Novel preparation method of Velciguat intermediate

Abstract

The invention provides a novel preparation method of a Velciguat intermediate. Specifically, the synthesis method of the Vilciguat intermediate provided by the invention comprises the following steps: taking 2-fluoropropionic acid as a starting material, cyclizing with 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-formate, and then dechlorinating to obtain a key intermediate compound (5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridine-3-formate) of the Vilciguat. The preparation method disclosed by the invention has the advantages of cheap and easily available raw materials, simple reaction operation, few steps, simple purification operation, high yield, high purity, relatively mild and safe reaction conditions and convenience for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry. Specifically, the present invention relates to a new preparation method of a vericiguat intermediate and a new intermediate for preparing vericiguat and a preparation method thereof. Background Art

[0002] Heart failure is associated with impaired synthesis of vitamin C, reduced nitric oxide (NO) and soluble guanylate cyclase (sGC) activities, which may lead to myocardial and vascular dysfunction. Vericiguat is a drug developed by Bayer for the treatment of symptomatic chronic heart failure patients with an ejection fraction of less than 45% after experiencing a heart failure worsening event, with the trade name Verquvo. The drug was launched in the United States on January 20, 2021. It is the first innovative drug approved by the FDA in 2021 and the first soluble guanylate cyclase agonist for the treatment of patients with worsening chronic heart failure.

[0003] Ethyl 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (i.e., compound (1) of the present application) is an important intermediate for the synthesis of vericiguat. The prior art (such as patent application CN104159898A, literature J. Med. Chem. 2017, 60, 12, 5146–5161, etc.) discloses that it is mainly synthesized by the following methods:

[0004]

[0005] Wherein: R a and R b are methyl, ethyl, isopropyl, phenyl, The main defects of the prior art methods are as follows: 1) The raw materials of compound (I-E) are difficult to obtain, the synthetic route is long, the yield is low, and the cost is high; 2) The atom economy of the synthetic route of compound (I-E) is poor, and only one of the four F atoms of the starting material compound (B) is finally used; 3) A large amount of reagents such as methanesulfonic anhydride, methyl methanesulfonate and base are required in the synthesis process, which is not environmentally friendly; 4) The obtained methanesulfonate intermediate is prone to moisture absorption and is not easy to store, which is not conducive to industrial scale-up. Therefore, it is urgent to develop a better preparation method suitable for industrial production. Summary of the Invention

[0006] The preparation method provided by the present invention uses 2-fluoromalonic acid as the starting material. After cyclization with compound (III) (such as ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate), dechlorination is carried out to obtain the key intermediate compound (I) (ethyl 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate) of vericiguat. The preparation method disclosed by the present invention has cheap and easily available raw materials, simple reaction operations, few synthesis steps, simple purification, high yield, high purity, relatively mild reaction conditions, safety, and is convenient for industrial production.

[0007] On the one hand, the present invention provides a method for preparing a compound represented by formula (I), characterized in that the method comprises step 1),

[0008]

[0009] Step 1): An intermolecular cyclization reaction occurs between compound (A) and compound (III) to obtain compound (II),

[0010]

[0011] wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl-CH2- or phenyl-(CH2)2-.

[0012] In some embodiments of the present invention, the cyclization reaction is carried out in the presence of an acylating agent.

[0013] In some embodiments of the present invention, the acylating agent is phosphorus oxychloride.

[0014] In some embodiments of the present invention, the addition order of the reaction raw materials is: mixing compound (A) with the acylating agent, stirring and reacting, then adding compound (III) in batches, and then continuing to stir and react.

[0015] In some embodiments of the present invention, the reaction between compound (A) and the acylating agent in step 1) is carried out at 85-105 °C, preferably at 90-100 °C.

[0016] In some embodiments of the present invention, the reaction after adding compound (III) is carried out at 95 °C to 110 °C, preferably at 100 °C - 105 °C.

[0017] In some embodiments of the present invention, the addition amount of compound (III) is 0.9-1.5 eq of compound (A), and the eq is the molar equivalent, such as adding 0.9-1.5 moles of compound (III) per mole of compound (A).

[0018] In some embodiments of the present invention, the method further includes the post-treatment of the reaction in step 1), which is: quenching the reaction with water, extracting, concentrating the organic phase under reduced pressure, and recrystallizing the concentrated product in solvent A to obtain compound (II).

[0019] In some embodiments of the present invention, solvent A is a mixed solvent of ethyl acetate and n-hexane.

[0020] In some embodiments of the present invention, the method further includes step 2).

[0021]

[0022] Step 2): Compound (II) undergoes a reduction reaction in the presence of a catalyst and H2 to obtain compound (I).

[0023] In some embodiments of the present invention, the catalyst is palladium on carbon or Raney nickel.

[0024] In some embodiments of the present invention, the reaction solvent for the reduction reaction is ethanol, DMF, DMAc, THF, or a mixed solvent thereof with water.

[0025] In some embodiments of the present invention, the reduction reaction is carried out at a temperature of 40 °C to 80 °C, preferably at a temperature of 40 °C to 60 °C, and more preferably at a temperature of 40 °C to 50 °C.

[0026] In some embodiments of the present invention, the method further includes the post-treatment of the reaction in step 2), which is: filtering the reaction mixture after the reaction, concentrating the filtrate under reduced pressure to obtain compound (I); or, the post-treatment of step 2) is: filtering the reaction mixture after the reaction, dropping the filtrate into water at 50 °C, stirring and then filtering to obtain compound (I).

[0027] On the other hand, the present invention provides a method for preparing compound (II), which is: compound (A) undergoes an intermolecular cyclization reaction with compound (III) to obtain compound (II).

[0028]

[0029] Wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl-CH2- or phenyl-(CH2)2-.

[0030] In some embodiments of the present invention, the cyclization reaction is carried out in the presence of an acylating agent.

[0031] In some embodiments of the present invention, the acylating agent is phosphorus oxychloride.

[0032] In some embodiments of the present invention, the addition sequence of the reaction raw materials is as follows: Compound (A) is mixed with an acylating reagent and stirred for reaction, and then compound (III) is added in batches, followed by continued stirring for reaction.

[0033] In some embodiments of the present invention, the reaction between compound (A) and the acylating reagent in step 1) is carried out at 85 - 105 °C, preferably at 90 - 100 °C.

[0034] In some embodiments of the present invention, the reaction after adding compound (III) is carried out at 95 °C to 110 °C, preferably at 100 °C - 105 °C.

[0035] In some embodiments of the present invention, the addition amount of compound (III) is 0.9 - 1.5 eq of compound (A), where "eq" is the molar equivalent, for example, 0.9 - 1.5 moles of compound (III) are added per mole of compound (A).

[0036] In some embodiments of the present invention, the method further includes the post-treatment of the reaction of the crude product of compound (II), which is: quenching the reaction with water, extracting, concentrating the organic phase under reduced pressure, and recrystallizing the concentrated product in solvent A to obtain compound (II).

[0037] In some embodiments of the present invention, solvent A is a mixed solvent of ethyl acetate and n-hexane.

[0038] On the other hand, the present invention provides a method for preparing compound (I).

[0039]

[0040] Compound (II) undergoes a reduction reaction in the presence of a catalyst and H2 to obtain compound (I).

[0041] In some embodiments of the present invention, the catalyst is palladium on carbon or Raney nickel.

[0042] In some embodiments of the present invention, the reaction solvent for the reduction reaction is ethanol, DMF, DMAc, THF, or a mixed solvent thereof with water.

[0043] In some embodiments of the present invention, the reduction reaction is carried out at a temperature of 40 °C to 80 °C, preferably at 40 °C to 60 °C, more preferably at 40 °C to 50 °C.

[0044] In some embodiments of the present invention, the method further comprises post-treatment of the crude product of compound (I), and the post-treatment may be: filtering the reaction mixture after the reaction, and concentrating the filtrate under reduced pressure to obtain compound (I); or, the post-treatment is: filtering the reaction mixture after the reaction, dripping water into the filtrate at 50°C, stirring and then filtering to obtain compound (I).

[0045] In the preparation method of the Vericipirax intermediate disclosed in the present invention, the raw materials are cheap and readily available, the reaction operation is simple, the synthesis steps are few, the purification is simple, and the yield and purity are high. The reaction conditions are relatively mild, safe, and convenient for industrial production.

[0046] In another aspect, the present invention provides a compound having a structure as shown in formula (II):

[0047]

[0048] Wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or phenyl-(CH2)2-.

[0049] The compound represented by formula (II) of the present invention can be used for the preparation of compound (I) (5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate), and can further be used for the preparation of vericiguat.

[0050] General Synthesis Methods of Compounds Described in the Present Invention

[0051] Generally, the compounds of the present invention can be prepared by the methods described in the present invention. The following reaction schemes and examples are provided to further illustrate the present invention.

[0052] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0053] The chromatographic column used is a silica gel column, and the silica gel (200 - 300 mesh) was purchased from Qingdao Marine Chemical Factory. Nuclear magnetic resonance spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvents (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet), q (quartet), and the coupling constant J is expressed in hertz (Hz).

[0054] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of the Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316ATCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315B DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0055] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of the Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316ATCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315D DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0056] Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a specification of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peaks were recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0057] Table 1: Gradient elution conditions

[0058]

[0059] The purity of the compound was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was performed at 210 nm and 254 nm, using a Zorbax SB-C18 column with a specification of 2.1×30 mm, 4 μm, for 10 minutes, at a flow rate of 0.6 mL / min, with a mobile phase gradient of 5-95% (0.1% formic acid in acetonitrile solution) in (0.1% formic acid in aqueous solution), and the column temperature was maintained at 40 °C.

[0060] Abbreviations: DMF N,N-dimethylformamide

[0061] h hour

[0062] RT, rt room temperature

[0063] THF tetrahydrofuran

[0064] min refers to minute;

[0065] Room temperature refers to 10 - 35 °C, preferably 20 - 30 °C;

[0066] DMAc dimethylacetamide

[0067] Synthetic route of the compound (1) of the present invention

[0068]

[0069] Example 1

[0070] Synthesis of Compound (3):

[0071] Compound (A) (5.00 g, 40.97 mmol, 1.0 eq) and phosphorus oxychloride (50 mL) were added to a reaction flask and reacted at 90 °C for 1 h. Then the temperature was lowered to 50 °C, and compound (2) (10.79 g, 40.97 mmol, 1.0 eq) was added in batches. After addition, the temperature was raised to 105 °C and reacted for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, then dropped into water (50 mL) to quench the reaction, and then extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with water (15 mL), and then concentrated under reduced pressure to obtain a yellow oil. The obtained yellow oil was recrystallized with ethyl acetate and n-hexane to obtain compound (3) as an off-white solid (7.83 g, yield 49.5%). MS (ESI, pos. ion) m / z: 386.1 [M + H] + 。

[0072] Synthesis of Compound (1):

[0073] Compound (3) (5.00 g, 12.95 mmol, 1.0 eq), palladium / carbon (250 mg, 5% wt), and methanol (40 mL) were added to a reaction flask, and the reaction was carried out at 40 °C under a hydrogen balloon (pressure about 20 - 80 psi) for 3 h. After the reaction was completed, the mixture was filtered, and the organic phase was concentrated to obtain compound (1) as a pale white solid, 3.78 g (yield 92.1%, purity 94.6%).

[0074] MS(ESI,pos.ion)m / z:318.10[M+H] + 。

[0075] 1 H NMR(400MHz,CDCl3)δ8.52(dd,J=2.6,1.5Hz,1H),8.16(dd,J=7.8,2.7Hz,1H),7.28(s,1H),7.18–7.00(m,3H),5.90(s,2H),4.54(q,J=7.1Hz,2H),1.49(t,J=7.1Hz,3H);

[0076] 13 C NMR(101MHz,CDCl3)δ161.72(s),161.58(s),159.11(s),157.98(s),155.50(s),147.97(s),140.07(s),139.76(s),134.58(d,J=5.2Hz),129.78(dd,J=21.1,5.8Hz),124.28(d,J=3.7Hz),122.96(d,J=14.5Hz),115.61(dd,J=21.3,7.2Hz),61.47(s),45.46(d,J=4.8Hz),14.42(s).

[0077] Example 2

[0078] Synthesis of Compound (3):

[0079] Compound (A) (5.00 g, 40.97 mmol, 1.0 eq) and phosphorus oxychloride (60 mL) were added to a reaction flask and reacted at 100 °C for 1 h. Then the temperature was lowered to 45 °C, and compound (2) (11.86 g, 45.06 mmol, 1.1 eq) was added in batches. After addition, the temperature was raised to 105 °C and the reaction was carried out for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and then dropped into water (60 mL) to quench the reaction. The resulting mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with water (20 mL), and then concentrated under reduced pressure to obtain a yellow oil. The obtained oil was recrystallized with ethyl acetate and n-hexane to obtain compound (3) as an off-white solid (8.12 g, yield 51.3%).

[0080] Synthesis of Compound (1):

[0081] Compound (3) (6.00 g, 15.54 mmol, 1.0 eq), Raney nickel (600 mg) and DMF (60 mL) were added to a reaction flask and reacted at 50 °C under a hydrogen balloon (pressure about 20 - 80 psi) for 4 h. After the reaction was completed, the mixture was filtered. The filtrate was heated to 50 °C, and water (120 mL) was dropped in. Solids precipitated during the dropping process. After the dropping was completed, the temperature was lowered to room temperature, and after stirring for 2 h, it was filtered. The solid was dried in vacuo at 60 °C to obtain 4.40 g of compound (1) as an off-white solid, with a yield of 89.2% and a purity of 95.5%.

[0082] Example 3

[0083] Synthesis of Compound (1):

[0084] Compound (3) (4.00 g, 10.36 mmol, 1.0 eq), palladium / carbon (200 mg, 10% wt), THF (40 mL) and purified water (5 mL) were added to a reaction flask. The reaction mixture was reacted at 40 °C under a hydrogen balloon (pressure about 20 - 80 psi) for 6 h. After the reaction was completed, the filtrate was heated to 50 °C, and water (80 mL) was dropped in. Solids precipitated during the dropping process. After the dropping was completed, the temperature was lowered to room temperature, and after stirring for 2 h, it was filtered. The solid was dried in vacuo at 60 °C to obtain compound (1) as an off-white solid (3.06 g, yield 93.2%, purity 96.0%).

[0085] In the description of this specification, the descriptions referring to terms such as "one embodiment", "an embodiment", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0086] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a compound represented by formula (I), characterized in that, The method includes step 1), Step 1): An intermolecular cyclization reaction occurs between compound (A) and compound (III) to obtain compound (II), wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl-CH2- or phenyl-(CH2)2-.

2. The preparation method according to claim 1, characterized in that, The cyclization reaction is carried out in the presence of an acylating agent.

3. The preparation method according to claim 2, characterized in that, The acylating agent shown is phosphorus oxychloride.

4. The preparation method according to any one of claims 1-3, characterized in that, The addition order of the reaction raw materials is: Mix compound (A) with the acylating agent, stir and react, then add compound (III) in batches, and then continue to stir and react.

5. The preparation method according to claim 4, characterized in that, The reaction between compound (A) and the acylating agent in step 1) is carried out at 85 - 105 °C, preferably at 90 - 100 °C; Optionally, the reaction after adding compound (III) is carried out at 95 °C to 110 °C, preferably at 100 °C - 105 °C.

6. The preparation method according to any one of claims 1-5, characterized in that, The addition amount of compound (III) is 0.9 - 1.5 eq of compound (A).

7. The preparation method according to any one of claims 1-6, characterized in that, The method further includes step 2), Step 2): Compound (II) undergoes a reduction reaction in the presence of a catalyst and H2 to obtain compound (I).

8. The preparation method according to claim 7, characterized in that, The catalyst is palladium carbon or Raney nickel; Optionally, the reaction solvent for the reduction reaction is ethanol, DMF, DMAc, THF or a mixed solvent thereof with water; Optionally, the reduction reaction is carried out at a temperature of 40 °C to 80 °C, preferably at 40 °C to 60 °C, more preferably at 40 °C to 50 °C.

9. The preparation method according to any one of claims 1-8, characterized in that, The method further includes the post-treatment of the reaction in step 1): Quench the reaction with water, extract, concentrate the organic phase under reduced pressure, and recrystallize the concentrated product in solvent A to obtain compound (II); Optionally, the method further includes the post-treatment of the reaction in step 2): Filter the reaction mixture after the reaction, concentrate the filtrate under reduced pressure to obtain compound (I); or, filter the reaction mixture after the reaction, drop water into the filtrate at 50 °C, stir and then filter to obtain compound (I).

10. A compound having a structure represented by formula (II), wherein, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or phenyl-(CH2)2-.

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