CN102115452A - (E)-3-(3-substituted-5-methylphenyl)acrylonitrile and preparation method thereof - Google Patents
(E)-3-(3-substituted-5-methylphenyl)acrylonitrile and preparation method thereof Download PDFInfo
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- CN102115452A CN102115452A CN200910247676XA CN200910247676A CN102115452A CN 102115452 A CN102115452 A CN 102115452A CN 200910247676X A CN200910247676X A CN 200910247676XA CN 200910247676 A CN200910247676 A CN 200910247676A CN 102115452 A CN102115452 A CN 102115452A
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- 0 CCc1cc(C=C*)cc([N+]([O-])=O)c1 Chemical compound CCc1cc(C=C*)cc([N+]([O-])=O)c1 0.000 description 4
- ADONPOPXPJWBAM-NSCUHMNNSA-N Cc1cc(/C=C/C#N)cc([N+]([O-])=O)c1 Chemical compound Cc1cc(/C=C/C#N)cc([N+]([O-])=O)c1 ADONPOPXPJWBAM-NSCUHMNNSA-N 0.000 description 2
- ZUIQGRPOLDGCNE-UHFFFAOYSA-N CCOC(c([n](c(c1c2)ccc2Cl)S(c2ccc(C)cc2)(=O)=O)c1Br)=O Chemical compound CCOC(c([n](c(c1c2)ccc2Cl)S(c2ccc(C)cc2)(=O)=O)c1Br)=O ZUIQGRPOLDGCNE-UHFFFAOYSA-N 0.000 description 1
- IZDBOEJXLNFDDV-UHFFFAOYSA-N CCOC(c([n](c(c1c2)ccc2Cl)S(c2ccc(C)cc2)(=O)=O)c1P(OCC)=O)=O Chemical compound CCOC(c([n](c(c1c2)ccc2Cl)S(c2ccc(C)cc2)(=O)=O)c1P(OCC)=O)=O IZDBOEJXLNFDDV-UHFFFAOYSA-N 0.000 description 1
- NVMAXYYASOREEL-UHFFFAOYSA-N CCOC(c([n](c(c1c2)ccc2Cl)S(c2ccc(C)cc2)(=O)=O)c1P(c1cc(C)cc(Br)c1)(OC)=O)=O Chemical compound CCOC(c([n](c(c1c2)ccc2Cl)S(c2ccc(C)cc2)(=O)=O)c1P(c1cc(C)cc(Br)c1)(OC)=O)=O NVMAXYYASOREEL-UHFFFAOYSA-N 0.000 description 1
- IANFSJIVYQPUBC-JAMMHHFISA-N C[C@@H](C1C)[N]1(c(c1c2)ccc2Cl)c(C(N)=O)c1P(OC)=O Chemical compound C[C@@H](C1C)[N]1(c(c1c2)ccc2Cl)c(C(N)=O)c1P(OC)=O IANFSJIVYQPUBC-JAMMHHFISA-N 0.000 description 1
- CGBYTKOSZYQOPV-ONEGZZNKSA-N Cc1cc(/C=C/C#N)cc(P(c(c2c3)c(C(N)=O)[nH]c2ccc3Cl)(OC)=O)c1 Chemical compound Cc1cc(/C=C/C#N)cc(P(c(c2c3)c(C(N)=O)[nH]c2ccc3Cl)(OC)=O)c1 CGBYTKOSZYQOPV-ONEGZZNKSA-N 0.000 description 1
- ZEODKRPOHHFQBF-DUXPYHPUSA-N Cc1cc(/C=C/CC#N)cc(Br)c1 Chemical compound Cc1cc(/C=C/CC#N)cc(Br)c1 ZEODKRPOHHFQBF-DUXPYHPUSA-N 0.000 description 1
- YHOJFQTZLNKCGN-IHWYPQMZSA-N Cc1cc(/C=C\C#N)cc(Br)c1 Chemical compound Cc1cc(/C=C\C#N)cc(Br)c1 YHOJFQTZLNKCGN-IHWYPQMZSA-N 0.000 description 1
- DPKKOVGCHDUSAI-UHFFFAOYSA-N Cc1cc(Br)cc(Br)c1 Chemical compound Cc1cc(Br)cc(Br)c1 DPKKOVGCHDUSAI-UHFFFAOYSA-N 0.000 description 1
- LMFRTSBQRLSJHC-UHFFFAOYSA-N Cc1cc(Br)cc(C)c1 Chemical compound Cc1cc(Br)cc(C)c1 LMFRTSBQRLSJHC-UHFFFAOYSA-N 0.000 description 1
- MWFDNXJPZUOTJB-UHFFFAOYSA-N Cc1cc(Br)cc([N+]([O-])=O)c1 Chemical compound Cc1cc(Br)cc([N+]([O-])=O)c1 MWFDNXJPZUOTJB-UHFFFAOYSA-N 0.000 description 1
- NYVSKQQLHJSHJG-ONEGZZNKSA-N Cc1cc(C)cc(/C=C/C#N)c1 Chemical compound Cc1cc(C)cc(/C=C/C#N)c1 NYVSKQQLHJSHJG-ONEGZZNKSA-N 0.000 description 1
- DMSLPBFUZSQMQT-UHFFFAOYSA-N Cc1cc(C=O)cc(Br)c1 Chemical compound Cc1cc(C=O)cc(Br)c1 DMSLPBFUZSQMQT-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/35—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
Abstract
The invention relates to a 3-(3-substituted-5-methylphenyl)acrylonitrile disclosed as the general formula III, an (E)-3-(3-substituted-5-methylphenyl)acrylonitrile disclosed as the general formula I, and a preparation method and application thereof. The method comprises the following steps: carrying out Heck reaction on a compound disclosed as the general formula II and acrylonitrile to obtain a compound disclosed as the general formula III; and unnecessarily, carrying out separation and purification according to the cis/trans isomer ratio of the compound disclosed as the general formula III, and recrystallizing or pulping to obtain the (E)-3-(3-substituted-5-methylphenyl)acrylonitrile disclosed as the general formula I, or recrystallizing or pulping after carrying out double-bond spatial configuration transform to obtain the (E)-3-(3-substituted-5-methylphenyl)acrylonitrile disclosed as the general formula I. When non-nucleoside reverse transcriptase inhibitor IDX-899 and important intermediate thereof are prepared according to the method provided by the invention, the Heck reaction has the advantages of high selectivity, mild reaction conditions, low requirements for reaction equipment, fewer side reactions, high yield and low environmental pollution, and is easy to control and simple to operate.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, more specifically, relate to the 3-shown in the following general formula III (3-replacement-5-aminomethyl phenyl) vinyl cyanide, particularly (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide, and their preparation method and purposes.
Background technology
IDX-899, shown in the following general formula I d:
Be a kind of novel non-nucleoside reverse transcriptase inhibitor (NNRTI), be mainly used in the treatment that HIV infects.This product is carrying out II phase clinical study at present by the development of American I denix biopharmaceutical company.Although non-nucleoside reverse transcriptase inhibitor is considered to HIV treatment of infection first-line treatment scheme commonly used, but the medicine efavirenz (efavirenz that first goes through to go on the market in such medicine, Sustiva) drug-fast tendency has but appearred, simultaneously also with the relevant untoward reaction of central nervous system.And studies show that according to a series of the low dosage of IDX-899 just has higher usefulness, in addition, this product also has the activity that can resist the non-nucleoside reverse transcriptase inhibitor Resistant strain.And the angle from using, the formulation of taking its every day has once not only been brought facility for patient treatment, also is that itself and efabirenz (NRTIs) drug combination provide a kind of possible new departure simultaneously.
U.S. Patent application US2008213217A1 discloses the preparation method of general formula I d compound:
But this method is used n-Butyl Lithium and cyanogen methyl acid phosphate diethyl ester, not only costs an arm and a leg, the cost height, and also big for environment pollution; The second step Wittig reaction needed anhydrous and oxygen-free, reaction conditions is comparatively harsh, and conversion unit is required height, is not suitable for large-scale industrial production.Therefore, seek mild condition, yield height, cost is low, environmental pollution is little, the preparation method that is suitable for suitability for industrialized production just seems particularly urgent.
Summary of the invention
At above-mentioned weak point, the purpose of this invention is to provide a kind of easy, safe, efficient, cost is low, environmental pollution is little, be fit to the preparation method of 3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide, particularly (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide that large-scale industrialization produces.
An also purpose of the present invention provides the purposes that general formula I a, Ib or Ic compound become general formula I d compound (being IDX-899).
Another object of the present invention provides the new 3-of a class (3-replacement-5-aminomethyl phenyl) vinyl cyanide, especially (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide.
According to the present invention, the invention provides a kind of employing Heck prepared in reaction 3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide, especially the method for (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide, this method comprises: compound and vinyl cyanide shown in the general formula I I carry out the Heck reaction, obtain the 3-shown in the general formula III (3-replacement-5-aminomethyl phenyl) vinyl cyanide; Then not necessarily, the 3-shown in the described general formula III (3-replacement-5-aminomethyl phenyl) vinyl cyanide can pass through separation method commonly used such as recrystallization, making beating, liquid phase separation or the conversion of two key configuration and separate, and obtains the compound of single E or Z configuration.
Its reaction formula is as follows:
Especially, in the present invention, compound and vinyl cyanide shown in the general formula I I carry out Heck reaction, obtain based on compound shown in the trans general formula III, wherein ratio 〉=6 of compound trans shown in the general formula III and cis: 4; Then, ratio according to the cis-trans-isomer of compound shown in the general formula III is taked corresponding separation, purification process, obtain (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide by recrystallization or making beating, perhaps carry out earlier carrying out recrystallization or making beating again after two key steric configuration conversions, obtain (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide;
Reaction formula is as follows:
Wherein, R
1Be NO
2, NH
2, NH-W, Br or PG, W represents amino protecting group, and R
1Be preferably NO
2, NH
2, Br or PG,
PG is
R
2Be suitable leavings group, described leavings group is halogen, COCl, trifyl, tosyl group or methyl sulphonyl etc. for example, and more preferably halogen or COCl most preferably are Br, I or COCl;
And work as R
1During for Br, R
2Be not Cl or F.
In the present invention, described halogen is F, Cl, Br or I.
For amino protecting group, the method for amino protecting group well known to those skilled in the art and deprotection base is referring to " protecting group in the organic synthesis ", and the 4th edition, T.W.Greene and P.G.M.Wuts, John Wiley﹠amp; Sons, 2007,696 pages.
In aforesaid method of the present invention:
Compound and vinyl cyanide shown in the general formula I I carry out the Heck reaction, obtain based on compound shown in the trans general formula III.More specifically, 3,5-two replaces toluene (compound shown in the general formula I I) and vinyl cyanide and reacts under suitable palladium catalyst, suitable alkali, suitable solvent and suitable temperature, generates 3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide (compound of formula III).Wherein, palladium catalyst can be homogeneous palladium catalysts, and for example four (triphenylphosphines) close palladium (0) (Pd (PPh
3)
4), Palladous chloride (II) (PdCl
2), palladium (II) (Pd (OAc)
2), two (triphenylphosphine) palladium chloride (II) (Pd (PPh
3)
2Cl
2) or three (dibenzalacetone) two palladium (Pd
2(dba)
3) etc., perhaps be heterogeneous Pd catalyzer, for example palladium/carbon, palladium/metal oxide or palladium/zeolite etc.; Suitable alkali can be mineral alkali, for example salt of wormwood, yellow soda ash, cesium carbonate, sodium bicarbonate, sodium hydroxide or potassiumphosphate etc. perhaps are organic bases, for example triethylamine, sodium-acetate, Potassium ethanoate, N, N-dimethyl benzylamine, N, N-diethyl ethamine, tributylamine or trolamine etc.; Suitable solvent can be N, dinethylformamide, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide, p-Xylol, water, 1-Methyl-2-Pyrrolidone, toluene, dioxane, acetone or N,N-dimethylacetamide etc.; Reaction times is 0.5-30 hour; Temperature of reaction is 20-180 ℃.
Compound and vinyl cyanide shown in the general formula I I carry out the Heck reaction, obtain based on compound shown in the trans general formula III, then, compound shown in the general formula III obtains (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide by recrystallization or making beating, perhaps carry out recrystallization or making beating again after two key steric configurations conversions earlier, obtain (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide.Especially:
1) works as R
1Be NO
2, NH
2Or during NH-W, compound of formula III (being IIIa or IIIb compound) trans (E) is in the great majority, and can remove cis (Z) by recrystallization or methods of beating, obtain (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide (being Ia or Ib compound).Recrystallization and making beating all are purification process well known to those skilled in the art.Recrystallization is that crude product is dropped into heating for dissolving in the solvent, adds activated carbon decolorizing in case of necessity, and cooling crystallization filters again; Perhaps crude product is added in the easily molten solvent, dropping is difficult for molten solvent and makes it crystallization again.Making beating is that the crude product input is difficult for stirring in the solvent of dissolved product, the method for the impurity dissolving after-filtration that is soluble in solvent.Described solvent can be single solvent or mixed solvent.
2) work as R
1And R
2When being Br, the ratio of cis-trans is more or less the same, and need transform by two key steric configurations to transfer unwanted cis to needs trans, improves yield.Recrystallization or making beating again after compound of formula III (being the IIIc compound) is changed by two key steric configurations obtains (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide (being the Ic compound).According to document (" tetrahedron ", 1980,36 (5), 557-604; " organic chemistry ", 1976,41 (20), 3279-83; " chemical reagent ", 1985,7 (6), 340-5) reported method, the method for two key steric configuration conversions commonly used has: 1) transmit energy with photosensitizers under illumination and make alkene that suitable, anti-isomerization take place.Used photosensitizers is generally ketone or aromatic compound, as acetone, methyl phenyl ketone, acetonaphthone, toluene or dimethylbenzene etc.; 2) utilize acid catalyst example hydrochloric acid or free radical catalyst; 3) utilize addition-elimination reaction reagent.In the present invention, employing method 3), actual conditions is the experimental technique and the table 1 of face as follows, and addition reagent is selected liquid bromine or N-bromo-succinimide for use.Optimum condition is: 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide generates 2 with liquid bromine generation addition reaction earlier, 3-two bromo-3-(3-bromo-5-aminomethyl phenyl)-propionitrile, trans elimination obtains (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide, i.e. general formula I c compound under zinc/acetic acid condition then.Surprisingly, compare, use liquid bromo-zinc/acetic acid just can obtain general formula I c compound with high purity, high-conversion rate with other condition.
Experimental technique:
3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide (E: Z=7: 3) be dissolved in the organic solvent, add addition reagent, add initiator in case of necessity and react, reaction is finished, the intermediate that aftertreatment obtains directly is dissolved in acetic acid, adds zinc powder, and stirring reaction is 0.5 hour under the room temperature, reaction solution is poured in the frozen water, use dichloromethane extraction, organic layer washs with 5% sodium bicarbonate aqueous solution, uses anhydrous sodium sulfate drying again, filter, concentrate and obtain Compound I c.Concrete outcome is as shown in the table:
Table 1
3) work as R
1Be Br, R
2During for COCl, direct recrystallization of compound of formula III (being the IIIc compound) or making beating obtain (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide (being the Ic compound);
4) work as R
1During for PG, compound of formula III (being the IIId compound) obtains (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide (being the Id compound) by recrystallization or making beating.
Method according to preparation of the present invention (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide, this method comprises further general formula I a, Ib or Ic compound is become general formula I V compound and general formula I d compound that wherein general formula I V compound is the key intermediate of preparation general formula I d compound:
Work as R
1Be NO
2The time, general formula I a compound replaces three-step reaction through nitroreduction, diazotization, iodine and obtains compound IV; Perhaps
Work as R
1Be NH
2The time, general formula I b compound replaces two-step reaction through diazotization, iodine and obtains compound IV; Perhaps
Work as R
1During for NH-W, general formula I b compound replaces three-step reaction through deaminizating protecting group, diazotization, iodine and obtains compound IV; Perhaps
Work as R
1During for Br, general formula I c compound can prepare compound IV with reference to U.S. Patent application US2008213217A1 disclosed method, and promptly general formula I c compound and sodium iodide react under cuprous iodide catalysis, obtain compound IV;
Then; equally with reference to U.S. Patent application US2008213217A1 disclosed method; compound IV is with (2-formamyl-5-chloro-1H-indoles-3-)-phospho acid methyl esters carries out substitution reaction, obtains (the E)-3-shown in the general formula I d (3-replacement-5-aminomethyl phenyl) vinyl cyanide.
More specifically, described nitro-reduction reaction is that (E)-3-(3-nitro-5-aminomethyl phenyl) vinyl cyanide (Ia) carries out reduction reaction in the presence of reductive agent, generate (E)-3-(3-amino-5-aminomethyl phenyl) vinyl cyanide (Ib), employed reductive agent is selected from iron powder, zinc powder, tin protochloride, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium sulphite, ammonium bisulfite and the V-Brite B; Temperature of reaction is 0～120 ℃.
Described diazotization reaction is that (E)-3-(3-amino-5-aminomethyl phenyl) vinyl cyanide (Ib) reacted under 0～5 ℃ low temperature 0.5～2 hour with Sodium Nitrite and acid, generate diazonium salt, wherein acid can be mineral acid, example hydrochloric acid or sulfuric acid etc., perhaps can be organic acid, as trifluoroacetic acid etc.
Described iodine substitution reaction is diazonium salt and iodide reaction, generate (E)-3-(3-iodo-5-aminomethyl phenyl) vinyl cyanide (IV), wherein iodide can be potassiumiodide or sodium iodide etc., its mole dosage is 1～5 times of diazonium salt, 0.5～6 hour reaction times, 0～100 ℃ of temperature of reaction is used catalyzer in case of necessity.
In the present invention, the raw material of described employing (being general formula I I compound), 3-bromo-5-nitrotoluene can be bought by market and obtain, or with reference to " pharmaceutical chemistry " (1997,40 (4), 437-448) and " organic chemistry " (1990,55 (3), 1040-3) replace through bromo, diazotization, by hydrogen by 4-nitro-2-Tolylamine or 2-nitro-4-Tolylamine and prepare.The preparation of 3-iodo-5-nitrotoluene is replaced through iodo, diazotization, by hydrogen by 2-nitro-4-Tolylamine with reference to European patent application EP 303387A1 and prepares.3-bromo-5-phenylmethylamine can be bought by market, or is prepared through reduction by 3-bromo-5-nitrotoluene.3-iodo-5-phenylmethylamine can be bought by market, or is prepared through reduction by 3-iodo-5-nitrotoluene.3, the 5-dibromomethylbenzene can be bought by market.3-bromo-5-toluene iodide can be bought by market, or reference " Englishize association will " (1928,1913-1916) prepare through reduction, diazotization, iodo by 3-bromo-5-nitrotoluene.The preparation of 3-methyl-5-nitro Benzoyl chloride with reference to " microbiotic magazine " (1994,47 (12), 1456-65) by 2-nitro-4-Tolylamine through bromo, diazotization, prepared by hydrogen replacement, cyano group replacement, hydrolysis, acidylate.3-methyl-5-amino benzoyl chloride can be prepared through reduction, acidylate by 3-methyl-5-nitro phenylformic acid.Compound I Id prepares with reference to US2006074054A1.
According to the present invention, the invention provides the new 3-of a class (3-replacement-5-aminomethyl phenyl) vinyl cyanide, (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide and (Z)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide, that is:
3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide
(E)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
(E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
(Z)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
(Z)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
(Z)-3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide
The invention has the advantages that, reaction conditions gentleness, easy to control, easy and simple to handle, low to the conversion unit requirement, side reaction is few, the yield height; Raw material and reagent are cheap and easy to get, and cost is low, environmental pollution is little, be suitable for scale operation; Avoid using expensive butyllithium and cyanogen methyl acid phosphate diethyl ester.Advantage is especially, and the Heck reaction has higher configuration selectivity, and the products therefrom configuration is used for preparation (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide and has greater advantage based on trans.
Embodiment
Further specify the present invention by following examples, following examples only are used for the preferred embodiments of the invention more specifically are described, are not used in technical scheme of the present invention is limited.Among the following embodiment, hydrogen is composed by Bruker AMX-300 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; Purity is by Agilent 1100 hplc determinations, chromatographic column model: ZORBAXXDB C8; UV-detector detects wavelength: 272nm.
Embodiment 1 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide, (E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide and (Z)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide synthetic
With 3-bromo-5-nitrotoluene (42.7g, 0.2mol), vinyl cyanide (12.6g, 0.24mol), palladium (0.45g, 2mmol), triethylamine (28.3g, 0.28mol), triphenylphosphine (1g, 4mmol) and N, dinethylformamide (300ml) adds in the reaction flask, 120 ℃ of reacting by heating 16 hours.Then reaction solution is cooled to room temperature, adds ethyl acetate (200ml) dilution and filtration.Filtrate with saturated aqueous common salt (50ml * 1) washing, is used anhydrous Na with 1N HCl (50ml * 3) washing again
2SO
4Dry.The filtering siccative concentrates, and gets 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide 31.7g.
1HNMR (CDCl
3) δ 2.51 (s, 3H), 5.63 (d, J=12.0), 6.03 (d, 1H, J=16.2), 7.42 (d, 1H), 7.56 (s, 1H), 8.10 (s, 1H), 8.13 (s, 1H); HPLC: trans-isomer(ide) retention time 10.903min, purity 87%; Cis-isomeride retention time 10.523min, purity 13%.
(E)-separation of 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
(2: 1, recrystallization by volume) got off-white color solid (E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide 23.6g, yield 63.5% with ether-dehydrated alcohol with this cis-trans-isomer mixture.
Mp:146.9 ℃ (decomposition).
1HNMR(CDCl
3)δ2.51(s，3H)，6.03(d，1H)，7.42(d，1H)，7.56(s，1H)，8.10(s，1H)，8.13(s，1H)。
HPLC: retention time 10.903min, purity 98.6%.
(Z)-separation of 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
Mother liquor behind the above-mentioned cis-trans-isomer mixture recrystallization is separated by preparation type high performance liquid phase, get solid
(Z)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide.
1HNMR(CDCl
3)δ2.51(s，3H)，5.63(d，1H)，7.42(d，1H)，7.56(s，1H)，8.10(s，1H)，8.13(s，1H)；
HPLC: retention time 10.523min.
Embodiment 2 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide and (E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide synthetic
With 3-bromo-5-nitrotoluene (15.12g, 70mmol), vinyl cyanide (5.57g, 105mmol), palladium (0.8g, 3.56mmol), Potassium ethanoate (20.6g, 210mmol), Tetrabutyl amonium bromide (1.5g, 4.56mmol) and N, dinethylformamide (100ml) adds in the reaction flask, reacts 6 hours down at 130 ℃～140 ℃, and the TLC detection reaction is (petrol ether/ethyl acetate=4/1 fully, v/v), stop heating.When question response liquid is cooled to 40 ℃～50 ℃, it is slowly poured in the frozen water of stirring, separate out solid, filter.Methylene dichloride (150ml) dissolving is used in filter cake water (50ml * 3) flushing again, filters, and reclaims palladium catalyst.Concentrated filtrate obtains crude product 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide (HPLC: trans-isomer(ide) retention time 10.779min, purity 82%; Cis-isomeride retention time 10.391min, purity 18%.)。The gained crude product gets off-white color solid (E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide 10.7g, yield 81.2%, HPLC: trans-isomer(ide) purity 97%, cis-isomeride purity 2% with ethanol or ether making beating.
Nuclear magnetic resonance data is with embodiment 1.
Synthesizing of embodiment 3 (E)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
Method one:
With 3-bromo-5-phenylmethylamine (5.0g, 26.8mmol), vinyl cyanide (4.75g, 89.6mmol), palladium (1.2g, 5.37mmol), triethylamine (10.9g, 107mmol), three (o-tolyl) phosphine (8.1g, 26.8mmol) and acetonitrile (50ml) add in the reaction flask, 140 ℃ of reactions 18 hours down.After the cooling,, filtrate is poured in the water, and extract with methylene dichloride (15ml * 3) with this reactant diatomite filtration.With the organic layer dried over mgso, filter, concentrate, obtain crude product, with dehydrated alcohol-ether recrystallization, get yellow solid (E)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide 3.6g, yield 84.7%.
mp：95.7℃-98.0℃；
1HNMR(DMSO-d6)δ2.17(s，3H)，5.18(s，2H)，6.18(d，1H)，6.43(s，1H)，6.52(s，1H)，6.62(s，1H)，7.42(d，1H)。
Method two:
(E)-(12g 64mmol) is dissolved in the Glacial acetic acid (100ml) 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide, adds zinc powder (12.5g in batches, 0.19mol),, there is heat to emit therebetween, control reaction temperature finishes at 20 ℃～60 ℃, and stirring reaction is 2 hours under the room temperature.With reacting liquid filtering, use the small amount of acetic acid flush cake, more resulting filtrate is slowly poured in the frozen water (500ml) of stirring, separate out solid, filter.The flushing of gained filter cake water is removed residual acetate for several times, and drying gets yellow solid (E)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide 9.4g, yield 93%.
Synthesizing of embodiment 4 (E)-3-(3-iodo-5-aminomethyl phenyl)-2-vinyl cyanide
With (E)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide (5.74g, 36.2mmol) mix with 37% hydrochloric acid (17ml) and frozen water (11.3g), place 0～5 ℃ of ice-water bath, slow dropping Sodium Nitrite under this temperature (2.76g, water 40.0mmol) (7.0ml) solution carries out diazotization reaction; Dropwise the back and continue to stir the aqueous solution that obtained diazonium salt in 15 minutes.
(18g, water 109.0mmol) (40.0ml) solution at room temperature drip the aqueous solution through the above-mentioned diazonium salt after the coarse filtration to add potassiumiodide in another reaction flask; And stirring reaction 2 hours at room temperature.Add methylene dichloride (50ml) extraction, organic layer water (10ml), 5% aqueous solution of sodium bisulfite (10ml) and saturated aqueous common salt (10ml) successively washs 1 time, uses anhydrous Na again
2SO
4Dry.Filter, concentrate, residue with activated carbon decolorizing after, (2/1, v/v) recrystallization obtains off-white color solid (E)-3-(3-iodo-5-aminomethyl phenyl)-2-vinyl cyanide 6.2g, yield 63.5% to use petroleum ether/ethyl ether again.
mp：97.8℃-102.9℃。
1HNMR(CDCl3)δ2.33(s，3H)，5.85(d，1H)，7.19(s，1H)，7.25(d，1H)，7.59(s，2H)。
HPLC: trans-isomer(ide) retention time 12.427min, purity 99%; Cis-isomeride retention time 12.055min, purity of 50 percent .3%.
Synthesizing of embodiment 5 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide
With 3; 5-dibromomethylbenzene (10g; 40mmol), vinyl cyanide (2.122g; 40mmol), palladium (90mg, 0.4mmol), triethylamine (11ml, 56mmol), triphenylphosphine (210mg; 0.8mmol) and N; dinethylformamide (200ml) adds in the reaction flask, and under nitrogen protection, 100 ℃～120 ℃ reactions are spent the night.Reaction soln is cooled to room temperature, adds ethyl acetate (380ml) extraction, organic phase is washed with 1N HCl (100ml), and water (50ml) is washed again, through anhydrous Na
2SO
4Dry, filter, concentrate, the residue column chromatography purification (elutriant is a petrol ether/ethyl acetate=20: 1, v/v), 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide 8.1g, yield 45.6%.
1HNMR(CDCl3)δ2.38(s，3H)，5.48(d，J＝12.0)，5.86(d，1H，J＝16.2)，7.18～7.40(m，4H)。HPLC: trans-isomer(ide) retention time 9.964min, purity 70%; Cis-isomeride retention time 9.844min, purity 30%.
Synthesizing of embodiment 6 (E)-3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide
3-(3-bromo-5-the aminomethyl phenyl)-2-vinyl cyanide (2.22g of embodiment 5 preparations, 10.0mmol) be dissolved in the methylene dichloride (10ml), dropping liquid bromine (3.2g under stirring at room, 20.0mmol), dropwise the back and continued stirring reaction 3 hours, with the directly concentrated intermediate 2,3-two bromo-3-(3-bromo-5-aminomethyl phenyl)-propionitrile of obtaining of reaction solution; It is dissolved in the Glacial acetic acid (20ml), under stirring at room, add zinc powder (4.25g, 65.0mmol), and stirring reaction 0.5 hour at room temperature, reaction solution is poured in the frozen water (60ml), with methylene dichloride (50ml) extraction, organic layer is used anhydrous Na again with 5% sodium bicarbonate aqueous solution (10ml) washing
2SO
4Dry, filtration, concentrated, residue is pulled an oar with anhydrous diethyl ether, gets off-white color solid 1.88g, yield 84.7%.HPLC: trans-isomer(ide) retention time 9.990min, purity 99.4%; Cis-isomeride retention time 9.869min, purity of 50 percent .6%).
1HNMR(CDCl3)δ2.38(s，3H)，5.85(d，1H)，7.18～7.40(m，4H)。
Embodiment 7 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide and (E)-3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide synthetic
3-bromo-5-tolyl acid (8.8g 0.04mol) is dissolved in the methylene dichloride (30ml), dripping thionyl chloride (11g 0.09mol), dropwises, reflux 1.5 hours, be concentrated into dried, acyl chlorides crude product 9.3g, yield: 97%.Not purified, be directly used in the next step.
Above-mentioned gained acyl chlorides (9.3g, 0.04mol) and vinyl cyanide (3.2g 0.06mol) is dissolved in the p-Xylol (50ml), add again palladium (1g, 4mmol) and N, the N-dimethyl benzylamine (8.1g, 0.06mol), at N
2Protect following 135 ℃ to reflux 18 hours.Stop heating, add ethyl acetate (120ml) behind the question response liquid naturally cooling, filter; Concentrated filtrate adds sherwood oil (120ml) in the residue, stir 10min under the room temperature, filters, and concentrated filtrate gets crude product 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide 6.4g, HPLC: trans-isomer(ide) retention time 12.088min, purity 94%; Cis-isomeride retention time 11.680min, purity 6%.This crude product dehydrated alcohol recrystallization gets off-white color solid (E)-3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide 5.4g, yield 61%, HPLC: trans-isomer(ide) retention time 12.088min, purity 99.5%; Cis-isomeride retention time 11.680min, purity of 50 percent .5%.
Nuclear magnetic resonance data is with embodiment 5 and 6.
Synthesizing of embodiment 8 3-methyl-5-nitro benzene nitriles
Anhydrously dry cross, in the reaction flask of nitrogen protection, (18.6g, 86mmol), new distillatory N, (7.84g, 87mmol), this reaction system backflow is spent the night for dinethylformamide (100ml) and the dry cuprous cyanide of crossing to add 3-bromo-5-nitrotoluene.Reaction system is as cold as room temperature, pours in the water (500ml), with ethyl acetate (400ml) extraction, wash successively again, saturated sodium bicarbonate solution (50ml) is washed, water (50ml) is washed again, uses the anhydrous sodium sulfate drying organic layer then by water (50ml) for organic layer; Organic layer is filtered, concentrates, and (petrol ether/ethyl acetate=4/1 v/v) obtains light yellow solid 3-methyl-5-nitro benzene nitrile 8.51g, yield 61% to residue through column chromatography.
Embodiment 9 3-methyl-5-nitros are benzoic synthetic
(3.73g, 23mmol), 75% aqueous sulfuric acid (50ml) was 150 ℃ of reactions 1 hour for the 3-methyl-5-nitro benzene nitrile of adding embodiment 8 preparations in reaction flask.Be as cold as room temperature, pour in the frozen water (150ml), with ethyl acetate (150ml) extraction, the organic phase anhydrous sodium sulfate drying filters, and concentrates, and obtains off-white color solid 3-methyl-5-nitro phenylformic acid 3.22g, yield 77.4%.
1HNMR(DMSO-d6)δ2.38(s，3H)，7.67(s，1H)，7.74(s，1H)，7.82(s，1H)。
Synthesizing of embodiment 10 (E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
Sulfur oxychloride (2.96g, (3.0g is in methylene dichloride 16.56mmol) (50ml) solution 24.9mmol) to be added drop-wise to 3-methyl-5-nitro phenylformic acid, finish, reflux 2 hours concentrates, get 3-methyl-5-nitro Benzoyl chloride crude product 3.27g, yield: 99%.This can be directly used in next step reaction.
3-methyl-5-nitro Benzoyl chloride (3.27g, 16.4mmol) and vinyl cyanide (1.3g 24.6mmol) is dissolved in the p-Xylol (100ml), add again palladium (0.42g, 1.87mmol) and N, the N-dimethyl benzylamine (3.36g, 24.8mmol), at N
2Protect following 135 ℃ to reflux 18 hours.Question response liquid cooling but back adds ethyl acetate (100ml), filters, and concentrated filtrate gets crude product 3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide 2.53g, HPLC: trans-isomer(ide) retention time 10.760min, purity 93%; Cis-isomeride retention time 10.372min, purity 7%.This crude product gets off-white color solid 2.28g, yield 74%, HPLC: trans-isomer(ide) retention time 10.760min, purity 99.2% through ether-dehydrated alcohol (2: 1) recrystallization; Cis-isomeride retention time 10.372min, purity of 50 percent .8%.
Synthesizing of embodiment 11 N-p-toluenesulfonyl-5-chloro-1H-indole-2-ethyl formate
(12.0g 53.65mmol) is dissolved in the dry DMF (100ml) 5-chloro-1H-indole-2-ethyl formate, when being as cold as 0 ℃, adds NaH (3.22g, 80.5mmol, content 60%) in reaction solution in batches; After adding, 0 ℃ of stirring reaction 20 minutes, (whole dropping process made reacting liquid temperature maintain 0～5 ℃ for 15.3g, dry DMF 80.5mmol) (20ml) solution, then stirring at room reaction 1 hour to drip Tosyl chloride again.Reaction solution is poured in the frozen water (450ml), separated out solid, filter, water (100ml * 3) flush cake, dry N-p-toluenesulfonyl-5-chloro-1H-indole-2-ethyl formate 18.87g, the yield 93.1% of getting.
1HNMR(CDCl
3)δ1.40(dd，3H)，2.36(s，3H)，4.39(m，2H)，7.05(s，1H)，7.27(t，2H)，7.37(dd，1H)，7.51(d，1H)，7.90(d，2H)，8.02(d，1H)。
Synthesizing of embodiment 12 N-p-toluenesulfonyl-3-bromo-5-chloro-1H-indole-2-ethyl formate
(18.0g 47.64mmol) is dissolved in the methylene dichloride (150ml) N-p-toluenesulfonyl-5-chloro-1H-indole-2-ethyl formate, adds pyridine (10ml), and (7.63g 47.64mmol), finishes stirred overnight at room temperature to the dropping liquid bromine again.Reaction solution washs with the 1N HCl aqueous solution (100ml * 3), water (100ml * 1) washing, anhydrous sodium sulfate drying.Filter, concentrate, (petrol ether/ethyl acetate=20/1 by volume), gets N-p-toluenesulfonyl-3-bromo-5-chloro-1H-indole-2-ethyl formate 20.4g, yield 93.75% to the residue column chromatography purification.
1HNMR(CDCl
3)δ1.46(t，3H)，2.35(s，3H)，4.52(m，2H)，7.22(s，2H)，7.37(dd，1H)，7.48(d，1H)，7.83(d，2H)，7.94(d，1H)。
Embodiment 13 (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indoles-3-)-phosphinicacid ethyl ester synthetic
The N-p-toluenesulfonyl-(11.96g 26.19mmol) is dissolved in the anhydrous tetrahydro furan (300ml) 3-bromo-5-chloro-1H-indole-2-ethyl formate.Under nitrogen protection, in dry ice/ether is cooled to this solution of-76.0 ℃, drip n-BuLi (15.7ml, 2.5M, THF solution 39.3mmol), temperature is controlled at-76.0 ℃～-72.0 ℃.Add the back and stirred 20 minutes in this temperature, slowly drip again the torak diethyl phthalate (4.51g, 28.8mmol), after adding again-76.0 ℃ of stirring reactions 2 hours.Reaction solution dilutes with ethyl acetate (300ml) and is warmed up to-40 ℃, adds the aqueous hydrochloric acid (100ml) of 0.5N, is raised to stirring at room then 1 hour.Tell organic layer, water layer is used ethyl acetate (100ml * 1) extraction again.Merge organic layer, wash with saturated aqueous common salt (80ml * 1), behind the anhydrous sodium sulfate drying, filter, concentrate, (petrol ether/ethyl acetate=15/1 by volume), gets off-white color solid title compound 9.05g, yield 73.5% to the residue column chromatography.
1HNMR(CDCl
3)δ1.30-1.47(m，6H)，2.39(d，3H)，4.09-4.22(m，2H)，4.49-4.56(m，2H)，6.75-8.74(s，s，0.5H+0.5H)，7.29-7.40(m，4H)，7.90-8.02(m，3H)。
Synthesizing of embodiment 14 (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phosphinicacid ethyl ester
In reaction flask, add (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indoles-3-)-phosphinicacid ethyl ester (2.32g; 4.95mmol); 3; 5-dibromomethylbenzene (2.5g; 9.9mmol); tetrakis triphenylphosphine palladium (200mg; catalytic amount), and triethylamine (600mg, 5.94mmol) and toluene (50ml); this reaction solution 110 ℃ of stirring reactions 18 hours in nitrogen environment; concentrate and remove solvent, and the residue column chromatography (petrol ether/ethyl acetate=10/1, by volume); get solid title compound 2.15g, yield 68%.
1HNMR(CDCl
3)δ1.30-1.47(m，6H)，2.37(d，6H)，4.07-4.15(m，2H)，4.47-4.56(m，2H)，7.27-7.34(m，3H)，7.46(s，1H)，7.52-7.96(m，6H)。
Synthesizing of embodiment 15 (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phospho acid methyl esters
(N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phosphinicacid ethyl ester (2.0g; 3.13mmol) be dissolved in the methylene dichloride (10ml); add bromotrimethylsilane (2.3g when being as cold as 0 ℃; 15.0mmol); 40 ℃ of reactions 1.5 hours, concentrate and remove solvent and excessive bromotrimethylsilane then.Add methylene dichloride (10ml) in reaction flask, be as cold as 0 ℃, (0.6ml 6.26mmol) and DMF (0.5ml), stirring at room reaction 1 hour, concentrates and removes solvent and excessive oxalyl chloride to add oxalyl chloride.In reaction flask, add methylene dichloride (10ml), add methyl alcohol (30ml) when being as cold as 0～5 ℃,, concentrate the removal solvent and get title compound 1.9g, yield 97.2% stirring at room reaction 2 hours.
1HNMR(CDCl
3)δ1.40-1.46(m，3H)，2.35(d，6H)，3.90(d，3H)，4.48-4.55(m，2H)，7.28-7.35(m，3H)，7.46-7.98(m，7H)。
Synthesizing of embodiment 16 (2-carboxyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phospho acid methyl esters
In reaction flask, add (N-p-toluenesulfonyl-2-ethoxycarbonyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phospho acid methyl esters (1.23g; 1.97mmol); Lithium Hydroxide Monohydrate (331mg; 7.88mmol) with the solution of water (5.6ml); tetrahydrofuran (THF) (2.0ml), this reaction system was stirring at room 16 hours.Concentrate and remove tetrahydrofuran (THF), make pH ≈ 2 with the acidifying of 0.5N aqueous hydrochloric acid again, with ethyl acetate (20ml * 2) extraction, the organic layer anhydrous sodium sulfate drying filters, and concentrates residue column chromatography (CH
2Cl
2/ MeOH=10/1 by volume), gets solid title compound 620mg, yield 71.2%.
1HNMR(CDCl
3)δ2.33(s，3H)，3.91(d，3H)，7.20(s，1H)，7.35(dd，1H)，7.41(s，1H)，7.46(s，2H)，7.56-7.60(m，2H)，10.7(brs，1H)
Synthesizing of embodiment 17 (2-formamyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phospho acid methyl esters
In reaction flask, add (2-carboxyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phospho acid methyl esters (550mg, 1.24mmol), 1,1 '-carbonyl dimidazoles (402mg, 2.48mmol), glycol dimethyl ether (5.0ml), this reaction system stirring at room is after 2 hours, be as cold as 5 ℃, fed ammonia about 10 minutes, again stirring at room 1 hour in ammonia environment.Add entry (8ml) in the reaction solution, with ethyl acetate (10ml * 2) extraction, organic layer anhydrous sodium sulfate drying after-filtration concentrates, and (petrol ether/ethyl acetate=10/1 by volume), gets solid title compound 492mg, yield 89.8% to the residue column chromatography.
1HNMR(DMSO-d6)δ2.32(s，3H)，3.77(d，3H)，7.34(dd，1H)，7.47-7.59(m，5H)，8.04(brs，1H)，10.04(brs，1H)，12.88(brs，1H)。
Synthesizing of embodiment 18 (2-formamyl-5-chloro-1H-indol-3-yl) [3-((1E)-2-cyano group vinyl)-5-aminomethyl phenyl]-phospho acid methyl esters
In reaction flask, add (2-formamyl-5-chloro-1H-indol-3-yl) (3-bromo-5-aminomethyl phenyl)-phospho acid methyl esters (442mg; 1.0mmol); DMF (5ml), and vinyl cyanide (64mg, 1.2mmol); triethylamine (143mg; 1.4mmol), triphenylphosphine (6mg, 0.02mmol) and palladium (3mg; 0.01mmol), this reaction solution places 120 ℃ of oil bath reactions 8 hours in nitrogen environment.Then, stop to heat, be cooled to room temperature, add entry (20ml), with ethyl acetate (10ml * 3) extraction, merge organic layer, saturated aqueous common salt (10ml * 1) is washed, and the anhydrous sodium sulfate drying after-filtration concentrates, and gets solid 322mg, yield 77.8%.
1HNMR(CDCl
3)δ2.39(s，3H)，3.87(d，3H)，5.89(d，1H，J＝16.5)，5.96(brs，1H)，7.33-7.67(m，7H)，10.45(s，1H)，10.88(brs，1H)；
HPLC: trans-isomer(ide) retention time 13.250min, purity 76%; Cis-isomeride retention time 12.458min, purity 24%.
This cis-trans-isomer mixture with ether/ethyl acetate=100/1 (v/v) making beating 10 minutes, is filtered, and oven dry gets solid title compound 231mg, yield 56%.
1HNMR(CDCl
3)δ2.39(s，3H)，3.87(d，3H)，5.89(d，1H)，5.96(brs，1H)，7.33-7.67(m，7H)，10.45(s，1H)，10.88(brs，1H)。
HPLC: trans-isomer(ide) retention time 13.250min, purity 99.87%; Cis-isomeride retention time 12.458min, purity of 50 percent .13%.
Claims (10)
1. the preparation method of a 3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide, this method comprises:
Compound and vinyl cyanide shown in the general formula I I carry out the Heck reaction, obtain the 3-shown in the general formula III (3-replacement-5-aminomethyl phenyl) vinyl cyanide,
Reaction formula is as follows:
Wherein, R
1Be NO
2, NH
2, NH-W, Br or PG, W represents amino protecting group, PG is
R
2Be suitable leavings group, described suitable leavings group is halogen, COCl, trifyl, tosyl group or methyl sulphonyl;
And work as R
1During for Br, R
2Be not Cl or F.
Described halogen is F, Cl, Br or I.
2. preparation method according to claim 1 is characterized in that, wherein compound and vinyl cyanide shown in the general formula I I carry out Heck reaction, obtains based on compound shown in the trans general formula III, wherein ratio 〉=6 of compound trans shown in the general formula III and cis: 4; Then, ratio according to the cis-trans-isomer of compound shown in the general formula III is taked corresponding purification process, obtain (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide by recrystallization or making beating, perhaps carry out earlier carrying out recrystallization or making beating again after two key steric configuration conversions, obtain (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide;
Reaction formula is as follows:
Wherein, R
1Be NO
2, NH
2, NH-W, Br or PG, W represents amino protecting group, PG is
R
2Be suitable leavings group, described suitable leavings group is halogen, COCl, trifyl, tosyl group or methyl sulphonyl;
And work as R
1During for Br, R
2Be not Cl or F.
Described halogen is F, Cl, Br or I.
3. preparation method according to claim 1 and 2 is characterized in that, described R
1Be NO
2, NH
2, Br or PG.
4. preparation method according to claim 1 and 2 is characterized in that, described R
1Be NO
2, NH
2, Br or PG; Described R
2Be Br, I or COCl.
5. according to each described preparation method among the claim 1-4, it is characterized in that, compound and vinyl cyanide shown in the general formula I I carry out the Heck reaction, described Heck reaction is to carry out under suitable palladium catalyst, suitable alkali, suitable solvent and suitable temperature, wherein, suitable palladium catalyst is homogeneous palladium catalysts or heterogeneous Pd catalyzer, and described homogeneous palladium catalysts is that four (triphenylphosphines) close palladium (O) (Pd (PPh
3)
4), Palladous chloride (II) (PdCl
2), palladium (II) (Pd (OAc)
2), two (triphenylphosphine) palladium chloride (II) (Pd (PPh
3)
2Cl
2) or three (dibenzalacetone) two palladium (Pd
2(dba)
3), described heterogeneous Pd catalyzer is palladium/carbon, palladium/metal oxide or palladium/zeolite; Suitable alkali is mineral alkali or organic bases, described mineral alkali is salt of wormwood, yellow soda ash, cesium carbonate, sodium bicarbonate, sodium hydroxide or potassiumphosphate, described organic bases is triethylamine, sodium-acetate, Potassium ethanoate, N, N-dimethyl benzylamine, N, N-diethyl ethamine, tributylamine or trolamine; Suitable solvent is N, dinethylformamide, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide, p-Xylol, water, 1-Methyl-2-Pyrrolidone, toluene, dioxane, acetone or N,N-dimethylacetamide; Reaction times is 0.5-30 hour; Temperature of reaction is 20-180 ℃.
6. according to each described preparation method among the claim 1-5, it is characterized in that, compound and vinyl cyanide shown in the general formula I I carry out the Heck reaction, obtain based on compound shown in the trans general formula III, then, compound shown in the general formula III obtains (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide by recrystallization or making beating, perhaps carry out recrystallization or making beating again after two key steric configurations conversions earlier, obtain (the E)-3-shown in the general formula I (3-replacement-5-aminomethyl phenyl) vinyl cyanide, that is:
1) works as R
1Be NO
2, NH
2Or during NH-W, compound of formula III is that IIIa or IIIb compound are removed cis by recrystallization or methods of beating, and obtaining (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide is Ia or Ib compound;
2) work as R
1And R
2When being Br, compound of formula III is recrystallization or making beating again after the IIIc compound is changed by two key steric configurations, and obtaining (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide is the Ic compound; Wherein said pair of key steric configuration conversion comprises: 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide generates 2 with liquid bromine or N-bromo-succinimide generation addition reaction earlier, 3-two bromo-3-(3-bromo-5-aminomethyl phenyl)-propionitrile, trans elimination obtains (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide, i.e. general formula I c compound under zinc/acetic acid condition then;
3) work as R
1Be Br, R
2During for COCl, compound of formula III is that to obtain (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide be the Ic compound for direct recrystallization of IIIc compound or making beating;
4) work as R
1During for PG, compound of formula III is that to obtain (E)-3-(3-replacement-5-aminomethyl phenyl) vinyl cyanide by recrystallization or making beating be the Id compound to the IIId compound.
7. preparation method according to claim 6 is characterized in that, works as R
1And R
2When being Br, compound of formula III is recrystallization or making beating again after the IIIc compound is changed by two key steric configurations, and obtaining (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide is the Ic compound; Wherein said pair of key steric configuration conversion comprises: 3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide generates 2 with liquid bromine generation addition reaction earlier, 3-two bromo-3-(3-bromo-5-aminomethyl phenyl)-propionitrile, trans elimination obtains (E)-3-(3-bromo-5-aminomethyl phenyl) vinyl cyanide, i.e. general formula I c compound under zinc/acetic acid condition then.
8. preparation method according to claim 6 is characterized in that, this method further comprises general formula I a, Ib or Ic compound are become general formula I d compound:
Work as R
1Be NO
2The time, general formula I a compound replaces three-step reaction through nitroreduction, diazotization, iodine and obtains compound IV; Perhaps
Work as R
1Be NH
2The time, general formula I b compound replaces two-step reaction through diazotization, iodine and obtains compound IV; Perhaps
Work as R
1During for NH-W, general formula I b compound replaces three-step reaction through deaminizating protecting group, diazotization, iodine and obtains compound IV; Perhaps
Work as R
1During for Br, general formula I c compound and sodium iodide react under cuprous iodide catalysis, obtain compound IV;
Then, compound IV is with (2-formamyl-5-chloro-1H-indoles-3-)-phospho acid methyl esters carries out substitution reaction, obtains (the E)-3-shown in the general formula I d (3-replacement-5-aminomethyl phenyl) vinyl cyanide.
9. preparation method according to claim 8, it is characterized in that, described nitro-reduction reaction is that (E)-3-(3-nitro-5-aminomethyl phenyl) vinyl cyanide (Ia) carries out reduction reaction in the presence of reductive agent, generate (E)-3-(3-amino-5-aminomethyl phenyl) vinyl cyanide (Ib), employed reductive agent is selected from iron powder, zinc powder, tin protochloride, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium sulphite, ammonium bisulfite and the V-Brite B; Temperature of reaction is 0～120 ℃;
Described diazotization reaction is that (E)-3-(3-amino-5-aminomethyl phenyl) vinyl cyanide (Ib) reacted under 0～5 ℃ low temperature 0.5～2 hour with Sodium Nitrite and acid, generates diazonium salt, and wherein acid is hydrochloric acid, sulfuric acid or trifluoroacetic acid;
Described iodine substitution reaction is diazonium salt and iodide reaction, generate (E)-3-(3-iodo-5-aminomethyl phenyl) vinyl cyanide (IV), wherein iodide are potassiumiodide or sodium iodide, its mole dosage is 1～5 times of diazonium salt, 0.5～6 hour reaction times, 0～100 ℃ of temperature of reaction is used catalyzer in case of necessity.
10. the new 3-that a class formation formula is following (3-replacement-5-aminomethyl phenyl) vinyl cyanide:
3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide
(E)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
(E)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
(Z)-3-(3-amino-5-aminomethyl phenyl)-2-vinyl cyanide
(Z)-3-(3-nitro-5-aminomethyl phenyl)-2-vinyl cyanide
(Z)-3-(3-bromo-5-aminomethyl phenyl)-2-vinyl cyanide
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| PCT/CN2010/079700 WO2011079704A1 (en) | 2009-12-30 | 2010-12-13 | (e)-3-(3-substituted-5-methylphenyl) arylonitrile and preparation methods thereof |
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|---|---|---|---|---|
| WO2014190457A1 (en) * | 2013-05-28 | 2014-12-04 | 兰州大学 | Method for stereo-selectively synthesizing 3-site phosphorylated indole |
| CN110028430A (en) * | 2019-05-24 | 2019-07-19 | 杭州卢普生物科技有限公司 | A kind of preparation method of sulindac |
| CN110256424A (en) * | 2019-07-03 | 2019-09-20 | 武汉工程大学 | A kind of synthetic method of Pa Boxini key intermediate V |
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| JP5118972B2 (en) * | 2004-10-29 | 2013-01-16 | テイボテク・フアーマシユーチカルズ | HIV inhibitory bicyclic pyrimidine derivatives |
| BRPI0717511A2 (en) * | 2006-09-29 | 2013-11-19 | Idenix Pharmaceuticals Inc | PURE COMPOUND, PHARMACEUTICAL COMPOSITION, METHODS TO TREAT HIV INFECTION, PREVENT HIV INFECTION, INHIBIT HIV REPLICATION, AND USE OF COMPOUND |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014190457A1 (en) * | 2013-05-28 | 2014-12-04 | 兰州大学 | Method for stereo-selectively synthesizing 3-site phosphorylated indole |
| CN110028430A (en) * | 2019-05-24 | 2019-07-19 | 杭州卢普生物科技有限公司 | A kind of preparation method of sulindac |
| CN110028430B (en) * | 2019-05-24 | 2020-04-10 | 杭州卢普生物科技有限公司 | Preparation method of sulindac |
| CN110256424A (en) * | 2019-07-03 | 2019-09-20 | 武汉工程大学 | A kind of synthetic method of Pa Boxini key intermediate V |
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