JPH01149747A - Production of terpenediol derivative - Google Patents
Production of terpenediol derivativeInfo
- Publication number
- JPH01149747A JPH01149747A JP62307819A JP30781987A JPH01149747A JP H01149747 A JPH01149747 A JP H01149747A JP 62307819 A JP62307819 A JP 62307819A JP 30781987 A JP30781987 A JP 30781987A JP H01149747 A JPH01149747 A JP H01149747A
- Authority
- JP
- Japan
- Prior art keywords
- formulas
- formula
- tables
- compound
- iii
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 21
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims abstract 4
- -1 terpene diol Chemical class 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 6
- 235000007586 terpenes Nutrition 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 11
- 150000002431 hydrogen Chemical class 0.000 claims 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 8
- SUWYPNNPLSRNPS-UNTSEYQFSA-N plaunotol Chemical compound CC(C)=CCC\C(C)=C\CC\C(CO)=C\CC\C(C)=C\CO SUWYPNNPLSRNPS-UNTSEYQFSA-N 0.000 abstract description 4
- SUWYPNNPLSRNPS-UHFFFAOYSA-N plaunotol Natural products CC(C)=CCCC(C)=CCCC(CO)=CCCC(C)=CCO SUWYPNNPLSRNPS-UHFFFAOYSA-N 0.000 abstract description 4
- 229950009291 plaunotol Drugs 0.000 abstract description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 2
- PFRQBZFETXBLTP-UHFFFAOYSA-N Vitamin K2 Natural products C1=CC=C2C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C(=O)C2=C1 PFRQBZFETXBLTP-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- DKHGMERMDICWDU-GHDNBGIDSA-N menaquinone-4 Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 DKHGMERMDICWDU-GHDNBGIDSA-N 0.000 abstract 1
- 235000019143 vitamin K2 Nutrition 0.000 abstract 1
- 239000011728 vitamin K2 Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000008096 xylene Substances 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は下記一般式（１）
（式（１）においてｎはＯ〜２の整数を１１はベンジル
基または１−アルコキシアルキル基ｔ−１Ｒハ水素また
はフェニルチオ基を、Ｒは水素、ベンジル基または１−
アルコキシアルキル基を表わす。）Ｋよシ示されるテル
ペンジオール誘導体の製造方法に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to the following general formula (1) (in formula (1), n is an integer of O to 2, and 11 is a benzyl group or a 1-alkoxyalkyl group t-1R) R is hydrogen or a phenylthio group, R is hydrogen, a benzyl group or a 1-
Represents an alkoxyalkyl group. ) A method for producing a terpene diol derivative represented by K.
本発明により製造されるテルペンジオール誘導体（以下
化合物（Ｉ）と記す。）はプラウノトールなどの医薬品
、ビタミンに２の製造用中間体として使用することがで
きる。The terpene diol derivative (hereinafter referred to as compound (I)) produced according to the present invention can be used as an intermediate for producing pharmaceutical products such as Praunotol and vitamins 2.
化合物（１）の製造方法については従来天然物を起源と
する方法が知られているのみである。Conventionally, the only known method for producing compound (1) is a method based on natural products.
化合物（１）を大量かつ安価に供給することが望まれて
おり、本発明はこのことを可能にする本のである。It is desired to supply compound (1) in large quantities and at low cost, and the present invention is intended to make this possible.
本発明者らは化合物（１）を大量かつ安価に供給す不こ
とを目的として、種々検討を重ねた結果、−般式
（式（Ｉｔ）においてｎはＯ〜２の整数を、Ｒ１はベン
ジル基または１−アルコキシアルキル基を表わし、Ｒ２
は水素またはフェニルチオ基を表わす。）により示され
る化合物（以下化合物（Ｉｆ）と記す。）と一般式
（式（＠においてＸはハロダン原子を Ｒ３は水素、ベ
ンジル基または１−アルコキシアルキル基ヲ表わす。）
により示される化合物（以下化合物（Ｂと記す）とを塩
基の存在下に反応させることによシ、好収率かつ立体選
択的に化合物（１）が得られることを見い出し、本発明
圧到達した。The present inventors conducted various studies with the aim of supplying compound (1) in large quantities at low cost, and as a result found that in the general formula (Formula (It), n is an integer of O to 2, and R1 is benzyl. or 1-alkoxyalkyl group, R2
represents hydrogen or a phenylthio group. ) (hereinafter referred to as compound (If)) and a compound represented by the general formula (in the formula (@, X is a halodane atom, R3 represents hydrogen, a benzyl group, or a 1-alkoxyalkyl group) (hereinafter referred to as compound (If)) It has been discovered that compound (1) can be obtained in good yield and stereoselectively by reacting a compound (denoted as B) in the presence of a base, and the present invention has been achieved.
前記一般式におけるＲ１． Ｒ２およびＲ５について詳
しく説明する。Ｒ１はベンジル基または１−アルコキシ
アルキル基を表わす。１−アルコキシアルキル基の具体
例としてはメトキシメチル基、エトキシメチル基、１−
メトキシエチル基、テトラヒドロピラン−２−イル基、
テトラヒドロフラン−２−イル基などがある。Ｒは水素
またはフェニルチオ基を表わす。Ｒ５は水素、ベンジル
基または１−アルコキシアルキル基を表わす。１−アル
コキシアルキル基の具体例としてはメトキシメチル基、
エトキシメチル基、ｌ−メトキシエチル基、テトラヒド
ロピラン−２−イル基、テトラヒドロフラン−２−イル
基などがある。R1 in the above general formula. R2 and R5 will be explained in detail. R1 represents a benzyl group or a 1-alkoxyalkyl group. Specific examples of the 1-alkoxyalkyl group include methoxymethyl group, ethoxymethyl group, 1-
methoxyethyl group, tetrahydropyran-2-yl group,
Examples include tetrahydrofuran-2-yl group. R represents hydrogen or a phenylthio group. R5 represents hydrogen, a benzyl group or a 1-alkoxyalkyl group. Specific examples of the 1-alkoxyalkyl group include methoxymethyl group,
Examples include ethoxymethyl group, l-methoxyethyl group, tetrahydropyran-2-yl group, and tetrahydrofuran-2-yl group.
以下化合物（Ｉ）、化合物（Ｕ）および化合物（ｎＤの
具体例を示す。Specific examples of compound (I), compound (U) and compound (nD) are shown below.
（１） 化合物（１）
ｎ Ｒ’ Ｒ” Ｒ３化合
物番号０ −ＣＨ７Ｐｈ −８Ｐｈ
（１） −２ｌ−ＣＨ２０ＣＩ（３）Ｉ
１ （１）−４１−ＣＨ２Ｐｈ
−８Ｐｈ −ＣＨ２Ｐｈ （１） −
６２−ＣＨ２Ｐｈ Ｈ−０Ｈ２Ｐｈ （
１） −７２−ＣＨ２Ｐｈ Ｈ−ＣＨ２０ＣＨ
３（１）−８（２）化合物（ＩＩ）
ｎ Ｒ’ Ｒ２化合物番号０
−ＣＨ２Ｐｈ −８Ｐｈ （ｎ）
−２ｌ−ＣＨ２０ＣＨ３Ｈ（ＩＩ） −４
１−ＣＨ２Ｐｈ Ｈ（ｎ）−５１−ＣＨ２Ｐｈ
−３Ｐｈ （Ｉｆ） −６２−ＣＨ２
Ｐｈ Ｈ（ｎｉ ７（３）化合物（頂
Ｒ３Ｘ 化合物番号
−ＣＨ２Ｐｈ Ｉ （１１０−
ｌ−ＣＨ２Ｆ ｈ Ｂｒ （ｎ
Ｄ −２本発明で用いられる塩基としてはｎ−ブチルリ
チウム、寞−ブチルリチウムなどのアルキルリチウム、
カリウムメトキシド、カリウムエトキシｒ、ナトリウム
メトキシド、ナトリウムエトキシドなどのアルカリ金属
アルコキシド、水酸化カリウム、水酸化す） ＩＪウム
などのアルカリ金属水酸化物があるＯ
本発明において用いられる化合物＋Ｉｔ）と化合物（ｍ
の使用モル比は特に制限はないが、収率および未反応原
料の回収の点から０．５〜２．０の範囲にあるのが好ま
しい。また用いられる塩基は使用される化合物（Ｉｎ）
１モルに対し１〜１．５モル使用するのが好ましい。(1) Compound (1) n R'R" R3 compound number 0 -CH7Ph -8Ph
(1) -2l-CH20CI(3)I
1 (1)-41-CH2Ph
-8Ph -CH2Ph (1) -
62-CH2Ph H-0H2Ph (
1) -72-CH2Ph H-CH20CH
3(1)-8(2) Compound (II) n R' R2 Compound No. 0
-CH2Ph -8Ph (n)
-2l-CH20CH3H(II) -4 1-CH2Ph H(n)-51-CH2Ph
-3Ph (If) -62-CH2
Ph H(ni 7(3) compound (top R3X compound number-CH2Ph I (110-
l-CH2F hBr (n
D-2 Bases used in the present invention include alkyl lithiums such as n-butyllithium and di-butyllithium;
Alkali metal alkoxides such as potassium methoxide, potassium ethoxide, sodium methoxide, sodium ethoxide, potassium hydroxide, alkali metal hydroxides such as sodium hydroxide, etc. Compound (m
The molar ratio used is not particularly limited, but is preferably in the range of 0.5 to 2.0 from the viewpoint of yield and recovery of unreacted raw materials. Also, the base used is the compound used (In)
It is preferable to use 1 to 1.5 mol per mol.
本発明の反応は通常溶媒の存在下に行なわれる。用いら
れる溶媒としてはテトラヒドロフラン、１．４−ジオキ
サン、テトラヒドロピランなどの環状エーテル類、ジエ
チルエーテル、ジイソグロビルエーテル、１，２−ジメ
トキシエタンなどの鎖状エーテル類、ｎ−ヘキサン、ｎ
−ヘゲタン、ベンゼン、トルエン、キシレンナトノ炭化
水素類、酢酸エチル、酢酸イングロビル、酢酸ｎ−ブチ
ルなどのエステル顛、ヘキサメチルホスホロアミｒなど
が具体的に示される。またアルカリ金属の水酸化物を用
いる場合は前記した溶媒と共に水を溶媒として用いるこ
とができるが、この場合はベンジルトリメチルアンモニ
ウムクロライドなどの４級アンモニウム塩を化合物（Ｉ
Ｉに対し編璋貝〜０．０５モル係共存させるのが好まし
い。The reaction of the present invention is usually carried out in the presence of a solvent. Solvents used include cyclic ethers such as tetrahydrofuran, 1,4-dioxane, and tetrahydropyran, chain ethers such as diethyl ether, diisoglobyl ether, and 1,2-dimethoxyethane, n-hexane, n-hexane, and n-hexane.
Specific examples include esters such as hegetane, benzene, toluene, xylene natonohydrocarbons, ethyl acetate, inglovir acetate, and n-butyl acetate, and hexamethylphosphoroamyl. In addition, when using an alkali metal hydroxide, water can be used as a solvent together with the above-mentioned solvent, but in this case, a quaternary ammonium salt such as benzyltrimethylammonium chloride is used as a compound (I
It is preferable to coexist in a proportion of 0.05 to 0.05 mol per mol.
本発明を実施するにあたり、反応温度は通常−１００〜
１００℃の範囲で実施されるが、より好ましい反応温度
は一８０〜５０℃である。In carrying out the present invention, the reaction temperature is usually -100 to
Although the reaction temperature is carried out in the range of 100°C, a more preferable reaction temperature is -80 to 50°C.
本発明において用いられる化合物（ＩＱは例えば次の様
な方法で製造することができる。The compound (IQ) used in the present invention can be produced, for example, by the following method.
（＋） Ｒ２が水素原子の場合
双下奈白
（ＩＩ） Ｒ２がフェニルチオ基の場合また化合物（Ｉ
［Ｄは例えば次の様な方法で製造することができる。(+) When R2 is a hydrogen atom, the compound (II) When R2 is a phenylthio group, the compound (I
[D can be produced, for example, by the following method.
化合物（１）においてｎが１の場合、化合物（１）は抗
の原料になシ得る。例えば化合物（１）−３は還元反応
および加水分解反応を行なうことによシプラウノトール
に変換できる。また化合物（１）−６は還元反応を行な
うことによシプラウノトーールに変換できる。とれらの
場合の還元反応に液体アンモニア、低級アルキルアミン
、低級アルコールなどの活性水素を持つ化合物とリチウ
ム、ナトリウム、カリウムなどのアルカリ金属化合物に
よる還元剤が通常用いられる。また加水分解の触媒とし
てはアセタールの加水分解に用いられる触媒（通常は酸
触媒）が使用される。When n is 1 in compound (1), compound (1) can be used as a raw material for anti-oxidants. For example, compound (1)-3 can be converted to ciplaunotol by performing a reduction reaction and a hydrolysis reaction. Further, compound (1)-6 can be converted to ciplaunotol by performing a reduction reaction. For reduction reactions in these cases, reducing agents consisting of compounds with active hydrogen such as liquid ammonia, lower alkyl amines, and lower alcohols and alkali metal compounds such as lithium, sodium, and potassium are usually used. Further, as a catalyst for hydrolysis, a catalyst used for hydrolysis of acetal (usually an acid catalyst) is used.
実施例１ 化合物（１１６の合成
化合物（ｌ −１３，６２，９（６，１２ｍｍｏｌ）を
テトラヒドロフラン８０ｄとＨＭＰＡ ５ ｄの混合溶
液に懸濁させ、−６５℃でｎ−ブチルリチウムのヘキサ
ン溶液（１，５Ｍ） ４．５ｍ１（６，７５ｍｍｏｌ）
を加え３．５時間−６５℃で攪拌した。これに化合物（
ｎ） −６３，０１１（７，３ｍｍｏｌ）のテトラヒド
ロフラン１５ゴ溶液を一６５℃で滴下し、１時間同温度
で攪拌したのち、ゆっくり室温に戻し、さらに約１５時
間撹拌した。メタノール（１０ｍｌ）水（１０ｍＡりを
加え減圧下で溶媒を留去し、残留物にメタノール５０ｄ
、水１０ Ｑｍ／を加えた後ジエチルエーテルとヘキサ
ンの１対１（体積比）の混合溶媒１００ ｍｌで抽出し
た。抽出液は飽和食塩水にて洗浄、次いで硫酸マグネシ
ウムにて乾燥後溶媒留去した。留去後の残渣をカラムク
ロマトグラフィーにより精製し、化合物ｍ −６１，９
６１（３，３ｍｍｏｌ）を得た。Example 1 Compound (Synthesis of Compound (116) -13,62,9 (6,12 mmol) was suspended in a mixed solution of 80 d of tetrahydrofuran and 5 d of HMPA, and a hexane solution of n-butyllithium (1 ,5M) 4.5m1 (6.75mmol)
was added and stirred at -65°C for 3.5 hours. Add to this the compound (
n) A solution of -63,011 (7.3 mmol) in tetrahydrofuran 15 was added dropwise at -65°C, and after stirring at the same temperature for 1 hour, the mixture was slowly returned to room temperature and further stirred for about 15 hours. Add methanol (10 ml) and water (10 mA), remove the solvent under reduced pressure, and add 50 d of methanol to the residue.
After adding 10 Qm of water, the mixture was extracted with 100 ml of a mixed solvent of diethyl ether and hexane in a ratio of 1:1 (by volume). The extract was washed with saturated brine, then dried over magnesium sulfate, and the solvent was distilled off. The residue after distillation was purified by column chromatography to obtain compound m-61,9.
61 (3.3 mmol) was obtained.
収率５４係 同定データは別表に示す。Yield Section 54 Identification data are shown in the attached table.
実施例２
実施例１により得られた化合物（１）−６０，５，Ｆ（
０，７７８ｍｍｏｌ ）をジエチルエーテルｌｏｍｊに
溶解させた。このものを金属ナトリウム０．２５．Ｆを
液体アンモニア１５ｍ１に溶かした溶液に一６０℃で滴
下し３０分攪拌した。同温度でイソプレンを反応液の濃
紺色が消えるまで加えたのちメタノール１０＋＋＋／を
加え室温にもどし、アンモニアを留去した。反応液を水
にあけ、食塩にて塩析し、酢酸エチル−ジエチルエーテ
ルの１対１の混合液にて抽出し、硫酸マグネシウムにて
乾燥後濃縮した。Example 2 Compound (1)-60,5,F (obtained in Example 1)
0,778 mmol) was dissolved in diethyl ether lomj. This material has 0.25% of metallic sodium. A solution of F dissolved in 15 ml of liquid ammonia was added dropwise at -60°C and stirred for 30 minutes. At the same temperature, isoprene was added until the dark blue color of the reaction solution disappeared, and then 10+++/ml of methanol was added, the temperature was returned to room temperature, and ammonia was distilled off. The reaction solution was poured into water, salted out with common salt, extracted with a 1:1 mixture of ethyl acetate and diethyl ether, dried over magnesium sulfate, and concentrated.
残液をカラムクロマトグラフィーにて精製し、３゜１１
．１５−トリメチル−７−ヒドロキシメチル−２゜６．
１０．１４−へキサデカテトラエン−１−オール（プラ
ウノトール）０．１６７、Ｆ（０，５４５ｍｍｏｌ ）
を得た。収率７０壬
実施例３ 化合物（１）−３の合成
化合物（Ｉ［Ｄ −１２，４８１（４，２ｍｍｏｌ ）
をＴＨＦ６５１ｄ−ＨＭＰＡ ３，５ｍＪからなる混
合溶媒に懸濁させ、−６５’Ｃｆ ｎ−ブチルリチウム
のヘキサン溶液（１，５Ｍ）３、 Ｏａｔ （４，５ｍ
ｍｏｌ）を加え３．５時間−６５℃で攪拌した。これに
化合物（Ｉ［１３１，４６ｇ（４，９６ｍｍｏｌ）のＴ
Ｉ（Ｆ １０ ｒｎｌ溶液を一６５℃で滴下し１時間同
温度で攪拌したのち、ゆっ〈シ室温にもどし、さらに約
１１時間攪拌した。メタノール１０−および水１０−を
加え減圧下で溶媒を留去し、残留物だメタノール５０ゴ
、水１００ ｍｌを加えたのちジエチルエーテル／ｎ−
ヘキサンの１対１の混合溶媒で抽出し、飽和食塩水で洗
浄した。次いで硫酸マグネシウムで乾燥後、溶媒留去、
更にはカラムクロマトグラフィーを行ない、化合物（１
１３１，５１９（３，１４ｍｍｏｌ）を得た。収率７５
壬、同定データは別表に示す。The residual liquid was purified by column chromatography, and the
．． 15-trimethyl-7-hydroxymethyl-2゜6.
10.14-Hexadecatetraen-1-ol (Plaunotol) 0.167, F (0,545 mmol)
I got it. Yield: 70 mm Example 3 Synthesis of compound (1)-3 Compound (I[D-12,481 (4.2 mmol)
was suspended in a mixed solvent consisting of 3.5 mJ of THF651d-HMPA, -65'Cf n-butyllithium in hexane solution (1.5M), Oat (4.5m
mol) was added and stirred at -65°C for 3.5 hours. To this was added the compound (I [131.46 g (4.96 mmol) of T
A solution of I(F 10 rnl) was added dropwise at -65°C and stirred at the same temperature for 1 hour, then slowly returned to room temperature and stirred for further about 11 hours. 10-methanol and 10-water were added and the solvent was removed under reduced pressure. After evaporation, 50 g of methanol and 100 ml of water were added to the residue, and then diluted with diethyl ether/n-
It was extracted with a 1:1 mixed solvent of hexane and washed with saturated brine. Then, after drying with magnesium sulfate, the solvent was distilled off,
Furthermore, column chromatography was performed to obtain compound (1
131,519 (3.14 mmol) was obtained. Yield 75
Identification data is shown in the attached table.
実施例４７°ラウノトールの合成
メカニカルスターラーを装備したフラスコに液体アンモ
ニア３０ゴを入れ、−６０℃以下に冷却した。薄くスラ
イスした金属ナトリウム１．０９を加え、−６０℃で３
０分間攪拌した。溶液は濃青色になる。化合物（Ｉ）
−３１，２１（２，４ｍｍｏｌ）の無水エーテル溶液２
０ＴＩＬｔを−６５〜−６０℃で約１０分かけて滴下し
、更に同温で５分間反応させた。Example 4 Synthesis of 7° Launotol 30 g of liquid ammonia was placed in a flask equipped with a mechanical stirrer and cooled to below -60°C. Add 1.09 kg of thinly sliced metallic sodium and heat at -60°C for 3.
Stirred for 0 minutes. The solution turns dark blue. Compound (I)
- Anhydrous ether solution of 31,21 (2,4 mmol) 2
0TILt was added dropwise at -65 to -60°C over about 10 minutes, and the mixture was further reacted at the same temperature for 5 minutes.
塩化アンモニウムを一６０℃以下で濃青色が消えるまで
ゆり〈シ加えた。液体アンモニアを留去し。Ammonium chloride was added at -60°C or below until the deep blue color disappeared. Distill liquid ammonia.
残留物を１０ｒＩＬｌの水にあけ、エーテル抽出し、洗
浄（ｓａｔ、食塩水）、乾燥（硫酸マグネシウム）、濃
縮し、粗生成物（ＴＨＰ基はそのまま）０．９３．Ｆ（
収率９５係）を得だ。更にこの粗生成物をメタノール４
０ｍＡ！に溶ＭＬ、ｐ−）ルエンスルホン酸１水和物４
５１Ｑ（０，２３５ｍｍｏｌ）を加え、室温にて１５時
間攪拌した。飽和炭酸水素ナトリウムを加えて、反応液
を中和した後、減圧下で濃縮した。The residue was poured into 10 ml of water, extracted with ether, washed (sat, brine), dried (magnesium sulfate), and concentrated to give a crude product (THP group intact) of 0.93. F(
A yield of 95% was obtained. Furthermore, this crude product was mixed with methanol 4
0mA! ML, p-)luenesulfonic acid monohydrate 4 dissolved in
51Q (0,235 mmol) was added and stirred at room temperature for 15 hours. The reaction solution was neutralized by adding saturated sodium hydrogen carbonate, and then concentrated under reduced pressure.
水で希釈し、抽出（ジエチルエーテル）、洗浄（ｓａｔ
。Dilute with water, extract (diethyl ether), wash (sat
.
食塩水）、乾燥（硫酸マグネシウム）後、＠縮し、カラ
ム精製でプラウノトール０．６０．９ （収率８６憾）
を得た。After drying (magnesium sulfate), condensation, and column purification, Plaunotol was 0.60.9 (yield: 86)
I got it.
双下奈臼・
同定データ
〔発明の効果〕
本発明によれば、プラウノトールなどの医薬品、ビタミ
ンに２の製造用中間体として有用な一般式（１）で示さ
れるテルペンジオール誘導体を好収率かつ立体選択的に
得ることができる。Identification Data [Effects of the Invention] According to the present invention, the terpene diol derivative represented by the general formula (1), which is useful as an intermediate for the production of pharmaceuticals such as Praunotol and vitamins 2, can be produced in good yield. can be obtained stereoselectively.
特許出願人 株式会社 り ラ しPatent applicant: RiRashi Co., Ltd.
Claims (6)
はベンジル基または１−アルコキシアルキル基を表わし
、Ｒ＾２は水素またはフェニルチオ基を表わす。）によ
り示される化合物と 一般式 ▲数式、化学式、表等があります▼………（III） （式（III）においてＸはハロゲン原子を、Ｒ＾３は水
素、ベンジル基または１−アルコキシアルキル基を表わ
す。） により示される化合物とを塩基の存在下に反応させるこ
とを特徴とする 一般式 ▲数式、化学式、表等があります▼………（ I ） （式（ I ）においてｎ、Ｒ＾１、Ｒ＾２およびＲ＾３
は式（II）および式（III）におけると同じ意味を持つ
。） で示されるテルペンジオール誘導体の製造方法。(1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼……(II) (In formula (II), n represents an integer from 0 to 2, and R^1
represents a benzyl group or a 1-alkoxyalkyl group, and R^2 represents hydrogen or a phenylthio group. ) Compounds and general formulas ▲ Numerical formulas, chemical formulas, tables, etc.▼……(III) (In formula (III), X is a halogen atom, R^3 is hydrogen, a benzyl group, or a 1-alkoxyalkyl group ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(I) (In formula (I), n, R^ 1, R^2 and R^3
has the same meaning as in formula (II) and formula (III). ) A method for producing a terpene diol derivative shown in
る特許請求の範囲第一項に記載の方法。(2) The method according to claim 1, wherein n is 1 in general formulas (I) and (II).
＾１、Ｒ＾２、Ｒ＾３がそれぞれベンジル基、フェルチ
オ基、ベンジル基である特許請求の範囲第一項に記載の
方法。(3) In general formulas (I), (II) and (III), R
The method according to claim 1, wherein ^1, R^2, and R^3 are each a benzyl group, a ferthio group, or a benzyl group.
＾１、Ｒ＾２、Ｒ＾３がそれぞれ１−アルコキシアルキ
ル基、水素、ベンジル基である特許請求の範囲第一項に
記載の方法。(4) In general formulas (I), (II) and (III), R
The method according to claim 1, wherein ^1, R^2, and R^3 are each a 1-alkoxyalkyl group, hydrogen, or a benzyl group.
とを塩基の存在下に反応させ下記式 ▲数式、化学式、表等があります▼………（ I ）′ により示される化合物を得、次いで還元および加水分解
反応を行なうことを特徴とする下記式により示されるプ
ラウノトールの製造方法。 ▲数式、化学式、表等があります▼(5) The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ...... (II)' Compounds and general formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ...... (III) ' (Formula (III) )', X represents a halogen atom.)
The following formula is obtained by reacting with and in the presence of a base to obtain the compound represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing Praunotol shown by. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼
とを塩基の存在下に反応させ下記式 ▲数式、化学式、表等があります▼………（ I ）″ により示される化合物を得、次いで還元反応を行なうこ
とを特徴とする下記式により示されるプラウノトールの
製造方法。 ▲数式、化学式、表等があります▼(6) Compounds and general formulas represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼……(II)″ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼……(III)″ (Formula (III )'', X represents a halogen atom.)
is reacted in the presence of a base to obtain a compound represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Manufacturing method of Praunotol. ▲There are mathematical formulas, chemical formulas, tables, etc.▼
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62307819A JP2558301B2 (en) | 1987-12-04 | 1987-12-04 | Method for producing terpene diol derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62307819A JP2558301B2 (en) | 1987-12-04 | 1987-12-04 | Method for producing terpene diol derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01149747A true JPH01149747A (en) | 1989-06-12 |
| JP2558301B2 JP2558301B2 (en) | 1996-11-27 |
Family
ID=17973591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62307819A Expired - Fee Related JP2558301B2 (en) | 1987-12-04 | 1987-12-04 | Method for producing terpene diol derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2558301B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264638A (en) * | 1990-06-14 | 1993-11-23 | Chulalongkorn University | Process for extraction and purification of plaunotol |
-
1987
- 1987-12-04 JP JP62307819A patent/JP2558301B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264638A (en) * | 1990-06-14 | 1993-11-23 | Chulalongkorn University | Process for extraction and purification of plaunotol |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2558301B2 (en) | 1996-11-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106928227A (en) | The synthetic method and its midbody compound of Entecavir | |
| CN110305010B (en) | Preparation method of 2, 5-dimethylphenylacetic acid | |
| US4929748A (en) | Method of preparing dialkyl dicarbonates | |
| US4982016A (en) | Conversion of diethyl phenylmalonate to 2-phenyl-1,3-propanediol | |
| CN109535120B (en) | Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone | |
| US5091595A (en) | Reduction of diethyl phenylmalonate to 2-phenyl-1,3-propanediol | |
| JPH01149747A (en) | Production of terpenediol derivative | |
| US2870164A (en) | Process for making d, l-methysticin and d, l-dihydromethysticin | |
| US3366688A (en) | Process for the preparation of alpha, alpha-disubstituted-gema-hydroxyamines | |
| Youn et al. | Highly diastereoselective additions of methoxyallene and acetylenes to chiral α-keto amidesElectronic supplementary information (ESI) available: synthesis and spectroscopic data for 4b, 5g, 6b and 7b. See http://www. rsc. org/suppdata/cc/b1/b100355k | |
| CN110857284B (en) | Method for synthesizing N-methyl aliphatic amine | |
| JPH0696564B2 (en) | α- (ω-hydroxyalkyl) furfuryl alcohol and process for producing the same | |
| JPS61176564A (en) | Production of 4-hydroxy-2-pyrrolidone | |
| JP3779452B2 (en) | Method for producing alcohols | |
| KR101925198B1 (en) | METHOD OF SYNTHESIZING β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS, β-SUBSTITUTED GAMMA NITRO DI-THIOESTERS COMPOUNDS SYNTHESIZED BY THE METHOD, GAMMA AMINO ACID COMPOUND DERIVATED FROM THE β-SUBSTITUTED GAMMA NITRO DI-THIOESTERS COMPOUNDS, AND METHOD OF SYNTHESIZING GAMMA AMINO BUTYRIC ACID FROM THE β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS OR THE GAMMA AMINO ACID COMPOUND | |
| KR20060024550A (en) | THE METHOD OF PREPARING beta-HYDROXYBUTYRIC ACID ALKYL ESTERS | |
| JPS5840938B2 (en) | Method for producing substituted or unsubstituted α-oxysuccinic acid ester | |
| JP3272340B2 (en) | Method for producing 1-[(cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione | |
| JPS6213935B2 (en) | ||
| JPH029835A (en) | Preparation of bicyclohumulenone | |
| CN115710238A (en) | Beta-carbonyl carbamate compound, preparation method and application thereof | |
| JPH0159266B2 (en) | ||
| JPS647973B2 (en) | ||
| CN114920633A (en) | Synthesis process of aldehyde ketone compound | |
| JP2642680B2 (en) | Reduction of β-ketoester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |