A preparation method of (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride

Abstract

The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride, wherein the preparation of the (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride is carried out by using trifluoroacetylbenzene as a starting material, and undergoing amination reaction, asymmetric reduction reaction, and HCl salt-forming reaction, and a three-step reaction to obtain a finished product. The method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride provided by the invention is a brand-new preparation method, which has the advantages of safety, environmental protection, and easy amplification of production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride. Background Art

[0002] The structural formula of the existing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride is as follows:

[0003]

[0004] After searching, there are mainly three methods for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride:

[0005] 1) The first method is as follows:

[0006]

[0007] The above document reports a synthesis method, first synthesizing an imine intermediate, then catalyzing hydrogen transfer isomerization with a chiral quinine ligand to obtain a chiral phenylethylamine derivative, and finally preparing the target product through a hydrolysis reaction. Step 2 uses a complex chiral quinine to catalyze isomerization and generate a chiral center, the reaction time is as long as 48 hours, and the yield is 75%. The overall efficiency of this reaction route is low.

[0008] 2) The second method is as follows:

[0009]

[0010] The above-mentioned document reports a synthetic method, which uses a chiral borane ligand to achieve asymmetric reductive amination to obtain the target compound, but requires the preparation of a silane derivative intermediate.

[0011] 3) The third method is as follows:

[0012]

[0013] The above document reports a synthesis method, but it requires the preparation of a chiral sulfenamide intermediate, and the introduction of a trifluoromethyl group requires the use of gaseous trifluoromethane and an ultra-low temperature reaction of -78°C for 12 hours, which is insufficient in terms of economy and operability.

[0014] Therefore, it is necessary to provide a new, safe, environmentally friendly and easy to scale up production method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride. Summary of the invention

[0015] The purpose of the present invention is to overcome the above problems existing in the conventional technology and provide a method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride.

[0016] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0017] A method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride comprises the following steps: using trifluoroacetylbenzene as a starting material, and performing amination reaction, asymmetric reduction reaction, and HCl salt-forming reaction to obtain a finished product.

[0018] Furthermore, the reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0019]

[0020] Furthermore, the specific steps of the first step reaction are: adding anhydrous ethanol and trifluoroacetylbenzene to a reaction kettle in sequence, stirring and dissolving, adding 25% ammonia water at room temperature, heating and stirring, and reacting at 60°C for a period of time; monitoring the complete reaction of the raw materials by TLC, cooling to room temperature, filtering the precipitated crystals, washing the filter cake with ethanol aqueous solution, draining the filter cake, and vacuum drying at 80°C for a period of time to obtain intermediate A.

[0021] Furthermore, the ethanol aqueous solution is obtained by mixing ethanol and water in a volume ratio of 1:1.

[0022] Furthermore, the reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0023]

[0024] Furthermore, the specific steps of the reaction in the second step are: adding dry tetrahydrofuran, methanol, intermediate A and (R)-1,1'-bi-2,2'-naphthol to a reaction kettle, stirring and cooling at -20°C, taking sodium borohydride and adding it to the reaction system in batches, and stirring and reacting for a period of time after the addition is completed; monitoring the reaction of the raw materials by TLC, adding a saturated sodium sulfate solution to quench the reaction, concentrating the reaction solution, extracting and separating the liquids with ethyl acetate and a saturated sodium carbonate aqueous solution, washing the organic phase with a saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering to remove the desiccant, concentrating under reduced pressure to obtain a crude product, and transferring it to a refiner for vacuum distillation to obtain an intermediate B.

[0025] Further, the 110-115° C. fraction is collected by vacuum distillation.

[0026] Furthermore, the reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction:

[0027]

[0028] Furthermore, the specific steps of the reaction in the third step are: adding methyl tert-butyl ether and intermediate B into a reaction kettle, stirring at room temperature, and passing freshly prepared dry hydrogen chloride gas into the reaction system; monitoring the complete reaction of the raw materials by TLC, filtering, washing the filter cake with methyl tert-butyl ether, draining, and vacuum drying at 40° C. for a period of time to obtain the finished product of (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride.

[0029] The beneficial effects of the present invention are:

[0030] The preparation method of (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride in the present invention uses trifluoroacetylbenzene as a starting material, and undergoes three steps of amination reaction, asymmetric reduction reaction, and HCl salt-forming reaction to obtain a finished product; this is a brand-new preparation method, which has the advantages of safety, environmental protection, and easy scale-up production.

[0031] Of course, any product implementing the present invention does not necessarily need to achieve all of the above advantages at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0033] Figure 1 This is a schematic diagram of the HNMR test results of the finished product of the present invention;

[0034] Figure 2 This is a schematic diagram of the LCMS test results of the finished product of the present invention;

[0035] Figure 3 This is a schematic diagram of the HPLC test results of the finished product of the present invention;

[0036] Figure 4 This is a schematic diagram of the HPLC-ee test results of the finished product of the present invention;

[0037] Figure 5 It is a schematic diagram of the MeOH optical rotation detection results of the finished product of the present invention. DETAILED DESCRIPTION

[0038] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] The specific designations of the abbreviations in this embodiment are as follows:

[0040] SM: Trifluoroacetylbenzene

[0041] EtOH: ethanol

[0042] (R)-BINOL: (R)-1,1'-Bis-2,2'-naphthol

[0043] MeOH: Methanol

[0044] THF: Tetrahydrofuran

[0045] MTBE: Methyl tert-butyl ether

[0046] The specific embodiments of the present invention are:

[0047] Example 1

[0048] A method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride comprises the following steps: using trifluoroacetylbenzene as a starting material, and performing amination reaction, asymmetric reduction reaction, and HCl salt-forming reaction to obtain a finished product.

[0049] The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0050]

[0051] The specific steps of the first step are as follows: anhydrous ethanol (8.0 L) and SM (1000 g, 1.0 eq) are added to the reaction kettle in sequence and stirred to dissolve, 25% ammonia water (4.0 L, 10 eq) is added at room temperature, heated and stirred at 60°C for 4 h. TLC monitors the complete reaction of the raw materials, cools to room temperature, filters the precipitated crystals, washes the filter cake twice with ethanol: water = 1:1 solution, drains the filter cake, and vacuum-dries at 80°C for 12 h to obtain 965.6 g of intermediate A off-white solid with a yield of 97.1%.

[0052] Mass spectrum: MS-ESI: 174.1[M+H] +

[0053] The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0054]

[0055] The specific steps of the second step reaction are: add dry THF (8L), methanol (1L), intermediate A (965.6g, 1.0eq), (R)-BINOL (319.3g, 0.2eq) to the reactor, stir and cool at -20℃, take sodium borohydride (231.9g, 1.1eq) and add it to the reaction system in batches, add it for 2h, keep warm and stir and react for 8h. TLC monitors the reaction of the raw materials, add saturated sodium sulfate solution (1L) to quench the reaction, concentrate the reaction solution to 3L, extract and separate the liquid with ethyl acetate (5L) and saturated sodium carbonate aqueous solution (5L), wash the organic phase with saturated sodium chloride aqueous solution (3L) once, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is transferred to a refiner for vacuum distillation (collecting 110-115℃ fractions) to obtain 827.3g of pure intermediate B with a yield of 84.7%.

[0056] Mass spectrum: MS-ESI: 176.2 [M+H] + .

[0057] The reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction:

[0058]

[0059] The specific steps of the third step are: add MTBE (5L) and intermediate B (827.3g, 1.0eq) into the reaction kettle, stir at room temperature, and pass the newly prepared dry hydrogen chloride gas into the reaction system. TLC monitors the complete reaction of the raw materials, filter, wash the filter cake with MTBE, drain, and vacuum dry at 40°C for 12h to obtain 940.5g of the finished product, with a yield of 94.1%, a purity of 99.5%, and an ee value of 99.3%.

[0060] Mass spectrum: MS-ESI: 176.2 [M+H] + .

[0061] Finished product related tests and results such as Figures 1 to 5 shown.

[0062] The preferred embodiments of the present invention disclosed above are only used to help explain the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to specific implementation methods. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride, characterized in that: The preparation of (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride is carried out by using trifluoroacetylbenzene as a starting material, and undergoing amination reaction, asymmetric reduction reaction, and HCl salt-forming reaction to obtain a finished product in three steps. The amination reaction is shown in formula (I), and the intermediate A is obtained after the reaction: （I） The specific steps of the amination reaction are: adding anhydrous ethanol and trifluoroacetylbenzene to a reaction kettle in sequence, stirring and dissolving, adding 25% ammonia water at room temperature, heating and stirring, and reacting at 60° C.; monitoring the reaction of the raw materials by TLC, cooling to room temperature, filtering, washing the filter cake with ethanol aqueous solution, draining the filter cake, and vacuum drying at 80° C. to obtain intermediate A; the ethanol aqueous solution is obtained by mixing ethanol and water in a volume ratio of 1:1; The asymmetric reduction reaction is shown in formula (II), and the intermediate B is obtained after the reaction: (II) The specific steps of the asymmetric reduction reaction are: adding dry tetrahydrofuran, methanol, intermediate A and (R)-1,1'-bi-2,2'-naphthol to a reaction kettle, stirring and cooling at -20°C, taking sodium borohydride and adding it to the reaction system in batches, and stirring and reacting after the addition; monitoring the reaction of the raw materials to be complete, adding a saturated sodium sulfate solution to quench the reaction, concentrating the reaction solution, extracting and separating the liquid with ethyl acetate and a saturated sodium carbonate aqueous solution, washing the organic phase with a saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering to remove the desiccant, concentrating under reduced pressure to obtain a crude product, transferring it to a distillation device for vacuum distillation to obtain an intermediate B; and collecting a 110-115°C fraction by vacuum distillation; The HCl salt-forming reaction is shown in formula (III), and the finished product is obtained after the reaction: (III) The specific steps of the HCl salt-forming reaction are: adding methyl tert-butyl ether and intermediate B into a reaction kettle, stirring at room temperature, and introducing freshly prepared dry hydrogen chloride gas into the reaction system; monitoring the complete reaction of the raw materials by TLC, filtering, washing the filter cake with methyl tert-butyl ether, draining, and vacuum drying at 40° C. to obtain a finished product of (R)-2,2,2-trifluoro-1-phenylethylamine hydrochloride.

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