CN101381389B - Chemical synthesis method of 5,7-diene steroids compounds - Google Patents
Chemical synthesis method of 5,7-diene steroids compounds Download PDFInfo
- Publication number
- CN101381389B CN101381389B CN2008101214430A CN200810121443A CN101381389B CN 101381389 B CN101381389 B CN 101381389B CN 2008101214430 A CN2008101214430 A CN 2008101214430A CN 200810121443 A CN200810121443 A CN 200810121443A CN 101381389 B CN101381389 B CN 101381389B
- Authority
- CN
- China
- Prior art keywords
- formula
- hydrazone
- diene
- hour
- organic solvent
- 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.)
- Active
Links
- 238000003786 synthesis reaction Methods 0.000 title claims description 9
- 238000000034 method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 150000007857 hydrazones Chemical class 0.000 claims abstract description 43
- 239000003513 alkali Substances 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 138
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 238000010792 warming Methods 0.000 claims description 38
- 238000001953 recrystallisation Methods 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000009413 insulation Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000006309 butyl amino group Chemical group 0.000 claims description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052744 lithium Chemical group 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 239000011591 potassium Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 44
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 2
- 230000003637 steroidlike Effects 0.000 abstract 2
- 238000004064 recycling Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 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 84
- 239000007787 solid Substances 0.000 description 43
- 235000012000 cholesterol Nutrition 0.000 description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000009835 boiling Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 239000007810 chemical reaction solvent Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 5
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 235000019166 vitamin D Nutrition 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- 0 CC(CCCC(C)(C)*)C(CC1)C(C)(CCC2C(C)(CCC(C3)O*)C3=C3)C1[C@@]2C3=NN* Chemical compound CC(CCCC(C)(C)*)C(CC1)C(C)(CCC2C(C)(CCC(C3)O*)C3=C3)C1[C@@]2C3=NN* 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention discloses a method for synthesizing a 5, 7-diene steroidal compound as shown in a formula (I), which comprises the following steps of allowing a hydrazone as shown in a formula (II) to react with an alkali as shown in a formula (III) in an organic solvent for 0 to 6 hours at the temperature of between minus 20 and 50 DEG C, then heating to 25 and 150 DEG C, preserving the temperature to react for 0.5 to 6 hours, de-protecting the reaction solution, recycling the solvent to obtain a crude product, and recystallizing the crude product to obtain the finished product 5, 7-diene steroidal compound. The method has mild reaction conditions, high reaction yield (generally more than 85 percent, and even more than 95 percent), low production cost and good selectivity, and therefore isan advanced technique route.
Description
(1) technical field
The present invention relates to a kind of 5, the chemical synthesis process of 7-diene steroids compounds.
(2) background technology
5, the 7-diene steroids compounds is the precursor of vitamins D class medicine, is widely used in fields such as medicine, food, agricultural chemicals, chemical industry, has very high practical value.The main effect of vitamins D class medicine is the metabolism of regulating calcium, phosphorus, promotes the absorption and the sclerotin calcification of calcium, phosphorus in the intestines, keeps the balance of blood calcium and serium inorganic phosphorus, is people and growth of animal, growth, breeds, earns a bare living and keep fit requisite VITAMIN.
Before the present invention makes, original technology 5, to be raw material with 5-alkene-7-bromine steroid mostly obtain 5 through debrominate to the chemical synthesis process of 7-diene steroids compounds, and the 7-diene steroids compounds is such as at Bu
4N
+F
-, trimethylpyridine (WO2008089093, US2571330) etc. debrominate obtains 5 in the system, the 7-diene steroids compounds, this method yield is on the low side, and is probably at 30-50%, seriously polluted.5, the 7-diene steroids compounds also can obtain (J.Org.Chem., 1981,46,1030 through eliminating reaction from 7-sulfoxide group substituent; Tetrahedron Lett., 1991,32,5171; US20080171728) yield is medium; Also can obtain (Tetrahedron Lett., 1992,33,2549 through precious metals pd catalysis or heating high temperature elimination reaction from 7-ester group substituent; J.Am.Chem.Soc., 1952,74,3318), this method is used expensive Pd catalyzer, and cost is higher.In addition, aforesaid method also can produce the impurity that some can't be removed, and has a strong impact on the photochmeical reaction of vitamins D class medicine in synthetic.
(3) summary of the invention
The technical problem to be solved in the present invention provides that a kind of technology is reasonable, selectivity good, reaction yield is high, production cost is low, eco-friendly 5, the chemical synthesis process of 7-diene steroids compounds.
For solving the problems of the technologies described above, the present invention prepares 5 with hydrazone and alkali, the 7-diene steroids compounds, and concrete technical scheme is as follows:
Shown in a kind of formula (I) 5, the synthetic method of 7-diene steroids compounds, it is characterized in that described synthetic method is: the alkali shown in hydrazone shown in the formula (II) and the formula (III) reacts in organic solvent, and reaction solution obtains final product 5 through aftertreatment, 7-diene steroids compounds (I);
(I) (II) (III)
In formula (I), formula (II) or the formula (III), R
1Be selected from the acyl group of hydrogen or C1～C8; R
2Be selected from benzenesulfonyl, p-toluenesulfonyl or methylsulfonyl; R
3Be selected from hydrogen, hydroxyl or acyloxy (ester group); R
4Be selected from the alkyl of C1～C6, alkoxyl group, amino, diisopropylaminoethyl, tertiary butyl amino or the hydrogen of C1～C6; M is sodium, potassium or lithium.
Reaction formula is as follows:
Further, described synthetic method is preferably carried out according to following steps: earlier the alkali shown in hydrazone shown in the formula (II) and the formula (III) was reacted 0～6 hour in organic solvent is molten at-20～50 ℃, be warmed up to 25～150 ℃ then, insulation reaction 0.5～6 hour, reaction solution reclaims solvent and obtains crude product after going protecting group to handle, crude product obtains final product 5 behind recrystallization, the 7-diene steroids compounds; The amount of substance ratio that feeds intake of the alkali shown in hydrazone shown in the described formula (II) and the formula (III) is recommended as 1:1.0～6.0, and the total mass consumption of described organic solvent is 2～30 times of the hydrazone quality shown in the formula (II).Alkali shown in the formula (III) can add with solid form, also can use organic solvent dissolution earlier, and then adds reaction system.Preferred elder generation uses organic solvent dissolution alkali, adds reaction system again.
The present invention reactant feed intake finish after, preferred be warmed up to 50～120 ℃ then earlier-20～20 ℃ of insulation reaction 0.5～3 hour, insulation reaction 1～3 hour, the gained reaction solution goes protecting group to handle again.
Describedly go protecting group to handle to be recommended as: add entry or alcohol in the reaction solution and remove to protect reagent, be warming up to reflux temperature and fully react and remove protecting group.Preferably removing to protect reagent is one of the following: sodium hydroxide, potassium hydroxide, lithium hydroxide, going to protect the reagent mole dosage is 0.01～2.0 times of hydrazone mole number, is preferably 0.1～1.5 times.The consumption that adds entry or alcohol does not have particular requirement.
Reclaim solvent treatment after going protecting group to handle: when going protecting group to add entry in handling and when going to protect reagent, get the organic phase anhydrous sodium sulfate drying behind the first standing demix of need, and then boil off solvent and obtain crude product aforementioned.Pure and mild when going to protect reagent when going protecting group to add in handling, can directly boil off solvent reclaiming solvent step.
Organic solvent of the present invention can be one or more combinations by arbitrary proportion of following formula: the 1. alkane of C4～C12, the 2. aromatic hydrocarbons of C6～C12, the 3. ethers of C2～C18.
Specifically, described organic solvent is one or more combinations by arbitrary proportion of following formula: hexane, sherwood oil, benzene,toluene,xylene, isopropyl benzene, trimethylphenylmethane, chlorobenzene, bromobenzene, dichlorobenzene, dibromobenzene, oil of mirbane, ether, propyl ether, isopropyl ether, butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide.
Preferred organic is one of the following or following arbitrarily several combinations by arbitrary proportion: 1. hexane, 2. sherwood oil, 3. methyl-phenoxide, 4. 2-methyltetrahydrofuran, 5. toluene, 6. dimethylbenzene, 7. chlorobenzene, 8. oil of mirbane, 9. tetrahydrofuran (THF).
Preferred recrystallization solvent is one of the following or following several mixing by arbitrary proportion arbitrarily: toluene, normal hexane, hexanaphthene, acetone, pimelinketone, ether, sherwood oil, methyl alcohol, ethanol.When adopting mixing solutions to carry out recrystallization, the relative volume ratio of each component of mixing solutions does not have special requirement.
The amount of substance ratio that feeds intake of described hydrazone and alkali is recommended as 1:1.0～6.0, preferred 1:1.0～3.0.The total mass consumption of employed organic solvent is 2～30 times of the hydrazone quality shown in the formula (II), preferred 5～10 times.If the alkali shown in the formula (III) is used earlier organic solvent dissolution before adding reaction, then the total mass of organic solvent comprises the summation that is used for dissolving hydrazone and is used for molten antalkaline organic solvent, is used for the amount of organic solvent of the alkali shown in the dissolution type (III) to get final product with the alkali shown in can dissolution type (III).
The described synthetic method of concrete recommendation is carried out according to following steps: earlier the alkali shown in hydrazone shown in the formula (II) and the formula (III) is used organic solvent dissolution respectively, holding temperature joins in the organic solvent solution of the hydrazone shown in the formula (II) at-20～20 ℃ of organic solvent solutions with alkali then, holding temperature reaction 0.5～3 hour, slowly be warmed up to 50～120 ℃, insulation reaction 1～3 hour, reaction solution adds entry or alcohol and removes to protect reagent, be warming up to reflux temperature reaction 0.1～2 hour, with about acid for adjusting pH to 7, reclaim solvent and obtain crude product, crude product obtains final product 5 through recrystallization, the 7-diene steroids compounds; Alkali shown in hydrazone shown in the described formula (II), the formula (III) protects the amount of substance ratio that feeds intake of reagent to be 1:1.0～3.0:0.1～1.5 with going, and the total mass consumption of described organic solvent is 5～10 times of the hydrazone quality shown in the formula (II); Described to remove to protect reagent be one of following: sodium hydroxide, potassium hydroxide, lithium hydroxide.
The product 5 that synthetic method of the present invention makes, 7-diene steroids compounds yield can reach more than 85%.
The present invention compares with original technology, and advantage is embodied in:
1. reaction yield height (generally more than 85%, even can reach more than 95%), production cost are low;
2. operational path advanced person, reaction conditions gentleness;
3. selectivity is good, does not have the by product of rearrangement substantially.
(4) embodiment
The invention will be further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited thereto.
Embodiment 1
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-tolysulfonyl hydrazone 100mmol (61g), dissolve with toluene 400mL, be cooled to-20 ℃, (holding temperature is at-20 ℃ for 6.6g, toluene 300mmol) (50mL) solution to add lithium methide, reacted 0.5 hour, and be warming up to 25 ℃ then and stirred 2 hours.Reaction finishes, and adds water 100mL and fully stirs, and adds sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, and transferred to PH=7, organic phase anhydrous sodium sulfate drying behind the standing demix with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 36.1g is light yellow solid, fusing point 145-146 ℃, yield 94%.
Embodiment 2
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-tolysulfonyl hydrazone 100mmol (61g), dissolve with toluene 400mL, be cooled to-20 ℃, (holding temperature is at-20 ℃ for 6.6g, toluene 300mmol) (50mL) solution to add lithium methide, reacted 0.5 hour, and be warming up to 25 ℃ then and stirred 2 hours.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 36.6g, be light yellow solid, fusing point 145-146 ℃, yield 95%.
Embodiment 3
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-tolysulfonyl hydrazone 100mmol (61g), dissolve with toluene 400mL, be cooled to-20 ℃, (holding temperature is at-20 ℃ for 6.6g, toluene 300mmol) (50mL) solution to add lithium methide, reacted 0.5 hour, and be warming up to 25 ℃ then and stirred 2 hours.Reaction finishes, add ethanol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 36.6g, be light yellow solid, fusing point 145-146 ℃, yield 95%.
Embodiment 4
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-benzene sulfonyl hydrazone 100mmol (59.6g), dissolve with toluene 400mL, be cooled to-20 ℃, (holding temperature is at-20 ℃ for 6.6g, toluene 300mmol) (50mL) solution to add lithium methide, reacted 0.5 hour, and be warming up to 25 ℃ then and stirred 2 hours.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 35.3g, be light yellow solid, fusing point 145-146 ℃, yield 92%.
Embodiment 5
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-methylsulfonyl hydrazone 100mmol (53.4g), dissolve with toluene 400mL, be cooled to-20 ℃, (holding temperature is at-20 ℃ for 6.6g, toluene 300mmol) (50mL) solution to add lithium methide, reacted 0.5 hour, and be warming up to 25 ℃ then and stirred 2 hours.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 32.3g, be light yellow solid, fusing point 145-146 ℃, yield 84%.
Embodiment 6
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 0 ℃, (holding temperature is at 0 ℃ for 6.9g, toluene 300mmol) (50mL) solution to add Lithamide, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 27.3g, be light yellow solid, fusing point 145-146 ℃, yield 71%.
Embodiment 7
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 0 ℃, (holding temperature is at 0 ℃ for 32.1g, toluene 300mmol) (50mL) solution to add lithium diisopropylamine, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 30.0g, be light yellow solid, fusing point 145-146 ℃, yield 78%.
Embodiment 8
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 0 ℃, (holding temperature is at 0 ℃ for 23.7g, toluene 300mmol) (50mL) solution to add tertiary butyl Lithamide, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 32.6g, be light yellow solid, fusing point 145-146 ℃, yield 85%.
Embodiment 9
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 20 ℃, (holding temperature is at 20 ℃ for 16.2g, toluene 300mmol) (50mL) solution to add sodium methylate, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 29.2g, be light yellow solid, fusing point 145-146 ℃, yield 76%.
Embodiment 10
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 20 ℃, (holding temperature is at 20 ℃ for 20.4g, toluene 300mmol) (50mL) solution to add sodium ethylate, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 28.4g, be light yellow solid, fusing point 145-146 ℃, yield 74%.
Embodiment 11
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 20 ℃, (holding temperature is at 20 ℃ for 33.6g, toluene 300mmol) (50mL) solution to add potassium tert.-butoxide, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 30.7g, be light yellow solid, fusing point 145-146 ℃, yield 80%.
Embodiment 12
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 0 ℃, (holding temperature is at 0 ℃ for 7.2g, toluene 300mmol) (50mL) solution to add sodium hydride, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 34.6g, be light yellow solid, fusing point 145-146 ℃, yield 90%.
Embodiment 13
In thermometer, reflux condensing tube and churned mechanically 1000ml four-hole boiling flask are housed, add 3-acetoxyl group cholesterol-7-to benzene sulfonyl hydrazone 100mmol (61.0g), dissolve with toluene 400mL, be cooled to 0 ℃, (holding temperature is at 0 ℃ for 2.4g, toluene 300mmol) (50mL) solution to add lithium hydride, reacted 0.5 hour, and be warming up to 110 ℃ of reactions 2 hours then.Reaction finishes, add methyl alcohol 100mL and fully stir, add sodium hydroxide 4g, be warming up to backflow, reacted 30 minutes, transfer to PH=7 with hydrochloric acid or acetic acid, boil off solvent, obtain target product 5 with the ethanol/toluene recrystallization, 7-diene cholesterol 33.4g, be light yellow solid, fusing point 145-146 ℃, yield 87%.
Embodiment 14
Reaction solvent is the 2-methyltetrahydrofuran, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 35.3g is light yellow solid, fusing point 145-146 ℃, and yield 92%.
Embodiment 15
Reaction solvent is a tetrahydrofuran (THF), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 34.9g is light yellow solid, fusing point 145-146 ℃, and yield 91%.
Embodiment 16
Reaction solvent is a normal hexane, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 31.5g is light yellow solid, fusing point 145-146 ℃, and yield 82%.
Embodiment 17
Reaction solvent is a sherwood oil, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.4g is light yellow solid, fusing point 145-146 ℃, and yield 87%.
Embodiment 18
Reaction solvent is a methyl-phenoxide, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 36.1g is light yellow solid, fusing point 145-146 ℃, and yield 94%.
Embodiment 19
Reaction solvent is a chlorobenzene, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.8g is light yellow solid, fusing point 145-146 ℃, and yield 88%.
Embodiment 20
Reaction solvent is a dimethylbenzene, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 35.7g is light yellow solid, fusing point 145-146 ℃, and yield 93%.
Embodiment 21
Reaction solvent is an oil of mirbane, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 34.9g is light yellow solid, fusing point 145-146 ℃, and yield 91%.
Embodiment 22
Add the alkali temperature and be-20 ℃, reacted 1 hour, be warming up to 50 ℃ of reactions 2 hours then, other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.0g is light yellow solid, and fusing point 145-146 ℃, yield 86%.
Embodiment 23
Add the alkali temperature and be-20 ℃, reacted 1 hour, be warming up to 100 ℃ of reactions 2 hours then, other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.8g is light yellow solid, and fusing point 145-146 ℃, yield 88%.
Embodiment 24
Adding the alkali temperature is 0 ℃, reacts 1 hour, is warming up to 50 ℃ of reactions 2 hours then, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 31.1g is light yellow solid, fusing point 145-146 ℃, and yield 81%.
Embodiment 25
Adding the alkali temperature is 0 ℃, reacts 1 hour, is warming up to 100 ℃ of reactions 2 hours then, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 32.6g is light yellow solid, fusing point 145-146 ℃, and yield 85%.
Embodiment 26
Adding the alkali temperature is 20 ℃, reacts 1 hour, is warming up to 100 ℃ of reactions 2 hours then, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 29.2g is light yellow solid, fusing point 145-146 ℃, and yield 76%.
Embodiment 27
Adding the alkali temperature is 50 ℃, reacts 1 hour, is warming up to 100 ℃ of reactions 2 hours then, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 26.9g is light yellow solid, fusing point 145-146 ℃, and yield 70%.
Embodiment 28
Solvent is a methyl-phenoxide, adds the alkali temperature and is-20 ℃, reacts 1 hour, is warming up to 150 ℃ of reactions 6 hours then, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 37.6g is light yellow solid, fusing point 145-146 ℃, and yield 98%.
Embodiment 29
Solvent is a methyl-phenoxide, and adding the alkali temperature is 50 ℃, reacts 1 hour, is warming up to 150 ℃ of reactions 6 hours then, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 36.5g is light yellow solid, fusing point 145-146 ℃, and yield 95%.
Embodiment 30
The alkali consumption is 200mmol (2.0 equivalent), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 30.7g is light yellow solid, fusing point 145-146 ℃, and yield 80%.
Embodiment 31
The alkali consumption is 400mmol (4.0 equivalent), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 36.1g is light yellow solid, fusing point 145-146 ℃, and yield 94%.
Embodiment 32
Recrystallization solvent is sherwood oil/toluene, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.1g is light yellow solid, fusing point 145-146 ℃, and yield 86%.
Embodiment 33
Recrystallization solvent is an acetone/methanol, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.8g is light yellow solid, fusing point 145-146 ℃, and yield 88%.
Embodiment 34
Recrystallization solvent is normal hexane/ethanol, and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 30.7g is light yellow solid, fusing point 145-146 ℃, and yield 80%.
Embodiment 35
The substrate hydrazone is 3-benzoyloxy cholesterol-7-tolysulfonyl hydrazone, and charging capacity is 100mmol (67.2g), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 34.6g is light yellow solid, fusing point 145-146 ℃, and yield 90%.
Embodiment 36
The substrate hydrazone be 3-to toluyl oxygen base cholesterol-7-tolysulfonyl hydrazone, charging capacity is 100mmol (68.6g), other is operated with embodiment 2, obtains target product 5,7-diene cholesterol 34.9g is light yellow solid, fusing point 145-146 ℃, yield 91%.
Embodiment 37
The substrate hydrazone is 3-propionyloxy cholesterol-7-tolysulfonyl hydrazone, and charging capacity is 100mmol (62.4g), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 34.6g is light yellow solid, fusing point 145-146 ℃, and yield 90%.
Embodiment 38
The substrate hydrazone is 3-butyryl acyloxy cholesterol-7-tolysulfonyl hydrazone, and charging capacity is 100mmol (63.8g), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 35.3g is light yellow solid, fusing point 145-146 ℃, and yield 92%.
Embodiment 39
The substrate hydrazone is 3-tribromo-acetyl oxygen base cholesterol-7-tolysulfonyl hydrazone, and charging capacity is 100mmol (71.4g), and other is operated with embodiment 2, obtains target product 5, and 7-diene cholesterol 33.8g is light yellow solid, fusing point 145-146 ℃, and yield 88%.
Embodiment 40
The substrate hydrazone is 3,25-diacetoxy cholesterol-7-tolysulfonyl hydrazone, charging capacity is 100mmol (66.9g), sodium hydroxide concentration is 8g, and other is operated with embodiment 2, obtains target product 25-hydroxyl-5,7-diene cholesterol 38.0g, be light yellow solid, fusing point 175-176 ℃, yield 95%.
Embodiment 41
The substrate hydrazone is 3,25-dibenzoyl oxygen base cholesterol-7-tolysulfonyl hydrazone, and charging capacity is 100mmol (79.2g), sodium hydroxide concentration is 8g, and other is operated with embodiment 2, obtains target product 25-hydroxyl-5,7-diene cholesterol 37.2g is light yellow solid, fusing point
175-176℃, yield 93%.
Embodiment 42
The substrate hydrazone is 3-acetoxyl group-25-benzoyloxy cholesterol-7-tolysulfonyl hydrazone, charging capacity is 100mmol (73.0g), sodium hydroxide concentration is 8g, other operation is with embodiment 2, obtain target product 25-hydroxyl-5,7-diene cholesterol 36.8g is light yellow solid, fusing point 175-176 ℃, yield 92%.
Claims (8)
1. 5 shown in the formula (I), the synthetic method of 7-diene steroids compounds, it is characterized in that described synthetic method comprises the steps: earlier the alkali shown in hydrazone shown in the formula (II) and the formula (III) to be reacted 0.5～6 hour at-20～50 ℃ in organic solvent, be warmed up to 25～150 ℃ then, insulation reaction 0.5～6 hour, reaction solution reclaims solvent and obtains crude product after going protecting group to handle, crude product obtains final product 5 through recrystallization, the 7-diene steroids compounds; The amount of substance ratio that feeds intake of the alkali shown in hydrazone shown in the described formula (II) and the formula (III) is 1: 1.0～6.0; Described organic solvent is the mixing of following one or more arbitrary proportions: hexane, sherwood oil, benzene,toluene,xylene, isopropyl benzene, trimethylphenylmethane, chlorobenzene, bromobenzene, dichlorobenzene, dibromobenzene, oil of mirbane, ether, propyl ether, isopropyl ether, butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide;
In formula (I), formula (II) or the formula (III), R
1Be selected from the acyl group of hydrogen or C1～C8; R
2Be selected from benzenesulfonyl, p-toluenesulfonyl or methylsulfonyl; R in the formula (I)
3Be selected from hydrogen or hydroxyl, the R in the formula (II)
3Be selected from hydrogen, hydroxyl or acyloxy; R
4Be selected from the alkyl of C1～C6, alkoxyl group, amino, diisopropylaminoethyl, tertiary butyl amino or the hydrogen of C1～C6; M is sodium, potassium or lithium.
2. as claimed in claim 15, the synthetic method of 7-diene steroids compounds is characterized in that the described protecting group of going is treated to: add entry or alcohol in the reaction solution and remove to protect reagent, be warming up to reflux temperature and fully react and remove protecting group; Described to remove to protect reagent be one of following: sodium hydroxide, potassium hydroxide, lithium hydroxide, described mole dosage of removing to protect reagent are 0.01～2.0 times of the hydrazone mole number shown in the formula (II).
3. as claimed in claim 15, the chemical synthesis process of 7-diene steroids compounds is characterized in that described organic solvent is the mixing of following one or more arbitrary proportions: hexane, sherwood oil, methyl-phenoxide, 2-methyltetrahydrofuran, toluene, dimethylbenzene, chlorobenzene, oil of mirbane, tetrahydrofuran (THF).
4. as claimed in claim 15, the synthetic method of 7-diene steroids compounds is characterized in that recrystallization reagent is selected from the mixing of following one or more arbitrary proportions: toluene, normal hexane, hexanaphthene, acetone, pimelinketone, ether, sherwood oil, methyl alcohol, ethanol.
5. described 5 as one of claim 1～4, the synthetic method of 7-diene steroids compounds, it is characterized in that feeding intake finish after, hydrazone and alkali-20～20 ℃ of insulation reaction 0.5～3 hour, are warmed up to 50～120 ℃, insulation reaction 1～3 hour earlier then.
6. described 5 as one of claim 1～4, the chemical synthesis process of 7-diene steroids compounds is characterized in that the amount of substance ratio that feeds intake of the alkali shown in hydrazone shown in the described formula (II) and the formula (III) is 1: 1.0～3.0.
7. described 5 as one of claim 1～4, the chemical synthesis process of 7-diene steroids compounds, the quality consumption that it is characterized in that employed organic solvent are 5～10 times of the hydrazone quality shown in the formula (II).
8. as claimed in claim 35, the chemical synthesis process of 7-diene steroids compounds, it is characterized in that described synthetic method carries out according to following steps: earlier the alkali shown in hydrazone shown in the formula (II) and the formula (III) is used organic solvent dissolution respectively, holding temperature joins in the organic solvent solution of the hydrazone shown in the formula (II) at-20～20 ℃ of organic solvent solutions with the alkali shown in the formula (III) then, insulation reaction 0.5～3 hour, slowly be warmed up to 50～120 ℃, insulation reaction 1～3 hour, reaction solution adds entry or alcohol and removes to protect reagent, be warming up to reflux temperature reaction 0.1～2 hour, with acid for adjusting pH to 7, reclaim solvent and obtain crude product, crude product obtains final product 5 through recrystallization, the 7-diene steroids compounds; Alkali shown in hydrazone shown in the described formula (II), the formula (III) is 1: 1.0～3.0: 0.1～1.5 with going to protect the amount of substance ratio that feeds intake of reagent, and the total mass consumption of described organic solvent is 5～10 times of the hydrazone quality shown in the formula (II); Described to remove to protect reagent be one of following: sodium hydroxide, potassium hydroxide, lithium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101214430A CN101381389B (en) | 2008-09-29 | 2008-09-29 | Chemical synthesis method of 5,7-diene steroids compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101214430A CN101381389B (en) | 2008-09-29 | 2008-09-29 | Chemical synthesis method of 5,7-diene steroids compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101381389A CN101381389A (en) | 2009-03-11 |
| CN101381389B true CN101381389B (en) | 2011-05-25 |
Family
ID=40461459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101214430A Active CN101381389B (en) | 2008-09-29 | 2008-09-29 | Chemical synthesis method of 5,7-diene steroids compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101381389B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910231B (en) * | 2015-05-18 | 2016-08-24 | 浙江工业大学 | A kind of synthetic method of 25-hydroxyl-7-DHC |
| CN105131071B (en) * | 2015-07-14 | 2017-09-12 | 浙江花园生物高科股份有限公司 | A kind of synthetic method of the Tosylhydrazone of 25 hydroxy cholesterol acetate 7 |
| CN105646632A (en) * | 2016-01-19 | 2016-06-08 | 浙江新和成股份有限公司 | Method for preparing 7-dehydrogenized cholesteryl ester from 7-tosylhydrazones-3-cholesteryl ester |
| EP4139324A1 (en) * | 2020-04-23 | 2023-03-01 | DSM IP Assets B.V. | Organic solvent nanofiltration of 7-dehydrocholesterol or 25-hydroxy-7-dehydrocholesterol or their oh protected forms |
| CN115427424A (en) * | 2020-04-23 | 2022-12-02 | 帝斯曼知识产权资产管理有限公司 | Preparation of 7-dehydrocholesterol using specific aromatic solvents |
| CN112707779B (en) * | 2020-12-26 | 2023-06-30 | 蚌埠中实化学技术有限公司 | Preparation method of vinylcyclohexane |
| CN113621015B (en) * | 2021-08-11 | 2022-05-17 | 浙江新和成药业有限公司 | 7-dehydrocholesterol and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4116985A (en) * | 1976-07-26 | 1978-09-26 | The Upjohn Company | Novel method for preparing cholesta-5,7-diene 3β,25-diol and derivatives thereof |
| GB2114569A (en) * | 1979-09-14 | 1983-08-24 | Hoffmann La Roche | Cholestenes for use in preparing cholecalciferol derivatives |
| US4407754A (en) * | 1979-09-14 | 1983-10-04 | Hoffmann-La Roche Inc. | Cholecalciferol derivatives |
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
-
2008
- 2008-09-29 CN CN2008101214430A patent/CN101381389B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4116985A (en) * | 1976-07-26 | 1978-09-26 | The Upjohn Company | Novel method for preparing cholesta-5,7-diene 3β,25-diol and derivatives thereof |
| GB2114569A (en) * | 1979-09-14 | 1983-08-24 | Hoffmann La Roche | Cholestenes for use in preparing cholecalciferol derivatives |
| US4407754A (en) * | 1979-09-14 | 1983-10-04 | Hoffmann-La Roche Inc. | Cholecalciferol derivatives |
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101381389A (en) | 2009-03-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101381389B (en) | Chemical synthesis method of 5,7-diene steroids compounds | |
| EP3166612B1 (en) | Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids | |
| US20070078273A1 (en) | Process for preparing 5-methyl-2-furfural | |
| WO2019128983A1 (en) | Method for preparing elagolix intermediate and composition thereof | |
| US10259789B2 (en) | Process for the preparation of 4-alkoxy-3-acetoxypicolinic acids | |
| CN101265271A (en) | Method for synthesizing penem-like pharmaceutical intermediate 4AA | |
| JP6481689B2 (en) | Method for producing phenolic compound | |
| CN102001979B (en) | Preparation method of 2-(2', 2'-difluoroethoxyl)-6-trifluoromethyl phenyl propyl sulfide | |
| CN100509616C (en) | Reclaiming method of inorganic iodide | |
| CN101400647A (en) | Method for nitrating isourea | |
| CN110128345A (en) | A kind of preparation method of e derivatives | |
| ES2378081T3 (en) | Process for the preparation of 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid | |
| CN109206396B (en) | Preparation method of 2-C-methyl-4,5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester | |
| WO1999029699A1 (en) | Process for producing toluene derivatives | |
| CN102791678A (en) | Process for the preparation of 4-bromomethyl-[1,1'-biphenyl]-2'-carbonitrile | |
| CN102786429A (en) | Synthesis method of tolfenamic acid | |
| CN102391175A (en) | Green synthesis method for 2,2'-bipyridine-4,4'-dicarboxaldehydes | |
| CN106795080A (en) | Method for preparing halo trifluoroacetophenone | |
| CN103183592B (en) | The preparation method of chloro-1,1, the 1-tri-alkoxy ethane of 2- | |
| Gamenara et al. | Hetero Diels-Alder adduct formation between nitrosobenzene and tetra-methyl purpurogallin and its retro-Diels-Alder reaction | |
| CN104817482A (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin | |
| EP1535898B1 (en) | Method of producing aromatic amine compound having alkylthio group | |
| JPS6210046A (en) | Nitration of phenol compound | |
| CN102675259A (en) | Method for preparing 16,17-dihydro-gibberellin 5 and preparing acetic ester thereof | |
| CN1974567B (en) | Preparation process of sertaconazole nitrate as antifungal medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |