JPH02202897A - Production of hydrocortisone hemisuccinate - Google Patents
Production of hydrocortisone hemisuccinateInfo
- Publication number
- JPH02202897A JPH02202897A JP2237989A JP2237989A JPH02202897A JP H02202897 A JPH02202897 A JP H02202897A JP 2237989 A JP2237989 A JP 2237989A JP 2237989 A JP2237989 A JP 2237989A JP H02202897 A JPH02202897 A JP H02202897A
- Authority
- JP
- Japan
- Prior art keywords
- hydrocortisone
- succinic anhydride
- add
- solution
- hemisuccinate
- 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.)
- Granted
Links
- 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 title claims description 13
- 229950006240 hydrocortisone succinate Drugs 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 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 abstract description 35
- 229960000890 hydrocortisone Drugs 0.000 claims abstract description 17
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000000703 anti-shock Effects 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000003880 polar aprotic solvent Substances 0.000 abstract 2
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000000034 method Methods 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 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
- 239000000203 mixture Substances 0.000 description 3
- 238000005406 washing Methods 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 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
- 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
- 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
- 241000237502 Ostreidae Species 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
- -1 aliphatic tertiary amine Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 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
- 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
- 235000020636 oyster Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 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)
Abstract
Description
【発明の詳細な説明】
〈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ョック剤等の医薬
品として有用なノ・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。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for obtaining hydrocortisone hemisuccinate, which is useful as a pharmaceutical such as an anti-shock agent, from hydrocortisone in a short time and with high purity.
〈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
ン溶媒中においてノ・イドロコーチプンと無水コハク酸
とを室温で反応させることにより、製造していた。<Prior Art and Problems to be Solved by the Invention> Conventionally, hydrocortisone hemisuccinate has been produced by reacting hydrocortisone with succinic anhydride in a pyridine solvent at room temperature.
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（ｄｌ−ＨＣ−８）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。However, in this method, the reaction time is about 20 hours, and there is also the problem of by-product of dihydrocortisone succinate (dl-HC-8), which is an impurity, and the color of the product is large, so activated carbon is used for purification. This has required complicated processes such as using
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。The present inventors have conducted intensive studies to improve the drawbacks of these conventional methods and obtain hydrocortisone hemisuccinate in a short time and with high purity, and as a result, have arrived at the present invention.
〈問題点を解決するための手段〉
即ち、本発明の要旨は、ノ・イドロコーチゾンを非プロ
トン性極性溶媒中で、下記−形成ＣＩ）（式中、Ｒ□、
Ｒ２およびＲ１３はそれぞれ独立して、炭素数／−，１
のアルキル基を表わし、隣接するＲ□、Ｒ２あるいはＲ
３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。<Means for Solving the Problems> That is, the gist of the present invention is to prepare hydrocortisone in an aprotic polar solvent to form CI) (in the formula, R□,
R2 and R13 each independently have carbon number/-, 1
represents an alkyl group, and adjacent R□, R2 or R
3 may be bonded to each other to form a ring. ) A method for producing hydrocortisone hemisuccinate, which comprises reacting with succinic anhydride using an aliphatic tertiary amine or N,N-dimethylaminopyridine as a catalyst.
以下、具体例を示し、本発明の詳細な説明する。Hereinafter, the present invention will be explained in detail by showing specific examples.
本発明で使用する触媒は上記−形成（１）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。The catalyst used in the present invention is shown in the above-mentioned formation (1), and specific examples of such catalysts include triethylamine,
Examples include N,N-diethylmethylamine, tripropylamine, N-methylpyrrolidine, and N-methylpiperidine. Among these, triethylamine is particularly preferred. Examples of the aprotic polar solvent used in the present invention include tetrahydrofuran (THF), N-methylpyrrolidone (NMP), N,N-dimethylformamide, acetone, and diglyme, with THF being particularly preferred. .
本発明の実施にあたっては、ノ・イドロコーチゾンに対
して／、５〜２倍モル量の無水コハク酸およびｏ３〜３
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、！！±２°Ｃで添加し
、２０ 〜３０℃でＯＪ〜を時間反応させ、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。In carrying out the present invention, succinic anhydride and o3-3 in an amount of 5 to 2 times the molar amount per
Add 3 to 7 times the molar amount of catalyst to hydrocortisone.
Dissolve in 5 times the amount of solvent. Next, add the starting material hydrocortisone to the above mixed solution! ! The mixture is added at ±2°C, and OJ~ is reacted at 20 to 30°C for a period of time to obtain the desired hydrocortisone hemisuccinate.
反応の進行状況と終点とは高速液体クロマトグラフィー
（ＨＰＬＣ）によシチェノ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ｆ過洗浄し、得られた粗結晶を再結晶
することによシ精製される。The progress and end point of the reaction can be determined 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.), washing the precipitated solid with filtration, and recrystallizing the obtained crude crystals.
次に本発明を実施例によシ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如何ら制限を
受けるものではない。Next, the present invention will be explained in more detail with reference to examples, but the present invention is not limited to these examples in any way unless it goes beyond the gist.
実施例／
四ツロフラスコをＮ２置換し、無水コノ・り酸［ＬＪ
Ｆ、！よｍｍｏｌｅ、：ｌ 、）リエチルアミンＣ７，
７ｙｔｌ、 ｒ ｊ ｍｍｏｌｅ’ ：］ 及びテ
トラヒドロフラン〔？ ｇ ｍｌ） ：ｌを加え、２夕
±２℃で完溶させる。次にハイドロコーチゾン〔１０１
ｉ、２７ｊｍｍｏｌｅ ） 全１４度２夕±λ°Ｃで
一括添加する。Example / A Yotsuro flask was replaced with N2, and cono-phosphoric anhydride [LJ
F,! mmole, :l,) ethylamine C7,
7ytl, r j mmole' :] and tetrahydrofuran [? g ml): 1 is added and allowed to completely dissolve at ±2°C for 2 nights. Next, hydrocortisone [101
i, 27 mmole) Add all at once at 14 degrees ± λ°C for 2 nights.
添加後、反応温度２ｊ＋Ｘ２°Ｃで３ｊ時間反応させ、
）（ＰＬＣによシ転化率タタ、ｊ％以上である事を確認
する。反応終了後、硫酸水溶液〔硫酸ｊ ｊ ｍｍｏ
１ ｅ を含む水３ｏｏｍｌ：］を反応液に温度見合
ｒ−ｉｏ℃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ｆ取水洗後、乾燥温度７０
′Ｃで真空乾燥し、／ ２．！＋２の粗ハイドロコーチ
ゾンヘミサクシネートを得た。After addition, react at a reaction temperature of 2j+X2°C for 3j hours,
) (Check that the conversion rate is at least J% by PLC. After the reaction is complete, add sulfuric acid aqueous solution [Sulfuric acid j j mmo
3 ooml of water containing 1 e is added dropwise to the reaction solution at a temperature below r-io°C. After completing the dropping, the precipitated crystals were aged at 10±2°C for 2 hours, washed with water, and dried at a temperature of 70°C.
2. Vacuum dry at 'C. ! +2 crude hydrocortisone hemisuccinate was obtained.
この粗ハイドロコーチゾンヘミサクシネート〔１０，Ｏ
ｆ、ｘ ｌ、Ａ ｍｍｏｌｅ ：］をアセトン［７，０
，９ｍｌ 、］にグＯ′Ｇで溶解させた後、 ０．２μ
ｍメンブランフィルタ−で熱時ｒ過を行った。This crude hydrocortisone hemisuccinate [10,O
f, x l, A mmole: ] in acetone [7,0
, 9 ml, ] with G O'G, and then 0.2 μ
The mixture was subjected to thermal filtration using a m membrane filter.
アセトン〔，２３，６ｒｒｔｌ〕でフィルターを洗浄し
、ｒ液と合わせた後、この液を３ｊ℃に保持しながら精
製水［ｉ１９．０ｒｎｌ：］を滴下した。析出した結晶
を含むスラリー液を／ｊ”ｃ、で２時間熟成させ、結晶
をＦ取、洗浄後減圧乾燥し、精ノ・イドロコーチゾンヘ
ミサクシネートタ、ｊ ｏ ｒ （収率タタ、θ％）を
得た。After washing the filter with acetone [23,6 rrtl] and combining it with the r solution, purified water [i19.0 rnl:] was added dropwise to the solution while keeping this solution at 3J°C. The slurry containing the precipitated crystals was aged for 2 hours at /j''c, and the crystals were collected by F, washed, and dried under reduced pressure to obtain purified hydrocortisone hemisuccinate, j o r (yield, θ%). ) was obtained.
ＩＲ（σ−′） ： ３夕００．．２り００．／７２０
．／１２０旋光度〔α〕ゎ＝ｌ≠９ （ＥｔＯＨ）実
施例２
四ツロフラスコに無水コハク酸２．７！ｒ？Ｎ−メチル
ピロリドンｊＯｄおよびトリエチルアミン３．♂３ ｍ
ｌを加え、２０℃に冷却した後ハイドロコーチゾン！、
０２を加える。この溶液を２！°Ｃで３．夕時間攪拌後
、ＨＰＬＣによシ分析すると転化率がｔｏｏ％であるこ
とが確認された。IR(σ-'): 3pm 00. ．． 2ri00. /720
．． /120 Optical rotation [α]ゎ=l≠9 (EtOH) Example 2 Succinic anhydride 2.7! r? N-methylpyrrolidone jOd and triethylamine 3. ♂3m
After cooling to 20℃, add hydrocortisone! ,
Add 02. 2 times this solution! 3 at °C. After stirring in the evening, HPLC analysis confirmed that the conversion rate was too%.
この溶液を冷却後、濃塩酸λ、１１３ｖｔｌを水７！罰
で希釈した塩酸水溶液を滴下し、析出した結晶をｆ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ｔ、３とグを得た。After cooling this solution, add 113 vtl of concentrated hydrochloric acid λ to 7 liters of water! Add dropwise an aqueous solution of hydrochloric acid diluted with water, and collect the precipitated crystals. The crystals were washed with water and dried under reduced pressure to obtain crude hydrocortisone hemisuccinates t, 3 and g.
実施例３
四ツ目フラスコに無水コハク酸Ｏｊ ｊ ！ｉ’ 、Ｎ
、Ｎ−ジメチルアミノピリジン０．ｔ７ｆｉｌおよびテ
トラヒドロフラン／夕ｖｔｌを加え、２０℃に冷却した
後、ハイドロコーチゾンｉ、ｏ ｙを加える。この溶液
を２０℃で６時間攪拌後、ＨＰＬＣによシ転化率がり２
．７％であることを確認した。Example 3 Succinic anhydride Oj j in a four-eye flask! i', N
, N-dimethylaminopyridine 0. Add t7fil and tetrahydrofuran/vtl, cool to 20°C, then add hydrocortisone i,o y. After stirring this solution at 20°C for 6 hours, HPLC showed that the conversion rate was 2.
．． It was confirmed that it was 7%.
この溶液を冷却後、濃塩酸ｏ３２ｍｌを水３０罰で希釈
した塩酸水溶液を滴下し、析出した結晶をｆ取する。After cooling this solution, a hydrochloric acid aqueous solution prepared by diluting 32 ml of concentrated hydrochloric acid with 30 parts of water is added dropwise, and the precipitated crystals are collected.
この結晶を水洗後、減圧乾燥して、粗ノ・イドロコーチ
ゾンヘミサクシネートｉ、ｉ’ｙｔを得た。The crystals were washed with water and dried under reduced pressure to obtain crude hydrocortisone hemisuccinates i and i'yt.
典寺→傘
四ツ目フラスコに無水コハク酸ｏ、ｓ、ｔｙ、トリエチ
ルアミン０．７７ＷＬｌ！ｆ；ｙよびアセトン／ｊ、１
を加え、２０℃に冷却した後、ハイドロコーチゾン八０
２を加える。この溶液を２４− ’Ｃで６時間攪拌し、
’ＨＰＬＣにより転化率がタタ、グ％であることを確認
した。この溶液を冷却後、濃塩酸０、Ａ７ｒｒｔｌを水
３０．１で希釈した塩酸水溶液を滴下し、析出した結晶
をｆ取する。この結晶を水洗後、減圧乾燥して、粗・・
イドロコーチゾンヘミサクシネー）／、／タグを得た。Tonoji → Umbrella 4-eye flask contains succinic anhydride o, s, ty, and triethylamine 0.77WLl! f; y and acetone/j, 1
After cooling to 20℃, add 80% hydrocortisone.
Add 2. The solution was stirred at 24-'C for 6 hours,
'It was confirmed by HPLC that the conversion rate was 1.5%. After cooling this solution, a hydrochloric acid aqueous solution prepared by diluting 0 of concentrated hydrochloric acid and 30.1 of A7rrtl with water is added dropwise, and the precipitated crystals are collected. After washing the crystals with water and drying them under reduced pressure,...
Idrocortisone hemisaxine)/,/obtained the tag.
参考例
無水コハク酸／ ／、０ ’１ｔ１７’とピリジン７２
ｍ／！ 全混合攪拌し、２０℃においてハイドロコー
チゾンざ、ｏｙを加えた。Reference example Succinic anhydride / /, 0 '1t17' and pyridine 72
m/! The whole mixture was mixed and stirred, and hydrocortisone, oyster, was added at 20°C.
この混合溶液を２０±２℃で２弘時間反応させた後、Ｈ
ＰＬＣにて転化率を測定すると約ｉｏｏ係であった。After reacting this mixed solution at 20±2°C for 2 hours, H
When the conversion rate was measured by PLC, it was about 100%.
この溶液をｉｏ℃以下に冷却後、濃硫酸２夕、２２ｄを
水／ ７ Ａ ｗｔｌ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ｆ取
する。この結晶を水洗後、減圧乾燥して、粗ハイドロコ
ーチゾンへ７サクＩＲおよび旋光度は、実施例／と同様
であった。After cooling this solution to io℃ or less, concentrated sulfuric acid was added for 2 nights, and a sulfuric acid aqueous solution prepared by diluting 22d with water/7 A wtl was added dropwise.
After aging at 10°C±2°C for 2 hours, the precipitated crystals were collected. The crystals were washed with water and dried under reduced pressure to give crude hydrocortisone.The IR and optical rotation were the same as in Example.
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）によシ合成し、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
） （ｄｉ−ＨＣ−８）の量および吸光度を常法によシ
測定し、製造法の違いによる生成物の質的比較を行った
。その結果を下記衣／に示す。Test Example Hydrocortisone hemisuccinate was prepared using the method of the present invention (
Example 1) and the conventional method (Reference example) were synthesized, and the purity of the crystal, the amount and absorbance of the impurity dihydrocortisone succinate (di-HC-8) were measured by the conventional method, A qualitative comparison was made of the products produced by different manufacturing methods. The results are shown below.
表１
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、従来法によシ合成したものに
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。Table 1 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.
〈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
。<Effects of the Invention> According to the present invention, highly purified hydrocortisone hemisuccinate can be obtained from hydrocortisone in a short time.
Claims (1)
、下記一般式（ I ） ▲数式、化学式、表等があります▼………（ I ） （式中、Ｒ＿１、Ｒ＿２およびＲ＿３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Ｒ＿１
、Ｒ＿２あるいはＲ＿３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(1) Add hydrocortisone to an aprotic polar solvent using the following general formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. Represents an alkyl group having 1 to 5 carbon atoms, and adjacent R_1
, R_2 or R_3 may be bonded to each other to form a ring. ) or N,N-
A method for producing hydrocortisone hemisuccinate, which comprises reacting with succinic anhydride using dimethylaminopyridine as a catalyst.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2237989A JPH02202897A (en) | 1989-01-31 | 1989-01-31 | Production of hydrocortisone hemisuccinate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2237989A JPH02202897A (en) | 1989-01-31 | 1989-01-31 | Production of hydrocortisone hemisuccinate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02202897A true JPH02202897A (en) | 1990-08-10 |
| JPH0541637B2 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 of hydrocortisone hemisuccinate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02202897A (en) |
Cited By (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 |
Families Citing this family (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 |
-
1989
- 1989-01-31 JP JP2237989A patent/JPH02202897A/en active Granted
Cited By (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 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0541637B2 (en) | 1993-06-24 |
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