Pharmaceutical intermediate and preparation method thereof

Abstract

The application discloses a pharmaceutical intermediate and a preparation method thereof, and particularly discloses a compound of formula (I) and a preparation method thereof.

Description

[0001] This application claims priority to Chinese patent application 2022112756796 with the filing date of 2022 / 10 / 18. This application incorporates the entire text of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to a pharmaceutical intermediate and a preparation method thereof, in particular to a compound of formula (I) and a preparation method thereof. BACKGROUND

[0003] SARS-CoV-2 belongs to single-stranded RNA virus, and has high homology with SARS-CoV and MERS-CoV. After the virus infects into the host cell, with the help of the host cell, its genetic material RNA is first translated to express two polyprotein precursors (ppla and pplab), which are cut intramolecularly by 3CL protease and PL protease to produce multiple non-structural proteins. Since 3CL protease is responsible for at least 11 sites of cleavage, it is also called main protease (Mpro). Non-structural proteins are involved in the production of viral subgenomic RNA and four structural proteins (E protein, M protein, S protein and N protein), and then complete the propagation and release of progeny virus; 3CL protease belongs to cysteine protease, and the active form is a homodimer. 3CL protease is relatively conserved in coronavirus, and the substrates of different coronavirus 3CL proteases have common characteristics; since there is no protease homologous to 3CL protease in the human body, 3CL protease becomes an ideal target for anti-coronavirus.

[0004] Developing drugs that can effectively resist the new coronavirus is currently needed in clinical drug use. Patent PCT / CN2022 / 087511 found a 3CL protease inhibitor with good anti-new coronavirus activity. In order to further improve the accessibility of the drug and be more conducive to scale-up production, it is necessary to develop new methods for obtaining intermediates of the 3CL protease inhibitor to overcome the problems associated with the known methods in PCT / CN2022 / 087511, including the availability and price of reagents, the scalability of large-scale production, the safety of process production, and the overall production cost. The molecular structure of the 3CL protease inhibitor is as follows:

[0005] SUMMARY

[0006] The present application provides a preparation method of the compound of formula (I),

[0007]

[0008] characterized in that it comprises a step of synthesizing compound D from compound A:

[0009]

[0010] wherein,

[0011] R1 is selected from H, C 1-4 alkyl and benzyl;

[0012] R2 is an amino protecting group.

[0013] In some embodiments of the present application, R1 is selected from H, methyl, ethyl, isopropyl, tert-butyl and benzyl, preferably methyl.

[0014] In some embodiments of the present application, R2 is selected from Boc.

[0015] In some embodiments of the present application, the method for preparing compound of formula (I) further comprises a step of synthesizing compound of formula (I) from compound D.

[0016] In some embodiments of the present application, the method for preparing compound of formula (I) further comprises a step of synthesizing compound of formula (I) from compound D.

[0017]

[0018] In some embodiments of the present application, the method for preparing compound of formula (I) further comprises a process of slurry purification of the crude compound obtained after step 5 reaction:

[0019] 1) adding a mixed solvent of isopropyl acetate and n-heptane to the crude product, the ratio of the mixed solvent of isopropyl acetate and n-heptane being 1:4 to 2:3, preferably 1:3;

[0020] 2) slurry at 40-60°C for 1-2 hours, preferably at 50°C;

[0021] 3) cooling to 10-20°C;

[0022] 4) filtering.

[0023] The present application also provides an intermediate of the following formula, a hydrochloride salt or a sulfate salt thereof,

[0024]

[0025] Definitions and explanations:

[0026] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed to be indefinite or unclear unless specifically defined, but should be construed in accordance with the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0027] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Those skilled in the art can refer to the contents of the present invention to appropriately change the raw materials, process conditions, and other aspects to achieve corresponding other purposes. Such related changes do not depart from the contents of the present invention. All similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of the present invention.

[0028] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0029] An important consideration in planning any synthetic route in this field is the selection of an appropriate protecting group for a reactive functional group, such as the amino group in the present invention.

[0030] The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0031] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 1-3 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0032] All solvents used in the present invention are commercially available.

[0033] The present invention uses the following abbreviations: Me represents methyl; Boc represents tert-butyloxycarbonyl; TFAA represents trifluoroacetic anhydride; EtOAc represents ethyl acetate; IBX represents 2-iodoacetylbenzoic acid; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; and HOBt represents 1-hydroxybenzotriazole.

[0034] The compounds are named by conventional methods in the art or Software naming, commercially available compounds use supplier catalog names.

[0035] Technical Effects

[0036] The synthesis process of the intermediate provided by the present invention has the beneficial effects of: cheap and readily available raw materials, low production cost, elimination of potential safety hazards in the production process, and greater suitability for large-scale production.

[0037] Specifically:

[0038] 1. Lower cost: In the new route, Boc-tert-leucine is used more efficiently, the yield of each step is better, the more expensive condensation step is moved later, and the material cost is greatly reduced.

[0039] 2. Reagents are cheaper and more readily available: In the original process route, the olefination step used TEBBE reagent; the new process route replaced it with the more widely available Wittig reagent.

[0040] 3. Process safety: The IBX used in the original process route posed safety hazards during the production process. The new process route replaced it with Tempo reagent, eliminating the safety hazards.

[0041] 4. More suitable for large-scale production: The new process route involves more conventional process conditions, a simpler purification process, and is more suitable for large-scale production. DETAILED DESCRIPTION

[0042] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0043] Example 1

[0044]

[0045] Synthesis route:

[0046]

[0047] Step 1: Synthesis of Intermediate 1-B

[0048] Intermediate 1-A (70 g) and 2,2,6,6-tetramethylpiperidine N-oxide (0.2 g) were dissolved in dichloromethane (700 mL), cooled to 0-5 °C, sodium bicarbonate (33.81 g), sodium bromide (2.65 g) were dissolved in water (420 mL), added to the reaction solution, sodium hypochlorite solution (372.12 g, 8% content), water (200 mL) were mixed uniformly, added dropwise to the reaction solution at 0-10 °C, stirred for 1 hour, after the reaction was completed, sodium sulfite (100 g) was dissolved in water (1000 mL), added to the reaction solution to quench for 0.5 hours, separated, dichloromethane (1 L) was added to extract again, the organic phase was combined, washed with brine (1 L) once, concentrated to obtain intermediate 1-B (68 g, yield: 98%). 1 H NMR (400 MHz, CDC13) δ ppm major [4.66 (s, 1H), 4.00 (s, 1H), 3.69 (s, 3H), 2.94 (s, 1H), 2.37-2.12 (m, 3H), 1.80 (s, 1H), 1.33 (s, 9H)]. minor [4.53 (s, 1H), 4.09 (s, 1H), 3.69 (s, 3H), 2.96 (s, 1H), 2.37-2.12 (m, 3H), 1.77 (s, 1H), 1.41 (s, 9H)]. MS m / z: 168.0 [M-Boc] +

[0049] Step 2: synthesis of intermediate 1-C

[0050] Methyltriphenylphosphonium bromide (103.47 g) was dissolved in toluene (650 mL), replaced with nitrogen for 3 times, cooled to 0-5 °C, added potassium tert-butoxide (29.79 g), warmed to 20-25 °C, stirred for 1 hour, added intermediate 1-B (65 g), stirred at 20-25 °C for 16 hours, after the reaction was completed, added water (1000 mL), extracted and separated, the aqueous phase was extracted again with methyl tert-butyl ether, the organic phase was combined, washed with brine (1000 mL), the organic phase was concentrated to dryness under reduced pressure, the concentrate was purified by column chromatography with petroleum ether-ethyl acetate to obtain intermediate 1-C (33 g, yield: 51%). 1H NMR (400MHz, CDCl3) δppm major[5.15(d, J=6.0Hz, 1H), 4.85(d, J=6.0Hz, 1H), 4.45(s, 1H), 3.87(s, 1H), 3. 72(s, 3H), 3.09(s, 1H), 2.41-2.22(m, 3H), 1.84(s, 1H), 1.37(s, 9H)].minor[5.1 5 (d, J=6.0Hz, 1H), 4.85 (d, J=6.0Hz, 1H), 4.31 (s, 1H), 3.97 (s, 1H), 3.72 (s, 3H), 3.11(s, 1H), 2.37-2.12(m, 3H), 2.06(s, 1H), 1.40(s, 9H)].MSm / z: 166.0[M-Boc] +

[0051] Step 3: Synthesis of Intermediate 1-D

[0052] Chlorobenzene (250 mL) was cooled to -10-0 ° C, and diethylzinc n-hexane solution (1 mol / L, 561 mL) was added. After the addition was complete, boron trifluoride etherate (119.46 g) was added dropwise. After the addition was complete, stirring was continued for 0.5 hours. The temperature was lowered to -10 ° C, and diiodomethane (300.57 g) was added dropwise. After the addition was complete, stirring was continued for 0.5 hours. Intermediate 1-C (50 g) was dissolved in chlorobenzene (50 mL) and added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 35-40 ° C and the reaction was carried out for 4 hours. After the reaction was completed, the temperature was lowered to -10 ~ -5 ° C, and 20% citric acid aqueous solution was added dropwise. (1000mL), after the dropwise addition is completed, ethyl acetate (500mL) is added, stirring is continued for 10 minutes, the liquid is separated, the organic phase is washed with 20% citric acid aqueous solution (250mL), the aqueous phase is combined, the aqueous phase is extracted with ethyl acetate (300mL*2), the aqueous phase is added with potassium sodium tartrate aqueous solution [potassium sodium tartrate (316g) + water (750mL)], the pH is adjusted to 9-10 with ammonia water, dichloromethane (500mL) is added, the liquid is separated, the aqueous phase is extracted again with dichloromethane (300mL), and the combined organic phases are concentrated under reduced pressure to obtain intermediate 1-D (24g, yield: 70%). 1H NMR (400MHz, CDCl3) δppm 3.71 (s, 3H), 3.69 (s, 1H), 3.64 (d, J=3.6Hz, 1H), 1.86 (s, 1H), 1.72-1.67 (m, 2H), 1.52-1.47 (m, 2H), 0.70-0.59 (m, 3H), 0.40-0.38 (m, 1H).MS m / z: 182.1[M+H] +

[0053] Step 4: Synthesis of Intermediate 1-E

[0054] Intermediate 1-D (137 g), (S)-N-Boc tert-leucine (192.32 g) was dissolved in a mixed solution of acetonitrile (1370 mL) and N,N-dimethylformamide (137 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (159.41 g), N-methylmorpholine (152.93 g), 1-hydroxybenzotriazole (102.14 g) was added at 25 °C, and the reaction was continued for 16 hours. After the reaction was completed, most of the acetonitrile was removed by concentration under reduced pressure, ethyl acetate (1000 mL), water (1000 mL) was added, and the mixture was extracted and separated. The organic phase was washed with 10% citric acid (500 mL*2), saturated sodium bicarbonate (500 mL), and saturated brine (500 mL), and concentrated to dryness under reduced pressure. The concentrate was added with hydrochloric acid ethyl acetate solution (4 mol / L, 1.89 L), and methanol (200 mL) at 10-15 °C, and stirred at 20-25 °C for 0.5 hours after the addition was completed. After the reaction was completed, 1 L of solvent was removed by concentration, and stirred at 25 °C for 0.5 hours. After filtration, the filter cake was washed with ethyl acetate (200 mL), and the residue was removed from the filter cake to obtain intermediate 1-E (212 g, yield: 85%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.49 (s, 3H), 4.51 (s, 1H), 4.42 (s, 1H), 4.03 (d, J = 4.8 Hz, 1H), 3.70 (s, 3H), 2.26 (d, J = 10.8 Hz, 1H), 2.07 (s, 1H), 1.97 (s, 1H), 1.90 (d, J = 10.0 Hz, 1H), 1.90 (d, J = 10.0 Hz, 1H), 1.80 (d, J = 12.4 Hz, 1H), 1.23 (s, 9H), 0.81-0.64 (m, 3H), 0.48-0.46 (m, 1H). MS m / z: 294.9 [M+H] +

[0055] Step 5: Synthesis of intermediate 1

[0056] Intermediate 1-E (211.59 g) was dissolved in dichloromethane (1300 mL), and trifluoroacetic anhydride (201.48 g) was added at 10-15°C, followed by triethylamine (64.71 g). After the addition was complete, the reaction was continued at 20-25°C for 1 hour. After the reaction was completed, the reaction solution was cooled to 10-15°C, water (500 mL) was added dropwise, and the liquid was separated. The organic phase was washed with 10% citric acid aqueous solution (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), and saturated brine (500 mL), and concentrated to dryness to obtain the crude product of intermediate 1. Isopropyl acetate (50 mL) and n-heptane (500 mL) were added to the crude product, and the mixture was beaten at 50°C for 1-2 hours. The temperature was lowered to 10-20°C, and the mixture was filtered to obtain intermediate 1 (212 g, yield: 85%). 1 H NMR (400MHz, CDCl3) δppm 1.99 (s, 1H), 1.92-1.86 (m, 2H), 1.59 (dd, J=12.4Hz, 2.4Hz, 1H), 1.10 (s, 9H), 0.75-0.63 (m, 3H), 0.49-0.47 (m, 1H).MS m / z: 391.1[M+H] + .

[0057] Example 2 Synthesis of Intermediate 1-A

[0058]

[0059] Under nitrogen protection, S1 (39 g, 141.6 mmol, 1 eq) was put into a 1000 mL round-bottom flask, and 160 g of methanol and acetic acid (10.2 g, 170 mmol, 1.2 eq) were added and stirred to dissolve; 4.0 g of 10% palladium carbon was added, the hydrogen pressure was set to 0.3-0.5 MPa, the temperature was 10-20 ° C, and the mixture was stirred for 8-10 hours; the TLC spot plate of the central control showed that the raw material point disappeared; filtered; the filtrate was transferred to a 1000 mL round-bottom flask, triethylamine was added dropwise at 5-5 ° C, di-tert-butyl dicarbonate was added dropwise at 0-10 ° C, and the temperature was raised to 15- 20 ℃, keep warm and stir for 2-2.5 hours, control by TLC until the raw material point disappears; the reaction solution is concentrated under reduced pressure, 180 g of ethyl acetate and 100 g of drinking water are added to extract and separate the layers; the aqueous phase is re-extracted with ethyl acetate; the organic phases are combined and washed with 12% aqueous sodium bicarbonate solution and 30% aqueous sodium chloride solution in sequence; the organic phase is dried over anhydrous sodium sulfate for 2 hours and filtered; concentrated under reduced pressure to dryness, 80.4 g of n-heptane is added to the mixture after concentration, and the mixture is beaten at room temperature for 2-3 hours, filtered, and the filter cake is collected and dried in vacuo at 40-45 ℃ to obtain the target product intermediate 1-A (33.0 g, yield: 85.9%). 1 H NMR (400MHz, DMSO-d6, 298K, δin ppm): 5.03 (m, 1H, CH), 3.94 (m, 1H, CH), 3.71 (s, 9H, C (CH3)3), 3.64 (d, 3H, CH3), 3. 60 (d, 1H, CH), 3.34 (m, 2H, CH2), 2.41 (m, 1H, OH), 1.86 (m, 1H, CH), 1.63 (m, 2H, CH2).

Claims

1. A method for preparing a compound of formula (I), It is characterized by: The method comprises the steps of synthesizing compound D using compound A as a raw material: in, R1 is selected from H, C 1-4 alkyl and benzyl groups; R2 is an amino protecting group.

2. The method for preparing the compound of formula (I) according to claim 1, wherein R1 is selected from H, methyl, ethyl, isopropyl, tert-butyl and benzyl.

3. The method for preparing the compound of formula (I) according to claim 2, wherein R1 is methyl.

4. The method for preparing a compound of formula (I) according to claim 1, wherein R2 is selected from Boc.

5. The method for preparing the compound of formula (I) according to claim 1, further comprising the step of synthesizing the compound of formula (I) from compound D.

6. A method for preparing the compound of formula (I) according to claim 1, comprising the following steps:

7. The method for preparing the compound of formula (I) according to claim 6, wherein The process also includes beating and purifying the crude product of the compound obtained after the reaction in step 5: 1) adding a mixed solvent of isopropyl acetate and n-heptane to the crude product, wherein the volume ratio of the mixed solvent of isopropyl acetate and n-heptane is 1:10; 2) Beating at 40-60°C for 1-2 hours; 3) Cool down to 10-20°C; 4) Filter.

8. The method for preparing the compound of formula (I) according to claim 7, wherein Beat at 50°C for 1 to 2 hours.

9. The intermediate of the following formula, its hydrochloride or sulfate,

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