JPS60500133A - Method for producing cycloaddition compounds - Google Patents
Method for producing cycloaddition compoundsInfo
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- JPS60500133A JPS60500133A JP83503376A JP50337683A JPS60500133A JP S60500133 A JPS60500133 A JP S60500133A JP 83503376 A JP83503376 A JP 83503376A JP 50337683 A JP50337683 A JP 50337683A JP S60500133 A JPS60500133 A JP S60500133A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/05—Alcohols containing rings other than six-membered aromatic rings
- C07C33/14—Alcohols containing rings other than six-membered aromatic rings containing six-membered rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 シクロ付加化合物の製造方法 本発明はシクロ付加化合物の製造方法に関するものである。[Detailed description of the invention] Method for producing cycloaddition compounds The present invention relates to a method for producing a cycloaddition compound.
このため本発明においては、ケテンを触媒としてのキラル第三アミンの存在下、 カルボニル基に対しα−位に高い電子吸引基を有する別紙（１）式のカルボニル 基含有化合物と反応させて別紙（２）式のシクロ付加化合物を生成させる。Therefore, in the present invention, in the presence of a chiral tertiary amine using ketene as a catalyst, Carbonyl of Attachment (1) formula having a high electron-withdrawing group at the α-position with respect to the carbonyl group A cycloaddition compound of the formula (2) in the attached sheet is produced by reacting with a group-containing compound.
驚くべきことに、ケテンと別紙（１）式の化合物との反応においてキラル第三ア ミンを使用すると、生成する反応生成物に対し高い光学選択性（ｅｎａｎｔｉｏ ｓｅｌｅｃｔｉｖｅ）を示し９０〜９５％の値および更に高い値が得られる。Surprisingly, in the reaction between ketene and the compound of the formula (1) in the attached sheet, a chiral tertiary atom appears. The use of amines provides high enantioselectivity (enantioselectivity) for the reaction products formed. selective) and values of 90-95% and even higher values are obtained.
カルボニル基と該カルボニル基に対しα−位に高い電子吸引基とを有する（１） 式の化合物を例示すると、クロラール、特に１，１．１− ）リクロロプロパノ ン−２がある。この最後に掲げた化合物を使用することによって生成した反応生 成物によりコレカルシフェロール化合物、例えば２５（Ｓ）およ２５（Ｒ）−１ α、２５．２６−１リヒドロキシコレ力ルシフエロールの両者並ヒに２５ （Ｓ ）および（２５）−ジヒドロキシコレカルシフェロールの両者全容易に且つ立体 選択的に製造することができ、尚これらコレカルシフェロール化合物は人体にお いて役割をはたし、例えば２５（Ｓ） 、 ２Ｇ−ジヒドロキシコレカルシフェ ロールは重要なビタミンＤ３代謝産物である。Having a carbonyl group and a high electron-withdrawing group at the α-position with respect to the carbonyl group (1) Examples of compounds of the formula include chloral, especially 1,1.1-)lichloropropano There is N-2. The reaction products produced by using this last listed compound Depending on the composition, cholecalciferol compounds such as 25(S) and 25(R)-1 α, 25.25 (S ) and (25)-dihydroxycholecalciferol, both readily and sterically These cholecalciferol compounds can be selectively produced, and these cholecalciferol compounds are safe for the human body. For example, 25(S), 2G-dihydroxycholecalcifer Roll is an important vitamin D3 metabolite.
本発明の方法において使用する触媒を例示すると、以下に示すＡ表に掲げたキラ ル第三アミンがある。Examples of catalysts used in the method of the present invention include the catalysts listed in Table A below. There are three tertiary amines.
Ａ表の■、■および■欄に示した相互に関係する値の比較は、触媒の選択により ケテンと（１）式の化合物としてのクロラールとの主反応に対し何についてまた どの程度影響が及ぶかを示している。Comparison of the interrelated values shown in columns ■, ■, and ■ of Table A shows that depending on the choice of catalyst, What about the main reaction between ketene and chloral as a compound of formula (1)? It shows how much of an impact it will have.
Ａ表： 形成されたβラクトンの絶対、立体配置と触媒ａの配置との関係 ａ標準状態ニー５０℃におけるトルエン中の触媒４モル％ ｂ窒素原子に隣接する炭素原子の配置 （１〜８番についてＣ８，８および１ｏ番についてＣ２）。Table A: Relationship between the absolute and steric configuration of the formed β-lactone and the configuration of catalyst a a 4 mol% catalyst in toluene at standard conditions 50°C b Arrangement of carbon atoms adjacent to nitrogen atoms (C8 for numbers 1 to 8, C2 for numbers 8 and 1o).
Ｃ置換の変化による命名法の変更 ｄ触媒の溶解度問題のためＣＨＣｌ３中で行なった反応 ｅ分子内水素結合（エピキニ−２）および触媒に関し窒素の有効性を減する塩素 による窒素の立体ブロッキングにピクロロシンコニジン）のため、これらの場合 に化学収率が低くなる （５８０％）。Change in nomenclature due to change in C substitution d Reactions carried out in CHCl3 due to catalyst solubility issues. e intramolecular hydrogen bonding (epikini-2) and chlorine reducing the availability of nitrogen with respect to the catalyst. In these cases, due to steric blocking of nitrogen by pichlorocinchonidine) The chemical yield becomes lower (580%).
また、本発明は別紙（２）式、特にＲがＨまたはＯＨ３を表わす別紙（３）式の シクロ付加化合物に関するものである。別紙（２）式または（３）式のシクロ付 加化合物のうちＲ−またはＳ−鏡像体のものが特に好適である。（２）式または （３）式で表わされるかかるシクロ付加化合物は新規であり、キラル化合物、例 えばリンゴ酸の如きヒドロキシアルカンジカルボン酸の不斉合成に関する出発物 質とて極めて有益である。更に、これらシクロ付加化合物は新規なアセトニド化 合物の製造に関する出発化合物として適当である。The present invention also applies to the formula (2) in the attached sheet, especially the formula (3) in the attached sheet in which R represents H or OH3. It concerns cycloaddition compounds. Attached sheet (2) or (3) with cyclo Among the adducts, R- or S-enantiomers are particularly preferred. (2) or Such cycloaddition compounds of formula (3) are novel and include chiral compounds, e.g. Starting materials for the asymmetric synthesis of hydroxyalkanedicarboxylic acids such as malic acid The quality is extremely beneficial. Furthermore, these cycloaddition compounds are novel acetonidation compounds. Suitable as starting compounds for the preparation of compounds.
このため本発明は、別紙（２）式の化合物をそれ自体知られた方法で別紙（３２ ）式のアセトニドに・転化し、特にＲｔｆｉＣ，Ｈ３である別紙（３）式の化合 物を別紙（３３）式の化合物に転化することを特徴とする７セトニドの製造方法 にも関するものである。好ましくは別紙（３２）式および（３３）式中のＸは夫 ｈ ＯＴｓ、ＯＨ，Ｃ！；Ｌ、ＢｒまたはＪを表わし、ここでＯＴｓはトシレー トである。。Therefore, the present invention provides a compound of the formula (2) in the appendix (32) using a method known per se. ) is converted into the acetonide of the formula, especially RtfiC, H3, the compound of the formula (3) in the attached sheet A method for producing 7cetonide, which is characterized by converting a compound into a compound of formula (33) in the attached sheet. It also relates to Preferably, X in the attached formulas (32) and (33) is a husband. h OTs, OH, C! ; represents L, Br or J, where OTs is It is. .
別紙（２）式または（３）式の化合物の対応する鏡像体から出発することにより 別紙（３２）式または（３３）式のアセトニド化合物のＲ−またはＳ−鏡像体を 製造するのか一層好ましい。By starting from the corresponding enantiomer of the compound of the attached formula (2) or (3), Attachment R- or S-enantiomer of the acetonide compound of formula (32) or formula (33) It is even more preferable to manufacture it.
（３２）式の化合物、例えばＸがＣ１、ＢｒまたはＪである（３３）式の化合物 の製造に関して、（３）式の化合物、例えばＲがＣＨ３である（３）式の化合物 のＲ−鏡像体から出発するのが有効であり、同化合物を次の化学的操作に供する （別紙（１４）式）。Compounds of formula (32), for example compounds of formula (33) where X is C1, Br or J For the preparation of compounds of formula (3), for example compounds of formula (3) in which R is CH3 It is useful to start from the R-enantiomer of and subject the same compound to the following chemical manipulations. (Attachment formula (14)).
ａ） （２３）式のオキセタノン（０ズｅｔａｎｏｎｅ）を３−ヒドロキシ−３ −（トリクロロメチル）ブタン酸（（８）式）へ酸により加水分解し； ｂ）（８）式の化合物を２−メチル−２−ヒドロキシ−コハク酸（（９）式）へ 塩基↓こより加水分解しくイオン交換器で処理することにより単Ｉｔ）； Ｃ） （！３）式の化′合物をジエステル（例えばジエチルまたはジメチルエス テル） （Ｎｏ）式）へエステル化し； ｄ） ジエステルを（１１）式の２−メチル−１，２，４−ブタントリオールへ 還元し； ｅ）２−メチル−１，２，４−ブタントリオールノ１．２−ア七ト二ドから（１ ２）式の化合物を生成し；ｆ） この化合物を（１３）式の２−メチル−１，２ ，４−ブタントリオ−ルー１．２−７セトニドー４−トシレートへトシレー ト 化（ｔｏｓｙｍａｔｉｏｎ ） し ；ｇ）ハロゲン（Ｊ、Ｂｒ、 Ｃ１）によ るで１３９式の化合物中の４−トシル基の置換により、ＸがＪ 、Ｂｒ互たノよ Ｃ立である（３３）式の化合物を得る。a) Oxetanone of formula (23) is converted into 3-hydroxy-3 - Hydrolyzed with acid to (trichloromethyl)butanoic acid (formula (8)); b) Compound of formula (8) to 2-methyl-2-hydroxy-succinic acid (formula (9)) Base ↓ is then hydrolyzed and treated with an ion exchanger to form a single It); C) The compound of formula (!3) is converted into a diester (e.g. diethyl or dimethyl ester) esterification to (No) formula); d) Diester to 2-methyl-1,2,4-butanetriol of formula (11) give back; e) From 2-methyl-1,2,4-butanetriolno-1,2-a7tonide (1 2) produce a compound of formula; f) convert this compound into 2-methyl-1,2 of formula (13); ,4-butanetriol-1.2-7cetonide to 4-tosylate tosymation; g) by halogen (J, Br, C1) By substitution of the 4-tosyl group in the compound of formula 139, A compound of formula (33) which is C-standing is obtained.
４−位で置換された（３２）式の化合物、特に４−置換２−メチル−１，２−ブ タンジオール−１，２−アセトニド類またはこれらのＲ−またはＳ−鏡像体も本 発明に属する。Compounds of formula (32) substituted at the 4-position, especially 4-substituted 2-methyl-1,2-butyl Tandiol-1,2-acetonides or their R- or S-enantiomers are also included in this book. belongs to invention.
４−ハロゲン−２−メチル−１，２−ブタンジオール−１゜２−７セトニド類の グリニヤール化合物は、 １α、２５゜２６−トリヒドロキシコレカルシフエロ ール式）および２５．２６−シヒドロキシコレカルシフエロール類（（５）式） の新規製造方法に関する重要な中間体である。この製造方法は、（３３）式の７ セトニド類のグリニヤール化合物を用いるので、これによりこれらコレカルシフ ェロール類の合成に用いられる方法全体に亘り極めて有益°である。（Ｊ．Ｊ． Ｐａｒｔｒｉｄｇｅ， Ｍ．Ｒ。4-halogen-2-methyl-1,2-butanediol-1゜2-7cetonides The Grignard compound is 1α, 25゜26-trihydroxycholecalcifero (formula (5)) and 25,26-cyhydroxycholecalciferols (formula (5)) It is an important intermediate for a new manufacturing method. This manufacturing method is based on 7 of equation (33). Since Grignard compounds of the cetonides are used, these cholecalcif This is highly beneficial throughout the methods used to synthesize ferrols. (J.J. Partridge, M. R.
Ｕｓｋｏｋｏｖｉｃ ｅｔ ａｌ． Ｊ． Ａｍ． Ｃｈｅｗ． Ｓａｃ．、 １９８１， １０３。Uskokovic et al. J. Am. Chew. Sac. , 1981, 103.
１２５３、 Ｊ．Ｊ．Ｐａｒｔｒｉｄｇｅ， Ｍ．Ｒ． Ｕｓｋｏｋｏｖｉｃ ｅｔ ａｌ．。1253, J. J. Partridge, M. R. Uskokovic etal. .
Ｈｅｌｖ． Ｃｈｅｗ． Ａｃｔ． ６４． ２１３８ （１９８１） 。Helv. Chew. Act. 64. 2138 (1981).
（２３）式のハロゲン化合物による（２２）式のカルバニオンのアルキル化（別 紙（１５）式）が開示されている）。Alkylation of the carbanion of formula (22) with a halogen compound of formula (23) (separately) Paper (15) formula) is disclosed).
更に、トシレートに関する出発化合物（（７）式）は（２２）式のカルバニオン に関する出発化合物よりも一層容易に入手できる。Furthermore, the starting compound for tosylate (formula (7)) is the carbanion of formula (22). are more readily available than the starting compounds.
（３３）式の化合物の製造に関し要となる化合物は、ＲカＣＨ３である（３）式 のトメチル−４−（トリクロロメチル）−２−オキセタノンである。この化合物 から（Ｓ）および（Ｒ） ノ両鏡像体（別紙（４ａ）、（４ｂ）式参照）を１． １．１−トリクロロプロパノン−２とケテンとのシクロ付加により純粋な形態で 製造することができる。（４ａ）および（４ｂ）式の２種の純粋な鏡像体オキセ タノン類のいずれか一方から出発して、（３３）式の化合物と同様に化合物（１ １）式を介して２種の鏡像形態の化合物８を製造することができ（別紙（１４） 式）、尚かかる（３３）式の化合物のグリニヤール化合物は２５（ｓ）−オヨび ２５（Ｒ）−２５’，２Ｂ−ジヒドロキシコレカルシフェロール（（’］）式） の両者の製造同様に２５（Ｓ）−および２５（Ｒ）−１α，２５．２６− トリ ヒドロキシコレカルシフェロール（（８）式）の両者の製造にも使用することが できる。The key compound for the production of the compound of the formula (33) is the formula (3), which is RCH3. is tomethyl-4-(trichloromethyl)-2-oxetanone. this compound From (S) and (R), both enantiomers (see Attachments (4a) and (4b) formulas) are 1. 1.1-Trichloropropanone-2 in pure form by cycloaddition with ketene can be manufactured. Two pure enantiomeric oxenes of formulas (4a) and (4b) Starting from either one of the tanones, compound (1 1) Two mirror image forms of Compound 8 can be produced via the formula (Attachment (14) Formula), and the Grignard compound of the compound of formula (33) is 25(s)-Oyobin. 25(R)-25',2B-dihydroxycholecalciferol ((']) formula) Similarly to the production of both 25(S)- and 25(R)-1α, 25.26-tri It can also be used to produce both hydroxycholecalciferol (formula (8)). can.
本発明を以下の実施例、により説明する。The invention is illustrated by the following examples.
実 施 例 ′１ ａ） （Ｓ）−β−（トリクロロメチル）−β−プロピオラクトン（別紙（１６ ）式）の製造 温度計、トルエン表面下へのケテン入口および滴下漏斗を備えた三ツ−丸底フラ スコ（１０００ｍ３）に、８３ｍｇ（０．２５ｍ ｍｏｌ）の精製キニジンを５ ０ｃｆｆ１３のトルエンに入れて導入した。この溶液を−５ ０ ’Ｃまで冷却 した。次いでマグネチックスターラでかきまぜた該溶液にケテンを通し、同時に トルエン２０ｃｍ３に溶解した１、４７ｇ（０，０１ｍｏｌ）の無水クロラール を０．７５〜１時間に亘り滴下した。過剰量のケテンを避けてジケテンの生成を 最少にした。反応終了後、混合物を室温まで加温し、分離漏斗に移した。４Ｎの ８０文で繰返し洗浄（２回）を行うことにより触媒を除去した。トルエン相を飽 和ＮａＣ： ｌ溶液で洗浄し、Ｍｇ５Ｏ，で乾燥した。ろ過によりＭｇ５Ｏ，を 除去した後、トルエンを減圧下で除去した。残留物を蒸留により精製した：１２ ０°Ｃ（０，５＋ｎｍＨｇ、） ；収量１．８７ｇ（８９％）；［α］”−１５ ，３°（０文、シクロヘキサン）８８％のｅｅに５７＋１ 相当、 ＮＭＲ３，７（２Ｈ，ｍ） 、 ５．０ｐｐｍ（ＩＨ，ｔ）ｂ）光学的 に純粋な（Ｒ）−および（Ｓ）−β−（トリクロロメチル）−β−プロピオラク トン（別紙（１６）式）の製造（１６）式のラクトン１８ｇ（ｅｅ９５％）を４ ．１ ａｍ３のメチルシクロヘキサンに加温することにより溶解した。この溶液 をろ過し、室温まで冷却した。ろ過し少量のメチルシクロヘキサンで洗浄した後 に、１５．５ｇの（Ｓ）−ラクトン生成物を回収することができた（収率８５％ ）。Implementation example '1 a) (S)-β-(trichloromethyl)-β-propiolactone (Attachment (16) ) production of formula) Three-round bottom flask with thermometer, toluene subsurface ketene inlet and dropping funnel 83 mg (0.25 mmol) of purified quinidine was added to Sco (1000 m3). It was introduced in 0cff13 of toluene. Cool this solution to -50’C did. Then, ketene is passed through the solution stirred with a magnetic stirrer, and at the same time 1.47 g (0.01 mol) of anhydrous chloral dissolved in 20 cm3 of toluene was added dropwise over 0.75 to 1 hour. Avoid excessive amounts of ketene to reduce the formation of diketene Minimized. After the reaction was complete, the mixture was warmed to room temperature and transferred to a separatory funnel. 4N's The catalyst was removed by repeated washing (twice) at 80 min. saturate the toluene phase Washed with NaC:1 solution and dried with Mg5O. Mg5O, by filtration After removal, toluene was removed under reduced pressure. The residue was purified by distillation: 12 0°C (0,5+nmHg, ); Yield 1.87g (89%); [α]”-15 , 3° (0 sentences, cyclohexane) 57+1 to 88% ee Equivalent, NMR 3,7 (2H, m), 5.0 ppm (IH, t) b) Optical Pure (R)- and (S)-β-(trichloromethyl)-β-propiolac Production of 18 g (ee 95%) of the lactone of formula (16) to 4 ．． It was dissolved in 1 am3 of methylcyclohexane by heating. This solution was filtered and cooled to room temperature. After filtering and washing with a small amount of methylcyclohexane 15.5 g of (S)-lactone product could be recovered (yield 85%). ).
［α］”−１５，’８° （ｃｉ、シクロヘキサン） 、 ｍｐ、 ５１〜Ｓフ ８ ５２°Ｃ比旋光度は更に晶出させた後でも変化しなかった。[α]”-15,’8° (ci, cyclohexane), mp, 51~S frame 8 The 52°C specific rotation did not change after further crystallization.
１１０ｃｍ３のメチルシクロヘキサンから（１６）式のラクトン１９．７ｇ （ ７２％ｅｅ）を出発物質として同じ方法で行ったところ、１２．８ｇの（Ｒ）− ラクトン（収率６５％）を得た： ［α］２０１５゜４°（Ｃ立、シクロヘキサ ン）７ｇ ｍｐ５１〜５２°Ｃ０更に晶出させた後でも比旋光度は変化しないことが判明し た。（１６）式のラセミラクトンはｍｐ、 ３８〜３７℃を有した。19.7 g of lactone of formula (16) from 110 cm3 of methylcyclohexane ( When the same method was carried out using 72% ee) as the starting material, 12.8 g of (R)- Lactone (yield 65%) was obtained: [α]2015°4° (C, cyclohexane ) 7g mp51-52°C0 It was found that the specific rotation did not change even after further crystallization. Ta. The racemic lactone of formula (16) had an mp of 38-37°C.
実施例２ ケテンと１．１．１− ）リクロロプロバノン−２との反応において触媒として キニジンを用いることにより、（４）式の純粋な鏡像体化合物を次のようにして 得ることができた。Example 2 As a catalyst in the reaction between ketene and 1.1.1-)lichloroprobanone-2 By using quinidine, the pure enantiomeric compound of formula (4) can be prepared as follows: I was able to get it.
乾燥窒素雰囲気下で、３８９ｍｇ （１，２ｍ ｍｏｌ）のキニジンを、温度計 とケテン入口とを備えた三ツロフラスコ１００ｃｍ３内の３５０ｆｆｉ３のトル エンに溶解した。次いで１０ｇ （ｆ３３ｍ ｍｏｌ）の１．１．１− トリク ロロプロパノン−２を添加した。混合物を一２５°Ｃまで冷却した。ケテンをか きまぜながら５時間に７亘り通した（約１０ｍ ｍｏｌ／時）。５時間経過後、 反応混合物のＮＭＲによる約５０％のｉ、ｔ４−トリクロロプロパノン−２が所 望の２−オキセタノンに転化されていた。反応を２５ｃ＋ａ３の４Ｎ Ｈ（４を 添加することにより停止した。次いで分離漏斗において反応混合物を１０ｃｍ３ ４Ｎ Ｈｆｄｌで３回洗浄し、更に１０ｃｍ＋３の飽和Ｎａ０文溶液で洗浄し、 ＭｇＳＯ４で乾燥した。ろ過し溶媒を蒸発させた後、バルブ ツー バルブ（ｂ ｕｌｂ ｔ。Under a dry nitrogen atmosphere, 389 mg (1.2 mmol) of quinidine was added using a thermometer. of 350ffi3 in a 100cm3 Mitsulo flask with a ketene inlet and Dissolved in ene. Then 10g (f33m mol) of 1.1.1-tric Lolopropanone-2 was added. The mixture was cooled to -25°C. Keten? It was passed for 7 hours over 5 hours while stirring (approximately 10 mmol/hour). After 5 hours, Approximately 50% i,t4-trichloropropanone-2 was present by NMR of the reaction mixture. It had been converted to the desired 2-oxetanone. The reaction was carried out using 25c+a3 of 4N H (4 It was stopped by adding The reaction mixture was then diluted with 10 cm3 in a separatory funnel. Washed 3 times with 4N Hfdl, further washed with 10cm+3 saturated Na0 solution, Dry with MgSO4. After filtering and evaporating the solvent, the valve-to-valve (b ulb t.
ｂｕｌｂ） ７５留によ刃残留物を精製した（０．ｌｍｍＨｇ／１２０℃）。Bulb) The blade residue was purified by distillation 75 (0.1 mmHg/120°C).
収量５．６ｇ（４５％）； Ｓ−鏡像体に相当。メチルシクロヘキサンからの１回の晶出により、２−オキセ タノン鏡像体を純粋な形態で得ることができた。Yield 5.6g (45%); Corresponds to S-enantiomer. A single crystallization from methylcyclohexane yielded 2-oxe It was possible to obtain the tanone enantiomer in pure form.
［α］ ” ＋６．３５（Ｃ＝１．９１３％エタノール）（Ｓ−鏡像５７！１ 体） 、 ｍｐ、 ３９．５〜４０．５℃キニジンの代りにキニーネから出発し て２−オキセタノンの（Ｒ）−鏡（を体を８８％ｅｅで単離でき、シンコニジン から出発して（Ｒ）−鏡像体を８６％ｅｅで単離でき、またシンコニンから出発 して（Ｓ）−鏡像体を９２％ｅｅで単離できた。[α]” +6.35 (C = 1.913% ethanol) (S-mirror image 57!1 body), mp, 39.5-40.5℃ Starting from quinine instead of quinidine The (R)-carbohydrate of 2-oxetanone was isolated with 88% ee, and cinchonidine Starting from cinchonine, the (R)-enantiomer can be isolated with 86% ee. The (S)-enantiomer could be isolated with 92% ee.
手続補正書（方式） 昭和５９年１１月１３日 特許庁長官 志 賀 学 殿 １、事件の表示 ＰＣＴ／ＮＬ８３１０００４０ ２、発明の名称 シクロ付加化合物の製造方法 ３、補正をする者 事件との関係 特許出願人 住 所 オランダ王国 ８７５２ ピー・ニー ハーレン。Procedural amendment (formality) November 13, 1980 Mr. Manabu Shiga, Commissioner of the Patent Office 1.Display of the incident PCT/NL83100040 2. Name of the invention Method for producing cycloaddition compounds 3. Person who makes corrections Relationship to the incident: Patent applicant Address: 8752 Pe Ni Haren, Kingdom of the Netherlands.
フイゲンスベーク ４ 氏名 ウィンベルク、 ハンス 住 所 オランダ王国 ９７１５ エル・ビー グロニンゲン。Huygensbake 4 Name Winberg, Hans Address: 9715 L.B. Groningen, Kingdom of the Netherlands.
チモルストラート ２７エー 氏 名 スターリング、 エミール グラダス ヨノ翫ネス４、代理人 〒１０ ７ 住 所 東京都港区赤坂５丁目１番３１号第６セイコービル３階 ５、補正命令の日付 昭和５８年ＩＯ月１１日（発送日 昭和５９年１０月２３日）６、補正の対象 特許法第１８４条の５第１項の規定による書面の特許出願人の欄 、委任状およ び図面。Timol Strat 27A Name: Sterling, Emil Gradus Yono Kannes 4, Agent: 10 7 Address: 3rd floor, Seiko Building 6, 5-1-31 Akasaka, Minato-ku, Tokyo 5. Date of amendment order 11th IO, 1988 (Shipping date: 23rd October 1980) 6. Subject to amendment Patent applicant column in the document pursuant to Article 184-5, Paragraph 1 of the Patent Law, power of attorney and and drawings.
７、補正の内容 （１）別紙の通り （２）図面の浄書 （内容に変更なし）国際調査報告 ｌｎ＋ａｔｎｓ＋ｏｎａ＋ｈｏｐ１−ｃａ＋１ｏｎｕｏ、ＰＣＴ／ＮＬ８３１０ ００４０Ｉｎ＋ｅ＋ｎａ＋ｌｏ−＾ｐｐＨｃｍｔｌｏｆ１１１１ｅ、ＰＣＴ／Ｍ Ｌ８３１０００４０ダス ヨハネス7. Contents of correction (1) As per attached sheet (2) Engraving of drawings (no change in content) international search report ln+atns+ona+hop1-ca+1onuo, PCT/NL8310 0040In+e+na+lo-^ppHcmtlof1111e, PCT/M L83100040 Das Johannes
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8204070A NL8204070A (en) | 1982-10-21 | 1982-10-21 | METHOD FOR PREPARING A CYCLO ADDITION COMPOUND |
| NL8204070 | 1982-10-21 | ||
| PCT/NL1983/000040 WO1984001577A1 (en) | 1982-10-21 | 1983-10-21 | A process for preparing a cycloaddition compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS60500133A true JPS60500133A (en) | 1985-01-31 |
Family
ID=19840446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP83503376A Pending JPS60500133A (en) | 1982-10-21 | 1983-10-21 | Method for producing cycloaddition compounds |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0122279A1 (en) |
| JP (1) | JPS60500133A (en) |
| NL (1) | NL8204070A (en) |
| WO (1) | WO1984001577A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013535440A (en) * | 2010-07-21 | 2013-09-12 | ロンザ リミテッド | Process for the production of carnitine from β-lactone |
| JP2013536172A (en) * | 2010-07-21 | 2013-09-19 | ロンザ リミテッド | Process for the manufacture of carnitine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000061776A1 (en) * | 1999-04-14 | 2000-10-19 | Mercian Corporation | Vitamin d derivatives and process for producing the same |
-
1982
- 1982-10-21 NL NL8204070A patent/NL8204070A/en not_active Application Discontinuation
-
1983
- 1983-10-21 JP JP83503376A patent/JPS60500133A/en active Pending
- 1983-10-21 EP EP83903420A patent/EP0122279A1/en not_active Withdrawn
- 1983-10-21 WO PCT/NL1983/000040 patent/WO1984001577A1/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013535440A (en) * | 2010-07-21 | 2013-09-12 | ロンザ リミテッド | Process for the production of carnitine from β-lactone |
| JP2013536172A (en) * | 2010-07-21 | 2013-09-19 | ロンザ リミテッド | Process for the manufacture of carnitine |
Also Published As
| Publication number | Publication date |
|---|---|
| NL8204070A (en) | 1984-05-16 |
| EP0122279A1 (en) | 1984-10-24 |
| WO1984001577A1 (en) | 1984-04-26 |
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