Preparation method of itramod intermediate

Abstract

The invention discloses a preparation method of an itramod intermediate, and relates to the technical field of preparation of compounds. The synthesis method of the etramod intermediate comprises the following steps: providing a compound A, replacing hydrogen in an N-H group on the compound A with a compound B, then carrying out a substitution reaction with a compound C containing a halogen substituent group to generate a compound D, and carrying out hydrolysis, decarboxylation, demethylation and esterification reaction on the compound D to obtain the etramod intermediate. The preparation method of the itramod intermediate provided by the invention is high in yield, and the obtained itramod intermediate is high in purity, low in cost and easy to popularize and use.

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and in particular to a method for preparing an etramod intermediate. Background Art

[0002] Etramod is a sphingosine 1-phosphate receptor modulator. The FDA-approved indication in 2023 is mainly for the treatment of 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 structure is shown below:

[0003]

[0004] Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate is one of the key intermediates for preparing etramod, and its chemical structure is shown in Formula I below:

[0005]

[0006] Formula I

[0007] The common preparation method, such as WO2010 / 11316; Tetrahedron Letters; vol.56; nb.2; (2015); p.378-381, discloses a method for preparing the compound of formula I, which is to prepare A1 by reacting SM1 and SM3, and then condense with SM2 to prepare A2, and then hydrolyze to prepare A3, decarboxylate to prepare A4, and finally demethylate to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The synthesis route is as follows:

[0008] .

[0009] Also disclosed is a synthesis route of preparing A1 by reacting SM1 and SM3, then condensing with SM4 to prepare A6, then hydrolyzing to prepare A7, decarboxylating to prepare A8, debenzylating on palladium carbon to prepare A9, and finally esterifying under acidic conditions to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The synthesis route is as follows:

[0010] .

[0011] In addition, CN103221391B, CN112955431A and the like also reported similar methods using SM4 condensation and palladium carbon debenzylation.

[0012] In the above-mentioned synthetic routes of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, the synthetic routes are all adopted to keep the NH group, that is, the amino group in each intermediate in the synthetic route carries an active NH group, and this group has good activity but poor stability, and is prone to produce more side reactions during the reaction process, so that the prepared ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate contains more impurities, and the impurities formed based on this group are difficult to purify, which is not conducive to industrial production; in addition, the route of benzyl protection uses an expensive metal palladium catalyst during debenzylation, which is costly and not conducive to widespread promotion and use.

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

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

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

[0016] The present invention provides a method for preparing an etramod intermediate, wherein the structural formula of the etramod intermediate is:

[0017]

[0018] Formula I

[0019] The synthesis method of the etramod intermediate comprises:

[0020] Providing a compound A, using a compound B to replace the hydrogen in the NH group on the compound A, and then reacting with a compound C containing a halogen substituent to generate a compound D, and the compound D is subjected to hydrolysis, decarboxylation, demethylation, and esterification to obtain an etramod intermediate;

[0021] Wherein, 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 compound A, the compound B and the triethylamine is: 1:(1.00-2.00):(1.00-3.00);

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

[0032] .

[0033] Furthermore, in some embodiments of the present application, the compound M2 and compound C undergo a substitution reaction in the presence of a base, and the molar ratio of the compound M2, compound C and 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 compound D to the base is: 1:(2.00-6.00);

[0035] The structural formula of the compound M4 generated 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 compound M4 to the weak acid is: 1:(20-40);

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

[0039] .

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

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

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

[0043] The reaction temperature for the substitution reaction with the compound C containing a halogen substituent is 5 to 80° C., and the reaction time is 8 to 24 hours; 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 to 100° C. and the reaction time is 12 to 24 hours; and / or

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

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

[0047] Furthermore, 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-closure reaction is: 1:(0.90-1.5):(0.90-1.50); ​​and / or

[0049] The reaction temperature is 30-90° C., the reaction time is 10-24 hours, and 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 invention provides a method for preparing an etramod intermediate, which utilizes di-tert-butyl dicarbonate to protect an active NH group on indole, so that the NH group of the intermediate does not participate in the reaction during the reaction process, thereby reducing the occurrence of side reactions in which byproducts are difficult to remove due to the participation of the NH group in the reaction during the generation of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, thereby improving the purity of the prepared ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate; and in the preparation route, no expensive metal catalyst is required, so the cost is low and the method is easy to promote and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG1 is a hydrogen spectrum of the etramod intermediate prepared in Example 1 provided in the present application.

[0053] Figure 2 HPLC spectrum of the etramod intermediate prepared in Example 1 provided in the present application; DETAILED DESCRIPTION

[0054] The technical solution of the present application will be described clearly and completely below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0055] It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as generally understood by those skilled in the art to which this application belongs. It should also be understood that terms such as those defined in common dictionaries should be understood to have meanings consistent with the meanings in the context of the prior art, and will not be interpreted with idealized or overly formal meanings unless specifically defined as here.

[0056] Those skilled in the art will appreciate that, unless otherwise stated, the singular forms "a", "an", "said" and "the" used herein may also include plural forms. It should be further understood that the term "comprising" used in the specification of the present application refers to the presence of the 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 groups thereof. The term "and / or" used herein includes all or any unit and all combinations of one or more associated listed items.

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

[0058]

[0059] Formula I

[0060] The synthesis method of the etramod intermediate comprises: providing a compound A, using a compound B to replace the hydrogen in the NH group on the compound A, and then performing a substitution reaction with a compound C containing a halogen substituent to generate a compound D, and the compound D is subjected to hydrolysis, decarboxylation, demethylation, and esterification to obtain the etramod intermediate;

[0061] Wherein, 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] Wherein, X is a halogen;

[0067] The structural formula of compound D is:

[0068] .

[0069] Exemplarily, the specific synthesis route is:

[0070]

[0071] Its specific synthesis method comprises the following steps:

[0072] S1, ethyl 2-oxocyclopentanecarboxylate and 4-methoxyphenylhydrazine hydrochloride in the presence of acetic acid undergo a ring-closing reaction to obtain compound A, wherein the molar ratio of ethyl 2-oxocyclopentanecarboxylate, 4-methoxyphenylhydrazine hydrochloride and 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 10-24 h;

[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 and 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, M2 and compound C (halogenated compound, such as ethyl 2-halogenated ethyl acetate, wherein ethyl halide can be ethyl bromoacetate or ethyl iodoacetate) are subjected to substitution reaction under alkaline conditions to prepare compound D, the molar ratio of M2, compound C and 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 8-24h; the base used in the reaction is one of potassium carbonate and sodium carbonate;

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

[0076] S5 and M4 undergo 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; wherein the weak acid can be a common weak acid, such as acetic acid and propionic acid.

[0077] S6 and M5 undergo a demethylation reaction in the presence of boron tribromide to generate a phenolic hydroxyl group on the indole, and then undergo an esterification reaction in the presence of anhydrous 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 anhydrous ethanol is 1:(2-4.00):(3-5.00), the reaction solvent is at least one of dichloromethane and acetonitrile, and the reaction temperature is -10-60°C.

[0078] Preferably, the reaction temperature in step S1 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); so that the starting material ethyl 2-oxocyclopentanecarboxylate reacts completely.

[0079] The reaction temperature in step S2 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); so that it is fully substituted and the reaction is complete.

[0080] The reaction temperature in step S3 is 30-50° C., the reaction time is 16-24 h, and the molar ratio of M2, compound C and base is: 1: (1.3-1.7): (1.8-2.2); to achieve 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 compound D to strong base is 1:3.5-4.5; so as to completely hydrolyze the compound.

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

[0083] The reaction temperature in step S6 is 0-50° C., the reaction time is 0.5-1 h, and the molar ratio of M5, boron tribromide and anhydrous ethanol is 1: (2.5-3.5: (3.5-4.5); to achieve sufficient demethylation and ethyl esterification.

[0084] The present invention directly uses 2-oxocyclopentanecarboxylic acid ethyl ester and 4-methoxyphenylhydrazine hydrochloride to prepare compound A by ring-closing reaction, and then reacts with compound B, thereby avoiding the situation that the reaction of 2-oxocyclopentanecarboxylic acid ethyl ester and compound B is difficult to handle and the yield is low. Secondly, the unstable NH amino intermediate is Boc-protected to obtain a stable intermediate, reduce side reactions, and facilitate the separation and purification of the intermediate. That is, compound A is used to prepare Boc-protected M2, and Boc-protected M2 reacts with compound C to prepare NH-protected compound D, which is then hydrolyzed to obtain M4, decarboxylated to obtain M5, and finally demethylated, deprotected and esterified to obtain the desired intermediate product. This method improves the stability of the intermediates in the entire synthesis process and avoids the influence of unstable NH amino intermediates on the purification and quality of the entire synthesis process. Thirdly, the present invention is easier to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate after Boc protection, without the need for expensive precious metal catalysts, and is more conducive to industrial production.

[0085] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0086] Among them, anhydrous ethanol was purchased from Chengdu Kelong Chemical Co., Ltd., analytical grade 500ml / bottle;

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

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

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

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

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

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

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

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

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

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

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

[0098] Example 1

[0099] S1: Preparation of Compound A

[0100] 7.50 g of ethyl 2-oxocyclopentanecarboxylate, 8.40 g of 4-methoxyphenylhydrazine hydrochloride, 22.50 g of anhydrous ethanol, and 2.91 g of glacial acetic acid were added to a reaction vessel; the temperature was raised to 50-60°C; the reaction was kept warm for 18 hours under nitrogen protection; the TLC reaction was complete, the reaction solution was adjusted to a neutral pH with a saturated sodium bicarbonate solution, filtered, and the ethanol was concentrated under reduced pressure at 45°C; 45 mL of ethyl acetate was added to the residue, stirred and filtered, the liquids were separated, the organic phase was washed with water, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate; filtered, and concentrated to dryness under reduced pressure at 45°C; 12 g of a light yellow liquid, i.e., compound A, was obtained with a yield of 91.32%.

[0101] S2: Preparation of M2

[0102] 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 were added to the reaction vessel and reacted at room temperature for 14 hours. The reaction was complete by TLC. The pH was adjusted to neutral, the liquids were separated, dried, filtered, and concentrated under reduced pressure at 45°C to obtain 15.60 g of yellow oil M2 with a yield of 95.15%.

[0103] S3: Preparation of Compound D

[0104] 15.6 g of M2, 10.46 g of compound C, 11.53 g of potassium carbonate and 156.00 g of acetone were added to the reaction container and reacted at room temperature for 24 hours. The reaction was complete by TLC. The mixture was filtered and concentrated to dryness under reduced pressure at 45°C to obtain 19.00 g of brown solid, which was compound D with a yield of 102.10%.

[0105] S4: Preparation of M4

[0106] 19.00 g of compound D and 76.00 g of anhydrous ethanol were added to the reaction container, and 13.64 g of 50% sodium hydroxide was added dropwise at room temperature. The temperature was raised to 45-50 ° C and kept for reaction for 24 hours. The reaction was complete by TLC. The pH was adjusted to neutral with hydrochloric acid. The ethanol was concentrated to dryness under reduced pressure at 45 ° C. The residue was separated into ethyl acetate and water. The pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid. 15.80 g of brown solid M4 was obtained by filtration 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 to the reaction vessel, heat to 60-65°C, keep the temperature at 60-65°C for 4 hours, and the reaction is complete by TLC. Concentrate at 60°C to dryness under reduced pressure, wash the residual solid with water, and dry in vacuo at 45°C to constant weight 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] 12.00 g of M5 and 36.00 g of dichloromethane were added to the reaction vessel, and the temperature was lowered to 0-10 ° C. 26.11 g of boron tribromide was added dropwise at 0-10 ° C. The reaction was kept at 0-10 ° C for 1 hour. 48.00 g of anhydrous ethanol was added dropwise at 0-10 ° C. After the dropwise addition, the temperature was raised to 40-45 ° C. The reaction was kept at 40-45 ° C for 0.5 h. The TLC reaction was complete, the pH was adjusted to 8 with 40% sodium hydroxide, and the ethanol was concentrated under reduced pressure at 45 ° C. The pH was adjusted to 7 with 6N hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and recrystallized to obtain 7.58 g of off-white to white solid formula I with a yield of 84.16%.

[0111] Example 2

[0112] S1: Preparation of Compound A

[0113] 15.00 g of ethyl 2-oxocyclopentanecarboxylate, 18.45 g of 4-methoxyphenylhydrazine hydrochloride, 45.00 g of anhydrous ethanol, and 6.34 g of glacial acetic acid were added to the reaction vessel; the temperature was raised to 58°C; the reaction was kept warm for 20 hours under nitrogen protection; the TLC reaction was complete, the reaction solution was adjusted to neutral pH with saturated sodium bicarbonate solution, filtered, and the ethanol was concentrated under reduced pressure at 45°C; 90 mL of ethyl acetate was added to the residue, stirred and filtered, the liquids were separated, the organic phase was washed with water, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate; filtered, and concentrated to dryness under reduced pressure at 45°C; 24.6 g of light yellow liquid, i.e., compound A, was obtained with a yield of 93.71%.

[0114] S2: Preparation of M2

[0115] To the reaction vessel, 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 were added. The mixture was reacted at 35°C for 16 hours. The reaction was complete by TLC. The pH was adjusted to neutral. The mixture was separated, dried, filtered and concentrated under reduced pressure at 45°C to obtain 30.90 g of a yellow oil 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 container, react at 35°C for 20 hours, and the reaction is complete by TLC. Filter and concentrate under reduced pressure at 45°C to obtain 34.21 g of brown solid, which is compound D, with a yield of 98.93%.

[0118] S4: Preparation of M4

[0119] 34.00 g of compound D and 136 g of anhydrous ethanol were added to the reaction container, and 25.27 g of 50% sodium hydroxide was added dropwise at room temperature. The temperature was raised to 50°C and kept for reaction for 22 hours. The reaction was complete by TLC. The pH was adjusted to neutral by hydrochloric acid. The ethanol was concentrated to dryness under reduced pressure at 45°C. The residue was separated into ethyl acetate and water. The aqueous phase was adjusted to pH 3 by hydrochloric acid and filtered to obtain 30.16 g of 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 to 65-70°C, keep the temperature at 65-70°C for 4.5 hours, and the reaction is complete by TLC. Concentrate at 60°C to dryness under reduced pressure, wash the residual solid with water, and dry in vacuo at 45°C to constant weight to obtain 25.36 g of 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] 25.00 g of M5 and 75.00 g of dichloromethane were added to the reaction vessel, and the temperature was lowered to -5~5°C. 54.39 g of boron tribromide was added dropwise at -5~5°C, and the reaction was kept at 0~10°C for 1 hour. 100.00 g of anhydrous ethanol was added dropwise at 0~10°C. After the dropwise addition, the temperature was raised to 40°C, and the reaction was kept at 40°C for 0.5 h. The TLC reaction was complete, and the pH was adjusted to 8 with 40% sodium hydroxide. The ethanol was concentrated under reduced pressure at 45°C, and the pH was adjusted to 7 with 6N hydrochloric acid solution. The solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and recrystallized to obtain 16.70 g of off-white to white solid formula I with a yield of 88.97%.

[0124] The product obtained in the above example was subjected to 'H NMR (400 MHz, DMSO-d) detection, and the detection results are as follows Figure 1 As shown, its H NMR spectrum peaks include:

[0125] 1.20 (t, J = 7. 1Hz, 3H), 2. 10-2.03 (m, 1H), 2.42 (dd, J = 15.7, 8.9Hz, 1H), 2. 70-2. 55 (m, 3H), 2. 76 (dd, J = 15. 7, 5. 5Hz, 1H), 3. 48-3. 42 (m,1H), 4. 11 (q, J = 7. 1Hz, 2H), 6.49 (dd, J = 8.6, 2. 3Hz, 1H), 6.62 (d, J = 2.1Hz, 1H), 7.07 (d, J = 8.6Hz, 1H), 8.51 (s, 1H), 10. 29(s, 1H).

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

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

[0128] Table 1

[0129] Retention time area Area percentage Peak height Peak Height Percent 23.520 98841613 99.57 9319253 99.34 27.657 110257 0.11 18790 0.20 30.733 313093 0.32 43402 0.46

[0130] from Figure 2The HPLC spectrum shows 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 the present application is high, and can be obtained above 99%.

[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 it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, 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 method for preparing an etramod intermediate, characterized in that: The structural formula of the etramod intermediate is: ， Formula I Characterized in that the synthesis method of the etramod intermediate comprises: Providing a compound A, using a compound B to replace the hydrogen in the NH group on the compound A, and then reacting with a compound C containing a halogen substituent to generate a compound D, and the compound D is subjected to hydrolysis, decarboxylation, demethylation, and esterification to obtain an etramod intermediate; Wherein, 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 method for preparing an etramod intermediate according to claim 1, characterized in that: The compound A and the compound B undergo a substitution reaction in the presence of triethylamine, and the molar ratio of the compound A, the compound B and the triethylamine is: 1:(1.00-2.00):(1.00-3.00); The structural formula of the compound M2 generated by the reaction of compound A and compound B is: 。 3. The method for preparing an etramod intermediate according to claim 2, characterized in that: The compound M2 and the compound C undergo a substitution reaction in the presence of a base, and the molar ratio of the compound M2, the compound C and the base is: 1:(1.00-2.00):(1.50-3.00).

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

7. The method for preparing an etramod intermediate according to claim 5, characterized in that: The esterification reaction occurs in the presence of anhydrous ethanol, and the molar ratio of the compound M5 to the anhydrous ethanol is 1:(3.00-5.00).

8. The method for preparing an etramod 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 to 60° C., and the reaction time is 12 to 24 hours; the solvent is at least one of methanol, ethanol, and isopropanol; and / or The reaction temperature for the substitution reaction with the compound C containing a halogen substituent is 5 to 80° C., and the reaction time is 8 to 24 hours; the solvent is at least one of acetone, dichloromethane, ethyl acetate, and acetonitrile; and / or The reaction temperature of the hydrolysis reaction is 30 to 100° C. and the reaction time is 12 to 24 hours; and / or The reaction temperature of the decarboxylation reaction is 30 to 90° C., and the reaction time is 3 to 12 hours; and / or The reaction temperatures of the demethylation reaction and the esterification reaction are both -10 to 60°C; the solvent is one of dichloromethane and acetonitrile.

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

10. The method for preparing an etramod intermediate according to claim 9, characterized in that: 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 The reaction temperature is 30-90° C., the reaction time is 10-24 hours, and the solvent is at least one of methanol, ethanol, isopropanol and n-butanol.

Images