JPH0149708B2 - - Google Patents
Info
- Publication number
- JPH0149708B2 JPH0149708B2 JP138781A JP138781A JPH0149708B2 JP H0149708 B2 JPH0149708 B2 JP H0149708B2 JP 138781 A JP138781 A JP 138781A JP 138781 A JP138781 A JP 138781A JP H0149708 B2 JPH0149708 B2 JP H0149708B2
- Authority
- JP
- Japan
- Prior art keywords
- product
- reaction
- distilled
- stirring
- present
- 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
- 238000004519 manufacturing process Methods 0.000 claims description 6
- QNYBOILAKBSWFG-SNVBAGLBSA-N (2s)-2-(phenylmethoxymethyl)oxirane Chemical compound C([C@H]1OC1)OCC1=CC=CC=C1 QNYBOILAKBSWFG-SNVBAGLBSA-N 0.000 claims description 5
- -1 malonic acid diester Chemical class 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000047 product Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- JVPPZBQIEINDEG-LLVKDONJSA-N (5r)-5-(phenylmethoxymethyl)oxolan-2-one Chemical compound O1C(=O)CC[C@@H]1COCC1=CC=CC=C1 JVPPZBQIEINDEG-LLVKDONJSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- QNYBOILAKBSWFG-UHFFFAOYSA-N 2-(phenylmethoxymethyl)oxirane Chemical compound C1OC1COCC1=CC=CC=C1 QNYBOILAKBSWFG-UHFFFAOYSA-N 0.000 description 1
- JVPPZBQIEINDEG-UHFFFAOYSA-N 5-(phenylmethoxymethyl)oxolan-2-one Chemical compound O1C(=O)CCC1COCC1=CC=CC=C1 JVPPZBQIEINDEG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- 229930182847 D-glutamic acid Natural products 0.000 description 1
- QGLBZNZGBLRJGS-UHFFFAOYSA-N Dihydro-3-methyl-2(3H)-furanone Chemical compound CC1CCOC1=O QGLBZNZGBLRJGS-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Furan Compounds (AREA)
Description
【発明の詳細な説明】
本発明は（Ｒ）−（−）−５−ベンジルオキシメ
チルテトラヒドロフラン−２−オンの新規な製造
方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing (R)-(-)-5-benzyloxymethyltetrahydrofuran-2-one.
（Ｒ）−（−）−５−ベンジルオキシメチルテト
ラヒドロフラン−２−オンは抗腫瘍剤剤として用
いられるビンブラスチンやビンクリスチンなどの
ような生理活性アルカロイドを誘導するに当つて
（Ｒ）（−）配置をする重要な中間体である。 (R)-(-)-5-benzyloxymethyltetrahydrofuran-2-one has the (R)(-) configuration when inducing bioactive alkaloids such as vinblastine and vincristine, which are used as antitumor agents. It is an important intermediate for
従来、５−ベンジルオキシメチルテトラヒドロ
フラン−２−オンの（Ｒ）（−）体を得るには、
非天然系で高価なＤ−グルタミン酸（Ｒ配置）を
出発原料とする方法が提案されていたが、本発明
者らは安価にしてかつ容易に入手し得る物質を原
料として該化合物を得る方法について鋭意研究し
本発明を完成した。 Conventionally, to obtain the (R)(-) form of 5-benzyloxymethyltetrahydrofuran-2-one,
A method using non-natural and expensive D-glutamic acid (R configuration) as a starting material has been proposed, but the present inventors have developed a method for obtaining this compound using an inexpensive and easily available substance as a starting material. After extensive research, the present invention was completed.
すなわち本発明は公知の方法で得た（Ｓ）−
（―）―ベンジル―２，３−エポキシプロピルエ
ーテルを出発原料とし、マロン酸ジエステルを反
応させて（Ｒ）−（−）−５−ベンジルオキシメチ
ル−３−（Ｒ／Ｓ）−カルボアルコキシテトラヒド
ロフラン−２−オンとなし、このものを脱カルボ
アルコキシ化して目的の（Ｒ）−（−）−５−ベン
ジルオキシメチルテトラヒドロフラン−２−オン
を誘導する方法を提供するものである。 That is, the present invention provides (S)-
Using (-)-benzyl-2,3-epoxypropyl ether as a starting material, reacting malonic acid diester with (R)-(-)-5-benzyloxymethyl-3-(R/S)-carboalkoxytetrahydrofuran -2-one, and decarbalkoxylates this product to derive the desired (R)-(-)-5-benzyloxymethyltetrahydrofuran-2-one.
本発明方法について、その一実施態様を示せ
ば、（Ｓ）−（−）−ベンジル―２，３−エポキシプ
ロピルエーテルとマロン酸ジエステルをナトリウ
ムアルコキシドのような有機アルカリの存在下に
加熱して反応させて、両者を縮合・環化して５−
ベンジルオキシメチル−３−カルボアルコキシテ
トラヒドロフラン−２−オンとする。この際生成
物の立体構造は５の位置の炭素については（Ｒ）
体を形成し、３の位置についてはエピマーの混合
体を形成する。次にこの化合物をジメチルアセト
アミドのような非プロトン性極性溶媒中塩化マグ
ネシウム及び少量の水分の存在下に加熱して反応
させ、反応生成物を常法によつて処理して目的物
を得る。 In one embodiment of the method of the present invention, (S)-(-)-benzyl-2,3-epoxypropyl ether and malonic acid diester are heated and reacted in the presence of an organic alkali such as sodium alkoxide. to condense and cyclize both to form 5-
Benzyloxymethyl-3-carbalkoxytetrahydrofuran-2-one. In this case, the three-dimensional structure of the product is (R) for the carbon at position 5.
For position 3, a mixture of epimers is formed. This compound is then reacted by heating in the presence of magnesium chloride and a small amount of water in an aprotic polar solvent such as dimethylacetamide, and the reaction product is treated in a conventional manner to obtain the desired product.
本発明を実施するに当り、出発物質の（Ｓ）−
（−）−ベンジル―２，３−エポキシプロピルエー
テルは例えば参考例１〜３で示すように
天然産Ｄ−マンニト−ルから(D)−マンニトー
ル１，２；５，６ジアセトナイドを得る。 In carrying out the present invention, the starting material (S)-
(-)-Benzyl-2,3-epoxypropyl ether is obtained by obtaining (D)-mannitol 1,2;5,6 diacetonide from naturally occurring D-mannitol, as shown in Reference Examples 1 to 3, for example.
の生成物をメタ過沃素酸ナトリウムで酸化
開裂した後、生成物を還元して（Ｓ）−（＋）−
グリセロール１，２−アセトナイドとする。 After oxidative cleavage of the product with sodium metaperiodate, the product was reduced to (S)-(+)-
Glycerol 1,2-acetonide.
の生成物に臭化ベンジルを作用させた後、
希硫酸中で加熱して（Ｒ）−（＋）−１−０−ベ
ンジルグリセロールとする。 After reacting the product with benzyl bromide,
Heating in dilute sulfuric acid gives (R)-(+)-1-0-benzylglycerol.
の生成物とＰ−トルエンスルホニルクロリ
ドとを反応させた後、生成物の低級アルコール
溶液に金属ナトリウムを加えて反応させ（Ｓ）
−（−）−ベンジル−２，３−エポキシプロピル
エーテルを得る。 After reacting the product with P-toluenesulfonyl chloride, add metallic sodium to a lower alcohol solution of the product and react (S)
-(-)-benzyl-2,3-epoxypropyl ether is obtained.
本発明方法で実施される二つ反応はいずれも加
熱下に行われるが、還流下に行うことが好まし
い。 Both reactions carried out in the method of the present invention are carried out under heating, but preferably carried out under reflux.
本発明方法がすぐれている点は入手容易で安価
な天然産Ｄ−マンニトールを出発原料とし、他に
特別な副原料を必要とせず、反応に際しても特別
な操作を要せずに目的物が得られ、反応による化
学収率及び光学収率が極めて高い。すなわち後述
する参考例及び実施例においてＤ−マンニトール
から（Ｒ）−（−）−５−ベンジルオキシメチルテ
トラヒドロフラン−２−オンまでの総化学収率は
46％に達し光学収率は90％である。 The superiority of the method of the present invention is that it uses easily available and inexpensive naturally produced D-mannitol as a starting material, does not require any other special auxiliary materials, and the desired product can be obtained without requiring special operations during the reaction. The chemical and optical yields of the reaction are extremely high. That is, in the Reference Examples and Examples described below, the total chemical yield from D-mannitol to (R)-(-)-5-benzyloxymethyltetrahydrofuran-2-one is
The optical yield reaches 46% and is 90%.
次に本発明方法に関連する反応を化学式で示す
と次の通りである。ここで参考例１は(2)から(4)
を、同２は(4)から(6)を、同３は(6)から(8)を、又、
実施例１は(8)から(9)を、同２は(9)から(10)の化合物
をそれぞれ誘導する工程であつて、本発明方法は
(8)から(10)までの工程である。 Next, the chemical formula of the reaction related to the method of the present invention is as follows. Here, reference example 1 is (2) to (4)
, 2) (4) to (6), 3 (6) to (8), and
Example 1 is a process for deriving compounds (8) to (9), and Example 2 is a process for deriving compounds (9) to (10), respectively, and the method of the present invention
This is the process from (8) to (10).
以下参考例及び実施例により本発明を詳細に説
明する。なお、参考例はB.T.Golding：
Synthesis423（1977）に準じて実施した。 The present invention will be explained in detail below with reference to Reference Examples and Examples. The reference example is BTGolding:
It was carried out according to Synthesis 423 (1977).
参考例 １
（Ｓ）−（＋）−グリセロール―１，２−アセト
ナイドの製造
Ｄ−マンニトールから誘導した(D)−マンニトー
ル−１，２：５，６−ジアセトナイド32g（0.12ユ
モル）を５％重炭酸ナトリウム水溶液40mlを含む
メタノール150mlに溶解し、この溶液を撹拌しな
がら０℃に保つてメタ過沃素酸ナトリウム37.4g
（0.174モル）を水130mlに溶解した溶液を滴下し
た。同温度で１時間撹拌して反応を行い。アルデ
ヒド体を生させ、次いで水素化ほう素ナトリウム
9.44g（0.25モル）を加えて０〜10℃保つて還元反
応を行つた。還元終了後メタノール150mlを加え
て10℃に保つて撹拌し、析出した無機化合物の沈
殿を過して除いた。液の溶媒を留去し、残つ
た水分はベンゼンの添加による共沸で除去した。
残留物をエーテルで抽出して抽出液を無水硫酸ナ
トリウムで乾燥した後溶媒を留去し、減圧蒸留を
行つて26.2gの純品を得た。このものを分析した
ところ次のような結果が得られ、標題の化合物で
あることが認められた。反応の理論収率は81.3％
であつた。Reference Example 1 Production of (S)-(+)-glycerol-1,2-acetonide 32 g (0.12 umole) of (D)-mannitol-1,2:5,6-diacetonide derived from D-mannitol was dissolved at 5% weight. 37.4 g of sodium metaperiodate was dissolved in 150 ml of methanol containing 40 ml of sodium carbonate aqueous solution, and the solution was kept at 0°C with stirring.
(0.174 mol) dissolved in 130 ml of water was added dropwise. The reaction was carried out by stirring at the same temperature for 1 hour. The aldehyde form is produced, and then sodium borohydride
9.44 g (0.25 mol) was added and a reduction reaction was carried out while maintaining the temperature at 0 to 10°C. After the reduction was completed, 150 ml of methanol was added and stirred while maintaining the temperature at 10°C, and the precipitated inorganic compound was removed by filtration. The solvent of the liquid was distilled off, and the remaining water was removed azeotropically by the addition of benzene.
The residue was extracted with ether, the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and vacuum distillation was performed to obtain 26.2 g of a pure product. When this product was analyzed, the following results were obtained, and it was recognized as the title compound. Theoretical yield of the reaction is 81.3%
It was hot.
沸点：86〜87℃／16mmHg
旋光度：〔α〕D＋11.4゜（Ｃ，5.29，MeOH）
参考例 ２
（Ｒ）−（＋）−１−０−ベンジルグリセロール
の製造
参考例１で得た化合物20g（0.152モル）と臭化
ベンジル32.4ml（0.272ml）に相間移動触媒とし
てベンジルトリエチルアンモニウムクロリド
0.93gを用いて反応させ、粗（Ｒ）−（＋）−１−０
−ベンジルグリセロール−２，３−アセトナイド
を得、このものを精製することなく、1.5N硫酸
120ml中で５時間加熱還流して反応させた後蒸留
して21.3gの生成物を得た。このものを分析した
ところ次のような結果を得、標題の化合物である
ことが認められ、理論収率は77.2％であつた。
Boiling point: 86-87℃/16mmHg Optical rotation: [α] D +11.4° (C, 5.29, MeOH) Reference example 2 Production of (R)-(+)-1-0-benzylglycerol Obtained in Reference example 1 benzyltriethylammonium chloride as a phase transfer catalyst to 20 g (0.152 mol) of the compound and 32.4 ml (0.272 ml) of benzyl bromide.
0.93g of crude (R)-(+)-1-0
-benzylglycerol-2,3-acetonide was obtained, without purification, using 1.5N sulfuric acid.
The reaction mixture was heated under reflux in 120 ml for 5 hours and then distilled to obtain 21.3 g of product. When this product was analyzed, the following results were obtained, confirming that it was the title compound, and the theoretical yield was 77.2%.
沸点：110〜120℃／0.15mmHg
旋光度：〔α〕D＋3.71゜（C19.9，CHC3）
参考例 ３
（Ｓ）−（−）−ベンジル−２，３−エポキシプ
ロピルエーテルの製造
参考例２で得た化合物15.35g（84ミリモル）を
ビリジン45mlに溶解した溶液を氷冷し、この中へ
ρ−トルエンスルホニルクロリド16.0g（84ミリモ
ル）を撹拌下に加えた。1.5時間撹拌を継続した
後減圧下にピリジンを留去し、残留物をエーテル
で抽出した。この抽出液をIN塩酸で洗浄後５％
重炭酸ナトリウム水溶液で洗浄して無水硫酸ナト
リウムで乾燥した。減圧下に溶媒を留去してモノ
トシレートの粗製物23.8gを得た。このものの
9.48gをメタノール30ml及びエーテル15mlに溶解
し、溶液を０℃に保つて、金属ナトリウム0.65g
（2.82ミリモル）を少量ずつ撹拌しながら加えた。
同温度に保つて２時間撹拌して反応させた後反応
生成物に炭酸ガスを導入し、さらに水を加えた後
クロロホルムで抽出した。抽出液を水洗した後無
水硫酸ナトリウムで乾燥した後溶媒を留去後、シ
リカゲルクロマトグラフイーで精製し、純品
4.52gを得た。分析の結果標題の化合物であるこ
とが認められ、理論収率は97.5％であつた。
Boiling point: 110-120℃/0.15mmHg Optical rotation: [α] D +3.71° (C19.9, CHC 3 ) Reference example 3 Production of (S)-(-)-benzyl-2,3-epoxypropyl ether A solution of 15.35 g (84 mmol) of the compound obtained in Reference Example 2 dissolved in 45 ml of pyridine was cooled with ice, and 16.0 g (84 mmol) of ρ-toluenesulfonyl chloride was added thereto with stirring. After continued stirring for 1.5 hours, pyridine was distilled off under reduced pressure, and the residue was extracted with ether. After washing this extract with IN hydrochloric acid, 5%
It was washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 23.8 g of a crude monotosylate. of this
Dissolve 9.48g in 30ml of methanol and 15ml of ether, keep the solution at 0℃, and dissolve 0.65g of metallic sodium.
(2.82 mmol) was added in portions with stirring.
After stirring and reacting at the same temperature for 2 hours, carbon dioxide gas was introduced into the reaction product, water was further added, and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and purified by silica gel chromatography to obtain a pure product.
Obtained 4.52g. As a result of analysis, it was confirmed to be the title compound, and the theoretical yield was 97.5%.
旋光度：〔α〕D＋1.79゜（C5.02，CHC3），−
11.7゜（neat）
実施例 １
（Ｒ）−（−）−５−ベンジルオキシメチル−
（Ｒ／Ｓ）−３−カルボエトキシテトラヒドロフ
ラン−２−オンの製造
金属ナトリウム0.40gをエタノール13ml中に加
えて調整したナトリウムエトキシド−エタノール
溶液中にマロン酸ジエチルエステル3.00g（18.7ミ
リモル）を加え、この中へ室温下に撹拌しながら
参考例３で得たエポキシド2.4g（14.6ミリモル）
を５mlのエタノールに溶解した溶液を滴下した。
この溶液を１時間加熱還流した後冷却し、５％塩
酸で中和後ジクロロメタンで抽出し、抽出液を水
洗した後無水硫酸ナトリウムで乾燥した。減圧下
に溶媒を留去して粗製物を得、シリカゲルクロマ
トグラフイーで精製し、精製物3.42gを得た。こ
のものは分析の結果標題の化合物であることが確
認され、理論収率は84％であつた。分析値は次の
通りである。
Optical rotation: [α] D +1.79° (C5.02, CHC 3 ), -
11.7° (neat) Example 1 (R)-(-)-5-benzyloxymethyl-
Production of (R/S)-3-carboethoxytetrahydrofuran-2-one Add 3.00 g (18.7 mmol) of diethyl malonate to a sodium ethoxide-ethanol solution prepared by adding 0.40 g of sodium metal to 13 ml of ethanol. , 2.4 g (14.6 mmol) of the epoxide obtained in Reference Example 3 was added to this while stirring at room temperature.
A solution prepared by dissolving this in 5 ml of ethanol was added dropwise.
This solution was heated under reflux for 1 hour, then cooled, neutralized with 5% hydrochloric acid, extracted with dichloromethane, and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel chromatography to obtain 3.42 g of purified product. Analysis of this product confirmed that it was the title compound, and the theoretical yield was 84%. The analytical values are as follows.
沸点：180℃／0.37mmHg
旋光度：〔α〕D−21.8゜（C5.16，MeOH）
IRvneat nax（cm-1）：1765，1725
NMR（CDC3）δ：7.6〜7.3（5H，ｍ），5.0〜
4.7（1H，ｍ），4.63（2H，ｄ，Ｊ＝２Hz），4.3
（2H，ｑ，Ｊ＝７Hz），3.9〜3.6（3H，ｍ），2.9〜
2.3（2H，ｍ），1.3（3H，ｔ，Ｊ＝７Hz）
MS（ｍ／ｅ）279（M+＋１），278（M+），250，
172，154，129，126，111，91
C15H18O5
計算値 Ｃ，64.73；Ｈ，6.52
実測値 Ｃ，64.61；Ｈ，6.47
実施例 ２
（Ｒ）−（−）−５−ベンジルオキシメチルテト
ラヒドロフラン−２−オンの製造
実施例１で得た化合物2.0g（7.2ミリモル）と塩
化マグネシウム６水和物7.3g（36ミリモル）をジ
メチルアセトアミド16ml（３滴の水を含む）中に
加え、撹拌しながら２時間還流して反応させた。
反応液を冷却した後ベンゼンで抽出し、抽出液を
水洗した後無水硫酸ナトリウムで乾燥し、減圧下
に溶媒を留去した。残留物を真空蒸留に附し、
160〜170℃／0.4〜0.6mmHgの留分1.33gを得た。
このものを分析した結果標題の化合物の純品であ
ることが確認され、理論収率は89.7％であつた。
分析値は次の通りである。 Boiling point: 180℃/0.37mmHg Optical rotation: [α] D −21.8゜ (C5.16, MeOH) IRv neat nax (cm -1 ): 1765, 1725 NMR (CDC 3 ) δ: 7.6 to 7.3 (5H, m ), 5.0～
4.7 (1H, m), 4.63 (2H, d, J=2Hz), 4.3
(2H, q, J=7Hz), 3.9~3.6 (3H, m), 2.9~
2.3 (2H, m), 1.3 (3H, t, J = 7Hz) MS (m/e) 279 (M + +1), 278 (M + ), 250,
172, 154, 129, 126, 111, 91 C 15 H 18 O 5 Calculated value C, 64.73; H, 6.52 Actual value C, 64.61; H, 6.47 Example 2 (R)-(-)-5-benzyloxy Preparation of methyltetrahydrofuran-2-one 2.0 g (7.2 mmol) of the compound obtained in Example 1 and 7.3 g (36 mmol) of magnesium chloride hexahydrate were added to 16 ml of dimethylacetamide (containing 3 drops of water). The mixture was refluxed and reacted for 2 hours while stirring.
After cooling the reaction solution, it was extracted with benzene, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to vacuum distillation,
1.33 g of a fraction of 160-170°C/0.4-0.6 mmHg was obtained.
Analysis of this product confirmed that it was a pure product of the title compound, and the theoretical yield was 89.7%.
The analytical values are as follows.
旋光度：〔α〕D−18.5゜（C5.18，EtOH） Optical rotation: [α] D −18.5° (C5.18, EtOH)
Claims (1)
ルエーテルとマロン酸ジエステルとを反応させ
て、（Ｒ）−（−）−５−ベンジルオキシメチル−
（Ｒ／Ｓ）−３−カルボアルコキシテトラヒドロフ
ラン−２−オンを得、このものを非プロトン性極
性溶媒中、塩化マグネシウム及び少量の水の存在
下に反応させることを特徴とする（Ｒ）−（−）−
５−ベンジルオキシメチルテトラヒドロフラン−
２−オンの製造方法。1 (S)-Benzyl-2,3-epoxypropyl ether and malonic acid diester are reacted to form (R)-(-)-5-benzyloxymethyl-
(R/S)-( −)−
5-Benzyloxymethyltetrahydrofuran-
Method for producing 2-one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP138781A JPS57116060A (en) | 1981-01-08 | 1981-01-08 | Preparation of (r)-(-)-5- benzyloxymethyltetrahydrofuran-2-one |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP138781A JPS57116060A (en) | 1981-01-08 | 1981-01-08 | Preparation of (r)-(-)-5- benzyloxymethyltetrahydrofuran-2-one |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57116060A JPS57116060A (en) | 1982-07-19 |
| JPH0149708B2 true JPH0149708B2 (en) | 1989-10-25 |
Family
ID=11500066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP138781A Granted JPS57116060A (en) | 1981-01-08 | 1981-01-08 | Preparation of (r)-(-)-5- benzyloxymethyltetrahydrofuran-2-one |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57116060A (en) |
-
1981
- 1981-01-08 JP JP138781A patent/JPS57116060A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57116060A (en) | 1982-07-19 |
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