CN103613541A - Preparation method of tetra-substituted olefin and its pyrazole derivatives - Google Patents

Preparation method of tetra-substituted olefin and its pyrazole derivatives Download PDF

Info

Publication number
CN103613541A
CN103613541A CN201310518573.9A CN201310518573A CN103613541A CN 103613541 A CN103613541 A CN 103613541A CN 201310518573 A CN201310518573 A CN 201310518573A CN 103613541 A CN103613541 A CN 103613541A
Authority
CN
China
Prior art keywords
reaction
alpha
intermediate product
boric acid
carbonyl
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.)
Granted
Application number
CN201310518573.9A
Other languages
Chinese (zh)
Other versions
CN103613541B (en
Inventor
余正坤
金伟伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Institute of Chemical Physics of CAS
Original Assignee
Dalian Institute of Chemical Physics of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dalian Institute of Chemical Physics of CAS filed Critical Dalian Institute of Chemical Physics of CAS
Publication of CN103613541A publication Critical patent/CN103613541A/en
Application granted granted Critical
Publication of CN103613541B publication Critical patent/CN103613541B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention discloses a method for preparing pyrazole derivatives and a clinic breast cancer treatment drug tetra-substituted olefin (Z)-Tamoxifen from sulfopolysubstituted olefin. The method comprises the following steps: carrying out a condensation cyclization reaction of a raw material alpha-carbonyloxo ketene monothioacetal and a nucleophilic reagent hydrazine to prepare the pyrazole derivatives; and carrying out a coupling reaction of the alpha-carbonyloxo ketene monothioacetal raw material and arylboric acid to prepare the tetra-substituted olefin Tamoxifen. Compared with pyrazole derivatives and (Z)-Tamoxifen prepared through reported preparation methods, the above products in the invention have the advantages of good regioselectivity and stereoselectivity, easily available raw materials, simple operation, mild preparation reaction conditions and high efficiency.

Description

The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof
Technical field
The present invention relates to a kind of method of preparing pyrazole derivatives and treatment mammary cancer clinical medicine four substituted olefines (Z)-Tamoxifen.Under reflux temperature, the alpha-carbonyl list ketene thioacetal of easily preparing, have structure diversity and many reactive centers of take reacts and prepares pyrazole derivatives as raw material and nucleophilic reagent hydrazine carry out condensation and cyclization; 50 ℃ with palladium catalytic condition under, the alpha-carbonyl dithio keteal of take is prepared four substituted olefines (Z)-Tamoxifen as raw material and aryl boric acid carry out substep linked reaction.Compare with the preparation method of the pyrazole derivatives of having reported and (Z)-Tamoxifen, product regioselectivity of the present invention and stereoselectivity is good, raw material is easy to get, easy and simple to handle, preparation feedback mild condition and efficiency high.
Background technology
Pyrazoles is the important five yuan of N-heterogeneous ring compounds with potential source biomolecule activity and medical active of a class.Its structural unit is extensively present in natural product and drug molecule, and they are just being subject to people's close attention as important organic synthesis structural unit and part.Research shows, 1,5-diaryl pyrazole oxazole derivatives is the important Cyclooxygenase-2 Inhibitor of a class (Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.; Carter, J.S.J.Med.Chem.1997,40,1347).Up to now, conventional pyrazole derivatives preparation method comprises: (1) 1,3-diketone reacts (Armstrong, A. with the condensation and cyclization of hydrazine; Jones, L.H.; Knight, J.D.; Kelsey, R.D.Org.Lett.2005,7,713; Heller, S.T.; Natarajan, S.R.Org.Lett.2006,8,2675); (2) 1 of alkynes and azo-compound, 3-Dipolar Cycloaddition (Mohanan, K.; Martin, A.R.; Toupet, L.; Smietana, M.; Vasseur, J.-J.Angew.Chem.Int.Ed.2010,49,3196; Okitsu, T.; Sato, K.; Wada, A.Org.Lett.2010,12,3506); (3) condensation reaction of alpha, beta-unsaturated ketone and hydrazine (Grotjahn, D.B.; Van, S.; Combs, D.; Lev, D.A.; Schneider, C.; Rideout, M.; Meyer, C.; Hernandez, G.; Mejorado, L.J.Org.Chem.2002,67,9200; Bishop, B.C.; Brands, K.M.J.; Gibb, A.D.; Kennedy, D.J.Synthesis2004,43); (4) other reaction (Matsumura, N.; Kunugihara, A.; Yoneda, S.Tetrahedron Lett.1983,24,3239; Wang, X.-J.; Tan, J.; Grozinger, K.Tetrahedron Lett.2000,41,4713).Yet, being subject to the restriction of raw molecule structure, the molecular structure of the pyrazole derivatives that aforesaid method can be prepared is also restricted, and gained pyrazole derivatives is usually the mixture of regional isomer, has therefore greatly limited the application of prepared pyrazole derivatives.The present invention utilizes easy preparation, has alpha-carbonyl list ketene thioacetal 3 and the hydrazine 4 generation condensation and cyclization reactions of structure diversity and many reactive centers, by regulating and controlling R in 3 1and R 2r in substituting group and hydrazine 4 3substituting group, has efficiently prepared the pyrazole derivatives 1 of serial different structure.
Tamoxifen(tamoxifen) be hormones and hormone antagonist series antineoplastic medicament, cis (being Z-type) configuration has strong estrogenic antagonist.Tamoxifen can be competed combination with hormone receptor after entering cell, forms receptor complex, suppresses oestrogenic hormon and plays a role, thereby suppress Cells Proliferation of Human Breast Cancer.(Z)-Tamoxifen is generally by corresponding dehydrating alkanes (Hungarian Patant178253,1979) or corresponding dehydration of alcohols (Nemeth, G.; Kapiller-Dezsofi, R.; Lax, G.; Simig, G.Tetrahedron1996,52,12821) preparation, but it is poor to generate the stereoselectivity of product, and what obtain is (Z) and (E) mix products of configuration, and needs repeatedly recrystallization just can obtain (Z)-Tamoxifen.(Z)-Tamoxifen and derivative thereof have been prepared respectively in the carbon metallization reaction of Miller and Itami application alkynyl silane stereospecificity, but syntheti c route lengthy and tedious (maximum nine steps), severe reaction conditions, raw material rare (Miller, R.B.; Al-Hassan, M.I.J.Org.Chem.1985,50,2121; Kamei, T.; Itami, K.; Yoshda, J.Adv.Synth.Catal.2004,346,1824).The present invention utilizes easy preparation, has the substep linked reaction of alpha-carbonyl dithio keteal 5a and aryl boric acid 6a and the 6b of structure diversity and many reactive centers, has efficiently prepared (Z)-Tamoxifen (2).
Figure BDA0000402220400000021
Summary of the invention
The object of the present invention is to provide that a kind of raw material is easy to get, reaction conditions gentleness, wide adaptability, good product selectivity, can prepare simply and easily the method for pyrazole derivatives and (Z)-Tamoxifen.
To achieve these goals, technical scheme of the present invention is as follows:
Under nitrogen protection, with Pd (PPh 3) 4for catalyzer, CuTC are α-benzoinoxime, Cs 2cO 3make the linked reaction generation alpha-carbonyl list ketene thioacetal 3 that alkali carries out alpha-carbonyl dithio keteal 5 and aryl boric acid 6 in organic solvent.Then by 3, carry out condensation and cyclization with hydrazine 4 and react (reaction formula 1).After reaction finishes, separation purification method carries out product separation and sign routinely, obtains pyrazole derivatives 1.
Under nitrogen protection, with Pd (PPh 3) 4for catalyzer, dppe are that phosphine part, CuTC are α-benzoinoxime, Cs 2cO 3and K 2cO 3be respectively alkali and in organic solvent, carry out the substep linked reaction of alpha-carbonyl dithio keteal (5a') and aryl boric acid 6a and 6b, then through carbonyl reduction, generate (Z)-Tamoxifen(2) (reaction formula 2).
Figure BDA0000402220400000022
Figure BDA0000402220400000031
Wherein: 5a' is by phenyl-acetone (7) and CS 2(8) and monobromoethane EtBr(9) and K 2cO 3alkali reacts preparation in DMF, and (preparation of other alpha-carbonyl dithio keteal is similar with the method for preparing 5a', and reference is shown in Zhang, L.; Liang, F.; Cheng, X.; Liu, Q.J.Org.Chem.2009,74,899.).
Concrete technical scheme:
1. take alpha-carbonyl list ketene thioacetal 3 and alpha-carbonyl dithio keteal 5 is raw material, and its substituting group is:
1) substituent R 1alkyl, benzyl C for carbonatoms 1-10 6h 5-ax a-CH 2-and C 6h 5-ax aone of-CHR ' '-, wherein R ' ' is alkyl, the aryl C of carbonatoms 1-10 6h 5-ax a; Or R 1for aryl C 6h 5-ax awith naphthyl C 10h 8-bx bone of; Or R 1for hexa-atomic, five-membered ring aryl C 5h 4-cyX cand C 4h 3-dyX done of; Or R 1for with methyl C hexa-atomic, five-membered ring aryl 5h 4-cyX c-CH 2-and C 4h 3-dyX d-CH 2one of-; X is that substituted radical on aryl or heterocycle, Y are heteroatoms in heterocycle; Wherein: the integer that a is 0-5, the integer that b is 0-8, the integer that c is 0-4, the integer that d is 0-3; Y is N or O or S; X is hydrogen, or carbonatoms be 1-4 alkyl, cyclohexyl, carbonatoms be 1-4 alkoxyl group, aryl, halogen atom or trifluoromethyl; Or R 1for one of allyl group, aryl vinyl and heterocyclic aryl vinyl.
2) substituent R 2for aryl C 6h 5-ax a, naphthyl C 10h 8-bx bone of, hexa-atomic or five-membered ring aryl C 5h 4-cyX cand C 4h 3-dyX done of, aryl vinyl and heterocyclic aryl vinyl; X is that substituted radical on aryl or heterocycle, Y are heteroatoms in heterocycle; Wherein: the integer that a is 0-5, the integer that b is 0-8, the integer that c is 0-4, the integer that d is 0-3; Y is N or O or S; X is hydrogen, or carbonatoms be 1-4 alkyl, cyclohexyl, carbonatoms be 1-4 alkoxyl group, aryl, halogen atom or trifluoromethyl.
3) substituent R 3for aryl C 6h 5-ax awith naphthyl C 10h 8-bx bone of, hydrogen, benzyl, pyridyl; Wherein: the integer that a is 0-5, the integer that b is 0-8; X is hydrogen, or carbonatoms be 1-4 alkyl, cyclohexyl, carbonatoms be 1-4 alkoxyl group, aryl, halogen atom or trifluoromethyl.
4) substituent R 4for carbonatoms be 1-4 alkyl, allyl group or benzyl.
5) heterocyclic aryl is furyl, thienyl, pyrryl, pyridyl.
2. reaction solvent is one or more organic solvent methyl alcohol, ethanol, tetrahydrofuran (THF) (THF), Isosorbide-5-Nitrae-dioxane, the trimethyl carbinol and toluene.Wherein, 3 in protic solvent ethanol or the trimethyl carbinol, to carry out effect best with reacting of hydrazine 4; 5 in non-protonic solvent tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and toluene, to carry out effect best with reacting of aryl boric acid 6.
3.3 with the mol ratio of hydrazine 4 be 1:1-1:5.When wherein, mol ratio is 1:1.2-1:1.5, reaction effect is best.5 and the mol ratio of intermediate product A and aryl boric acid 6 be 1:1-1:2.When wherein, mol ratio is 1:1.5, reaction effect is best.
4.3 with reaction times of hydrazine 4 be 1-24 hour, optimum reacting time is 5-16 hour.5 and reaction times of intermediate product A and aryl boric acid 6 be 1-48 hour, optimum reacting time is 12-24 hour.
5. temperature of reaction is 25-110 ℃.Wherein, optimal reaction temperature is 70-110 ℃.
The present invention has the following advantages:
1) alpha-carbonyl list ketene thioacetal 3 has structure diversity, can be used for preparing dissimilar and pyrazole derivatives 1 structure.
2) alpha-carbonyl list ketene thioacetal 3 and alpha-carbonyl dithio keteal 5 are easily prepared, and its raw materials is cheaply easy to get.
3) pyrazole derivatives 1 preparation feedback mild condition, step is simple, efficiency is high, product regioselectivity is good.(Z)-Tamoxifen preparation feedback mild condition, step is simple, product yield is high with stereoselectivity good.
In a word, the present invention utilizes the structure diversity of alpha-carbonyl list ketene thioacetal 3 and many reactive centers can efficiently prepare dissimilar and pyrazole derivatives 1 structure; Utilize alpha-carbonyl dithio keteal 5 to prepare (Z)-Tamoxifen, raw material is cheaply easy to get, easy and simple to handle highly-solid selectively, and product yield is high.
Embodiment
By following embodiment, contribute to further to understand the present invention, but content of the present invention is not limited in this.
Embodiment 1
Figure BDA0000402220400000041
Under nitrogen atmosphere, in 25mL reaction flask, add successively alpha-carbonyl dithio keteal 5b(95mg, 0.50mmol), aryl boric acid 6b(91mg, 0.75mmol), Pd (PPh 3) 4(43mg, 0.0375mmol), CuTC(191mg, 1.0mmol), Cs 2cO 3(326mg, 1.0mmol) and 5mL solvent THF, stirring reaction 2h at 50 ℃.After reaction finishes, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, under filtrate decompression, remove volatilization component, (elutriant is sherwood oil (60-90 ℃)/ethyl acetate, v/v=30:1) then to use silica gel column chromatography separation, obtain yellow liquid intermediate product 3a(100mg, yield 97%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Under nitrogen atmosphere, in 25mL reaction flask, add successively 3a(103mg, 0.50mmol), phenylhydrazine 4a(65mg, 0.60mmol), potassium tert.-butoxide (112mg, 1.0mmol) and 5mL solvent tertiary butanol, stirring and refluxing reaction 9h.After reaction finishes, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, under filtrate decompression, remove volatilization component, (elutriant is sherwood oil (60-90 ℃)/ethyl acetate, v/v=20:1) then to use silica gel column chromatography separation, obtain yellow liquid target product 1a(102mg, yield 87%).Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 2
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, second step temperature of reaction is 25 ℃ of room temperatures, reaction times 24h.Stopped reaction, through obtaining target product 1a(10mg with above-mentioned identical aftertreatment, yield 9%).Illustrate that temperature of reaction reduces, and reacts slack-off.
Embodiment 3
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, second step reaction solvent is toluene.Stopped reaction, obtains target product 1a(30mg through aftertreatment, yield 26%).Illustrate and use non-protonic solvent to be unfavorable for that 3 react and carry out with hydrazine 4 condensation and cyclizations.
Embodiment 4
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, 75 ℃ of second step temperature of reaction.Stopped reaction, obtains target product 1a(62mg through aftertreatment, yield 53%).Illustrate that rising temperature promotes reaction to carry out.
Embodiment 5
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, 95 ℃ of second step temperature of reaction, reaction times 5h.Stopped reaction, obtains target product 1a(104mg through identical aftertreatment, yield 89%).Illustrate that raising temperature of reaction can Reaction time shorten.
Embodiment 6
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, in second step reaction, the add-on of phenylhydrazine (4a) is 54mg(0.50mmol).Stopped reaction, obtains target product 1a(82mg through aftertreatment, yield 70%).When the hydrazine that only uses equivalent is described, can not obtain target product with optimal yield.
Embodiment 7
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, in second step reaction, phenylhydrazine (4a) add-on is 81mg(0.75mmol).Stopped reaction, obtains target product 1a(102mg through aftertreatment, yield 87%).Illustrate that excessive too many hydrazine there is no need.
Embodiment 8
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, in second step reaction, phenylhydrazine (4a) add-on is 216mg(2.0mmol).Stopped reaction, obtains target product 1a(104mg through identical aftertreatment, yield 89%).Illustrate and there is no need to use greatly excessive hydrazine.
Embodiment 9
Figure BDA0000402220400000061
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is aryl boric acid 4-MeOC 6h 4b (OH) 2(6c).Reaction obtains yellow liquid intermediate product 3b(115mg, yield 97%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3b.Stopped reaction, obtains yellow solid target product 1b(115mg, yield 87% through aftertreatment).Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 10
Figure BDA0000402220400000062
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is aryl boric acid 4- tbuC 6h 4b (OH) 2(6d).Reaction obtains yellow solidliquid mixture intermediate product 3c(110mg, yield 84%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3c.Stopped reaction, obtains yellow solid target product 1c (134mg, yield 92%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 11
Figure BDA0000402220400000063
Reactions steps is with operation with embodiment 1, and difference is, what in the first step reaction, add is aryl boric acid 3,4-F 2c 6h 3b (OH) 2(6e).Reaction 4h, obtains yellow liquid intermediate product 3d(99mg, yield 82%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3d.Stopped reaction, obtains reddish-brown solid target product 1d (111mg, yield 82%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 12
Figure BDA0000402220400000071
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is aryl boric acid 2-naphthylB (OH) 2(6f).Reaction obtains reddish-brown liquid intermediate product 3e(139mg, yield 92%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3e.Stopped reaction, obtains red liquid target product 1e (108mg, yield 76%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 13
Figure BDA0000402220400000073
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is aryl boric acid trans-PhCH=CHB (OH) 2(6g).Reaction obtains reddish-brown liquid intermediate product 3f(103mg, yield 89%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3f.Stopped reaction, obtains yellow liquid target product 1f (108mg, yield 83%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 14
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5c(126mg, 0.50mmol) and aryl boric acid PhB (OH) 2(6b) (91mg, 0.75mmol).Reaction obtains yellow solid intermediate product 3g(130mg, yield 97%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3g(134mg, 0.5mmol).Stopped reaction, obtains white solid target product 1g (136mg, yield 92%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 15
Figure BDA0000402220400000081
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5d(141mg, 0.50mmol) and aryl boric acid 4-ClC 6h 4b (OH) 2(6h) (117mg, 0.75mmol).Reaction obtains yellow liquid intermediate product 3h(153mg, yield 92%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3h(166mg, 0.5mmol).Stopped reaction, obtains white solid target product 1h (143mg, yield 79%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 16
Figure BDA0000402220400000082
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5e(143mg, 0.50mmol) and aryl boric acid 6h(117mg, 0.75mmol).Reaction 6h, obtains yellow liquid intermediate product 3i(140mg, yield 83%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3i(169mg, 0.5mmol).Stopped reaction, obtains yellow solid target product 1i (174mg, yield 95%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 17
Figure BDA0000402220400000083
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5f(121mg, 0.50mmol) and aryl boric acid 6h(117mg, 0.75mmol).Reaction obtains yellow solid intermediate product 3j(133mg, yield 91%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3j(146mg, 0.5mmol).Stopped reaction, obtains yellow solid target product 1j (125mg, yield 78%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 18
Figure BDA0000402220400000091
Reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5g(129mg, 0.50mmol) and aryl boric acid 6h(117mg, 0.75mmol).Reaction obtains yellow solid intermediate product 3k(141mg, yield 91%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Reactions steps is with operation with embodiment 1, and difference from Example 1 is, what in second step reaction, add is that alpha-carbonyl list ketene thioacetal is 3k(154mg, 0.5mmol).Stopped reaction, obtains reddish-brown solid target product 1k (148mg, yield 88%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 19
Figure BDA0000402220400000092
Reactions steps is with operation with embodiment 1, and difference is, what in the first step reaction, add is aryl boric acid 3,5-F 2c 6h 3b (OH) 2(6i) (118mg, 0.75mmol).Reaction 4h, obtains yellow solid intermediate product 3l(88mg, yield 73%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Under nitrogen atmosphere, in 25mL reaction flask, add successively 3l(121mg, 0.50mmol), 85% hydrazine hydrate 4b(38mg, 0.75mmol), Glacial acetic acid AcOH(19mg, 0.3mmol) and 5mL solvent tertiary butanol t-BuOH, stirring and refluxing reaction 12h.After reaction finishes, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, under filtrate decompression, remove volatilization component, (elutriant is sherwood oil (60-90 ℃)/ethyl acetate, v/v=20:1) then to use silica gel column chromatography separation, obtain yellow solid target product 1l(78mg, yield 80%).Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 20
Figure BDA0000402220400000093
Reactions steps is with operation with embodiment 19, and difference is, what in second step reaction system, add is that alpha-carbonyl list ketene thioacetal is 3g(134mg, 0.5mmol).Stopped reaction, obtains white solid target product 1m (100mg, yield 91%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 21
Figure BDA0000402220400000101
The first step reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5f(121mg, 0.50mmol) and aryl boric acid 6b(91mg, 0.75mmol).Reaction obtains yellow solidliquid mixture intermediate product 3m(123mg, yield 95%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Second step reactions steps is with operation with embodiment 19, and difference is, that in second step reaction system, add is alpha-carbonyl list ketene thioacetal 3m(129mg, 0.5mmol).Stopped reaction, obtains white solid target product 1n (87mg, yield 83%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 22
Figure BDA0000402220400000102
The first step reactions steps is with operation with embodiment 1, and difference is, that in the first step reaction, add is alpha-carbonyl dithio keteal 5g(129mg, 0.50mmol) and aryl boric acid 6b(91mg, 0.75mmol).Reaction obtains yellow liquid intermediate product 3n(125mg, yield 91%).Intermediate product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Second step reactions steps is with operation with embodiment 19, and difference is, that in second step reaction system, add is alpha-carbonyl list ketene thioacetal 3n(137mg, 0.5mmol).Stopped reaction, obtains white solid target product 1o (108mg, yield 95%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 23
Figure BDA0000402220400000103
Reactions steps is with operation with embodiment 19, and difference is, what in second step reaction system, add is that alpha-carbonyl list ketene thioacetal is 3a(103mg, 0.5mmol) and benzyl hydrazine dihydrochloride 4c(146mg, 0.75mmol).Stopped reaction, obtains colourless liquid target product 1p (119mg, yield 96%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 24
Figure BDA0000402220400000111
Reactions steps is with operation with embodiment 19, and difference is, what in second step reaction system, add is that alpha-carbonyl list ketene thioacetal is 3a(103mg, 0.5mmol) and 2-hydrazino pyridine 4d(82mg, 0.75mmol).Stopped reaction, obtains colourless liquid target product 1q (88mg, yield 75%) through aftertreatment.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 25
In 100mL reaction flask, add successively phenyl-acetone 7(6.99g, 52mmol), K 2cO 3(15.8g, 114mmol) and 30mL solvent DMF, stir 0.5h.Be chilled to 0 ℃, add dithiocarbonic anhydride 8(4.4g, 57mmol), continue to stir 0.5h, then add monobromethane 9(12.5g, 114mmol), under room temperature, react 12h.To reaction system, add 100mL water, methylene dichloride (3 * 30mL) extraction, phase-splitting, merge organic phase, anhydrous sodium sulfate drying, then (elutriant is sherwood oil (60-90 ℃)/ethyl acetate to use silica gel column chromatography separation, v/v=10:1), obtain yellow oily compound 5a'(9.3g, yield 67%).5a' is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Press reaction formula (2), under nitrogen atmosphere, in 25mL reaction flask, add successively 5a'(133mg, 0.50mmol), Me 2n (CH 2) 2oC 6h 4b (OH) 2(6a) (157mg, 0.75mmol), Pd (PPh 3) 4(43mg, 0.0375mmol), CuTC(191mg, 1.0mmol), Cs 2cO 3(326mg, 1.0mmol) and 5mL solvent THF, stirring reaction 24h at 50 ℃.After reaction finishes, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, under filtrate decompression, remove volatilization component, (elutriant is sherwood oil (60-90 ℃)/ethyl acetate, v/v=30:1) then to use silica gel column chromatography separation, obtain yellow intermediate product A(166mg, yield 90%).Intermediate product A is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Under nitrogen atmosphere, in 25mL reaction flask, add successively intermediate product A(185mg, 0.50mmol), PhB (OH) 2(6b) (92mg, 0.75mmol), Pd (PPh 3) 4(43mg, 0.0375mmol), dppe(15mg, 0.0375mmol), CuTC(191mg, 1.0mmol), K 2cO 3(138mg, 1.0mmol) and 5mL solvent THF, stirring reaction 24h at 50 ℃.After reaction finishes, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, under filtrate decompression, remove volatilization component, (elutriant is sherwood oil (60-90 ℃)/ethyl acetate, v/v=30:1) then to use silica gel column chromatography separation, obtain white solid intermediate product B(150mg, yield 78%).Intermediate product B is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Under nitrogen atmosphere, in 25mL Schlenk reaction flask, add successively intermediate product B(193mg, 0.50mmol), LiAlH 4(35mg, 0.90mmol) and 10mL solvent THF, stirring and refluxing reaction 24h.After reaction finishes, mixture is cooled to room temperature, be added dropwise to the 2mL shrend reaction of going out, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, removes volatilization component under filtrate decompression, then (elutriant is sherwood oil (60-90 ℃)/ethyl acetate to use silica gel column chromatography separation, v/v=30:1), obtain white solid target product (Z)-Tamoxifen (2) (149mg, yield 80%).Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 26
Under nitrogen atmosphere, in 25mL reaction flask, add successively alpha-carbonyl dithio keteal 5f(121mg, 0.50mmol), aryl boric acid 6b(244mg, 2.0mmol), Pd (PPh 3) 4(43mg, 0.0375mmol), CuTC(286mg, 1.5mmol), K 2cO 3(207mg, 1.5mmol) and 5mL solvent THF, stirring reaction 13h at 50 ℃.After reaction finishes, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, under filtrate decompression, remove volatilization component, (elutriant is sherwood oil (60-90 ℃)/ethyl acetate, v/v=30:1) then to use silica gel column chromatography separation, obtain yellow solid target product 10a(130mg, yield 95%).Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Embodiment 27
Figure BDA0000402220400000122
Reactions steps is with operation with embodiment 24, and difference is, the alpha-carbonyl list ketene thioacetal adding is 3m(129mg, 0.50mmol), aryl boric acid is 6h(313mg, 2.0mmol).After reaction finishes, through aftertreatment, obtain yellow liquid target product 10b(116mg, yield 75%).Target product is measured and is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.
Alpha-carbonyl dithio keteal has raw material and is easy to get, prepares the advantages such as simple, structure diversity and many reactive centers, the linked reaction mild condition of they and aryl boric acid, and product stereoselectivity is good, is the effective ways of preparing Polysubstituted Olefins.
Typical compound characterization data
Pyrazole derivatives 1a, 1b, 1g, 1h, 1i, 1k, 1m, 1n, 1o, 1p, 1q and (Z)-Tamoxifen are known compounds, their nuclear magnetic resonance spectrum 1h NMR and 13c{ 1h}NMR, high resolution mass spectrum HRMS and fusing point data (Han, B. consistent with bibliographical information; Liu, Z.G.; Liu, Q.; Yang, L.; Liu, Z.-L.; Yu, W.Tetrahedron2006,62,2492; Foote, R.S.; Beam, C.F.; Hauser (I), C.R.J.Heterocycl.Chem.1970,7,589; Azarifar, D.; Gharshasbi, A.Heterocycles2006,68,1209; Liu, H.-L.; Jiang, H.-F.; Zhang, M.; Yao, W.-J.; Zhu, Q.-H.; Tang, Z.Tetrahedron Lett.2008,49,3805; Potts, K.T.; Cipullo, M.J.; Ralli, P.; Theodoridis, G.J.Org.Chem.1982,47,3027; Werner, A.; S á nchez-Migall ó n, A.; Fruchier, A.; Elguero, J.;
Figure BDA0000402220400000123
, C.; Foces-Foces, C.Tetrahedron1995,51,4779; Curini, M.; Rosati, O.; Campagna, V.; Montanari, F.; Cravotto, G.; Boccalini, M.Synlett2005,2927; Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi, K.J.Am.Chem.Soc.2003,125,14670).
5-(4-tert-Butyl-phenyl)-3-methyl-1-phenyl-1H-pyrazole (1c): yellow solid, fusing point 54-56 ℃. 1H?NMR(CDCl 3,400MHz,23℃)δ7.32-7.26(m,7H),7.15(d,2H,J=8.0Hz),6.29(s,1H),2.38(s,3H),1.30(s,9H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz)δ151.3,149.5,143.9,140.5,128.9,128.3,127.9,127.1,125.4,125.3,107.7,34.8,31.4,13.7。C 20h 22n 2hRMS theoretical value ([M +]): 290.1783; Measured value: 290.1783.
5-(3,4-Difluoro-phenyl)-3-methyl-1-phenyl-1H-pyrazole (1d): reddish-brown solid, fusing point 59-62 ℃. 1H?NMR(CDCl 3,400MHz,23℃)δ7.35-7.24(m,5H),7.08-7.00(m,2H),6.92-6.91(m,1H),6.28(s,1H),2.36(s,3H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz)δ151.5,149.7,148.9,141.7,139.8,129.2,127.7,125.3,125.0,117.9,117.7,117.5,108.1,13.7。C 16h 12n 2f 2hRMS theoretical value ([M +]): 270.0969; Measured value: 270.0965.
3-Methyl-5-naphthalen-2-yl-1-phenyl-1H-pyrazole (1e): red liquid. 1HNMR(CDCl 3,400MHz,23℃)δ7.80-7.72(m,4H),7.34(m,2H),7.31-7.26(m,6H),6.44(s,1H),2.46(s,3H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz)δ149.6,143.7,140.3,133.2,132.8,129.0,128.2,128.1,127.8,127.8,127.2,126.6,126.5,126.4,125.2,108.2,13.7。C 20h 16n 2hRMS theoretical value ([M +]): 284.1313; Measured value: 284.1324.
3-Methyl-1-phenyl-5-styryl-1H-pyrazole (1f): yellow liquid. 1H?NMR(CDCl 3,400MHz,23℃)d7.50-7.31(m,10H),7.06and6.89(d?each,J=16.3Hz,1:1H),6.48(s,1H),2.39(s,3H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz)δ149.5,141.8,139.7,136.6,131.7,129.2,128.8,128.2,127.7,126.6,125.4,115.9,103.9,13.6。C 18h 16n 2hRMS theoretical value ([M +]): 260.1313; Measured value: 260.1309.
5-(4-Chloro-phenyl)-3-furan-2-yl-1-phenyl-1H-pyrazole (1j): yellow solid, fusing point 102-104 ℃. 1H?NMR(CDCl 3,400MHz,23℃)δ7.54(s,1H),7.41-7.37(m,5H),7.33and7.23(d?each,J=8.4Hz,2:2H),6.84(d,J=3.3Hz,1H),6.79(s,1H),6.54(s,1H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz)δ148.5,144.8,143.1,142.3,139.8,134.7,130.1,129.2,129.0,128.8,128.0,125.6,111.5,106.6,105.1。C 19h 13n 2hRMS the theoretical value ([M of OCl +]): 320.0716; Measured value: 320.0720.
5-(3,5-Difluoro-phenyl)-3-methyl-1H-pyrazole (1l): yellow solid, fusing point 123-125 ℃. 1H?NMR(CDCl 3,400MHz,23℃)δ7.61,7.60and7.27(s?each,1:1:1H),6.33(s,1H),2.32(s,3H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz)δ149.2,141.9,136.2,135.4,127.6,124.2,102.6,11.3。C 10h 8n 2f 2hRMS theoretical value ([M-1 +]): 193.0577; Measured value: 193.0358.
4,4-Bis-ethylsulfanyl-3-phenyl-but-3-en-2-one (5a'): yellow liquid. 1H?NMR(CDCl 3,400MHz,23℃)δ7.34-7.26(m,5H),2.85and2.63(q?each,2:2H),2.25(s,1H),1.30and1.12(t?each,3:3H); 13C{ 1H}NMR(C?DCl 3,23℃,100MHz.)δ201.3,149.4,136.3,135.4,129.0,128.3,128.1,30.4,28.3,28.0,14.6,14.6。C 14h 18oS 2hRMS theoretical value ([M +]): 266.0799; Measured value: 266.0793.
4-[4-(2-Dimethylamino-ethoxy)-phenyl]-4-ethylsulfanyl-3-phenyl-but-3-en-2-one (A): yellow liquid. 1H?NMR(CDCl 3,400MHz,23℃)δ7.55-6.90(m,9H),4.17(t,2H),2.86(q,2H),2.91(t,2H),2.45(s,3H),2.27(s,6H),1.31(s,3H); 13C{ 1H}NMR(CDCl 3,23℃100MHz.)d197.0,157.8,148.5,134.7,127.9,127.7,126.7,126.5,125.4,121.3,114.6,70.9,59.0,41.9,23.6,21.9,15.9。C 22h 27nO 2hRMS the theoretical value ([M of S +]): 369.1762; Measured value: 369.1759.
4-[4-(2-Dimethylamino-ethoxy)-phenyl]-3,4-diphenyl-but-3-en-2-one (B): white solid, fusing point 115-117 ℃. 1H?NMR(CDCl 3,400MHz,23℃)δ7.53-7.35(m,14H),4.14(t,2H),2.83(t,2H),2.47(s,3H),2.25(s,6H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz.)d196.5,157.3,141.6,134.7,128.4,128.3,128.0,127.8,127.5,127.3,127.0,126.5,126.2,125.9。C 26h 27nO 2hRMS theoretical value ([M +]): 385.2042; Measured value: 385.2049.
(Z)-Tamoxifen (2): white solid, fusing point 95-98 ℃. 1H?NMR(CDCl 3,400MHz,23℃)d7.39-7.08(m,10H),6.75and6.57(d?each,J=8.7Hz2:2H),3.95(t,2H),2.74(t,2H),2.45(q,2H),2.29(s,6H),1.03(t,3H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz.)d157.0,143.9,143.5,141.7,138.7,135.9,132.0,130.0,129.8,128.3,127.9,126.7,126.1,113.5,65.8,58.3,45.9,29.3,13.9。C 26h 29hRMS the theoretical value ([M of NO +]): 371.2249; Measured value: 371.2253.
1-Furan-2-yl-3,3-diphenyl-propenone (10a): yellow solid, fusing point 109-111 ℃. 1H?NMR(CDCl 3,400MHz,23℃)d7.44(s,1H,CH-O),7.32-7.25(m,8H),7.16-7.13(m,2H),7.09(s,1H),7.05(d,J=3.5Hz,1H),6.39(q,1H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz.)δ179.0,156.4,154.2,146.2,121.5,117.4,129.7,128.8,128.6,128.5,128.1,141.6,139.1,112.5。C 19h 14o 2hRMS theoretical value ([M +]): 274.0994; Measured value: 274.1001.
3-(4-Chloro-phenyl)-1-furan-2-yl-3-phenyl-propenone (10b): yellow liquid. 1H?NMR(CDCl 3,400MHz,23℃)δ7.48(s,1H,CH-O),7.33-7.24(m,7H),7.14-7.09(m,4H),6.44(t,1H); 13C{ 1H}NMR(CDCl 3,23℃,100MHz.)δ178.5,155.3,154.2,146.3,121.5,117.5,141.1,137.5,134.4,131.0,129.9,128.7,128.7,128.4,112.6。C 19h 13o 2hRMS the theoretical value ([M of Cl +]): 308.0604; Measured value: 308.0601.

Claims (7)

1. a preparation method of four substituted olefines (Z)-Tamoxifen (2),
Figure FDA0000402220390000011
It is characterized in that: preparation feedback route, as shown in following reaction formula, be take alpha-carbonyl dithio keteal 5a as raw material and aryl boric acid 6a and 6b carry out substep linked reaction, then through lithium aluminium hydride reducing carbonyl, generates (Z)-Tamoxifen(2);
Figure FDA0000402220390000012
Substituent R 4alkyl, allyl group or benzyl for carbonatoms 1-4;
Wherein: aryl boric acid is Me 2n (CH 2) 2o-C 6h 4b (OH) 2(6a) and PhB (OH) 2(6b), catalyzer is Pd (PPh 3) 4, Pd 2(dba) 3(dba=dibenzalacetone), Pd (dba) 2and Pd (PPh 3) 2cl 2one of; Alkali is Na 2cO 3, K 2cO 3and Cs 2cO 3one of; α-benzoinoxime is one of CuTC (TC=thiophene-2-carboxylate), CuI, CuBr and CuCl; Part is dppe (two (diphenyl phosphine) ethane of 1,2-), (±) BINAP (racemize dinaphthalene diphenylphosphine), dppf (two (diphenylphosphino) ferrocene) and PPh 3one of (triphenyl phosphorus); Reaction solvent is one or two or more kinds in organic solvent methyl alcohol, ethanol, tetrahydrofuran (THF) (THF), Isosorbide-5-Nitrae-dioxane, the trimethyl carbinol and toluene; The mol ratio of 5a and intermediate product A and 6a or 6b is 1:1-1:2; Reaction times 1-48 hour; Temperature of reaction 25-110 ℃; After reaction finishes, separation purification method carries out product separation routinely, obtains (Z)-Tamoxifen (2).
2. according to preparation method claimed in claim 1, it is characterized in that:
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reacting of aryl boric acid 6a and 6b, its optimum catalyst is Pd (PPh 3) 4and Pd (PPh 3) 2cl 2one of, consumption is 5 or the 0.05-0.10 equivalent of A;
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reacting of aryl boric acid 6a and 6b, its optimum response alkali is Cs 2cO 3and K 2cO 3one of, consumption is 5 or the 1-2 equivalent of A;
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reacting of aryl boric acid 6a and 6b, its optimum response α-benzoinoxime is one of CuI and CuTC, consumption is 5 or the 1-2 equivalent of A;
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reacting of aryl boric acid 6a and 6b, its optimum response part is one of (±) BINAP and dppe, consumption is 5 or the 0.05-0.10 equivalent of A;
Alpha-carbonyl dithio keteal 5a and intermediate product A are preferably in one of non-protonic solvent tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and toluene and carry out with reacting of aryl boric acid 6a and 6b respectively.
3. according to preparation method claimed in claim 1, it is characterized in that: when alpha-carbonyl dithio keteal 5a and intermediate product A react with aryl boric acid 6a and 6b respectively, its optimum molar ratio is all 1:1.5; The volumetric molar concentration of 5a and A is 0.05-1.0M, optimum with 0.1M.
4. according to preparation method claimed in claim 1, it is characterized in that: when alpha-carbonyl dithio keteal 5a and intermediate product A react with aryl boric acid 6a and 6b respectively, optimum reacting time is 12-24 hour.
5. according to preparation method claimed in claim 1, it is characterized in that: the optimum temps that alpha-carbonyl dithio keteal 5a and intermediate product A react with aryl boric acid 6a and 6b is respectively 70-110 ℃.
6. according to preparation method claimed in claim 1, it is characterized in that: the carbonyl reduction best reductive agent used of intermediate product B is lithium aluminium hydride (LiAlH 4), reaction is carried out in room temperature tetrahydrofuran (THF).
7. according to preparation method claimed in claim 1, it is characterized in that: alpha-carbonyl dithio keteal is that 5a'(is R 4=Et(ethyl)) time, the best results of preparation (Z)-Tamoxifen;
Figure FDA0000402220390000021
CN201310518573.9A 2011-01-28 2011-01-28 The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof Expired - Fee Related CN103613541B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110031782.1A CN102617472B (en) 2011-01-28 2011-01-28 Preparation method of pyrazole derivative

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201110031782.1A Division CN102617472B (en) 2011-01-28 2011-01-28 Preparation method of pyrazole derivative

Publications (2)

Publication Number Publication Date
CN103613541A true CN103613541A (en) 2014-03-05
CN103613541B CN103613541B (en) 2015-09-23

Family

ID=46557735

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201110031782.1A Expired - Fee Related CN102617472B (en) 2011-01-28 2011-01-28 Preparation method of pyrazole derivative
CN201310518573.9A Expired - Fee Related CN103613541B (en) 2011-01-28 2011-01-28 The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201110031782.1A Expired - Fee Related CN102617472B (en) 2011-01-28 2011-01-28 Preparation method of pyrazole derivative

Country Status (1)

Country Link
CN (2) CN102617472B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108610276A (en) * 2016-12-09 2018-10-02 中国科学院大连化学物理研究所 A kind of method of two steps synthesis 3- (2- vinyls) indole derivatives
CN115466159A (en) * 2021-06-10 2022-12-13 中国科学院大连化学物理研究所 Tetra-substituted allene derivative and synthesis method thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974091B (en) * 2014-04-10 2018-01-02 沈阳药科大学 Diaryl pyrazole azole compound of 3 methyl 1,5 and its production and use
CN111302990B (en) * 2018-12-11 2021-02-26 中国科学院大连化学物理研究所 Conjugated diene compound and synthetic method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007668A1 (en) * 1994-04-25 1999-02-18 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
CN1247860A (en) * 1999-09-13 2000-03-22 上海华联制药有限公司 Preparation of high-purity E-type Tamoxifen or its citrate
EP1680175A2 (en) * 2003-11-06 2006-07-19 Lifescan, Inc. Drug delivery pen with event notification means

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999007668A1 (en) * 1994-04-25 1999-02-18 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
CN1247860A (en) * 1999-09-13 2000-03-22 上海华联制药有限公司 Preparation of high-purity E-type Tamoxifen or its citrate
EP1680175A2 (en) * 2003-11-06 2006-07-19 Lifescan, Inc. Drug delivery pen with event notification means

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ABDUL H.FAUQ ET AL: "A convenient syhthesis of (Z)-4-hydroxy-N-desmethyltamoxifen(endoxifen)", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, 3 April 2010 (2010-04-03), pages 3036 - 3038, XP027036784 *
YOSHIYUKI SANO ET AL: "Short-step synthesis of droloxifene via the three-component coupling reaction among aromatic aldehyde,cinnamyltromethylsilane ,and β-chlorophenetole", 《TETRAHEDRON LETTERS》, vol. 45, 6 March 2006 (2006-03-06), pages 1631 - 1635 *
梅和珊 等: "他莫昔芬合成路线图解", 《中国医药工业杂志》, vol. 32, no. 1, 8 January 2004 (2004-01-08), pages 45 - 47 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108610276A (en) * 2016-12-09 2018-10-02 中国科学院大连化学物理研究所 A kind of method of two steps synthesis 3- (2- vinyls) indole derivatives
CN115466159A (en) * 2021-06-10 2022-12-13 中国科学院大连化学物理研究所 Tetra-substituted allene derivative and synthesis method thereof
CN115466159B (en) * 2021-06-10 2024-03-15 中国科学院大连化学物理研究所 Tetra-substituted diene derivative and synthesis method thereof

Also Published As

Publication number Publication date
CN102617472B (en) 2014-12-03
CN102617472A (en) 2012-08-01
CN103613541B (en) 2015-09-23

Similar Documents

Publication Publication Date Title
Raushel et al. Efficient synthesis of 1-sulfonyl-1, 2, 3-triazoles
Baykov et al. The first one-pot ambient-temperature synthesis of 1, 2, 4-oxadiazoles from amidoximes and carboxylic acid esters
Qiu et al. Brønsted acid catalyzed and NIS-promoted cyclization of diynones: selective synthesis of 4-pyrone, 4-pyridone, and 3-pyrrolone derivatives
CN101774978B (en) Preparation method of linezolid and intermediate thereof
JP5108506B2 (en) Cyanopyrrole-containing cyclic carbamates and thiocarbamate biaryls and methods for their production
Zhou et al. Metal-free radical oxidative cyclization of o-azidoaryl acetylenic ketones with sulfinic acids to access sulfone-containing 4-quinolones
Lukashenko et al. Complementary pairing of o-quinone methides with 3-(N, N-diethylamino) acrolein–synthesis of 1 H-benzo [f] chromene-2-carbaldehydes
CN103613541B (en) The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof
Wang et al. Combined Photoredox and Carbene Catalysis for the Synthesis of γ‐Aryloxy Ketones
US9975856B2 (en) Process for the preparation of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
Sato et al. Synthesis of Biaryls via Palladium‐Catalyzed [2+ 2+ 2] Cocyclization of Arynes and Diynes: Application to the Synthesis of Arylnaphthalene Lignans
Kotovshchikov et al. Regioselective approach to 5-carboxy-1, 2, 3-triazoles based on palladium-catalyzed carbonylation
Swartz II et al. Synthesis and hydroamination catalysis with 3-aryl substituted pyrrolyl and dipyrrolylmethane titanium (iv) complexes
Mariappan et al. Remote alkylation of N-(quinolin-8-yl) benzamides with alkyl bromides via ruthenium (ii)-catalyzed C–H bond activation
Zhang et al. Gold-catalyzed cascade C–H/C–H cross-coupling/cyclization/alkynylation: an efficient access to 3-alkynylpyrroles
Chang et al. NBS-mediated cyclization of trans-cinnamic alcohols
Chang et al. One-pot synthesis of multifunctionalized m-terphenyls
Liu et al. Tandem metal-free oxidative radical 5-exo dearomative spirocyclization and ester migration: Generation of 3-functionalized coumarins from alkynoates
Arcadi et al. 2, 5, 7-Trisubstituted benzo [b] furans through a copper-and/or palladium-catalyzed assembly and functionalization process
Matsuda et al. Rhodium-catalysed arylative annulation of 1, 4-enynes with arylboronic acids
CN103012241B (en) Polysubstitution indole, synthesis method for same and synthesis application of polysubstitution indole to indomethacin
Yadav et al. Well‐Defined N‐Heterocyclic Carbene‐Palladium Complexes as Efficient Catalysts for Domino Sonogashira Coupling/Cyclization Reaction and C‐H bond Arylation of Benzothiazole
Picado et al. A Serendipitous Synthesis of Bis-Heterocyclic Spiro 3 (2 H)-Furanones
Zhao et al. Catalyst-and solvent-free approach to 2-arylated quinolines via [5+ 1] annulation of 2-methylquinolines with diynones
Usami et al. Divergent Synthesis and Evaluation of Inhibitory Activities against Cyclooxygenases-1 and-2 of Natural Withasomnines and Analogues

Legal Events

Date Code Title Description
PB01 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
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150923

Termination date: 20180128