CN104496854B - Dimethyl carbamide compounds of 3 cyclohexyl 1,1 and its preparation method and application - Google Patents
Dimethyl carbamide compounds of 3 cyclohexyl 1,1 and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of dimethyl carbamide compounds of 3 cyclohexyl 1,1 and its preparation method and application, 3 described cyclohexyl 1; 1 dimethyl carbamide compounds; for preparing anti-schizophrenia medicine Cariliprazine, compared with prior art and report document, without Deprotection; such as take off Boc groups; Atom economy is high, and raw material is cheap and easy to get, reaction condition is gentle, stable yield, easy to operate, and product quality is controllable; purity is high, and three-waste pollution is few and is easy to the remarkable advantages such as industrialized production.General structure is such as shown in (I)：
Description
Technical field
The present invention relates to 3- cyclohexyl -1,1- dimethyl carbamide compounds and its preparation method and application.
Background technology
Cariliprazine (Cariprazine), chemical entitled anti-form-1-{ 4- [2- [4- (2,3- dichlorophenyl)-piperazine-1-
Base]-ethyl]-cyclohexyl } -3,3- dimethyl urea hydrochlorides are Hungary Gedeon Richter Ltd and U.S. Forest
The D that Laboratories companies develop jointly3/D2Acceptor portion agonist, it is manic for treating schizophrenia (before registration)
Disease (before registration), major depressive disorder (III phases), it is contemplated that listed at the beginning of 2015 as antischizophrinic in the U.S..Its structure
Formula is as follows：
Schizophrenia is a kind of disease for having a strong impact on human health, and the normal life of the population of the world 1% is about influenceed at present
It is living, it is that patient and its family bring serious consequence, it is the big disease of burden on society the 7th.
Antipsychotics is broadly divided into classical antipsychotic thing and atypical antipsychotic, a current clinical line
Medication is with atypical antipsychotic (such as D2/5-HT2aDual antagonist) based on, and clinical conventional non-classical anti-essence at present
God's division disease drug such as Risperidone, Aripiprazole, Ziprasidone, Quetiapine etc. is while positive symptom is treated, to negative disease
Shape also has certain improvement, but it is that side effect (EPS) probability is higher to be respectively provided with outside the side effect of respective feature, such as centrum, is sat quietly not
Can, insomnia, anxiety, cardiac toxic etc., a medicine is there is no while schizophrenia entirety pedigree is improved, effectively in reduction
State side effect.
Cariliprazine is applied to the D that anti-schizophrenia is studied for first report3/D2Partial agonist, has preferential combination concurrently
D3The characteristics of R and DA partial agonists, more than ED50Under the conditions of 100 times of dosage, have no that catalepsis behavior occurs for mouse
(catalepsy is antischizophrinic common adverse effect), extrapyramidal side effect (EPS) is low, in water maze laboratory, significantly
Improve the learning cognition function of hyoscine memory impairment rat.Therefore, Cariliprazine has wide in antipsychotic field
Wealthy potential applicability in clinical practice.
In the prior art, hungarian patent Hu 0302451 discloses the preparation method of Cariliprazine first.It is special at this
In profit, application method A prepares Cariliprazine, i.e., with intermediate 5 and dimethylcarbamyl chloride in triethylamine/dichloromethane system
It is specific as follows to state shown in synthetic route obtained by lower reaction.The yield that this method obtains product is relatively low, only 65%, reaction time
It is long, up to 48h.
Patent CN 102256955 is made improvements on the basis of the above method, i.e., phase is added in reaction system and is turned
Shifting catalyst, such as tetra-n-butyl ammonium bromide, and Cariliprazine is prepared instead of organic bases triethylamine with dense inorganic base such as NaOH, instead
It is 92% to answer yield.
In patent CN 102256954, intermediate 3 and triphosgene reaction are prepared into its isocyanates, and react with dimethylamine
Cariliprazine is prepared, reaction need to be carried out (~10 DEG C -0 DEG C) at a lower temperature, and operated relatively complicated.
It is initiation material with compound 5 in said synthesis route, thus it is to prepare in the middle of the key of Cariliprazine
Body.Patent WO 03029233 discloses a kind of prepare compound 5 (trans 4- { 2- [4- (2,3- dichlorophenyls)-piperazine -1-
Base]-ethyl-cyclohexylamine dihydrochloride) method.This method is not described the yield number of prepare compound 7, compound 5
According to.
Compound 6 need to be by trans 2- { 1- [4- (N- tert-butoxycarbonyls)-amino]-cyclohexyl }-acetic acid esters less than -70
Prepared under the conditions of DEG C, condition is harsh, and reaction yield is relatively low (55%), such as document J.Med.Chem.2000,43 (9):1878-
Described by 1885.Highly flammable diisobutyl aluminium hydride has been used in reaction, has been not suitable for industrialized production.
Document Bioorganic ＆ Medicinal Chemistry Letters, 1997,7:2403-2408 and
Bioorganic & Medicinal Chemistry Letters,2012,22:The conjunction of intermediate 5 is reported in 3437-3440
Into route, but it is only to be referred to by generality, and does not do detailed description and any data characterization.
Patent CN 102256953 is raw material with compound 8, and through five step prepare compounds 5, reaction scheme is as follows.But
In the route, the carboxylic acid form of initiation material 8, i.e., trans 4- aminocyclohexyls acid synthesis difficulty is big, is difficult commercially available.Patent
CN101778820 respectively describes the preparation method of trans 4- aminocyclohexyls acid, but reaction condition is acutely, 130 DEG C of reaction temperature,
Pressure 140bar, reaction time length (5 days), is unfavorable for industrialized production.Patent CN 102224130 is also in autoclave, pressurization
Under the conditions of hydro-reduction 4- nitrobenzoic acids, prepare trans 4- aminocyclohexyls acid.
The content of the invention
Present disclosure is to provide a kind of 3- cyclohexyl -1,1- dimethyl carbamide compounds and its preparation and application,
To overcome the drawbacks described above that prior art is present.
Described 3- cyclohexyl -1,1- dimethyl carbamide compounds, for the compound with following general structure (I)：
Wherein：
M is 0 or 1；
N is 0 or 1；
X represents hydrogen atom, halogen, hydroxyl or sulfonyloxy；
It is preferred that, when X is hydrogen atom, m is that 0, n is 1；
It is preferred that, when X is not hydrogen atom, m is that 1, n is 0；
It is preferred that, described halogen includes fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine；
It is preferred that, described sulfonyloxy includes mesyloxy or tolysulfonyl epoxide；
It is preferred that, described 3- cyclohexyl -1,1- dimethyl carbamide compounds include：
I-11,1- dimethyl -3- (trans -4- (2- oxoethyls) cyclohexyl) urea,
II-13- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas,
III-13- (trans -4- (2- fluoro ethyls) cyclohexyl) -1,1- dimethyl ureas,
III-23- (trans -4- (2- chloroethyls) cyclohexyl) -1,1- dimethyl ureas,
III-33- (trans -4- (2- bromoethyls) cyclohexyl) -1,1- dimethyl ureas,
III-43- (trans -4- (2- iodine ethyl) cyclohexyl) -1,1- dimethyl ureas,
IV-12- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl methane sulfonate esters or
IV-22- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl 4- toluene sulfonic acide esters.
The structure of above-mentioned preferred compound such as following table：
The preparation method of described 3- cyclohexyl -1,1- dimethyl carbamide compounds, comprises the following steps：
(1) using 4- aminocyclohexanones as raw material, in dichloromethane, react and be acylated with dimethylaminoethyl chloride, Ran Houcong
Compound 1 is collected in reaction product；
The mol ratio of 4- aminocyclohexanones and dimethylaminoethyl chloride is 1:0.8~1:2, reaction temperature is 0~30 DEG C；Instead
It is 1~10h between seasonable；
(2) in a solvent, alkaline matter effect is lower to react, and is then produced from reaction for compound 1 and phosphonoacetate
Compound 2 is collected in thing；
Described solvent is selected from the mixing of THF, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene or above-mentioned solvent
Solvent, described alkaline matter is selected from NaH, potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol lithium, n-BuLi or the silicon substrate of hexamethyl two
Lithium amide；
Compound 1 and the mol ratio of phosphonoacetate are 0.8:1~1:3；
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；
(3) then the compound 2 is collected into chemical combination in a solvent through catalyst hydro-reduction from reaction product
Thing 3；
The preferred Pd/C of described catalyst, solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, THF, methyl tetrahydrochysene furan
Mutter, the mixed solvent of toluene, methyl tertiary butyl ether(MTBE) or above-mentioned solvent；
Reaction temperature is 10~120 DEG C；Reaction time is 2~24h；
The weight consumption of catalyst is the 1~20% of compound 2；
The content of compound 2 is 0.01~1g/mL in solvent；
(4) by compound 3 in solvent, reacted with reduction system, 3- cyclohexyl -1,1- is then collected from reaction product
Dimethyl carbamide compounds A-1；
The reduction system is NaBH4/ methanol system, KBH4/ methanol system, NaBH4/AlCl3System, LiBH4Or
LiAlH4；
Term " reduction system NaBH4/ methanol system " refers to NaBH4With with compound 3 flow back 0.5~2h after, be added dropwise one
Determine the methanol solvate of volume, wherein, reducing agent is NaBH4, the volume of methanol is NaBH41~8 times of weight；
Term " reduction system KBH4The KBH that/methanol system " refers to4Flowed back with compound 3 after 0.5~2h, certain body is added dropwise
Long-pending methanol, wherein, reducing agent is KBH4, the volume of methanol is KBH41~8 times of weight；
Term " reduction system NaBH4/AlCl3The NaBH that system " refers to4It is stirred at room temperature after 0.5~2h, drips with compound 3
Plus AlCl3THF solution, wherein, reducing agent is NaBH4, AlCl3Consumption and NaBH4Consumption mol ratio is 1:1；
The mixing that the solvent is selected from THF, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene or above-mentioned solvent is molten
Agent；
Reaction temperature is -10~100 DEG C, and the reaction time is 1~20h；
The molar ratio of compound 3 and reducing agent is 1:1~1:10；
The content of compound 3 is 0.01~1g/mL in solvent；
Or：
By compound 3 in solvent, reacted with reducing agent 2, then collection 3- cyclohexyl -1,1- dimethyl from reaction product
Carbamide compounds B-1；
The reducing agent 2 is diisobutyl aluminium hydride；
The mixing that the solvent is selected from THF, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene or above-mentioned solvent is molten
Agent；
Reaction temperature is -10~100 DEG C, and the reaction time is 1~20h；
The molar ratio of compound 3 and reducing agent is 1:1~1:10；
The content of compound 3 is 0.01~1g/mL in solvent；
(5) by compound A-1 in a solvent, reacted with halogenating agent, described 3- rings are then collected from reaction product
Hexyl -1,1- dimethyl carbamide compounds C-1；
Described solvent is selected from dichloromethane, THF, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, acetic acid second
The mixed solvent of ester or above-mentioned solvent；
Described halogenating agent is selected from diethylaminosulfurtrifluoride, SOCl2, oxalyl chloride, carbon tetrabromide or iodine；
The mol ratio of compound A-1 and halogenating agent is 1:1~1:1.5；
Reaction temperature is -50~110 DEG C；Reaction time is 0.5~12h；
Or：
Compound A-1 reacts under the conditions of solvent and alkaline matter with sulfonylation agent, and reaction temperature is -10~60 DEG C；
Reaction time is 0.5~12h；Then described 3- cyclohexyl -1,1- dimethyl carbamide compounds D- is collected from reaction product
1；
Described solvent is selected from dichloromethane, THF, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, acetic acid second
The mixed solvent of ester or above-mentioned solvent；
Described alkaline matter is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, sodium acid carbonate, carbon
Sour sodium, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide；
Described sulfonylation agent is selected from mesyl chloride or paratoluensulfonyl chloride；
The mol ratio of compound A-1 and sulfonylation agent is 1:1~1:2；
Alkali and compound A-1 mol ratio are 1:1~3:1；
Compound A-1 content is 0.01~1g/mL in solvent；
3- cyclohexyl -1,1- dimethyl carbamide compounds B-1,3- cyclohexyl -1,1- dimethyl carbamide compounds A-1,3-
Cyclohexyl -1,1- dimethyl carbamide compounds C-1 and 3- cyclohexyl -1,1- dimethyl carbamide compounds D-1, is foregoing formula
(I) the 3- cyclohexyl -1,1- dimethyl carbamide compounds shown in；Reaction expression is as follows：
Wherein, Y represents fluorine, chlorine, bromine or iodine, and Z represents mesyloxy or tolysulfonyl epoxide.
4- aminocyclohexanones can be directly commercially available.
3- cyclohexyl -1,1- dimethyl carbamide compounds that the present invention is obtained, are used to prepare anti-spirit point available for preparing
Split medicine Cariliprazine.
3- cyclohexyl -1,1- dimethyl carbamide compounds of the present invention, for preparing anti-schizophrenia medicine Cariliprazine,
Compared with prior art and report document, without Deprotection, such as de- Boc groups, Atom economy is high, raw material is cheap and easy to get,
Reaction condition is gentle, stable yield, easy to operate, and product quality is controllable, and purity is high, and three-waste pollution is few and is easy to industrialized production
Deng remarkable advantage.
Embodiment
Embodiment 1
The preparation of 1,1- dimethyl -3- (trans -4- (2- oxoethyls) cyclohexyl) urea (I-1)；
(1) synthesis of 1,1- dimethyl -3- (4- oxocyclohexyls) ureas (1)
By 4- aminocyclohexanones (113.16g, 1.0mol), dichloromethane (566mL), tetra-n-butyl ammonium bromide (0.6g,
1.9mmol), DMAP (0.6g, 4.9mmol), the 40%NaOH aqueous solution (NaOH:60g) it is added in 1000mL four-hole bottles, ice bath
0 DEG C is cooled to, dimethylaminoethyl chloride (129g, 1.2mol) is slowly added dropwise, temperature control is no more than 10 DEG C, finishes, 2h is stirred at room temperature,
Back flow reaction 6h, is cooled to room temperature, adds H2O (200mL) is stirred, point liquid, and organic layer is successively with 10%HCl (20mL × 2), saturation
Saline solution (200mL × 1) is washed, anhydrous MgSO4It is evaporated, filters, be evaporated, obtain white solid 159.16g, yield 86.5%, directly
Connect for next step reaction.
(2) synthesis of 2- (4- (3,3- dimethyl urea groups) cyclohexyl alkenyl) ethyl acetate (2)
Potassium tert-butoxide (112.21g, 2.0mol), THF (1120mL) are added in 2000mL four-hole bottles, ice bath is cooled to
5 DEG C, THF (50mL) solution of phosphonoacetate (168.14g, 0.75mol) is added dropwise, temperature control is no more than 10 DEG C, room temperature
Stirring reaction 0.5h.Reaction solution is cooled to 5 DEG C, be added dropwise 1,1- dimethyl -3- (4- oxocyclohexyls) urea (1) (92.12g,
THF (460mL) solution 0.5mol), temperature control is no more than 10 DEG C, finishes, and 6h is stirred at room temperature, and adds water (100mL), stirring
0.5h, point liquid, takes upper solution, and solvent is evaporated off, and dichloromethane (300mL) is added, successively with water (50mL × 2), saturated common salt
Water (100mL × 1) is washed, and is evaporated, is obtained white solid 119.15g, yield 93.7%.
(3) synthesis of trans -2- (4- (3,3- dimethyl urea groups) cyclohexyl) ethyl acetate (3)
By 2- (4- (3,3- dimethyl urea groups) cyclohexyl alkenyl) ethyl acetate (2) (64.1g, 0.25mmol), 10%Pd/
C (3.2g), absolute ethyl alcohol DMF (510mL) are added in 1000mL single port bottles, and normal pressure is passed through hydrogen, and outer 45 DEG C of temperature reacts 14h,
Filtering, filter cake is washed with ethanol (20mL × 2), and merging filtrate is evaporated, and residue is with ethyl acetate/petroleum ether (5:1) tie again
Crystalline substance, obtains intermediate 358.8g, white solid, yield 91.7%.
(4) target compound I-1 preparation
By trans -2- (4- (3,3- dimethyl urea groups) cyclohexyl) ethyl acetate (3) (20g, 78.02mmol), toluene
(40mL) is added in 1000mL four-hole bottles, nitrogen protection under, -78 DEG C, be slowly added dropwise diisobutyl aluminium hydride (1M,
130.8mL, 130.8mmol), 0.5h is stirred, the mixed solution of methanol (10mL)/toluene (22mL) is added dropwise, reaction solution is poured into
Into saturation aqueous sodium potassium tartrate (600mL), extracted with methyl tertiary butyl ether(MTBE) (500mL × 4), anhydrous Na2SO4Dry, mistake
Filter, concentration, purifies through silicagel column, obtains 9.94g white solids, yield 60%.
1H NMR(DMSO-d6,δ:ppm):0.88-0.93(m,2H,A-H),1.12-1.17(m,5H,A-H),2.41-
2.43(m,2H,A-H),2.73(s,6H,CH3), 3.41 (m, 1H, A-H), 5.84 (d, 1H, J=7.6Hz, NH-H), 9.58 (t,
1H, J=2.4Hz)
ESI-MS:213[M+H+]
Embodiment 2
The preparation (Cariprazine) of Cariliprazine
By 1,1- dimethyl -3- (trans -4- (2- oxoethyls) cyclohexyl) urea (I-1) (9.0g, 42.39mmol), 1-
(2,3- dichlorophenyls) piperazine (9.8g, 42.39mmol), sodium triacetoxy borohydride (13.1g, 61.8mmol), 1,2- bis-
Chloroethanes (300mL) is added in 500mL single port bottles, and 18h is stirred at room temperature, and adds wet chemical (250mL), point liquid, water
Layer is extracted with 1,2- dichloroethanes (150mL × 1), is merged organic layer, is washed with saturated aqueous common salt (150mL × 1), anhydrous sodium sulfate
Dry, filter, concentration removes most of solvent, and filtering, filter cake is washed with ethyl acetate (50mL × 3), merging filtrate, and concentration is obtained
16.2g white solids, yield 89.5%.Gained white solid, ethanol (160mL), 10%HCl (39.84mmol) are added to
In 250mL single port bottles, flow back 1h, is cooled to room temperature, filters, obtains Cariliprazine (white solid) 16.7g, yield 95.0%.
1H NMR(DMSO-d6,δ:ppm):0.90-0.99(m,2H,A-H),1.18-1.21(m,3H,A-H),1.35-
1.36 (m, 2H, A-H), 1.74-2.76 (m, 4H, A-H), 2.35 (t, 2H, J=4.8Hz), 2.75 (s, 6H, CH3),2.98-
3.00(m,1H,A-H),3.33(s,8H,piperazine-CH2), 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+]
Embodiment 3
The preparation of 3- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1)
By trans -2- (4- (3,3- dimethyl urea groups) cyclohexyl) ethyl acetate (3) (51.27g, 0.2mol), NaBH4
(37.8g, 1mol), THF (190mL) are added in 500mL single port bottles, and back flow reaction 1h is cooled to 50 DEG C, methanol is added portionwise
(80mL), is finished, and back flow reaction 7h, reaction solution is cooled to room temperature, and reaction solution is adjusted into pH1~2 with concentrated hydrochloric acid, stirs 1h, with
Reaction solution is adjusted to pH7~8 by the 20%NaOH aqueous solution, stirs 1h, is extracted with dichloromethane (200mL × 3), saturated aqueous common salt
(100 × 1) wash, anhydrous MgSO4Dry, filter, concentration obtains colorless oil, stands, solidification obtains white solid 37.7g,
Yield 88%.
1H NMR(DMSO-d6,δ:ppm):0.89-0.95(m,2H,A-H),1.13-1.19(m,5H,A-H),1.67-
1.75(m,4H,A-H),2.75(s,6H,CH3), 3.35-3.44 (m, 3H, A-H), 4.32 (t, 1H, J=4.8Hz, OH-H),
5.86 (d, 1H, J=7.6Hz, NH-H)
ESI-MS:215[M+H+]
Embodiment 4
The preparation (Cariprazine) of Cariliprazine
Oxalyl chloride (22.7g, 178.88mmol), dichloromethane (1000mL) are added in 2000mL four-hole bottles, temperature
- 78 DEG C are down to, DMSO (28.6g, 365.5mmol) dichloromethane (150mL) solution is added dropwise, finishes, 1h is stirred, 3- is added dropwise
The dichloromethane of (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1) (20.0g, 93.33mmol)
(500mL) solution, is finished, and stirs 2h, and triethylamine (56g, 552mmol) is added dropwise, and is warming up to room temperature, and water (200mL) is added dropwise, point
Liquid, water layer is extracted with dichloromethane (100mL × 2), merges organic layer, with anhydrous sodium sulfate drying, is filtered, concentration, through silica gel
Post is purified, and obtains white solid 16.76g, yield 84.6%.
By gained white solid (16.76g, 78.96mmol), 1- (2,3- dichlorophenyls) piperazine (18.25g,
78.96mmol), sodium triacetoxy borohydride (24.4g, 115.1mmol), 1,2- dichloroethanes (500mL) are added to
In 1000mL single port bottles, 20h is stirred at room temperature, wet chemical (400mL) is added, point liquid, water layer is with 1,2- dichloroethanes
(300mL × 1) is extracted, and is merged organic layer, is washed with saturated aqueous common salt (200mL × 2), anhydrous sodium sulfate drying, is filtered, concentration,
Most of solvent is removed, filtering, filter cake is washed with ethyl acetate (100mL × 3), merging filtrate, concentration, obtain 28.65g whites solid
Body, yield 84.9%.Gained white solid, ethanol (280mL), 10%HCl (70.38mmol) are added to 500mL single port bottles
In, flow back 1h, is cooled to room temperature, filters, obtains Cariliprazine (white solid) 29.9g, yield 96.1%.
Embodiment 5
The preparation of 3- (trans -4- (2- fluoro ethyls) cyclohexyl) -1,1- dimethyl ureas (III-1)
Diethylaminosulfurtrifluoride (4.0g, 24.8mmol), diethylene glycol dimethyl ether (16mL) are added to 50mL there-necked flasks
In, be cooled to -50 DEG C, be added dropwise 3- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1) (5.3g,
Diethylene glycol dimethyl ether (10mL) solution 24.8mmol), finishes, is warmed to room temperature, and reacts 2h, is concentrated under reduced pressure, is purified through silicagel column,
Obtain 3.8g off-white powders, yield 71%.
1H NMR(DMSO-d6,δ:ppm):0.98-1.02(m,2H,A-H),1.21-1.27(m,5H,A-H),1.74-
1.79(m,4H,A-H),2.81(s,6H,CH3),3.52-3.54(m,1H,A-H),4.38-4.40(m,2H,A-H),5.91(d,
1H, J=8.0Hz, NH-H) .ESI-MS:217[M+H+]
Embodiment 6
The preparation (Cariprazine) of Cariliprazine
By 3- (trans -4- (2- fluoro ethyls) cyclohexyl) -1,1- dimethyl ureas (III-1) (3.8g, 17.6mmol), 1-
(2,3- dichlorophenyls) piperazine (4.06g, 17.6mmol), sodium carbonate (2.8g, 26.4mmol), acetonitrile (50mL) are added to
In 100mL single port bottles, back flow reaction 20h is cooled to room temperature, filtering, and filter cake is washed with acetonitrile (10mL × 2) successively, water (20mL) is beaten
Wash and starch, filter, filter cake vacuum drying, 5h obtains white solid 6.7g, yield 89.2%.By gained white solid, ethanol
(80mL), 10%HCl (16.48mmol) are added in 250mL single port bottles, and flow back 1h, is cooled to room temperature, filters, get Ka Lila
Piperazine (white solid) 6.9g, yield 95.4%.
Embodiment 7
The preparation of 3- (trans -4- (2- chloroethyls) cyclohexyl) -1,1- dimethyl ureas (III-2)
By 3- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1) (6.0g, 28.0mmol), pyrrole
Pyridine (2.43g, 30.8mmol) is added in 50mL there-necked flasks, under ice-water bath, and SOCl is added dropwise2(4.1g, 34.6mmol), is warming up to
110 DEG C, 5h is stirred, is cooled to room temperature, reaction solution is poured into frozen water (50g), reaction solution is adjusted to by highly acid with concentrated hydrochloric acid, point
Liquid, takes organic layer, and water layer is extracted with dichloromethane (10mL × 2), merges organic layer, successively with 10%HCl (10mL × 1), full
Wash, anhydrous sodium sulfate drying, filter with saline solution (10mL × 1), concentration obtains 5.8g off-white powders, yield 89.3%.1H
NMR(DMSO-d6,δ:ppm):0.87-0.93(m,2H,A-H),1.10-1.16(m,5H,A-H),1.64-1.72(m,4H,A-
H),2.74(s,6H,CH3), 3.32-3.34 (m, 1H, A-H), 4.18 (t, 2H, J=6.4Hz, A-H), 5.84 (d, 1H, J=
7.6Hz,NH-H).
ESI-MS:233[M+H+]
Embodiment 8
The preparation (Cariprazine) of Cariliprazine
By 3- (trans -4- (2- chloroethyls) cyclohexyl) -1,1- dimethyl ureas (III-2) (5.8g, 24.9mmol), 1-
(2,3- dichlorophenyls) piperazine (5.8g, 24.9mmol), sodium carbonate (4.0g, 37.35mmol), acetone (60mL) are added to
In 100mL single port bottles, back flow reaction 18h is cooled to room temperature, filtering, and filter cake is washed with acetone (10mL × 2) successively, water (30mL) is beaten
Wash and starch, filter, filter cake vacuum drying, 5h obtains white solid 9.7g, yield 91.3%.By gained white solid, ethanol
(100mL), 10%HCl (23.87mmol) are added in 250mL single port bottles, and flow back 1h, is cooled to room temperature, filters, get Ka Lila
Piperazine (white solid) 9.8g, yield 92.6%.
Embodiment 9
The preparation of 3- (trans -4- (2- bromoethyls) cyclohexyl) -1,1- dimethyl ureas (III-3)
By 3- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1) (6.0g, 28.0mmol), three
Phenylphosphine (8.8g, 33.7mmol), carbon tetrabromide (11.2,33.7mmol), dichloromethane (80mL) are added to 250mL there-necked flasks
In, under the conditions of 0 DEG C, 1h is stirred, is warmed to room temperature, react 1h, concentration purifies through silicagel column, obtains white solid 7.37g, yield
95%.
1H NMR(DMSO-d6,δ:ppm):0.86-0.91(m,2H,A-H),1.09-1.15(m,5H,A-H),1.62-
1.71(m,4H,A-H),2.72(s,6H,CH3), 3.37-3.46 (m, 3H, A-H), 5.84 (d, 1H, J=7.6Hz, NH-H)
ESI-MS:277[M+H+]
Embodiment 10
The preparation (Cariprazine) of Cariliprazine
By 3- (trans -4- (2- bromoethyls) cyclohexyl) -1,1- dimethyl ureas (III-3) (7.0g, 25.3mmol), 1-
(2,3- dichlorophenyls) piperazine (5.84g, 25.3mmol), potassium carbonate (5.2g, 38.0mmol), acetone (80mL) are added to
In 250mL single port bottles, back flow reaction 15h is cooled to room temperature, filtering, and filter cake is washed with acetone (10mL × 2) successively, water (40mL) is beaten
Wash and starch, filter, filter cake vacuum drying, 5h obtains white solid 9.3g, yield 85.7%.By gained white solid, ethanol
(100mL), 10%HCl (22.84mmol) are added in 250mL single port bottles, and flow back 1h, is cooled to room temperature, filters, get Ka Lila
Piperazine (white solid) 9.1g, yield 90.1%.
Embodiment 11
The preparation of 3- (trans -4- (2- iodine ethyl) cyclohexyl) -1,1- dimethyl ureas (III-4)
Triphenylphosphine (9.5g, 36.4mmol), imidazoles (2.6g, 37.8mmol), dichloromethane (100mL) are added to
In 250mL there-necked flasks, under ice-water bath, iodine (9.2g, 36.4mmol) is added portionwise, 0.5h is stirred, 3- (trans -4- (2- hydroxyls are added dropwise
Base ethyl) cyclohexyl) -1,1- dimethyl ureas (II-1) (6.0g, 28.0mmol) dichloromethane (50mL) solution, finish, room
Warm stirring reaction 6h, adds NaHSO3Water (16mL) solution of (3.8g, 36.4mmol), point liquid, water layer is with dichloromethane (10mL
× 2) extract, merge organic layer, concentration purifies through silicagel column, obtains white solid 8.1g, yield 89.2%.
1H NMR(DMSO-d6,δ:ppm):0.75-0.80(m,2H,A-H),0.98-1.04(m,5H,A-H),1.51-
1.60(m,4H,A-H),2.70(s,6H,CH3), 3.26-3.29 (t, 2H, J=6.4Hz, A-H), 3.586-3.61 (m, 1H, A-
), H 5.84 (d, 1H, J=7.6Hz, NH-H)
ESI-MS:325[M+H+]
Embodiment 12
The preparation (Cariprazine) of Cariliprazine
By 3- (trans -4- (2- iodine ethyl) cyclohexyl) -1,1- dimethyl ureas (III-4) (8.0g, 24.7mmol), 1-
(2,3- dichlorophenyls) piperazine (5.7g, 24.7mmol), sodium carbonate (3.9g, 37.0mmol), acetonitrile (100mL) are added to
In 250mL single port bottles, back flow reaction 18h is cooled to room temperature, filtering, and filter cake is washed with acetonitrile (20mL × 2) successively, water (50mL) is beaten
Wash and starch, filter, filter cake vacuum drying, 5h obtains white solid 10.3g, yield 97.6%.By gained white solid, ethanol
(100mL), 10%HCl (25.31mmol) are added in 250mL single port bottles, and flow back 1h, is cooled to room temperature, filters, get Ka Lila
Piperazine (white solid) 10.8g, yield 96.8%.
Embodiment 13
The preparation of 2- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl methane sulfonate ester (IV-1)
By 3- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1) (6.0g, 28.0mmol), three
Ethamine (4.3mL, 30.8mmol), dichloromethane (50mL) are added in 100mL there-necked flasks, under the conditions of 0 DEG C, and mesyl chloride is added dropwise
Dichloromethane (10mL) solution of (3.5g, 30.8mmol), is finished, and 3h is stirred, successively with water (20mL × 1), saturated sodium carbonate
The aqueous solution (10mL × 1), saturated aqueous common salt (20mL × 1) washing, anhydrous sodium sulfate drying are filtered, and concentration obtains white solid
8.0g, yield 97.5%.
1H NMR(DMSO-d6,δ:ppm):0.95-0.98(m,2H,A-H),1.18-1.21(m,3H,A-H),1.54-
1.59(m,2H,A-H),1.71-1.76(m,4H,A-H),2.75(s,6H,CH3),3.17(s,3H,CH3),3.33-3.34(m,
1H, A-H), 4.22 (t, 2H, J=6.4Hz, A-H) 5.87 (d, 1H, J=8.0Hz, NH-H)
ESI-MS:293[M+H+]
Embodiment 14
The preparation (Cariprazine) of Cariliprazine
By 2- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl methane sulfonate ester (IV-1) (8.0g, 27.4mmol),
1- (2,3- dichlorophenyls) piperazine (6.3g, 27.4mmol), sodium carbonate (4.4g, 41.1mmol), acetonitrile (100mL) are added to
In 250mL single port bottles, back flow reaction 17h is cooled to room temperature, filtering, and filter cake is washed with acetonitrile (20mL × 2) successively, water (50mL) is beaten
Wash and starch, filter, filter cake vacuum drying, 5h obtains white solid 11.1g, yield 94.8%.By gained white solid, ethanol
(100mL), 10%HCl (27.27mmol) are added in 250mL single port bottles, and flow back 1h, is cooled to room temperature, filters, get Ka Lila
Piperazine (white solid) 11.6g, yield 96.2%.
Embodiment 15
The preparation of 2- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl 4- toluene sulfonic acides ester (IV-2)
By 3- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas (II-1) (6.0g, 28.0mmol), three
Ethamine (4.3mL, 30.8mmol), dichloromethane (50mL) are added in 100mL there-necked flasks, under the conditions of 0 DEG C, are added dropwise to toluene sulphur
Dichloromethane (10mL) solution of acyl chlorides (5.9g, 30.8mmol), is finished, and 4h is stirred, successively with water (20mL × 1), saturated carbon
Acid sodium aqueous solution (10mL × 1), saturated aqueous common salt (20mL × 1) washing, anhydrous sodium sulfate drying are filtered, concentration, acetic acid second
Ester/petroleum ether recrystallization, obtains white solid 9.3g, yield 90.4%.
1H NMR(DMSO-d6,δ:ppm):0.97-1.00(m,2H,A-H),1.21-1.24(m,3H,A-H),1.56-
1.61(m,2H,A-H),1.73-1.78(m,4H,A-H),2.45(s,3H,CH3),2.76(s,6H,CH3),3.64-3.65(m,
1H, A-H), 4.25 (t, 2H, J=6.4Hz, A-H) 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+]
Embodiment 16
The preparation (Cariprazine) of Cariliprazine
By 2- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl 4- toluene sulfonic acides ester (IV-2) (9.0g,
24.4mmol), 1- (2,3- dichlorophenyls) piperazine (5.6g, 24.4mmol), potassium carbonate (5.1g, 36.6mmol), acetonitrile
(150mL) is added in 250mL single port bottles, back flow reaction 22h, is cooled to room temperature, filtering, and filter cake is successively with acetonitrile (30mL × 2)
Wash, water (60mL) mashing is washed, and is filtered, filter cake vacuum drying, 5h obtains white solid 9.2g, yield 88.1%.Gained white is solid
Body, ethanol (100mL), 10%HCl (22.57mmol) are added in 250mL single port bottles, and flow back 1h, is cooled to room temperature, filters,
Obtain Cariliprazine (white solid) 9.2g, yield 92.5%.
Claims (13)
1.3- cyclohexyl -1,1- dimethyl carbamide compounds, it is characterised in that be the compound with following general structure (I)：
Wherein：
M is 1；
N is 0；
X represents halogen, hydroxyl or sulfonyloxy, and described sulfonyloxy is mesyloxy or tolysulfonyl epoxide.
2. 3- cyclohexyl -1,1- dimethyl carbamide compounds according to claim 1, it is characterised in that described halogen
Including fluorine, chlorine, bromine or iodine.
3.3- cyclohexyl -1,1- dimethyl carbamide compounds, it is characterised in that be：
II-13- (trans -4- (2- hydroxyethyls) cyclohexyl) -1,1- dimethyl ureas,
III-13- (trans -4- (2- fluoro ethyls) cyclohexyl) -1,1- dimethyl ureas,
III-23- (trans -4- (2- chloroethyls) cyclohexyl) -1,1- dimethyl ureas,
III-33- (trans -4- (2- bromoethyls) cyclohexyl) -1,1- dimethyl ureas,
III-43- (trans -4- (2- iodine ethyl) cyclohexyl) -1,1- dimethyl ureas,
IV-12- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl methane sulfonate esters or
IV-22- (trans -4- (3,3- dimethyl urea groups) cyclohexyl) ethyl 4- toluene sulfonic acide esters.
The preparation method of 4.3- cyclohexyl -1,1- dimethyl carbamide compounds, it is characterised in that comprise the following steps：
(1) using 4- aminocyclohexanones as raw material, in dichloromethane, react and be acylated with dimethylaminoethyl chloride, then from reaction
Compound 1 is collected in product；
(2) in a solvent, alkaline matter effect is lower to react, then from reaction product for compound 1 and phosphonoacetate
Collect compound 2；
(3) then the compound 2 is collected into compound 3 in a solvent through catalyst hydro-reduction from reaction product；
(4) by compound 3 in solvent, reacted with reduction system, 3- cyclohexyl -1,1- diformazans are then collected from reaction product
Base carbamide compounds B-1；
(5) by compound B-1 in a solvent, reacted with halogenating agent, then collected from reaction product described 3- cyclohexyl-
1,1- dimethyl carbamide compounds C-1；
Or：
Compound B-1 reacts under the conditions of solvent and alkaline matter with sulfonylation agent, then collects described from reaction product
3- cyclohexyl -1,1- dimethyl carbamide compounds D-1；
Reaction expression is as follows：
Wherein, Y represents fluorine, chlorine, bromine or iodine, and Z represents mesyloxy or tolysulfonyl epoxide.
5. method according to claim 4, it is characterised in that in step (1), 4- aminocyclohexanones and dimethylamino formyl
The mol ratio of chlorine is 1:0.8~1:2, reaction temperature is 0~30 DEG C；Reaction time is 1~10h.
6. method according to claim 4, it is characterised in that in step (2), described solvent is selected from THF, methyl tetrahydrochysene
Furans, methyl tertiary butyl ether(MTBE), ether, the mixed solvent of toluene or above-mentioned solvent, described alkaline matter are selected from NaH, the tert-butyl alcohol
Potassium, sodium tert-butoxide, tert-butyl alcohol lithium, n-BuLi or lithium hexamethyldisilazide；
Compound 1 and the mol ratio of phosphonoacetate are 0.8:1~1:3；
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.
7. method according to claim 4, it is characterised in that in step (3), described catalyst is Pd/C, solvent choosing
From the mixed of methanol, ethanol, isopropanol, ethyl acetate, THF, methyltetrahydrofuran, toluene, methyl tertiary butyl ether(MTBE) or above-mentioned solvent
Bonding solvent；Reaction temperature is 10~120 DEG C；Reaction time is 2~24h；The weight consumption of catalyst for compound 2 1~
20%；The content of compound 2 is 0.01~1g/mL in solvent.
8. method according to claim 4, it is characterised in that in step (4), the reduction system is NaBH4/ methanol body
System, KBH4/ methanol system, NaBH4/AlCl3System, LiBH4Or LiAlH4；
The solvent is selected from the mixed solvent of THF, methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene or above-mentioned solvent；
Reaction temperature is -10~100 DEG C, and the reaction time is 1~20h；The molar ratio of compound 3 and reducing agent is 1:1~1:10；
The content of compound 3 is 0.01~1g/mL in solvent.
9. method according to claim 4, it is characterised in that in step (5), when being reacted with halogenating agent, described halogen
Diethylaminosulfurtrifluoride, SOCl are selected from for reagent2, oxalyl chloride, carbon tetrabromide or iodine.
10. method according to claim 9, it is characterised in that described solvent is selected from dichloromethane, THF, methyl tetrahydrochysene
Furans, methyl tertiary butyl ether(MTBE), ether, toluene, the mixed solvent of ethyl acetate or above-mentioned solvent；Compound B-1 and halogenating agent
Mol ratio be 1:1~1:1.5；Reaction temperature is -50~110 DEG C；Reaction time is 0.5~12h.
11. method according to claim 4, it is characterised in that in step (5), compound B-1 is in solvent and alkaline matter
Under the conditions of, when being reacted with sulfonylation agent, reaction temperature is -10~60 DEG C；Reaction time is 0.5~12h.
12. method according to claim 11, it is characterised in that described solvent is selected from dichloromethane, THF, methyl four
Hydrogen furans, methyl tertiary butyl ether(MTBE), ether, toluene, the mixed solvent of ethyl acetate or above-mentioned solvent；
Described alkaline matter is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, sodium acid carbonate, carbonic acid
Sodium, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide；
Described sulfonylation agent is selected from mesyl chloride or paratoluensulfonyl chloride；
The mol ratio of compound B-1 and sulfonylation agent is 1:1~1:2；
Alkali and compound B-1 mol ratio are 1:1~3:1；Compound B-1 content is 0.01~1g/mL in solvent.
13. the application of 3- cyclohexyl -1,1- dimethyl carbamide compounds according to any one of claims 1 to 3, its feature
It is, for preparing anti-schizophrenia medicine Cariliprazine.
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| CN111925304A (en) * | 2015-09-22 | 2020-11-13 | 江苏恩华药业股份有限公司 | Compound for preparing kalilazine and preparation method thereof |
| CN106565510B (en) * | 2015-10-09 | 2018-04-27 | 浙江京新药业股份有限公司 | The preparation method of trans 4- Amino-cyclohexvls acetic ester derivative |
| CN110115714B (en) * | 2018-02-06 | 2022-05-24 | 上虞京新药业有限公司 | Preparation method of cariprazine pharmaceutical composition |
| CN110818678B (en) * | 2018-08-14 | 2022-04-01 | 浙江京新药业股份有限公司 | Method for preparing cyclohexane derivative |
| WO2020034946A1 (en) * | 2018-08-14 | 2020-02-20 | 浙江京新药业股份有限公司 | Method for preparing cyclohexane derivative |
| CN110818677A (en) * | 2018-08-14 | 2020-02-21 | 浙江京新药业股份有限公司 | Process for the preparation of cyclohexane derivatives |
| CN111269203A (en) * | 2018-12-04 | 2020-06-12 | 上海中泽医药科技有限公司 | N-cyclohexyl-furan-2-formamide compound and preparation method and application thereof |
| CN111320594A (en) * | 2018-12-13 | 2020-06-23 | 江苏恩华药业股份有限公司 | Carilazine impurity and preparation process and application thereof |
| CN111320593B (en) * | 2018-12-13 | 2022-04-22 | 江苏恩华药业股份有限公司 | Refining method of high-purity Carilazine |
| CN114262283B (en) * | 2021-11-23 | 2024-03-12 | 苏州旺山旺水生物医药有限公司 | Method for preparing kali lazine and intermediate thereof |
| CN115806510B (en) * | 2023-02-03 | 2023-04-21 | 成都福柯斯医药技术有限公司 | Synthesis method of 3-trans-4- (2-hydroxyethyl) cyclohexyl-1, 1-dimethylurea |
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