JPH0436283A - Production of imidazoquinazoline compound - Google Patents
Production of imidazoquinazoline compoundInfo
- Publication number
- JPH0436283A JPH0436283A JP14247990A JP14247990A JPH0436283A JP H0436283 A JPH0436283 A JP H0436283A JP 14247990 A JP14247990 A JP 14247990A JP 14247990 A JP14247990 A JP 14247990A JP H0436283 A JPH0436283 A JP H0436283A
- Authority
- JP
- Japan
- Prior art keywords
- tetrahydroimidazo
- piperidino
- quinazolin
- hydrochloric acid
- alcohol
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- -1 imidazoquinazoline compound Chemical class 0.000 title description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 82
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 78
- 239000013078 crystal Substances 0.000 claims abstract description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 9
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 claims description 6
- 150000004682 monohydrates Chemical class 0.000 claims 4
- DFSRRGSKSUOZBK-UHFFFAOYSA-N O.Cl.Cl.C1=CC=C2NC(=O)N=CC2=C1 Chemical compound O.Cl.Cl.C1=CC=C2NC(=O)N=CC2=C1 DFSRRGSKSUOZBK-UHFFFAOYSA-N 0.000 claims 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- FVACZQHQBKPPMX-UHFFFAOYSA-N quinazolin-2-one Chemical compound C1=C[CH]C2=NC(=O)N=CC2=C1 FVACZQHQBKPPMX-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000004455 differential thermal analysis Methods 0.000 description 3
- 150000004683 dihydrates Chemical class 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- NJTHFMDEILOTLJ-UHFFFAOYSA-N 1H-quinazolin-2-one dihydrochloride Chemical compound Cl.Cl.O=c1ncc2ccccc2[nH]1 NJTHFMDEILOTLJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- AWISGSJZNFRYNE-UHFFFAOYSA-N ethanol;dihydrochloride Chemical compound Cl.Cl.CCO AWISGSJZNFRYNE-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 150000004684 trihydrates Chemical class 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、血小板凝集抑制作用を示す化合物である７−
（１−ピペリジノ）−１，２，３，５−テトラヒドロイ
ミダゾ［２，１−ｂ］キナゾリン−−２−オン・２塩酸
塩・１水和物の製法に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention provides 7-
The present invention relates to a method for producing (1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride monohydrate.
〈技術の背景〉
塩酸ビミゾグレル（７−（１−ピペリジノ）−１，２，
３５−テトラヒドロイミダゾ（２，１−ｂ］キナゾリン
−２オン・２塩酸塩・１水和物、ＪＡＮ （日本の医薬
品の一般的名称。））は血小板凝集抑制作用を有する化
合物であるが、製造法としては７− （１−ピペリジノ
ｌ−１，２，３，５−テトラヒドロイミダゾ［２，１−
ｂ］キナゾリン−２−オンの結晶をメタノール、水、濃
塩酸の混合物に溶解した後に溶媒を減圧下に除去し、残
留物にエタノールを加え、析出する結晶を集める方法が
知られている（特公昭６３−５０３０号公報参照）。<Technical background> Bimizogrel hydrochloride (7-(1-piperidino)-1,2,
35-tetrahydroimidazo(2,1-b)quinazoline-2one dihydrochloride monohydrate, JAN (common name for pharmaceuticals in Japan)) is a compound that inhibits platelet aggregation. The method is 7-(1-piperidino-1,2,3,5-tetrahydroimidazo[2,1-
b] A known method is to dissolve crystals of quinazolin-2-one in a mixture of methanol, water, and concentrated hydrochloric acid, remove the solvent under reduced pressure, add ethanol to the residue, and collect the precipitated crystals (particularly (See Publication No. 63-5030).
一方、この７−（１−ピペリジノ１４，２，３．５−テ
トラヒドロイミダゾ［２，１−ｂ］キナゾリン−−２−
オンには２塩酸塩・ｌ水和物の他、２塩酸塩・２水和物
、２塩酸塩・３水和物、あるいは１塩酸塩・無水物等の
塩や水和物を構成する酸や水の分子数の異なる結晶が存
在することが明らかとなっている（日本藁学会第１０５
年会、講演要旨集３５７頁）。On the other hand, this 7-(1-piperidino14,2,3.5-tetrahydroimidazo[2,1-b]quinazoline--2-
In addition to dihydrochloride/l-hydrate, ions include acids constituting salts and hydrates such as dihydrochloride/dihydrate, dihydrochloride/trihydrate, or monohydrochloride/anhydride. It has become clear that there are crystals with different numbers of water and water molecules (Japan Straw Society No. 105).
Annual meeting, collection of lecture abstracts, page 357).
方、前記の方法で得られた塩酸ビミゾグレルの結晶中に
は２塩酸塩・２水和物及び／または１塩酸塩・無水物の
結晶が混入し易いことが粉末Ｘ線回折分析によって明ら
かとなり、高純度でなければならない医薬品の製造法と
しては上記の方法が品質面で十分ではないことが判明し
た。On the other hand, powder X-ray diffraction analysis revealed that crystals of dihydrochloride/dihydrate and/or monohydrochloride/anhydride were likely to be mixed into the crystals of bimizogrel hydrochloride obtained by the above method. It has been found that the above method is not sufficient in terms of quality as a method for manufacturing pharmaceutical products that must be highly pure.
本発明者等は、塩酸ビミゾグレルの製造法に関し、付加
している酸や結晶水の数の異なる結晶が混入するという
問題点を解決すべく鋭意検討した。The present inventors have conducted extensive studies regarding the method for producing bimizogrel hydrochloride in order to solve the problem of mixing of crystals with different numbers of added acids and crystallization water.
その結果、新規な結晶である７−（１−ピペリジノ）１
．２，３．５〜テトラヒドロイミダゾ［２，１−ｂ］キ
ナゾリン−−２−オン・２塩酸塩のアルコール含有晶が
特定の含水率の有機溶媒中、塩酸存在下で容易に塩酸ピ
ミゾグレルの結晶に転換することを見いだして本発明を
完成した。ここで、アルコール含有晶とはその結晶の中
にアルコール分子を含んで結晶を形成した結晶をいう。As a result, a new crystal, 7-(1-piperidino)1
．． Alcohol-containing crystals of 2,3.5~tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride easily turn into crystals of pimizogrel hydrochloride in the presence of hydrochloric acid in an organic solvent with a specific moisture content. The present invention was completed by discovering that this can be converted. Here, the alcohol-containing crystal refers to a crystal that contains alcohol molecules therein.
なお、実施例ではアルコル和物と称している。In addition, in the examples, it is called an alcoholate.
〈発明の構成〉
本発明は７−（１−ピペリジノｌ−１，２，３５−テト
ラヒドロイミダゾ［２，ｌ−ｂ］キナゾｌ／ンー２−オ
ンを低級アルコールと塩酸で処理し、 ７−（ｌ−ピペ
リジノ）１．２．３．５−テトラヒドロイミダゾ［２，
１−ｂｌ キナゾリン−２−オン・２塩酸塩の低級アル
コール含有晶に変換し、次いでこれを含水率５〜１０％
の有機溶媒中塩酸存在下で処理することを特徴とする７
−（１ピペリジノｌ−１，２，３，５−テトラヒドロイ
ミダゾ［２，１ｂ１キナゾリン−２−オン・２塩酸塩・
ｌ水和物の製法に関し、さらに、 ７−（１−ピペリジ
ノ＋−１，２，３，５テトラヒドロイミダゾ［２，１−
ｂｌ キナゾリン−２−オン・２塩酸塩の低級アルコー
ル含有晶およびその製法に関する。<Structure of the Invention> The present invention provides the treatment of 7-(1-piperidino-1,2,35-tetrahydroimidazo[2,lb-b]quinazol/-2-one with a lower alcohol and hydrochloric acid to produce 7-( l-piperidino) 1.2.3.5-tetrahydroimidazo[2,
1-bl is converted into lower alcohol-containing crystals of quinazolin-2-one dihydrochloride, which is then converted to a crystal with a water content of 5 to 10%.
7 characterized in that the treatment is carried out in the presence of hydrochloric acid in an organic solvent of
-(1piperidinol-1,2,3,5-tetrahydroimidazo[2,1b1quinazolin-2-one dihydrochloride
Regarding the method for producing l-hydrate, further, 7-(1-piperidino+-1,2,3,5tetrahydroimidazo[2,1-
The present invention relates to a lower alcohol-containing crystal of quinazolin-2-one dihydrochloride and a method for producing the same.
本発明の方法について以下に説明する。The method of the present invention will be explained below.
７−（１−ピペリジノ） −１，２，３，５−テトラヒ
ドロイミダゾ［２，１−ｂ］キナゾリン−−２〜オンの
結晶を低級アルコール、水、塩酸の混合物少量に溶解す
る。Crystals of 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one are dissolved in a small amount of a mixture of lower alcohol, water, and hydrochloric acid.
この溶液を低級アルコールに滴下すると、結晶中にアル
コール分子を含有するアルコール含有晶が析出する。次
いで、この混合物中に水を加えて撹拌しながら処理をす
ると、アルコール含有晶が含水晶に転換されて塩酸ビミ
ゾグレルの結晶が得られる。この転換に際しては中間で
生成するアルコール含有晶を一旦単離し、改めて合本有
機溶媒中塩酸存在下で処理する方法でも塩酸ピミゾグレ
ルが得られる。When this solution is dropped into a lower alcohol, alcohol-containing crystals containing alcohol molecules in the crystals are precipitated. Next, when water is added to this mixture and treated while stirring, the alcohol-containing crystals are converted to hydrate-containing crystals to obtain bimizogrel hydrochloride crystals. In this conversion, pimizogrel hydrochloride can also be obtained by a method in which the alcohol-containing crystals produced in the intermediate stage are once isolated and then combined and treated again in the presence of hydrochloric acid in an organic solvent.
本発明で用いる低級アルコールとしては炭素数２〜４の
アルコールがよ（、特にエタノール、イソプロパノール
またはｎ−プロパノールが好ましい。また、結晶転換時
に用いる有機溶媒としては前記アルコールの他、アセト
ンも使用できる。The lower alcohol used in the present invention is preferably an alcohol having 2 to 4 carbon atoms (especially ethanol, isopropanol or n-propanol). In addition to the above-mentioned alcohols, acetone can also be used as the organic solvent used during crystal conversion.
アルコール含有晶は以下の方法によって製造できる。
７−（１−ピペリジノ）−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−２−オンを０．
３〜１．０倍（体積／重量、Ｉｇに対してｌ ｍｌの割
合の場合に１倍という。以下同様。）の水、０．５〜１
．５倍（体積／重量）のアルコール、塩酸２．５〜４．
０倍モルの混合液に溶解する。この溶液を７−（ｌ−ピ
ペリジノｌ−１，２，３，５−テトラヒドロイミダゾ［
２，１−ｂｌ キナゾリン−２−オンに対し２０〜５０
倍（体積／重量）の低級アルコールに温度１５〜３０℃
で滴下し、その後同温度で２〜６時間撹拌して熟成させ
る方法である。Alcohol-containing crystals can be produced by the following method.
7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one at 0.
3 to 1.0 times (volume/weight, 1 time when the ratio is 1 ml to Ig. The same applies hereinafter) water, 0.5 to 1
．． 5 times (volume/weight) alcohol, hydrochloric acid 2.5-4.
Dissolve in a 0-fold molar mixture. This solution was mixed with 7-(l-piperidinol-1,2,3,5-tetrahydroimidazo[
20-50 for 2,1-bl quinazolin-2-one
Double (volume/weight) lower alcohol at a temperature of 15-30℃
This method involves dropping the mixture at the same temperature and then stirring for 2 to 6 hours at the same temperature to age it.
アルコール含有晶から塩酸ビミゾグレルへの転換は、ア
ルコール含有晶に対して塩酸０．５〜２．０モル、含水
率５〜１０％（体積比）の有機溶媒の５〜５０倍量（体
積／重量）中、温度１５〜３５℃で２〜８時間撹拌して
実施され、析出する結晶を集めることで目的物が得られ
る。Conversion from alcohol-containing crystals to bimizogrel hydrochloride is carried out using 0.5 to 2.0 mol of hydrochloric acid and 5 to 50 times the amount (volume/weight) of an organic solvent with a water content of 5 to 10% (volume ratio) to the alcohol-containing crystals. ), stirring is carried out at a temperature of 15 to 35°C for 2 to 8 hours, and the desired product is obtained by collecting the precipitated crystals.
なお、塩酸が０．５モル以下の時には１塩酸塩・無水物
が生成混入し易い。また、含水率が５％以下の時は水和
物への転換が進行し難く、１０％を越える時は２塩酸塩
・２水和物が生成混入し易い。Note that when the amount of hydrochloric acid is 0.5 mol or less, monohydrochloride/anhydride is likely to be formed and mixed. Furthermore, when the water content is less than 5%, conversion to hydrates is difficult to proceed, and when it exceeds 10%, dihydrochloride/dihydrate is likely to be mixed in.
工業的にはアルコール含有晶を生成させた後、このアル
コール含有晶を単離せずに、引き続き反応液に水を添加
して含水率を調整した後に撹拌処理して結晶の転換を実
施して塩酸ピミゾグレルを製造する方法が有利である。Industrially, after producing alcohol-containing crystals, without isolating the alcohol-containing crystals, water is subsequently added to the reaction solution to adjust the water content, and then stirring is performed to convert the crystals into hydrochloric acid. Advantageous are methods of producing pimizogrel.
本発明のアルコール含有晶は７−（１−ピペリジノ）−
１，２，３，５−テトラヒドロイミダゾ［２，１−ｂ］
キナゾリン−２−オンの１分子に対し、通常は２分子の
塩酸が付加して塩を形成し、さらにアルコールが結晶中
に含有されているものである。このアルコール含有晶に
含まれるアルコール分子の数は、通常は上記の組成の塩
酸塩に対して１分子である。The alcohol-containing crystal of the present invention is 7-(1-piperidino)-
1,2,3,5-tetrahydroimidazo[2,1-b]
Usually, two molecules of hydrochloric acid are added to one molecule of quinazolin-2-one to form a salt, and alcohol is further contained in the crystal. The number of alcohol molecules contained in this alcohol-containing crystal is usually one molecule per hydrochloride having the above composition.
また、含有されるアルコールとしては特に制限はないが
、エタノール、プロパノール類、あるいはブタノール類
等の低級アルコールが好ましい。The alcohol to be contained is not particularly limited, but lower alcohols such as ethanol, propanols, or butanols are preferred.
本発明を以下に示す実施例によってさらに詳細に説明す
るが、本発明はこれに限定されるものではない。The present invention will be explained in more detail with reference to Examples shown below, but the present invention is not limited thereto.
実施例１
７−（１−ピペリジノｌ−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−２−オン２０．
０ ｇを濃塩酸２０ｍ１、水１０ ｍｌ、エタノール２
０ ｍｌの混合液に湾解し、この溶液を温度２０〜２５
℃のエタノール６００ ｍｌに１時間を要し滴下した。Example 1 7-(1-piperidinol-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one 20.
0 g in 20 ml of concentrated hydrochloric acid, 10 ml of water, and 2 ml of ethanol.
Dissolve the mixture to 0 ml and heat this solution to a temperature of 20-25 ml.
The mixture was added dropwise to 600 ml of ethanol at a temperature of 1 hour.
その後２５℃で２時間撹拌した後５℃まで冷却した。析
出した結晶を濾取して７−（１−ピペリジノｌ−１，２
，３，５−テトラヒドロイミダゾ［２，１−ｂ］キナゾ
リン−−２−オン・２塩酸塩・エタノール和物２３．（
ｌ ｇを得た。Thereafter, the mixture was stirred at 25°C for 2 hours and then cooled to 5°C. The precipitated crystals were collected by filtration to give 7-(1-piperidino l-1,2
, 3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride ethanolate 23. (
lg was obtained.
元素分析値 Ｃ＋ｓ旧、Ｎ４０２ＨＣＩＣ２Ｈ，ＯＨと
して計算値： Ｃ５２，４５，Ｈ６，７３，Ｎ １４．
３９． Ｃ１１８，２１実測値： Ｃ５２，４０，Ｈ６
，６９，Ｎ １４．２９ Ｃ１１８，２３エタノール
含量（ＧＣ分析法）
計算値： １１．８％ 分析値： １１．６％
示差熱分析（セイコーＩ＆Ｅ製、ＴＧ／ＤＴＡ２０、コ
ントローラー、ＥＳＣ７５８０を使用して測定した。）
１４０〜２００℃にかけ２１％の重量減少と吸熱ピーク
が認められた。Elemental analysis value Calculated value as C+s old, N402HCIC2H, OH: C52,45,H6,73,N 14.
39. C118,21 actual measurement value: C52,40,H6
,69,N 14.29 C118,23 Ethanol content (GC analysis method) Calculated value: 11.8% Analyzed value: 11.6%
Differential thermal analysis (measured using Seiko I&E, TG/DTA20, controller, ESC7580)
A weight loss of 21% and an endothermic peak were observed from 140 to 200°C.
分解点＝２５０〜２６０℃、極大ピーク：２６５℃（サ
ンプル量： ７．３３ ｍｇ、窒素流量： １００ ｍ
ｌ ／分、昇温速度：１０℃／分）
前記のエタノール和物１０．０ ｇを濃塩酸３ ｍｌ。Decomposition point = 250-260°C, maximum peak: 265°C (sample amount: 7.33 mg, nitrogen flow rate: 100 m
l/min, heating rate: 10°C/min) 10.0 g of the above ethanolate was added to 3 ml of concentrated hydrochloric acid.
水５ ｍｌ、エタノール１００ ｍｌの混合液に加え、
２５℃で４時間撹拌した後に５℃まで冷却した。析出し
た結晶を濾取して塩酸ビミゾグレル８．６ｇを得た。Add to a mixture of 5 ml of water and 100 ml of ethanol,
After stirring at 25°C for 4 hours, the mixture was cooled to 5°C. The precipitated crystals were collected by filtration to obtain 8.6 g of bimizogrel hydrochloride.
ここで得られた塩酸ピミゾグレルは、粉末ｘｍ回折分析
で塩酸ピミゾグレル以外の特性吸収を認めなかった。The pimizogrel hydrochloride obtained here showed no characteristic absorption other than pimizogrel hydrochloride in powder xm diffraction analysis.
元素分析値 Ｃ，、Ｈ，、Ｎ４０・２ＨＣ１・ｌＨ２Ｏ
として計算値： Ｃ４９，８７，Ｈ６，１４，Ｎ １５
．５１． Ｃ１１９，６３実測値： Ｃ４９，８２，Ｈ
６，０９，Ｎ １５．５５． ＣＩ １９．７０水分含
量Ｃカールフィシャー法）
計算値： ４．９９ 分析値： ４．９５実
施例２
実施例１で得たエタノール和物１０．０ ｇを濃塩酸１
．５ ｍｌ、水６ ｍｌ、アセトン１００ ｍｌの混合
液に加えた。３０℃で４時間撹拌した後５℃まで冷却し
て析出した結晶を濾取し塩酸ピミゾグレル８．７ｇを得
た。Elemental analysis value C,,H,,N40・2HC1・lH2O
Calculated value as: C49,87,H6,14,N 15
．． 51. C119,63 actual value: C49,82,H
6,09,N 15.55. CI 19.70 Moisture content (C Karl Fischer method) Calculated value: 4.99 Analyzed value: 4.95 Example 2 10.0 g of the ethanolate obtained in Example 1 was dissolved in concentrated hydrochloric acid 1
．． 5 ml of water, 6 ml of water, and 100 ml of acetone. After stirring at 30° C. for 4 hours, the mixture was cooled to 5° C., and the precipitated crystals were collected by filtration to obtain 8.7 g of pimizogrel hydrochloride.
ここで得られた塩酸ピミゾグレルは、粉末Ｘ線回折分析
で塩酸ピミゾグレル以外の特性吸収を認めなかった。The pimizogrel hydrochloride obtained here showed no characteristic absorption other than pimizogrel hydrochloride in powder X-ray diffraction analysis.
実施例３
７−（ｌ−ピペリジノ）−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−２−オン２００
ｇを濃塩酸２２ ｍｌ、水１０ｍ１、エタノール２０
ｍｌの混合液に溶解した後、温度２０〜２５℃のエタノ
ール６００ｍ１に１時間を要して滴下した。２５℃で３
時間撹拌した後、水２５ ｍｌを添加し、更に２５℃で
５時間撹拌した後５℃まで冷却し、析出した結晶を濾取
して塩酸ピミゾグレル２１．３ ｇを得た。Example 3 7-(l-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one 200
g, 22 ml of concentrated hydrochloric acid, 10 ml of water, 20 ml of ethanol
ml of the mixed solution, and then added dropwise to 600 ml of ethanol at a temperature of 20 to 25° C. over a period of 1 hour. 3 at 25℃
After stirring for an hour, 25 ml of water was added, and the mixture was further stirred at 25°C for 5 hours, then cooled to 5°C, and the precipitated crystals were collected by filtration to obtain 21.3 g of pimizogrel hydrochloride.
ここで得られた塩酸ピミゾグレルは、粉末Ｘ線回折分析
で塩酸ビミゾグレル以外の特性吸収を認めなかった。The pimizogrel hydrochloride obtained here showed no characteristic absorption other than bimizogrel hydrochloride in powder X-ray diffraction analysis.
実施例４
７−（１−ピペリジノｌ−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−２−オン１０
ｇを塩酸１０ｍ１、水６ｍ１．インプロパノール１０
ｍｌの混合液に溶解した後、温度２０〜２５℃のインプ
ロパノール３００ ｍｌに０．５時間を要して滴下し、
２５℃で２時間撹拌した後５℃まで冷却し、析出した結
晶を濾取して７−（ｌ−ピペリジノ）−１，２，３，５
−テトラヒドロイミダゾ［２，１−ｂ］キナゾリン−２
−オン・２塩酸塩・インプロパノール和物１３．０ ｇ
を得た。Example 4 7-(1-piperidinol-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one 10
g, hydrochloric acid 10ml, water 6ml. Impropanol 10
ml of the mixed solution, and then added dropwise to 300 ml of inpropanol at a temperature of 20 to 25°C over a period of 0.5 hours.
After stirring at 25°C for 2 hours, it was cooled to 5°C, and the precipitated crystals were collected by filtration to give 7-(l-piperidino)-1,2,3,5
-tetrahydroimidazo[2,1-b]quinazoline-2
-one dihydrochloride impropanol hydrate 13.0 g
I got it.
元素分析値 Ｃ，、Ｈ，、Ｎ４０２ＨＣ１・Ｃ，Ｈ，Ｏ
Ｈとして計算値： Ｃ５３，６０，Ｈ７，００，Ｎ １
３．８９． Ｃ１１７，５８実測値： Ｃ５３，５６，
Ｈ６，８６，Ｎ １３．８６ Ｃ１１７，５５イソプ
ロパノール含量（ＧＣ分析法）
計算値＝ １４９ 分析値：１４８示差熱分析
１３５〜１９０℃にかけ２４％の重量減少と吸熱ピーク
が認められた。Elemental analysis value C,,H,,N402HC1・C,H,O
Calculated value as H: C53,60, H7,00, N 1
3.89. C117,58 actual measurement value: C53,56,
H6,86,N 13.86 C117,55 isopropanol content (GC analysis method) Calculated value = 149 Analysis value: 148 Differential thermal analysis 24% weight loss and endothermic peak were observed at 135-190°C.
分解点：２５５〜２８５℃、極大ピーク＝２７５℃（サ
ンプル量： １１．４０ ｍｇ、窒素流量： １００
ｍｌ ７分、昇温速度＝１０℃／分）
前記インプロパノール和物１０ ｇを製塩１ｉｉ ３ｍ
ｌ。Decomposition point: 255-285°C, maximum peak = 275°C (sample amount: 11.40 mg, nitrogen flow rate: 100
ml 7 minutes, heating rate = 10°C/min) 10 g of the above impropanolate was salted 1ii 3 m
l.
水５ ｍｌ、インプロパノール１００ ｍｌの混合液に
加え、２５℃で３時間撹拌した後５℃まで冷却し、析出
した結晶を濾取して塩酸ビミゾグレル８．５ｇを得た。The mixture was added to a mixture of 5 ml of water and 100 ml of inpropanol, stirred at 25°C for 3 hours, cooled to 5°C, and the precipitated crystals were collected by filtration to obtain 8.5 g of bimizogrel hydrochloride.
ここで得られた塩酸ピミゾグレルは、粉末Ｘ線回折分析
で塩酸ピミゾグレル以外の特性吸収を認めなかった。The pimizogrel hydrochloride obtained here showed no characteristic absorption other than pimizogrel hydrochloride in powder X-ray diffraction analysis.
実施例５
７−（１−ピペリジノｌ−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−−２−オン１０
ｇを濃塩酸１２ ｍｌ、水５ ｍｌ、ｎ−プロパノー
ル１０ｍ１の混合液に溶解した。この溶液を温度２５〜
３０℃のｎ−プロパツル３５０ｍ１に０，５時間を要し
て滴下し、３０℃で２時間撹拌して５℃まで冷却した。Example 5 7-(1-piperidinol-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one 10
g was dissolved in a mixture of 12 ml of concentrated hydrochloric acid, 5 ml of water, and 10 ml of n-propanol. This solution is heated to a temperature of 25~
The mixture was added dropwise to 350 ml of n-propazole at 30°C over 0.5 hours, stirred at 30°C for 2 hours, and cooled to 5°C.
析出した結晶を濾取して７− （１−ピペリジノ＋−１
，２３５−テトラヒドロイミダゾ［２，１−ｂ］キナゾ
リン−−２−オン・２塩酸塩・Ｉｎ−プロパノール和物
１２０ｇを得た。The precipitated crystals were collected by filtration and 7-(1-piperidino+-1
, 235-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride/In-propanolate (120 g) was obtained.
元素分析値 Ｃ，５Ｈ，、Ｎ、０２ＨＣＩＣ，Ｈ，ＯＨ
として計算値： Ｃ５３，６０，Ｈ７，００，Ｎ １３
．８９ ＣＩ １７．５８実測値： Ｃ５３，４５，
Ｈ６，９５，Ｎ １３．９２ Ｃ１１７，６Ｏｎ−プ
ロパノール含量（ＧＣ分析法）
計算値： １４９ 分析値＋ １５．０示差熱分
析
１３０〜１９０℃にかけ２４％の重量減少と吸熱ビーク
が詔められた。Elemental analysis value C, 5H,, N, 02HCIC, H, OH
Calculated value as: C53,60,H7,00,N 13
．． 89 CI 17.58 Actual value: C53,45,
H6,95,N 13.92 C117,6On-propanol content (GC analysis method) Calculated value: 149 Analysis value + 15.0 Differential thermal analysis 24% weight loss and endothermic peak observed at 130-190°C .
分解点＝２５０〜２８０℃、極大ビーク：２７０℃（サ
ンプル量： １１．４２ ｍｇ、窒素流量： １００
ｍｌ ／分。Decomposition point = 250-280°C, maximum peak: 270°C (sample amount: 11.42 mg, nitrogen flow rate: 100
ml/min.
昇温速度：１０℃／分）
前記ロープロバノール和物１０．０ ｇを濃塩酸３ａ＋
１、水５ ｍｌ、ローブロバノール１００ ｍｌの混合
液へ加え、２０℃で７時間撹拌した後５℃まで冷却し、
析出した結晶を濾取し塩酸ビミゾグレル８．１ｇを得た
。Heating rate: 10°C/min) 10.0 g of the above-mentioned lowobanol hydrate was added to concentrated hydrochloric acid 3a+.
1. Add to a mixture of 5 ml of water and 100 ml of lobanol, stir at 20°C for 7 hours, and then cool to 5°C.
The precipitated crystals were collected by filtration to obtain 8.1 g of bimizogrel hydrochloride.
こくで得られた塩酸ピミゾグレルは、粉末Ｘ＃１回折分
析で塩酸ビミゾグレル以外の特性吸収を詔めなかった。The pimizogrel hydrochloride obtained in this study did not show any characteristic absorption other than bimizogrel hydrochloride in powder X#1 diffraction analysis.
〈発明の効果〉
本発明の製造法は、新規な結晶であるアルコール含有晶
を経由することによって塩酸ビミゾグレルを高純度で工
業的に製造できる極めて優れたものである。<Effects of the Invention> The production method of the present invention is extremely excellent in that bimizogrel hydrochloride can be industrially produced with high purity via a novel alcohol-containing crystal.
Claims (10)
ラヒドロイミダゾ［２，１−ｂ］キナゾリン−２−オン
を低級アルコールと塩酸で処理し、７−（１−ピペリジ
ノ）−１，２，３，５−テトラヒドロイミダゾ［２，１
−ｂ］キナゾリン−２−オン・２塩酸塩の低級アルコー
ル含有晶に変換し、次いでこれを含水率５〜１０％の有
機溶媒中塩酸存在下で処理することを特徴とする７−（
１−ピペリジノ）−１，２，３，５−テトラヒドロイミ
ダゾ［２，１−ｂ］キナゾリン−２−オン・２塩酸塩・
１水和物の製法(1) 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was treated with lower alcohol and hydrochloric acid, and 7-(1-piperidino)- 1,2,3,5-tetrahydroimidazo[2,1
7-(
1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride.
Production method of monohydrate
ラヒドロイミダゾ［２，１−ｂ］キナゾリン−２−オン
・２塩酸塩の低級アルコール含有晶を含水率５〜１０％
の有機溶媒中、塩酸存在下に処理することを特徴とする
７−（１−ピペリジノ）−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−２−オン・２塩
酸塩・１水和物の製法(2) Lower alcohol-containing crystals of 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride with a water content of 5 to 10%
7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride, characterized in that it is treated in an organic solvent in the presence of hydrochloric acid.・Production method of monohydrate
ラヒドロイミダゾ［２，１−ｂ］キナゾリン−２−オン
・２塩酸塩の低級アルコール含有晶(3) Lower alcohol-containing crystals of 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride
ラヒドロイミダゾ［２，１−ｂ］キナゾリン−２−オン
を低級アルコールと塩酸で処理することを特徴とする、
７−（１−ピペリジノ）−１，２，３，５−テトラヒド
ロイミダゾ［２，１−ｂ］キナゾリン−２−オン・２塩
酸塩の低級アルコール含有晶の製法(4) characterized by treating 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one with a lower alcohol and hydrochloric acid,
Method for producing lower alcohol-containing crystals of 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride
ール、プロパノールまたはブタノールよりなる群から選
ばれるアルコールである請求項１、２または４記載の製
法(5) The method according to claim 1, 2 or 4, wherein the lower alcohol of the lower alcohol-containing crystal is an alcohol selected from the group consisting of ethanol, propanol or butanol.
ール、プロパノールまたはブタノールよりなる群から選
ばれるアルコールである請求項３記載の化合物(6) The compound according to claim 3, wherein the lower alcohol of the lower alcohol-containing crystal is an alcohol selected from the group consisting of ethanol, propanol, or butanol.
はブタノールよりなる群から選ばれるアルコールである
請求項１または２記載の製法(7) The method according to claim 1 or 2, wherein the lower alcohol is an alcohol selected from the group consisting of ethanol, propanol, or butanol.
ノールよりなる群から選ばれるアルコールである請求項
１、２または７記載の製法(8) The method according to claim 1, 2 or 7, wherein the organic solvent is an alcohol selected from the group consisting of ethanol, propanol or butanol.
ラヒドロイミダゾ［２，１−ｂ］キナゾリン−２−オン
を、エタノールと塩酸で処理し、７−（１−ピペリジノ
）−１，２，３，５−テトラヒドロイミダゾ［２，１−
ｂ］キナゾリン−２−オン・２塩酸塩のエタノール含有
晶に変換し、次いでこれを含水率５〜１０％のエタノー
ル中塩酸存在下で処理することを特徴とする７−（１−
ピペリジノ）−１，２，３，５−テトラヒドロイミダゾ
［２，１−ｂ］キナゾリン−２−オン・２塩酸塩・１水
和物の製法(9) 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was treated with ethanol and hydrochloric acid, and 7-(1-piperidino)- 1,2,3,5-tetrahydroimidazo[2,1-
b] 7-(1-
Method for producing quinazolin-2-one dihydrochloride monohydrate
トラヒドロイミダゾ［２，１−ｂ］キナゾリン−２−オ
ン・２塩酸塩のエタノール含有晶を含水率５〜１０％の
エタノール中塩酸存在下で処理することを特徴とする７
−（１−ピペリジノ）−１，２，３，５−テトラヒドロ
イミダゾ［２，１−ｂ］キナゾリン−２−オン・２塩酸
塩・１水和物の製法(10) Ethanol-containing crystals of 7-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride were added to ethanol with a water content of 5 to 10%. 7 characterized in that the treatment is carried out in the presence of hydrochloric acid in
-(1-piperidino)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride monohydrate manufacturing method
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14247990A JPH0436283A (en) | 1990-05-31 | 1990-05-31 | Production of imidazoquinazoline compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14247990A JPH0436283A (en) | 1990-05-31 | 1990-05-31 | Production of imidazoquinazoline compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0436283A true JPH0436283A (en) | 1992-02-06 |
Family
ID=15316278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14247990A Pending JPH0436283A (en) | 1990-05-31 | 1990-05-31 | Production of imidazoquinazoline compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0436283A (en) |
-
1990
- 1990-05-31 JP JP14247990A patent/JPH0436283A/en active Pending
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