CN110818678B - Method for preparing cyclohexane derivative - Google Patents
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- C07C273/1836—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid
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Abstract
The invention relates to a method for preparing cyclohexane derivatives, comprising the following steps: a cyclohexane derivative is obtained by subjecting a compound represented by the formula SM01, namely 2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde, to a condensation imine reduction reaction with a compound represented by the formula SM 02. The method has the advantages of less side reaction, high product yield and high purity, and is beneficial to industrial scale production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a cyclohexane derivative.
Background
CN106518841A discloses a class of cyclohexane derivatives, or stereoisomers or salts thereof, wherein the structure of the cyclohexane derivatives is shown as formula IB below:
wherein X is N or C; r is:
these cyclohexane derivatives are useful for dopamine D3Receptor, 5-hydroxytryptamine, has a strong affinity for D2The receptor has weak affinity and shows a weak affinity for D3/D2The receptor has high selectivity, strong effect of resisting schizophrenia symptoms, extremely low toxicity and good safety, and can be used for preparing medicines for treating neuropsychiatric diseases.
In CN106518841A, piperazine and R-Br are butted to form a compound shown in a formula IV, and then the compound is reacted to prepare the cyclohexane derivatives. However, in subsequent experiments, it was found that the reaction formed more disubstituted impurities.
Since many drug candidates fail clinical trials due to unexpected effects or toxicity of unwanted impurities on human metabolism, elimination of these impurities is necessary in early preclinical studies.
Disclosure of Invention
The inventors have found that, by using the synthetic route in CN106518841A to dock N, N-dimethylcarbamoyl chloride in the last step, the reaction in this step is incomplete, especially the dimeric and demethylated impurities in which urea is nucleophilically substituted are high. How to avoid the generation of byproducts and improve the product yield is an urgent problem to be solved. In large scale preparation of cyclohexane derivatives of formula IB, the final product often contains two classes of unwanted impurities, namely dimeric impurities imp6 and imp8, in which urea is nucleophilically substituted, respectively, and monomethyl impurities (or demethylated, monomethyl) imp 1:
moreover, the removal and purification of these two types of impurities cannot be achieved by the purification techniques commonly used in the industry at present, such as recrystallization and column chromatography.
Aiming at the defects of low product yield, high impurity content, low purity and the like in the prior art, the inventor develops a new way, changes the synthetic route of the cyclohexane derivative shown in the formula IB and provides a preparation method with less side reaction and high product purity. Specifically, the present invention adopts the following technical solutions.
A process for preparing a cyclohexane derivative of formula IB comprising the steps of:
subjecting the compound 2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde of formula SM01 to a reductive amination reaction with a compound of formula SM02 or a salt thereof to give a cyclohexane derivative of formula IB:
wherein R is:
the methods and conditions for the reductive amination reaction described above may be those conventional in the art, among others. In the invention, the reducing agent for the reductive amination reaction is preferably selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and acetic acid or potassium borohydride and acetic acid, and the equivalent weight of the reducing agent is preferably 1-10 eq.
The solvent for the reductive amination is preferably dichloromethane, tetrahydrofuran, toluene, acetic acid, or a mixture of two or more thereof.
The reaction temperature of the reductive amination is preferably-20-100 ℃, and the reaction time is preferably 1-48 h.
In one embodiment, the starting material for the reductive amination reaction described above is SM02 free base, and in the case of free base, no additional base needs to be added to the reductive amination reaction.
In another embodiment, the starting material for the reductive amination reaction described above is a salt of SM02, wherein the salt of the compound of formula SM02 is selected from the group consisting of hydrochloride, sulfate, acetate, sulfonate, methanesulfonate, and p-toluenesulfonate, preferably the hydrochloride.
Salts of the compounds of formula SM02 above can be prepared by reacting compound SM02 with an acid selected from hydrochloric acid, sulfuric acid, acetic acid, sulfonic acid, methanesulfonic acid or p-toluenesulfonic acid.
Preferably, the reductive amination reaction is carried out in the presence of a base such as triethylamine, DIPEA, DBU or the like.
In the present invention, the SM01 compound can be prepared according to a preparation method which is conventional in the art.
In one embodiment, the compound of formula SM01 described above is preferably prepared by a process comprising the steps of:
1) carrying out acylation reaction on the compound 2- (4-aminocyclohexyl) ethyl acetate shown in the formula I and N, N-dimethylcarbamoyl chloride to obtain the compound 2- (4- (3, 3-dimethylureido) cyclohexyl) ethyl acetate shown in the formula II;
2) carrying out reduction reaction on the compound shown in the formula II to generate a compound 3- (4- (2-hydroxyethyl) cyclohexyl) -1, 1-dimethylurea shown in the formula III;
3) and (3) carrying out oxidation reaction on the compound shown in the formula III to obtain the compound 2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde shown in the formula SM 01.
The synthetic route is as follows:
preferably, the acylation reaction in the step 1) is carried out in the presence of a base, wherein the base is selected from triethylamine, DIPEA, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, and the equivalent weight of the base is 1-10 eq.
Preferably, the solvent for the acylation reaction in the above step 1) is selected from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, DMF, acetonitrile, toluene or a mixture of two or more thereof.
The reaction temperature of the acylation reaction in the step 1) is preferably-20-100 ℃, and the reaction time is preferably 1-48 h.
Preferably, the reducing agent in the reduction reaction in the step 2) is selected from sodium borohydride and potassium borohydride, and the equivalent weight of the reducing agent is 1-10 eq.
The solvent for the reduction reaction in the step 2) is preferably methanol, tetrahydrofuran, ethanol or a mixture of two or more thereof.
The reaction temperature of the reduction reaction in the step 2) is preferably-20-100 ℃, and the reaction time is preferably 1-48 h.
The oxidation reaction in step 3) may be a conventional oxidation reaction in the art, including but not limited to Swern oxidation, TEMPO oxidation, and the like, as is common in the art. In the present invention, the oxidation conditions of the oxidation reaction are preferably selected from: oxalyl chloride, DMSO; sulfur trioxide pyridine, DMSO; TEMPO; sodium hypochlorite; PCC; PDC; alternatively, periodate esters.
The solvent for the oxidation reaction in the step 3) is preferably dichloromethane, tetrahydrofuran, methyltetrahydrofuran or a mixture of two or more thereof.
The reaction temperature of the oxidation reaction in the step 3) is preferably-80-100 ℃, and the reaction time is preferably 1-48 h.
In the present invention, the SM02 compound can be prepared according to a preparation method which is conventional in the art.
In one embodiment, the compound of formula SM02 is prepared by coupling R-X with piperazine via the following synthetic route:
wherein X is Cl, Br or I, preferably X is Br. R is as defined above.
The above coupling reaction is generally carried out in the presence of a strongly basic substance, catalyzed by a palladium catalyst, as is common in the art. The temperature of the coupling reaction is preferably 50-150 ℃, and the molar ratio of piperazine to R-X is preferably 1-5: 1.
The above palladium catalyst is preferably selected from Pd2(dba)3Tetrakistriphenylphosphine palladium or dppf palladium dichloride, and the phosphine ligand BINAP. The strong alkaline substance is preferably selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
In another alternative embodiment, the compound of formula SM02 above is prepared by a process comprising the steps of:
carrying out coupling reaction on R-X and Pg-piperazine to generate SM 02-A;
protecting SM02-A, removing amino protecting group Pg to obtain compound SM 02;
the synthetic route is as follows:
wherein X is Cl, Br or I, preferably X is Br; pg is an amino protecting group selected from benzyl Bn, benzyl formate CBz or tert-butyloxycarbonyl Boc; r is as defined above.
The coupling reaction in the above step (i) is generally carried out, according to the general knowledge in the art, under the catalysis of a palladium catalyst, preferably selected from Pd2(dba)3Tetrakistriphenylphosphine palladium or dppf palladium dichloride, and the phosphine ligand BINAP.
Preferably, the coupling reaction in step (r) is carried out in the presence of a base, preferably selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.
The solvent for the coupling reaction in step (i) above is preferably selected from toluene, xylene or a mixture thereof.
The reaction temperature of the coupling reaction in the step I is preferably-20-180 ℃, and the reaction time is preferably 1-48 h.
Preferably, the deprotection reaction in step (c) is carried out in the presence of an acid, preferably selected from hydrogen chloride (such as ethanolic hydrogen chloride), hydrochloric acid, sulfuric acid, p-toluenesulfonic acid.
The solvent used in the deprotection reaction in the step (c) is preferably dichloromethane, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixture of two or more of the above.
In the step II, the deprotection reaction temperature is preferably-80-100 ℃, and the reaction time is preferably 1-48 h.
More specifically, when Pg is Boc in the deprotection reaction in the step (II), adding acid to deaminate the protecting group, wherein the acid is hydrogen chloride organic solution (such as hydrogen chloride ethanol solution) or trifluoroacetic acid and the like; alternatively, when Pg is benzyl Bn or benzyl formate CBz, palladium on carbon is used for hydrogenation to remove the amino protecting group at a hydrogenation pressure of 0.1-1 MPa.
Another aspect of the present invention provides a composition comprising a cyclohexane derivative of formula IB as described above and a compound imp1, wherein the mass ratio of the cyclohexane derivative of formula IB to the compound imp1 is above 99.5: 0.05:
wherein the radicals R are as defined above.
Preferably, in the composition, the mass ratio of the cyclohexane derivative shown as the formula IB to imp1 is more than 99.7: 0.02.
Another aspect of the present invention provides a composition comprising the cyclohexane derivative of formula IB, wherein the cyclohexane derivative of formula IB constitutes more than 99.5% by mass of the composition; the mass ratios of imp1, imp6 and imp8 to the cyclohexane derivative represented by formula IB are all 0.1% or less:
wherein the radicals R are as defined above.
Preferably, the mass ratio of imp6 and imp8 relative to the cyclohexane derivative of formula IB is each independently 0.05% or less.
More preferably, the mass ratio of imp6 and imp8 to the cyclohexane derivative represented by formula IB is each independently 0.02% or less.
More preferably, the mass ratio of the compound imp1 to the cyclohexane derivative represented by the formula IB is 0.05% or less, and further 0.02% or less.
Most preferably, imp6 and/or imp8 are absent from the composition.
In a preferred embodiment of the invention, the cyclohexane derivative of formula IB is present in the composition in an amount of more than 99.6%, for example 99.6%, 99.7%, 99.8% or 99.9% by mass of the composition.
The method has few side reactions, and the cyclohexane derivative IB product prepared by the method has high purity and high yield, greatly reduces the impurity content, particularly has low contents of dimer impurities imp6 and imp8 and monomethyl impurity imp1 (the single impurity is less than 0.1 percent), so the product has high purity, is easy to reach the drug quality standard, and is more suitable for industrial large-scale production.
Detailed Description
Herein, the term "compound represented by the formula X" is sometimes expressed as "compound X", which can be understood by those skilled in the art. Compared with the compound shown in the formula I and the compound I, the compound shown in the formula I and the compound I are the same. Similarly, both the compound of formula IB and compound IB refer to the same compound.
Herein, the compounds imp6 and imp8 belong to dimer impurities, and the compound imp1 belongs to monomethyl impurities (or demethyl impurities).
Starting from a commercial raw material, namely the compound 2- (4-aminocyclohexyl) ethyl acetate shown in the formula I, and the preparation of a final product, namely a cyclohexane derivative IB, the preparation method disclosed by the invention is generally divided into four steps:
1) carrying out acylation reaction on the compound 2- (4-aminocyclohexyl) ethyl acetate shown in the formula I and N, N-dimethylcarbamoyl chloride to obtain the compound 2- (4- (3, 3-dimethylureido) cyclohexyl) ethyl acetate shown in the formula II;
2) carrying out reduction reaction on the compound shown in the formula II to generate a compound 3- (4- (2-hydroxyethyl) cyclohexyl) -1, 1-dimethylurea shown in the formula III;
3) carrying out oxidation reaction on the compound shown in the formula III to obtain a compound 2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde shown in a formula SM 01;
4) subjecting a compound represented by formula SM01 to a reductive amination reaction with a compound represented by formula SM02 to obtain a cyclohexane derivative represented by formula IB;
the synthetic route is as follows:
wherein R is:
in a preferred embodiment, after the reaction in each step is completed, purification operations such as filtration, washing, and drying may be performed according to the general knowledge in the art. After the reductive amination reaction of the last step, step 4), the product purification operation carried out may even not involve column chromatography purification, but may also yield a product free of dimeric impurities imp6 and imp8, monomethyl impurity imp1, or at a very low content, almost undetectable. By eliminating the column chromatography purification step, productivity can be greatly improved and production cost can be significantly reduced.
It will be appreciated that when the cyclohexane derivative of formula IB has a particular steric configuration, then compound SM01, and its corresponding reaction starting materials, all have the corresponding steric configuration, as is common in the art. For example, in one embodiment, when the compound of formula IB is N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (formula IB-1 below), then SM01 is 1, 1-dimethyl-3- (trans-4- (2-oxoethyl) cyclohexyl) urea, and trans-ethyl 2- (4-aminocyclohexyl) acetate can be used to prepare the SM 01.
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.
It should be noted that the inventors have also verified the prior art methods including CN106518841A, and experiments have shown that urea groups are present in the last step of the prior art methods, and that the products all have monomethyl impurity imp 1; and dimerization impurities imp6 and imp8 with nucleophilic substitution of the urea group exist in the product by adopting an alkylation route whether urea is added firstly or is added in the last step.
The positive progress effects of the invention are as follows: the preparation method of the invention can prepare the cyclohexane derivative of the formula IB in high yield, and the product has low impurity content, especially low content of dimer impurities imp6 and imp8 and monomethyl impurity imp1 (single impurity is less than 0.1 wt%). Moreover, the reaction condition is mild and easy to control, so the operation is simple and safe.
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.
The addition amount, content and concentration of various substances are referred to herein, wherein the percentage refers to the mass percentage unless otherwise specified.
In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 30 ℃).
Examples
Reagent: the reactants and the catalyst used in the embodiment of the invention are chemically pure, and can be directly used or simply purified according to the requirement; the organic solvent and the like are analytically pure and are directly used. The reagents were purchased from Shanghai chemical reagent company, China medicine (group).
A detection instrument:
nuclear magnetic resonance apparatus type: bruker affinity HD 600MHz, Bruker affinity III 400 MHz;
mass spectrometer (liquid mass spectrometry (LCMS)), type: agilent 6120B, detector DAD.
EXAMPLE 1 preparation of trans-2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde (Compound SM01-1)
Preparation of ethyl trans-2- (4- (3, 3-dimethylurea) cyclohexyl) acetate (compound II):
in a 500ml single-neck flask, trans-2- (4-aminocyclohexyl) ethyl acetate hydrochloride (compound I) (44.2g, 0.2mol), triethylamine (84ml, 0.6mol, 3eq), and dichloromethane (250ml) were added, mixed and stirred, cooled to 10 ℃ or below in an ice bath, and a dichloromethane solution of N, N-dimethylcarbamoyl chloride (N, N-dimethylcarbamoyl chloride 32.2g, 0.3mol, 1.5eq was dissolved in 50ml dichloromethane) was added dropwise, followed by natural temperature rise and stirring for 2 hours. Sampling to detect that the raw materials completely react, pouring the reaction liquid into 100ml of ice-cooled 1N diluted hydrochloric acid, stirring for 30min, separating liquid, extracting an aqueous phase by using dichloromethane (100ml x 2), combining organic phases, sequentially using saturated sodium bicarbonate aqueous solution, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, performing suction filtration and spin-drying to obtain a trans-2- (4- (3, 3-dimethyl urea) cyclohexyl) ethyl acetate intermediate (compound II) and 55g of white solid.
Preparation of trans-2- (4- (3, 3-dimethylurea) cyclohexyl) ethanol (compound III):
in a 1L single-neck flask, intermediate compound II (55g, 0.2mol), tetrahydrofuran (500ml) were added and the mixture was stirred to dissolve. Sodium borohydride (38g, 1mol, 5eq) was added in portions. After the addition was completed, the mixture was stirred for 15min, and then methanol (250ml) was added dropwise. After dripping, heating and refluxing for reacting overnight, sampling to detect that the raw materials completely react, stopping heating, after the reaction is cooled to room temperature, spin-drying the reaction liquid, adding water (300ml) and ethyl acetate (250ml) into the residue, stirring and dissolving the residue clearly, separating the liquid, extracting the water phase with ethyl acetate (150 ml. times.2), combining the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, carrying out suction filtration, and spin-drying to obtain trans-2- (4- (3, 3-dimethyl urea) cyclohexyl) ethanol (compound III) and 31.2g of white solid.
Preparation of trans-2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde (SM 01-1):
swern oxidation
DMSO (4.37g, 0.056mol, 3eq) was added to a 250ml three-necked flask, dissolved in 50ml dichloromethane, purged with nitrogen, and cooled to-78 ℃ in a dry ice bath. Oxalyl chloride (4.74g, 0.0373mol, 2eq) was added dropwise, the temperature was controlled not to exceed-65 ℃. After dripping, the temperature is kept between minus 70 ℃ and minus 78 ℃ for reaction for 1 hour. A dichloromethane solution of compound III (trans-2- (4- (3, 3-dimethylurea) cyclohexyl) ethanol 4g, 0.0187mol, dissolved in 30ml dichloromethane) was added dropwise at a temperature not exceeding-65 ℃. After dripping, the temperature is kept between minus 70 ℃ and minus 78 ℃ for reaction for 1 hour. Triethylamine (26ml, 0.1867mol, 10eq) was added and the temperature was controlled to not exceed-45 ℃. After the addition, the dry ice bath was removed, the temperature was naturally raised to-20 ℃ and the reaction mixture was poured into ice-cold 1N hydrochloric acid (100ml) and stirred for 15 min. The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered with suction and spin-dried to give 3.8g of a pale yellow solid. Purifying by column chromatography, and eluting: petroleum ether: ethyl acetate ═ 1: 1-0: 1, to obtain trans-2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde (compound SM01-1) as a white solid (3 g).
ESI:M+1＝213
TEMPO oxidation
Into a 250ml three-necked flask, compound III (4.28g, 0.02mol), TEMPO (0.03g, 0.0002mol, 0.01eq), sodium hydrogencarbonate (4.2g, 0.05mol, 2.5eq), sodium bromide (0.2g, 0.002mol, 0.1eq), dichloromethane (50ml) and water (50ml) were charged, mixed, stirred and dissolved, and then cooled to 0 ℃ in an ice salt bath. And dropwise adding a 10% sodium hypochlorite solution, and controlling the temperature to be not more than 5 ℃. After dripping, reacting for 30min at 0-10 ℃, and sampling to detect that the raw materials are basically completely reacted. The reaction mixture was separated, the aqueous phase was extracted with dichloromethane (30 ml. times.2), the organic phases were combined, washed successively with saturated aqueous sodium thiosulfate solution, saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and spin-dried to give 5g of a light brown oil. Purifying by column chromatography, and eluting: petroleum ether: ethyl acetate ═ 1: 1-0: 1, to obtain trans-2- (4- (3, 3-dimethylurea) cyclohexyl) ethanol (compound III) as a white solid (3.1 g).
ESI:M+1＝213
Example 21 preparation of (benzo [ b ] thiophen-7-yl) piperazine (Compound SM02-1)
In a 500ml single-neck flask, 7-bromobenzothiophene (21.2g, 0.1mol), Boc piperazine (20.5g, 0.11mol, 1.1eq), potassium tert-butoxide (16.8g, 0.15mol, 1.5eq), toluene (300ml) were added, mixed and stirred, and replaced with nitrogen gas 3 times. BINAP (3.74g), Pd, was added2(dba)3(2g) After that, nitrogen gas was replaced 3 times. Put into an oil bath to be heated to 100 ℃ and stirred to react overnight (8 h). The sample point plate (developing solvent: petroleum ether: ethyl acetate: 10: 1) was taken, and the reaction of the raw materials was almost completed. Stopping heating, cooling the reaction solution to room temperature, suction-filtering with diatomaceous earth, leaching the filter cake with toluene (300ml), mixing filtrates, and saturatingWashed with brine and spin-dried (water bath 45-60 ℃) to obtain 38g of brownish red oily matter. Purifying by column chromatography, and eluting: petroleum ether: ethyl acetate 50: 1-30: 1, intermediate SM02-a1 was obtained as 21.2g of a light yellow oil.
1H NMR(400MHz，CDCl3)δ：7.55 1H d，7.42 1H d，7.33 2H m，6.93 1H d，3.674H m，3.17 4H m，1.51 9H s
A500L single-neck flask was charged with the above intermediate SM02-A1(21.2g), a hydrogen chloride ethanol solution (20ml), and absolute ethanol (150ml), and the mixture was heated in an oil bath at 55 ℃ for reaction for 2 hours, whereupon a white solid precipitated during the reaction. The sample point plate (developing solvent: petroleum ether: ethyl acetate: 10: 1) was taken, and the reaction of the raw materials was almost completed. Stopping heating, cooling the reaction solution to room temperature, carrying out suction filtration, leaching the filter cake with ethanol, and drying to obtain SM02-1 hydrochloride as a white solid 15 g.
After 15g of the hydrochloride is dissociated by a sodium hydroxide solution, DCM is used for extraction, saturated saline solution is used for washing, anhydrous sodium sulfate is used for drying, and after suction filtration and spin drying, 12g of yellow oily matter is obtained, namely 1- (benzo [ b ] thiophene-7-yl) piperazine (SM 02-1).
ESI:M+1＝219
EXAMPLE 3 preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (Compound IB-1)
Preparation of IB-1 from SM02-1 hydrochloride
In a 100ml single-neck flask, SM01-1(1.7g, 0.008mol), SM02-1 hydrochloride (2.03g, 0.008mol, 1eq), triethylamine (1.3ml, 0.0096mol, 1.2eq), and 50ml of dichloromethane were added, mixed and stirred to a clear solution, and sodium triacetoxyborohydride (2.6g, 0.0241mol, 1.5eq) was added in portions. After the addition, the reaction was stirred for 4 hours. Sampling and detecting, wherein the raw materials are basically reacted completely, the reaction solution is poured into 50ml of saturated sodium bicarbonate aqueous solution, stirring is carried out for 15min, liquid separation is carried out, a water phase is extracted by dichloromethane (50ml x 2), an organic phase is combined, the saturated sodium chloride aqueous solution is washed by saturated saline solution, drying is carried out by anhydrous sodium sulfate, suction filtration is carried out, rotary drying is carried out to obtain 3.4g of crude product, recrystallization is carried out by ethyl acetate, 1.6g of IB-1 white solid is obtained by active carbon decoloration, single impurity is less than 0.1% by HPLC (high performance liquid chromatography), and the yield is 48%.
1H NMR(400MHz,CDCl3)δ:7.52 1H d，7.41 1H d，7.32 2H m，6.94 1H d，4.12 1H d，3.59 1H m，3.29 4H s，2.88 6H s，2.72 4H m，2.50 2H m，2.03 2H m，1.79 2H m，1.50 2H m，1.26 1H m，1.11 4H m；
MS(EI)m/z:M+1＝415
HPLC, imp 10.02%; 99.76% of a target product; imp6N/A, imp 8N/A; no single impurity greater than 0.1%.
Preparation of IB-1 with SM02-1 free base:
in a 100ml single-neck flask, SM01-1(1.7g, 0.008mol), SM02-1 free base (1.75g, 0.008mol, 1eq), and dichloromethane (50ml) were charged, mixed with stirring to dissolve, and sodium triacetoxyborohydride (2.6g, 0.0241mol, 1.5eq) was added in portions. After the addition, the reaction was stirred for 4 hours. Sampling and detecting, wherein the raw materials are basically reacted completely, the reaction solution is poured into 50ml of saturated sodium bicarbonate aqueous solution, stirring is carried out for 15min, liquid separation is carried out, the water phase is extracted by dichloromethane (50ml × 2), the organic phase is combined, the washing is carried out by saturated saline solution, the drying is carried out by anhydrous sodium sulfate, the suction filtration is carried out, and the spin drying is carried out, so that 3.2g of crude products are obtained. Recrystallization from ethyl acetate and decolorization with activated carbon gave 1.7g of IB-1 as a white solid with less than 0.1% single impurities by HPLC, 51% yield.
Examples 4-8 Synthesis of IB Compounds with different R substituents
IB compounds with different R substituents were synthesized according to the following synthetic routes, with reference to the synthetic methods in examples 1-3. The corresponding structures and yields are given in table 1 below.
TABLE 1 yield of various IB compounds
HPLC detection shows that the products prepared in examples 4-8 have no single impurity greater than 0.1%, and the IB compound accounts for over 99.5%.
COMPARATIVE EXAMPLE 1 preparation of IB-1 from SM02 with trans-p-toluenesulfonic acid 2- (4- (3, 3-dimethylurea) cyclohexyl) ethyl ester (formula TM)
Into a 100ml single-neck flask, trans-p-toluenesulfonic acid 2- (4- (3, 3-dimethylurea) cyclohexyl) ethyl ester (compound TM) (1.47g, 0.004mol), SM02(0.96g, 0.0044mol, 1.1eq), potassium carbonate (1.1g, 0.008mol, 2eq), acetonitrile (40ml) were added, mixed and stirred, and the mixture was heated in an oil bath at 75 ℃ for reaction overnight. Sampling and detecting, and stopping heating after the raw materials are completely reacted. After the reaction mixture was cooled to room temperature, the solvent was evaporated, and the residue was dissolved in water (50ml) and methylene chloride (30ml) with stirring and separated. The aqueous phase was extracted with dichloromethane (50ml x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction and dried by spinning to give 2.5g of a brown solid. Purifying by column chromatography, and eluting: dichloromethane: methanol 50: 1-30: 1, obtaining 1.8g of light yellow solid, and recrystallizing by ethyl acetate to obtain 0.8g of IB-1 white solid.
HPLC: IB-1, 86.35%; the dimeric impurity imp8, 13.22%.
The product contains a dimer impurity imp8, and the structural formula is as follows:
comparative example 2 preparation of IB-1 Using an alternative synthetic route
Adding a compound A (100g) and 700ml of absolute methanol into a 2L single-neck flask, mixing and stirring, adding a hydrogen chloride ethanol solution (100ml), heating in an oil bath to 55 ℃, stirring for reaction, separating out white solids along with the reaction, sampling after the reaction is carried out for 2 hours, detecting that the intermediate A completely reacts, stopping heating, cooling the reaction liquid to room temperature, carrying out suction filtration, leaching a filter cake with ethanol, and drying to obtain an intermediate B, wherein 85g of the white-like solids are obtained.
A2L single-neck flask was charged with intermediate B (62.28g, 0.15mol), aqueous sodium hydroxide (60 g, 1.5mol, 10eq, dissolved in 375ml water), dichloromethane (375ml), mixed, tetrabutyl phosphonium bromide (6g) added, and the solution was stirred. The mixture was cooled to 5 ℃ in an ice bath, and dimethylcarbamoyl chloride (64.2g, 0.6mol, 4eq) was added dropwise over about 45 min. After dropping, the reaction was stirred overnight at 25 ℃ in an oil bath with heating (8 h). Sampling and detecting, wherein the raw materials are basically reacted completely, the reaction solution is separated, the water phase is extracted by dichloromethane (200ml 2), the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered and dried in a spinning mode to obtain 100g of IB-1 crude product which is light yellow viscous solid.
HPLC: imp 132.25%; 61.35 percent of target product; imp 60.28%.
And purifying the IB-1 crude product by column chromatography, and eluting the solvent: dichloromethane: methanol 50: 1-30: 1, 80g of a pale yellow solid was obtained, and the above solid was recrystallized from 800ml of ethyl acetate to obtain 35g of IB-1 as a white solid.
HPLC: imp 10.06%; 99.64 percent of target product; imp 60.29%.
In the last step of the route, the reaction with dimethylcarbamoyl chloride gives a crude product with about 30% of the monomethyl impurity, imp1, which cannot be removed by recrystallization from ethyl acetate, and cannot be reduced to below 0.05% by multiple column chromatography.
The product contains a dimer impurity imp6, and the structural formula is as follows:
in the last step of the urea treatment in patent CN106518841A, as in comparative example 2, a large amount of monomethyl impurities and dimerization impurities were present and could not be removed.
The experiment shows that the product IB-1 prepared by the method has high purity, greatly reduces the impurity content, particularly the dimer impurity and the monomethyl impurity content (the single impurity is less than 0.1 percent), and easily reaches the quality standard of the medicine. And the post-treatment is simple, and the production cost can be obviously reduced, so that the method is more suitable for industrial large-scale production.
Claims (7)
1. A process for preparing a cyclohexane derivative of formula IB comprising the steps of:
subjecting the compound 2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde of formula SM01 to a reductive amination reaction with a compound of formula SM02 or a salt thereof to give a cyclohexane derivative of formula IB:
wherein R is:
The product purification operation performed after the reductive amination reaction does not include column chromatography purification.
2. The method according to claim 1, wherein the reducing agent for the reductive amination reaction is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride plus acetic acid, or potassium borohydride plus acetic acid, and the equivalent weight of the reducing agent is 1-10 eq.
3. The process according to claim 1, characterized in that the starting material for the reductive amination is a salt of SM02, wherein the salt of the compound of formula SM02 is selected from the group consisting of hydrochloride, sulfate, acetate, sulfonate, methanesulfonate and p-toluenesulfonate.
4. The process of claim 1, wherein the compound of formula SM01 is prepared by a process comprising the steps of:
1) carrying out acylation reaction on the compound 2- (4-aminocyclohexyl) ethyl acetate shown in the formula I and N, N-dimethylcarbamoyl chloride to obtain the compound 2- (4- (3, 3-dimethylureido) cyclohexyl) ethyl acetate shown in the formula II;
2) carrying out reduction reaction on the compound shown in the formula II to generate a compound 3- (4- (2-hydroxyethyl) cyclohexyl) -1, 1-dimethylurea shown in the formula III;
3) carrying out oxidation reaction on the compound shown in the formula III to obtain a compound 2- (4- (3, 3-dimethylureido) cyclohexyl) acetaldehyde shown in a formula SM 01;
the synthetic route is as follows:
。
5. the process of claim 1, wherein the compound of formula SM02 is prepared by coupling R-X with piperazine via the synthetic route:
wherein X is Cl, Br or I.
6. The method of claim 1, wherein the compound of formula SM02 is prepared by a method comprising:
carrying out coupling reaction on R-X and Pg-piperazine to generate SM 02-A;
② SM02-A is deprotected, amino protecting group Pg is removed, compound SM02 is obtained,
the synthetic route is as follows:
wherein X is Cl, Br or I; pg is an amino protecting group selected from benzyl Bn, benzyl formate CBz or tert-butyloxycarbonyl Boc.
7. The process of claim 6 wherein the deprotection reaction of step (ii) is carried out in the presence of an acid selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid and p-toluenesulfonic acid.
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| WO2015056164A1 (en) * | 2013-10-14 | 2015-04-23 | Chemo Research, S.L. | 1,4-cyclohexylamine derivatives and processes for the preparation thereof |
| CN106518841A (en) * | 2015-09-15 | 2017-03-22 | 浙江京新药业股份有限公司 | Cyclohexane derivative or stereoisomer or salt and preparation and application thereof |
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| WO2015056164A1 (en) * | 2013-10-14 | 2015-04-23 | Chemo Research, S.L. | 1,4-cyclohexylamine derivatives and processes for the preparation thereof |
| CN104496854A (en) * | 2015-01-06 | 2015-04-08 | 上海医药工业研究院 | 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof |
| CN106518841A (en) * | 2015-09-15 | 2017-03-22 | 浙江京新药业股份有限公司 | Cyclohexane derivative or stereoisomer or salt and preparation and application thereof |
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