JPH10136993A - Synthesis of butyrophenone-based compound intermediate - Google Patents
Synthesis of butyrophenone-based compound intermediateInfo
- Publication number
- JPH10136993A JPH10136993A JP8299037A JP29903796A JPH10136993A JP H10136993 A JPH10136993 A JP H10136993A JP 8299037 A JP8299037 A JP 8299037A JP 29903796 A JP29903796 A JP 29903796A JP H10136993 A JPH10136993 A JP H10136993A
- Authority
- JP
- Japan
- Prior art keywords
- fluorophenyl
- chloro
- butanol
- lipase
- butyrophenone
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 14
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 230000015572 biosynthetic process Effects 0.000 title description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 29
- 108090001060 Lipase Proteins 0.000 claims abstract description 20
- 102000004882 Lipase Human genes 0.000 claims abstract description 20
- 239000004367 Lipase Substances 0.000 claims abstract description 20
- 235000019421 lipase Nutrition 0.000 claims abstract description 20
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims description 9
- -1 butyrophenone compound Chemical class 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 2
- 239000012279 sodium borohydride Substances 0.000 abstract description 2
- 239000000164 antipsychotic agent Substances 0.000 abstract 1
- 229940005529 antipsychotics Drugs 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- 229960003878 haloperidol Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WNZBBTJFOIOEMP-UHFFFAOYSA-N Hydroxyhaloperidol Chemical compound C=1C=C(F)C=CC=1C(O)CCCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 WNZBBTJFOIOEMP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000002036 chloroform fraction Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- SHBHYINHXNTBRP-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-methylsulfonylethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCS(=O)(=O)C)C=CC=1 SHBHYINHXNTBRP-UHFFFAOYSA-N 0.000 description 1
- UHSBCAJZDUQTHH-UHFFFAOYSA-N 3-hydroxyhexan-2-one Chemical compound CCCC(O)C(C)=O UHSBCAJZDUQTHH-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- RKLNONIVDFXQRX-UHFFFAOYSA-N Bromperidol Chemical compound C1CC(O)(C=2C=CC(Br)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 RKLNONIVDFXQRX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 101710098556 Lipase A Proteins 0.000 description 1
- 101710099648 Lysosomal acid lipase/cholesteryl ester hydrolase Proteins 0.000 description 1
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002973 anti-dopamine Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 229960004037 bromperidol Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、ラセミ体の４−ク
ロロ−４’−フロロフェニル−１−ブタノールにリパー
ゼ存在下で酢酸ビニルを反応させることを特徴とする、
ブチロフェノン系化合物中間体の合成方法に関する。本
発明により、簡便且つ収率良く、ブチロフェノン系化合
物中間体である（Ｒ）及び（Ｓ）−４−クロロ−４’−
フロロフェニル−１−ブタノールを立体選択的に合成す
ることができる。TECHNICAL FIELD The present invention is characterized by reacting racemic 4-chloro-4'-fluorophenyl-1-butanol with vinyl acetate in the presence of lipase.
The present invention relates to a method for synthesizing a butyrophenone-based compound intermediate. According to the present invention, butyrophenone-based compound intermediates (R) and (S) -4-chloro-4'-
Fluorophenyl-1-butanol can be synthesized stereoselectively.
【０００２】[0002]
【従来の技術】従来より、ハロペリドールはメジャート
ランキライザー（向精神薬）として、精神分裂病或いは
躁病等の疾患に内服又は注射により多く用いられてい
る。ハロペリドールは抗ドパミン作用を有し、不安、緊
張、興奮状態、幻覚、妄想などを迅速且つ強力に抑制す
る。ところで、薬物の代謝物を探索し、その効果を調
べ、薬物の副作用低減や吸収性の増大（薬効の上昇）を
目的とするいわゆるプロドラッグ化が行われている。ハ
ロペリドールもその一つであり、この薬物は体内で代謝
され、還元型ハロペリドールをその代謝物として生じる
ことが知られており、その代謝物に少なからず活性を有
することも知られている。この還元型ハロペリドールは
不斉炭素を有するため、立体異性体が存在することが考
えられるが、体内代謝物にその異性体が存在すること
は、未だ確認されていないのが現状である。しかし、そ
の立体異性体を有機合成によって合成する方法が報告さ
れている（J.C.Jean et al., Pharm. Res., Vol.8, p10
02 (1991) ：化１）。2. Description of the Related Art Hitherto, haloperidol has been widely used as a major tranquilizer (psychotropic drug) by internal administration or injection for diseases such as schizophrenia or mania. Haloperidol has an anti-dopamine action and rapidly and strongly suppresses anxiety, tension, arousal, hallucinations, delusions, and the like. By the way, so-called prodrugs have been used for the purpose of searching for metabolites of drugs, examining their effects, and reducing the side effects of drugs and increasing the absorbability (increase of drug efficacy). Haloperidol is one of them, and it is known that this drug is metabolized in the body to produce reduced haloperidol as its metabolite, and it is also known that the drug has some activity. Since this reduced form of haloperidol has an asymmetric carbon atom, it is considered that a stereoisomer is present. However, the existence of the isomer in metabolites in the body has not yet been confirmed. However, a method of synthesizing the stereoisomer by organic synthesis has been reported (JC Jean et al., Pharm. Res., Vol. 8, p10
02 (1991): Chemical 1).
【０００３】[0003]
【化１】 Embedded image
【０００４】しかし、上述の方法では、合成された還元
型ハロペリドールは不斉炭素を有するために、ＨＰＬＣ
を用いて（Ｒ）及び（Ｓ）体を立体選択的に分離しなけ
ればならず、又、それぞれの異性体の収率も非常に低い
（１％）。このような状況から、さらに簡便且つ収率良
く立体異性体を合成できる方法が求められていた。However, in the above-mentioned method, the synthesized reduced haloperidol has an asymmetric carbon, so
And the (R)-and (S) -isomers must be separated stereoselectively, and the yield of each isomer is very low (1%). Under such circumstances, a method capable of synthesizing a stereoisomer more easily and with high yield has been demanded.
【０００５】[0005]
【発明が解決しようとする課題】本発明者らは、上述の
状況に鑑み鋭意研究の結果、リパーゼ存在下で酢酸ビニ
ルを反応させることにより、簡便且つ収率良く、ブチロ
フェノン系化合物の中間体である（Ｒ）及び（Ｓ）−４
−クロロ−４’−フロロフェニル−１−ブタノールを立
体選択的に合成する方法を見出した。即ち、本発明は、
ラセミ体の４−クロロ−４’−フロロフェニル−１−ブ
タノールにリパーゼ存在下で酢酸ビニルを反応させるこ
とを特徴とする、（Ｒ）及び（Ｓ）−４−クロロ−４’
−フロロフェニル−１−ブタノールの簡便且つ収率の良
い立体選択的な合成方法を提供することを課題とする。DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies in view of the above situation, and as a result, have found that by reacting vinyl acetate in the presence of lipase, the intermediate of a butyrophenone compound can be obtained easily and with good yield. Certain (R) and (S) -4
A method for stereoselectively synthesizing -chloro-4'-fluorophenyl-1-butanol was found. That is, the present invention
(R) and (S) -4-chloro-4 ', characterized by reacting racemic 4-chloro-4'-fluorophenyl-1-butanol with vinyl acetate in the presence of lipase.
It is an object of the present invention to provide a simple and selective stereoselective synthesis method of -fluorophenyl-1-butanol.
【０００６】[0006]
【課題を解決するための手段】本発明は、ラセミ体の４
−クロロ−４’−フロロフェニル−１−ブタノールにリ
パーゼ存在下で酢酸ビニルを反応させることを特徴とす
る、ブチロフェノン系化合物中間体の合成方法に関す
る。本発明により、簡便且つ収率良く、ブチロフェノン
系化合物中間体である（Ｒ）及び（Ｓ）−４−クロロ−
４’−フロロフェニル−１−ブタノールを、立体選択的
に合成することができる。得られた（Ｒ）及び（Ｓ）−
４−クロロ−４’−フロロフェニル−１−ブタノール
は、ブチロフェノン系化合物、例えばハロペリドール、
ブロムペリドール、ジヒドロハロペリドール、ジヒドロ
ブロムペリドールなどの合成の中間体、特に立体異性体
の合成中間体として有用である。DISCLOSURE OF THE INVENTION The present invention provides a racemic 4
The present invention relates to a method for synthesizing a butyrophenone-based compound intermediate, which comprises reacting -chloro-4'-fluorophenyl-1-butanol with vinyl acetate in the presence of lipase. According to the present invention, butyrophenone-based compound intermediates (R) and (S) -4-chloro-
4′-Fluorophenyl-1-butanol can be synthesized stereoselectively. The obtained (R) and (S)-
4-Chloro-4′-fluorophenyl-1-butanol is a butyrophenone-based compound such as haloperidol,
It is useful as an intermediate in the synthesis of bromperidol, dihydrohaloperidol, dihydrobromoperidol, and the like, particularly as a synthetic intermediate of a stereoisomer.
【０００７】[0007]
【発明の実施の形態】本発明の合成方法は、以下の化２
の方法により行われる。即ち、ラセミ体であるＤＬ−４
−クロロ−４’−フロロフェニル−１−ブタノールを適
当な溶媒に溶解し、リパーゼ存在下でビニルアセテート
を加える。この時、溶媒は特に限定されないが、tert−
ブチルメチルエーテルが好ましい。又、リパーゼは特に
限定されないが、好ましくはリパーゼＡＫ、リパーゼＡ
Ｙ、リパーゼＡＨ、リパーゼＡＹ「アマノ」３０、リパ
ーゼＭ「アマノ」１０（全て天野製薬社）、特に好まし
くはリパーゼＰＳ（天野製薬社）が挙げられる。この反
応を１０〜５０時間、特に好ましくは２０〜３０時間行
い、反応液をカラムクロマトグラフィーに付すことによ
り、（Ｒ）−４−クロロ−４’−フロロフェニル−１−
アセチルブタノールを得ることができる。これを常法に
より加水分解することにより、（Ｒ）−４−クロロ−
４’−フロロフェニル−１−ブタノールが得られる。
又、前述と同様にＤＬ−４−クロロ−４’−フロロフェ
ニル−１−ブタノールを適当な溶媒に溶解、リパーゼ存
在下でビニルアセテートを加え、１００〜３００時間、
特に好ましくは１２０時間〜２６０時間反応を行う。反
応液の溶媒を留去し、残渣をカラムクロマトグラフィー
に付すことにより、（Ｓ）−４−クロロ−４’−フロロ
フェニル−１−ブタノールを得ることができる。BEST MODE FOR CARRYING OUT THE INVENTION The synthesis method of the present invention is represented by the following chemical formula 2.
The method is performed in the following manner. That is, the racemic DL-4
-Chloro-4'-fluorophenyl-1-butanol is dissolved in a suitable solvent, and vinyl acetate is added in the presence of lipase. At this time, the solvent is not particularly limited, but tert-
Butyl methyl ether is preferred. The lipase is not particularly limited, but is preferably lipase AK, lipase A
Y, lipase AH, lipase AY "Amano" 30, lipase M "Amano" 10 (all from Amano Pharmaceutical), particularly preferably lipase PS (Amano Pharmaceutical). This reaction is carried out for 10 to 50 hours, particularly preferably 20 to 30 hours, and the reaction solution is subjected to column chromatography to give (R) -4-chloro-4'-fluorophenyl-1-.
Acetylbutanol can be obtained. This is hydrolyzed by a conventional method to give (R) -4-chloro-
4'-Fluorophenyl-1-butanol is obtained.
In the same manner as described above, DL-4-chloro-4′-fluorophenyl-1-butanol was dissolved in an appropriate solvent, and vinyl acetate was added in the presence of lipase, and the mixture was added for 100 to 300 hours.
Particularly preferably, the reaction is carried out for 120 hours to 260 hours. By evaporating the solvent of the reaction solution and subjecting the residue to column chromatography, (S) -4-chloro-4′-fluorophenyl-1-butanol can be obtained.
【０００８】[0008]
【化２】 Embedded image
【０００９】[0009]
【実施例】以下の実施例をもって本発明をより詳細に説
明するが、これらは単に例示したのみであり、これらに
よって本発明は何ら限定されるものではない。The present invention will be described in more detail with reference to the following examples, which are merely illustrative, and do not limit the present invention in any way.
【００１０】[0010]
【実施例１】Ｒ体の製造方法 ４−クロロ−４’−フロロフェニル−１−ブタノン（東
京化成社）１．２ｇを水素化ホウ素ナトリウム（和光純
薬社）０．２ｇで還元し、４−クロロ−４’−フロロフ
ェニル−１−ブタノールを得た。この４−クロロ−４’
−フロロフェニル−１−ブタノール１ｇをtert−ブチル
メチルエーテル（和光純薬社）２０ｍｌに溶かし、これ
にリパーゼＰＳ（天野製薬社）５００ｍｇ、酢酸ビニル
（和光純薬社）３ｇを加え、３０℃で２７．５時間撹拌
した。この溶液を濾紙で濾過したのち、母液の溶媒を留
去した。残渣をシリカゲル（ワコーゲルＣ−２００、和
光純薬社）を用いたカラムクロマトグラフィーに付し、
クロロホルム留分からアセチル体を２１０ｍｇ得た。次
に、このアセチル体２１０ｍｇをエーテル２０ｍｌに溶
かし、２０％ＮａＯＨ水溶液を３ｍｌ加え、５時間室温
で撹拌した。エーテル層を分離し水洗した後、Ｎａ2 Ｓ
Ｏ4 で乾燥した。溶媒を留去することにより、化合物１
３０ｍｇが得られた。本化合物の性質を確認したとこ
ろ、施光度 [α] D ＝＋５８．７であり、又その他の物
性値も文献に記載されているデータと完全に一致したこ
とから、（Ｒ）−４−クロロ−４’−フロロフェニル−
１−ブタノールであることが確認された。Example 1 Method for producing R-isomer 1.2 g of 4-chloro-4′-fluorophenyl-1-butanone (Tokyo Kasei) was reduced with 0.2 g of sodium borohydride (Wako Pure Chemical Industries), and -Chloro-4'-fluorophenyl-1-butanol was obtained. This 4-chloro-4 '
1 g of fluorophenyl-1-butanol was dissolved in 20 ml of tert-butyl methyl ether (Wako Pure Chemical), 500 mg of lipase PS (Amano Pharmaceutical) and 3 g of vinyl acetate (Wako Pure Chemical) were added, and the mixture was added at 30 ° C. Stirred for 27.5 hours. After the solution was filtered with filter paper, the solvent of the mother liquor was distilled off. The residue was subjected to column chromatography using silica gel (Wakogel C-200, Wako Pure Chemical Industries),
210 mg of an acetyl form was obtained from the chloroform fraction. Next, 210 mg of the acetyl compound was dissolved in 20 ml of ether, 3 ml of a 20% aqueous NaOH solution was added, and the mixture was stirred at room temperature for 5 hours. After the ether layer was separated and washed with water, Na 2 S
Dried over O 4 . By distilling off the solvent, compound 1
30 mg were obtained. When the properties of this compound were confirmed, it was found that the degree of luminous intensity [α] D = + 58.7 and the other physical properties were completely consistent with the data described in the literature. -4'-Fluorophenyl-
It was confirmed to be 1-butanol.
【００１１】[0011]
【実施例２】Ｓ体の製造方法 実施例１と同様の方法により得られた４−クロロ−４’
−フロロフェニル−１−ブタノール１ｇをtert−ブチル
メチルエーテル（和光純薬社）２０ｍｌに溶かし、これ
にリパーゼＰＳ（天野製薬社）５００ｍｇ、酢酸ビニル
（和光純薬社）３ｇを加え、３０℃で１４０時間撹拌し
た。この溶液を濾紙で濾過したのち、母液の溶媒を留去
した。残渣をシリカゲル（ワコーゲルＣ−２００、和光
純薬社）を用いたカラムクロマトグラフィーに付し、ク
ロロホルム留分から、化合物４２０ｍｇが得られた。本
化合物の性質を確認したところ、施光度 [α] D ＝−３
６．６であり、又その他の物性値も文献に記載されてい
るデータと完全に一致したことから、（Ｓ）−４−クロ
ロ−４’−フロロフェニル−１−ブタノールであること
が確認された。Example 2 Method for producing S-isomer 4-chloro-4 ′ obtained by the same method as in Example 1
1 g of fluorophenyl-1-butanol was dissolved in 20 ml of tert-butyl methyl ether (Wako Pure Chemical), 500 mg of lipase PS (Amano Pharmaceutical) and 3 g of vinyl acetate (Wako Pure Chemical) were added, and the mixture was added at 30 ° C. Stir for 140 hours. After the solution was filtered with filter paper, the solvent of the mother liquor was distilled off. The residue was subjected to column chromatography using silica gel (Wakogel C-200, Wako Pure Chemical Industries, Ltd.) to obtain 420 mg of a compound from a chloroform fraction. When the properties of this compound were confirmed, the degree of luminescence [α] D = −3
6.6, and the other physical properties were completely consistent with the data described in the literature. Thus, it was confirmed to be (S) -4-chloro-4′-fluorophenyl-1-butanol. Was.
【００１２】[0012]
【発明の効果】以上の結果より、本発明によりラセミ体
の４−クロロ−４’−フロロフェニル−１−ブタノール
にリパーゼ存在下で酢酸ビニルを反応させることを特徴
とする、ブチロフェノン系化合物中間体の合成方法が提
供される。本発明により、簡便且つ収率良く、ブチロフ
ェノン系化合物中間体である（Ｒ）及び（Ｓ）−４−ク
ロロ−４’−フロロフェニル−１−ブタノールを、立体
選択的に合成することができる。又、得られたＲ体及び
Ｓ体の化合物をそれぞれ用いることにより、立体選択的
にブチロフェノン系化合物が合成された。As can be seen from the above results, according to the present invention, a butyrophenone compound intermediate is obtained by reacting racemic 4-chloro-4'-fluorophenyl-1-butanol with vinyl acetate in the presence of lipase. Are provided. According to the present invention, (R) and (S) -4-chloro-4′-fluorophenyl-1-butanol, which are butyrophenone-based compound intermediates, can be synthesized stereoselectively in a simple and high yield. By using the obtained R-form and S-form compounds, a butyrophenone-based compound was synthesized stereoselectively.
Claims (3)
ェニル−１−ブタノールにリパーゼ存在下で酢酸ビニル
を反応させることを特徴とする、ブチロフェノン系化合
物中間体の合成方法。1. A method for synthesizing a butyrophenone-based compound intermediate, comprising reacting racemic 4-chloro-4′-fluorophenyl-1-butanol with vinyl acetate in the presence of a lipase.
ことにより（Ｒ）−４−クロロ−４’−フロロフェニル
−１−ブタノールを得ることを特徴とする、請求項１記
載のブチロフェノン系化合物中間体の合成方法。2. The butyrophenone compound intermediate according to claim 1, wherein (R) -4-chloro-4′-fluorophenyl-1-butanol is obtained by reacting the lipase for about 10 to 50 hours. How to synthesize the body.
せることにより（Ｓ）−４−クロロ−４’−フロロフェ
ニル−１−ブタノールを得ることを特徴とする、請求項
１記載のブチロフェノン系化合物中間体の合成方法。3. The butyrophenone compound intermediate according to claim 1, wherein (S) -4-chloro-4′-fluorophenyl-1-butanol is obtained by reacting the lipase for about 100 to 300 hours. How to synthesize the body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8299037A JPH10136993A (en) | 1996-11-11 | 1996-11-11 | Synthesis of butyrophenone-based compound intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8299037A JPH10136993A (en) | 1996-11-11 | 1996-11-11 | Synthesis of butyrophenone-based compound intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10136993A true JPH10136993A (en) | 1998-05-26 |
Family
ID=17867404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8299037A Pending JPH10136993A (en) | 1996-11-11 | 1996-11-11 | Synthesis of butyrophenone-based compound intermediate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH10136993A (en) |
-
1996
- 1996-11-11 JP JP8299037A patent/JPH10136993A/en active Pending
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