CN111269203A - N-cyclohexyl-furan-2-formamide compound and preparation method and application thereof - Google Patents

N-cyclohexyl-furan-2-formamide compound and preparation method and application thereof Download PDF

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CN111269203A
CN111269203A CN201811475559.4A CN201811475559A CN111269203A CN 111269203 A CN111269203 A CN 111269203A CN 201811475559 A CN201811475559 A CN 201811475559A CN 111269203 A CN111269203 A CN 111269203A
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furan
cyclohexyl
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carboxamide
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李建其
陈晓文
周爱南
浦强
齐阳历
苏晓静
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Shanghai Zawa Pharmaceutical Technology Co Ltd
Shanghai Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
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Abstract

The invention discloses an N-cyclohexyl-furan-2-formamide compound, a preparation method and application thereof, the N-cyclohexyl-furan-2-formamide compound can be used for preparing an anti-schizophrenia drug SIPI6398, and compared with the prior art and reported documents, the N-cyclohexyl-furan-2-formamide compound has the following remarkable advantages: 1. the SIPI6398 synthesized by the N-cyclohexyl-furan-2-formamide compound does not need to be subjected to the reaction processes of protecting group grafting and protecting group removing, and the atom economy is high; 2. the SIPI6398 is prepared from the N-cyclohexyl-furan-2-formamide compound, the raw materials are cheap and easy to obtain, the cost is low, the reaction condition is mild, the yield is stable, the operation is simple and convenient, the three-waste pollution is less, and the industrial production is easy to realize, wherein the N-cyclohexyl-furan-2-formamide compound is a compound with the following structural general formula (I)：

Description

N-cyclohexyl-furan-2-formamide compound and preparation method and application thereof
Technical Field
The invention relates to an N-cyclohexyl-furan-2-formamide compound and application thereof.
Background
SIPI6398 with the chemical name N- (trans-4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) cyclohexyl) furan-2-carboxamide hydrochloride as D3/D2Receptor subtype selective antagonists for the treatment of schizophrenia. The structural formula is as follows:
Figure BDA0001892098000000011
schizophrenia is a disease that seriously affects human health, is one of the most serious of mental diseases, affects the normal lives of about 1% of the population worldwide, and brings serious consequences and economic burden to patients and their families.
Currently, the clinical antipsychotic drugs are mainly classified into typical antipsychotic drugs and atypical antipsychotic drugs, the latter being common drugs such as risperidone, aripiprazole, ziprasidone, etc. The medicines have certain improvement effect on negative symptoms while treating positive symptoms, but have respective characteristic side effects, such as extravertebral system side Effect (EPS), akathisia, insomnia, anxiety, postural hypotension and the like. Meanwhile, all antipsychotic drugs sold in the market have the cognitive disorder improving effect and are difficult to meet the clinical requirement.
SIPI6398 is D3/D2Receptor subtype selective antagonists combined with strong 5-HT1AAnd 5-HT2AThe receptor antagonism has strong anti-schizophrenia activity, good pharmacokinetic property and low extrapyramidal side Effect (EPS), can obviously improve the learning and memory function of rats in an animal new object recognition experiment, and has strong potential cognitive impairment improvement effect (Eur.J.Med.Ch)em.,123(2016)332-353, CN 104140421A). Therefore, SIPI6398 has wide clinical application prospect in the field of schizophrenia resistance.
In the prior art, chinese patent CN 104140421a first discloses a preparation method of SIPI 6398. In the patent, SIPI6398 is prepared by taking N-Boc protected cyclohexylacetic acid (5) as a raw material and carrying out five-step reaction, which is concretely shown in the following synthetic route. The method needs to remove the Boc protecting group and then prepare SIPI6398 by acylation, and has poor atom economy. Meanwhile, trifluoroacetic acid (TFA) with strong corrosivity is used for removing the Boc group, so that the production safety is low, and equipment is easy to corrode.
Figure BDA0001892098000000021
The document Eur.J.Med.chem.,123(2016)332-353 reports the preparation of SIPI6398 starting from 4-acetamido-cyclohexanone via the following synthetic route. In this route, intermediate 16 hydrolyzes acetyl under dilute hydrochloric acid (5% HCl) to produce key intermediate 9, which produces a large amount of wastewater, which is not environmentally friendly.
Figure BDA0001892098000000022
Disclosure of Invention
The invention aims to provide an N-cyclohexyl-furan-2-formamide compound, a preparation method and application thereof, which aim to overcome the defects in the prior art.
The N-cyclohexyl-furan-2-formamide compound is a compound with the following structural general formula (I):
Figure BDA0001892098000000031
wherein:
p is 0 or 1;
q is 0 or 1;
x represents a hydrogen atom, a halogen atom or a sulfonyloxy group;
preferably, when M is a hydrogen atom, M is 0 and n is 1;
preferably, when M is not a hydrogen atom, M is 1 and n is 0;
preferably, the halogen comprises chlorine, bromine or iodine;
preferably, the sulfonyloxy group includes methanesulfonyloxy group or p-toluenesulfonyloxy group;
preferably, the N-cyclohexyl-furan-2-carboxamide compound:
I-1N- (trans-4- (2-oxoethyl) cyclohexyl) furan-2-carboxamide,
II-1N- (trans-4- (2-chloroethyl) cyclohexyl) furan-2-carboxamide,
II-2N- (trans-4- (2-bromoethyl) cyclohexyl) furan-2-carboxamide,
II-3N- (trans-4- (2-iodoethyl) cyclohexyl) furan-2-carboxamide,
III-12- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl methanesulfonate or
III-22- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl 4-methylbenzenesulfonate.
The structures of the preferred compounds are shown in the following table:
Figure BDA0001892098000000032
Figure BDA0001892098000000041
the preparation method of the N-cyclohexyl-furan-2-formamide compound comprises the following steps:
(1) 4-aminocyclohexanone hydrochloride is taken as a raw material, and is subjected to acylation reaction with furan-2-formyl chloride in a dichloromethane solution, and then a compound 1 is collected from a reaction solution;
the molar ratio of the 4-aminocyclohexanone hydrochloride to the furan-2-formyl chloride is 1: 0.9-1: 1.5, and the reaction temperature is 0-35 ℃; the reaction time is 0.5-3 h;
(2) reacting the compound 1 with triethyl phosphonoacetate in a solvent under the action of an alkaline substance, and collecting a compound 2 from a reaction solution;
the solvent is selected from THF, methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, toluene or a mixed solvent of the solvents, and the alkaline substance is selected from potassium tert-butoxide, sodium tert-butoxide or lithium tert-butoxide;
the molar ratio of the compound 1 to the triethyl phosphonoacetate is 0.9: 1-1: 2;
the molar ratio of the alkaline substance to the compound 1 is 1: 1-3: 1;
in the solvent, the content of the compound 1 is 0.01-0.5 g/mL;
(3) the compound 2 is subjected to catalytic hydrogenation reduction by a catalyst in a solvent, is purified by crystallization, and then is collected from a reaction product to obtain a compound 3;
the catalyst is preferably Pd/C, and the solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, THF, methyl tetrahydrofuran, methyl tert-butyl ether or a mixed solvent of the solvents;
the reaction temperature is 10-100 ℃; the reaction time is 2-24 h;
the weight amount of the catalyst is 1-10% of that of the compound 2;
the content of the compound 2 in the solvent is 0.01-0.5 g/mL;
(4) reacting the compound 3 with a reduction system in a solvent, and collecting a compound 4 from a reaction solution;
the reduction system is NaBH4Methanol System, KBH4Methanol System, NaBH4/AlCl3System, LiBH4Or LiAlH4；
The term "reducing System NaBH4The methanol system refers to NaBH4And refluxing the mixture and the compound 3 for 0.5-2 h, and then dropwise adding a certain volume of methanol solvent, wherein the reducing agent is NaBH4Volume of methanol is NaBH40.5-6 times of the weight;
the term "reduction System KBH4KBH of the methanol System4And refluxing the mixture and the compound 3 for 0.5-2 h, and then dropwise adding a certain volume of methanol, wherein the reducing agent is KBH4Volume of methanol is KBH40.5-6 times of the weight;
the term "reducing System NaBH4/AlCl3System "refers to NaBH4And stirring the mixture and the compound 3 at room temperature for 0.5-2 h, and then dropwise adding AlCl3Wherein the reducing agent is NaBH4，AlCl3In an amount corresponding to NaBH4The molar ratio of the dosage is 1: 1;
the solvent is selected from THF, methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, toluene or the mixed solvent of the solvents;
the reaction temperature is-10-100 ℃, and the reaction time is 1-24 h;
the feeding molar ratio of the compound 3 to the reducing agent is 1: 1-1: 10;
the content of the compound 3 in the solvent is 0.01-0.5 g/mL;
or:
reacting the compound 3 with a reducing agent 1 in a solvent, and collecting an N-cyclohexyl-furan-2-formamide compound X-1 from a reaction product;
the reducing agent 1 is diisobutyl aluminum hydride;
the solvent is selected from THF, methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, toluene or the mixed solvent of the solvents;
the reaction temperature is-10-100 ℃, and the reaction time is 1-24 h;
the feeding molar ratio of the compound 3 to the reducing agent is 1: 1-1: 10;
the content of the compound 3 in the solvent is 0.01-0.5 g/mL;
(5) reacting the compound 4 with a halogenating agent in a solvent, and then collecting the N-cyclohexyl-furan-2-formamide compound Y-1 from a reaction product;
the solvent is selected from dichloromethane, THF, methyl tetrahydrofuran, methyl tert-butyl ether, diethyl ether, toluene, ethyl acetate or the mixed solvent of the solvents;
the halogenating agent is selected from SOCl2Oxalyl chloride, carbon tetrabromide, or iodine;
the molar ratio of the compound 4 to the halogenating reagent is 1: 1-1: 2;
the reaction temperature is 0-100 ℃; the reaction time is 0.5-24 h;
or:
reacting the compound 4 with a sulfonylation reagent under the conditions of a solvent and an alkaline substance, wherein the reaction temperature is-10-50 ℃; the reaction time is 0.5-24 h; then collecting the N-cyclohexyl-furan-2-formamide compound Z-1 from the reaction product;
the solvent is selected from dichloromethane, THF, methyl tetrahydrofuran, methyl tert-butyl ether, diethyl ether, toluene, ethyl acetate or the mixed solvent of the solvents;
the alkaline substance is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide;
the sulfonylation reagent is selected from methanesulfonyl chloride or p-toluenesulfonyl chloride;
the molar ratio of the compound 4 to the sulfonylation reagent is 1: 1-1: 1.5;
the molar ratio of the alkali to the compound 4 is 1.1: 1-2: 1;
the content of the compound 4 in the solvent is 0.01-0.5 g/mL;
n-cyclohexyl-furan-2-carboxamide compound X-1, N-cyclohexyl-furan-2-carboxamide compound Y-1 and N-cyclohexyl-furan-2-carboxamide compound Z-1 are all the N-cyclohexyl-furan-2-carboxamide compounds shown in the formula (I); the reaction formula is as follows:
Figure BDA0001892098000000061
wherein A represents chlorine, bromine or iodine, and B represents a methanesulfonyloxy group or a p-toluenesulfonyloxy group.
4-aminocyclohexanone hydrochloride is directly commercially available.
The N-cyclohexyl-furan-2-formamide compound obtained by the invention can be used for preparing an anti-schizophrenia drug SIPI 6398.
The N-cyclohexyl-furan-2-formamide compound is used for preparing an anti-schizophrenia drug SIPI6398, and the synthetic route is as follows:
Figure BDA0001892098000000071
compared with the prior art and reported documents, the SIPI6398 prepared by the N-cyclohexyl-furan-2-formamide compound has the following remarkable advantages:
1. the SIPI6398 synthesized by the N-cyclohexyl-furan-2-formamide compound does not need to be connected with a protecting group and to be removed, such as a Boc group and an acetyl group, and has high atom economy;
2. the SIPI6398 is prepared from the N-cyclohexyl-furan-2-formamide compound, the raw materials are cheap and easy to obtain, the cost is low, the reaction condition is mild, the yield is stable, the operation is simple and convenient, the three-waste pollution is less, and the industrial production is easy.
Detailed Description
Example 1
Preparation of N- (trans-4- (2-oxoethyl) cyclohexyl) furan-2-carboxamide (I-1);
(1) synthesis of N- (4-oxocyclohexyl) furan-2-carboxamide (1)
Adding 4-aminocyclohexanone hydrochloride (1496.2g,10.0mol), dichloromethane (7481mL) and 20% NaOH aqueous solution (NaOH:1000g) into a 10L four-neck bottle, cooling to 0 deg.C in ice bath, slowly adding dropwise furan-2-formyl chloride (1435.8 g,11.0mol), controlling the temperature not to exceed 10 deg.C, stirring at room temperature for 2H after addition, adding H2O (1000mL) was stirred, the layers were separated, and the organic layer was washed with 5% HCl (200 mL. times.2) and saturated brine (2000 mL. times.1) in that order, and anhydrous NaSO4Drying, filtering and concentrating to obtain 1968.7g of white solid with the yield of 95 percent, which is directly used for the next reaction.
(2) Synthesis of ethyl 2- (4- (furan-2-carboxamide) cyclohexylalkenyl) acetate (2)
Sodium tert-butoxide (1153.2g,12mol) and THF (3000mL) are added into a 10000mL four-necked bottle, the bottle is cooled to 5 ℃ in an ice bath, a solution of triethyl phosphorylacetate (1972.9g,8.8mol) in THF (1000mL) is added dropwise, the temperature is controlled not to exceed 10 ℃, and the reaction is stirred at room temperature for 0.5 h. The reaction mixture was cooled to 5 ℃ and a solution of N- (4-oxocyclohexyl) furan-2-carboxamide (1) (1657.8g,8mol) in THF (1500mL) was added dropwise thereto at a temperature not exceeding 10 ℃ and after the addition, the mixture was stirred at room temperature for 2 hours, water (1000mL) was added thereto and stirred for 0.5 hour, liquid separation was carried out, the upper layer solution was taken, the solvent was distilled off, methylene chloride (3000mL) was added thereto, and the mixture was washed with water (500 mL. times.2) and saturated brine (1000 mL. times.1) in this order and evaporated to dryness to obtain 2129.8g of a white solid with a yield of 96%.
(3) Synthesis of ethyl 2- (trans-4- (furan-2-carboxamido) cyclohexyl) acetate (3)
Ethyl 2- (4- (furan-2-carboxamide) cyclohexylalkenyl) acetate (2) (1663.9g,6mol), 10% Pd/C (13.6 g) and absolute ethyl alcohol (15L) were added to a 50L reactor, hydrogen was passed through at normal pressure, the external temperature was 45 ℃ for 15h, filtration was performed, the filter cake was washed with ethanol (200 mL. times.2), the filtrates were combined, evaporated to dryness and the residue was recrystallized from ethyl acetate/petroleum ether (3:1) to give 31691 g of intermediate as a white solid with a yield of 83%.
(4) Preparation of target Compound I-1
Adding ethyl 2- (trans-4- (furan-2-carboxamido) cyclohexyl) acetate (3) (500g,1.8mol) and toluene (4000 mL) into a 10L four-necked flask, stirring for 0.5h at-78 ℃ under nitrogen protection, slowly adding diisobutylaluminum hydride (1M,3.6L,3.6mol) dropwise, adding a mixed solution of methanol (500 mL)/toluene (1100mL), pouring the reaction solution into a saturated aqueous solution of sodium potassium tartrate (6000mL), extracting with methyl tert-butyl ether (1L × 4), and extracting with anhydrous Na2SO4Drying, filtering and concentrating gave 304.9g of a white solid with a yield of 72%.
1H NMR(DMSO-d6,δ:ppm):1.12-1.17(m,2H),1.23-1.27(m,2H),1.46-1.54(m,3H),1.80-1.86(m,2H),2.35(d,2H,J＝4.4Hz),3.89-3.92(m,1H),6.18(d,1H,J＝5.2 Hz),6.49(dd,1H,J＝1.2Hz,J＝2.4Hz),7.11(d,1H,J＝2.4Hz),7.43(d,1H, J＝1.2Hz),9.74(s,1H).
ESI-MS:236[M+H+]
Example 2
Preparation of SIPI6398
N- (trans-4- (2-oxoethyl) cyclohexyl) furan-2-carboxamide (I-1) (100.0g,0.43mol), 3- (piperazin-1-yl) benzo [ d ] isothiazole (94.3g,0.43mol), sodium triacetoxyborohydride (137.8g,0.65mol), 1, 2-dichloroethane (1000mL) were added to a 2000mL one-neck flask, stirring at room temperature for 15h, adding potassium carbonate aqueous solution (2500mL), separating, extracting aqueous layer with 1, 2-dichloroethane (1500mL × 1), combining organic layers, washed with saturated brine (1000 mL. times.1), dried over anhydrous sodium sulfate, filtered, concentrated, freed of most of the solvent, filtered, the filter cake washed with ethyl acetate (200 mL. times.3), the filtrates combined and concentrated to give 188.6g of a white solid in 91% yield. The resulting white solid, ethanol (1800mL), 10% HCl (0.43mol) were added to a 3000mL single-neck flask, refluxed for 0.5h, cooled to room temperature, stirred for 1h, filtered to give 171g of SIPI6398 as a white solid in 92% yield.
1H NMR(DMSO-d6,δ:ppm):δ1.03-1.09(m,2H),1.30-1.40(m,3H),1.65-1.68(m,2H),1.77-1.82(m,4H),3.18-3.25(m,4H),3.48(t,2H,J＝7.6Hz),3.59-3.61(m,2 H),3.68-3.73(m,1H),4.07-4.08(m,4H),6.60-6.61(m,1H),7.09-7.10(m,1H),7.47 -7.49(m,1H),7.59-7.62(m,1H),7.80-7.81(m,1H),8.11(d,1H,J＝5.2Hz),8.14- 8.16(m,2H),10.81(brs,1H).
ESI-MS:439[M+H+]
HPLC purity: 99.91 percent
Example 3
Preparation of N- (trans-4- (2-chloroethyl) cyclohexyl) furan-2-carboxamide (II-1)
Ethyl 2- (trans-4- (furan-2-carboxamido) cyclohexyl) acetate (3) (200.0g,0.72mol), NaBH4(83.2 g,2.2mol) and THF (1000mL) are added into a 2000mL single-mouth bottle, the reflux reaction is carried out for 0.5h, the temperature is reduced to 40 ℃, methanol (160mL) is added in batches, after the addition, the reflux reaction is carried out for 5h, the reaction liquid is cooled to room temperature, the pH of the reaction liquid is adjusted to 1-2 by concentrated hydrochloric acid, the stirring is carried out for 0.5h, the reaction liquid is adjusted to pH 8-9 by 10 percent NaOH aqueous solution, the stirring is carried out for 0.5h, dichloromethane (500mL multiplied by 3) is used for extraction, saturated saline (500 multiplied by 1) is used for washing, anhydrous Na2SO4Drying, filtering and concentrating to obtain 158.9g of white solid of N- (trans-4- (2-hydroxyethyl) cyclohexyl) furan-2-formamide with the yield of 93 percent.
N- (trans-4- (2-hydroxyethyl) cyclohexyl) furan-2-carboxamide (50.0g,0.21mol), pyridine (18.3g,0.23 mol) were added to a 500mL three-necked flask, and SOCl was added dropwise thereto in an ice-water bath2(30.9g,0.26mol), heating to 110 ℃, stirring for 3h, and cooling to room temperatureThe reaction mixture was poured into ice water (500g), the reaction mixture was made strongly acidic with concentrated hydrochloric acid, the organic layer was separated, the aqueous layer was extracted with dichloromethane (100 mL. times.3), the organic layers were combined, washed successively with 10% HCl (30 mL. times.1) and saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 47.3g of an off-white solid with a yield of 88%.
1H NMR(DMSO-d6,δ:ppm):1.11-1.16(m,2H),1.21-1.25(m,2H),1.44-1.52(m,3H),1.78-1.84(m,2H),2.06-2.09(m,2H),3.52(t,2H,J＝4.4Hz),3.88-3.89(m,1H),6. 19(d,1H,J＝5.2Hz),6.48(dd,1H,J＝1.2Hz,J＝2.4Hz),7.09(d,1H,J＝2. 4Hz),7.42(d,1H,J＝1.2Hz).
ESI-MS:256[M+H+]
Example 4
Preparation of SIPI6398
N- (trans-4- (2-chloroethyl) cyclohexyl) furan-2-carboxamide (II-1) (40.0g,0.16mmol), 3- (piperazin-1-yl) benzo [ d ] isothiazole (35.1g,0.16mol), sodium carbonate (33.9g,0.32mol), acetone (400mL) were added to a 1000mL single vial, the reaction was refluxed for 20h, cooled to room temperature, filtered, the filter cake was washed sequentially with acetone (50 mL. times.2) and water (200mL), filtered, the filter cake was dried under vacuum for 4h to give 58.2g of a white solid in 83% yield. The obtained white solid, ethanol (600mL) and 10% HCl (0.13mmol) were added to a 1000mL single-neck flask, refluxed for 0.5h, cooled to room temperature, stirred for 1h, and filtered to obtain SIPI6398 as a white solid 56.8g with a yield of 90%.
HPLC purity: 99.93 percent
Example 5
Preparation of N- (trans-4- (2-bromoethyl) cyclohexyl) furan-2-carboxamide (II-2)
N- (trans-4- (2-hydroxyethyl) cyclohexyl) furan-2-carboxamide (50.0g,0.21mol), triphenylphosphine (65.6g, 0.25mol), carbon tetrabromide (82.9,0.25mol), methylene chloride (500mL) were added to a 1000mL three-necked flask, stirred at 0 ℃ for 1h, warmed to room temperature, reacted for 1h, concentrated, and recrystallized from ethyl acetate/petroleum ether (1:5) to give 56.1g of a white solid with a yield of 89%.
1H NMR(DMSO-d6,δ:ppm):1.10-1.15(m,2H),1.20-1.24(m,2H),1.43-1.50(m,3H),1.78-1.83(m,2H),2.05-2.08(m,2H),3.50(t,2H,J＝4.4Hz),3.87-3.88(m,1H),6. 17(d,1H,J＝5.2Hz),6.44(dd,1H,J＝1.2Hz,J＝2.4Hz),7.07(d,1H,J＝2. 4Hz),7.39(d,1H,J＝1.2Hz).
ESI-MS:300[M+H+]
Example 6
Preparation of SIPI6398
N- (trans-4- (2-bromoethyl) cyclohexyl) furan-2-carboxamide (II-2) (50.0g,0.17mol), 3- (piperazin-1-yl) benzo [ d ] isothiazole (37.3g,0.17mol), potassium carbonate (46.9g,0.34mmol), acetone (500mL) were added to a 1000mL single vial, the reaction was refluxed for 14h, cooled to room temperature, filtered, the filter cake was washed sequentially with acetone (100 mL. times.2) and water (400mL), filtered, the filter cake was dried under vacuum for 6h to give 67.8g of a white solid in 91% yield. The obtained white solid, ethanol (600mL) and 10% HCl (0.17mol) are added into a 1000mL single-neck bottle, refluxed for 0.5h, cooled to room temperature, stirred for 2h and filtered to obtain 62.4g of SIPI6398 white solid with the yield of 85%.
HPLC purity: 99.90 percent
Example 7
Preparation of N- (trans-4- (2-iodoethyl) cyclohexyl) furan-2-carboxamide (II-3)
Triphenylphosphine (42.0g,0.16mol), imidazole (10.0g,0.17mol), and dichloromethane (300mL) were added to a 1000mL three-necked flask, iodine (40.6g,0.16mol) was added in portions under ice-water bath, stirring was performed for 0.5h, a solution of N- (trans-4- (2-hydroxyethyl) cyclohexyl) furan-2-carboxamide (30.0g,0.13mol) in dichloromethane (90mL) was added dropwise, reaction was performed at room temperature for 8h, and NaHSO was added3(16.6g,0.16mol) in water (50mL), the layers were separated, the aqueous layer was extracted with dichloromethane (100 mL. times.2), the organic layers were combined, concentrated, and recrystallized from ethyl acetate/petroleum ether (4:1) to give 36.6g of a white solid in 81% yield.
1H NMR(DMSO-d6,δ:ppm):1.10-1.16(m,2H),1.21-1.26(m,2H),1.42-1.50(m,3H),1.76-1.81(m,2H),2.03-2.06(m,2H),3.54(t,2H,J＝4.4Hz),3.88-3.91(m,1H),6. 16(d,1H,J＝5.2Hz),6.44(dd,1H,J＝1.2Hz,J＝2.4Hz),7.08(d,1H,J＝2. 4Hz),7.40(d,1H,J＝1.2Hz).
ESI-MS:348[M+H+]
Example 8
Preparation of SIPI6398
N- (trans-4- (2-iodoethyl) cyclohexyl) furan-2-carboxamide (II-3) (20.0g,57.6mmol), 3- (piperazin-1-yl) benzo [ d ] isothiazole (12.6g,57.6mmol), sodium carbonate (18.3g,172.8mmol), acetonitrile (300mL) were added to a 500mL single vial, the reaction was refluxed for 20h, cooled to room temperature, filtered, the filter cake was washed with acetonitrile (50 mL. times.2) and then with water (300mL), filtered, the filter cake was dried under vacuum for 5h to give 23.2g of a white solid in 92% yield. The resulting white solid, ethanol (200mL), 10% HCl (63.0mmol) were added to a 500mL single-neck flask, refluxed for 1h, cooled to room temperature, stirred for 1h, filtered to give SIPI6398 as a white solid 22.7g with a yield of 90%.
HPLC purity: 99.94 percent
Example 9
Preparation of 2- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl methanesulfonate (III-1)
N- (trans-4- (2-hydroxyethyl) cyclohexyl) furan-2-carboxamide (50.0g,0.21mol), triethylamine (32.0g, 0.32mol) and dichloromethane (200mL) were added to a 500mL three-necked flask, and a dichloromethane (30mL) solution of methanesulfonyl chloride (26.5g,0.23mol) was added dropwise at 0 ℃ and stirred for 2 hours after the addition, followed by washing with water (50 mL. times.1), a saturated aqueous sodium carbonate solution (30 mL. times.1) and a saturated common salt solution (100 mL. times.1) in this order, drying over anhydrous sodium sulfate, filtration and concentration to obtain 61.6.0g of a pale yellow solid with a yield of 93%.
1H NMR(DMSO-d6,δ:ppm):1.13-1.16(m,2H),1.24-1.27(m,2H),1.62-1.69(m,3H),1.84-1.86(m,2H),2.08-2.10(m,2H),3.02(s,3H),3.86-3.92(m,1H),4.28(t,2H,J ＝4.0Hz),6.16(d,1H,J＝4.0Hz),6.49(s,1H),7.09(d,1H,J＝4.0Hz),7.42 (s,1H).
ESI-MS:316[M+H+]
Example 10
Preparation of SIPI6398
2- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl methanesulfonate (III-1) (40.0g,0.13mol), 3- (piperazin-1-yl) benzo [ d ] isothiazole (27.8g,0.13mol), sodium carbonate (27.6g,0.26mol), acetonitrile (600mL) were added to a 1000mL single vial, the reaction was refluxed for 24h, cooled to room temperature, filtered, the filter cake was washed with acetonitrile (50 mL. times.2) and then with water (500mL), filtered, and the filter cake was dried under vacuum for 5h to give 49.6g of a white solid in 87.87% yield. The obtained white solid, ethanol (500mL) and 10% HCl (0.12mol) were added to a 1000mL single-neck flask, refluxed for 1h, cooled to room temperature, stirred for 1h, and filtered to obtain SIPI6398 as a white solid 51.6g with a yield of 96%.
HPLC purity: 99.92 percent
Example 11
Preparation of 2- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl 4-methylbenzenesulfonate (III-2)
N- (trans-4- (2-hydroxyethyl) cyclohexyl) furan-2-carboxamide (50.0g,0.21mol), triethylamine (32.0g, 0.32mol) and dichloromethane (200mL) were added to a 500mL three-necked flask, a solution of p-toluenesulfonyl chloride (43.8g,0.23mol) in dichloromethane (50mL) was added dropwise at 0 ℃ and stirred for 2 hours, followed by washing with water (80 mL. times.1), a saturated aqueous sodium carbonate solution (30 mL. times.2) and a saturated brine (100 mL. times.1) in this order, drying over anhydrous sodium sulfate, filtering, concentrating, and recrystallizing with ethyl acetate/petroleum ether (2:1) to obtain 72.3g of a white solid with a yield of 88%.
1H NMR(DMSO-d6,δ:ppm):1.14-1.17(m,2H),1.25-1.28(m,2H),1.63-1.71(m,3H),1.83-1.85(m,2H),2.07-2.09(m,2H),2.45(s,3H),3.85-3.90(m,1H),4.29(t,2H,J ＝4.0Hz),6.16(d,1H,J＝4.0Hz),6.50(s,1H),7.08(d,1H,J＝4.0Hz),7.43 (s,1H),7.48-7.49(m,2H),7.78-7.79(m,2H).
ESI-MS:392[M+H+]
Example 12
Preparation of SIPI6398
2- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl 4-methylbenzenesulfonate (III-2) (20.0g,51.2 mmol), 3- (piperazin-1-yl) benzo [ d ] isothiazole (11.2g,51.2mmol), potassium carbonate (14.1g,102.4mmol), acetonitrile (300mL) were added to a 500mL single-necked flask, reacted under reflux for 21h, cooled to room temperature, filtered, the filter cake was washed sequentially with acetonitrile (60 mL. times.2), slurried with water (600mL), filtered, and the filter cake was dried under vacuum for 5h to give 18.6g of a white solid in 83% yield. The resulting white solid, ethanol (200mL), 10% HCl (46.7mmol) were added to a 500mL single-neck flask, refluxed for 0.5h, cooled to room temperature, stirred for 1h, filtered to give SIPI6398 as a white solid 18.2g with a yield of 90%.
HPLC purity: 99.91 percent.

Claims (8)

  1. A compound of the N-cyclohexyl-furan-2-carboxamide formula (I) characterized in that it is a compound of the following general structural formula (I):
    Figure FDA0001892097990000011
    wherein:
    p is 0 or 1;
    q is 0 or 1;
    m represents a hydrogen atom, a halogen atom or a sulfonyloxy group.
  2. 2. The N-cyclohexyl-furan-2-carboxamide compound as claimed in claim 1, characterized in that when M is a hydrogen atom, p is 0 and q is 1; when M is not a hydrogen atom, p is 1 and q is 0.
  3. 3. The N-cyclohexyl-furan-2-carboxamide compound as claimed in claim 1, characterized in that said halogen comprises chlorine, bromine or iodine.
  4. 4. The N-cyclohexyl-furan-2-carboxamide compound as claimed in any of claims 1 to 3, characterized in that said sulfonyloxy group comprises a methanesulfonyloxy group or a p-toluenesulfonyloxy group.
  5. An N-cyclohexyl-furan-2-carboxamide compound, comprising:
    I-1N- (trans-4- (2-oxoethyl) cyclohexyl) furan-2-carboxamide,
    II-1N- (trans-4- (2-chloroethyl) cyclohexyl) furan-2-carboxamide,
    II-2N- (trans-4- (2-bromoethyl) cyclohexyl) furan-2-carboxamide,
    II-3N- (trans-4- (2-iodoethyl) cyclohexyl) furan-2-carboxamide,
    III-12- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl methanesulfonate or
    III-22- (trans-4- (furan-2-carboxamido) cyclohexyl) ethyl 4-methylbenzenesulfonate.
  6. A method for preparing an N-cyclohexyl-furan-2-carboxamide compound, comprising the steps of:
    (1) 4-aminocyclohexanone hydrochloride is taken as a raw material, and is subjected to acylation reaction with furan-2-formyl chloride in a dichloromethane solution, and then a compound 1 is collected from a reaction solution;
    (2) reacting the compound 1 with triethyl phosphonoacetate in a solvent under the action of an alkaline substance, and collecting a compound 2 from a reaction solution;
    (3) the compound 2 is subjected to catalytic hydrogenation reduction by a catalyst in a solvent, is purified by crystallization, and then is collected from a reaction product to obtain a compound 3;
    (4) reacting the compound 3 with a reduction system in a solvent, and collecting a compound 4 from a reaction solution;
    (5) reacting the compound 4 with a halogenating reagent in a solvent, and then collecting the N-cyclohexyl-furan-2-formamide compound Y-1 from a reaction solution;
    or:
    reacting the compound 4 with a sulfonylation reagent under the action of a solvent and an alkaline substance, and then collecting the N-cyclohexyl-furan-2-formamide Z-1 from a reaction solution;
    or:
    reacting the compound 3 with a reducing agent 1 in a solvent, and collecting an N-cyclohexyl-furan-2-formamide compound X-1 from a reaction product; the reducing agent 1 is diisobutyl aluminum hydride;
    the reaction formula is as follows:
    Figure FDA0001892097990000021
    wherein A represents chlorine, bromine or iodine, and B represents a methanesulfonyloxy group or a p-toluenesulfonyloxy group.
  7. 7. The method of claim 6, wherein the reducing system is NaBH4Methanol System, KBH4Methanol System, NaBH4/AlCl3System, LiBH4Or LiAlH4。
  8. 8. Use of N-cyclohexyl-furan-2-carboxamide according to any of claims 1 to 4, characterized in that it is used for the preparation of the anti-schizophrenic drug N- (trans-4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) cyclohexyl) furan-2-carboxamide hydrochloride (SIPI 6398).
CN201811475559.4A 2018-12-04 2018-12-04 N-cyclohexyl-furan-2-formamide compound and preparation method and application thereof Pending CN111269203A (en)

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Publication number Priority date Publication date Assignee Title
CN1361768A (en) * 1999-06-02 2002-07-31 Nps药物有限公司 Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
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CN104496854A (en) * 2015-01-06 2015-04-08 上海医药工业研究院 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1361768A (en) * 1999-06-02 2002-07-31 Nps药物有限公司 Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
CN104140421A (en) * 2013-05-08 2014-11-12 上海医药工业研究院 Benzisothiazole compound and application thereof in preparation of drug for resisting schizophrenia
CN104496854A (en) * 2015-01-06 2015-04-08 上海医药工业研究院 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof
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