Background technology:
Carbonyl reduction is that the method for directed hydroxyl is very necessary in the preparation of some medicines in the conjugation unsaturated ketone compound.As in the modification of carrying out the vitamin d compounds side chain: MC903 (calcipotriol is seen formula III) or 1,24-(OH)
2D
3(seeing formula IV).
Formula III MC903 formula IV 1,24-(OH)
2D
3
In the preparation of novel vitamin D analogues, the specific stereochemistry of C-24 hydroxyl is essential for bioactive expressed intact.According to present method, can introduce the stereochemistry that needs by three kinds of methods: (1) Calverley, Tetrahedron4609-4619,1987 have reported the non-enantiomer mixture by chromatography separation of C-24 hydroxyl epimer; (2) US6262283 has disclosed Stereoselective reduction corresponding C-24 ketone; (3) Calverley, Synlett 157-159,1990 have reported that the hydroxyl side chain that makes enantiomer-pure is attached on the vitamins D skeleton.
Some researchists are equipped with phrenosterol (cerebrosterol), MC 903 and 1 α to three-dimensional selectively producing, 24 (R)-(OH)
2D
3Study.Koch etc. are at Bulletin de la Societe Chimique de France, and 1983, (No.7-8), Vol.II, 189-194pp. disclose (24R) that a stereoselectivity prepares optical purity-and (24S)-24 method of hydroxycholesterol oxycholesterol; Calverley is at Tetrahedron, and 1987, Vol.43, No.20 discloses the synthetic method of a kind of bioactive vitamin D interior metabolism product analogue MC 903 among the pp.4609-4619.; Okamot etc. are at Tetrahedron:Asymmetry, and 1995, Vol.6, No.3, disclosing among the pp.767-778 with asymmetric different third steroidal-24-aldehyde is the method for feedstock production 24 (R)-hydroxycholesterol oxycholesterol.
Calverley adopts NaBH
4/ CeCl
3(Tetrahedron Vol43, No.20pp 4609 to 4619,1987) or AlLiH
4Carry out reduction reaction as reductive agent, stereoselectivity is poor, with vitamins D
3-22-alkene-24-ketone is 24-alcohol, and the ratio of the product of 24S and 24R configuration is 38: 61, because of target hydroxylic species content is low, and purification difficult, inferior separating effect, it is higher to separate preparation cost; M.Ishiguro etc. are at J.C.S.Chem.Comm., and 115-117 has reported that Stereoselective reduction C-24 ketone is the method for conceivable epimer C-24 alcohol in 1981, as has been used to prepare cholesterin derivative; Patent 2005087719 has been reported in the presence of chiral auxiliary(reagent), to contain boron derivative is reductive agent, is used for the method for synthetic calcipotriol, and this method selectivity is good, the ratio of 24S and 24R configuration was not less than 56: 44 in the product, needed to adopt SO but be reduced thing before participating in reduction reaction
2Protect, also need deprotection after the reduction reaction, program is more.
Summary of the invention:
The objective of the invention is general formula I I conjugation beta-unsaturated ketone derivative 24-carbonyl reduction is directed hydroxyl, obtains the compound of Formula I of orientation (configuration with 24 (S) or 24 (R)).This method stereoselectivity height, the target product yield height, step is short, lower cost.
Below be the not structural formula of isomorphism type of two kinds of compound of Formula I:
General formula I 24 (S) general formula I 24 (R)
In the formula:
R
1, R
2Be selected from hydrogen or hydroxyl protecting group respectively; Work as R
1, R
2When being hydroxy-protective group, described hydroxy-protective group can be identical, also can be different;
R
3Be selected from hydrogen or methylene radical, R
4Also be selected from hydrogen or methylene radical, but R
3, R
4Different.Promptly work as R
3When being hydrogen atom, R
4Be with the parent ring with doubly linked methylene radical; Work as R
3Be with the parent ring during with doubly linked methylene radical, R
4It is hydrogen atom.
R
5Be selected from the cycloalkyl of alkyl or 3~6 carbon atoms of 1~6 carbon atom;
Silylation such as that described hydroxy-protective group can be selected from is trimethyl silicon based, tertiary butyl dimethyl is silica-based.
The method of directed synthesis of conjugate unsaturated alcohol provided by the invention is as described below:
Formula II formula I
Concrete method is that formula II compound and chiral reduction agent BINAL-H are reacted; Temperature of reaction is-100 ℃~30 ℃, and the reaction times is 0.5~10 hour; Reaction is finished, and can obtain the formula I compound of the directed configuration of high-optical-purity through aftertreatment.
Reaction should be carried out in hydroxyl not, amido, imido grpup, carboxyl isoreactivity hydrogen and the organic solvent that can dissolve each other with reductive agent BINAL-H solution, comprise the ether, alcohol ether, the oxirane that do not contain active hydrogen, haloalkane and nitrogen oxa-lopps organic solvent, as be selected from ether, tetrahydrofuran (THF), acetonitrile, ethylene glycol diethyl ether, glycol dimethyl ether, 1, in 2-ethylene dichloride, the N-methylmorpholine a kind of, two or more.Preferred tetrahydrofuran (THF).If containing active hydrogen, solvent can react with reductive agent.
(R) or (S) configuration of chiral reduction agent BINAL-H if ask the formula I compound that obtains (R) configuration, then should adopt the chiral reduction agent BINAL-H of (R) configuration to participate in reaction in the reaction; If instead require to obtain the formula I compound of (S) configuration, then should adopt the chiral reduction agent BINAL-H of (S) configuration to participate in reaction.
In the above-mentioned reaction, formula II compound and chiral reduction agent BINAL-H feed molar proportioning should be 1: 1~1: 3 scopes; Preferred 1: 1.
Temperature of reaction is low more, and the optical purity of product is high more, but speed of response is slow more, and the required reaction times is also long more.Take all factors into consideration two kinds of factors of purity and speed of response, preferred temperature of reaction is-60 ℃~10 ℃.
The advantage of directional synthesis method provided by the invention is: stereoselectivity height, C
19And C
16The position does not need to use SO
2Reaction forms protecting group can directly carry out reduction reaction, and the content of 24 (S) or 24 (R) target configuration product can reach 70~95%; Yield can reach more than 70%.
Embodiment:
The invention will be further described below in conjunction with embodiment, can make this area professional and technical personnel understand the present invention more all sidedly, but not limit the present invention in any way.
The existing a large amount of bibliographical information of the preparation method of raw material formula II compound among the embodiment, as Calverley, Tetrahedron4609-4619,1987; WO8700834.
BINAL-H is available from Chongqing Ensky Chemical Co., Ltd. for the agent of chiral reduction described in the embodiment.This reagent also can prepare voluntarily, is the technology of those skilled in the art's grasp.
Embodiment 1[1S, 1 ' E, 3R, 5Z, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-hydroxypropyl-1 '-alkene)-1,3-two (tertiary butyl dimethyl Si base)-5,7,10 (19)-triolefins] preparation
At 0~10 ℃, to be dissolved with 7.3g (20mmol) (S)-drip formula II compound [1S in the 200ml tetrahydrofuran solution of BINAL-H, 1 ' E, 3R, 5Z, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-carbonyl propyl group-1 '-alkene)-1,3-two (tertiary butyl dimethyl Si base)-5,7,10 (19)-triolefins] 12.8g (20mmol) and the solution that tetrahydrofuran (THF) 12ml forms, finish and stir 1~2h, change in the container that fills the 100ml methanol solution, stir evenly the back and add 200ml water, carry inferior 3 times with the 100ml ether, united extraction liquid is used the Na of 300ml 5% respectively
2CO
3The aqueous solution, 300ml water washing, the dry 0.5h of anhydrous MgSO4 filters, and concentrated mother liquor obtains light yellow oil 11.8g, yield 92.2%.The product content of HPLC detection 24 (S) is that the content of 72.3%, 24 (R) is 28.7%.
Embodiment 2[1S, 1 ' E, 3R, 5Z, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-sec.-propyl-3 '-hydroxypropyl-1 '-alkene)-5,7,10 (19)-triolefins] preparation
At-20~0 ℃, to be dissolved with 21.9g (60mmol) (S)-drip formula II compound [1S in the 200ml tetrahydrofuran solution of BINAL-H, 1 ' E, 3R, 5Z, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-sec.-propyl-3 '-carbonyl propyl group-1 '-alkene)-5,7,10 (19)-triolefins] solution formed of 8.2g (20mmol) and tetrahydrofuran (THF) 12ml, finish and stir 5~6h, change in the container that fills the 100ml methanol solution, stir evenly the back and add 200ml water, carry inferior 3 times with the 100ml ether, united extraction liquid is used the Na of 300ml5% respectively
2CO
3The aqueous solution, 300ml water washing, the dry 0.5h of anhydrous MgSO4 filters, and concentrated mother liquor obtains light yellow oil 7.7g, yield 93.4%.The product content of HPLC detection 24 (S) is that the content of 82.1%, 24 (R) is 17.9%.
Embodiment 3[(1S, 1 ' E, 3R, 5Z, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclohexyl-3 '-hydroxypropyl-1 '-alkene)-1,3-two (tertiary butyl dimethyl Si base)-5,7,10 (19)-triolefins] preparation
At-60~-30 ℃, to be dissolved with 7.3g (20mmol) (S)-drip formula II compound [[1S in the 200ml tetrahydrofuran solution of BINAL-H, 1 ' E, 3R, 5Z, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclohexyl-3 '-carbonyl propyl group-1 '-alkene)-1,3-two (tertiary butyl dimethyl Si base)-5,7,10 (19)-triolefins] 13.6g (20mmol) and the solution that tetrahydrofuran (THF) 12ml forms, finish and stir 8~10h, change in the container that fills the 100ml methanol solution, stir evenly the back and add 200ml water, carry inferior 3 times with the 100ml ether, united extraction liquid is used the Na of 300ml 5% respectively
2CO
3The aqueous solution, 300ml water washing, the dry 0.5h of anhydrous MgSO4 filters, and concentrated mother liquor obtains yellow oil 11.9g, yield 87.2%.The product content of HPLC detection 24 (S) is that the content of 85.1%, 24 (R) is 14.9%.
Embodiment 4[1S, 1 ' E, 3R, 5E, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-hydroxypropyl-1 '-alkene)-l, 3-two (trimethylsiloxy group)-5,7,10 (19)-triolefins] preparation
At-30~-10 ℃, to be dissolved with 7.3g (40mmol) (S)-drip formula II compound [[1S in the 200ml tetrahydrofuran solution of BINAL-H, 1 ' E, 3R, 5E, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-carbonyl propyl group-1 '-alkene)-1,3-two (trimethylsiloxy group)-5,7,10 (19)-triolefins] 11.1g (20mmol) and the solution that tetrahydrofuran (THF) 110ml forms, finish and stir 7~8h, change in the container that fills the 100ml methanol solution, stir evenly the back and add 200ml water, carry inferior 3 times with the 100ml ether, united extraction liquid is used the Na of 300ml 5% respectively
2CO
3The aqueous solution, 300ml water washing, the dry 0.5h of anhydrous MgSO4 filters, and concentrated mother liquor obtains yellow oil 9.3g, yield 83.6%.The product content of HPLC detection 24 (S) is that the content of 77.4%, 24 (R) is 22.6%.
Embodiment 5[1S, 1 ' E, 3R, 5E, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-hydroxypropyl-1 '-alkene)-1,3-two (tertiary butyl dimethyl Si base)-5,7,10 (19)-triolefins] preparation
At-50~-30 ℃, to be dissolved with 7.3g (20mmol) (S)-drip formula II compound [[1S in the 200ml tetrahydrofuran solution of BINAL-H, 1 ' E, 3R, 5E, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-carbonyl propyl group-1 '-alkene)-1,3-two (tertiary butyl dimethyl Si base)-5,7,10 (19)-triolefins] 12.8g (20mmol) and the solution that ethylene glycol ethyl ether 12ml forms, finish and stir 8~9h, change in the container that fills the 100ml methanol solution, stir evenly the back and add 200ml water, carry inferior 3 times with the 100ml ether, united extraction liquid is used the Na of 300ml 5% respectively
2CO
3Aqueous solution 300ml water washing, the dry 0.5h of anhydrous MgSO4 filters, and concentrated mother liquor obtains light yellow oil 10.5g, yield 82.0%.The product content of HPLC detection 24 (S) is that the content of 73.3%, 24 (R) is 26.7%.
Embodiment 6[1S, 1 ' E, 3R, 5E, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-hydroxypropyl-1 '-alkene)-1 tertiary butyl dimethyl Si base-5,7,10 (19)-triolefins] preparation
At-10~10 ℃, to be dissolved with 14.6g (40mmol) (R)-drip formula II compound [[1S in the 200ml tetrahydrofuran solution of BINAL-H, 1 ' E, 3R, 5E, 7E, 20R)-9,10-open loop courage steroid-20-(3 '-cyclopropyl-3 '-carbonyl propyl group-1 '-alkene)-1 tertiary butyl dimethyl Si base-5,7,10 (19)-triolefins] solution formed of 10.5g (20mmol) and tetrahydrofuran (THF) 110ml, finish and stir 2~3h, change in the container that fills the 100ml methanol solution, stir evenly the back and add 200ml water, carry inferior 3 times with the 100ml ether, united extraction liquid is used the Na of 300ml 5% respectively
2CO
3The aqueous solution, 300ml water washing, the dry 0.5h of anhydrous MgSO4 filters, and concentrated mother liquor obtains light yellow oil 9.7g, yield 92.0%.The product content of HPLC detection 24 (S) is that the content of 7.8%, 24 (R) is 92.2%.