JPS6352023B2 - - Google Patents
Info
- Publication number
- JPS6352023B2 JPS6352023B2 JP61281976A JP28197686A JPS6352023B2 JP S6352023 B2 JPS6352023 B2 JP S6352023B2 JP 61281976 A JP61281976 A JP 61281976A JP 28197686 A JP28197686 A JP 28197686A JP S6352023 B2 JPS6352023 B2 JP S6352023B2
- Authority
- JP
- Japan
- Prior art keywords
- methoxy
- bromo
- naphthyl
- ethyl
- propionic acid
- 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
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 claims description 7
- CMWTZPSULFXXJA-UHFFFAOYSA-N 2-(6-methoxy-2-naphthalenyl)propanoic acid Chemical compound C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000004795 grignard reagents Chemical class 0.000 claims description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- XNIGURFWNPLWJM-UHFFFAOYSA-N 1-bromo-2-methoxynaphthalene Chemical compound C1=CC=CC2=C(Br)C(OC)=CC=C21 XNIGURFWNPLWJM-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- FSJHKLJLLBYDHQ-UHFFFAOYSA-N ethyl 2-(5-bromo-6-methoxynaphthalen-2-yl)-2-oxoacetate Chemical compound BrC1=C(OC)C=CC2=CC(C(=O)C(=O)OCC)=CC=C21 FSJHKLJLLBYDHQ-UHFFFAOYSA-N 0.000 claims description 2
- IZPFPKSKRZEOLX-UHFFFAOYSA-N ethyl 2-naphthalen-1-ylpropanoate Chemical compound C1=CC=C2C(C(C)C(=O)OCC)=CC=CC2=C1 IZPFPKSKRZEOLX-UHFFFAOYSA-N 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- -1 2-substituted propionic acid Chemical class 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 4
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- APWZAIZNWQFZBK-UHFFFAOYSA-N 1-ethoxynaphthalene Chemical compound C1=CC=C2C(OCC)=CC=CC2=C1 APWZAIZNWQFZBK-UHFFFAOYSA-N 0.000 description 1
- JZRWXNBIQCMXSU-UHFFFAOYSA-N 2-(5-bromo-6-methoxynaphthalen-2-yl)propanoic acid Chemical compound C1=C(C(C)C(O)=O)C=CC2=C(Br)C(OC)=CC=C21 JZRWXNBIQCMXSU-UHFFFAOYSA-N 0.000 description 1
- LUZDYPLAQQGJEA-UHFFFAOYSA-N 2-Methoxynaphthalene Chemical compound C1=CC=CC2=CC(OC)=CC=C21 LUZDYPLAQQGJEA-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SCBFEFZUAPMQCZ-UHFFFAOYSA-N ethyl 2-(6-methoxynaphthalen-2-yl)-2-oxoacetate Chemical compound C1=C(OC)C=CC2=CC(C(=O)C(=O)OCC)=CC=C21 SCBFEFZUAPMQCZ-UHFFFAOYSA-N 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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、２−置換プロピオン酸の製法に係
り、殊に２−（６−メトキシ−２−ナフチル）プ
ロピオン酸の製法に係る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 2-substituted propionic acid, and particularly to a process for producing 2-(6-methoxy-2-naphthyl)propionic acid.
２−芳香族置換プロピオン酸類が抗炎症性、鎮
痛性、解熱性等の薬理作用を有していることは既
に周知であり、従つて本発明方法により得られる
化合物は医薬として且つ又この種の医薬製造用の
中間体として有用である。 It is already well known that 2-aromatic substituted propionic acids have pharmacological effects such as anti-inflammatory, analgesic, and antipyretic properties, and therefore, the compounds obtained by the method of the present invention can be used as pharmaceuticals and in this type of It is useful as an intermediate for pharmaceutical manufacturing.
従来、医薬として有用な斯かる２−置換プロピ
オン酸類は、一般に５乃至７工程を経て製造され
ており、然かも反応試薬としてシアン化水素酸、
アルカリ金属シアン化物を用いる方法が汎用され
ている。従つて、工程数が多い故に精製操作が煩
雑なものとなり、毒性の高い反応試薬を用いるが
故に斯かる有害物が残存しないように最大限の注
意を払わねばならず且つ作業環境上の問題を生ず
る等の点で、従来法は工業的に不利であつた。 Conventionally, such 2-substituted propionic acids useful as pharmaceuticals have generally been produced through 5 to 7 steps, and in addition, hydrocyanic acid, hydrocyanic acid, etc. are used as reaction reagents.
A method using an alkali metal cyanide is widely used. Therefore, the purification operation is complicated due to the large number of steps, and since highly toxic reaction reagents are used, maximum care must be taken to ensure that no harmful substances remain, and there are problems in the working environment. The conventional method was industrially disadvantageous in that
斯くて、本発明の主たる目的は工程数が少なく
且つ反応試薬としてシアン化物のような高毒性物
質を必要とせず、これによつて２−（６−メトキ
シ−２−ナフチル）プロピオン酸を工業的に有利
に製造し得る方法を提供することにある。 Therefore, the main purpose of the present invention is to reduce the number of steps and eliminate the need for highly toxic substances such as cyanide as a reaction reagent, thereby making 2-(6-methoxy-2-naphthyl)propionic acid industrially viable. The object of the present invention is to provide a method that can be advantageously manufactured.
本発明の付随的目的は、廉価に且つ容易に入手
し得る物質から出発し、廉価に且つ容易に入手し
得る試薬及び溶媒を用いて実施でき、然かも収率
が比較的良好な２−（６−メトキシ−２−ナフチ
ル）プロピオン酸の製法を提供することにある。 Ancillary objects of the present invention are that 2-(2-( An object of the present invention is to provide a method for producing 6-methoxy-2-naphthyl)propionic acid.
本発明方法によれば、これらの目的は、無水塩
化アルミニウムの存在下に−70℃乃至−40℃にお
いて１−ブロム−２−メトキシナフタレンにエチ
ルオキザリルクロリドを添加し、−10℃以下で反
応させ、得たる（５−ブロム−６−メトキシ−２
−ナフチル）グリオキシル酸エチルをグリニヤー
ル試薬にて処理し、得たる２−ヒドロキシ−２−
（５−ブロム−６−メトキシ−２−ナフチル）プ
ロピオン酸エチルを加水分解し、次いで赤燐と沃
素の存在下に還元することを特徴とする、２−
（６−メトキシ−２−ナフチル）プロピオン酸の
製法により達成される。 According to the method of the present invention, these objects are achieved by adding ethyloxalyl chloride to 1-bromo-2-methoxynaphthalene at -70°C to -40°C in the presence of anhydrous aluminum chloride, and reacting at -10°C or lower. to obtain (5-bromo-6-methoxy-2
- Naphthyl) ethyl glyoxylate is treated with Grignard reagent to obtain 2-hydroxy-2-
2-, characterized in that ethyl (5-bromo-6-methoxy-2-naphthyl)propionate is hydrolyzed and then reduced in the presence of red phosphorus and iodine.
This is achieved by a method for producing (6-methoxy-2-naphthyl)propionic acid.
本発明方法において、出発物質としてβ−メト
キシナフタレンのα−ブロム体である１−ブロム
−２−メトキシナフタレンを用い且つ極めて低温
な条件下即ち−70℃乃至−40℃の温度条件下にエ
チルオキザリルクロリドを添加して反応させるの
は、副反応を有効に抑制して（５−ブロム−６−
メトキシ−２−ナフチル）グリオキシル酸エチル
を比較的高収率で且つ安定に得るためである。
尚、−70℃乃至−40℃の温度条件は、「クリーンガ
ス」等として市販されている圧縮ガスの気化を利
用することにより、比較的容易に設定することが
できる。この第１工程であるフリーデル・クラフ
ト反応に際しては高純度の無水塩化アルミニウム
を使用するのが好ましく、溶媒としては二硫化炭
素、ニトロベンゼン又はジクロルメタンを使用す
ることができる。エチルオキザリルクロリドの添
加は上記の−70℃乃至−40℃の温度条件下に行わ
れるが、この場合に添加を滴下により実施し、こ
の滴下終了後に−10℃に昇温させ該温度条件下に
反応を継続させるのが有利である。この場合の反
応所要時間はエチルオキザリルクロリドの適下終
了後約６時間である。尚、この第１工程の実施に
より５−位にブロムが云わば保護基として導入さ
れた形態となるが、このブロムは最終目的物質で
ある２−（６−メトキシ−２−ナフチル）プロピ
オン酸になすための最終工程である還元工程の実
施により脱離するので、この保護基除去のための
格別な工程を必要としない。第２工程であるグリ
ニヤール反応は、０℃以下において（５−ブロム
−６−メトキシ−２−ナフチル）グリオキシル酸
エチル溶液をグリニヤール試薬に滴下し、次いで
室温条件下で撹拌することによつて実施すること
ができ、この場合の反応所要時間は約30分間であ
る。 In the method of the present invention, 1-bromo-2-methoxynaphthalene, which is the α-bromine form of β-methoxynaphthalene, is used as a starting material, and ethyl oxynaphthalene is Adding zaryl chloride to the reaction effectively suppresses side reactions (5-bromo-6-
This is to obtain ethyl methoxy-2-naphthyl)glyoxylate in a relatively high yield and stably.
Note that the temperature condition of -70°C to -40°C can be set relatively easily by using vaporization of compressed gas commercially available as "clean gas" or the like. In this first step, the Friedel-Crafts reaction, it is preferable to use highly pure anhydrous aluminum chloride, and carbon disulfide, nitrobenzene or dichloromethane can be used as the solvent. The addition of ethyl oxalyl chloride is carried out under the above-mentioned temperature conditions of -70°C to -40°C. In this case, the addition is carried out by dropwise addition, and after the completion of the dropwise addition, the temperature is raised to -10°C and the temperature is maintained under the above temperature conditions. It is advantageous to continue the reaction. In this case, the reaction time is about 6 hours after the addition of ethyl oxalyl chloride is completed. By carrying out this first step, bromine is introduced as a protecting group at the 5-position, but this bromine is not added to the final target substance, 2-(6-methoxy-2-naphthyl)propionic acid. Since the protecting group is removed by carrying out the reduction step, which is the final step, there is no need for a special step for removing this protecting group. The second step, the Grignard reaction, is carried out by dropping the ethyl (5-bromo-6-methoxy-2-naphthyl)glyoxylate solution into the Grignard reagent at 0°C or below, and then stirring at room temperature. The reaction time in this case is approximately 30 minutes.
次に、実施例及び比較参考例により本発明を更
に詳細に説明する。 Next, the present invention will be explained in more detail with reference to Examples and Comparative Reference Examples.
実施例
(a) （５−ブロム−６−メトキシ−２−ナフチ
ル）グリオキシル酸エチルの製造
１−ブロム−２−メトキシナフタレン13.5ｇ
と、二硫化炭素100mlと、無水塩化アルミニウ
ム23ｇとを−70乃至−40℃に冷却し撹拌下にエ
チルオキザリルクロリド15.5ｇを滴下する。滴
下完了後−10℃以下の温度にて６時間にわたり
反応せしめた後に、反応混合物を氷水中に注下
し、エチルエーテルにて抽出し、有機層を乾燥
させ、溶媒を留去させ、残渣をベンゼンより再
結晶させれば、融点136−138℃の所望化合物が
8.2ｇ（収率42.7％）得られる。Example (a) Production of ethyl (5-bromo-6-methoxy-2-naphthyl)glyoxylate 1-bromo-2-methoxynaphthalene 13.5 g
, 100 ml of carbon disulfide, and 23 g of anhydrous aluminum chloride are cooled to -70 to -40°C, and 15.5 g of ethyloxalyl chloride is added dropwise with stirring. After the completion of the dropwise addition, the reaction mixture was allowed to react for 6 hours at a temperature below -10°C, and then the reaction mixture was poured into ice water, extracted with ethyl ether, the organic layer was dried, and the solvent was distilled off to remove the residue. If recrystallized from benzene, the desired compound with a melting point of 136-138℃ is obtained.
8.2g (yield 42.7%) is obtained.
元素分析：C15H13O4Br
理論 Ｃ 53.43％ Ｈ 3.89％
実測 Ｃ 53.58％ Ｈ 3.83％
IRスペクトル（νcm-1）：
1710（エステル）、1680（Ｃ＝０）
(b) ２−ヒドロキシ−２−（５−ブロム−６−メ
トキシ−２−ナフチル）プロピオン酸エチルの
製造
マグネシウム２ｇと、沃化メチル５mlと、エ
チルエーテル30mlとを用いてグリニヤール試薬
を調製する。このグリニヤール試薬を撹拌しつ
つ、これに上記の(a)工程で得た（５−ブロム−
６−メトキシ−２−ナフチル）グリオキシル酸
エチル４ｇをベンゼン100mlに溶解させた溶液
を滴下する。滴下完了後、得られた溶液全体を
室温において更に30分間撹拌し、次いで塩化ア
ンモニウム水溶液を添加して分解させ、エーテ
ル層を抽出し、有機層を乾燥させ、溶媒を留去
させ、残渣を含水エタノールから再結晶させれ
ば、融点84℃の所望化合物が3.3ｇ（収率78.8
％）得られる。Elemental analysis: C 15 H 13 O 4 Br Theory C 53.43% H 3.89% Actual measurement C 53.58% H 3.83% IR spectrum (νcm -1 ): 1710 (ester), 1680 (C=0) (b) 2-hydroxy- Preparation of ethyl 2-(5-bromo-6-methoxy-2-naphthyl)propionate A Grignard reagent is prepared using 2 g of magnesium, 5 ml of methyl iodide, and 30 ml of ethyl ether. While stirring, this Grignard reagent was added to the (5-bromo-
A solution of 4 g of ethyl 6-methoxy-2-naphthyl glyoxylate dissolved in 100 ml of benzene is added dropwise. After the addition is complete, the entire solution obtained is stirred for another 30 minutes at room temperature, then an aqueous ammonium chloride solution is added for decomposition, the ether layer is extracted, the organic layer is dried, the solvent is evaporated, and the residue is hydrated. Recrystallization from ethanol yields 3.3 g of the desired compound with a melting point of 84°C (yield 78.8
%)can get.
元素分析：C16H17O4Br
理論 Ｃ 54.40％ Ｈ 4.85％
実測 Ｃ 54.39％ Ｈ 4.76％
IRスペクトル（νcm-1）：
3550（OH）、1735（Ｃ＝０）
(c) ２−ヒドロキシ−２−（５−ブロム−６−メ
トキシ−２−ナフチル）プロピオン酸の製造
水酸化カリウム２ｇをエタノール20mlと水４
mlとからなる溶液中に添加し、加温して溶解さ
せる。この溶液に、上記(b)工程で得た２−ヒド
ロキシ−２−（５−ブロム−６−メトキシ−２
−ナフチル）プロピオン酸エチル1.6ｇを少量
ずつ添加すれば、添加した結晶が一旦溶解した
後に直ちに再び析出する。得られた懸濁液を撹
拌下に２時間還流処理し、残渣をエタノールに
て洗浄し、撹拌しつつ塩酸水溶液中に添加す
る。析出する結晶を含水エタノールから再結晶
させれば融点199−201℃の所望化合物が1.3ｇ
（収率88.3％）得られる。Elemental analysis: C 16 H 17 O 4 Br Theory C 54.40% H 4.85% Actual measurement C 54.39% H 4.76% IR spectrum (νcm -1 ): 3550 (OH), 1735 (C=0) (c) 2-hydroxy- Production of 2-(5-bromo-6-methoxy-2-naphthyl)propionic acid 2 g of potassium hydroxide, 20 ml of ethanol and 4 ml of water
ml of solution and warm to dissolve. Add 2-hydroxy-2-(5-bromo-6-methoxy-2-2-(5-bromo-6-methoxy-2) obtained in step (b) above to this solution.
- If 1.6 g of ethyl (naphthyl) propionate is added little by little, the added crystals will once dissolve and then immediately precipitate again. The resulting suspension is refluxed for 2 hours with stirring, and the residue is washed with ethanol and added to an aqueous hydrochloric acid solution with stirring. If the precipitated crystals are recrystallized from aqueous ethanol, 1.3g of the desired compound with a melting point of 199-201℃ can be obtained.
(yield 88.3%).
元素分析：C14H13O4Br
理論 Ｃ 51.71％ Ｈ 4.03％
実測 Ｃ 51.92％ Ｈ 3.99％
IRスペクトル（νcm-1）：
3440（OH）1740（Ｃ＝０）
(d) ２−（６−メトキシ−２−ナフチル）プロピ
オン酸の製造
上記の(c)工程で得た２−ヒドロキシ−２−
（５−ブロム−６−メトキシ−２−ナフチル）
プロピオン酸１ｇに赤燐１ｇと、沃素0.5ｇと、
酢酸15mlとを添加して１時間還流処理する。次
いで赤燐を濾別し、該赤燐をエチルエーテルに
て充分に洗浄した後に再び濾液に添加する。そ
の後に濾液を留去させ、得られる残渣を少量の
エチルエーテルに溶解させ、この溶液をシリカ
ゲル充填カラムに注入する。これをエチルエー
テルと石油エーテルとの混合溶媒（２：１）を
溶離剤として展開させ、最初に溶出されてくる
物質を採取し、該溶出液を留去させて得た残渣
をアセトン及びｎ−ヘキサンから再結晶させれ
ば、融点155−157℃の最終目的化合物が390mg
（収率55.7％）得られる。Elemental analysis: C 14 H 13 O 4 Br Theory C 51.71% H 4.03% Actual measurement C 51.92% H 3.99% IR spectrum (νcm -1 ): 3440(OH)1740(C=0) (d) 2-(6- Production of methoxy-2-naphthyl)propionic acid 2-hydroxy-2-propionic acid obtained in step (c) above
(5-bromo-6-methoxy-2-naphthyl)
1 g of propionic acid, 1 g of red phosphorus, and 0.5 g of iodine.
Add 15 ml of acetic acid and reflux for 1 hour. Next, the red phosphorus is filtered off, washed thoroughly with ethyl ether, and then added to the filtrate again. The filtrate is then distilled off, the resulting residue is dissolved in a small amount of ethyl ether, and this solution is injected into a column packed with silica gel. This was developed using a mixed solvent of ethyl ether and petroleum ether (2:1) as an eluent, the first eluted substance was collected, and the eluate was distilled off, and the resulting residue was mixed with acetone and n- Recrystallization from hexane yields 390 mg of the final target compound with a melting point of 155-157°C.
(yield 55.7%).
元素分析：C14H14O3
理論 Ｃ 73.02％ Ｈ 6.13％
実測 Ｃ 72.98％ Ｈ 6.11％
IRスペクトル（νcm-1）：
1710（Ｃ＝０）
比較参考例
（５−ブロム−６−メトキシ−２−ナフチル）
グリオキシル酸エチルの製造
１−ブロム−２−メトキシナフタレン1.18ｇ
と、二硫化炭素15mlと、無水塩化アルミニウム
2.00ｇとを−20乃至−10℃に冷却し撹拌下にエチ
ルオキザリルクロリド1.36ｇを滴下する。滴下完
了後−10℃の温度条件下で６時間にわたり反応せ
しめた後に、反応混合物を氷水中に注下し、エチ
ルエーテルにて抽出し、有機層を乾燥させ、溶媒
を留去させた。得られた残渣を薄層クロマトグラ
フ分析（シリカゲル、展開溶媒：ベンゼン）した
処、８成分を含有していることが判明した。そこ
で、上記の残渣をシリカゲルカラムクロマトグラ
フイー（展開溶媒：ベンゼン）により分離精製し
た処、表題化合物が118ml（収率6.98％）得られ
た。Elemental analysis: C 14 H 14 O 3 Theory C 73.02% H 6.13% Actual measurement C 72.98% H 6.11% IR spectrum (νcm -1 ): 1710 (C=0) Comparative reference example (5-bromo-6-methoxy-2 −naphthyl)
Production of ethyl glyoxylate 1-bromo-2-methoxynaphthalene 1.18g
, 15ml of carbon disulfide, and anhydrous aluminum chloride
2.00 g of ethyl oxalyl chloride was cooled to -20 to -10°C, and 1.36 g of ethyloxalyl chloride was added dropwise with stirring. After completion of the dropwise addition, the reaction mixture was allowed to react for 6 hours at a temperature of -10°C, and then the reaction mixture was poured into ice water, extracted with ethyl ether, the organic layer was dried, and the solvent was distilled off. The resulting residue was analyzed by thin layer chromatography (silica gel, developing solvent: benzene) and was found to contain 8 components. Therefore, the above residue was separated and purified by silica gel column chromatography (developing solvent: benzene), and 118 ml (yield: 6.98%) of the title compound was obtained.
この比較参考例による結果と、既述の実施例に
おける第ａ工程における結果とを対比すれば明ら
かなように、この場合のフリーデル・クラフト反
応は温度条件を極めて低温（−70乃至−40℃）に
設定するのが有利であり、これによつて副生成の
生成が著しく抑制されて収率が向上すると共に、
精製処理を簡素化し得ることが判明した。 As is clear from the comparison between the results of this comparative reference example and the results of step a in the examples described above, the Friedel-Crafts reaction in this case is carried out under extremely low temperature conditions (-70 to -40°C). ), which significantly suppresses the formation of by-products and improves the yield.
It has been found that the purification process can be simplified.
Claims (1)
−40℃において１−ブロム−２−メトキシナフタ
レンにエチルオキザリルクロリドを添加し−10℃
以下で反応させ、得たる（５−ブロム−６−メト
キシ−２−ナフチル）グリオキシル酸エチルをグ
リニヤール試薬にて処理し、得たる２−ヒドロキ
シ−２−（５−ブロム−６−メトキシ−２−ナフ
チル）プロピオン酸エチルを加水分解し、次いで
赤燐と沃素の存在下に還元することを特徴とす
る、２−（６−メトキシ−２−ナフチル）プロピ
オン酸の製法。1 Ethyloxalyl chloride is added to 1-bromo-2-methoxynaphthalene at -70°C to -40°C in the presence of anhydrous aluminum chloride, and the mixture is heated at -10°C.
The following reaction is performed, and the obtained ethyl (5-bromo-6-methoxy-2-naphthyl)glyoxylate is treated with a Grignard reagent to obtain 2-hydroxy-2-(5-bromo-6-methoxy-2- A process for producing 2-(6-methoxy-2-naphthyl)propionic acid, which comprises hydrolyzing ethyl naphthylpropionate and then reducing it in the presence of red phosphorus and iodine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28197686A JPS62142138A (en) | 1986-11-28 | 1986-11-28 | Production of 2-6-methoxy-2-naphthyl propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28197686A JPS62142138A (en) | 1986-11-28 | 1986-11-28 | Production of 2-6-methoxy-2-naphthyl propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62142138A JPS62142138A (en) | 1987-06-25 |
| JPS6352023B2 true JPS6352023B2 (en) | 1988-10-17 |
Family
ID=17646517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28197686A Granted JPS62142138A (en) | 1986-11-28 | 1986-11-28 | Production of 2-6-methoxy-2-naphthyl propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62142138A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB971700A (en) * | 1961-02-02 | 1964-09-30 | Boots Pure Drug Co Ltd | Anti-Inflammatory Agents |
| DE1934460A1 (en) * | 1968-07-30 | 1970-02-05 | Syntex Corp | Process for the preparation of 2- (6'-methoxynaphth-2'-yl) -propionic acid, corresponding 5'-halogen compounds and intermediates |
-
1986
- 1986-11-28 JP JP28197686A patent/JPS62142138A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB971700A (en) * | 1961-02-02 | 1964-09-30 | Boots Pure Drug Co Ltd | Anti-Inflammatory Agents |
| DE1934460A1 (en) * | 1968-07-30 | 1970-02-05 | Syntex Corp | Process for the preparation of 2- (6'-methoxynaphth-2'-yl) -propionic acid, corresponding 5'-halogen compounds and intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62142138A (en) | 1987-06-25 |
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