A method for preparing benzo[5] nitrogen-containing heterocyclic compounds
A benzo[1] five-membered nitrogen-containing heterocyclic compound was prepared by reacting compound 1 with sodium methoxide, reducing, acidifying, coupling, and cyclizing with phosphorus oxychloride. This method solves the high cost problem caused by the use of expensive reagents in existing technologies and enables low-cost large-scale production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- RUICHEN KANGDA BIOMEDICAL (WUHAN) CO LTD
- Filing Date
- 2022-12-21
- Publication Date
- 2026-06-30
AI Technical Summary
Existing methods for preparing benzo[a] pentagonal nitrogen-containing heterocyclic compounds use expensive reagents, resulting in high production costs and making them unsuitable for large-scale industrial production.
Compound 2 was obtained by reacting compound 1 with sodium methoxide, followed by reduction and acidification to obtain hydrochloride compound 3, which was then coupled with compound 9 and deprotected to obtain compound 5. Finally, compound 8 was obtained by cyclization with phosphorus oxychloride, thus avoiding the use of expensive Burgrss reagent.
This method significantly reduces preparation costs, is suitable for large-scale industrial production, and provides a low-cost method for preparing benzo[5] nitrogen-containing heterocyclic compounds.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing benzo[a] pentagonal nitrogen-containing heterocyclic compounds. Background Technology
[0002] Somatostatin (SST), also known as growth hormone-releasing inhibitor, is a broad-spectrum neurohormone that inhibits the levels of growth hormone and various endocrine substances. It can act as a neurotransmitter, regulating brain motor function, and as a hormone-regulating peptide, inhibiting tumor cell growth. The somatostatin receptor (SSTR) is a family of seven G protein-coupled transmembrane receptors. The biological effects of somatostatin are likely mediated by tissue-specific expression of this family of G protein-coupled receptors, including the somatostatin receptor subtypes SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5. SSTR4 is a member of this superfamily with seven transmembrane segments and is expressed at the highest levels in the fetal and adult brain and lungs. SSTR4 is highly expressed in the central nervous system and mediates effective analgesic and anti-inflammatory effects. Studies have shown that SSTR4 agonists hold promise for non-opioid pain control, particularly for chronic neuropathic, inflammatory, and mixed pain.
[0003] Benzopentacyclic nitrogen-containing heterocyclic compounds are intermediates in the preparation of SSTR4 agonists. The preparation methods of these intermediates and the synthesis of the corresponding SSTR4 agonists are described in patents, such as the agonist compound in Example 23o of CN105473574A, and the agonist compound in Example 49e of WO2016075239A1 and CN 107108592A. The preparation methods of these benzopentacyclic nitrogen-containing heterocyclic compounds all involve a three-step reaction using (3-methoxy-2-pyridine)methylamine hydrochloride and 2-tert-butoxycarbonylamino-2-methylpropionic acid as substrates: coupling, cyclization, and deacetylation. The Burgrss reagent used for cyclization (see page 118 of CN105473574A) is expensive, especially in large-scale production, leading to high production costs.
[0004] Therefore, it is necessary to develop a low-cost method for preparing benzo[5] nitrogen-containing heterocyclic compounds. Summary of the Invention
[0005] The purpose of this invention is to provide a method for preparing benzo[8] pentagonal nitrogen-containing heterocyclic compounds, which avoids the use of expensive reagents, is low in cost, and is suitable for large-scale industrial production.
[0006] To achieve the above objectives, the present invention provides the following technical solution:
[0007] A method for preparing the benzo[5] nitrogen-containing heterocyclic compound shown in formula (8),
[0008]
[0009] The method includes the following steps:
[0010] 1) Compound 1 reacts with sodium methoxide to give compound 2;
[0011] 2) Compound 2 undergoes reduction and acidification reactions to yield hydrochloride compound 3;
[0012] 3) Compound 3 and compound 9 undergo a coupling reaction to give compound 4;
[0013] 4) Compound 4 is deprotected to give compound 5;
[0014] 5) Compound 6 is obtained from compound 5;
[0015] 6) Compound 6 was cyclized to give compound 7;
[0016] 7) Compound 8 is obtained from compound 7;
[0017] The reaction route is as follows:
[0018]
[0019] The method may include one or more of the following features:
[0020] In one embodiment, in step 1), compound 1 reacts with sodium methoxide to obtain compound 2;
[0021] In one embodiment, in step 1), the molar ratio of compound 1 to sodium methoxide is 1:5.2.
[0022] In one embodiment, in step 1), the reaction solvent is dimethyl sulfoxide;
[0023] In one embodiment, in step 2), compound 2 undergoes a reduction reaction and an acidification reaction to obtain hydrochloride compound 3; the reducing agent in the reduction reaction is selected from Raney nickel, and the acid is selected from concentrated hydrochloric acid;
[0024] In one embodiment, in step 2), the reaction solvent is methanol;
[0025] In one embodiment, in step 3), compound 3 is coupled with compound 9 in the presence of a condensing agent and a base to obtain compound 4; the condensing agent is selected from at least one of 1-hydroxybenzotriazole (HOBT), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU); the base is selected from triethylamine.
[0026] In one embodiment, in step 3), the molar ratio of compound 3 to condensing agent is 1:1.3; the molar ratio of compound 3 to base is 1:4.
[0027] In one embodiment, in step 3), the reaction solvent is N,N-dimethylformamide (DMF);
[0028] In one embodiment, in step 3), the reaction temperature is room temperature;
[0029] In one embodiment, in step 4), compound 4 is deprotected by a tert-butyloxycarbonyl (Boc) protecting group in the presence of an acid to obtain compound 5, wherein the acid is selected from concentrated hydrochloric acid;
[0030] In one embodiment, in step 4), the reaction is carried out in a mixed solution, wherein the mixed solvent is a mixture of ethanol and ethyl acetate; wherein the volume ratio of ethanol to ethyl acetate is 1:(1-2);
[0031] In one embodiment, in step 4), the reaction temperature is 50-80°C;
[0032] In one embodiment, in step 4), after the reaction is completed, the reaction solution is concentrated, and the crude compound 5 obtained is directly fed into the next reaction step.
[0033] In one embodiment, in step 5), compound 5 reacts with acetic anhydride to give compound 6;
[0034] In one embodiment, in step 5), the molar ratio of compound 5 to acetic anhydride is 1:1.5.
[0035] In one embodiment, in step 5), the reaction solvent is dichloromethane;
[0036] In one embodiment, in step 6), compound 6 is cyclized in the presence of phosphorus oxychloride to obtain compound 7;
[0037] In one embodiment, in step 6), the molar ratio of compound 6 to phosphorus oxychloride is 1:(5-15), preferably 1:15;
[0038] In one embodiment, in step 6), the reaction temperature is 40-60°C;
[0039] In one embodiment, in step 6), the reaction solvent is selected from at least one of tetrahydrofuran, acetonitrile, methyl ether, and 1,4-dioxane, with tetrahydrofuran being the preferred solvent.
[0040] In one embodiment, in step 6), the reaction is preferably carried out under alkaline conditions, wherein the base may be selected from at least one of pyridine and triethylamine; the addition of a base helps to improve the yield.
[0041] In one embodiment, in step 7), compound 7 is deacetylated under alkaline conditions to obtain compound 8; the base is selected from sodium hydroxide.
[0042] The present invention further provides a method for preparing a benzo[5] nitrogen-containing heterocyclic compound of formula (8), comprising the steps of:
[0043] i) Compound 4 is deprotected to give compound 5;
[0044] ii) Compound 5 yields compound 6;
[0045] iii) Compound 6 was cyclized to give compound 7;
[0046] iv) Compound 8 was obtained from compound 7;
[0047] The reaction route is as follows:
[0048]
[0049] In one embodiment, in step i), compound 4 is deprotected by a tert-butyloxycarbonyl protecting group in the presence of an acid, wherein the acid is selected from concentrated hydrochloric acid.
[0050] In one embodiment, in step i), the reaction is carried out in a mixed solution, wherein the mixed solvent is a mixture of ethanol and ethyl acetate; wherein the volume ratio of ethanol to ethyl acetate is 1:(1-2);
[0051] In one embodiment, in step i), the reaction temperature is 50-80°C;
[0052] In one embodiment, after the reaction is completed in step i), the reaction solution is concentrated, and the crude product of compound 5 is directly fed into the next reaction step.
[0053] In one embodiment, in step ii), compound 5 reacts with acetic anhydride to give compound 6;
[0054] In one embodiment, in step ii), the molar ratio of compound 5 to acetic anhydride is 1:1.5.
[0055] In one embodiment, in step ii), the reaction solvent is dichloromethane;
[0056] In one embodiment, in step iii), compound 6 is cyclized in the presence of phosphorus oxychloride to obtain compound 7;
[0057] In one embodiment, in step iii), the molar ratio of compound 6 to phosphorus oxychloride is 1:(5-15), preferably 1:15;
[0058] In one embodiment, in step iii), the reaction temperature is 40-60°C;
[0059] In one embodiment, in step iii), the reaction solvent is selected from at least one of tetrahydrofuran, acetonitrile, methyl ether, and 1,4-dioxane, with tetrahydrofuran being the preferred solvent.
[0060] In one embodiment, in step iii), the reaction is preferably carried out under alkaline conditions, wherein the base may be selected from at least one of pyridine and triethylamine; the addition of a base helps to improve the yield.
[0061] In one embodiment, in step iv), compound 7 is deacetylated under alkaline conditions to give compound 8; the base is selected from sodium hydroxide.
[0062] The invention provides a method for preparing a benzo5-membered nitrogen-containing heterocyclic compound (compound 8). This method uses a simple method to prepare compound 4, then compound 4 is de-tert-butoxycarbonyl (Boc), acetyl (Ac) is added, and then cyclized with phosphorus oxychloride reagent to prepare compound 8. This method avoids the use of expensive reagents (such as Burgrss reagent), significantly reduces costs, and is very suitable for industrial production applications. Detailed Implementation
[0063] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be considered as specific limitations thereof. The compounds in the embodiments are all publicly disclosed compounds, wherein compounds 1, 2, and 3 can be obtained commercially (e.g., starting material 1 can be purchased from Shanghai Leyan Biotechnology Co., Ltd.), or prepared using methods disclosed in the literature (e.g., compound 4 can be prepared according to the method in CN105473574A, or it can be prepared using the method described in the embodiments of the present invention). Unless otherwise specified, other reagents and materials in the present invention are commercially available products.
[0064] Example 1: Preparation of Compound 2
[0065]
[0066] Sodium methoxide (17.2 kg) was dissolved in dimethyl sulfoxide (40 L) in a reaction vessel. Compound 1 (2-cyano-3-fluoropyridine) (7.5 kg) was dissolved in dimethyl sulfoxide (35 L) and then slowly added dropwise to the reaction vessel. The reaction was carried out overnight at 25 °C. Water (150 L) and ethyl acetate (50 L) were added, and the mixture was stirred and allowed to stand to separate into layers. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with brine, dried, and evaporated to dryness. The crude product was rapidly passed through a column and slurryed with petroleum ether to give compound 2 (5.5 kg, 59.8%) as a white solid.
[0067] Example 2 Preparation of Compound 3
[0068]
[0069] The reaction vessel was purged with nitrogen, and methanol (70 L), Raney nickel (250 g), compound 2 (3.5 kg), and concentrated hydrochloric acid (6 L) were added. Hydrogen was then purged three times, and the mixture was stirred for three days. After the reaction was complete, the mixture was filtered through diatomaceous earth, concentrated to obtain a crude product, and washed with ethanol and ethyl acetate to obtain compound 3 (3.2 kg, 65%).
[0070] Example 3 Preparation of Compound 4
[0071]
[0072] Compound 3 (154 g) was dissolved in DMF (1200 mL), and carbodiimide hydrochloride (EDCI) (219 g, 1.3 eq), HOBt (154.8 g, 1.3 eq), triethylamine (356 g, 4.0 eq) were added. Compound 9 (179 g, 1.0 eq) was added and reacted at room temperature. After the reaction was completed, water and ethyl acetate were added to separate the layers. The organic phase was retained, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried, and slurried with a solvent of petroleum ether:ethyl acetate in a ratio of 5:1 to obtain compound 4 (193 g, 68%).
[0073] Example 4 Preparation of Compound 5
[0074]
[0075] Method 4-1: Dissolve compound 4 (10g) in 60mL of a mixed solution of ethyl acetate and ethanol (volume ratio 2:1), add 20mL of hydrochloric acid, react at 60℃ for 2 hours, and a solid precipitates out. Dry the solid to obtain compound 5 (9.8g crude product).
[0076] Method 4-2: Dissolve compound 4 (50g) in 150mL of a mixed solution of ethyl acetate and ethanol in a volume ratio of 1:1, add 75mL of hydrochloric acid, react at 50℃ until a solid precipitates, reflux at 80℃ for 0.5 hours, and evaporate to dryness to obtain compound 5 (50g of crude product).
[0077] Example 5 Preparation of Compound 6
[0078]
[0079] The crude compound 5 (10 g) was dissolved in dichloromethane, and triethylamine (8.94 g, 3 eq) and acetic anhydride (4.51 g, 1.5 eq) were added. The reaction was carried out at room temperature for 1 hour, quenched with water, extracted with dichloromethane, and slurried with petroleum ether and ethyl acetate (1:1 v / v) to give compound 6 (6.9 g). The two-step yield from compound 3 to compound 5 was 83%.
[0080] Example 6 Preparation of Compound 7
[0081]
[0082] Method 6-1: Compound 6 (50 mg) was dissolved in tetrahydrofuran (5 mL), POCl3 (433.31 mg, 15 eq) was added, the reaction was carried out overnight at 45 °C, water was added to quench the reaction, ethyl acetate was diluted, sodium carbonate was added in an ice bath to adjust the pH to neutral, dichloromethane was extracted, and column chromatography (petroleum ether: ethyl acetate volume ratio = 1:1) was performed to obtain compound 7 (33.5 mg, 72%).
[0083] Method 6-2: Compound 6 (50 mg) was dissolved in tetrahydrofuran (5 mL), POCl3 (433.31 mg, 15 eq) and pyridine (44.65 mg, 3 eq) were added, and the reaction was carried out at 45 °C for 3 hours. The reaction was quenched with water, diluted with ethyl acetate, and the pH was adjusted to neutral by adding sodium carbonate in an ice bath. The mixture was extracted with dichloromethane and subjected to column chromatography (petroleum ether: ethyl acetate volume ratio = 1:1) to obtain compound 7 (45 mg, 97%).
[0084] Method 6-3: Compound 6 (50 mg) was dissolved in tetrahydrofuran (5 mL), POCl3 (433.31 mg, 15 eq) and triethylamine (57 mg, 3 eq) were added, the reaction was carried out at 40 °C for 1 hour, quenched with water, diluted with ethyl acetate, and the pH was adjusted to neutral by adding sodium carbonate in an ice bath. The mixture was extracted with dichloromethane and subjected to column chromatography (petroleum ether: ethyl acetate volume ratio = 1:1) to obtain compound 7 (43.8 mg, 94%).
[0085] Method 6-4: Compound 6 (50 mg) was dissolved in 1,4-dioxane (5 mL), POCl3 (433.31 mg, 15 eq) was added, the reaction was carried out at 50 °C for 1.5 h, quenched with water, diluted with ethyl acetate, and the pH was adjusted to neutral by adding sodium carbonate in an ice bath. The mixture was extracted with dichloromethane and subjected to column chromatography (petroleum ether: ethyl acetate volume ratio = 1:1) to obtain compound 7 (24 mg, 51%).
[0086] Example 7 Preparation of Compound 8
[0087]
[0088] Compound 7 (5 g) was dissolved in ethanol (50 mL, 10 V), sodium hydroxide (4 g, 5 eq) was added, the temperature was raised to 110 °C and the reaction was carried out under reflux. After the reaction was completed, the ethanol was evaporated by rotary evaporation, water was added, and a solid precipitated out. The solid compound 8 (3.5 g, 85%) was obtained by filtration.
[0089] The above embodiments are merely illustrative of the features and advantages of the present invention. Those skilled in the art can make any technical changes and modifications based on the content disclosed in the present invention and the nature of the invention. Such changes and modifications, as long as they do not violate the spirit of the present invention, shall fall within the protection scope of the present invention.
Claims
1. A method for preparing a benzo[5] nitrogen-containing heterocyclic compound of formula (8), （8） The method includes the following steps: 1) Compound 1 reacts with sodium methoxide to give compound 2; 2) Compound 2 undergoes reduction and acidification reactions to yield hydrochloride compound 3; 3) Compound 3 and compound 9 undergo a coupling reaction to give compound 4; 4) Compound 4 is deprotected to give compound 5; 5) Compound 6 is obtained from compound 5; 6) Compound 6 was cyclized to give compound 7; 7) Compound 8 is obtained from compound 7; The reaction route is as follows: 。 2. The method of claim 1, wherein in step 1), the molar ratio of compound 1 to sodium methoxide is 1:5.
2.
3. The method according to claim 1, wherein in step 2), compound 2 undergoes a reduction reaction and an acidification reaction to obtain hydrochloride compound 3; the reducing agent in the reduction reaction is selected from Raney nickel, and the acid is selected from concentrated hydrochloric acid.
4. The method of claim 1, wherein in step 3), compound 3 is coupled with compound 9 in the presence of a condensing agent and a base to obtain compound 4; the condensing agent is selected from at least one of 1-hydroxybenzotriazole (HOBT), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU); the base is selected from triethylamine.
5. The method of claim 1, wherein in step 4), compound 4 is deprotected by a tert-butyloxycarbonyl protecting group in the presence of an acid to obtain compound 5, wherein the acid is selected from concentrated hydrochloric acid.
6. The method according to claim 1, wherein in step 4), after the reaction is completed, the reaction solution is concentrated, and the crude product of compound 5 is directly fed into the next reaction.
7. The method of claim 1, wherein in step 5), compound 5 reacts with acetic anhydride to give compound 6.
8. The method of claim 1, wherein in step 6), compound 6 is cyclized in the presence of phosphorus oxychloride to obtain compound 7.
9. The method of claim 1, wherein in step 7), compound 7 is deacetylated under alkaline conditions to obtain compound 8; the base is selected from sodium hydroxide.
10. A method for preparing a benzo[5] nitrogen-containing heterocyclic compound of formula (8), the method comprising the steps of: i) Compound 4 is deprotected to give compound 5; ii) Compound 5 yields compound 6; iii) Compound 6 was cyclized to give compound 7; iv) Compound 8 was obtained from compound 7; The reaction route is as follows: The method described herein includes one or more of the following technical features: 1) In step i), compound 4 is deprotected by a tert-butyloxycarbonyl protecting group in the presence of an acid to obtain compound 5, wherein the acid is selected from concentrated hydrochloric acid; 2) In step i), the reaction is carried out in a mixed solution, wherein the mixed solvent is a mixture of ethanol and ethyl acetate; wherein the volume ratio of ethanol to ethyl acetate is 1:(1-2); 3) In step i), the reaction temperature is 50-80℃; 4) In step i), after the reaction is completed, the reaction solution is concentrated, and the crude product of compound 5 is directly fed into the next reaction step; 5) In step ii), compound 5 reacts with acetic anhydride to give compound 6; 6) In step ii), the molar ratio of compound 5 to acetic anhydride is 1:1.5; 7) In step ii), the reaction solvent is dichloromethane; 8) In step iii), compound 6 undergoes cyclization in the presence of phosphorus oxychloride to give compound 7; 9) In step iii), the molar ratio of compound 6 to phosphorus oxychloride is 1:(5-15); 10) In step iii), the reaction temperature is 40-60℃; 11) In step iii), the reaction solvent is selected from at least one of tetrahydrofuran, acetonitrile, dimethyl ether, and 1,4-dioxane; 12) In step iv), compound 7 is deacetylated under alkaline conditions to give compound 8; the base is selected from sodium hydroxide.
11. The method of claim 10, wherein in step iii), the molar ratio of compound 6 to phosphorus oxychloride is 1:
15.
12. The method of claim 10, wherein in step iii), the reaction solvent is tetrahydrofuran.
13. The method of claim 10, wherein in step iii), the reaction is carried out under alkaline conditions, wherein the base is selected from at least one of pyridine and triethylamine.