Preparation method of 4-chloro-6, 7-dihydro-5H-cyclopenta [B] pyridine-7-ol

Abstract

The invention provides a preparation method of 4-chloro-6, 7-dihydro-5H-cyclopenta [B] pyridine-7-alcohol, and relates to the technical field of organic synthesis. A compound 1 and first m-chloroperoxybenzoic acid are subjected to a first oxidation reaction to obtain a compound 2 crude product, the compound 2 crude product and acid anhydride are directly subjected to a Boekelhede reaction to obtain a compound 3, the water solubility of the compound 3 is poor, the compound 3 is easily separated from a water-soluble byproduct m-chlorobenzoic acid, and a large amount of loss of the compound 3 in the subsequent separation process cannot be caused; the yield of the compound 3 is improved; and carrying out a second oxidation reaction on the compound 3 and second m-chloroperoxybenzoic acid, carrying out a chlorination reaction on the obtained compound 4 and phosphorus oxychloride, and carrying out a hydrolysis reaction on the obtained compound 5 to obtain the 4-chloro-6, 7-dihydro-5H-cyclopenta [B] pyridine-7-ol. According to the preparation method provided by the invention, the total yield of the 4-chloro-6, 7-dihydro-5H-cyclopenta [B] pyridine-7-alcohol is high.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol. Background Art

[0002] p53 is a tumor suppressor protein that plays a key role in regulating the balance between cell proliferation and cell growth arrest / apoptosis. Under normal conditions, the half-life of p53 is very short, so the level of p53 in cells is very low. When cellular DNA damage or cellular stress (such as oncogene activation, telomere erosion, hypoxia) occurs, p53 levels increase. Increased p53 levels lead to the activation of transcription of many genes, driving cells into growth arrest or apoptosis. Therefore, an important function of p53 is to prevent the uncontrolled proliferation of damaged cells, thereby protecting the body from the development of cancer.

[0003] MDM2 is a key negative regulator of p53 function. By binding to the amino-terminal transactivation domain of p53, it forms a negative autoregulatory loop, thereby enabling MDM2 to both inhibit p53-activated transcription and target p53 for proteolytic degradation. Under normal circumstances, this regulatory loop is responsible for maintaining low levels of p53. However, in tumors with wild-type p53, the equilibrium concentration of active p53 can be increased through an antagonistic interaction between MDM2 and p53, leading to the restoration of the pro-apoptotic and anti-proliferative effects of p53 in such tumor cells.

[0004] MDM2-p53 antagonists can be used for the treatment or prevention of mammals, in particular bradykinin B1 receptor (BDKRB1 or B1R) antagonists or inverse agonist intermediates, for the treatment or prevention of glomerulonephritis, Henoch-Schönlein purpura nephropathy (HSPN), ANCA-associated crescentic nephritis, lupus nephritis and IgA nephritis.

[0005] 4-Chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol is an important intermediate for the preparation of MDM2-p53 antagonists. Its preparation route is as follows:

[0006]

[0007] However, during the first oxidation reaction of the above preparation method, a water-soluble byproduct, m-chlorobenzoic acid, is produced. If the m-chlorobenzoic acid is not purified and removed, the remaining m-chlorobenzoic acid will undergo competitive side reactions, greatly reducing the overall yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol (6). Summary of the Invention

[0008] In view of this, the present invention aims to provide a method for preparing 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol. In the preparation method provided by the present invention, the crude compound 2 obtained by a first oxidation reaction of compound 1 with a first m-chloroperbenzoic acid does not require purification to remove m-chlorobenzoic acid and can be directly used in subsequent reactions. Furthermore, the overall yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol is high.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] The present invention provides a method for preparing 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol, comprising the following steps:

[0011] Compound 1 and a first m-chloroperbenzoic acid are subjected to a first oxidation reaction to obtain a crude compound 2;

[0012] The crude compound 2 is subjected to a Boekelheide reaction with an acid anhydride to obtain compound 3; the acid anhydride includes acetic anhydride, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;

[0013] The compound 3 is subjected to a second oxidation reaction with a second m-chloroperbenzoic acid to obtain compound 4;

[0014] The compound 4 is subjected to a chlorination reaction with phosphorus oxychloride under a protective atmosphere to obtain compound 5;

[0015] The compound 5 is subjected to a hydrolysis reaction to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol;

[0016]

[0017] Wherein, R includes -COOCH3, -COOCF3 or -SO3CF3.

[0018] Preferably, the molar ratio of the compound 1 to the first m-chloroperbenzoic acid is 1:1 to 1.5.

[0019] Preferably, the first oxidation reaction is carried out under the conditions of a first polar solvent, wherein the first polar solvent comprises one or more of an ester solvent, an ether solvent and a chloroalkane solvent;

[0020] The temperature of the first oxidation reaction is 15-30° C., and the time is 5-15 hours.

[0021] Preferably, the molar ratio of compound 2 to acid anhydride in the crude compound 2 is 1:1.5-15.

[0022] Preferably, the Boekelheide reaction is carried out in the absence of a solvent or in the presence of a second polar solvent, wherein the second polar solvent comprises one or more of an ester solvent, an ether solvent and a chloroalkane solvent;

[0023] The temperature of the Boekelheide reaction is 20 to 110° C., and the time is 2 to 12 hours.

[0024] Preferably, the molar ratio of the compound 3 to the second m-chloroperbenzoic acid is 1:1 to 1.5.

[0025] Preferably, the second oxidation reaction is carried out under the conditions of a third polar solvent, wherein the third polar solvent comprises one or more of an ester solvent, an ether solvent and a chloroalkane solvent;

[0026] The temperature of the second oxidation reaction is 15 to 30° C., and the time is 8 to 15 hours.

[0027] Preferably, the molar ratio of compound 4 to phosphorus oxychloride is 1:10-40.

[0028] Preferably, the chlorination reaction is carried out under reflux conditions, and the chlorination reaction time is 1.5 to 3 hours.

[0029] Preferably, the hydrolysis reaction is carried out under alkaline conditions, the temperature of the hydrolysis reaction is 15 to 30° C., and the time is 12 to 48 hours.

[0030] The preparation method provided by the present invention uses compound 1 as the initial raw material, sequentially undergoes a first oxidation reaction with a first m-chloroperbenzoic acid to obtain a crude compound 2, then undergoes a Boekelheide reaction with an acid anhydride to obtain compound 3, then undergoes a second oxidation reaction with a second m-chloroperbenzoic acid, then undergoes a chlorination reaction with phosphorus oxychloride, and finally undergoes a hydrolysis reaction. Compared with existing preparation methods, the present invention reverses the order of the second and fourth steps. The byproduct m-chlorobenzoic acid produced during the first oxidation reaction does not react with the acid anhydride, so that the crude compound 2 does not need to be purified to remove the byproduct m-chlorobenzoic acid, and can directly undergo a Boekelheide reaction with the acid anhydride, thereby avoiding the loss of the crude compound 2 during the purification process and improving the overall yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol. Moreover, the crude compound 2 is directly subjected to the Boekelheide reaction with anhydride, the yield of this step reaction is high, and the water solubility of the obtained compound 3 is poor, and it is easy to separate from the water-soluble byproduct m-chlorobenzoic acid, and it will not cause a large amount of loss of compound 3 in the subsequent separation process, thereby improving the yield of compound 3 and the total yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol. The preparation method provided by the present invention adopts a specific reaction sequence, and the total yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol is high. As shown in the test results of the embodiment, the total yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol in the preparation method provided by the present invention is 55.1~64.0%, and the total yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the hydrogen spectrum of compound 2 prepared in Example 1;

[0032] Figure 2 This is the hydrogen spectrum of compound 5 prepared in Example 1;

[0033] Figure 3 This is the hydrogen spectrum of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol prepared in Example 1. DETAILED DESCRIPTION

[0034] The present invention provides a method for preparing 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol, comprising the following steps:

[0035] Compound 1 and a first m-chloroperbenzoic acid are subjected to a first oxidation reaction to obtain a crude compound 2;

[0036] The crude compound 2 is subjected to a Boekelheide reaction with an acid anhydride to obtain compound 3; the acid anhydride includes acetic anhydride, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;

[0037] The compound 3 is subjected to a second oxidation reaction with a second m-chloroperbenzoic acid to obtain compound 4;

[0038] The compound 4 is subjected to a chlorination reaction with phosphorus oxychloride under a protective atmosphere to obtain compound 5;

[0039] The compound 5 is subjected to a hydrolysis reaction to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol;

[0040]

[0041] Wherein, R includes -COOCH3, -COOCF3 or -SO3CF3(-Tf).

[0042] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0043] In the present invention, compound 1 and a first m-chloroperbenzoic acid are subjected to a first oxidation reaction to obtain a crude compound 2.

[0044] In the present invention, the molar ratio of the compound 1 to the first m-chloroperbenzoic acid is preferably 1:1 to 1.5, and in specific embodiments, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5. In the present invention, the compound 1 is preferably added in batches or all at once. When added in batches, the addition time of the compound 1 is preferably 1 to 3 hours, and in specific embodiments, it can be 1 hour, 2 hours, or 3 hours. The temperature of the system during batch addition is preferably 15 to 30°C, and in specific embodiments, it can be 15°C, 20°C, 25°C, or 30°C.

[0045] In the present invention, the first oxidation reaction is preferably carried out under the conditions of a first polar solvent. Specifically, compound 1, a first m-chloroperbenzoic acid and a first polar solvent are mixed to carry out the first oxidation reaction.

[0046] In the present invention, the first polar solvent preferably includes one or more of an ester solvent, an ether solvent, and a chloroalkane solvent; the ester solvent preferably includes ethyl acetate; the ether solvent preferably includes ethylene glycol dimethyl ether; and the chloroalkane solvent preferably includes dichloromethane and / or chloroform. In the present invention, the ratio of the amount of compound 1 to the volume of the first polar solvent is preferably 1 mol:1 to 5 L, and in specific embodiments, it can be 1 mol:1 L, 1 mol:2 L, 1 mol:2.4 L, 1 mol:3 L, 1 mol:4 L, or 1 mol:5 L.

[0047] In the present invention, the temperature of the first oxidation reaction is preferably 15-30°C, and in specific embodiments it can be 15°C, 20°C, 25°C or 30°C; the time of the first oxidation reaction is preferably 5-15h, and in specific embodiments it can be 5h, 8h, 10h, 12h or 15h.

[0048] After completing the first oxidation reaction, the present invention preferably further comprises: cooling the reaction liquid obtained by the first oxidation reaction, separating the solid and the liquid, washing the obtained solid component and then drying it to obtain a crude compound 2. In the present invention, the temperature of the cooled reaction liquid is preferably 5 to 10°C, and in specific embodiments, it can be 5°C, 8°C or 10°C. The present invention has no special restrictions on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as filtration, suction filtration or centrifugation. In the present invention, the washing is preferably carried out using a first cold solvent, and the optional type of the first cold solvent is preferably the same as the first polar solvent, which will not be repeated here; the temperature of the first cold solvent is preferably 5 to 15°C, and in specific embodiments, it can be 5°C, 8°C, 10°C, 12°C or 15°C. In the present invention, the crude compound 2 preferably includes compound 2 and m-chlorobenzoic acid, and the crude compound 2 is directly subjected to the subsequent Boekelheide reaction without purification. In the present invention, the drying temperature is preferably 25-50°C, and in specific embodiments can be 25°C, 30°C, 40°C or 50°C; the present invention has no special limitation on the drying time, and the drying time can be until constant weight.

[0049] In the present invention, the by-product m-chlorobenzoic acid produced during the first oxidation reaction does not react with the acid anhydride, so that the crude compound 2 does not need to be purified to remove the by-product m-chlorobenzoic acid, and can directly undergo a Boekelheide reaction with the acid anhydride, thereby avoiding the loss of compound 2 during the purification process and improving the overall yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol.

[0050] After obtaining the crude compound 2, the present invention conducts a Boekelheide reaction between the crude compound 2 and an acid anhydride to obtain compound 3; the acid anhydride includes acetic anhydride, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride.

[0051] In the present invention, the molar ratio of compound 2 to acid anhydride in the crude compound 2 is preferably 1:1.5-15, and in specific embodiments can be 1:1.5, 1:1.8, 1:2, 1:4, 1:5, 1:8, 1:10, 1:12 or 1:15.

[0052] In the present invention, the Boekelheide reaction is preferably carried out in the absence of a solvent or in a second polar solvent. In the present invention, when the acid anhydride is acetic anhydride or trifluoroacetic anhydride, the Boekelheide reaction is preferably carried out in the absence of a solvent. In the present invention, when the acid anhydride is trifluoromethanesulfonic anhydride, the Boekelheide reaction is preferably carried out in the presence of a second polar solvent. Specifically, the crude compound 2, the acid anhydride and the second polar solvent are mixed to carry out the Boekelheide reaction. In the present invention, the second polar solvent preferably includes one or more of an ester solvent, an ether solvent and a chloroalkane solvent; the ester solvent preferably includes ethyl acetate; the ether solvent preferably includes ethylene glycol dimethyl ether; the chloroalkane solvent preferably includes dichloromethane and / or chloroform. In the present invention, the ratio of the amount of compound 2 in the crude compound 2 to the volume of the second polar solvent is preferably 1 mol: 1 to 5 L, and in specific embodiments it can be 1 mol: 1 L, 1 mol: 2 L, 1 mol: 2.4 L, 1 mol: 3 L, 1 mol: 4 L or 1 mol: 5 L.

[0053] In the present invention, the temperature of the Boekelheide reaction is preferably 20-110°C, and in specific embodiments, it can be 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 95°C, 100°C, 105°C, or 110°C; the time of the Boekelheide reaction is preferably 2-12 hours, and in specific embodiments, it can be 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In the present invention, when the acid anhydride is acetic anhydride or trifluoroacetic anhydride, the temperature of the Boekelheide reaction is more preferably 90-110°C, and the time is more preferably 2-4 hours; when the acid anhydride is trifluoromethanesulfonic anhydride, the temperature of the Boekelheide reaction is more preferably 20-30°C, and the time is more preferably 5-12 hours.

[0054] When the Boekelheide reaction is carried out under solvent-free conditions, after the Boekelheide reaction is completed, the present invention preferably further comprises: stirring and mixing the reaction solution obtained from the Boekelheide reaction with ethanol, concentrating, mixing the residue with ice water, extracting with ethyl acetate, washing the obtained organic phase with saturated brine, drying with a desiccant, and solid-liquid separation, and distilling the obtained liquid component under reduced pressure to obtain compound 3. In the present invention, the ethanol is preferably added dropwise; the ratio of the amount of compound 2 to the volume of ethanol is preferably 1 mol:0.5-1 L, and in specific embodiments can be 1 mol:0.5 L, 1 mol:0.6 L, 1 mol:0.7 L, 1 mol:0.8 L, 1 mol:0.9 L, or 1 mol:1 L. In the present invention, the stirring and mixing temperature is preferably ≤ 60°C, more preferably 50-60°C, and in specific embodiments, it can be 50°C, 55°C, or 60°C; the stirring and mixing time is preferably 0.5-1.5 hours, and in specific embodiments, it can be 0.5 hours, 1 hour, or 1.5 hours; the stirring and mixing time is counted from the completion of the addition of ethanol. In the present invention, the concentration preferably includes reduced pressure concentration, and the concentration temperature is preferably 50-60°C, and in specific embodiments, it can be 50°C, 55°C, or 60°C; the reduced pressure concentration pressure is preferably 0.1-0.5 Torr, and in specific embodiments, it can be 0.1 Torr, 0.2 Torr, 0.3 Torr, 0.4 Torr, or 0.5 Torr. In the present invention, the ratio of the amount of compound 2 to the volume of ice water is preferably 1 mol:0.5-1 L, and in specific embodiments, it can be 1 mol:0.5 L, 1 mol:0.6 L, 1 mol:0.7 L, 1 mol:0.8 L, 1 mol:0.9 L, or 1 mol:1 L. In the present invention, the desiccant preferably includes anhydrous sodium sulfate and / or anhydrous magnesium sulfate. In the present invention, the number of ethyl acetate extractions is preferably 2-4 times, and in specific embodiments, it can be 2 times, 3 times, or 4 times. The present invention has no particular limitation on the solid-liquid separation, and any solid-liquid separation method familiar to those skilled in the art can be used, such as filtration, suction filtration, or centrifugation. In the present invention, the temperature of the reduced pressure distillation is preferably 95-115°C, and in specific embodiments it can be 95°C, 100°C, 105°C, 110°C or 115°C; the pressure of the reduced pressure distillation is preferably 0.1-0.5 torr, and in specific embodiments it can be 0.1 torr, 0.2 torr, 0.3 torr, 0.4 torr or 0.5 torr; during the reduced pressure distillation process, a fraction at 92-95°C is collected to obtain compound 3.

[0055] When the Boekelheide reaction is carried out under the conditions of a second polar solvent, after the Boekelheide reaction is completed, the present invention preferably further comprises: adjusting the pH of the reaction solution obtained from the Boekelheide reaction to 9-11 using an alkaline aqueous solution, separating the phases to obtain an organic phase and an aqueous phase; extracting the aqueous phase with ethyl acetate to obtain an ethyl acetate phase; combining the organic phase and the ethyl acetate phase, drying with a desiccant, performing solid-liquid separation, and concentrating the resulting liquid component to obtain compound 3, which is directly subjected to subsequent reactions without purification. In the present invention, the alkaline aqueous solution preferably comprises a saturated alkaline aqueous solution, and the alkaline agent in the alkaline aqueous solution preferably comprises an alkali metal bicarbonate and / or an alkali metal carbonate, which in specific embodiments can be one or more of Na2HCO3, K2HCO3, Na2CO3, and K2CO3. In specific embodiments of the present invention, the pH value can be 9, 9.5, 10, 10.5, or 11. In the present invention, the desiccant preferably comprises anhydrous sodium sulfate and / or anhydrous magnesium sulfate. In the present invention, the number of ethyl acetate extractions is preferably 2 to 4 times, and in specific embodiments, can be 2, 3, or 4 times. The present invention has no particular limitations on the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be employed, such as filtration, suction filtration, or centrifugation. The present invention has no particular limitations on the concentration, and any concentration method known to those skilled in the art can be employed to completely remove the solvent.

[0056] In the present invention, the crude compound 2 is directly subjected to a Boekelheide reaction with an acid anhydride. The yield of this reaction step is high, and the obtained compound 3 has poor water solubility. Compound 3 is easily separated from the water-soluble by-product m-chlorobenzoic acid, and no large amount of compound 3 is lost in the subsequent separation process. This improves the yield of compound 3 and the total yield of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol.

[0057] After obtaining compound 3, the present invention performs a second oxidation reaction on compound 3 and a second m-chloroperbenzoic acid to obtain compound 4.

[0058] In the present invention, the molar ratio of the compound 3 to the second meta-chloroperbenzoic acid is preferably 1:1 to 1.5, and in specific embodiments, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5. In the present invention, the second meta-chloroperbenzoic acid is preferably added in batches or all at once. When added in batches, the addition time of the second meta-chloroperbenzoic acid is preferably 1 to 3 hours, and in specific embodiments, it can be 1 hour, 2 hours or 3 hours. When added in batches, the temperature of the system is preferably ≤25°C, more preferably 15 to 25°C, and in specific embodiments, it can be 15°C, 20°C or 25°C.

[0059] In the present invention, the second oxidation reaction is preferably: compound 3, a second m-chloroperbenzoic acid and a third polar solvent are mixed to perform the second oxidation reaction.

[0060] In the present invention, the third polar solvent preferably includes one or more of an ester solvent, an ether solvent, and a chloroalkane solvent; the ester solvent preferably includes ethyl acetate; the ether solvent preferably includes ethylene glycol dimethyl ether; and the chloroalkane solvent preferably includes dichloromethane and / or chloroform. In the present invention, the ratio of the amount of compound 3 to the volume of the third polar solvent is preferably 1 mol:1 to 5 L, and in specific embodiments, it can be 1 mol:1 L, 1 mol:1.4 L, 1 mol:2 L, 1 mol:2.1 L, 1 mol:3 L, 1 mol:4 L, or 1 mol:5 L.

[0061] In the present invention, the temperature of the second oxidation reaction is preferably 15-30°C, and in specific embodiments it can be 15°C, 20°C, 25°C or 30°C; the time of the second oxidation reaction is preferably 8-15h, and in specific embodiments it can be 8h, 9h, 10h, 11h, 12h, 13h, 14h or 15h.

[0062] After completing the second oxidation reaction, the present invention preferably further comprises: cooling the reaction solution obtained from the second oxidation reaction to 2-8°C, adjusting the pH to 10-11 using an alkaline aqueous solution, separating the phases to obtain an organic phase and an aqueous phase; extracting the aqueous phase with ethyl acetate to obtain an ethyl acetate phase; combining the organic phase and the ethyl acetate phase, drying with a desiccant, performing solid-liquid separation, and concentrating the resulting liquid component to obtain Compound 4. In the present invention, the alkaline aqueous solution preferably comprises a saturated alkaline aqueous solution, and the alkaline agent in the alkaline aqueous solution preferably comprises an alkali metal bicarbonate and / or an alkali metal carbonate, and in specific embodiments, may be one or more of Na2HCO3, K2HCO3, Na2CO3, and K2CO3. In specific embodiments of the present invention, the pH may be 10, 10.5, or 11. In the present invention, the desiccant preferably comprises anhydrous sodium sulfate and / or anhydrous magnesium sulfate. In the present invention, the ethyl acetate extraction is preferably performed 2-4 times, and in specific embodiments, may be performed 2, 3, or 4 times. The present invention has no particular limitation on the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art may be used, such as filtration, suction filtration, or centrifugation. The present invention has no particular limitation on the concentration, and any concentration method known to those skilled in the art may be used to completely remove the solvent.

[0063] After obtaining compound 4, the present invention conducts a chlorination reaction between compound 4 and phosphorus oxychloride under a protective atmosphere to obtain compound 5.

[0064] In the present invention, the molar ratio of compound 4 to phosphorus oxychloride is preferably 1:10-40, and in specific embodiments can be 1:10, 1:15, 1:20, 1:24.6, 1:25, 1:28.7, 1:30, 1:35 or 1:40.

[0065] In the present invention, the chlorination reaction is preferably carried out under reflux conditions, and the chlorination reaction time is preferably 1.5 to 3 hours, and in specific embodiments it can be 1.5 hours, 2 hours, 2.5 hours or 3 hours.

[0066] After the chlorination reaction is completed, the present invention preferably further comprises: concentrating the reaction solution obtained from the chlorination reaction until no liquid flows out, mixing the residue with ice water, cooling to ≤10°C, adjusting the pH to 9-11 with an alkaline aqueous solution, stirring, and extracting with ethyl acetate to obtain an aqueous phase and an organic phase, respectively; extracting the aqueous phase with ethyl acetate to obtain an ethyl acetate phase; combining the organic and ethyl acetate phases, washing with water, washing with saturated brine, drying with a desiccant, separating the solid and the liquid, and distilling the resulting liquid component under reduced pressure to obtain compound 5. In the present invention, before concentrating until no liquid flows out, the reaction solution is preferably cooled to 35-45°C. In specific embodiments, the reaction solution can be cooled to 35°C, 40°C, or 45°C. In the present invention, the ratio of the amount of compound 4 to the volume of ice water is preferably 1 mol:1-5L. In specific embodiments, the ratio can be 1 mol:1L, 1 mol:2L, 1 mol:3L, 1 mol:4L, or 1 mol:5L. In the present invention, the alkaline agent in the alkaline aqueous solution preferably comprises an alkali metal hydroxide and / or an alkali metal carbonate, and in specific embodiments, it may be one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. The mass concentration of the alkaline aqueous solution is preferably 10-50%, and in specific embodiments, it may be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. The alkaline aqueous solution is preferably added dropwise. The system temperature during addition of the alkaline aqueous solution is preferably ≤ 10°C. By controlling the system temperature during addition of the alkaline solution, the present invention prevents side reactions caused by temperature increases. In specific embodiments of the present invention, the pH value may be 9, 9.5, 10, 10.5, or 11. In the present invention, the stirring time is preferably 15-30 minutes, and in specific embodiments, it may be 15 minutes, 20 minutes, 25 minutes, or 30 minutes. In the present invention, the first ethyl acetate extraction is preferably performed once, and the second ethyl acetate extraction is preferably performed 2-4 times, and in specific embodiments, it may be 2, 3, or 4 times. In the present invention, the desiccant preferably includes anhydrous sodium sulfate and / or anhydrous magnesium sulfate. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be used to completely remove the solvent. In the present invention, the temperature of the vacuum distillation is preferably 90-110°C, and in specific embodiments it can be 90°C, 95°C, 100°C, 105°C, or 110°C; the pressure of the vacuum distillation is preferably 0.1-0.5 torr, and in specific embodiments it can be 0.1 torr, 0.2 torr, 0.3 torr, 0.4 torr or 0.5 torr; during the vacuum distillation process, a fraction at 80-84°C is collected to obtain compound 5.

[0067] After obtaining compound 5, the present invention performs a hydrolysis reaction on the compound 5 to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol.

[0068] In the present invention, the hydrolysis reaction is preferably carried out under alkaline conditions. The alkaline solution used in the alkaline conditions preferably includes an alkaline reagent and a solvent. The alkaline reagent preferably includes one or more of ammonia, alkali metal carbonates and alkali metal hydroxides, and in specific embodiments, it can be one or more of ammonia, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide. The solvent preferably includes a lower alcohol and / or water, and the lower alcohol preferably includes methanol and / or ethanol. The concentration of the alkaline solution is preferably 4-7 mol / L, and in specific embodiments, it can be 4 mol / L, 4.5 mol / L, 6 mol / L, 6.5 mol / L or 7 mol / L.

[0069] In the present invention, when the solvent in the alkali solution is water, the hydrolysis reaction is preferably carried out in a fourth polar solvent, wherein the fourth polar solvent preferably includes one or more of an ester solvent, an ether solvent, and a chloroalkane solvent; the ester solvent preferably includes ethyl acetate; the ether solvent preferably includes ethylene glycol dimethyl ether; and the chloroalkane solvent preferably includes dichloromethane and / or chloroform. In the present invention, the ratio of the amount of compound 5 to the volume of the fourth polar solvent is preferably 1 mol:1 to 5 L, and in specific embodiments, it can be 1 mol:1 L, 1 mol:1.5 L, 1 mol:2 L, 1 mol:2.5 L, 1 mol:3 L, 1 mol:4 L, 1 mol:4.3 L, or 1 mol:5 L.

[0070] In the present invention, the molar ratio of the compound 5 to the alkaline agent is preferably 1:1.5 to 6.5, and in specific embodiments can be 1:1.5, 1:1.7, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.2 or 1:6.5.

[0071] In the present invention, the temperature of the hydrolysis reaction is preferably 15-30°C, and in specific embodiments it can be 15°C, 20°C, 25°C or 30°C; the time of the hydrolysis reaction is preferably 12-48h, and in specific embodiments it can be 12h, 15h, 20h, 25h, 30h, 35h, 40h, 45h or 48h.

[0072] When the solvent in the alkali solution is a lower alcohol, after the hydrolysis reaction is completed, the present invention preferably further comprises: concentrating the reaction solution obtained from the hydrolysis reaction to remove the solvent, performing a third ethyl acetate extraction to obtain an organic phase and an aqueous phase, respectively; performing a fourth ethyl acetate extraction on the aqueous phase to obtain an ethyl acetate phase; combining the organic and ethyl acetate phases, washing with saturated brine, drying with a desiccant, performing solid-liquid separation, concentrating the resulting liquid component to dryness, mixing the resulting concentrated residue with methyl tert-butyl ether, performing solid-liquid separation to obtain a solid component and a liquid component, respectively; eluting the solid component with methyl tert-butyl ether to obtain an eluate; combining the liquid component and the eluate and drying to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol. In the present invention, the third ethyl acetate extraction is preferably performed once; the fourth ethyl acetate extraction is preferably performed 2 to 4 times, and in specific embodiments, can be performed 2, 3, or 4 times. In the present invention, the desiccant preferably comprises anhydrous sodium sulfate and / or anhydrous magnesium sulfate. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation. The present invention has no special limitation on the two concentrations, and a concentration method well known to those skilled in the art can be used to completely remove the solvent. In the present invention, the stirring and mixing time is preferably 20 to 50 minutes, and in specific embodiments it can be 20 minutes, 30 minutes, 40 minutes or 50 minutes. In the present invention, the drying preferably includes drying under reduced pressure; the drying temperature is preferably 35 to 55°C, and in specific embodiments it can be 35°C, 40°C, 45°C, 50°C or 55°C; the drying pressure is preferably 0.1 torr to 0.5 torr, and in specific embodiments it can be 0.1 torr, 0.2 torr, 0.3 torr, 0.4 torr or 0.5 torr; the present invention has no special limitation on the drying time, and it can be dried to constant weight.

[0073] When the solvent in the alkali solution is a lower alcohol, after the hydrolysis reaction is completed, the present invention preferably further comprises: separating the reaction solution obtained from the hydrolysis reaction to obtain an aqueous phase and an organic phase; extracting the aqueous phase with ethyl acetate to obtain an ethyl acetate phase; combining the organic phase and the ethyl acetate phase, concentrating to remove the solvent, mixing the resulting concentrated residue with methyl tert-butyl ether, and performing solid-liquid separation to obtain a solid component and a liquid component, respectively; eluting the solid component with methyl tert-butyl ether to obtain an eluate; combining the liquid component and the eluate and drying them to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol. In the present invention, the number of ethyl acetate extractions is preferably 2 to 4 times, and in specific embodiments, it can be 2, 3, or 4 times. In the present invention, the stirring and mixing time is preferably 15 to 50 minutes, and in specific embodiments, it can be 15 minutes, 20 minutes, 30 minutes, 40 minutes, or 50 minutes. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as filtration, suction filtration or centrifugal separation. The present invention has no special limitation on the two concentrations, and a concentration method well known to those skilled in the art can be used to completely remove the solvent. In the present invention, the drying preferably includes drying under reduced pressure; the drying temperature is preferably 35 to 55°C, and in specific embodiments it can be 35°C, 40°C, 45°C, 50°C or 55°C; the drying pressure is preferably 0.1 torr to 0.5 torr, and in specific embodiments it can be 0.1 torr, 0.2 torr, 0.3 torr, 0.4 torr or 0.5 torr; the present invention has no special limitation on the drying time, and it can be dried to constant weight.

[0074] To further illustrate the present invention, the preparation method of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol provided by the present invention is described in detail below with reference to the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0075] Example 1

[0076]

[0077] (1) Add 3 L of ethyl acetate, add 224.3 g of m-chloroperbenzoic acid at a temperature of ≤25°C, add 150 g of compound 1 in batches at 25°C, and add the mixture over 2 h. React at 25°C for 8 h, cool to 5°C, filter, and wash the filter cake with cold ethyl acetate at a temperature of ≤15°C. Dry at 40°C to constant weight to obtain a crude compound 2.

[0078] (2) Add 520 g of acetic anhydride and the crude compound 2 obtained in step (1), heat to 100 ° C and keep the reaction for 3 h. The reaction is complete according to TLC. Cool to 50-60 ° C, add 1 L of ethanol dropwise, stir for 1 h, and concentrate under reduced pressure to 50 mL at 50-60 ° C. Then pour into 1 L of ice water and extract with ethyl acetate three times (single amount 500 mL). The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate is distilled under reduced pressure at 108 ° C and 0.3 torr. The fraction at 92-95 ° C is collected to obtain compound 3 (brown liquid, 187.8 g, the total yield of steps (1) to (2) is 84.2%, and the purity is 98.6%).

[0079] (3) Add 1.0 L of ethyl acetate and 99.2 g of compound 3, add 114 g of m-chloroperbenzoic acid in batches at 10-25 ° C, react at 25 ° C for 10 h, cool to 5 ° C, add saturated sodium carbonate solution to adjust the pH value to 10-11, separate the phases to obtain an organic phase and an aqueous phase respectively; the aqueous phase is extracted with ethyl acetate three times (single amount 300 mL) to obtain an ethyl acetate phase; the organic phase and the ethyl acetate phase are combined, washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate is decompressed to remove the solvent at 40 ° C and 0.3 torr, and dried at 40 ° C to constant weight to obtain compound 4 (102.8 g, yield 95%, purity 98.8%).

[0080] (4) Under nitrogen protection, 0.90 L of phosphorus oxychloride and 65 g of compound 4 were added, the temperature was raised to reflux, the reaction was continued for 2 h, the temperature was lowered to 40°C, and the mixture was concentrated until no liquid was discharged. The residue was poured into 1 kg of ice and stirred rapidly, the temperature was controlled at ≤10°C, 10 wt% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 9, the mixture was stirred for 20 min, and the mixture was extracted once with 1 L of ethyl acetate to obtain an organic phase and an aqueous phase respectively; the aqueous phase was extracted three times with ethyl acetate (each time using 500 mL) to obtain an ethyl acetate phase; the organic phase and the ethyl acetate phase were combined, washed once with 500 mL of water and once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated at 40°C to remove the solvent to obtain a brown liquid. The mixture was then distilled under reduced pressure at 90°C and 0.15 torr (collecting the 80-84°C fraction) to obtain compound 5 (light brown liquid, 62.8 g, yield 88.2%, purity 99.3%).

[0081] (5) Add 200 mL of a 6 mol / L methanol solution of ammonia and 20.5 g of compound 5, seal the reaction mixture and react at 25 ° C for 48 h, concentrate under reduced pressure to remove the solvent, add 100 mL of ethyl acetate and extract once to obtain an organic phase and an aqueous phase respectively; the aqueous phase is extracted with ethyl acetate three times (single amount 100 mL) to obtain an ethyl acetate phase; the organic phase and the ethyl acetate phase are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered; the filtrate is concentrated at 40 ° C and 0.3 torr, 100 mL of methyl tert-butyl ether is added and stirred for 30 min, and filtered to obtain a filtrate and a filter cake respectively; the filter cake is rinsed with 20 mL of methyl tert-butyl ether to obtain an eluent; the filtrate and the eluent are combined and dried under reduced pressure at 40 ° C and 0.15 torr to constant weight to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol (compound 6, gray solid, 14.9 g, yield 90.7%, purity 98.4%).

[0082] Figure 1 This is the hydrogen spectrum of compound 2 prepared in Example 1, Figure 2 is the hydrogen spectrum of compound 5 prepared in Example 1, Figure 3 This is the hydrogen spectrum of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol prepared in Example 1. It can be seen that the present invention successfully prepared 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol.

[0083] Example 2

[0084]

[0085] (1) Dissolve 250 g of compound 1 in 5 L of dichloromethane, add 400 g of m-chlorobenzoic acid, stir and react at room temperature for 15 h, cool to 10°C, filter, wash the filter cake with cold ethyl acetate at 10°C, and dry at 40°C to constant weight to obtain crude compound 2.

[0086] (2) The crude compound 2 obtained in step (1) was dissolved in 5 L of dichloromethane, and 1.06 kg of trifluoromethanesulfonic anhydride was added dropwise at 0 ° C. within 20 min. The mixture was reacted for 8 h at room temperature under stirring. A saturated aqueous solution of NaHCO3 was added to adjust the pH to 9. The phases were separated to obtain an organic phase and an aqueous phase, respectively. The aqueous phase was extracted with ethyl acetate three times (single amount 300 mL) to obtain an ethyl acetate phase. The organic phase and the ethyl acetate phase were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was decompressed and the solvent was removed at 40 ° C. and 0.15 torr to obtain compound 3 (brown oily substance), which was directly used in subsequent reactions without purification.

[0087] (3) The above compound 3 was dissolved in 5 L of ethyl acetate, 2.1 mol of m-chloroperbenzoic acid was added at a temperature of ≤25°C, the reaction was carried out at 25°C for 8 h, the mixture was cooled to 5°C, a saturated sodium carbonate solution was added to adjust the pH value of the aqueous phase to 10-11, and the phases were separated to obtain an organic phase and an aqueous phase respectively; the aqueous phase was extracted with ethyl acetate three times (single amount 300 mL) to obtain an ethyl acetate phase; the organic phase and the ethyl acetate phase were combined, washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to remove the solvent at 40°C and 0.15 torr, and dried at 35°C to constant weight to obtain compound 4 (420 g, the total yield of steps (1) to (3) was 70.7%, and the purity was 98.3%).

[0088] (4) 800 mL of phosphorus oxychloride was added to 99.1 g of compound 4, and the mixture was refluxed for 3 h. The mixture was concentrated under reduced pressure until no liquid was discharged. The residue was poured into 1.0 kg of ice and stirred. The temperature was controlled at ≤10°C. A 15 wt% sodium hydroxide solution was added dropwise to adjust the pH to 9. The mixture was extracted once with 1 L of ethyl acetate to obtain an organic phase and an aqueous phase; 3 times (single amount 500 mL) to obtain an ethyl acetate phase. The organic phase and the ethyl acetate phase were combined, washed once with 500 mL of water and once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness at 40°C and 0.15 torr to obtain compound 5 (brown oil, which was directly used for the next step without purification).

[0089] (5) Compound 5 was dissolved in 1.5 L of dichloromethane and stirred with 1.5 L of 1 mol / L LiOH aqueous solution at room temperature for 12 h. The phases were separated to obtain an organic phase and an aqueous phase, respectively. The aqueous phase was extracted with ethyl acetate three times (250 mL each time) to obtain an ethyl acetate phase. The organic phase and the ethyl acetate phase were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure at 40°C and 0.15 torr to remove the solvent. 100 mL of methyl tert-butyl ether was added and stirred for 30 min. The mixture was filtered to obtain a methyl tert-butyl ether filtrate and a filter cake, respectively. The filter cake was rinsed with 50 mL of methyl tert-butyl ether to obtain an eluent. The filtrate and the eluent were combined and dried under reduced pressure at 40°C and 0.15 torr to constant weight to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol (compound 6, gray solid, 46.3 g, total yield of steps (4) and (5) was 78%, purity was 98.8%).

[0090] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridine-7-ol, characterized in that: The following steps are involved: Compound 1 and a first m-chloroperbenzoic acid are subjected to a first oxidation reaction to obtain a crude compound 2; The crude compound 2 is subjected to a Boekelheide reaction with an acid anhydride to obtain compound 3; the acid anhydride includes acetic anhydride, trifluoroacetic anhydride or trifluoromethanesulfonic anhydride; The compound 3 is subjected to a second oxidation reaction with a second m-chloroperbenzoic acid to obtain compound 4; The compound 4 is subjected to a chlorination reaction with phosphorus oxychloride under a protective atmosphere to obtain compound 5; The compound 5 is subjected to a hydrolysis reaction to obtain 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol; Wherein, R includes -COOCH3, -COOCF3 or -SO3CF3.

2. The preparation method according to claim 1, characterized in that The molar ratio of the compound 1 to the first m-chloroperbenzoic acid is 1:1 to 1.

5.

3. The preparation method according to claim 1 or 2, characterized in that The first oxidation reaction is carried out under the conditions of a first polar solvent, wherein the first polar solvent comprises one or more of an ester solvent, an ether solvent and a chloroalkane solvent; The temperature of the first oxidation reaction is 15-30° C., and the time is 5-15 hours.

4. The preparation method according to claim 1, characterized in that The molar ratio of compound 2 to acid anhydride in the crude compound 2 is 1:1.5-15.

5. The preparation method according to claim 1 or 4, characterized in that The Boekelheide reaction is carried out in the absence of a solvent or in a second polar solvent, wherein the second polar solvent comprises one or more of an ester solvent, an ether solvent and a chloroalkane solvent; The temperature of the Boekelheide reaction is 20 to 110° C., and the time is 2 to 12 hours.

6. The preparation method according to claim 1, characterized in that The molar ratio of the compound 3 to the second m-chloroperbenzoic acid is 1:1 to 1.

5.

7. The preparation method according to claim 1 or 6, characterized in that The second oxidation reaction is carried out under the condition of a third polar solvent, wherein the third polar solvent includes one or more of an ester solvent, an ether solvent and a chloroalkane solvent; The temperature of the second oxidation reaction is 15 to 30° C., and the time is 8 to 15 hours.

8. The preparation method according to claim 1, characterized in that The molar ratio of the compound 4 to phosphorus oxychloride is 1:10-40.

9. The preparation method according to claim 1 or 8, characterized in that The chlorination reaction is carried out under reflux conditions, and the time of the chlorination reaction is 1.5 to 3 hours.

10. The preparation method according to claim 1, characterized in that The hydrolysis reaction is carried out under alkaline conditions, the temperature of the hydrolysis reaction is 15 to 30° C., and the time is 12 to 48 hours.

Images