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JP2001106696A - Production process for aspartame derivative - Google Patents

Production process for aspartame derivative

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Publication number
JP2001106696A
JP2001106696A JP28739999A JP28739999A JP2001106696A JP 2001106696 A JP2001106696 A JP 2001106696A JP 28739999 A JP28739999 A JP 28739999A JP 28739999 A JP28739999 A JP 28739999A JP 2001106696 A JP2001106696 A JP 2001106696A
Authority
JP
Japan
Prior art keywords
group
mmol
aspartyl
reaction
propyl
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.)
Withdrawn
Application number
JP28739999A
Other languages
Japanese (ja)
Inventor
Kazutaka Nagashima
一孝 長嶋
Shigeru Kawahara
滋 河原
Tadashi Takemoto
正 竹本
Eriko Ono
恵理子 小野
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Priority to JP28739999A priority Critical patent/JP2001106696A/en
Priority to EP00961236A priority patent/EP1227104A4/en
Priority to KR1020027004405A priority patent/KR20020038798A/en
Priority to CN00813952A priority patent/CN1378558A/en
Priority to AU73218/00A priority patent/AU7321800A/en
Priority to PCT/JP2000/006625 priority patent/WO2001025259A1/en
Publication of JP2001106696A publication Critical patent/JP2001106696A/en
Priority to US10/108,426 priority patent/US6841183B2/en
Withdrawn legal-status Critical Current

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Abstract

PROBLEM TO BE SOLVED: To provide a practical and industrial production process for 1-mthyl N-[N-[3-(2-hydroxy-substituted phenyl)propyl]-L-α-aspartyl]-L-phenylalanine that is important as a sweetener having excellent sweet taste of high degree of sweetness. SOLUTION: 3,4-Dihydro-substituted-2H-1-benzopyran-2-ol derivative and aspartame are subjected to the reductive alkylation reaction whereby the objective derivative can be efficiently obtained in high yield and the process is practically useful as an industrial process for the objective sweetener.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【0001】[0001]

【発明の属する技術分野】本発明は甘味剤として重要な
N−[N−[3−(2−ヒドロキシ−置換フェニル)プ
ロピル]−L−α−アスパルチル]−L−フェニルアラ
ニン 1−メチルエステル誘導体の新規製造方法に関す
る。
TECHNICAL FIELD The present invention relates to a 1-methyl ester derivative of N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine which is important as a sweetener. It relates to a new manufacturing method.

【0002】[0002]

【従来の技術】近年、食生活の高度化に伴い特に糖分の
摂取過多による肥満及びこれに伴う各種の疾病が問題と
なっており、砂糖に替わる低カロリー甘味剤の開発が望
まれている。現在、広汎に使用されている甘味剤とし
て、安全性と甘味の質の面で優れているアスパルテーム
が存在するが安定性にやや問題があった。以上の背景の
中、本発明者等の一部等によりアスパルテームと比較し
て安定性に優れ、かつ甘味度がはるかに高い、即ち甘味
当たりの価格で優位性のある甘味料として新規にN−
[N−[3−(2−ヒドロキシ−置換フェニル)プロピ
ル]−L−α−アスパルチル]−L−フェニルアラニン
1−メチルエステル誘導体が見出されている。
2. Description of the Related Art In recent years, obesity due to excessive intake of sugar and various diseases associated therewith have become a problem with the sophistication of dietary habits, and development of a low-calorie sweetener instead of sugar has been desired. At present, aspartame, which is widely used as a sweetener, is excellent in safety and sweetness quality, but has a problem in stability. Against this background, some of the present inventors have newly added N- as a sweetener that is superior in stability and much higher in sweetness compared to aspartame, that is, has a superior price per sweetness.
[N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester derivatives have been found.

【0003】[0003]

【発明が解決しようとする課題】前記新規なN−[N−
[3−(2−ヒドロキシ−置換フェニル)プロピル]−
L−α−アスパルチル]−L−フェニルアラニン 1−
メチルエステル誘導体の製造方法として、β−O−ベン
ジル−α−L−アスパルチル−L−フェニルアラニンメ
チルエステルを2−ベンジルオキシ−置換シンナムアル
デヒド誘導体とNaB(OAc)3Hとにより還元的に
アルキル化した後、保護基のベンジル基の除去及び二重
結合の還元を実施する方法が前記発明者等の一部により
見出されている。この方法によれば、原料の合成が煩雑
であることに加え、前記のように還元的アルキル化と脱
保護等の反応を別途実施する必要があり、工業的にはや
や煩雑な工程を要する。
The novel N- [N-
[3- (2-hydroxy-substituted phenyl) propyl]-
L-α-aspartyl] -L-phenylalanine 1-
As a method for producing a methyl ester derivative, β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester was reductively alkylated with a 2-benzyloxy-substituted cinnamaldehyde derivative and NaB (OAc) 3 H. Later, some of the inventors have found a method for removing the benzyl group of the protecting group and reducing the double bond. According to this method, in addition to the complicated synthesis of the raw materials, it is necessary to separately carry out a reaction such as reductive alkylation and deprotection as described above, which requires a somewhat complicated industrial process.

【0004】一方、本発明者等の検討とは別に、アスパ
ルテームを構成するアスパラギン酸のアミノ基にアルキ
ル基を導入した類似化合物が検討され、国際特許WO9
4/11391号公開公報に記載されている。この公報
には本発明者等が見出したN−[N−[3−(2−ヒド
ロキシ−置換フェニル)プロピル]−L−α−アスパル
チル]−L−フェニルアラニン 1−メチルエステル誘
導体と比較的構造が類似したN−[N−[3−(3−メ
トキシ−4−ヒドロキシフェニル)プロピル]−L−α
−アスパルチル]−L−フェニルアラニン 1−メチル
エステルが記載されているが、原料のみならず、どのよ
うな製法により合成を行ったかを示すべき具体的記載は
何ら見当たらない。
On the other hand, apart from the study by the present inventors, a similar compound in which an alkyl group has been introduced into the amino group of aspartic acid constituting aspartame has been studied, and international patent WO 9
No. 4,113,391. This publication has a comparatively similar structure to the N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester derivative found by the present inventors. Similar N- [N- [3- (3-methoxy-4-hydroxyphenyl) propyl] -L-α
-Aspartyl] -L-phenylalanine 1-methyl ester is described, but there is no specific description to indicate not only the raw material but also the production method used for the synthesis.

【0005】このような情況下に、工業的により有利に
前記誘導体を製造する方法の開発が求められている。
[0005] Under such circumstances, there is a demand for a more industrially advantageous method for producing the derivative.

【0006】本発明の課題は、優れた高甘味度甘味料で
あるN−[N−[3−(2−ヒドロキシ−置換フェニ
ル)プロピル]−L−α−アスパルチル]−L−フェニ
ルアラニン 1−メチルエステル誘導体の実用的かつ工
業的により有利な製造方法を提供することにある。
An object of the present invention is to provide N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl, which is an excellent high-intensity sweetener. It is to provide a practical and industrially more advantageous method for producing an ester derivative.

【0007】[0007]

【課題を解決するための手段】本発明者等は、上記課題
を解決すべく鋭意検討した結果、3,4−ジヒドロ−置
換−2H−1−ベンゾピラン−2−オール誘導体とアス
パルテームとを、還元的にアルキル化反応を行うことに
より、効率よく高収率にN−[N−[3−(2−ヒドロ
キシ−置換フェニル)プロピル]−L−α−アスパルチ
ル]−L−フェニルアラニン 1−メチルエステル誘導
体を製造できることを見出し本発明を完成するに到っ
た。
The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a 3,4-dihydro-substituted-2H-1-benzopyran-2-ol derivative and aspartame can be reduced. N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester derivative by efficiently performing an alkylation reaction with high yield And found that the present invention was completed.

【0008】[0008]

【発明の実施の形態】本発明は、下記一般式(1)で示
される3,4−ジヒドロ−置換−2H−1−ベンゾピラ
ン−2−オール誘導体とアスパルテームとを、溶剤を使
用し触媒の存在下で還元的アルキル化反応に付して、下
記一般式(2)で示されるN−[N−[3−(2−ヒド
ロキシ−置換フェニル)プロピル]−L−α−アスパル
チル]−L−フェニルアラニン 1−メチルエステル誘
導体を製造する方法である。
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing a 3,4-dihydro-substituted-2H-1-benzopyran-2-ol derivative represented by the following general formula (1) and aspartame using a solvent and a catalyst. And then subjected to a reductive alkylation reaction to give N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine represented by the following general formula (2). This is a method for producing a 1-methyl ester derivative.

【0009】[0009]

【化3】 Embedded image

【0010】[0010]

【化4】 Embedded image

【0011】上記式(1)及び(2)において、R1
2、R3及びR4はそれぞれ相互に独立していて、水素
原子、水酸基、炭素数が1〜3のアルコキシ基、ベンジ
ルオキシ基、炭素数が1〜3のアルキル基及び炭素数が
2又は3のヒドロキシアルキルオキシ基から選ばれる置
換基を表し、更にR1とR2の二つ及び/又はR3とR4
二つ、又はR2とR3二つは、それぞれ二つが一緒になっ
てメチレンジオキシ基を表してもよい。例えば、R1
2が一緒になる場合、R3とR4の二つは一緒になって
メチレンジオキシ基を表してもよいし、一緒にならなく
てもよい。このように一緒にならない場合R1及びR2
前記R1及びR2と同じ意味を有する。R3とR4が一緒に
なる場合のR1とR2の意味についても同様である。一
方、R2とR3が一緒になってメチレンジオキシ基を表す
場合、R1及びR4は、それぞれ前記R 1及びR4の意味を
有する。
In the above formulas (1) and (2), R1,
RTwo, RThreeAnd RFourAre independent of each other
Atom, hydroxyl group, alkoxy group having 1 to 3 carbon atoms, benzyl
Roxy group, alkyl group having 1 to 3 carbon atoms and carbon number
A position selected from 2 or 3 hydroxyalkyloxy groups
Represents a substituent,1And RTwoTwo and / or RThreeAnd RFourof
Two or RTwoAnd RThreeTwo, each two together
May represent a methylenedioxy group. For example, R1When
RTwoAre together, then RThreeAnd RFourThe two are together
May represent a methylenedioxy group,
You may. If they don't come together like this R1And RTwoIs
The R1And RTwoHas the same meaning as RThreeAnd RFourTogether
R if1And RTwoThe same applies to the meaning of. one
One, RTwoAnd RThreeTogether represent a methylenedioxy group
If R1And RFourIs the R 1And RFourThe meaning of
Have.

【0012】また、式(2)においては、R1、R2、R
3及びR4は、何れもベンジルオキシ基を表すことはな
い。これは、一般式(1)においてR1、R2、R3及び
4の何れかがベンジルオキシ基を表す場合、本発明に
おける反応により目的物を製造する際に、ベンジルオキ
シ部分のうちベンジル基の脱ベンジル化により水酸基に
変換することによる。
In the formula (2), R 1 , R 2 , R
Neither 3 nor R 4 represents a benzyloxy group. This is because when any one of R 1 , R 2 , R 3 and R 4 in the general formula (1) represents a benzyloxy group, the benzyl group of the benzyloxy moiety may be used when the target product is produced by the reaction in the present invention. By conversion to a hydroxyl group by debenzylation of the group.

【0013】以下、本発明の代表的かつより好ましい方
法について説明する。本発明にはこれ等が当然含まれる
が本発明の要旨を逸脱しない限りこれ等に限定されるも
のではない。
Hereinafter, a representative and more preferred method of the present invention will be described. The present invention naturally includes these, but is not limited thereto without departing from the gist of the present invention.

【0014】本発明に使用する重要原料としての3,4
−ジヒドロ−置換−2H−1−ベンゾピラン−2−オー
ル誘導体は公知技術を利用して調製又は入手することが
でき、例えば公知の方法(J.Org.Chem.19
82,47,946或いはJ.Org.Chem.19
89,54,3282等参照。)により、相当する置換
フェノールとアクロレインアセタール誘導体或いはアレ
ン誘導体を酸触媒の存在下に環化反応せて環状アセター
ルとした後、酸加水分解することにより容易にかつ安価
に合成することができる。
3,4 as important raw materials used in the present invention
The -dihydro-substituted-2H-1-benzopyran-2-ol derivative can be prepared or obtained by using a known technique, for example, by a known method (J. Org. Chem. 19).
82, 47, 946 or J.P. Org. Chem. 19
89, 54, 3282, etc. ), The corresponding substituted phenol and an acrolein acetal derivative or an allene derivative are subjected to a cyclization reaction in the presence of an acid catalyst to form a cyclic acetal, which is then easily and inexpensively synthesized by acid hydrolysis.

【0015】次いで、得られた3,4−ジヒドロ−置換
−2H−1−ベンゾピラン−2−オール誘導体とアスパ
ルテームとを、これらを溶解する溶剤、例えば有機溶剤
(1種による単独溶剤又は複数による混合溶剤)或いは
このような有機溶剤と水との混合溶剤中で、還元アルキ
ル化触媒、例えば水素添加触媒の存在下に水素によって
還元的アルキル化反応を行い、より好ましくは適当又は
効果的な反応温度と圧力の下に還元的アルキル化反応を
行い、目的化合物であるN−[N−[3−(2−ヒドロ
キシ−置換フェニル)プロピル]−L−α−アスパルチ
ル]−L−フェニルアラニン 1−メチルエステル誘導
体を効率よく高収率に製造することができる。
Next, the obtained 3,4-dihydro-substituted-2H-1-benzopyran-2-ol derivative and aspartame are dissolved in a solvent such as an organic solvent (one kind of a single solvent or a mixture of a plurality thereof). Solvent) or a mixed solvent of such an organic solvent and water, the reductive alkylation reaction is carried out with hydrogen in the presence of a reductive alkylation catalyst, for example, a hydrogenation catalyst, and more preferably an appropriate or effective reaction temperature. Alkylation reaction under pressure and pressure to obtain N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester as the target compound Derivatives can be efficiently produced in high yield.

【0016】更に、反応終了後、濾過等により触媒を除
去し、必要に応じてクロマト精製或いは晶析等の精製手
段により、高純度のN−[N−[3−(2−ヒドロキシ
−置換フェニル)プロピル]−L−α−アスパルチル]
−L−フェニルアラニン 1−メチルエステル誘導体を
得ることもできる。
After completion of the reaction, the catalyst is removed by filtration or the like, and if necessary, high-purity N- [N- [3- (2-hydroxy-substituted phenyl) is purified by purification means such as chromatographic purification or crystallization. ) Propyl] -L-α-aspartyl]
-L-phenylalanine 1-methyl ester derivative can also be obtained.

【0017】還元的アルキル化反応には出発原料や生成
物を溶解する有機溶剤を使用すればよい。例えば、メタ
ノール、エタノール、イソプロピルアルコール、テトラ
ヒドロフラン、アセトニトリル、酢酸及び酢酸エチルの
中から選択された少なくとも1種、又はこれら有機溶剤
の少なくとも1種と水との混合溶剤を好ましい溶剤とし
て使用することができる。より好ましくはアルコール、
更にコストの点から好ましくはメタノール、更に好まし
くはメタノールと水の混合溶剤を使用する。有機溶剤と
水の混合溶剤を使用する場合の両者の組成比には特に制
限は無く、アスパルテーム、3,4−ジヒドロ−置換−
2H−1−ベンゾピラン−2−オール誘導体及び目的化
合物であるN−[N−[3−(2−ヒドロキシ−置換フ
ェニル)プロピル]−L−α−アスパルチル]−L−フ
ェニルアラニン 1−メチルエステル誘導体が十分に溶
解することが望ましい。
In the reductive alkylation reaction, an organic solvent that dissolves starting materials and products may be used. For example, at least one selected from methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetonitrile, acetic acid, and ethyl acetate, or a mixed solvent of at least one of these organic solvents and water can be used as a preferred solvent. . More preferably alcohol,
From the viewpoint of cost, methanol is preferably used, and a mixed solvent of methanol and water is more preferably used. When a mixed solvent of an organic solvent and water is used, the composition ratio of both is not particularly limited, and aspartame, 3,4-dihydro-substituted-
The 2H-1-benzopyran-2-ol derivative and the target compound, N- [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester derivative, It is desirable that it be sufficiently dissolved.

【0018】還元的アルキル化反応に使用する触媒とし
ては、例えば、パラジウム炭素等のパラジウム系触媒、
プラチナ炭素等の白金系触媒、ロジウム−アルミナ等の
ロジウム系触媒或いはラネーニッケル等のニッケル系触
媒等、一般的な水素添加触媒を使用することができる。
用いる触媒の使用量は特に制約は無いが、例えば、10
%パラジウム炭素(50%含水)の場合、アスパルテー
ムに対する重量比で100分の1〜3分の1程度の範囲
で使用することが望ましい。
The catalyst used for the reductive alkylation reaction includes, for example, a palladium-based catalyst such as palladium-carbon.
A general hydrogenation catalyst such as a platinum-based catalyst such as platinum carbon, a rhodium-based catalyst such as rhodium-alumina, or a nickel-based catalyst such as Raney nickel can be used.
The amount of the catalyst used is not particularly limited.
In the case of% palladium carbon (containing 50% water), it is desirable to use it in a range of about 1/100 to 1/100 by weight relative to aspartame.

【0019】前記反応は水素添加により行うことがで
き、その際の水素圧は0.1MPaで十分反応が進行す
るが、0.1〜1.0MPa程度の水素圧下に反応を行
うこともできる。
The above reaction can be carried out by hydrogenation. At that time, the reaction proceeds sufficiently at a hydrogen pressure of 0.1 MPa, but the reaction can also be carried out under a hydrogen pressure of about 0.1 to 1.0 MPa.

【0020】反応の温度については、常温程度、好まし
くは10〜30℃程度で容易に反応が進行するが、出発
原料或いは生成物の溶解度を向上させるため或いは副反
応を抑えて目的の反応速度を向上させるために、60℃
程度まで温度を上げて反応することもできる。好ましく
は、20〜50℃程度の温度範囲、更に好ましくは25
〜45℃程度を選択することができる。
The reaction proceeds easily at about normal temperature, preferably about 10 to 30 ° C., but the desired reaction rate is improved in order to improve the solubility of the starting materials or products or to suppress side reactions. 60 ° C to improve
The reaction can be performed by raising the temperature to a certain degree. Preferably, the temperature range is about 20 to 50 ° C, more preferably 25
About 45 ° C. can be selected.

【0021】反応時間には特に制限は無いが、2〜72
時間程度の範囲で行えばよい。
The reaction time is not particularly limited.
It may be performed within a time range.

【0022】前記反応の原料として使用する3,4−ジ
ヒドロ−置換−2H−1−ベンゾピラン−2−オール誘
導体とアスパルテームとのモル比については、好ましく
は0.5〜2程度の範囲で反応を行うことができる。
The molar ratio of the 3,4-dihydro-substituted-2H-1-benzopyran-2-ol derivative to aspartame used as a raw material for the reaction is preferably in the range of about 0.5 to 2. It can be carried out.

【0023】本発明の方法で得られる化合物として、特
に下記方法により得られる化合物を挙げることができ
る。
The compounds obtained by the method of the present invention include, in particular, compounds obtained by the following method.

【0024】1. 前記一般式(1)及び(2)におい
て、R2がメトキシ基であり、R1、R 3及びR4が水素原
子である式(2)の化合物。
1. In the general formulas (1) and (2)
And RTwoIs a methoxy group, and R1, R ThreeAnd RFourIs a hydrogen source
A compound of formula (2) which is a child.

【0025】2.前記一般式(1)及び(2)におい
て、R2が水酸基であり、R1、R3及びR4が水素原子で
ある式(2)の化合物。但し、式(1)においてR2
ベンジルオキシ基でもよい。
2. In the above general formulas (1) and (2), the compound of the formula (2) wherein R 2 is a hydroxyl group and R 1 , R 3 and R 4 are hydrogen atoms. However, in the formula (1), R 2 may be a benzyloxy group.

【0026】3. 前記一般式(1)及び(2)におい
て、R2がメチル基であり、R1、R3及びR4が水素原子
である式(2)の化合物。
3. In the above general formulas (1) and (2), the compound of the formula (2) wherein R 2 is a methyl group and R 1 , R 3 and R 4 are hydrogen atoms.

【0027】[0027]

【実施例】以下、参考例及び実施例により本発明を更に
詳細に説明するが、本発明はその要旨を超えない限り以
下の実施例により限定されるものではない。
EXAMPLES Hereinafter, the present invention will be described in more detail by reference examples and examples, but the present invention is not limited to the following examples unless it exceeds the gist.

【0028】(参考例1)ラセミ−3,4−ジヒドロ−7−メトキシ−2H−1−
ベンゾピラン−2−オールの合成 3−メトキシフェノール12.4g(100mmol)
をジクロロメタン100mlに加え、この溶液を氷浴中
で3℃以下に冷却した後、溶液の温度が3℃以下を保持
するようにp−トルエンスルホン一酸水和物0.210
g(1.16mmol)を加え、更にアクロレインジエ
チルアセタール14.3g(110mmol)を40分
かけて滴下した。滴下終了後、反応液が10℃以下を保
持するようにして2時間20分撹拌して反応を行った。
Reference Example 1 Racemic-3,4-dihydro-7-methoxy-2H-1-
Synthesis of benzopyran-2-ol 3-methoxyphenol 12.4 g (100 mmol)
Was added to 100 ml of dichloromethane, and the solution was cooled to 3 ° C. or less in an ice bath. Then, p-toluenesulfonic acid monohydrate 0.210 was added so that the temperature of the solution was maintained at 3 ° C. or less.
g (1.16 mmol) was added, and 14.3 g (110 mmol) of acrolein diethyl acetal was further added dropwise over 40 minutes. After completion of the dropwise addition, the reaction was stirred for 2 hours and 20 minutes while maintaining the reaction solution at 10 ° C. or lower.

【0029】反応終了後、反応液に飽和重曹水50ml
を加え抽出して有機層を得た。更に、水層にジクロロメ
タン50mlを加えて再抽出し、先に得られた有機層と
合わせた。有機層を飽和食塩水50mlで洗浄し、無水
硫酸マグネシウムで乾燥後、硫酸マグネシウムを濾過し
て除き、濾液を減圧濃縮して油状物21.0gを得た。
この油状物をシリカゲルカラムクロマトグラフィー(溶
離液:トルエン)で精製し、目的物が含まれる画分を濃
縮してラセミ−3,4−ジヒドロ−2−エトキシ−7−
メトキシ−2H−1−ベンゾピラン6.73g(32.
3mmol)を無色の油状物として得た。得られたラセ
ミ−3,4−ジヒドロ−2−エトキシ−7−メトキシ−
2H−1−ベンゾピラン5.50g(26.4mmo
l)に、アセトニトリル94ml、水33ml及び35
%塩酸5.8ml(65.6mmol)を加え、60℃
で1時間撹拌反応させた。反応終了後、反応液に水50
ml及びジエチルエーテル200mlを加え抽出して有
機層を得た。
After completion of the reaction, 50 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution.
And extracted to obtain an organic layer. Further, the aqueous layer was re-extracted with 50 ml of dichloromethane and combined with the previously obtained organic layer. The organic layer was washed with 50 ml of a saturated saline solution, dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure to obtain 21.0 g of an oily substance.
The oily product is purified by silica gel column chromatography (eluent: toluene), and the fraction containing the desired product is concentrated to give racemic-3,4-dihydro-2-ethoxy-7-.
6.73 g of methoxy-2H-1-benzopyran (32.
3 mmol) were obtained as a colorless oil. Racemic-3,4-dihydro-2-ethoxy-7-methoxy- obtained
5.50 g of 2H-1-benzopyran (26.4 mmol
l), 94 ml of acetonitrile, 33 ml of water and 35 ml
5.8 ml (65.6 mmol) of hydrochloric acid at 60%
For 1 hour with stirring. After completion of the reaction, add 50
The mixture was extracted with 200 ml of diethyl ether and 200 ml of diethyl ether to obtain an organic layer.

【0030】更に、水層にジエチルエーテル100ml
を加えて再抽出し、先に得られた有機層と合わせた。有
機層を飽和重曹水100mlで2回洗浄し、次いで飽和
食塩水100mlで洗浄し、無水硫酸マグネシウムで乾
燥後、硫酸マグネシウムを濾過して除き、濾液を減圧濃
縮して油状物4.77gを得た。この油状物をシリカゲ
ルカラムクロマトグラフィー(溶離液:ヘキサン/酢酸
エチル=4/1)で精製し、目的物が含まれる画分を濃
縮してラセミ−3,4−ジヒドロ−7−メトキシ−2H
−1−ベンゾピラン−2−オール3.49g(19.4
mmol)を微黄色の油状物として得た。
Further, 100 ml of diethyl ether was added to the aqueous layer.
Was added and the mixture was extracted again, and combined with the organic layer obtained above. The organic layer was washed twice with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, then with 100 ml of a saturated saline solution, dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure to obtain 4.77 g of an oily substance. Was. The oily product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1), and the fraction containing the desired product was concentrated to give racemic-3,4-dihydro-7-methoxy-2H.
3.49 g of 1-benzopyran-2-ol (19.4
mmol) as a pale yellow oil.

【0031】(参考例2)ラセミ−3,4−ジヒドロ−7−ベンジルオキシ−2H
−1−ベンゾピラン−2−オールの合成 レゾルシノール11.0g(100mmol)をジエチ
ルエーテル100mlに加え、本溶液を氷浴中で3℃以
下に冷却した後、溶液の温度が3℃以下を保持するよう
にp−トルエンスルホン酸一水和物0.230g(1.
21mmol)を加え、更にアクロレインジメチルアセ
タール13ml(110mmol)を35分かけて滴下
した。滴下終了後、反応液が10℃以下を保持するよう
にして4時間撹拌反応した。反応終了後、反応液に飽和
重曹水50mlを加え抽出して有機層を得た。更に水層
にジエチルエーテル50mlを加えて再抽出し、先に得
られた有機層と合わせた。有機層を飽和食塩水100m
lで洗浄し、無水硫酸マグネシウムで乾燥後、硫酸マグ
ネシウムを濾過して除き、濾液を減圧濃縮して油状物1
9.1gを得た。
Reference Example 2 Racemic-3,4-dihydro-7-benzyloxy-2H
Synthesis of 1-benzopyran-2-ol 11.0 g (100 mmol) of resorcinol was added to 100 ml of diethyl ether, and the solution was cooled to 3 ° C or lower in an ice bath, and the temperature of the solution was maintained at 3 ° C or lower. To 0.230 g of p-toluenesulfonic acid monohydrate (1.
21 mmol), and 13 ml (110 mmol) of acrolein dimethyl acetal was added dropwise over 35 minutes. After the completion of the dropwise addition, the reaction solution was stirred and reacted for 4 hours while maintaining the temperature of the reaction solution at 10 ° C. or lower. After completion of the reaction, 50 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for extraction to obtain an organic layer. Further, the aqueous layer was re-extracted with 50 ml of diethyl ether, and combined with the previously obtained organic layer. The organic layer was washed with saturated saline 100m
After washing with anhydrous magnesium sulfate and drying over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain an oily substance 1.
9.1 g were obtained.

【0032】得られた油状物をシリカゲルカラムクロマ
トグラフィー(溶離液:ヘキサン/酢酸エチル=4/
1)で精製し、目的物が含まれる画分を濃縮してラセミ
−3,4−ジヒドロ−2−メトキシ−7−ヒドロキシ−
2H−1−ベンゾピラン7.72g(42.8mmo
l)を無色の油状物として得た。得られたラセミ−3,
4−ジヒドロ−2−メトキシ−7−ヒドロキシ−2H−
1−ベンゾピラン7.72g(42.8mmol)に、
ジメチルホルムアミド45ml,無水炭酸カリウム1
3.7g(99.2mmol)及びベンジルブロマイド
8.3ml(70.3mmol)を加え、室温で一晩撹
拌反応させた。反応終了後、反応液に水200ml及び
酢酸エチル200mlを加え抽出して有機層を得た。更
に、水層に酢酸エチル100mlを加え、同様の操作で
2回再抽出し、先に得られた有機層と合わせた。有機層
を水150mlで4回洗浄し、無水硫酸マグネシウムで
乾燥後、硫酸マグネシウムを濾過して除き、濾液を減圧
濃縮して油状物14.6gを得た。この油状物をシリカ
ゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢
酸エチル=12/1)で精製し、目的物が含まれる画分
を濃縮してラセミ−3,4−ジヒドロ−2−メトキシ−
7−ベンジルオキシ−2H−1−ベンゾピラン11.3
g(41.6mmol)を無色の油状物として得た。
The obtained oil was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 4 /
Purification in 1), concentration of the fraction containing the target compound, and racemic-3,4-dihydro-2-methoxy-7-hydroxy-
7.72 g of 2H-1-benzopyran (42.8 mmol
1) was obtained as a colorless oil. The resulting racemic-3,
4-dihydro-2-methoxy-7-hydroxy-2H-
To 7.72 g (42.8 mmol) of 1-benzopyran,
Dimethylformamide 45 ml, anhydrous potassium carbonate 1
3.7 g (99.2 mmol) and 8.3 ml (70.3 mmol) of benzyl bromide were added, and the mixture was stirred and reacted at room temperature overnight. After completion of the reaction, 200 ml of water and 200 ml of ethyl acetate were added to the reaction solution for extraction to obtain an organic layer. Further, 100 ml of ethyl acetate was added to the aqueous layer, and the mixture was re-extracted twice by the same operation, and combined with the previously obtained organic layer. The organic layer was washed four times with 150 ml of water, dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure to obtain 14.6 g of an oily substance. This oily product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 12/1), and the fraction containing the desired product was concentrated to give racemic-3,4-dihydro-2-methoxy-
7-benzyloxy-2H-1-benzopyran 11.3
g (41.6 mmol) were obtained as a colorless oil.

【0033】このようにして得られたラセミ−3,4−
ジヒドロ−2−メトキシ−7−ベンジルオキシ−2H−
1−ベンゾピラン10.2g(37.5mmol)に、
テトラヒドロフラン130ml、水40ml及び60%
過塩素酸水12ml(71.7mmol)を加え、60
℃で4時間撹拌反応させた。反応終了後、反応液に水1
50ml及びジエチルエーテル300mlを加え抽出し
て有機層を得た。更に水層にジエチルエーテル300m
lを加えて再抽出し、先に得られた有機層と合わせた。
有機層を飽和重曹水150mlで2回洗浄し、次いで飽
和食塩水150mlで洗浄し、無水硫酸マグネシウムで
乾燥後、硫酸マグネシウムを濾過して除き、濾液を減圧
濃縮して油状物10.0gを得た。この油状物をシリカ
ゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢
酸エチル=5/1)で精製して、目的物が含まれる画分
を濃縮してラセミ−3,4−ジヒドロ−7−ベンジルオ
キシ−2H−1−ベンゾピラン−2−オール6.32g
(24.7mmol)を無色の油状物として得た。
The thus obtained racemic-3,4-
Dihydro-2-methoxy-7-benzyloxy-2H-
To 10.2 g (37.5 mmol) of 1-benzopyran,
130 ml of tetrahydrofuran, 40 ml of water and 60%
12 ml (71.7 mmol) of perchloric acid water was added, and 60
The mixture was stirred and reacted at 4 ° C. for 4 hours. After the reaction is completed, add 1
50 ml and 300 ml of diethyl ether were added and extracted to obtain an organic layer. Further, 300 m of diethyl ether was added to the aqueous layer.
1 was added and re-extracted, and combined with the organic layer obtained above.
The organic layer was washed twice with 150 ml of a saturated aqueous sodium hydrogen carbonate solution, then with 150 ml of a saturated saline solution, dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure to obtain 10.0 g of an oily substance. Was. The oily substance is purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1), and the fraction containing the target substance is concentrated to give racemic-3,4-dihydro-7-benzyloxy- 6.32 g of 2H-1-benzopyran-2-ol
(24.7 mmol) was obtained as a colorless oil.

【0034】(参考例3)ラセミ−3,4−ジヒドロ−7−メチル−2H−1−ベ
ンゾピラン−2−オールの合成 m−クレゾール61.0g(564mmol)にジエチ
ルエーテル490mlを加え、本溶液を氷浴中で5℃以
下に冷却した後、溶液の温度が5℃以下を保持するよう
にp−トルエンスルホン酸一水和物1.07g(5.6
4mmol)を加え、更にアクロレインジエチルアセタ
ール95ml(620mmol)を80分かけて滴下し
た。滴下終了後、反応液が5℃以下を保持するようにし
て1時間10分撹拌反応した。反応終了後、反応液にジ
エチルエーテル100ml、1M水酸化ナトリウム水溶
液250mlを2回に分けて加え、抽出して有機層を得
た。更に水層にジエチルエーテル400mlを加えて再
抽出し、先に得られた有機層と合わせた。有機層を飽和
食塩水500mlで洗浄し、無水硫酸マグネシウムで乾
燥後、硫酸マグネシウムを濾過して除き、濾液を減圧濃
縮して油状物52.9gを得た。
Reference Example 3 Racemic-3,4-dihydro-7-methyl-2H-1-be
Synthesis of nzopyran-2-ol To 61.0 g (564 mmol) of m-cresol, 490 ml of diethyl ether was added, and the solution was cooled to 5 ° C or lower in an ice bath, and the temperature of the solution was maintained at 5 ° C or lower. 1.07 g of p-toluenesulfonic acid monohydrate (5.6
4 mmol), and 95 ml (620 mmol) of acrolein diethyl acetal was added dropwise over 80 minutes. After the completion of the dropwise addition, the mixture was stirred and reacted for 1 hour and 10 minutes while maintaining the reaction solution at 5 ° C. or lower. After completion of the reaction, 100 ml of diethyl ether and 250 ml of a 1 M aqueous sodium hydroxide solution were added to the reaction solution in two portions, followed by extraction to obtain an organic layer. The aqueous layer was re-extracted with 400 ml of diethyl ether and combined with the previously obtained organic layer. The organic layer was washed with 500 ml of saturated saline, dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 52.9 g of an oil.

【0035】得られた油状物をシリカゲルカラムクロマ
トグラフィー(溶離液:ヘキサン/酢酸エチル=19/
1)で精製し、目的物が含まれる画分を濃縮してラセミ
−3,4−ジヒドロ−2−エトキシ−7−メチル−2H
−1−ベンゾピラン4.64g(24.1mmol)を
微黄色の油状物として得た。得られたラセミ−3,4−
ジヒドロ−2−エトキシ−7−メチル−2H−1−ベン
ゾピラン4.59g(23.9mmol)に、アセトニ
トリル75ml、水25ml及び35%塩酸5.3ml
(60.0mmol)を加え、60℃で1時間撹拌反応
させた。反応終了後、反応液に水50ml及びジエチル
エーテル200mlを加え抽出して有機層を得た。更に
水層にジエチルエーテル100mlを加えて再抽出し、
先に得られた有機層と合わせた。有機層を飽和重曹水1
00mlで2回洗浄し、次いで飽和食塩水100mlで
洗浄し、無水硫酸マグネシウムで乾燥後、硫酸マグネシ
ウムを濾過して除き、濾液を減圧濃縮して油状物3.9
0gを得た。この油状物に60℃で酢酸エチル0.5m
l、ヘキサン10mlを加えて均一化し、5℃まで冷却
して晶析すると結晶が析出した。更に、母液を減圧濃縮
後、シリカゲルカラムクロマトグラフィー(溶離液:ヘ
キサン/酢酸エチル=7/1)で精製し、目的物が含ま
れる画分を濃縮した。この濃縮液にヘキサン15mlを
加えて均一化し、5℃まで冷却して晶析すると結晶が析
出した。これらの結晶を濾過して集め、常温で7時間減
圧乾燥してラセミ−3,4−ジヒドロ−7−メチル−2
H−1−ベンゾピラン−2−オール2.68g(16.
3mmol)を得た。
The obtained oil was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 19 /
Purification in 1), concentration of the fraction containing the target substance, and racemic-3,4-dihydro-2-ethoxy-7-methyl-2H
4.64 g (24.1 mmol) of -1-benzopyran were obtained as a pale yellow oil. Racemic-3,4- obtained
To 4.59 g (23.9 mmol) of dihydro-2-ethoxy-7-methyl-2H-1-benzopyran, 75 ml of acetonitrile, 25 ml of water and 5.3 ml of 35% hydrochloric acid.
(60.0 mmol) was added, and the mixture was stirred and reacted at 60 ° C. for 1 hour. After completion of the reaction, 50 ml of water and 200 ml of diethyl ether were added to the reaction solution for extraction to obtain an organic layer. Further, the aqueous layer was re-extracted with 100 ml of diethyl ether,
Combined with the previously obtained organic layer. Organic layer is saturated aqueous sodium bicarbonate 1
After washing twice with 00 ml and then with 100 ml of saturated saline, drying over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to an oily substance 3.9.
0 g was obtained. Ethyl acetate 0.5m at 60 ° C
1 and hexane (10 ml) were added to homogenize, cooled to 5 ° C. and crystallized to precipitate crystals. Further, the mother liquor was concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/1), and the fraction containing the desired product was concentrated. 15 ml of hexane was added to this concentrated liquid to homogenize, cooled to 5 ° C., and crystallized to precipitate. These crystals were collected by filtration, dried at room temperature under reduced pressure for 7 hours, and dried in racemic-3,4-dihydro-7-methyl-2.
2.68 g of H-1-benzopyran-2-ol (16.
3 mmol).

【0036】(実施例1)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(1) ラセミ−3,4−ジヒドロ−7−メトキシ−2H−1−
ベンゾピラン−2−オール0.870g(4.83mm
ol)及びアスパルテーム1.50g(5.10mmo
l)をメタノールと水の混合溶剤(混合比3:2v/
v)50mlに加え、温度45℃でしばらく撹拌して溶
解した。この溶液に10%パラジウム炭素(50%含
水)0.520gを加え、常圧(0.1MPa)の水素
雰囲気下に45℃で48時間撹拌反応した。反応液を濾
過して触媒を除き、高速液体クロマトグラフィー(HP
LC)で定量したところ、N−[N−[3−(2−ヒド
ロキシ−4−メトキシフェニル)プロピル]−L−α−
アスパルチル]−L−フェニルアラニン 1−メチルエ
ステルが1.33g(2.90mmol、60%)生成
していた。
Example 1 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nylalanine 1-methyl ester (1) Racemic-3,4-dihydro-7-methoxy-2H-1-
0.870 g of benzopyran-2-ol (4.83 mm
ol) and 1.50 g of aspartame (5.10 mmol)
l) in a mixed solvent of methanol and water (mixing ratio 3: 2 v /
v) Added to 50 ml and dissolved by stirring at a temperature of 45 ° C for a while. To this solution was added 0.520 g of 10% palladium carbon (containing 50% water), and the mixture was stirred and reacted at 45 ° C. for 48 hours under a hydrogen atmosphere at normal pressure (0.1 MPa). The reaction solution was filtered to remove the catalyst, and then subjected to high performance liquid chromatography (HP
LC), N- [N- [3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α-
Aspartyl] -L-phenylalanine 1-methyl ester was found to be 1.33 g (2.90 mmol, 60%).

【0037】(実施例2)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(2) メタノールと水の混合溶剤(混合比3:2v/v)の代
わりにメタノールと水の混合溶剤(混合比4:1v/
v)を使用した以外は、実施例1と同様に反応を実施し
た。反応液を濾過して触媒を除き、HPLCで定量した
ところ、N−[N−[3−(2−ヒドロキシ−4−メト
キシフェニル)プロピル]−L−α−アスパルチル]−
L−フェニルアラニン 1−メチルエステルが1.42
g(3.10mmol、64%)生成していた。
Example 2 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nilalanine 1-methyl ester (2) A mixed solvent of methanol and water (mixing ratio of 4: 1 v / v) instead of a mixed solvent of methanol and water (mixing ratio of 3: 2 v / v)
The reaction was carried out as in Example 1, except that v) was used. The reaction solution was filtered to remove the catalyst, and quantified by HPLC. N- [N- [3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl]-
1.42 L-phenylalanine 1-methyl ester
g (3.10 mmol, 64%).

【0038】(実施例3)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(3) メタノールと水の混合溶剤(混合比3:2v/v)の代
わりにメタノールを使用、反応時間を18時間とした以
外は、実施例1と同様に反応を実施した。反応液を濾過
して触媒を除き、HPLCで定量したところ、N−[N
−[3−(2−ヒドロキシ−4−メトキシフェニル)プ
ロピル]−L−α−アスパルチル]−L−フェニルアラ
ニン 1−メチルエステルが1.22g(2.66mm
ol、55%)生成していた。
Example 3 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nylalanine 1-methyl ester (3) The reaction was performed in the same manner as in Example 1 except that methanol was used instead of a mixed solvent of methanol and water (mixing ratio 3: 2 v / v), and the reaction time was changed to 18 hours. Carried out. The reaction solution was filtered to remove the catalyst, and quantified by HPLC, N- [N
1.22 g (2.66 mm) of-[3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester
ol, 55%).

【0039】(実施例4)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(4) 酢酸0.11mlを併用、反応時間を24時間とした以
外は、実施例2と同様に反応を実施した。反応液を濾過
して触媒を除き、HPLCで定量したところ、N−[N
−[3−(2−ヒドロキシ−4−メトキシフェニル)プ
ロピル]−L−α−アスパルチル]−L−フェニルアラ
ニン 1−メチルエステルが1.59g(3.47mm
ol、72%)生成していた。
Example 4 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nylalanine 1-methyl ester (4) The reaction was carried out in the same manner as in Example 2 except that 0.11 ml of acetic acid was used in combination and the reaction time was set to 24 hours. The reaction solution was filtered to remove the catalyst, and quantified by HPLC, N- [N
1.59 g (3.47 mm) of-[3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester
ol, 72%).

【0040】(実施例5)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(5) アスパルテーム2.14g(7.27mmol)を使
用、反応時間を24時間とした以外は、実施例2と同様
に反応を実施した。反応液を濾過して触媒を除き、HP
LCで定量したところ、N−[N−[3−(2−ヒドロ
キシ−4−メトキシフェニル)プロピル]−L−α−ア
スパルチル]−L−フェニルアラニン 1−メチルエス
テルが1.68g(3.67mmol、76%)生成し
ていた。
Example 5 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nylalanine 1-methyl ester (5) The reaction was carried out in the same manner as in Example 2 except that 2.14 g (7.27 mmol) of aspartame was used and the reaction time was set to 24 hours. The reaction solution is filtered to remove the catalyst and HP
As determined by LC, N- [N- [3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester was 1.68 g (3.67 mmol, 76%).

【0041】(実施例6)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(6) ラセミ−3,4−ジヒドロ−7−メトキシ−2H−1−
ベンゾピラン−2−オール0.580g(3.22mm
ol)及びアスパルテーム1.00g(3.40mmo
l)をメタノールと水の混合溶剤(混合比3:2v/
v)33mlに加え、温度35℃でしばらく撹拌して溶
解した。この溶液に10%パラジウム炭素(50%含
水)0.330gを加え、常圧(0.1MPa)の水素
雰囲気下に35℃で70時間撹拌反応した。反応液を6
0℃まで加温して濾過により触媒を除き、更に触媒をメ
タノール10mlで洗浄した。濾液と洗浄液を合わせ、
HPLCで定量したところ、N−[N−[3−(2−ヒ
ドロキシ−4−メトキシフェニル)プロピル]−L−α
−アスパルチル]−L−フェニルアラニン 1−メチル
エステルが0.992g(2.16mmol、67%)
生成していた。
Example 6 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nylalanine 1-methyl ester (6) Racemic-3,4-dihydro-7-methoxy-2H-1-
0.580 g of benzopyran-2-ol (3.22 mm
ol) and 1.00 g (3.40 mmol) of aspartame
l) in a mixed solvent of methanol and water (mixing ratio 3: 2 v /
v) Added to 33 ml, and dissolved by stirring at a temperature of 35 ° C. for a while. 0.330 g of 10% palladium carbon (containing 50% water) was added to this solution, and the mixture was stirred and reacted at 35 ° C. for 70 hours under a hydrogen atmosphere at normal pressure (0.1 MPa). Reaction solution 6
The mixture was heated to 0 ° C., and the catalyst was removed by filtration. The catalyst was further washed with 10 ml of methanol. Combine the filtrate and wash solution,
As determined by HPLC, N- [N- [3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α
-Aspartyl] -L-phenylalanine 1-methyl ester in 0.992 g (2.16 mmol, 67%)
Had been generated.

【0042】(実施例7)N−[N−[3−(2−ヒドロキシ−4−メトキシフェ
ニル)プロピル]−L−α−アスパルチル]−L−フェ
ニルアラニン 1−メチルエステルの合成(7) ラセミ−3,4−ジヒドロ−7−メトキシ−2H−1−
ベンゾピラン−2−オール4.37g(24.3mmo
l)及びアスパルテーム7.52g(25.6mmo
l)をメタノールと水の混合溶剤(混合比3:2v/
v)250mlに加え、温度40℃でしばらく撹拌して
溶解した。この溶液に10%パラジウム炭素(50%含
水)2.56gを加え、常圧(0.1MPa)の水素雰
囲気下に40℃で48時間撹拌反応した。反応液を濾過
して触媒を除き、更に触媒をメタノール40mlで洗浄
した。濾液と洗浄液を合わせ、減圧濃縮してメタノール
を60ml除去した後、10℃まで冷却して晶析すると
結晶が析出した。この結晶を濾過して集め、少量の水で
洗浄し、40℃で3時間減圧乾燥して乾燥結晶7.75
gを得た。この結晶をHPLCで定量したところ、N−
[N−[3−(2−ヒドロキシ−4−メトキシフェニ
ル)プロピル]−L−α−アスパルチル]−L−フェニ
ルアラニン 1−メチルエステルが7.38g(16.
1mmol、63%)生成していた。
Example 7 N- [N- [3- (2-hydroxy-4-methoxyphen)
Nyl) propyl] -L-α-aspartyl] -L-fe
Synthesis of nylalanine 1-methyl ester (7) Racemic-3,4-dihydro-7-methoxy-2H-1-
4.37 g of benzopyran-2-ol (24.3 mmol
l) and 7.52 g (25.6 mmol) of aspartame
l) in a mixed solvent of methanol and water (mixing ratio 3: 2 v /
v) It was added to 250 ml, and stirred at a temperature of 40 ° C for a while to dissolve. 2.56 g of 10% palladium carbon (containing 50% water) was added to this solution, and the mixture was stirred and reacted at 40 ° C. for 48 hours under a hydrogen atmosphere at normal pressure (0.1 MPa). The reaction solution was filtered to remove the catalyst, and the catalyst was washed with 40 ml of methanol. The filtrate and the washings were combined, concentrated under reduced pressure to remove 60 ml of methanol, and then cooled to 10 ° C. for crystallization to precipitate crystals. The crystals were collected by filtration, washed with a small amount of water, and dried under reduced pressure at 40 ° C. for 3 hours to obtain 7.75 dry crystals.
g was obtained. When these crystals were quantified by HPLC, N-
7.38 g of [N- [3- (2-hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester (16.
(1 mmol, 63%).

【0043】(実施例8)N−[N−[3−(2,4−ジヒドロキシフェニル)プ
ロピル]−L−α−アスパルチル]−L−フェニルアラ
ニン 1−メチルエステルの合成 ラセミ−3,4−ジヒドロ−7−ベンジルオキシ−2H
−1−ベンゾピラン−2−オール0.950g(3.7
1mmol)及びアスパルテーム1.15g(3.90
mmol)をメタノールと水の混合溶剤(混合比3:2
v/v)40mlに加え、温度40℃でしばらく撹拌し
た。このスラリーに10%パラジウム炭素(50%含
水)0.40gを加え、常圧(0.1MPa)の水素雰
囲気下に40℃で48時間撹拌反応した。反応液を濾過
して触媒を除き、減圧濃縮して乾固させた。この乾固物
1H−NMR(DMSO−d6,300MHz,内部標
準物質:1,1,2,2−テトラクロロエタン)で定量
したところ、N−[N−[3−(2,4−ジヒドロキシ
フェニル)プロピル]−L−α−アスパルチル]−L−
フェニルアラニン 1−メチルエステルが1.37g
(3.08mmol、83%)生成していた。
Example 8 N- [N- [3- (2,4-dihydroxyphenyl) p
Ropyl] -L-α-aspartyl] -L-phenylara
Synthesis of Nin 1-Methyl Ester Racemic-3,4-dihydro-7-benzyloxy-2H
-1-benzopyran-2-ol 0.950 g (3.7
1 mmol) and 1.15 g of aspartame (3.90 g)
mmol) in a mixed solvent of methanol and water (mixing ratio 3: 2).
v / v) and stirred for a while at a temperature of 40 ° C. To this slurry, 0.40 g of 10% palladium carbon (containing 50% water) was added, and the mixture was stirred and reacted at 40 ° C. for 48 hours under a hydrogen atmosphere at normal pressure (0.1 MPa). The reaction solution was filtered to remove the catalyst, and concentrated under reduced pressure to dryness. When this dried product was quantified by 1 H-NMR (DMSO-d 6 , 300 MHz, internal standard: 1,1,2,2-tetrachloroethane), N- [N- [3- (2,4- Dihydroxyphenyl) propyl] -L-α-aspartyl] -L-
1.37 g of phenylalanine 1-methyl ester
(3.08 mmol, 83%).

【0044】(実施例9)N−[N−[3−(2−ヒドロキシ−4−メチルフェニ
ル)プロピル]−L−α−アスパルチル]−L−フェニ
ルアラニン 1−メチルエステルの合成 ラセミ−3,4−ジヒドロ−7−メチル−2H−1−ベ
ンゾピラン−2−オール2.50g(15.2mmo
l)及びアスパルテーム4.71g(16.0mmo
l)をメタノールと水の混合溶剤(混合比4:1v/
v)155mlに加え、温度45℃でしばらく撹拌して
溶解した。この溶液に10%パラジウム炭素(50%含
水)1.41gを加え、常圧(0.1MPa)の水素雰
囲気下に45℃で24時間撹拌反応した。反応液を濾過
して触媒を除き、更に触媒をメタノール10mlで洗浄
した。濾液と洗浄液を合わせ、HPLCで定量したとこ
ろ、N−[N−[3−(2−ヒドロキシ−4−メチルフ
ェニル)プロピル]−L−α−アスパルチル]−L−フ
ェニルアラニン 1−メチルエステルが3.84g
(8.68mmol、57%)生成していた。
Example 9 N- [N- [3- (2-hydroxy-4-methylphenyi)
Ru) propyl] -L-α-aspartyl] -L-phenyl
Synthesis of L-alanine 1-methyl ester Racemic-3,4-dihydro-7-methyl-2H-1-benzopyran-2-ol 2.50 g (15.2 mmol
l) and 4.71 g (16.0 mmo) of aspartame
l) in a mixed solvent of methanol and water (mixing ratio 4: 1 v /
v) The mixture was added to 155 ml, and dissolved by stirring at a temperature of 45 ° C for a while. To this solution, 1.41 g of 10% palladium carbon (containing 50% water) was added, and the mixture was stirred and reacted at 45 ° C. for 24 hours under a hydrogen atmosphere at normal pressure (0.1 MPa). The reaction solution was filtered to remove the catalyst, and the catalyst was further washed with 10 ml of methanol. The filtrate and the washing solution were combined and quantified by HPLC. N- [N- [3- (2-hydroxy-4-methylphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester was 3. 84g
(8.68 mmol, 57%).

【0045】[0045]

【発明の効果】本発明に従い、3,4−ジヒドロ−置換
−2H−1−ベンゾピラン−2−オール誘導体とアスパ
ルテームとを、還元的アルキル化反応に付することによ
り、高甘味度甘味料として優れているN−[N−[3−
(2−ヒドロキシ−置換フェニル)プロピル]−L−α
−アスパルチル]−L−フェニルアラニン 1−メチル
エステル誘導体を効率的良くかつ高収率に製造すること
ができる。
According to the present invention, by subjecting a 3,4-dihydro-substituted-2H-1-benzopyran-2-ol derivative and aspartame to a reductive alkylation reaction, it is excellent as a high-intensity sweetener. N- [N- [3-
(2-Hydroxy-substituted phenyl) propyl] -L-α
-Aspartyl] -L-phenylalanine 1-methyl ester derivative can be produced efficiently and in high yield.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 竹本 正 神奈川県川崎市川崎区鈴木町1−1 味の 素株式会社アミノサイエンス研究所内 (72)発明者 小野 恵理子 神奈川県川崎市川崎区鈴木町1−1 味の 素株式会社アミノサイエンス研究所内 Fターム(参考) 4B047 LB04 LB08 LE06 LG17 LP16 4H045 AA20 BA11 EA02  ──────────────────────────────────────────────────続 き Continuing on the front page (72) Tadashi Takemoto 1-1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto Co., Inc. Amino Science Research Laboratories (72) Eriko Ono 1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa -1 F-term in Ajinomoto Co., Inc. Amino Science Laboratory (reference) 4B047 LB04 LB08 LE06 LG17 LP16 4H045 AA20 BA11 EA02

Claims (6)

【特許請求の範囲】[Claims] 【請求項1】下記一般式(1)で示される3,4−ジヒ
ドロ−置換−2H−1−ベンゾピラン−2−オール誘導
体とアスパルテームとを、還元的アルキル化反応に付す
ることを特徴とする下記一般式(2)で示されるN−
[N−[3−(2−ヒドロキシ−置換フェニル)プロピ
ル]−L−α−アスパルチル]−L−フェニルアラニン
1−メチルエステル誘導体の製造方法。 【化1】 【化2】 上記式(1)及び(2)において、R1、R2、R3及び
4はそれぞれ相互に独立していて、水素原子、水酸
基、炭素数が1〜3のアルコキシ基、ベンジルオキシ
基、炭素数が1〜3のアルキル基及び炭素数が2又は3
のヒドロキシアルキルオキシ基からなる群から選ばれる
置換基を表し、ここでR1とR2の二つ及び/又はR3
4の二つ、又はR2とR3の二つは、それぞれ二つが一
緒になってメチレンジオキシ基を表してもよい。但し、
式(2)においては、R1、R2、R3及びR4は、何れも
ベンジルオキシ基を表すことはない。
1. A reductive alkylation reaction of a 3,4-dihydro-substituted-2H-1-benzopyran-2-ol derivative represented by the following general formula (1) with aspartame. N- represented by the following general formula (2)
A method for producing [N- [3- (2-hydroxy-substituted phenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester derivative. Embedded image Embedded image In the above formulas (1) and (2), R 1 , R 2 , R 3 and R 4 are each independently of one another, and represent a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, a benzyloxy group, An alkyl group having 1 to 3 carbon atoms and 2 or 3 carbon atoms
Represents a substituent selected from the group consisting of hydroxyalkyloxy groups, wherein two of R 1 and R 2 and / or two of R 3 and R 4 , or two of R 2 and R 3 are each The two may together represent a methylenedioxy group. However,
In the formula (2), R 1 , R 2 , R 3 and R 4 do not represent any benzyloxy group.
【請求項2】式(1)及び(2)において、R2がメト
キシ基であり、R1、R3及びR4が水素原子である請求
項1記載の方法。
2. The method according to claim 1, wherein in formulas (1) and (2), R 2 is a methoxy group, and R 1 , R 3 and R 4 are hydrogen atoms.
【請求項3】式(1)及び(2)において、R2が水酸
基であり、R1、R3及びR4が水素原子である請求項1
記載の方法。但し、式(1)においてR2はベンジルオ
キシ基でもよい。
3. In the formulas (1) and (2), R 2 is a hydroxyl group, and R 1 , R 3 and R 4 are hydrogen atoms.
The described method. However, in the formula (1), R 2 may be a benzyloxy group.
【請求項4】式(1)及び(2)において、R2がメチ
ル基であり、R1、R3及びR4が水素原子である請求項
1記載の方法。
4. The method according to claim 1, wherein in formulas (1) and (2), R 2 is a methyl group, and R 1 , R 3 and R 4 are hydrogen atoms.
【請求項5】還元的アルキル化反応が溶剤中で行われ、
当該溶剤が、メタノール、エタノール、イソプロピルア
ルコール、テトラヒドロフラン、アセトニトリル、酢酸
及び酢酸エチルの中から選択された少なくとも1種、又
はこれら有機溶媒の少なくとも1種と水との混合溶媒で
ある請求項1記載の方法。
5. The reductive alkylation reaction is performed in a solvent,
The solvent according to claim 1, wherein the solvent is at least one selected from methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetonitrile, acetic acid, and ethyl acetate, or a mixed solvent of at least one of these organic solvents and water. Method.
【請求項6】還元的アルキル化反応が水素添加触媒の存
在下で行われ、当該触媒が、パラジウム、白金及びロジ
ウム系触媒の少なくとも1種である請求項1記載の方
法。
6. The method according to claim 1, wherein the reductive alkylation reaction is performed in the presence of a hydrogenation catalyst, and the catalyst is at least one of a palladium, platinum, and rhodium-based catalyst.
JP28739999A 1999-10-07 1999-10-07 Production process for aspartame derivative Withdrawn JP2001106696A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP28739999A JP2001106696A (en) 1999-10-07 1999-10-07 Production process for aspartame derivative
EP00961236A EP1227104A4 (en) 1999-10-07 2000-09-26 Processes for producing and purifying aspartame derivatives and process for producing production intermediates
KR1020027004405A KR20020038798A (en) 1999-10-07 2000-09-26 Processes for producing and purifying aspartame derivatives and process for producing production intermediates
CN00813952A CN1378558A (en) 1999-10-07 2000-09-26 Processes for producing and purifying aspartame derivatives and process for producing intemediates
AU73218/00A AU7321800A (en) 1999-10-07 2000-09-26 Processes for producing and purifying aspartame derivatives and process for producing production intermediates
PCT/JP2000/006625 WO2001025259A1 (en) 1999-10-07 2000-09-26 Processes for producing and purifying aspartame derivatives and process for producing production intermediates
US10/108,426 US6841183B2 (en) 1999-10-07 2002-03-29 Process for producing aspartame derivatives, process for purifying aspartame derivatives, production intermediates, and process for producing production intermediates

Applications Claiming Priority (1)

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Country Link
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7623488B2 (en) 2000-08-25 2009-11-24 Kyocera Corporation Radio base station and program for radio base station

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7623488B2 (en) 2000-08-25 2009-11-24 Kyocera Corporation Radio base station and program for radio base station

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