JPS6341376B2 - - Google Patents
Info
- Publication number
- JPS6341376B2 JPS6341376B2 JP56128236A JP12823681A JPS6341376B2 JP S6341376 B2 JPS6341376 B2 JP S6341376B2 JP 56128236 A JP56128236 A JP 56128236A JP 12823681 A JP12823681 A JP 12823681A JP S6341376 B2 JPS6341376 B2 JP S6341376B2
- Authority
- JP
- Japan
- Prior art keywords
- methylnon
- hydroxy
- formula
- group
- enes
- 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 t-butyldimethylsilyl group Chemical group 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000001711 saccadic effect Effects 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 150000001875 compounds Chemical group 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 238000006596 Alder-ene reaction Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- KZZNMIMGMUSNMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene-2,3-diol Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=C(C=3O)O)=CC=CC2=C1 KZZNMIMGMUSNMW-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は３（Ｓ）−ヒドロキシ−５−メチルノナ
−１−エン類およびその製造法に関する。更に詳
細には本発明はプロスタグランジン類の合成中間
体として有用な光学活性体である３（Ｓ）−ヒドロ
キシ−５（Ｓ）又は（Ｒ）−メチルノナ−１−エン
類およびその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3(S)-hydroxy-5-methylnon-1-enes and a method for producing the same. More specifically, the present invention relates to 3(S)-hydroxy-5(S) or (R)-methylnon-1-enes, which are optically active substances useful as synthetic intermediates for prostaglandins, and a method for producing the same. .
しかして本発明によれば、下記式〔〕
〔式中、Ｘはハロゲン原子、Ａは水素原子又は
水酸基の保護基を表わす。〕
で表わされる３（Ｓ）−ヒドロキシ−５（Ｓ）又は
（Ｒ）−メチルノナ−１−エン類が提供される。 According to the present invention, the following formula [] [In the formula, X represents a halogen atom, and A represents a hydrogen atom or a hydroxyl group-protecting group. ] 3(S)-hydroxy-5(S) or (R)-methylnon-1-enes represented by these are provided.
上記式〔〕において５位の炭素原子は不斎炭
素原子であるため、本発明の３（Ｓ）−ヒドロキシ
−５−メチルノナ−１−エン類は次の化合物群を
包含する。 Since the carbon atom at the 5th position in the above formula [] is an inhospitable carbon atom, the 3(S)-hydroxy-5-methylnon-1-enes of the present invention include the following compound group.
すなわち、下記式〔−１〕
〔式中Ａ、Ｘは式〔〕に同じ〕
で表わされる３（Ｓ）−ヒドロキシ−５（Ｓ）−メチ
ルノナ−１−エン類、および下記式〔−２〕
〔式中、Ａ、Ｘは式〔〕に同じ。〕
で表わされる３（Ｓ）−ヒドロキシ−５（Ｒ）−メチ
ルノナ−１−エン類である。 That is, the following formula [-1] [In the formula, A and X are the same as the formula []] 3(S)-hydroxy-5(S)-methylnon-1-enes represented by the following formula [-2] [In the formula, A and X are the same as in the formula []. ] These are 3(S)-hydroxy-5(R)-methylnon-1-enes represented by the following.
本発明の如きアリルアルコール類として、特開
昭55−149217号公報には一般式
〔式中、R1は単結合、又は炭素数１〜４の直
鎖もしくは分枝鎖アルキレン基を表わし、R2は
水素原子、又は炭素数１〜８の直鎖もしくは分枝
鎖アルキル基、又は置換されていないか少なくと
も一個の炭素数１〜８の直鎖もしくは分枝鎖アル
キル基で置換されている炭素数４〜７のシクロア
ルキル基、又は置換されていないか少なくとも一
個のハロゲン原子、トリフルオロメチル基、炭素
数１〜４の低級アルキル基で置換されているフオ
ニル又はフエノキシ基を表わし、Ｘはハロゲン原
子を表わし、二重結合はトランスを表わす。〕
で表わされるアリルアルコールが記載されてい
る。しかしながら上記公報には本発明の如く、そ
の３位のヒドロキシ基、及びその５位のメチル基
が結合した不整炭素原子がともにＳ又はＲ−配置
のいずれかである光学活性なアルコール類は記載
されていてよい。 As allyl alcohols as used in the present invention, JP-A-55-149217 discloses the general formula [In the formula, R 1 represents a single bond or a straight chain or branched alkylene group having 1 to 4 carbon atoms, and R 2 represents a hydrogen atom or a straight chain or branched alkyl group having 1 to 8 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms which is unsubstituted or substituted with at least one linear or branched alkyl group having 1 to 8 carbon atoms, or unsubstituted or having at least one halogen atom, It represents a trifluoromethyl group, a phonyl or phenoxy group substituted with a lower alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and the double bond represents trans. ] Allyl alcohol represented by these is described. However, the above-mentioned publication does not describe optically active alcohols in which the asymmetric carbon atom to which the hydroxy group at the 3-position and the methyl group at the 5-position are bonded are either S- or R-configuration, as in the present invention. It's okay to stay.
そして本発明で提供される上記式〔〕の３
（Ｓ）−ヒドロキシ−５（Ｓ）又は（Ｒ）−メチルノ
ナ−１−エン類は、例えば次のフローシート−
１、
で示されるように、上記式〔−１〕で表わされ
る３（Ｓ）−ヒドロキシ−５（Ｓ）−メチルノナ−１
−エン類を用いた時には、上記フローシート−１
の(5)で表わされるようにその15位及び17位が共に
Ｓ−配置である光学活性な４−チアプロスタグラ
ンジン類に導びくことができる（かかる製造法に
関しては本発明者らはすでに特願昭56−50491に
おいて提案している）。このように本発明の３
（Ｓ）−ヒドロキシ−５（Ｓ）又は（Ｒ）−メチルノ
ナ−１−エン類は光学活性なプロスタグランジン
類に導びくことが可能である。そして上記の如き
４−チアプロスタグランジン類は、平滑筋、血
圧、脂質代謝、血小板凝集等に作用する医薬品と
して有用であり、それ故に本発明の３（Ｓ）−ヒド
ロキシ−５（Ｓ）又は（Ｒ）−メチルノナ−１−エ
ン類はプロスタグランジン類等の医薬品の中間体
として極めて有用なものである。 And 3 of the above formula [] provided by the present invention
(S)-Hydroxy-5(S) or (R)-methylnon-1-enes can be used, for example, in the following flow sheet -
1, As shown, 3(S)-hydroxy-5(S)-methylnona-1 represented by the above formula [-1]
-When using enes, the above flow sheet-1
As shown in (5), optically active 4-thiaprostaglandins in which both the 15th and 17th positions are in the S-configuration can be obtained (the present inventors have already reported on such a production method). (proposed in patent application No. 56-50491). In this way, the third aspect of the present invention
(S)-hydroxy-5(S) or (R)-methylnon-1-enes can lead to optically active prostaglandins. The above-mentioned 4-thiaprostaglandins are useful as pharmaceuticals that act on smooth muscle, blood pressure, lipid metabolism, platelet aggregation, etc. Therefore, the 3(S)-hydroxy-5(S) or (R)-Methylnon-1-enes are extremely useful as intermediates for pharmaceuticals such as prostaglandins.
本発明で提供される上記式〔〕で表わされる
３（Ｓ）−ヒドロキシ−５（Ｓ）又は（Ｒ）−メチル
ノナ−１−エン類において、Ｘはハロゲン原子で
あり、かかるハロゲン原子としては、例えばフツ
素原子、塩素原子、臭素原子、ヨウ素原子が挙げ
られるが、特にヨウ素原子がプロスタグランジン
類の中間体として好ましい。 In the 3(S)-hydroxy-5(S) or (R)-methylnon-1-enes represented by the above formula [] provided by the present invention, X is a halogen atom, and the halogen atom is Examples include fluorine atom, chlorine atom, bromine atom, and iodine atom, and iodine atom is particularly preferred as an intermediate for prostaglandins.
Ａの水酸基の保護基としては、例えば、メトキ
シメチル基、１−エトキシエチル基、２−エトキ
シ−２−プロピル基、２−テトラヒドロピラニル
基等のエーテル結合を有する基；トリメチルシリ
ル基、ｔ−ブチルジフエニルシリル基、ジメチル
−ｔ−ブチルシリル基等のトリ（C1〜C7）炭化
水素シリル基などがあるが、好ましくはジメチル
−ｔ−ブチルシリル基である。 As the protecting group for the hydroxyl group of A, for example, groups having an ether bond such as methoxymethyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, 2-tetrahydropyranyl group; trimethylsilyl group, t-butyl group. Examples include tri( C1 - C7 ) hydrocarbon silyl groups such as diphenylsilyl group and dimethyl-t-butylsilyl group, and dimethyl-t-butylsilyl group is preferred.
かかる上記式〔〕の化合物の好ましい具体例
として、例えば次の如き化合物を例示することが
できる。 Preferred specific examples of the compound of the above formula [] include the following compounds.
３（Ｓ）−ヒドロキシ−１−ヨードー５（Ｓ）−
メチルノナ−１−エン，
３（Ｓ）−ヒドロキシ−１−ヨードー５（Ｒ）−
メチルノナ−１−エン，
３（Ｓ）−ｔ−ブチルジメチルシリルオキシ−
１−ヨード−５（Ｓ）−メチルノナ−１−エ
ン，
３（Ｓ）−ｔ−ブチルジメチルシリルオキシ−
１−ヨード−５（Ｒ）−メチルノナ−１−エ
ン，
本発明の上記式〔〕で表わされる３（Ｓ）−ヒ
ドロキシ−５（Ｓ）又は（Ｒ）−メチルノナ−１−
エン類は、下記式〔〕
〔式中、Ｘは上記定義に同じ。〕
で表わされるエノン類を下記式〔〕
で表わされる不斎還元剤で不斎還元し、次いで必
要に応じて反応生成物の５位の不整炭素原子にお
ける立体異性体を分離し、更に必要に応じて保護
反応に付することによつて製造される。3(S)-hydroxy-1-iodo 5(S)-
Methylnon-1-ene, 3(S)-hydroxy-1-iodo 5(R)-
Methylnon-1-ene, 3(S)-t-butyldimethylsilyloxy-
1-iodo-5(S)-methylnon-1-ene, 3(S)-t-butyldimethylsilyloxy-
1-iodo-5(R)-methylnon-1-ene, 3(S)-hydroxy-5(S) or (R)-methylnon-1- of the present invention represented by the above formula []
Ens are the following formula [] [In the formula, X is the same as the above definition. ] The enones represented by the following formula [ ] By carrying out a non-saccadic reduction with a non-saccadic reducing agent represented by the formula, then separating the stereoisomer at the asymmetric carbon atom at the 5-position of the reaction product as necessary, and further subjecting it to a protection reaction as necessary. Manufactured.
本発明の製造法における原料化合物であるエノ
ン類は例えば以下のフローシート−２で示される
ようにして公知の方法で製造される。 Enones, which are raw material compounds in the production method of the present invention, are produced, for example, by a known method as shown in Flow Sheet-2 below.
上記フローシート−２から明らかなように１位
のハロゲン原子例えば塩素原子はNaIと反応せし
めることによつてヨウ素原子に変換することが可
能である。 As is clear from Flow Sheet-2 above, a halogen atom such as a chlorine atom at the 1st position can be converted into an iodine atom by reacting with NaI.
かかる原料化合物であるエノン類を不斎還元す
るには上記式〔〕で表わされる不斎還元剤が用
いられる。 In order to reduce enones, which are such raw material compounds, in an inactive manner, an inactive reducing agent represented by the above formula [] is used.
かかる不斎還元剤は、水素化リチウムアルミニ
ウムの不活性有機溶液を調整し、これにエタノー
ルを含む不活性有機溶液を加えて撹拌し、これに
（Ｓ）−（−）−２，2′−ジヒドロキシ−１，1′−ビ
ナフチル（Bull.Soc.Chim.Fr参照）の不活性有機
溶液を、加えて更に撹拌することによつて調整さ
れる。 Such an inert reducing agent is prepared by preparing an inert organic solution of lithium aluminum hydride, adding an inert organic solution containing ethanol to it and stirring it, and adding (S)-(-)-2,2'- Prepared by addition of an inert organic solution of dihydroxy-1,1'-binaphthyl (see Bull.Soc.Chim.Fr) and further stirring.
ここで用いられる不活性有機溶媒としては、テ
トラヒドロフラン、ジエチルエーテル、ジオキサ
ン、ジグライム、アニソール等の脂肪族もしくは
芳香族エーテル類が好ましい。 As the inert organic solvent used here, aliphatic or aromatic ethers such as tetrahydrofuran, diethyl ether, dioxane, diglyme, anisole, etc. are preferable.
また上記の如くして調整される不斎還元剤の使
用量は上記式〔〕のエノン類に対して１〜４当
量が好ましい。 Further, the amount of the non-saccadic reducing agent adjusted as described above to be used is preferably 1 to 4 equivalents relative to the enone of the above formula [].
実際に不斎還元を行なうには、上記した如くし
て調整された不斎還元剤の不活性有機溶液中に、
冷却下、上記式〔〕のエノン類を滴下すること
によつて行なわれる。 In order to actually carry out the inert reduction, in an inert organic solution of the inert reducing agent prepared as described above,
This is carried out by dropping the enone of the above formula [] under cooling.
反応温度は０℃〜−200℃の範囲であり、好ま
しくは−70℃から−100℃の範囲である。 The reaction temperature ranges from 0°C to -200°C, preferably from -70°C to -100°C.
反応時間は、反応量、使用する溶媒の種類、温
度等により変化するが、通常数分間〜５時間程度
である。 The reaction time varies depending on the amount of reaction, the type of solvent used, the temperature, etc., but is usually about several minutes to about 5 hours.
還元反応の後、過剰の還元剤をアルコール、水
を加えて分解し、有機溶媒で抽出して、乾燥、濃
縮し、蒸留、カラムクロマトグラフイー等の通常
の手段によつて目的物が単離精製される。 After the reduction reaction, excess reducing agent is decomposed by adding alcohol and water, extracted with an organic solvent, dried and concentrated, and the target product is isolated by conventional means such as distillation and column chromatography. Refined.
ここで原料化合物として、上記式〔〕のエノ
ン類でその５位の不整炭素が光学活性であるもの
を用いた時には、３（Ｓ）−ヒドロキシ−５（Ｓ）
又は（Ｒ）−メチルノナ−１−エン類が反応後に
得られる。 Here, when an enone of the above formula [] whose asymmetric carbon at the 5th position is optically active is used as a raw material compound, 3(S)-hydroxy-5(S)
Or (R)-methylnon-1-enes are obtained after the reaction.
また、原料化合物としてその５位の不整炭素が
光学活性でないエノン類を用いた時には反応後に
３（Ｓ）−ヒドロキシ−５−メチルノナ−１−エン
類が得られるため、その５位の立体異性体を分離
する必要がある。かかる分離は通常、カラムクロ
マトグラフイー、薄層クロマトグラフイー、液体
クロマトグラフイー等のクロマト分離によつて好
ましく行なわれる。 Furthermore, when enones whose 5-position asymmetric carbon is not optically active are used as raw material compounds, 3(S)-hydroxy-5-methylnon-1-enes are obtained after the reaction, so the 5-position stereoisomer need to be separated. Such separation is usually preferably carried out by chromatographic separation such as column chromatography, thin layer chromatography, liquid chromatography, or the like.
かくして上記式〔〕の３（Ｓ）−ヒドロキシ−
５（Ｓ）又は（Ｒ）−メチルノナ−１−エン類が得
られる。 Thus, 3(S)-hydroxy- of the above formula []
5(S) or (R)-methylnon-1-enes are obtained.
かかる化合物の３位の水酸基を保護するため、
必要に応じ更に保護反応に付してもよい。 In order to protect the hydroxyl group at the 3-position of such a compound,
If necessary, it may be further subjected to a protection reaction.
保護反応は公知の反応を採用することができ
る。 A known reaction can be used for the protection reaction.
すなわち保護基がトリアルキルシリル基の場合
には、トリアルキルシリルハロゲン化物とイミダ
ゾールとを反応せしめることによつて保護基を導
入することができる。また保護基が２−テトラヒ
ドロピラニル基の如きエーテル結合を有する基の
場合には対応するビニルエーテル化合物、例えば
ジヒドロピランなどをパラトルエンスルホン酸な
どの酸性触媒存在下に接触せしめることによつて
保護基を導入することができる。 That is, when the protecting group is a trialkylsilyl group, the protecting group can be introduced by reacting the trialkylsilyl halide and imidazole. When the protecting group is a group having an ether bond such as 2-tetrahydropyranyl group, the protecting group can be prepared by contacting the corresponding vinyl ether compound such as dihydropyran in the presence of an acidic catalyst such as para-toluenesulfonic acid. can be introduced.
かくして、本発明の３（Ｓ）−ヒドロキシ−５
（Ｓ）又は（Ｒ）−メチルノナ−１−エン類が得ら
れる。かかる化合物は新規プロスタグランジン類
を合成するために非常に有用な化合物である。 Thus, the 3(S)-hydroxy-5 of the present invention
(S) or (R)-methylnon-1-enes are obtained. Such compounds are very useful compounds for synthesizing new prostaglandins.
以下、本発明を実施例により更に詳細に説明す
る。 Hereinafter, the present invention will be explained in more detail with reference to Examples.
参考例 １
１−ヨード−５−メチルノナ−１−エン−３−
オンの合成
ヨウ化ナトリウム10.34ｇ（69ｍmol）を50ml．
のアセトンに飽和させ、１−クロロ−５−メチル
ノナ−１−エン−３−オン6.41ｇ（34.5ｍmol）
を加え、36時間加熱還流する。反応後水を加え、
エーテル抽出を行ない、無水硫酸マグネシウム上
で乾燥する。Reference example 1 1-iodo-5-methylnon-1-ene-3-
Synthesis of 10.34g (69mmol) of sodium iodide in 50ml.
of 1-chloro-5-methylnon-1-en-3-one 6.41 g (34.5 mmol)
and heated under reflux for 36 hours. After the reaction, add water and
Perform ether extraction and dry over anhydrous magnesium sulfate.
溶媒を減圧下留去することにより目的物である
５−メチル−１−ヨードノナ−１−エン−３−オ
ンを7.65ｇ（収率；79％）得た。 By distilling off the solvent under reduced pressure, 7.65 g (yield: 79%) of 5-methyl-1-iodononan-1-en-3-one, which was the target product, was obtained.
NMR（CDCl3δppm）；
7.8（1H，ｄ，Ｊ＝15Hz），
7.1（1H，ｄ，Ｊ＝15Hz），
2.35（2H，ｍ），
1.8（1H，ｍ），
1.25（6H，ｍ），
0.85（3H，ｄ，Ｊ＝６Hz），
0.8（3H，ｍ）．
参考例 ２
１−ヨード−５（Ｓ）−メチルノナ−１−エン−
３−オンの合成
参考例１と同様にして、１−クロロ−５（Ｓ）−
メチルノナ−１−エン−３−オン210mg（1.1ｍ
mol）とヨウ化ナトリウム330mg（2.2ｍmol）か
ら５（Ｓ）−メチル−１−ヨードノナ−１−エン−
３−オンを231mg（収率75％）得た。NMR (CDCl 3 δppm); 7.8 (1H, d, J = 15Hz), 7.1 (1H, d, J = 15Hz), 2.35 (2H, m), 1.8 (1H, m), 1.25 (6H, m), 0.85 (3H, d, J=6Hz), 0.8 (3H, m). Reference example 2 1-iodo-5(S)-methylnon-1-ene-
Synthesis of 3-one In the same manner as in Reference Example 1, 1-chloro-5(S)-
Methyl non-1-en-3-one 210mg (1.1m
mol) and 330 mg (2.2 mmol) of sodium iodide to 5(S)-methyl-1-iodononan-1-ene-
231 mg (yield 75%) of 3-one was obtained.
NMRは参考例１に同じ
〔α〕23 D＝＋4.22゜ Ｃ＝3.85 inMeOH
実施例 １
３（Ｓ）−ヒドロキシ−１−ヨードー５（Ｓ）−メ
チルノナ−１−エンおよび３（Ｓ）−ヒドロキシ
−１−ヨードー５（Ｒ）−メチルノナ−１−エン
の合成
水素化リチウムアルミニウムのテトラヒドロフ
ラン溶液（1.04M）80.6ml（83.8ｍmol）に対し、
アルゴン雰囲気下、無水エタノールの無水テトラ
ヒドロフラン溶液（1.0M）を83.8ml（83.8ｍ
mol）、０℃にて10分間で加え、さらに室温にて
10分間撹拌した。この溶液に（Ｓ）−（−）−２，
2′−ジヒドロキシ−１，1′−ビナフチル24ｇ
（83.8ｍmol）の120mlのテトラヒドロフラン溶液
を０℃において10分間で加え、さらに室温にて30
分間撹拌する。参考例１で得られた１−ヨード−
５−メチルノナ−１−エン−３−オンを15.6ｇ
（55.8ｍmol）の無水テトラヒドロフラン溶液
（60ml）を−100℃で加え、そのまま２時間撹拌
し、さらに−78℃で１時間撹拌する。残つた還元
剤を24mlのメタノールを加えて分解し、室温にも
どして水28mlを加え30分間撹拌する。 NMR is the same as Reference Example 1 [α] 23 D = +4.22° C = 3.85 inMeOH Example 1 3(S)-Hydroxy-1-iodo 5(S)-methylnon-1-ene and 3(S)- Synthesis of hydroxy-1-iodo-5(R)-methylnon-1-ene For 80.6 ml (83.8 mmol) of lithium aluminum hydride in tetrahydrofuran solution (1.04 M),
Under an argon atmosphere, add 83.8 ml (83.8 m
mol) at 0°C for 10 minutes, then at room temperature.
Stir for 10 minutes. (S)-(-)-2,
2'-dihydroxy-1,1'-binaphthyl 24g
(83.8 mmol) in 120 ml of tetrahydrofuran was added at 0 °C for 10 min, and then at room temperature for 30 min.
Stir for a minute. 1-Iodo- obtained in Reference Example 1
15.6g of 5-methylnon-1-en-3-one
(55.8 mmol) in anhydrous tetrahydrofuran (60 ml) was added at -100°C, the mixture was stirred for 2 hours, and further stirred at -78°C for 1 hour. Add 24 ml of methanol to decompose the remaining reducing agent, return to room temperature, add 28 ml of water, and stir for 30 minutes.
酢酸エチルを500ml加え、無水硫酸マグネシウ
ム約200ｇを加え乾燥する。 Add 500 ml of ethyl acetate, add about 200 g of anhydrous magnesium sulfate, and dry.
溶媒を減圧下留去後ヘキサンを加えてビナフト
ールを結晶化させて分離し、母液をシリカ上でク
ロマトグラフイーし、ｎ−ヘキサン−酢酸エチル
（18：１）混液で溶離し、原料である１−ヨード
−５−メチルノナ−１−エン−３−オン５ｇ（回
収率32％）および３（Ｓ）−ヒドロキシ−１−ヨー
ドー５（Ｒ）−メチルノナ−１−エン3.61ｇ（収率
23.1％）および３（Ｓ）−ヒドロキシ−１−ヨード
ー５（Ｓ）−メチルノナ−１−エン3.74ｇ（収率24
％）を得た。 After evaporating the solvent under reduced pressure, hexane was added to crystallize and separate the binaphthol, and the mother liquor was chromatographed on silica, eluting with a mixture of n-hexane and ethyl acetate (18:1), and the starting material 1 -Iodo-5-methylnon-1-en-3-one 5 g (32% recovery) and 3.61 g (32% recovery) of 3(S)-hydroxy-1-iodo-5(R)-methylnon-1-ene (yield
23.1%) and 3.74 g (yield 24
%) was obtained.
NMR（in CDCl3 δppm）（５（Ｒ）体，５
（Ｓ）体ともに同じ）；
6.55（1H，dd，Ｊ＝14Hz，５Hz），
6.2（1H，ｄ，Ｊ＝14Hz），
4.1（1H，ｍ），
1.2〜1.6（7H，ｍ），
0.85（3H，ｄ，Ｊ＝６Hz），
0.8（3H，ｍ）．
５（Ｒ）メチル体：
〔α〕23 D＝＋1.45゜ Ｃ＝0.41 in MeOH
５（Ｓ）メチル体：
〔α〕23 D＝＋8.97゜ Ｃ＝0.39 in MeOH
実施例 ２
３（Ｓ）−ヒドロキシ−１−ヨードー５（Ｓ）−メ
チルノナ−１−エンの合成
実施例１と同様にして、１−ヨード−５（Ｓ）−
メチルノナ−１−エン−３−オン220mg（0.786ｍ
mol）と（Ｓ）−（−）−２，2′−ジヒドロキシ−
１，1′−ビナフチル690mg（2.4ｍmol）から目的
物３（Ｓ）−ヒドロキシ−１−ヨードー５（Ｓ）−メ
チルノナ−１−エン204mg（収率92％）が得られ
た。NMR (in CDCl 3 δppm) (5(R) form, 5
(S) Both bodies are the same); 6.55 (1H, dd, J = 14Hz, 5Hz), 6.2 (1H, d, J = 14Hz), 4.1 (1H, m), 1.2 to 1.6 (7H, m), 0.85 ( 3H, d, J=6Hz), 0.8 (3H, m). 5(R) methyl form: [α] 23 D = +1.45° C = 0.41 in MeOH 5(S) methyl form: [α] 23 D = +8.97° C = 0.39 in MeOH Example 2 3 (S )-Hydroxy-1-iodo-5(S)-methylnon-1-ene Synthesis of 1-iodo-5(S)-
Methyl non-1-en-3-one 220mg (0.786m
mol) and (S)-(-)-2,2'-dihydroxy-
From 690 mg (2.4 mmol) of 1,1'-binaphthyl, 204 mg (yield 92%) of the target product 3(S)-hydroxy-1-iodo-5(S)-methylnon-1-ene was obtained.
〔α〕23 D＝−8.85゜ Ｃ＝0.41 in MeOH
実施例 ３
３（Ｓ）−ｔ−ブチルジメチルシリルオキシ−１
−ヨード−５（Ｓ）−メチルノナ−１−エンの合
成
３（Ｓ）−ヒドロキシ−１−ヨードー５（Ｓ）−メ
チルノナ−１−エン3.6ｇ（12.8ｍmol）とイミダ
ゾール1.3ｇ（19.2ｍmol）を10mlの無水DMFに
とかす。０℃において、ｔ−ブチルジメチルシリ
ルクロリド5.8ｇ（39.3ｍmol）を加え、そのまま
20分間撹拌し、さらに室温にて15時間撹拌する。
反応混合物をｎ−ヘキサン80mlと水80mlの溶液に
加え、ｎ−ヘキサンで抽出後、溶媒を留去すると
5.9ｇの粗生成物が得られシリカ上カラムクロマ
トグラフイーし、ｎ−ヘキサンで溶離して目的物
である３（Ｓ）−ｔ−ブチルジメチルシリルオキシ
−１−ヨード−５（Ｓ）−メチルノナ−１−エンが
4.1ｇ（収率80.8％）得られた。 [α] 23 D = -8.85° C = 0.41 in MeOH Example 3 3(S)-t-butyldimethylsilyloxy-1
Synthesis of -iodo-5(S)-methylnon-1-ene 3.6 g (12.8 mmol) of 3(S)-hydroxy-1-iodo-5(S)-methylnon-1-ene and 1.3 g (19.2 mmol) of imidazole were added. Dissolve in 10 ml of anhydrous DMF. At 0°C, add 5.8g (39.3mmol) of t-butyldimethylsilyl chloride and leave as is.
Stir for 20 minutes and further stir for 15 hours at room temperature.
The reaction mixture was added to a solution of 80 ml of n-hexane and 80 ml of water, extracted with n-hexane, and the solvent was distilled off.
5.9 g of crude product was obtained and subjected to column chromatography on silica and eluted with n-hexane to obtain the desired product, 3(S)-t-butyldimethylsilyloxy-1-iodo-5(S)-methylnona. -1-ene is
4.1g (yield 80.8%) was obtained.
NMR（in CDCl3 δppm）；
6.5（1H，dd Ｊ＝14Hz，５Hz），
6.1（1H，ｄ Ｊ＝14Hz），
4.1（1H，ｍ），
1.1〜1.4（7H，ｍ），
0.9（15H，Ｓ），
0.05（6H，Ｓ），
〔α〕26 D＝−34.5゜ Ｃ＝0.55 in MeOH
実施例 ４
３（Ｓ）−ｔ−ブチルジメチルシリルオキシ−１
−ヨード−５（Ｒ）−メチルノナ−１−エンの合
成
実施例３と同様にして、３（Ｓ）−ヒドロキシ−
１−ヨードー５（Ｒ）−メチルノナ−１−エン3.3
ｇ（11.7ｍmol）およびイミダゾール1.2ｇ（17.6
ｍmol）およびｔ−ブチルジメチルシリルクロリ
ド5.3ｇ（35ｍmol）から３（Ｓ）−ｔ−ブチルジ
メチルシリルオキシ−１−ヨード−５（Ｒ）−メチ
ルノナ−１−エン3.67ｇ（収率79％）を得た。NMR (in CDCl 3 δppm); 6.5 (1H, dd J=14Hz, 5Hz), 6.1 (1H, dJ=14Hz), 4.1 (1H, m), 1.1~1.4 (7H, m), 0.9 (15H, S), 0.05 (6H, S), [α] 26 D = -34.5° C = 0.55 in MeOH Example 4 3(S)-t-butyldimethylsilyloxy-1
Synthesis of -iodo-5(R)-methylnon-1-ene 3(S)-hydroxy-
1-Iodo5(R)-methylnon-1-ene3.3
g (11.7 mmol) and imidazole 1.2 g (17.6
3.67 g (yield 79%) of 3(S)-t-butyldimethylsilyloxy-1-iodo-5(R)-methylnon-1-ene was obtained from 5.3 g (35 mmol) of t-butyldimethylsilyl chloride (mmol) and t-butyldimethylsilyl chloride. Obtained.
NMRは実施例３に同じ。 NMR is the same as in Example 3.
〔α〕26 D＝−48゜ Ｃ＝0.67 in MeOH。 [α] 26 D = −48° C = 0.67 in MeOH.
Claims (1)
トリ（C1〜C7）炭化水素シリル基を表わす。〕 で表わされる３（Ｓ）−ヒドロキシ−５（Ｓ）又は
（Ｒ）−メチルノナ−１−エン類。 ２ 上記式〔〕において、Ｘがヨウ素原子であ
る特許請求の範囲第１項記載の３（Ｓ）−ヒドロキ
シ−５（Ｓ）又は（Ｒ）−メチルノナ−１−エン
類。 ３ 上記式〔〕において、Ａがｔ−ブチルジメ
チルシリル基である特許請求の範囲第１項又は第
２項記載の３（Ｓ）−ヒドロキシ−５（Ｓ）又は
（Ｒ）−メチルノナ−１−エン類。 ４ 下記式〔〕 〔式中、Ｘは上記定義に同じ。〕 で表わされるエノン類を下記式〔〕 で表わされる不斎還元剤で不斎還元し、次いで必
要に応じて反応生成物の５位の不整炭素原子にお
ける立体異性体を分離し、更に保護反応に付する
ことを特徴とする下記式〔〕 〔式中、Ｘ及びA′はトリ（C1〜C7）炭化水素
シリル基を表わす。〕 で表わされる３（Ｓ）−ヒドロキシ−５（Ｓ）又は
（Ｒ）−メチルノナ−１−エン類の製造法。[Claims] 1. The following formula [] [In the formula, X represents a halogen atom, and A represents a hydrogen atom or a tri(C 1 to C 7 ) hydrocarbon silyl group. ] 3(S)-hydroxy-5(S) or (R)-methylnon-1-enes represented by these. 2. 3(S)-hydroxy-5(S) or (R)-methylnon-1-enes according to claim 1, wherein in the above formula [], X is an iodine atom. 3 3(S)-hydroxy-5(S) or (R)-methylnona-1- according to claim 1 or 2, wherein in the above formula [], A is a t-butyldimethylsilyl group. en-class. 4 The following formula [] [In the formula, X is the same as the above definition. ] The enones represented by the following formula [ ] The following formula is characterized in that the reaction product is subjected to non-saccadic reduction with an non-saccadic reducing agent, and then, if necessary, the stereoisomer at the asymmetric carbon atom at the 5-position of the reaction product is separated, and further subjected to a protection reaction. ] [In the formula, X and A' represent a tri(C 1 -C 7 ) hydrocarbon silyl group. ] A method for producing 3(S)-hydroxy-5(S) or (R)-methylnon-1-enes represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56128236A JPS5832834A (en) | 1981-08-18 | 1981-08-18 | 3(s)-hydroxy-5-methylnon-1-ene compound and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56128236A JPS5832834A (en) | 1981-08-18 | 1981-08-18 | 3(s)-hydroxy-5-methylnon-1-ene compound and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5832834A JPS5832834A (en) | 1983-02-25 |
| JPS6341376B2 true JPS6341376B2 (en) | 1988-08-17 |
Family
ID=14979852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56128236A Granted JPS5832834A (en) | 1981-08-18 | 1981-08-18 | 3(s)-hydroxy-5-methylnon-1-ene compound and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5832834A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2016133020A1 (en) * | 2015-02-16 | 2017-11-24 | 日産化学工業株式会社 | Method for producing optically active allyl alcohol compound |
-
1981
- 1981-08-18 JP JP56128236A patent/JPS5832834A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5832834A (en) | 1983-02-25 |
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