JPS6247199B2 - - Google Patents
Info
- Publication number
- JPS6247199B2 JPS6247199B2 JP7980180A JP7980180A JPS6247199B2 JP S6247199 B2 JPS6247199 B2 JP S6247199B2 JP 7980180 A JP7980180 A JP 7980180A JP 7980180 A JP7980180 A JP 7980180A JP S6247199 B2 JPS6247199 B2 JP S6247199B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- dihydroxy
- group
- steroids
- methyl
- 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
Links
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 150000003431 steroids Chemical class 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000004593 Epoxy Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960001524 hydrocortisone butyrate Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229950000210 beclometasone dipropionate Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- AKYUZBFQLWFNOB-UHFFFAOYSA-K trisodium 2-hydroxypropane-1,2,3-tricarboxylate hydrochloride Chemical compound [Na+].[Na+].[Na+].Cl.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O AKYUZBFQLWFNOB-UHFFFAOYSA-K 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、17α・21−ジヒドロキシコルチコス
テロイド 17−モノエステル類の製造法の改良に
関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing 17α·21-dihydroxycorticosteroid 17-monoesters.
17α・21−ジヒドロキシコルチコステロイド
17α−モノエステル類は高い抗炎症作用をもつこ
とが知られており、興味ある化合物群である。そ
の代表的な17α−モノエステル類としては、ハイ
ドロコーチゾン17−ブチレート、ベータメタゾン
17−バレレート等が挙げられ、また、17−モノ
エステルを経由して製造されうるベクロメタゾン
ジプロピオネート（９α−クロロ−16β−メチ
ル−プレドニソロン 17α・21−ジプロピオネー
ト）がある。 17α・21-dihydroxycorticosteroid
17α-monoesters are known to have high anti-inflammatory effects and are an interesting group of compounds. Typical 17α-monoesters include hydrocortisone 17-butyrate, betamethasone
Examples include 17-valerate, and beclomethasone dipropionate (9α-chloro-16β-methyl-prednisolone 17α·21-dipropionate), which can be produced via 17-monoester.
従来、17α・21−ジヒドロキシコルチコステロ
イド 17α−モノエステル類の製造法としては米
国特許3152154号明細書に記載されている17α・
21−ジヒドロキシコルチコステロイドの17α・21
−環状オルトエステルを、塩酸、硫酸、リン酸、
ホウ酸、過塩素酸等の無機およびギ酸、酢酸、プ
ロピオン酸、クロロ酢酸、蓚酸等の有機のプロト
ン酸〔ブレンシユテツド（Brｏ／nsted）酸〕を触
媒にして、水溶液中で加水分解させて、17α・21
−ジヒドロキシコルチコステロイド 17α−モノ
エステルを得る方法がある。しかし、この製造法
によると希望する17−エステルの外に副生成物と
して21−エステルが多量に生じ好ましくない。ま
た、その改良法として特公昭48−15288が開示さ
れている。それによると、酢酸−酢酸ナトリウ
ム、塩酸−クエン酸ナトリウム、塩酸−グリシン
等のプロトン酸と塩基の組合せによる緩衝液系を
設定し、反応媒体のPHを4.5〜5.5に調節すれば副
生成の21−エステルの生成を著しく減少させうる
ことが述べられている。しかし、PH4.5〜5.5とひ
じようにせまい範囲でPHをコントロールしなけれ
ばならず、また反応温度も事実上メタノール還流
下という苛酷な条件を必要とするので、１〜５％
の21−エステルのほかにさらに加水分解を受けた
17α・21−ジオールも１％程度ではあるが副生し
てくる。 Conventionally, 17α・21-dihydroxycorticosteroid 17α-monoesters have been produced using the 17α・21-dihydroxycorticosteroid 17α-monoester described in US Pat. No. 3,152,154.
21-dihydroxycorticosteroid 17α・21
- Cyclic orthoester can be converted into hydrochloric acid, sulfuric acid, phosphoric acid,
17α is hydrolyzed in an aqueous solution using inorganic protonic acids such as boric acid and perchloric acid, and organic protonic acids such as formic acid, acetic acid, propionic acid, chloroacetic acid, and oxalic acid (Bro/nsted acid) as a catalyst. ·twenty one
-There is a method for obtaining dihydroxycorticosteroid 17α-monoester. However, according to this production method, a large amount of 21-ester is produced as a by-product in addition to the desired 17-ester, which is undesirable. In addition, Japanese Patent Publication No. 15288/1984 has been disclosed as an improved method. According to this, by setting a buffer system using a combination of protic acid and base such as acetic acid-sodium acetate, hydrochloric acid-sodium citrate, or hydrochloric acid-glycine, and adjusting the pH of the reaction medium to 4.5 to 5.5, 21 by-products can be reduced. - It is stated that the formation of esters can be significantly reduced. However, the pH must be controlled within an elbow-length range of 4.5 to 5.5, and the reaction temperature requires harsh conditions of virtually refluxing methanol, so 1 to 5%
In addition to the 21-ester of
17α・21-diol is also produced as a by-product, although it accounts for about 1%.
この17α・21−ジオールは一般に有機溶媒に対
して溶解度が小さく、通常の再結晶法による精製
法では除去し難い性質があるので、たとえ微量で
あつても、17α・21−ジオールが生成することは
好ましくない。本発明によれば、21−エステルの
生成をひじよう少なくし、かつ17α・21−ジオー
ルも実質的に生成させずに17−エステルを高収率
で得ることができる。 This 17α・21-diol generally has a low solubility in organic solvents and is difficult to remove by ordinary purification methods such as recrystallization, so even if it is in a trace amount, 17α・21-diol is generated. is not desirable. According to the present invention, 17-ester can be obtained in high yield with significantly less production of 21-ester and substantially no production of 17α·21-diol.
すなわち、本発明の要旨はＤ環の17位およびそ
の側鎖が部分構造式（）
（式中Ｒは炭素数１〜10のアルキル基、アラルキ
ル基、シクロアルキル基またはアリール基を示
し、R′は炭素数１〜４の低級アルキル基を示
す。）
で示される17α・21−ジヒドロキシ−20−ケト−
ステロイド類の17α・21−環状オルトエステル類
を、ルイス酸の共存下に、水性アルコール媒質中
で加水分解することを特徴とする17α・21−ジヒ
ドロキシ−20−ケト−ステロイド類の17−モノエ
ステルの製造法に存する。 That is, the gist of the present invention is that the 17th position of the D ring and its side chain have the partial structural formula () (In the formula, R represents an alkyl group, aralkyl group, cycloalkyl group, or aryl group having 1 to 10 carbon atoms, and R' represents a lower alkyl group having 1 to 4 carbon atoms.) -20-keto-
17-monoester of 17α/21-dihydroxy-20-keto-steroids characterized by hydrolyzing 17α/21-cyclic orthoesters of steroids in an aqueous alcoholic medium in the presence of a Lewis acid. It consists in the manufacturing method of
以下に本発明を詳細に説明する。 The present invention will be explained in detail below.
部分構造式（）において、Ｒは例えばメチ
ル、エチル、プロピル、ブチル基等の炭素数が10
以下のアルキル基、ベンジル等のアラルキル基、
シクロペンチル、シクロヘキシル等のシクロアル
キル基またはフエニル等のアリール基である。ま
た、R′はメチル、エチル等の低級アルキル基で
ある。 In the partial structural formula (), R is a group having 10 carbon atoms, such as a methyl, ethyl, propyl, or butyl group.
The following alkyl groups, aralkyl groups such as benzyl,
These are cycloalkyl groups such as cyclopentyl and cyclohexyl, or aryl groups such as phenyl. Further, R' is a lower alkyl group such as methyl or ethyl.
17α・21−ジヒドロキシ−20−ケト−ステロイ
ド類の17α・21−環状オルトエステル類の17位以
外の置換基や、不飽和結合はあつてもさしつかえ
ない。 Substituents other than the 17th position of the 17α·21-cyclic orthoesters of the 17α·21-dihydroxy-20-keto-steroids and unsaturated bonds may be present.
17α・21−ジヒドロキシ−20−ケト−ステロイ
ド類の17α・21−還状オルトエステル類（以下
「ステロイド（）」という）としては、たとえ
ば、ヒドロコルチゾン−17α・21−メチル−オル
トブチレート、ベータメタゾン−17α・21−メチ
ル−オルトバレレート、プレドニソロン−17α・
21−メチル−オルトベンゾエート、プレドニソロ
ン−17α・21−メチル−オルトシクロヘキサンカ
ルボキシレート、17α・21−（1′−エトキシ−ｎ
−プロピリデンジオキシ）−16β−メチル−９
β・11β−エポキシプレグナ−１・４−ジエン−
３・20−ジオン等が挙られる。 Examples of 17α/21-cyclic orthoesters of 17α/21-dihydroxy-20-keto-steroids (hereinafter referred to as "steroids") include hydrocortisone-17α/21-methyl-orthobutyrate, betamethasone- 17α・21-methyl-orthovalerate, prednisolone-17α・
21-methyl-orthobenzoate, prednisolone-17α・21-methyl-orthocyclohexanecarboxylate, 17α・21-(1′-ethoxy-n
-propylidenedioxy)-16β-methyl-9
β・11β-epoxy pregna-1,4-diene-
Examples include 3,20-dione.
とくに、９β・11β−エポキシステロイドで
は、エポキシ環の開裂のため、特公昭48−15288
号公報の実施例４に示される様に17−エステルの
収率（78％）は低い。しかし、本方法では97％以
上の収率が期待できることは注目に値する。 In particular, for 9β/11β-epoxy steroids, due to the cleavage of the epoxy ring,
As shown in Example 4 of the publication, the yield of 17-ester (78%) is low. However, it is noteworthy that a yield of 97% or more can be expected with this method.
反応媒質に使用する水性アルコールとはメタノ
ール、、エタノール、プロパノール、ブタノール
等の低級アルコール類と水との混合物であり、な
かでもメタノールと水との混合物が最も好まし
い。アルコール類と水との混合比は任意に選べる
が、ステロイド（）あるいは生成17−モノエス
テル類を溶解させるため、通常水に対し１〜100
容量倍、好しくは１〜20容量倍のアルコールが使
用される。 The aqueous alcohol used as the reaction medium is a mixture of lower alcohols such as methanol, ethanol, propanol, butanol, and water, and of these, a mixture of methanol and water is most preferred. The mixing ratio of alcohol and water can be selected arbitrarily, but in order to dissolve the steroid () or the produced 17-monoester, it is usually 1 to 100% of the water.
Two times the volume of alcohol is used, preferably 1 to 20 times the volume.
ルイス酸としては、塩化アルミニウム、塩化亜
鉛、塩化第２スズ等が使用でき、そのなかでも塩
化アルミニウムが最も好ましい。 As the Lewis acid, aluminum chloride, zinc chloride, stannic chloride, etc. can be used, and among them, aluminum chloride is the most preferred.
ルイス酸の使用は従来のプロトン酸を触媒とす
る方法に比べ著るしく加水分解速度を促進するの
で、室温で充分なる転化率を期待することがで
き、そのため対応する21−エステル類、また更に
加水分解の進んだ17α・21−ジヒドロキシ類の副
生を極端に抑制できる。とくに、17α・21−ジヒ
ドロキシ類の生成は薄層クロマトグラフイー、高
速液体クロマトグラフイーでは検知できず、その
生成量は0.1％以下である。従つて本発明の方法
で得られる17−エステル類は極めて容易に精製で
きる。 Since the use of Lewis acids significantly accelerates the hydrolysis rate compared to conventional protonic acid-catalyzed methods, sufficient conversion can be expected at room temperature, and therefore the corresponding 21-esters or even By-products of highly hydrolyzed 17α/21-dihydroxy can be extremely suppressed. In particular, the production of 17α/21-dihydroxy cannot be detected by thin layer chromatography or high performance liquid chromatography, and the amount produced is less than 0.1%. Therefore, the 17-esters obtained by the method of the present invention can be purified very easily.
ルイス酸の使用量は水性アルコールに対し、通
常0.01〜5.0％、好ましくは0.03〜2.0％である。 The amount of Lewis acid used is usually 0.01 to 5.0%, preferably 0.03 to 2.0%, based on the aqueous alcohol.
ルイス酸濃度が低すぎると反応が進行しないか
あるいは反応速度が著しくおそくなり、また高す
ぎると21−エステルの副生が多くなり何れも好ま
しくない。 If the Lewis acid concentration is too low, the reaction will not proceed or the reaction rate will be extremely slow, and if it is too high, a large amount of 21-ester will be produced as a by-product, both of which are undesirable.
反応温度も通常80℃以下、好ましくは−10〜35
℃である。 The reaction temperature is also usually below 80°C, preferably between -10 and 35°C.
It is ℃.
反応温度が高すぎると21−エステルおよび17
α・21−ジオールの副生が多くなり、低すぎると
反応速度が著しくおそくなるので何れも好ましく
ない。 If the reaction temperature is too high, 21-ester and 17
Both are unfavorable, since a large amount of α·21-diol will be produced as a by-product, and if it is too low, the reaction rate will be extremely slow.
次に実施例で本発明を更に詳細に説明する。 Next, the present invention will be explained in more detail with reference to Examples.
実施例 １
17α・21−（1′−エトキシ−ｍ−プロピリデン
ジオキシ）−16β−メチルプレグナ−１・４・
9(11)−トリエン−３・20−ジオン1.063ｇにメタ
ノール20ml、0.28（ｗ／ｗ）％塩化アルミニウム
水溶液10ml加え、室温（25℃）で３時間撹拌す
る。反応液に水100ml添加し、析出結晶を別す
る。粗16β−メチルプレグナ−１・４・9(11)−
トリエン−17α・21−ジヒドロキシ−３・20−ジ
オン 17−プロピオネート1.114ｇを得る。高速
液体クロマトグラフイーによる分析では、対応す
る21−プロピオネートを0.9％を含む。17α・21
−ジオールは検知できない。17−プロピオネート
収率97.2％。Example 1 17α・21-(1′-ethoxy-m-propylidenedioxy)-16β-methylpregna-1・4・
9 (11) -To 1.063 g of -triene-3.20-dione, 20 ml of methanol and 10 ml of a 0.28 (w/w)% aluminum chloride aqueous solution are added, and the mixture is stirred at room temperature (25°C) for 3 hours. Add 100 ml of water to the reaction solution and separate the precipitated crystals. Crude 16β-methylpregna-1, 4, 9 (11) −
1.114 g of triene-17α.21-dihydroxy-3.20-dione 17-propionate are obtained. Contains 0.9% of the corresponding 21-propionate when analyzed by high performance liquid chromatography. 17α・21
- Diols cannot be detected. 17-propionate yield 97.2%.
実施例 ２
17α・21−（1′−エトキシ−ｎ−プロピリデン
ジオキシ）−16β−メチルプレグナ−１・４・
9(11)−トリエン−３・20−ジオン1.043ｇにメタ
ノール20ml、5.5％（ｗ／ｗ）塩化アルミニウム
水溶液10mlを加え、室温（26℃）で１時間撹拌す
る。反応液に水100mlを添加し、析出結晶を別
する。粗16β−メチルプレグナ−１・４・９−ト
リエン−17α・21−ジヒドロキシ−３・20−ジオ
ン 17−プロピオネート1.022ｇ得る。高速液体
クロマトグラフイーによる分析では対応する21−
プロピオネートを1.0％含む。収率98.4％、17
α・21−ジオールは検知できない。Example 2 17α・21-(1′-ethoxy-n-propylidenedioxy)-16β-methylpregna-1・4・
20 ml of methanol and 10 ml of 5.5% (w/w) aqueous aluminum chloride solution are added to 1.043 g of 9 (11) -triene-3.20-dione, and the mixture is stirred at room temperature (26°C) for 1 hour. Add 100 ml of water to the reaction solution and separate the precipitated crystals. 1.022 g of crude 16β-methyl pregna-1,4,9-triene-17α,21-dihydroxy-3,20-dione 17-propionate is obtained. In high-performance liquid chromatography analysis, the corresponding 21−
Contains 1.0% propionate. Yield 98.4%, 17
α・21-diol cannot be detected.
実施例 ３
17α・21−（1′−エトキシ−ｎ−プロピリデン
ジオキシ）−16β−メチル−９β・11β−エポキ
シプレグナ−１・４−ジエン−３・20−ジオン
1.021ｇにメタノール５ml、0.28％（ｗ／ｗ）塩
化アルミニウム水溶液１mlを加え、室温（18℃）
で４時間撹拌する。反応液に水300mlを加え、析
出結晶を別する。粗16β−メチル−９β・11β
−エポキシプレグナ−１・４−ジエン−17α・21
−ジヒドロキシ−３・20−ジオン 17−プロピオ
ネート0.960ｇを得る。高速液体クロマトグラフ
イーによる分析では対応する21−プロピオネート
を0.9％含む。収率98.0％、17α・21−ジオール
体は検知できない。Example 3 17α・21-(1′-ethoxy-n-propylidenedioxy)-16β-methyl-9β・11β-epoxy pregna-1・4-diene-3・20-dione
Add 5 ml of methanol and 1 ml of 0.28% (w/w) aluminum chloride aqueous solution to 1.021 g, and mix at room temperature (18°C).
Stir for 4 hours. Add 300 ml of water to the reaction solution and separate the precipitated crystals. Crude 16β-methyl-9β/11β
-Epoxy pregna-1,4-diene-17α・21
-Dihydroxy-3.20-dione 0.960 g of 17-propionate is obtained. Contains 0.9% of the corresponding 21-propionate when analyzed by high performance liquid chromatography. Yield: 98.0%, 17α・21-diol compound cannot be detected.
実施例 ４
17α・21−（1′−エトキシ−ｎ−ブチリデンジ
オキシ）−11β−ヒドロキシプレグナ−４−エン
−３・20−ジオン0.51ｇにメタノール4.5ml、0.28
％（ｗ／ｗ）塩化アルミニウム水溶液0.5mlを加
え、室温（18℃）で２時間撹拌する。これに水を
100ml加え、析出結晶を別する。粗ハイドロコ
ーチゾン 17−ブチレート0.610ｇを得る。高速
液体クロマトグラフイーによる分析では、対応す
る21−ブチレートを1.2％を含む。収率97.8％、
17α・21−ジオール体は検知できない。Example 4 0.51 g of 17α・21-(1′-ethoxy-n-butylidenedioxy)-11β-hydroxypregna-4-ene-3・20-dione, 4.5 ml of methanol, 0.28
% (w/w) aluminum chloride aqueous solution is added, and the mixture is stirred at room temperature (18°C) for 2 hours. Add water to this
Add 100ml and separate the precipitated crystals. 0.610 g of crude hydrocortisone 17-butyrate is obtained. Contains 1.2% of the corresponding 21-butyrate when analyzed by high performance liquid chromatography. Yield 97.8%,
17α・21-diol cannot be detected.
Claims (1)
（） （式中Ｒは炭素数１〜10のアルキル基、アラルキ
ル基、シクロアルキル基、またはアリール基を示
し、R′は炭素数１〜４の低級アルキル基を示
す。） で示される17α・21−ジヒドロキシ−20−ケト−
ステロイド類の17α・21−環状オルトエステル類
を、ルイス酸の共存下に、水性アルコール媒質中
にて加水分解することを特徴とする17α・21−ジ
ヒドロキシ−20−ケト−ステロイド類の17−モノ
エステルの製法。[Claims] 1 The 17th position of the D ring and its side chain have the partial structural formula () (In the formula, R represents an alkyl group, an aralkyl group, a cycloalkyl group, or an aryl group having 1 to 10 carbon atoms, and R' represents a lower alkyl group having 1 to 4 carbon atoms.) dihydroxy-20-keto-
A 17-mono-17-mono-steroid of 17α-21-dihydroxy-20-keto-steroids characterized by hydrolyzing 17α-21-cyclic orthoesters of steroids in an aqueous alcoholic medium in the presence of a Lewis acid. Production method of ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7980180A JPS577499A (en) | 1980-06-13 | 1980-06-13 | Improved preparation of steroid 17-ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7980180A JPS577499A (en) | 1980-06-13 | 1980-06-13 | Improved preparation of steroid 17-ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS577499A JPS577499A (en) | 1982-01-14 |
| JPS6247199B2 true JPS6247199B2 (en) | 1987-10-06 |
Family
ID=13700313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7980180A Granted JPS577499A (en) | 1980-06-13 | 1980-06-13 | Improved preparation of steroid 17-ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS577499A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63164296U (en) * | 1987-04-15 | 1988-10-26 | ||
| US10981746B2 (en) | 2017-07-04 | 2021-04-20 | Tombow Pencil Co., Ltd. | Coating film transfer tool |
-
1980
- 1980-06-13 JP JP7980180A patent/JPS577499A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63164296U (en) * | 1987-04-15 | 1988-10-26 | ||
| US10981746B2 (en) | 2017-07-04 | 2021-04-20 | Tombow Pencil Co., Ltd. | Coating film transfer tool |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS577499A (en) | 1982-01-14 |
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