JPH0390082A - Racemization of optically active quinazolinone derivative - Google Patents
Racemization of optically active quinazolinone derivativeInfo
- Publication number
- JPH0390082A JPH0390082A JP22650589A JP22650589A JPH0390082A JP H0390082 A JPH0390082 A JP H0390082A JP 22650589 A JP22650589 A JP 22650589A JP 22650589 A JP22650589 A JP 22650589A JP H0390082 A JPH0390082 A JP H0390082A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- optically active
- quinazolinone derivative
- racemization
- salt
- 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.)
- Pending
Links
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 230000006340 racemization Effects 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 abstract description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 2
- 235000019253 formic acid Nutrition 0.000 abstract description 2
- 229940098779 methanesulfonic acid Drugs 0.000 abstract description 2
- 229910017604 nitric acid Inorganic materials 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical class C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical class O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- CEJLBZWIKQJOAT-UHFFFAOYSA-N dichloroisocyanuric acid Chemical compound ClN1C(=O)NC(=O)N(Cl)C1=O CEJLBZWIKQJOAT-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、光学活性キナゾリノン誘導体の新規ラセミ化
方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel racemization method for optically active quinazolinone derivatives.
（従来技術〉
３−メチル−１，２，３，４−テトラヒドロキナゾリン
−４−スピロ−４゛ −イ箋ダシリジン−２，２′、５
” −トリオン及びその６−クロロ置換体、とりわけそ
れらの光学活性体は、優れたアルドースリダクターゼ阻
害作用を有する有用な医薬化合物であり、この光学活性
体は、例えば対応するラセミ体をブルシン、キニーネな
どの分割剤で光学分割して製造しうろことが知られてい
る（特開昭６２−９６４７７号〉。しかしながら、ラセ
ミ体の光学分割によるときは、所望の光学活性体ととも
に不用な光学活性体も同時に得られるが、従来かか゛る
活性体のラセミ化方法が知られていなかったため、不用
な光学活性体の再利用を図ることは困難であった。(Prior art) 3-Methyl-1,2,3,4-tetrahydroquinazoline-4-spiro-4゛-yellow silidine-2,2',5
-Trione and its 6-chloro substituted products, especially their optically active forms, are useful pharmaceutical compounds having excellent aldose reductase inhibitory effects. It is known that it can be produced by optical resolution using a resolving agent (JP-A No. 62-96477). However, when optically resolving a racemate, an unnecessary optically active substance is also separated along with the desired optically active substance. However, since there was no known method for racemizing such an active substance, it was difficult to reuse the unnecessary optically active substance.
（発明の構成及び効果）
本発明によれば、
一般式
（但し、Ｒは水素原子又はハロゲン原子を表す。）で示
されるキナゾリノン誘導体の光学活性体は、加熱処理す
ることによりラセミ化することができる。(Structure and Effects of the Invention) According to the present invention, the optically active form of the quinazolinone derivative represented by the general formula (where R represents a hydrogen atom or a halogen atom) can be racemized by heat treatment. can.
当該ラセミ化は、無溶媒又は溶媒中のいずれでも好適に
実施することができる。例えば、キナゾリノン誘導体（
１）の光学活性体を低級アルカノール、ジクロルベンゼ
ン等の適当な溶媒に溶解するか、又はかかる溶媒に溶解
することなく、そのまま加熱処理、例えば６０〜１９０
℃で処理することにより、好適に実施できる。The racemization can be suitably carried out either without a solvent or in a solvent. For example, quinazolinone derivatives (
The optically active substance of 1) is dissolved in a suitable solvent such as a lower alkanol or dichlorobenzene, or heat-treated as it is without dissolving it in such a solvent, for example, at a temperature of 60 to 190 ml.
This can be suitably carried out by processing at °C.
キナゾリノン誘導体（１）の光学活性体としては、光学
的に純粋なもののほか、対掌体が一部混在する混合物も
使用することができる。また、キナゾリノン誘導体（１
）は遊離のまま及び塩のいずれの形ででも用いることが
でき、かかる塩としては例えば、アルカリ金属塩、アン
モニウム塩等の無機塩基付加塩又は、モノ−、ジー又は
トリ低級アルキルアミン塩、ブルシン塩、キニーネ塩等
の有機塩基付加塩等を好適に使用することができる。As the optically active form of the quinazolinone derivative (1), in addition to optically pure forms, mixtures containing some enantiomers can also be used. In addition, quinazolinone derivatives (1
) can be used both in the free form and in the form of salts, such as addition salts with inorganic bases such as alkali metal salts, ammonium salts, mono-, di- or tri-lower alkylamine salts, brucine salts, etc. Salts, organic base addition salts such as quinine salts, etc. can be suitably used.
本ラセミ化反応は、酸の存在下で実施するのがとりわけ
好ましい、この場合、酸としては、例えば塩酸、硫酸、
硝酸、燐酸等の無機酸又は蟻酸、酢酸、ｐ−トシル酸、
メタンスルホン酸等の有機酸をいずれも好適に使用する
ことができる。その使用量は特に制限されないが、通常
、原料に対して１〜５０倍モル量、特に３〜１５倍モル
量であるのが好ましい。The present racemization reaction is particularly preferably carried out in the presence of an acid, in which case the acid may be, for example, hydrochloric acid, sulfuric acid,
Inorganic acids such as nitric acid and phosphoric acid, or formic acid, acetic acid, p-tosylic acid,
Any organic acid such as methanesulfonic acid can be suitably used. The amount used is not particularly limited, but it is usually preferably 1 to 50 times the molar amount, particularly 3 to 15 times the molar amount, relative to the raw material.
上記本発明方法によれば、原料化合物（１）のラセミ体
を光学分割して得られる一方の光学活性体を、簡便な操
作でラセミ化しうるという利点が得られ、不用な光学活
性体の再利用を図るための工業的に有利な方法となるも
のである。According to the method of the present invention, one of the optically active forms obtained by optically resolving the racemic form of the starting compound (1) can be racemized by a simple operation, and the unnecessary optically active form can be recycled. This is an industrially advantageous method for its utilization.
実施例 １
６−３−メチル−１，２，３，４−テトラヒドロキナゾ
リン−４−スピロ−４“−イミダゾリジン−２，２′、
５’ −トリオン１１９．７ｇ（〔α〕。−３１，１°
（Ｃ・１、ジメチルホルムアミド〉）に１０％塩酸６
００−を加え、該溶液を８０〜９０℃で３時間攪拌する
。反応液を冷却後析出品をろ取し、水洗後乾燥すること
によりａ−３−メチル−１，２，３，４−テトラヒドロ
キナゾリン−４−スピロ−４゛ −イミダゾリジン−２
，２°、５″ −トリオン１１３．７ｇを得る。Example 1 6-3-methyl-1,2,3,4-tetrahydroquinazoline-4-spiro-4"-imidazolidine-2,2',
5'-trion 119.7g ([α].-31,1°
(C.1, dimethylformamide) with 10% hydrochloric acid 6
00- is added and the solution is stirred at 80-90°C for 3 hours. After cooling the reaction solution, the precipitated product was collected by filtration, washed with water, and dried to obtain a-3-methyl-1,2,3,4-tetrahydroquinazoline-4-spiro-4'-imidazolidine-2.
, 2°, 5″-113.7 g of trion are obtained.
収率：９５％
〔α〕。−０，２” （Ｃ＝１、ジメチルホルムアミ
ド）ｍ、ｐ、＞２１３０℃
実施例 ２
１−６−クロロ−３−メチル−１，２，３，４−テトラ
ヒドロキナゾリン−４−スピロ−４“イミダゾリジン−
２，２°、５”−トリオン１５．８ｇ（（α）Ｄ−２３
”（Ｃ・１、ジメチルホルムアミド））に３５％塩酸６
５Ｉｗｌを加え、該溶液を８０〜９０℃で３時間攪拌す
る。反応液を冷却後析出晶をろ取し、水洗後乾燥するこ
とによりｄｌ−６−クロロ−３−メチル−１，２，３，
４−テトラヒドロキナゾリン−４−スピロ−４゛ −イ
ミダゾリジン−２，２’ 、５’ −トリオン１４．
６ｇを得る。 収率：９２．４％〔α〕。−０，２°
（Ｃ＝１、ジメチルホルムアミド）ｍ、ｐ、＞２８０℃
実施例 ３
ｄ−３−メチル−１，２，３，４−テトラヒドロキナプ
リン−４−スピロ−４゛ −イミダゾリジン−２，２’
、５’−１−リオン０．５０ｇ（〔α〕。＋４２．２
’ （Ｃ−１、ジメチルホルムアミド））に１．２
−ジクロルベンゼン５ ｗｄｌを加え、該溶液を１７時
間加熱還流する。反応液を冷却後析出晶をろ取し、エー
テルで洗浄後乾燥することにより設−３−メチル−１，
２，３，４−テトラヒドロキナゾリン−４−スピロ−４
゛ −イミダゾリジン−２，２°、５’ −トリオン０
．４９ｇを得る。 収率：９８％Yield: 95% [α]. -0,2" (C=1, dimethylformamide) m, p, >2130°C Example 2 1-6-chloro-3-methyl-1,2,3,4-tetrahydroquinazoline-4-spiro-4" imidazolidine
2,2°, 5”-trione 15.8g ((α)D-23
”(C・1, dimethylformamide)) with 35% hydrochloric acid 6
5 Iwl is added and the solution is stirred at 80-90°C for 3 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration, washed with water and dried to give dl-6-chloro-3-methyl-1,2,3,
4-Tetrahydroquinazoline-4-spiro-4'-imidazolidine-2,2',5'-trione 14.
Obtain 6g. Yield: 92.4% [α]. -0,2°
(C=1, dimethylformamide) m, p, >280°C Example 3 d-3-methyl-1,2,3,4-tetrahydroquinapurine-4-spiro-4'-imidazolidine-2,2'
, 5'-1-ion 0.50g ([α].+42.2
'(C-1, dimethylformamide)) to 1.2
- Add 5 wdl of dichlorobenzene and heat the solution to reflux for 17 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration, washed with ether, and dried to give 3-methyl-1,
2,3,4-tetrahydroquinazoline-4-spiro-4
゛ -Imidazolidine-2,2°,5'-trione 0
．． Obtain 49g. Yield: 98%
Claims (3)
されるキナゾリノン誘導体の光学活性体、又はその塩、
を加熱処理することを特徴とする光学活性キナゾリノン
誘導体又はその塩のラセミ化方法。(1) An optically active substance of a quinazolinone derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (where R represents a hydrogen atom or a halogen atom), or a salt thereof;
1. A method for racemizing an optically active quinazolinone derivative or a salt thereof, which comprises heat-treating.
ラセミ化方法。(2) The racemization method according to claim 1, wherein R is a hydrogen atom or a chlorine atom.
ミ化方法。(3) The racemization method according to claim 1 or 2, which is carried out in the presence of an acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22650589A JPH0390082A (en) | 1989-08-31 | 1989-08-31 | Racemization of optically active quinazolinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22650589A JPH0390082A (en) | 1989-08-31 | 1989-08-31 | Racemization of optically active quinazolinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0390082A true JPH0390082A (en) | 1991-04-16 |
Family
ID=16846172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22650589A Pending JPH0390082A (en) | 1989-08-31 | 1989-08-31 | Racemization of optically active quinazolinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0390082A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2827595A1 (en) * | 2001-07-18 | 2003-01-24 | Sumitomo Chemical Co | Process for racemization of vinyl-substituted cyclopropanecarboxylic acid, useful as pyrethrin-type insecticides and intermediates |
-
1989
- 1989-08-31 JP JP22650589A patent/JPH0390082A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2827595A1 (en) * | 2001-07-18 | 2003-01-24 | Sumitomo Chemical Co | Process for racemization of vinyl-substituted cyclopropanecarboxylic acid, useful as pyrethrin-type insecticides and intermediates |
| GB2378442A (en) * | 2001-07-18 | 2003-02-12 | Sumitomo Chemical Co | Process for racemizing optically active vinyl-substituted cyclopropanecarboxylic acid compound |
| US6750370B2 (en) | 2001-07-18 | 2004-06-15 | Sumitomo Chemical Company, Limited | Process for racemizing optically active vinyl-substituted cyclopropanecarboxylic acid compound |
| GB2378442B (en) * | 2001-07-18 | 2004-09-22 | Sumitomo Chemical Co | Process for racemizing optically active vinyl-substituted cyclopropanecarboxylic acid compound |
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