JPH0254329B2 - - Google Patents
Info
- Publication number
- JPH0254329B2 JPH0254329B2 JP50782A JP50782A JPH0254329B2 JP H0254329 B2 JPH0254329 B2 JP H0254329B2 JP 50782 A JP50782 A JP 50782A JP 50782 A JP50782 A JP 50782A JP H0254329 B2 JPH0254329 B2 JP H0254329B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- represented
- carboxylic acid
- general formula
- grignard reagent
- 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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- 150000001735 carboxylic acids Chemical class 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000007818 Grignard reagent Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- 150000007934 α,β-unsaturated carboxylic acids Chemical class 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229960002179 ephedrine Drugs 0.000 claims description 4
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 3
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DVESMWJFKVAFSP-ZETCQYMHSA-N (3s)-3-methylheptanoic acid Chemical compound CCCC[C@H](C)CC(O)=O DVESMWJFKVAFSP-ZETCQYMHSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- -1 Ph-gBr Chemical compound 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 1
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([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
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明はカルボン酸類の製造法に関し、さらに
詳しくは光学活性カルボン酸類の製造法に関す
る。
従来、光学活性カルボン酸類の製造に関して
は、種々の方法が提案されているが、使用原料等
に難点を有するものが多く、必ずしも満足できる
方法とはいえなかつた。
本発明者らは、これらの難点を克服して、効率
的な方法を見出すべく種々検討した結果、本発明
に到達した。
すなわち、本発明の要旨は、一般式（）
（式中、Ｒは置換されていてもよいアリール基
又はアルキル基、Ａはエフエドリンの残基をあら
わす）
で示されるα，β−不飽和カルボン酸アミドを、
一般式（）
R′MgX （）
（式中、R′は、アリール基又はアルキル基、
Ｘはハロゲン原子をあらわす）
で示されるグリニヤール試薬と反応させて、つい
で得られた反応生成物を加水分解して、一般式
（）又は（′）
（式中、Ｒ，R′は前記と同義）
で示される光学活性β−置換カルボン酸を得るこ
とを特徴とするカルボン酸類の製造法、に存す
る。
以下、本発明を詳細に説明する。まず、本発明
において使用されるα，β−不飽和カルボン酸ア
ミドは一般式（）
で示されるものである。ここで式中、Ｒは置換さ
れていてもよいアリール基又はアルキル基をあら
わす。アリール基としてはフエニル、トリル、キ
シリル、ナフチル基等、アルキル基としては、メ
チル、エチル、ｎ−ブチル、ｎ−ヘキシル、ｎ−
オクチル等、任意の炭素数のものが挙げられる。
Ａはエフエドリンの残基をあらわす。すなわち、
一般式（）で示されるα，β−不飽和カルボン
酸アミドは、次式（′）で示される。
また、一般式（）で示されるグリニヤール試
薬において、R′はアリール基又はアルキル基、
Ｘはハロゲン原子をあらわす。このグリニヤール
試薬としては、たとえば、ｎ−BuMgBr，
EtMgCl，Ph−gBr，PhMgCl，ｎ−BuMgI，ｎ
−BuMgCl，等が挙げられるが、ｎ−BuMgBr，
ｎ−BuMgCl等が好適に使用される。
本発明方法においては、上記のα，β−不飽和
カルボン酸アミドを、通常、溶媒中で過剰の上記
グリニヤール試薬と反応させる。溶媒としては、
特に制限されないが、通常、ジエチルエーテル、
テトラヒドロフラン等のエーテル類、ベンゼン、
トルエン等の芳香族炭化水素類、等が使用され
る。反応温度は、通常、一数十度〜室温程度から
選択される。反応時間は0.5〜72時間程度である。
得られる反応生成物は、ついで、加水分解され
て、目的とする一般式（）又は（′）で示さ
れるカルボン酸類が得られる。
加水分解は、通常、酢酸等の有機酸又は硫酸等
の無機酸の存在下に、室温〜80℃程度で行なわれ
る。
本発明方法の一例として前記（′）で示され
るα，β−不飽和カルボン酸アミド及びグリニヤ
ール試薬としてR′MgBr（′）を用いる場合につ
いて、推測される反応式を次に示す。
式（′）で示されるα，β−不飽和カルボン
酸アミドは、たとえば、次のような方法によつて
容易に高収率で得られる。
すなわち、対応する酸ハロゲン化物とＬ−エフ
エドリンを、ピリジン、Ｎ，Ｎ，N′，N′−テト
ラメチル−１，８−ジアミノナフタレン等の塩基
の存在下に反応させて得られる。
本発明方法においては、反応終了後、常法によ
り分離、精製して目的とするカルボン酸類を得る
ことができる。本発明方法によれば、光学的純度
の高いβ−置換カルボン酸類を簡易に、効率よく
得ることができる。
次に、本発明を実施例によつてさらに詳細に説
明するが、本発明はその要旨を超えないかぎり、
これら実施例に限定されない。
実施例 １
〔Ｓ〕−３−メチルヘプタン酸の製造
一般式（′）（Ｒ＝Me）で示されるα，β−
不飽和カルボン酸アミド（537mg、2.3mmol）の
エーテル溶液（35ml）に、ｎ−BuMgBr
（0.88mmol／ml、13.8mmol）のエーテル溶液
（15.7ml）を−78℃、アルゴン雰囲気下に添加し
た。−40℃で48時間撹拌したのち、反応混合物に
リン酸塩緩衝溶液（PH７、20ml）を添加した。得
られる不溶性物質をケイソウ土でろ過し、酢酸エ
チルで洗浄した。有機層を酢酸エチルで抽出し、
抽出物を無水MgSO4で乾燥し、次いで真空中で
蒸留する。
蒸留物をシリカゲルカラムクロマトグラフイー
で精製すると、ミツチエル（Michael）付加物
（４）（Ｒ＝Me，R′＝ｎ−Bu）（426mg、
1.5mmol）が得られた（収率63％）。この付加物
酢酸（５ml）及び硫酸（10ml）中に溶解され、次
いで３時間還流される。有機層はエーテルで抽出
され、抽出物は飽和食塩水で洗浄し、無水
MgSO4で乾燥され、真空中で蒸留される。
残留物はクーゲルーローア（Kugel−Rohr）
法（浴温150℃／４mmHg）により蒸留され、目的
とする〔Ｓ〕−３−メチルヘプタン酸（177mg）が
得られた（収率84％）。〔α〕D：3.59（neat）（23±
２℃、589nm）、光学的純度85（％ee）、絶対配
置：Ｓ。
実施例 ２
実施例１の方法と同様にして、表１に示す原料
を用いて反応を行ない表１に示す結果を得た。
The present invention relates to a method for producing carboxylic acids, and more particularly to a method for producing optically active carboxylic acids. Conventionally, various methods have been proposed for the production of optically active carboxylic acids, but many of them have drawbacks such as the raw materials used, and these methods cannot necessarily be considered satisfactory. The present inventors conducted various studies to overcome these difficulties and find an efficient method, and as a result, they arrived at the present invention. That is, the gist of the present invention is that the general formula () (In the formula, R is an optionally substituted aryl group or alkyl group, and A represents a residue of ephedrin.) An α,β-unsaturated carboxylic acid amide represented by the general formula () R′MgX () (In the formula, R' is an aryl group or an alkyl group,
(X represents a halogen atom) is reacted with a Grignard reagent represented by (wherein R and R' are the same as defined above) A method for producing carboxylic acids characterized by obtaining an optically active β-substituted carboxylic acid represented by the following formula. The present invention will be explained in detail below. First, the α,β-unsaturated carboxylic acid amide used in the present invention has the general formula () This is shown in . In the formula, R represents an optionally substituted aryl group or alkyl group. Aryl groups include phenyl, tolyl, xylyl, naphthyl, etc.; alkyl groups include methyl, ethyl, n-butyl, n-hexyl, n-
Examples include those having any number of carbon atoms, such as octyl.
A represents a residue of ephedrin. That is,
The α,β-unsaturated carboxylic acid amide represented by the general formula () is represented by the following formula (′). Furthermore, in the Grignard reagent represented by the general formula (), R' is an aryl group or an alkyl group,
X represents a halogen atom. Examples of the Grignard reagent include n-BuMgBr,
EtMgCl, Ph-gBr, PhMgCl, n-BuMgI, n
-BuMgCl, etc., but n-BuMgBr,
n-BuMgCl and the like are preferably used. In the method of the present invention, the α,β-unsaturated carboxylic acid amide described above is reacted with an excess of the Grignard reagent described above, usually in a solvent. As a solvent,
Although not particularly limited, usually diethyl ether,
Ethers such as tetrahydrofuran, benzene,
Aromatic hydrocarbons such as toluene are used. The reaction temperature is usually selected from about 100 degrees to room temperature. The reaction time is about 0.5 to 72 hours. The resulting reaction product is then hydrolyzed to obtain the desired carboxylic acids represented by the general formula () or ('). Hydrolysis is usually carried out at room temperature to about 80°C in the presence of an organic acid such as acetic acid or an inorganic acid such as sulfuric acid. As an example of the method of the present invention, a predicted reaction formula is shown below when using the α,β-unsaturated carboxylic acid amide shown in (') above and R'MgBr (') as the Grignard reagent. The α,β-unsaturated carboxylic acid amide represented by formula (') can be easily obtained in high yield by, for example, the following method. That is, it is obtained by reacting the corresponding acid halide and L-ephedrin in the presence of a base such as pyridine or N,N,N',N'-tetramethyl-1,8-diaminonaphthalene. In the method of the present invention, after the reaction is completed, the target carboxylic acids can be obtained by separation and purification by conventional methods. According to the method of the present invention, β-substituted carboxylic acids with high optical purity can be obtained easily and efficiently. Next, the present invention will be explained in more detail with reference to Examples.
The invention is not limited to these examples. Example 1 Production of [S]-3-methylheptanoic acid α,β- represented by general formula (′) (R=Me)
In an ether solution (35 ml) of the unsaturated carboxylic acid amide (537 mg, 2.3 mmol) was added n-BuMgBr.
An ether solution (15.7 ml) of (0.88 mmol/ml, 13.8 mmol) was added at −78° C. under an argon atmosphere. After stirring at -40°C for 48 hours, phosphate buffer solution (PH7, 20ml) was added to the reaction mixture. The resulting insoluble material was filtered through diatomaceous earth and washed with ethyl acetate. The organic layer was extracted with ethyl acetate,
The extract is dried over anhydrous MgSO 4 and then distilled in vacuo. The distillate was purified by silica gel column chromatography to yield Michael adduct (4) (R=Me, R′=n-Bu) (426 mg,
1.5 mmol) was obtained (63% yield). This adduct is dissolved in acetic acid (5 ml) and sulfuric acid (10 ml) and then refluxed for 3 hours. The organic layer was extracted with ether, and the extract was washed with saturated brine and dried.
Dry with MgSO 4 and distill in vacuo. The residue is Kugel-Rohr.
The desired [S]-3-methylheptanoic acid (177 mg) was obtained by distillation using the method (bath temperature: 150° C./4 mmHg) (yield: 84%). [α] D : 3.59 (neat) (23±
2°C, 589 nm), optical purity 85 (%ee), absolute configuration: S. Example 2 A reaction was carried out in the same manner as in Example 1 using the raw materials shown in Table 1, and the results shown in Table 1 were obtained.
【表】【table】
Claims (1)
又はアルキル基、Ａはエフエドリンの残基をあら
わす） で示されるα，β−不飽和カルボン酸アミドを、 一般式（） R′MgX （） （式中、R′は、アリール基又はアルキル基、
Ｘはハロゲン原子をあらわす） で示されるグリニヤール試薬と反応させて、つい
で得られた反応生成物を加水分解して、一般式
（）又は（′） （式中、Ｒ，R′は前記と同義） で示される光学活性β−置換カルボン酸を得るこ
とを特徴とするカルボン酸類の製造法。 ２ グリニヤール試薬がｎ−BuMgBrである特
許請求の範囲第１項記載の製造法。 ３ 加水分解を酸の存在下に行なう特許請求の範
囲第１項記載の製造法。[Claims] 1 General formula () (In the formula, R is an optionally substituted aryl group or alkyl group, and A represents a residue of ephedrin.) An α,β-unsaturated carboxylic acid amide represented by the general formula () R′MgX () (In the formula, R' is an aryl group or an alkyl group,
(X represents a halogen atom) is reacted with a Grignard reagent represented by (In the formula, R and R' have the same meanings as above.) A method for producing carboxylic acids, which is characterized by obtaining an optically active β-substituted carboxylic acid represented by the following formula. 2. The production method according to claim 1, wherein the Grignard reagent is n-BuMgBr. 3. The production method according to claim 1, wherein the hydrolysis is carried out in the presence of an acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50782A JPS58118539A (en) | 1982-01-05 | 1982-01-05 | Preparation of carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50782A JPS58118539A (en) | 1982-01-05 | 1982-01-05 | Preparation of carboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58118539A JPS58118539A (en) | 1983-07-14 |
| JPH0254329B2 true JPH0254329B2 (en) | 1990-11-21 |
Family
ID=11475676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50782A Granted JPS58118539A (en) | 1982-01-05 | 1982-01-05 | Preparation of carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58118539A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5488131A (en) * | 1994-03-23 | 1996-01-30 | California Institute Of Technology | Synthesis of compounds with predetermined chirality |
-
1982
- 1982-01-05 JP JP50782A patent/JPS58118539A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58118539A (en) | 1983-07-14 |
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