Preparation method of deuterated nitrogen-containing heterocyclic compound
阅读说明：本技术 一种氘代含氮杂环化合物的制备方法 (Preparation method of deuterated nitrogen-containing heterocyclic compound ) 是由 高章华 江之江 吴涛 李岩 陈佳 于 2021-08-25 设计创作，主要内容包括：本发明公开了一种氘代含氮杂环化合物的制备方法,以式1至式5其中之一所示的含氮杂环化合物为原料,在氘源试剂及惰性气体的存在下,无机碱作为催化剂,60-120℃下进行氘代反应,控制反应时间,获得式1a至式5a其中之一所示的氘代含氮杂环化合物或式1b至式5b其中之一所示的氘代含氮杂环化合物。本发明具有反应条件温和,操作简便,氘代效果好,收率高的优点。(The invention discloses a preparation method of a deuterated nitrogen-containing heterocyclic compound, which takes a nitrogen-containing heterocyclic compound shown in one of formulas 1 to 5 as a raw material, takes inorganic base as a catalyst in the presence of a deuterium source reagent and inert gas, carries out a deuterated reaction at 60-120 ℃, and controls the reaction time to obtain the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1a to 5a or the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1b to 5 b. The method has the advantages of mild reaction conditions, simple and convenient operation, good deuteration effect and high yield.)
1. A preparation method of a deuterated nitrogen-containing heterocyclic compound is characterized in that a nitrogen-containing heterocyclic compound shown in one of formulas 1 to 5 is used as a raw material, in the presence of a deuterium source reagent and inert gas, inorganic base is used as a catalyst, a deuteration reaction is carried out at 60-120 ℃, and the reaction time is controlled to obtain the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1a to 5a or the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1b to 5 b;
2. the method according to claim 1, wherein the inorganic base is one selected from potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium carbonate, potassium phosphate, potassium acetate, and potassium hydroxide.
3. The method of claim 1, wherein the deuterium source reagent is deuterated dimethyl sulfoxide.
4. The preparation method according to claim 1, wherein the molar ratio of the materials in the reaction is that the nitrogen-containing heterocyclic compound: inorganic base: deuterium source reagent 1:0.1-2.5: 5.0-60.
5. The method according to claim 1, wherein the inert gas atmosphere is an inert gas atmosphere of nitrogen or argon.
6. The method according to claim 1, wherein the reaction time is controlled to 4 to 6 hours, and the deuterated nitrogen-containing heterocyclic compound represented by one of formulae 1a to 5a is obtained.
7. The method according to claim 1, wherein the reaction time is controlled to 12 to 48 hours, and the deuterated nitrogen-containing heterocyclic compound represented by one of formulae 1b to 5b is controlled.
8. The preparation method according to claim 1, wherein the R group is one or more of a hydrogen atom, a bromine atom, a methyl group, a tert-butyl group, a phenyl group, a p-tolyl group, a 3-biphenyl group, a cyano group, an amino group, a dimethylamino group and a methoxy group.
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of a deuterated nitrogen-containing heterocyclic compound.
Background
Deuterium is an isotope of hydrogen, and since the discovery, deuterium is widely used in various fields such as nuclear energy, military, analysis and detection, medical inspection, synthesis and modification of high polymer materials, pharmacy and the like due to its unique properties. For example, in the field of medicinal chemistry, deuterium is introduced into non-metabolic sites and non-action sites of a medicinal molecule, and an isotope tracing method is adopted, so that the absorption, distribution, metabolism, excretion and the like of the medicinal molecule can be researched under the condition of not influencing the action of the medicament; in the field of material research, the stability of the C-D bond is better than that of the C-H bond, so that the service life of equipment can be prolonged under the condition of not influencing other properties of the material.
The nitrogen-containing heterocyclic compound is a heterocyclic compound containing nitrogen heteroatom, is one of the most widely applied and developed compounds in heterocyclic compounds, is used as an important raw material in chemical industry, particularly fine chemical industry, and has a wide application range, for example, 3-methylpyridine can be used for synthesizing nicotinic acid or nicotinamide, can be used as a vasodilation therapeutic agent, can be used for treating optic atrophy and retinopathy, and can also be used for synthesizing agricultural chemicals, namely herbicide. The deuterium-substituted product of the nitrogen-containing heterocyclic compound is used as an intermediate to synthesize medicaments, agricultural chemicals, feeds, spices, daily chemical products and the like, so that the performance can be improved, and the product is more excellent.
At present, the research on deuteration of nitrogen-containing heterocyclic compounds is still in the starting stage, the existing deuteration method is mainly a chemical synthesis method, transition metal compounds containing Ir, Pd, Ru, Fe and the like are mostly adopted as catalysts for synthesis, a plurality of auxiliaries are needed to participate in the reaction, the experiment is complicated, the operation is complex, and the yield is low.
Disclosure of Invention
The invention aims to provide a preparation method of a deuterated nitrogen-containing heterocyclic compound, which takes a safe and low-toxicity nitrogen-containing heterocyclic compound as a raw material, completes the synthesis of the deuterated nitrogen-containing heterocyclic compound through one-pot reaction in the presence of inert gas, and has the advantages of mild reaction conditions, simple and convenient operation, good deuterated effect and high yield.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of a deuterated nitrogen-containing heterocyclic compound takes a nitrogen-containing heterocyclic compound shown in one of formulas 1 to 5 as a raw material, carries out deuterated reaction at 60-120 ℃ in the presence of a deuterated reagent and an inert gas and an inorganic base as a catalyst, and controls the reaction time to obtain the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1a to 5a or the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1b to 5 b;
the inorganic base is selected from one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium carbonate, potassium phosphate, potassium acetate and potassium hydroxide.
The deuterium source reagent is deuterated dimethyl sulfoxide.
The molar use ratio of the materials in the reaction is nitrogen-containing heterocyclic compound: inorganic base: deuterium source reagent 1:0.1-2.5: 5.0-60.
The inert atmosphere is an inert gas environment consisting of nitrogen or argon.
Controlling the reaction time to be 4-6 hours to obtain the deuterated nitrogen-containing heterocyclic compound shown in one of the formulas 1a to 5 a.
And controlling the reaction time to be 12-48 hours, wherein the deuterated nitrogen-containing heterocyclic compound is shown in one of the formulas 1b to 5 b.
The R group is one or more of hydrogen atom, bromine atom, methyl, tert-butyl, phenyl, p-tolyl, 3-biphenyl, cyano, amino, dimethylamino and methoxyl.
The invention has the beneficial effects that:
1. the invention can carry out selective deuteration, which is selectively reflected on the deuteration of the pyridine ring, can obtain partial site deuteration products after short-time reaction, and can continue to prolong the time to carry out deuteration on the rest sites.
2. The technical route is completed under the conventional laboratory conditions, the solvent is not required to be replaced midway in the one-step one-pot reaction, the dosage of a deuterium source is not required to be increased, the reaction time is short, the deuteration effect is good, the yield is high, and the reaction operation is simple.
3. The method has good universality and can be used for preparing various nitrogen-containing heterocyclic compound deuterated products.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
General description of the embodiments
A preparation method of a deuterated nitrogen-containing heterocyclic compound takes a nitrogen-containing heterocyclic compound shown in one of formulas 1 to 5 as a raw material, carries out deuterated reaction at 60-120 ℃ in the presence of a deuterated reagent and an inert gas and an inorganic base as a catalyst, and controls the reaction time to obtain the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1a to 5a or the deuterated nitrogen-containing heterocyclic compound shown in one of formulas 1b to 5 b;
the inorganic base is selected from one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium carbonate, potassium phosphate, potassium acetate and potassium hydroxide. The inorganic base is preferably potassium tert-butoxide. The deuterium source reagent is deuterated dimethyl sulfoxide.
The molar use ratio of the materials in the reaction is nitrogen-containing heterocyclic compound: inorganic base: deuterium source reagent 1:0.1-2.5: 5.0-60.
The inert atmosphere is an inert gas environment consisting of high-purity nitrogen or argon.
Controlling the reaction time to be 4-6 hours to obtain the deuterated nitrogen-containing heterocyclic compound shown in one of the formulas 1a to 5 a.
And controlling the reaction time to be 12-48 hours, wherein the deuterated nitrogen-containing heterocyclic compound is shown in one of the formulas 1b to 5 b.
The R group is one or more of hydrogen atom, bromine atom, methyl, tert-butyl, phenyl, p-tolyl, 3-biphenyl, cyano, amino, dimethylamino and methoxyl.
Example 1 Selective deuteration of Nitrogen-containing heterocyclic Compounds
In a 15mL dry pressure-resistant bottle, 2-bromopyridine (95. mu.L, 1.0mmol,1eq), potassium tert-butoxide (112.2mg,1.0mmol) and deuterated dimethyl sulfoxide (2mL) were weighed, and the reaction system was purged with nitrogen and stirred at 100 ℃ for 4 hours.
After the reaction, dichloromethane extraction, organic phase saturated brine washing, Na2SO4After drying, concentration and subsequent purification by silica gel column (PE: EA ═ 30:1, Rf ═ 0.5) gave 106.7mg of colorless liquid with a deuteration of 151% D in 67% yield.1H NMR(399MHz,DMSO-d6)δ8.38(dt,J＝4.8,1.1Hz,1H),7.46–7.40(m,1H).MS(EI)159.6。
Under the same conditions, from each pyridine compound, a deuterated product was obtained under the above conditions, and the results are shown in the following table:
compound numbering
Degree of deuteration (% D)
Yield (%)
1
297
94
2
360
98
3
644
39
4
595
65
5
670
10
6
620
97
7
714
78
8
430
42
9
95
29
10
478
59
11
157
55
12
589
67
13
389
32
14
94
32
15
142
95
。
Deuterated 2-phenylpyridine-d (1).1H NMR(399MHz,Chloroform-d)δ8.71(s,1H),8.03–7.96(m,2H),7.52–7.45(m,2H),7.45–7.39(m,1H)。
Deuterated 5-methyl-2-phenylpyridine-d (2).1H NMR(399MHz,DMSO-d6)δ8.48(q,J＝1.1Hz,1H),8.06–8.00(m,2H),7.86–7.81(m,1H),7.71–7.64(m,1H),7.50–7.42(m,2H),7.42–7.35(m,1H).
Deuterated 2,5-dimethylpyridine-d (3).1H NMR(399MHz,DMSO-d6)δ8.25(t,J＝1.2Hz,1H),7.11(ddd,J＝4.5,3.3,0.9Hz,1H)。
Deuterated 3,4-dimethylpyridine-d (4).1H NMR(399MHz,DMSO-d6)δ8.26(d,J＝0.7Hz,1H),8.25–8.21(m,1H),7.13(dd,J＝4.8,0.7Hz,1H)。
Deuterated 2,3-dimethylpyridine-d (5).1H NMR(399MHz,DMSO-d6)δ8.26–8.19(m,1H)。
Deuterated 2,6-dimethylpyridine-d (6).1H NMR(399MHz,DMSO-d6)δ8.07(s,1H),7.07–6.93(m,1H),3.89(s,1H)。
Deuterated 5-methyl-2- (4-tolyl) pyridine 5-methyl-2- (p-tolyl) pyridine-d (7).1H NMR(399MHz,DMSO-d6)δ8.49–8.42(m,1H),7.97–7.90(m,2H),7.79(d,J＝8.1Hz,1H),7.67–7.60(m,1H),7.26(d,J＝7.9Hz,2H),2.32(d,J＝12.5Hz,6H)。
Deuterated 2-bromopyridine 2-bromopyrdine-d (8).1H NMR(399MHz,DMSO-d6)δ8.24–8.18(m,1H),7.57(dt,J＝2.2,0.9Hz,1H)。
Deuterated 2-bromo-5-phenylpyridine-d (9).1H NMR(399MHz,DMSO-d6)δ8.77–8.61(m,1H),8.07–8.00(m,1H),7.75–7.68(m,2H),7.59–7.34(m,3H)。
Deuterated 3-amino-6-bromopyridine 6-bromopyrridin-3-amine-d (10).1H NMR(399MHz,DMSO-d6)δ7.06(s,1H),6.91–6.77(m,1H),5.21(s,39H),2.18(p,J＝2.3Hz,2H)。
Deuterated 3-cyano-6-bromopyridine 6-bromonicotininolide-d (11).1H NMR(399MHz,DMSO-d6)δ8.87(d,J＝1.0Hz,1H),7.94–7.89(m,1H)。
Deuterated 2-bromo-3,5-dimethylpyridine-d (12).1H NMR(399MHz,DMSO-d6)δ8.04–7.99(m,1H),7.56(dd,J＝2.4,0.5Hz,1H)。
Deuterated 2-bromo-3-fluoro-6-methylpyridine-d (13).1H NMR(399MHz,DMSO-d6)δ7.36(d,J＝3.7Hz,1H)。
Deuterated 2-bromo-3-methoxypyridine-d (14).1H NMR(399MHz,DMSO-d6)δ7.98–7.92(m,1H),7.40(d,J＝4.6Hz,1H),3.91–3.85(m,2H)。
Deuterated 4-dimethylaminopyridine-4-amine-d (15).1H NMR(399MHz,DMSO-d6)δ8.10(d,J＝2.9Hz,1H),2.95(s,3H)。
Under the same conditions, from biphenyl, pyrimidine, indole, azaanthracene compounds, from the conditions to obtain deuterium products, the results are shown in the following table:
。
2-([1,1'-biphenyl]-3-yl)pyridine-d(16).1H NMR(399MHz,Chloroform-d)δ8.74(s,1H),8.28–8.22(m,1H),7.97(ddd,J＝7.7,1.8,1.1Hz,1H),7.72–7.68(m,2H),7.68–7.64(m,1H),7.59–7.53(m,1H),7.50–7.43(m,2H),7.40–7.34(m,1H)。
deuterated 2,9-dimethyl-1,10-phenanthroline-d (17).1H NMR(399MHz,Chloroform-d)δ8.14–8.09(m,3H),7.96–7.88(m,1H),7.70(s,5H),7.52–7.46(m,3H),7.35(d,J＝1.1Hz,1H),2.92(p,J＝2.2Hz,2H)。
Deuterated 4,7-di-tert-butyl-1,10-phenanthroline-d (18).1H NMR(399MHz,Chloroform-d)δ8.61–8.56(m,2H),8.41(s,2H),7.31(dd,J＝5.2,2.0Hz,1H),1.41(s,15H)。
Deuterated 2,2' -bipyridine-d (19).1H NMR(399MHz,DMSO-d6)δ8.67(d,J＝1.0Hz,9H),8.37(d,J＝1.0Hz,5H),7.95–7.90(m,1H),7.44(d,J＝4.7Hz,1H)。
Deuterated 2,2' -bipyrimidine-d (20).1H NMR(399MHz,DMSO-d6)δ9.02–8.95(m,3H),7.64(t,J＝4.9Hz,1H)。
Deuterated biquinoline-2, 2' -biquinoline-d (21).1H NMR(399MHz,Chloroform-d)δ8.93–8.77(m,1H),8.32(dt,J＝8.7,1.2Hz,1H),8.24(ddt,J＝8.5,4.6,1.0Hz,2H),8.05(ddd,J＝8.3,1.4,0.7Hz,1H),7.94–7.83(m,1H),7.76(ddp,J＝8.3,6.8,1.2Hz,2H),7.59(tdd,J＝8.0,6.8,1.2Hz,2H)。
Deuterated 1H-indole-d (22).1H NMR(399MHz,DMSO-d6)δ11.05(s,1H),7.53(dd,J＝7.9,1.0Hz,1H),7.39(dd,J＝8.1,1.0Hz,1H),7.32(t,J＝2.1Hz,1H),7.07(ddd,J＝8.1,6.9,1.2Hz,1H),6.97(ddd,J＝7.9,6.9,1.1Hz,1H)。
Deuterated Isoquinoline-d (23).1H NMR(399MHz,DMSO-d6)δ7.94–7.89(m,1H),7.76(dddd,J＝10.7,8.1,6.9,1.3Hz,1H),7.66(tdd,J＝8.3,6.8,1.3Hz,1H)。
Deuterated Acridine-d (24).1H NMR(399MHz,DMSO-d6)δ8.20–8.13(m,4H),7.85(ddd,J＝8.8,6.6,1.4Hz,2H),7.61(ddd,J＝8.3,6.5,1.1Hz,2H)。
Example 2 Perdeuteration of Nitrogen-containing heterocyclic Compound
The procedure is as in example 1, except that the reaction time is extended to 24 hours.
Compound numbering
Degree of deuteration (% D)
Yield (%)
25
326
100
26
228
58
27
43
99
28
175
74
Deuterated 2,5-diphenylpyridine-d (25).1H NMR(399MHz,DMSO-d6)δ8.99(s,1H),8.18–8.11(m,2H),7.83–7.76(m,2H),7.55–7.48(m,4H),7.47–7.40(m,2H)。
Deuterated 1,10-phenanthroline-d (26).1H NMR(399MHz,DMSO-d6)δ9.10–9.05(m,1H),7.98(s,1H),7.79–7.72(m,1H)。
Deuterated 2-methyl-1H-indole-d (27).1H NMR(399MHz,DMSO-d6)δ10.86(s,1H),7.38(ddt,J＝7.6,1.5,0.8Hz,1H),7.25(dq,J＝7.9,1.0Hz,1H),6.97(ddd,J＝8.1,7.0,1.3Hz,1H),6.93–6.88(m,1H),6.10(dt,J＝2.0,1.0Hz,1H),2.38(d,J＝0.9Hz,3H)。
Deuterated Quinoline Quinoline-d (28).1H NMR(399MHz,DMSO-d6)δ8.90(d,J＝1.3Hz,1H),8.02(ddd,J＝8.5,1.2,0.7Hz,1H),7.97(ddt,J＝8.1,1.7,0.8Hz,1H),7.75(ddd,J＝8.5,6.9,1.5Hz,1H),7.60(ddd,J＝8.1,6.8,1.2Hz,1H)。
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
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