A preparation method of an itraconazole intermediate

Abstract

The present invention discloses a preparation method of an itraconazole intermediate, which relates to the technical field of compound preparation; the synthesis method of the itraconazole intermediate includes: providing compound A, using compound B to replace the hydrogen in the N-H group of compound A, and then reacting with compound C containing a halogen substituent to generate compound D, and the compound D is subjected to hydrolysis, decarboxylation, demethylation, and esterification reactions to obtain the itraconazole intermediate. The preparation method of the itraconazole intermediate provided by the present invention has a high yield, high purity of the obtained itraconazole intermediate, low cost, and is easy to promote and use.

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and specifically relates to a preparation method of an etrasimod intermediate. Background Art

[0002] Etrasimod is a sphingosine 1-phosphate receptor modulator. The indications approved by the FDA in 2023 are mainly applicable to adult patients with moderate to severe active ulcerative colitis. In addition, the drug also has potential applications in other inflammation-driven immune system diseases, including Crohn's disease, atopic dermatitis, eosinophilic esophagitis, and alopecia areata. Its chemical structural formula is shown as follows:

[0003]

[0004] And ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate is one of the key intermediates for the preparation of etrasimod, and its chemical structural formula is shown as Formula I below:

[0005]

[0006] Formula I

[0007] Typical preparation methods, such as WO2010 / 11316; Tetrahedron Letters; vol.56; nb.2; (2015); p.378-381, etc., disclose that the preparation method of the compound of Formula I is to react SM1 and SM3 to prepare A1, then condense with SM2 to obtain A2, then hydrolyze to obtain A3, decarboxylate to prepare A4, and finally de-methyl esterify to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The synthetic route is as follows:

[0008] .

[0009] It also discloses a synthetic route in which SM1 and SM3 react to prepare A1, then condense with SM4 to obtain A6, then hydrolyze to obtain A7, decarboxylate to prepare A8, and palladium-carbon debenzylation to prepare A9, and finally esterify under acidic conditions to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The synthetic route is as follows:

[0010] .

[0011] In addition, CN103221391B, CN112955431A, etc. also report similar methods using SM4 condensation and palladium-carbon debenzylation.

[0012] In the synthetic routes of the above-mentioned ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, synthetic routes that maintain the N-H group are adopted, that is, each intermediate in the synthetic route has an active N-H group on the amino group, and the activity of this group is good, but the stability is poor, and it is easy to produce more side reactions during the reaction, resulting in more impurities in the prepared ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, and the impurities formed based on this group are difficult to purify, which is not conducive to industrial production; in addition, the route with benzyl protection uses an expensive metal palladium catalyst during debenzylation protection, with high costs and is not conducive to wide promotion and use.

[0013] Based on this, there is an urgent need for a new preparation method of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate with fewer impurities, high product purity, and lower costs. Summary of the Invention

[0014] The purpose of the present invention is to provide a preparation method of an ezetimibe intermediate. The purity of the ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate prepared by this preparation method can reach more than 99%, and there is no need for an expensive metal catalyst.

[0015] The present invention is achieved through the following technical solutions:

[0016] The present invention provides a preparation method of an ezetimibe intermediate, and the structural formula of the ezetimibe intermediate is:

[0017]

[0018] Formula I

[0019] The synthetic method of the ezetimibe intermediate includes:

[0020] Provide compound A, use compound B to replace the hydrogen in the N-H group of compound A, and then carry out a substitution reaction with compound C containing a halogen substituent to generate compound D. Compound D undergoes hydrolysis, decarboxylation, demethylation, and esterification reactions to obtain the ezetimibe intermediate;

[0021] Among them, the structural formula of compound A is:

[0022]

[0023] The structural formula of compound B is:

[0024] ((CH3)3COCO)2O;

[0025] The structural formula of compound C is:

[0026]

[0027] Wherein, X is a halogen;

[0028] The structural formula of compound D is:

[0029] .

[0030] Further, in some embodiments of the present application, the compound A and the compound B undergo a substitution reaction in the presence of triethylamine, and the molar ratio of the feed of the compound A, the compound B to triethylamine is: 1:(1.00 - 2.00):(1.00 - 3.00);

[0031] The structural formula of the compound M2 formed by the reaction of the compound A and the compound B is:

[0032] .

[0033] Further, in some embodiments of the present application, the compound M2 and the compound C undergo a substitution reaction in the presence of a base, and the molar ratio of the feed of the compound M2, the compound C to the base is: 1:(1.00 - 2.00):(1.50 - 3.00).

[0034] Further, in some embodiments of the present application, the hydrolysis reaction occurs in the presence of a strong base, and the molar ratio of the feed of the compound D to the base is: 1:(2.00 - 6.00);

[0035] The structural formula of the compound M4 formed by the hydrolysis of the compound D is:

[0036] .

[0037] Further, in some embodiments of the present application, the decarboxylation reaction occurs in the presence of a weak acid, and the molar ratio of the feed of the compound M4 to the weak acid is: 1:(20 - 40);

[0038] The structural formula of the compound M5 formed by the decarboxylation of the compound M4 is:

[0039] .

[0040] Further, in some embodiments of the present application, the demethylation reaction occurs in the presence of boron tribromide, and the molar ratio of the feed of the compound M5 to boron tribromide is: 1:(2.00 - 4.00).

[0041] Further, in some embodiments of the present application, the esterification reaction occurs in the presence of absolute ethanol, and the molar ratio of the compound M5 to absolute ethanol in the feed is: 1:(3.00 - 5.00).

[0042] Further, in some embodiments of the present application, the reaction temperature of the substitution reaction between the compound A and the compound B is 5 - 60 °C, and the reaction time is 12 - 24 h; the solvent is at least one of methanol, ethanol, and isopropanol; and / or

[0043] When reacting with the compound C containing a halogen substituent, the reaction temperature is 5 - 80 °C, and the reaction time is 8 - 24 h; the solvent is at least one of acetone, dichloromethane, ethyl acetate, and acetonitrile; and / or

[0044] The reaction temperature of the hydrolysis reaction is 30 - 100 °C, and the reaction time is 12 - 24 h; and / or

[0045] The reaction temperature of the decarboxylation reaction is 30 - 90 °C, and the reaction time is 3 - 12 h; and / or

[0046] The reaction temperatures of the demethylation reaction and the esterification reaction are both -10 - 60 °C; the solvent is one of dichloromethane and acetonitrile.

[0047] Further, in some embodiments of the present application, the compound A is obtained by a ring - closing reaction of ethyl 2 - oxocyclopentanecarboxylate and 4 - methoxyphenylhydrazine hydrochloride in the presence of acetic acid.

[0048] Further, in some embodiments of the present application, the molar ratio of ethyl 2 - oxocyclopentanecarboxylate, 4 - methoxyphenylhydrazine hydrochloride, and acetic acid in the ring - closing reaction is: 1:(0.90 - 1.5):(0.90 - 1.50); and / or

[0049] The reaction temperature is 30 - 90 °C, and the reaction time is 10 - 24 h; the solvent is at least one of methanol, ethanol, isopropanol, and n - butanol.

[0050] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0051] The present invention provides a method for preparing an intermediate of eterimod. By using di-tert-butyl dicarbonate to protect the active N-H group on indole, during the reaction of the intermediate, the N-H group does not participate in the reaction, reducing the side reaction that by-products are difficult to remove caused by the participation of the N-H group in the reaction during the formation of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, and improving the purity of the prepared ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. At the same time, in this preparation route, there is no need to use expensive metal catalysts, and the cost is low, which is convenient for popularization and use. Description of the Drawings

[0052] Figure 1 is the hydrogen spectrum of the eterimod intermediate prepared in Example 1 provided by the present application.

[0053] Figure 2 is the HPLC spectrum of the eterimod intermediate prepared in Example 1 provided by the present application; Detailed Embodiments

[0054] The technical solutions of the present application will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are some, but not all, of the embodiments of the present application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without creative efforts shall fall within the protection scope of the present application.

[0055] Those skilled in the art of the present technology can understand that, unless otherwise defined, all terms (including technical terms and scientific terms) used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present application belongs. It should also be understood that terms such as those defined in a general dictionary should be understood to have a meaning consistent with the meaning in the context of the prior art, and will not be interpreted in an idealized or overly formal sense unless specifically defined as herein.

[0056] Those skilled in the art of the present technology can understand that, unless specifically stated, the singular forms "a", "an", "the" and "said" used herein may also include the plural forms. It should be further understood that the term "comprising" used in the specification of the present application means the presence of the described features, integers, steps, operations, elements and / or components, but does not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or their groups. The phrase "and / or" used herein includes all or any unit and all combinations of one or more related listed items.

[0057] The present invention provides a method for preparing an intermediate of eterimod, and the structural formula of the eterimod intermediate is:

[0058]

[0059] Formula I

[0060] The synthetic method of the etrimoxine intermediate is as follows: providing compound A, substituting the hydrogen in the N-H group of compound A with compound B, and then carrying out a substitution reaction with compound C containing a halogen substituent to generate compound D, and compound D is subjected to hydrolysis, decarboxylation, demethylation, and esterification reactions to obtain the etrimoxine intermediate;

[0061] Among them, the structural formula of compound A is:

[0062]

[0063] Compound B is di-tert-butyl dicarbonate ((Boc)2O)

[0064] The structural formula of compound C is:

[0065]

[0066] Among them, X is a halogen;

[0067] The structural formula of compound D is:

[0068] .

[0069] Exemplarily, the specific synthetic route is:

[0070]

[0071] The specific synthetic method includes the following steps:

[0072] S1. Ethyl 2-oxocyclopentanecarboxylate and 4-methoxyphenylhydrazine hydrochloride are subjected to a ring-closure reaction in the presence of acetic acid to obtain compound A. Among them, the molar ratio of ethyl 2-oxocyclopentanecarboxylate, 4-methoxyphenylhydrazine hydrochloride to acetic acid is: 1: (0.90 - 1.5): (0.90 - 1.50), the solvent is at least one of methanol, ethanol, isopropanol, and n-butanol, the reaction temperature is 30 - 90°C, and the reaction time is 10 - 24h;

[0073] S2. Compound A reacts with compound B ((Boc)2O) in the presence of triethylamine to prepare M2. The molar ratio of compound A, (Boc)2O to triethylamine is: 1: (1.00 - 2.00): (1.00 - 3.00), the solvent is at least one of methanol, ethanol, and isopropanol, the reaction temperature is 5 - 60°C, and the reaction time is 12 - 24h;

[0074] S3. Under alkaline conditions, M2 reacts with compound C (a halogenated compound, such as ethyl 2-haloacetate, where ethyl haloacetate can exemplarily be ethyl bromoacetate or ethyl iodoacetate) to prepare compound D. The molar ratio of M2, compound C, and the base is: 1: (1.00 - 2.00): (1.50 - 3.00). The solvent is at least one of acetone, dichloromethane, ethyl acetate, and acetonitrile. The reaction temperature is 5 - 80 °C, and the reaction time is 8 - 24 h. The base used in the reaction is one of potassium carbonate and sodium carbonate.

[0075] S4. Compound D is hydrolyzed under strongly alkaline conditions to obtain M4. The molar ratio of compound D to the strong base is: 1: 2.00 - 6.00. The reaction temperature is 30 - 100 °C, and the reaction time is 12 - 24 h. The strong base used in the reaction is one of sodium hydroxide and potassium hydroxide.

[0076] S5. M4 undergoes a decarboxylation reaction in the presence of a weak acid to prepare M5. The molar ratio of M4 to the weak acid is: 1: 20 - 40. The reaction temperature is 30 - 90 °C, and the reaction time is 3 - 12 h. Among them, the weak acid can be common weak acids, such as acetic acid and propionic acid.

[0077] S6. M5 undergoes a demethylation reaction in the presence of boron tribromide to form a phenolic hydroxyl group on the indole, and then undergoes an esterification reaction in the presence of absolute ethanol to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The molar ratio of M5, boron tribromide, and absolute ethanol is: 1: (2 - 4.00): (3 - 5.00). The reaction solvent is at least one of dichloromethane and acetonitrile. The reaction temperature is -10 - 60 °C.

[0078] Preferably, in step S1, the reaction temperature is 50 - 60 °C, the reaction time is 16 - 24 h, and the molar ratio of ethyl 2-oxocyclopentanecarboxylate, 4-methoxyphenylhydrazine hydrochloride, and acetic acid is: 1: (1.0 - 1.2): (1.0 - 1.2); to ensure complete reaction of the starting material ethyl 2-oxocyclopentanecarboxylate.

[0079] In step S2, the reaction temperature is 30 - 40 °C, the reaction time is 14 - 18 h, and the molar ratio of compound A, (Boc)2O, and triethylamine is: 1: (1.3 - 1.8): (1.8 - 2.3); to ensure full substitution and complete reaction.

[0080] In step S3, the reaction temperature is 30 - 50 °C, the reaction time is 16 - 24 h, and the molar ratio of M2, compound C, and the base is: 1: (1.3 - 1.7): (1.8 - 2.2); to ensure full substitution.

[0081] The reaction temperature in step S4 is 40 - 60 °C, the reaction time is 20 - 24 h, and the molar ratio of the feed of compound D to the strong base is 1:3.5 - 4.5; to make it hydrolyze completely.

[0082] The reaction temperature in step S5 is 55 - 70 °C, the reaction time is 3 - 5 h, and the molar ratio of the feed of M4 to the weak acid is 1:25 - 30; to make it decarboxylate fully.

[0083] The reaction temperature in step S6 is 0 - 50 °C, the reaction time is 0.5 - 1 h, and the molar ratio of the feed of M5, boron tribromide to absolute ethanol is 1:(2.5 - 3.5):(3.5 - 4.5); to make it demethylate and ethyl esterify fully.

[0084] The present invention directly uses ethyl 2 - oxocyclopentanecarboxylate and 4 - methoxyphenylhydrazine hydrochloride to carry out a ring - closing reaction to prepare compound A, and then reacts with compound B, avoiding the difficult - to - handle situation and low yield in the reaction between ethyl 2 - oxocyclopentanecarboxylate and compound B. Secondly, by carrying out Boc protection on the unstable N - H amino intermediate to obtain a stable intermediate, reducing side reactions and facilitating the separation and purification of the intermediate. That is, using compound A to prepare Boc - protected M2, and reacting Boc - protected M2 with compound C to prepare NH - protected compound D, then hydrolyzing to obtain M4, decarboxylating to obtain M5, and finally demethylating, de - protecting and esterifying to obtain the required intermediate product. This method improves the stability of the intermediate in the whole synthesis process and avoids the influence of the unstable NH amino intermediate on the purification and quality of the whole synthesis process. Thirdly, after Boc protection in the present invention, it is easier to obtain ethyl 2 - (7 - hydroxy - 1,2,3,4 - tetrahydrocyclopenta[b]indol - 3 - yl)acetate, without the need for expensive noble metal catalysts, which is more conducive to industrial production.

[0085] Next, the technical solutions of the present invention will be described clearly and completely in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts belong to the scope of protection of the present invention.

[0086] Among them, absolute ethanol is purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0087] Ethyl 2 - oxocyclopentanecarboxylate is purchased from Wanhua Research Selection (Shanghai) Chemical Co., Ltd., chemical product, 100 g / bag;

[0088] 4 - Methoxyphenylhydrazine hydrochloride is purchased from Wanhua Research Selection (Shanghai) Chemical Co., Ltd.; chemical product, 100 g / bag

[0089] Dichloromethane was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0090] Triethylamine was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0091] Di-tert-butyl dicarbonate was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0092] Potassium carbonate was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 g / bottle;

[0093] Acetone was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0094] Sodium hydroxide was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 g / bottle;

[0095] Hydrochloric acid was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0096] Glacial acetic acid was purchased from Chengdu Kelong Chemical Co., Ltd., analytical pure, 500 ml / bottle;

[0097] Boron tribromide was purchased from Wanghua Research Selection (Shanghai) Chemical Co., Ltd., analytical pure, 200 g / bottle.

[0098] Example 1

[0099] S1: Preparation of Compound A

[0100] Add 7.50 g of ethyl 2-oxocyclopentanecarboxylate, 8.40 g of 4-methoxyphenylhydrazine hydrochloride, 22.50 g of absolute ethanol, and 2.91 g of glacial acetic acid to the reaction vessel; heat up to 50 - 60 °C; keep the reaction under nitrogen protection for 18 hours; when the reaction is complete by TLC, adjust the pH of the reaction solution to neutral with saturated sodium bicarbonate solution and filter, concentrate ethanol under reduced pressure at 45 °C; add 45 mL of ethyl acetate to the residue, stir and filter, separate the layers, wash the organic phase with water, wash with saturated sodium chloride solution, and dry with anhydrous sodium sulfate; filter and concentrate to dryness under reduced pressure at 45 °C; obtain 12 g of a pale yellow liquid, which is Compound A, with a yield of 91.32%.

[0101] S2: Preparation of M2

[0102] Add 12.00 g of Compound A, 120.00 g of dichloromethane, 14.37 g of di-tert-butyl dicarbonate, and 8.87 g of triethylamine to the reaction vessel, react at room temperature for 14 hours, when the reaction is complete by TLC, adjust the pH to neutral, separate the layers, dry, filter, and concentrate to dryness under reduced pressure at 45 °C; obtain 15.60 g of a yellow oil, M2, with a yield of 95.15%.

[0103] S3: Preparation of Compound D

[0104] Add 15.6 g of M2, 10.46 g of Compound C, 11.53 g of potassium carbonate, and 156.00 g of acetone into the reaction vessel, react at room temperature for 24 hours. When the reaction is complete by TLC, filter and concentrate to dryness under reduced pressure at 45 °C; obtain 19.00 g of brown solid, which is Compound D, with a yield of 102.10%.

[0105] S4: Preparation of M4

[0106] Add 19.00 g of Compound D and 76.00 g of absolute ethanol into the reaction vessel, dropwise add 13.64 g of 50% sodium hydroxide at room temperature, heat up to 45 - 50 °C and keep the reaction for 24 hours. When the reaction is complete by TLC, adjust the pH to neutral with hydrochloric acid, concentrate the ethanol to dryness under reduced pressure at 45 °C. Separate the residue with ethyl acetate and water, adjust the pH of the aqueous phase to 3 - 4 with hydrochloric acid, filter to obtain 15.80 g of brown solid M4, with a yield of 95.18%.

[0107] S5: Preparation of M5

[0108] Add 15.80 g of M4 and 63.82 g of glacial acetic acid into the reaction vessel, heat up to 60 - 65 °C, keep the reaction at 60 - 65 °C for 4 hours. When the reaction is complete by TLC, concentrate to dryness under reduced pressure at 60 °C. Wash the residual solid with water and dry it to constant weight under vacuum at 45 °C to obtain 12.00 g of brown solid M5, with a yield of 85.65%.

[0109] S6: Preparation of Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate

[0110] Add 12.00 g of M5 and 36.00 g of dichloromethane into the reaction vessel, cool down to 0 - 10 °C, dropwise add 26.11 g of boron tribromide while controlling the temperature at 0 - 10 °C, keep the reaction at 0 - 10 °C for 1 hour, dropwise add 48.00 g of absolute ethanol while controlling the temperature at 0 - 10 °C. After dropping, heat up to 40 - 45 °C and keep the reaction at 40 - 45 °C for 0.5 h. When the reaction is complete by TLC, adjust the pH to 8 with 40% sodium hydroxide, concentrate the ethanol to dryness under reduced pressure at 45 °C, adjust the pH to 7 with 6N hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium bicarbonate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and recrystallize to obtain 7.58 g of off-white to white solid of Formula I, with a yield of 84.16%.

[0111] Example 2

[0112] S1: Preparation of Compound A

[0113] Add 15.00 g of ethyl 2 - oxocyclopentanecarboxylate, 18.45 g of 4 - methoxyphenylhydrazine hydrochloride, 45.00 g of absolute ethanol, and 6.34 g of glacial acetic acid to the reaction vessel; heat up to 58 °C; keep the reaction under nitrogen protection for 20 hours; when the TLC reaction is complete, adjust the pH of the reaction solution to neutral with saturated sodium bicarbonate solution and filter, concentrate ethanol under reduced pressure at 45 °C; add 90 mL of ethyl acetate to the residue, stir and filter, separate the liquid, wash the organic phase with water, wash with saturated sodium chloride solution, and dry with anhydrous sodium sulfate; filter, concentrate to dryness under reduced pressure at 45 °C; obtain 24.6 g of a pale yellow liquid, which is compound A, with a yield of 93.71%.

[0114] S2: Preparation of M2

[0115] Add 24.00 g of compound A, 240.00 g of dichloromethane, 30.66 g of di - tert - butyl dicarbonate, and 17.80 g of triethylamine to the reaction vessel, react at 35 °C for 16 hours, when the TLC reaction is complete, adjust the pH to neutral, separate the liquid, dry, filter, and concentrate to dryness under reduced pressure at 45 °C; obtain 30.90 g of a yellow oily substance M2, with a yield of 94.24%.

[0116] S3: Preparation of compound D

[0117] Add 30.00 g of M2, 20.12 g of compound C, 22.21 g of potassium carbonate, and 300 g of acetone to the reaction vessel, react at 35 °C for 20 hours, when the TLC reaction is complete, filter, and concentrate to dryness under reduced pressure at 45 °C; obtain 34.21 g of a brown solid, which is compound D, with a yield of 98.93%.

[0118] S4: Preparation of M4

[0119] Add 34.00 g of compound D and 136 g of absolute ethanol to the reaction vessel, drop 25.27 g of 50% sodium hydroxide at room temperature, heat up to 50 °C and keep the reaction for 22 hours, when the TLC reaction is complete, adjust the pH to neutral with hydrochloric acid, concentrate ethanol under reduced pressure at 45 °C, separate the ethyl acetate and water in the residue, adjust the pH of the aqueous phase to 3 with hydrochloric acid and filter to obtain 30.16 g of a brown solid M4, with a yield of 95.18%.

[0120] S5: Preparation of M5

[0121] Add 30.00 g of M4 and 124.91 g of glacial acetic acid to the reaction vessel, heat up to 65 - 70 °C, keep the reaction at 65 - 70 °C for 4.5 hours, when the TLC reaction is complete, concentrate to dryness under reduced pressure at 60 °C, wash the residual solid with water, and dry in vacuo at 45 °C to constant weight to obtain 25.36 g of a brown solid M5, with a yield of 95.30%.

[0122] S6: Preparation of Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate

[0123] Add 25.00 g of M5 and 75.00 g of dichloromethane to the reaction vessel, cool the temperature to -5~5 °C, dropwise add 54.39 g of boron tribromide while controlling the temperature at -5~5 °C, keep the temperature at 0~10 °C for 1 hour for reaction, dropwise add 100.00 g of absolute ethanol while controlling the temperature at 0~10 °C. After dropping, heat up to 40 °C and keep the temperature at 40 °C for 0.5 h. When the reaction is complete by TLC, adjust the pH to 8 with 40% sodium hydroxide, concentrate under reduced pressure at 45 °C to dry the ethanol, adjust the pH to 7 with 6N hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium bicarbonate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and perform recrystallization to obtain 16.70 g of a light yellowish-white to white solid of Formula I, with a yield of 88.97%.

[0124] The product obtained in the above example was detected by 1H NMR (400 MHz, DMSO-d6), and the detection results are as Figure 1 shown. The peaks in its 1H NMR spectrum include:

[0125] 1.20 (t, J = 7.1 Hz, 3H), 2.10 - 2.03 (m, 1H), 2.42 (dd, J = 15.7, 8.9 Hz, 1H), 2.70 - 2.55 (m, 3H), 2.76 (dd, J = 15.7, 5.5 Hz, 1H), 3.48 - 3.42 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 6.49 (dd, J = 8.6, 2.3 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 10.29 (s, 1H).

[0126] It can be seen that the preparation method provided in this application can obtain the intermediate ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, and the yield of this preparation method is high.

[0127] In addition, the applicant also detected the product obtained in the above example by high performance liquid chromatography, and the detection result spectrum is as Figure 2 shown. The results of its HPLC spectrum are shown in Table 1.

[0128] Table 1

[0129]

[0130] From Figure 2It can be seen from the HPLC chromatogram that the purity of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate prepared by the preparation method provided in this application is high, and more than 99% can be obtained.

[0131] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A preparation method of an itraconazole intermediate, characterized in that, The structural formula of the intermediate of etrimoide is as follows: ， Formula I, Characterized in that the synthesis method of the intermediate of etrimoide includes: Providing compound A, replacing the hydrogen in the N-H group of compound A with compound B, and then undergoing a substitution reaction with compound C containing a halogen substituent to generate compound D, and the compound D undergoes hydrolysis, decarboxylation, demethylation, and esterification reactions to obtain the intermediate of etrimoide; Among them, the structural formula of compound A is: ， The structural formula of compound B is: ((CH3)3COCO)2O; The structural formula of compound C is: ， Wherein, X is a halogen; The structural formula of compound D is: 。 2. The preparation method of the itraconazole intermediate according to claim 1, characterized in that, The substitution reaction between compound A and compound B occurs in the presence of triethylamine, and the molar ratio of compound A, compound B, and triethylamine in the feed is: 1:(1.00 - 2.00):(1.00 - 3.00); The structural formula of compound M2 formed by the reaction of compound A and compound B is: 。 3. The preparation method of the itraconazole intermediate according to claim 2, wherein, The substitution reaction between compound M2 and compound C occurs in the presence of a base, and the molar ratio of compound M2, compound C, and the base in the feed is: 1:(1.00 - 2.00):(1.50 - 3.00).

4. The preparation method of the itraconazole intermediate according to claim 1, characterized in that, The hydrolysis reaction occurs in the presence of a strong base, and the molar ratio of compound D to the base in the feed is: 1:(2.00 - 6.00); The structural formula of compound M4 formed by the hydrolysis of compound D is: 。 5. The preparation method of the itraconazole intermediate according to claim 4, characterized in that, The decarboxylation reaction occurs in the presence of a weak acid, and the molar ratio of compound M4 to the weak acid in the feed is: 1:(20 - 40); The structural formula of compound M5 formed by the decarboxylation of compound M4 is: 。 6. The preparation method of the itraconazole intermediate according to claim 5, characterized in that, The demethylation reaction occurs in the presence of boron tribromide, and the molar ratio of compound M5 to boron tribromide in the feed is: 1:(2.00 - 4.00).

7. The preparation method of the itraconazole intermediate according to claim 5, characterized in that, The esterification reaction occurs in the presence of absolute ethanol, and the molar ratio of compound M5 to absolute ethanol in the feed is: 1:(3.00 - 5.00).

8. The preparation method of the etrasimod intermediate according to any one of claims 1 to 7, characterized in that, The reaction temperature of the substitution reaction between compound A and compound B is 5 - 60 °C, and the reaction time is 12 - 24 h; the solvent is at least one of methanol, ethanol, and isopropanol; and / or When undergoing a substitution reaction with compound C containing a halogen substituent, the reaction temperature is 5 - 80 °C, and the reaction time is 8 - 24 h; the solvent is at least one of acetone, dichloromethane, ethyl acetate, and acetonitrile; and / or The reaction temperature of the hydrolysis reaction is 30 - 100 °C, and the reaction time is 12 - 24 h; and / or The reaction temperature of the decarboxylation reaction is 30 - 90 °C, and the reaction time is 3 - 12 h; and / or The reaction temperatures of the demethylation reaction and the esterification reaction are both -10 - 60 °C; the solvent is one of dichloromethane and acetonitrile.

9. The preparation method of the itraconazole intermediate according to any one of claims 1 to 7, characterized in that, Compound A is obtained by a ring - closing reaction of ethyl 2 - oxocyclopentanecarboxylate and 4 - methoxyphenylhydrazine hydrochloride in the presence of acetic acid.

10. The preparation method of the itraconazole intermediate according to claim 9, wherein, In the ring - closing reaction, the molar ratio of ethyl 2 - oxocyclopentanecarboxylate, 4 - methoxyphenylhydrazine hydrochloride, and acetic acid in the feed is: 1:(0.90 - 1.5):(0.90 - 1.50); and / or The reaction temperature is 30 to 90 °C, and the reaction time is 10 to 24 h; the solvent is at least one of methanol, ethanol, isopropanol, and n-butanol.

Images