JP3879025B2 - Crystals of bromo-substituted azetidinone compounds - Google Patents
Crystals of bromo-substituted azetidinone compounds Download PDFInfo
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- JP3879025B2 JP3879025B2 JP2002063315A JP2002063315A JP3879025B2 JP 3879025 B2 JP3879025 B2 JP 3879025B2 JP 2002063315 A JP2002063315 A JP 2002063315A JP 2002063315 A JP2002063315 A JP 2002063315A JP 3879025 B2 JP3879025 B2 JP 3879025B2
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- Prior art keywords
- bromo
- substituted azetidinone
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- crystals
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Description
【0001】
【発明の属する技術分野】
本発明は、ブロモ置換アゼチジノン化合物の結晶に関する。
【0002】
【従来の技術】
WO01/72704号に記されているように、式(1)
【0003】
【化2】
で表される3(S)−1−ブロモ−3−[(R)−1’−tert−ブチルジメチルシリルオキシエチル]−2−アゼチジノンは、一般式(2)
【0004】
【化3】
[式中、Rは水素原子又はC1-4アルキル基を示す。]
で表されるカルバペナム抗生物質を製造するための中間体として有用である。
【0005】
WO01/72704号の実施例2において、上記式(1)で表されるブロモ置換アゼチジノン化合物の製造例が示されている。この製造例によれば、式(1)のブロモ置換アゼチジノン化合物は、反応終了後に抽出及び濃縮を行うことにより無色液体の形態で製造されている。
【0006】
しかしながら、本発明者の研究によれば、液状の式(1)のブロモ置換アゼチジノン化合物は、極めて不安定であり、例えば20℃前後の室内で遮光条件下に保管しておいた場合でも数時間も経過しないうちに該化合物の分解が始まり、24時間後には全体の約10%程度が分解し、純度等の品質が大きく低下することが判明した。更に、本発明者の研究によれば、時間の経過と共に、式(1)のブロモ置換アゼチジノン化合物の分解が加速され、48時間後には全体の30%以上が、100時間後には全体の70%以上が分解することも判明した。この原因は、式(1)のブロモ置換アゼチジノン化合物は、分子内に反応活性な臭素原子を有しており、この臭素原子が分解の際に臭化水素酸となり、自己分解を促進するためであると考えられる。
【0007】
式(1)のブロモ置換アゼチジノン化合物は、カルバペナム抗生物質を製造するための中間体として有用な化合物であるが、特に高純度であることが要望されていることから、長時間に亘って分解が生じ難い式(1)のブロモ置換アゼチジノン化合物の開発が望まれている。
【0008】
【発明が解決しようとする課題】
本発明は、長時間に亘って分解が生じ難い式(1)のブロモ置換アゼチジノン化合物を提供することを課題とする。
【0009】
【課題を解決するための手段】
本発明者は、上記課題を解決するために鋭意研究を重ねた結果、液状形態の上記式(1)で表されるブロモ置換アゼチジノン化合物を特定の有機溶剤に溶解し、この溶液を水に添加することにより、結晶形態の上記式(1)で表されるブロモ置換アゼチジノン化合物が得られ、該化合物が長時間に亘って分解が生じ難い安定な化合物であることを見い出した。本発明は、このような知見に基づき完成されたものである。
1.本発明は、上記式(1)で表される3(S)−1−ブロモ−3−[(R)−1’−tert−ブチルジメチルシリルオキシエチル]−2−アゼチジノンの結晶である。
2.本発明は、粉末X線回折パターンにおいて、回折角5.26°付近、7.00°付近、13.34°付近、13.64°付近、16.32°付近、16.62°付近、18.76°付近及び21.10°付近に、回折強度のピークを示す、上記1に記載の結晶である。
【0010】
【発明の実施の形態】
本発明の結晶は、粉末X線回折パターンにおいて、回折角5.26°付近、7.00°付近、13.34°付近、13.64°付近、16.32°付近、16.62°付近、18.76°付近及び21.10°付近に、回折強度のピークを示すことを特徴とする。
【0011】
本発明の結晶は、例えば、液状形態の上記式(1)で表されるブロモ置換アゼチジノン化合物を有機溶剤に溶解し、この溶液を水に添加することにより得られる。
【0012】
液状形態の上記式(1)で表されるブロモ置換アゼチジノン化合物は、公知であり、例えばWO01/72704号の実施例2に記載されている方法に従い製造される。
【0013】
有機溶剤としては、液状形態の上記式(1)で表されるブロモ置換アゼチジノン化合物を溶解することができ、且つ水と混和性のある有機溶剤を広く使用でき、例えばアセトン、メチルエチルケトン等のケトン系溶媒、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、ジメチルホルムアミド、ジメチルアセトアミド等のアミド系溶媒、ジメチルスルホキシド等のスルホキシド系溶媒等を、好ましくはアセトン等を挙げることができる。これら有機溶剤は、1種単独で又は2種以上混合して使用される。
【0014】
有機溶剤の使用量は、液状形態の上記式(1)で表されるブロモ置換アゼチジノン化合物に対して、通常1〜10倍重量程度、好ましくは2〜10倍重量程度である。
【0015】
上記アゼチジノン化合物の有機溶剤溶液に対する水の添加量は、該有機溶剤溶液当たり、少なくとも10倍重量程度以上、通常10〜1000倍重量程度、好ましくは10〜300倍重量程度である。
【0016】
上記有機溶剤溶液を水に添加するに際しては、該溶液を水に徐々に添加するのがよく、好ましくは撹拌下に該溶液を水に滴下するのがよい。また、添加に当たり、水及び上記溶液は、通常1〜10℃程度、好ましくは3〜5℃程度に冷却しておくのがよい。このようにして、上記アゼチジノン化合物の結晶化が速やかに進行する。
【0017】
上記有機溶剤溶液の水への添加時間は、通常5〜120分程度、好ましくは10〜60分程度である。
【0018】
斯くして上記アゼチジノン化合物の結晶が溶液中に析出してくるので、この結晶を公知の単離精製手段により、単離、精製すればよい。単離精製手段としては、濾過、洗浄、乾燥等を挙げることができる。
【0019】
【発明の効果】
本発明のブロモ置換アゼチジノン化合物結晶は、安定性に優れており、長時間に亘って分解が生じ難い性質を備えている。
【0020】
上記式(1)のブロモ置換アゼチジノン化合物は、カルバペナム抗生物質を製造するための中間体として有用な化合物であり、特に高純度であることが要求されていることから、安定性に優れた上記結晶は、工業的に利用価値が極めて高い。
【0021】
本発明の上記方法に従えば、上記所望の性質を備えた結晶を簡易に製造することができる。
【0022】
【実施例】
以下に実施例及び試験例を掲げて、本発明をより一層明らかにする。
【0023】
実施例1
200mlのナス型フラスコに蒸留水80mlを入れ、予め3℃に冷却した。
これとは別に、液状の3(S)−1−ブロモ−3−[(R)−1’−tert−ブチルジメチルシリルオキシエチル]−2−アゼチジノン10gをアセトン20mlに溶解し、この溶液を3℃に冷却しておいた。3〜5℃に冷却した蒸留水中に上記アセトン溶液を滴下し、撹拌したところ、3(S)−1−ブロモ−3−[(R)−1’−tert−ブチルジメチルシリルオキシエチル]−2−アゼチジノンが結晶として析出した。
【0024】
この結晶を減圧下に濾取し、含水アセトン洗浄(水/アセトン=9/1)を行った後、減圧下且つ遮光条件下にて5時間乾燥を行うと、3(S)−N−ブロモ−3−[(R)−1’−tert−ブチルジメチルシリルオキシエチル]−2−アゼチジノンの結晶が9.1g(純度99.3%、HPLC面積百分率)得られた。
【0025】
得られた結晶のNMRは、以下の通りであった。
1H−NMR(CDCl3)δppm:0.05(s,6H),0.85(s,9H),1.15(d,J=6.3Hz,3H),3.45(m,1H),3.49(m,1H),3.59(m,1H),4.23(dq,J=3.3Hz,J=6.3Hz,1H)。
【0026】
得られた結晶の元素分析結果は、以下の通りであった。
【0027】
得られた結晶の粉末X線回折パターンを表1に示す。尚、粉末X線回折の測定条件は、次の通りであった。
【0028】
測定条件
対陰極:Cu
フィルター:モノクロメーター
管電圧:40KV
管電流:40Ma
検出器:シンチレーションカウンター
ピーク強度しきい値(600cp)
【0029】
【表1】
試験例(安定性試験)
本発明の結晶及び液状の3(S)−1−ブロモ−3−[(R)−1’−tert−ブチルジメチルシリルオキシエチル]−2−アゼチジノン(以下「液状化合物」という)につき、安定性を調べた。
【0030】
即ち、本発明の結晶及び液状化合物をそれぞれ遮光容器に入れ、20℃の室内に放置した。放置前、放置から26時間後、放置から48時間後及び放置から100時間後に、容器内の結晶又は液状化合物の一部を取り出し、HPLCを用いて本発明の結晶又は液状化合物の残存率(%)を求めた。分解率(%)は、100%から残存率(%)を差し引いた値とした。
【0031】
結果を表2に示す。
【0032】
【表2】
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to crystals of bromo-substituted azetidinone compounds.
[0002]
[Prior art]
As described in WO 01/72704, the formula (1)
[0003]
[Chemical 2]
3 (S) -1-bromo-3-[(R) -1′-tert-butyldimethylsilyloxyethyl] -2-azetidinone represented by the general formula (2)
[0004]
[Chemical 3]
[Wherein, R represents a hydrogen atom or a C 1-4 alkyl group. ]
It is useful as an intermediate for producing a carbapenam antibiotic represented by:
[0005]
In Example 2 of WO01 / 72704, a production example of a bromo-substituted azetidinone compound represented by the above formula (1) is shown. According to this production example, the bromo-substituted azetidinone compound of formula (1) is produced in the form of a colorless liquid by performing extraction and concentration after completion of the reaction.
[0006]
However, according to the study of the present inventor, the liquid bromo-substituted azetidinone compound of the formula (1) is extremely unstable, for example several hours even when stored in a room at around 20 ° C. under light-shielding conditions. It was found that the decomposition of the compound started before a lapse of time and about 10% of the whole decomposed after 24 hours, and the quality such as purity was greatly lowered. Furthermore, according to the study of the present inventor, the decomposition of the bromo-substituted azetidinone compound of the formula (1) is accelerated with the lapse of time, more than 30% of the whole after 48 hours and 70% of the whole after 100 hours. It was also found that the above decomposed. This is because the bromo-substituted azetidinone compound of the formula (1) has a reactive bromine atom in the molecule, and this bromine atom becomes hydrobromic acid upon decomposition and promotes self-decomposition. It is believed that there is.
[0007]
The bromo-substituted azetidinone compound of formula (1) is a useful compound as an intermediate for the production of carbapenam antibiotics, but since it is particularly required to have high purity, it can be decomposed over a long period of time. Development of a bromo-substituted azetidinone compound of formula (1) that is difficult to occur is desired.
[0008]
[Problems to be solved by the invention]
It is an object of the present invention to provide a bromo-substituted azetidinone compound of the formula (1) that hardly decomposes over a long period of time.
[0009]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventor dissolved the bromo-substituted azetidinone compound represented by the above formula (1) in a liquid form in a specific organic solvent, and added this solution to water Thus, a bromo-substituted azetidinone compound represented by the above formula (1) in a crystalline form was obtained, and the compound was found to be a stable compound that hardly decomposes over a long period of time. The present invention has been completed based on such findings.
1. The present invention is a crystal of 3 (S) -1-bromo-3-[(R) -1′-tert-butyldimethylsilyloxyethyl] -2-azetidinone represented by the above formula (1).
2. In the powder X-ray diffraction pattern of the present invention, the diffraction angle is around 5.26 °, around 7.00 °, around 13.34 °, around 13.64 °, around 16.32 °, around 16.62 °, 18 2. The crystal as described in 1 above, which shows diffraction intensity peaks at around .76 ° and around 21.10 °.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
In the powder X-ray diffraction pattern, the crystal of the present invention has a diffraction angle of around 5.26 °, around 7.00 °, around 13.34 °, around 13.64 °, around 16.32 °, around 16.62 °. The diffraction intensity peaks are shown around 18.76 ° and 21.10 °.
[0011]
The crystal of the present invention can be obtained, for example, by dissolving a bromo-substituted azetidinone compound represented by the above formula (1) in a liquid form in an organic solvent and adding this solution to water.
[0012]
The bromo-substituted azetidinone compound represented by the above formula (1) in a liquid form is known and is produced, for example, according to the method described in Example 2 of WO01 / 72704.
[0013]
As the organic solvent, a bromo-substituted azetidinone compound represented by the above formula (1) in a liquid form can be dissolved, and an organic solvent miscible with water can be widely used. For example, ketones such as acetone and methyl ethyl ketone Solvents, ether solvents such as tetrahydrofuran and dioxane, amide solvents such as dimethylformamide and dimethylacetamide, sulfoxide solvents such as dimethyl sulfoxide, and the like, preferably acetone. These organic solvents are used alone or in combination of two or more.
[0014]
The amount of the organic solvent used is usually about 1 to 10 times by weight, preferably about 2 to 10 times by weight with respect to the bromo-substituted azetidinone compound represented by the above formula (1) in liquid form.
[0015]
The amount of water added to the organic solvent solution of the azetidinone compound is at least about 10 times the weight, usually about 10 to 1000 times the weight, preferably about 10 to 300 times the weight per the organic solvent solution.
[0016]
When the organic solvent solution is added to water, the solution is preferably gradually added to water, and the solution is preferably added dropwise to water with stirring. In addition, water and the above solution are usually cooled to about 1 to 10 ° C, preferably about 3 to 5 ° C. In this way, the crystallization of the azetidinone compound proceeds rapidly.
[0017]
The time for adding the organic solvent solution to water is usually about 5 to 120 minutes, preferably about 10 to 60 minutes.
[0018]
Thus, since the crystal of the azetidinone compound is precipitated in the solution, the crystal may be isolated and purified by a known isolation and purification means. Examples of isolation and purification means include filtration, washing and drying.
[0019]
【The invention's effect】
The bromo-substituted azetidinone compound crystal of the present invention is excellent in stability and has the property that decomposition does not easily occur over a long period of time.
[0020]
The bromo-substituted azetidinone compound of the above formula (1) is a useful compound as an intermediate for producing carbapenam antibiotics, and is particularly required to have high purity. Has a very high industrial utility value.
[0021]
According to the method of the present invention, a crystal having the desired properties can be easily produced.
[0022]
【Example】
The present invention will be further clarified by the following examples and test examples.
[0023]
Example 1
A 200 ml eggplant-shaped flask was charged with 80 ml of distilled water and cooled to 3 ° C in advance.
Separately, 10 g of liquid 3 (S) -1-bromo-3-[(R) -1′-tert-butyldimethylsilyloxyethyl] -2-azetidinone was dissolved in 20 ml of acetone, Allowed to cool to ° C. When the acetone solution was added dropwise to distilled water cooled to 3 to 5 ° C. and stirred, 3 (S) -1-bromo-3-[(R) -1′-tert-butyldimethylsilyloxyethyl] -2 -Azetidinone precipitated out as crystals.
[0024]
The crystals were collected by filtration under reduced pressure, washed with water-containing acetone (water / acetone = 9/1), and then dried for 5 hours under reduced pressure and under light-shielding conditions, to give 3 (S) -N-bromo. 9.1 g (purity 99.3%, HPLC area percentage) of crystals of -3-[(R) -1′-tert-butyldimethylsilyloxyethyl] -2-azetidinone was obtained.
[0025]
NMR of the obtained crystal was as follows.
1 H-NMR (CDCl 3 ) δ ppm: 0.05 (s, 6H), 0.85 (s, 9H), 1.15 (d, J = 6.3 Hz, 3H), 3.45 (m, 1H) ), 3.49 (m, 1H), 3.59 (m, 1H), 4.23 (dq, J = 3.3 Hz, J = 6.3 Hz, 1H).
[0026]
The results of elemental analysis of the obtained crystals were as follows.
[0027]
Table 1 shows the powder X-ray diffraction pattern of the obtained crystals. The measurement conditions for powder X-ray diffraction were as follows.
[0028]
Measurement conditions: Cathode: Cu
Filter: Monochromator tube voltage: 40KV
Tube current: 40 Ma
Detector: Scintillation counter peak intensity threshold (600 cp)
[0029]
[Table 1]
Test example (stability test)
The stability of the crystal of the present invention and liquid 3 (S) -1-bromo-3-[(R) -1′-tert-butyldimethylsilyloxyethyl] -2-azetidinone (hereinafter referred to as “liquid compound”) I investigated.
[0030]
That is, the crystal and liquid compound of the present invention were each put in a light shielding container and left in a room at 20 ° C. Before standing, after 26 hours from standing, after 48 hours from standing and after 100 hours from standing, a part of the crystal or liquid compound in the container was taken out, and the residual ratio of the crystal or liquid compound of the present invention (% ) The decomposition rate (%) was a value obtained by subtracting the remaining rate (%) from 100%.
[0031]
The results are shown in Table 2.
[0032]
[Table 2]
Claims (2)
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