の３―〔２―（ジメチ
ルアミノ）エトキシ〕―ｐ―シメン（式（））
を副生する。
上記式の化合物の生成は主として、溶媒、試
薬、反応系の環境などに含まれる水分の影響によ
り、グリニヤール化合物（式（））から生じた
ものである。
一般にグリニヤール化合物とボランの反応を経
由するフエノール誘導体の合成例は少なく（たと
えばS.W.Breuer，F.A.Broster，J.Organometal.
Chem.，35，C5（1972））、オルトー置換以外のフ
エノール類の収率は60〜70％と報告されている。
当該グリニヤール化合物（式（）はオルト―位
にメチル基を、またメタ―位にイソプロピル基を
有し、立体的に比較的障害を受けているにもかか
わらず、フエノール体（式（））の収率が70％
以上という好結果が得られる。
ホウ素誘導体を酸化して対応するアルコールま
たはフエノールに転換する反応で、酸化剤とし
て、アルカリの存在下に過酸化水素を使用するの
が一般的な方法である（H.C.Brown，G.
Zweifel，“Organic Reactions”、Vol.13，p22，
John Wiley ＆ Sons，Inc.，New York
（1963））。当該反応においては、特にアルカリを
添加する必要のないことが明らかになつた。さら
にこの酸化反応に用いる過酸化水素の水溶液の濃
度は、10％程度が好ましい。
一般に第３アミンは過酸化水素と反応してＮ―
オキシドを生成することは、良く知られている事
実である（たとえばJ.Thesing らChem.Ber.，
92，1748（1959）；A.C.Cope，E.R.Trumbull，
“Organic Reactions”，Vol.11，p317，John
Wiley ＆ Sons，New York（1960））。本発明
の過酸化水素による酸化反応において、被反応物
（式（））および目的物（式（））はともに側
鎖に第３アミノ基を有するにもかかわらず、使用
する過酸化水素を10％程度の濃度にした場合に
は、過酸化水素が過剰に反応系に供給されたとし
ても、Ｎ―オキシドをほとんど生成しないという
結果が得られた。
ここに得られた目的物（式（））は無色また
はわずかに黄色を呈し、冷後固化する高純度の物
質である。さらに副生物（式（））は、ハロゲ
ン化することによつて１工程で、本発明の出発原
料（式（））に転換し、再利用することができ
ることも本発明の長所の１つである。
本発明において、ハロゲン誘導体（式（））
からグリニヤール化合物（式（））を経て目的
とするカルバクロール誘導体（式（））にいた
る反応は、反応式からみると３工程であるが、反
応操作上からは、これら３工程は、特に反応物を
とり出すことなく、連続して実施されることか
ら、実質的には１工程の反応とみなすことができ
る。
以上述べたように、本発明の方法によれば、従
来の方法に比し、はるかに短い工程で、かつ簡便
な方法で、高純度の５―〔２―（ジメチルアミ
ノ）エトキシ〕カルバクロール（式（））を高
収率で取得することができる。
以下に本発明の方法を実施例で示す。
実施例
活性化したマグネシウム0.32ｇ（0.013グラム
原子）および乾燥テトラヒドロフラン８ml中に、
窒素雰囲気下で５―〔２―（ジメチルアミノ）エ
トキシ〕―２―ブロム―ｐ―シメン（式（））
3.00ｇ（0.01モル）を乾燥テトラヒドロフラン10
mlにとかした溶液を滴下し、グリニヤール化合物
を製する。この反応液を、氷―食塩系寒剤浴中で
冷却した1M濃度のボラン―テトラヒドロフラン
コンプレツクス溶液10ml（0.01モル）および乾燥
テトラヒドロフラン10mlの混液中に、徐々に滴下
した。滴下終了後、30分間かきまぜをつづけ、こ
の反応液に水５mlを、つづいて10％過酸化水素水
6.8ml（0.02モル）を加えて酸化反応を行なつた。
つづいて過剰の過酸化水素をヨウ化カリウム―チ
オ硫酸ナトリウムを含む水溶液で分解し、3.6％
塩酸５mlを加え、分離した有機層を分取し、水層
をベンゼンで抽出した。両方の有機層を合し、飽
和食塩水で洗浄後、溶媒を留去することによつて
淡黄色の油状物を得た。この油状物を水酸化ナト
リウム1.20ｇ（0.03モル）および水30mlよりなる
水溶液にとかし、少量の不溶物をヘキサンで抽出
した。ヘキサン抽出液を水洗して、硫酸マグネシ
ウムで乾燥した後、濃縮すると、高純度の３―
〔２―（ジメチルアミノ）エトキシ〕―ｐ―シメ
ン（式（））を、淡黄色液体として0.54ｇ（収
率24％）の量で得た。一方、アルカリ性水層に炭
酸ガスを導通すると、淡黄色の固型物が析出し
た。これをベンゼンで抽出し、水洗後、硫酸マグ
ネシウムで乾燥し、濃縮すると、５―〔２―（ジ
メチルアミノ）エトキシ〕カルバクロール（式
（））を、ほとんど純粋な淡黄色固体として1.74
ｇ（収率73％）の量で得た。酢酸エチルから再結
晶して無色のプリズム晶を得た。
融点 91.6 −92.4℃
元素分析値 C14H23NOとして
Ｃ％ Ｈ％ Ｎ％
計算値： 70.85 9.77 5.90
実験値： 70.88 9.82 5.84 [Detailed Description of the Invention] The present invention is based on the following formula () 5-[2-dimethylamino)ethoxy]
Regarding the manufacturing method of carvacrol. The present invention is based on the following formula () (wherein X represents chlorine, bromine, or iodine), 5-[2-(dimethylamino)ethoxy]-2-halo-p-cymene is reacted with magnesium, and the general formula By making a Grignard compound represented by the formula (wherein X is the same as above) and reacting this Grignard compound with borane (borohydride),
formula() (In the above formula, m represents an integer of 0 to 2, n represents an integer of 1 to 3, and has a function of m + n = 3), and then oxidized with hydrogen peroxide. -[2-(dimethylamino)
This invention relates to a method for producing [ethoxy]carvacrol (formula ()). 5-[2-(dimethylamino)ethoxy]carvacrol (formula ()) has sympathoinhibitory effects (see Arzneim.-Forsch., 17 , 305 (1967)), and is also used as a drug for the cardiovascular system. The following formula () is also listed in the British Pharmacopoeia (British Pharmacopoeia, p455, 1980). It is also a useful compound as an intermediate for synthesizing thymoxamine hydrochloride shown by Regarding the method for producing 5-[2-dimethylamino)ethoxy]carvacrol (formula ()),
German Patent No. 905738, British Patent No. 745070 or A.Buza et al., Bull.Soc.Chim.France,
Already reported in 1959, 839. However, the methods described in these documents all convert thymol into 7-nitrosothymol via 6-nitrosothymol.
This process leads to 5-[2-(dimethylamino)ethoxy]carvacrol (formula ()). This method involves a large number of synthesis steps, and in the seventh step, the diazonium salt is decomposed to convert it into a phenol derivative (formula ()), resulting in a significant amount of the target product (formula ()) lacking stability. Since it is accompanied by coloration (dark brown), it is not possible to obtain the target product (formula ()) with high purity, so it is not an advantageous method as an industrial production method. We obtained 5 from thymol in two steps.
-[2-dimethylamino)ethoxy]-2-halo-p-cymene (formula ()) is used as a starting material and a simple 5-method via Grignard compound (formula ())
We have discovered a method for producing -[2-(dimethylamino)ethoxy]carvacrol (formula ()). That is, 5-[2-(dimethylamino)ethoxy]-2-halo-p-cymene (formula ()) is reacted with an equivalent amount of magnesium in anhydrous tetrahydrofuran to produce the corresponding Grignard compound (formula ()). do. This reaction solution is added to a solution of borane in tetrahydrofuran at a low temperature to produce a boron derivative (formula ()). By subsequently adding hydrogen peroxide in an equivalent or slightly excess amount to the reaction solution containing this boron derivative, 5-[2-dimethylamino)ethoxy]carvacrol ( Formula ()) is obtained in high yield. At this time, 3-[2-(dimethylamino)ethoxy]-p-cymene (formula ()) insoluble in alkali
as a by-product. The compound of the above formula is produced mainly from the Grignard compound (formula ()) under the influence of water contained in the solvent, reagent, environment of the reaction system, etc. Generally, there are few examples of synthesis of phenol derivatives via the reaction of Grignard compounds and borane (for example, SWBreuer, FABroster, J.Organometal.
Chem., 35 , C5 (1972)), the yield of phenols other than ortho-substituted phenols is reported to be 60-70%.
The Grignard compound (formula ()) has a methyl group at the ortho-position and an isopropyl group at the meta-position, and although it is relatively sterically hindered, the phenolic compound (formula ()) Yield is 70%
The above results are good. A common method for oxidizing boron derivatives to convert them to the corresponding alcohols or phenols is to use hydrogen peroxide in the presence of an alkali as the oxidizing agent (HCBrown, G.
Zweifel, “Organic Reactions”, Vol.13, p22,
John Wiley & Sons, Inc., New York
(1963)). It has become clear that there is no particular need to add an alkali in this reaction. Further, the concentration of the aqueous hydrogen peroxide solution used in this oxidation reaction is preferably about 10%. Generally, tertiary amines react with hydrogen peroxide to form N-
It is a well-known fact that oxides are formed (e.g. J. Thesing et al. Chem. Ber.,
92, 1748 (1959); ACCope, ERTrumbull,
“Organic Reactions”, Vol.11, p317, John
Wiley & Sons, New York (1960)). In the oxidation reaction using hydrogen peroxide of the present invention, although both the reactant (formula ()) and the target object (formula ()) have a tertiary amino group in their side chains, the hydrogen peroxide used is %, even if hydrogen peroxide was supplied in excess to the reaction system, almost no N-oxide was produced. The target product (formula ()) obtained here is a highly pure substance that is colorless or slightly yellow and solidifies after cooling. Furthermore, one of the advantages of the present invention is that the by-product (formula ()) can be converted into the starting material (formula ()) of the present invention in one step by halogenation and reused. be. In the present invention, a halogen derivative (formula ())
From the reaction formula, the reaction leading to the desired carvacrol derivative (formula ()) via the Grignard compound (formula ()) is 3 steps, but from the viewpoint of reaction operation, these 3 steps are particularly important for the reaction. Since the reaction is carried out continuously without taking out the product, it can be substantially regarded as a one-step reaction. As described above, according to the method of the present invention, highly purified 5-[2-(dimethylamino)ethoxy]carvacrol ( Formula ()) can be obtained in high yield. Examples of the method of the present invention are shown below. EXAMPLE In 0.32 g (0.013 gram atom) of activated magnesium and 8 ml of dry tetrahydrofuran,
5-[2-(dimethylamino)ethoxy]-2-bromo-p-cymene (formula ()) under nitrogen atmosphere
3.00g (0.01mol) of dry tetrahydrofuran 10
A Grignard compound is prepared by dropping the solution dissolved in ml. This reaction solution was gradually added dropwise to a mixture of 10 ml (0.01 mol) of a 1M borane-tetrahydrofuran complex solution and 10 ml of dry tetrahydrofuran cooled in an ice-salt cryogen bath. After dropping, continue stirring for 30 minutes, add 5 ml of water to the reaction solution, and then add 10% hydrogen peroxide solution.
An oxidation reaction was carried out by adding 6.8 ml (0.02 mol).
Next, excess hydrogen peroxide was decomposed with an aqueous solution containing potassium iodide-sodium thiosulfate.
5 ml of hydrochloric acid was added, the separated organic layer was separated, and the aqueous layer was extracted with benzene. Both organic layers were combined, washed with saturated brine, and the solvent was distilled off to obtain a pale yellow oil. This oil was dissolved in an aqueous solution consisting of 1.20 g (0.03 mol) of sodium hydroxide and 30 ml of water, and a small amount of insoluble matter was extracted with hexane. The hexane extract is washed with water, dried over magnesium sulfate, and then concentrated to obtain highly pure 3-
[2-(dimethylamino)ethoxy]-p-cymene (formula ()) was obtained as a pale yellow liquid in an amount of 0.54 g (yield 24%). On the other hand, when carbon dioxide gas was passed through the alkaline aqueous layer, a pale yellow solid substance was precipitated. This was extracted with benzene, washed with water, dried over magnesium sulfate, and concentrated to yield 5-[2-(dimethylamino)ethoxy]carvacrol (formula ()) as an almost pure pale yellow solid at 1.74%
g (yield 73%). Recrystallization from ethyl acetate gave colorless prismatic crystals. Melting point 91.6 -92.4℃ Elemental analysis value C 14 H 23 As NO C% H% N% Calculated value: 70.85 9.77 5.90 Experimental value: 70.88 9.82 5.84
Claims (1)
す）で示される５―〔２―（ジメチルアミノ）エ
トキシ〕―２―ハロ―ｐ―シメンをマグネシウム
と反応せしめ、一般式（） （上式中Ｘは前記と同じ）で示されるグリニヤー
ル化合物に導き、このグリニヤール化合物とボラ
ンを作用させて、一般式（） （上式中ｍは０〜２、ｎは１〜３の整数をあらわ
し、ｍ＋ｎ＝３の関数を有する）で示されるホウ
素誘導体となし、このホウ素誘導体を過酸化水素
で酸化することを特徴とする式（） で示される５―〔２―（ジメチルアミノ）エトキ
シ〕カルバクロールの製法。[Claims] 1 General formula () (In the above formula, X represents chlorine, bromine, or iodine) 5-[2-(dimethylamino)ethoxy]-2-halo-p-cymene is reacted with magnesium, and the general formula () (In the above formula, X is the same as above), and by reacting this Grignard compound with borane, the general formula () (In the above formula, m represents an integer of 0 to 2, n represents an integer of 1 to 3, and has a function of m + n = 3), and this boron derivative is oxidized with hydrogen peroxide. expression () A method for producing 5-[2-(dimethylamino)ethoxy]carvacrol shown by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP341882A JPS58121250A (en) | 1982-01-14 | 1982-01-14 | Preparation of 5-(2-(dimethylamino)ethoxy)carvacrol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP341882A JPS58121250A (en) | 1982-01-14 | 1982-01-14 | Preparation of 5-(2-(dimethylamino)ethoxy)carvacrol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58121250A JPS58121250A (en) | 1983-07-19 |
| JPH029571B2 true JPH029571B2 (en) | 1990-03-02 |
Family
ID=11556829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP341882A Granted JPS58121250A (en) | 1982-01-14 | 1982-01-14 | Preparation of 5-(2-(dimethylamino)ethoxy)carvacrol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58121250A (en) |
-
1982
- 1982-01-14 JP JP341882A patent/JPS58121250A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58121250A (en) | 1983-07-19 |
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