A zinc carbonyl reagent, its preparation method and application

Abstract

This invention discloses a zinc carbonyl reagent, its preparation method, and its application. The general structural formula of the zinc carbonyl reagent is: where R... 1 R 2 The reagent is independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl, or benzyl groups. This invention synthesizes and prepares a zinc carbonyl reagent, which is then applied to the synthesis of urea and thiocarbamate drugs. This provides a new reaction pathway for drug molecule synthesis, and is safe, reliable, and non-toxic. It solves the problem that the synthesis of urea and thiocarbamate drugs in existing technologies requires the use of toxic carbon monoxide, phosgene, and its derivative triphosgene, resulting in a high risk factor in the synthesis process. The synthesis method of this invention uses simple raw materials, has mild reaction conditions, and the synthesized zinc carbonyl reagent can be directly used in the reaction as a solid, making the operation simple.

Description

Technical Field

[0001] This invention relates to the field of synthetic organic chemistry, specifically to a zinc carbonyl reagent, its preparation method, and its application. Background Technology

[0002] Acyl anions are important structural segments in organic molecules, including ester groups, amides, and urea thiocarbamates. They are used in the synthesis of a wide variety of chemical products and fine chemicals, thus playing an irreplaceable role in pharmaceuticals, pesticides, and materials production. Current methods for synthesizing acyl anions generally include: inserting CO into copper amine or lithium amine; and at low temperatures, metallizing various formamide compounds with lithium alkali metals. The classic method for preparing urinary derivatives generally uses phosgene or its derivative triphosgene; thiocarbamate drugs are also generally synthesized from phosgene and similar reagents. Recently, carbon monoxide has been used as a reliable alternative to phosgene; however, phosgene, its derivative triphosgene, and carbon monoxide are all toxic and dangerous. Therefore, developing a safe and non-toxic zinc carbonyl reagent for the synthesis of urea and thiocarbamate drugs provides an alternative reaction pathway for drug molecule synthesis. Summary of the Invention

[0003] The technical problem to be solved by this invention is to provide a zinc carbonyl reagent and its preparation method and application, so as to prepare a safe and non-toxic zinc carbonyl reagent and use it for the synthesis of urea and thiocarbamate drug molecules, providing a new reaction route for drug molecule synthesis, which is safe, reliable and non-toxic, and solves the problem that the synthesis of urea and thiocarbamate drugs in the prior art requires the use of toxic carbon monoxide, phosgene and its derivative triphosgene, resulting in a high risk factor in the synthesis process.

[0004] To address the aforementioned technical problems, the first aspect of the present invention provides a zinc carbonyl reagent, the general structural formula of which is: Among them, R 1 R 2 The individual compounds are selected independently from chain alkyl, cyclic alkyl, substituted alkyl, aryl, or benzyl.

[0005] Furthermore, the zinc carbonyl reagent is selected from one of the following compounds:

[0006] The second aspect of the present invention provides a method for preparing the carbonyl zinc reagent described in the first aspect, comprising the following steps: mixing and reacting a formamide compound and zinc pivalate (Zn(OPiv)2) in an organic solvent under the action of lithium 2,2,6,6-tetramethylpiperidine (LiTMP) to obtain the carbonyl zinc reagent.

[0007] Furthermore, the structural formula of the formamide compound is as follows: Among them, R 1 R 2 The individual compounds are selected independently from chain alkyl, cyclic alkyl, substituted alkyl, aryl, or benzyl.

[0008] Furthermore, the molar ratio of the formamide compound, lithium 2,2,6,6-tetramethylpiperidine, and zinc pentovalinate is 1:(1-2):(1-3).

[0009] Furthermore, the temperature of the mixing reaction is 0-25℃, and the reaction time is 15-30 min.

[0010] Furthermore, the structural formula of the 2,2,6,6-tetramethylpiperidine lithium is:

[0011] Furthermore, the preparation method of the 2,2,6,6-tetramethylpiperidine lithium includes the following steps:

[0012] S1. Under a protective atmosphere, 2,2,6,6-tetramethylpiperidine is added to an organic solvent and mixed and reacted at -40°C for 5-10 min to obtain a reaction solution;

[0013] S2. Slowly add n-butyllithium dropwise to the reaction solution, then heat to 0°C and react for 1-2 hours to obtain 2,2,6,6-tetramethylpiperidine lithium.

[0014] Furthermore, in S1, the protective atmosphere is selected from nitrogen or argon.

[0015] Furthermore, the molar ratio of 2,2,6,6-tetramethylpiperidine to n-butyllithium is 1:(1-1.2).

[0016] The third aspect of this invention provides the application of the carbonyl zinc reagent described in the first aspect in the synthesis of drug molecules.

[0017] Furthermore, the general structural formula of the drug molecule is: Among them, R 1 R 2 Independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl, or benzyl, R 3 Selected from chain alkyl, cyclic alkyl, substituted alkyl, or benzyl groups, R 4 Selected from hydrogen or alkyl, R 5 Selected from alkyl or benzyl groups.

[0018] Furthermore, the preparation method of the drug molecule includes the following steps: in an organic solvent, compound I and the zinc carbonyl reagent are mixed and reacted under the action of a catalyst to obtain the drug molecule;

[0019] The general structural formula of compound I is: Among them, R 3 Selected from chain alkyl, cyclic alkyl, substituted alkyl, or benzyl groups, R 4 R5 is selected from hydrogen or alkyl, and R5 is selected from alkyl or benzyl.

[0020] Furthermore, in this invention, the organic solvent is selected solely from tetrahydrofuran or dichloromethane.

[0021] Furthermore, compound I is At that time, the reaction temperature was 25-50℃, and compound I was The reaction temperature is 0-50℃.

[0022] Furthermore, the molar ratio of compound I to the zinc carbonyl reagent is 1:(1-1.5).

[0023] Furthermore, the catalyst is selected from one or more of Co, Fe, Cr, Ni and Cu.

[0024] The beneficial effects of this invention are:

[0025] This invention utilizes zinc carbonyl reagent for the synthesis of urea and thiocarbamate drugs, providing a new reaction pathway for drug molecule synthesis that is safe, reliable, and non-toxic. It solves the problem that the synthesis of urea and thiocarbamate drugs in the prior art requires the use of toxic carbon monoxide, phosgene, and the derivative triphosgene, resulting in a high risk factor in the synthesis process.

[0026] The synthesis method of this invention uses simple raw materials, mild reaction conditions, and the synthesized carbonyl zinc reagent can be extracted into a solid and used directly in the reaction, making the operation simple. Attached Figure Description

[0027] Figure 1 This is a feasibility study of the preparation of the carbonyl zinc reagent and urea and thiocarbamate compounds of the present invention;

[0028] Figure 2 The structural formula and conversion rate of the carbonyl zinc reagent prepared in Example 1 of this invention are shown below.

[0029] Figure 3 This is the extended substrate structural formula and conversion rate of urea compounds and thiocarbamate compounds in Example 2 of the present invention;

[0030] Figure 4 Examples 3 and 4 of this invention describe the drug molecule synthesis process and its conversion rate. Detailed Implementation

[0031] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0032] Example 1

[0033] This embodiment relates to a method for synthesizing a zinc carbonyl reagent, comprising the following steps: under a protective gas (N2) atmosphere, Zn(OPiv)2 (1 mmol) and a formamide compound (1 mmol) are dissolved in the organic solvent THF (2 mL), and LiTMP (1 mmol) is slowly added dropwise at 15°C. The reaction is carried out at this temperature for 30 min to obtain the product, the zinc carbonyl reagent. Among them, R 1 R 2 Independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl, or benzyl groups, the feasibility of the reaction is explained as follows: Figure 1 As shown in Chinese formula (1). Among them, formamide compounds are... When reacted, zinc carbonyl reagent 1 was obtained. Other formamide compounds with different structural formulas were then reacted to obtain zinc carbonyl reagents 2-22. The structural formulas and conversion rates of zinc carbonyl reagents 1-22 are shown below. Figure 2 As shown.

[0034] Example 2

[0035] This embodiment involves substrate expansion of urea compounds and thiocarbamate compounds, and the reaction process is as follows: Figure 1 As shown in formulas (2) and (3), the carbonyl zinc reagent obtained in Example 1 was slowly added dropwise to... The reaction was carried out in an organic solution with a copper catalyst for 12 hours to obtain substrate extensions of urea compounds or thiocarbamate compounds, with the following structural formulas: Figure 3 As shown.

[0036] Example 3

[0037] This embodiment relates to a method for synthesizing a urea drug molecule, and the feasibility of the reaction is explained as follows: Figure 1 As shown in Chinese formula (2), it includes the following steps: using zinc carbonyl reagent and The carbonyl zinc reagent obtained in Example 1 was slowly added dropwise to a molar ratio of 1:1. In an organic solution with a copper catalyst, a reaction was carried out at 50°C for 12 h to obtain urea drug molecules 1a, 5a, 9a, 10a, 12a-1, 17a, and 22a. The reaction process and conversion rates are as follows. Figure 4 As shown.

[0038] Example 4

[0039] This embodiment relates to a method for synthesizing a thiocarbamate drug molecule, and the feasibility of the reaction is explained as follows. Figure 1 As shown in Chinese formula (3), it includes the following steps: using zinc carbonyl reagent and The carbonyl zinc reagent obtained in Example 1 was slowly added dropwise to a molar ratio of 1:1. In an organic solution with a copper catalyst, the reaction was carried out at 50°C for 12 h to obtain thiocarbamate drug molecules 2a and 12a-2. The reaction process and conversion rate are as follows. Figure 4 As shown.

[0040] The substrate expansion of Example 2 and the NMR characterization data of the drug molecules in Examples 3 and 4 are as follows: 1,1-Dibutyl-3-phenethylurea (a)

[0041] 1 H-NMR (400MHz, CDCl3): δ = 7.30 (t, J = 7.2Hz, 2H), 7.24-7.17 (m, 3H), 4.22 (t, J = 5.2Hz,1H),3.49(dd,J=12.5,6.6Hz,2H),3.09(t,J=7.6Hz,4H),2.83(t,J=6.7 Hz,2H),1.45-1.38(m,4H),1.28-1.19(m,4H),0.88(t,J=7.3 Hz,6H). 13 C-NMR (100 MHz, CDCl3): δ = 157.7, 139.7, 129.0, 128.7, 126.5, 47.2, 42.0, 36.4, 30.8, 20.3, 14.0. HR-MS (EI) m / zcalcd for: C 17 H 28 N2O[M+H + ]277.2274, found 277.2273.

[0042] N-Phenethylpiperidine-1-carboxamide(b)

[0043] 1 H-NMR (400 MHz, CDCl3): δ = 7.30 (t, J = 7.3 Hz, 2H), 7.24-7.17 (m, 3H), 4.42 (s, 1H), 3.48 (dd, J = 12.7, 6.8 Hz, 2H), 3.30-3.22 (m, 4H), 2.82 (t, J = 6.9 Hz,2H),1.61-1.54(m,2H),1.54-1.47(m,4H). 13C-NMR(100 MHz,CDCl3):δ=157.7,139.7,129.0,128.7,126.4,44.9,42.2,36.6,25.7,24.5.HR-MS(EI)m / z calcd for:C 14 H 20 N2O[M+H + ]233.1648,found 233.1653.

[0044] N-Phenethylmorpholine-4-carboxamide(c)

[0045] 1 H-NMR(400 MHz,CDCl3):δ=7.31(dd,J=10.1,4.5 Hz,2H),7.25-7.15(m,3H),4.50(s,1H),3.66-3.62(m,4H),3.49(dd,J=12.6,6.9 Hz,2H),3.29-3.24(m,4H),2.82(t,J=6.9 Hz,2H). 13 C-NMR(100 MHz,CDCl3):δ=157.8,139.4,128.9,128.7,126.6,66.6,44.0,42.1,36.4.HR-MS(EI)m / z calcd for:C 13 H 18 N2O2[M+H + ]235.1441,found 235.1443.

[0046] 1-Benzyl-1-methyl-3-phenethylurea(d)

[0047] 1 H-NMR(400 MHz,CDCl3):δ=7.34-7.24(m,5H),7.22-7.14(m,5H),4.52-4.38(m,3H),3.51(dd,J=12.7,6.7 Hz,2H),2.84-2.77(m,5H). 13 C-NMR(100 MHz,CDCl3):δ=158.4,139.5,138.0,128.9,128.8,128.7,127.4,127.3,126.4,52.3,42.2,36.5,34.4.HR-MS(EI)m / z calcd for:C 17 H 20 N2O[M+H+ ]269.1648,found 269.1644.

[0048] N-Phenethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide(e)

[0049] 1 H-NMR(400 MHz,CDCl3):δ=7.30(t,J=7.2 Hz,2H),7.25-7.17(m,3H),7.12(d,J=5.2 Hz,1H),6.75(d,J=5.2 Hz,1H),4.58(t,J=4.7 Hz,1H),4.37(s,2H),3.69(t,J=5.7 Hz,2H),3.53(dd,J=12.6,6.8 Hz,2H),2.86-2.82(m,4H). 13 C-NMR(100 MHz,CDCl3):δ=157.7,139.5,133.9,131.7,129.0,128.7,126.5,124.9,123.4,44.4,42.3,41.6,36.5,25.1.HR-MS(EI)m / z calcd for:C 16 H 18 N2OS[M+H + ]287.1213,found 287.1210.

[0050] N-phenethyl-4-(pyrimidin-2-yl)piperazine-1-carboxamide(f)

[0051] 1 H-NMR(400 MHz,CDCl3):δ=8.31(d,J=4.7 Hz,2H),7.31(t,J=7.3 Hz,2H),7.24-7.19(m,3H),6.52(t,J=4.7 Hz,1H),4.49(t,J=5.0 Hz,1H),3.87-3.77(m,4H),3.52(dd,J=12.7,6.8 Hz,2H),3.44-3.37(m,4H),2.84(t,J=6.9Hz,2H). 13C-NMR(100MHz,CDCl3):δ=161.6,157.9,157.7,139.4,129.0,128.8,126.6,110.4,43.5,43.4,42.2,36.5.HR-MS(EI)m / z calcd for:C 17 H 21 N5O[M+H + ]312.1819,found 312.1818.

[0052] 1,1-Dibutyl-3-(1-(2,6-dimethylphenoxy)propan-2-yl)urea(g)

[0053] 1 H-NMR(400 MHz,CDCl3):δ=7.00(d,J=7.4 Hz,2H),6.91(dd,J=8.2,6.6Hz,1H),4.80(d,J=8.0 Hz,1H),4.27-4.16(m,1H),3.84(dd,J=8.9,3.8 Hz,1H),3.71(dd,J=8.9,3.1 Hz,1H),3.29-3.12(m,4H),2.26(s,6H),1.60-1.50(m,4H),1.41(d,J=6.8 Hz,3H),1.37-1.28(m,4H),0.93(t,J=7.3 Hz,6H). 13 C-NMR(100 MHz,CDCl3):δ=157.2,155.1,130.9,129.0,124.1,74.7,47.2,46.7,30.9,20.3,18.5,16.2,14.0.HR-MS(EI)m / zcalcd for:C 20 H 34 N2O2[M+H + ]335.2693,found 335.2695.

[0054] 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-(1-(2,6-dimethylphenoxy)propan-2-yl)-1-methylurea(h)

[0055] 1H-NMR(400 MHz,CDCl3):δ=6.99(d,J=7.4 Hz,2H),6.91(dd,J=8.2,6.7Hz,1H),5.31(d,J=7.5 Hz,1H),4.28-4.11(m,1H),3.84-3.67(m,4H),3.48(ddd,J=14.9,6.9,4.2 Hz,1H),3.30(dt,J=14.9,4.5 Hz,1H),2.96(s,3H),2.27(s,6H),1.40(d,J=6.8Hz,3H),0.89(s,9H),0.06(d,J=2.5 Hz,6H). 13 C-NMR(100MHz,CDCl3):δ=158.5,155.3,131.0,129.0,124.0,74.9,62.5,52.1,46.7,35.6,26.1,18.6,18.5,16.3,-5.3.HR-MS(EI)m / z calcd for:C 21 H 38 N2O3Si[M+H + ]395.2724,found 395.2728.

[0056] (1R,5S)-N-(1-(2,6-Dimethylphenoxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carb oxamide(i)

[0057] 1 H-NMR(400 MHz,CDCl3):δ=6.99(d,J=7.5 Hz,2H),6.91(dd,J=8.2,6.6Hz,1H),4.65(d,J=8.1 Hz,1H),4.26-4.17(m,1H),3.78(dd,J=8.9,3.9 Hz,1H),3.71(dd,J=8.9,3.1 Hz,1H),3.54(t,J=10.2 Hz,2H),3.44-3.37(m,2H),2.25(s,6H),1.58-1.50(m,2H),1.40(d,J=6.8 Hz,3H),0.71(td,J=7.8,5.0 Hz,1H),0.23(dd,J=8.7,4.2 Hz,1H). 13C-NMR(100 MHz,CDCl3):δ=157.0,155.1,130.9,129.1,124.1,74.7,48.2,48.1,46.4,18.6,16.3,16.0,9.8.HR-MS(EI)m / z calcd for:C 17 H 24 N2O2[M+H + ]289.1911,found289.1908.

[0058] 1,1-Dibutyl-3-(((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahy drophenanthren-1-yl)methyl)urea(j)

[0059] 1 H-NMR(400 MHz,CDCl3):δ=7.16(d,J=8.2 Hz,1H),6.98(dd,J=8.1,1.6Hz,1H),6.88(s,1H),4.32(t,J=6.1 Hz,1H),3.22-3.07(m,6H),2.95-2.74(m,3H),2.29(d,J=12.5 Hz,1H),1.91(dd,J=13.3,7.3 Hz,1H),1.79-1.63(m,3H),1.48(dd,J=15.3,7.6Hz,4H),1.43-1.34(m,2H),1.33-1.24(m,6H),1.23(s,3H),1.21(d,J=3.9 Hz,6H),0.92(s,3H),0.86(t,J=7.3 Hz,6H). 13 C-NMR(100MHz,CDCl3):δ=157.8,147.4,145.6,135.0,127.0,124.3,123.9,51.3,47.4,45.8,38.7,37.6,37.6,36.6,33.6,31.0,30.6,25.5,24.1,24.1,20.4,19.1,18.8,18.7,14.0.HR-MS(EI)m / z calcd for:C 29 H 48 N2O[M+H + ]441.3839,found 441.3836.

[0060] 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(1-(2,6-dimethylphenoxy)propan-2-yl)piperidine-1-carboxamide(k)

[0061] 1 H-NMR(400 MHz,CDCl3):δ=8.40(d,J=1.4 Hz,1H),8.39(d,J=1.5 Hz,1H),7.43(d,J=0.7 Hz,1H),7.42(d,J=0.6 Hz,1H),7.14(d,J=13.4 Hz,6H),7.09(d,J=4.8Hz,1H),7.07(d,J=4.8 Hz,1H),6.98(d,J=7.4 Hz,4H),6.93-6.87(m,2H),4.98(dd,J=7.9,4.9 Hz,2H),4.23(ddd,J=10.8,7.1,3.6 Hz,2H),3.80(dd,J=8.9,3.9 Hz,2H),3.71(tt,J=6.6,5.5 Hz,6H),3.42-3.30(m,4H),3.22-3.10(m,4H),2.89-2.76(m,4H),2.57(ddd,J=13.8,9.0,4.5 Hz,2H),2.40(dddd,J=19.3,14.6,7.1,3.5 Hz,6H),2.24(s,12H),1.40(s,3H),1.39(s,3H). 13 C-NMR(100 MHz,CDCl3):δ=157.1,157.1,156.9,156.9,155.0,155.0,146.8,139.6,139.6,137.7,137.7,137.6,137.6,137.4,134.3,133.4,133.0,130.8,130.6,130.6,129.1,129.1,129.0,126.2,124.1,122.4,74.6,74.6,46.7,44.7,44.6,31.8,31.7,31.6,31.5,30.6,30.4,18.4,16.2.HR-MS(EI)m / z calcd for:C 31 H 34 ClN3O2[M+H + ]516.2412,found 516.2415.

[0062] (3S,4R)-3-((Benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-N-methyl-N-((S)-1-phenylethyl)piperidine-1-carboxamide(l)

[0063] 1 H-NMR(400 MHz,CDCl3):δ=7.38-7.34(m,4H),7.30-7.26(m,1H),7.20-7.15(m,2H),6.98(t,J=8.7 Hz,2H),6.62(d,J=8.5 Hz,1H),6.28(d,J=2.5 Hz,1H),6.09(dd,J=8.5,2.5 Hz,1H),5.87(s,2H),5.32(q,J=7.0 Hz,1H),4.05(ddd,J=13.1,3.6,1.9 Hz,1H),3.81(dd,J=12.7,2.1 Hz,1H),3.59(dd,J=9.4,2.9 Hz,1H),3.45(dd,J=9.4,7.5Hz,1H),2.95-2.88(m,1H),2.84(dd,J=13.2,11.3 Hz,1H),2.67-2.60(m,4H),2.22-2.10(m,1H),1.88-1.79(m,2H),1.58(d,J=7.0 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=165.0,161.7(d,J C-F =244.5 Hz),154.3,148.3,141.7,141.4,139.3(d,J C-F =3.1 Hz),128.9(d,J C-F =7.7Hz),128.5,127.3,127.2,115.6(d,J C-F =21.1 Hz),107.9,105.5,101.2,98.0,69.0,54.6,51.0,47.7,44.6,42.1,34.2,31.2,16.4. 19 F-NMR(376 MHz,CDCl3):δ=-116.13.HR-MS(EI)m / z calcd for:C 29 H 31 FN2O4[M+H + ]491.2341,found491.2343.

[0064] N,N-Dibutyl-4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-carboxamide(m)

[0065] 1 H-NMR(400 MHz,CDCl3):δ=7.39-7.34(m,4H),7.30-7.21(m,4H),7.21-7.16(m,1H),4.20(s,1H),3.25-3.17(m,4H),3.14-3.07(m,4H),2.42-2.32(m,4H),1.51-1.40(m,4H),1.25(dd,J=14.9,7.4 Hz,4H),0.89(t,J=7.3Hz,6H). 13 C-NMR(100 MHz,CDCl3):δ=164.9,142.1,141.3,132.8,129.3,128.8,128.8,127.9,127.4,75.7,51.9,47.5,47.3,30.1,20.2,14.0.HR-MS(EI)m / z calcd for:C 26 H 36 ClN3O[M+H + ]442.2620,found 442.2618.

[0066] 1,1-Dibutyl-3-((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylurea(n)

[0067] 1H-NMR(400 MHz,CDCl3):δ=7.31(d,J=8.3 Hz,2H),7.29-7.24(m,1H),7.17(t,J=7.3 Hz,1H),7.08(d,J=2.0 Hz,1H),6.94(d,J=7.5 Hz,1H),6.81(dd,J=8.3,2.0 Hz,1H),5.17(t,J=8.6 Hz,1H),4.18(d,J=3.2 Hz,1H),3.18(td,J=7.0,2.6 Hz,4H),2.62(s,3H),2.35-2.22(m,1H),2.06-1.97(m,1H),1.83-1.73(m,2H),1.60-1.50(m,4H),1.32(dq,J=14.6,7.3 Hz,4H),0.93(t,J=7.3 Hz,6H). 13 C-NMR(100 MHz,CDCl3):δ=165.9,147.4,138.3,137.4,132.3,130.8,130.8,130.1,130.1,128.2,127.6,127.5,127.2,56.6,48.4,43.2,32.0,30.4,30.4,21.4,20.4,14.1.HR-MS(EI)m / z calcd for:C 26 H 34 Cl2N2O[M+H + ]461.2121,found461.2122.

[0068] S-Phenyl dibutylcarbamothioate(o)

[0069] 1 H-NMR(400 MHz,CDCl3):δ=7.50(dd,J=6.4,2.9 Hz,2H),7.41-7.35(m,3H),3.39-3.32(m,4H),1.74-1.51(m,4H),1.45-1.24(m,4H),0.96(d,J=34.2Hz,6H). 13 C-NMR(100 MHz,CDCl3):δ=166.2,135.9,129.1,129.0,48.2,48.0,30.7,30.0,20.2,13.9.HR-MS(EI)m / z calcd for:C 15 H 23 NOS[M+H +]266.1573,found 266.1575.

[0070] S-(4-Cyanophenyl)dibutylcarbamothioate(p)

[0071] 1 H-NMR(400 MHz,CDCl3):δ=7.68-7.55(m,4H),3.34(t,J=7.5 Hz,4H),1.70-1.50(m,4H),1.45-1.23(m,4H),1.05-0.85(m,6H). 13 C-NMR(100 MHz,CDCl3):δ=164.2,135.9,135.8,132.2,118.6,112.4,48.2,48.2,30.7,29.9,20.2,13.9.HR-MS(EI)m / zcalcd for:C 16 H 22 N2OS[M+H + ]291.1526,found 291.1525.S-Cyclohexyldibutylcarbamothioate(q)

[0072] 1 H-NMR(400 MHz,CDCl3):δ=3.46-3.36(m,1H),3.26(d,J=30.6 Hz,4H),1.98(dd,J=8.2,4.5 Hz,2H),1.70(t,J=6.2 Hz,2H),1.61-1.47(m,5H),1.45-1.36(m,4H),1.29(dt,J=18.7,8.9 Hz,5H),1.00-0.85(m,6H). 13 C-NMR(100MHz,CDCl3):δ=167.7,47.9,47.3,43.8,34.0,30.6,30.1,26.4,25.8,20.2,13.9.HR-MS(EI)m / z calcd for:C 15 H 29 NOS[M+H + ]272.2043,found 272.2044.S-(1-Phenyl-1H-tetrazol-5-yl)dibutylcarbamothioate(r)

[0073] 1H-NMR(400 MHz,CDCl3):δ=7.54(pd,J=5.3,1.4 Hz,5H),3.21(t,J=7.1Hz,4H),1.55(dt,J=15.0,7.6 Hz,2H),1.36(td,J=14.6,7.0 Hz,2H),1.27(dd,J=16.2,8.7Hz,2H),1.14(dq,J=14.6,7.3 Hz,2H),0.92(t,J=7.3 Hz,3H),0.84(t,J=7.2 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=159.5,147.4,134.2,130.5,129.4,125.3,48.8,48.2,30.6,29.6,19.9,19.8,13.8.HR-MS(EI)m / z calcd for:C 16 H 23 N5OS[M+H + ]334.1696,found334.1694.

[0074] S-(5-(Trifluoromethyl)pyridin-2-yl)

[0075] (S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carbothioate(s)

[0076] 1 H-NMR(400 MHz,CDCl3):δ=8.83(s,1H),7.93(s,2H),7.25(dd,J=15.7,9.1 Hz,9H),6.75(s,1H),3.90(s,1H),3.59(s,1H),3.14(s,1H),2.89(d,J C-F =14.4Hz,1H). 13 C-NMR(100 MHz,CDCl3):δ=163.7,157.5,146.6(q,J C-F =4.1 Hz),141.3,134.6,134.3,133.9(q,J C-F =3.3 Hz),130.1,129.0,128.6,127.9,127.6,126.6,125.9(q,J C-F =33.5 Hz),124.9(q,J C-F =272.9 Hz),58.2,40.6,28.6. 19F-NMR(376 MHz,CDCl3):δ=-62.44.HR-MS(EI)m / z calcd for:C 22 H 17 F3N2OS[M+H + ]415.1086,found 415.1089.

[0077] 3-Cyclooctyl-1,1-dimethylurea(Cycluron,1a)

[0078] 1 H-NMR(400 MHz,CDCl3):δ=4.25(d,J=6.4 Hz,1H),3.84(dt,J=8.0,4.3Hz,1H),2.85(s,6H),1.80(ddd,J=10.6,6.9,2.9 Hz,2H),1.53(ddd,J=24.5,15.9,10.4 Hz,12H). 13 C-NMR(100 MHz,CDCl3):δ=157.8,50.5,36.2,33.2,27.3,25.6,23.9.HR-MS(EI)m / z calcd for C 11 H 22 N2O[M+H + ]199.1805,found 199.1800.Methyl(morpholine-4-carbonyl)-L-leucinate(Cathepsin Inhibitor precursor,5a)

[0079] 1 H-NMR(400 MHz,CDCl3):δ=4.84(d,J=8.0 Hz,1H),4.51(td,J=8.6,5.4Hz,1H),3.73(s,3H),3.68(t,J=4.9 Hz,4H),3.37(dd,J=9.7,4.6 Hz,4H),1.72-1.57(m,2H),1.55-1.47(m,1H),0.95(d,J=2.5 Hz,3H),0.93(d,J=2.6 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=175.0,157.4,66.6,52.4,52.2,44.1,42.1,25.0,23.0,22.2.HR-MS(EI)m / zcalcd for C 12 H 22N2O4[M+H + ]259.1652,found259.1653.

[0080] N-(2,4-Dichlorobenzyl)-4-phenoxypiperidine-1-carboxamide(solubleEpoxide Hydrolase(sEH)inhibitor,9a)

[0081] 1 H-NMR(400 MHz,CDCl3):δ=7.36(dd,J=5.1,3.0 Hz,2H),7.28(dd,J=12.9,4.4Hz,2H),7.21(dd,J=8.2,2.0 Hz,1H),6.95(t,J=7.3 Hz,1H),6.90(d,J=7.9 Hz,2H),5.15(t,J=5.6 Hz,1H),4.50(dq,J=10.1,3.4 Hz,1H),4.44(d,J=5.8 Hz,2H),3.66-3.56(m,2H),3.37-3.28(m,2H),1.92(ddd,J=11.6,7.4,3.4Hz,2H),1.84-1.76(m,2H). 13 C-NMR(100 MHz,CDCl3):δ=157.3,157.1,135.6,134.1,133.7,131.2,129.7,129.3,127.4,121.2,116.2,71.6,42.4,40.9,30.3.HR-MS(EI)m / z calcd for C 19 H 20 Cl2N2O2[M+H + ]379.0975,found 379.0978.

[0082] 4-(2-Chlorophenyl)-N-(4-cyanobenzyl)piperazine-1-carboxamide(solubleEpoxide Hydrolase(sEH)inhibitor precursor,10a)

[0083] 1H-NMR(400 MHz,CDCl3):δ=7.58(d,J=8.2 Hz,2H),7.41(d,J=8.1 Hz,2H),7.36(dd,J=5.6,2.5 Hz,1H),7.25-7.19(m,1H),7.05-6.95(m,2H),5.22(t,J=5.5 Hz,1H),4.48(d,J=5.7 Hz,2H),3.62-3.51(m,4H),3.08-2.96(m,4H). 13 C-NMR(100 MHz,CDCl3):δ=157.7,148.8,145.5,132.4,130.8,129.0,128.1,127.8,124.4,120.6,119.0,110.9,51.1,44.5,44.3.HR-MS(EI)m / z calcd for C 19 H 19 ClN4O[M+H + ]355.1320,found355.1325.

[0084] Methyl(azepane-1-carbonyl)-D-valinate(Ca 2+ Channel Blocker precursor,12a-1)

[0085] 1 H-NMR(400 MHz,CDCl3):δ=4.82(d,J=8.1 Hz,1H),4.44(dd,J=8.4,4.9Hz,1H),3.69(s,3H),3.39(t,J=6.0 Hz,4H),2.10(dd,J=11.9,6.8 Hz,1H),1.69(d,J=3.6Hz,4H),1.59-1.47(m,4H),0.92(d,J=6.8 Hz,3H),0.87(d,J=6.9 Hz,3H). 13 C-NMR(100MHz,CDCl3):δ=174.2,157.5,58.4,52.0,46.6,31.5,28.6,27.2,19.1,18.0.HR-MS(EI)m / z calcd for C 13 H 24 N2O3[M+H + ]257.1860,found257.1859.

[0086] tert-Butyl 4-(benzyl(ethyl)carbamoyl)piperazine-1-carboxylate(Amperozide precursor,17a)

[0087] 1 H-NMR(400 MHz,CDCl3):δ=7.33(t,J=7.2 Hz,2H),7.25(dt,J=8.2,5.6Hz,3H),4.41(s,2H),3.42(dd,J=6.2,4.1 Hz,4H),3.24-3.19(m,4H),3.16(d,J=7.1 Hz,2H),1.45(s,9H),1.11(t,J=7.1 Hz,3H). 13 C-NMR(100 MHz,CDCl3):δ=164.7,154.9,138.0,128.7,127.5,127.3,80.1,50.8,47.1,42.5,28.5,12.8.HR-MS(EI)m / z calcd forC 19 H 29 N3O3[M+H + ]348.2282,found 348.2285.

[0088] 1-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea(Pimavanserin,22a)

[0089] 1 H-NMR(400 MHz,CDCl3):δ=7.16(dd,J=8.3,5.4 Hz,2H),6.97(dd,J=15.3,8.5Hz,4H),6.76(d,J=8.5 Hz,2H),4.49(t,J=5.2 Hz,1H),4.35-4.28(m,3H),4.26(d,J=5.4 Hz,2H),3.66(d,J=6.5 Hz,2H),2.84(d,J=11.6 Hz,2H),2.24(s,3H),2.10-1.99(m,3H),1.75-1.57(m,4H),0.99(d,J=6.7 Hz,6H). 13 C-NMR(100 MHz,CDCl3):δ=162.1(d,J C-F =245.6 Hz),158.5,158.2,134.2(d,JC-F =3.0 Hz),131.3,128.7,127.8(d,J C-F =8.0Hz),115.8(d,J C-F =21.5 Hz),114.6,74.5,55.4,52.3,46.2,45.2,44.5,30.2,28.3,19.3. 19 F-NMR(376 MHz,CDCl3):δ=-115.36(s).HR-MS(EI)m / z calcd for C 25 H 34 FN3O2[M+H + ]428.2708,found 428.2705.

[0090] S-(4-Chlorobenzyl)diethylcarbamothioate(Thiocarbamates,2a)

[0091] 1 H-NMR(400 MHz,CDCl3):δ=7.27(q,J=8.6 Hz,4H),4.10(s,2H),3.37(d,J=30.0 Hz,4H),1.16(t,J=6.8 Hz,6H). 13 C-NMR(100 MHz,CDCl3):δ=166.4,137.3,132.9,130.4,128.7,42.2,33.9,13.8,13.3.HR-MS(EI)m / z calcd for C 12 H 16 ClNOS[M+H + ]258.0714,found 258.0713.

[0092] S-Ethyl azepane-1-carbothioate(Molinate,12a-2)

[0093] 1 H-NMR(400MHz,CDCl3):δ=3.60-3.49(m,2H),3.43(t,J=5.9Hz,2H),2.89(q,J=7.4Hz,2H),1.76-1.68(m,4H),1.55(d,J=2.7Hz,4H),1.27(t,J=7.4Hz,3H). 13C-NMR (100MHz, CDCl3): δ=168.0,47.7,47.4,28.5,28.0,27.3,27.1,24.7,15.5.HR-MS(EI)m / zcalcd for C9H 17 NOS[M+H + ]188.1104,found188.1106.

[0094] In summary, this invention synthesizes and prepares a safe and non-toxic zinc carbonyl reagent, which is then used in the synthesis of drug molecules, especially urea and thiocarbamate drugs, providing a new reaction pathway for drug molecule synthesis. The synthesis method uses simple raw materials, has mild reaction conditions, and yields high output.

[0095] The embodiments described above are merely preferred embodiments for fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A zinc carbonyl reagent, characterized in that, The general structural formula of the zinc carbonyl reagent is: Specifically selected from one of the following compounds:

2. A method for preparing the zinc carbonyl reagent according to claim 1, characterized in that, The process includes the following steps: in an organic solvent, a formamide compound and zinc pivalate are mixed and reacted in the presence of lithium 2,2,6,6-tetramethylpiperidine to obtain the carbonyl zinc reagent.

3. The method for preparing the zinc carbonyl reagent as described in claim 2, characterized in that, The molar ratio of the formamide compound, lithium 2,2,6,6-tetramethylpiperidine, and zinc tervastatin is 1:(1-2):(1-3).

4. The application of the carbonyl zinc reagent according to claim 1 in the synthesis of drug molecules, characterized in that, The preparation method of the drug molecule includes the following steps: in an organic solvent, compound I and the zinc carbonyl reagent are mixed and reacted under the action of a catalyst to obtain the drug molecule; The general structural formula of compound I is: The general structural formula of the drug molecule is: Specifically selected from one of the following compounds:

5. The application as described in claim 4, characterized in that, The compound I is At that time, the reaction temperature was 25-50℃, and compound I was The reaction temperature is 0-50℃.

6. The application as described in claim 4, characterized in that, The molar ratio of compound I to the zinc carbonyl reagent is 1:(1-1.5).

7. The application as described in claim 4, characterized in that, The catalyst is selected from one or more of Co, Fe, Cr, Ni and Cu.

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