JPH0541637B2 - - Google Patents
Info
- Publication number
- JPH0541637B2 JPH0541637B2 JP2237989A JP2237989A JPH0541637B2 JP H0541637 B2 JPH0541637 B2 JP H0541637B2 JP 2237989 A JP2237989 A JP 2237989A JP 2237989 A JP2237989 A JP 2237989A JP H0541637 B2 JPH0541637 B2 JP H0541637B2
- Authority
- JP
- Japan
- Prior art keywords
- hydrocortisone
- present
- add
- hemisuccinate
- succinic anhydride
- 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
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 28
- VWQWXZAWFPZJDA-CGVGKPPMSA-N hydrocortisone succinate Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 VWQWXZAWFPZJDA-CGVGKPPMSA-N 0.000 claims description 16
- 229950006240 hydrocortisone succinate Drugs 0.000 claims description 16
- 229960000890 hydrocortisone Drugs 0.000 claims description 14
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 9
- 229940014800 succinic anhydride Drugs 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- -1 aliphatic tertiary amine Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- YCLWEYIBFOLMEM-AGIMVQGUSA-N 4,5-dihydrocortisone Chemical compound C1C(=O)CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC21 YCLWEYIBFOLMEM-AGIMVQGUSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000703 anti-shock Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
＜産業上の利用分野＞
本発明はハイドロコーチゾンから坑シヨツク剤
等の医薬品として有用なハイドロコーチゾンヘミ
サクシネートを短時間でかつ高純度で得るための
方法に関する。
＜従来の技術および発明が解決しようとする問題
点＞
従来、ハイドロコーチゾンヘミサクシネート
は、ピリジン溶媒中においてハイドロコーチゾン
と無水コハク酸とを室温で反応させることによ
り、製造していた。
しかしながら、かかる方法では、反応時間を20
時間程度も要し、さらに不純物であるジハイドロ
コーチゾンサクシネート（di−HC・Ｓ）の副生
の問題が生じるとともに製品の着色が大きいた
め、精製に活性炭を用いる等の繁雑な工程を必要
としてきた。
本発明者らは、これら従来法の欠点を改良し、
ハイドロコーチゾンヘミサクシネートを短時間で
かつ高純度で得るために鋭意検討した結果、本発
明に到達した。
＜問題点を解決するための手段＞
即ち、本発明の要旨は、ハイドロコーチゾンを
非プロトン性極性溶媒中で、下記一般式（）
（式中、R1、R2およびR3はそれぞれ独立して、
炭素数１〜５のアルキル基を表わし、隣接する
R1、R2あるいはR3が互いに結合して環を形成し
てもよい。）で示される脂肪族３級アミンまたは
Ｎ，Ｎ−ジメチルアミノピリジンを触媒として、
無水コハク酸と反応させることを特徴とするハイ
ドロコーチゾンヘミサクシネートの製造法に存す
る。
以下、具体例を示し、本発明を詳細に説明す
る。
本発明で使用する触媒は上記一般式（）で示
されるが、このような触媒の具体例としてはトリ
エチルアミン、Ｎ，Ｎ−ジエチルメチルアミン、
トリプロピルアミン、Ｎ−メチルピロリジン、Ｎ
−メチルピペリジン等が挙げられる。この中でも
特にトリエチルアミンが好適である。また、本発
明で使用する非プロトン性極性溶媒としては、テ
トラヒドロフラン（THF）、Ｎ−メチルピロリド
ン（NMP）、Ｎ，Ｎ−ジメチルホルムアミド、
アセトン、ジグライム等が挙げられるが、特に
THFが好適である。
本発明の実施にあたつては、ハイドロコーチゾ
ンに対して1.5〜２倍モル量の無水コハク酸およ
び0.5〜３倍モル量の触媒をハイドロコーチゾン
に対して３〜7.5倍量の溶媒に溶解させる。次に
出発原料であるハイドロコーチゾンを上記混合溶
液に25±２℃で添加し、20〜30℃で0.5〜６時間
反応させ、目的とするハイドロコーチゾンヘミサ
クシネートを得る。
反応の進行状況と終点とは高速液体クロマトグ
ラフイー（HPLC）によりチエツクすることがで
きる。本発明の目的化合物は、反応終了後、酸
（塩酸、硫酸等）で中和し、析出固体を過洗浄
し、得られた粗結晶を再結晶することにより精製
される。
次に本発明を実施例により更に詳しく説明する
が本発明は、要旨を越えない限りこれら実施例に
より何ら制限を受けるものではない。
実施例 １
四ツ口フラスコをN2置換し、無水コハク酸
〔5.5g、5mmole〕、トリエチルアミン〔7.7ml、
55mmole〕及びテトラヒドロフラン〔75ml〕を
加え、25±２℃で完溶させる。次にハイドロコー
チゾン〔10g、27.5mmole〕を温度25±２℃で一
括添加する。添加後、反応温度25±２℃で3.5時
間反応させ、HPLCにより転化率99.5％以上であ
る事を確認する。反応終了後、硫酸水溶液〔硫酸
55mmoleを含む水300ml〕を反応液に温度見合
〔10℃以下〕で滴下する。滴下終了後析出する結
晶を10±２℃で２時間熟成し取水洗後、乾燥温
度70℃で真空乾燥し、12.5gの粗ハイドロコーチ
ゾンヘミサクシネートを得た。
この粗ハイドロコーチゾンヘミサクシネート
〔10.0g、21.6mmole〕をアセトン〔7.0.9ml〕に40
℃で溶解させた後、0.2μmメンブランフイルター
で熱時過を行つた。アセトン〔23.6ml〕でフイ
ルターを洗浄し、液と合わせた後、この液を35
℃に保持しながら精製水〔189.0ml〕を滴下した。
析出した結晶を含むスラリー液を15℃で２時間熟
成させ、結晶を取、洗浄後減圧乾燥し、精ハイ
ドロコーチゾンヘミサクシネート9.50g（収率95.0
％）を得た。
IR（cm-1）：3500，2900，1720，1620
旋光度〔α〕D＝149゜（EtOH）
実施例 ２
四ツ口フラスコに無水コハク酸2.75gN−メチ
ルピロリドン50mlおよびトリエチルアミン3.83ml
を加え、20℃に冷却した後ハイドロコーチゾン
5.0gを加える。この溶液を25℃で3.5時間撹拌後、
HPLCにより分析すると転化率が100％であるこ
とが確認された。
この溶液を冷却後、濃塩酸2.43mlを水75mlで希
釈した塩酸水溶液を滴下し、析出した結晶を取
する。この結晶を水洗後、減圧乾燥して、粗ハイ
ドロコーチゾンヘミサクシネート6.38gを得た。
実施例 ３
四ツ口フラスコに無水コハク酸0.55g、Ｎ，Ｎ
−ジメチルアミノピリジン0.67gおよびテトラヒ
ドロフラン15mlを加え、20℃に冷却した後、ハイ
ドロコーチゾン1.0gを加える。この溶液を20℃で
６時間撹拌後、HPLCにより転化率が99.7％であ
ることを確認した。
この溶液を冷却後、濃塩酸0.49mlを水30mlで希
釈した塩酸水溶液を滴下し、析出した結晶を取
する。
この結晶を水洗後、減圧乾燥して、粗ハイドロ
コーチゾンヘミサクシネート1.17gを得た。
実施例 ４
四ツ口フラスコに無水コハク酸0.55g、トリエ
チルアミン0.77mlおよびアセトン15mlを加え、20
℃に冷却した後、ハイドロコーチゾン1.0gを加え
る。この溶液を25℃で６時間撹拌し、HPLCによ
り転化率が99.4％であることを確認した。この溶
液を冷却後、濃塩酸0.67mlを水30mlで希釈した塩
酸水溶液を滴下し、析出した結晶を取する。こ
の結晶を水洗後、減圧乾燥して、粗ハイドロコー
チゾンヘミサクシネート1.19gを得た。
参考例
無水コハク酸11.04gとピリジン72mlを混合撹拌
し、20℃においてハイドロコーチゾン8.0gを加え
た。
この混合溶液を20±２℃で24時間反応させた
後、HPLCにて転化率を測定すると約100％であ
つた。
この溶液を10℃以下に冷却後、濃硫酸25.92ml
を水176mlで希釈した硫酸水溶液を滴下し、10℃
±２℃で２時間熟成した後、析出した結晶を取
する。この結晶を水洗後、減圧乾燥して、粗ハイ
ドロコーチゾンヘミサクシネート10.16gを得た。
この粗結晶は前述の実施例１と同様の精製法によ
り精製を行つた。IRおよび旋光度は、実施例１
と同様であつた。
試験例
ハイドロコーチゾンヘミサクシネートを本発明
の方法（実施例１）および従来法（参考例）によ
り合成し、結晶の純度、不純物であるジハイドロ
コーチゾンサクシネート（di−HC・Ｓ）の量お
よび吸光度を常法により測定し、製造法の違いに
よる生成物の質的比較を行つた。その結果を下記
表１に示す。
<Industrial Application Field> The present invention relates to a method for obtaining hydrocortisone hemisuccinate, which is useful as a pharmaceutical agent such as an anti-shock agent, from hydrocortisone in a short time and with high purity. <Prior Art and Problems to be Solved by the Invention> Conventionally, hydrocortisone hemisuccinate has been produced by reacting hydrocortisone and succinic anhydride in a pyridine solvent at room temperature. However, in such a method, the reaction time is 20
It takes a long time, and there is also the problem of the by-product of dihydrocortisone succinate (di-HC・S), which is an impurity, and the product is highly colored, requiring complicated processes such as using activated carbon for purification. came. The present inventors improved the drawbacks of these conventional methods,
As a result of intensive studies to obtain hydrocortisone hemisuccinate with high purity in a short period of time, the present invention was achieved. <Means for solving the problems> That is, the gist of the present invention is to prepare hydrocortisone in an aprotic polar solvent using the following general formula (). (In the formula, R 1 , R 2 and R 3 are each independently,
Represents an alkyl group having 1 to 5 carbon atoms, and adjacent
R 1 , R 2 or R 3 may be combined with each other to form a ring. ) using an aliphatic tertiary amine or N,N-dimethylaminopyridine as a catalyst,
The present invention relates to a method for producing hydrocortisone hemisuccinate, which comprises reacting it with succinic anhydride. Hereinafter, the present invention will be explained in detail by showing specific examples. The catalyst used in the present invention is represented by the above general formula (), and specific examples of such catalysts include triethylamine, N,N-diethylmethylamine,
Tripropylamine, N-methylpyrrolidine, N
-Methylpiperidine and the like. Among these, triethylamine is particularly preferred. In addition, examples of the aprotic polar solvent used in the present invention include tetrahydrofuran (THF), N-methylpyrrolidone (NMP), N,N-dimethylformamide,
Examples include acetone, diglyme, etc., especially
THF is preferred. In carrying out the present invention, succinic anhydride in an amount of 1.5 to 2 times the molar amount of hydrocortisone and a catalyst in a molar amount of 0.5 to 3 times the amount of hydrocortisone are dissolved in a solvent of 3 to 7.5 times the amount of hydrocortisone. . Next, hydrocortisone as a starting material is added to the above mixed solution at 25±2°C and reacted at 20 to 30°C for 0.5 to 6 hours to obtain the desired hydrocortisone hemisuccinate. The progress of the reaction and the end point can be checked by high performance liquid chromatography (HPLC). After completion of the reaction, the target compound of the present invention is purified by neutralizing with an acid (hydrochloric acid, sulfuric acid, etc.), over-washing the precipitated solid, and recrystallizing the obtained crude crystals. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited in any way by these Examples unless the gist is exceeded. Example 1 A four-neck flask was replaced with N2 , and succinic anhydride [5.5 g, 5 mmole] and triethylamine [7.7 ml,
55 mmole] and tetrahydrofuran [75 ml] and dissolve completely at 25±2°C. Next, hydrocortisone [10 g, 27.5 mmole] is added all at once at a temperature of 25±2°C. After the addition, the reaction was carried out for 3.5 hours at a reaction temperature of 25±2°C, and it was confirmed by HPLC that the conversion rate was 99.5% or higher. After the reaction is complete, add sulfuric acid aqueous solution [sulfuric acid
Add 300 ml of water containing 55 mmole to the reaction solution dropwise at a temperature of 10°C or below. After completion of the dropwise addition, the precipitated crystals were aged at 10±2° C. for 2 hours, washed with water, and dried under vacuum at a drying temperature of 70° C. to obtain 12.5 g of crude hydrocortisone hemisuccinate. Add this crude hydrocortisone hemisuccinate [10.0g, 21.6mmole] to acetone [7.0.9ml] for 40 minutes.
After dissolving at °C, heat filtration was performed using a 0.2 μm membrane filter. After washing the filter with acetone [23.6ml] and combining it with the liquid, add 35 ml of this liquid.
Purified water [189.0 ml] was added dropwise while maintaining the temperature at °C.
The slurry containing the precipitated crystals was aged at 15°C for 2 hours, the crystals were collected, washed and dried under reduced pressure to obtain 9.50 g of purified hydrocortisone hemisuccinate (yield: 95.0).
%) was obtained. IR (cm -1 ): 3500, 2900, 1720, 1620 Optical rotation [α] D = 149° (EtOH) Example 2 Succinic anhydride 2.75g N-methylpyrrolidone 50ml and triethylamine 3.83ml in a four-necked flask
Add hydrocortisone after cooling to 20℃
Add 5.0g. After stirring this solution at 25°C for 3.5 hours,
Analysis by HPLC confirmed that the conversion rate was 100%. After cooling this solution, a hydrochloric acid aqueous solution prepared by diluting 2.43 ml of concentrated hydrochloric acid with 75 ml of water is added dropwise to collect the precipitated crystals. The crystals were washed with water and dried under reduced pressure to obtain 6.38 g of crude hydrocortisone hemisuccinate. Example 3 0.55 g of succinic anhydride, N, N in a four-necked flask
- Add 0.67 g of dimethylaminopyridine and 15 ml of tetrahydrofuran, cool to 20°C, and then add 1.0 g of hydrocortisone. After stirring this solution at 20° C. for 6 hours, it was confirmed by HPLC that the conversion rate was 99.7%. After cooling this solution, a hydrochloric acid aqueous solution prepared by diluting 0.49 ml of concentrated hydrochloric acid with 30 ml of water is added dropwise to collect the precipitated crystals. The crystals were washed with water and dried under reduced pressure to obtain 1.17 g of crude hydrocortisone hemisuccinate. Example 4 Add 0.55 g of succinic anhydride, 0.77 ml of triethylamine, and 15 ml of acetone to a four-neck flask, and add 20 ml of acetone.
After cooling to °C, add 1.0 g of hydrocortisone. This solution was stirred at 25° C. for 6 hours, and the conversion rate was confirmed to be 99.4% by HPLC. After cooling this solution, a hydrochloric acid aqueous solution prepared by diluting 0.67 ml of concentrated hydrochloric acid with 30 ml of water is added dropwise to collect the precipitated crystals. The crystals were washed with water and dried under reduced pressure to obtain 1.19 g of crude hydrocortisone hemisuccinate. Reference Example 11.04 g of succinic anhydride and 72 ml of pyridine were mixed and stirred, and 8.0 g of hydrocortisone was added at 20°C. After reacting this mixed solution at 20±2° C. for 24 hours, the conversion rate was measured by HPLC and was found to be about 100%. After cooling this solution to below 10℃, 25.92ml of concentrated sulfuric acid
Add dropwise a sulfuric acid aqueous solution diluted with 176 ml of water, and heat at 10℃.
After aging at ±2°C for 2 hours, the precipitated crystals are collected. The crystals were washed with water and dried under reduced pressure to obtain 10.16 g of crude hydrocortisone hemisuccinate.
This crude crystal was purified by the same purification method as in Example 1 above. IR and optical rotation are as in Example 1.
It was the same. Test Example Hydrocortisone hemisuccinate was synthesized by the method of the present invention (Example 1) and the conventional method (Reference Example), and the purity of crystals, the amount of dihydrocortisone succinate (di-HC・S) as an impurity, and The absorbance was measured using a conventional method to qualitatively compare the products produced by different manufacturing methods. The results are shown in Table 1 below.
【表】
上記結果から、本発明の方法で合成したハイド
ロコーチゾンヘミサクシネートは、従来法により
合成したものに比べ、不純物が少なく、純度や透
明度の高い良質なものであることがわかる。
＜発明の効果＞
本発明によれば、ハイドロコーチゾンから短時
間で、高純度のハイドロコーチゾンヘミサクシネ
ートが得られる。[Table] From the above results, it can be seen that hydrocortisone hemisuccinate synthesized by the method of the present invention has fewer impurities and is of high quality with high purity and transparency compared to that synthesized by the conventional method. <Effects of the Invention> According to the present invention, highly purified hydrocortisone hemisuccinate can be obtained from hydrocortisone in a short time.
Claims (1)
中で、下記一般式（） （式中、R1，R2およびR3はそれぞれ独立して
炭素数１〜５のアルキル基を表わし、隣接する
R1，R2あるいはR3が互いに結合して環を形成し
てもよい。）で示される脂肪族３級アミンまたは
Ｎ，Ｎ−ジメチルアミノピリジンを触媒として、
無水コハク酸と反応させることを特徴とするハイ
ドロコーチゾンヘミサクシネートの製造法。[Claims] 1 Hydrocortisone is prepared by the following general formula () in an aprotic polar solvent. (In the formula, R 1 , R 2 and R 3 each independently represent an alkyl group having 1 to 5 carbon atoms, and the adjacent
R 1 , R 2 or R 3 may be combined with each other to form a ring. ) using an aliphatic tertiary amine or N,N-dimethylaminopyridine as a catalyst,
A method for producing hydrocortisone hemisuccinate, which comprises reacting it with succinic anhydride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2237989A JPH02202897A (en) | 1989-01-31 | 1989-01-31 | Production method of hydrocortisone hemisuccinate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2237989A JPH02202897A (en) | 1989-01-31 | 1989-01-31 | Production method of hydrocortisone hemisuccinate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02202897A JPH02202897A (en) | 1990-08-10 |
| JPH0541637B2 true JPH0541637B2 (en) | 1993-06-24 |
Family
ID=12081016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2237989A Granted JPH02202897A (en) | 1989-01-31 | 1989-01-31 | Production method of hydrocortisone hemisuccinate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02202897A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180763A (en) * | 2018-08-08 | 2019-01-11 | 河南利华制药有限公司 | A kind of production technology of hydrocortisone monomester succinate |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112225772A (en) * | 2020-10-20 | 2021-01-15 | 安徽海洋药业有限公司 | Synthesis process of hydrocortisone hemisuccinate |
-
1989
- 1989-01-31 JP JP2237989A patent/JPH02202897A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180763A (en) * | 2018-08-08 | 2019-01-11 | 河南利华制药有限公司 | A kind of production technology of hydrocortisone monomester succinate |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02202897A (en) | 1990-08-10 |
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