Carbonyl zinc reagent as well as preparation method and application thereof

Abstract

The invention discloses a carbonyl zinc reagent as well as a preparation method and application thereof, the structural general formula of the carbonyl zinc reagent is # imgabs0 #, and R1 and R2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl. The carbonyl zinc reagent is synthesized and prepared and is applied to synthesis of urea and thiocarbamate drug molecules, a new reaction path is provided for synthesis of drug molecules, and the carbonyl zinc reagent is safe, reliable, non-toxic and free of toxic and side effects. The problem that in the prior art, toxic carbon monoxide, phosgene and derivative triphosgene need to be adopted for synthesizing urea and thiocarbamate drugs, and consequently the danger coefficient in the synthesis process is high is solved. The synthesis method has the advantages of simple raw materials and mild reaction conditions, the synthesized carbonyl zinc reagent can be extracted into a solid to be directly used in the reaction, and the operation is simple.

Description

Technical Field

[0001] The invention relates to the technical field of synthetic organic chemistry, and in particular to a carbonyl zinc reagent and a preparation method and application thereof. Background Art

[0002] Acyl anions are important structural fragments in organic molecules, including esters, amides, urea thiocarbamates, etc., which are synthesized through chemical reactions to produce a variety of chemical products and fine chemicals. Therefore, acyl anions occupy an irreplaceable position in the production of medicines, pesticides, and materials. At present, the methods for synthesizing acyl anions generally include: inserting CO into amide copper or amide lithium; and metallizing various formamide compounds with lithium alkali metal at low temperatures. The classic method for preparing urea derivatives generally uses reagents such as phosgene or its derivative triphosgene; and thiocarbamate drug molecules are generally synthesized from reagents such as phosgene. Recently, carbon monoxide has been used as a reliable substitute for phosgene, but phosgene, its derivative triphosgene, and carbon monoxide are all toxic and dangerous. Therefore, the development of a safe and non-toxic carbonyl zinc reagent for the synthesis of urea and thiocarbamate drugs provides another reaction pathway for the synthesis of drug molecules. Summary of the invention

[0003] The technical problem to be solved by the present invention is to provide a carbonyl zinc reagent and a preparation method and application thereof, to prepare a safe and non-toxic carbonyl zinc reagent, and to use it for the synthesis of urea and thiocarbamate drug molecules, to provide a new reaction path for the synthesis of drug molecules, and to solve the problem that in the prior art, toxic carbon monoxide, phosgene and a derivative triphosgene are required to be used in the synthesis of urea and thiocarbamate drugs, resulting in a high risk factor in the synthesis process.

[0004] In order to solve the above technical problems, the first aspect of the present invention provides a carbonyl zinc reagent, the general structural formula of the carbonyl zinc reagent is: Among them, R 1 , R 2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl.

[0005] Further, the carbonyl zinc 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: in an organic solvent, a formamide compound and zinc pivalate (Zn(OPiv)2) are mixed and reacted under the action of 2,2,6,6-tetramethylpiperidinium lithium (LiTMP) to obtain the carbonyl zinc reagent.

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

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

[0009] Furthermore, the temperature of the mixed reaction is 0-25°C, and the reaction time is 15-30 minutes.

[0010] Further, the structural formula of the 2,2,6,6-tetramethylpiperidinium lithium is:

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

[0012] S1. Under a protective atmosphere, add 2,2,6,6-tetramethylpiperidine to an organic solvent, mix and react at -40°C for 5-10 minutes to obtain a reaction solution;

[0013] S2. Slowly drop n-butyl lithium into the reaction solution, then heat the temperature to 0° C. and react for 1-2 hours to obtain 2,2,6,6-tetramethylpiperidinium 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 the present invention provides the use 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 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, R 3 is selected from chain alkyl, cyclic alkyl, substituted alkyl or benzyl, R 4 is selected from hydrogen or alkyl, R 5 Selected from alkyl or benzyl.

[0018] Furthermore, the preparation method of the drug molecule comprises the following steps: in an organic solvent, mixing compound I with the carbonyl zinc reagent under the action of a catalyst to obtain the drug molecule;

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

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

[0021] Further, the compound I is When the reaction temperature is 25-50°C, the compound Ⅰ is The reaction temperature is 0-50°C.

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

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

[0024] Beneficial effects of the present invention:

[0025] The invention uses a carbonyl zinc reagent for the synthesis of urea and thiocarbamate drug molecules, provides a new reaction path for drug molecule synthesis, and is safe, reliable and non-toxic, thereby solving the problem that in the prior art, urea and thiocarbamate drugs need to be synthesized using toxic carbon monoxide, phosgene and a derivative triphosgene, resulting in a high risk factor in the synthesis process.

[0026] The synthesis method of the invention has simple raw materials and mild reaction conditions, and the synthesized carbonyl zinc reagent can be extracted into a solid and directly used in the reaction, and the operation is simple. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0028] Figure 2 is the structural formula of the carbonyl zinc reagent prepared in Example 1 of the present invention and its conversion rate;

[0029] Figure 3 The substrate expanded structural formula and conversion rate of the urea compound and the thiocarbamate compound of Example 2 of the present invention;

[0030] Figure 4 The synthesis process and conversion rate of the drug molecules of Example 3 and Example 4 of the present invention; DETAILED DESCRIPTION

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

[0032] Example 1

[0033] The present embodiment relates to a method for synthesizing a carbonyl zinc reagent, comprising the following steps: dissolving Zn(OPiv)2 (1 mmol) and a formamide compound (1 mmol) in an organic solvent THF (2 mL) under a protective gas (N2) atmosphere, slowly adding LiTMP (1 mmol) dropwise at a temperature of 15°C, reacting at this temperature for 30 minutes, and obtaining a product carbonyl zinc reagent. Among them, R 1 , R 2 Independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, the reaction feasibility is as follows Figure 1 As shown in the formula (1). Wherein, the formamide compound is When the carbonyl zinc reagent 1 is obtained by reaction, the carbonyl zinc reagent 2-22 is obtained by reaction with formamide compounds of other structural formulas. The structural formulas and conversion rates of the carbonyl zinc reagents 1-22 are as follows: Figure 2 shown.

[0034] Example 2

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

[0036] Example 3

[0037] This embodiment relates to a method for synthesizing a urea drug molecule. The feasibility of the reaction is as follows: Figure 1 As shown in formula (2), the process comprises the following steps: using a carbonyl zinc reagent and The carbonyl zinc reagent obtained in Example 1 was slowly added dropwise to The reaction was carried out in an organic solution containing a copper catalyst 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 rate are shown in Figure 4 shown.

[0038] Example 4

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

[0040] The NMR characterization data of the substrate expansion of Example 2 and the drug molecules of 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, the present invention synthesizes and prepares a safe and non-toxic carbonyl zinc reagent, and is used for the synthesis of drug molecules, especially urea and thiocarbamate drug molecules, providing a new reaction pathway for the synthesis of drug molecules; the synthesis method has simple raw materials, mild reaction conditions and high yield.

[0095] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A carbonyl zinc reagent, characterized in that The general structural formula of the carbonyl zinc reagent is: Among them, R 1 , R 2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl.

2. The carbonyl zinc reagent according to claim 1, characterized in that The carbonyl zinc reagent is selected from one of the following compounds:

3. A method for preparing the carbonyl zinc reagent according to any one of claims 1 to 2, characterized in that: The method comprises the following steps: in an organic solvent, a formamide compound and zinc pivalate are mixed and reacted under the action of 2,2,6,6-tetramethylpiperidinium lithium to obtain the carbonyl zinc reagent.

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

5. Use of the carbonyl zinc reagent according to any one of claims 1 to 2 in the synthesis of drug molecules.

6. The use according to claim 5, characterized in that The general structural formula of the drug molecule is: Among them, R 1 , R 2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, R 3 is selected from chain alkyl, cyclic alkyl, substituted alkyl or benzyl, R 4 is selected from hydrogen or alkyl, R 5 Selected from alkyl or benzyl.

7. The use according to claim 6, characterized in that The preparation method of the drug molecule comprises the following steps: in an organic solvent, compound I and the carbonyl zinc reagent are mixed and reacted under the action of a catalyst to obtain the drug molecule; The general structural formula of the compound I is: Among them, R 3 is selected from chain alkyl, cyclic alkyl, substituted alkyl or benzyl, R 4 R is selected from hydrogen or alkyl, and R5 is selected from alkyl or benzyl.

8. The use according to claim 7, characterized in that The compound I is When the reaction temperature is 25-50°C, the compound Ⅰ is The reaction temperature is 0-50°C.

9. The use according to claim 7, characterized in that The molar ratio of the compound I to the carbonyl zinc reagent is 1:(1-1.5).

10. The use according to claim 7, characterized in that The catalyst is selected from one or more of Co, Fe, Cr, Ni and Cu.

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