TW201238603A - Method for preparation of 3-(2,3-dimethylphenyl)-2-butenal - Google Patents

Abstract

The invention discloses the aldehyde 3-(2, 3-dimethylphenyl)-2-butenal, a method for its preparation from 1-bromo-2, 3-dimethylbenzene and crotonaldehyde, and its use in perfumes.

Description

201238603 VI. Description of the invention: The present invention discloses an aldehyde 3-(2 3 _田~, 1, 1 3-methyl-1-yl)-2-butenal, which is from 1 to 2,3-- And the preparation of crotonic acid + ^ preparation method, and its use in perfumes < In cosmetics, perfumes and Shiji _ μ + β and a large number of household products, aromatic aldehydes are widely used as flavors and fragrances. Alpha, β-unsaturated aromatic aldehydes, such as substituted meats, are considered to have a unique aromatic odor and are therefore used in the perfume industry. W0 98/45237A discloses certain aromatic blends, a process for preparing such aromatic aldehydes starting from phenylethyl acetal, and its use as a perfume and for the preparation of 3-arylpropionaldehyde Intermediates. It has a musky-like odor.

Littke et al., J. Am. Chem. Soc. 2001, 123, 6989-7000, specifically discloses aryl bromides and α,β-unsaturated esters in the presence of Pd/P(t-Bu)3/Cy2NMe Reaction. No aldehydes are used as substrates in this disclosure. W0 03/048 1 07Α discloses the reaction of _ atoms with olefins in the presence of a nitrogen-containing base and a dipolar aprotic solvent that conform to the spatial conformation requirements. The only example of such an olefin is acrylamide.

Stadler et al., Synlett 2008, 4, 597-599, disclose the presence of 1 molar equivalent of tetrabutylammonium hydride, 2 mol% Pd(OAc)2, and excess molar NaOAc. The base bromide reacts with crotonaldehyde in NMP 201238603 bath. When using 2, transcript as the aryl bromide, it has a yield of 46%; when 2 2, -Me, r η & * — ' ,

MeaCeH3 has no yield when it is used as a substrate. The perfume and habit industry has a continuing need for new and unobtainable new weight bars that are of interest to eight people to enhance the choice of perfumes and to satisfy the changing fashions of perfumes. demand. Further, the various substances need to be economically synthesized and have a shifted quality, thus requiring a high-purity and strong-scented toon. The present invention provides unsaturated aryl(tetra)3-(2,3-xylphenyl)_2-butan, which has a strong, interesting aromatic-taste, intense spicy and sweet taste, and the present invention also provides for the preparation of 3_(2) 3_ _ , , J - T base ) An improved method of 2-butan. Further, there is a need for a process for the preparation of 3-(2,3-dimethylphenyl).2-butenal which has a high yield, which reduces the amount of input to the purification process and provides a possibility of high-efficiency preparation. In the following, halogen 疋 means F, CM' Br or I, preferably α, Br or work; if not otherwise stated, "alkyl" means a linear, branched or cyclic alkyl group; Examples of the "hospital group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, and ring. Butyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and the like. "cyclical" is understood to include cycloaliphatic, bis5, aliphatic and tricyclic fats. Residues of the family; if there is no other statement, Ac means ethyl (base); DIpEA means 4 201238603 N-ethyl-N,N-diisopropylamine; DABCO means 1,4-diazabicyclo [2.2.2] Octane; tBu means tributyl; DMF means N,N-dimercaptocaramine; NMP means N-mercapto-2-0 to 0 pyrrolidone, 1-mercapto-2-0 is compared to pyrrolidone or N-methyl-2-pyrrolidone; DMA means N,N-dimethylacetamide; THF means tetrahydrofuran And dba means 1,5-diphenylpentan-1,4-dien-3-one; hexane It refers to a mixture of various hexane isomers. The terms "palladium source" and "Pd source," have the same meaning and are used. It is an object of the present invention to provide a process (A) for the preparation of a compound of formula (I),

(I) wherein in the formula (I) the double bond labeled (a) has a configuration of (z) or (E); the method (a) comprises: a compound of the formula (Π) and a crotonaldehyde in the presence Reaction (a) occurs in the case of source (Aa) and base (Ab);

(II) R1 is a group selected from the group consisting of Cl, Br, I, 0-S02-CF3, 0-S02-C6H4-CH3 5 201238603 and 0-S〇2_Ph; wherein: the source (Aa) is selected from the group consisting of a group of Pd ( 0 ) , Pd ( 〇 ) complexes and Pd ( Π ) complexes on the body; test (8 1 〇 is selected from > 1 (112) (113) 114, 1, 4 a group consisting of diazabicyclo[2.2.2;|octane, carboxylate, carbonate, argon carbonate, phosphoric acid, monohydrogen phosphate or sodium dihydrogen phosphate or potassium salt, and mixtures thereof; R2 R3 and R4 are the same or different and independent of each other, and are selected from the group consisting of hydrazine, C!, 5-alkyl, cs.6 cyclic alkyl and phenyl. Preferably, 'R1 is selected from gas. More preferably, R1 is gas or bromine, and even more preferably, R1 is bromine. If the palladium source (Aa) used is Pd(0) on a carrier, the carrier Preferably, it is barium sulfate or activated carbon. Preferably, the palladium source (Aa) is selected from the group consisting of PdCl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2(PhCN)2, PdCl2. (MeCN)2, PdCl2(PPh3)2, Pd(P(tBu)3)2, Pd2(P(tBu)3)3, Pd(P(l-adamantyl)3)2, Pd2(P (1 - adamantyl) 3) 3, Pd(PPh3) 4 and a group of le on activated carbon; more preferably, selected from PdCl2, Pd(OAc)2, Pd(dba)2, Pd2( Dba)3, PdCl2(PhCN)2, PdCl2(MeCN)2, PdCl2(PPh3)2, Pd(P(tBu)3)2, Pd(P(l-adamantyl)3)2, Pd(PPh3) 4 group consisting of; further more than the servant, selected from Pd(OAc)2, Pd(dba)2, Pd2(dba)3, Pd(P(tBu)3)2, Pd(P(l-adamantane) Groups of 3)2, PdCl2(MeCN)2; 6 201238603 In particular, the palladium source (Aa) is pd(〇Ac)2, Pd2(dba)3 and Pd(P(tBu)3)2 Preferably, the base (Ab) is selected from the group consisting of N(R2)(R3)R4, ruthenium diazide [2.2.2] octane, Ci. 1 () carboxylate, carbonate, hydrogencarbonate a group consisting of salt, phosphoric acid, acid monohydrogen or sodium dihydrogen phosphate or potassium salt, and mixtures thereof; more preferably, the base (Ab) is selected from the group consisting of N_ethyl·Ν,Ν_:isopropyl Amine, heart 13, diazabicyclo[2.2.2]octane, quinone dimethylaniline, dicyclohexyl decylamine, dicyclohexylamine, diisopropylamine, NaOAc, Na2C03 'NaHC03, KOAc, a group consisting of K2C03 and K3P04; further preferably, the (Ab ) is selected from the group consisting of N-ethyl-ν, Ν-diisopropylamine, Net3, hydrazine, decyl-didecyl aniline, dicyclohexylmethylamine, NaOAc, Na2C03, NaHC03, KOAc, K2C03 and κ3Ρ〇 a group consisting of; in particular, selected from the group consisting of NaOAc, Ν-ethyl-hydrazine, hydrazine-diisopropylamine, Net3; more particularly, the base (Ab) is Na〇Ac or N -ethyl-N,N-diisopropylamine. In a preferred embodiment, the completion or progress of the reaction (A) is carried out without the addition of a ligand (Ac) or a salt (Ae). In another preferred embodiment, the completion of the reaction (A) or the presence of a ligand (Ac). A ligand () is added to the reaction mixture, and thus the reaction mixture contains a palladium source (Aa), a base (Ab), and a ligand (Ac). The ligand (Ac), the palladium source (Aa), and the test (Ab) may be added in any order. The ligand (Ac) is p(R5)(R6)R7; 201238603 R5, R6 and R7 are the same or different and mutually independent substituents selected from the group consisting of the following substituents:

Cu alkyl; phenyl, biphenyl and naphthyl, the phenyl, biphenyl and naphthyl are unsubstituted, or via 1, 2, 3 or 4 identical or different and mutually independent substituents Substituted, the substituent is selected from the group consisting of a hydroxyl group, an alkyl group, a C 4 alkoxy group, a cyano group and a nitro group; a ferrocenyl group; a ferrocenyl-substituted di(t-butyl)phosphine; Aryl, s-heteroaryl is a 5- or 6-membered aromatic carbocyclic ring having - or two inner ring heteroatoms selected from the group consisting of ruthenium, 8 and N

Substituted by the group consisting of; C I -1 5 alkoxy;

Replaced by a group;

Replaced by its group of violent violent. Optional 0, S and N constitute 2 or 3 identical or different, Ci-4 alkoxy, cyano and 8 201238603 Preferably, the ligand (Ac) is selected from PBu3, P (〇-tolyl) 3, PPh3, P(l-adamantyl) 3, P(Bu)(l-adamantyl) 2, tris(2,4-di-t-butylphenyl)-salt, P(tBu) 2) 2-(2-biphenyl), P(tBu)3, tri(cyclohexyl)phosphine, triphenyl phosphite, tris(1-naphthyl)phosphine and ι,ι·-二(二_三丁More preferably, selected from the group consisting of P(0-fluorenylphenyl)3, P(l-adamantyl)3, P(Bu)(l.adamantyl) a group consisting of 2, P(tBu) 2 (2-biphenyl), P(tBu) 3, tris(cyclohexyl)phosphine and tris(1-naphthyl)phosphine; further more preferably 'selected from Ρ(〇·tolyl)3, p(l_adamantyl)3, P(Bu)(l-adamantyl)2, p(tBu)3 and P(tBu)2(2-biphenyl) a group consisting of; in particular, the ligand (Ac) is P(tBu)3. In another preferred embodiment, the completion of the reaction (A) or the presence of a salt (Ae). An ammonium salt (Ae) is added to the reaction mixture, and thus the reaction mixture contains a palladium source (Aa), a base (Ab), and an ammonium salt (Ae). The ammonium salt (Ae), the source (Aa) and the base (Ab) may be added in either order. The ammonium salt (Ae) is N(R10)(R11)(R12)R13)+X-; 〇 Rll R12 and R13 are the same or different and mutually independent substituents' which are selected from the group consisting of the following substituents:

Cl-i5 alkyl; phenyl, biphenyl and naphthyl, the phenyl, biphenyl and naphthyl are unsubstituted, or via oxime, 2, 3 or 4 identical or different and independent Substituted by a substituent selected from the group consisting of halogen, cMo alkyl, Ci 4 alkoxy, cyano and nitro; 201238603

Cl-decyl aryl, aryl of the aryl group of aryl is a strepto, biphenyl or naphthyl group. The phenyl, biphenyl and naphthyl groups are unsubstituted, or via 1, 2 Substituting 3 or 4 identical or different and mutually independent substituents selected from the group consisting of halogen, C^oalkyl 'C, .4 alkoxy, cyano and nitro; X Is selected from the group consisting of fluorine, chlorine, bromine, phosphate, hydrogen phosphate, dihydrogen phosphate, carboxylate, sulfate, and hydrogen sulfate; preferably, X is selected from the group consisting of gas, bromine, A group consisting of hydrogen phosphate, acetate, and hydrogen sulfate. Preferably, RIO, R11, R12 and R13 are the same or different and independent of each other' selected from the group consisting of:

Cl-I2 alkyl; a phenyl group which is unsubstituted or substituted by 1 or 2 identical or different and mutually independent substituents selected from the group consisting of fluorine, chlorine, and C. a group consisting of 4 alkyl groups, C|-4 alkoxy groups; benzyl group; X is selected from the group consisting of fluorine, gas, bromine, phosphate, hydrogen phosphate, dihydrogen phosphate, and having 1 to 1 carbon atoms. A group consisting of carboxylic acid salts, sulfates, and hydrogen sulfates; preferably, X is selected from the group consisting of gas, bromine, hydrogen phosphate, acetate, and hydrogen sulfate. More preferably, the ammonium salt (Ae ) is selected from the group consisting of Bu4N+X_,

MeN(Bu)3+X_, dodecyl-N(Me)3 + x-, benzyl i(Bu)3+X-, stupid methyl N(Me)3+X_ and Me4N+X- a group consisting of; and X is a group selected from the group consisting of chlorine, bromine, hydrogen phosphate, acetate, and hydrogen sulfate selected from 201238603. Still more preferably, the ammonium salt (Ae) is selected from the group consisting of Bu4N+x-, MeN(Bu)3+X-, dodecyl-N(Me)3+x-, alum-based n(Bu) a group consisting of 3+x_ and benzyl N(Me)3+X-; and hydrazine is gas; more particularly, the ammonium salt (Ae) is Bu4N+Cr. Both the ligand (Ac) and the ammonium salt (Ae) may be present in the reaction (A). In a preferred embodiment, the solvent (Ad) is absent in the completion or in progress of the reaction (A). In another preferred embodiment, the reaction (A) is carried out or carried out in a solvent (Ad). The solvent (Ad) is selected from the group consisting of DMF, NMP, DMA, N-methylacetamide, acetonitrile, propionitrile, ethyl acetate, butyl acetate, THF, methyl-tetrahydrofuran, dioxane, toluene, and A group consisting of terpene and its mixtures. Preferably, the solvent (Ad) is selected from the group consisting of j) MF, NMP, DMA, N-mercaptoamine, B guess and C.; more preferably, the solvent (Ad) is Selecting a group consisting of DMF, NMP and DMA; more particularly the solvent (Ad) is DMF or NMP » In a preferred embodiment (PE 1 ), the palladium source (Aa) is Pd2(dba)3 The base (Ab) is N-ethyl-N,N-diisopropylamine, and the ligand (Ac) is p(tBu)3. In another preferred embodiment (PE2), the palladium source (Aa) is Pd(P(t-Bu)3)2, and the base (Ab) is N-ethyl·ν, Ν-diisopropyl Amine, more specific 201238603 In addition, in this preferred embodiment, no ligand (Ac) is used. In another preferred embodiment (PE3), the palladium source (Aa) is Pd(OAc)2, the base (Ab) is NaOAc, and the ammonium salt (Ae) is Bu4N+C1_. Preferably, the solvent (Ad) used in the preferred embodiments (PEI), (PE2) and (PE3) is DMF or NMP. More preferably, the solvent (Ad) used in the preferred embodiments (PE) and (PE2) is DMF; the solvent (Ad) used in the preferred embodiment (PE3) is NMP. Typically, reaction (A) will yield a mixture of the two stereoisomers (E) and (Z) of the compound of formula (j). The two stereoisomers can be separated by conventional methods well known in the art of organic chemistry. Preferably, the reaction temperature of the reaction (A) is from 〇 to 2〇〇. Further, it is more preferably from 10 to 150 C, still more preferably from 2 to 13 Å. Hey. Preferably, the reaction (A) is carried out at a pressure of from normal pressure to 1 Torr, more preferably, the pressure is from atmospheric pressure to 5 bar, still more preferably from atmospheric pressure to 4 bar. The progress of the reaction is carried out by standard techniques such as nuclear magnetic resonance (NMR), infrared absorption spectroscopy (IR), high performance liquid chromatography (HPLC), liquid chromatography f-spectroscopy (LCMS) or thin layer chromatography ( T]U Monitoring" When the conversion of the starting material exceeds 95%, or when it is no longer possible to detect the starting material, 'starting to test the reaction mixture. The time required for the occurrence depends on the exact reaction temperature and The accuracy of the two catalysts, and the situation between batches will be different. 12 201238603 Preferably, the reaction time of the reaction (A) is from 3 to 48 hours, more preferably 'i hours to 36 hours' is further preferably from 2 hours to 24 hours. Preferably, the amount of mulberry in the 'croton is 0.5 to H times the molar amount of the compound of the formula (n), more preferably! Up to 5 times, still more preferably i to 3 times. Preferably, the amount of the palladium source is from 0. 01 mol% to 10 mol%, more preferably from 〇 mol % to 5 mol, based on the molar amount of the compound of the formula (Π). % ' is further preferably from 〇.3 mol% to 3 mol%, in particular from 0.3 mol% to 1.2 mol%. Preferably, the molar amount of the base (Ab) is 0.5 to 5 times the molar amount of the compound of the formula (η)', more preferably 丨 to 3 times, and further more preferably [to 2 times. Preferably, if a ligand (Ac) is present in the reaction (Α), the molar amount of the ligand (Ac) is from 7 to 7 times the molar amount of the palladium source (Aa), more preferably It is 1 to 4 times, and more preferably 1 to 21 times. Preferably, if the ammonium salt (Ae) is present in the reaction (A), the molar amount of the ammonium salt (Ae) is from 1 to 5 times the molar amount of the compound of the formula (π), more preferably It is 0.05 to 2 times, and more preferably 〇1 to times. Preferably, the amount of the solvent (Ad) is 〇 5 to 50 times, more preferably 2 to 40 times, still more preferably 5 to 35 times the weight of the compound of the formula (n). In another preferred embodiment (PE 10), the molar amount of the batonic disk is 1 to 3 times the molar amount of the compound of the formula (Π); 13 201238603 and the amount of the palladium source (Aa) is 0.3 mol% Up to 3 mol%, preferably 〇3 mol% to 1.2 mol%', the mol% is based on the molar amount of the compound of the formula (π); and the molar amount of the base (Ab) is Π) i to 2 times the molar amount of the compound; and the molar amount of the ligand (Ac) is 4 times, more preferably 1 to 2.1 times, the enthalpy of the palladium source (Aa). In another preferred embodiment (PE2〇), the amount of molybdenum aldehyde is up to 3 times the molar amount of the compound of formula (n); (4) The amount of (Aa) is from 〇3 mol% to 3 mol%, preferably (a) mol. /❶ to i.2 mole %, the mole % is based on the compound of the formula (η); and the molar amount of the base (Ab) is the mole of the compound of the formula (η).另一 In another preferred embodiment (ΡΕ3〇), 1 to 3 times; the molar amount of crotonic acid is the molar amount of the compound of the formula (Π) and the amount of the source (Aa) is G. 3 mole% Up to 3 mol %, preferably Μ = /. To K2 mole %, the mole % is based on the formula "); and the molar amount of the six (test) (10) is a multiple of the molar amount of the compound of the formula (π); and Ζ 201238603 recorded salt (Ae) The molar amount is 0.05 to 2 times the molar amount of the compound of the formula (π), and more preferably 〇丨 to 11 times. • Preferably, the amount of solvent (Ad) in the preferred embodiments (ΡΕ10), (ΡΕ20) and (ΡΕ30) is from 5 to 35 times the weight of the compound of formula (η). In a more preferred embodiment (ΡΕ 1-10), the embodiment (ΡΕ1) is combined with the embodiment (ΡΕ10). In another more preferred embodiment (ΡΕ 2-20), the embodiment (ΡΕ2) is combined with the embodiment (ΡΕ20). In another more preferred embodiment (ΡΕ 3-30), the embodiment (ΡΕ3) is combined with the embodiment (ΡΕ30). Further more particularly, in the embodiments (PEl_l〇), (ΡΕ2-20) and (ΡΕ3-30), the solvent (Ad) is dmf or ΝΜΡ. More particularly, in the embodiments (ΡΕμο ) and (PE2-20), the solvent (Ad) is DMF; in the embodiment (PE3-30) the solvent (Ad) is ΝΜΡ in a further embodiment When the reaction rate is similar to its consumption rate, the amount of crotonaldehyde is administered to the crotonaldehyde when reacting to at least 5 mol% of the starting molybdenum of the formula (π), but not more than 5 mol%. Stable unchanged' at this time the corresponding speed is better. The stable amount of crotonaldehyde in the reaction mixture during the reaction is measured by standard technique I, preferably by on-line monitoring or after sampling by infrared absorption spectroscopy (IR), gas chromatography (GC) or nuclear magnetic resonance (NmR). )monitor. In a further embodiment, the palladium source (Aa) and the ligand (Ac) are premixed in a small amount of solvent (Ad) when the coordination element (Ac) is used by 15 201238603 'the small amount of solvent The amount is preferably from 重量·〇〇1 to 20% by weight, more preferably from 0.01% by weight to 5% by weight, based on the total weight of the solvent (Ad) used. Preferably, the premix is stirred at a temperature of 0 ° C to 1 ° C for 1 to 60 minutes, preferably 20 ° C to 100 ° C, and then the premix is added to the formula (jj) a mixture of a compound and a solvent (Ad). Preferably, the reaction (A) is carried out under inert gas conditions. Following the reaction (A), the compound of formula (I) can be isolated from the reaction mixture obtained in reaction (A) by standard methods known to those skilled in the art, for example, evaporating volatile components from the reaction mixture, The reaction mixture is diluted with water, acidified, extracted, washed, dried, concentrated, crystallized, distilled, and any group thereof. Preferably, the ruthenium hydride is accomplished by the addition of an acid (acidification of type A), preferably an aqueous solution of an acid (acidification of type A). Preferably, the acid (acidification of type A) is selected from the group consisting of hydrochloric acid and sulfuric acid. § Acid (A type acidification) is an acid commonly used to separate organic reactants from the reaction mixture. Preferably, the acid (indole acidification) is added in an amount such that the resulting mixture has a pH of from 〇 to 7, more preferably from 丨 to 4, still more preferably from 2 to 4. The palladium source (Aa) is selectively added by adding an insoluble material or a commercially available precious metal scavenger known to those skilled in the art to the reaction mixture obtained in Reaction 16 201238603 (A). Upon recovery, the insoluble matter such as activated carbon or barium sulfate' can be bonded to palladium, and then the insoluble matter carrying the palladium source (Aa) is filtered off. Preferably, the volatile components of the reaction mixture are removed by evaporation under reduced pressure. The extraction of any aqueous liquid is preferably carried out with a solvent (A-extr) selected from the group consisting of toluene, benzene, dioxane, chloroform, acetic acid C 8 · 8 esters and mixtures thereof 〗 and into groups. Preferably, the acetic acid c 8 alkyl ester is acetic acid q 4 alkyl ester, more preferably ethyl acetate, isopropyl acetate or butyl acetate. The reaction is diluted with water, acidified, then extracted with a solvent (A_extr), and then concentrated, and the extract is selectively distilled to thereby obtain a compound of the formula (j). Preferably, the washing is effected selectively with water or concentrated brine for any organic phase during the separation step after the end of the reaction. Still more preferably, the reaction mixture is first concentrated under reduced pressure, then diluted and then acidified with an aqueous acid, and then extracted with toluene. Alternatively, any organic phase can be dried, preferably with magnesium sulfate or sodium sulfate. Any concentration is preferably achieved by steaming, preferably under reduced pressure. The compound of formula (I) can be purified' preferably by crystallization or under reduced pressure. In some cases the aldehyde is isolated in its hydrated form. Add 17 201238603 A compound of the formula (ϊ) may be isolated after forming a hydrate form under water under certain separation parameters. The e• and z_ isomers will generally be obtained using the methods described herein. Both isomers, as well as mixtures thereof, can be used as perfumes. Further objects of the invention are the compounds of formula (1), the compounds of formula (I) as defined above, and the compounds of formula (I) in all preferred embodiments, and the z-isomerization of compounds of formula (ϊ) Mixed body: body. A further object of the invention is the use of the W isomer as a perfume' preferably in perfumery or household products. A further object of the present invention is the use of a compound of the formula (9) to prepare a compound of the formula (I) by reacting a compound of the formula I with a crotonaldehyde. The method of the present invention makes it possible to construct the entire carbon skeleton of the compound of the formula (1) alone, and it has a high conversion ratio, which uses two fragments having similar molecular weights. The method of the present invention will increase its overall yield if compared to a linear, stepwise process such as that described in WO 98/45237. Furthermore, since the two molecular weight-like fragments are used in the final stage of the synthesis, they are easily separated from the compound of the formula (I) having a higher boiling point, and the final product prepared by the method is more easily purified. It is also easier to obtain a high aromatic scent pure or high-purity type because the final production of the molecular weight-like fragment is known to be used in an intermediate step. α, a carbon-carbon bond is formed. This is especially important for products used as fragrances. Due to its extremely aromatic odor, this product is a very good product that has been pursued by the perfumer 201238603. EXAMPLES Method: GC apparatus: Thermo Focus; Column: RXi-5MS 15 m, ID 320 μπι, df 0.25 μιη; Flow rate: 2.5 ml/min; Gas carrier: Helium; Split ratio: 32; Injector temperature: 230 °C ; Injection volume: 1 μΐ; Detection: flame ionization; Detector temperature: 250 ° C GC-method: Starting temperature: 60 ° C; Starting time: 2. 〇 min; Temperature change rate: 4 〇 K /min termination temperature: 250X:; final feed time: 1 〇 min; 1 〇〇 μΐ reaction mixture was diluted with U ml acetonitrile (MeCN) for gas chromatography (GC) analysis and determination of yield. The yield of the compound of the formula (I), which is a mixture of Z/EI silane J3A ^, A, ^ isomers, is determined by gas chromatography 'using the fourteenth hospital as the meat secret 1 4e, + as the internal standard Or by the nuclear magnetic resonance method, using the compound 4-nitro astringent as a reference. In order to achieve this goal, the response factor of the gas chromatographic test is determined by the spectrum, and the product peak area and all the raw material peaks to the yield. Comparison of the area of the crucible (sum) The compound of formula (I) was used as a reference in the determination of the yield, which was prepared according to Example 1 c, and was further isolated by the following method: Filter and concentrate under reduced pressure. The residue obtained was redissolved in dioxane and washed with water and brine. The di-methane phase is concentrated and the residue obtained is purified by column chromatography (gel column, heptane / ethyl acetate: 9.1) and then reduced by bulb-to-bulb (140 to 180. 匚, 〇 12 mbar). The compound of the formula (1) produced by 1. 〇 (5.4〇111111〇1) 1-bromo-2,3-xylene is 〇_51g (yield 59%), and the compound of the formula (1) is almost colorless. The oil was found to have a purity of 95% by gas chromatography. Nuclear magnetic resonance argon (1 H-NMR) showed the oil to be a mixture of two stereoisomers. 1H NMR (400 MHz, CDC13) δ 2.16, 2.18, 2.22, 2.31, 2.45 (5 xs, 9Η), 5·94 and 6.14 (2 xd, J = 8 Ηζ, 1Η), 6.93 (m, 1H), 7.12 (m, 2H), 9·22 and 10.16 (2 xd, J = 8 Hz, 1H). Example la to lh In a mixture of 1-,; odor-2,3-diphenylbenzene (100 mg, 0.54 mmol), crotonaldehyde (76 mg, 1.08 mmol), tetradecane (13.4 mg, internal standard) And solvent (3.0 ml), test (0.8 1 mmol) and ligand solution (0.2 M, 0.054 mmol) and Pd2(dba)3 (0.014 mmol) dissolved in toluene. The mixture is at 100. (: The mixture was stirred for 18 h. The detailed results are shown in Table! 201238603 Table 1 Example Coordination Solvents The yield of the compound of formula (I) la P(2-tolyl)3 K2C〇3 DMF 11% lb P(t-Bu)3 NaOAc Dioxane 29% lc P(t-Bu)3 DIPEA DMF 83% Id P(t-Bu)3 NaOAc Toluene 13% le n-Butylbis(1-adamantane Phosphine NaOAc Dioxane 15% If Tris(2,4-di-tert-butylphenyl) phosphite K3PO4 DMF 26% Tris(2,4-di-tert-butyl) phosphite K2C03 DMF 24 % lh Tris(2,4-di-tert-butylphenyl) phosphite NaOAc DMF 21% Example 2a to 2f In a mixture of 1-bromo-2,3-xylene (100 mg, 0.54 mmol), add croton Take (76 mg, 1.08 mmol), fourteen burns (13.4 mg, internal standard) and solvent (3 · 0 m 1), test (0.8 1 mm ο 1) and ligand solution (0 · 2 Μ, 0.01 Lmmol) and Pd2(dba)3 (0.0028 mmol) dissolved in toluene. The mixture was stirred at 100 ° C for 18 h. The detailed results are shown in Table 2. Table 2 Example ligand base solvent (I) Yield of the compound 2a 2-(di-t-butylphosphoric acid)-linked stupid NaOAc DMF 12% 2b P(2-tolyl)3 NaOAc D MF 18% 2c P(t-Bu)3 DIPEA DMF 78% 2d Tricyclohexylphosphine NaOAc DMF 5% 2e Tris(1-Cai)phosphine NaOAc DMF 12% 2f Trisphosphite tris (2,4-di-tert-butyl) Phenyl) ester NaOAc DMF 4% Example 3 a to 3 e In a mixture of the compound of formula (Π) (0.64 mmol), croton (76 mg, 1.08 mmol), tetradecene (13.4 mg, internal standard) And DMF (3.0 21 201238603 ml), DIPEA (0.81 mmol) and ligand solution (0.2 M, 0.0 limm〇i) and a source of Pd (0.0054 mmol) dissolved in toluene. The mixture is in i. The mixture was stirred for 2 1 h. The detailed results are shown in Table 3. Table 3 - ^ Example ligand Pd source R1 Yield of the compound of formula (I) 3a P(t-Bu)3 Pd(OAc)2 Br 30 % 3b P(t-Bu"h PdCl2(PhCN)2 Br 34% 3c Pft-Bu)·, Pd on charcoal Br 48% 3d P(t-Bu), Pd(OAc)2 Cl 4% — 3e P( t-Bifh PdCl2(PhCN)2 Cl 3% ~~ Examples 4a to 4f in a mixture of 1-> odorous-2,3-diindenylbenzene (1 〇〇 mg, 0.54 mmol), added croton (76 Mg,1·〇8 mmol), fourteen burns (13.4 mg, internal standard) and DMF (3.0 ml), DIPEA (0.81 mmol), Pd source (0.0054 mmol) and ligand toluene The liquid has a concentration of in 2 inm〇l ligand per 1 ml of toluene. 4 The mixture was stirred at 1 ° C for 18 h. The detailed results are shown in Table 4. Table 3 Example molar ratio of ligand ligand to Pd source. Yield of compound of formula (I) 4a P(t-Bu)! 2 1 Pd2(dba)3 73% 4b P(t-Bu ) ^ 1 2 Pd/C 12% 4c P(t-Bu)^ 1 1 Pd/C 25% 4d P(t-Bu)3 1 2 Pd/C 44% 4e --- 0 1 Pd(P(t -Bu)3)2 82% 4f 0 1 Pd2Br2(P(t-Bu)3)4 30% Example 5 22 201238603

Pd(OAc)2 (5.3 mg, 0.023 mmol), N-methyl-2-. Bisalone (11.5 ml), 1-bromo-2,3-diindenyl (0.405 g, 2.18 mmol), Bu4NC1 (0.382 g, 1.3 8 mmol), powdered NaOAc (0.22 g, 2.68 mmol) A mixture of crotonaldehyde (0.31 g, 4.43 mmol) was stirred at ll ° C for 2 h. Aqueous saturated NaHC03 solution (40 ml) was added thereto, and the obtained mixture was extracted with toluene (3×20 ml). The combined extracts were washed once with concentrated brine, dried with anhydrous MgSCU and concentrated under reduced pressure to yield 〇 .79g oil. It is expected that a certain amount of 1-bromo-2,3-xylene can be used to form a compound of the formula (1) in a yield of 18 Å/0, and the amount of the odoro 2,3-xylene used is nuclear magnetic resonance hydrogen. Spectral (1H-NMR) internal standard method. [Simple description of the diagram] None [Key component symbol description] None 23

Claims (1)

201238603 VII. Patent application scope: 1 · A method (A) for preparing a compound of formula (I), Wherein the double bond labeled as (a) in formula (I) has the configuration of (z) or (E); and the method (a) comprises the compound of formula (jj) with crotonic acid at the source (Aa) and base (Ab) the reaction in the presence of (A); R1 is selected from the group consisting of Cl, Br, I, 〇_s〇2-CF3, 〇-S〇2_c6H4-cii3 and 0-S02-Ph; wherein: the source of the source (Aa) is selected from a carrier a group consisting of a pd (〇), a pd (〇) complex, and a Pd (Π) complex; the test (Ab) is selected from n(R2)(R3)R4, 1,4-diazabicyclo[ 2.2·2] Group of Xinyuan, carboxylate, carbonate, bicarbonate, citrate, acid monohydrogen or dihydrogen sodium or potassium sulphate and mixtures thereof; R2, R3 and R4 They are the same or different and are independently selected from the group consisting of hydrazine, Cl. "homo-based C5·6 cycloalkyl and phenyl. The method of claim 3, wherein R1 is selected from the group consisting of Cb Br and I. • 3. According to the scope of the patent application! Or the method of 2 (A), in which the illusion is desert. 4. The method (a) according to any one of claims 1 to 3, wherein the carrier is barium sulfate or activated carbon. 5. The method (A) according to any one of claims 1 to 4, wherein the source (Aa) is selected from the group consisting of PdCl2, pd(〇Ac)2, pd(dba)2, Pd2(dba) 3. PdCl2(PhCN)2, PdCl2(MeCN)2, PdCl2(PPh3)2, Pd(P(tBu)3)2, Pd2(P(tBu)3)3, Pd(P(l-adamantyl) 3) 2. A group consisting of pd2 (p(1_adamantyl) 3)3, Pd(PPh3)4 and palladium on activated carbon. 6. The method according to any one of the preceding claims, wherein the test (Ab) is selected from the group consisting of N_ethyl_N,N-diisopropylamine, diazabicyclo[2.2.2 a group consisting of octane, N,N-dimethylaniline, dicyclohexylmethylamine, dicyclohexylamine, diisopropylamine, Na〇Ac, Na2C〇3, (3)3, KOAc, K2C03 and Κ3Ρ04. 7. The method according to any one of claims 1 to 6 (Α) 'where < «Xuan Jiyuan (Aa) is Pd(P(tBu)3)2, and the test (Ab) is N -ethyl-N,N-diisopropylamine. 8. The method according to any one of claims 1 to 7 of claim 25 201238603 wherein the reaction (A) is carried out in the presence of a ligand (Ac); the ligand (Ac) is P(R5)(R6)R7 R5, R6 and R7 are the same or different and are independently selected from the group consisting of: Cl-i5 alkyl; phenyl, biphenyl and naphthyl, the phenyl, biphenyl and The naphthyl group is unsubstituted or substituted by 1, 2, 3 or 4 identical or different and mutually independent substituents, wherein the substituent is selected from the group consisting of dentate, Cii decyl, Ci4 alkoxy, cyano a group consisting of a nitro group; a ferrocenyl group; a ferrocenyl group substituted with a di(tert-butyl)phosphine; a heteroaryl group which is 5 or 1 having one or two inner ring heteroatoms a 6-membered aromatic carbocyclic ring, wherein the hetero atom is selected from the group consisting of hydrazine, s, and N, the ring system being unsubstituted or substituted with hydrazine, 2 or 3 identical or different and independent substituents, wherein The substituent is selected from the group consisting of a phytochemical, a cadaveric group, a Cu alkoxy group, a cyano group, and a nitro group; a C 1 -丨5 oxime; 0-phenyl, 0-biphenyl, a naphthyl group, which is unsubstituted or substituted via i, 2, 3 or 4 identical or different and mutually independent substituents, wherein the substituent is selected from a group consisting of halogen, q alkyl, C 1 ·4 oxy, cyano and nitro; 0-heteroaryl, which is a heterocyclic ring having 5 or a 6-membered aromatic carbocyclic ring, wherein the hetero atom is selected from the group consisting of ruthenium, s, and ν 26 201238603, the ring system being unsubstituted or via hydrazine, 2 or 3 identical or different and independent substituents Substituted wherein the substituent is selected from the group consisting of a peptidin, an alkyl group, a Cw alkoxy group, a cyano group, and a nitro group. 9. The method (a) according to item 8 of the patent application, wherein the ahai ligand (Ac) is selected from the group consisting of PBu3, Ρ(0.tolyl)3, pph3, _adamantyl)3, P(Bu) (l-adamantyl) 2' tris(2,4-di-t-butylphenyl) phosphite, P(tBu)2(2-biphenyl), p(tBu)3, tri (ring) A group consisting of hexylphosphine, diphenyl phosphite, tris(1-naphthyl)phosphine, and bis(di-t-butylphosphino)-ferrocene. 1 〇 A method (a) according to item 8 of the patent application, wherein the ligand (Ac) is P(tBu)3. 11. The method according to claim 8 (A), wherein the source (Aa) is Pd2(dba)3', the base (Ab) is N-ethyl-oxime, Ν-diisopropylamine, And the ligand (Ac) is p(tBu)3. 12. Method (A) according to one or more of claims 1 to 7 wherein the reaction (A) is carried out in the presence of a salt (Ae); the ammonium salt (Ae) is n (R10) (R11) (R12)R13)+X-; Rl〇, R11, R12 and R13 are the same or different and are independently selected from the group consisting of Ci-15 alkyl; phenyl, phenyl and Naphthyl, the phenyl, biphenyl and naphthyl are unsubstituted or substituted by 1, 2, 3 or 4 identical or different and mutually independent substituents selected from the group consisting of C 〇 〇 alkyl, c 27 201238603 Group of alkoxy, cyano and nitro groups; c ^ o alkyl aryl, the aryl group of the Ci_i () alkylene aryl group is phenyl, hydrazino or Naphthyl 'S-decyl, biphenyl and naphthyl are unsubstituted or substituted by 1, 2, 3 or 4 identical or different and mutually independent substituents selected from halogens, a group consisting of Cl 1 decyl, C 4 alkoxy, cyano and nitro; X is selected from the group consisting of F, C, Br, phosphate, hydrogen phosphate, dihydrogen phosphate, C 1 1 Q acid Salt, sulfate and sulfuric acid Group salts thereof. 13. The method (a) according to claim 12, wherein RIO, R11, R12 and R13 are the same or different and are independent of each other selected from the group consisting of: CI - 1 2 alkyl; a phenyl group which is unsubstituted or substituted by 1 or 2 identical or different and mutually independent substituents selected from the group consisting of F, Cl, Br, C1 _4 alkyl, C a group consisting of _4 alkoxy groups; phenyl fluorenyl; X is selected from the group consisting of F, Cl, Br, phosphate, hydrogen phosphate, dihydrogen phosphate, C ii carboxylic acid salt, sulfate and hydrogen sulfate Group. 14_ According to the method (a) of claim 12, wherein the recorded salt (Ae) is selected from the group consisting of Bu4N+X~, MeN(Bu)3+X_, and twelve-base-N(Me)3+X a group consisting of benzoinyl n(Bu)3 + X', benzyl N(Me)3H Me4N+X_; and hydrazine is selected from the group consisting of c, Br, hydrogen phosphate, acetate and hydrogen sulfate The group consisting of. 15. Process (a) according to claim 12, wherein 28 201238603 the ammonium salt (Ae ) is Bu4N+C1_. 16. The method (a) of claim 12, wherein the source (Aa) is Pd(〇Ac)2, the base (Ab) is Na〇Ac, and the salt (Ae) is Bu4N+ C1-. 17. According to the scope of the patent application! To one or more of the items of 16 (A) 'wherein the reaction (a) is carried out in a solvent (Ad). 'N, decylhexyl' Tup, the solvent (Ad) is selected from DMF, Groups consisting of NMP, DMA, lanthanum, acetonitrile, propionitrile, ethyl acetate, butyl acetate, THF, methyldioxane, toluene, diphenylbenzene, and mixtures thereof 18. According to claim 17 The method (A) wherein the cockroach (Ad) is selected from the group consisting of DMF, NMP, DMA, methyl decylamine, acetonitrile, and propionitrile. 19. According to the method of claim 17 (Α), where. Xuan/Valent (Ad) is DMF or ΝΜΡ 〇 8. Pattern: None 29