A method for synthesizing 6-thiopurine derivatives by copper-catalyzed three-component coupling reaction

Abstract

The invention discloses a method for synthesizing 6-thiopurine derivatives by a copper-catalyzed three-component coupling reaction, using 6-chloropurine compounds, sodium sulfide and iodide as raw materials, in an alkali-free system, using polyethylene glycol as a reaction medium, under the action of a copper catalyst, a three-component coupling reaction forming two C-S bonds occurs, and a one-pot method efficiently prepares 6-thiopurine derivatives. The present invention saves the pre-synthesis step of 6-mercaptopurine, and is highly economical; using odorless inorganic salt sodium sulfide as a sulfur source, the use of thiol with a foul odor is avoided, there is no special requirement for the environment, the operation is simple, and it is suitable for industrial large-scale production; using polyethylene glycol as a reaction medium, the use of volatile organic solvents is avoided, and it is green and environmentally friendly; without the addition of alkaline additives, the reaction conditions are mild; the copper catalyst used is low-toxic, cheap and easy to obtain, and has good stability; with good substrate applicability, it is applicable to 6-chloropurine and iodide containing different substituents.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of purine derivatives, and specifically relates to a method for preparing 6-thiopurine derivatives by using a copper catalyst to catalyze a three-component coupling reaction of 6-chloropurine compounds, sodium sulfide and an iodide. Background Art

[0002] Purine heterocycles are widely present in organisms and are also important drug intermediates. They are widely used in the fields of biochemistry and medicinal chemistry. Thiopurine derivatives have shown antibacterial, antitumor, protein and enzyme inhibition activities and have been used in the treatment of cancer and organ rejection. For example, 6-mercaptopurine and 6-mercaptoguanine can be used to treat cancer (Med Chem, 2005, 48, 4482-4486), azathioprine can be used to treat organ rejection (J Clin Invest, 2003, 111, 1122-1124; Transplantation, 2004, 78, 1802-1808; Pediatr Transplant, 2004, 8, 571-575), and compounds containing 6-alkylthiopurine also show anticancer activity (Lett Drug Des Discov, 2016, 13, 570-576). Therefore, the synthesis of thiopurine compounds has important research significance.

[0003] At present, there are three methods for synthesizing 6-thiopurine derivatives, namely, the nucleophilic substitution reaction of 6-halogenated purine with thiol, the nucleophilic substitution reaction of 6-mercaptopurine with alkyl halide (J Med Chem, 2004, 47, 273-276; J Serb Chem Soc, 2011, 76 (10), 1355-1364), and the coupling reaction of 6-mercaptopurine compounds and aryl / alkyl iodides proposed by our research group (CN202210445465.2). The first reaction of 6-halogenated purine with thiol has the following disadvantages: it is carried out in an organic solvent, which causes great environmental pollution; it is more suitable for alkyl thiol substrates, and the yield of aromatic thiols with lower nucleophilicity is low; even if a larger equivalent number of thiol is used, the yield of thiol is still low; thiol is a kind of reagent with a foul odor, which increases the difficulty of operating the reaction. The second nucleophilic substitution reaction of 6-mercaptopurine with alkyl halides also needs to be carried out in a volatile organic solvent. Although the use of odorous sulfur reagents is avoided, the activity of the electrophilic substrate halogenated hydrocarbon is required to be high. Only the more active primary halogenated hydrocarbon substrate (carbon is sp 3The third type of coupling reaction of 6-mercaptopurine with aryl / alkyl halides has a significantly wider substrate range than the second type, and aryl halides with lower activity can also react; however, this reaction needs to be carried out with the assistance of additives such as TBAI and in a strong alkaline environment, and the substrate mercaptopurine needs to be pre-synthesized, with too many steps and poor step economy. Summary of the invention

[0004] The purpose of the present invention is to overcome the shortcomings of the existing synthesis methods of thiopurine compounds, such as the use of malodorous substrates, narrow substrate applicability, and the need for pre-synthesis of substrates, and to provide a method for synthesizing 6-thiopurine derivatives through a copper-catalyzed three-component coupling reaction that is efficient, simple, inexpensive, and easy to obtain with good step economy.

[0005] In view of the above purpose, the technical solution adopted by the present invention is: a 6-chloropurine compound shown in formula I, an iodide shown in formula II, sodium sulfide, and a copper catalyst are added to a reaction medium, and a coupling reaction is carried out at 100 to 120° C. under a nitrogen atmosphere to obtain a 6-thiopurine derivative shown in formula III.

[0006]

[0007] In the formula, R1 represents any one of -H or -NH2; R2 represents any one of C1~C4 alkyl, cyclohexyl, phenyl, C1~C4 alkyl substituted phenyl, C1~C3 alkoxy substituted phenyl, nitro substituted phenyl, pyridyl, biphenyl, naphthyl, quinolyl, piperidyl, ethyl benzoate, acetophenone, etc.

[0008] In the above method, the molar ratio of the 6-chloropurine compound to sodium sulfide and iodide is preferably 1 to 1.2:1 to 1.2:1.

[0009] In the above method, the copper catalyst is any one of cuprous oxide, cuprous chloride, cuprous bromide and cuprous iodide; preferably, the amount of the copper catalyst added is 3% to 10% of the molar amount of the iodide.

[0010] In the above method, the reaction medium is polyethylene glycol, specifically any one of PEG-600, PEG-200, PEG-400, and PEG-800.

[0011] In the above method, it is further preferred to carry out the coupling reaction at 100 to 120° C. for 12 to 15 hours under a nitrogen atmosphere.

[0012] The beneficial effects of the present invention are as follows:

[0013] The present invention uses PEG as a solvent and catalyzes the coupling reaction of 6-chloropurine compounds, sodium sulfide and iodide under the action of a copper catalyst. The method has the following advantages: (1) the three-component one-pot method constructs two CS bonds at a time, omitting the presynthesis step of 6-mercaptopurine, and the step economy is high; (2) the use of odorless inorganic salt Na2S as a sulfur source avoids the use of raw materials such as thiols with a foul odor, has no special requirements for the synthetic operating environment, is simple to operate, and is suitable for industrial large-scale production; (3) PEG is used as a reaction medium, avoiding the use of organic solvents, and is green and environmentally friendly; (4) no alkaline additives are required, and the reaction conditions are mild; (5) the copper catalyst used is low in toxicity, cheap and easy to obtain, and has good stability; (6) it has good substrate applicability and is applicable to 6-chloropurine and iodide containing different substituents. Therefore, the method for catalytic synthesis of 6-thiopurine derivatives of the present invention has important application prospects. DETAILED DESCRIPTION

[0014] The present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0015] Example 1

[0016] Under nitrogen protection, 92.7 mg (0.6 mmol) of 6-chloropurine, 46.8 mg (0.6 mmol) of sodium sulfide, 117 mg (0.5 mmol) of p-iodoanisole, and 4.8 mg (0.025 mmol) of cuprous iodide were added to 3.7 mL of PEG-600, and the mixture was reacted at 110° C. for 14 h. The mixture was extracted with ethyl acetate and subjected to column chromatography with an eluent of DCM:MeOH=20:1 to obtain a 6-thiopurine derivative with the following structural formula in a yield of 91%.

[0017]

[0018] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.52(s,1H),8.48(s,1H),7.53(d,J=8.4Hz,2H),7.05(d,J=8.6Hz,2H),3.82(s,3H); 13 C NMR (151MHz, DMSO-d6) δ160.43,158.95,151.62,149.56,143.26,137.38,129.61,117.08,114.99,55.33.

[0019] Example 2

[0020] In this example, iodobenzene was used to replace the p-iodoanisole used in Example 1 in an equal mole, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, with a yield of 84%.

[0021]

[0022] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.59(s,1H),8.54(s,1H),8.49(s,1H),7.66–7.60(m,2H),7.56-7.46(m,3H); 13 C NMR (151MHz, DMSO-d6) δ157.99,151.61,149.63,143.62,135.43,129.42,129.33,127.03.

[0023] Example 3

[0024] In this example, 2-iodopropane was used in an equal molar amount to replace the p-iodoanisole used in Example 1, and the other steps were the same as those in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 25%.

[0025]

[0026] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.47(s,1H),8.67(s,1H),8.40(s,1H),4.34–4.21(m,1H),1.41(d,J=6.9Hz,6H); 13 CNMR(151MHz,DMSO-d6)δ159.15,151.47,149.25,142.75,130.18,33.51,23.06.

[0027] Example 4

[0028] In this example, the p-iodoanisole used in Example 1 was replaced by an equal molar amount of p-iodoacetophenone, and the other steps were the same as those in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, with a yield of 51%.

[0029]

[0030] The structural characterization data of the obtained product are: 1H NMR (600MHz, DMSO-d6) δ13.66(s,1H),8.58(s,1H),8.54(s,1H),8.03(d,J=7.9Hz,2H),7.78(d,J=7.9Hz,2H),2.63(s,3H); 13 C NMR (151MHz, DMSO-d6) δ197.43,156.11,151.57,150.93,144.16,136.93,134.75,133.46,129.22,128.74,26.82.

[0031] Example 5

[0032] In this example, 4-tert-butyl iodobenzene was used in place of the p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 79%.

[0033]

[0034] The structural characterization data of the obtained product are: 1 H NMR (400MHz, Chloroform-d) δ8.69 (s, 1H), 8.24 (s, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.48 (d, J = 8.4Hz, 2H), 1.33 (s, 9H); 13 C NMR (151MHz, Chloroform-d) δ153.17,152.11,142.18,135.26,126.79,123.46,34.94,31.30.

[0035] Example 6

[0036] In this example, 2-iodopyridine was used in place of the p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 47%.

[0037]

[0038] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.65(s,1H),8.64(s,1H),8.57(d,J=4.0Hz,1H),8.53(s,1H),7.89-7.84(m,1H),7.81(d,J=7.3Hz,1H),7.44–7.40(m,1H); 13C NMR (101MHz, DMSO-d6) δ156.66,152.14,151.65,150.26,143.98,137.53,130.61,129.63,123.43.

[0039] Example 7

[0040] In this example, iodocyclohexane was used to replace the p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, with a yield of 15%.

[0041]

[0042] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.47(s,1H),8.66(s,1H),8.40(s,1H),4.18(t,J=8.7Hz,1H),2 .14–2.02(m,2H),1.77–1.66(m,2H),1.59(m,1H),1.55–1.40(m,4H),1.35–1.24(m,1H); 13 C NMR (151MHz, DMSO-d6) δ158.87,151.47,149.19,142.70,130.15,40.85,32.78,25.46,25.13.

[0043] Example 8

[0044] In this example, the p-iodoanisole used in Example 1 was replaced by an equal molar amount of o-iodotoluene, and the other steps were the same as those in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 82%.

[0045]

[0046] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.60(s,1H),8.50(s,2H),7.59(d,J=7.6Hz,1H),7.45–7.39(m,2H),7.32–7.24(m,1H),2.30(s,3H); 13 C NMR (151MHz, DMSO-d6) δ151.60,149.72,143.33,142.90,136.71,130.66,130.13,126.76,126.47,20.52.

[0047] Example 9

[0048] In this example, 4-nitroiodobenzene was used in place of the p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 90%.

[0049]

[0050] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.69(s,1H),8.62(s,1H),8.55(s,1H),8.28(d,J=8.3Hz,2H),7.92(d,J=8.3Hz,2H); 13 C NMR (151MHz, DMSO-d6) δ151.59,147.54,144.41,136.78,135.09,123.90.

[0051] Example 10

[0052] In this example, ethyl p-iodobenzoate was used to replace p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as those in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 47%.

[0053]

[0054] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.65(s,1H),8.58(s,1H),8.54(s,1H),8.02(d,J=7. 9Hz, 2H), 7.78 (d, J = 8.0Hz, 2H), 4.34 (q, J = 7.5Hz, 2H), 1.33 (t, J = 7.2Hz, 3H); 13 C NMR (151MHz, DMSO-d6) δ165.22,156.81,151.57,150.06,143.78,134.80,133.63,130.30,130.03,129.64,60.98,14.11.

[0055] Example 10

[0056] In this example, 1-iodonaphthalene was used in place of the p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 89%.

[0057]

[0058] The structural characterization data of the obtained product are: 1 H NMR(600MHz,DMSO-d6)δ13.62(s,1H),8.55(s,1H),8.36(s,1H),8.13(d,J=8.3Hz,2H),8.07–8.01 (m,1H),7.96(d,J=7.0Hz,1H),7.61(t,J=7.7Hz,1H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ158.45,151.65,149.86,143.63,136.13,134.60, 133.89,131.02,129.88,128.69,127.33,126.46,126.00,125.38,124.37.

[0059] Example 12

[0060] In this example, 4-iodobiphenyl was used to replace the p-iodoanisole used in Example 1 in an equal mole, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, and the yield was 91%.

[0061]

[0062] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.60(s,1H),8.56(s,1H),8.51(s,1H),7.78(d,J=8.0Hz ,2H),7.72(dd,J=13.2,7.8Hz,4H),7.50(t,J=7.6Hz,2H),7.41(t,J=7.4Hz,1H); 13 C NMR (151MHz, DMSO-d6) δ158.01,151.64,149.73,143.49,141.15,139.16,135.94,129.78,129.05,127.95,127.54,126.79,126.09.

[0063] Example 13

[0064] In this example, 6-iodoquinoline was used in place of the p-iodoanisole used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative having the following structural formula, with a yield of 82%.

[0065]

[0066] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ13.64(s,1H),8.99(dd,J=4.3,1.8Hz,1H),8.53(s,2H),8.43(dd,J=8.4,1.8Hz,1 H),8.37(d,J=2.1Hz,1H),8.09(d,J=8.7Hz,1H),7.91(dd,J=8.8,2.1Hz,1H),7.61(dd,J=8.3,4.2Hz,1H); 13 C NMR (101MHz, DMSO-d6) δ157.72,151.67,151.64,149.88,147.57,143.66,135.97,135.75,134.94,129.66,128.24,125.64,122.05.

[0067] Embodiment 14

[0068] In this example, the p-iodoanisole used in Example 1 was replaced by an equal molar amount of iodobenzene, and the 6-chloropurine used was replaced by an equal molar amount of 2-amino-6-chloropurine. The other steps were the same as in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, and the yield was 85%.

[0069]

[0070] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ12.59(s,1H),7.96(s,1H),7.60(dd,J=6.9,2.5Hz,2H),7.47–7.40(m,3H),6.21(s,2H); 13 C NMR (151MHz, DMSO-d6) δ159.79,157.74,152.29,139.44,134.64,129.13,128.81,128.30,123.65.

[0071] Embodiment 15

[0072] In this example, the p-iodoanisole used in Example 1 was replaced by an equal mole of 1-iodonaphthalene, and the 6-chloropurine used was replaced by an equal mole of 2-amino-6-chloropurine. The other steps were the same as in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, and the yield was 88%.

[0073]

[0074] The structural characterization data of the obtained product are: 1 H NMR(600MHz,DMSO-d6)δ12.57(s,1H),8.19–8.14(m,1H),8.08(d,J=8.2Hz, 1H),8.04–8.00(m,1H),7.96–7.90(m,2H),7.62–7.53(m,3H),6.02(s,2H); 13 C NMR(151MHz,DMSO-d6)δ159.81,158.46,152.40,139.60,135.81,134.60, 133.89,130.60,128.69,127.21,126.42,126.00,125.51,125.31,123.84.

[0075] Example 16

[0076] In this example, the 6-chloropurine used was replaced by an equal molar amount of 2-amino-6-chloropurine, and the other steps were the same as in Example 1 to obtain a 6-thiopurine derivative with the following structural formula, with a yield of 26%.

[0077]

[0078] The structural characterization data of the obtained product are: 1 H NMR (600MHz, DMSO-d6) δ12.57(s,1H),7.95(s,1H),7.50(d,J=8.5Hz,2H),6.99(d,J=8.5Hz,2H),6.16(s,2H),3.78(s,3H); 13 C NMR (151MHz, DMSO-d6) δ160.07,159.79,158.77,152.17,139.36,136.92,123.32,118.10,114.78,55.29.

[0079] Embodiment 17

[0080] In this example, cuprous oxide was used to replace the cuprous iodide in Example 1 in an equal mole, and the other steps were the same as those in Example 1. The yield of the obtained 6-thiopurine derivative was 70%.

[0081] Embodiment 18

[0082] In this example, an equal volume of PEG-400 was used to replace the PEG-600 used in Example 1. The other steps were the same as in Example 1. The yield of the obtained 6-thiopurine derivative was 75%.

Claims

1. A method for synthesizing 6-thiopurine derivatives by a copper-catalyzed three-component coupling reaction, characterized in that: Adding a 6-chloropurine compound represented by formula I, an iodide represented by formula II, sodium sulfide, and a copper catalyst into a reaction medium, and performing a coupling reaction at 100-120° C. under a nitrogen atmosphere to obtain a 6-thiopurine derivative represented by formula III; In formula I and formula III, R1 represents any one of -H or -NH2; in formula II and formula III, R2 represents any one of C1-C4 alkyl, cyclohexyl, phenyl, C1-C4 alkyl substituted phenyl, C1-C3 alkoxy substituted phenyl, nitro substituted phenyl, pyridyl, biphenyl, naphthyl, quinolyl, piperidinyl, ethyl benzoate, and acetophenone; The copper catalyst is any one of cuprous iodide, cuprous oxide, cuprous chloride, and cuprous bromide; The reaction medium is any one of PEG-600, PEG-200, PEG-400 and PEG-800.

2. The method for synthesizing 6-thiopurine derivatives by copper-catalyzed three-component coupling reaction according to claim 1, characterized in that: The molar ratio of the 6-chloropurine compound to sodium sulfide and iodide is 1-1.2:1-1.2:

1.

3. The method for synthesizing 6-thiopurine derivatives by copper-catalyzed three-component coupling reaction according to claim 1, characterized in that: The amount of the copper catalyst added is 3% to 10% of the molar amount of the iodide.

4. The method for synthesizing thiopurine derivatives by copper-catalyzed three-component coupling reaction according to claim 1, characterized in that: The coupling reaction was carried out at 100-120°C under a nitrogen atmosphere for 12-15 h.

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