JPS626697B2 - - Google Patents
Info
- Publication number
- JPS626697B2 JPS626697B2 JP2863880A JP2863880A JPS626697B2 JP S626697 B2 JPS626697 B2 JP S626697B2 JP 2863880 A JP2863880 A JP 2863880A JP 2863880 A JP2863880 A JP 2863880A JP S626697 B2 JPS626697 B2 JP S626697B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- represented
- formula
- cyclohexen
- compounds
- 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
- -1 3-(4-substituted benzoyl)propionic acid Chemical class 0.000 claims description 8
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 15
- 238000000034 method Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YKJFOAUMSHLSEB-UHFFFAOYSA-N ethyl 4-(4-chlorophenyl)-4-oxobutanoate Chemical compound CCOC(=O)CCC(=O)C1=CC=C(Cl)C=C1 YKJFOAUMSHLSEB-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KMQLIDDEQAJAGJ-UHFFFAOYSA-N 4-oxo-4-phenylbutyric acid Chemical compound OC(=O)CCC(=O)C1=CC=CC=C1 KMQLIDDEQAJAGJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は次の一般式〔〕で表わされる4―オ
キソ―2―(4―置換フエニル)―2―シクロヘ
キセン―1―イル酢酸の製造法に関する。
ただしR1は水素又はハロゲンを表わす。
一般式〔〕で表わされる化合物のうちR1が
水素の化合物は文献既知(J.Chem.Soc.Perkin
,1973,1451)であるがR1が塩素の化合物は
文献未知である。
本発明で製造される化合物は、例えばこれを低
級アルキルエステルとなした後ヨード化剤と反応
させて化合物〔〕となし、これを例えばカセイ
アルカリで加水分解することにより容易に化合物
〔〕に導くことができる。
ただしR1は前記と同じ、R2は低級アルキルを
表わす。
化合物〔〕はすぐれた抗炎症作用、鎮痛作
用、血小板擬集抑制作用を有し、医薬品として有
用である。よつて本発明で製造される化合物は、
医薬品合成中間体として有用である。
一般式〔〕の化合物のうち、R1が塩素の化
合物については、文献記載(J.Chem.Soc.Perkin
,1973,1451)の反応条件を準用して製造する
ことができなかつた。従来一般式〔〕において
R1が水素である化合物は3―(ベンゾイル)プ
ロピオン酸を出発原料として下に示す経路で製造
されており、反応式からわかる様に、マンニツヒ
塩基の形成、メチルエステルの製造、環化からな
つている。しかしR1が塩素である化合物の製造
においては、第一段階のマンニツヒ塩基の形成が
全く進行せず、このことから公知の方法の幅広い
応用性には擬問が持たれる。
本発明者らは更に簡便で一般的に応用し得る製
造法の確立を目的として種々研究を重ねた結果、
一般式〔〕で表わされる3―(4―置換ベンゾ
イル)プロピオン酸エステルを塩基の存在下でメ
チルビニルケトンと反応させると一段階で一般式
〔〕で表わされる化合物が生成するという簡便
な方法を確立し、本発明を完成したのである。
ただしR1,R2は前記と同じ。
本発明で使用される塩基は通常の有機合成反応
で繁用されるものでよいが、好ましくは、カリウ
ム第3級プトオキシド、DBUを用いるのがよ
く、又、溶媒は不活性溶媒、好ましくは、トルエ
ン、第3級ブタノールがよい。好適な反応温度は
0℃〜110℃である。本発明の生成物である一般
式〔〕で表わされる2―(4―置換フエニル)
―2―シクロヘキセン―1―イル酢酸は通常の分
離法を用い容易に分離できる。この方法によつて
既知の化合物である一般式〔〕で表わされる化
合物のうちR1が水素のものも文献既知の方法に
比較し、格段に簡便に製造できる。従つて本発明
の方法は一般式〔〕で表わされる化合物の最も
簡便な製造法といえる。次に実施例を掲げ本発明
を一層明らかにする。
実施例 1
3―(4―クロロベンゾイル)プロピオン酸エ
チル28.8gとメチルビニルケトン15gを第3級ブ
タノール120mlに溶解し、別に金属カリウム5g
と第3級ブタノール100mlから調製した溶液の1/1
0量を氷冷下にゆつくり滴下し室温にて一夜放置
したのち、反応液を撹拌還流下に更に9/10量を滴
下し3時間反応させる。放冷後減圧下に第3級ブ
タノールを溜去し、残渣に10%塩酸を加えて酸性
にする。ベンゼンで抽出し、ベンゼン溶液を炭酸
水素ナトリウム水溶液で抽出する。抽出液を酸性
とし析出結晶をメタノールから再結晶して4―オ
キソ―2―(4―クロロフエニル)―2―シクロ
ヘキセン―1―イル酢酸14.1g、収率41%、融点
176〜178℃を得る。
元素分析値 C14H18ClO3として
計算値 C:63.52、H:4.95、Cl:13.39
実験値 C:63.70、H:5.02、Cl:13.27
赤外線吸収スペクトル(KBr法)3200〜2600(微
細吸収)1728(−COOH)、1635(C=C)1607
The present invention relates to a method for producing 4-oxo-2-(4-substituted phenyl)-2-cyclohexen-1-yl acetic acid represented by the following general formula []. However, R 1 represents hydrogen or halogen. Among the compounds represented by the general formula [], compounds in which R 1 is hydrogen are known from the literature (J.Chem.Soc.Perkin
, 1973, 1451), but compounds in which R 1 is chlorine are unknown in the literature. The compound produced in the present invention is, for example, converted into a lower alkyl ester and then reacted with an iodinating agent to form the compound [], which can be easily led to the compound [] by hydrolyzing it with, for example, caustic alkali. be able to. However, R 1 is the same as above, and R 2 represents lower alkyl. Compound [] has excellent anti-inflammatory effect, analgesic effect, and platelet aggregation inhibitory effect, and is useful as a pharmaceutical. Therefore, the compound produced by the present invention is
It is useful as an intermediate in pharmaceutical synthesis. Among the compounds of the general formula [], compounds in which R 1 is chlorine are described in the literature (J.Chem.Soc.Perkin
, 1973, 1451). In the conventional general formula []
Compounds in which R 1 is hydrogen are produced using 3-(benzoyl)propionic acid as a starting material by the route shown below. ing. However, in the production of compounds in which R 1 is chlorine, the formation of the Mannitz base in the first step does not proceed at all, which casts doubt on the wide applicability of the known method. As a result of various research aimed at establishing a simpler and generally applicable manufacturing method, the present inventors found that
A simple method in which the compound represented by the general formula [] is produced in one step by reacting 3-(4-substituted benzoyl)propionic acid ester represented by the general formula [] with methyl vinyl ketone in the presence of a base. They established this and completed the present invention. However, R 1 and R 2 are the same as above. The base used in the present invention may be one frequently used in ordinary organic synthesis reactions, but potassium tertiary nitoxide, DBU is preferably used, and the solvent is an inert solvent, preferably, Toluene and tertiary butanol are preferable. The preferred reaction temperature is 0°C to 110°C. 2-(4-substituted phenyl) represented by the general formula [] which is a product of the present invention
-2-Cyclohexen-1-yl acetic acid can be easily separated using conventional separation methods. By this method, known compounds represented by the general formula [], in which R 1 is hydrogen, can be produced much more easily than with methods known in the literature. Therefore, the method of the present invention can be said to be the simplest method for producing the compound represented by the general formula []. Next, examples will be given to further clarify the present invention. Example 1 28.8 g of ethyl 3-(4-chlorobenzoyl)propionate and 15 g of methyl vinyl ketone were dissolved in 120 ml of tertiary butanol, and separately 5 g of metallic potassium was dissolved.
and 1/1 of the solution prepared from 100 ml of tertiary butanol.
0 amount was slowly added dropwise under ice-cooling and allowed to stand overnight at room temperature, and then an additional 9/10 amount was added dropwise to the reaction solution while stirring and refluxing, and the mixture was allowed to react for 3 hours. After cooling, tertiary butanol is distilled off under reduced pressure, and 10% hydrochloric acid is added to the residue to make it acidic. Extract with benzene and extract the benzene solution with aqueous sodium bicarbonate solution. The extract was acidified and the precipitated crystals were recrystallized from methanol to give 14.1 g of 4-oxo-2-(4-chlorophenyl)-2-cyclohexen-1-yl acetic acid, yield 41%, melting point.
Obtain 176-178°C. Elemental analysis value C 14 H 18 ClO 3 Calculated value C: 63.52, H: 4.95, Cl: 13.39 Experimental value C: 63.70, H: 5.02, Cl: 13.27 Infrared absorption spectrum (KBr method) 3200-2600 (fine absorption) 1728 (-COOH), 1635 (C=C) 1607
【式】827cm-1核磁気吸収スペクトル
(CDCl3)、δ、2.2〜2.7(6H、m、
[Formula] 827cm -1 nuclear magnetic absorption spectrum (CDCl 3 ), δ, 2.2-2.7 (6H, m,
【式】及び[Formula] and
【式】)3.3〜3.7 (1H、m、[Formula]) 3.3 to 3.7 (1H, m,
【式】)6.33(1H、s、[Formula]) 6.33 (1H, s,
【式】)7.44(4H、s、[Formula]) 7.44 (4H, s,
【式】)7.8〜8.2(1H、−COOH、
D2O添加によつて消失する)マススペクトル:
m/e 264(M+、ベースピーク)219(M+−
COOH)、204[Formula]) 7.8-8.2 (1H, -COOH, disappears upon addition of D2O ) Mass spectrum:
m/e 264 (M + , base peak) 219 (M + −
COOH), 204
【式】
実施例 2
3―(4―クロロベンゾイル)プロピオン酸エ
チル2.4gとメチルビニルケトン1.4gを乾燥トル
エン10mlに溶解しDBU1.6gを加えて室温にて2
時間撹拌したのち、更に2時間還流撹拌する。溶
媒を溜去し、残渣を実施例1の後処理法に準じて
処理し、4―オキソ―2―(4―クロロフエニ
ル)―2―シクロヘキセン―1―イル酢酸1.4
g、収率45%を得る。これは実施例1で得られた
ものと融点、スペクトルデーターが完全に一致す
る。
同様の方法で既知の4―オキソ―2―フエニル
―2―シクロヘキセン―1―イル酢酸、融点139
〜142℃(文献値136〜137℃)〔2,4―ジニトロ
フエニルヒドラゾン融点232〜233℃(文献値232
℃)〕が製造できる。[Formula] Example 2 2.4 g of ethyl 3-(4-chlorobenzoyl)propionate and 1.4 g of methyl vinyl ketone were dissolved in 10 ml of dry toluene, 1.6 g of DBU was added, and 2.
After stirring for an hour, the mixture was further stirred under reflux for 2 hours. The solvent was distilled off, and the residue was treated according to the post-treatment method of Example 1 to give 1.4% of 4-oxo-2-(4-chlorophenyl)-2-cyclohexen-1-yl acetic acid.
g, yield 45%. This completely matches the melting point and spectrum data obtained in Example 1. 4-oxo-2-phenyl-2-cyclohexen-1-yl acetic acid, melting point 139, known in a similar manner.
~142℃ (Literature value 136-137℃) [2,4-dinitrophenylhydrazone melting point 232-233℃ (Literature value 232
℃)] can be produced.
Claims (1)
オン酸エステルを、塩基の存在下でメチルビニル
ケトンと反応させることを特徴とする次の一般式
〔〕 で表わされる4―オキソ―2―(4―置換フエニ
ル)―2―シクロヘキセン―1―イル酢酸の製造
法。 ただしR1は水素又はハロゲンを表わし、R2は
低級アルキルを表わす。[Claims] First-order general formula [] The following general formula [] is characterized by reacting a 3-(4-substituted benzoyl)propionic acid ester represented by with methyl vinyl ketone in the presence of a base. A method for producing 4-oxo-2-(4-substituted phenyl)-2-cyclohexen-1-yl acetic acid represented by However, R 1 represents hydrogen or halogen, and R 2 represents lower alkyl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2863880A JPS56123937A (en) | 1980-03-06 | 1980-03-06 | Preparation of cyclohexene derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2863880A JPS56123937A (en) | 1980-03-06 | 1980-03-06 | Preparation of cyclohexene derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS56123937A JPS56123937A (en) | 1981-09-29 |
JPS626697B2 true JPS626697B2 (en) | 1987-02-13 |
Family
ID=12254064
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2863880A Granted JPS56123937A (en) | 1980-03-06 | 1980-03-06 | Preparation of cyclohexene derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS56123937A (en) |
-
1980
- 1980-03-06 JP JP2863880A patent/JPS56123937A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS56123937A (en) | 1981-09-29 |
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