JPH0436252A - Production of optically active alkinyl alcohol - Google Patents
Production of optically active alkinyl alcoholInfo
- Publication number
- JPH0436252A JPH0436252A JP2138391A JP13839190A JPH0436252A JP H0436252 A JPH0436252 A JP H0436252A JP 2138391 A JP2138391 A JP 2138391A JP 13839190 A JP13839190 A JP 13839190A JP H0436252 A JPH0436252 A JP H0436252A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- catalyst
- formula
- aliphatic
- expressed
- 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
- -1 alkinyl alcohol Chemical compound 0.000 title claims description 30
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 150000002430 hydrocarbons Chemical group 0.000 claims abstract description 7
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 4
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 4
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 4
- VCOJPHPOVDIRJK-UHFFFAOYSA-N 1-Methylpyrrolidine-2-methanol Chemical compound CN1CCCC1CO VCOJPHPOVDIRJK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001414 amino alcohols Chemical class 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000011701 zinc Substances 0.000 abstract description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 3
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 abstract description 3
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 abstract description 3
- 229960000395 phenylpropanolamine Drugs 0.000 abstract description 3
- 229910052725 zinc Inorganic materials 0.000 abstract description 3
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 150000003333 secondary alcohols Chemical class 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- 125000002723 alicyclic group Chemical group 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 150000001299 aldehydes Chemical class 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003446 ligand Substances 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical compound C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000005905 alkynylation reaction Methods 0.000 description 3
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- GUFUWKKDHIABBW-UHFFFAOYSA-N pyrrolidin-1-ylmethanol Chemical compound OCN1CCCC1 GUFUWKKDHIABBW-UHFFFAOYSA-N 0.000 description 2
- 238000006894 reductive elimination reaction Methods 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DZZWMODRWHHWFR-HNNXBMFYSA-N (1r)-1,3-diphenylprop-2-yn-1-ol Chemical compound C([C@H](O)C=1C=CC=CC=1)#CC1=CC=CC=C1 DZZWMODRWHHWFR-HNNXBMFYSA-N 0.000 description 1
- BRRGNOFUBFINSX-NVXWUHKLSA-N (1s,2r)-2-(dibutylamino)-1-phenylpropan-1-ol Chemical compound CCCCN(CCCC)[C@H](C)[C@@H](O)C1=CC=CC=C1 BRRGNOFUBFINSX-NVXWUHKLSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XIJAGFLYYNXCAB-KRWDZBQOSA-N [(2s)-1-methylpyrrolidin-2-yl]-diphenylmethanol Chemical compound CN1CCC[C@H]1C(O)(C=1C=CC=CC=1)C1=CC=CC=C1 XIJAGFLYYNXCAB-KRWDZBQOSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- GYHFUZHODSMOHU-UHFFFAOYSA-N nonanal Chemical compound CCCCCCCCC=O GYHFUZHODSMOHU-UHFFFAOYSA-N 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical compound [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
光学活性な第２級アルキニルアルコールは医薬、農薬等
の重要な合成原料である０本発明は、ジアルキニル亜鉛
を用いてアルデヒド基を持つ不飽和化合物を不斉アルキ
ニル化することによって、光学活性な第２級アルギニル
アルコールを製造する方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application Optically active secondary alkynyl alcohol is an important synthetic raw material for pharmaceuticals, agricultural chemicals, etc. The present invention uses dialkynyl zinc to synthesize unsaturated compounds with aldehyde groups. The present invention relates to a method for producing optically active secondary arginyl alcohol by asymmetric alkynylation.
従来の技術
光学活性な第２級アルキニルアルコールを得る方法とし
ては、従来からアルキニルケトンの還元、アルデヒドの
アルキニル化、及びアルキニルアセタールの還元的開裂
等の方法が知られている。たとえば、次の■〜■に示す
方法が挙げられる。BACKGROUND OF THE INVENTION Conventional methods for obtaining optically active secondary alkynyl alcohols include reduction of alkynyl ketones, alkynylation of aldehydes, and reductive cleavage of alkynyl acetals. For example, methods shown in the following (1) to (2) may be mentioned.
■ Ｒ，Ｎｏ７ｏｒｉ らのＪ、 Ａｍ、 Ｃｈ
ｅ＋ｓ−５ｅｅ−、１０８，８７１７（１９８４）に記
載されている、パイナフトールを不斉配位子として用い
、アルキニルケトンをリチウムアルミニウムハイドライ
ド等で還元する方法。■ J, Am, Ch of R, No7ori et al.
e+s-5ee-, 108, 8717 (1984), a method of reducing an alkynyl ketone with lithium aluminum hydride or the like using pinephthol as an asymmetric ligand.
■ Ｂ、Ｔ、ＣｈｏらのＢｕｌｌ、 Ｋｏｒｅａｎ Ｇ
ｂｅｍ、 Ｓｏｃ、、 ８゜２５７（１９８７）に記載
されている。グルコライド系の不斉配位子で修飾したポ
ロハイドライドでアルキニルケトンを還元する方法。■ Bull, Korean G by B, T, Cho et al.
bem, Soc, 8° 257 (1987). A method for reducing alkynyl ketones with polyhydrides modified with glucoride-based chiral ligands.
■ＴＪｕｋａｉｙａｍａらのＣｈｅｗ、 Ｌｅｔｔ、、
４４７（１８７’ｌ）に記載されている、ピロリジニ
ルメタノールを不斉配位子として用い、アセチレンをア
ルデヒドに付加する方法。■Chew, Lett, by Tjukaiyama et al.
447 (187'l), in which acetylene is added to an aldehyde using pyrrolidinylmethanol as an asymmetric ligand.
■に、ｌ５ｈｉｈａｒａ らのＴｅｔｒａｈｅｄｒｏｎ
Ｌｅｔｔ、、 ２８．９８３（１９８Ｂ）に記載され
ている、光学活性ジオールとケトンから得られたアセタ
ールをアルミニウムハイドライド等で還元開裂する方法
。In ■, Tetrahedron of l5hihara et al.
A method of reductive cleavage of an acetal obtained from an optically active diol and a ketone using aluminum hydride or the like, as described in J. Lett., 28.983 (198B).
■に、５ｏａｉ らのＣｈｅｗ、 Ｌｅｔｔ、 ４８１
（１９８９） ニ記載されている、ピロリジニルメタノ
ールを配位子として用い、アルキニルケトンを不斉アル
キル化する方法。■, Chew, Lett, 5oai et al., 481
(1989) D. A method for asymmetric alkylation of alkynyl ketones using pyrrolidinylmethanol as a ligand.
発明が解決しようとする課題
しかし前述の方法においては、たとえば■〜■において
は、いずれも光学活性をもたらすための不斉配位子とし
て高価な光学活性体を多量必要としたり、■においては
、原料のアルキニルケトンの合ｊ＆が煩雑かつ困難な手
法によるという欠点があった。Problems to be Solved by the Invention However, in the above-mentioned methods, for example, in (1) to (3), a large amount of an expensive optically active substance is required as an asymmetric ligand to bring about optical activity, and in (2), There was a drawback that the synthesis of the raw material alkynyl ketones was performed using a complicated and difficult method.
本発明は上記の課題を解決するもので、アルデヒドのア
ルキニル化による光学活性な第２級アルキニルアルコー
ルの合成を１反応剤よりずっと低いモル数の不斉源（本
発明ではこれを触媒という、）を使用して効率よく達成
する方法を提供するものである。The present invention solves the above problems, and aims to synthesize optically active secondary alkynyl alcohols by alkynylation of aldehydes using a chiral source with a much lower number of moles than one reactant (this is referred to as a catalyst in the present invention). This provides a method to efficiently achieve this using
課題を解決するための手段
本発明者は触媒として光学活性なアミン類を用い、アル
デヒド類をジアルキニル亜鉛で不斉アルキニル化するこ
とによって、本発明を完成した。Means for Solving the Problems The present inventor completed the present invention by asymmetrically alkynylating aldehydes with dialkynylzinc using optically active amines as catalysts.
即ち本発明は、アルデヒド基を有する不飽和化合物をジ
アルキニル亜鉛によって不斉アルキニル化することによ
って、下記一般式（Ｉ）で示される光学活性第２級アル
キニルアルコールを製造する方法において、
（但しＲ’、Ｒ２は炭化水素基を示し、脂肪族、環式脂
肪族、又は芳香族炭化水素基から選ばれる０本は光学活
性な炭素原子を示す、）下記一般式（ｎ）ジアルキルノ
ルエフェドリン、（ｍ）ジアルキル（１−メチルピロリ
ジン−２−イル）メタノール、及び（ＩＴ）ジアルキル
ピペラジンＣＵ）
（ｍ） （ＩＶ）
（但しＲ，Ｉ’ｒは水素原子又は炭化水素基を示し、炭
化水素としては、脂肪族、環式脂肪族、もしくは芳香族
から選ばれる０本は光学活性な炭素原子を示す、）
で示される光学活性なアミン類およびアミノアルコール
類を触媒として使用することを特徴とする光学活性アル
キニルアルコールの製造方法である。That is, the present invention provides a method for producing an optically active secondary alkynyl alcohol represented by the following general formula (I) by asymmetrically alkynylating an unsaturated compound having an aldehyde group with dialkynylzinc (where R' , R2 represents a hydrocarbon group, and 0 selected from aliphatic, cycloaliphatic, or aromatic hydrocarbon groups represents an optically active carbon atom) The following general formula (n) dialkylnorephedrine, (m ) dialkyl(1-methylpyrrolidin-2-yl)methanol, and (IT) dialkylpiperazine CU) (m) (IV) (where R and I'r represent a hydrogen atom or a hydrocarbon group, and as a hydrocarbon, Optical activity characterized by using optically active amines and amino alcohols represented by (0 selected from aliphatic, cycloaliphatic, or aromatic) represents an optically active carbon atom as a catalyst. This is a method for producing alkynyl alcohol.
本発明で触媒として用いられる光学活性アミン類のうち
、ジアルキルノルエフェドリンは、一般式（ＩＩ）で示
される構造を有し、Ｒ，Ｒ’は炭化水素基で脂肪族、環
式脂肪族、又は芳香族基から選ばれる。脂肪族基として
は炭素数１〜１２程度のものが代表的であるがこれに限
定するものではない、環式脂肪族または芳香族基として
は未置換のもの及びハロゲン若しくはニトロ基がｌ〜Ｓ
ａｔ換されたものを含む、ＲとＫは同一でも異なってい
てもよい。Among the optically active amines used as a catalyst in the present invention, dialkylnorephedrine has a structure represented by the general formula (II), where R and R' are hydrocarbon groups, and are aliphatic, cycloaliphatic, or selected from aromatic groups. Typical aliphatic groups include those with about 1 to 12 carbon atoms, but are not limited thereto; cycloaliphatic or aromatic groups include unsubstituted ones and halogen or nitro groups, such as l to S
R and K may be the same or different, including at-substituted ones.
代表的なものとしては次のようなものが挙げられる。Representative examples include:
（＋）−Ｎ、Ｎ−ジブチルノルエフェドリン（−）−Ｎ
、Ｎ−ジブチルノルエフェドリンこれらは一般に市販さ
れているノルエフェドリンとアルキルハライドとの反応
等により容易に誘導できる。(+)-N,N-dibutylnorephedrine (-)-N
, N-dibutylnorephedrine These can be easily derived by reacting commercially available norephedrine with an alkyl halide.
ジアルキル（ｌ−メチルピロリジン−２−イル）メタノ
ールは、一般式（ｍ）で示される構造を有し、Ｒ，には
水素、又は脂肪族、環式脂肪族、もしくは芳香族炭化水
素基から選ばれる。脂肪族基としては炭素数１〜１２程
度のものが代表的であるがこれに限定するものではない
、環式脂肪族または芳香族基としては未置換のもの及び
ハロゲン若しくはニトロ基が１〜５個置換されたものを
含む、ＲとＫは同一でも異なっていてもよい。Dialkyl(l-methylpyrrolidin-2-yl)methanol has a structure represented by general formula (m), where R is hydrogen, or an aliphatic, cycloaliphatic, or aromatic hydrocarbon group. It will be done. Typical aliphatic groups include those having about 1 to 12 carbon atoms, but are not limited thereto; cycloaliphatic or aromatic groups include unsubstituted ones and halogen or nitro groups with 1 to 5 carbon atoms. R and K may be the same or different, including substitutions.
代表的なものとしては次のものが挙げられる。Representative examples include:
（Ｓ）−（−）−ジフェニル（１メチルピロリジン−２
−イル）メタノール
これらは一般に市販されているプロリンからグリニアー
ル法によるアルキル化及びリチウムアルミニウムハイド
ライドによる還元により容易に誘導できるものである。(S)-(-)-diphenyl(1-methylpyrrolidine-2
-yl)methanol These can be easily derived from commercially available proline by alkylation by the Grignard method and reduction with lithium aluminum hydride.
ジアルキルピペラジンは、一般式（ＩＴ）で示される構
造を有し、Ｒ，には炭化水素基で脂肪族、環式脂肪族、
又は芳香族基から選ばれる。脂肪族基としては炭素数１
〜１２程度のものが代表的であるがこれに限定するもの
ではない、環式脂肪族または芳香族基としては未置換の
もの及びＩ＼ロゲン若しくはニトロ基が１〜５個置換さ
れたものを含む、ＲとＫは同一でも異なっていてもよい
。Dialkylpiperazine has a structure represented by the general formula (IT), where R is a hydrocarbon group such as aliphatic, cycloaliphatic,
or aromatic groups. As an aliphatic group, the number of carbon atoms is 1
The cycloaliphatic or aromatic group is typically about 12, but not limited to, unsubstituted and substituted with 1 to 5 I\rogen or nitro groups. Including, R and K may be the same or different.
代表的なものとしては次のものが挙げられる。Representative examples include:
（２Ｓ−５５）−ジ（フェニルメチル）ピペラジ二／こ
れらは一般に市販されているペプチド類の環状２量体と
して得られるジケトピペラジンのポロハイドライド−四
塩化炭素還元により容易に誘導できるものである。(2S-55)-Di(phenylmethyl)piperazidi/These can be easily derived by polyhydride-carbon tetrachloride reduction of diketopiperazine obtained as a cyclic dimer of commercially available peptides. .
原料として用いられるジアルキニル亜鉛は一般式（Ｖ）
で示される構造のもので、Ｒは脂肪族、環式脂肪族、も
しくは芳香族炭化水素基、又はシリル基を示し、これら
は同一でも異なっていてもよい。The dialkynyl zinc used as a raw material has the general formula (V)
In the structure shown, R represents an aliphatic, cycloaliphatic, or aromatic hydrocarbon group, or a silyl group, and these may be the same or different.
（ＲＣ＝ Ｃ）２２ｎ ・ ・ 争
（Ｖ）脂肪族基としては炭素数１〜１２程度のものが代
表的であるがこれに限定するものではない、環式脂肪族
又は芳香族基としては未置換のもの及びアルキル基、ハ
ロゲン、若しくはニトロ基が１〜５側置換したものを含
む。(RC=C)22n ・ ・ Conflict
(V) The aliphatic group typically has about 1 to 12 carbon atoms, but is not limited to this. Examples of the cycloaliphatic or aromatic group include unsubstituted alkyl groups, halogens, Alternatively, it includes those substituted with 1 to 5 nitro groups.
シリル基としては一般式Ｒ’Ｒ２Ｒ３Ｓｉで示されるト
リアルキルシリル基が用いられ、Ｒ１、Ｒ２−１Ｒ５ハ
アルキル基で炭素数１〜６のものが代表的であるがこれ
に限定するものではない、またこれらのアルキル基は同
一でも異なっていてもよい。As the silyl group, a trialkylsilyl group represented by the general formula R'R2R3Si is used, and a R1, R2-1R5 haalkyl group having 1 to 6 carbon atoms is typical, but is not limited to this. These alkyl groups may be the same or different.
ジアルキニル亜鉛類は対応するアルキニル系炭化水素と
ジエチル亜鉛から容易に合成できる。Dialkynylzincs can be easily synthesized from the corresponding alkynyl hydrocarbon and diethylzinc.
他方の原料であるアルデヒドとしては一般式（ＶＩ）で
示される構造を有し、Ｒは脂肪族、環式脂肪族、芳香族
炭化水素基、又はこれらに！ｉ換基を付加したもので総
炭素数１〜２０のものが代表的であるが、これらに限定
するものではない。The aldehyde, which is the other raw material, has a structure represented by the general formula (VI), and R is an aliphatic, cycloaliphatic, aromatic hydrocarbon group, or any of these! Those with an i substituent added thereto and having a total carbon number of 1 to 20 are typical, but are not limited to these.
ＲＣ：ＨＯ・・Φ （ＶＩ） 本発明の反応は次式のように進行する。RC:HO・・Φ (VI) The reaction of the present invention proceeds as shown in the following equation.
本発明の製造方法例においては、まず必要とするジアル
キニル亜鉛に対応するアルキニル化合物をヘキサン、テ
トラヒドロフラン、テトラヒドロビラン等の溶媒、又は
それらを混合した溶媒に溶解し、これにジエチル亜鉛を
加えた後、７０℃の浴中で５時間加温した後、室温まで
冷却してジアルキニル亜鉛を得る。In an example of the production method of the present invention, first, an alkynyl compound corresponding to the required dialkynylzinc is dissolved in a solvent such as hexane, tetrahydrofuran, tetrahydrobilane, or a mixed solvent thereof, and diethylzinc is added thereto. After heating in a 70°C bath for 5 hours, it is cooled to room temperature to obtain dialkynylzinc.
次にこの溶液に触媒、たとえばノルエフェドリンを加え
、室温で約２０分間攪拌する０次いでこれに原料アルデ
ヒドを加え、室温で約１４時間攪拌する０反応終了後Ｉ
Ｎ−ＨＣｔを加えて反応を停止させ、抽出・乾燥等の後
処理を経て製品を得る。Next, add a catalyst, such as norephedrine, to this solution and stir at room temperature for about 20 minutes.Next, add the raw material aldehyde to this and stir at room temperature for about 14 hours.After the reaction is completed, I
The reaction is stopped by adding N-HCt, and a product is obtained through post-treatments such as extraction and drying.
使用するアルデヒドとジアルキニル亜鉛のモル比は、ｌ
；ｌ〜３の範囲で、好ましくは１〜２前後である。触媒
量はアルデヒドに対するモル比で０．０５〜１．２であ
り、好ましくは０．０５〜０．５であるが、触媒量を上
げても光学純度が上らなくなるので、最も経済性のよい
のは、０．０５〜０．２の範囲である。 ０．０５〜０
−５の範囲では得られる不斉収率の変動は大きくはない
。The molar ratio of aldehyde and dialkynylzinc used is l
; in the range of 1 to 3, preferably around 1 to 2. The amount of catalyst is 0.05 to 1.2 in molar ratio to aldehyde, preferably 0.05 to 0.5, but since increasing the amount of catalyst does not increase the optical purity, it is the most economical method. ranges from 0.05 to 0.2. 0.05~0
In the range of -5, the variation in the asymmetric yield obtained is not large.
なお、アルキル亜鉛のアルデヒドへの付加反応はＢ、Ｍ
ａｒｘらがＣ−Ｒ，Ａｃａｄ、 Ｓｃｉ、、 ５ｅｔ−
Ｃ，２６４゜５２７（１９Ｂ？）に記載しているように
、無触媒では非常に起りにくく、またマグネシウムハラ
イドのような促進剤を加えると付加速度は上るが光学活
性体は得られない、たとえば
Ｅｔ２Ｚｎのｐｂｃｎｏへの付加は収率４０％、Ｅｔ２
ＺｎのＥｔＣ）１０への付加は収率５％と記載されてい
る。In addition, the addition reaction of alkylzinc to aldehyde is B, M
arx et al. CR, Acad, Sci, 5et-
C, 264° 527 (19B?), this is very unlikely to occur without a catalyst, and addition of a promoter such as magnesium halide increases the addition rate, but does not result in an optically active substance, e.g. Addition of Et2Zn to pbcno yields 40%, Et2
Addition of Zn to EtC) 10 is stated in 5% yield.
実施例 以下実施例を挙げて説明する。Example This will be explained below with reference to examples.
実施例１
４．０６ミリモルのエチニルベンゼンのテトラヒドロフ
ラン（ＴＨＦ）溶液（２シ）にジエチル亜鉛２．０ミリ
モルのヘキサン溶液（２−）を加えた。混合液を７０℃
の浴中で５時間加温した後室温に冷却した。Example 1 A hexane solution (2-) of 2.0 mmol diethylzinc was added to a solution (2-) of 4.06 mmol ethynylbenzene in tetrahydrofuran (THF). Mixed liquid at 70℃
After heating in a bath for 5 hours, the mixture was cooled to room temperature.
次に触媒として（Ｉｓ、 ２Ｒ）−（−）Ｎ、 Ｎ−ジ
ブチルノルエフェドリン０．０５ミリモルのＴＨＦ溶液
（１−）を加えて室温で２０分間攪拌した。Next, a THF solution (1-) of 0.05 mmol of (Is, 2R)-(-)N,N-dibutylnorephedrine (1-) was added as a catalyst, and the mixture was stirred at room temperature for 20 minutes.
次いでベンツアルデヒド１．０ミリモル（０，１５ｍ１
＞を加えて室温で１４時間攪拌した。 ｌＮ−ＨＣｌ
５＋＋ａＱを加えて反応を停止させた後、抽出・乾燥・
濃縮の精製操作を行い、０．２０２ｇの（Ｒ）−１，３
−ジフェニル−１プロピン−３−オールを得た（収率９
９％、純度８９％、不斉収率３４％ｅ、ｅ、） 、この
ものの旋光度は（（ａ ）２％＋ ２．２°（ｃ ８．
８３、ＣＨＣｌ３） ）であった。Then 1.0 mmol of benzaldehyde (0.15 ml
> and stirred at room temperature for 14 hours. lN-HCl
After adding 5++aQ to stop the reaction, extraction, drying,
Perform concentration purification operation to obtain 0.202 g of (R)-1,3
-diphenyl-1propyn-3-ol was obtained (yield 9
9%, purity 89%, asymmetric yield 34% e, e,), and the optical rotation of this product is ((a) 2% + 2.2° (c 8.
83, CHCl3)).
なお、純度と不斉収率は、ダイセルキラルセルＯＤ（光
学活性カラム）を用いた液体クロマトグラフィーにより
求めた。（分析条件二カラム長２５ｃ厘。Note that the purity and asymmetric yield were determined by liquid chromatography using Daicel Chiralcel OD (optical active column). (Analysis conditions: 2 columns, length 25 cm.
ＵＶ検出器、溶出液（２−プロパツールの１０％へキサ
ン溶液）、溶出速度１−／分０面積比大（優先）ピーク
の保持時間１３分０面積比小のピークの保持時間２４分
、）
実施例２
実施例１において触媒のみを（２Ｓ、 ５Ｓ）−ジ（フ
ェニルメチル）ピペラジンに代え、各原料の濃度・モル
比、温度条件等はすべて同様で反応を行った。UV detector, eluent (10% hexane solution of 2-propanol), elution rate 1-/min, retention time for 0 large area ratio (priority) peak 13 minutes, retention time for 0 small area ratio peak 24 minutes, ) Example 2 The reaction was carried out in Example 1 except that only the catalyst was replaced with (2S, 5S)-di(phenylmethyl)piperazine, and the concentrations, molar ratios, temperature conditions, etc. of each raw material were all the same.
その結果（Ｓ）−１，３−ジフェニル−ニープロピン−
３−オールを収率９１％、純度８９％、不斉収率１５％
ｅ、ｅ。As a result, (S)-1,3-diphenyl-nipropyne-
3-ol yield 91%, purity 89%, asymmetric yield 15%
e, e.
で得た。純度、不斉収率は実施例１と同様にして決定し
た。液クロ分析での優先（面積大）ピークの保持時間が
実施例１とは逆に２４分になることから、立体配置は（
Ｓ）である。I got it. Purity and asymmetric yield were determined in the same manner as in Example 1. Since the retention time of the priority (large area) peak in liquid chromatography analysis is 24 minutes, contrary to Example 1, the configuration is (
S).
実施例３
実施例１において触媒のみを（Ｓ）−（÷）−ジフェニ
ル（１−ピロリジン−２−イル）メタノールに代え。Example 3 In Example 1, only the catalyst was replaced with (S)-(÷)-diphenyl(1-pyrrolidin-2-yl)methanol.
その他は同様条件で反応を行った。その結果（Ｒ）−ｉ
、３−ジフェニル−１−プロピン−３−オールを収率９
２％、純度３９％、不斉収率４％ｅ、ｅ、で得た。The reaction was otherwise carried out under the same conditions. The result (R)-i
, 3-diphenyl-1-propyn-3-ol with a yield of 9
2%, purity 39%, and asymmetric yield 4% e, e.
実施例４
実施例１において原料のエチニルベンゼンの代わりにト
リメチルシリルアセチレン、ベンツアルデヒドの代わり
にｎ−ノニルアルデヒドを用い、同様のモル比、条件で
反応させた。その結果（Ｒ）−１−（２−）リメチルシ
リル）エチニル−ノナン−１−オールが収率８０％、純
度８９％、不斉収率２４％ｅ、ｅ、で得られた。Example 4 In Example 1, trimethylsilylacetylene was used instead of the raw materials ethynylbenzene, and n-nonylaldehyde was used instead of benzaldehyde, and the reaction was carried out under the same molar ratio and conditions. As a result, (R)-1-(2-)limethylsilyl)ethynyl-nonan-1-ol was obtained in a yield of 80%, purity of 89%, and asymmetric yield of 24%e,e.
発明の効果
本発明の方法により高収率で光学活性の第２級アルコー
ルが製造できる。Effects of the Invention By the method of the present invention, optically active secondary alcohols can be produced in high yield.
又、必要な触媒の量は従来の技術と異なり、極めて少量
で光学純度の高い化合物が得られる。またこれ以上触媒
、を増しても得られる効果は殆ど変わらない、また原料
のアルデヒドの調製が容易である。Moreover, the amount of catalyst required is different from that of conventional techniques, and a compound with high optical purity can be obtained with an extremely small amount. Further, even if the amount of catalyst is increased, the effect obtained will hardly change, and the aldehyde as a raw material can be easily prepared.
このように本発明の方法により、触媒量の不斉配位子の
使用により、光学活性ｔＭ４２級アルキニルアルコール
の合成が容易になった。As described above, the method of the present invention facilitates the synthesis of optically active tM4 secondary alkynyl alcohol by using a catalytic amount of an asymmetric ligand.
Claims (1)
を用いて不斉アルキニル化することによって、下記一般
式（ I ）で示される光学活性第２級アルキニルアルコ
ールを製造する方法において、 ▲数式、化学式、表等があります▼…（ I ） （但しＲ＾１、Ｒ＾２は炭化水素基を示し、脂肪族、環
式脂肪族、又は芳香族炭化水素基から選ばれる、＊は光
学活性な炭素原子を示す、） 下記一般式（II）ジアルキルノルエフェドリン、（III
）ジアルキル（１−メチルピロリジン−２−イル）メタ
ノール、及び（IV）ジアルキルピペラジン（II）（III
）（IV） ▲数式、化学式、表等があります▼▲数式、化学式、表
等があります▼▲数式、化学式、表等があります▼ （但しＲ、Ｒ′は水素原子又は炭化水素基を示し、炭化
水素としては、脂肪族、環式脂肪族、もしくは芳香族か
ら選ばれる、＊は光学活性な炭素原子を示す。） で示される光学活性なアミン類およびアミノアルコール
類を触媒として使用することを特徴とする光学活性アル
キニルアルコールの製造方法。[Claims] A method for producing an optically active secondary alkynyl alcohol represented by the following general formula (I) by asymmetrically alkynylating an unsaturated compound having an aldehyde group using dialkynylzinc, ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (However, R^1 and R^2 represent hydrocarbon groups, and are selected from aliphatic, cycloaliphatic, or aromatic hydrocarbon groups, * indicates (representing an optically active carbon atom), the following general formula (II) dialkylnorephedrine, (III
) dialkyl(1-methylpyrrolidin-2-yl)methanol, and (IV) dialkylpiperazine (II) (III
) (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R and R' represent hydrogen atoms or hydrocarbon groups, The hydrocarbon is selected from aliphatic, cycloaliphatic, or aromatic, and * indicates an optically active carbon atom.) It is recommended to use optically active amines and amino alcohols as a catalyst. Characteristic method for producing optically active alkynyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2138391A JPH0436252A (en) | 1990-05-30 | 1990-05-30 | Production of optically active alkinyl alcohol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2138391A JPH0436252A (en) | 1990-05-30 | 1990-05-30 | Production of optically active alkinyl alcohol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0436252A true JPH0436252A (en) | 1992-02-06 |
Family
ID=15220849
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2138391A Pending JPH0436252A (en) | 1990-05-30 | 1990-05-30 | Production of optically active alkinyl alcohol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0436252A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996037457A1 (en) * | 1995-05-25 | 1996-11-28 | Merck & Co., Inc. | Asymmetric synthesis of (-) 6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2h-3,1-benzoxazin-2-one |
| WO1998027073A1 (en) * | 1996-12-16 | 1998-06-25 | Dupont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones |
| KR100708560B1 (en) * | 1999-10-13 | 2007-04-19 | 엔.브이.오가논 | Orally disintegrating composition comprising mirtazapine |
| JP2007297285A (en) * | 2006-04-27 | 2007-11-15 | Kobe Univ | Method for preparing optically active hydroxy compound |
-
1990
- 1990-05-30 JP JP2138391A patent/JPH0436252A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996037457A1 (en) * | 1995-05-25 | 1996-11-28 | Merck & Co., Inc. | Asymmetric synthesis of (-) 6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2h-3,1-benzoxazin-2-one |
| WO1998027073A1 (en) * | 1996-12-16 | 1998-06-25 | Dupont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones |
| CZ297168B6 (en) * | 1996-12-16 | 2006-09-13 | Dupont Pharmaceuticals Company | Novel method for asymmetric synthesis of benzoxazinone derivative |
| KR100708560B1 (en) * | 1999-10-13 | 2007-04-19 | 엔.브이.오가논 | Orally disintegrating composition comprising mirtazapine |
| JP2007297285A (en) * | 2006-04-27 | 2007-11-15 | Kobe Univ | Method for preparing optically active hydroxy compound |
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