CN104496854A - 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof - Google Patents

Abstract

The invention discloses a 3-cyclohexyl-1,1-dimethylurea compound and its preparation method and application. The 3-cyclohexyl-1,1-dimethylurea compound is used for preparing The anti-schizophrenic drug cariprazine, compared with the prior art and reported literature, does not require deprotection groups, such as de-Boc group, high atom economy, cheap and easy-to-obtain raw materials, mild reaction conditions, stable yield, and easy operation. Simple, controllable product quality, high purity, less pollution of three wastes and easy industrial production. General structural formula is as shown in (I): .

Description

3-cyclohexyl-1,1-dimethylurea compound and its preparation method and application

technical field

The present invention relates to 3-cyclohexyl-1,1-dimethylurea compound and its preparation method and application.

Background technique

Cariprazine (Cariprazine), the chemical name is trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl }-3,3-Dimethylurea hydrochloride, a D ₃ /D ₂ receptor partial agonist jointly developed by Gedeon Richter Ltd of Hungary and Forest Laboratories of the United States, is used for the treatment of schizophrenia (before registration), mania Mania (before registration), major depressive disorder (Phase III), and is expected to be launched in the US as an anti-schizophrenia drug in early 2015. Its structural formula is as follows:

Schizophrenia is a disease that seriously affects human health. It currently affects the normal life of about 1% of the world's population and has brought serious consequences for patients and their families. It is the seventh largest disease in social burden.

Antipsychotic drugs are mainly divided into typical antipsychotic drugs and atypical antipsychotic drugs. At present, atypical antipsychotic drugs (such as D ₂ /5-HT _2a dual antagonists) are the main first-line clinical drugs. Anti-schizophrenia drugs such as risperidone, aripiprazole, ziprasidone, and quetiapine can improve negative symptoms while treating positive symptoms, but they all have their own side effects, such as extrapyramidal The probability of side effects (EPS) is high, akathisia, insomnia, anxiety, cardiotoxicity, etc. There is no drug that can effectively reduce the above side effects while improving the overall spectrum of schizophrenia.

Cariprazine is the first D ₃ /D ₂ partial agonist reported to be used in anti-schizophrenia research. It has the characteristics of preferential binding to D ₃ R and DA partial agonists. Under the condition of more than 100 times the ED ₅₀ dose, no Mice develop tonic stupor behavior (catalepsy is a common side effect of anti-schizophrenia drugs), and the extrapyramidal side effects (EPS) are low. In the water maze test, it can significantly improve the learning and cognitive functions of scopolamine memory-impaired rats. Therefore, cariprazine has broad clinical application prospects in the field of anti-schizophrenia.

In the prior art, Hungarian patent Hu 0302451 first discloses the preparation method of cariprazine. In this patent, method A is used to prepare cariprazine, which is obtained by reacting intermediate 5 with dimethylcarbamoyl chloride in a triethylamine/dichloromethane system, as shown in the following synthetic route. The yield of the product obtained by this method is low, only 65%, and the reaction time is long, reaching 48h.

Patent CN 102256955 improves the above method on the basis of adding a phase transfer catalyst such as tetra-n-butylammonium bromide to the reaction system, and replaces the organic base triethylamine with a concentrated inorganic base such as NaOH to prepare Kali Perazine, the reaction yield is 92%.

In patent CN 102256954, intermediate 3 is reacted with triphosgene to prepare its isocyanate, and reacted with dimethylamine to prepare cariprazine. The reaction needs to be carried out at a relatively low temperature (~10°C-0°C), and the operation is relatively cumbersome .

In the above synthetic routes, compound 5 is used as the starting material, so it is the key intermediate for the preparation of cariprazine. Patent WO 03029233 discloses a preparation compound 5 (trans 4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexylamine dihydrochloride salt) method. The method does not describe the yield data for the preparation of Compound 7, Compound 5.

Compound 6 needs to be prepared from trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetate at a temperature below -70°C, the conditions are harsh, and the reaction yield The rate is low (55%), as described in the literature J.Med.Chem.2000,43(9):1878-1885. The highly flammable diisobutylaluminum hydride is used in the reaction, which is not suitable for industrial production.

The synthesis route of intermediate 5 is reported in the literature Bioorganic & Medicinal Chemistry Letters, 1997, 7:2403-2408 and Bioorganic & Medicinal Chemistry Letters, 2012, 22: 3437-3440, but it is only mentioned in general and not detailed description and any data representations.

Patent CN 102256953 uses compound 8 as raw material to prepare compound 5 through five steps, and the reaction route is as follows. However, in this route, the carboxylic acid form of the starting material 8, that is, trans-4-aminocyclohexanoic acid, is difficult to synthesize and is not commercially available. Patent CN101778820 respectively describes the preparation method of trans-4-aminocyclohexanoic acid, but the reaction conditions are severe, the reaction temperature is 130° C., the pressure is 140 bar, and the reaction time is long (5 days), which is not conducive to industrial production. Patent CN 102224130 also hydrogenates and reduces 4-nitrobenzoic acid in an autoclave under pressurized conditions to prepare trans-4-aminocyclohexanoic acid.

Contents of the invention

The content of the present invention is to provide a 3-cyclohexyl-1,1-dimethylurea compound and its preparation and application, so as to overcome the above-mentioned defects in the prior art.

The 3-cyclohexyl-1,1-dimethylurea compound is a compound having the following structural formula (I):

in:

m is 0 or 1;

n is 0 or 1;

X represents a hydrogen atom, halogen, hydroxyl or sulfonyloxy;

Preferably, when X is a hydrogen atom, m is 0 and n is 1;

Preferably, when X is not a hydrogen atom, m is 1 and n is 0;

Preferably, said halogen includes fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine;

Preferably, the sulfonyloxy group includes methanesulfonyloxy or p-toluenesulfonyloxy;

Preferably, the 3-cyclohexyl-1,1-dimethylurea compound includes:

I-11,1-Dimethyl-3-(trans-4-(2-oxoethyl)cyclohexyl)urea,

II-13-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea,

III-13-(trans-4-(2-fluoroethyl)cyclohexyl)-1,1-dimethylurea,

III-23-(trans-4-(2-chloroethyl)cyclohexyl)-1,1-dimethylurea,

III-33-(trans-4-(2-bromoethyl)cyclohexyl)-1,1-dimethylurea,

III-4 3-(trans-4-(2-iodoethyl)cyclohexyl)-1,1-dimethylurea,

IV-12-(trans-4-(3,3-dimethylureido)cyclohexyl)ethyl methanesulfonate or

IV-2 2-(trans-4-(3,3-dimethylureido)cyclohexyl)ethyl 4-methylbenzenesulfonate.

The structure of above-mentioned preferred compound is as follows:

The preparation method of the described 3-cyclohexyl-1,1-dimethylurea compound comprises the following steps:

(1) Using 4-aminocyclohexanone as a raw material, react acylation with dimethylcarbamoyl chloride in dichloromethane, and then collect compound 1 from the reaction product;

The molar ratio of 4-aminocyclohexanone to dimethylcarbamoyl chloride is 1:0.8~1:2, the reaction temperature is 0~30°C; the reaction time is 1~10h;

(2) Compound 1 reacts with triethyl phosphoacetate in a solvent under the action of an alkaline substance, and then collects Compound 2 from the reaction product;

The solvent is selected from THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene or a mixed solvent of the above solvents, and the alkaline substance is selected from NaH, potassium tert-butoxide, sodium tert-butoxide, tert-butoxide Lithium butoxide, n-butyllithium or lithium hexamethyldisilazide;

The molar ratio of compound 1 to triethyl phosphoroacetate is 0.8:1 to 1:3;

The molar ratio of basic substance to compound 1 is 1:1～5:1;

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

(3) The compound 2 is catalytically hydrogenated and reduced by a catalyst in a solvent, 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, toluene, methyl tert-butyl ether or a mixed solvent of the above solvents;

The reaction temperature is 10～120℃; the reaction time is 2～24h;

The weight dosage of the catalyst is 1-20% of the compound 2;

The content of compound 2 in the solvent is 0.01-1g/mL;

(4) React compound 3 in a solvent with a reducing system, and then collect 3-cyclohexyl-1,1-dimethylurea compound A-1 from the reaction product;

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

The term "reducing system NaBH ₄ /methanol system" refers to NaBH ₄ and compound 3 refluxed for 0.5 ~ 2h, dropwise adding a certain volume of methanol solvent, wherein the reducing agent is NaBH ₄ , and the volume of methanol is 1% of the weight of NaBH ₄ ~8 times;

The term "reduction system KBH ₄ /methanol system" refers to the KBH ₄ and compound 3 refluxed for 0.5 ~ 2h, a certain volume of methanol is added dropwise, wherein the reducing agent is KBH ₄ , and the volume of methanol is 1 ~ 8% of the weight of KBH ₄ times;

The term "reducing system NaBH ₄ /AlCl ₃ system" refers to NaBH ₄ and compound 3 after stirring at room temperature for 0.5 to 2 hours, then adding a 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;

The solvent is selected from THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene or a mixed solvent of the above solvents;

The reaction temperature is -10～100℃, and the reaction time is 1～20h;

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

The content of compound 3 in the solvent is 0.01-1g/mL;

or:

React compound 3 with reducing agent 2 in a solvent, and then collect 3-cyclohexyl-1,1-dimethylurea compound B-1 from the reaction product;

The reducing agent 2 is diisobutyl aluminum hydride;

The solvent is selected from THF, methyl tetrahydrofuran, methyl tert-butyl ether, ether, toluene or a mixed solvent of the above solvents;

The reaction temperature is -10～100℃, and the reaction time is 1～20h;

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

The content of compound 3 in the solvent is 0.01-1g/mL;

(5) react compound A-1 with a halogenating reagent in a solvent, and then collect the 3-cyclohexyl-1,1-dimethylurea compound C-1 from the reaction product;

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

The halogenating reagent is selected from diethylaminosulfur trifluoride, SOCl ₂ , oxalyl chloride, carbon tetrabromide or iodine;

The molar ratio of compound A-1 to halogenated reagent is 1:1～1:1.5;

The reaction temperature is -50～110℃; the reaction time is 0.5～12h;

or:

Compound A-1 is reacted with a sulfonylating reagent under the condition of a solvent and an alkaline substance, the reaction temperature is -10-60°C; the reaction time is 0.5-12h; then the 3-cyclohexyl- 1,1-Dimethylurea compound D-1;

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

The basic substance is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium bicarbonate, 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 compound A-1 to sulfonylation reagent is 1:1～1:2;

The molar ratio of the base to the compound A-1 is 1:1 to 3:1;

The content of compound A-1 in the solvent is 0.01-1g/mL;

3-cyclohexyl-1,1-dimethylurea compound B-1, 3-cyclohexyl-1,1-dimethylurea compound A-1, 3-cyclohexyl-1,1-dimethylurea compound Urea compound C-1 and 3-cyclohexyl-1,1-dimethylurea compound D-1 are 3-cyclohexyl-1,1-dimethylurea shown in the aforementioned formula (I) Class compound; General reaction formula is as follows:

Wherein, Y represents fluorine, chlorine, bromine or iodine, and Z represents methanesulfonyloxy or p-toluenesulfonyloxy.

4-Aminocyclohexanone is directly commercially available.

The 3-cyclohexyl-1,1-dimethylurea compound obtained in the present invention can be used to prepare cariprazine, an antipsychotic drug.

The 3-cyclohexyl-1,1-dimethylurea compound of the present invention is used to prepare the anti-schizophrenic drug cariprazine. Compared with the prior art and reported documents, it does not need deprotection group, such as de-Boc group Group, high atom economy, cheap raw materials, mild reaction conditions, stable yield, easy operation, controllable product quality, high purity, less pollution of three wastes and easy industrial production.

Detailed ways

Example 1

Preparation of 1,1-dimethyl-3-(trans-4-(2-oxoethyl)cyclohexyl)urea (I-1);

(1) Synthesis of 1,1-dimethyl-3-(4-oxocyclohexyl)urea (1)

4-aminocyclohexanone (113.16g, 1.0mol), dichloromethane (566mL), tetra-n-butylammonium bromide (0.6g, 1.9mmol), DMAP (0.6g, 4.9mmol), 40% NaOH aqueous solution (NaOH: 60g) was added to a 1000mL four-neck flask, cooled to 0°C in an ice bath, and dimethylcarbamoyl chloride (129g, 1.2mol) was slowly added dropwise, with the temperature controlled not to exceed 10°C. React for 6h, cool to room temperature, add H ₂ O (200mL) and stir, separate the layers, wash the organic layer with 10% HCl (20mL×2) and saturated brine (200mL×1) successively, evaporate to dryness with anhydrous MgSO ₄ , filter , and evaporated to dryness to obtain 159.16 g of a white solid with a yield of 86.5%, which was directly used in the next reaction.

(2) Synthesis of ethyl 2-(4-(3,3-dimethylureido)cyclohexylenyl)acetate (2)

Potassium tert-butoxide (112.21g, 2.0mol) and THF (1120mL) were added to a 2000mL four-neck flask, cooled to 5°C in an ice bath, and THF ( 50mL) solution, the temperature was controlled not to exceed 10°C, and the reaction was stirred at room temperature for 0.5h. The reaction solution was cooled to 5°C, and a solution of 1,1-dimethyl-3-(4-oxocyclohexyl)urea (1) (92.12g, 0.5mol) in THF (460mL) was added dropwise, and the temperature was controlled not to exceed 10 ℃, after addition, stir at room temperature for 6h, add water (100mL), stir for 0.5h, separate the liquids, take the upper layer solution, evaporate the solvent, add dichloromethane (300mL), successively wash with water (50mL×2), saturated saline (100mL×1) was washed and evaporated to dryness to obtain 119.15g of white solid with a yield of 93.7%.

(3) Synthesis of trans-2-(4-(3,3-dimethylureido) cyclohexyl) ethyl acetate (3)

2-(4-(3,3-Dimethylureido) cyclohexyl enyl) ethyl acetate (2) (64.1g, 0.25mmol), 10% Pd/C (3.2g), absolute ethanol DMF (510mL) was added to a 1000mL single-necked bottle, hydrogen gas was introduced under normal pressure, and the external temperature was 45°C, reacted for 14h, filtered, the filter cake was washed with ethanol (20mL×2), the combined filtrate was evaporated to dryness, and the residue was washed with ethyl acetate/ Petroleum ether (5:1) was recrystallized to obtain 358.8 g of the intermediate as a white solid with a yield of 91.7%.

(4) Preparation of target compound I-1

Add trans-2-(4-(3,3-dimethylureido)cyclohexyl)ethyl acetate (3) (20g, 78.02mmol) and toluene (40mL) into a 1000mL four-neck flask, nitrogen protection At -78°C, diisobutylaluminum hydride (1M, 130.8mL, 130.8mmol) was slowly added dropwise, stirred for 0.5h, a mixed solution of methanol (10mL)/toluene (22mL) was added dropwise, and the reaction solution was poured into Saturated sodium potassium tartrate aqueous solution (600mL), extracted with methyl tert-butyl ether (500mL×4), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, purified by silica gel column to obtain 9.94g white solid, yield 60 %.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.88-0.93(m,2H,AH),1.12-1.17(m,5H,AH),2.41-2.43(m,2H,AH),2.73(s ,6H,CH ₃ ),3.41(m,1H,AH),5.84(d,1H,J=7.6Hz,NH-H),9.58(t,1H,J=2.4Hz).

ESI-MS:213[M+H ⁺ ]

Example 2

Preparation of Cariprazine (Cariprazine)

1,1-Dimethyl-3-(trans-4-(2-oxoethyl)cyclohexyl)urea (I-1) (9.0g, 42.39mmol), 1-(2,3-di Add chlorophenyl)piperazine (9.8g, 42.39mmol), sodium triacetoxyborohydride (13.1g, 61.8mmol), and 1,2-dichloroethane (300mL) into a 500mL single-necked bottle, and stir at room temperature for 18h , add potassium carbonate aqueous solution (250mL), separate the layers, extract the aqueous layer with 1,2-dichloroethane (150mL×1), combine the organic layers, wash with saturated brine (150mL×1), and dry over anhydrous sodium sulfate , filtered, concentrated, most of the solvent was removed, filtered, the filter cake was washed with ethyl acetate (50mL×3), the filtrates were combined, and concentrated to obtain 16.2g of white solid, yield 89.5%. The resulting white solid, ethanol (160 mL), and 10% HCl (39.84 mmol) were added to a 250 mL one-necked flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 16.7 g of cariprazine (white solid), with a yield of 95.0%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.90-0.99(m,2H,AH),1.18-1.21(m,3H,AH),1.35-1.36(m,2H,AH),1.74-2.76 (m,4H,AH),2.35(t,2H,J＝4.8Hz),2.75(s,6H,CH ₃ ),2.98-3.00(m,1H,AH),3.33(s,8H,piperazine-CH ₂ ),5.85(d,1H,J=8.0Hz,NH-H),7.15(d×d,1H,J=2.4Hz,J=6.8Hz,Ar-H),7.30-7.35(m,2H, Ar-H).

ESI-MS:428[M+H ⁺ ]

Example 3

Preparation of 3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1)

Ethyl trans-2-(4-(3,3-dimethylureido)cyclohexyl)acetate (3) (51.27g, 0.2mol), NaBH ₄ (37.8g, 1mol), THF (190mL) Add it into a 500mL single-necked bottle, reflux for 1h, cool down to 50°C, add methanol (80mL) in batches, complete the addition, reflux for 7h, cool the reaction solution to room temperature, adjust the reaction solution to pH 1-2 with concentrated hydrochloric acid, and stir For 1h, the reaction solution was adjusted to pH 7-8 with 20% NaOH aqueous solution, stirred for 1h, extracted with dichloromethane (200mL×3), washed with saturated brine (100×1), dried over anhydrous MgSO ₄ , filtered, concentrated, A colorless oily substance was obtained, which solidified upon standing to obtain 37.7 g of a white solid, with a yield of 88%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.89-0.95(m,2H,AH),1.13-1.19(m,5H,AH),1.67-1.75(m,4H,AH),2.75(s ,6H,CH ₃ ),3.35-3.44(m,3H,AH),4.32(t,1H,J=4.8Hz,OH-H),5.86(d,1H,J=7.6Hz,NH-H).

ESI-MS:215[M+H ⁺ ]

Example 4

Preparation of Cariprazine (Cariprazine)

Add oxalyl chloride (22.7g, 178.88mmol) and dichloromethane (1000mL) into a 2000mL four-neck flask, lower the temperature to -78°C, add dropwise a solution of DMSO (28.6g, 365.5mmol) in dichloromethane (150mL) , the addition was completed, stirred for 1h, and added dropwise 3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (20.0g, 93.33mmol) in di Chloromethane (500mL) solution was added, stirred for 2h, triethylamine (56g, 552mmol) was added dropwise, warmed up to room temperature, water (200mL) was added dropwise, the layers were separated, and the aqueous layer was extracted with dichloromethane (100mL×2), The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column to obtain 16.76 g of white solid with a yield of 84.6%.

The resulting white solid (16.76g, 78.96mmol), 1-(2,3-dichlorophenyl)piperazine (18.25g, 78.96mmol), sodium triacetoxyborohydride (24.4g, 115.1mmol), 1 , 2-dichloroethane (500mL) was added to a 1000mL single-necked bottle, stirred at room temperature for 20h, an aqueous solution of potassium carbonate (400mL) was added, the layers were separated, and the aqueous layer was extracted with 1,2-dichloroethane (300mL×1), Combine the organic layers, wash with saturated brine (200mL×2), dry over anhydrous sodium sulfate, filter, concentrate, remove most of the solvent, filter, wash the filter cake with ethyl acetate (100mL×3), combine the filtrates, concentrate, 28.65 g of white solid was obtained, yield 84.9%. The resulting white solid, ethanol (280 mL), and 10% HCl (70.38 mmol) were added to a 500 mL one-necked flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 29.9 g of cariprazine (white solid), with a yield of 96.1%.

Example 5

Preparation of 3-(trans-4-(2-fluoroethyl)cyclohexyl)-1,1-dimethylurea (III-1)

Diethylaminosulfur trifluoride (4.0g, 24.8mmol) and diglyme (16mL) were added to a 50mL three-necked flask, cooled to -50°C, and 3-(trans-4-(2 -Hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (5.3g, 24.8mmol) in diglyme (10mL) solution, after addition, rise to room temperature, react for 2h , concentrated under reduced pressure, and purified by a silica gel column to obtain 3.8 g of off-white solid with a yield of 71%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.98-1.02(m,2H,AH),1.21-1.27(m,5H,AH),1.74-1.79(m,4H,AH),2.81(s ,6H,CH ₃ ),3.52-3.54(m,1H,AH),4.38-4.40(m,2H,AH),5.91(d,1H,J＝8.0Hz,NH-H).ESI-MS:217 [M+H ⁺ ]

Example 6

Preparation of Cariprazine (Cariprazine)

3-(trans-4-(2-fluoroethyl)cyclohexyl)-1,1-dimethylurea (III-1) (3.8g, 17.6mmol), 1-(2,3-dichloro Phenyl)piperazine (4.06g, 17.6mmol), sodium carbonate (2.8g, 26.4mmol), and acetonitrile (50mL) were added to a 100mL single-necked flask, refluxed for 20h, cooled to room temperature, filtered, and the filter cake was washed with acetonitrile ( 10mL×2) washing, beating and washing with water (20mL), filtering, and drying the filter cake in vacuum for 5h to obtain 6.7g of white solid with a yield of 89.2%. The resulting white solid, ethanol (80 mL), and 10% HCl (16.48 mmol) were added to a 250 mL one-necked bottle, refluxed for 1 h, cooled to room temperature, and filtered to obtain 6.9 g of cariprazine (white solid), with a yield of 95.4%.

Example 7

Preparation of 3-(trans-4-(2-chloroethyl)cyclohexyl)-1,1-dimethylurea (III-2)

Add 3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (6.0g, 28.0mmol), pyridine (2.43g, 30.8mmol) Into a 50mL three-necked flask, add SOCl ₂ (4.1g, 34.6mmol) dropwise under an ice-water bath, raise the temperature to 110°C, stir for 5h, cool to room temperature, pour the reaction solution into ice water (50g), and wash with concentrated hydrochloric acid Adjust the reaction solution to strong acidity, separate the layers, take the organic layer, extract the aqueous layer with dichloromethane (10mL×2), combine the organic layers, and sequentially wash with 10% HCl (10mL×1), saturated saline (10mL×1 ), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.8 g of off-white solid, with a yield of 89.3%. ¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.87-0.93(m,2H,AH),1.10-1.16(m,5H,AH),1.64-1.72(m,4H,AH),2.74(s ,6H,CH ₃ ),3.32-3.34(m,1H,AH),4.18(t,2H,J=6.4Hz,AH),5.84(d,1H,J=7.6Hz,NH-H).

ESI-MS:233[M+H ⁺ ]

Example 8

Preparation of Cariprazine (Cariprazine)

3-(trans-4-(2-chloroethyl)cyclohexyl)-1,1-dimethylurea (III-2) (5.8g, 24.9mmol), 1-(2,3-dichloro Phenyl)piperazine (5.8g, 24.9mmol), sodium carbonate (4.0g, 37.35mmol), and acetone (60mL) were added to a 100mL single-necked flask, refluxed for 18h, cooled to room temperature, filtered, and the filter cake was washed with acetone ( 10mL×2) washing, beating and washing with water (30mL), filtering, and drying the filter cake in vacuum for 5h to obtain 9.7g of white solid with a yield of 91.3%. The resulting white solid, ethanol (100 mL), and 10% HCl (23.87 mmol) were added to a 250 mL one-necked flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 9.8 g of cariprazine (white solid), with a yield of 92.6%.

Example 9

Preparation of 3-(trans-4-(2-bromoethyl)cyclohexyl)-1,1-dimethylurea (III-3)

3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (6.0g, 28.0mmol), triphenylphosphine (8.8g, 33.7 mmol), carbon tetrabromide (11.2, 33.7mmol), and dichloromethane (80mL) were added to a 250mL three-necked flask, stirred for 1h at 0°C, raised to room temperature, reacted for 1h, concentrated, and purified by a silica gel column to obtain White solid 7.37g, yield 95%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.86-0.91(m,2H,AH),1.09-1.15(m,5H,AH),1.62-1.71(m,4H,AH),2.72(s ,6H,CH ₃ ),3.37-3.46(m,3H,AH),5.84(d,1H,J＝7.6Hz,NH-H).

ESI-MS:277[M+H ⁺ ]

Example 10

Preparation of Cariprazine (Cariprazine)

3-(trans-4-(2-bromoethyl)cyclohexyl)-1,1-dimethylurea (III-3) (7.0g, 25.3mmol), 1-(2,3-dichloro Phenyl)piperazine (5.84g, 25.3mmol), potassium carbonate (5.2g, 38.0mmol), and acetone (80mL) were added to a 250mL single-necked bottle, refluxed for 15h, cooled to room temperature, filtered, and the filter cake was washed with acetone ( 10 mL×2) washing, beating and washing with water (40 mL), filtering, and drying the filter cake in vacuum for 5 hours to obtain 9.3 g of white solid with a yield of 85.7%. The resulting white solid, ethanol (100 mL), and 10% HCl (22.84 mmol) were added to a 250 mL one-necked bottle, refluxed for 1 h, cooled to room temperature, and filtered to obtain 9.1 g of cariprazine (white solid), with a yield of 90.1%.

Example 11

Preparation of 3-(trans-4-(2-iodoethyl)cyclohexyl)-1,1-dimethylurea (III-4)

Add triphenylphosphine (9.5g, 36.4mmol), imidazole (2.6g, 37.8mmol), and dichloromethane (100mL) into a 250mL three-necked flask, and add iodine (9.2g, 36.4mmol) in batches under an ice-water bath , stirred for 0.5h, added dropwise 3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (6.0g, 28.0mmol) in dichloromethane (50mL) solution, after the addition was completed, the reaction was stirred at room temperature for 6h, a solution of NaHSO ₃ (3.8g, 36.4mmol) in water (16mL) was added, the layers were separated, the aqueous layer was extracted with dichloromethane (10mL×2), and the organic layers were combined. Concentrate and purify through a silica gel column to obtain 8.1 g of white solid with a yield of 89.2%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.75-0.80(m,2H,AH),0.98-1.04(m,5H,AH),1.51-1.60(m,4H,AH),2.70(s ,6H, CH ₃ ), 3.26-3.29(t, 2H, J=6.4Hz, AH), 3.586-3.61(m, 1H, AH), 5.84(d, 1H, J=7.6Hz, NH-H).

ESI-MS:325[M+H ⁺ ]

Example 12

Preparation of Cariprazine (Cariprazine)

3-(trans-4-(2-iodoethyl)cyclohexyl)-1,1-dimethylurea (III-4) (8.0g, 24.7mmol), 1-(2,3-dichloro Phenyl)piperazine (5.7g, 24.7mmol), sodium carbonate (3.9g, 37.0mmol), and acetonitrile (100mL) were added to a 250mL single-necked flask, refluxed for 18h, cooled to room temperature, filtered, and the filter cake was washed with acetonitrile ( 20mL×2) washing, beating and washing with water (50mL), filtering, and drying the filter cake in vacuum for 5h to obtain 10.3g of white solid with a yield of 97.6%. The resulting white solid, ethanol (100 mL), and 10% HCl (25.31 mmol) were added to a 250 mL one-necked flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 10.8 g of cariprazine (white solid), with a yield of 96.8%.

Example 13

Preparation of 2-(trans-4-(3,3-dimethylureido)cyclohexyl)ethyl methanesulfonate (IV-1)

3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (6.0g, 28.0mmol), triethylamine (4.3mL, 30.8mmol ), dichloromethane (50mL) were added to a 100mL three-necked flask, and at 0°C, a solution of methanesulfonyl chloride (3.5g, 30.8mmol) in dichloromethane (10mL) was added dropwise. (20mL×1), saturated aqueous sodium carbonate solution (10mL×1), saturated brine (20mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 8.0 g of white solid with a yield of 97.5%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.95-0.98(m,2H,AH),1.18-1.21(m,3H,AH),1.54-1.59(m,2H,AH),1.71-1.76 (m,4H,AH),2.75(s,6H,CH ₃ ),3.17(s,3H,CH ₃ ),3.33-3.34(m,1H,AH),4.22(t,2H,J＝6.4Hz, AH)5.87(d,1H,J=8.0Hz,NH-H).

ESI-MS:293[M+H ⁺ ]

Example 14

Preparation of Cariprazine (Cariprazine)

2-(trans-4-(3,3-dimethylureido)cyclohexyl)ethyl methanesulfonate (IV-1) (8.0g, 27.4mmol), 1-(2,3-di Chlorophenyl)piperazine (6.3g, 27.4mmol), sodium carbonate (4.4g, 41.1mmol), and acetonitrile (100mL) were added to a 250mL single-necked bottle, refluxed for 17h, cooled to room temperature, filtered, and the filter cake was successively washed with acetonitrile (20mL×2), beating and washing with water (50mL), filtered, and the filter cake was vacuum-dried for 5h to obtain 11.1g of white solid with a yield of 94.8%. The resulting white solid, ethanol (100 mL), and 10% HCl (27.27 mmol) were added to a 250 mL one-necked flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 11.6 g of cariprazine (white solid), with a yield of 96.2%.

Example 15

Preparation of 2-(trans-4-(3,3-dimethylureido)cyclohexyl)ethyl 4-methylbenzenesulfonate (IV-2)

3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1) (6.0g, 28.0mmol), triethylamine (4.3mL, 30.8mmol ), dichloromethane (50mL) were added to a 100mL three-necked flask, and at 0°C, a dichloromethane (10mL) solution of p-toluenesulfonyl chloride (5.9g, 30.8mmol) was added dropwise. Wash with water (20mL×1), saturated aqueous sodium carbonate solution (10mL×1), saturated brine (20mL×1), dry over anhydrous sodium sulfate, filter, concentrate, and recrystallize from ethyl acetate/petroleum ether to give a white solid 9.3 g, yield 90.4%.

¹ H NMR(DMSO-d ⁶ ,δ:ppm):0.97-1.00(m,2H,AH),1.21-1.24(m,3H,AH),1.56-1.61(m,2H,AH),1.73-1.78 (m,4H,AH),2.45(s,3H,CH ₃ ),2.76(s,6H,CH ₃ ),3.64-3.65(m,1H,AH),4.25(t,2H,J＝6.4Hz, AH)5.88(d,1H,J=8.0Hz,NH-H),7.52-7.53(m,2H,Ar-H),7.83-7.84(m,2H,Ar-H).

ESI-MS:293[M+H ⁺ ]

Example 16

Preparation of Cariprazine (Cariprazine)

2-(trans-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-methylbenzenesulfonate (IV-2) (9.0g, 24.4mmol), 1-(2 , 3-dichlorophenyl)piperazine (5.6g, 24.4mmol), potassium carbonate (5.1g, 36.6mmol), acetonitrile (150mL) were added to a 250mL single-necked bottle, refluxed for 22h, cooled to room temperature, filtered, filtered The cake was washed successively with acetonitrile (30mL×2), beaten with water (60mL), filtered, and the filter cake was vacuum-dried for 5h to obtain 9.2g of white solid with a yield of 88.1%. The resulting white solid, ethanol (100 mL), and 10% HCl (22.57 mmol) were added to a 250 mL one-necked flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 9.2 g of cariprazine (white solid), with a yield of 92.5%.

Claims (16)

1.3-cyclohexyl-1,1-dimethyl urea compounds, is characterized in that, for having the compound of following general structure (I):

Wherein:

M is 0 or 1;

N is 0 or 1;

X represents hydrogen atom, halogen, hydroxyl or sulfonyloxy.

2. 3-cyclohexyl-1,1-dimethyl urea compounds according to claim 1, is characterized in that, when X is hydrogen atom, m is 0, n is 1, and when X is not hydrogen atom, m is 1, n is 0.

3. 3-cyclohexyl-1,1-dimethyl urea compounds according to claim 1, it is characterized in that, described halogen comprises fluorine, chlorine, bromine or iodine.

4. 3-cyclohexyl-1, the 1-dimethyl urea compounds according to any one of claims 1 to 3, is characterized in that, described sulfonyloxy comprises mesyloxy or tolysulfonyl oxygen base.

5.3-cyclohexyl-1,1-dimethyl urea compounds, is characterized in that, comprising:

I-11,1-dimethyl-3-(trans-4-(2-oxoethyl) cyclohexyl) urea,

II-13-(trans-4-(2-hydroxyethyl) cyclohexyl)-1,1-dimethyl urea,

III-13-(trans-4-(2-fluoro ethyl) cyclohexyl)-1,1-dimethyl urea,

III-23-(trans-4-(2-chloroethyl) cyclohexyl)-1,1-dimethyl urea,

III-33-(trans-4-(2-bromotrifluoromethane) cyclohexyl)-1,1-dimethyl urea,

III-43-(trans-4-(2-iodine ethyl) cyclohexyl)-1,1-dimethyl urea,

IV-12-(trans-4-(3,3-dimethyl urea groups) cyclohexyl) ethyl methane sulfonate ester or

IV-22-(trans-4-(3,3-dimethyl urea groups) cyclohexyl) ethyl 4-toluene sulfonic acide ester.

The preparation method of 6.3-cyclohexyl-1,1-dimethyl urea compounds, is characterized in that, comprise the steps:

(1) with 4-aminocyclohexanone for raw material, in methylene dichloride, react acidylate with dimethylaminoethyl chloride, then from reaction product, collect compound 1;

(2) compound 1 and phosphonoacetate in a solvent, react under alkaline matter effect, then from reaction product, collect compound 2;

(3) by described compound 2 in a solvent through catalyst hydro-reduction, then from reaction product, collect compound 3;

(4) by compound 3 in solvent, react with reduction system, from reaction product, then collect 3-cyclohexyl-1,1-dimethyl urea compounds A-1;

Or:

By compound 3 in solvent, react with reductive agent 2, then from reaction product, collect 3-cyclohexyl-1,1-dimethyl urea compounds B-1; Described reductive agent 2 is diisobutyl aluminium hydride;

(5) by compd A-1 in a solvent, react with halogenating agent, from reaction product, then collect described 3-cyclohexyl-1,1-dimethyl urea compounds C-1;

Or:

Compd A-1, under solvent and alkaline matter condition, reacts with sulfonylation agent, from reaction product, then collect described 3-cyclohexyl-1,1-dimethyl urea compounds D-1;

Reaction expression is as follows:

Wherein, Y represents fluorine, chlorine, bromine or iodine, and Z represents mesyloxy or tolysulfonyl oxygen base.

7. method according to claim 6, is characterized in that, in step (1), the mol ratio of 4-aminocyclohexanone and dimethylaminoethyl chloride is 1:0.8 ~ 1:2, and temperature of reaction is 0 ~ 30 DEG C; Reaction times is 1 ~ 10h.

8. method according to claim 6, it is characterized in that, in step (2), described solvent is selected from the mixed solvent of THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene or above-mentioned solvent, and described alkaline matter is selected from NaH, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, n-Butyl Lithium or lithium hexamethyldisilazide;

Compound 1 is 0.8:1 ~ 1:3 with the mol ratio of phosphonoacetate;

The mol ratio of alkaline matter and compound 1 is 1:1 ~ 5:1;

In solvent, the content of compound 1 is 0.01 ~ 1g/mL.

9. method according to claim 6, it is characterized in that, in step (3), described catalyzer is Pd/C, the mixed solvent of solvent selected from methanol, ethanol, Virahol, ethyl acetate, THF, methyltetrahydrofuran, toluene, methyl tertiary butyl ether or above-mentioned solvent; Temperature of reaction is 10 ~ 120 DEG C; Reaction times is 2 ~ 24h; The weight consumption of catalyzer is 1 ~ 20% of compound 2; In solvent, the content of compound 2 is 0.01 ~ 1g/mL.

10. method according to claim 6, is characterized in that, in step (4), described reduction system is NaBH ₄/ methanol system, KBH ₄/ methanol system, NaBH ₄/ AlCl ₃system, LiBH ₄or LiAlH ₄;

Described solvent is selected from the mixed solvent of THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene or above-mentioned solvent; Temperature of reaction is-10 ~ 100 DEG C, and the reaction times is 1 ~ 20h; Compound 3 is 1:1 ~ 1:10 with the molar ratio of reductive agent; In solvent, the content of compound 3 is 0.01 ~ 1g/mL.

11. methods according to claim 6, it is characterized in that, in step (4), by compound 3 in solvent, react with reductive agent 2, described solvent is selected from the mixed solvent of THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene or above-mentioned solvent; Temperature of reaction is-10 ~ 100 DEG C, and the reaction times is 1 ~ 20h; Compound 3 is 1:1 ~ 1:10 with the molar ratio of reductive agent; In solvent, the content of compound 3 is 0.01 ~ 1g/mL.

12. methods according to claim 6, is characterized in that, in step (5), when reacting with halogenating agent, described halogenating agent is selected from diethylaminosulfurtrifluoride, SOCl ₂, oxalyl chloride, carbon tetrabromide or iodine.

13. methods according to claim 12, is characterized in that, described solvent is selected from the mixed solvent of methylene dichloride, THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene, ethyl acetate or above-mentioned solvent; Compd A-1 is 1:1 ~ 1:1.5 with the mol ratio of halogenating agent; Temperature of reaction is-50 ~ 110 DEG C; Reaction times is 0.5 ~ 12h.

14. methods according to claim 6, is characterized in that, in step (5), compd A-1 is under solvent and alkaline matter condition, and when reacting with sulfonylation agent, temperature of reaction is-10 ~ 60 DEG C; Reaction times is 0.5 ~ 12h.

15. methods according to claim 14, is characterized in that, described solvent is selected from the mixed solvent of methylene dichloride, THF, methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene, ethyl acetate or above-mentioned solvent;

Described alkaline matter is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, sodium bicarbonate, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide or lithium hydroxide;

Described sulfonylation agent is selected from methylsulfonyl chloride or Tosyl chloride;

Compd A-1 is 1:1 ~ 1:2 with the mol ratio of sulfonylation agent;

The mol ratio of alkali and compd A-1 is 1:1 ~ 3:1; In solvent, the content of compd A-1 is 0.01 ~ 1g/mL.

The application of 16. 3-cyclohexyl-1,1-dimethyl urea compounds according to any one of Claims 1 to 4, is characterized in that, draw piperazine for the preparation of for the preparation of anti-schizophrenia medicine Cali.