CN111269203A - N-Cyclohexyl-furan-2-carboxamide compounds, preparation method and application - Google Patents

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-carboxamide compounds, preparation method and application

technical field

The present invention relates to N-cyclohexyl-furan-2-carboxamide compounds and applications thereof.

Background technique

SIPI6398, chemical name is N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-methyl Amide hydrochloride, a D ₃ /D ₂ receptor subtype-selective antagonist for the treatment of schizophrenia. Its structural formula is as follows:

Schizophrenia is a disease that seriously affects human health. It is the most serious type of mental illness. It affects the normal life of about 1% of the world's population, and brings serious consequences and economic burdens to patients and their families.

At present, clinical antipsychotics are mainly divided into typical antipsychotics and atypical antipsychotics, the latter are commonly used drugs, such as risperidone, aripiprazole, ziprasidone and so on. While treating positive symptoms, these drugs can also improve negative symptoms to a certain extent, but they all have their own characteristic side effects, such as extrapyramidal side effects (EPS), akathisia, insomnia, anxiety, orthostatic hypotension, etc. . At the same time, all antipsychotic drugs on the market are cognitive impairment improving effects, which are difficult to meet clinical needs.

SIPI6398 is a D ₃ /D ₂ receptor subtype-selective antagonist with strong 5-HT _1A and 5-HT _2A receptor antagonism, strong anti-schizophrenia activity, good pharmacokinetic properties, extrapyramidal Low side effects (EPS), in the animal novel object recognition experiment, it can significantly improve the learning and memory function of rats, and has a strong effect on improving potential cognitive impairment (Eur.J.Med.Chem.,123(2016)332-353,CN 104140421A). Therefore, SIPI6398 has broad clinical application prospects in the field of anti-schizophrenia.

In the prior art, Chinese patent CN 104140421A firstly disclosed the preparation method of SIPI6398. In this patent, using N-Boc protected cyclohexylacetic acid (5) as raw material, SIPI6398 is prepared through five-step reaction, as shown in the following synthetic route. In this method, the Boc protecting group needs to be removed first, and then acylation is performed to prepare SIPI6398, and the atom economy is poor. At the same time, the highly corrosive trifluoroacetic acid (TFA) is used to remove the Boc group, which has low production safety and is easy to corrode equipment.

The document Eur.J.Med.Chem., 123(2016) 332-353 reported that SIPI6398 was prepared by the following synthetic route using 4-acetamidocyclohexanone as a raw material. In this route, the acetyl group of the intermediate 16 is hydrolyzed under the condition of dilute hydrochloric acid (5% HCl) to obtain the key intermediate 9, which produces a large amount of waste water, which is not conducive to environmental protection.

SUMMARY OF THE INVENTION

The content of the present invention is to provide a kind of N-cyclohexyl-furan-2-carboxamide compound, preparation method and application, in order to overcome the above-mentioned defects existing in the prior art.

The N-cyclohexyl-furan-2-carboxamide compound is a compound with the following general formula (I):

in:

p is 0 or 1;

q is 0 or 1;

X represents a hydrogen atom, halogen or sulfonyloxy;

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 includes 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-1 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethylmethanesulfonate or

III-2 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethyl 4-methylbenzenesulfonate.

The structures of the above-mentioned preferred compounds are as follows:

The preparation method of described N-cyclohexyl-furan-2-carboxamide compound, comprises the steps:

(1) using 4-aminocyclohexanone hydrochloride as raw material, in dichloromethane solution, acylation reaction with furan-2-formyl chloride, then collecting compound 1 from the reaction solution;

The molar ratio of 4-aminocyclohexanone hydrochloride to furan-2-formyl chloride is 1:0.9～1:1.5, the reaction temperature is 0～35°C, and the reaction time is 0.5～3h;

(2) Compound 1 reacts with triethyl phosphoryl acetate in a solvent under the action of a basic substance, and then compound 2 is collected from the reaction solution;

Described solvent is selected from THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene or the mixed solvent of above-mentioned solvent, described basic substance is selected from potassium tert-butoxide, sodium tert-butoxide or tert-butanol lithium;

The molar ratio of compound 1 to triethyl phosphoryl acetate is 0.9:1 to 1:2;

The molar ratio of basic substance to compound 1 is 1:1～3:1;

In the solvent, the content of compound 1 is 0.01-0.5 g/mL;

(3) the compound 2 is reduced by catalytic hydrogenation with a catalyst in a solvent, purified by crystallization, and then the compound 3 is collected from the reaction product;

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 above-mentioned solvents;

The reaction temperature is 10～100℃; the reaction time is 2～24h;

The weight amount of the catalyst is 1-10% of compound 2;

The content of compound 2 in the solvent is 0.01-0.5 g/mL;

(4) reacting compound 3 in a solvent with a reduction system, and then collecting compound 4 from the reaction solution;

The reduction system is NaBH ₄ /methanol system, KBH ₄ /methanol system, NaBH ₄ /AlCl ₃ system, LiBH ₄ or LiAlH ₄ ;

The term "reduction system NaBH ₄ /methanol system" refers to the addition of a certain volume of methanol solvent dropwise after NaBH ₄ and compound 3 are refluxed for 0.5 to 2 hours, wherein the reducing agent is NaBH ₄ , and the volume of methanol is 0.5% of the weight of NaBH ₄ ~6 times;

The term "reduction system KBH ₄ /methanol system" refers to KBH ₄ and compound 3 after refluxing for 0.5 to 2 hours, and then adding a certain volume of methanol dropwise, wherein the reducing agent is KBH ₄ , and the volume of methanol is 0.5 to 6% of the weight of KBH ₄ times;

The term "reduction system NaBH ₄ /AlCl ₃ system" refers to NaBH ₄ and compound 3 after stirring at room temperature for 0.5 to 2 hours, and then adding the THF solution of AlCl ₃ dropwise, wherein the reducing agent is NaBH ₄ , the amount of AlCl ₃ and the amount of NaBH ₄ The molar ratio is 1:1;

Described solvent is selected from THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene or the mixed solvent of above-mentioned solvent;

The reaction temperature is -10～100℃, and the reaction time is 1～24h;

The molar ratio of compound 3 to the reducing agent is 1:1 to 1:10;

The content of compound 3 in the solvent is 0.01-0.5 g/mL;

or:

Compound 3 is reacted with reducing agent 1 in a solvent, and N-cyclohexyl-furan-2-carboxamide compound X-1 is collected from the reaction product;

Described reducing agent 1 is diisobutylaluminum hydride;

Described solvent is selected from THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene or the mixed solvent of above-mentioned solvent;

The reaction temperature is -10～100℃, and the reaction time is 1～24h;

The molar ratio of compound 3 to the reducing agent is 1:1 to 1:10;

The content of compound 3 in the solvent is 0.01-0.5 g/mL;

(5) reacting compound 4 with a halogenated reagent in a solvent, and then collecting the N-cyclohexyl-furan-2-carboxamide compound Y-1 from the reaction product;

Described solvent is selected from dichloromethane, THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene, ethyl acetate or the mixed solvent of above-mentioned solvent;

The halogenated reagent is selected from SOCl ₂ , oxalyl chloride, carbon tetrabromide or iodine;

The molar ratio of compound 4 to halogenated reagent is 1:1～1:2;

The reaction temperature is 0～100℃; the reaction time is 0.5～24h;

or:

Compound 4 is reacted with a sulfonylation reagent under the conditions of a solvent and a basic substance, the reaction temperature is -10-50 ° C; the reaction time is 0.5-24 h; then the N-cyclohexyl-furan- 2-carboxamide compound Z-1;

Described solvent is selected from dichloromethane, THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene, ethyl acetate or the mixed solvent of above-mentioned solvent;

Described alkaline substance is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide;

Described sulfonylation reagent is selected from methanesulfonyl chloride or p-toluenesulfonyl chloride;

The molar ratio of compound 4 to the sulfonylation reagent is 1:1 to 1:1.5;

The molar ratio of base to compound 4 is 1.1:1～2:1;

The content of 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, N-cyclohexyl-furan-2-carboxamide compound Z-1 , are the N-cyclohexyl-furan-2-carboxamide compounds shown in the aforementioned formula (I); the general reaction formula is as follows:

wherein A represents chlorine, bromine or iodine, and B represents methanesulfonyloxy or p-toluenesulfonyloxy.

4-Aminocyclohexanone hydrochloride is commercially available directly.

The N-cyclohexyl-furan-2-carboxamide compounds obtained in the present invention can be used for preparing the antipsychotic drug SIPI6398.

The N-cyclohexyl-furan-2-carboxamide compound of the present invention is used for the preparation of anti-schizophrenia drug SIPI6398, and the synthetic route is as follows:

The above-mentioned preparation of SIPI6398 with the N-cyclohexyl-furan-2-carboxamide compounds of the present invention has the following significant advantages compared with the prior art and reported documents:

1, synthesizing SIPI6398 with N-cyclohexyl-furan-2-carboxamide compounds of the present invention does not need to receive protective groups and remove protective groups, such as Boc group, acetyl group, and the atom economy is high;

2. Using the N-cyclohexyl-furan-2-carboxamide compound of the present invention to prepare SIPI6398, the raw materials are cheap and easy to obtain, the cost is low, the reaction conditions are mild, the yield is stable, the operation is simple, the three wastes are less polluted, and the industrial production is easy.

Detailed ways

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)

Add 4-aminocyclohexanone hydrochloride (1496.2g, 10.0mol), dichloromethane (7481mL), 20% NaOH aqueous solution (NaOH: 1000g) into a 10L four-necked flask, cool to 0°C in an ice bath, slowly Furan-2-formyl chloride (1435.8 g, 11.0 mol) was added dropwise, and the temperature was controlled not to exceed 10°C. After the addition was completed, the mixture was stirred at room temperature for 2 h, and H ₂ O (1000 mL) was added and stirred, and the layers were separated. 200 mL×2), washed with saturated brine (2000 mL×1), dried over anhydrous NaSO ₄ , filtered and concentrated to obtain 1968.7 g of white solid with a yield of 95%, which was directly used in the next reaction.

(2) Synthesis of ethyl 2-(4-(furan-2-carboxamide)cyclohexylalkenyl)acetate (2)

Sodium tert-butoxide (1153.2g, 12mol) and THF (3000mL) were added to a 10000mL four-necked flask, cooled to 5°C in an ice bath, and THF (1000mL) of triethyl phosphoryl acetate (1972.9g, 8.8mol) was added dropwise. ) solution, the temperature was controlled not to exceed 10 °C, and the reaction was stirred at room temperature for 0.5 h. The reaction solution was cooled to 5°C, and a solution of N-(4-oxocyclohexyl)furan-2-carboxamide (1) (1657.8g, 8mol) in THF (1500mL) was added dropwise, and the temperature was controlled not to exceed 10°C. , stirred at room temperature for 2h, added water (1000mL), stirred for 0.5h, separated the layers, took the upper layer solution, evaporated the solvent, added dichloromethane (3000mL), followed by water (500mL×2), saturated brine (1000mL×1 ) was washed and evaporated to dryness to obtain 2129.8 g of a white solid with a yield of 96%.

(3) Synthesis of 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethyl acetate (3)

Ethyl 2-(4-(furan-2-carboxamide)cyclohexylalkenyl)acetate (2) (1663.9 g, 6 mol), 10% Pd/C (13.6 g), absolute ethanol (15 L) were added to In a 50L reaction kettle, hydrogen was passed under normal pressure, the external temperature was 45°C, reacted for 15h, filtered, the filter cake was washed with ethanol (200mL×2), the filtrates were combined, evaporated to dryness, and the residue was washed with ethyl acetate/petroleum ether (3: 1) Recrystallization to obtain 1691 g of Intermediate 3 as a white solid with a yield of 83%.

(4) Preparation of target compound I-1

Add 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethyl acetate (3) (500g, 1.8mol) and toluene (4000 mL) into a 10L four-neck flask, under nitrogen protection , -78°C, slowly add diisobutylaluminum hydride (1M, 3.6L, 3.6mol) dropwise, stir for 0.5h, add dropwise a mixed solution of methanol (500mL)/toluene (1100mL), pour the reaction solution into saturated In an aqueous solution of sodium potassium tartrate (6000 mL), extracted with methyl tert-butyl ether (1 L×4), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 304.9 g of white solid with a yield of 72%.

¹ H NMR (DMSO-d ⁶ , 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＝5.2Hz),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) (100.0 g, 0.43 mol), 3-(piperazin-1-yl)benzene Add [d]isothiazole (94.3g, 0.43mol), sodium triacetoxyborohydride (137.8g, 0.65mol), and 1,2-dichloroethane (1000mL) into a 2000mL single-neck flask, and stir at room temperature for 15h , potassium carbonate aqueous solution (2500 mL) was added, the layers were separated, the aqueous layer was extracted with 1,2-dichloroethane (1500 mL×1), the organic layers were combined, washed with saturated brine (1000 mL×1), and anhydrous sodium sulfate Dry, filter, concentrate, remove most of the solvent, filter, wash the filter cake with ethyl acetate (200 mL×3), combine the filtrates, and concentrate to obtain 188.6 g of white solid with a yield of 91%. The obtained white solid, ethanol (1800 mL), and 10% HCl (0.43 mol) were added to a 3000 mL single-neck flask, refluxed for 0.5 h, cooled to room temperature, stirred for 1 h, and filtered to obtain 171 g of SIPI6398 white solid with a yield of 92%.

¹ H NMR(DMSO-d ⁶ ,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,2H),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%

Example 3

Preparation of N-(trans-4-(2-chloroethyl)cyclohexyl)furan-2-carboxamide (II-1)

2-(trans-4-(furan-2-carboxamido)cyclohexyl)acetate ( ₃ ) (200.0 g, 0.72 mol), NaBH4 (83.2 g, 2.2 mol), THF (1000 mL) were added Put it into a 2000mL single-neck flask, reflux for 0.5h, cool to 40°C, add methanol (160mL) in batches, and after the addition, reflux for 5h, cool the reaction solution to room temperature, adjust the pH of the reaction solution to 1～2 with concentrated hydrochloric acid, Stir for 0.5 h, adjust the pH of the reaction solution to 8-9 with 10% NaOH aqueous solution, stir for 0.5 h, extract with dichloromethane (500 mL×3), wash with saturated brine (500×1), anhydrous Na ₂ SO ₄ Dry, filter and concentrate to obtain 158.9 g of N-(trans-4-(2-hydroxyethyl)cyclohexyl)furan-2-carboxamide as a white solid with a yield of 93%.

N-(trans-4-(2-hydroxyethyl)cyclohexyl)furan-2-carboxamide (50.0g, 0.21mol) and pyridine (18.3g, 0.23mol) were added to a 500mL there-necked flask, and an ice-water bath was added. Then, SOCl ₂ (30.9 g, 0.26 mol) was added dropwise, the temperature was raised to 110 ° C, stirred for 3 h, cooled to room temperature, the reaction solution was poured into ice water (500 g), and the reaction solution was adjusted to strong acidity with concentrated hydrochloric acid, Separate the layers, take the organic layer, extract the aqueous layer with dichloromethane (100 mL × 3), combine the organic layers, wash with 10% HCl (30 mL × 1) and saturated brine (50 mL × 2) successively, and dry over anhydrous sodium sulfate , filtered, and concentrated to obtain 47.3 g of off-white solids with a yield of 88%.

¹ H NMR (DMSO-d ⁶ , 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) (40.0 g, 0.16 mmol), 3-(piperazin-1-yl)benzoyl [d] Isothiazole (35.1g, 0.16mol), sodium carbonate (33.9g, 0.32mol), and acetone (400mL) were added to a 1000 mL single-neck flask, refluxed for 20 h, cooled to room temperature, filtered, and the filter cake was successively treated with acetone (50 mL×2) washing, water (200 mL) beating and washing, filtration, and the filter cake was vacuum-dried for 4 h to obtain 58.2 g of white solid with a yield of 83%. The obtained white solid, ethanol (600 mL), and 10% HCl (0.13 mmol) were added to a 1000 mL single-neck flask, refluxed for 0.5 h, cooled to room temperature, stirred for 1 h, and filtered to obtain 56.8 g of SIPI6398 white solid with a yield of 90%.

HPLC purity: 99.93%

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) and dichloromethane (500mL) were added into a 1000mL three-necked flask, stirred at 0°C for 1h, warmed to room temperature, reacted for 1h, concentrated, and recrystallized with ethyl acetate/petroleum ether (1:5), 56.1 g of white solid were obtained with a yield of 89%.

¹ H NMR (DMSO-d ⁶ , 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) (50.0 g, 0.17 mol), 3-(piperazin-1-yl)benzoyl [d] Isothiazole (37.3g, 0.17mol), potassium carbonate (46.9g, 0.34mmol) and acetone (500mL) were added to a 1000mL single-neck flask, refluxed for 14h, cooled to room temperature, filtered, and the filter cake was successively treated with acetone ( 100mL×2) washing, beating and washing with water (400mL), filtration, and the filter cake was vacuum-dried for 6h to obtain 67.8g of white solid with a yield of 91%. The obtained white solid, ethanol (600 mL), and 10% HCl (0.17 mol) were added to a 1000 mL single-neck flask, refluxed for 0.5 h, cooled to room temperature, stirred for 2 h, and filtered to obtain 62.4 g of SIPI6398 white solid with a yield of 85%.

HPLC purity: 99.90%

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, and iodine (40.6g, 0.16mol) was added in batches under an ice-water bath. , stirred for 0.5h, added dropwise a solution of N-(trans-4-(2-hydroxyethyl)cyclohexyl)furan-2-carboxamide (30.0g, 0.13mol) in dichloromethane (90mL), after the addition, The reaction was stirred at room temperature for 8 h, a solution of NaHSO ₃ (16.6 g, 0.16 mol) in water (50 mL) was added, the layers were separated, the aqueous layer was extracted with dichloromethane (100 mL×2), the organic layers were combined, concentrated, ethyl acetate/petroleum ether (4:1) Recrystallization to obtain 36.6 g of white solid with a yield of 81%.

¹ H NMR (DMSO-d ⁶ , 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) (20.0 g, 57.6 mmol), 3-(piperazin-1-yl)benzoyl [d] Isothiazole (12.6g, 57.6mmol), sodium carbonate (18.3g, 172.8mmol), and acetonitrile (300mL) were added to a 500mL single-neck flask, refluxed for 20h, cooled to room temperature, filtered, and the filter cake was successively treated with acetonitrile ( 50mL × 2), washed with water (300mL), filtered, and the filter cake was vacuum-dried for 5h to obtain 23.2g of white solid with a yield of 92%. The obtained white solid, ethanol (200 mL), and 10% HCl (63.0 mmol) were added to a 500 mL single-neck flask, refluxed for 1 h, cooled to room temperature, stirred for 1 h, and filtered to obtain 22.7 g of SIPI6398 white solid with a yield of 90%.

HPLC purity: 99.94%

Example 9

Preparation of 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethylmethanesulfonate (III-1)

N-(trans-4-(2-hydroxyethyl)cyclohexyl)furan-2-carboxamide (50.0 g, 0.21 mol), triethylamine (32.0 g, 0.32 mol), dichloromethane (200 mL) It was added to a 500mL three-necked flask, and at 0°C, a solution of methanesulfonyl chloride (26.5g, 0.23mol) in dichloromethane (30mL) was added dropwise, the addition was completed, stirred for 2h, followed by water (50mL×1), saturated carbonic acid Sodium aqueous solution (30 mL×1) and saturated brine (100 mL×1) were washed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 61.6.0 g of a pale yellow solid with a yield of 93%.

¹ H NMR (DMSO-d ⁶ , 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)ethylmethanesulfonate (III-1) (40.0 g, 0.13 mol), 3-(piperazin-1-yl) Benzo[d]isothiazole (27.8g, 0.13mol), sodium carbonate (27.6g, 0.26mol), and acetonitrile (600mL) were added to a 1000mL single-neck flask, refluxed for 24h, cooled to room temperature, filtered, and the filter cake was followed by Washed with acetonitrile (50 mL×2), washed with water (500 mL), filtered, and the filter cake was vacuum-dried for 5 h to obtain 49.6 g of white solid with a yield of 87%. The obtained white solid, ethanol (500 mL), and 10% HCl (0.12 mol) were added to a 1000 mL single-neck flask, refluxed for 1 h, cooled to room temperature, stirred for 1 h, and filtered to obtain 51.6 g of SIPI6398 white solid with a yield of 96%.

HPLC purity: 99.92%

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 (50.0 g, 0.21 mol), triethylamine (32.0 g, 0.32 mol), dichloromethane (200 mL) It was added to a 500mL three-necked flask, and at 0°C, a solution of p-toluenesulfonyl chloride (43.8g, 0.23mol) in dichloromethane (50mL) was added dropwise. Sodium carbonate aqueous solution (30mL×2), saturated brine (100mL×1), washed, dried over anhydrous sodium sulfate, filtered, concentrated, recrystallized with ethyl acetate/petroleum ether (2:1) to obtain 72.3g of white solid, which was collected rate 88%.

¹ H NMR (DMSO-d ⁶ , 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) (20.0 g, 51.2 mmol), 3-(piperazine- 1-yl)benzo[d]isothiazole (11.2g, 51.2mmol), potassium carbonate (14.1g, 102.4mmol) and acetonitrile (300mL) were added to a 500mL single-neck flask, refluxed for 21h, cooled to room temperature, filtered, The filter cake was washed with acetonitrile (60 mL×2) and washed with water (600 mL) successively, filtered, and the filter cake was vacuum-dried for 5 h to obtain 18.6 g of white solid with a yield of 83%. The obtained white solid, ethanol (200 mL), and 10% HCl (46.7 mmol) were added to a 500 mL single-neck flask, refluxed for 0.5 h, cooled to room temperature, stirred for 1 h, and filtered to obtain 18.2 g of SIPI6398 white solid with a yield of 90%.

HPLC purity: 99.91%.

Claims (8)

1. N-cyclohexyl-furan-2-carboxamide compound, is characterized in that, is the compound with following general formula (I):

in: p is 0 or 1; q is 0 or 1; M represents a hydrogen atom, halogen or sulfonyloxy. 2. N-cyclohexyl-furan-2-carboxamide compound according to claim 1, is 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. The N-cyclohexyl-furan-2-carboxamide compound according to claim 1, wherein the halogen comprises chlorine, bromine or iodine. 4. The N-cyclohexyl-furan-2-carboxamide compound according to any one of claims 1 to 3, wherein the sulfonyloxy group includes methanesulfonyloxy group or p-toluenesulfonic acid Acyloxy. 5. N-cyclohexyl-furan-2-carboxamide compound, is characterized in that, comprises: 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-1 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethylmethanesulfonate or III-2 2-(trans-4-(furan-2-carboxamido)cyclohexyl)ethyl 4-methylbenzenesulfonate. 6. the preparation method of N-cyclohexyl-furan-2-carboxamide compound, is characterized in that, comprises the steps: (1) using 4-aminocyclohexanone hydrochloride as a raw material, in a dichloromethane solution, an acylation reaction occurs with furan-2-formyl chloride, and then compound 1 is collected from the reaction solution; (2) Compound 1 reacts with triethyl phosphoryl acetate in a solvent under the action of a basic substance, and then compound 2 is collected from the reaction solution; (3) the compound 2 is reduced by catalytic hydrogenation with a catalyst in a solvent, purified by crystallization, and then the compound 3 is collected from the reaction product; (4) reacting compound 3 in a solvent with a reduction system, and then collecting compound 4 from the reaction solution; (5) reacting compound 4 with a halogenated reagent in a solvent, and then collecting the N-cyclohexyl-furan-2-carboxamide compound Y-1 from the reaction solution; or: Compound 4 reacts with a sulfonylation reagent under the action of a solvent and a basic substance, and then the N-cyclohexyl-furan-2-carboxamides Z-1 are collected from the reaction solution; or: Compound 3 is reacted with reducing agent 1 in a solvent, and N-cyclohexyl-furan-2-carboxamide compound X-1 is collected from the reaction product; the reducing agent 1 is diisobutylaluminum hydride; The general reaction formula is as follows:

wherein A represents chlorine, bromine or iodine, and B represents methanesulfonyloxy or p-toluenesulfonyloxy. 7. The method according to claim 6, wherein the reduction system is NaBH ₄ /methanol system, KBH ₄ /methanol system, NaBH ₄ /AlCl ₃ system, LiBH ₄ or LiAlH ₄ . 8. The application of the N-cyclohexyl-furan-2-carboxamide compound according to any one of claims 1 to 4, characterized in that, for the preparation of anti-schizophrenia drug N-(trans-4-( 2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide hydrochloride (SIPI6398).