Preparation method of ethyl bicyclic compound

Abstract

The invention belongs to the technical field of drug synthesis methods, and relates to a preparation method of an ethyl bicyclic compound. Specifically, the invention discloses a preparation method of a compound as shown in a formula II, which comprises the following steps: in the presence of a catalyst, carrying out addition reaction on a compound as shown in a formula I and trimethylsilyl cyanide in a first solvent to obtain a solution of the compound as shown in the formula II. On the basis, a compound shown in the formula III, a compound shown in the formula IV and salts (such as benzene sulfonate) thereof can be prepared step by step. The method is green, efficient, safe, environment-friendly, low in cost, mild in reaction condition, simple to operate, high in product yield, good in chiral purity and suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis methods and relates to a method for preparing an ethylbicyclic compound. Background Art

[0002] Currently, gabapentin and pregabalin are marketed as treatments for neuropathic pain, both of which are severely deficient in clinical practice. 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (hereinafter referred to as "the compound of Formula IV") is an α2δ ligand that, when administered orally, preferentially and selectively binds to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2). These calcium channels are widely present in the nervous system, mediating pain transmission and processing throughout the body. The compound of Formula IV exhibits unique binding properties and long-lasting effects on these calcium channels. Clinical results have demonstrated significantly greater efficacy than gabapentin and pregabalin.

[0003] As a drug for treating neuropathic pain, the compound of formula IV has the following structural formula:

[0004]

[0005] For the synthesis of the compound of formula IV, the synthesis processes in the prior art all involve the use of highly dangerous reagents, such as the highly toxic NaCN or the flammable and explosive nitromethane, which makes the prior art routes extremely dangerous.

[0006] CN201480002091.0 discloses a method for synthesizing a compound of formula IV. This route involves conjugate addition, hydrolytic decarboxylation, and cyano reduction to obtain the compound of formula IV. This process requires the use of highly toxic chemicals such as NaCN or KCN, which pose serious risks to humans and the environment and are difficult to commercialize.

[0007]

[0008] CN201480002091.0 also discloses a method for synthesizing a compound of formula IV. This route involves conjugate addition, hydrolytic decarboxylation, and nitro reduction to obtain the compound of formula IV. This process requires the use of nitromethane, a flammable and explosive substance. Nitromethane vapor is prone to explosion when mixed with air, posing significant safety risks in its use and transportation.

[0009]

[0010] Furthermore, all of the aforementioned technologies require the isolation of the cyano or nitro addition intermediates, followed by decarboxylation, hydrolysis, and salt purification. Furthermore, the ammonium salt intermediates require acidification and desalination before hydrogenation reduction. The processes involve multiple extraction, concentration, and other separation operations, making them cumbersome and unsuitable for scale-up production.

[0011] CN200880118892.8 discloses a method for synthesizing a compound of formula IV. This route involves conjugate addition, chiral column preparation, iron powder reduction, amino protection, and deprotection to obtain the compound of formula IV. Because the process requires chiral column preparation to separate isomers, the production cost is very high, making it unsuitable for industrial scale-up.

[0012] Moreover, the process involves protection and deprotection, and the atom economy of the reaction is not high.

[0013]

[0014] As can be seen from the aforementioned literature, the prior art lacks a green, efficient, safe, environmentally friendly, and low-cost synthesis method for the compound of Formula IV. Therefore, the need for a greener, safer, and more cost-effective method for preparing the compound of Formula IV and its salts, or intermediates for their synthesis, has become a major technical challenge in the synthesis of drugs for the treatment of neuropathic pain. Summary of the Invention

[0015] Problems to be solved by the invention

[0016] To address existing problems, the present invention provides a method for preparing 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid and its salts, or intermediates used in the synthesis of the compound or salts. This method is environmentally friendly, efficient, safe, environmentally friendly, and low-cost. It features mild reaction conditions, simple operation, high product yield, and good chiral purity, making it suitable for large-scale industrial production.

[0017] Solutions for solving problems

[0018] [1] A method for preparing a compound of formula II, comprising the following steps:

[0019]

[0020] In the presence of a catalyst, the compound of formula I and trimethylsilyl cyanide are stirred in a first solvent to carry out an addition reaction, a saline solution is added to quench the reaction, and the organic phase is collected after separation to obtain a solution of the compound of formula II;

[0021] in,

[0022] R 1 and R 2Each independently represents hydrogen, -COOH, -COO-C 1-15 Alkyl or -COO-CH2-C 6-20 Aryl, but not hydrogen; preferably hydrogen, -COOH, -COO-C 1-12 Alkyl or -COO-CH2-C 6-15 Aryl, but not hydrogen; more preferably hydrogen, -COOH, -COO-C 1-8 Alkyl or -COO-CH2-C 6-12 Aryl, but not hydrogen; further preferably hydrogen, -COOH, -COO-C 1-6 Alkyl or -COO-CH2-C 6-10 Aryl, but not hydrogen at the same time; further preferably hydrogen, -COOH, -COOCH3, -COOEt, -COOtBu or -COO-CH2-C6H5, but not hydrogen at the same time; most preferably hydrogen, -COOEt or -COO-CH2-C6H5, but not hydrogen at the same time;

[0023] Preferably, the saline solution is selected from a sodium chloride aqueous solution, a potassium chloride aqueous solution and an ammonium chloride aqueous solution, preferably a sodium chloride aqueous solution;

[0024] and / or,

[0025] The molar ratio of the compound of formula I to the trimethylsilyl cyanide is 1.0:1.5 to 1.0:2.5, preferably 1.0:1.5 to 1.0:2.0, and more preferably 1.0:2.0.

[0026] [2] The preparation method according to [1], characterized in that

[0027] The catalyst is a magnesium salt or a quaternary ammonium salt, preferably MgI2 or tetrabutylammonium fluoride, more preferably MgI2;

[0028] and / or,

[0029] The molar ratio of the compound of formula I to the catalyst is 1.0:1.5 to 1.0:2.5, preferably 1.0:1.5 to 1.0:2.0, more preferably 1.0:2.0.

[0030] [3] The preparation method according to [1] or [2], characterized in that

[0031] The first solvent is an ether solvent, preferably methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or ethylene glycol dimethyl ether, more preferably tetrahydrofuran.

[0032] [4] The preparation method according to any one of [1] to [3], characterized in that

[0033] The temperature of the addition reaction is 50-120°C, preferably 55-80°C.

[0034] [5] A method for preparing a compound of formula III, comprising the following steps:

[0035]

[0036] A solution of the compound of formula II is stirred with an alkaline solution to perform a hydrolysis reaction, the reaction solution is concentrated to remove the first solvent, an acid is added to adjust to a target pH value, a second solvent is added to extract, and an organic phase is collected, and an organic amine is added and stirred to perform a salt-forming reaction to obtain a compound of formula III;

[0037] in,

[0038] R 1 and R 2 Each independently represents hydrogen, -COOH, -COO-C 1-15 Alkyl or -COO-CH2-C 6-20 Aryl, but not hydrogen; preferably hydrogen, -COOH, -COO-C 1-12 Alkyl or -COO-CH2-C 6-15 Aryl, but not hydrogen; more preferably hydrogen, -COOH, -COO-C 1-8 Alkyl or -COO-CH2-C 6-12 Aryl, but not hydrogen; further preferably hydrogen, -COOH, -COO-C 1-6 Alkyl or -COO-CH2-C 6-10 Aryl, but not hydrogen at the same time; further preferably hydrogen, -COOH, -COOCH3, -COOEt, -COOtBu or -COO-CH2-C6H5, but not hydrogen at the same time; most preferably hydrogen, -COOEt or -COO-CH2-C6H5, but not hydrogen at the same time;

[0039] Preferably, the temperature of the hydrolysis reaction is 50 to 120°C, preferably 55 to 80°C;

[0040] More preferably, the preparation method further comprises the following steps:

[0041] A solution of the compound of formula II is obtained according to the preparation method according to any one of [1] to [4].

[0042] [6] The preparation method according to [5], characterized in that

[0043] The organic amine is R-NH2, wherein R is C 1-4 Alkyl or C 3-6 Cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by C6-10 Aryl substituted, preferably (R)-1-phenylethylamine, tert-butylamine, n-butylamine, benzylamine or cyclohexylamine, more preferably cyclohexylamine;

[0044] and / or,

[0045] The molar ratio of the compound of formula II to the organic amine is 1.0:1.0 to 1.0:2.0, preferably 1.0:1.2.

[0046] [7] The preparation method according to [5] or [6], characterized in that:

[0047] The second solvent is an ether, ketone, hydrocarbon or ester solvent, preferably methyl tert-butyl ether, acetone, toluene or ethyl acetate, more preferably toluene or ethyl acetate;

[0048] and / or,

[0049] The alkaline solution is an aqueous solution of an alkali metal hydroxide or a hydrate thereof, preferably an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide or a hydrate thereof, more preferably an aqueous solution of potassium hydroxide;

[0050] and / or,

[0051] The molar ratio of the compound of formula II to the base is 1.0:1.0 to 1.0:4.0, preferably 1.0:3.0 to 1.0:4.0, more preferably 1.0:3.0;

[0052] and / or,

[0053] The acid is hydrochloric acid, sulfuric acid, nitric acid or acetic acid, preferably hydrochloric acid;

[0054] and / or,

[0055] The target pH value is 1-4, preferably 2-3.

[0056] [8] A method for preparing a compound of formula IV, comprising the following steps:

[0057]

[0058] In the presence of a metal catalyst, the compound of formula III is stirred in a third solvent to carry out a hydrogenation reaction, an alkaline solution is added, stirred, and filtered to remove the metal catalyst, a fourth solvent is added for extraction, and the aqueous phase is taken, an acid is added to adjust to a target pH value, and filtered to obtain a compound of formula IV;

[0059] Preferably, the third solvent is water, an ether or an alcohol solvent, preferably methanol, ethanol, isopropanol, tetrahydrofuran or water, more preferably water;

[0060] and / or,

[0061] Preferably, the fourth solvent is a hydrocarbon solvent, preferably an aromatic hydrocarbon solvent, more preferably toluene;

[0062] and / or,

[0063] Preferably, the temperature of the hydrogenation reaction is 30 to 60°C, preferably 40 to 50°C;

[0064] More preferably, the preparation method further comprises the following steps:

[0065] The compound of formula III is obtained according to the preparation method according to any one of [5] to [7].

[0066] [9] The preparation method according to claim [8], characterized in that:

[0067] The metal catalyst is Raney nickel or palladium carbon, preferably Raney nickel, 5% palladium carbon or 10% palladium carbon, more preferably Raney nickel;

[0068] and / or,

[0069] The weight ratio of the compound of formula III to the metal catalyst is 3.0:1.0 to 15.0:1.0, preferably 5.0:1.0 to 10.0:1.0, more preferably 5.0:1.0;

[0070] and / or,

[0071] The alkaline solution is an aqueous solution of an alkali metal hydroxide or a hydrate thereof, preferably an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide or a hydrate thereof, more preferably an aqueous solution of potassium hydroxide;

[0072] and / or,

[0073] The molar ratio of the compound of formula III to the base is 1.0:1.0 to 1.0:2.0, preferably 1.0:1.0 to 1.0:1.5, more preferably 1.0:1.0;

[0074] and / or,

[0075] The acid is hydrochloric acid, sulfuric acid, nitric acid or acetic acid, preferably hydrochloric acid;

[0076] and / or,

[0077] The target pH value is 5-8, preferably 6-7.

[0078]

[10] A method for preparing a benzenesulfonate salt of a compound of formula IV, comprising the following steps:

[0079] The compound of formula IV is salified with benzenesulfonic acid to obtain a benzenesulfonate salt of the compound of formula IV;

[0080] Preferably, the salt formation is carried out in a fifth solvent;

[0081] and / or,

[0082] The fifth solvent is a single solvent or a mixed solvent, preferably water, anisole, acetone, acetonitrile, water-acetone, water-acetonitrile, more preferably anisole;

[0083] and / or,

[0084] Preferably, the compound of formula IV and the benzenesulfonic acid form a salt in equimolar amounts;

[0085] More preferably, the preparation method further comprises the following steps:

[0086] The compound of formula IV is obtained according to the preparation method described in [8] or [9].

[0087] Effects of the Invention

[0088] Compared with the prior art, the present invention has the following beneficial effects:

[0089] 1) TMSCN replaces highly toxic NaCN (or KCN) or flammable and explosive nitromethane, overcoming the shortcomings of the existing technology of using highly toxic or flammable and explosive materials;

[0090] 2) The two-step reaction of cyano group introduction and decarboxylation hydrolysis is integrated to achieve a continuous "two-step one-pot process", reducing production costs and improving yields;

[0091] 3) The obtained amine salt intermediate can be directly used for hydrogenation reduction without desalting, which simplifies the operation process;

[0092] 4) The obtained high-purity compound of formula IV is converted into the raw material drug compound of formula IV benzenesulfonate after salification with benzenesulfonic acid, and its HPLC purity is greater than or equal to 99.6%, meeting the pharmaceutical grade requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] Figure 1 This is the HPLC spectrum of compound III-1 in Example 1.

[0094] Figure 2 This is the HPLC spectrum of compound IV in Example 1.

[0095] Figure 3 HPLC spectrum of compound IV benzenesulfonate in Example 1. DETAILED DESCRIPTION

[0096] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below.

[0097] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents or instruments used, if the manufacturer is not specified, are commercially available conventional products.

[0098] The structures of the compounds were determined by nuclear magnetic resonance ( 1 The purity of the compounds was determined by high performance liquid chromatography (HPLC).

[0099] 1 H NMR was measured using a BRUKER AVANCE III HD 400 MHz nuclear magnetic resonance spectrometer. The solvent was deuterated methanol (CD3OD), the internal standard was tetramethylsilane (TMS), and the chemical shifts (δ) were given in parts per million (ppm).

[0100] The HPLC-MS instrument was an Agilent-1260 mass spectrometer, and the mass spectrometry test conditions were positive ion mode, ES-API ionization source, and a scanning range of 103 m / z to 2000 m / z.

[0101] HPLC conditions: Agilent 1260 HPLC with VWD detector; Waters Xbridge C18 column, 4.6 x 150 mm, 3.5 μm; column temperature, 25°C; flow rate, 1.0 ml / min; detection wavelength, 215 nm; binary mobile phase system, mobile phase A: 0.01 M ammonium phosphate aqueous solution / ACN = 90 / 10, mobile phase B: ACN; elution was performed as specified in the table below. The results are shown in the table below. Figure 1-3 shown.

[0102] Table 1

[0103] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 6 22 78 11 22 78

[0104] Definition of terms

[0105] The term "C 1-6 "Alkyl" alone or in combination means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc. Accordingly, the term "C 1-4 "Alkyl" alone or in combination means a straight or branched chain alkyl group containing 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

[0106] The term "C 3-6The term "cycloalkyl" alone or in combination refers to a monocyclic or polycyclic cycloalkyl group containing 3 to 6 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0107] The term "C 6-10 The term "aryl" alone or in combination refers to a monocyclic or bicyclic (at least one of which is aromatic) aromatic group containing 6 to 10 carbon atoms, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindanyl, and the like.

[0108] The term "room temperature" is also called normal temperature or general temperature, and is generally defined as 10-30°C.

[0109] The meanings of main abbreviations or chemical formulae used in the description of this specification are as follows.

[0110] TMSCN: trimethylsilyl cyanide TiCl4: titanium tetrachloride

[0111] TBAF: Tetrabutylammonium fluoride NaH: Sodium hydride

[0112] MgI2: magnesium iodide THF: tetrahydrofuran

[0113] NaCl: sodium chloride NaOH: sodium hydroxide

[0114] LiOH: lithium hydroxide KOH: potassium hydroxide

[0115] eq.: molar equivalent ACN: acetonitrile

[0116] Preparation of starting materials:

[0117] Preparation of I-3: TiCl4 (24 mL, 221 mmol) was added dropwise to THF (450 mL) with the temperature controlled at ≤10°C. (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (15.02 g, 110 mmol) and diethyl malonate (19.43 g, 121 mmol) were then added. The mixture was stirred for 2 h, and then pyridine (35.00 g, 442 mmol) was added. The mixture was reacted at 0°C for 2 h, then stirred at room temperature for 15 h. Water (150 mL) and toluene (150 mL) were added, stirred, and the phases were separated. The organic phase was concentrated to dryness to obtain I-3 (30.05 g).

[0118] Preparation of I-2: 60% NaH (1.62 g, 40.7 mmol) was added to THF (50 mL). Ethyl (diethoxyphosphoryl)acetate (9.05 g, 40.7 mmol) and (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (5.00 g, 37 mmol) were added dropwise at a temperature of ≤10°C. The mixture was stirred at room temperature for 15 h. 10% brine (50 mL) was added, stirred, and the phases separated. The organic phase was concentrated to dryness to yield I-2 (6.82 g).

[0119] The preparation of I-1 was carried out according to the preparation of I-3, wherein dibenzyl malonate was used instead of diethyl malonate.

[0120] Example 1: Synthesis of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid and benzenesulfonate

[0121]

[0122] Step 1: Combine I-1 (4.02 g, 10 mmol), TMSCN (1.49 g, 15 mmol, 1.5 eq.), 1.0 M TBAF / THF solution (15 mL, 15 mmol, 1.5 eq.), and tetrahydrofuran (14 mL). Stir and react at 60°C for 4 h (TLC indicates complete reaction). Quench the reaction by adding 10% aqueous NaCl (30 mL). Allow to stand for phase separation to obtain a tetrahydrofuran solution of II-1, which is used directly in the next step.

[0123] Step 2: To the tetrahydrofuran solution of II-1 above, add LiOH monohydrate (1.68 g, 40 mmol, 4 eq.) and water (10 mL), and stir at 60°C for 1 h. Concentrate the reaction solution until almost no fraction is dropped, then add concentrated hydrochloric acid to adjust the pH to 2, and add ethyl acetate (20 mL) for extraction to obtain an ethyl acetate solution. Add cyclohexylamine (1.19 g, 12 mmol, 1.2 eq.) to the above ethyl acetate solution, stir at room temperature for 2 h, filter, and wash to obtain 2.59 g of cyclohexyl 2-[(1R,5S,6S)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]ammonium acetate (III-1), with a yield of 85.0% and a purity of 97.2% (as Figure 1 shown).

[0124] Step 3: Mix III-1 (2.43 g, 8 mmol) with methanol (8 mL), stir at room temperature to dissolve, add Raney nickel (0.48 g, 20% wt), replace with nitrogen, increase the hydrogen pressure to 0.6 MPa, and stir at 45 ° C for 9 h. Add 1N KOH (8 mL, 1 eq.) aqueous solution to the reaction solution, stir for 10 min, and then filter to remove Raney nickel. Add toluene (16 mL) to the filtrate for extraction. Adjust the pH of the remaining aqueous phase to 6.0 with concentrated hydrochloric acid and filter to obtain 1.35 g of 2-[(1R, 5S, 6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (Compound IV). The yield is 81.0% and the purity is 96.7% (as Figure 2 shown).

[0125] Characterization data of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (Compound IV) obtained in this example: 1 H-NMR (400 MHz, CD3OD): δ 1.10 (3H, t, J = 8.0 Hz), 1.48 (1H, dd, J = 8.0, 12.0 Hz), 2.03-2.09 (2H, m), 2.15 (2H, q, J = 8.0 Hz), 2.44-2.53 (3H, m), 2.85 (1H, quint, J = 8.0 Hz), 3.10 (1H, br. s), 3.13-3.21 (2H, m), 5.37 (1H, s); LCMS (ESI) requires: 210.1, found: 210.2 [M+H] + .

[0126] Step 4: Compound IV (1.30 g, 6.2 mmol) was mixed with anisole (13 mL), stirred at room temperature until dissolved, and then a solution of benzenesulfonic acid (0.98 g, 6.2 mmol) in anisole (5 mL) was added dropwise. After addition, the mixture was stirred at room temperature for 2 h, and then cooled to 3°C. Filtration gave 2.20 g of 2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid (Compound IV) benzenesulfonate, with a yield of 96.5% and a purity of 99.6% (as Figure 3 shown).

[0127] Example 2: Synthesis of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid

[0128]

[0129] Step 1: Combine I-2 (2.06 g, 10 mmol), TMSCN (1.98 g, 20 mmol, 2 eq.), MgI2 (5.56 g, 20 mmol, 2 eq.), and 2-methyltetrahydrofuran (14 mL) and stir at 65°C for 5 h (TLC indicates complete reaction). Quench the reaction by adding 10% aqueous NaCl (28 mL) and allow to stand for phase separation to obtain a solution of II-2 in 2-methyltetrahydrofuran, which is used directly in the next step.

[0130] Step 2: To the above solution of II-2 in 2-methyltetrahydrofuran, add KOH (1.68 g, 30 mmol, 3 eq.) and water (10 mL). Stir the reaction at 65°C for 1 h. Concentrate the reaction solution until almost no fraction is released. Adjust the pH to 3 with concentrated hydrochloric acid, and extract with ethyl acetate (20 mL) to obtain an ethyl acetate solution. Add benzylamine (1.29 g, 12 mmol, 1.2 eq.) to the above ethyl acetate solution. Stir at room temperature for 2 h, filter, and wash to obtain 2.50 g of III-2, with a yield of 80.0% and a purity of 97.3%.

[0131] Step 3: Mix III-2 (1.56 g, 5 mmol) with purified water (5 mL), stir at room temperature to dissolve, then add Raney nickel (0.31 g, 20% wt). After nitrogen replacement, the hydrogen pressure was increased to 0.6 MPa, and the reaction was stirred at 45 ° C for 7 h. 1N KOH (5 mL, 1 eq.) aqueous solution was added to the reaction solution, stirred for 10 min, and then filtered to remove the Raney nickel. The filtrate was extracted with toluene (10 mL). The remaining aqueous phase was adjusted to pH = 6.0 with concentrated hydrochloric acid and filtered to obtain 0.94 g of 2-[(1R, 5S, 6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (Compound IV), with a yield of 90.0% and a purity of 96.3%.

[0132] Characterization data of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (Compound IV) obtained in this example: 1 H-NMR (400 MHz, CD3OD): δ 1.10 (3H, t, J = 8.0 Hz), 1.48 (1H, dd, J = 8.0, 12.0 Hz), 2.03-2.09 (2H, m), 2.15 (2H, q, J = 8.0 Hz), 2.44-2.53 (3H, m), 2.85 (1H, quint, J = 8.0 Hz), 3.10 (1H, br. s), 3.13-3.21 (2H, m), 5.38 (1H, s); LCMS (ESI) requires: 210.1, found: 210.2 [M+H] + .

[0133] Example 3: Synthesis of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid

[0134]

[0135] Step 1: Combine I-3 (2.78 g, 10 mmol), TMSCN (1.98 g, 20 mmol, 2 eq.), MgI2 (5.56 g, 20 mmol, 2 eq.), and THF (14 mL). Stir and react at 65°C for 3 h (TLC indicates complete reaction). Quench the reaction by adding 10% aqueous NaCl (28 mL). Allow to stand for phase separation to obtain a tetrahydrofuran solution of II-3, which is used directly in the next step.

[0136] Step 2: To the tetrahydrofuran solution of II-3 above, add NaOH (1.20 g, 30 mmol, 3 eq.) and water (10 mL), and stir at 65°C for 1 h. Concentrate the reaction solution until almost no fraction is released, then adjust the pH to 2 with concentrated hydrochloric acid. Extract with toluene (20 mL) to obtain a toluene solution. Benzylamine (1.29 g, 12 mmol, 1.2 eq.) is added to the toluene solution, and the mixture is stirred at room temperature for 2 h. Filter and wash to obtain 2.34 g of benzyl 2-[(1R,5S,6S)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]ammonium acetate (III-3), with a yield of 75.0% and a purity of 97.7%.

[0137] Step 3: Mix III-3 (1.56 g, 5 mmol) with purified water (5 mL), stir at room temperature to dissolve, then add 5% palladium on carbon (0.16 g, 10% wt). After nitrogen displacement, the hydrogen pressure was increased to 0.5 MPa, and the reaction was stirred at 45°C for 8 h. 1N KOH (5 mL, 1 eq.) aqueous solution was added to the reaction solution, stirred for 10 min, and filtered to remove the palladium on carbon. The filtrate was extracted with toluene (10 mL). Concentrated hydrochloric acid was added to the remaining aqueous phase to adjust the pH to 6.0, and filtered to obtain 0.74 g of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (Compound IV), with a yield of 70.0% and a purity of 97.0%.

[0138] Characterization data of 2-[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (Compound IV) obtained in this example: 1H-NMR (400 MHz, CD3OD): δ 1.10 (3H, t, J = 8.0 Hz), 1.48 (1H, dd, J = 8.0, 12.0 Hz), 2.03-2.09 (2H, m), 2.15 (2H, q, J = 8.0 Hz), 2.44-2.53 (3H, m), 2.85 (1H, quint, J = 8.0 Hz), 3.10 (1H, br. s), 3.13-3.21 (2H, m), 5.37 (1H, s); LCMS (ESI) requires: 210.1, found: 210.2 [M+H] + .

[0139] Comparative Example 1: Cyanide Addition Reaction of Potassium Ferrocyanide (K4[Fe(CN)6])

[0140] Mix Ⅰ-2 (2.06 g, 10 mmol, 1 eq.), K4[Fe(CN)6]·3H2O (8.44 g, 20 mmol, 2 eq.), MgI2 (5.56 g, 20 mmol, 2 eq.) and 2-methyltetrahydrofuran (14 mL), stir and react at 79°C for 10 h. TLC detection showed that no cyanide addition product was generated.

[0141] Potassium ferrocyanide (K4[Fe(CN)6]), which has similar low toxicity, was used as a cyanide source for the cyanide addition reaction, but the target product was not obtained.

[0142] Comparative Example 2: Low temperature reaction at 30°C

[0143]

[0144] Step 1: Combine I-2 (2.06 g, 10 mmol, 1 eq.), TMSCN (1.98 g, 20 mmol, 2 eq.), MgI2 (5.56 g, 20 mmol, 2 eq.), and 2-methyltetrahydrofuran (14 mL). Stir and react at 30°C for 15 h (TLC analysis indicated a significant amount of starting material remaining). Add 10% aqueous NaCl (28 mL) to quench the reaction, allow the phases to separate, and obtain a solution of II-2 in 2-methyltetrahydrofuran, which is used directly in the next step.

[0145] Step 2: To the above solution of II-2 in 2-methyltetrahydrofuran, add KOH (1.68 g, 30 mmol, 3 eq.) and water (10 mL). Stir the reaction at 65°C for 1.5 h. Concentrate the reaction solution until almost no fraction is released. Adjust the pH to 3 with concentrated hydrochloric acid, and extract with ethyl acetate (20 mL) to obtain an ethyl acetate solution. Add benzylamine (1.29 g, 12 mmol, 1.2 eq.) to the above ethyl acetate solution. Stir at room temperature for 2 h, filter, and wash to obtain 1.34 g of III-2, with a yield of 43.0% and a purity of 96.0%.

[0146] Comparative Example 3: ZnCl2 as a catalyst reaction

[0147]

[0148] Step 1: Combine I-2 (2.06 g, 10 mmol, 1 eq.), TMSCN (1.98 g, 20 mmol, 2 eq.), ZnCl2 (2.72 g, 20 mmol, 2 eq.), and 2-methyltetrahydrofuran (14 mL). Stir and react at 65°C for 10 h (only a small amount of product was produced by TLC). 10% aqueous NaCl solution (28 mL) was added to quench the reaction. The phases were allowed to separate, yielding a solution of II-2 in 2-methyltetrahydrofuran, which was used directly in the next step.

[0149] Step 2: To the above solution of II-2 in 2-methyltetrahydrofuran, add KOH (1.68 g, 30 mmol, 3 eq.) and water (10 mL). Stir the mixture at 65°C for 2 h. Concentrate the reaction mixture until almost no fraction is released. Adjust the pH to 3 with concentrated hydrochloric acid, and extract with ethyl acetate (20 mL) to obtain an ethyl acetate solution. Add benzylamine (1.29 g, 12 mmol, 1.2 eq.) to the above ethyl acetate solution. Stir at room temperature for 2 h, filter, and wash to obtain 0.63 g of III-2, a 20.1% yield with a purity of 80.5%.

Claims

1. A method for preparing a compound of formula II, comprising the following steps: In the presence of a catalyst, the compound of formula I is subjected to an addition reaction with trimethylsilyl cyanide in a first solvent to obtain a solution of the compound of formula II; in, R 1 and R 2 Each independently represents hydrogen, -COOH, -COO-C 1-15 Alkyl or -COO-CH2-C 6-20 Aryl, but not hydrogen; preferably hydrogen, -COOH, -COO-C 1-12 Alkyl or -COO-CH2-C 6-15 Aryl, but not hydrogen; more preferably hydrogen, -COOH, -COO-C 1-8 Alkyl or -COO-CH2-C 6-12 Aryl, but not hydrogen; further preferably hydrogen, -COOH, -COO-C 1-6 Alkyl or -COO-CH2-C 6-10 Aryl, but not hydrogen at the same time; further preferably hydrogen, -COOH, -COOCH3, -COOEt, -COOtBu or -COO-CH2-C6H5, but not hydrogen at the same time; most preferably hydrogen, -COOEt or -COO-CH2-C6H5, but not hydrogen at the same time.

2. The preparation method according to claim 1, characterized in that The catalyst is a magnesium salt or a quaternary ammonium salt, preferably MgI2 or tetrabutylammonium fluoride, more preferably MgI2.

3. The preparation method according to claim 1 or 2, characterized in that The first solvent is an ether solvent, preferably methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or ethylene glycol dimethyl ether, more preferably tetrahydrofuran.

4. The preparation method according to any one of claims 1 to 3, characterized in that The temperature of the addition reaction is 50-120°C, preferably 55-80°C.

5. A method for preparing a compound of formula III, comprising the following steps: The solution of the compound of formula II is subjected to a hydrolysis reaction with an alkaline solution, an acid is added to adjust the pH to a target value, a second solvent is added for extraction, and an organic amine is added to carry out a salt-forming reaction to obtain a compound of formula III; in, R 1 and R 2 Each independently represents hydrogen, -COOH, -COO-C 1-15 Alkyl or -COO-CH2-C 6-20 Aryl, but not hydrogen; preferably hydrogen, -COOH, -COO-C 1-12 Alkyl or -COO-CH2-C 6-15 Aryl, but not hydrogen; more preferably hydrogen, -COOH, -COO-C 1-8 Alkyl or -COO-CH2-C 6-12 Aryl, but not hydrogen; further preferably hydrogen, -COOH, -COO-C 1-6 Alkyl or -COO-CH2-C 6-10 Aryl, but not hydrogen at the same time; further preferably hydrogen, -COOH, -COOCH3, -COOEt, -COOtBu or -COO-CH2-C6H5, but not hydrogen at the same time; most preferably hydrogen, -COOEt or -COO-CH2-C6H5, but not hydrogen at the same time; Preferably, the preparation method further comprises the following steps: A solution of the compound of formula II is obtained according to the preparation method according to any one of claims 1 to 4.

6. The preparation method according to claim 5, characterized in that The organic amine is R-NH2, wherein R is C 1-4 Alkyl or C 3-6 Cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by C 6-10 The aryl group is substituted, preferably (R)-1-phenylethylamine, tert-butylamine, n-butylamine, benzylamine or cyclohexylamine, more preferably cyclohexylamine.

7. The preparation method according to claim 5 or 6, characterized in that: The second solvent is an ether, ketone, hydrocarbon or ester solvent, preferably methyl tert-butyl ether, acetone, toluene or ethyl acetate, more preferably toluene or ethyl acetate.

8. A method for preparing a compound of formula IV, comprising the following steps: In the presence of a metal catalyst, the compound of formula III is subjected to a hydrogenation reaction in a third solvent, an alkaline solution is added, the metal catalyst is removed, a fourth solvent is added for extraction, and an acid is added to adjust the pH to a target value to obtain a compound of formula IV; Preferably, the preparation method further comprises the following steps: The compound of formula III is obtained according to the preparation method according to any one of claims 5 to 7.

9. The preparation method according to claim 8, characterized in that The metal catalyst is Raney nickel or palladium carbon, preferably Raney nickel, 5% palladium carbon or 10% palladium carbon, more preferably Raney nickel.

10. A method for preparing a benzenesulfonate salt of a compound of formula IV, comprising the following steps: The compound of formula IV is salified with benzenesulfonic acid to obtain a benzenesulfonate salt of the compound of formula IV; Preferably, the salt formation is carried out in a fifth solvent; and / or, The fifth solvent is a single solvent or a mixed solvent, preferably water, anisole, acetone, acetonitrile, water-acetone, water-acetonitrile, more preferably anisole; More preferably, the preparation method further The following steps are involved: The compound of formula IV is obtained according to the preparation method according to claim 8 or 9.

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