CN111269199B - Preparation method of cariprazine - Google Patents
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention provides a preparation method of cariprazine, which comprises the following steps: reacting trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine with dimethylamine in the presence of an organic solvent, an acid-binding agent and an additive to obtain calicheazine; the preparation method of the Carilazine has the advantages of short reaction time, high reaction yield, few byproducts, simple post-treatment and suitability for industrial production, and solves the problems of difficult solvent recovery, environmental pollution, complex operation and the like in the prior art.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of cariprazine.
Background
Carragazine (Cariprazine, CAS number: 839712-12-8), Gedeon Richter Ltd, Hungary, and D jointly developed by the United states of Forest Laboratories, Inc3/D2Partial receptor agonists for the treatment of schizophrenia (pre-enrollment), mania (pre-enrollment), major depression (stage III); approved by the U.S. food and drug administration for marketing on 17 days 9/2015. The chemical name of the compound is trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazine-1-yl]-ethyl } -N, N-dimethylformyl-cyclohexylamine of the formula:
antipsychotic drugs are mainly classified into typical antipsychotic drugs and atypical antipsychotic drugs, and the current first-line clinical drugs are atypical antipsychotic drugs (e.g. D)2/5-HT2aDual antagonist) as the first report of the application of cariprazine in anti-schizophrenic studies3/D2Partial agonists combined with preferential binding D3Partial agonists of R and DA characterized by an excess of ED50Under the condition of 100 times dosage, no rat has rigidityThe stupefied behavior (stupor is a common side effect of anti-schizophrenia medicines) and the extrapyramidal side Effect (EPS) are low, and the learning cognitive function of rats with scopolamine memory impairment is obviously improved in the water maze experiment. Therefore, the kalilazine has wide clinical application prospect in the field of schizophrenia resistance.
In the prior art, Hungarian patent Hu 0302451 first discloses a preparation method of cariprazine. In this patent, the preparation of cariprazine is carried out using method a, i.e. by reacting trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine with dimethylcarbamoyl chloride in a triethylamine/dichloromethane system, as shown in the following synthetic scheme. The yield of the product obtained by the method is low, only 65%, and the reaction time is long and reaches 48 h. In addition, the method adopts instable and toxic acyl chloride as a raw material, and has the problems of low reaction yield, unstable raw material reagent and the like.
Patent CN102256955 improves the method, namely adding a phase transfer catalyst such as tetra-n-butylammonium bromide into a reaction system, and replacing organic base triethylamine with concentrated inorganic base such as NaOH to prepare the Carilazine, wherein the reaction yield is 92%; in addition, the method adopts instable and toxic acyl chloride as a raw material, and has the problems of instable raw material reagent and the like.
In patent CN102256954, the intermediate 1 is reacted with chloroformate to prepare cariprazine, the reaction yield is 67% to 72%, the yield is relatively low and byproducts are relatively more, and the problems of unstable raw material reagent and the like exist by using relatively unstable and toxic acyl chloride as the raw material.
In patent CN106543039A, 1- (2, 3-dichlorophenyl) piperazine hydrochloride is used as a raw material, and through a reaction, Boc removal reaction in methanol hydrochloride and N, N-dimethyl formyl chloride acylation reaction are performed, and in the case of this route, all the prior art uses Boc amino protection, and then deprotection is performed, and unstable and toxic acyl chloride is used as a raw material, which results in problems of long reaction route, complicated operation, low yield, unstable raw material reagent, and the like.
According to the invention, 1- (2, 3-dichlorophenyl) piperazine hydrochloride is used as a raw material, and is reacted with dimethylamine, so that the synthesis process has the advantages of few reaction steps, few reaction byproducts, simple post-treatment, high yield and high purity of the cariprazine.
Disclosure of Invention
The invention solves the technical problems of more by-products in a synthetic route 1), complex post-treatment 2), low yield 3) and the like in the prior art, and provides a novel preparation method of the cariprazine.
The preparation method of the cariprazine provided by the invention has the advantages of mild synthesis reaction conditions, few reaction byproducts, simple post-treatment, high yield, high purity and easiness in industrial production.
The invention solves the problems through the following technical scheme.
A method for preparing cariprazine, comprising the steps of:
reacting trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine with dimethylamine in the presence of an organic solvent, an acid-binding agent and an additive to obtain calicheazine; the reaction formula is as follows:
wherein, trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine reacts with dimethylamine under the conditions of an organic solvent, an acid-binding agent and an additive, and after the reaction is finished, the cariprazine is obtained by extraction, concentration, recrystallization, rinsing and drying.
Wherein the methods and conditions for extraction, concentration, recrystallization, rinsing, drying may be conventional in the art for such reactions; preferably, the extraction is to perform extraction separation after purified water is added; the concentration is to concentrate the extracted organic phase; the recrystallization is to add acetonitrile into the concentrated material after concentration and carry out recrystallization; the rinsing is to rinse the filtered filter cake by using acetonitrile; the drying condition is decompression or blast drying at 50-60 ℃.
Wherein the dimethylamine comprises one of dimethylamine hydrochloride and dimethylamine gas.
Wherein the organic solvent comprises one or more of dichloromethane, toluene, xylene, chlorobenzene, diethyl ether, dichloroethane and chloroform; preferably, the organic solvent comprises one or more of dichloromethane and toluene.
Wherein the acid-binding agent comprises one or more of triethylamine, 4-dimethylaminopyridine, 2-chloropyridine, pyridine, 2-methylpyridine, 2-fluoropyridine and 2-bromopyridine; the acid-binding agent comprises one or more of triethylamine, 2-chloropyridine, 2-fluoropyridine and 2-bromopyridine; more preferably, the acid-binding agent is 2-chloropyridine or triethylamine.
Wherein the molar ratio of the 2-chloropyridine to the triethylamine is 1: (2-5); preferably, the molar ratio of the 2-chloropyridine to the triethylamine is 1: 3.
wherein the additive comprises one of trifluoromethanesulfonic anhydride, trifluoroacetyl trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride and methanesulfonyl chloride; preferably, the additive is trifluoromethanesulfonic anhydride.
Wherein the reaction temperature is-5-10 ℃, and the reaction time is 2-10 h; preferably, the reaction temperature is-5-2 ℃, and the reaction time is 2-5 h.
Wherein the preparation method of the trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine comprises the following steps:
reacting 1- (2, 3-dichlorophenyl) piperazine hydrochloride with trans 2- (1- (4- (N-tert-butoxycarbonyl) -amino) -cyclohexyl) -ethyl-4-methylbenzenesulfonate in a polar solvent under the condition of an inorganic base to obtain trans N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine; the reaction formula is as follows:
wherein, 1- (2, 3-dichlorophenyl) piperazine hydrochloride and trans-2- (1- (4- (N-tert-butoxycarbonyl) -amino) -cyclohexyl) -ethyl-4-methylbenzenesulfonate react under the conditions of a polar solvent and an inorganic base, and after the reaction is finished, trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine is obtained through material separation, rinsing and drying;
preferably, the methods and conditions of the stripping, rinsing, drying may be those conventional in the art for such reactions; the material precipitation is to add purified water for material precipitation; the rinsing is to rinse the filtered filter cake by using ethanol; the drying condition is 50 ℃ reduced pressure or forced air drying.
In the present invention, the precursor of the compound 3 of the formula is
CAS number: 917342-29-1.
Compound 4 of formula (la) was purchased from huntinghou foster pharmaceutical limited, CAS: 119532-26-2.
Wherein the polar solvent comprises one or more of methanol, ethanol, isopropanol and acetonitrile; the inorganic base comprises one or more of potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate and sodium bicarbonate; preferably, the polar solvent comprises one of methanol, ethanol; the inorganic base comprises one of potassium carbonate, sodium carbonate and lithium carbonate; more preferably, the polar solvent is ethanol; the inorganic base is potassium carbonate.
Wherein the reaction temperature is 60-80 ℃, and the reaction time is 10-20 h; preferably, the reaction temperature is 70-80 ℃ and the reaction time is 12-18 h.
Wherein the molar ratio of the 1- (2, 3-dichlorophenyl) piperazine hydrochloride to the trans 2- (1- (4- (N-tert-butoxycarbonyl) -amino) -cyclohexyl) -ethyl-4-methylbenzenesulfonate is 1: (0.95-1.2); preferably, the molar ratio of the 1- (2, 3-dichlorophenyl) piperazine hydrochloride to the trans 2- (1- (4- (N-tert-butoxycarbonyl) -amino) -cyclohexyl) -ethyl-4-methylbenzenesulfonate is 1: (1.0-1.1); more preferably, the molar ratio of the 1- (2, 3-dichlorophenyl) piperazine hydrochloride to the trans 2- (1- (4- (N-tert-butoxycarbonyl) -amino) -cyclohexyl) -ethyl-4-methylbenzenesulfonate is 1: 1.05.
wherein the weight ratio of the 1- (2, 3-dichlorophenyl) piperazine hydrochloride to the polar solvent to the inorganic base is 1: (10-15): (0.7-1); preferably, the weight ratio of the 1- (2, 3-dichlorophenyl) piperazine hydrochloride to the polar solvent to the inorganic base is 1: (11-13): (0.75-0.9); more preferably, the weight ratio of the 1- (2, 3-dichlorophenyl) piperazine hydrochloride to the polar solvent to the inorganic base is 1: 12: 0.81.
wherein, the compound 5 and the compound 6 are reacted under the conditions of polar solvent and inorganic base to obtain the compound 2; the reaction formula is as follows:
in the invention, a compound 5 in a formula, a compound 6 in a formula, an inorganic base and a polar solvent are mixed, heated and refluxed to react, and after the reaction is finished, the compound is concentrated, extracted, washed, dried, filtered, concentrated and purified by column chromatography to obtain a compound 2 in a formula; the methods and conditions for concentration, extraction, washing, drying, filtration, concentration, column chromatography purification may be those conventional in the art for such reactions; preferably, the compound of formula 5, the compound of formula 6, an inorganic base and a polar solvent are mixed, heated and refluxed for reaction, after the sampling detection reaction is completed, the solvent is dried, the residue is added with water and ethyl acetate for stirring, liquid separation is carried out, the water phase is extracted by ethyl acetate, the organic phase is combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered, dried by suction, purified by column chromatography, and an eluent: petroleum ether: ethyl acetate ═ 1: 1-0: 1 to obtain a compound 2 of formula (I).
Wherein, the compound 7 in the formula is reacted with the compound 4 in the formula to obtain a compound in the formula 2; the reaction formula is as follows:
in the invention, the compound 7 and the compound 6 of the formula are reacted under the conditions of an organic solvent and an organic base, and after the reaction is finished, the compound 2 of the formula is obtained through extraction, drying, concentration and recrystallization.
Dissolving a compound 4 and a compound 7 in a formula, adding triethylamine into the mixture, slowly stirring the mixture at room temperature, then gradually adding sodium triacetoxyborohydride, continuously stirring the mixture at room temperature for reaction, adding a 10% sodium bicarbonate solution after the reaction is finished, directly extracting and separating the reaction system, drying an organic phase by using anhydrous sodium sulfate, filtering and rotatably steaming the organic phase to dryness, and recrystallizing the solid by using ethyl acetate to obtain a target product.
The methods and conditions for extraction, drying, concentration, recrystallization described in the present invention may be those conventional in such reactions in the art.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine and dimethylamine are reacted under the conditions of an organic solvent, an acid-binding agent and an additive, so that the method has the advantages of short reaction time, high reaction yield, few reaction steps (the step of amino deprotection reaction is not needed, and the kalilazine is obtained by a one-pot method), few byproducts, simple post-treatment and suitability for industrial production, and the problems of difficult solvent recovery, environmental pollution, complex operation and the like in the prior art are solved.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the present invention, the term "compound represented by the formula X" is sometimes expressed as "Compound X", which can be understood by those skilled in the art. The compound shown in formula 1 and the compound 1 are the same compound.
In the following examples, the detection method and conditions of HPLC are as follows:
the model is as follows: agilent HPLC-1260;
a chromatographic column: kromasil 100-5C18 250mm*4.6mm E79084
Column temperature: 25 ℃; flow rate: 1.0 ml/min; sample introduction amount: 10 mu l of the mixture; detection wavelength: 220 nm; mobile phase: mobile phase A: 0.1mol aqueous dipotassium hydrogenphosphate (PH 6), mobile phase B: post-acetonitrile run time: 5 min; solvent: and (3) acetonitrile.
Nuclear magnetic resonance apparatus type: bruker affinity III 400.
Example 1
The preparation method of the compound 3 in the formula is that trans-1- (BOC-amino) -4- (2-hydroxyethyl) cyclohexane: adding 20g (0.082mol) of trans-1- (BOC-amino) -4- (2-hydroxyethyl) cyclohexane into a 500ml single-neck bottle, adding 200ml of dichloromethane for dissolving, adding 12.5g (0.123mol) of triethylamine, adding 18.76g (0.0984mol) of p-toluenesulfonyl chloride under stirring, stirring at room temperature for reaction for 20h, checking that the reaction is complete by TLC (developing solvent ratio: dichloromethane: methanol 10:1), adding 200ml of water into the reaction system, stirring for dissolving, carrying out fine layering, separating out an aqueous phase, concentrating the organic phase until the organic phase has no flow rate basically, adding 200ml of n-hexane into the concentrate, pulping for 2h, filtering, rinsing a filter cake with n-hexane, and drying at 50-60 ℃ under reduced pressure for 8-10h to obtain 26.5g of white solid with the yield of 81.3%;
wherein of formula 31The H NMR data are:
δ7.76-7.78(d,2H),7.43-7.45(d,2H),4.02-4.05(t,2H),3.18-3.29(m,1H),2.45(s,3H),1.80-1.83(t,2H),1.57-1.61(m,2H),1.46-1.51(m,2H),1.41(s,9H),1.18-1.25(m,1H),0.89-1.10(m,4H)。
example 2
Preparation of the Compound of formula (I) 2 trans-N-tert-Butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine
Adding 33.7g of 1- (2, 3-dichlorophenyl) piperazine hydrochloride (compound 4 shown in the formula), 400g of ethanol, 27.2g of potassium carbonate, 50g of trans 2- (1- (4- (N-tert-butoxycarbonyl) -amino) -cyclohexyl) -ethyl-4-methylbenzenesulfonate (compound 3 shown in the formula) into a 1L single-neck bottle, reacting at 75 ℃ for 12-18h, cooling to room temperature after the reaction is finished, adding 400g of water into the reaction system, stirring for 2h, filtering, rinsing a filter cake with ethanol, and drying at 50 ℃ to constant weight to obtain 63g of trans N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine;
wherein the 1H NMR data for compound 2 of formula (la) is:
δ10.7(s,1H),7.33-7.38(m,2H),7.18-7.21(m,1H),6.67-6.69(d,1H),3.40-3.57(m,2H),3.15-3.33(m9H),1.70-1.77(t,4H),1.61-1.62(t,2H),1.37(s,9H),1.21-1.23(d,4H),1.14-1.18(d,2H)。
example 3
Preparation of Compound 2 of formula
Adding 21g (0.052mol) of compound 6 crude product into a reaction bottle, adding 12.6g (0.052mol) of compound 5, 14.4g (0.104mol) of potassium carbonate and 200ml of acetonitrile, carrying out reflux stirring reaction for 12h, after the central control reaction is finished, adding 200ml of water into a reaction system, stirring for 1h, filtering, rinsing a filter cake by using water and acetonitrile respectively, and drying the solid at 50-60 ℃ for 6h to obtain 18.8g of compound 2 as a white solid with the yield of 79.3%;
wherein the 1H NMR data for compound 2 of formula (la) is:
δ10.7(s,1H),7.33-7.38(m,2H),7.18-7.21(m,1H),6.67-6.69(d,1H),3.40-3.57(m,2H),3.15-3.33(m9H),1.70-1.77(t,4H),1.61-1.62(t,2H),1.37(s,9H),1.21-1.23(d,4H),1.14-1.18(d,2H)。
example 4
Preparation of Compound 5 of formula
Dissolving trans-p-toluenesulfonic acid-2- (4-Boc aminocyclohexyl) ethyl ester (3.97g, 0.01mol, 1eq) in DMF (20ml), adding sodium azide (0.8g, 0.012mol, 1.2eq), stirring at room temperature for 4h after addition, sampling to detect that raw materials are completely reacted, pouring the reaction liquid into 150ml of ice water, extracting with ethyl acetate (50 ml. times.3), combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, performing suction filtration and spin drying to obtain a white solid 3.2 g;
dissolving 3.2g of the intermediate in THF (30ml), adding palladium carbon (0.5g), replacing 3 times with hydrogen, stirring at room temperature for reacting for 4h, sampling to detect that the raw material reacts completely, filtering the palladium carbon, and spin-drying to obtain 2.3g of light yellow solid (compound 5);
wherein, compound 5 of formula1H NMR(CDCl3) The data are as follows:
δ4.37(1H，br)，3.39(1H，br)，2.25(2H，d，J＝6.8Hz)，2.06(2H，m)，1.90(2H，m)，1.65(2H，m)，1.44(9H，s)，1.29-1.08(5H，m)。
example 5
Preparation of Compound 6 of formula
Adding 10.0g (0.062mol) of 2, 3-dichloroaniline, 27.3g (0.62mol) of ethylene oxide and 200ml of tetrahydrofuran into a 500ml single-neck flask, stirring the mixed solution at room temperature for reaction for 12 hours, concentrating the reaction system until no flow exists basically after the center control reaction is finished, obtaining 14.8g of oily matter, and directly feeding the crude product to the next step for reaction;
adding 200ml of dichloromethane into 14.8g (0.059mol) of the crude product for dissolving, adding 15.0g (0.148mol) of triethylamine, cooling the reaction system to 5-10 ℃, dropwise adding 14.2g (0.124mol) of methanesulfonyl chloride, heating the system to room temperature after the addition is finished, continuing stirring for reaction for 5 hours, sampling and detecting, pouring the reaction liquid into ice water after the raw materials are completely reacted, stirring, separating liquid, extracting the aqueous phase with dichloromethane, combining organic phases, washing with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated salt water in sequence, drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the organic phase to obtain 21g of the compound 6 with the yield of 87.5%;
wherein the mass spectral data for compound 6 of formula (la) is: MS (ESI) M/z 406.0(M + H)+)。
Example 6
Preparation of Compound 2 of formula
Adding 9.3g (0.039mol) of compound 7 into a reaction bottle, adding 200ml of dichloromethane, 5.97g (0.059mol) of triethylamine and 10.4g (0.039mol) of compound 4, stirring to dissolve, adding 14.9g (0.07mol) of sodium triacetoxyborohydride, stirring to react for 6 hours after the addition is finished, sampling and detecting, wherein the raw materials are basically completely reacted, pouring the reaction solution into 100ml of saturated sodium bicarbonate aqueous solution, stirring for 15 minutes, separating liquid, extracting the aqueous phase with dichloromethane (50 ml. times.2), combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, performing suction filtration and spin-drying, adding 100ml of acetonitrile and 100ml of water into the spin-dried substance, stirring for 2 hours, filtering, respectively rinsing the filter cake with water and acetonitrile, and drying the solid for 6 hours at 50-60 ℃ to obtain 13.4g of compound 2 as a white solid, wherein the yield is 75.3%;
wherein the compound of formula 21The H NMR data are:
δ10.7(s,1H),7.33-7.38(m,2H),7.18-7.21(m,1H),6.67-6.69(d,1H),3.40-3.57(m,2H),3.15-3.33(m9H),1.70-1.77(t,4H),1.61-1.62(t,2H),1.37(s,9H),1.21-1.23(d,4H),1.14-1.18(d,2H)。
example 7
Preparation of Compound 7 of formula
DMSO (9.6g, 0.123mol, 3eq) was added to a 500ml three-necked flask, dissolved in 50ml dichloromethane, replaced with nitrogen, cooled to-78 ℃ in a dry ice bath, and oxalyl chloride (10.4g, 0.082mol, 2eq) was added dropwise, controlled at a temperature not exceeding-65 ℃. After finishing dripping, reacting for 1 hour at the temperature of-70 to-78 ℃, dripping dichloromethane solution of trans-1- (BOC-amino) -4- (2-hydroxyethyl) cyclohexane (solution consisting of 10g (0.041mol) of trans-1- (BOC-amino) -4- (2-hydroxyethyl) cyclohexane and 100ml dichloromethane), controlling the temperature not to exceed-65 ℃, finishing dripping, reacting for 1 hour at the temperature of-70 to-78 ℃, adding triethylamine (41.5g, 0.41mol and 10eq), controlling the temperature not to exceed-45 ℃, removing the dry ice bath, naturally heating to-20 ℃, pouring the reaction solution into ice-cold 1N hydrochloric acid (200ml), stirring for 10 minutes, separating, extracting the water phase with dichloromethane (100ml 2), merging organic phases, sequentially using saturated sodium bicarbonate water solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating the organic phase until no flow exists, to obtain 9.3g of compound 7 with a yield of 94%;
wherein the mass spectral data for compound 7 of formula (lb) is: ms (esi) M/z 186.1 (M-55).
Example 8
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 7.5g (0.066mol) of 2-chloropyridine with stirring, adding 9.3g (0.033mol) of trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the HPLC control reaction is finished, adding 100ml of water into the reaction system, stirring to dissolve, standing for layering, removing the aqueous phase, concentrating the organic layer to have no basic flow, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, drying the filter cake with acetonitrile at 50-60 ℃ for 10h, 8.2g of white solid is obtained, and the yield is 87.6 percent;
wherein the cariprazine1The HNMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 9
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 500ml pressure resistant kettle, adding 100ml of toluene to dissolve, adding 5.0g (0.044mol) of 2-chloropyridine with stirring, adding 8.2g (0.029mol) of trifluoromethanesulfonic anhydride, stirring for 10min, introducing dimethylamine gas into the reaction solution to maintain the pressure in the kettle between 0.02 and 0.05MPa, maintaining the pressure and stirring for reaction for 3h, slowly evacuating the pressure in the kettle after the HPLC control reaction is finished, adding 100ml of water into the reaction system, stirring to dissolve, standing for layering, removing the aqueous phase, concentrating the organic layer to have no basic flow, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, using acetonitrile for a filter cake, drying the filter cake for 10 hours at 50-60 ℃ to obtain 8.48g of white solid with the yield of 90.6%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 10
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 7.5g (0.066mol) of 2-chloropyridine with stirring, adding 7.4g (0.0264mol) of trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the HPLC control reaction is finished, adding 100ml of water into the reaction system, stirring for dissolving, standing for layering, removing the aqueous phase, concentrating the organic layer until no basic flow, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, baking the filter cake with acetonitrile, baking at 50-60 ℃ for 10h, 7.8g of white solid is obtained, and the yield is 83.3%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 11
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 7.5g (0.066mol) of 2-chloropyridine with stirring, adding 11.2g (0.0396mol) of trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the reaction is controlled by HPLC, adding 100ml of water into the reaction system, stirring to dissolve, standing for layering, separating an aqueous phase, concentrating an organic layer to a zero basic flow rate, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, rinsing the filter cake with acetonitrile, baking the filter cake at 50-60 ℃ for 10h, 7.5g of white solid is obtained, and the yield is 80.1%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 12
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 6.4g (0.066mol) of 2-fluoropyridine with stirring, adding 9.3g (0.033mol) of trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the HPLC control reaction is finished, adding 100ml of water into the reaction system, stirring for dissolving, standing for layering, removing the aqueous phase, concentrating the organic layer to have no basic flow, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, drying the filter cake with acetonitrile at 50-60 ℃ for 10h, 8.0g of white solid is obtained, and the yield is 85.5%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 13
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 10.4g (0.066mol) of 2-bromopyridine with stirring, adding 9.3g (0.033mol) of trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the HPLC control reaction is finished, adding 100ml of water into the reaction system, stirring for dissolving, standing for layering, removing the aqueous phase, concentrating the organic layer to have no basic flow, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, drying the filter cake with acetonitrile at 50-60 ℃ for 10h, 7.68g of white solid is obtained, and the yield is 82.1%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 14
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 5.2g (0.066mol) of pyridine under stirring, adding 9.3g (0.033mol) of trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the reaction is controlled by HPLC, adding 100ml of water into the reaction system, stirring to dissolve, standing for layering, separating the aqueous phase, concentrating the organic layer to an unorganized flow rate, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, rinsing the filter cake with acetonitrile, baking the filter cake at 50-60 ℃ for 10h, 7.4g of white solid is obtained, and the yield is 79.1%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
example 15
Preparation of the Compound of formula 1 trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] ethyl ] cyclohexyl } -3, 3-dimethylurea
Adding 10.0g (0.022mol) of trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazin-1-yl) -ethyl) -cyclohexylamine into a 250ml single-neck flask, adding 100ml of dichloromethane to dissolve, adding 7.5g (0.066mol) of 2-chloropyridine with stirring, adding 4.9g (0.033mol) of trifluoroacetyl trifluoromethanesulfonic anhydride, stirring for 10min, adding 5.4g (0.066mol) of dimethylamine hydrochloride, slowly dropping 13.4g (0.132mol) of triethylamine under ice bath, stirring for 4h after dropping, after the reaction is controlled by HPLC, adding 100ml of water into the reaction system, stirring for dissolving, standing for layering, removing the aqueous phase, concentrating the organic layer to a zero-flow rate, adding 100ml of acetonitrile into the concentrate, stirring for 1h, filtering, rinsing the filter cake with acetonitrile, baking at 50-60 ℃ for 10h, 7.85g of white solid is obtained, and the yield is 83.9%;
wherein the cariprazine1The H NMR data are:
δ7.31-7.33(m,2H),7.18-7.20(m,1H),3.2-3.5(m,9H),2.89(s,6H),1.8-1.9(m,4H)1.71-1.77(m,2H),1.31-1.34(m,3H),1.14-1.18(m,2H)。
Claims (5)
1. a preparation method of cariprazine is characterized by comprising the following steps:
reacting trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine with dimethylamine in the presence of an organic solvent, an acid-binding agent and an additive to obtain calicheazine; the reaction formula is as follows:
the preparation method of the trans-N-tert-butoxycarbonyl-4- (2- (4- (2, 3-dichlorophenyl) -piperazine-1-yl) -ethyl) -cyclohexylamine comprises the following steps:
reacting a compound 5 in a formula with a compound 6 in a formula under the conditions of a polar solvent and inorganic base to obtain a compound 2 in a formula; the reaction formula is as follows:
the preparation method of the compound 5 comprises the following steps of preparing the compound 5 by the following reaction formula:
the preparation method of the compound 6 comprises the following steps:
adding 10.0g (0.062mol) of 2, 3-dichloroaniline, 27.3g (0.62mol) of ethylene oxide and 200ml of tetrahydrofuran into a 500ml single-neck flask, stirring the mixed solution at room temperature for reaction for 12 hours, concentrating the reaction system until no flow exists basically after the center control reaction is finished, obtaining 14.8g of oily matter, and directly feeding the crude product to the next step for reaction;
adding 200ml of dichloromethane into 14.8g (0.059mol) of the crude product for dissolving, adding 15.0g (0.148mol) of triethylamine, cooling the reaction system to 5-10 ℃, dropwise adding 14.2g (0.124mol) of methanesulfonyl chloride, heating the system to room temperature after the addition is finished, continuing stirring for reaction for 5 hours, sampling and detecting, pouring the reaction liquid into ice water after the raw materials are completely reacted, stirring, separating liquid, extracting the aqueous phase with dichloromethane, combining organic phases, washing with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated salt water in sequence, drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating and drying the organic phase to obtain 21g of the compound 6 of the formula.
2. The process of claim 1, wherein the organic solvent comprises one or more of dichloromethane, toluene, xylene, chlorobenzene, diethyl ether, dichloroethane, chloroform.
3. The process of claim 1, wherein the acid scavenger comprises one or more of triethylamine, 4-dimethylaminopyridine, 2-chloropyridine, pyridine, 2-methylpyridine, 2-fluoropyridine, and 2-bromopyridine.
4. The process of claim 1, wherein the additive comprises one of triflic anhydride, trifluoroacetyl triflic anhydride, p-toluenesulfonyl chloride, and methanesulfonyl chloride.
5. The process for the preparation of cariprazine according to claim 1, wherein the reaction temperature is from-5 to 10 ℃ and/or the reaction time is from 2 to 10 hours.
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| US5424313A (en) * | 1984-12-21 | 1995-06-13 | Duphar International Research B.V. | Bibyclic heteroacrylpiperazine derivatives having psychotropic activity, and pharmaceutical compositions containing these derivatives |
| CN102256953A (en) * | 2008-12-17 | 2011-11-23 | 吉瑞工厂 | Piperazine salt and a process for the preparation thereof |
| CN106543039A (en) * | 2015-09-22 | 2017-03-29 | 江苏恩华药业股份有限公司 | It is a kind of for preparing compound of Cariliprazine and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424313A (en) * | 1984-12-21 | 1995-06-13 | Duphar International Research B.V. | Bibyclic heteroacrylpiperazine derivatives having psychotropic activity, and pharmaceutical compositions containing these derivatives |
| CN102256953A (en) * | 2008-12-17 | 2011-11-23 | 吉瑞工厂 | Piperazine salt and a process for the preparation thereof |
| CN106543039A (en) * | 2015-09-22 | 2017-03-29 | 江苏恩华药业股份有限公司 | It is a kind of for preparing compound of Cariliprazine and preparation method thereof |
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| Synthesis of Urea Derivatives in Two Sequential Continuous-Flow Reactors;Peter Bana et al.;《Org. Process Res. Dev. 》;20170309(第21期);611-622 * |
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