JPS6141360B2 - - Google Patents
Info
- Publication number
- JPS6141360B2 JPS6141360B2 JP13879478A JP13879478A JPS6141360B2 JP S6141360 B2 JPS6141360 B2 JP S6141360B2 JP 13879478 A JP13879478 A JP 13879478A JP 13879478 A JP13879478 A JP 13879478A JP S6141360 B2 JPS6141360 B2 JP S6141360B2
- Authority
- JP
- Japan
- Prior art keywords
- reacted
- trihydroxy
- reaction
- cholestane
- solution
- 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
- 238000006243 chemical reaction Methods 0.000 claims description 39
- DGABKXLVXPYZII-UHFFFAOYSA-N Hyodeoxycholic acid Natural products C1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DGABKXLVXPYZII-UHFFFAOYSA-N 0.000 claims description 9
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 claims description 7
- DGABKXLVXPYZII-SIBKNCMHSA-N hyodeoxycholic acid Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DGABKXLVXPYZII-SIBKNCMHSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- -1 methylmagnesium halide Chemical class 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 claims description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 150000003461 sulfonyl halides Chemical class 0.000 claims 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 35
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 9
- INBGSXNNRGWLJU-ZHHJOTBYSA-N 25-hydroxycholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCCC(C)(C)O)C)[C@@]1(C)CC2 INBGSXNNRGWLJU-ZHHJOTBYSA-N 0.000 description 8
- INBGSXNNRGWLJU-UHFFFAOYSA-N 25epsilon-Hydroxycholesterin Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(CCCC(C)(C)O)C)C1(C)CC2 INBGSXNNRGWLJU-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000000638 solvent extraction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 2
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 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 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- AAHFRWRQQDVWPX-UHFFFAOYSA-N prop-2-ene-1-sulfonyl chloride Chemical compound ClS(=O)(=O)CC=C AAHFRWRQQDVWPX-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 2
- 239000011647 vitamin D3 Substances 0.000 description 2
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 1
- OMIHGPLIXGGMJB-UHFFFAOYSA-N 7-oxabicyclo[4.1.0]hepta-1,3,5-triene Chemical compound C1=CC=C2OC2=C1 OMIHGPLIXGGMJB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DRQPUIWNQWKUJQ-PPUMZTHNSA-N C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C(O)C(O)(O)[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C(O)C(O)(O)[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 DRQPUIWNQWKUJQ-PPUMZTHNSA-N 0.000 description 1
- 235000021318 Calcifediol Nutrition 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- DSBZSDSUGSYUHV-UHFFFAOYSA-N [17-(6-hydroxy-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(CCCC(C)(C)O)C)C1(C)CC2 DSBZSDSUGSYUHV-UHFFFAOYSA-N 0.000 description 1
- VHHPDZDTKZOHTB-UHFFFAOYSA-M [Br-].[Mg+]C.C1CCOC1 Chemical compound [Br-].[Mg+]C.C1CCOC1 VHHPDZDTKZOHTB-UHFFFAOYSA-M 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- KPUNOVLMCQQCSK-UHFFFAOYSA-N diazomethane;ethoxyethane Chemical compound C=[N+]=[N-].CCOCC KPUNOVLMCQQCSK-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- VIJMMQUAJQEELS-UHFFFAOYSA-N n,n-bis(ethenyl)ethenamine Chemical compound C=CN(C=C)C=C VIJMMQUAJQEELS-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
本発明は、3β・25−ジヒドロキシコレスト−
5−エン、すなわち25−ヒドロキシコレステロー
ルまたはその3β−アセテートの新規な製造法に
関する。
さらに詳しくは、活性型ビタミンD3として近
年注目をあびている25−ヒドロキシコレカルシフ
エロールに容易に導き得る中間体である25−ヒド
ロキシコレステロールまたはその3β−アシレー
トの新規な製造法に関する。
25−ヒドロキシコレステロールの製造法として
は、従来、レイヤー(A.I.Ryer)等の方法〔ジヤ
ーナル・オブ・アメリカン・ケミカル・ソサイエ
テイ(J.Am.Chem.Soa、)72 4247(1950)参
照〕およびダウベン(W.G.Dauben)等の方法
(J.Am.Chem.Soc、72 4248(1950)参照)が知
られている。
レイヤー等の方法は3β−アセトキシ−5−コ
レステン−25−オンにメチルマグネシウムヨウダ
イドを作用して25−ヒドロキシコレステロールを
得るものであり、後者の方法は原料として上記ス
テロールエステルの遊離ヒドロキシ体である、3
β−ヒドロキシ−5−コレステン−25−オンを使
用することを除いてはほぼ前者と同じ方法であ
る。
これらの方法の原料であるノルコレステロール
−25−オンは、コレステロールを酸化して得られ
るものであるが、収率が悪く且つ種々の酸化成績
体からノルコレステロール−25−オンのみを分離
精製しなければならないから、大量に入手するこ
とが困難であるという大きな欠点を有しており、
それ故、これらの方法は25−ヒロドロキシコレス
テロールの工業的製造法としては望ましい方法と
は言い難い。
本発明の目的は入手の容易な原料から出発して
簡易な操作で収率よく25−ヒドロキシコレステロ
ールを工業的に製造する方法を提供することにあ
る。
本発明の方法は、いくつかの反応工程よりなつ
ており、これを反応式で表わせば次の通りであ
る。
上記反応式中、AcはCH3CO−基を表わし、
R′は脂肪族基、R″は水素原子またはCH3CO−基
を表わし、Rはアルキル基またはアリール基を表
わし、Xは塩素、臭素または沃素原子を表わして
いる。
本発明は上記の反応より一見して明らかな通
り、全プロセスは第1工程より第6工程までの6
つの工程より成つているが、第4工程までで得ら
れる中間体は3α・6α・25−トリヒドロキシ−
5β−コレスタンであり、3個の水酸基が遊離の
形にあるものである。このことは、第1工程ない
し第3工程で用いられるハロゲン化剤ないしはエ
ステル残基が結果として全て外れるということを
意味している。
また、同様なことが第5工程および第6工程に
ついても言うことができる。
以下、本発明方法を上記各工程別に詳細に説明
するが、本発明の出発物質であるヒオデオキシコ
ール酸3α・6α−ジアセテートは市販試薬とし
てまたは工業製品として安価に入手できるヒオデ
キシコール酸を通常のアセチル化方法により容易
に且つ収率よく製造できるものであり、25−ヒド
ロキシコレステロールおよびそのエステルさらに
は活性型ビタミンD3の工業的製造の原料とし
て、価値の高い物質である。
第1工程では、ヒオデオキシコール酸−3α・
6α−ジアセテート体()とハロゲン化剤(例
えばチオニルクロライド)を必要に応じて塩基触
媒(例えばピリジン)の存在下に反応させる。反
応はハロゲン化剤に不活性な溶媒中で冷却下また
は室温で行なう。特に好ましい溶媒系は無水ベン
ゼンである。反応は2〜3時間で完了し反応液も
そのまま減圧濃縮して得られた残渣は数回ベンゼ
ンに溶解後、減圧濃縮をくり返すことにより過剰
のチオニルクロライドを除去して粗ヒオデオキシ
コール酸ハライドジアセテート()が得られ
る。得られた粗生成物()はそのまま第二工程
の原料として利用できる。
第2工程では、粗ヒオデオキシコール酸ハライ
ドジアセテート体()にジアゾメタンを反応さ
せる。反応はジアゾメタンに不活性な溶媒中で冷
却下で行なうことができる。特に好ましいの溶媒
系はベンゼンエーテル混合溶媒である。反応は1
〜2時間で完了し、反応液を室温に戻した後、過
剰のジアゾメタンを除去する為、窒素を1〜2時
間バブリングしながら撹拌した後、減圧濃縮する
事により、粗ジアゾケトン()を得ることがで
きる。得られた粗生成物()はそのまま第三工
程の原料として利用できる。
第3工程では、上記ジアゾケトン()に触媒
量の安息香酸銀および有機塩基(例えばトリエチ
ルアミン、ピリジン等)の存在下、脂肪族アルコ
ール(例えばメタノール、エタノール等)を作用
させる。反応は過剰のアルコールと原料()を
容易に溶解する不活性溶媒(例えばジクロルメタ
ン、クロロホルム等)の混合溶媒系で行なう。特
に好ましい溶媒系はメタノール、ジクロルメタン
(1:1)の混合溶媒である。反応は室温撹拌下
短時間で完了する。生成物の単離精製は通常の方
法、たとえば溶媒抽出、クロマトグラフイ再結晶
等によつて容易に行なうことができる。
第4工程では、上記操作で得られたメチル−25
−ホモヒオデオキシコレート3α・6α−ジアセ
テート()にメチルマグネシウムハライド(X
=CI Br、I)を反応させる。反応はグリニヤー
ル試薬に不活性な溶媒中で冷却または室温で行な
うことができる。特に好ましい溶媒系はエーテル
またはテトラヒドロフランである。反応は1晩撹
拌することにより終了し、生成物の3α・6α・
25−トリハイドロキシ−5β−コレスタン()
は通常の単離精製方法、たとえば溶媒抽出、再結
晶等によつて得易に行なうことができる。
第5工程では、3α・6α・25−トリヒドロキ
シ−5β−コレスタン()とアルキルまたはア
リルスルホニルクロライド(例えばp−トルエン
スルホニルクロライド等)を塩基性有機化合物中
(例えばピリジン、S−コリジン等)で反応させ
る。反応に用いるアルキルまたはアリルスルホニ
ルクロライドは3α・6α25−トリヒドロキシ体
に対し2〜3倍モルが望ましい。反応は冷却下も
しくは室温下、長時間静置することにより進行す
る。生成物の3α・6α・25−トリヒドロキシ−
5β−コレスタン−3α・6α−ジスルホネート
()は反応液を通常の単離方法、たとえば反応
液に氷水を加えた後に溶媒抽出し、乾燥剤で乾燥
後ろ過、濃縮し、粗生成物()として得られ
る。得られた粗生成物()はそのまま第六工程
の原料として用いることができる。
最後の第6工程では、上記生成物3α・6α25
−トリヒドロキシ−5β−コレスタン−3α・6
α−ジトシレート()と酢酸金属塩(例えば酢
酸カリウム等)を極性溶媒中(例えば酢酸、無
酢、ジメチルホルムアミド−H2O、N−メチルピ
リジン−H2O等)で反応させる。
反応は加熱条件下数時間で完了し、生成物の3
β・25−ジヒドロキシコレスト−5−エン−3β
−アセテート()−)は通常の単離方法とし
て、たとえば反応液に氷水を加え、溶媒抽出後、
濃縮し、あるいは残渣をそのまま加水分解反応に
付し、3β・25−ジヒドロキシコレスト−5−エ
ンとして、通常の精製方法であるクロマトグラフ
イー、再結晶によつて容易に得ることができる。
加水分解反応は上記生成物(−)を金属水酸
化物(例えばNaOH、KOH等)と反応させる。
反応は低級アルコールと化合物(−)を溶解
しうる混合溶媒中で室温または冷却下に行なう。
特に好ましい溶媒系はメタノールベンゼン混合液
である。反応は数時間で定量的に進み、生成物の
単離精製は、通常の方法、例えば溶媒抽出、クロ
マトグラフイー、再結晶等によつて容易に行なう
ことができる。
以下の実施例で本発明をさらに詳細に説明す
る。
実施例 1
(a) ヒオデオキシコール酸3α・6α−ジアセテ
ート()2231mg(4.59mmol)およびピリジ
ン0.09mlを無水ベンゼン46mlに加えた。得られ
た溶液を氷冷し(約5℃)撹拌下チオニルクロ
ライド2.07mlを徐々に滴下した。滴下後室温で
2.5時間撹拌した。
反応液を減圧濃縮した。その残渣にさらに無
水ベンゼン25ml加え、くり返し減圧濃縮するこ
とにより残渣に含有されるチオニルクロライド
を追い出した。
得られた固体生成物の粗ヒオデオキシコール
酸クロライド3α・6α−ジアセテートは精製
せずに原料化合物()として用いた。
IR(KBr;cm-1);1810、1735、1250。
(b) 実施例1−(a)で得られた粗ヒオデオキシコー
ル酸クロライド3α・6α−ジアセテート
()を無水ベンゼン27.5mlに溶解し、0.5N−
ジアゾメタンエーテル溶液60ml中に冷却撹拌下
滴下した。滴下後冷却下(約5℃)1時間撹拌
した。
反応液を室温に戻し、過剰のジアゾメタンを
除去する為に窒素をバブリングしながら1時間
撹拌した。さらに反応液を減圧濃縮することに
より粗ジアゾケトン体を得た。得られたジアゾ
ケトン体は精製せずに原料化合物()として
用いた。
IR(KBr、cm-1);2950、2090、1735、1640、
1240。
(c) 実施例1−(b)で得られた粗ジアゾケトン体
()を塩化メチレン14.9mlおよびメタノール
19.3mlに溶解した混合溶液に、室温撹拌下、安
息香酸銀85.5mgをトリエチレンアミン0.86mlに
溶解した溶液をゆつくり滴下した。滴下後、30
分室温で撹拌した。薄層分析で反応が完了して
いる事を確認した後、水を加え、生成物を塩化
メチレンで抽出した。
抽出液を希塩酸、水、重炭酸ナトリウム溶液
および水で順次洗浄した。
抽出液を無水硫酸ナトリウムで乾燥後、ろ過
し濃縮した。濃縮残渣をシリカゲルを充填した
カラムクロマトグラフイー(溶剤ベンゼン−酢
エチ系)に付すことによつて、メチル−25−ホ
モヒオデキシコレート−3α・6α−ジアセテ
ート()を1755mg得た。
(ヒオデオキシコール酸3α・6α−ジアセテ
ート()よりの収量74.4%)。
融点;93〜95℃(メタノール)
IR(KBr)cm-1);2945、2860、1730、1450、
1360、1235、1020。
NMR(CDCI3)δ(ppm));0.63(S、3H、
C−18−CH3)0.96(S、3H、C−19−
CH3)2.02(S、6H、
The present invention provides 3β・25-dihydroxycholesto-
The present invention relates to a novel method for producing 5-ene, i.e., 25-hydroxycholesterol or its 3β-acetate. More specifically, the present invention relates to a novel method for producing 25-hydroxycholesterol or its 3β-acylate, which is an intermediate that can easily be converted into 25-hydroxycholecalciferol, which has recently attracted attention as active vitamin D3 . Conventionally, methods for producing 25-hydroxycholesterol include the method of AIRyer et al. [see Journal of American Chemical Society (J.Am. ) and other methods (see J. Am. Chem. Soc, 72 4248 (1950)) are known. In the method of Layer et al., 25-hydroxycholesterol is obtained by reacting 3β-acetoxy-5-cholesten-25-one with methylmagnesium iodide, and in the latter method, the free hydroxy form of the above-mentioned sterol ester is used as the raw material. ,3
This method is almost the same as the former except that β-hydroxy-5-cholesten-25-one is used. Norcholesterol-25-one, which is the raw material for these methods, is obtained by oxidizing cholesterol, but the yield is poor and only norcholesterol-25-one must be separated and purified from various oxidized products. The major drawback is that it is difficult to obtain in large quantities because of the
Therefore, these methods cannot be said to be desirable as industrial methods for producing 25-hydroxycholesterol. An object of the present invention is to provide a method for industrially producing 25-hydroxycholesterol in good yield using simple operations starting from easily available raw materials. The method of the present invention consists of several reaction steps, which can be expressed by the following reaction formula. In the above reaction formula, Ac represents a CH 3 CO- group,
R' is an aliphatic group, R'' is a hydrogen atom or a CH 3 CO- group, R is an alkyl group or an aryl group, and X is a chlorine, bromine or iodine atom. As is clear at first glance, the entire process consists of 6 steps from the 1st step to the 6th step.
It consists of two steps, but the intermediate obtained up to the fourth step is 3α・6α・25-trihydroxy-
5β-cholestane, with three hydroxyl groups in free form. This means that all of the halogenating agents or ester residues used in the first to third steps are removed as a result. Further, the same can be said about the fifth step and the sixth step. Hereinafter, the method of the present invention will be explained in detail for each of the above-mentioned steps.Hyodeoxycholic acid 3α,6α-diacetate, which is the starting material of the present invention, is prepared by using ordinary hyodeoxycholic acid, which is available at low cost as a commercially available reagent or as an industrial product. It can be easily produced with good yield by an acetylation method, and is a highly valuable substance as a raw material for the industrial production of 25-hydroxycholesterol and its esters, as well as active vitamin D3 . In the first step, hyodeoxycholic acid-3α・
The 6α-diacetate () and a halogenating agent (for example, thionyl chloride) are reacted in the presence of a base catalyst (for example, pyridine) if necessary. The reaction is carried out in a solvent inert to the halogenating agent under cooling or at room temperature. A particularly preferred solvent system is anhydrous benzene. The reaction was completed in 2 to 3 hours, and the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in benzene several times and concentrated under reduced pressure repeatedly to remove excess thionyl chloride and obtain crude hyodeoxycholic acid halide. Diacetate () is obtained. The obtained crude product () can be used as it is as a raw material for the second step. In the second step, the crude hyodeoxycholic acid halide diacetate () is reacted with diazomethane. The reaction can be carried out under cooling in a solvent inert to diazomethane. A particularly preferred solvent system is a benzene ether mixed solvent. The reaction is 1
The reaction was completed in ~2 hours, and after returning the reaction solution to room temperature, it was stirred while bubbling nitrogen for 1 to 2 hours to remove excess diazomethane, and then concentrated under reduced pressure to obtain crude diazoketone (). I can do it. The obtained crude product () can be used as it is as a raw material for the third step. In the third step, the diazoketone (2) is reacted with an aliphatic alcohol (eg, methanol, ethanol, etc.) in the presence of a catalytic amount of silver benzoate and an organic base (eg, triethylamine, pyridine, etc.). The reaction is carried out in a mixed solvent system of excess alcohol and an inert solvent that easily dissolves the raw material (eg, dichloromethane, chloroform, etc.). A particularly preferred solvent system is a mixed solvent of methanol and dichloromethane (1:1). The reaction is completed in a short time under stirring at room temperature. Isolation and purification of the product can be easily carried out by conventional methods such as solvent extraction, chromatography, recrystallization, etc. In the fourth step, the methyl-25 obtained in the above operation is
- Homohyodeoxycholate 3α・6α-diacetate () to methylmagnesium halide (X
=CI Br, I) is reacted. The reaction can be carried out in a solvent inert to the Grignard reagent, cooled or at room temperature. Particularly preferred solvent systems are ether or tetrahydrofuran. The reaction was terminated by stirring overnight, and the products 3α, 6α,
25-trihydroxy-5β-cholestane ()
can be easily obtained by conventional isolation and purification methods such as solvent extraction and recrystallization. In the fifth step, 3α, 6α, 25-trihydroxy-5β-cholestane () and an alkyl or allylsulfonyl chloride (e.g., p-toluenesulfonyl chloride, etc.) are mixed in a basic organic compound (e.g., pyridine, S-collidine, etc.). Make it react. The amount of alkyl or allylsulfonyl chloride used in the reaction is preferably 2 to 3 times the molar amount of the 3α·6α 25 -trihydroxy compound. The reaction proceeds by standing for a long time under cooling or at room temperature. Product 3α・6α・25-trihydroxy-
5β-Cholestane-3α・6α-disulfonate () can be obtained by isolating the reaction solution using a conventional method, such as adding ice water to the reaction solution, solvent extraction, drying with a desiccant, filtering and concentrating, and obtaining the crude product (). obtained as. The obtained crude product () can be used as it is as a raw material for the sixth step. In the final sixth step, the above product 3α・6α25
-trihydroxy-5β-cholestane-3α・6
α-Ditosylate () and a metal acetate (for example, potassium acetate) are reacted in a polar solvent (for example, acetic acid, acetic acid-free, dimethylformamide-H 2 O, N-methylpyridine-H 2 O, etc.). The reaction was completed in several hours under heating conditions, and 3 of the products were
β・25-dihydroxycholest-5-ene-3β
-Acetate ()-) can be isolated using the usual method, for example, by adding ice water to the reaction solution, and after solvent extraction,
By concentrating or directly subjecting the residue to a hydrolysis reaction, 3β25-dihydroxycholest-5-ene can be easily obtained by conventional purification methods such as chromatography and recrystallization.
In the hydrolysis reaction, the above product (-) is reacted with a metal hydroxide (eg, NaOH, KOH, etc.).
The reaction is carried out at room temperature or under cooling in a mixed solvent that can dissolve the lower alcohol and the compound (-).
A particularly preferred solvent system is a methanol benzene mixture. The reaction proceeds quantitatively in several hours, and the product can be easily isolated and purified by conventional methods such as solvent extraction, chromatography, recrystallization, etc. The invention will be explained in further detail in the following examples. Example 1 (a) 2231 mg (4.59 mmol) of hyodeoxycholic acid 3α·6α-diacetate () and 0.09 ml of pyridine were added to 46 ml of anhydrous benzene. The resulting solution was ice-cooled (approximately 5°C), and 2.07 ml of thionyl chloride was gradually added dropwise while stirring. At room temperature after dropping
Stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure. An additional 25 ml of anhydrous benzene was added to the residue, and the mixture was repeatedly concentrated under reduced pressure to drive out thionyl chloride contained in the residue. The obtained solid product, crude hyodeoxycholic acid chloride 3α·6α-diacetate, was used as a raw material compound () without being purified. IR (KBr; cm -1 ); 1810, 1735, 1250. (b) The crude hyodeoxycholic acid chloride 3α・6α-diacetate () obtained in Example 1-(a) was dissolved in 27.5 ml of anhydrous benzene, and 0.5N-
The mixture was added dropwise to 60 ml of diazomethane ether solution while cooling and stirring. After the dropwise addition, the mixture was stirred for 1 hour while cooling (approximately 5° C.). The reaction solution was returned to room temperature and stirred for 1 hour while bubbling nitrogen to remove excess diazomethane. Further, the reaction solution was concentrated under reduced pressure to obtain a crude diazoketone body. The obtained diazoketone body was used as a raw material compound () without purification. IR (KBr, cm -1 ); 2950, 2090, 1735, 1640,
1240. (c) The crude diazoketone body () obtained in Example 1-(b) was mixed with 14.9 ml of methylene chloride and methanol.
A solution of 85.5 mg of silver benzoate dissolved in 0.86 ml of triethyleneamine was slowly added dropwise to the mixed solution of 19.3 ml under stirring at room temperature. After dripping, 30
The mixture was stirred at room temperature for several minutes. After confirming that the reaction was complete by thin layer analysis, water was added and the product was extracted with methylene chloride. The extract was washed sequentially with dilute hydrochloric acid, water, sodium bicarbonate solution and water. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was subjected to column chromatography packed with silica gel (solvent: benzene-ethyl acetate system) to obtain 1755 mg of methyl-25-homohyodexycholate-3α/6α-diacetate (). (Yield 74.4% from hyodeoxycholic acid 3α·6α-diacetate ()). Melting point; 93-95℃ (methanol) IR (KBr) cm -1 ); 2945, 2860, 1730, 1450,
1360, 1235, 1020. NMR (CDCI 3 ) δ (ppm)); 0.63 (S, 3H,
C-18- CH3 ) 0.96 (S, 3H, C-19-
CH 3 ) 2.02 (S, 6H,
【式】 )3.64(S、3H、【formula】 )3.64(S, 3H,
【式】
)4.70、5.12(mb、2H、C−3&C−6−
H)
High Mars(M+−2×CH3COON);384、
3068(C26H40O2)。
実施例 2
メチル−25−ホモ−ヒオデオキシコレート−3
α6α−ジアセテート()1.7gr(3.3ml)を無
水テトラヒドロフラン39.5mlに溶解し、氷冷した
溶液に撹拌下、1M−メチルマグネシウムブロマ
イド−テトラヒドロフラン(THF)溶液を49.4
mlをゆつくり滴下した。
滴下後、反応液を室温に戻し、さらに1晩撹拌
した。
薄層分析で反応が完了している事を確認した後
反応液を氷冷し20%塩化アンモニウム水溶液を滴
下した。混合液を分液し、塩化アンモニウム水溶
液よりTHFで抽出を行なつた。THF分液とTHF
抽出液を合わせて減圧濃縮した。残渣に水とエー
テルを加え完全に溶解するまで撹拌し、エーテル
溶液を分液し、無水硫酸ナトリウムで乾燥後、ろ
過、減圧濃縮することにより、3α・6α・25−
トリヒドロキシ−5β−コレスタン()を含む
残渣を得た。精製の為、残渣はシリカゲルを充填
したカラムクロマトグラフイー(溶剤ベンゼン−
アセトン系)に付し、生成物を含有するフラクシ
ヨンを合せ減圧濃縮することにより、3α・6
α・25−トリヒドロキシ−5β−コレスタン
1.197gr(収量86%)を得た。
融点;192〜193.5℃(メタノール−塩化メチレ
ン)
IR(KBr;cm-1);3375、2940、2860、1463、
1370、1030
NMR(CD3OD;δ(ppm));0.68(S、3H、
C−18−CH3)0.92(S、3H、C−19−CH3)
1.16(S、6H、C−26&27−CH3)3.52(4.02
(bm、2H、C−3&6−H)
Mass;420(M〓)、402、384、376
High Mass(M〓−H2O);402、3515。
実施例 3
(a) 3α・6α・25−トリヒドロキシ−5β−コ
レスタン420mg(1mmol)を無水ピリジン2.5
mlに溶解した。
得られた溶液にp−トルエンスルホニルクロ
ライド572mg(3mmol)を添加し、溶液後室
温で19時間静置した。
反応液に氷水を加えた後、希塩酸を加え酸性
(PH3〜4)とし、塩化メチレン10mlで3回抽
出を行つた。
抽出液を水洗後、無水硫酸ナトリウムで乾燥
しろ過後濃縮することにより、固体成績体粗3
α・6α・25−トリヒドロキシ−5β−コレス
タン3α・6α−ジトシレート()621mg得
た。得られた粗ジトシレート体()は精製せ
ずにそのまま中間原料化合物()として用い
た。
IR(KBr;cm-1);3440、2950、2870、1600、
1450、1354、1170、810。
NMR(CDCI3、δ(ppm));0.59(S、3H、
C−18−CH3)0.81(S、3H、C−19−
CH3)1.20(S、6H、C−26&27−CH3)
2.44(S、6H、C−3&6−トシル基CH3)
7.20〜7.90(M、8H、アロマテイクプロト
ン)。
(b) 実施例3−(a)で得られた3α・6α・25−ト
リヒドロキシ−5β−コレスタン3.6−ジトシ
レート364mg(0.5mmol)をジメチルホルムア
ミド3.6mlおよび水0.4mlの混合溶媒に溶解し
た。
得られた溶液に酢酸カリウム546mg(7m
mol)を添加溶解し、バス値110〜120℃で5時
間加熱撹拌した。
反応終了後、反応液を放冷し、氷水10ml中に
注ぎ、水溶液より酢酸エチル10mlで3回抽出を
行つた。得られた酢酸エチル抽出液を水洗後、
無水硫酸ナトリウムで乾燥し、ろ過後減圧濃縮
した。
得られた3β・25−ジヒドロキシコレスト−
5−エンおよびその3β−アセテートを含む残
渣をメタノール−ベンゼン(1:1)混合溶液
4mlに溶解した。
得られた混合溶液に5%水酸化カリウム−メ
タノール溶液を滴下した。
滴下後、室温で2.5時間撹拌し、薄層分析で
反応が終了している事を確賑した後、反応液に
水6mlおよびエーテル6mlを加え分液した。水
溶液よりエーテル6mlで2回抽出を行ないエー
テル分液とエーテル抽出液を合せ希塩酸、飽和
炭酸水素ナトリウム水溶液、飽和食塩水で洗浄
した。
得られたエーテル溶液を無水硫酸ナトリウム
で乾燥後、ろ過、濃縮することにより、生成物
を含む残渣が得られた。
残渣をシリカゲル薄層プレート(溶剤ベンゼ
ン−酢エチ5:1)で分離後、酢酸エチル抽出
することにより、3β−25−ジヒドロキシコレ
スト−5−エン(25−ヒドロキシコレステロー
ル)121/mg(収量60%)を得た。
融点;177〜80℃(メタノール)
IR(KBr;cm-1);3400、2940、1465、1373、
1050
NMR(CDCI3、δ(ppm));0.68(S、3H、
C−18−CH3)1.01(S、3H、C−19−
CH3)1.22(S、6H、C−26&27−CH3)
1.44(S、2H、C−3&25−OH)3.52
(bm、1H、C−3−H)5.35(bm、1H、C
−6−H)
High Mass(M+・);402、3489
(C27H46O2)、理論値402、3498
実施例 4
(a) 3α・6α・25−トリヒドロキシ−5β−コ
レスタン210mg(0.5mmol)を無水ピリジン
1.25mlに溶解した。得られた溶液にp−トルエ
ンスルホニルクロライド285.8mg(1.5mmol)
を添加し、溶解後室温22時間静置した。
反応液に氷水を加えた後、希塩酸を加え酸性
(PH3〜4)とし、塩化メチレン5mlで4回抽
出を行つた。
抽出液を水洗後、無水硫酸ナトリウムで乾燥
し、ろ過後濃縮することにより粗3α・6α・
25−トリヒドロキシ−5β−コレスタン−3
α・6α−ジトシレート()356mg得た。
(b) 実施例4−(a)で得られた粗3α・6α・25−
トリヒドロキシ−5β−コレスタン−3α・6
α−ジトシレート3.56mgをジメチルホルムアミ
ド3.6mlおよび水0.36mlの混合溶媒に溶解し
た。
得られた溶液に酢酸カリウム534mg(6.85m
mol)を添加溶解し、バス温110〜120℃で5時
間加熱撹拌した。
反応終了後、反応液を放冷し、氷水10ml中に
注ぎ、水溶液より酢酸エチル10mlで3回抽出を
行つた。得られた酢酸エチル抽出液を水洗後、
無水硫酸ナトリウムで乾燥し、ろ過後濃縮し
た。
得られた3β・25−ジヒドロキシコレスト−
5−エンおよびその3β−アセテートを含む残
渣を無水ピリジン2.7mlと無水酢酸1.9mlの混合
溶液に溶解し、室温で5時間撹拌した。薄層分
析で3β・25−ジヒドロキシコレスト−5−エ
ンが消失している事を確認後、反応液を減圧濃
縮した。得られた残渣にエーテル5mlおよび水
3mlを加え、完全に溶解後分液し、エーテル溶
液を希塩酸、飽和炭酸水素ナトリウム水溶液お
よび水で洗浄後、無水硫酸ナトリウムで乾燥し
ろ過、濃縮することにより、生成物を含む残渣
が得られた。
残渣をシリカゲル薄層プレート(溶剤;ベン
ゼン:酢エチ=9:1)で分離後、酢酸エチル
抽出することにより、3β・25−ジヒドロキシ
コレスト−5−エン−3β−アセテート(25−
ヒドロキシコレステロール−3−アセテート)
108.5mg(収量49%を得た。
融点;138〜141℃(アセトン)
IR(KBr、cm-1);3460、2940、1735、1466、
1375、1245、1030
NMR(CDCI3、δ(ppm));0.68(S、3H、
C−18−CH3)1.02(S、3H、C−19−
CH3)1.21(S、6H、C−26&27−CH3)
2.02(S、3H、[Formula] )4.70, 5.12 (mb, 2H, C-3 & C-6-
H) High Mars (M + −2×CH 3 COON); 384,
3068 ( C26H40O2 ) . Example 2 Methyl-25-homo-hyodeoxycholate-3
Dissolve 1.7gr (3.3ml) of α6α-diacetate () in 39.5ml of anhydrous tetrahydrofuran, and add 49.4ml of 1M methylmagnesium bromide-tetrahydrofuran (THF) solution to the ice-cooled solution with stirring.
ml was slowly added dropwise. After the dropwise addition, the reaction solution was returned to room temperature and further stirred overnight. After confirming the completion of the reaction by thin layer analysis, the reaction solution was cooled with ice, and a 20% ammonium chloride aqueous solution was added dropwise. The mixture was separated and extracted from an aqueous ammonium chloride solution with THF. THF separation and THF
The extracts were combined and concentrated under reduced pressure. Add water and ether to the residue, stir until completely dissolved, separate the ether solution, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3α, 6α, 25-
A residue containing trihydroxy-5β-cholestane () was obtained. For purification, the residue was subjected to column chromatography packed with silica gel (solvent: benzene).
3α・6 by combining the fractions containing the product and concentrating under reduced pressure.
α・25-trihydroxy-5β-cholestane
1.197gr (86% yield) was obtained. Melting point: 192-193.5℃ (methanol-methylene chloride) IR (KBr; cm -1 ); 3375, 2940, 2860, 1463,
1370, 1030 NMR (CD 3 OD; δ (ppm)); 0.68 (S, 3H,
C-18- CH3 ) 0.92 (S, 3H, C-19- CH3 )
1.16 (S, 6H, C-26 & 27-CH 3 ) 3.52 (4.02
(bm, 2H, C-3 & 6-H) Mass; 420 (M〓), 402, 384, 376 High Mass (M〓- H2O ); 402, 3515. Example 3 (a) 420 mg (1 mmol) of 3α・6α・25-trihydroxy-5β-cholestane was added to 2.5 mg of anhydrous pyridine.
Dissolved in ml. 572 mg (3 mmol) of p-toluenesulfonyl chloride was added to the obtained solution, and the solution was left standing at room temperature for 19 hours. After adding ice water to the reaction solution, dilute hydrochloric acid was added to make it acidic (PH 3 to 4), and extraction was performed three times with 10 ml of methylene chloride. After washing the extract with water, drying with anhydrous sodium sulfate, filtering, and concentrating, a crude solid product was obtained.
621 mg of α·6α·25-trihydroxy-5β-cholestane 3α·6α-ditosylate () was obtained. The obtained crude ditosylate compound () was used as an intermediate raw material compound () without being purified. IR (KBr; cm -1 ); 3440, 2950, 2870, 1600,
1450, 1354, 1170, 810. NMR (CDCI 3 , δ (ppm)); 0.59 (S, 3H,
C-18- CH3 ) 0.81 (S, 3H, C-19-
CH3 ) 1.20 (S, 6H, C-26 & 27- CH3 )
2.44 (S, 6H, C-3 & 6-tosyl group CH3 )
7.20-7.90 (M, 8H, aroma take proton). (b) 364 mg (0.5 mmol) of 3α·6α·25-trihydroxy-5β-cholestane 3.6-ditosylate obtained in Example 3-(a) was dissolved in a mixed solvent of 3.6 ml of dimethylformamide and 0.4 ml of water. Add 546 mg (7 m) of potassium acetate to the resulting solution.
mol) was added and dissolved, and the mixture was heated and stirred at a bath value of 110 to 120°C for 5 hours. After the reaction was completed, the reaction solution was allowed to cool, poured into 10 ml of ice water, and the aqueous solution was extracted three times with 10 ml of ethyl acetate. After washing the obtained ethyl acetate extract with water,
It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Obtained 3β・25-dihydroxycholesto
The residue containing 5-ene and its 3β-acetate was dissolved in 4 ml of a methanol-benzene (1:1) mixed solution. A 5% potassium hydroxide-methanol solution was added dropwise to the resulting mixed solution. After the dropwise addition, the mixture was stirred at room temperature for 2.5 hours, and after confirming the completion of the reaction by thin layer analysis, 6 ml of water and 6 ml of ether were added to the reaction solution to separate the layers. The aqueous solution was extracted twice with 6 ml of ether, and the ether separation and ether extract were combined and washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. The obtained ether solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue containing the product. The residue was separated on a silica gel thin layer plate (solvent benzene-ethyl acetate 5:1) and extracted with ethyl acetate to give 3β-25-dihydroxycholest-5-ene (25-hydroxycholesterol) 121/mg (yield 60 %) was obtained. Melting point: 177-80℃ (methanol) IR (KBr; cm -1 ); 3400, 2940, 1465, 1373,
1050 NMR (CDCI 3 , δ (ppm)); 0.68 (S, 3H,
C-18- CH3 ) 1.01 (S, 3H, C-19-
CH3 ) 1.22 (S, 6H, C-26 & 27- CH3 )
1.44 (S, 2H, C-3 & 25-OH) 3.52
(bm, 1H, C-3-H) 5.35 (bm, 1H, C
-6-H) High Mass (M +・); 402, 3489
(C 27 H 46 O 2 ), theoretical value 402, 3498 Example 4 (a) 210 mg (0.5 mmol) of 3α・6α・25-trihydroxy-5β-cholestane was added to anhydrous pyridine.
Dissolved in 1.25ml. 285.8 mg (1.5 mmol) of p-toluenesulfonyl chloride was added to the resulting solution.
was added, and after dissolution, the solution was allowed to stand at room temperature for 22 hours. After adding ice water to the reaction solution, dilute hydrochloric acid was added to make it acidic (PH 3-4), and extraction was performed four times with 5 ml of methylene chloride. After washing the extract with water, drying with anhydrous sodium sulfate, filtering and concentrating, crude 3α, 6α,
25-trihydroxy-5β-cholestane-3
356 mg of α·6α-ditosylate () was obtained. (b) Crude 3α・6α・25− obtained in Example 4-(a)
Trihydroxy-5β-cholestane-3α・6
3.56 mg of α-ditosylate was dissolved in a mixed solvent of 3.6 ml of dimethylformamide and 0.36 ml of water. Add 534mg (6.85ml) of potassium acetate to the resulting solution.
mol) was added and dissolved, and the mixture was heated and stirred at a bath temperature of 110 to 120°C for 5 hours. After the reaction was completed, the reaction solution was allowed to cool, poured into 10 ml of ice water, and the aqueous solution was extracted three times with 10 ml of ethyl acetate. After washing the obtained ethyl acetate extract with water,
It was dried over anhydrous sodium sulfate, filtered, and concentrated. Obtained 3β・25-dihydroxycholesto
The residue containing 5-ene and its 3β-acetate was dissolved in a mixed solution of 2.7 ml of anhydrous pyridine and 1.9 ml of acetic anhydride, and stirred at room temperature for 5 hours. After confirming that 3β·25-dihydroxycholest-5-ene had disappeared by thin layer analysis, the reaction solution was concentrated under reduced pressure. Add 5 ml of ether and 3 ml of water to the resulting residue, completely dissolve and separate the layers, wash the ether solution with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dry over anhydrous sodium sulfate, filter, and concentrate. A residue containing the product was obtained. The residue was separated on a silica gel thin layer plate (solvent: benzene:ethyl acetate = 9:1) and extracted with ethyl acetate to obtain 3β-25-dihydroxycholest-5-ene-3β-acetate (25-
hydroxycholesterol-3-acetate)
108.5 mg (49% yield was obtained. Melting point: 138-141°C (acetone) IR (KBr, cm -1 ): 3460, 2940, 1735, 1466,
1375, 1245, 1030 NMR (CDCI 3 , δ (ppm)); 0.68 (S, 3H,
C-18- CH3 ) 1.02 (S, 3H, C-19-
CH3 ) 1.21 (S, 6H, C-26 & 27- CH3 )
2.02 (S, 3H,
【式】
)4.62(bm、1H、C−3−H)5.38(bm、
1H、C−6−H)
マス・スペクトル;426(M+・−H2O)、384
(M+・−CH3COOH)366(M+・−
CH3COOH−H2O)[Formula] ) 4.62 (bm, 1H, C-3-H) 5.38 (bm,
1H, C-6-H) Mass spectrum; 426 (M + -H 2 O), 384
(M +・−CH 3 COOH)366(M +・−
CH3COOH − H2O )
Claims (1)
レスタンを下記式 R−SO2Cl (式中、Rはアルキル基またはアリール基であ
る。) で表わされる有機スルホニルクロライドと反応さ
せ、下記式 (式中、Rの定義は上記に同じ) で表わされる3α・6α・25−トリハイドロキシ
−5β−コレスタン−3α・6α−ジトシレート
を生成させ、次いでこれを極性溶媒中で酢酸金属
塩と反応せしめることを特徴とする3β・25−ジ
ヒドロキシ−5α−コレスタ−5−エン−3β−
アセテートの製造方法。 2 ヒオデオキシコール酸−3α・6α−ジアセ
テートとハロゲン化剤とを反応させてヒオデオキ
シコール酸ハライド−3α・6α−ジアセテート
を生成せしめ、次いでこれをジアメタンと反応さ
せて下記式 で表わされるジアゾケトンを生成させ、次いでこ
れを安息香酸銀および有機塩基の存在下、脂肪族
アルコールと反応させてメチル−25−ホモヒオデ
キシコレート3α・6α−ジアセテートを生成せ
しめ、次いでこれをメチルマグネシウムハライド
と反応せしめて3α・6α・25−トリヒドロキシ
−5β−コレスタンを生成せしめ、次いでこれを
下記式、 R−SO2Cl 式中、Rはアルキル基またはアリール基であ
る。 で表わされる有機スルホニルハライドと反応さ
せ、下記式、 (式中、Rの定義は上記に同じ) で表わされる3α・6α・25−トリヒドロキシ−
5β−コレスタン−3α・6α−ジトシレートを
生成させ、次いでこれを極性溶媒中で酢酸金属塩
と反応せしめることを特徴とする3β・25−ジヒ
ドロキシ−5α−コレスタ−5−エン−3β−ア
セテートの製造法。[Claims] 1 Reacting 3α・6α・25-trihydroxy-5β-cholestane with an organic sulfonyl chloride represented by the following formula R-SO 2 Cl (wherein R is an alkyl group or an aryl group). and the following formula (In the formula, the definition of R is the same as above) 3α·6α·25-trihydroxy-5β-cholestane-3α·6α-ditosylate is produced, and then this is reacted with a metal acetate in a polar solvent. 3β・25-dihydroxy-5α-cholest-5-ene-3β-
Method of manufacturing acetate. 2 Hyodeoxycholic acid-3α,6α-diacetate is reacted with a halogenating agent to produce hyodeoxycholic acid halide-3α,6α-diacetate, which is then reacted with dimethane to form the following formula: The diazoketone represented by is formed, which is then reacted with an aliphatic alcohol in the presence of silver benzoate and an organic base to form methyl-25-homohyodexycholate 3α·6α-diacetate, which is then reacted with 3α.6α.25-Trihydroxy-5β-cholestane is produced by reaction with methylmagnesium halide, which is then converted into the following formula: R-SO 2 Cl where R is an alkyl group or an aryl group. It is reacted with an organic sulfonyl halide represented by the following formula, (In the formula, the definition of R is the same as above.) 3α・6α・25-trihydroxy-
Production of 3β·25-dihydroxy-5α-cholest-5-ene-3β-acetate, characterized in that 5β-cholestane-3α·6α-ditosylate is produced and then reacted with a metal acetate in a polar solvent. Law.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13879478A JPS5566600A (en) | 1978-11-13 | 1978-11-13 | Preparation of 3beta,25-dehydroxy-5alpha-cholest-5-ene or its 3beta- acetate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13879478A JPS5566600A (en) | 1978-11-13 | 1978-11-13 | Preparation of 3beta,25-dehydroxy-5alpha-cholest-5-ene or its 3beta- acetate |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5566600A JPS5566600A (en) | 1980-05-20 |
JPS6141360B2 true JPS6141360B2 (en) | 1986-09-13 |
Family
ID=15230366
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13879478A Granted JPS5566600A (en) | 1978-11-13 | 1978-11-13 | Preparation of 3beta,25-dehydroxy-5alpha-cholest-5-ene or its 3beta- acetate |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5566600A (en) |
-
1978
- 1978-11-13 JP JP13879478A patent/JPS5566600A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5566600A (en) | 1980-05-20 |
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