Process for the preparation of a key intermediate precursor of obiseplimab and a key intermediate

Abstract

This invention belongs to the field of organic synthesis technology and relates to a precursor of an obisec key intermediate and a method for preparing the key intermediate. The method involves a [4+2] cycloaddition reaction of 4-trifluoromethylaniline, propionaldehyde, and N-vinylformamide under the catalysis of chiral phosphoric acid, yielding the obisec key intermediate precursor with high enantioselectivity. N -((2) R 4 S )-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-yl)formamide; subsequently, the key intermediate of obisetri can be obtained through a deprotection reaction under acidic conditions. The method provided by this invention uses a small amount of chiral catalyst and commercially available reagents to efficiently obtain the key intermediate of obisetri in just two steps. R 4 S )-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine; under mild conditions without the need for chiral resolution, the utilization of starting materials is greatly improved, thereby significantly increasing the yield of the target product and the economic efficiency of the process.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a method for preparing a key intermediate of ocbisequ. Background Technology

[0002] As a novel oral, low-dose cholesterol ester transfer protein (CETP) inhibitor, obicetrapib is intended for the treatment of dyslipidemia and Alzheimer's disease, and is expected to reverse the unfavorable situation of previous CETP inhibitor research, becoming the world's first CETP inhibitor to be put into clinical application.

[0003] Although WO 2024 / 009144 describes the synthesis of obisetri, the synthesis of the key intermediate (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine still has many drawbacks. For example, the current method requires first synthesizing racemic 2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine, then resolving it with di-p-methylbenzoyl tartaric acid, and finally obtaining highly enantioselective (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine after multiple recrystallizations. This results in a significant reduction in the utilization rate of the reaction raw materials and low economic efficiency of the reaction steps. According to... RSC Adv , 2013, 3 573-578; J. Am. Chem. Soc., 2009, 131 The chiral phosphoric acid-catalyzed synthesis strategy reported in 4598–4599 can also synthesize (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine, an important precursor, but it still has the following limitations: (1) the expensive chiral phosphoric acid catalyst is used in large quantities, (2) expensive starting materials are required, and (3) the reaction needs to be carried out under low temperature conditions. These limitations result in high reaction costs, which greatly limits the practical application of this reaction strategy. Based on the above reasons, it is of great significance to develop a chiral catalytic strategy with high catalytic efficiency, inexpensive starting materials, and mild reaction conditions to achieve the synthesis of the key intermediate (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine, an ocbisetri.

[0004] The structural formula of (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine is shown below: . Summary of the Invention

[0005] The purpose of this invention is to solve the above-mentioned technical problems and provide a method for preparing the key intermediate of obisetri. The method provided by this invention uses a small amount of chiral catalyst and commercially available reagents to efficiently obtain the key intermediate of obisetri in just two steps. Under mild conditions without chiral resolution, the utilization of starting materials is greatly improved, thereby significantly increasing the yield of the target product and the economic efficiency of the process.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing a key intermediate precursor of obisetrix. The method involves a [4+2] cycloaddition reaction of 4-trifluoromethylaniline, propionaldehyde, and N-vinylformamide in the presence of a chiral phosphoric acid catalyst under a protective atmosphere, yielding the key intermediate precursor of obisetrix, N-((2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-yl)formamide, with high enantioselectivity. The chemical reaction formula is shown below: .

[0007] By employing the aforementioned technical solution, 4-trifluoromethylaniline undergoes in-situ dehydration condensation with propionaldehyde to generate an imine, which then undergoes a [4+2] cycloaddition reaction with N-vinylformamide in the presence of a chiral phosphoric acid catalyst, thus economically and efficiently yielding the target precursor compound. This precursor compound can then be further reacted to obtain the key intermediate of obisetri while maintaining its chirality.

[0008] Preferably, the reaction is carried out in a solvent, more preferably at least one selected from 1,2-dichloroethane and acetonitrile. More preferably, the amount of solvent used, based on the concentration of 4-trifluoromethylaniline, is (0.1-1) mol / L; the most preferred reaction concentration is 0.2 mol / L.

[0009] Preferably, the chiral phosphoric acid catalyst is at least one selected from C1, C14, C16, C19, C20, C21, C22, C23, C24, C27, C30, C32, C33, and C34. Using such a chiral phosphoric acid catalyst, the er value of the reaction product is not less than 80%. The chemical structural formula is shown below:

[0010] More preferably, the chiral phosphoric acid catalyst is at least one of C1, C16, C19, C20, C22, and C23. The most preferred chiral phosphoric acid catalyst is C1, namely (11aR)-10,11,12,13-tetrahydro-5-hydroxy-3,7-di-9-anthrayl-diindeno[7,1-de:1',7'-fg][1,3,2]dioxophosphatacyclo-5-oxide. The specific structure of the chiral phosphoric acid catalyst is described in the specific embodiments.

[0011] Preferably, the molar ratio of 4-trifluoromethylaniline, propionaldehyde, N-vinylformamide and chiral phosphoric acid catalyst is 1:(1-5):(1-5):(0.005-0.5), wherein the preferred molar ratio is 1:(1-2):(1-5):(0.005-0.1), and the most preferred feed ratio is 1:1.2:1.2:0.01.

[0012] Preferably, the reaction temperature is (5-80°C). o C. More preferably, the reaction is carried out at room temperature without heating, with a room temperature of 15-40°C and an optimal reaction temperature of 25-30°C. o C. More preferably, the reaction time is 10-72 h, and the most preferred reaction time is 24 h.

[0013] Preferably, after the reaction is completed, the key intermediate precursor of ocbisetrix is ​​obtained through post-processing. The post-processing includes removing the solvent by vacuum distillation, preferably with a water bath temperature not exceeding 50°C, and obtaining a white solid by sonication and filtration and drying in a mixed solution of methyl tert-butyl ether and petroleum ether. More preferably, the post-processing is as follows: removing the reaction solvent by vacuum distillation in a rotary evaporator (water bath temperature ≤ 50°C), then adding a mixed solution of methyl tert-butyl ether and petroleum ether (volume ratio 4:1) and sonicating in an ultrasonic cleaner for 5-10 minutes to produce a white solid, filtering and washing the white solid with a mixed solution of methyl tert-butyl ether and petroleum ether (volume ratio 4:1), and then drying the white solid in a vacuum drying oven (drying temperature ≤ 40°C).

[0014] This invention also provides a method for preparing a key intermediate of obisetrix, wherein the method involves a deprotection reaction of the obisetrix key intermediate precursor under acidic conditions to obtain the chiral-preserved key intermediate (2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-amine, as shown in the following chemical reaction formula:

[0015] Preferably, the precursor of the obisetrix key intermediate is N-((2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide, preferably prepared by any of the above-described preparation methods of the present invention. By employing the above technical solution, the present invention can efficiently obtain the target obisetrix key intermediate, and the preparation method uses readily available raw materials, is low in cost, and has extremely high economic applicability. Furthermore, the reaction conditions are mild, with high catalytic efficiency and yield, and the reaction can be completed in only two steps. It still possesses excellent stereoselectivity without the need for subsequent chiral treatment steps, effectively improving the utilization rate of raw materials. This is of great significance for the preparation and synthesis of obisetrix key intermediates.

[0016] Preferably, the pH of the acidic condition is 2-5, and more preferably, the acidic environment is adjusted by concentrated hydrochloric acid. More preferably, the concentration of concentrated hydrochloric acid is 12 mol / L, and the mass ratio of the obisetri key intermediate precursor to concentrated hydrochloric acid is 1:(1-3), more preferably 1:1.26.

[0017] Preferably, the reaction is carried out in a solvent, more preferably the solvent is at least one of ethanol and methanol (supplementary all applicable solvents). More preferably, ethanol is used, and the amount of solvent used is (0.1-0.5) kg / L (supplementary feasible range) based on the mass-volume concentration of the obisetri key intermediate precursor, more preferably 0.285 kg / L.

[0018] Preferably, the reaction temperature is 30-70°C. o C, more preferably, the reaction temperature is 50°C. o C. The reaction time is 2-8 hours, more preferably 5 hours.

[0019] Preferably, after the reaction is completed, the key intermediate of OBISATER is obtained through post-processing. The post-processing includes removing about half of the reaction solvent by vacuum distillation, then placing it in an ice-water bath and adjusting it to an alkaline system, followed by extraction, washing, drying and other steps to obtain the key intermediate of OBISATER.

[0020] Preferably, the preparation method of the key intermediate of obisetri includes the following steps: (1) In a protective atmosphere, at room temperature without heating, 4-trifluoromethylaniline undergoes in-situ dehydration condensation with propionaldehyde to form an imine, which then undergoes a [4+2] cycloaddition reaction with N-vinylformamide in the presence of a chiral phosphoric acid catalyst to give N-((2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-yl)formamide with high enantioselectivity; (2) After obtaining the N-formyl-substituted 4-aminotetrahydroquinoline derivative, a deprotection reaction is carried out under acidic conditions to obtain the key intermediate of OBICET, (2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-amine, with chiral retention. The chemical formula for the reaction is as follows:

[0021] Preferably, the protective atmosphere described in this invention is at least one of nitrogen, helium, and argon.

[0022] Compared with existing technologies, the method provided by this invention has the following advantages: This invention requires only two reaction steps to obtain the key intermediate of obisetrix, (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine. The reaction steps are short, exhibiting excellent stereoselectivity and simple operation. Chiral resolution is not required, greatly improving the reaction yield and process economy. It has broad market application prospects and large-scale industrial application potential. Attached Figure Description

[0023] Figure 1 The 1H NMR spectrum of the key intermediate precursor of the product OBISTER in Example 1 of this invention; Figure 2 This is a high-performance liquid chromatogram of the racemic precursor of the key intermediate of obisetri, the product of Example 1 of this invention; Figure 3 This is a high-performance liquid chromatogram of the chiral precursor, a key intermediate of the product obisetri, from Example 1 of this invention. Figure 4 The 1H NMR spectrum of the key intermediate of the product obisetri in Example 37 of this invention; Figure 5 This is a high-performance liquid chromatogram of the key racemic intermediate of the product obisetri in Example 37 of the present invention; Figure 6 This is a high-performance liquid chromatogram of the key chiral intermediate of the product obisetri in Example 37 of the present invention. Detailed Implementation

[0024] To facilitate understanding, the technical solutions and implementation methods of the present invention will be further described clearly, completely, and in detail below through specific embodiments and in conjunction with the accompanying drawings. It should be understood that the embodiments described herein are implemented based on the technical solutions of the present invention, providing detailed implementation methods and specific operating procedures, but are only some embodiments of the present invention, not all embodiments. The specific implementation methods described are limited to illustrating and explaining the present invention and do not limit the present invention. Based on the embodiments of the present invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used in the examples are commercially available unless otherwise specified. The reaction conditions described in the invention can achieve the reactions and obtain the desired products. Due to space limitations, only some examples are listed below to further illustrate the advantages of the technical solution of the invention. The room temperature described in this invention is 15-40°C. o C, including 15 o C, 20 o C, 25 o C, 30 o C, 35 o C, 40 o C, preferably 25℃.

[0026] Example 1

[0027] This invention provides a method for preparing N-((2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-yl)formamide, a key intermediate precursor for obisecide, comprising the following steps:

[0028] Chiral phosphoric acid catalyst C1 (0.02 mmol, 0.01 equivalent) was added to the reaction tube, and the air in the test tube was replaced with high-purity nitrogen. 4-Trifluoromethylaniline (2.0 mmol, 1 equivalent) and propionaldehyde (2.4 mmol, 1.2 equivalent) were added using a syringe, followed by 2 mL of 1,2-dichloroethane as a solvent. Finally, N-vinylformamide (2.4 mmol, 1.2 equivalent) was added, and the reaction was stirred at room temperature for 24 h.

[0029] After the reaction is complete, use a rotary evaporator (water bath temperature <50°C) oC) Remove the reaction solvent under reduced pressure, then add 4 mL of a mixed solution of methyl tert-butyl ether and petroleum ether (volume ratio 4:1) and sonicate in an ultrasonic cleaner for 5-10 min to produce a white solid. Filter and wash with 10 mL of the methyl tert-butyl ether and petroleum ether mixture (volume ratio 4:1) to obtain the white solid. Place the white solid in a vacuum drying oven (drying temperature <40°C). o After drying in C), a white solid N-((2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide A 0.37 g was finally obtained, with a yield of 68% and an enantiomeric excess of 99%. 1 HNMR (400 MHz, MeCN-d3) δ 8.27 (s, 1H), 7.28 – 7.19 (m, 2H), 6.72 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.28 – 5.14 (m, 1H), 5.02 (s, 1H), 3.47 – 3.37 (m, 1H), 2.16 – 2.10 (m, 1H), 1.60 – 1.47 (m, 3H), 0.97 (t, J = 7.5 Hz, 3H). Detailed spectra are shown below. Figure 1 As shown, Daicel Chiralcel OD-H, n -hexane / i PrOH = 95 / 5, 1.0 mL / min, λ = 254 nm.

[0030] Examples 2-36

[0031] Based on Example 1, the reaction conditions were changed. Due to space limitations, some of the reaction conditions and results are listed in the table below:

[0032] The structure of the C2-C35 catalyst is as follows:

[0033] As shown in the table above, a total of 35 chiral phosphoric acid catalysts with different skeletal structures were selected for the synthesis of N-((2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-yl)formamide. It was first found that when (S)-H8-BINOL was used as the core skeleton, the product ee value ranged from -30.8% to -47.4%. When the core structure was changed to (R)-H8-BINOL, the product ee value was 27.2%, indicating that chiral phosphoric acid catalysts with (R)-H8-BINOL or (S)-H8-BINOL as the core skeleton were not effective in catalyzing this reaction. When the core structure was changed to (R)-BINOL, the product ee value reached a maximum of 91.4% (Example 16). Four catalysts using (R)-SPINO as the core skeleton achieved product ee values ​​above 90%, with the ee value reaching as high as 98.1% and the yield reaching 65% when the chiral phosphoric acid's side arm was 9-anthrayl. This demonstrates that the method can efficiently construct the key intermediate of obisetrix (2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-amine without chiral resolution, thus greatly improving the reaction yield and step economy.

[0034] Example 37

[0035] 0.71 g of N-((2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide A prepared in Example 1 was added to a reaction tube, followed by 2.5 mL of ethanol and 0.8 mL of concentrated hydrochloric acid. The resulting reaction system was then placed in a 50 mL container. o Stir in an oil bath for 5 hours.

[0036] After the reaction is cooled, it is evaporated using a rotary evaporator (water bath temperature <50°C). o C) Remove approximately half of the reaction solvent under reduced pressure. Then, place the resulting solvent in an ice-water bath and slowly add 2 N sodium hydroxide aqueous solution to adjust the pH to 12-13. Extract with 10 mL of dichloromethane. Combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. Place in a vacuum drying oven (drying temperature <40°C). o After drying in C), 0.61 g of a white solid (2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-amine B was finally obtained, with a yield of 96% and an enantiomeric excess of 99%. 1¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.22 (dd, J = 8.4, 2.1 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 4.03 (dd, J = 11.6, 4.9 Hz, 2H), 3.46 – 3.35 (m, 1H), 2.24 – 2.14 (m, 1H), 1.60 – 1.52 (m, 4H), 1.45 (q, J = 11.7 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H). Detailed spectra are shown below. Figure 1 As shown, Daicel Chiralcel AY-H, n-hexane / i PrOH = 95 / 5, 1.0 mL / min, λ = 254 nm.

[0037] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications may be made without departing from the technical solutions described in the claims.

Claims

1. A method for preparing a key intermediate precursor of obisetrix, comprising: in a protective atmosphere, 4-trifluoromethylaniline, propionaldehyde, and N-vinylformamide undergo a cycloaddition reaction in the presence of a chiral phosphoric acid catalyst to obtain the key intermediate precursor of obisetrix, N-((2R,4S)-2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-4-yl)formamide with high enantioselectivity, wherein the chemical formula of the reaction is shown below: 。 2. The method for preparing a key intermediate precursor of OBISATER according to claim 1, characterized in that, The reaction is carried out in a solvent, which is at least one of 1,2-dichloroethane and acetonitrile.

3. The method for preparing a key intermediate precursor of OBISATER according to claim 1, characterized in that, The chiral phosphoric acid catalyst is at least one of C1, C14, C16, C19, C20, C21, C22, C23, C24, C27, C30, C32, C33, and C34, and its chemical structure is shown below: 。 4. The method for preparing a key intermediate precursor of OBISATER according to claim 3, characterized in that, The chiral phosphoric acid catalyst is at least one of C1, C16, C19, C20, C22, and C23.

5. The method for preparing a key intermediate precursor of OBISATER according to claim 1, characterized in that, The molar ratio of 4-trifluoromethylaniline, propionaldehyde, N-vinylformamide and chiral phosphoric acid catalyst is 1:(1-5):(1-5):(0.005-0.5).

6. The method for preparing a key intermediate precursor of OBISATER according to claim 1, characterized in that, The reaction temperature is 5℃-80℃.

7. A method for preparing a key intermediate precursor of obisequ, characterized in that, The method involves the deprotection reaction of the obisetre key intermediate precursor N-((2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide under acidic conditions, chirally retaining the obisetre key intermediate (2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-4-amine, as shown in the chemical formula below: 。 8. The method for preparing a key intermediate of OBISATER according to claim 7, characterized in that, The pH of acidic conditions is 2-5.

9. The method for preparing a key intermediate of OBISATER according to claim 7, characterized in that, The reaction temperature is 30-70℃.

10. The method for preparing a key intermediate of OBISATER according to claim 7, characterized in that, The aforementioned key intermediate precursor of OBISATER is prepared by the preparation method of any one of claims 1-6.

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