CN1181049C - Alpha-alkylacyl-beta-substituted benzoyl-beta-phenylpropionyl aniline and its synthesis and use - Google Patents
Alpha-alkylacyl-beta-substituted benzoyl-beta-phenylpropionyl aniline and its synthesis and use Download PDFInfo
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Abstract
The present invention relates to alpha-alkylacyl-beta-substituted benzoyl-beta-benzyl acetophenoneamine whose molecular formula is shown as the right formula in the specification, wherein R1=H, F, Cl, CH3, CH2CH3, C(CH3), OCH3; R2=CH3, CH(CH3)2. When R1=F, R2 is not equal to CH(CH3)2. The compound is prepared from phenylacetic acid as a raw material by acyl chlorination, friedel-crafts reaction bromination and a substitution coupling reaction. The present invention is not only suitable for the synthesis of the compound in which R2=CH(CH3)2 when R1=F, but also has the advantages of easy obtainment of raw material, low cost, mild condition and easy operation. The present invention is suitable for industrial production.
Description
The present invention relates to a class 1,4-dicarbonyl compound, synthetic and purposes, i.e. α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its, synthetic and purposes.
1, the 4-dicarbonyl compound is the important organic synthesis intermediate of a class, and especially for the preparation of pyrrole derivatives, utilizing this compounds and primary amine to close ring is a kind of method that is most widely used.Such as hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor Atorvastatin; the most effective up to now a kind of reducing blood-fat compound; it promptly is a kind of unitary compound of pyrrole structure that contains; its synthetic precursor is 1,4-dicarbonyl compound α-isobutyryl-β-and to fluorobenzene acyl group-β-phenylpropionyl aniline and its.Document [Tetrahedron Lett.; 1992; 33 (17), 2283~2284] α-isobutyryl-β-to the synthetic method of fluorobenzene acyl group-β-phenylpropionyl aniline and its, wherein need react through 2-isobutyryl-3-phenylacryloyl aniline Stetter with p-Fluorobenzenecarboxaldehyde is disclosed.This step reaction needs the thiazole salt derivative of 20% molar weight to make catalyzer, and cost is higher, and severe reaction conditions, and from our experimental result, its yield is not high, and repeatability also is not fine.So, necessaryly seek more effective and cheap route of synthesis and prepare this compound, be that the blood lipid-lowering medicine of composition is (as Lipitor with Atorvastatin particularly, Sortis etc.) successfully listing, and become the today of the main flow blood lipid-lowering medicine on the world market day by day, this work outstanding tool meaning that seems.So synthetic α-isobutyryl-β-to more economic, the novel method easily of fluorobenzene acyl group-β-phenylpropionyl aniline and its is developed in people expectation.
One of purpose of the present invention provides α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its.
Two of purpose of the present invention provides the method for synthetic α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its.And this method can be used as the universal method of synthetic this compounds.Utilize this method can synthesize a series of 1 of bibliographical informations of not seeing, 4-dicarbonyl compound.
Three of purpose of the present invention provides the purposes of above-mentioned α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its.
α-alkyloyl of the present invention-beta substitution benzoyl group-β-phenylpropionyl aniline and its has following molecular formula:
Wherein, R
1=H, F, Cl, CH
3, CH
2CH
3, C (CH
3)
3, OCH
3, R
2=CH
3, CH (CH
3)
2. and work as R
1During=F, R
2≠ CH (CH
3)
2
Method of the present invention is to be that raw material makes its chloride derivative with the toluylic acid earlier, carries out friedel-crafts reaction with substituted benzene compound then, obtains 1-substituted-phenyl-2-methyl phenyl ketone.This compound bromination is obtained 2-bromo-1-substituted-phenyl-2-methyl phenyl ketone, under alkaline condition, react then, make target product with the alkyloyl Acetanilide.Its reaction formula is as follows:
Wherein: R
1=H, F, Cl, CH
3, CH
2CH
3, C (CH
3)
3, OCH
3R
2=CH
3, CH (CH
3)
2, and work as R
1During=F, R
2≠ CH (CH
3)
2
In the reaction formula, 1: chloride; 2: friedel-crafts reaction 1; 3: bromination; 4: replace linked reaction.
Specifically, synthetic method provided by the present invention is: acyl chloride reaction is in solvent and room temperature-during reflux temperature, and as raw material and chloride reagent reaction 1-6 hour, described chloride reagent was SOCl with toluylic acid
2, PCl
3, PCl
5Or POCl
3, wherein toluylic acid and chloride reagent mol ratio are 1: 0.5-5.The mol ratio of recommending is 1: 1.0-1.5, and temperature of reaction is 60~90 ℃, the time is 2~3 hours.
Friedel-crafts reaction is to be raw material with above-mentioned acyl chloride reaction gained phenyllacetyl chloride, and molecular formula is
Substituted benzene as aromatic yl reagent-ing, in solvent and under the lewis acidic katalysis,, obtain molecular formula and be in 0-50 ℃ of reaction 1-24 hour
1-substituted-phenyl-2-methyl phenyl ketone, wherein the mol ratio of phenyllacetyl chloride, substituted benzene and catalyzer is 1: 0.5-5: 0.8-2.Described Lewis acid is aluminum trichloride (anhydrous), tin chloride etc.
With 1-substituted-phenyl-2-methyl phenyl ketone is raw material, uses Br
2, Br
2/ Fe or N-bromo-succinimide (NBS) are as bromizating agent, and benzoyl peroxide or azo diisopropyl nitrile are as initiator, and the mol ratio of 1-substituted-phenyl-2-methyl phenyl ketone, bromizating agent and initiator is 1: 1-4: 0-0.02, temperature of reaction is a room temperature-90 ℃.React after 0.5-24 hour and to generate molecular formula and be
2-bromo-1-substituted-phenyl-2-methyl phenyl ketone.Wherein, utilize Br
2/ Fe is in the bromination reaction of bromide reagent, and iron powder and liquid bromine mol ratio are 1: 0.4-2, and the optimal reaction temperature scope is 40-70 ℃, Best Times is 1-3 hour.When utilizing NBS for the bromination reaction of bromizating agent, need add initiator, 1-is 1 to the optimum mole ratio of fluorophenyl-2-methyl phenyl ketone, NBS and initiator: 1-2: 0.001-0.02, and the optimal reaction temperature scope is 70-85 ℃, Best Times is 3-5 hour.
With 2-bromo-1-substituted-phenyl-2-methyl phenyl ketone is raw material, with molecular formula is
The isobutyryl Acetanilide under mineral alkali and solvent action, take place to replace linked reaction, obtain α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its.Wherein the mol ratio of 2-bromo-1-substituted-phenyl-2-methyl phenyl ketone, isobutyryl Acetanilide and mineral alkali is 1: 1-5: 0-2.The favourable reaction that exists of mineral alkali is carried out, and recommending the mol ratio of 2-bromo-1-substituted-phenyl-2-methyl phenyl ketone and mineral alkali is 1: 1-2.Temperature of reaction is a room temperature to 100 ℃, and the reaction times is 2-24 hour.The optimal reaction temperature scope is 25-40 ℃, and Best Times is 5-12 hour.Described mineral alkali is NaH, NaOMe, NaOEt, Na, K, KH or KOMe etc.Solvent described in the above-mentioned reaction can be ether, sherwood oil, methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, hexane, heptane, octane, hexanaphthene, tetrahydrofuran (THF) (THF), N, the mixed solvent of any in dinethylformamide (DMF), benzene or the toluene or above-mentioned solvent.
The prolongation reaction times does not all have influence to reaction in above-mentioned each reaction.
The present invention is for preparation α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its; compared with prior art; expensive and the severe condition of bringing by the Stetter reaction have been overcome; have advantages such as reaction raw materials is easy to get, cost is low, mild condition, reaction easy handling, especially be easy to suitability for industrialized production.Wherein for preparation 1-substituted-phenyl-2-acetophenone compounds, the present invention passes through the Grignard reaction than common employing, and method such as oxidation then obviously has mild condition, easy to operate advantage.
Following examples help to understand the present invention, but are not limited to content of the present invention:
Embodiment 1
α-isobutyryl-β-to the preparation of fluorobenzene acyl group-β-phenylpropionyl aniline and its
1, chloride: reflux condensing tube, CaCl are being housed
2Drying tube and alkali lye absorption unit 1 liter of there-necked flask in, add 1mol toluylic acid, 250ml ethylene dichloride or hexanaphthene, stirring and refluxing drips 1~2mol sulfur oxychloride, drips off the back and refluxes 2~5 hours.Normal pressure heats up in a steamer ethylene dichloride and excessive sulfur oxychloride then, and the cut 136g of 105 ℃~107 ℃/17mmHg, yield 90% are collected in underpressure distillation again.
2, friedel-crafts reaction: CaCl is housed one
2In the 250ml there-necked flask of drying tube and alkali lye absorption unit, add 0.2mol phenyllacetyl chloride, 0.2~3mol fluorobenzene and 50ml methylene dichloride, N
2Gas shiled adds 0.2~3mol AlCl in batches under the room temperature
3, or add 0.2~3mol tin chloride, added in about 1 hour, at room temperature stir then and spend the night or 40 ℃ of reactions 5~10 hours, slowly pour reaction solution into excessive N aHCO
3In the aqueous solution, tell water, with dichloromethane extraction (50ml * 2).Merge all oil phases, through anhydrous Na
2SO
4Drying, desolventizing obtains yellow solid.Heavy brilliant with sherwood oil, get faint yellow solid 37g, 63~65 ℃ of fusing points, yield 86%.
3, bromination:
Method one: be equipped with in the there-necked flask of reflux condensing tube and alkali lye absorption unit 250ml one, add 60mmol 1-to fluorophenyl-2-methyl phenyl ketone, 100ml tetracol phenixin and 40~90mmol iron powder, the oil bath heating, stirring is warming up to 50~70 ℃, slowly drips the 50ml carbon tetrachloride solution of 62mmol liquid bromine.Dripping off the back stirred 1 hour at 40~60 ℃.Cooling is filtered, and filtrate is used Na successively
2SO
3The aqueous solution and water washing, behind anhydrous sodium sulfate drying, desolventizing obtains yellow oil 16g.This oily matter can be not purified, is directly used in the next step.
Method two: be equipped with in the 250ml there-necked flask of reflux condensing tube one, add 60mmol 1-to fluorophenyl-2-methyl phenyl ketone, 100 milliliters of tetracol phenixin and 50~80mmol NBS and 0.1~0.6g benzoyl peroxide, stirring and refluxing 1~4 hour.Cooling is filtered, and filtrate removes tetracol phenixin, obtains yellow oil 17g.This oily matter can be not purified, is directly used in the next step.
4, replace linked reaction: under the nitrogen protection; in an exsiccant 250ml there-necked flask, add 30~100mmol sodium hydride or potassium; slowly splash into the solution of 60~80mmol isobutyryl Acetanilide and 100ml dry THF under the room temperature; dripped off in about 30 minutes; at room temperature stirred then 30 minutes, and obtained a clarifying reaction liquid.60mmol 2-bromo-1-is slowly splashed into the solution of fluorophenyl-2-methyl phenyl ketone and 50ml dry THF, at room temperature stir then and spend the night.Add the Sodium Bromide that water dissolution generates, separatory, water merges oil phase, desolventizing with dichloromethane extraction (50ml * 2).The resistates ethyl alcohol recrystallization obtains white crystal 20.6g.207~209 ℃ of fusing points.Yield 82%.Do not add mineral alkali, yield is 61%
C
26H
24FNO
3Calculated value: C 74.80, H 5.79, and N 3.36
417.48 measured value: C 74.51, H 5.26, and N 3.75
IR(KCl),ν(cm
-1):3260,1730,1700,1668,1592,1500,1443。
1H NMR(CDCl
3,300MHz),δ(ppm):1.05(d,3H),1.24(d,3H),3.00(m,1H),4.90(d,1H),5.53(d,1H),6.97~7.42(m,12H),8.17(dd,2H),9.40(br,1H)。
19F NMR(TFA),δ(ppm):29。
MS(EI),m/e(%):417(M
+,50)。
Embodiment 2
Reaction conditions such as embodiment 1, used different reaction raw materials and result such as following table:
The product sequence number | R 1 | R 2 | Replace the linked reaction yield |
1 | H | CH 3 | 75 |
2 | F | CH 3 | 86 |
3 | Cl | CH 3 | 69 |
4 | CH 3 | CH 3 | 88 |
5 | CH 2CH 3 | CH 3 | 84 |
6 | C(CH 3) 3 | CH 3 | 72 |
7 | OCH 3 | CH 3 | 77 |
8 | H | CH(CH 3) 2 | 80 |
9 | Cl | CH(CH 3) 2 | 71 |
10 | CH 3 | CH(CH 3) 2 | 87 |
11 | CH 2CH 3 | CH(CH 3) 2 | 85 |
12 | C(CH 3) 3 | CH(CH 3) 2 | 78 |
13 | OCH 3 | CH(CH 3) 2 | 70 |
Spectral data:
Product 1:
C
24H
21NO
3Calculated value: C 77.61, H 5.70, and N 3.77
371.44 measured value: C 77.84, H 5.53, and N 3.49
IR(KCl),ν(cm
-1):3267,1730,1717,1655,1595,1508,1450。
1H NMR(CDCl
3,300MHz),δ(ppm):2.30(s,3H),4.11(d,1H),5.38(d,1H),7.06~7.70(m,15H),9.25(br,1H)。
MS(EI),m/e(%):371(M
+,60)。
Product 2:
C
24H
20FNO
3Calculated value: C 74.02, H 5.18, and N 3.60
389.43 measured value: C 73.90, H 5.44, and N 3.73
IR(KCl),ν(cm
-1):3275,1738,1704,1665,1582,1501,1443。
1H NMR(CDCl
3,300MHz),δ(ppm):2.31(s,3H),4.21(d,1H),5.45(d,1H),6.91~7.47(m,12H),8.09(dd,2H),9.33(br,1H)。
19F NMR(TFA),δ(ppm):28。
MS(EI),m/e(%):389(M
+,20)。
Product 3:
C
24H
20ClNO
3Calculated value: C 71.02, H 4.97, and N 3.45
405.88 measured value: C 71.66, H 4.70, and N 3.35
IR(KCl),ν(cm
-1):3286,1731,1718,1650,1580,1499,1441。
1H NMR(CDCl
3,300MHz),δ(ppm):2.30(s,3H),4.89(d,1H),5.55(d,1H),7.24~7.47(m,12H),7.89(dd,2H),9.10(br,1H)。
MS(EI),m/e(%):406(M
+,25)。
Product 4:
C
25H
23NO
3Calculated value: C 77.90, H 6.01, and N 3.63
385.47 measured value: C 77.52, H 5.86, and N 3.69
IR(KCl),ν(cm
-1):3273,1725,1710,1665,1596,1515,1453。
1H NMR(CDCl
3,300MHz),δ(ppm):2.30(s,3H),2.37(s,3H),4.54(d,1H),5.39(d,1H),7.16~7.50(m,12H),7.96(dd,2H),9.37(br,1H)。
MS(EI),m/e(%):385(M
+,50)。
Product 5:
C
26H
25NO
3Calculated value: C 78.17, H 6.31, and N 3.51
399.49 measured value: C 78.51, H 6.04, and N 3.55
IR(KCl),ν(cm
-1):3263,1732,1711,1665,1587,1500,1439。
1H NMR(CDCl
3,300MHz),δ(ppm):1.16(t,3H),2.50(q,2H),2.30(s,3H),4.81(d,1H),5.47(d,1H),7.21~7.50(m,12H),7.95(dd,2H),9.41(br,1H)。
MS(EI),m/e(%):399(M
+,30)。
Product 6:
C
28H
29NO
3Calculated value: C 78.66, H 6.84, and N 3.28
427.55 measured value: C 78.88, H 6.59, and N 3.03
IR(KCl),ν(cm
-1):3278,1730,1706,1665,1543,1500,1445。
1H NMR(CDCl
3,300MHz),δ(ppm):1.35(s,9H),2.31(s,3H),4.90(d,1H),5.53(d,1H),7.21~7.49(m,12H),8.18(dd,2H),9.33(br,1H)。
MS(EI),m/e(%):427(M
+,25)。
Product 7:
C
25H
23NO
4Calculated value: C 74.80, H 5.77, and N 3.49
401.47 measured value: C 74.50, H 5.49, and N 3.61
IR(KCl),ν(cm
-1):3266,1731,1708,1666,1596,1517,1437。
1H NMR(CDCl
3,300MHz),δ(ppm):2.32(s,3H),3.76(s,3H),4.77(d,1H),5.46(d,1H),6.82(dd,2H),7.21~7.47(m,10H),8.20(dd,2H),9.40(br,1H)。
MS(EI),m/e(%):401(M
+,40)。
Product 8:
C
26H
25NO
3Calculated value: C 78.17, H 6.31, and N 3.51
399.49 measured value: C 78.24, H 6.00, and N 3.68
IR(KCl),ν(cm
-1):3260,1730,1700,1665,1590,1500,1445。
1H NMR(CDCl
3,300MHz),δ(ppm):1.05(d,3H),1.24(d,3H),3.02(m,1H),4.91(d,1H),5.53(d,1H),7.10~7.71(m,15H),9.29(br,1H)。
MS(EI),m/e(%):399(M
+,50)。
Product 9:
C
26H
24ClNO
3Calculated value: C 71.97, H 5.57, and N 3.23
433.94 measured value: C 71.72, H 5.80, and N 3.04
IR(KCl),ν(cm
-1):3282,1739,1709,1665,1590,1511,1449。
1H NMR(CDCl
3,300MHz),δ(ppm):1.07(d,3H),1.31(d,3H),2.98(m,1H),4.88(d,1H),5.49(d,1H),6.97~7.42(m,12H),8.11(dd,2H),9.35(br,1H)。
MS(EI),m/e(%):434(M
+,60)。
Product 10:
C
27H
27NO
3Calculated value: C 78.42, H 6.58, and N 3.39
413.52 measured value: C 78.33, H 6.79, and N 3.18
IR(KCl),ν(cm
-1):3268,1728,1703,1663,1589,1520,1450。
1H NMR(CDCl
3,300MHz),δ(ppm):1.06(d,3H),1.24(d,3H),2.37(s,3H),3.02(m,1H),4.91(d,1H),5.53(d,1H),7.00~7.44(m,12H),7.89(dd,2H),9.36(br,1H)。
MS(EI),m/e(%):413(M
+,45)。
Product 11:
C
28H
29NO
3Calculated value: C 78.66, H 6.84, and N 3.28
427.55 measured value: C 78.53, H 6.95, and N 3.27
IR(KCl),ν(cm
-1):3264,1733,1717,1672,1599,1498,1445。
1H NMR(CDCl
3,300MHz),δ(ppm):1.06~1.25(m,9H),2.48(q,2H),3.00(m,1H),4.90(d,1H),5.52(d,1H),7.10~7.45(m,12H),8.08(dd,2H),9.33(br,1H)。
MS(EI),m/e(%):427(M
+,30)。
Product 12:
C
30H
33NO
3Calculated value: C 79.09, H 7.30, and N 3.07
455.60 measured value: C 79.38, H 7.22, and N 2.85
IR(KCl),ν(cm
-1):3277,1728,1701,1658,1595,1507,1444。
1H NMR(CDCl
3,300MHz),δ(ppm):1.05(d,3H),1.24(d,3H),1.38(s,9H),3.03(m,1H),4.89(d,1H),5.50(d,1H),6.99~7.48(m,12H),8.16(dd,2H),9.42(br,1H)。
MS(EI),m/e(%):455(M
+,20)。
Product 13:
C
27H
27NO
4Calculated value: C 75.50, H 6.34, and N 3.26
429.52 measured value: C 75.17, H 6.55, and N 3.36
IR(KCl),ν(cm
-1):3259,1741,1707,1669,1591,1500,1446。
1H NMR(CDCl
3,300MHz),δ(ppm):1.03(d,3H),1.25(d,3H),3.00(m,1H),3.89(s,3H),4.90(d,1H),5.51(d,1H),6.91~7.43(m,12H),8.10(dd,2H),9.38(br,1H)。
MS(EI),m/e(%):429(M
+,30)。
Claims (9)
2. the synthetic method of α-alkyloyl as claimed in claim 1-beta substitution benzoyl group-β-phenylpropionyl aniline and its, α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its has following molecular formula:
Wherein, R
1=H, F, Cl, CH
3, CH
2CH
3, C (CH
3)
3Or OCH
3, R
2=CH
3Or CH (CH
3)
2It is characterized in that comprising the steps:
Acyl chloride reaction: in solvent neutralization reaction temperature is room temperature~reflux temperature, and the mol ratio of toluylic acid and chloride reagent is 1: 0.5~5 o'clock, reacts 1-6 hour, and described chloride reagent is SOCl
2, PCl
3, PCl
5Or POCl
3
Friedel-crafts reaction: in solvent neutralization reaction temperature is 0-50 ℃, and phenyllacetyl chloride and molecular formula are
Substituted benzene as aromatic yl reagent-ing, reaction is 1-24 hour under lewis acidic katalysis, obtains molecular formula and is
1-substituted-phenyl-2-methyl phenyl ketone, wherein the mol ratio of phenyllacetyl chloride, substituted benzene and catalyzer is 1: 0.5~5: 0.8~2;
Bromination reaction: in solvent and room temperature~90 ℃, the mol ratio of 1-substituted-phenyl-2-methyl phenyl ketone, bromide reagent and initiator is reaction in 1: 1~4: 0~0.02 o'clock 0.5-24 hour, generates molecular formula and is
2-bromo-1-substituted-phenyl-2-methyl phenyl ketone, described bromizating agent is Br
2, Br
2/ Fe or N-bromo-succinimide, described initiator are benzoyl peroxide or azo diisopropyl nitrile;
Replace linked reaction: in solvent and under the mineral alkali effect, 2-bromo-1-substituted-phenyl-2-methyl phenyl ketone and molecular formula are
The reaction 2~24 hours when room temperature to 100 ℃ of alkyloyl Acetanilide; obtain α-alkyloyl-beta substitution benzoyl group-β-phenylpropionyl aniline and its, wherein the mol ratio of 2-bromo-1-substituted-phenyl-2-methyl phenyl ketone, alkyloyl Acetanilide and mineral alkali is 1: 1~5: 0~2.
3. synthetic α-alkyloyl as claimed in claim 2-β-, it is characterized in that adopting Br in the described bromination reaction to the method for fluorobenzene acyl group-β-phenylpropionyl aniline and its
2When/Fe is bromide reagent, Fe and Br
2Mol ratio be 1: 0.4~2.
4. the method for synthetic α-alkyloyl as claimed in claim 2-beta substitution benzoyl group-β-phenylpropionyl aniline and its; when it is characterized in that adopting in the described bromination reaction N-bromo-succinimide to be bromide reagent, the mol ratio of 1-substituted-phenyl-2-methyl phenyl ketone, bromide reagent and initiator is 1: 1~2: 0.001~0.02.
5. the method for synthetic α-alkyloyl as claimed in claim 2-beta substitution benzoyl group-β-phenylpropionyl aniline and its is characterized in that described Lewis acid is aluminum trichloride (anhydrous) or tin chloride.
6. the method for synthetic α-alkyloyl as claimed in claim 2-beta substitution benzoyl group-β-phenylpropionyl aniline and its is characterized in that described mineral alkali is NaH, KH, NaOMe, NaOEt, Na, K or KOMe.
7. the method for synthetic α-alkyloyl as claimed in claim 2-beta substitution benzoyl group-β-phenylpropionyl aniline and its; it is characterized in that described solvent is ether, sherwood oil, methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, hexane, heptane, octane, hexanaphthene, tetrahydrofuran (THF), N, the mixed solvent of any in dinethylformamide, benzene, the toluene or above-mentioned solvent.
8. the purposes of α-alkyloyl as claimed in claim 1-beta substitution benzoyl group-β-phenylpropionyl aniline and its is characterized in that being used to prepare pyrrole derivatives.
9. the purposes of α-alkyloyl as claimed in claim 1-beta substitution benzoyl group-β-phenylpropionyl aniline and its is characterized in that being used to prepare hypolipemic preparation.
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JP2008510797A (en) * | 2004-08-26 | 2008-04-10 | バイオコン・リミテッド | Process for producing 4-fluoro-α- [2-methyl-1-oxopropyl] γ-oxo-N-β-diphenylbenzenebutanamide |
CN101306988B (en) * | 2007-05-15 | 2011-11-30 | 浙江京新药业股份有限公司 | New method for synthesizing alpha-brom-4-fluoro phenylpropiophenone |
CN104892409B (en) * | 2015-04-16 | 2018-08-28 | 巨化集团技术中心 | A kind of general formula is CH3The synthetic method containing bromo-ester of CXBrCOOR |
CN104829450B (en) * | 2015-04-16 | 2018-08-03 | 巨化集团技术中心 | A kind of preparation method containing bromo-ester |
CN106397296B (en) * | 2016-08-29 | 2019-03-19 | 江苏阿尔法药业有限公司 | A kind of preparation process of Atorvastatin calcium |
CN113480517B (en) * | 2021-07-30 | 2022-09-09 | 海南海神同洲制药有限公司 | Synthetic method of 3-bromomethyl-7-chlorobenzo [ b ] thiophene |
CN114195670B (en) * | 2021-12-31 | 2024-03-15 | 河南豫辰药业股份有限公司 | Refining method of atorvastatin mother nucleus M4 |
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