Preparation method for C5 site methylation of pyrrole-2-carboxylic ester

Abstract

The invention discloses a preparation method for C5 site methylation of pyrrole-2-carboxylic ester, and belongs to the field of organic synthesis. According to the method, a pyrrole-2-carboxylic ester derivative and a methylation reagent are used as initial raw materials and are stirred to react in an organic solvent at 60-80 DEG C under the action of a palladium catalyst, norbornene and alkali, and the C5-methylated pyrrole-2-carboxylic ester derivative can be obtained. The method is good in process, mild in reaction condition, free of water-free and oxygen-free operation, low in requirement for reaction equipment and high in practicability and industrial value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a preparation method of methylating the C5 position of pyrrole-2-carboxylate. Background Art

[0002] As a heterocyclic fragment, pyrrole has certain application potential in biological activity. By fusing different drug groups with the pyrrole ring, compounds with more prominent activity can be created. In addition, pyrrole skeletons are also found in a variety of natural products. The active molecules with drug value containing pyrrole rings currently under development have shown diversified biological properties. They are used in antipsychotic treatment, as β-adrenergic receptor antagonists, anti-anxiety drugs, and in the treatment of cancer (such as leukemia, lymphoma and myelofibrosis). They also have multiple pharmacological effects such as antibacterial, antifungal, antiprotozoal and antimalarial. The active molecules shown in the figure below all have pyrrole structures.

[0003]

[0004] In the field of drug synthesis, methyl, as the simplest alkyl group, plays a vital role. When it is cleverly introduced into drug active molecules as a bio-electronic equivalent substitute for hydrogen atoms, it can often significantly optimize the bioavailability and pharmacological properties of the molecule, thereby greatly improving the efficacy of the drug and its metabolic stability. The industry affectionately likens this significant change to the "magical methyl effect." It is worth noting that a statistical data reveals a striking phenomenon: among the top 200 drugs in global sales in 2020, about 40% of the drug molecular structures contain C-methyl units. This high proportion undoubtedly highlights the core importance of methyl in modern drug design and its wide practicality.

[0005] It is expected that during the construction and optimization of drug molecule libraries, the introduction of methyl groups on the pyrrole ring may lead to the emergence of some molecules with better activity. Currently, the introduction of methyl groups at the C2 or C5 positions adjacent to the NH group of the pyrrole ring is mainly carried out through a two-step method as shown in the figure below: first, a formyl group is introduced through the Vilsmeier reaction (POCl3 / DMF), and then the methylated pyrrole product is obtained through reduction with lithium aluminum hydride (LiAlH4) (Org. Lett. 2006.4951–4954; Org. Biomol. Chem., 2010.2204-2211).

[0006]

[0007] This strategy has the following problems: (1) The synthesis cost is relatively high. For example, in the first step, the Vilsmeier reagent needs to be prepared and used immediately, and generally requires anhydrous DMF solvent. In the second step, anhydrous tetrahydrofuran is generally required as a solvent. (2) The functional groups of the substrate are limited. Lithium aluminum hydride is a strong reducing agent, and is incompatible with nitro, cyano, ester, carboxyl, and amide groups. Substrates such as pyrrole-2-carboxylates are not suitable for methylation at the C5 position by lithium aluminum hydride reduction. Therefore, it is still very necessary to develop a more convenient preparation method to achieve C5 methylation of pyrrole-2-carboxylates. Summary of the invention

[0008] In order to solve the problems existing in the prior art, the purpose of the present invention is to provide a preparation method of pyrrole-2-carboxylate C5 methylation, aiming to reduce its preparation cost.

[0009] To achieve the above purpose, the technical solution provided by the present invention is as follows:

[0010] Using pyrrole-2-carboxylate derivative A and methylating agent B as starting materials, under the action of palladium catalyst C, norbornene derivative D and base E, stirring in organic solvent F at 60-80° C. until the reaction is completed, the reaction mixture is filtered, concentrated and purified by column chromatography to obtain pyrrole-2-carboxylate derivative G methylated at the C5 position as shown in the reaction formula. The reaction formula of the reaction is shown as follows:

[0011]

[0012] Among them, R in the general formula A 1 is a substituent on the C2 side chain of pyrrole, R 2 is a substituent on the pyrrole ring.

[0013] Furthermore, R in the general formula A 1 is selected from methyl, ethyl, benzyl, R 2 It is one of methyl and phenyl.

[0014] Furthermore, the molar ratio of the pyrrole-2-carboxylate A, methylating agent B, palladium catalyst C, norbornene derivative D, and base E is 1:(3-6):(0.05-0.5):(1-5):(3-6), wherein the preferred molar ratio is A:B:C:D:E=1:4:0.15:2:5.

[0015] Furthermore, the methylating agent B is triethyl phosphate, and the structural formula is

[0016]

[0017] Furthermore, the palladium catalyst C is one of palladium acetate, palladium chloride, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, di(cyanobenzene)palladium dichloride, and tetrakis(triphenylphosphine)palladium, wherein di(cyanobenzene)palladium dichloride is preferred.

[0018] Furthermore, the norbornene derivative D is: One of the following, preferably

[0019] Furthermore, the base E is one of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate, and sodium bicarbonate, among which potassium bicarbonate is preferred.

[0020] Furthermore, the solvent F is one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, among which N,N-dimethylformamide is preferred.

[0021] Furthermore, in the preparation method, the heating process can use an oil bath, which can be silicone oil or paraffin oil; the filtration process uses a sand core funnel and filters under reduced pressure; the concentration process can use atmospheric distillation or reduced pressure distillation, preferably using a rotary evaporator to concentrate under reduced pressure; the purification process is to obtain a pure product through column chromatography.

[0022] The method of the present invention can efficiently realize the synthesis of methylation at the C5 position of pyrrole-2-carboxylate. Compared with the prior art, the present invention has the following advantages:

[0023] 1. The methylation reagent triethyl phosphate involved in the present invention can be directly used as a commercial reagent without special treatment and is inexpensive;

[0024] 2. The preparation method of the present invention does not require anhydrous and oxygen-free operation, does not involve strong acid or strong base conditions, has better reaction conditions, is highly operable, and is easy for large-scale production;

[0025] 3. The method involved in the present invention has a short process step, and a one-step reaction is sufficient. Compared with the traditional two-step reaction, it has step economy and lower industrial production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 For compound G-2 1 H-NMR (400MHz, CDCl3) chart;

[0027] Figure 2 For compound G-2 13 C-NMR (100 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0028] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0029] Example 1: Preparation of Compound G-1

[0030]

[0031] To a reaction tube (10 mL) pre-equipped with a magnetic stirrer, methyl pyrrole-2-carboxylate (0.20 mmol, 25.1 mg), trimethyl phosphate (0.80 mmol, 112.0 mg, 4 eq.), norbornene (0.40 mmol, 37.6 mg, 2 eq.), potassium bicarbonate (1.00 mmol, 100.5 mg, 5 eq.), Pd(PhCN)2Cl2 (0.03 mmol, 11.5 mg, 0.15 eq.), and DMF (1 mL) were added in sequence. After the addition of the above reagents, the reaction tube was transferred to an oil bath at 70°C and continued to stir for 48 h. TLC detection was performed. The reaction was terminated after the conversion of the raw materials was complete. The mixture was cooled to room temperature, saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The target product G-1 (15.3 mg, yield 55%) was obtained as a white solid by purification by column chromatography (ethyl acetate:petroleum ether=1:25, V:V). 1 H NMR (400MHz, CDCl3) δ9.39 (s, 1H), 6.82 (t, J = 3.0Hz, 1H), 5.95 (t, J = 3.2Hz, 1H), 3.83 (s, 3H), 2.33 (s, 3H). 13 C NMR (101MHz, CDCl3) δ161.77,133.99,121.18,116.34,109.14,51.39,13.30.

[0032] Example 2: Preparation of Compound G-2

[0033]

[0034] The operation steps and conditions were the same as those in Example 1, except that the pyrrole substrate used was ethyl 3-methylpyrrole-2-carboxylate (0.2 mmol, 30.7 mg), and compound G-2 (white solid, 26.4 mg, yield 79%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.88 (s, 1H), 5.79 (d, J = 2.9Hz, 1H), 4.30 (q, J = 7.1Hz, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 1.35 (t, J = 7.1Hz, 3H). 13C NMR (101MHz, CDCl3) δ161.92,132.52,129.15,117.95,111.48,59.80,14.69,13.14,12.91.

[0035] Example 3: Preparation of Compound G-3

[0036]

[0037] The operation steps and conditions are the same as those in Example 1, except that the pyrrole substrate used is 3-methylpyrrole-2-carboxylic acid methyl ester (0.2 mmol, 27.8 mg), and compound G-3 (white solid, 22.4 mg, yield 73%) is obtained. 1 H NMR (400MHz, CDCl3) δ9.27(s,1H),5.79(s,1H),3.83(s,3H),2.30(s,3H),2.25ppm(s,3H). 13 C NMR (101MHz, CDCl3) δ163.43,132.97,129.14,117.53,111.34,50.92,12.96,12.82.

[0038] Example 4: Preparation of Compound G-4

[0039]

[0040] The operation steps and conditions are the same as those in Example 1, except that the pyrrole substrate used is 3-methylpyrrole-2-carboxylic acid benzyl ester (0.2 mmol, 43.1 mg), and compound G-4 (white solid, 31.2 mg, yield 68%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.67 (s, 1H), 7.42-7.30 (m, 5H), 5.80 (d, J = 2.8Hz, 1H), 5.29 (s, 2H), 2.32 (s, 3H), 2.23 (s, 3H). 13 C NMR (101MHz, CDCl3) δ161.3,136.6,132.7,127.7,128.6,128.1,117.4,111.6,65.5,13.1,12.9.

[0041] Example 5: Preparation of Compound G-5

[0042]

[0043] The operation steps and conditions are the same as those in Example 1, except that the pyrrole substrate used is 3,4-dimethylpyrrole-2-carboxylic acid ethyl ester (0.2 mmol, 25.3 mg), and compound G-5 (white solid, 31.2 mg, yield 70%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.85 (s, 1H), 4.29 (q, J = 7.1Hz, 2H), 2.25 (s, 3H), 2.18 (s, 3H), 1.91 (s, 3H), 1.34 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ161.9,129.5,127.4,117.0,111.6,59.5,14.5,11.3,10.6,8.7.

[0044] Example 6: Preparation of Compound G-6

[0045]

[0046] The operation steps and conditions are the same as those in Example 1, except that the pyrrole substrate used is 3-phenylpyrrole-2-carboxylic acid ethyl ester (0.2 mmol, 43.2 mg), and compound G-6 (yellow oil, 29.3 mg, yield 64%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.9 (s, 1H); 7.47 (m, 2H), 7.23 (m, 3H), 6.06 (dd, J = 2.9, 0.74, 1H), 4.23 (q, J = 7.1, 2H), 2.32 (s, 3H), 1.23 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ161.1,135.4,133.0,132.5,129.5,127.5,126.8,116.6,111.1,60.0,14.2,13.0.

[0047] The specific embodiments described herein are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A method for preparing pyrrole-2-carboxylate by methylation at C5 position, characterized in that: The preparation method is as follows: using pyrrole-2-carboxylate derivative A and methylating agent B as starting materials, stirring in organic solvent F under heating conditions of 60-80° C. until the reaction is completed, and filtering, concentrating, and purifying the reaction mixture by column chromatography to obtain pyrrole-2-carboxylate derivative G methylated at position C5 as shown in the reaction formula. The reaction formula of the reaction is shown as follows: Among them, R in the general formula A 1 is a substituent on the C2 side chain of pyrrole, R 2 is a substituent on the pyrrole ring.

2. The method for preparing pyrrole-2-carboxylate C5 methylated according to claim 1, characterized in that: R in Formula A 1 is selected from one of methyl, ethyl and benzyl, R 2 It is one of methyl and phenyl.

3. The method for preparing pyrrole-2-carboxylate C5 methylated according to claim 1, characterized in that: The molar ratio of the pyrrole-2-carboxylate A, the methylating agent B, the palladium catalyst C, the norbornene derivative D, and the base E is 1:(3-6):(0.05-0.5):(1-5):(3-6).

4. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 1, characterized in that: The molar ratio of the pyrrole-2-carboxylate A, the methylating agent B, the palladium catalyst C, the norbornene derivative D, and the base E is A:B:C:D:E=1:4:0.15:2:

5.

5. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 4, characterized in that: The methylating agent B is triethyl phosphate, and the structural formula is 6. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 1, characterized in that: The palladium catalyst C is one of palladium acetate, palladium chloride, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, di(cyanobenzene)palladium dichloride and tetrakis(triphenylphosphine)palladium.

7. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 1, characterized in that: The norbornene derivative D is: One of them.

8. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 1, characterized in that: The base E is one of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate and sodium bicarbonate.

9. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 1, characterized in that: The solvent F is one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

10. The method for preparing pyrrole-2-carboxylate by methylation at C5 position according to claim 1, characterized in that: In the preparation method, an oil bath is used in the heating process, and the oil used in the oil bath is silicone oil or paraffin oil; a sand core funnel is used in the filtration process, and the filtration is carried out under reduced pressure; and the concentration process can be carried out by atmospheric distillation or rotary evaporator under reduced pressure concentration; The purification process is to obtain pure products by column chromatography.

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