CN103613541B - The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof - Google Patents

The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof Download PDF

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CN103613541B
CN103613541B CN201310518573.9A CN201310518573A CN103613541B CN 103613541 B CN103613541 B CN 103613541B CN 201310518573 A CN201310518573 A CN 201310518573A CN 103613541 B CN103613541 B CN 103613541B
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intermediate product
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CN103613541A (en
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余正坤
金伟伟
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Dalian Institute of Chemical Physics of CAS
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Abstract

The invention discloses a kind of method preparing pyrazole derivatives and treatment mammary cancer clinical medicine four substituted olefine (Z)-Tamoxifen via sulfo-Polysubstituted Olefins.At a reflux temperature, react with the alpha-carbonyl list ketene thioacetal easily preparing, have structure diversity and many reactive centers prepare pyrazole derivatives for raw material and nucleophilic reagent hydrazine carry out condensation and cyclization; Under 50 DEG C with palladium chtalyst condition, prepare four substituted olefines (Z)-Tamoxifen with alpha-carbonyl dithio keteal for raw material and aryl boric acid carry out linked reaction.Preparation method with (Z)-Tamoxifen compares with the pyrazole derivatives reported, 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.

Description

The preparation method of a kind of four substituted olefines and pyrazole derivatives thereof
Technical field
The present invention relates to the method that one prepares pyrazole derivatives and treatment mammary cancer clinical medicine four substituted olefine (Z)-Tamoxifen.At a reflux temperature, react with the alpha-carbonyl list ketene thioacetal easily preparing, have structure diversity and many reactive centers prepare pyrazole derivatives for raw material and nucleophilic reagent hydrazine carry out condensation and cyclization; Under 50 DEG C with palladium chtalyst condition, react preparation four substituted olefine (Z)-Tamoxifen with alpha-carbonyl dithio keteal for raw material and aryl boric acid carry out coupled stepwise.Preparation method with (Z)-Tamoxifen compares with the pyrazole derivatives reported, 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 the active and medical active of potential source biomolecule of a class.Its structural unit is extensively present in natural product and drug molecule, and they are just being subject to the close attention of people as important organic synthesis structural unit and part.Research shows, 1,5-diaryl pyrazole oxazole derivatives is important Cyclooxygenase-2 Inhibitor (Penning, the T.D. of a class; Talley, J.J.; Bertenshaw, S.R.; Carter, J.S.J.Med.Chem.1997,40,1347).Up to now, conventional pyrazole derivatives preparation method comprises: the condensation and cyclization of (1) 1,3-diketone and hydrazine reacts (Armstrong, A.; 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) 1,3-Dipolar Cycloaddition (Mohanan, K. of alkynes and azo-compound; 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 (Grotjahn, the D.B. of alpha, beta-unsaturated ketone and hydrazine; 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).But by the restriction of raw molecule structure, the molecular structure of the pyrazole derivatives that aforesaid method can be prepared also is restricted, and gained pyrazole derivatives is usually the mixture of regional isomer, therefore greatly limit the application of prepared pyrazole derivatives.The present invention utilizes easy preparation, have the alpha-carbonyl list ketene thioacetal 3 of structure diversity and many reactive centers and condensation and cyclization reaction occurs hydrazine 4, 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 (i.e. Z-type) configuration has strong estrogenic antagonist.Tamoxifen to enter after cell can with hormone receptor competition binding, form receptor complex, suppress oestrogenic hormon to play a role, thus 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 the stereoselectivity generating product is poor, and what obtain is the mix products of (Z) and (E) configuration, needs repeatedly recrystallization just can obtain (Z)-Tamoxifen.The carbon metallization reaction of Miller and Itami application alkynyl silane, has prepared (Z)-Tamoxifen and derivative thereof respectively 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 reaction of the coupled stepwise of the alpha-carbonyl dithio keteal 5a of structure diversity and many reactive centers and aryl boric acid 6a and 6b, has efficiently prepared (Z)-Tamoxifen (2).
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, the method for pyrazole derivatives and (Z)-Tamoxifen can be prepared simply and easily.
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 alkali in organic solvent, to carry out alpha-carbonyl dithio keteal 5 generate alpha-carbonyl list ketene thioacetal 3 with the linked reaction of aryl boric acid 6.Then condensation and cyclization reaction (reaction formula 1) is carried out 3 with hydrazine 4.After reaction terminates, separation purification method carries out product separation and sign routinely, namely obtains pyrazole derivatives 1.
Under nitrogen protection, with Pd (PPh 3) 4for catalyzer, dppe be Phosphine ligands, CuTC is α-benzoinoxime, Cs 2cO 3and K 2cO 3be respectively the coupled stepwise that alkali carries out alpha-carbonyl dithio keteal (5a') and aryl boric acid 6a and 6b in organic solvent react, then through carbonyl reduction generation (Z)-Tamoxifen(2) (reaction formula 2).
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 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. with alpha-carbonyl list ketene thioacetal 3 and alpha-carbonyl dithio keteal 5 for raw material, its substituting group is:
1) substituent R 1for alkyl, the benzyl C of carbonatoms 1-10 6h 5-ax a-CH 2-and C 6h 5-ax aone of-CHR ' '-, wherein R ' ' be carbonatoms 1-10 alkyl, aryl C 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 that is hexa-atomic, five-membered ring aryl 5h 4-cyX c-CH 2-and C 4h 3-dyX d-CH 2one of-; X is substituted radical on aryl or heterocycle, Y is heteroatoms in heterocycle; Wherein: a is the integer of 0-5, b is the integer of 0-8, and c is the integer of 0-4, and d is the integer of 0-3; Y is N or O or S; X is hydrogen, or carbonatoms be the alkyl of 1-4, cyclohexyl, carbonatoms be the alkoxyl group of 1-4, aryl, halogen atom or trifluoromethyl; Or R 1for allyl group, one of 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 substituted radical on aryl or heterocycle, Y is heteroatoms in heterocycle; Wherein: a is the integer of 0-5, b is the integer of 0-8, and c is the integer of 0-4, and d is the integer of 0-3; Y is N or O or S; X is hydrogen, or carbonatoms be the alkyl of 1-4, cyclohexyl, carbonatoms be the alkoxyl group of 1-4, 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: a is the integer of 0-5, b is the integer of 0-8; X is hydrogen, or carbonatoms be the alkyl of 1-4, cyclohexyl, carbonatoms be the alkoxyl group of 1-4, aryl, halogen atom or trifluoromethyl.
4) substituent R 4for carbonatoms is the alkyl of 1-4, 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, carry out effect best with the reaction of hydrazine 4; 5 in non-protonic solvent tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and toluene, carry out effect best with the reaction of aryl boric acid 6.
3.3 is 1:1-1:5 with the mol ratio of hydrazine 4.Wherein, when 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.Wherein, when mol ratio is 1:1.5, reaction effect is best.
4.3 is 1-24 hour with reaction times of hydrazine 4, and 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 DEG C.Wherein, optimal reaction temperature is 70-110 DEG C.
The present invention has the following advantages:
1) alpha-carbonyl list ketene thioacetal 3 has structure diversity, can be used for preparing pyrazole derivatives 1 that is dissimilar and 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 good with stereoselectivity.
In a word, the present invention utilizes the structure diversity of alpha-carbonyl list ketene thioacetal 3 and many reactive centers efficiently can prepare dissimilar and pyrazole derivatives 1 that is structure; Utilize alpha-carbonyl dithio keteal 5 can prepare (Z)-Tamoxifen, raw material is cheaply easy to get, easy and simple to handle, and product yield is high highly-solid selectively.
Embodiment
Contribute to understanding the present invention further by following embodiment, but content of the present invention is not limited in this.
Embodiment 1
In a nitrogen atmosphere, in 25mL reaction flask, add alpha-carbonyl dithio keteal 5b(95mg, 0.50mmol successively), 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 DEG C.After reaction terminates, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, remove Volatile Colstituent under filtrate decompression, be then separated (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=30:1) with silica gel column chromatography, obtain yellow liquid intermediate product 3a(100mg, yield 97%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
In a nitrogen atmosphere, in 25mL reaction flask, add 3a(103mg, 0.50mmol successively), phenylhydrazine 4a(65mg, 0.60mmol), potassium tert.-butoxide (112mg, 1.0mmol) and 5mL solvent tertiary butanol, stirring and refluxing reaction 9h.After reaction terminates, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, remove Volatile Colstituent under filtrate decompression, be then separated (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=20:1) with silica gel column chromatography, obtain yellow liquid target product 1a(102mg, yield 87%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 2
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, second step temperature of reaction is room temperature 25 DEG C, reaction times 24h.Stopped reaction, through obtaining target product 1a(10mg with above-mentioned identical aftertreatment, yield 9%).Explanation temperature of reaction reduces, and reacts slack-off.
Embodiment 3
Reactions steps and operation are 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 use non-protonic solvent to be unfavorable for 3 react carry out with hydrazine 4 condensation and cyclizations.
Embodiment 4
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, second step temperature of reaction 75 DEG C.Stopped reaction, obtains target product 1a(62mg through aftertreatment, yield 53%).Illustrate that raised temperature promotes that reaction is carried out.
Embodiment 5
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, second step temperature of reaction 95 DEG C, 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 and operation are 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 only using equivalent is described, target product can not be obtained with optimal yield.
Embodiment 7
Reactions steps and operation are 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 and operation are 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
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is aryl boric acid 4-MeOC 6h 4b (OH) 2(6c).Be obtained by reacting yellow liquid intermediate product 3b(115mg, yield 97%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3b.Stopped reaction, obtains yellow solid target product 1b(115mg through aftertreatment, yield 87%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 10
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is aryl boric acid 4- tbuC 6h 4b (OH) 2(6d).Be obtained by reacting yellow solidliquid mixture intermediate product 3c(110mg, yield 84%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3c.Stopped reaction, obtains yellow solid target product 1c (134mg, yield 92%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 11
Reactions steps and operation are with embodiment 1, and difference is, what add in the first step reaction 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3d.Stopped reaction, obtains red brown solid target product 1d (111mg, yield 82%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 12
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is aryl boric acid 2-naphthylB (OH) 2(6f).Be obtained by reacting reddish-brown liquid intermediate product 3e(139mg, yield 92%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3e.Stopped reaction, obtains red liquid target product 1e (108mg, yield 76%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 13
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is aryl boric acid trans-PhCH=CHB (OH) 2(6g).Be obtained by reacting reddish-brown liquid intermediate product 3f(103mg, yield 89%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3f.Stopped reaction, obtains yellow liquid target product 1f (108mg, yield 83%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 14
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is alpha-carbonyl dithio keteal 5c(126mg, 0.50mmol) and aryl boric acid PhB (OH) 2(6b) (91mg, 0.75mmol).Be obtained by reacting yellow solid intermediate product 3g(130mg, yield 97%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3g(134mg, 0.5mmol).Stopped reaction, obtains desired product as white solid 1g (136mg, yield 92%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 15
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is alpha-carbonyl dithio keteal 5d(141mg, 0.50mmol) and aryl boric acid 4-ClC 6h 4b (OH) 2(6h) (117mg, 0.75mmol).Be obtained by reacting yellow liquid intermediate product 3h(153mg, yield 92%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3h(166mg, 0.5mmol).Stopped reaction, obtains desired product as white solid 1h (143mg, yield 79%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 16
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 17
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is alpha-carbonyl dithio keteal 5f(121mg, 0.50mmol) and aryl boric acid 6h(117mg, 0.75mmol).Be obtained by reacting yellow solid intermediate product 3j(133mg, yield 91%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 18
Reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is alpha-carbonyl dithio keteal 5g(129mg, 0.50mmol) and aryl boric acid 6h(117mg, 0.75mmol).Be obtained by reacting yellow solid intermediate product 3k(141mg, yield 91%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Reactions steps and operation are with embodiment 1, and difference from Example 1 is, what second step added in reacting is alpha-carbonyl list ketene thioacetal is 3k(154mg, 0.5mmol).Stopped reaction, obtains red brown solid target product 1k (148mg, yield 88%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 19
Reactions steps and operation are with embodiment 1, and difference is, what add in the first step reaction 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
In a nitrogen atmosphere, in 25mL reaction flask, add 3l(121mg, 0.50mmol successively), 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 terminates, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, remove Volatile Colstituent under filtrate decompression, be then separated (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=20:1) with silica gel column chromatography, obtain yellow solid target product 1l(78mg, yield 80%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 20
Reactions steps and operation are with embodiment 19, and difference is, what add in second step reaction system be alpha-carbonyl list ketene thioacetal is 3g(134mg, 0.5mmol).Stopped reaction, obtains desired product as white solid 1m (100mg, yield 91%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 21
The first step reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is alpha-carbonyl dithio keteal 5f(121mg, 0.50mmol) and aryl boric acid 6b(91mg, 0.75mmol).Be obtained by reacting yellow solidliquid mixture intermediate product 3m(123mg, yield 95%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Second step reactions steps and operation are with embodiment 19, and difference is, that add in second step reaction system is alpha-carbonyl list ketene thioacetal 3m(129mg, 0.5mmol).Stopped reaction, obtains desired product as white solid 1n (87mg, yield 83%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 22
The first step reactions steps and operation are with embodiment 1, and difference is, that add in the first step reaction is alpha-carbonyl dithio keteal 5g(129mg, 0.50mmol) and aryl boric acid 6b(91mg, 0.75mmol).Be obtained by reacting yellow liquid intermediate product 3n(125mg, yield 91%).Intermediate product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Second step reactions steps and operation are with embodiment 19, and difference is, that add in second step reaction system is alpha-carbonyl list ketene thioacetal 3n(137mg, 0.5mmol).Stopped reaction, obtains desired product as white solid 1o (108mg, yield 95%) through aftertreatment.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 23
Reactions steps and operation are with embodiment 19, and difference is, what add in second step reaction system be 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 24
Reactions steps and operation are with embodiment 19, and difference is, what add in second step reaction system be 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 by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 25
In 100mL reaction flask, add phenyl-acetone 7(6.99g, 52mmol successively), K 2cO 3(15.8g, 114mmol) and 30mL solvent DMF, stir 0.5h.Be chilled to 0 DEG C, add dithiocarbonic anhydride 8(4.4g, 57mmol), continue to stir 0.5h, then add monobromethane 9(12.5g, 114mmol), react 12h under room temperature.100mL water is added to reaction system, methylene dichloride (3 × 30mL) extraction, phase-splitting, merge organic phase, anhydrous sodium sulfate drying, then with silica gel column chromatography separation, (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=10:1), yellow oily compound 5a'(9.3g is obtained, yield 67%).5a' is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
By reaction formula (2), in a nitrogen atmosphere, in 25mL reaction flask, add 5a'(133mg, 0.50mmol successively), 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 DEG C.After reaction terminates, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, remove Volatile Colstituent under filtrate decompression, be then separated (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=30:1) with silica gel column chromatography, obtain yellow intermediate product A(166mg, yield 90%).Intermediate product A is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
In a nitrogen atmosphere, in 25mL reaction flask, add intermediate product A(185mg, 0.50mmol successively), 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 DEG C.After reaction terminates, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, remove Volatile Colstituent under filtrate decompression, be then separated (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=30:1) with silica gel column chromatography, obtain white solid intermediate product B(150mg, yield 78%).Intermediate product B is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
In a nitrogen atmosphere, in 25mL Schlenk reaction flask, add intermediate product B(193mg, 0.50mmol successively), LiAlH 4(35mg, 0.90mmol) and 10mL solvent THF, stirring and refluxing reaction 24h.After reaction terminates, mixture is cooled to room temperature, be added dropwise to 2mL shrend to go out reaction, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, removes Volatile Colstituent under filtrate decompression, then with silica gel column chromatography separation, (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=30:1), desired product as white solid (Z)-Tamoxifen (2) (149mg, yield 80%) is obtained.Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 26
In a nitrogen atmosphere, in 25mL reaction flask, add alpha-carbonyl dithio keteal 5f(121mg, 0.50mmol successively), 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 DEG C.After reaction terminates, mixture is cooled to room temperature, reaction solution diatomite filtration, filter cake 10mL washed with dichloromethane, remove Volatile Colstituent under filtrate decompression, be then separated (elutriant is sherwood oil (60-90 DEG C)/ethyl acetate, v/v=30:1) with silica gel column chromatography, obtain yellow solid target product 10a(130mg, yield 95%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Embodiment 27
Reactions steps and operation are with embodiment 24, and difference is, the alpha-carbonyl list ketene thioacetal added is 3m(129mg, 0.50mmol), aryl boric acid is 6h(313mg, 2.0mmol).After reaction terminates, obtain yellow liquid target product 10b(116mg through aftertreatment, yield 75%).Target product is measured by nuclear magnetic resonance spectrum and high resolution mass spectrum and is confirmed.
Alpha-carbonyl dithio keteal has raw material to be easy to get, to prepare the advantages such as simple, structure diversity and many reactive centers, and the linked reaction mild condition of they and aryl boric acid, product stereoselectivity is good, is the effective ways 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 (Han, B. consistent with bibliographical information melting point data; 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.; , 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 DEG C. 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): red brown solid, fusing point 59-62 DEG C. 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 DEG C. 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 DEG C. 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(CDCl 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 DEG C. 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 DEG C. 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 DEG C. 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 (8)

1. a preparation method of four substituted olefines (Z)-Tamoxifen (2),
It is characterized in that: preparation feedback route is as shown in following reaction formula, with alpha-carbonyl dithio keteal 5a for raw material and aryl boric acid 6a and 6b carry out substep linked reaction continuously, the carbonyl then through Lithium aluminum hydride reduction intermediate product generates (Z)-Tamoxifen (2);
Substituent R 4for the alkyl of carbonatoms 1-4, allyl group or benzyl;
Wherein: aryl boric acid is Me 2n (CH 2) 2o-C 6h 4b (OH) 2(6a) with PhB (OH) 2(6b), catalyzer is Pd (PPh 3) 4, Pd 2(dba) 3, Pd (dba) 2with Pd (PPh 3) 2cl 2one of; Alkali is Na 2cO 3, K 2cO 3and Cs 2cO 3one of; α-benzoinoxime is one of CuTC, CuI, CuBr and CuCl, wherein TC=thiophene-2-carboxylate; Part is dppe, (±) BINAP, dppf and PPh 3one of; Reaction solvent is one or two or more kinds in methyl alcohol, ethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, the trimethyl carbinol and toluene; The mol ratio of 5a and 6a or 6b is the mol ratio of 1:1-1:2 and intermediate product A and 6a or 6b is 1:1-1:2; Reaction times 1-48 hour; Temperature of reaction 25-110 DEG C; After reaction terminates, separation purification method carries out product separation routinely, obtains (Z)-Tamoxifen (2).
2., according to preparation method according to claim 1, it is characterized in that:
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reaction of aryl boric acid 6a and 6b, its optimum catalyst is Pd (PPh 3) 4with Pd (PPh 3) 2cl 2one of, consumption is the 0.05-0.10 equivalent of 5a or A;
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reaction of aryl boric acid 6a and 6b, its optimum response alkali is Cs 2cO 3and K 2cO 3one of, consumption is the 1-2 equivalent of 5a or A;
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reaction of aryl boric acid 6a and 6b, its optimum response α-benzoinoxime is one of CuI and CuTC, and consumption is the 1-2 equivalent of 5a or A;
Alpha-carbonyl dithio keteal 5a and intermediate product A respectively with the reaction of aryl boric acid 6a and 6b, its optimum response part is one of (±) BINAP and dppe, and consumption is the 0.05-0.10 equivalent of 5a or A;
Alpha-carbonyl dithio keteal 5a and intermediate product A carries out in non-protonic solvent tetrahydrofuran (THF), Isosorbide-5-Nitrae-one of dioxane and toluene with the reaction of aryl boric acid 6a and 6b respectively.
3. according to preparation method according to claim 1, it is characterized in that: when alpha-carbonyl dithio keteal 5a and intermediate product A reacts 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.
4. according to preparation method according to claim 3, it is characterized in that: when alpha-carbonyl dithio keteal 5a and intermediate product A reacts 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 0.1M.
5. according to preparation method according to claim 1, it is characterized in that: when alpha-carbonyl dithio keteal 5a and intermediate product A reacts with aryl boric acid 6a and 6b respectively, optimum reacting time is 12-24 hour.
6. according to preparation method according to claim 1, it is characterized in that: the optimum temps that alpha-carbonyl dithio keteal 5a and intermediate product A reacts with aryl boric acid 6a and 6b is respectively 70-110 DEG C.
7. according to preparation method according to claim 1, it is characterized in that: the carbonyl reduction best reductive agent used of intermediate product B is lithium aluminium hydride (LiAlH4), reacts and carries out in room temperature tetrahydrofuran (THF).
8. according to preparation method according to claim 1, it is characterized in that: when alpha-carbonyl dithio keteal is 5a', the best results of preparation Z-Tamoxifen;
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Citations (2)

* 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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060132434A (en) * 2003-11-06 2006-12-21 라이프스캔, 인코포레이티드 Drug delivery pen with event notification means

Patent Citations (2)

* 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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A convenient syhthesis of (Z)-4-hydroxy-N-desmethyltamoxifen(endoxifen);Abdul H.Fauq et al;《Bioorganic & Medicinal Chemistry Letters》;20100403;第20卷;3036-3038 *
Yoshiyuki Sano et al.Short-step synthesis of droloxifene via the three-component coupling reaction among aromatic aldehyde,cinnamyltromethylsilane,and β-chlorophenetole.《Tetrahedron Letters》.2006,第45卷1631-1635. *
他莫昔芬合成路线图解;梅和珊 等;《中国医药工业杂志》;20040108;第32卷(第1期);45-47 *

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