CN104693205A - Total synthesis method of amides alkaloid - Google Patents
Total synthesis method of amides alkaloid Download PDFInfo
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- CN104693205A CN104693205A CN201410770444.3A CN201410770444A CN104693205A CN 104693205 A CN104693205 A CN 104693205A CN 201410770444 A CN201410770444 A CN 201410770444A CN 104693205 A CN104693205 A CN 104693205A
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Abstract
The invention discloses a total synthesis method of amides alkaloid, and belongs to the technical field of the chemistry of natural products. The total synthesis method comprises the following steps: carrying out the synthesis by adopting malonate and 2-bromopropane or 2-bromopropane derivative as raw materials, thereby obtaining isopropyl malonate; (2) carrying out the synthesis by adopting 2-aminopyrrolidine as a raw material, thereby obtaining mid-body 2-amino tetralin pyrrolidine; and (3) synthesizing amides alkaloid 3-isopropyl-nafoxidine[1,2-alpha]pyrimidine-2,4(1H,3H)-diketone and a derivative by adopting the isopropyl malonate and the 2-2-amino tetralin pyrrolidine as a raw material. By adopting the total synthesis method, the defect that the extraction separation process in the natural product is complicated and the yield is low can be overcome, and the demand of perople for further researching the natural product can be satisfied; moreover, the synthesis method is simple in route, raw materials are cheap and easy to obtain, and the yield is relatively high.
Description
Technical field
The invention belongs to natural product chemistry technical field, relate to a kind of total synthesis method of amide alkaloid, be specifically related to the total synthesis method of 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof.
Background technology
3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, be a kind of novel small molecules amide alkaloid that extraction and isolation obtains from the domestic distinctive aconitum plant in Taibai County, Shaanxi Province of China too white rhizome of Chinese monkshood, structural formula is as follows:
It is reported, amide alkaloid has unique effect in leukemia, people in loop strain HL-60 and human erythroleukemia cell's strain K562 selects in this seminar, study this small molecules amide alkaloid to its restraining effect, result shows: 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone has good restraining effect to HL-60 propagation, and activity is better than Zorubicin.
Based on the activity that it is good, this seminar carries out deep research to it in advance, but too white rhizome of Chinese monkshood limited source, and being separated loaded down with trivial details, cost requirement is higher, and the cycle is longer, cannot meet the demand of research aspect.
Summary of the invention
The object of the present invention is to provide a kind of total synthesis method of amide alkaloid, the synthetic route of the method is reasonable in design, simple to operation, and raw material is easy to get, and productive rate is high, can meet the demand that people further investigate it.
The present invention is achieved through the following technical solutions:
A total synthesis method for amide alkaloid, comprises the following steps:
1) with malonic ester and 2-N-PROPYLE BROMIDE or 2-N-PROPYLE BROMIDE derivative for Material synthesis obtains isopropyl-malonic acid ester and derivative thereof;
2) carry out reduction reaction with 2-amino-pyrrolidine for raw material, obtain intermediate 2-amino tetrahydro pyrrolidine;
3) will with isopropyl-malonic acid ester and derivative thereof and the amino tetrahydro pyrrolidine of 2-for Material synthesis obtains amide alkaloid 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof.
A total synthesis method for amide alkaloid, comprises the following steps:
1) press the mol ratio of 1:1 ~ 2 with malonic ester and 2-N-PROPYLE BROMIDE or 2-N-PROPYLE BROMIDE derivative, react at 20 ~ 100 DEG C, generate intermediate isopropyl-malonic acid ester and derivative thereof;
2) with 2-amino-pyrrolidine for raw material, at-20 ~ 50 DEG C, carry out reduction reaction, obtained intermediate 2-amino tetrahydro pyrrolidine; The mol ratio of described 2-amino-pyrrolidine and reductive agent is 1:1 ~ 3;
3) by step 1) obtained intermediate isopropyl-malonic acid ester and derivative thereof and step 2) obtained intermediate 2-amino tetrahydro pyrrolidine is according to the mol ratio of 1:0.5 ~ 2, react at-20 ~ 100 DEG C, generate target product 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof.
Step 1) described in malonic ester be dimethyl malonate, diethyl malonate, dipropyl malonate or propanedioic acid ring isopropyl ester.
Step 1) described in 2-N-PROPYLE BROMIDE derivative be 2-n-butyl bromide, neo-pentyl bromine, cyclopropane bromide, tert-bromo butane, 2 cbloropropane isopropyl chloride, chloro-iso-butane or tert-butyl chloride.
Step 2) described in reductive agent be sodium borohydride.
Step 2) described in the existence form of 2-amino-pyrrolidine be liquid, solid or salt.
Step 2) existence form of intermediate 2-amino tetrahydro pyrrolidine that generates of reaction is liquid, solid or salt.
Described step 1) reaction solvent for use is ethanol, methyl alcohol, DMF, N,N-dimethylacetamide, methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), chloroform or ethyl acetate.
Described step 2) reaction solvent for use is ethanol, methyl alcohol, DMF, N,N-dimethylacetamide, methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), chloroform or ethyl acetate.
Described step 3) reaction solvent for use is ethanol, methyl alcohol, DMF, N,N-dimethylacetamide, methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), chloroform or ethyl acetate.
Compared with prior art, the present invention has following useful technique effect:
The inventive method adopts the method for chemosynthesis to prepare 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof, this synthetic method route only needs three steps, the first step is the hydrocarbyl reaction of typical malonic ester under sodium alkoxide catalysis, and productive rate can reach more than 80%; Second step makees reductive agent with tetrahydro boron sodium, reduction schiff bases, and reaction is clean, and by product is less, and operation is simple; 3rd step is the ring-closure reaction of bisamide, makees catalyzer with sodium alkoxide, and two nitrogen-atoms of the Sauerstoffatom in two ester bonds of malonic ester respectively with 2-in amino Pyrrolidine exchange and form acid amides, and row becomes six-ring and pentacyclic structure simultaneously.Total synthesis method of the present invention is reasonable in design, and aftertreatment is comparatively simple, and productive rate is higher.Overcome extraction and isolation process from natural product loaded down with trivial details, the shortcoming that productive rate is low, meet the demand that scientific research personnel furthers investigate it.
Accompanying drawing explanation
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of the intermediate product diethyl isopropyl that step 1 of the present invention obtains;
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of the amino tetrahydro pyrrolidine of intermediate product 2-that step 2 of the present invention obtains;
Fig. 3 is the nucleus magnetic hydrogen spectrum figure of target product 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone of the present invention;
Fig. 4 is the nuclear-magnetism carbon spectrogram for target product 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.
The total synthesis method of a kind of amide alkaloid disclosed by the invention (3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof), concrete synthetic route is as follows:
Specifically comprise the following steps:
1) with malonic ester and 2-N-PROPYLE BROMIDE or 2-N-PROPYLE BROMIDE derivative for Material synthesis obtains isopropyl-malonic acid ester and derivative thereof;
2) with 2-amino-pyrrolidine for Material synthesis obtains intermediate 2-amino tetrahydro pyrrolidine;
3) will with isopropyl-malonic acid ester and derivative thereof and the amino tetrahydro pyrrolidine of 2-for Material synthesis obtains target product 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof.
Embodiment 1
The total synthesis method of 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, comprises the following steps:
1, diethyl isopropyl is prepared
Sodium ethylate (5.61g, 82.5mmoL) is dissolved in 80mL absolute ethanol, under constantly stirring, drips diethyl malonate (12g, 75mmoL) wherein, dropwise rear temperature rising reflux 2 hours; Cooling, dropwise adds isopropyl bromide (13.84g, 112.5mmoL) under constantly stirring, dropwises rear intensification, reflux 6 hours.TLC follows the trail of, and after completion of the reaction, cooling, suction filtration, collects filtrate.Ice bath lowers pH to 5-6, revolves steaming, except desolventizing.Use 100mL acetic acid ethyl dissolution, 100mL saturated sodium-chloride washes three times, merges organic phase, anhydrous sodium sulfate drying, filters, and concentrated organic phase, underpressure distillation, obtains colourless transparent liquid 17.80g, is compound diethyl isopropyl, yield 81.46%.
The hydrogen nuclear magnetic resonance modal data of compound diethyl isopropyl: 1H NMR (400MHz, CDCL3) δ 4.20 (q, J=7.1Hz, 4H), 3.12 (d, J=8.8Hz, 1H), 2.49 – 2.33 (m, 1H), 1.28 (t, J=7.1Hz, 6H), 1.01 (d, J=6.8Hz, 6H).
The hydrogen nuclear magnetic resonance spectrogram of diethyl isopropyl is see Fig. 1.
2, the amino tetrahydro pyrrolidine of 2-is prepared
2-amino pyrrolidine hydrochloride (10g, 83mmoL) is dissolved in 80mL dehydrated alcohol, constantly stirs lower dropping 12.66mL triethylamine, room temperature reaction 30min.By tetrahydro boron sodium (6.88g, 182mmoL) 20mL anhydrous alcohol solution, dropwise add in reaction system under ice bath, after dropwising, room temperature reaction 5 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing.Use 100mL water dissolution, 100mL ethyl acetate washes three times, merges aqueous phase.Revolve steaming, except anhydrating, tetrahydrofuran (THF) dissolves, and filters, in the solution logical hydrogen chloride gas, and colored solid generates, and filters, obtains white solid 3.28g, is the amino tetrahydro pyrrolidine hydrochloride of compound 2-, yield 32.3%.
The hydrogen nuclear magnetic resonance modal data of the amino tetrahydro pyrrolidine hydrochloride of compound 2-: 1H NMR (400MHz, MeOD) δ 3.70 (t, J=7.1Hz, 2H), 3.34 (dt, J=3.2,1.6Hz, 1H), 2.91 (t, J=8.0Hz, 2H), 2.24 (dt, J=15.6,7.7Hz, 2H).
The nucleus magnetic hydrogen spectrum figure of the amino tetrahydro pyrrolidine of 2-is see Fig. 2.
3,3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is prepared
Amino tetrahydro pyrrolidine hydrochloride (1.33g, 10mmoL) of 2-is dissolved in 60mL dehydrated alcohol, dropwise adds 1.33mL triethylamine, room temperature reaction 10min under constantly stirring.Drip dehydrated alcohol (20mL) solution of sodium ethylate (1.36g, 20mmoL) under ice bath, dropwise rear room temperature reaction 45min.Dropwise add dehydrated alcohol (20mL) solution of diethyl isopropyl (2.0g, 10mmoL) under continuous stirring, heat up, reflux 15 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing, obtain yellow solid.100mL water dissolution, 100mL ethyl acetate divides three extractions, and removing oil-soluble impurities, merges aqueous phase.N-butanol extraction, collects n-butanol layer, revolves steaming, except desolventizing, obtain faint yellow solid.Trichloromethane dissolves, suction filtration, and removing is insoluble to the impurity of trichloromethane, collects filtrate, is spin-dried for, obtains white solid 0.603g, be compound 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, yield 31.08%.
Compound 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, the hydrogen nuclear magnetic resonance modal data of 3H)-diketone: 1H NMR (400MHz, CDCL3) δ 4.17 – 4.11 (m, 1H), 3.63 (t, J=7.1Hz, 2H), 2.96 (d, J=9.7Hz, 1H), 2.85 (t, J=8.1Hz, 2H), 2.33 – 2.24 (m, 1H), 2.18 – 2.12 (dt, 2H), 1.02 (d, J=6.7Hz, 3H), 0.95 (d, J=6.6Hz, 3H).
The nucleus magnetic hydrogen spectrum figure of 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is see Fig. 3.
Carbon-13 nmr spectra data are: 13C NMR (400MHz, CDCL3) δ 172.53,171.75,63.62,60.37,47.24,30.47,29.58,20.95,20.66,14.24.
The nuclear-magnetism carbon spectrogram of 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is see Fig. 4.
The present invention is not limited to above-mentioned preferred forms, anyone for the present invention any modification done under enlightenment of the present invention or change, and every have identical with the application or akin technical scheme, all drops within protection scope of the present invention.
Embodiment 2
The total synthesis method of the 3-tertiary butyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, comprises the following steps:
1, tertiary butyl diethyl malonate is prepared
Sodium ethylate (5.61g, 82.5mmoL) is dissolved in 80mL absolute ethanol, under constantly stirring, drips diethyl malonate (12g, 75mmoL) wherein, dropwise rear temperature rising reflux 2 hours; Cooling, dropwise adds tert-bromo butane (15.41g, 112.5mmoL) under constantly stirring, dropwises rear intensification, reflux 6 hours.TLC follows the trail of, and after completion of the reaction, cooling, suction filtration, collects filtrate.Ice bath lowers pH to 5-6, revolves steaming, except desolventizing.Use 100mL acetic acid ethyl dissolution, 100mL saturated sodium-chloride washes three times, merges organic phase, anhydrous sodium sulfate drying, filters, and concentrated organic phase, underpressure distillation, obtains colourless transparent liquid, is compound tertiary butyl diethyl malonate.
2, the amino tetrahydro pyrrolidine of 2-is prepared
2-amino pyrrolidine hydrochloride (10g, 83mmoL) is dissolved in 80mL dehydrated alcohol, constantly stirs lower dropping 12.66mL triethylamine, room temperature reaction 30min.Tetrahydro boron sodium (6.88g, 182mmoL) 20mL anhydrous methanol is dissolved, dropwise adds in reaction system under ice bath, after dropwising, room temperature reaction 5 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing.Use 100mL water dissolution, 100mL ethyl acetate washes three times, merges aqueous phase.Revolve steaming, except anhydrating, tetrahydrofuran (THF) dissolves, and filters, in the solution logical hydrogen chloride gas, and colored solid generates, and filters, obtains white solid, is the amino tetrahydro pyrrolidine hydrochloride of compound 2-.
3, the 3-tertiary butyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is prepared
Amino tetrahydro pyrrolidine hydrochloride (1.33g, 10mmoL) of 2-is dissolved in 60mL dehydrated alcohol, dropwise adds 1.33mL triethylamine, room temperature reaction 10min under constantly stirring.Drip dehydrated alcohol (20mL) solution of sodium ethylate (1.36g, 20mmoL) under ice bath, dropwise rear room temperature reaction 45min.Dropwise add dehydrated alcohol (20mL) solution of tertiary butyl diethyl malonate (2.38g, 10mmoL) under continuous stirring, heat up, reflux 15 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing, obtain yellow solid.100mL water dissolution, 100mL ethyl acetate divides three extractions, and removing oil-soluble impurities, merges aqueous phase.N-butanol extraction, collects n-butanol layer, revolves steaming, except desolventizing, obtain faint yellow solid.Trichloromethane dissolves, suction filtration, and removing is insoluble to the impurity of trichloromethane, collects filtrate, is spin-dried for, obtains white solid, be the compound 3-tertiary butyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone.
Embodiment 3
The total synthesis method of 3-cyclopropyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, comprises the following steps:
1, cyclopropyl dimethyl malonate is prepared
Sodium ethylate (5.61g, 82.5mmoL) is dissolved in 80mL absolute ethanol, under constantly stirring, drips dimethyl malonate (9.9g, 75mmoL) wherein, dropwise rear temperature rising reflux 2 hours; Cooling, dropwise adds cyclopropane bromide (13.61g, 112.5mmoL) under constantly stirring, dropwises rear intensification, reflux 6 hours.TLC follows the trail of, and after completion of the reaction, cooling, suction filtration, collects filtrate.Ice bath lowers pH to 5-6, revolves steaming, except desolventizing.Use 100mL acetic acid ethyl dissolution, 100mL saturated sodium-chloride washes three times, merges organic phase, anhydrous sodium sulfate drying, filters, and concentrated organic phase, underpressure distillation, obtains colourless transparent liquid, is compound cyclopropyl dimethyl malonate.
2, the amino tetrahydro pyrrolidine of 2-is prepared
2-amino pyrrolidine hydrochloride (10g, 83mmoL) is dissolved in 80mL dehydrated alcohol, constantly stirs lower dropping 12.66mL triethylamine, room temperature reaction 30min.Tetrahydro boron sodium (6.88g, 182mmoL) 20mL anhydrous methanol is dissolved, dropwise adds in reaction system under ice bath, after dropwising, room temperature reaction 5 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing.Use 100mL water dissolution, 100mL ethyl acetate washes three times, merges aqueous phase.Revolve steaming, except anhydrating, tetrahydrofuran (THF) dissolves, and filters, in the solution logical hydrogen chloride gas, and colored solid generates, and filters, obtains white solid, is the amino tetrahydro pyrrolidine hydrochloride of compound 2-.
3,3-cyclopropyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is prepared
Amino tetrahydro pyrrolidine hydrochloride (1.33g, 10mmoL) of 2-is dissolved in 60mL dehydrated alcohol, dropwise adds 1.33mL triethylamine, room temperature reaction 10min under constantly stirring.Drip dehydrated alcohol (20mL) solution of sodium ethylate (1.36g, 20mmoL) under ice bath, dropwise rear room temperature reaction 45min.Dropwise add dehydrated alcohol (20mL) solution of cyclopropyl diethyl malonate (2.0g, 10mmoL) under continuous stirring, heat up, reflux 15 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing, obtain yellow solid.100mL water dissolution, 100mL ethyl acetate divides three extractions, and removing oil-soluble impurities, merges aqueous phase.N-butanol extraction, collects n-butanol layer, revolves steaming, except desolventizing, obtain faint yellow solid.Trichloromethane dissolves, suction filtration, and removing is insoluble to the impurity of trichloromethane, collects filtrate, is spin-dried for, obtains white solid, be compound 3-cyclopropyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone.
Embodiment 4
The total synthesis method of 3-neo-pentyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, comprises the following steps:
1, neo-pentyl dimethyl malonate is prepared
Sodium ethylate (5.61g, 82.5mmoL) is dissolved in 80mL absolute ethanol, under constantly stirring, drips dimethyl malonate (9.9g, 75mmoL) wherein, dropwise rear temperature rising reflux 2 hours; Cooling, dropwise adds bromo neopentane (16.99g, 112.5mmoL) under constantly stirring, dropwises rear intensification, reflux 6 hours.TLC follows the trail of, and after completion of the reaction, cooling, suction filtration, collects filtrate.Ice bath lowers pH to 5-6, revolves steaming, except desolventizing.Use 100mL acetic acid ethyl dissolution, 100mL saturated sodium-chloride washes three times, merges organic phase, anhydrous sodium sulfate drying, filters, and concentrated organic phase, underpressure distillation, obtains colourless transparent liquid, is compound neo-pentyl dimethyl malonate.
2, the amino tetrahydro pyrrolidine of 2-is prepared
2-amino pyrrolidine hydrochloride (10g, 83mmoL) is dissolved in 80mL dehydrated alcohol, constantly stirs lower dropping 12.66mL triethylamine, room temperature reaction 30min.Tetrahydro boron sodium (6.88g, 182mmoL) 20mL anhydrous methanol is dissolved, dropwise adds in reaction system under ice bath, after dropwising, room temperature reaction 5 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing.Use 100mL water dissolution, 100mL ethyl acetate washes three times, merges aqueous phase.Revolve steaming, except anhydrating, tetrahydrofuran (THF) dissolves, and filters, in the solution logical hydrogen chloride gas, and colored solid generates, and filters, obtains white solid, is the amino tetrahydro pyrrolidine hydrochloride of compound 2-.
3,3-neo-pentyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is prepared
Amino tetrahydro pyrrolidine hydrochloride (1.33g, 10mmoL) of 2-is dissolved in 60mL dehydrated alcohol, dropwise adds 1.33mL triethylamine, room temperature reaction 10min under constantly stirring.Drip dehydrated alcohol (20mL) solution of sodium ethylate (1.36g, 20mmoL) under ice bath, dropwise rear room temperature reaction 45min.Dropwise add dehydrated alcohol (20mL) solution of neo-pentyl dimethyl malonate (2.02g, 10mmoL) under continuous stirring, heat up, reflux 15 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing, obtain yellow solid.100mL water dissolution, 100mL ethyl acetate divides three extractions, and removing oil-soluble impurities, merges aqueous phase.N-butanol extraction, collects n-butanol layer, revolves steaming, except desolventizing, obtain faint yellow solid.Trichloromethane dissolves, suction filtration, and removing is insoluble to the impurity of trichloromethane, collects filtrate, is spin-dried for, obtains white solid, be compound 3-neo-pentyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone.
Embodiment 5
The total synthesis method of 3-isobutyl--Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone, comprises the following steps:
1, iso-butyl diethyl malonate is prepared
Sodium ethylate (5.61g, 82.5mmoL) is dissolved in 80mL absolute ethanol, under constantly stirring, drips diethyl malonate (12g, 75mmoL) wherein, dropwise rear temperature rising reflux 2 hours; Cooling, dropwise adds chloro-iso-butane (10.63g, 112.5mmoL) under constantly stirring, dropwises rear intensification, reflux 10 hours.TLC follows the trail of, and after completion of the reaction, cooling, suction filtration, collects filtrate.Ice bath lowers pH to 5-6, revolves steaming, except desolventizing.Use 100mL acetic acid ethyl dissolution, 100mL saturated sodium-chloride washes three times, merges organic phase, anhydrous sodium sulfate drying, filters, and concentrated organic phase, underpressure distillation, obtains colourless transparent liquid, is compound iso-butyl diethyl malonate.
2, the amino tetrahydro pyrrolidine of 2-is prepared
2-amino pyrrolidine hydrochloride (10g, 83mmoL) is dissolved in 80mL dehydrated alcohol, constantly stirs lower dropping 12.66mL triethylamine, room temperature reaction 30min.Tetrahydro boron sodium (6.88g, 182mmoL) 20mL anhydrous methanol is dissolved, dropwise adds in reaction system under ice bath, after dropwising, room temperature reaction 5 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing.Use 100mL water dissolution, 100mL ethyl acetate washes three times, merges aqueous phase.Revolve steaming, except anhydrating, tetrahydrofuran (THF) dissolves, and filters, in the solution logical hydrogen chloride gas, and colored solid generates, and filters, obtains white solid, is the amino tetrahydro pyrrolidine hydrochloride of compound 2-.
3, the 3-tertiary butyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone is prepared
Amino tetrahydro pyrrolidine hydrochloride (1.33g, 10mmoL) of 2-is dissolved in 60mL dehydrated alcohol, dropwise adds 1.33mL triethylamine, room temperature reaction 10min under constantly stirring.Drip dehydrated alcohol (20mL) solution of sodium ethylate (1.36g, 20mmoL) under ice bath, dropwise rear room temperature reaction 45min.Dropwise add dehydrated alcohol (20mL) solution of iso-butyl diethyl malonate (2.16g, 10mmoL) under continuous stirring, heat up, reflux 15 hours.TLC follows the trail of, and after completion of the reaction, suction filtration, collects filtrate, revolve steaming, except desolventizing, obtain yellow solid.100mL water dissolution, 100mL ethyl acetate divides three extractions, and removing oil-soluble impurities, merges aqueous phase.N-butanol extraction, collects n-butanol layer, revolves steaming, except desolventizing, obtain faint yellow solid.Trichloromethane dissolves, suction filtration, and removing is insoluble to the impurity of trichloromethane, collects filtrate, is spin-dried for, obtains white solid, be compound 3-isobutyl--Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone.
Claims (10)
1. a total synthesis method for amide alkaloid, is characterized in that, comprises the following steps:
1) with malonic ester and 2-N-PROPYLE BROMIDE or 2-N-PROPYLE BROMIDE derivative for Material synthesis obtains isopropyl-malonic acid ester and derivative thereof;
2) carry out reduction reaction with 2-amino-pyrrolidine for raw material, obtain intermediate 2-amino tetrahydro pyrrolidine;
3) will with isopropyl-malonic acid ester and derivative thereof and the amino tetrahydro pyrrolidine of 2-for Material synthesis obtains amide alkaloid 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof.
2. the total synthesis method of a kind of amide alkaloid according to claim 1, is characterized in that, comprise the following steps:
1) press the mol ratio of 1:1 ~ 2 with malonic ester and 2-N-PROPYLE BROMIDE or 2-N-PROPYLE BROMIDE derivative, react at 20 ~ 100 DEG C, generate intermediate isopropyl-malonic acid ester and derivative thereof;
2) with 2-amino-pyrrolidine for raw material, at-20 ~ 50 DEG C, carry out reduction reaction, obtained intermediate 2-amino tetrahydro pyrrolidine; The mol ratio of described 2-amino-pyrrolidine and reductive agent is 1:1 ~ 3;
3) by step 1) obtained intermediate isopropyl-malonic acid ester and derivative thereof and step 2) obtained intermediate 2-amino tetrahydro pyrrolidine is according to the mol ratio of 1:0.5 ~ 2, react at-20 ~ 100 DEG C, generate target product 3-sec.-propyl-Pyrrolidine [1,2-a] pyrimidine-2,4 (1H, 3H)-diketone and derivative thereof.
3. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, is characterized in that, step 1) described in malonic ester be dimethyl malonate, diethyl malonate, dipropyl malonate or propanedioic acid ring isopropyl ester.
4. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, it is characterized in that, step 1) described in 2-N-PROPYLE BROMIDE derivative be 2-n-butyl bromide, neo-pentyl bromine, cyclopropane bromide, tert-bromo butane, 2 cbloropropane isopropyl chloride, chloro-iso-butane or tert-butyl chloride.
5. the total synthesis method of a kind of amide alkaloid according to claim 2, is characterized in that, step 2) described in reductive agent be sodium borohydride.
6. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, is characterized in that, step 2) described in the existence form of 2-amino-pyrrolidine be liquid, solid or salt.
7. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, is characterized in that, step 2) existence form of intermediate 2-amino tetrahydro pyrrolidine that generates of reaction is liquid, solid or salt.
8. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, it is characterized in that, described step 1) reaction solvent for use is ethanol, methyl alcohol, N, dinethylformamide, N,N-dimethylacetamide, methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), chloroform or ethyl acetate.
9. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, it is characterized in that, described step 2) reaction solvent for use is ethanol, methyl alcohol, N, dinethylformamide, N,N-dimethylacetamide, methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), chloroform or ethyl acetate.
10. the total synthesis method of a kind of amide alkaloid according to claim 1 and 2, it is characterized in that, described step 3) reaction solvent for use is ethanol, methyl alcohol, N, dinethylformamide, N,N-dimethylacetamide, methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), chloroform or ethyl acetate.
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| CN110229057A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of cyclopropaneacetic acid preparation method |
| CN113956411A (en) * | 2020-07-20 | 2022-01-21 | 中国石油天然气股份有限公司 | Regulator of conjugated diene and application thereof |
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| CN101851241A (en) * | 2010-07-02 | 2010-10-06 | 西安交通大学 | Anti-tumor compound and preparation method and application thereof |
| CN102503888A (en) * | 2011-10-08 | 2012-06-20 | 西安交通大学 | 2-aryl-1,3-isoquinoline diketone anti-tumor compound and synthesis method and application thereof |
| US20130196388A1 (en) * | 2010-07-29 | 2013-08-01 | Kyowa Hakko Bio Co., Ltd. | Process for producing optically active succinimide derivatives |
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| CN101851241A (en) * | 2010-07-02 | 2010-10-06 | 西安交通大学 | Anti-tumor compound and preparation method and application thereof |
| US20130196388A1 (en) * | 2010-07-29 | 2013-08-01 | Kyowa Hakko Bio Co., Ltd. | Process for producing optically active succinimide derivatives |
| CN102503888A (en) * | 2011-10-08 | 2012-06-20 | 西安交通大学 | 2-aryl-1,3-isoquinoline diketone anti-tumor compound and synthesis method and application thereof |
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| CN110229057A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of cyclopropaneacetic acid preparation method |
| CN113956411A (en) * | 2020-07-20 | 2022-01-21 | 中国石油天然气股份有限公司 | Regulator of conjugated diene and application thereof |
| CN113956411B (en) * | 2020-07-20 | 2024-03-01 | 中国石油天然气股份有限公司 | Regulator of conjugated diene and application thereof |
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