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Preparation method of 2-(chlorosulfonyl) cyclohexane-1-ene ethyl formate derivative
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A technology of ethyl olefin carboxylate and chlorosulfonyl, which is applied in the field of preparation of ethyl 2-cyclohexane-1-ene carboxylate derivatives, can solve the problems of high toxicity of chlorine gas, odor of hydrogen sulfide, and high cost of chlorine gas, and achieve operational Convenience, short route, cheap raw materials
Pending Publication Date: 2021-11-12
SHANGHAI HAOYUAN CHEMEXPRESS
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[0015] The two steps of the reaction use hydrogensulfide and chlorine gas respectively. Hydrogensulfide is odorous and toxic, while chlorine gas is highly toxic, and the cost of chlorine gas used in the laboratory is very high, and the yield of the two steps is only 33.5%.
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Embodiment 1
[0067]
[0068] To compound 1 (1 g, 5.88 mmol) in DCM (20 mL) was added NaH (0.29 g, 12 mmol) at 0 degrees. After nitrogen replacement, stirring for 30 minutes, trifluoromethanesulfonic anhydride Tf 2 O (2.0g, 7mmol) was added to the above reaction solution and slowly raised to room temperature and stirred for 1-24 hours. After the reaction was complete, 20ml of water was added to quench, dichloromethane (20mL) was extracted twice, and the organic phase was dried. After spin-drying, 2.0 g of crude compound 2 was obtained. The reaction was almost quantitative and could be directly used in the next step.
[0069] ESI / MS:m / z=303(M+H) + .
Embodiment 2
[0071]
[0072] To acetonitrile (40 mL) obtained from all of Example 1 crude compound 2 and potassiumcarbonate (4 g, 29 mmol) was added benzylmercaptan (1.38 g, 11.11 mmol). The reaction was carried out at room temperature for 20-24 hours, and TLC showed that the reaction was complete. Water (60 mL) was added to quench the reaction, extracted twice with ethyl acetate (60 mL), dried over anhydroussodiumsulfate and spin-dried to obtain 1.46 g of compound 3 as a solid. The two-step yield is 89.8%, and the purity is 98.0%.
[0073] 1 H NMR (400MHz, CDCl 3 ):7.20-7.40(m,5H),4.23(q,J=7.2Hz,2H),4.05(s,2H),2.30-2.60(m.4H),1.60-1.80(4H,m),1.32( t,J=7.2Hz,3H); ESI / MS: m / z=277(M+H) + .
Embodiment 3
[0075]
[0076] To compound 3 (1 g, 3.62 mmol) in acetic acid (20 ml) and water (2 mL) was added NCS (1.9 g, 14.2 mmol) in portions over 30 min under ice bath. After stirring for 1-5 hours, TLC showed that the reaction was essentially complete. After spin-drying, the crude product was washed with petroleumether (30 mL), filtered and the organic phase was spin-dried to obtain 0.73 g of colorless liquid compound 4 with a yield of 79.8% and a purity of 90.0%.
[0077] 1 H NMR (400MHz, CDCl 3 ):4.31(q, J=7.2Hz, 2H), 2.50-2.80(m, 4H), 1.70-1.95(m, 4H), 1.36(t, J=7.2Hz, 3H); ESI / MS: m / z=253(M+H) + .
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Abstract
The invention relates to a preparation method of a 2-(chlorosulfonyl) cyclohexane-1-ene ethyl formate derivative, the preparation method comprises the following steps: 1) dissolving a compound shown as a formula III in an organic solvent, and reacting in the presence of alkali to obtain a compound shown as a general formula IV; 2) adding the compound in the formula IV into N-chlorosuccinimide to prepare a compound in a formula I, wherein R1 is hydrogen, a C1-6 alkyl group or a C3-6 cycloalkyl group; and R2 is preferably selected from Tf trifluoromethanesulfonyl, Ts p-toluenesulfonyl or Ms methylsulfonyl. The method is a brand-new industrial synthesis route, and further provides a brand-new intermediate compound as shown in the formula IV. Meanwhile, hydrogensulfide and chlorine are not used in the route, the obtained compound in the formula I is good in purity and product stability, and the method has good methodological significance in preparation of Toll-like receptor 4 (TLR4) inhibitor drugs.
Description
technical field [0001] The invention relates to a preparation method of ethyl 2-(chlorosulfonyl)cyclohexane-1-enecarboxylate derivatives, belonging to the technical field of synthesis of Toll-like receptor 4 (TLR4) inhibitor drug intermediates. Background technique [0002] People such as Yamada M, Journal of Medicinal Chemistry, 2005,48 (23): 7457-7467 report, 2-(2-chloro-4-fluorophenyl) sulfonylcyclohexane-1-ene carboxylateethyl ester effect is the most Well, its synthesis is based on sulfonylchloride and aniline as raw materials, in the presence of triethylamine, through the coupling of sulfonylchloride and aniline and the double bond transfer reaction synthesis, the specific reaction formula is as follows: [0003] [0004] Currently the most studied compound is Tak-242 / resatrovid, which is a Toll-like receptor 4 (TLR4) inhibitor and is considered to be an effective inhibitor of innate inflammation. Its structural formula is: [0005] [0006] Michael A Plunk ...
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