CN109180648B - 7-alkyl-N-pyrimidine indoline compound and synthetic method thereof - Google Patents

7-alkyl-N-pyrimidine indoline compound and synthetic method thereof Download PDF

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CN109180648B
CN109180648B CN201811299498.0A CN201811299498A CN109180648B CN 109180648 B CN109180648 B CN 109180648B CN 201811299498 A CN201811299498 A CN 201811299498A CN 109180648 B CN109180648 B CN 109180648B
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朱新举
王秋灵
支昌磊
李静
刘爽
赵雪梅
郝新奇
宋毛平
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Zhengzhou University
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract

The invention discloses a 7-alkyl-N-pyrimidine indoline compound and a synthesis method thereof, wherein the structural general formula of the 7-alkyl-N-pyrimidine indoline compound is as follows:
Figure DDA0001851974300000011
the preparation method comprises the following steps: under argon atmosphere, adding N-pyrimidine indoline compound ethylene cyclopropane compound into a reaction tube, adding 1-adamantane carboxylic acid, [ Cp ] Rh (CH)3CN)3](SbF6)2Adding methanol into silver hexafluoroantimonate, and reacting for 12 hours at 80-120 ℃; and after the reaction is finished, leaching, separating by thin-layer chromatography, and drying to obtain a target product. According to the invention, metal rhodium (III) is used as a catalyst, methanol is used as a reaction solvent, the carbon-carbon bond breakage of vinyl cyclopropane and the 7-position carbon-hydrogen bond activation of indoline compounds are realized, and meanwhile, the long alkyl chain with double bonds can also realize further functional group reaction.

Description

7-alkyl-N-pyrimidine indoline compound and synthetic method thereof
Technical Field
The invention belongs to the technical field of synthesis and application of organic compounds, and particularly relates to a preparation method of a 7-alkyl-N-pyrimidine indoline compound.
Background
Indoline, also known as 2, 3-indoline, is a product obtained by hydrogenation of indole at the 2,3 position and is a bicyclic organic Heterocyclic compound (Comprehensive Heterocyclic Chemistry III) having aromatic properties. Indoline derivatives are used as characteristic structure fragments of a plurality of natural products and novel medicaments with biological activity, and the derivatives have good biological activity: for example, antiarrhythmic effect, treatment of glaucoma, prevention and treatment of cerebral ischemia, anti-tumor, etc. (org.Lett.2014,3, 345-348; J.Am.chem.Soc.2009,131, 8758-8759; org.Lett.2003,5, 269-271; org.Lett.2007,9, 279-282). Several classes of drugs have been successfully marketed, such as Pentopril (Pentopril), a peroxisome proliferator-activated receptor (PPAR α/γ), a liver X receptor modulator, mochida, et al (J.Clin.Pharm.1986,26, 156-164; Annu.Rev.Med.2002,53, 409-435; J.Clin.invest.2006,116, 607-614; J.Med.chem.1983,26, 394-403) which are potent drugs for the treatment of hypertension. In recent years, the study on the functionalization reaction of indoline is becoming mature, but the study on the naphthenation reaction of indoline and ethylene cyclopropane is rarely reported.
Vinylcyclopropane (VCP) is a five-carbon synthon with a carbon-carbon double bond directly connected to cyclopropane, and since cyclopropane and vinyl both belong to highly reactive functional groups, nucleophilic attack can be accepted, the reaction can generate certain regioselectivity to obtain 1,3 addition product and 1,5 addition product (Angew. chem. int. Ed.2016,55, 7408-42-type 7412; chem. Sci.2017,8, 3379-type 3383; chem. Commun.2015,51, 77-80; chem. Eur. J.2017,23, 5443-type 5447), and a series of heterocyclic compounds are synthesized. This reaction simultaneously achieves carbon-carbon cleavage of the vinylcyclopropane and carbon-hydrogen bond activation at the 7-position of the N-pyrimidineindoline. The method has important significance for the research of the alkylation reaction and the application of the synthetic belt with long chain.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a synthesis and preparation method of a 7-alkyl-N-pyrimidine indoline compound, which is simple and feasible and has better selectivity.
In order to solve the technical problems, the invention adopts the following technical scheme:
A7-alkyl-N-pyrimidine indoline compound has a structural general formula as follows:
Figure BDA0001851974290000021
wherein R is1Hydrogen, alkyl, alkoxy, ester group, halogen; EWG is carbonyl, methyl ester, ethyl ester, butyl ester, benzyl ester, acetonitrile.
The 7-alkyl-N-pyrimidines of the inventionThe preparation method of the indoline compound comprises the following steps: under the argon atmosphere, adding N-pyrimidine indoline compound and ethylene cyclopropane compound into a reaction tube, adding 1-adamantane carboxylic acid, [ Cp ] Rh (CH)3CN)3](SbF6)2Adding methanol into silver hexafluoroantimonate, and reacting for 12 hours at 80-120 ℃; after the reaction is finished, leaching, separating by thin-layer chromatography and drying to obtain a target product, wherein the reaction equation is as follows:
Figure BDA0001851974290000022
the general formula of the N-pyrimidine indoline compound is as follows:
Figure BDA0001851974290000031
the general structural formula of the vinyl cyclopropane compound is as follows:
wherein R is1Hydrogen, alkyl, alkoxy, ester group, halogen; EWG is carbonyl, methyl ester, ethyl ester, butyl ester, benzyl ester, acetonitrile.
The mass ratio of the N-pyrimidine indoline compound to the ethylene cyclopropane compound with the electron withdrawing group is 1 (1-2).
The dosage of the 1-adamantane carboxylic acid is 0.1 to 0.5 time of that of the N-pyrimidine indoline compound, [ Cp ] Rh (CH)3CN)3](SbF6)2The dosage of the compound is 0.01 to 0.1 time of the dosage of the N-pyrimidine indoline compound, and the dosage of the silver hexafluoroantimonate is 0.1 to 0.5 time of the dosage of the N-pyrimidine indoline compound.
The amount of the methanol is 0.5mL based on 0.2mmol of N-pyrimidine indoline compound.
The solvent adopted by the leaching is ethyl acetate.
And an eluent adopted by the chromatographic separation is an eluent with the volume ratio of 0-100: 100-0 of ethyl acetate and petroleum ether.
The invention has the beneficial effects that: the invention provides a simple and easy method for synthesizing a 7-alkyl-N-pyrimidine indoline compound. According to the reaction, metal rhodium (III) is used as a catalyst, methanol is used as a reaction solvent, carbon-carbon bond breakage of vinyl cyclopropane and 7-position carbon-hydrogen bond activation of indoline compounds are simultaneously realized, the 7-alkyl-N-pyrimidine indoline compounds are synthesized, and meanwhile, the long alkyl chain with double bonds can also realize further functional group reaction, so that more feasible ways are provided for the application of the method. The method is simple and efficient, has good selectivity and is easy to purify, the functionalization reaction types of the indoline compounds are enriched, and simultaneously, a new reaction mode for the vinyl cyclopropane compounds is realized. The method has important significance for the research and application of the long-chain alkylation reaction of the indoline compound.
Detailed Description
The present invention will be further described with reference to the following examples. It is to be understood that the following examples are illustrative only and are not intended to limit the scope of the invention, which is to be given numerous insubstantial modifications and adaptations by those skilled in the art based on the teachings set forth above.
Example 1
The compound of this example, diethyl (E) -2- (4- (1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, had the formula:
Figure BDA0001851974290000041
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of vinylcyclopropan compound and 0.002mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.04mmol of 1-adamantanecarboxylic acid, 0.02mmol of silver hexafluoroantimonate and 2mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, the mixture is leached by ethyl acetate, decompressed, concentrated and chromatographed (silica gel 20)0-300 mesh, eluent: eluting with ethyl acetate/petroleum ether gradient in 0/100-100/0), and drying to obtain light yellow oil with yield of 88% and E/Z ratio of 20: 1.1H NMR(400MHz,CDCl3)δ8.46–8.36(m,2H),7.13–6.98(m,3H),6.72–6.64(m,1H),5.69-5.59(m,1H),5.44-5.35(m,1H),4.45–4.36(m,2H),4.21–4.12(m,4H),3.41–3.19(m,3H),3.05(t,J＝7.6Hz,2H),2.66–2.53(m,2H),1.27-1.16(m,6H).13C NMR(101MHz,CDCl3)δ169.0,161.3,157.7,142.3,134.7,131.7,130.5,128.2,127.1,124.2,122.3,112.2,61.3,53.2,52.2,38.8,36.9,36.5,31.8,27.9,14.1.HRMS(positive ESI)Calcd.For C23H28N3O4(M+H+)410.2075,Found:410.2079.
Example 2
The compound of this example, diethyl (E) -2- (4- (2-methyl-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000051
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of vinylcyclopropan compound and 0.002mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.02mmol of 1-adamantanecarboxylic acid, 0.04mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by using ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 78 percent, wherein E/Z is 12: 1.1H NMR(600MHz,CDCl3)δ8.43–8.37(m,2H),7.09-7.00(m,3H),6.67(t,J＝4.2Hz,1H),5.64–5.56(m,1H),5.37–5.28(m,1H),4.98-4.95(m,1H),4.20–4.07(m,4H),3.48–3.16(m,4H),2.54(m,3H),1.36(t,J＝8.7Hz,3H),1.25-1.21(m,6H).13C NMR(101MHz,CDCl3)δ169.0,160.8,157.6,140.7,133.5,131.8,130.8,128.3,126.9,124.1,122.9,112.2,61.3,60.4,52.2,37.1,36.9,31.8,21.1,14.1.HRMS(positive ESI)Calcd.For C24H30N3O4(M+H+)424.2231,Found:424.2234.
Example 3
The compound of this example, diethyl (E) -2- (4- (3-methyl-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000061
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of cyclopropan compound and 0.016mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantanecarboxylic acid, 0.02mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 77 percent and the E/Z ratio of 15: 1.1H NMR(400MHz,CDCl3)δ8.45–8.37(m,2H),7.08-7.01(m,3H),6.70-6.66(m,1H),5.69-5.60(m,1H),5.43-5.36(m,1H),4.65–4.56(m,1H),4.21–4.12(m,4H),3.91-3.84(m,1H),3.42–3.19(m,4H),2.59(t,J＝7.0Hz,2H),1.28–1.21(m,9H).13C NMR(101MHz,CDCl3)δ169.0,161.5,157.7,142.0,139.9,131.7,130.4,128.3,127.2,124.4,121.1,112.2,61.3,61.0,52.2,36.8,36.5,31.8,18.4,14.1.HRMS(positive ESI)Calcd.For C24H30N3O4(M+H+)424.2231,Found:424.2235.
Example 4
The compound of this example, diethyl (E) -2- (4- (2-phenyl-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000071
the preparation method comprises the following steps: adding the mixture into a 35mL Schlenk tube under the argon protection environment0.2mmol of N-pyrimidineindoline compound, 0.2mmol of vinylcyclopropan compound, and 0.016mmol of [ Cp Rh (CH)3CN)3](SbF6)20.1mmol of 1-adamantanecarboxylic acid, 0.04mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 80 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 67 percent and the E/Z ratio of 3: 1.1H NMR(400MHz,CDCl3)δ8.45-8.39(m,2H[E]+2H[Z]),7.37-7.34(m,2H[E]+2H[Z]),7.30-7.26(m,2H[E]+2H[Z]),7.22-7.19(m,1H[E]+1H[Z]),7.07–6.98(m,3H[E]+3H[Z]),6.74-6.70(m,1H[E]+1H[Z]),6.04-5.96(m,1H[E]+1H[Z]),5.72-5.65(m,1H[E]+1H[Z]),5.48–5.44(m,1H[Z]),5.41-5.34(m,1H[E]),4.23–4.10(m,4H[E]+4H[Z]),3.84(dd,J＝15.5,9.1Hz,1H[E]+1H[Z]),3.59(dd,J＝16.5,7.5Hz,1H[Z]),3.44(dd,J＝15.9,6.9Hz,1H[E]),3.37-3.31(m,2H[E]+2H[Z]),2.97(d,J＝15.5Hz,1H[E]+1H[Z]),2.72–2.52(m,2H[E]+2H[Z]),1.25–1.21(m,6H[E]+6H[Z]).13C NMR(101MHz,CDCl3)δ169.0,161.3,157.8,143.5,141.8,132.9,131.8,130.5,128.6,128.5,127.2,127.0,125.6,124.6,122.7,112.8,66.9,61.3,52.1,38.5,37.2,31.8,14.1.HRMS(positive ESI)Calcd.For C29H32N3O4(M+H+)486.2388,Found:486.2390.
Example 5
The compound of this example, diethyl (E) -2- (4- (4-methyl-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000081
the preparation method comprises the following steps: under an argon protection environment, 0.2mmol of N-pyrimidineindoline compound, 0.4mmol of vinylcyclopropan compound and 0.02mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.1mmol of 1-adamantanecarboxylic acid, 0.04mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 100 ℃ for 12 hours; after the reaction is finished, eluting by using ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 72 percent and the E/Z ratio of 15: 1.1H NMR(400MHz,CDCl3)δ8.44–8.35(m,2H),6.97-6.93(m,1H),6.85-6.81(m,1H),6.70–6.64(m,1H),5.68-5.58(m,1H),5.42-5.33(m,1H),4.45–4.36(m,2H),4.21–4.11(m,4H),3.39–3.16(m,3H),2.96(t,J＝7.6Hz,2H),2.63-2.55(m,2H),2.23(s,3H),1.27-1.20(m,6H).13C NMR(101MHz,CDCl3)δ169.1,161.5,157.6,141.9,133.3,132.0,131.6,128.2,127.7,126.9,125.3,112.2,61.3,53.0,52.3,36.7,31.9,28.6,18.5,14.1.HRMS(positive ESI)Calcd.For C24H30N3O4(M+H+)424.2231,Found:424.2235.
Example 6
The compound of this example, diethyl (E) -2- (4- (4-methoxy-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000082
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of vinylcyclopropan compound and 0.004mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantane carboxylic acid, 0.06mmol of silver hexafluoroantimonate and 2mL of methanol react for 12 hours at 90 ℃; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily substance with the yield of 81 percent and E/Z of 13:1。1H NMR(400MHz,CDCl3)δ8.43-8.38(m,2H),7.00(d,J＝8.4Hz,1H),6.71-6.57(m,2H),5.68-5.58(m,1H),5.42–5.29(m,1H),4.45–4.36(m,2H),4.21–4.10(m,4H),3.83(s,3H),3.39–3.14(m,3H),2.98(t,J＝7.6Hz,2H),2.64–2.52(m,2H),1.27–1.21(m,6H).13C NMR(101MHz,CDCl3)δ169.05,161.47,157.60,154.25,143.57,132.17,129.22,126.73,123.09,121.68,112.31,106.83,61.31,55.49,53.63,52.26,36.35,31.83,26.65,14.08.HRMS(positive ESI)Calcd.ForC24H30N3O5(M+H+)440.2180,Found:440.2184.
Example 7
The compound of this example, diethyl (E) -2- (4- (4-bromo-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000091
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.4mmol of ethylene cyclopropane compound and 0.008mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantane carboxylic acid, 0.04mmol of silver hexafluoroantimonate and 1mL of methanol react for 12 hours at 110 ℃; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily matter, wherein the yield is 87 percent, and E/Z is E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.46–8.40(m,2H),7.14(dd,J＝8.3,3.7Hz,1H),6.95–6.89(m,1H),6.75–6.70(m,1H),5.65–5.55(m,1H),5.44–5.33(m,1H),4.46–4.37(m,2H),4.21–4.10(m,4H),3.39–3.13(m,3H),3.07(t,J＝7.7Hz,2H),1.27–1.21(m,6H).13C NMR(101MHz,CDCl3)δ169.0,161.2,157.6,143.4,135.1,131.2,130.0,129.4,127.6,126.9,116.6,112.8,61.4,52.5,52.1,36.6,31.8,31.3,14.1.HRMS(positive ESI)Calcd.For C23H27BrN3O4(M+H+)488.1180,Found:488.1182.
Example 8
The compound of this example, diethyl (E) -2- (4- (5-methyl-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000101
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.2mmol of cyclopropan compound and 0.006mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantanecarboxylic acid, 0.04mmol of silver hexafluoroantimonate and 2mL of methanol, and reacting at 120 ℃ for 12 hours; after the reaction is finished, eluting by using ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 75 percent and the E/Z ratio of 11: 1.1H NMR(400MHz,CDCl3)δ8.43–8.35(m,2H),6.99–6.82(m,2H),6.69–6.60(m,1H),5.71–5.58(m,1H),5.39-5.34(m,1H),4.43–4.33(m,2H),4.23–4.09(m,4H),3.42–3.17(m,3H),3.00(t,J＝7.6Hz,2H),2.63–2.53(m,2H),2.30(s,3H),1.30–1.16(m,6H).13C NMR(101MHz,CDCl3)δ169.0,161.5,157.6,140.0,134.9,133.9,131.8,130.2,128.7,127.0,123.2,112.0,61.3,53.3,52.2,36.8,31.9,29.9,29.7,21.0,14.1.HRMS(positive ESI)Calcd.For C24H30N3O4(M+H+)424.2231,Found:424.2233.
Example 9
The compound of this example, diethyl (E) -2- (4- (5-methoxy-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidine indoline compound, 0.24mmol of ethylene cyclopropane compound and 0.003mm of ethylene cyclopropane compound are added into a 35mL Schlenk tubeol of [ Cp Rh (CH)3CN)3](SbF6)20.06mmol of 1-adamantane carboxylic acid, 0.04mmol of silver hexafluoroantimonate and 1mL of methanol react for 12 hours at 100 ℃; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily matter, wherein the yield is 76 percent, and E/Z is E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.43–8.33(m,2H),6.72–6.57(m,3H),5.71–5.58(m,1H),5.39-5.34(m,1H),4.46–4.35(m,2H),4.22–4.11(m,4H),3.79(s,3H),3.40–3.19(m,3H),3.01(t,J＝7.5Hz,2H),2.68–2.53(m,4H),1.27–1.18(m,6H).13C NMR(101MHz,CDCl3)δ169.0,161.6,157.6,157.0,136.2,136.0,131.7,131.6,127.3,113.1,111.9,108.6,61.3,55.7,53.4,52.2,36.9,31.8,30.4,14.1.HRMS(positive ESI)Calcd.For C24H30N3O5(M+H+)440.2180,Found:440.2181.
Example 10
The compound of this example, diethyl (E) -2- (4- (5-chloro-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000121
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.36mmol of vinylcyclopropan compound and 0.02mmol of [ Cp Rh (CH) were added into a 35mL Schlenk tube3CN)3](SbF6)20.1mmol of 1-adamantanecarboxylic acid, 0.08mmol of silver hexafluoroantimonate and 1mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily matter with the yield of 70 percent, E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.45–8.37(m,2H),7.08-6.97(m,2H),6.72(t,J＝4.8Hz,1H),5.66–5.56(m,1H),5.47–5.37(m,1H),4.41(t,J＝7.7Hz,2H),4.24–4.12(m,4H),3.41–3.17(m,3H),3.03(t,J＝7.7Hz,2H),2.60(t,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,6H).13C NMR(101MHz,CDCl3)δ169.0,161.2,157.7,141.2,136.6,132.0,130.9,129.2,128.0,127.9,122.5,112.6,61.4,53.4,52.1,36.7,31.8,29.8,14.1.HRMS(positive ESI)Calcd.For C23H27ClN3O4(M+H+)444.1685,Found:444.1689.
Example 11
The compound of this example, diethyl (E) -2- (4- (5-bromo-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of cyclopropan compound and 0.006mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantane carboxylic acid, 0.04mmol of silver hexafluoroantimonate and 1mL of methanol react for 12 hours at 90 ℃; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily matter with the yield of 78 percent, E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.48–8.35(m,2H),7.21(s,1H),7.15(s,1H),6.72(dd,J＝6.6,2.9Hz,1H),5.65-5.54(m,1H),5.49–5.36(m,1H),4.40(t,J＝7.7Hz,2H),4.24–4.12(m,4H),3.41–3.16(m,3H),3.03(t,J＝7.6Hz,2H),2.60(t,J＝7.1Hz,2H),1.29–1.17(m,6H).13C NMR(101MHz,CDCl3)δ169.0,161.2,157.7,141.7,137.0,132.4,130.8,128.0,125.4,116.9,112.6,61.4,53.3,52.1,36.7,31.8,29.7,14.1.HRMS(positive ESI)Calcd.For C23H27BrN3O4(M+H+)488.1880,Found:488.1184.
Example 12
The compound of this example, diethyl (E) -2- (4- (5-methyl formate-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000132
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.36mmol of ethylene cyclopropane compound and 0.008mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.08mmol of 1-adamantanecarboxylic acid, 0.04mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily matter, wherein the yield is 81 percent, and E/Z is E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.49–8.39(m,2H),7.77(s,2H),6.79–6.74(m,1H),5.64-5.55(m,1H),5.40-5.29(m,1H),4.43(t,J＝7.9Hz,2H),4.22–4.11(m,4H),3.90(d,J＝3.7Hz,3H),3.40–3.23(m,3H),3.10(t,J＝7.8Hz,2H),2.57(t,J＝6.9Hz,2H),1.29–1.15(m,6H).13C NMR(101MHz,CDCl3)δ169.0,167.1,160.8,157.7,146.5,134.9,130.9,130.9,129.5,127.6,125.6,123.8,113.0,61.3,53.4,52.1,51.9,37.1,31.8,29.2,14.1.HRMS(positive ESI)Calcd.ForC25H30N3O6(M+H+)468.2129,Found:468.2133.
Example 13
The compound of this example, diethyl (E) -2- (4- (6-chloro-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000141
the preparation method comprises the following steps: under an argon protection environment, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of vinylcyclopropan compound and 0.02mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantane carboxylic acid, 0.04mmol of silver hexafluoroantimonate and 1mL of methanol react for 12 hours at 90 ℃; after the reaction is finished, leaching by using ethyl acetateConcentrating under reduced pressure, separating by chromatography (silica gel 200-300 mesh, eluent: ethyl acetate/petroleum ether gradient elution, ratio from 0/100 to 100/0), drying to obtain light yellow oily substance with yield of 79%, E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.42(d,J＝4.8Hz,2H),7.10–6.99(m,2H),6.73(t,J＝4.8Hz,1H),5.61–5.48(m,1H),5.23–5.11(m,1H),4.42(t,J＝7.6Hz,2H),4.20–4.05(m,4H),3.45(d,J＝5.9Hz,2H),3.31–3.23(m,1H),2.99(t,J＝7.6Hz,2H),2.49(m,2H),1.23–1.18(m,6H).13C NMR(101MHz,CDCl3)δ169.0,161.3,157.7,144.4,134.0,133.7,130.1,128.9,126.6,125.5,123.0,112.8,61.3,54.0,52.2,34.4,31.8,29.6,14.0.HRMS(positive ESI)Calcd.For C24H30N3O4(M+H+)424.2231,Found:424.2233.
Example 14
The compound (E) -dimethyl 2- (4- (1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate of this example has the structural formula:
Figure BDA0001851974290000151
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.2mmol of cyclopropanol compound and 0.016mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantanecarboxylic acid, 0.1mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by using ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 76 percent and the E/Z ratio of 13: 1.1H NMR(400MHz,CDCl3)δ8.47–8.36(m,2H),7.15–6.97(m,3H),6.72–6.65(m,1H),5.65-5.56(m,1H),5.43–5.26(m,1H),4.46–4.36(m,2H),3.75–3.64(m,6H),3.44–3.22(m,3H),3.05(t,J＝7.6Hz,2H),2.67-2.55(m,2H).13C NMR(101MHz,CDCl3)δ169.4,161.3,157.7,157.6,142.4,134.8,132,0,130.4,128.2,126.9,124.2,122.4,112.2,53.2,52.5,52.5,51.9,36.9,31.9,29.9.HRMS(positive ESI)Calcd.For C21H24N3O4(M+H+)382.1762,Found:382.1766.
Example 15
The compound of this example, di-tert-butyl (E) -2- (4- (1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000161
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of ethylene cyclopropane compound and 0.008mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.1mmol of 1-adamantanecarboxylic acid, 0.09mmol of silver hexafluoroantimonate and 0.5mL of methanol, and reacting at 100 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 79 percent, wherein E/Z is 20: 1.1H NMR(600MHz,CDCl3)δ8.44–8.37(m,2H),7.12-6.97(m,3H),6.68(dd,J＝11.9,7.9Hz,1H),5.69–5.59(m,1H),5.42–5.34(m,1H),4.41(t,J＝7.4Hz,2H),4.16–4.05(m,4H),3.37(t,J＝7.0Hz,1H),3.24(d,J＝6.7Hz,2H),3.05(t,J＝7.3Hz,2H),2.59(t,J＝7.1Hz,2H),1.67–1.52(m,6H),1.39–1.24(m,5H),0.91(t,J＝7.1Hz,6H).13C NMR(101MHz,CDCl3)δ169.1,161.4,157.6,142.3,134.7,131.7,130.5,128.2,127.2,124.2,122.3,112.2,65.2,53.2,52.3,36.9,31.8,30.5,29.9,19.0,13.6.HRMS(positive ESI)Calcd.For C27H36N3O4(M+H+)466.2701,Found:466.2705.
Example 16
The compound (E) -dinitrile 2- (4- (1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate of this example has the following structural formula:
Figure BDA0001851974290000171
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.36mmol of cyclopropan compound and 0.016mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.05mmol of 1-adamantanecarboxylic acid, 0.02mmol of silver hexafluoroantimonate and 2mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 77 percent and the E/Z ratio of 3: 1. Delta 8.45-8.44(m, 2H)[E]+2H[Z]),7.15–7.13(m,1H[E]+1H[Z]),7.06–7.03(m,2H[E]+2H[Z]),6.75-6.71(m,1H[E]+1H[Z]),5.93–5.85(m,1H[E]+1H[Z]),5.54–5.48(m,1H[Z]),5.40–5.34(m,1H[E]),4.42(q,J＝7.8Hz,2H[E]+2H[Z]),3.66(t,J＝6.7Hz,1H[E]),3.53(t,J＝7.1Hz,1H[Z]),3.43(t,J＝6.8Hz,2H[E]+2H[Z]),3.06(t,J＝7.7Hz,2H[E]+2H[Z]),2.68–2.65(m,2H[E]+2H[Z]).13C NMR(101MHz,CDCl3)δ166.2,166.1,161.3,157.7,157.7,142.4,135.0,134.9,134.5,133.6,130.1,129.8,128.4,128.0,124.4,124.2,123.2,122.6,116.2,112.4,53.5,53.4,53.3,53.2,37.8,37.3,37.1,33.0,31.9,29.9,29.9,27.7.HRMS(positive ESI)Calcd.For C19H18N5(M+H+)316.1557,Found:316.1561.
Example 17
The compound (E) -methyl 2- (4- (1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) acetonitrile of this example has the formula:
Figure BDA0001851974290000181
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidine indoline compound and 0.24mmol of ethylene cyclopropane are added into a 35mL Schlenk tubeComplex, 0.016mmol of [ Cp Rh (CH)3CN)3](SbF6)20.06mmol of 1-adamantanecarboxylic acid, 0.02mmol of silver hexafluoroantimonate and 1mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, performing chromatographic separation (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), and drying to obtain a light yellow oily substance with the yield of 77 percent and the E/Z ratio of 2: 1.1H NMR(400MHz,CDCl3)δ8.44-8.43(m,2H[E]+2H[Z]),7.12(d,J＝5.5Hz,1H[E]+1H[Z]),7.05–7.02(m,2H[E]+2H[Z]),6.72-6.69(m,1H[E]+1H[Z]),5.82-5.74(m,1H[E]+1H[Z]),5.50–5.47(m,1H[Z]),5.44–5.346(m,1H[E]),4.44–4.39(m,2H[E]+2H[Z]),3.78(d,J＝6.8Hz,3H[E]+3H[Z]),3.50(dd,J＝7.3,6.2Hz,1H[E]),3.47–3.42(m,1H[z]),3.40(d,J＝7.3Hz,2H[z]),3.34(d,J＝6.8Hz,2H[E]),3.06(t,J＝7.6Hz,2H[E]+2H[Z]),2.67-2.60(m,2H[E]+2H[Z]).13C NMR(101MHz,CDCl3)δ161.2,157.8,157.7,142.4,137.0,135.8,135.1,129.1,128.5,128.0,124.6,124.3,122.9,122.8,121.9,121.1,112.5,112.4,112.4,53.4,53.3,37.2,34.0,32.1,29.9,29.8,28.8,23.3,22.7.HRMS(positive ESI)Calcd.For C20H21N4O2(M+H+)349.1659,Found:349.1663.
Example 18
The compound of this example, dimethyl (E) -2- (4- (5-chloro-1- (2-pyrimidinyl) 7-indolinyl) 2-buten-1-yl) malonate, has the formula:
Figure BDA0001851974290000191
the preparation method comprises the following steps: under the protection of argon, 0.2mmol of N-pyrimidineindoline compound, 0.3mmol of vinylcyclopropan compound and 0.002mmol of [ Cp Rh (CH) are added into a 35mL Schlenk tube3CN)3](SbF6)20.06mmol of 1-adamantanecarboxylic acid, 0.02mmol of silver hexafluoroantimonate and 2mL of methanol, and reacting at 90 ℃ for 12 hours; after the reaction is finished, eluting by ethyl acetate, concentrating under reduced pressure, separating by chromatography (silica gel 200-300 meshes, eluent: ethyl acetate/petroleum ether gradient elution with the proportion from 0/100 to 100/0), drying to obtain light yellow oily matter, wherein the yield is 57 percent, and E/Z is E/Z>20:1。1H NMR(400MHz,CDCl3)δ8.45–8.37(m,2H),7.14–6.94(m,2H),6.75–6.67(m,1H),5.64–5.52(m,1H),5.45-5.37(m,1H),4.45–4.37(m,2H),3.79–3.68(m,6H),3.48–3.14(m,3H),3.03(t,J＝7.7Hz,2H),2.61(t,J＝6.9Hz,2H).13C NMR(101MHz,CDCl3)δ169.4,161.2,157.7,141.2,136.6,131.9,131.1,129.2,127.9,127.8,122.5,112.6,53.3,52.5,51.8,36.7,31.8,29.8.HRMS(positiveESI)Calcd.For C21H23ClN3O4(M+H+)416.1372,Found:416.1374.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (7)

1. 7-alkyl-N-a process for the preparation of pyrimidineindolines, characterized in that it comprises the following steps: under the argon atmosphere, the mixture isNThe pyrimidine indoline compound and the ethylene cyclopropane compound are added into a reaction tube, and 1-adamantane formic acid, [ Cp Rh (CH)3CN)3](SbF6)2Adding methanol into silver hexafluoroantimonate, reacting for 12 hours at 80 ~ 120 ℃, leaching, separating by thin-layer chromatography and drying after the reaction is finished to obtain a target product, wherein the reaction equation is as follows:
Figure DEST_PATH_IMAGE002
；
said 7-alkyl-NThe structural general formula of the pyrimidine indoline compound is as follows:
Figure DEST_PATH_IMAGE004
；
wherein R is1Hydrogen, alkyl, alkoxy, ester group, halogen; EWG is carbonyl, methyl ester, ethyl ester, butyl ester, benzyl ester, acetonitrile.
2. The 7-alkyl-substituted ketone as defined in claim 1NA process for the preparation of-pyrimidineindolines, characterized in that: the above-mentionedNThe general formula of the pyrimidine indoline compound is as follows:
Figure DEST_PATH_IMAGE006
；
the general structural formula of the vinyl cyclopropane compound is as follows:
Figure DEST_PATH_IMAGE008
；
wherein R is1Is hydrogen, alkyl, alkoxy, ester group or halogen; EWG is carbonyl, methyl ester, ethyl ester, butyl ester, benzyl ester or acetonitrile.
3. The 7-alkyl-substituted ketone as defined in claim 1NA process for the preparation of-pyrimidineindolines, characterized in that: the above-mentionedNThe mass ratio of the pyrimidine indoline compound to the ethylene cyclopropane compound is 1 (1 ~ 2).
4. The 7-alkyl-substituted ketone as defined in claim 1NA process for the preparation of-pyrimidineindolines, characterized in that: the dosage of the 1-adamantane carboxylic acid isN-pyrimidine indoline compound substance 0.1 ~ 0.5.5 times of amount, [ Cp Rh (CH)3CN)3](SbF6)2In an amount ofN-pyrimidineamidesThe dosage of the indole quinoline compound is 0.01 ~ 0.1.1 times of the dosage of the silver hexafluoroantimonateN-0.1 ~ 0.5.5 times the amount of the substance of the pyrimidine indolines.
5. The 7-alkyl-substituted ketone as defined in claim 1NA process for the preparation of-pyrimidineindolines, characterized in that: in an amount of 0.2mmolNThe amount of substance of the pyrimidine indoline compound is 0.5 mL.
6. The 7-alkyl-substituted ketone as defined in claim 1NA process for the preparation of-pyrimidineindolines, characterized in that: the solvent adopted by the leaching is ethyl acetate.
7. The 7-alkyl-substituted ketone as defined in claim 1NThe preparation method of the pyrimidine indoline compound is characterized in that ethyl acetate and petroleum ether are adopted as eluent in a volume ratio of (0 ~ 100) to (100 ~ 0) in the chromatographic separation.
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