JP5206926B2 - Method for producing imidapril hydrochloride - Google Patents
Method for producing imidapril hydrochloride Download PDFInfo
- Publication number
- JP5206926B2 JP5206926B2 JP2007198156A JP2007198156A JP5206926B2 JP 5206926 B2 JP5206926 B2 JP 5206926B2 JP 2007198156 A JP2007198156 A JP 2007198156A JP 2007198156 A JP2007198156 A JP 2007198156A JP 5206926 B2 JP5206926 B2 JP 5206926B2
- Authority
- JP
- Japan
- Prior art keywords
- imidapril hydrochloride
- imidapril
- acetate
- hydrochloride
- producing
- 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.)
- Expired - Fee Related
Links
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 title claims description 40
- 229960003409 imidapril hydrochloride Drugs 0.000 title claims description 36
- 238000004519 manufacturing process Methods 0.000 title claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- -1 acetate ester Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 150000001298 alcohols Chemical class 0.000 description 6
- 150000005690 diesters Chemical class 0.000 description 6
- VFAVNRVDTAPBNR-UBHSHLNASA-N imidaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)C(O)=O)CC1=CC=CC=C1 VFAVNRVDTAPBNR-UBHSHLNASA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 229960001195 imidapril Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000004492 methyl ester group Chemical group 0.000 description 2
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、塩酸イミダプリルの効率的な製造方法に関する物である。 The present invention relates to an efficient method for producing imidapril hydrochloride.
塩酸イミダプリルは高血圧症治療薬であり、長期に渡り投与される内服薬であることから、不純物の少ない原薬を製造、提供する必要がある。
塩酸イミダプリルを製造する過程において、生成する不純物としては、加水分解物であるイミダプリラート 式（３）、ジエステル体 一般式（４）などの塩酸イミダプリル若しくはその前駆体から変換された不純物等がある。
医薬品として利用するためには、これらの不純物等を効率よく除去する必要がある。 塩酸イミダプリルの製造方法としては、エタノールと酢酸エチルの混合液から再結晶する製造方法が知られている。（特許文献.1）
また、エタノールに溶解して濾過した後に酢酸エチルを添加して晶析，濾過した後、濾過した結晶を水で溶解し、冷却後に薄めた塩酸水を添加することにより再結晶する製造方法が知られている。（非特許文献.1）
In the process of producing imidapril hydrochloride, the impurities produced include impurities converted from imidapril hydrochloride such as imidaprilate formula (3) and diester general formula (4) which are hydrolysates or precursors thereof.
In order to use it as a medicine, it is necessary to remove these impurities and the like efficiently. As a method for producing imidapril hydrochloride, a production method in which recrystallization is performed from a mixed solution of ethanol and ethyl acetate is known. (Patent Document 1)
Also known is a production method in which ethyl acetate is added to crystallize and filter after dissolving in ethanol and filtered, and then the crystal is filtered and then recrystallized by adding diluted hydrochloric acid after cooling. It has been. (Non-patent document 1)
エタノールと酢酸エチルから再結晶させる方法では、塩酸イミダプリル結晶を溶解するために、１０倍容量のエタノールを必要とし、このエタノール溶液に３０倍容量の酢酸エチルを加えて晶析させなければならず、工業的製法として利用するには非常に効率が悪い。また、容積効率を上げるために、溶媒量を減量すると、エタノールに加温溶解する際にイミダプリルのカルボキシル基とエタノールが反応してジエチルエステル体が生成し、純度低下を招くという問題点があった。 In the method of recrystallization from ethanol and ethyl acetate, 10 times volume of ethanol is required to dissolve imidapril hydrochloride crystals, and 30 times volume of ethyl acetate must be added to this ethanol solution for crystallization. It is very inefficient to use as an industrial process. In addition, when the amount of the solvent is reduced in order to increase the volumetric efficiency, there is a problem that the carboxyl group of imidapril reacts with ethanol when it is dissolved in ethanol, and a diethyl ester form is generated, resulting in a decrease in purity. .
水溶媒での再結晶では、溶解時の加熱により塩酸イミダプリルが加水分解して不純物であるイミダプリラートが生成し、純度低下を招くという問題点があった。このため、工業生産規模で効率的に高純度の塩酸イミダプリルを得る製造方法が求められていた。 In recrystallization with an aqueous solvent, there is a problem that imidapril hydrochloride is hydrolyzed by heating at the time of dissolution to produce imidaprilate as an impurity, resulting in a decrease in purity. For this reason, the manufacturing method which obtains highly purified imidapril hydrochloride efficiently on an industrial production scale was calculated | required.
本発明の目的は、工業生産規模で効率的に高純度の塩酸イミダプリルを得る製造方法を提供する事にある。 An object of the present invention is to provide a production method for efficiently obtaining high-purity imidapril on an industrial production scale.
本発明者等は、上記目的を達成すべく鋭意検討した結果、塩酸イミダプリルを含水していてもよいアルコール類と酢酸エステル類の混合液で処理することにより、医薬品としては充分な純度の塩酸イミダプリルを得られることを見出し、本発明を完成するに至った。
本発明の製造方法は、生産効率も良好で且つ高収率、高純度で目的物が得られるため産業上の利用価値が極めて高い。
As a result of diligent studies to achieve the above-mentioned object, the present inventors have treated imidapril hydrochloride with sufficient purity as a pharmaceutical product by treating it with a mixture of alcohols and acetates which may contain water. The present invention was completed.
The production method of the present invention has a very high industrial utility value because the target product is obtained with good production efficiency and high yield and high purity.
すなわち、本発明は（１）
式１で表される塩酸イミダプリルを、含水していてもよいアルコール類と一般式２に示す酢酸エステル類の混合液で処理することを特徴とする塩酸イミダプリルの製造方法。
A process for producing imidapril hydrochloride, comprising treating imidapril hydrochloride represented by formula 1 with a mixture of alcohols optionally containing water and an acetate ester represented by general formula 2.
本発明の製造方法によると、工業生産規模で効率的に高純度の塩酸イミダプリルの製造が可能となる。 According to the production method of the present invention, high-purity imidapril hydrochloride can be efficiently produced on an industrial production scale.
以下に本発明の製造方法を詳細に説明する。本発明に使用されるアルコール類は、メタノール、エタノール、１−プロパノールまたは２−プロパノールであり、特に好ましくはメタノールまたは２−プロパノールである。これらのアルコール類には水が含まれていてもよい。 The production method of the present invention will be described in detail below. Alcohols used in the present invention are methanol, ethanol, 1-propanol or 2-propanol, particularly preferably methanol or 2-propanol. These alcohols may contain water.
本発明に使用される酢酸エステル類は酢酸プロピル、酢酸ブチル、酢酸ペンチルであり、特に好ましくは酢酸イソプロピル、酢酸n-ブチル、酢酸イソブチルである。これらの溶媒は、ジエステル体が生成し難い点で酢酸エチルを使用した製造法よりも優れており、また、容積効率を向上させるという利点も持ち合わせている。 Acetic acid esters used in the present invention are propyl acetate, butyl acetate and pentyl acetate, and particularly preferably isopropyl acetate, n-butyl acetate and isobutyl acetate. These solvents are superior to the production method using ethyl acetate in that diesters are hardly formed, and also have the advantage of improving volumetric efficiency.
本発明において、含水していてもよいアルコール類の使用量は塩酸イミダプリルに対して２〜５倍容量、好ましくは２〜３倍容量の範囲である。２倍容量未満では塩酸イミダプリルを溶解するために高温を必要とし、その際にジエステル体が生成してしまうため好ましくなく、５倍容量を超えると収率を低下させてしまうため好ましくない。 In the present invention, the amount of alcohol that may be hydrated is 2 to 5 times, preferably 2 to 3 times the volume of imidapril hydrochloride. If the volume is less than 2 times, a high temperature is required to dissolve imidapril hydrochloride, and a diester is formed at that time, and if it exceeds 5 volumes, the yield is reduced, which is not preferable.
本発明において、酢酸エステル類の使用量は塩酸イミダプリルに対して３〜１０倍容量、好ましくは５〜７倍容量の範囲である。３倍容量未満では収率の低下を招くため好ましくなく、１０倍容量を超えると工業生産として用いるには効率が悪く好ましくない。 In the present invention, the amount of acetate used is 3 to 10 times, preferably 5 to 7 times the volume of imidapril hydrochloride. If it is less than 3 times the capacity, it is not preferable because the yield is lowered.
本発明において、塩酸イミダプリルのアルコール類への溶解時間は２時間以内、好ましくは３０分〜１時間の範囲である。アルコール類への溶解時間が２時間を越えるとジエステル体が生成し、含水アルコール類への溶解時間が２時間を越えるとジエステル体および加水分解物であるイミダプリラートが生成し、純度の低下を招く事になる。 In the present invention, the dissolution time of imidapril hydrochloride in alcohol is within 2 hours, preferably in the range of 30 minutes to 1 hour. If the dissolution time in alcohol exceeds 2 hours, a diester form is formed. If the dissolution time in hydrous alcohol exceeds 2 hours, imidaprilate which is a diester form and a hydrolyzate is formed, resulting in a decrease in purity. become.
本発明において、塩酸イミダプリルのアルコール類または含水アルコール類への溶解温度は５０℃以下、好ましくは３０〜４０℃の範囲である。５０℃を越えるとジエステル体および加水分解物であるイミダプリラートの生成速度が増し、純度の低下を招くことになる。 In the present invention, the dissolution temperature of imidapril hydrochloride in alcohols or hydrous alcohols is 50 ° C. or lower, preferably 30 to 40 ° C. If it exceeds 50 ° C., the production rate of imidaprilate which is a diester and a hydrolyzate increases, leading to a decrease in purity.
このように処理された塩酸イミダプリルは、処理液から濾過することによって単離することができる。 The imidapril hydrochloride thus treated can be isolated by filtering from the treatment solution.
以下、実施例によって本発明を具体的に説明するが、本発明は、これらの実施例に限定されるものではない。
実施例における液体クロマトグラフィー純度は、下記条件にて液体クロマトグラフィー分析を行い、各成分ピークの面積％を用いたものであり純度の指標とした。
装置：SIMAZU LC-2010CHT（島津製作）
カラム：内径4.6mm，長さ15cmのステンレス管に5μmの液体クロマトグラフィー用オクタ デシル化シリカゲルを充填する。
移動相：リン酸二水素カリウム1.36ｇを水1000mLに溶かし、リン酸を加えてpH2.7に調製する。この液600mLにメタノール400mLを加える。
流量：イミダプリルの保持時間が約8分になるよう調整する。
面積測定範囲：溶媒ピークの後からイミダプリルの保持時間の約3倍の範囲。
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.
The liquid chromatography purity in the examples was obtained by performing liquid chromatography analysis under the following conditions and using the area% of each component peak, and was used as an index of purity.
Equipment: SIMAZU LC-2010CHT (manufactured by Shimadzu)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm octadecylated silica gel for liquid chromatography.
Mobile phase: Dissolve 1.36 g of potassium dihydrogen phosphate in 1000 mL of water and add phosphoric acid to adjust to pH 2.7. Add 400 mL of methanol to 600 mL of this solution.
Flow rate: Adjust so that imidapril retention time is about 8 minutes.
Area measurement range: The range after the solvent peak is about 3 times the retention time of imidapril.
比較例１
エタノールと酢酸エチルによる再結晶
フラスコ内に塩酸イミダプリル（５ｇ，１１．３mmol，HPLC面積百分率：９９．９％）、エタノール（５０ｍL）を加え、８０℃で３０分間撹拌溶解し、冷却後、酢酸エチル（１５０ｍL）を加え、１０℃で２時間撹拌した後、析出した結晶を濾過、乾燥し、４．１ｇ（収率：８２％）の塩酸イミダプリルを得た。
得られた塩酸イミダプリルのHPLC面積百分率は９９．６％であり、エチルエステル体のHPLC面積百分率は０．３％であった。
Comparative Example 1
Into a recrystallization flask with ethanol and ethyl acetate, imidapril hydrochloride (5 g, 11.3 mmol, HPLC area percentage: 99.9%) and ethanol (50 mL) were added and dissolved by stirring at 80 ° C. for 30 minutes. After cooling, ethyl acetate was added. (150 mL) was added, and the mixture was stirred at 10 ° C. for 2 hours. The precipitated crystals were filtered and dried to obtain 4.1 g (yield: 82%) of imidapril hydrochloride.
The HPLC area percentage of the obtained imidapril hydrochloride was 99.6%, and the HPLC area percentage of the ethyl ester was 0.3%.
比較例２
水による再結晶
フラスコ内に塩酸イミダプリル（５ｇ，１１．３mmol，HPLC面積百分率：９９．９％）、水（２５ｍL）を加え、８０℃で３０分間撹拌溶解し、１０℃で２時間撹拌した後、析出した結晶を濾過、乾燥し、２．９ｇ（収率：５８％）の塩酸イミダプリルを得た。
得られた塩酸イミダプリルのHPLC面積百分率は９９．７％であり、イミダプリラートのHPLC面積百分率は０．２％であった。
Comparative Example 2
Imidapril hydrochloride (5 g, 11.3 mmol, HPLC area percentage: 99.9%) and water (25 mL) were added to the recrystallization flask with water, stirred and dissolved at 80 ° C. for 30 minutes, and stirred at 10 ° C. for 2 hours. The precipitated crystals were filtered and dried to obtain 2.9 g (yield: 58%) of imidapril hydrochloride.
The HPLC area percentage of the obtained imidapril hydrochloride was 99.7%, and the HPLC area percentage of imidaprilate was 0.2%.
実施例１
メタノールと酢酸イソプロピルによる再結晶
フラスコ内に塩酸イミダプリル（５ｇ，１１．３ｍmol，HPLC面積百分率：９９．６％）、メタノール（１１ｍL）を加え、４０℃で３０分間撹拌溶解し、冷却後酢酸イソプロピル（３５ｍL）を加え、１０℃で２時間撹拌した後、析出した結晶を濾過、乾燥し、４．３ｇ（収率：８６％）の塩酸イミダプリルを得た。
得られた塩酸イミダプリルのHPLC面積百分率は９９．９％であり、メチルエステル体は検出限界以下であった。
Example 1
Into a recrystallization flask with methanol and isopropyl acetate, imidapril hydrochloride (5 g, 11.3 mmol, HPLC area percentage: 99.6%) and methanol (11 mL) were added and dissolved by stirring at 40 ° C. for 30 minutes. After cooling, isopropyl acetate ( 35 mL) was added, and the mixture was stirred at 10 ° C. for 2 hours. The precipitated crystals were filtered and dried to obtain 4.3 g (yield: 86%) of imidapril hydrochloride.
The HPLC area percentage of the obtained imidapril hydrochloride was 99.9%, and the methyl ester form was below the detection limit.
実施例２
イソプロピルアルコール，水と酢酸イソプロピルによる再結晶
フラスコ内に塩酸イミダプリル（５ｇ，１１．３mmol，HPLC面積百分率：９９．６％）、イソプロピルアルコール/水=7/3(v/v)の混合液（１２．５ｍL）を加え、４０℃で３０分間撹拌溶解し、冷却後酢酸イソプロピル（３５ｍL）を加え、１０℃で２時間撹拌した後、析出した結晶を濾過、乾燥し、４．１ｇ（収率：８２％）の塩酸イミダプリルを得た。
得られた塩酸イミダプリルのHPLC面積百分率は９９．９％であり、イソプロピルエステル体およびイミダプリラートは検出限界以下であった。
Example 2
In a recrystallization flask with isopropyl alcohol, water and isopropyl acetate, a mixture of imidapril hydrochloride (5 g, 11.3 mmol, HPLC area percentage: 99.6%), isopropyl alcohol / water = 7/3 (v / v) (12 0.5 mL), and dissolved by stirring at 40 ° C. for 30 minutes. After cooling, isopropyl acetate (35 mL) was added, and the mixture was stirred at 10 ° C. for 2 hours. The precipitated crystals were filtered and dried, and 4.1 g (yield: 82%) of imidapril hydrochloride was obtained.
The HPLC area percentage of the obtained imidapril hydrochloride was 99.9%, and the isopropyl ester and imidaprilate were below the detection limit.
実施例３
メタノールと酢酸イソプロピルによるケンダク処理
フラスコ内に塩酸イミダプリル（５ｇ，１１．３mmol，HPLC面積百分率：９９．６％）、メタノール（１１mL）、酢酸イソプロピル（３５ｍL）を加え、４０℃で３０分間撹拌し、１０℃で２時間撹拌した後、結晶を濾過、乾燥し、４．２ｇ（収率：８４％）の塩酸イミダプリルを得た。
得られた塩酸イミダプリルのHPLC面積百分率は９９．９％であり、メチルエステル体は検出限界以下であった。
Example 3
Imidapril hydrochloride (5 g, 11.3 mmol, HPLC area percentage: 99.6%), methanol (11 mL), isopropyl acetate (35 mL) were added to a kendaku-treated flask with methanol and isopropyl acetate, and the mixture was stirred at 40 ° C. for 30 minutes. After stirring at 10 ° C. for 2 hours, the crystals were filtered and dried to obtain 4.2 g (yield: 84%) of imidapril hydrochloride.
The HPLC area percentage of the obtained imidapril hydrochloride was 99.9%, and the methyl ester form was below the detection limit.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007198156A JP5206926B2 (en) | 2007-07-30 | 2007-07-30 | Method for producing imidapril hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007198156A JP5206926B2 (en) | 2007-07-30 | 2007-07-30 | Method for producing imidapril hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2009029760A JP2009029760A (en) | 2009-02-12 |
| JP5206926B2 true JP5206926B2 (en) | 2013-06-12 |
Family
ID=40400672
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007198156A Expired - Fee Related JP5206926B2 (en) | 2007-07-30 | 2007-07-30 | Method for producing imidapril hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP5206926B2 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6058233B2 (en) * | 1982-05-24 | 1985-12-19 | 田辺製薬株式会社 | 2-oxoimidazolidine derivative and its production method |
-
2007
- 2007-07-30 JP JP2007198156A patent/JP5206926B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2009029760A (en) | 2009-02-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101959840A (en) | Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates | |
| CN103582622A (en) | Method for producing bicyclic compound via iminium salt | |
| JP5649909B2 (en) | Nafamostat mesylate crystallization method | |
| CN105541844B (en) | Simple preparation method of high-purity linagliptin | |
| CN105348262B (en) | A kind of improved method preparing dabigatran etcxilate | |
| US10538507B2 (en) | Preparation process for high-purity dabigatran etexilate | |
| JP4892915B2 (en) | Epalrestat manufacturing method | |
| JP4967659B2 (en) | Method for purifying L-carnitine | |
| JP5206926B2 (en) | Method for producing imidapril hydrochloride | |
| US20130041150A1 (en) | Process for the preparation of chiral beta amino carboxamide derivatives | |
| JP2008201740A (en) | Method for purifying edaravone and highly pure edaravone | |
| US8853395B2 (en) | Process for the preparation of lurasidone hydrochloride | |
| CN103183602B (en) | The crystallization method of 2,2-dipropyl propanedioic acid | |
| WO2011010579A1 (en) | Process for production of optically active nipecotamide | |
| JP5460209B2 (en) | Method for purifying 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide | |
| WO2024114710A1 (en) | Method for preparing cabozantinib and intermediate thereof | |
| CN106349145B (en) | A method of preparing nootropics (S)-Oxiracetam | |
| CN106631962B (en) | A kind of preparation method of (S)-oxiracetam | |
| CN101565379B (en) | The preparation method of L-homoserine hydrochloride | |
| JP5397706B2 (en) | Method for producing high purity 1-benzyl-3-aminopyrrolidine | |
| JP7498147B2 (en) | Method for Purifying Apixaban | |
| JPWO2012002189A1 (en) | Method for producing valsartan | |
| JP2010189293A (en) | Method for producing 1,4-dihydropyridine derivative | |
| JP6433809B2 (en) | Process for producing 1- (3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine | |
| CN103588775A (en) | Pralatrexate degradation impurity and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100715 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121030 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121116 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130115 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130205 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160301 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |