WO2006121094A1 - Crystal or dydrate of magnesium salt of monoallyl malonate - Google Patents
Crystal or dydrate of magnesium salt of monoallyl malonate Download PDFInfo
- Publication number
- WO2006121094A1 WO2006121094A1 PCT/JP2006/309444 JP2006309444W WO2006121094A1 WO 2006121094 A1 WO2006121094 A1 WO 2006121094A1 JP 2006309444 W JP2006309444 W JP 2006309444W WO 2006121094 A1 WO2006121094 A1 WO 2006121094A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystal
- magnesium salt
- hydrate
- monoallyl
- monoallyl malonate
- 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.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
- C07C69/38—Malonic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
Definitions
- the present invention relates to a crystal or hydrate of monoallyl malonate magnesium salt useful as a pharmaceutical raw material for antibacterial drugs and the like.
- Non-patent Document 1 Lubapenem antibacterial drugs (Non-Patent Documents 2, 3, and 4), cyclosporine derivatives (Non-patent Document 5) and the like are useful as pharmaceutical raw materials.
- Patent Document 1 (P28, Preparation 1) includes reacting monoallyl malonate with magnesium methoxide in tetrahydrofuran and then distilling off the solvent under reduced pressure. It is described. However, the crystal is also described in the document of the deviation.
- Patent Documents 2 and 3 a crystal of mono p-trobenzylmalonate magnesium salt is known (Patent Documents 2 and 3).
- Patent Document 1 EP 244364A2
- Patent Document 2 JP-A 2 - No. 286649
- Patent Document 3 Japanese Patent Laid-Open No. 4-74183
- Non-patent literature l Synlett 1996, 324
- Non-Patent Document 2 Tetrahedron Letters, Vol. 35, No. 27, pp 4689-4692, 1994
- Non-Patent Document 3 Heterocycles, Vol.32, No.l, 1991
- Non-Patent Document 4 J. Org. Chem. 1991, 56, 3183-3187
- Non-Patent Document 5 Bioorganic & Medicinal Chemistry Letters, Vol.3, No.12, pp.2559- 25 64, 1993
- the present inventors have found that the monoallyl malonate magnesium salt crystallizes when converted to a solvate, preferably a hydrate, and have completed the following invention.
- Equation (6)
- the monoallyl malonate magnesium salt crystal or hydrate of the present invention is excellent in handleability, purity, etc., and is useful as a pharmaceutical raw material.
- FIG. 1 shows the powder X-ray diffraction pattern of the crystals obtained in Example 1.
- Solvents for the solvate include water, alcohols (preferably C1-C10 alcohols, eg, methanolol, ethanol, isopropanol, 2-propanol, 2-pentanol, 1-pentanol. , Tamyl alcohol, 1 propanol, benzyl alcohol), with water being preferred.
- alcohols preferably C1-C10 alcohols, eg, methanolol, ethanol, isopropanol, 2-propanol, 2-pentanol, 1-pentanol.
- Tamyl alcohol 1 propanol, benzyl alcohol
- the hydration number of the hydrate or its crystal is a force exemplified by 1 to 4, preferably 2.
- the crystals of monoallyl malonate magnesium salt are preferably solvate crystals, more preferably hydrate crystals, such as dihydrate crystals.
- the peak may cause some measurement error due to the measuring equipment, measurement conditions, presence of the attached solvent, etc.
- a measurement error of about ⁇ 0.2 may occur as the value of the surface separation d, and very precise equipment is used.
- Even in the case of measurement there may be a measurement error of ⁇ 0.01 to 0.1. Therefore, some errors should be taken into account in identifying the crystal structure, and all crystals characterized by X-ray patterns substantially similar to the above are within the scope of the present invention.
- the method for producing the crystal or hydrate of the present invention is exemplified below.
- a solvate crystal of monoallyl malonate magnesium salt is obtained by dissolving monoallyl malonate magnesium salt in solvent A and covering solvent B.
- the crystals preferably contain solvent B.
- Solvent A includes alcohols such as methanol, ethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol, ethers such as dioxane, tetrahydrofuran (THF), and dimethoxyethane, acetone, methyl ethyl ketone, and methyl isobutyl ketone.
- alcohols such as methanol, ethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol
- ethers such as dioxane, tetrahydrofuran (THF), and dimethoxyethane, acetone, methyl ethyl ketone, and methyl isobutyl ketone.
- Ketones such as methyl ester, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, dichloromethane, chloroform, tetra Organic halogenated hydrocarbons such as carbon chloride, 1,2-dichloroethane, trichloroethane, black benzene, dichlorobenzene, tolyls such as acetonitrile and propio-tolyl, dimethyl Fuorumuamido, dimethyl sulfoxide, N- methylpyrrolidone, quinoline, pyridines, Toryechiruamin, water or a mixed solvent thereof can be used.
- the solvate crystal of monoallyl malonate magnesium salt has low solubility and is a solvent.
- an organic solvent eg, ace
- the solvent B is preferably a solvent capable of forming a solvate with a monoallyl malonate magnesium salt, and water is exemplified.
- the amount of water added as the solvent B is important, and preferably 0.05 to Lml per lg of monoallyl malonate magnesium salt, preferably 0.1 to 0.5ml force
- the use ratio of the solvent A and the solvent B is usually 1: 0.001 to 1: 1, preferably 1: 0.005 to 1: 0.5, particularly preferably 1: 0.01 to 1: 0. 05.
- ethyl acetate, acetone, THF as solvent A and water as solvent B are used.
- the crystal or hydrate of the present invention can be obtained by the following method using monoallyl malonate as a starting material.
- Monoallyl malonate (HOOC—CH 2 —CO Allyl) as a solvent (eg ethyl acetate, acetone,
- magnesium alkoxide eg Mg (OMe), Mg (OEt)
- a solvent eg, water
- a solvate crystal eg, hydrate crystal
- the amount of magnesium alkoxide used is usually 0.45 to 0.55 equivalent, preferably 0.50 equivalent to monoallyl maleate.
- solvate crystals preferably hydrate crystals
- the amount of hydroxide or alkali metal or ammonia to be used is generally 0.45 to 0.55 equivalent, preferably 0.50 equivalent, relative to monoallyl malonate.
- magnesium oxide MgO
- the reaction solution is concentrated, and a solvent, preferably an organic solvent that can be azeotroped with water (eg, toluene) is added.
- a solvate crystal eg, hydrate crystal
- the amount of magnesium oxide used is usually 0.45 to 0.55 equivalent, preferably 0.50 equivalent, relative to monoallyl malonate.
- X, Y and ⁇ are each independently an integer (eg 1 to 4).
- K Li, Na, NH 4 , etc
- seed crystals may be added as desired.
- the temperature suitable for crystallization is about 10 to about 40 ° C, preferably 0 to 30 ° C.
- the crystals thus obtained can then be isolated by subjecting them to conventional separation and purification means (eg filtration, centrifugation, drying).
- the monoallyl malonate magnesium salt crystal or hydrate of the present invention can be obtained by, for example, a powerful rubapenem antibacterial agent (for example, doripenem; (+) — (4R, 5S, 6S) — 6— [(1R) — 1-Hide mouth kichetil] 4-methyl 7-oxo 3— [[(3S, 5S) — 5— [(sulfamoylamino) methyl] 3-pyrrolidyl-thio] 1-azabicyclo [3.2.0] hepto-2-en-2-strong rubonic acid) is useful as a raw material.
- a powerful rubapenem antibacterial agent for example, doripenem; (+) — (4R, 5S, 6S) — 6— [(1R) — 1-Hide mouth kichetil] 4-methyl 7-oxo 3— [[(3S, 5S) — 5— [(sulfamoylamino) methyl] 3-pyrrolidyl-
- TBS t-butyldimethylsilyl
- Ph phenyl
- Alloc C0 2 Allyl
- Example 1 And stirred at room temperature for 8 h. Thereafter, 5 mg of the crystals obtained in Example 1 were added as seed crystals, and then 4.18 ml of water was added dropwise and stirred for 3 hours. Thereafter, filtration and drying were performed to obtain 16.9 g of the same dihydrate crystal as in Example 1.
- the monoallyl malonate magnesium salt crystal of the present invention is useful as a pharmaceutical raw material.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
モノアリルマロネートマグネシウム塩の結晶または水和物 Crystal or hydrate of monoallyl malonate magnesium salt
技術分野 Technical field
[0001] 本発明は、抗菌薬等の医薬原料として有用なモノアリルマロネートマグネシウム塩 の結晶または水和物に関する。 [0001] The present invention relates to a crystal or hydrate of monoallyl malonate magnesium salt useful as a pharmaceutical raw material for antibacterial drugs and the like.
背景技術 Background art
[0002] 式： [0002] Formula:
[化 1]
(式中、 Allylはァリル基（：ー CH CH = CH )を示す） (In the formula, Allyl represents an aryl group (: -CH 2 CH = CH 2))
2 2 twenty two
で示されるモノアリルマロネートマグネシウム塩は、例えば、プロスタグランジン誘導体 A monoallyl malonate magnesium salt represented by, for example, a prostaglandin derivative
(非特許文献 1)、力ルバぺネム系抗菌薬 (非特許文献 2、 3、 4)、サイクロスポリン誘 導体 (非特許文献 5)等の医薬原料として有用である。モノアリルマロネートマグネシ ゥム塩の調製法としては、特許文献 1 (P28, Preparation 1)に、モノアリルマロネートを テトラヒドロフラン中でマグネシウムメトキサイドと反応させた後、溶媒を減圧留去する 方法が記載されて 、る。しかし 、ずれの文献にもその結晶は記載されて ヽな 、。 また別のマロネートマグネシウム塩の結晶として、モノ p— -トロベンジルマロネート マグネシウム塩の結晶が公知である（特許文献 2, 3)。 (Non-patent Document 1), Lubapenem antibacterial drugs (Non-Patent Documents 2, 3, and 4), cyclosporine derivatives (Non-patent Document 5) and the like are useful as pharmaceutical raw materials. As a method for preparing monoallyl malonate magnesium salt, Patent Document 1 (P28, Preparation 1) includes reacting monoallyl malonate with magnesium methoxide in tetrahydrofuran and then distilling off the solvent under reduced pressure. It is described. However, the crystal is also described in the document of the deviation. As another malonate magnesium salt crystal, a crystal of mono p-trobenzylmalonate magnesium salt is known (Patent Documents 2 and 3).
特許文献 1 : EP 244364A2 Patent Document 1: EP 244364A2
特許文献 2：特開平2 - 286649号 Patent Document 2: JP-A 2 - No. 286649
特許文献 3：特開平 4— 74183号 Patent Document 3: Japanese Patent Laid-Open No. 4-74183
非特許文献 l : Synlett 1996, 324 Non-patent literature l: Synlett 1996, 324
非特許文献 2 : Tetrahedron Letters, Vol. 35, No. 27, pp 4689-4692, 1994 非特許文献 3 : Heterocycles, Vol.32, No.l, 1991 Non-Patent Document 2: Tetrahedron Letters, Vol. 35, No. 27, pp 4689-4692, 1994 Non-Patent Document 3: Heterocycles, Vol.32, No.l, 1991
非特許文献 4 :J. Org. Chem. 1991, 56, 3183-3187 非特許文献 5 : Bioorganic & Medicinal Chemistry Letters, Vol.3, No.12, pp.2559- 25 64, 1993 Non-Patent Document 4: J. Org. Chem. 1991, 56, 3183-3187 Non-Patent Document 5: Bioorganic & Medicinal Chemistry Letters, Vol.3, No.12, pp.2559- 25 64, 1993
発明の開示 Disclosure of the invention
発明が解決しょうとする課題 Problems to be solved by the invention
[0003] モノアリルマロネートマグネシウム塩を医薬原料として効率よく使用するためには、 取り扱い性や純度等に優れた高品質の結晶が求められていた。 [0003] In order to efficiently use monoallyl malonate magnesium salt as a pharmaceutical raw material, high-quality crystals excellent in handleability and purity have been demanded.
課題を解決するための手段 Means for solving the problem
[0004] 本発明者らは、モノアリルマロネートマグネシウム塩を溶媒和物、好ましくは水和物 に変換すれば結晶化することを見出し、以下の発明を完成した。 [0004] The present inventors have found that the monoallyl malonate magnesium salt crystallizes when converted to a solvate, preferably a hydrate, and have completed the following invention.
(1)式： (1 set:
[化 2]
(式中、 Allylはァリル基を示す)で示されるモノアリルマロネートマグネシウム塩の結晶 (Wherein Allyl represents an aryl group) crystals of monoallyl malonate magnesium salt
(2)溶媒和物結晶である、上記（1)記載の結晶。 (2) The crystal according to (1) above, which is a solvate crystal.
(3)水和物結晶である、上記（1)記載の結晶。 (3) The crystal according to (1) above, which is a hydrate crystal.
(4) 2水和物結晶である、上記（1)記載の結晶。 (4) The crystal according to (1) above, which is a dihydrate crystal.
(5)粉末 X線回折ノターン【こお!ヽて、回折角（2 0 ) = 5. 5、 16. 7、 22. 0、 33. 8 ( 単位:度）に主ピークを示す、上記（1)〜 (4)のいずれか〖こ記載の結晶。 (5) Powder X-ray diffraction pattern [Oh! Hear, diffraction angle (2 0) = 5.5, 16. 7, 22. 0, 33.8 (unit: degree), showing the main peak above ( The crystal according to any one of 1) to (4).
(6)式： Equation (6):
[化 3]
(7)上記（1)〜（6)記載の化合物 (I)の結晶または水和物を用いる工程を包含する（ + )— (4R, 5S, 6S)— 6— [ (1R)— 1—ハイド口キシェチル] 4—メチル 7—ォ キソ 3— [ [ (3S, 5S)— 5— [ (スルファモイルァミノ）メチル] 3—ピロリジ -ル]チ ォ ] 1ーァザビシクロ [3. 2. 0]ヘプトー 2 ェンー2—力ルボン酸、その製薬上許 容される塩、または溶媒和物の製造方法。 (7) Includes a step of using a crystal or hydrate of compound (I) described in (1) to (6) above (+) — (4R, 5S, 6S) — 6— [(1R) — 1— Hyde Mouth Kichetil] 4-Methyl 7-oxo 3-— [[(3S, 5S) -5-[(Sulphamoylamino) methyl] 3-pyrrolidyl-thio] 1-azabicyclo [3. 2. 0 ] Heptoe-2-en-2-a method for producing strong rubonic acid, pharmaceutically acceptable salts or solvates thereof.
発明の効果 The invention's effect
[0005] 本発明のモノアリルマロネートマグネシウム塩の結晶または水和物は、取り扱い性 や純度等に優れており、医薬原料として有用である。 [0005] The monoallyl malonate magnesium salt crystal or hydrate of the present invention is excellent in handleability, purity, etc., and is useful as a pharmaceutical raw material.
図面の簡単な説明 Brief Description of Drawings
[0006] [図 1]実施例 1で得られた結晶の粉末 X線回折パターンを図 1に示す。 [0006] FIG. 1 shows the powder X-ray diffraction pattern of the crystals obtained in Example 1.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 溶媒和物の溶媒としては、水、アルコール (好ましくは C1〜C10アルコール、例：メ タノ一ノレ、エタノーノレ、イソプロパノーノレ、 2—プロパノーノレ、 2—ペンタノ一ノレ、 1ーぺ ンタノール、 tーァミルアルコール、 1 プロパノール、ベンジルアルコール）が例示さ れるが、好ましくは水である。 [0007] Solvents for the solvate include water, alcohols (preferably C1-C10 alcohols, eg, methanolol, ethanol, isopropanol, 2-propanol, 2-pentanol, 1-pentanol. , Tamyl alcohol, 1 propanol, benzyl alcohol), with water being preferred.
水和物またはその結晶の水和数としては、 1〜4が例示される力 好ましくは 2であ る。 The hydration number of the hydrate or its crystal is a force exemplified by 1 to 4, preferably 2.
モノアリルマロネートマグネシウム塩の結晶は、好ましくは溶媒和物結晶、より好まし くは水和物結晶、例えば 2水和物結晶である。 2水和物結晶は、好ましくは X線粉末 回折ノターン【こお ヽて、回折角 2 0 = 5. 5、 16. 7、 22. 0、 33. 8 (単位:角度）等【こ 相対強度の強!、ピークを示す (X線回折測定条件：管球 CuK a線、管電圧 40Kv、 管電流 30mA、 dsin Q =η λ (ηは整数、 Θは回折角）。より詳細には、図 1に示され るパターンを示す。 The crystals of monoallyl malonate magnesium salt are preferably solvate crystals, more preferably hydrate crystals, such as dihydrate crystals. The dihydrate crystal is preferably an X-ray powder diffraction pattern, where the diffraction angle 2 0 = 5.5, 16. 7, 22. 0, 33.8 (unit: angle) etc. Shows a peak (X-ray diffraction measurement conditions: tube CuK a line, tube voltage 40 Kv, tube current 30 mA, dsin Q = η λ (η is an integer, Θ is the diffraction angle). The pattern shown in 1 is shown.
なお一般に結晶を X線解析により測定した場合、そのピークは、測定機器、測定条 件、付着溶媒の存在等により、多少の測定誤差を生じることもある。例えば、面間隔 dの値として ±0.2程度の測定誤差が生じる場合があり、非常に精密な設備を使用し た場合でも、 ±0.01〜士 0.1程度の測定誤差が生じる場合がある。よって、結晶構造 の同定に当たっては多少の誤差も考慮されるべきであり、実質的に上記と同様の X 線パターンによって特徴付けられる結晶はすべて本発明の範囲内である。 In general, when the crystal is measured by X-ray analysis, the peak may cause some measurement error due to the measuring equipment, measurement conditions, presence of the attached solvent, etc. For example, a measurement error of about ± 0.2 may occur as the value of the surface separation d, and very precise equipment is used. Even in the case of measurement, there may be a measurement error of ± 0.01 to 0.1. Therefore, some errors should be taken into account in identifying the crystal structure, and all crystals characterized by X-ray patterns substantially similar to the above are within the scope of the present invention.
本発明の結晶または水和物の製法を以下に例示する。 The method for producing the crystal or hydrate of the present invention is exemplified below.
(方法 1) (Method 1)
モノアリルマロネートマグネシウム塩を溶媒 Aに溶解し、溶媒 Bをカ卩えることにより、 モノアリルマロネートマグネシウム塩の溶媒和物結晶を得る。当該結晶は好ましくは、 溶媒 Bを含有する。 A solvate crystal of monoallyl malonate magnesium salt is obtained by dissolving monoallyl malonate magnesium salt in solvent A and covering solvent B. The crystals preferably contain solvent B.
溶媒 Aとしては、メタノール、エタノール、エチレングリコール、メトキシエタノール、グ リセリン、プロピレングリコールなどのアルコール類、ジォキサン、テトラヒドロフラン (T HF)、ジメトキシェタンなどのエーテル類、アセトン、メチルェチルケトン、メチルイソ ブチルケトンなどのケトン類、メチルフオルメート、ェチルフオルメート、プロピルフオル メート、メチルアセテート、酢酸ェチル、プロピルアセテート、ブチルアセテート、メチ ルプロピオネート、ェチルプロピオネートなどのエステル類、ジクロロメタン、クロロホ ルム、四塩化炭素、 1, 2—ジクロロェタン、トリクロロェタン、クロ口ベンゼン、ジクロロ ベンゼンなどの有機ハロゲンィ匕炭化水素類、ァセトニトリル、プロピオ-トリルなどの- トリル類、ジメチルフオルムアミド、ジメチルスルホキサイド、 N—メチルピロリドン、キノ リン、ピリジン類、トリェチルァミン、水またはこれらの混合溶媒を使用できる。好ましく は、モノアリルマロネートマグネシウム塩の溶媒和物結晶の溶解性が低 、溶媒である 。例えば、水和物結晶を得たい場合には、溶媒 Aとして有機溶媒 (例:アセトン）が好 ましい。 Solvent A includes alcohols such as methanol, ethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol, ethers such as dioxane, tetrahydrofuran (THF), and dimethoxyethane, acetone, methyl ethyl ketone, and methyl isobutyl ketone. Ketones such as methyl ester, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, dichloromethane, chloroform, tetra Organic halogenated hydrocarbons such as carbon chloride, 1,2-dichloroethane, trichloroethane, black benzene, dichlorobenzene, tolyls such as acetonitrile and propio-tolyl, dimethyl Fuorumuamido, dimethyl sulfoxide, N- methylpyrrolidone, quinoline, pyridines, Toryechiruamin, water or a mixed solvent thereof can be used. Preferably, the solvate crystal of monoallyl malonate magnesium salt has low solubility and is a solvent. For example, when a hydrate crystal is desired, an organic solvent (eg, acetone) is preferable as the solvent A.
溶媒 Bとしては、好ましくはモノアリルマロネートマグネシウム塩と溶媒和物を形成し 得る溶媒であり、例えば水が例示される。例えば水和物結晶を晶析させたい場合、 溶媒 Bとしての水の添力卩量は重要であり、好ましくは、モノアリルマロネートマグネシゥ ム塩 lg当たり、 0. 05〜： Lml、好ましくは 0. 1〜0. 5ml力 ^添カロされる。 The solvent B is preferably a solvent capable of forming a solvate with a monoallyl malonate magnesium salt, and water is exemplified. For example, when it is desired to crystallize hydrate crystals, the amount of water added as the solvent B is important, and preferably 0.05 to Lml per lg of monoallyl malonate magnesium salt, preferably 0.1 to 0.5ml force
溶媒 Aと溶媒 Bとの使用割合は、重量比で通常 1 : 0. 001〜1 : 1、好ましくは 1 : 0. 005〜1 : 0. 5、特に好ましくは 1 : 0. 01〜1 : 0. 05である。好ましくは、溶媒 Aとして 酢酸ェチル、アセトン、 THF、溶媒 Bとして水が使用される。 本発明の結晶または水和物は、モノアリルマロネートを出発原料にして以下の方法 により得ることちでさる。 The use ratio of the solvent A and the solvent B is usually 1: 0.001 to 1: 1, preferably 1: 0.005 to 1: 0.5, particularly preferably 1: 0.01 to 1: 0. 05. Preferably, ethyl acetate, acetone, THF as solvent A and water as solvent B are used. The crystal or hydrate of the present invention can be obtained by the following method using monoallyl malonate as a starting material.
(A法） (Method A)
モノアリルマロネート（HOOC— CH -CO Allyl)を溶媒（例：酢酸ェチル、アセトン、 Monoallyl malonate (HOOC—CH 2 —CO Allyl) as a solvent (eg ethyl acetate, acetone,
2 2 twenty two
THF)に溶解後、マグネシウムアルコキサイド（例： Mg(OMe) , Mg(OEt) )を添カロした After dissolving in THF), magnesium alkoxide (eg Mg (OMe), Mg (OEt)) was added.
2 2 twenty two
後、溶媒 (例：水）を加えることにより、モノアリルマロネートマグネシウム塩の溶媒和物 結晶（例：水和物結晶）を得る。マグネシウムアルコキサイドの使用量は、モノアリルマ 口ネートに対して、通常 0. 45〜0. 55当量、好ましく ίま 0. 50当量である。 Thereafter, a solvent (eg, water) is added to obtain a solvate crystal (eg, hydrate crystal) of monoallyl malonate magnesium salt. The amount of magnesium alkoxide used is usually 0.45 to 0.55 equivalent, preferably 0.50 equivalent to monoallyl maleate.
(Β法） (Β 法)
モノアリルマロネートに水酸化アルカリ金属（例： LiOH、 KOH、 NaOH)またはアンモ ユア水をカ卩えた後、ハロゲン化マグネシウム（例： MgCl MgBr )の水溶液を加えること After adding alkali metal hydroxide (eg LiOH, KOH, NaOH) or ammonia water to monoallyl malonate, add an aqueous solution of magnesium halide (eg MgCl MgBr).
2、 2 twenty two
により、モノアリルマロネートマグネシウム塩の溶媒和物結晶（好ましくは水和物結晶） を得る。水酸ィ匕アルカリ金属またはアンモニアの使用量は、モノアリルマロネートに対 して、通常 0. 45〜0. 55当量、好ましくは 0. 50当量である。 To obtain solvate crystals (preferably hydrate crystals) of monoallyl malonate magnesium salt. The amount of hydroxide or alkali metal or ammonia to be used is generally 0.45 to 0.55 equivalent, preferably 0.50 equivalent, relative to monoallyl malonate.
(C法） (C method)
モノアリルマロネートに、水および酸化マグネシウム（MgO)をカ卩えた後、反応溶液を 濃縮し、溶媒、好ましくは水と共沸し得る有機溶媒 (例：トルエン)を加えることにより、 モノアリルマロネートマグネシウム塩の溶媒和物結晶（例：水和物結晶）を得る。酸ィ匕 マグネシウムの使用量は、モノアリルマロネートに対して、通常 0. 45〜0. 55当量、 好ましくは 0. 50当量である。 After adding water and magnesium oxide (MgO) to monoallyl malonate, the reaction solution is concentrated, and a solvent, preferably an organic solvent that can be azeotroped with water (eg, toluene) is added. A solvate crystal (eg, hydrate crystal) of a nate magnesium salt is obtained. The amount of magnesium oxide used is usually 0.45 to 0.55 equivalent, preferably 0.50 equivalent, relative to monoallyl malonate.
上記 A〜C法を以下に例示する。 X、 Y、 Ζはそれぞれ独立して整数 (例： 1〜4)。 The above A to C methods are exemplified below. X, Y and Ζ are each independently an integer (eg 1 to 4).
[化 4] 02Allyl[Chemical 4] 0 2 Allyl
02ナ Mg X H20
,C02Allyl KOHaq , C0 2 Allyl KOHaq
C02Allyl MgCI2 aq ,C02AllylC0 2 Allyl MgCI 2 aq, C0 2 Allyl
< < <<
'C02H CO2 K 'C02ナ Mg Y H2〇 'C0 2 H CO 2 K' C0 2 Na Mg YH 2 ○
K= Li, Na, NH4, etc K = Li, Na, NH 4 , etc
,C02Allyl , C0 2 Allyl
C < C <
、C02H Z H20
上記各方法において、所望により種晶を添加してもよい。また結晶化に適切な温度 は、約 10〜約 40°Cであり、好ましくは 0〜30°Cである。 このようにして得られる結 晶は、次いで、通常の分離、精製手段 (例:濾過、遠心分離、乾燥)に付すことにより 単離することができる。 In each of the above methods, seed crystals may be added as desired. The temperature suitable for crystallization is about 10 to about 40 ° C, preferably 0 to 30 ° C. The crystals thus obtained can then be isolated by subjecting them to conventional separation and purification means (eg filtration, centrifugation, drying).
本発明のモノアリルマロネートマグネシウム塩の結晶または水和物は、以下に例示 されるように、例えばジァゾィ匕法を利用した力ルバぺネム系抗菌薬 (例：ドリぺネム； ( + )— (4R, 5S, 6S)— 6— [ (1R)— 1—ハイド口キシェチル] 4—メチル 7—ォ キソ 3— [ [ (3S, 5S)— 5— [ (スルファモイルァミノ）メチル] 3—ピロリジ -ル]チ ォ ] 1ーァザビシクロ [3. 2. 0]ヘプトー 2 ェン 2—力ルボン酸）の製法における 原料として有用である。特に最終工程の脱保護反応は、カルボキシ保護基として PN B (： p -トロベンジル)等を使用する場合よりも Allyl (：ァリル)を使用する方が高収 率である。また PNBの場合、脱保護反応で生じる副生物を除去するために多量の溶 媒を必要とするが、 Allylの場合にはその溶媒使用量も削減できる。よって、本発明結 晶の使用は、工業的製法として非常に有用である。 The monoallyl malonate magnesium salt crystal or hydrate of the present invention can be obtained by, for example, a powerful rubapenem antibacterial agent (for example, doripenem; (+) — (4R, 5S, 6S) — 6— [(1R) — 1-Hide mouth kichetil] 4-methyl 7-oxo 3— [[(3S, 5S) — 5— [(sulfamoylamino) methyl] 3-pyrrolidyl-thio] 1-azabicyclo [3.2.0] hepto-2-en-2-strong rubonic acid) is useful as a raw material. In particular, in the deprotection reaction in the final step, higher yield is obtained when Allyl (: aryl) is used than when PNB (: p-trobenzyl) is used as the carboxy protecting group. In the case of PNB, a large amount of solvent is required to remove by-products generated in the deprotection reaction. In the case of Allyl, the amount of solvent used can be reduced. Therefore, the use of the crystal of the present invention is very useful as an industrial production method.
[化 5]
(式中、 TBS=t—ブチルジメチルシリル， Ph=フエニル， Alloc = C〇2Allyl) (In the formula, TBS = t-butyldimethylsilyl, Ph = phenyl, Alloc = C0 2 Allyl)
以下に実施例を示す。 Examples are shown below.
実施例 1 Example 1
[化 6] [Chemical 6]
C02Allyl Mg (OEt)2 xC02Allyl C02Allyl C0 2 Allyl Mg (OEt) 2 x C0 2 Allyl C0 2 Allyl
C02H 3 (oil) 、C02十 Mg •C〇2十 Mg 2H20 濃縮 C0 2 H 3 (oil), C0 2 tens Mg • C_〇 2 tens Mg 2H 2 0 concentrated
;C02Allyl
C02ナ Mg 4 (foam) モノアリルマロネート (3) 1.49gを THF 15mlに溶解し、マグネシウムェトキサイド 595m gを加え、室温で 8時間撹拌する。その後 THFを減圧留去し、泡状のモノァリルマロネ ートマグネシウム塩 (4) 1.78gを得た。該モノアリルマロネートマグネシウム塩 500mgを アセトン 7.5mlに溶解し、そこへ水 0.14mlを滴下したところ、結晶が析出した。そのま ま室温で 2h撹拌後、ろ過 ·乾燥を行い、二水和物の結晶 396.6mgを得た。 C0 2 Na Mg 4 (foam) Monoallyl malonate (3) 1.49 g of THF is dissolved in 15 ml of THF, 595 mg of magnesium ethoxide is added, and the mixture is stirred at room temperature for 8 hours. After that, THF was distilled off under reduced pressure to give foamy monoarylmalone. 1.78 g of magnesium salt (4) was obtained. When 500 mg of the monoallyl malonate magnesium salt was dissolved in 7.5 ml of acetone and 0.14 ml of water was added dropwise thereto, crystals were precipitated. The mixture was stirred at room temperature for 2 hours, filtered and dried to obtain 396.6 mg of dihydrate crystals.
元素分析 for C H MgO · 2H O Elemental analysis for C H MgO 2H O
12 14 8 2 12 14 8 2
理論値： C 41.59; H 5.23; O 46.16; Mg 7.01 Theoretical value: C 41.59; H 5.23; O 46.16; Mg 7.01
測定値: C 41.16; H 5.12 (O原子と Mg原子は未測定） Measurements: C 41.16; H 5.12 (O and Mg atoms not measured)
水分含量 (KF法）： 10.97 % Moisture content (KF method): 10.97%
粉末 X線回折パターン：図 1 Powder X-ray diffraction pattern: Fig. 1
[0011] 実施例 2 [0011] Example 2
[化 7] [Chemical 7]
1 ) seed 1) seed
,C02Allyl Mg (OEt)2 C02Allyl 2) H20 , C0 2 Allyl Mg (OEt) 2 C0 2 Allyl 2) H 2 0
< .C02Allyl <.C0 2 Allyl
、C02H 3 (oil) C02-)- g 4 'C02ナ Mg モノアリルマロネート (3) 14.9gを酢酸ェチル 150mlに溶解後、 Mg(OEt) 5.9gを投入 , C0 2 H 3 (oil) C0 2 -)-g 4 'C0 2 Na Mg monoallyl malonate (3) Dissolve 14.9g in 150ml ethyl acetate, then add 5.9g Mg (OEt)
2 し、室温で 8h撹拌した。その後、実施例 1で得られた結晶 5mgを種晶として添加、つ いで水 4.18mlを滴下して 3h撹拌を行った。その後、ろ過 '乾燥を行い、実施例 1と同 一の二水和物の結晶を 16.9g得た。 And stirred at room temperature for 8 h. Thereafter, 5 mg of the crystals obtained in Example 1 were added as seed crystals, and then 4.18 ml of water was added dropwise and stirred for 3 hours. Thereafter, filtration and drying were performed to obtain 16.9 g of the same dihydrate crystal as in Example 1.
実施例 3 Example 3
[化 8] [Chemical 8]
,002Allyl, 00 2 Allyl
.CO^IIy I MgO ,C02Al lyl 濃縮 ぐ .CO ^ IIy I MgO, C0 2 Al lyl concentrate
< < '002 <<'00 2
'C02-)-Mg ナ Mg 'C02H 3 (oil) 'C0 2 -)-Mg Na Mg' C0 2 H 3 (oil)
H20 i) Acetone モノアリルマロネート (3) 2.0gをアセトン 10mlに溶解後、 MgO 278mgを投入し、次い で水 10mlを注加し室温で 5h撹拌した。その後、 45°Cで水、アセトンを濃縮して結晶を 析出させ、アセトン 10 mlを加え熟成させた。その後、ろ過 ·乾燥を行い、実施例 1と同 一の二水和物の結晶を 1.9g得た。 H 20 i) Acetone monoallyl malonate (3) After dissolving 2.0 g of acetone in 10 ml of acetone, 278 mg of MgO was added, then 10 ml of water was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, water and acetone were concentrated at 45 ° C to precipitate crystals, and 10 ml of acetone was added and aged. Thereafter, filtration and drying were carried out to obtain 1.9 g of the same dihydrate crystal as in Example 1.
産業上の利用可能性 Industrial applicability
[0012] 本発明のモノアリルマロネートマグネシウム塩の結晶は、医薬原料として有用である The monoallyl malonate magnesium salt crystal of the present invention is useful as a pharmaceutical raw material.
60£/900Ζάΐ/13ά 6 ^60ΪΖΪ/900Ζ OAV 60 £ / 900Ζάΐ / 13ά 6 ^ 60ΪΖΪ / 900Ζ OAV
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005-140895 | 2005-05-13 | ||
| JP2005140895A JP2008214192A (en) | 2005-05-13 | 2005-05-13 | Crystal of magnesium salt of monoallyl malonate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006121094A1 true WO2006121094A1 (en) | 2006-11-16 |
Family
ID=37396602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2006/309444 Ceased WO2006121094A1 (en) | 2005-05-13 | 2006-05-11 | Crystal or dydrate of magnesium salt of monoallyl malonate |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2008214192A (en) |
| TW (1) | TW200720248A (en) |
| WO (1) | WO2006121094A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4870199A (en) * | 1986-04-30 | 1989-09-26 | Sandoz Pharm. Corp. | Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters |
| WO2004035540A1 (en) * | 2002-10-18 | 2004-04-29 | Meiji Seika Kaisha, Ltd. | Malonic acid monoesters and process for producing the same |
-
2005
- 2005-05-13 JP JP2005140895A patent/JP2008214192A/en active Pending
-
2006
- 2006-05-11 WO PCT/JP2006/309444 patent/WO2006121094A1/en not_active Ceased
- 2006-05-12 TW TW095116811A patent/TW200720248A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4870199A (en) * | 1986-04-30 | 1989-09-26 | Sandoz Pharm. Corp. | Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters |
| WO2004035540A1 (en) * | 2002-10-18 | 2004-04-29 | Meiji Seika Kaisha, Ltd. | Malonic acid monoesters and process for producing the same |
Non-Patent Citations (2)
| Title |
|---|
| MASTALERZ H. ET AL.: "The synthesis of a 6-carbamoyl-substituted carbapenem", HETEROCYCLES, vol. 32, no. 1, 1991, pages 93 - 98, XP008072503 * |
| RUEDIGER E.H. ET AL.: "Novel conversion of a 3-(1-hydroxyethyl)azetidinone to a 3-(hydroxymethyl)azetidinone: a synthesis of 6-(hydroxymethyl)-1beta-methylcarbapenem", JOURNAL OF ORGANIC CHEMISTRY, vol. 56, no. 9, 1991, pages 3183 - 3187, XP003002195 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2008214192A (en) | 2008-09-18 |
| TW200720248A (en) | 2007-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20170226114A1 (en) | Solid state forms of ibrutinib | |
| WO2011158248A2 (en) | Process for preparation of posaconazole and crystalline polymorphic form v of posaconazole | |
| WO2019026014A1 (en) | Processes for preparation of lifitegrast and intermediates thereof | |
| WO2018007927A1 (en) | Process for preparation of palbociclib | |
| EP2539321A1 (en) | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof | |
| US9708343B2 (en) | Process for preparing rifaximin κ | |
| EP3565819B1 (en) | Solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
| WO2009075516A2 (en) | Process for preparing pantoprazole sodium sesquihydrate | |
| KR101640504B1 (en) | Novel process of Entecavir monohydrate | |
| JP4530287B2 (en) | Oxacephem crystals | |
| WO2006121094A1 (en) | Crystal or dydrate of magnesium salt of monoallyl malonate | |
| CN108101934B (en) | Process for the preparation of trabectedin and intermediates thereof | |
| US20200339588A1 (en) | Novel polymorphs of ribociclib mono succinate | |
| JP3884063B2 (en) | Cefcapene pivoxil methanesulfonate | |
| US20180273490A1 (en) | Process for the Preparation of Eltrombopag Olamine | |
| JPH083170A (en) | Purification of cephalosporin salt | |
| JP5019389B2 (en) | Preparation of carbapenem derivatives and their intermediate crystals | |
| JP6462143B2 (en) | Solid crystalline form 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanenitrile | |
| EP1598347A1 (en) | Polymorphs of pantoprazole sodium salt and process for the preparation thereof | |
| CA3048771C (en) | Solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
| KR101640503B1 (en) | Improved process for the preparation of entecavir Monohydrate | |
| JPH08239381A (en) | Stable solvate of benzimidazole derivative metal salt, process for producing the same, and antiulcer agent containing the same | |
| WO2015186139A2 (en) | Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same | |
| WO2022081502A1 (en) | Solid state forms of lorecivivint | |
| JP2010526126A (en) | Method for producing valsartan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| NENP | Non-entry into the national phase |
Ref country code: RU |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 06746253 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: JP |