JPS6210239B2 - - Google Patents
Info
- Publication number
- JPS6210239B2 JPS6210239B2 JP3297976A JP3297976A JPS6210239B2 JP S6210239 B2 JPS6210239 B2 JP S6210239B2 JP 3297976 A JP3297976 A JP 3297976A JP 3297976 A JP3297976 A JP 3297976A JP S6210239 B2 JPS6210239 B2 JP S6210239B2
- Authority
- JP
- Japan
- Prior art keywords
- steroid
- keto
- steroids
- producing
- cholesten
- 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
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 18
- 239000005751 Copper oxide Substances 0.000 claims description 15
- 229910000431 copper oxide Inorganic materials 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 150000003431 steroids Chemical class 0.000 claims description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 5
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 3
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 claims description 3
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 claims description 3
- OILXMJHPFNGGTO-MPVBJYOVSA-N Brassicasterin Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@@]12C OILXMJHPFNGGTO-MPVBJYOVSA-N 0.000 claims description 3
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 claims description 3
- NLDBCFRIELDMRO-UHFFFAOYSA-N Stigmasterin Natural products CCCC(CC)C=CC(C)C1CCC2C3CC=C4CC(O)CCC4(C)C3CCC12C NLDBCFRIELDMRO-UHFFFAOYSA-N 0.000 claims description 3
- OILXMJHPFNGGTO-ZAUYPBDWSA-N brassicasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZAUYPBDWSA-N 0.000 claims description 3
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 claims description 3
- XIIAYQZJNBULGD-LDHZKLTISA-N cholestane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XIIAYQZJNBULGD-LDHZKLTISA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims description 3
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims description 3
- UIMGHSAOLFTOBF-VEIPTCAHSA-N (3r,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound C1CC2=C[C@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 UIMGHSAOLFTOBF-VEIPTCAHSA-N 0.000 claims description 2
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 claims description 2
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims description 2
- UPGTYLFCVNHBTN-OFAYOZIESA-N cholesta-5,22E-dien-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/CC(C)C)[C@@]1(C)CC2 UPGTYLFCVNHBTN-OFAYOZIESA-N 0.000 claims description 2
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 claims description 2
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 2
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 claims description 2
- -1 steroid compound Chemical class 0.000 claims 5
- UIMGHSAOLFTOBF-DPAQBDIFSA-N 3beta-Hydroxycholest-4-ene Chemical compound C1CC2=C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 UIMGHSAOLFTOBF-DPAQBDIFSA-N 0.000 claims 1
- QSHQKIURKJITMZ-BRPMRXRMSA-N cholane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC)[C@@]1(C)CC2 QSHQKIURKJITMZ-BRPMRXRMSA-N 0.000 claims 1
- UACIBCPNAKBWHX-CTBOZYAPSA-N gonane Chemical compound C1CCC[C@@H]2[C@H]3CC[C@@H]4CCC[C@H]4[C@@H]3CCC21 UACIBCPNAKBWHX-CTBOZYAPSA-N 0.000 claims 1
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane group Chemical group [C@@H]12CC[C@H](CC)[C@@]1(C)CC[C@H]1[C@H]2CCC2CCCC[C@]12C JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 6
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 3
- 239000005750 Copper hydroxide Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000009102 absorption Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229910001956 copper hydroxide Inorganic materials 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- NYOXRYYXRWJDKP-GYKMGIIDSA-N cholest-4-en-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 NYOXRYYXRWJDKP-GYKMGIIDSA-N 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical group [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- SUPOKHOQAKXOHJ-BYZMTCBYSA-N (8s,9s,10r,13r,14s,17s)-17-ethyl-10,13-dimethyl-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CC2=CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 SUPOKHOQAKXOHJ-BYZMTCBYSA-N 0.000 description 1
- LYFPAZBMEUSVNA-FZFXZXLVSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound C1C=C2CC(O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 LYFPAZBMEUSVNA-FZFXZXLVSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940116318 copper carbonate Drugs 0.000 description 1
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- GRXPVLPQNMUNNX-MHJRRCNVSA-N estrane Chemical compound C1CC2CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 GRXPVLPQNMUNNX-MHJRRCNVSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960000249 pregnenolone Drugs 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 229930193551 sterin Natural products 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
本発明は３−ケト−△４−ステロイドの製造
法、更に詳細には、３−ヒドロキシ−△4または5
−ステロイドを酸化銅触媒の存在下で減圧下加熱
脱水素せしめて３−ケト−△４−ステロイドを製
造する方法に関する。
３−ケト−△４−ステロイドの構造を有するも
のとしては、テストステロン（男性ホルモン）、
プロゲステロン（黄体ホルモン）、コルチゾン
（副腎皮質ホルモン）などの重要なステロイドが
ある。
従来、３−ケト−△４−ステロイドは、一般に
３−ヒドロキシ−△５−ステロイドをオツペンナ
ウア酸化する方法によつて製造していた〔例え
ば、デイー・エイ・シエフアード（D.A.
Shepherd）ら：Journal of the American
Chemical Society、第77巻、1212〜1215頁
（1955年）またはOrganic Synthesis、第21巻、
第18頁（1941年）参照〕。しかし、この方法は多
量の溶媒、２当量以上の水素受容体および0.5モ
ル当量程度のアルミニウムアルコラートを使用し
て反応させるため工業的操作上難点があつた。
また、３−ヒドロキシ−△５−ステロイドをラ
ネ−ニツケル−アセトンで酸化する方法〔S.K.
Banerjeeら：Tetrahedron、第24巻、6459〜6467
頁（1968年）〕が知られているが、この方法も多
量の触媒と水素受容体を必要とすると共に、収率
も30％位で工業的方法とは謂い得ない。
更にまた、イー・ヘルンホルツ（E.
Fernholz）は原料ステロイドの３倍量の酸化銅
を用いて、△５−プレグネン−３β−オール−20
−オンを310℃で20分間加熱して△４−プレグネ
ン−３・20−ジオンを得る方法〔Berichte der
Deutschen Chemischen Gesellschaft、第67巻、
第2027〜2031頁（1934年）〕を報告している。し
かし、この方法の収率は５％と極めて低く、到底
工業的に実施し得るものではない。
本発明者は、このイー・ヘルンホルツ氏の酸化
銅による脱水素反応を研究していたところ、脱水
素反応に伴つて酸化銅触媒の表面に水が生成附着
し、反応が阻害されて停止すること、反応温度を
170〜280℃の範囲、好ましくは240〜270℃におい
て、減圧度50〜600mmHg、好ましくは100〜300mm
Hgで反応を行つて触媒表面の水を反応系外に除
去すれば、斯る反応の阻害による停止を防止でき
ること、更に副反応の原因が酸化銅の表面が酸化
あるいは塩基性であることにあり、触媒表面のPH
を７〜８に調整することにより副反応を回避でき
ることを見出し、その反応率を80〜98％に高める
ことに成功し、本発明を完成した。
本発明方法を適用できる原料の３−ヒドロキシ
−△４または５−ステロイドとしては、例えばそ
の母核が次の一般式（）で表わされるものが挙
げられる。
ゴナン（Ａ、Ｂ、Ｒ＝Ｈ）
エストラン（Ａ、Ｒ＝Ｈ、Ｂ＝CH3）
アンドロスタン（Ａ、Ｂ＝CH3、Ｒ＝Ｈ）
プレグナン（Ａ、Ｂ＝CH3、Ｒ＝C2H5）
コラン（Ａ、Ｂ＝CH3、Ｒ＝CH（CH3）
CH2CH2CH3）
コレスタン（Ａ、Ｂ＝CH3、Ｒ＝CH（CH3）
CH2CH2CH2CH（CH3）2）
更に、上記以外の３−ヒドロキシ−△５−ステ
ロイドとして次のものが挙げられる。
ブラシカステリン（Ａ、Ｂ＝CH3、Ｒ＝CH
（CE3）CH＝CHCH（CH3）CH（CH3）2）
カンペステリン（Ａ、Ｂ＝CH3、Ｒ＝CH
（CH3）CH2CH2CH（CH3）CH（CH3）2）
スチグマステリン（Ａ、Ｂ＝CH3、Ｒ＝CH
（CH3）CH＝CHCH（C2H5）CH（CH3）2）
シストステリン（Ａ、Ｂ＝CH3、Ｒ＝CH
（CH3）CH2CH2CH（C2H5）CH（CH3）2）
本発明の酸化銅触媒としては、種々の銅塩を直
接熱分解するか、または水酸化銅を空気中で200
〜500℃で焼成した通常の酸化銅を用いることが
できる。銅塩の種類により生成した酸化銅触媒の
表面の性質が異なるが、これは蒸留水による洗浄
水のPHによつて知ることができる。しかし、本発
明では酸化銅触媒の表面のPHが７〜８であること
が必要であり、これは次のごとく調整される。例
えば、硝酸銅の加熱分解によつて得られた酸化銅
の表面は酸性を示すことが多いが、これは水で充
分洗浄することにより、また水酸化銅、炭酸銅の
焼成物は塩基性であることが多く、水洗のみで当
該PHにすることは困難であるが、希塩酸次いで水
で洗浄することにより容易にその表面をPH７〜８
に調整することができる。斯くしてPHを調整した
酸化銅は再び約200℃で焼成して触媒に供する。
触媒の使用量は原料ステロイドに対して５〜40
重量％、特に約20重量％が好ましい。前記の反応
温度ならびに減圧度で0.5〜1.5時間、通常１時間
行えば反応は完結する。反応の終了は水素ガスお
よび生成水の発生の停止を観察することによつて
確認される。
次に実施例を挙げて説明する。
実施例 １
硝酸銅溶液にアンモニア水を加えて水酸化銅を
分離し、空気中で180〜200℃に加熱して酸化銅を
得た。この洗浄水はPH８以上であつた（CuO−
）。これを1N塩酸で１回洗浄後水洗したときの
PHは４以下であつた（CuO−）。更に水で３回
洗浄することにより洗浄水のPHは7.2〜7.4となつ
た（CuO−）。この３種類の酸化銅を使用し
て、次の実験を行つた。
△５−コレステン−３β−オール（通称コレス
テロール）５ｇおよび酸化銅１ｇを無溶媒下、冷
却管を通して150mmHgに保ち、260℃で撹拌下１
時間加熱反応させた。生成物はガスクロマトグラ
フにより分析し、CuO−の場合は石油エーテ
ルより再結晶して△４−コレステン−３−オン
4.58ｇを得た。融点79〜82℃〔α〕D＋87゜（エタ
ノール）。その結果は第１表の如くである。
The present invention relates to a method for producing 3-keto-△ 4 -steroids, more specifically, 3-hydroxy-△ 4 or 5-steroids.
- A method for producing 3-keto- Δ4 -steroids by heating and dehydrogenating steroids under reduced pressure in the presence of a copper oxide catalyst. 3-Keto-△ 4 -Those with the structure of steroids include testosterone (male hormone),
There are important steroids such as progesterone (progesterone) and cortisone (adrenocortical hormone). Conventionally, 3-keto-△ 4 -steroids have generally been produced by the Otspenauer oxidation method of 3-hydroxy-△ 5 -steroids [for example, D.A.
Shepherd et al.: Journal of the American
Chemical Society, Vol. 77, pp. 1212-1215 (1955) or Organic Synthesis, Vol. 21,
See page 18 (1941)]. However, this method was difficult in terms of industrial operation because it required a large amount of solvent, 2 or more equivalents of hydrogen acceptor, and about 0.5 molar equivalent of aluminum alcoholate. In addition, a method of oxidizing 3-hydroxy-△ 5 -steroid with Raney-nickel-acetone [SK
Banerjee et al.: Tetrahedron, Volume 24, 6459-6467
(1968)], but this method also requires a large amount of catalyst and hydrogen acceptor, and the yield is only about 30%, so it cannot be called an industrial method. Furthermore, E. Hernholtz (E.
Fernholz) used copper oxide in an amount three times that of the raw material steroid to produce △ 5 -pregnen-3β-ol-20.
A method to obtain △ 4 -pregnene-3.20-dione by heating it at 310°C for 20 minutes [Berichte der
Deutschen Chemischen Gesellschaft, Volume 67,
No. 2027-2031 (1934)]. However, the yield of this method is extremely low at 5%, and it is not possible to implement it industrially. The present inventor was researching E. Hernholtz's dehydrogenation reaction using copper oxide, and found that water was formed and attached to the surface of the copper oxide catalyst during the dehydrogenation reaction, inhibiting the reaction and stopping it. , reaction temperature
In the range of 170-280℃, preferably 240-270℃, degree of vacuum 50-600mmHg, preferably 100-300mm
If the reaction is carried out with Hg and the water on the surface of the catalyst is removed from the reaction system, it is possible to prevent the reaction from stopping due to inhibition, and furthermore, the cause of the side reaction is that the surface of copper oxide is oxidized or basic. , PH of catalyst surface
It was discovered that side reactions could be avoided by adjusting the ratio to 7 to 8, and the present invention was completed by successfully increasing the reaction rate to 80 to 98%. Examples of the raw material 3-hydroxy- Δ4- or 5 -steroid to which the method of the present invention can be applied include those whose core is represented by the following general formula (). Gonan (A, B, R=H) Estran (A, R=H, B=CH 3 ) Androstane (A, B=CH 3 , R=H) Pregnane (A, B=CH 3 , R=C 2 H 5 ) Coran (A, B=CH 3 , R=CH (CH 3 )
CH 2 CH 2 CH 3 ) Cholestan (A, B=CH 3 , R=CH (CH 3 )
CH 2 CH 2 CH 2 CH(CH 3 ) 2 ) Furthermore, the following may be mentioned as 3-hydroxy- Δ5 -steroids other than those mentioned above. Brassicasterin (A, B=CH 3 , R=CH
(CE 3 ) CH=CHCH (CH 3 ) CH (CH 3 ) 2 ) Campesterin (A, B=CH 3 , R=CH
( CH3 ) CH2CH2CH ( CH3 )CH( CH3 ) 2 ) Stigmasterin (A , B= CH3 , R=CH
( CH3 )CH=CHCH( C2H5 )CH( CH3 ) 2 ) Cystosterin (A, B= CH3 , R= CH
( CH3 ) CH2CH2CH ( C2H5 )CH( CH3 ) 2 ) The copper oxide catalyst of the present invention can be produced by directly thermally decomposing various copper salts, or by directly thermally decomposing copper hydroxide in air. 200
Regular copper oxide fired at ~500°C can be used. The surface properties of the copper oxide catalyst produced differ depending on the type of copper salt, and this can be determined by the pH of the washing water with distilled water. However, in the present invention, it is necessary that the surface pH of the copper oxide catalyst is 7 to 8, and this is adjusted as follows. For example, the surface of copper oxide obtained by thermal decomposition of copper nitrate often shows acidity, but this can be fixed by washing thoroughly with water, and the baked products of copper hydroxide and copper carbonate can be made basic. It is difficult to bring the surface to pH 7 to 8 by washing with dilute hydrochloric acid and then water.
can be adjusted to The copper oxide whose pH has been adjusted in this way is fired again at about 200°C and used as a catalyst. The amount of catalyst used is 5 to 40% of the raw material steroid.
% by weight is preferred, especially about 20% by weight. The reaction is completed after 0.5 to 1.5 hours, usually 1 hour, at the above-mentioned reaction temperature and reduced pressure. Completion of the reaction is confirmed by observing the cessation of generation of hydrogen gas and produced water. Next, an example will be given and explained. Example 1 Aqueous ammonia was added to a copper nitrate solution to separate copper hydroxide, and the solution was heated to 180 to 200°C in air to obtain copper oxide. This washing water had a pH of 8 or higher (CuO−
). When this was washed once with 1N hydrochloric acid and then with water,
The pH was 4 or less (CuO−). By further washing with water three times, the pH of the washing water became 7.2 to 7.4 (CuO-). The following experiment was conducted using these three types of copper oxide. △ 5 g of 5-cholesten-3β-ol (commonly known as cholesterol) and 1 g of copper oxide were passed through a cooling tube without solvent, maintained at 150 mmHg, and stirred at 260°C for 1 hour.
The mixture was heated and reacted for an hour. The product was analyzed by gas chromatography, and in the case of CuO-, it was recrystallized from petroleum ether to produce △ 4 -cholesten-3-one.
4.58g was obtained. Melting point: 79-82°C [α] D +87° (ethanol). The results are shown in Table 1.
【表】
実施例 ２
実施例１のCuO−触媒１ｇを使用して、△
5、22−コレスタジエン−３β−オール５ｇを260
℃で常圧（760mmHg）および150mmHgにて、各々
１時間反応させた。沸点150mmHg下の生成物を石
油エーテルで再結晶し、△4、22−コレスタジエ
ン−３β−オン4.0ｇ得た。融点128.5〜129.5℃。
〔α〕D＋54.4゜。常圧下と150mmHg下の反応の比
較を第２表に示す。[Table] Example 2 Using 1 g of CuO-catalyst of Example 1, △
5 , 22 -cholestadien-3β-ol 5g at 260
The reaction was carried out at a temperature of 1 hour at normal pressure (760 mmHg) and 150 mmHg, respectively. The product having a boiling point of 150 mmHg was recrystallized from petroleum ether to obtain 4.0 g of Δ4,22 -cholestadien-3β-one. Melting point 128.5-129.5℃.
[α] D +54.4°. Table 2 shows a comparison of reactions under normal pressure and 150 mmHg.
【表】
実施例 ３
△５−アンドロステン−３β−オール５ｇに
CuO−２ｇ加え、230℃で200mmHg下に１時間
反応させ、生成物は石油エーテルより再結晶して
△４−アンドロステン−３−オン4.8ｇ得た。融
点105℃。〔α〕D＋110゜。
実施例 ４
△５−プレグネン−３β−オール−20−オン
（通称プレグネノロン）５ｇにCuO−２ｇを加
え、240℃で150mmHg下に１時間反応させ、生成
物を石油エーテルで再結晶し△４−プレグネン−
３・20−ジオン４ｇを得た。融点128℃。〔α〕D＋
192゜。
実施例 ５
△４−コレステン−３α−オール５ｇにCuO
−２ｇを加え、240℃で150mmHg下に１時間反
応させ、生成物は石油エーテルより再結晶して△
４−コレステン−３−オン4.5ｇを得た。融点80
℃。〔α〕D＋87゜。
実施例 ６
大豆油より得られる大豆ステリン（ブラシカス
テリン6.2％、カンペステリン25.5％、スチグマ
ステリン21.7％、シトステリン38.7％）20ｇに
CuO−を５ｇ加え、240℃で150mmHg下に１時
間反応させた生成物19ｇを得た。生成物の赤外線
吸収スペクトルによると原料大豆ステリンにおい
てヒドロキシ基の吸収を示す3390〜3270cm-1およ
び1044〜1037cm-1の吸収が消失し、３−ケト−△
４−ステロイドを示す1675cm-1の吸収が大きく出
現した。またガスクロマトグラフ分析で原料ステ
リンの各々が含有量に対応する３−ケト−△４−
ステロイドが確認された。[Table] Example 3 △ 5 -androsten-3β-ol 5g
2g of CuO was added, and the reaction was carried out at 230°C under 200mmHg for 1 hour, and the product was recrystallized from petroleum ether to obtain 4.8g of Δ4 -androsten-3-one. Melting point 105℃. [α] D +110°. Example 4 △ 5 - 2 g of CuO was added to 5 g of pregnen-3β-ol-20-one (commonly known as pregnenolone), and the reaction was carried out at 240°C and 150 mmHg for 1 hour, and the product was recrystallized with petroleum ether. △ 4 - Pregnen
4 g of 3,20-dione was obtained. Melting point: 128℃. [α] D +
192°. Example 5 △ 4 -Cholesten-3α-ol 5g and CuO
-2g was added and reacted at 240℃ for 1 hour under 150mmHg, and the product was recrystallized from petroleum ether.
4.5 g of 4 -cholesten-3-one was obtained. melting point 80
℃. [α] D +87°. Example 6 Soybean sterin obtained from soybean oil (brassicasterin 6.2%, campesterin 25.5%, stigmasterin 21.7%, sitosterin 38.7%) in 20 g
5 g of CuO- was added and reacted at 240° C. for 1 hour under 150 mmHg to obtain 19 g of a product. According to the infrared absorption spectrum of the product, the absorptions of 3390 to 3270 cm -1 and 1044 to 1037 cm -1 , which indicate absorption of hydroxyl groups in the raw soybean sterine, disappeared, and 3-keto-△
4 - A large absorption at 1675 cm -1 indicating steroids appeared. In addition, gas chromatographic analysis revealed that each of the raw material sterine was 3-keto-△ 4- corresponding to the content.
Steroids were confirmed.
Claims (1)
を、表面PH７〜８の酸化銅触媒の存在下、50〜
600mmHgの減圧下、170〜280℃に加熱することを
特徴とする３−ケト−△４−ステロイドの製造
法。 ２ ３−ヒドロキシ−△4または5−ステロイド
は、母核がゴナン、エストラン、アンドロスタ
ン、プレグナン、コランまたはコレスタンである
ステロイド化合物である特許請求の範囲第１項記
載の３−ケト−△４−ステロイドの製造法。 ３ ３−ヒドロキシ−△５−ステロイドがブラシ
カステリン、カンペステリン、スチグマステリン
またはシトステリンである特許請求の範囲第１項
記載の３−ケト−△４−ステロイドの製造法。 ４ 母核がアンドロスタンであるステロイド化合
物が△５−アンドロステン−３β−オールである
特許請求の範囲第２項記載の３−ケト−△４−ス
テロイドの製造法。 ５ 母核がプレグナンであるステロイド化合物が
△５−プレグネン−３β−オール−20−オンであ
る特許請求の範囲第２項記載の３−ケト−△４−
ステロイドの製造法。 ６ 母核がコレスタンであるステロイド化合物が
△５−コレステン−３β−オール、△5、22−コ
レスタジエン−３β−オール、△４−コレステン
−３β−オール、△４−コレステン−３α−オー
ルまたは△５−コレステン−３β−オールである
特許請求の範囲第２項記載の３−ケト−△４−ス
テロイドの製造法。 ７ 減圧度が100〜300mmHg、反応温度が240〜
270℃である特許請求の範囲第１項記載の３−ケ
ト−△４−ステロイドの製造法。[Claims] 1 3-Hydroxy-△ 4 or 5 -steroid in the presence of a copper oxide catalyst with a surface pH of 7 to 8,
A method for producing 3-keto- Δ4 -steroids, which comprises heating to 170 to 280°C under reduced pressure of 600 mmHg. 3-keto- Δ4- according to claim 1, wherein the 2-3-hydroxy- Δ4 or 5 -steroid is a steroid compound whose parent nucleus is gonane, etran, androstane, pregnane, cholan or cholestane. Method of manufacturing steroids. 3. The method for producing a 3-keto- Δ4 -steroid according to claim 1, wherein the 3-hydroxy- Δ5 -steroid is brassicasterin, campesterin, stigmasterin or sitosterin. 4. The method for producing a 3-keto- Δ4 -steroid according to claim 2, wherein the steroid compound whose core is androstane is Δ5 -androsten-3β-ol. 5. The 3-keto- Δ4- according to claim 2, wherein the steroid compound whose core is pregnane is Δ5 -pregnen-3β-ol-20-one.
Method of manufacturing steroids. 6 The steroid compound whose core is cholestane is △ 5 -cholesten-3β-ol, △ 5 , 22 -cholestadien-3β-ol, △ 4 -cholesten-3β-ol, △ 4 -cholesten-3α-ol or △ 5 -Cholesten-3β-ol, the method for producing 3-keto- Δ4 -steroid according to claim 2. 7 Degree of reduced pressure is 100~300mmHg, reaction temperature is 240~
The method for producing 3-keto- Δ4 -steroids according to claim 1, wherein the temperature is 270°C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3297976A JPS52116456A (en) | 1976-03-25 | 1976-03-25 | Preparation of 3-keto- #4-steroid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3297976A JPS52116456A (en) | 1976-03-25 | 1976-03-25 | Preparation of 3-keto- #4-steroid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS52116456A JPS52116456A (en) | 1977-09-29 |
| JPS6210239B2 true JPS6210239B2 (en) | 1987-03-05 |
Family
ID=12373992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3297976A Granted JPS52116456A (en) | 1976-03-25 | 1976-03-25 | Preparation of 3-keto- #4-steroid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS52116456A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7858603B2 (en) * | 2003-03-11 | 2010-12-28 | Trophos | Use of derivatives of cholest-4-en-3-one as medicaments, pharmaceutical compositions containing same, novel derivatives and preparation method thereof |
-
1976
- 1976-03-25 JP JP3297976A patent/JPS52116456A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52116456A (en) | 1977-09-29 |
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