CN105153151A - Method for synthesizing pyrimidinones compounds - Google Patents
Method for synthesizing pyrimidinones compounds Download PDFInfo
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- CN105153151A CN105153151A CN201510540965.4A CN201510540965A CN105153151A CN 105153151 A CN105153151 A CN 105153151A CN 201510540965 A CN201510540965 A CN 201510540965A CN 105153151 A CN105153151 A CN 105153151A
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- 0 CC(C(CN(C=C(C=C1)Cl)C1=N)Br)=* Chemical compound CC(C(CN(C=C(C=C1)Cl)C1=N)Br)=* 0.000 description 2
- VSIHSRYDDONNJL-UHFFFAOYSA-N CCCCNCNC(C=C)O Chemical compound CCCCNCNC(C=C)O VSIHSRYDDONNJL-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The invention relates to a method for synthesizing pyrimidinones compounds shown as a formula (III). The method includes adding compounds shown as a formula (I), compounds shown as a formula (II), catalysts, alkali, accelerators and auxiliaries into organic solvents at the room temperature; heating the compounds shown as the formula (I), the compounds shown as the formula (II), the catalysts, the alkali, the accelerators and the auxiliaries in the atmosphere of oxygen until the temperatures reach 60-80 DEG C; carrying out stirring reaction for 6-10 hours; carrying out post-treatment to obtain the compounds shown as the formula (III). An R<1> represents H, C<1>-C<6> alkyl or halogen; an R<2> represents C<1>-C<6> alkyl or benzyl; an X represents halogen. The method has the advantages that the solvents, the alkali, the accelerators, the auxiliaries and the organic solvents are appropriately selected and combined with one another, accordingly, target products can be obtained in a high-yield manner, and the method has an excellent application prospect and excellent industrial production potential in the organic synthesis field and particularly in the fields of medical intermediates.
Description
Technical field
The present invention relates to a kind of synthetic method of heterocyclic compound, relate more particularly to a kind of synthetic method of pyrimidinones, belong to technical field of organic synthesis especially medicine intermediate synthesis field.
Background technology
Pyrimdinone structure constructs the structural framework of multiple bioactive molecules, medicine and functional materials, such as, all contains Pyrimdinone chemical structure in the efflux pump inhibitor class of anti-antipsychotics risperidone, following structure etc.
At present, in prior art, there is the multiple method being used for building synthesis Pyrimdinone derivatives, such as:
YoshidaKen-ichi etc. (" MexAB-OprMspecificeffluxpumpinhibitorsinPseudomonasaerug inosa.Part5:Carbon-substitutedanaloguesattheC-2position ", Bioorganic & MedicinalChemistry, 2006,14,1993-2004) report a kind of 3-thiazolinyl-4H-pyrido [1,2-a] building-up reactions of pyrimidin-4-one compounds, its reaction formula is as follows:
AnnamariaMolnar etc. (" Suzuki – Miyauracross-couplingreactionsofhaloderivativesof4H-pyri do [1; 2-a] pyrimidin-4-ones ", Org.Biomol.Chem., 2011,9,6559-6565) report a kind of synthetic method of pyrimidinone compound, its reaction formula is as follows:
As mentioned above, disclose the synthetic method of multiple pyrimidinones in prior art, but these methods still exist certain defect, especially products collection efficiency still has much room for improvement.
Therefore, how simply, high productivity synthesis pyrimidinones, be still the study hotspot in current this field and emphasis, this be also the power place that is accomplished of the present invention and basis lean on.
Summary of the invention
In order to overcome above-mentioned pointed defect and the novel method for synthesizing seeking to synthesize pyrimidinones, present inventor has performed deep research and exploration, after having paid enough creative works, thus completing the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of pyrimidinones shown in a kind of following formula (III), described method comprises: under room temperature, following formula (I) compound, following formula (II) compound, catalyzer, alkali, promotor and auxiliary agent is added in organic solvent, 60-80 DEG C is warming up under oxygen atmosphere, and stirring reaction 6-10 hour, then through aftertreatment, thus obtain described formula (III) compound
Wherein, R
1for H, C
1-C
6alkyl or halogen;
R
2for C
1-C
6alkyl or benzyl;
X is halogen, is preferably Br.
In described synthetic method of the present invention, described C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described synthetic method of the present invention, described halogen is fluorine, chlorine, bromine, atomic iodine.
In described synthetic method of the present invention, described catalyzer is Pd (OAc)
2(acid chloride), Pd (TFA)
2(palladium trifluoroacetate), 1,2-two diphenyl phosphine oxide Palladous chloride (dppePdCl
2), Pd (dpbpf) Cl
2(1,1 '-bis-(two-tertiary butyl phosphine) ferrocene dichloro closes palladium) or PdCl
2(cod) any one in (1,5-cyclooctadiene Palladous chloride), most preferably is Pd (dpbpf) Cl
2.
In described synthetic method of the present invention, described alkali is NaOH, pyridine, sodium carbonate, piperazine, potassium tert.-butoxide, sodium ethylate, 1, any one in 4-diazabicylo [2.2.2] octane (DABCO), tri-isopropanolamine, Dimethylamino pyridine (DMPA), diethanolamine, Tetramethyl Ethylene Diamine, triethylamine etc., most preferably is DABCO.
In described synthetic method of the present invention, described promotor is Cu (OTf)
2(copper trifluoromethanesulfcomposite), Cu (acac)
2(acetylacetone copper), triphenylphosphine cuprous bromide (Cu (PPh
3) Br) or trifluoroacetylacetone copper in any one, most preferably be trifluoroacetylacetone copper.
In described synthetic method of the present invention, described auxiliary agent is N-sulfonic acid butyl-pyridinium tosilate.
In described synthetic method of the present invention, described organic solvent is DMF (N, dinethylformamide) with any one the mixture of selecting oneself in toluene, benzene, ethanol, acetonitrile, NMP (N-Methyl pyrrolidone), chlorobenzene, most preferably be the mixture of DMF and acetonitrile, wherein the volume ratio of DMF and acetonitrile is 2:1.
Wherein, the consumption of described organic solvent strict restriction, and those skilled in the art can carry out suitable selection according to practical situation and determine, such as its consumption size is carried out and aftertreatment to facilitate reaction, is no longer described in detail at this.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1.5-1.9, such as, can be 1:1.5,1:1.7 or 1:1.9.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyzer is 1:0.06-0.1, such as, can be 1:0.06,1:0.08 or 1:1.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and alkali is 1:2-3, such as, can be 1:2,1:2.5 or 1:3.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and promotor is 1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and auxiliary agent is 1:0.15-0.25, such as, can be 1:0.15,1:0.2 or 1:0.25.
In described synthetic method of the present invention, aftertreatment after reaction terminates such as can be as follows: after reaction terminates, filtered by gained mixture, add deionized water in filtrate, abundant vibration washing, then add extraction into ethyl acetate 2-3 time, layering, merge organic phase, then underpressure distillation, gained residue is crossed silica gel column chromatography to be separated, using the ethyl acetate of equal-volume ratio and acetone mixture as elutriant, thus obtain described formula (III) compound.
In sum, the invention provides a kind of synthetic method of pyrimidinones, the method is by the suitable selection of catalyzer, alkali, promotor, auxiliary agent and organic solvent and combination, thus high yield can obtain object product, have a good application prospect in organic synthesis field especially medicine intermediate and industrial production potentiality.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
Under room temperature, to in appropriate organic solvent (for the DMF of volume ratio 2:1 and the mixture of acetonitrile), add 100mmol above formula (I) compound, 150mmol above formula (II) compound, 6mmol catalyst P d (dpbpf) Cl
2, 200mmol alkali DABCO, 10mmol promotor trifluoroacetylacetone copper and 15mmol auxiliary agent N-sulfonic acid butyl-pyridinium tosilate, then continue to pass into oxygen to form oxygen atmosphere in gained system, and be warming up to 60 DEG C, stirring reaction 10 hours;
After reaction terminates, gained mixture is filtered, in filtrate, adds deionized water, abundant vibration washing, then add extraction into ethyl acetate 2-3 time, layering, merge organic phase, then underpressure distillation, gained residue is crossed silica gel column chromatography to be separated, using the ethyl acetate of equal-volume ratio and acetone mixture as elutriant, thus obtain above formula (III) compound (wherein, Bn is benzyl), productive rate is 96.5%.
1HNMR(CDCl
3,400MHz):δ9.12(d,J＝6.8Hz,1H),7.87(d,J＝15.6Hz,1H),7.76(m,1H),7.62(m,1H),7.47-7.33(m,6H),7.18(t,J＝7.0Hz,1H),5.28(s,2H),2.69(s,3H)。
Embodiment 2
Under room temperature, to in appropriate organic solvent (for the DMF of volume ratio 2:1 and the mixture of acetonitrile), add 100mmol above formula (I) compound, 170mmol above formula (II) compound, 8mmol catalyst P d (dpbpf) Cl
2, 250mmol alkali DABCO, 15mmol promotor trifluoroacetylacetone copper and 20mmol auxiliary agent N-sulfonic acid butyl-pyridinium tosilate, then continue to pass into oxygen to form oxygen atmosphere in gained system, and be warming up to 70 DEG C, stirring reaction 8 hours;
After reaction terminates, gained mixture is filtered, in filtrate, adds deionized water, washing of fully vibrating, then extraction into ethyl acetate is added 2-3 time, layering, merges organic phase, then underpressure distillation, gained residue is crossed silica gel column chromatography to be separated, using the ethyl acetate of equal-volume ratio and acetone mixture as elutriant, thus obtain above formula (III) compound, productive rate is 96.3%.
1HNMR(CDCl
3,400MHz):δ9.13(d,J＝7.2Hz,1H),7.88-7.76(m,J＝15.6Hz,J＝6.8Hz,2H),7.64(d,J＝9.2Hz,1H),7.40(d,J＝15.6Hz,1H),7.22(d,J＝6.8Hz,1H),3.81(s,3H),2.72(s,3H)。
MS(EI)m/z:245[M
+]。
Embodiment 3
Under room temperature, to in appropriate organic solvent (for the DMF of volume ratio 2:1 and the mixture of acetonitrile), add 100mmol above formula (I) compound, 190mmol above formula (II) compound, 10mmol catalyst P d (dpbpf) Cl
2, 300mmol alkali DABCO, 20mmol promotor trifluoroacetylacetone copper and 25mmol auxiliary agent N-sulfonic acid butyl-pyridinium tosilate, then continue to pass into oxygen to form oxygen atmosphere in gained system, and be warming up to 80 DEG C, stirring reaction 6 hours;
After reaction terminates, gained mixture is filtered, in filtrate, adds deionized water, washing of fully vibrating, then extraction into ethyl acetate is added 2-3 time, layering, merges organic phase, then underpressure distillation, gained residue is crossed silica gel column chromatography to be separated, using the ethyl acetate of equal-volume ratio and acetone mixture as elutriant, thus obtain above formula (III) compound (wherein n-Bu is normal-butyl), productive rate is 96.6%.
1HNMR(CDCl
3,400MHz):δ9.02(d,J＝7.2Hz,1H),7.81(d,J＝15.2Hz,1H),7.41(s,1H),7.35(d,J＝15.6Hz,1H),7.02(dd,J＝1.6Hz,J＝7.2Hz,1H),4.24(t,J＝6.8Hz,2H),2.68(s,3H),2.53(s,3H),1.72-1.66(m,2H),1.47-1.41(m,2H),0.96(t,J＝7.4Hz,3H)。
Embodiment 4
Under room temperature, to in appropriate organic solvent (for the DMF of volume ratio 2:1 and the mixture of acetonitrile), add 100mmol above formula (I) compound, 160mmol above formula (II) compound, 9mmol catalyst P d (dpbpf) Cl
2, 240mmol alkali DABCO, 18mmol promotor trifluoroacetylacetone copper and 17mmol auxiliary agent N-sulfonic acid butyl-pyridinium tosilate, then continue to pass into oxygen to form oxygen atmosphere in gained system, and be warming up to 65 DEG C, stirring reaction 9 hours;
After reaction terminates, gained mixture is filtered, in filtrate, adds deionized water, washing of fully vibrating, then extraction into ethyl acetate is added 2-3 time, layering, merges organic phase, then underpressure distillation, gained residue is crossed silica gel column chromatography to be separated, using the ethyl acetate of equal-volume ratio and acetone mixture as elutriant, thus obtain above formula (III) compound (wherein n-Bu is normal-butyl), productive rate is 96.1%.
1HNMR(CDCl
3,400MHz):δ9.11(d,J＝2.0Hz,1H),7.82(d,J＝15.6Hz,1H),7.72(dd,J＝2.4Hz,J＝9.2Hz,1H),7.54(d,J＝9.2Hz,1H),7.36(d,J＝15.2Hz,1H),4.23(t,J＝6.6Hz,2H),2.69(s,3H),1.73-1.65(m,2H),1.49-1.38(m,2H),0.95(t,J＝7.2Hz,3H)。
Embodiment 5-20
Embodiment 5-8: except catalyzer is replaced with Pd (OAc)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 5-8.
Embodiment 9-12: except catalyzer is replaced with Pd (TFA)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 9-12.
Embodiment 13-16: except catalyzer is replaced with dppePdCl
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 13-16.
Embodiment 17-20: except catalyzer is replaced with PdCl
2(cod) outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 17-20.
The results are shown in following table 1.
Table 1
From upper table 1 data, in all catalyzer, Pd (dpbpf) Cl
2have best catalytic effect, the effect of other catalyzer is all not as Pd (dpbpf) Cl
2catalytic effect, therefore as catalyzer, most preferably Pd (dpbpf) Cl
2.
Embodiment 21-31
Except adopting different alkali, other operation is all constant, thus is repeated embodiment 1-4, and obtain embodiment 21-31, the alkali used, embodiment corresponding relation and products collection efficiency are shown in subscript 2.
Table 2
As can be seen here, in alkali used in the present invention, DABCO has best effect, and other alkali is all to products collection efficiency decrease to some degree.
Embodiment 32-47
Embodiment 32-35: except promotor is replaced with Cu (OTf)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 32-35.
Embodiment 36-39: except promotor is replaced with Cu (acac)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 36-39.
Embodiment 40-43: except promotor is replaced with Cu (PPh
3) outside Br, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 40-43.
Embodiment 44-47: except promotor being omitted, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 44-47.
The results are shown in following table 3.
Table 3
From upper table 3, when not using any promotor, productive rate is sharply reduced to about 80%, and when using trifluoroacetylacetone copper, productive rate is then significantly improved (see embodiment 1-4), the effect of other promotor is then more or less the same with effect when not using promotor, even if the Cu very similar with trifluoroacetylacetone copper (acac)
2(acetylacetone copper) is also like this, this demonstrate that trifluoroacetylacetone copper has beyond thought promoter action.
Embodiment 48-51
Except auxiliary agent is omitted, other operation is all constant, thus be repeated embodiment 1-4, obtain embodiment 48-51, the productive rate of discovery product is 91.4-92.3%, than using N-sulfonic acid butyl-pyridinium tosilate as decrease to some degree during auxiliary agent, this proves that N-sulfonic acid butyl-pyridinium tosilate has gone to the positive effect improving productive rate.
Embodiment 52-56
Replace with except following component except by the acetonitrile in organic solvent, other operation is all constant, thus is repeated embodiment 1-4, and obtain embodiment 52-56, the component used, corresponding embodiment and products collection efficiency see the following form 4.
Table 4
As can be seen here, only have and use the mixture of DMF and acetonitrile as organic solvent, just can obtain high yield of the present invention.And when acetonitrile being replaced with other solvent composition, productive rate all has obvious reduction.
Embodiment 57-64
Proceed to investigate to solvent.
Embodiment 57-60: only use one-component solvent DMF, other operation is all constant, repeats to implement embodiment 1-4, obtains embodiment 57-60.
Embodiment 61-64: only use one-component solvent acetonitrile, other operation is all constant, repeats to implement embodiment 1-4, obtains embodiment 61-64.
The results are shown in following table 5.
Table 5
As can be seen here, when being used alone DMF or acetonitrile, productive rate all will lower than use both mixture time, this prove when use both mixture as solvent time, there is best solvent effect.
In sum, the invention provides a kind of synthetic method of pyrimidinones, the method is by the suitable selection of catalyzer, alkali, promotor, auxiliary agent and organic solvent and combination, thus high yield can obtain object product, have a good application prospect in organic synthesis field especially medicine intermediate and industrial production potentiality.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. the synthetic method of pyrimidinones shown in a following formula (III), described method comprises: under room temperature, following formula (I) compound, following formula (II) compound, catalyzer, alkali, promotor and auxiliary agent is added in organic solvent, 60-80 DEG C is warming up under oxygen atmosphere, and stirring reaction 6-10 hour, then through aftertreatment, thus described formula (III) compound is obtained
Wherein, R
1for H, C
1-C
6alkyl or halogen;
R
2for C
1-C
6alkyl or benzyl;
X is halogen.
2. synthetic method as claimed in claim 1, is characterized in that: described catalyzer is Pd (OAc)
2(acid chloride), Pd (TFA)
2(palladium trifluoroacetate), 1,2-two diphenyl phosphine oxide Palladous chloride (dppePdCl
2), Pd (dpbpf) Cl
2(1,1 '-bis-(two-tertiary butyl phosphine) ferrocene dichloro closes palladium) or PdCl
2(cod) any one in (1,5-cyclooctadiene Palladous chloride), most preferably is Pd (dpbpf) Cl
2.
3. synthetic method as claimed in claim 2, it is characterized in that: described alkali is NaOH, pyridine, sodium carbonate, piperazine, potassium tert.-butoxide, sodium ethylate, 1, any one in 4-diazabicylo [2.2.2] octane (DABCO), tri-isopropanolamine, Dimethylamino pyridine (DMPA), diethanolamine, Tetramethyl Ethylene Diamine, triethylamine etc., most preferably is DABCO.
4. the synthetic method as described in any one of claim 1-3, is characterized in that: described promotor is Cu (OTf)
2(copper trifluoromethanesulfcomposite), Cu (acac)
2(acetylacetone copper), triphenylphosphine cuprous bromide (Cu (PPh
3) Br) or trifluoroacetylacetone copper in any one, most preferably be trifluoroacetylacetone copper.
5. the synthetic method as described in any one of claim 1-4, is characterized in that: described auxiliary agent is N-sulfonic acid butyl-pyridinium tosilate.
6. the synthetic method as described in any one of claim 1-5, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1.5-1.9.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is 1:0.06-0.1.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described formula (I) compound and alkali is 1:2-3.
9. the synthetic method as described in any one of claim 1-8, is characterized in that: the mol ratio of described formula (I) compound and promotor is 1:0.1-0.2.
10. the synthetic method as described in any one of claim 1-9, is characterized in that: the mol ratio of described formula (I) compound and auxiliary agent is 1:0.15-0.25.
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| WO2015053232A1 (en) * | 2013-10-07 | 2015-04-16 | 日産化学工業株式会社 | Liquid-crystal alignment agent, liquid-crystal alignment film, and liquid-crystal display element |
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Application publication date: 20151216 |