Salt form of γ-aminobutyric acid derivative, crystal form thereof and preparation method therefor

Abstract

The present application belongs to the field of medicinal chemistry, and specifically relates to a salt form of a γ-aminobutyric acid derivative. Disclosed are a benzenesulfonate of the γ-aminobutyric acid derivative, a crystal form thereof and a preparation method therefor. The benzenesulfonate and the crystal form thereof have good physicochemical properties, and have a good stability, solubility, and bioavailability.

Description

Salt form, crystal form and preparation method of a γ-aminobutyric acid derivative Technical Field

[0001] This application belongs to the field of medicinal chemistry, specifically relating to pharmaceutically acceptable salt forms, crystal forms, and preparation methods of compounds of Formula I. Background Technology

[0002] Chronic neuropathic pain (CNP) is pain caused by nerve damage from various causes, such as long-term diabetes, certain viral infections, cancer, central nervous system damage, and the use of certain chemotherapy drugs. Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are two of the most common types of chronic neuropathic pain.

[0003] The main medications for treating chronic neuropathic pain currently fall into three categories: antidepressants, anticonvulsants (antiepileptics), and analgesics. Antidepressants used to treat chronic neuropathic pain can be broadly classified into tricyclic antidepressants and other antidepressants. Tricyclic antidepressants include amitriptyline, maprotiline, clomipramine, and doxepin. Tricyclic antidepressants have numerous side effects, such as anticholinergic effects (dry mouth, constipation, blurred vision, drowsiness, weight gain, etc.), central nervous system toxicity (poor concentration, seizures, social behavioral abnormalities, hallucinations, etc.), and cardiovascular toxicity (hypotension, tachycardia, arrhythmias, etc.). There are many precautions to take when using these drugs in combination, and drug interactions are complex. Other antidepressants are mostly selective serotonin and / or norepinephrine reuptake inhibitors, such as imipramine, paroxetine, fluoxetine, escitalopram, duloxetine, bupropion, venlafaxine, and sertraline. There are many precautions to take when using antidepressants in combination, and drug interactions are complex, posing significant challenges to clinical medication and patient compliance. Antiepileptic drugs used to treat chronic neuropathic pain are mainly sodium and calcium channel blockers, such as gabapentin, pregabalin, lamotrigine, topiramate, carbamazepine, oxcarbazepine, and sodium valproate. Gabapentin requires very high doses, needing to be between 1800 and 3600 mg daily for optimal effect; absorption saturation occurs at higher doses, resulting in a slower onset of action (it takes about two weeks to take effect after oral administration). Sodium channel blockers, such as lamotrigine and topiramate, have many adverse reactions, such as rash, nausea and vomiting, dizziness, fatigue, and blurred vision. There are also many precautions to take when using them in combination, and drug interactions are complex. Analgesics used to treat chronic neuropathic pain include opioids and tramadol, tapentadol, etc., the latter two of which incorporate a significant proportion of opioid mechanisms of action. Opioids have some effect on nerve pain, but the effect is not strong, there are many side effects, and they are addictive.Studies have shown that duloxetine at doses of 60 mg / day and 120 mg / day had clinical efficacy rates of only 49% and 52%, respectively, for the treatment of diabetic peripheral neuropathy (Goldstein, DJ; et al. Pain, 2005, 116(1-2), 109-118). Gabapentin at daily doses of up to 1800 mg / day, 2400 mg / day, and 3600 mg / day had clinical efficacy rates of 32%, 34%, and 43%, respectively, for postherpetic neuralgia (Rice, ASC; et al. Pain, 2001, 94(2), 215-224; Rowbotham, M.; et al.). (al.JAMA,1998,280(21),1837-1842.); When pregabalin is administered at 150-600 mg daily, the clinical efficacy rate for postherpetic neuralgia is 26%-50% (Dworkin,RH; et al.Neurology,2003,60(8),1274-1283; Sabatowski,R.; et al.Pain,2004,109(1-2),26-35.). These very low clinical efficacy data reflect the current dilemma of marketed drugs in terms of treatment efficacy: there is currently no specific drug for this type of disease, and there is no simple treatment plan that can prevent or reverse neurological lesions or completely relieve pain.

[0004] The α2δ subunit of voltage-gated calcium channels is an important target for drugs treating this disease. Pregabalin, one of the four FDA-approved drugs for diabetic peripheral neuropathy (pregabalin, duloxetine, fluoxetine, and tapentadol), targets this subunit (Field, MJ; et al. Proc. Natl. Acad. Sci. USA, 2006, 103, 17537-17542). In addition to treating chronic neuropathic pain, voltage-gated calcium channel α2δ subunit ligands, such as gabapentin, pregabalin, and mirogabalin, can also be used for anti-epileptic purposes (pregabalin, FDA-approved indication) and anti-anxiety purposes (pregabalin, EMA-approved indication).

[0005] WO2024093678A1 discloses the compound shown in Formula I, which is a voltage-gated calcium ion channel α2δ subunit ligand containing a polycyclic γ-aminobutyric acid structure.

[0006] Different salt forms of the same drug may exhibit significant differences in aspects such as melting point, density, solubility, stability, hygroscopicity, and bioavailability, thus affecting the drug's stability, bioavailability, and efficacy. Generally, stable salt forms have higher melting points, lower solubility, and slower dissolution rates; unstable salt forms, on the other hand, have the opposite characteristics. Selecting the most thermodynamically stable salt form can ensure the quality of the active pharmaceutical ingredient remains stable during production and storage. However, stable salt forms often have poor bioavailability due to their lower solubility. Therefore, developing salt forms of compounds represented by Formula I that simultaneously balance stability and solubility, and are more conducive to large-scale production, formulation development, and clinical trials, is of great significance. Summary of the Invention

[0007] This application discloses a salt form of the compound shown in Formula I, and discloses its benzenesulfonate, crystal form and preparation method. The benzenesulfonate has good physicochemical properties, good stability, solubility and bioavailability, which is beneficial for the subsequent processing, storage and transportation of the drug.

[0008] This application provides a pharmaceutically acceptable salt of a compound represented by Formula I, wherein the salt is an acid salt, a zwitterionic salt (internal salt), or a quaternary ammonium salt formed with an organic acid and / or an inorganic acid:

[0009] In some embodiments, the pharmaceutically acceptable salt is a compound represented by Formula II:

[0010] The HA is an organic acid or an inorganic acid.

[0011] In some embodiments, the organic acid is selected from benzenesulfonic acid, acetic acid, benzoic acid, propionic acid, oxalic acid, 4-aminosalicylic acid, ascorbic acid, p-toluenesulfonic acid, phthalic acid, butyric acid, camphorsulfonic acid, camphoric acid, cinnamic acid, 2,2-dichloroacetic acid, formic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, citric acid, fumaric acid, hippuric acid, glycolic acid, lactic acid, maleic acid, malonic acid, glutamic acid, salicylic acid, trifluoroacetic acid, aspartic acid, malic acid, succinic acid, gluconic acid, and tartaric acid; and the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, and sulfuric acid.

[0012] In some embodiments, the pharmaceutically acceptable salt is a benzenesulfonate, acetate, benzoate, propionate, oxalate, 4-aminosalicylate, ascorbate, p-toluenesulfonate, phthalate, butyrate, camphorsulfonate, camphorate, cinnamate, 2,2-dichloroacetate, formate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, citrate, fumarate, hydrochloride, hippurate, glycolate, hydrobromide, hydroiodate, lactate, maleate, malonate, glutamate, nitrate, phosphate, salicylate, perchlorate, trifluoroacetate, sulfate, aspartate, malate, succinate, gluconate, or tartrate. In some embodiments, the pharmaceutically acceptable salt is a benzenesulfonate.

[0013] This application provides a compound of Formula III:

[0014] In this application, the chemical name of the compound represented by Formula III is 2-((1R,2S,3R,5R,6S)-3-(aminomethyl)tricyclo[4.2.1.0] 2,5 Non-7-en-3-yl)acetic acid benzenesulfonate.

[0015] This application provides a method for preparing the compound shown in Formula III above.

[0016] In some embodiments, the preparation method of the compound represented by Formula III includes: step M-1) or step M-2):

[0017] In some embodiments, M-1) comprises: reacting the compound of formula IX with benzenesulfonic acid to obtain the compound of formula III;

[0018] in,

[0019] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups.

[0020] In some embodiments, R3 is selected from C1 to C6 alkyl groups, preferably butyl (e.g., -C(CH3)3).

[0021] In some embodiments, M-1) comprises: reacting the compound of formula IX with benzenesulfonic acid under solvent conditions to obtain the compound of formula III; in some embodiments, the solvent in M-1) is selected from tetrahydrofuran.

[0022] In some embodiments, M-1) comprises: reacting the compound of formula IX with benzenesulfonic acid under reflux to obtain the compound of formula III.

[0023] In some embodiments, M-1) comprises a molar ratio of the compound of formula IX to benzenesulfonic acid of 1:(1.0-3.0); for example, 1:1.0, 1:1.5, or 1:3.0. In some embodiments, the molar ratio of the compound of formula VIII to benzenesulfonic acid is selected from 1:1.5.

[0024] In some embodiments, M-2) comprises: reacting the compound of formula I with benzenesulfonic acid to obtain the compound of formula III;

[0025] In some embodiments, M-2) further includes a molar ratio of the compound of formula I to benzenesulfonic acid of 1:(1.0-3.0); for example, 1:1.0, 1:1.5, or 1:3.0. In some embodiments, the molar ratio of the compound of formula VIII to benzenesulfonic acid is selected from 1:1.5.

[0026] In some embodiments, M-2) further includes: a method for preparing the compound represented by Formula I.

[0027] In some embodiments, the preparation method of the compound represented by Formula I includes: ester hydrolysis of the compound represented by Formula IX to obtain the compound represented by Formula I;

[0028] in,

[0029] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups.

[0030] In some embodiments, R3 is selected from C1 to C6 alkyl groups, preferably butyl (e.g., -C(CH3)3).

[0031] In some embodiments, the ester hydrolysis of the compound represented by Formula IX is performed by hydrolyzing the compound represented by Formula IX under alkaline or acidic conditions; in some embodiments, the alkaline conditions are achieved by adding an alkaline reagent selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, or combinations thereof; in some embodiments, the acidic conditions are achieved by adding an acidic reagent selected from trifluoroacetic acid.

[0032] In some embodiments, the ester hydrolysis of the compound represented by formula IX is performed by ester hydrolysis of the compound represented by formula IX under solvent conditions; in some embodiments, the solvent is selected from dichloromethane, tetrahydrofuran, methanol, ethanol, or combinations thereof.

[0033] In some embodiments, the method for preparing the compound represented by Formula III further includes the method for preparing the compound represented by Formula IX.

[0034] This application provides a method for preparing the compound shown in Formula IX above.

[0035] In some embodiments, the preparation method of the compound shown in Formula III includes: freeing the compound shown in Formula VIII to obtain the compound shown in Formula IX;

[0036] in,

[0037] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0038] X is the resolving reagent.

[0039] In some embodiments, R3 is selected from C1-C6 alkyl groups, preferably butyl (e.g., -C(CH3)3). In some embodiments, the resolving agent is selected from chiral acids. In some embodiments, the resolving agent is selected from (S)-(+)-O-acetylmandelic acid, (S)-(+)mandelic acid, Boc-D-phenylglycine, or combinations thereof; in some embodiments, the resolving agent is selected from Boc-D-phenylglycine.

[0040] In some embodiments, the compound represented by Formula VIII is released under alkaline conditions. In some embodiments, this release is achieved by adding an alkaline reagent. In some embodiments, the alkaline reagent is selected from an aqueous solution of Na₂CO₃.

[0041] In some embodiments, the compound represented by Formula VIII is freed by the compound represented by Formula VIII being freed under solvent conditions; in some embodiments, the solvent is selected from dichloromethane.

[0042] In some embodiments, the preparation method of the compound represented by Formula III includes reacting the compound represented by Formula VIII with benzenesulfonic acid in a molar ratio of 1:(1.0-5.0), for example 1:1.0, 1:2.0, or 1:5.0. In some embodiments, the molar ratio of the compound represented by Formula VIII to benzenesulfonic acid is selected from 1:2.0.

[0043] This application provides a method for preparing the compound shown in Formula IX above.

[0044] In some embodiments, the method for preparing the compound represented by Formula III further includes the method for preparing the compound represented by Formula IX.

[0045] In some embodiments, the preparation method of the compound represented by Formula IX includes: freeing the compound represented by Formula VIII to obtain the compound represented by Formula IX;

[0046] in,

[0047] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0048] X is the resolving reagent.

[0049] In some embodiments, the compound represented by formula VIII is released under alkaline conditions; in some embodiments, the release is achieved by adding an alkaline reagent; in some embodiments, the alkaline reagent is selected from an aqueous solution of Na2CO3.

[0050] In some embodiments, the compound represented by Formula VIII is freed by the compound represented by Formula VIII being freed under solvent conditions; in some embodiments, the solvent is selected from dichloromethane.

[0051] This application provides a method for preparing the compound shown in Formula VIII above, which includes step L-1) or step L-2).

[0052] In some embodiments, the method for preparing the compound represented by Formula III further includes: (L-1) or (L-2).

[0053] In some embodiments, L-1) comprises: the compound of formula (±)VI undergoing a reduction reaction and then reacting with the resolving agent X to obtain the compound of formula VIII;

[0054] In some embodiments, the reaction with the resolving agent in L-1 is a resolving reaction occurring under conditions of a good solvent and an antisolvent; in some specific embodiments, the good solvent is selected as tetrahydrofuran; in some specific embodiments, the antisolvent is selected as isopropyl ether.

[0055] In some embodiments, in L-1), the molar ratio of the compound represented by formula (±)VI to the resolving agent is 1:(0.5-1.0), for example 1:0.5, 1:0.75 or 1:1.0; in some embodiments, the molar ratio of the compound represented by formula (±)VI to the resolving agent is 1:0.75.

[0056] In some embodiments, L-2) comprises: after the compound of formula (±) VII is freed, it undergoes a resolution reaction with the resolving agent X to obtain the compound of formula VIII;

[0057] in,

[0058] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0059] HB is an acidic reagent.

[0060] In some embodiments, the acidic reagent is selected from ammonium chloride, sodium dihydrogen phosphate, or a combination thereof.

[0061] In some embodiments, in L-2), the freeing of the compound represented by formula (±)VII means the freeing of the compound represented by formula (±)VII under alkaline conditions; in some embodiments, the freeing is achieved by adding an alkaline reagent; in some embodiments, the alkaline reagent is selected from an aqueous solution of Na2CO3.

[0062] In some embodiments, the resolution reaction in L-2) occurs under solvent conditions; in some embodiments, the resolution reaction occurs under conditions of a good solvent and an anti-solvent; in some specific embodiments, the good solvent is tetrahydrofuran; in some specific embodiments, the anti-solvent is isopropyl ether.

[0063] In some embodiments, in L-2), the molar ratio of the compound represented by formula (±)VII to the resolving agent is 1:(0.3-0.8), for example 1:0.3, 1:0.5, or 1:0.8. In some embodiments, the molar ratio of the compound represented by formula (±)VII to the resolving agent is 1:0.5.

[0064] This application provides a method for preparing the compound represented by formula (±)VII.

[0065] In some embodiments, the method for preparing the compound represented by Formula III further includes the method for preparing the compound represented by Formula (±)VII.

[0066] In some embodiments, the preparation method of the compound represented by formula (±)VII includes: after the compound represented by formula (±)VI undergoes a reduction reaction, it reacts with HB to form a salt, thereby obtaining the compound represented by formula (±)VII;

[0067] in,

[0068] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0069] HB is an acidic reagent.

[0070] In some embodiments, the reduction reaction of the compound represented by formula (±)VI is a reduction reaction of the compound represented by formula (±)VI under reducing agent conditions; in some embodiments, the reducing agent is selected from zinc powder, iron powder, or a combination thereof; in some embodiments, the reduction reaction of the compound represented by formula (±)VI is a reduction reaction of the compound represented by formula (±)VI under reducing agent and acidic reagent conditions; in some embodiments, the acidic reagent is selected from ammonium chloride, sodium dihydrogen phosphate, or a combination thereof.

[0071] In some embodiments, the reduction reaction of the compound represented by formula (±)VI is a reduction reaction of the compound represented by formula (±)VI under solvent conditions; in some embodiments, the solvent is selected from methanol.

[0072] In some embodiments, the salt-forming reaction is a salt-forming reaction under solvent conditions; the solvent is selected from 1,4-dioxane, acetonitrile, tetrahydrofuran, toluene, or combinations thereof.

[0073] In some embodiments, the method for preparing the compound represented by Formula III further includes the method for preparing the compound represented by Formula (±)VI.

[0074] In some embodiments, the preparation method of the compound represented by formula (±)VI includes: reacting the compound represented by formula (±)V with nitromethane to obtain the compound represented by formula (±)VI;

[0075] in,

[0076] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups.

[0077] In some embodiments, the compound represented by formula (±)V undergoes a Michael addition reaction with nitromethane to yield the compound represented by formula (±)VI.

[0078] In some embodiments, the compound represented by formula (±)V and nitromethane react under alkaline conditions to obtain the compound represented by formula (±)VI; in some embodiments, the alkaline conditions are achieved by adding an alkaline reagent selected from inorganic bases, organic bases, or combinations thereof; in some embodiments, the alkaline reagent is selected from potassium tert-butoxide, sodium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, or combinations thereof; in some embodiments, the alkaline reagent is selected from 1,5-diazabicyclo[4.3.0]non-5-ene.

[0079] In some embodiments, the reaction temperature of the compound represented by formula (±)V and the nitromethane is 50-120°C; in some embodiments, the reaction temperature of the compound represented by formula (±)V and the nitromethane is 70-80°C.

[0080] In some embodiments, in the preparation method of the compound represented by formula (±)VI, the molar ratio of the compound represented by formula (±)V to the nitromethane is 1:(1.0-5.0), for example 1:1.0, 1:2.0 or 1:5.0; in some embodiments, the molar ratio of the compound represented by formula (±)V to the nitromethane is 1:2.0.

[0081] In some embodiments, the method for preparing the compound represented by Formula III further includes the method for preparing the compound represented by Formula (±)V.

[0082] In some embodiments, the preparation method of the compound represented by formula (±)V includes: reacting compound (±)01 with the compound represented by formula IV to obtain the compound represented by formula (±)V;

[0083] in,

[0084] R1 and R2 are each independently selected from C1 to C6 alkyl groups;

[0085] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups.

[0086] In some embodiments, the compound (±)01 and the compound shown in Formula IV undergo a Wittig condensation reaction to obtain the compound shown in Formula V.

[0087] In some embodiments, the compound (±)01 and the compound shown in formula IV react under alkaline conditions to obtain the compound shown in formula (±)V; in some embodiments, the alkaline conditions are achieved by adding an alkaline reagent selected from organic bases, inorganic bases, or combinations thereof; in some embodiments, the alkaline reagent is selected from sodium tert-butoxide, potassium tert-butoxide, or combinations thereof.

[0088] In some embodiments, the compound (±)01 and the compound shown in Formula IV react under solvent conditions to give the compound shown in Formula (±)V; in some embodiments, the solvent is selected from tetrahydrofuran, acetonitrile, toluene, 1,4-dioxane, dimethyl sulfoxide, methyltetrahydrofuran or combinations thereof; in some embodiments, the solvent is selected from tetrahydrofuran.

[0089] In some embodiments, the reaction temperature of compound (±)01 and the compound represented by formula IV is -10 to 50°C; in some embodiments, the reaction temperature of compound (±)01 and the compound represented by formula IV is 0 to 10°C.

[0090] In some embodiments, in the preparation method of the compound represented by formula (±)V, the molar ratio of the compound (±)01 and the compound represented by formula IV is 1:(1.0-5.0), for example 1:1.0, 1:1.0, 1:5.0, or 1:1.2.

[0091] In some embodiments, the method for preparing the compound represented by Formula III includes:

[0092] 1) Preparation of the compound shown in formula (±)V:

[0093] Compound (±)01 reacts with the compound shown in Formula IV to give the compound shown in Formula V;

[0094] 2) Preparation of the compound shown in formula (±)VI:

[0095] The compound shown in formula (±)V reacts with nitromethane to give the compound shown in formula (±)VI;

[0096] 3) Preparation of the compound shown in Formula VIII:

[0097] The compound shown in formula (±)VI of L-1 undergoes a reduction reaction and then reacts with a resolving agent to obtain the compound shown in formula VIII.

[0098] Alternatively, after the compound shown in formula (±)VI of L-2 undergoes a reduction reaction, it reacts with HB to form a salt, yielding the compound shown in formula (±)VII.

[0099] The compound shown in formula (±) VII, after being released, undergoes a resolution reaction with a resolving agent to obtain the compound shown in formula VIII;

[0100] 4) Preparation of the compound shown in Formula IX:

[0101] The compound shown in formula VIII was released to obtain the compound shown in formula IX;

[0102] 5) Preparation of the compound shown in Formula III:

[0103] The compound of formula IX (M-1) reacts with benzenesulfonic acid to give the compound of formula III; or

[0104] Hydrolysis of the compound shown in Formula IX (M-2) yields the compound shown in Formula I.

[0105] The compound of Formula I reacts with benzenesulfonic acid to give the compound of Formula III.

[0106] in,

[0107] R1 and R2 are each independently selected from C1 to C6 alkyl groups;

[0108] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0109] HB is an acidic reagent;

[0110] X is the resolving reagent.

[0111] In some embodiments, the resolving agent is selected from chiral acids. In some embodiments, the resolving agent is selected from (S)-(+)-O-acetylmandelic acid, (S)-(+)mandelic acid, Boc-D-phenylglycine, or combinations thereof; in some embodiments, the resolving agent is selected from Boc-D-phenylglycine.

[0112] In some embodiments, the resolving agent does not include (S)-(+)mandelic acid.

[0113] In some embodiments, the HB is selected from organic or inorganic acids. In some embodiments, the HB is selected from p-toluenesulfonic acid, Boc-D-phenylglycine, or combinations thereof. In some specific embodiments, the HB is selected from Boc-D-phenylglycine.

[0114] In some embodiments, the HB does not include p-toluenesulfonic acid.

[0115] In some embodiments, R1 is -CH3. In some embodiments, R2 is -CH3. In some embodiments, R3 is -C(CH3)3.

[0116] This application provides a compound of formula (±)VII:

[0117] in,

[0118] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0119] HB is an acidic reagent, and HB does not include p-toluenesulfonic acid.

[0120] In some embodiments, the compound represented by formula (±)VII is compound (±)05;

[0121] This application provides a compound of formula IX or a salt thereof:

[0122] in,

[0123] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups.

[0124] In some embodiments, the compound represented by Formula IX is compound 07:

[0125] In some embodiments, the salt of the compound represented by Formula IX is the compound represented by Formula VIII:

[0126] in,

[0127] R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups;

[0128] X is a resolving agent, which does not include (S)-(+)-mandelate.

[0129] In some embodiments, the compound represented by formula VIII is compound 06:

[0130] This application provides a crystal form of the compound shown in Formula III:

[0131] In some embodiments, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at one or more of the following 2θ angles: 6.0±0.2°, 11.9±0.2°, and 23.8±0.2°.

[0132] In some embodiments, the X-ray powder diffraction pattern of the crystal form also has characteristic peaks at one or more of the 2θ angles of 29.9±0.2° and 36.0±0.2°; in some embodiments, the X-ray powder diffraction pattern of the crystal form also has characteristic peaks at one or more of the 2θ angles of 28.0±0.2°, 29.9±0.2°, and 36.0±0.2°. In some embodiments, the X-ray powder diffraction pattern of the crystal form also has characteristic peaks at the 2θ angles of 28.0±0.2°, 29.9±0.2°, and 36.0±0.2°.

[0133] In some embodiments, the X-ray powder diffraction patterns of the crystal form are at 2θ angles of 6.0±0.2°, 11.9±0.2°, and 23.8±0.2°.

[0134] Characteristic peaks are observed at 29.9±0.2° and 36.0±0.2°. In some embodiments, the X-ray powder diffraction pattern of the crystal form exhibits characteristic peaks at 2θ angles of 6.0±0.2°, 11.9±0.2°, 23.8±0.2°, 28.0±0.2°, 29.9±0.2°, and 36.0±0.2°.

[0135] In some embodiments, the X-ray powder diffraction pattern of the crystal form also has characteristic peaks at one or more of the following 2θ angles: 17.8±0.2°, 28.0±0.2°, 29.9±0.2°, 31.6±0.2°, 32.9±0.2°, 33.4±0.2°, 35.2±0.2°, and 36.0±0.2°; in some embodiments, the X-ray powder diffraction pattern of the crystal form also has characteristic peaks at the following 2θ angles: 17.8±0.2°, 28.0±0.2°, 29.9±0.2°, 31.6±0.2°, 32.9±0.2°, 33.4±0.2°, 35.2±0.2°, and 36.0±0.2°. In some embodiments, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 6.0±0.2°, 11.9±0.2°, 17.8±0.2°, 23.8±0.2°, 28.0±0.2°, 29.9±0.2°, and 36.0±0.2°. In some embodiments, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 6.0±0.2°, 11.9±0.2°, 17.8±0.2°, 23.8±0.2°, 28.0±0.2°, 29.9±0.2°, 33.4±0.2°, and 36.0±0.2°.

[0136] In some embodiments, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at one or more 2θ angles as shown in Table 2. In some embodiments, the 2θ angles of the X-ray powder diffraction pattern of the crystal form are shown in Table 2. In some embodiments, the crystal form has the relative intensities of the characteristic peaks of the X-ray powder diffraction patterns shown in Table 2.

[0137] "One or more places" means 1 or 2 places, 1 or 3 places, 1 or 4 places, 1 or 5 places, 1 or 6 places, 1 or 7 places, or 1 or 8 places.

[0138] In some embodiments, the X-ray powder diffraction pattern of the crystal form is essentially as shown in Figure 1.

[0139] In some embodiments, the TGA spectrum of the crystal form shows a weight loss of approximately 0.10% in the range of 30°C to 105°C.

[0140] In some embodiments, the TGA pattern of the crystal form is basically as shown in Figure 2.

[0141] In some embodiments, the DSC spectrum of the crystal form has an endothermic peak around 206.46°C.

[0142] In some embodiments, the DSC spectrum of the crystal form is basically as shown in Figure 3.

[0143] This application provides a method for preparing the crystal form of the compound shown in Formula III, comprising: mixing and suspending the compound shown in Formula III with solvent I.

[0144] In some embodiments, solvent I is one or more selected from acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyl carbonate, ethyl formate, methyl tert-butyl ether, petroleum ether, anisole, ethylene glycol dimethyl ether, dichloromethane, cyclohexane, n-heptane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene. In some embodiments, solvent I is ethyl acetate.

[0145] In some embodiments, the suspension is a room temperature stirred suspension.

[0146] This application provides a method for preparing the crystal form of the compound shown in Formula III, comprising: dissolving the compound shown in Formula III in solvent II, mixing the dissolved compound with solvent III, and then crystallizing.

[0147] In some embodiments, solvent II is selected from one or more of ethanol, trifluoroethanol, isopropanol, dimethyl sulfoxide, hexafluoroisopropanol, and ethylene glycol methyl ether.

[0148] In some embodiments, solvent III is selected from one or more of acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyl carbonate, ethyl formate, methyl tert-butyl ether, anisole, ethylene glycol dimethyl ether, dichloromethane, cyclohexane, n-heptane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene.

[0149] In some embodiments, solvent II is selected from ethanol, trifluoroethanol, isopropanol, and dimethyl sulfoxide, and solvent III is selected from ethyl acetate, methyl isobutyl ketone, methyl tert-butyl ether, and isopropyl acetate. In some embodiments, solvent II and solvent III are selected from: (1) ethanol and ethyl acetate; (2) trifluoroethanol and methyl isobutyl ketone; (3) isopropanol and methyl tert-butyl ether; and (4) dimethyl sulfoxide and isopropyl acetate.

[0150] In some embodiments, the dissolution is ultrasonic dissolution.

[0151] In some embodiments, the crystallization is performed by stirring at room temperature.

[0152] The beneficial effects of this application are:

[0153] This application provides multiple salt forms of the compounds shown in Formula I, providing a basis for the selection of drug solid forms.

[0154] This application provides benzenesulfonate of the compound shown in Formula I (compound shown in Formula III), which has excellent physical and chemical stability, and high solubility and bioavailability.

[0155] This application provides a mild and simple preparation method for the benzenesulfonate salt of the compound shown in Formula I (the compound shown in Formula III), with good process reproducibility, which makes the conditions for industrial production controllable and conducive to large-scale industrialization.

[0156] The compound shown in Formula III provided in this application exhibits excellent physical and chemical stability and superior bioavailability in animals. max Superior, faster onset of action, and lower exposure (C max It has a higher AUC, which is beneficial for clinical use; it has a voltage-gated calcium ion channel α2δ binding effect, and can be used as an active ingredient in the preparation of drugs for treating chronic neuropathic pain, epilepsy, and anxiety. Unexpectedly, compared with other salt forms of the compound shown in Formula I, the compound shown in Formula III provided in this application maintains a high melting point and thermal stability while also exhibiting high solubility and low hygroscopicity. The crystal form of the compound shown in Formula III possesses good solubility and stability, excellent overall performance, and excellent bioavailability in vivo, which is beneficial for clinical use. Furthermore, the preparation conditions for the crystal form of the compound shown in Formula III of this application are mild, the operation is simple, the process has good reproducibility, and the purity is high, making it suitable for industrial production. Attached Figure Description

[0157] Figure 1 shows the XRD pattern of the compound sample represented by Formula III.

[0158] Figure 2 shows the TGA spectrum of the compound sample represented by Formula III.

[0159] Figure 3 shows the DSC spectrum of the compound sample represented by Formula III. Detailed Implementation

[0160] To make this application easier to understand, the following detailed description will be provided with reference to embodiments. These embodiments are for illustrative purposes only and are not limited to the scope of application of this application.

[0161] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0162] The abbreviations used in this application are explained as follows:

[0163] XRD: X-ray powder diffraction

[0164] The X-ray powder diffraction (XRD) tests described in this application were performed using a Malvern-Panaco Empyrea powder diffractometer, and the specific parameters are shown in Table 1:

[0165] Table 1 Test parameters for X-ray powder diffraction (XRD)

[0166] In the X-ray powder diffraction pattern of this application, the error of the 2θ diffraction angle is ±0.20°. In this document, "the X-ray powder diffraction pattern is basically as shown in Figure 1" means that the X-ray powder diffraction pattern is substantially the same as that in Figure 1. The term "substantially the same" in X-ray powder diffraction pattern means that the aforementioned errors in the position and intensity of representative peaks are taken into account.

[0167] TGA: Thermogravimetric Analysis

[0168] The thermogravimetric analysis (TGA) described in this application was performed using a METTLER TOLEDO TGA-2 instrument with a heating rate of 10℃ / min and a temperature range of 30–300℃. The nitrogen purging rate during the test was 20 mL / min.

[0169] The error of TGA can be within approximately ±0.5% of mass. In this article, "the TGA spectrum is basically as shown in Figure 2" means that the TGA spectrum is basically the same as Figure 2. The term "basically the same" for the TGA spectrum means that this error variation is taken into account.

[0170] DSC: Differential Scanning Calorimetry

[0171] The differential scanning calorimetry (DSC) measurements described in this application were performed using a METTLER TOLEDO DSC-1 instrument with a heating rate of 10 °C / min and a temperature range of 25–250 °C. The nitrogen purging rate during the test was 50 mL / min.

[0172] The error of DSC can be within approximately ±5℃. In this article, "the DSC spectrum is basically as shown in Figure 3" means that the DSC spectrum is basically the same as Figure 3. The term "basically the same" in DSC spectrum means that this error variation is taken into account.

[0173] The compounds of this application may contain one or more isotopic forms, namely, hydrogen isotopes of D or T, or isotopes of any atom, such as all isotopes of C and N. Any isotopic forms of C, N, or H in compounds with optional structures in this application are covered within the scope of protection of this application. In this application, the term "deuterated compound" means that a hydrogen atom at any position in the compound of formula (I) of this application is replaced by deuterium (i.e., D), and the amount of deuterium at that position is far greater than (e.g., at least 1000 times greater) the abundance of naturally occurring deuterium.

[0174] The term "room temperature" as used in this application refers to a temperature of 10–30°C, for example, 10–25°C.

[0175] In this article, unless otherwise stated, percentages are mass percentages.

[0176] In this article, the compound represented by formula I is:

[0177] In this article, the compound represented by formula III is:

[0178] Example CN202211372369.6 discloses a method for preparing p-toluenesulfonate of the compound shown in Formula I:

[0179] Example 3 discloses (±)-18→(±)-20, with a combined yield of 29%;

[0180] Example 4 discloses (±)-20→(±)-22 p-toluenesulfonate, with a yield of 72%;

[0181] Example 8 discloses (±)-22 p-toluenesulfonate → (±)-22, yield 57%; (±)-22 → (+)-22 (S)-(+)-mandelate, yield 17%; (+)-22(S)-(+)-mandelate → (+)-I-4 p-toluenesulfonate, yield 73%.

[0182] This application provides a method for synthesizing the salt of the compound shown in Formula I and an intermediate, which has a higher yield than CN202211372369.6.

[0183] Example

[0184] General synthesis methods

[0185] Preparation Example:

[0186] Taking the preparation of the compound shown in Formula III of Example 1 as an example, the following example methods can be used for synthesis:

[0187] Path 1:

[0188] Path 2:

[0189] in,

[0190] The preparation method of compound I is as follows:

[0191] The preparation method of intermediate compound 07 is as follows:

[0192] Without being limited to the examples, those skilled in the art can prepare the corresponding products based on the chemical properties of the relevant intermediates and by following different reaction principles, based on the reaction processes shown in paths 1-2 above.

[0193] Preparation Example:

[0194] Intermediate: Compound (±)05

[0195] Preparation of compound (±)03:

[0196] Add 6.00 kg of tetrahydrofuran to a 50 L reactor, start stirring, and add 2.58 kg of sodium tert-butoxide. Lower the reaction solution temperature to 0 °C, and add 3.13 kg of compound O2 (tert-butyl dimethoxyphosphonoacetate) dropwise, controlling the reaction solution temperature at 5 °C. After the addition is complete, stir the reaction solution at 5 °C for 0.5 h. Add 1.7 kg of compound (±)01((±)(1R,2S,5R,6S)-tricyclic[4.2.1.0] dissolved in 2.0 kg of tetrahydrofuran dropwise. 2,5 Non-7-en-3-one was added, and the reaction solution temperature was controlled at 5℃. After the addition was complete, the reaction solution was reacted at 5℃. After the reaction was completed, 5.00 kg of drinking water and 7.00 kg of ethyl acetate were added, and the mixture was extracted and separated. Sodium chloride aqueous solution was added to the organic phase, and the mixture was extracted and separated. The organic phase was concentrated under reduced pressure to obtain compound (±)03, which was directly used in the next reaction.

[0197] Preparation of compound (±)04:

[0198] 6.68 kg of nitromethane was added to a 50 L reactor containing compound (±)03, and stirring was started. Then, 5.89 kg of 1,5-diazabicyclo[4.3.0]non-5-ene was added, and the reaction mixture was heated to 90±5 °C. After the reaction was complete, the system was cooled to room temperature, and 16.19 kg of methyl tert-butyl ether was added. Sodium dihydrogen phosphate aqueous solution was added dropwise to disrupt the reaction. After the addition was complete, the mixture was allowed to stand and separated. Sodium dihydrogen phosphate aqueous solution was added to the organic phase, stirred, allowed to stand, and then separated, retaining the organic phase. The organic phase was concentrated under reduced pressure to obtain compound (±)04, which was directly used in the next reaction step.

[0199] Preparation of compound (±)05:

[0200] 15.00 kg of methanol was added to a 50 L reactor, and stirring was started. Compound (±)04 and 3.33 kg of zinc powder were added, and nitrogen protection was maintained. The temperature of the reaction solution was lowered to 5 °C, and sodium dihydrogen phosphate aqueous solution was added, followed by dropwise addition of ammonium chloride aqueous solution. After the addition was complete, the reaction solution was heated to 60±5 °C. After the reaction was completed, the reaction system was filtered, and the reactor was rinsed with 3.00 kg of methanol and filtered under pressure. The filtrate was concentrated under reduced pressure. After concentration, 12.00 kg of ethyl acetate and potassium carbonate aqueous solution were added, stirred, allowed to stand, and separated. The organic phase was concentrated under reduced pressure. After concentration, 15.00 kg of acetonitrile was added to the reactor, and stirring was started. The temperature was raised to 40 °C, and Boc-D-phenylglycine acetonitrile solution was added. The mixture was kept at 40 °C and stirred for 2 hours, then cooled to 0 °C and stirred for 2 hours. The reaction solution was centrifuged, and the reactor was rinsed with 0.50 kg of acetonitrile and centrifuged and dried to obtain 3.10 kg of compound (±)05. The three-step yield was 46.99%.

[0201] 1 H NMR (400MHz, DMSO-d6) δ7.95(s,2H),7.33–7.13(m,5H),6.52(d,J=6.4Hz,1H),6.34(dd,J=5.8,3.0 Hz,1H),6.26(dd,J=5.8,3.2Hz,1H),4.62(d,J=6.4Hz,1H),2.97(d,J=12.8Hz,1H),2.85(dd,J=12. 8,1.7Hz,1H),2.82–2.74(m,2H),2.67(ddd,J=13.8,8.3,5.6Hz,1H),2.40–2.31(m,1H),2.27(d,J= 11.4Hz,2H),1.81–1.70(m,1H),1.41(s,9H),1.35(s,7H),1.17(s,1H),1.03(dd,J=7.3,5.1Hz,2H).

[0202] 13C NMR (101MHz, DMSO) δ172.15,171.03,154.73,142.39,137.46,137.01,128.06,127.20,126.62,80 .19,78.17,59.77,52.95,48.23,47.31,45.72,44.54,37.49,36.47,33.75,32.57,28.65,28.20.

[0203] Intermediate: Compound 06

[0204] Preparation of compound 06:

[0205] Add 15.00 kg of dichloromethane and 3.00 kg of compound (±)05 to the reactor. Add an aqueous sodium carbonate solution, stir, let stand, and separate the liquids, retaining the organic phase. Concentrate the organic phase under reduced pressure. After concentration, add 5.00 kg of tetrahydrofuran to the reactor, start stirring, and completely dissolve the concentrated oily substance. Add 1.00 kg of Boc-D-phenylglycine tetrahydrofuran suspension and stir. Add 7.14 kg of isopropyl ether dropwise, and keep at room temperature with stirring overnight. Centrifuge the reaction solution, rinse the reactor with 0.60 kg of isopropyl ether, and centrifuge again to obtain the centrifuged wet product.

[0206] Add 3.90 kg of tetrahydrofuran and 3.18 kg of isopropyl ether to the reaction vessel, add the centrifuged wet product, and stir overnight at room temperature. Centrifuge the reaction solution, and rinse the reaction vessel with 0.60 kg of isopropyl ether, then centrifuge again. Add 2.88 kg of tetrahydrofuran and 2.37 kg of isopropyl ether to the reaction vessel, add the centrifuged solid, and stir overnight at room temperature. Centrifuge the reaction solution, rinse the reaction vessel with 0.60 kg of isopropyl ether, then centrifuge again to obtain a centrifuged wet product. Add 2.49 kg of tetrahydrofuran and 2.07 kg of isopropyl ether to the reaction vessel, add the centrifuged wet product, and stir overnight at room temperature. Centrifuge the reaction solution, rinse the reaction vessel with 0.60 kg of isopropyl ether, then centrifuge again. Dry the centrifuged solid under reduced pressure to obtain 0.69 kg of compound 06, yield 23.0%.

[0207] 1H NMR (400MHz, DMSO-d6) δ7.95(s,2H),7.33–7.13(m,5H),6.52(d,J=6.4Hz,1H),6.34(dd,J=5.8,3.0 Hz,1H),6.26(dd,J=5.8,3.2Hz,1H),4.62(d,J=6.4Hz,1H),2.97(d,J=12.8Hz,1H),2.85(dd,J=12. 8,1.7Hz,1H),2.82–2.74(m,2H),2.67(ddd,J=13.8,8.3,5.6Hz,1H),2.40–2.31(m,1H),2.27(d,J= 11.4Hz,2H),1.81–1.70(m,1H),1.41(s,9H),1.35(s,7H),1.17(s,1H),1.03(dd,J=7.3,5.1Hz,2H).

[0208] 13 C NMR (101MHz, DMSO) δ172.15,171.03,154.73,142.39,137.46,137.01,128.06,127.20,126.62,80 .19,78.17,59.77,52.95,48.23,47.31,45.72,44.54,37.49,36.47,33.75,32.57,28.65,28.20.

[0209] Direct preparation of compound 06:

[0210] 110 g of zinc powder and 100 g of compound (±)04 dissolved in 600 mL of methanol were added to a reaction flask. The reaction system was cooled to 5±5 °C, and 109 g of ammonium chloride aqueous solution was slowly added dropwise. After the addition was complete, the reaction solution was heated to 60±5 °C. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was concentrated under reduced pressure. After concentration, 500 mL of ethyl acetate and 400 mL of saturated potassium carbonate aqueous solution were added to the reaction system and stirred for 1 hour. Solids were washed out from the reaction system. After filtration, the filtrate was allowed to stand and separated, and the organic phase was concentrated under reduced pressure. An oily substance was obtained by concentration. 500 g of tetrahydrofuran was added to it, and the mixture was heated to 40±5 °C to dissolve it. 800 g of Boc-D-phenylglycine tetrahydrofuran suspension was added and stirred. 700 g of isopropyl ether was added dropwise, and the mixture was kept at room temperature with stirring overnight. The reaction system was filtered, and the filter cake was dried. 100g of dried sample was added to 445g of tetrahydrofuran, heated to 45±5℃, and 363g of isopropyl ether was slowly added and stirred for half an hour. The system was then slowly cooled to 20±5℃ and stirred overnight. After filtration, 263g of tetrahydrofuran was added to the filter cake, the temperature was raised to 45±5℃, and 271g of isopropyl ether was slowly added. The mixture was kept at this temperature and stirred for half an hour. The system was then slowly cooled to 20±5℃ and stirred overnight. After filtration, the filter cake was dried under reduced pressure to obtain 0.69kg of compound 06, with a yield of 20%.

[0211] Intermediate: Compound 07

[0212] Preparation of compound 07:

[0213] 500.0 g of compound 06 (chromatographic purity: 99.42%, isomer content: 0.57%) was added to a 10 L reactor and dissolved in a mixture of 2 L dichloromethane and 750 mL saturated Na2CO3 aqueous solution. The mixture was stirred for 10 minutes until the solid was completely dissolved. The organic phase was separated, and the aqueous phase was extracted again with 1 L dichloromethane. The organic phases were combined and washed once with 500 mL saturated Na2CO3 aqueous solution. The mixture was dried (using MgSO4 as a desiccant), filtered to remove the MgSO4 desiccant, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain an oily substance (compound 07).

[0214] 1H NMR(400MHz, DMSO-d6)δ6.39(dd,J=5.9,3.0Hz,1H),6.22(dd,J=5.8,3.3Hz,1H),2.89–2.82(m,1H),2.75(td,J=3.9,3.3,1.7Hz,1H),2.69–2.52 (m,3H),2.30–2.24(m,1H),2.24–2.09(m,2H),1.60(ddd,J=12.3,8.3,1 .5Hz,1H),1.45(dd,J=7.9,1.7Hz,10H),1.23(s,1H),1.11–1.00(m,2H).

[0215] 13 C NMR (101MHz, DMSO-d6) δ171.57,137.33,136.90,79.48,53.21,51.77,47.93,45.81,44.61,40.65,37.02,34.41,32.55,28.20.

[0216] Example 1: Compound of Formula III (2-((1R,2S,3R,5R,6S)-3-(aminomethyl)tricyclic [4.2.1.0]) 2,5 Preparation of non-7-en-3-yl)acetic acid benzenesulfonate

[0217] 500.0 g of compound 06 (chromatographic purity: 99.42%, isomer content: 0.57%) was added to a 10 L reactor and dissolved in a mixture of 2 L dichloromethane and 750 mL saturated Na2CO3 aqueous solution. The mixture was stirred for 10 minutes until the solid was completely dissolved. The organic phase was separated, and the aqueous phase was extracted again with 1 L dichloromethane. The organic phases were combined and washed once with 500 mL saturated Na2CO3 aqueous solution. The mixture was dried (using MgSO4 as a desiccant), filtered to remove the MgSO4 desiccant, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain an oily substance (compound 07). The oily substance (compound 07) was dissolved in 2.5 L of THF. 335 g of benzenesulfonic acid was added to the reaction system at room temperature, and the mixture was heated to reflux and reacted for 10 hours. TLC showed that the reaction was complete. The reaction system was brought back to room temperature, filtered, and the filter cake was dried to obtain the target compound sample of formula III. The sample was a white solid, 250.0 g in size, with a chromatographic purity of 100%, an isomer content of 0.08%, a melting point of 194.2℃-195.4℃, and a yield of 70.4%. [α] D 20 = +37.4° (c = 0.99, CH3OH).

[0218] MS m / z (ES): 208.1 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),7.69(s,3H),7.61~7.59(m,2H),7.35~7. 30(m,3H),6.37(d,J=8.2Hz,1H),6.28(d,J=8.8Hz,1H),3.15–2.95(m,2H),2.83 ~2.71(m,3H),2.43(dd,J=9.1,4.6Hz,1H),2.32(d,J=5.5Hz,2H),1.80~1.74(m, 1H), 1.46 (d, J = 8.1Hz, 1H), 1.14 (dd, J = 12.9, 6.2Hz, 1H), 1.05 (d, J = 8.0Hz, 1H).

[0219] The compound sample of Formula III was subjected to X-ray powder analysis using Cu-Kα radiation. Its spectra showed diffraction angles, interplanar spacings, and relative intensities as shown in Table 2. Its XRD pattern is basically shown in Figure 1. The TGA pattern of the compound sample of Formula III is basically shown in Figure 2, with a weight loss of 0.10% in the temperature range of 30℃ to 105℃. The DSC pattern is basically shown in Figure 3, with an endothermic peak near 206.46℃.

[0220] Table 2. Diffraction angles, interplanar spacings, and relative intensities of the compound samples of exemplary formula III in this application.

[0221] Example 2: Preparation of the compound sample shown in Formula III

[0222] 10 mg of the compound of formula III prepared in Example 1 was added to 1 mL of ethyl acetate, stirred and suspended at room temperature for 1 day, and then filtered to obtain the crystal form of the compound of formula III. The obtained sample was subjected to Cu-Kα X-ray powder analysis, and its XRD pattern was basically consistent with that in Figure 1.

[0223] Example 3: Preparation of the compound sample shown in Formula III

[0224] 10 mg of the compound of formula III prepared in Example 1 was dissolved in 0.15 mL of ethanol, sonicated until dissolved, and then 2 mL of ethyl acetate was added. The mixture was stirred at room temperature to induce crystallization, and then filtered to obtain the crystal form of the compound of formula III. The obtained sample was subjected to Cu-Kα radiation X-ray powder diffraction, and its X-ray powder diffraction pattern was basically consistent with that in Figure 1.

[0225] Example 4: Preparation of the compound sample shown in Formula III

[0226] 10 mg of the compound of formula III prepared in Example 1 was dissolved in 0.1 mL of trifluoroethanol, sonicated until dissolved, and then 2 mL of methyl isobutyl ketone was added. The mixture was stirred at room temperature to induce crystallization, and then filtered to obtain the crystal form of the compound of formula III. The obtained sample was subjected to Cu-Kα radiation X-ray powder analysis, and its XRD pattern was basically consistent with that in Figure 1.

[0227] Example 5: Preparation of the compound sample shown in Formula III

[0228] 10 mg of the compound of formula III prepared in Example 1 was dissolved in 1 mL of isopropanol, sonicated until dissolved, and then 6 mL of methyl tert-butyl ether was added. The mixture was stirred at room temperature to induce crystallization, and then filtered to obtain the crystal form of the compound of formula III. The obtained sample was subjected to Cu-Kα X-ray powder analysis, and its XRD pattern was basically consistent with that in Figure 1.

[0229] Example 6: Preparation of the compound sample shown in Formula III

[0230] 10 mg of the compound of formula III prepared in Example 1 was dissolved in 0.05 mL of dimethyl sulfoxide, sonicated until dissolved, and then 3 mL of isopropyl acetate was added. The mixture was stirred at room temperature to induce crystallization, and then filtered to obtain the crystal form of the compound of formula III. The obtained sample was subjected to Cu-Kα radiation X-ray powder analysis, and its XRD pattern was basically consistent with that in Figure 1.

[0231] Example 7: Preparation of hydrochloride sample of compound shown in Formula I

[0232] Step 1: Synthesis of compound (±)-22 p-toluenesulfonate

[0233] (±)-22-p-toluenesulfonate was prepared according to step 1 of Example 4 of patent CN202211372369.6.

[0234] Step 2: Synthesis of compound (+)–22N-Boc-D-phenylglycine salt

[0235] (±)-22 p-toluenesulfonate (100.00 g, 0.23 mol) was added to a mixture of ethyl acetate (300 mL) and saturated sodium bicarbonate aqueous solution (1 L). After stirring for 5 minutes (until the solid was completely dissolved), the mixture was allowed to stand, and the layers were separated. The organic phase was separated, and the aqueous phase was extracted again with ethyl acetate (300 mL). The organic phases were combined. The organic phase was added to saturated sodium bicarbonate aqueous solution (600 mL), stirred for 5 minutes, and then allowed to stand, and the layers were separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain an oily substance. The oily substance was dissolved in tetrahydrofuran (250 mL), stirred, and the temperature was controlled at 24℃-26℃. A THF solution (200 mL) of N-Boc-D-phenylglycine (40.38 g, 0.16 mol) was added dropwise to the solution. After the addition was complete, the mixture was stirred for 30 minutes. Isopropyl ether (450 mL) was added dropwise to the solution. After the addition was complete, the mixture was stirred at 24℃-26℃ for 12 hours, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dried to obtain 40.48 g of white crude solid, with a yield of 34.3% and an ee value of 78.18%.

[0236] The crude product with an ee value of 78.18% was added to a mixed solvent of isopropyl ether (200 mL) and tetrahydrofuran (200 mL), heated to 38℃-42℃ and stirred for 10 minutes, then cooled to 22℃-25℃ and stirred for 12 hours (first crystallization purification). The solid was collected by filtration and dried to obtain 31.00 g of white solid. This solid was added to a mixed solvent of isopropyl ether (150 mL) and THF (150 mL), heated to 38℃-42℃ and stirred for 10 minutes, then cooled to 22℃-25℃ and stirred for 12 hours (second crystallization purification). The solid was collected by filtration and dried to obtain 28.71 g of white solid. The obtained solid was added to a mixed solvent of isopropyl ether (130 mL) and THF (130 mL), heated to 38℃-42℃ and stirred for 10 minutes, then cooled to 22℃-25℃ and stirred for 15 hours (third crystallization purification). Filter and dry the filter cake to obtain 27.02 g (+)–22N-Boc-D-phenylglycine salt.

[0237] Step 3: Synthesis of the hydrochloride salt of compound I

[0238] The (+)-22N-Boc-D-phenylglycine salt (2.40 g, 5.8 mmol) obtained in step 2 was added to a saturated Na₂CO₃ solution (100 mL), stirred for 20 min, and then extracted with ethyl acetate (180 mL). The organic phase was separated, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. This oil was then dissolved in dichloromethane (18 mL), and trifluoroacetic acid (14 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 5-6 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then concentrated again with dichloromethane (20 mL). The resulting oil was dried under vacuum using an oil pump to obtain a viscous product. The viscous product was dissolved in ethyl acetate (10 mL), and 37% hydrochloric acid (5.8 mmol) was added to the reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2-20 h. Filter and dry to obtain 1.26 g of the hydrochloride salt of compound I. Yield: 89.1%. Melting point: 187.8℃–189.0℃; [α] D 20 = +57.6° (c = 1.02, CH3OH); 1 H NMR(CD3OD,500MHz)δ:6.45-6.43(m,1H),6.32-6.31(m,1H),3.27-3.25(d,J=10.0 Hz,1H),3.14-3.12(d,J=10.0Hz,1H),2.94(s,1H),2.89-2.84(m,2H),2.61-2.57( d,J=20.0Hz,1H),2.55-2.52(m,1H),2.39-2.36(d,J=20.0Hz,1H),1.82-1.78(m,1 H),1.60-1.58(d,J=10.0Hz,1H),1.37-1.34(m,1H),1.17-1.16(d,J=10.0Hz,1H).

[0239] Example 8: Preparation of methanesulfonate sample of compound I

[0240] The (+)–22N-Boc-D-phenylglycine salt (2.40 g, 5.8 mmol) obtained in step 2 of Example 7 was added to a saturated Na₂CO₃ solution (100 mL), stirred for 20 min, and then extracted with ethyl acetate (180 mL). The organic phase was separated, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. This oil was then dissolved in dichloromethane (18 mL), and trifluoroacetic acid (14 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 5–6 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then concentrated again with dichloromethane (20 mL). The resulting oil was dried using a vacuum oil pump to obtain a viscous product. The viscous product was dissolved in methanol (2 mL), and then ethyl acetate (8 mL) was added. Methanesulfonic acid (5.8 mmol) was added to the reaction solution, and after the addition was complete, the mixture was stirred at room temperature for 2–20 h. The mixture was filtered and dried to give 0.91 g of the methanesulfonate of compound I, in 51.7% yield. Melting point: 146.8 °C–148.2 °C; [α] D 20 = +47.1° (c = 1.04, CH3OH); 1 H NMR(CD3OD,500MHz)δ:6.45-6.43(m,1H),6.32-6.30(m,1H),3.27-3.25(d,J=10.0Hz ,1H),3.14-3.12(d,J=10.0Hz,1H),2.94(s,1H),2.89-2.83(m,2H),2.70(s,3H),2.61 -2.57(d,J=20.0Hz,1H),2.55-2.52(m,1H),2.39-2.35(d,J=20.0Hz,1H),1.82-1.77( m,1H),1.60-1.58(d,J=10.0Hz,1H),1.37-1.33(m,1H),1.17-1.16(d,J=10.0Hz,1H).

[0241] Example 9: Preparation of p-toluenesulfonate sample of compound I

[0242] The p-toluenesulfonate of compound I was prepared according to steps 1, 3, and 5 of Example 8 of patent CN202211372369.6. Example 10: Compound III (2-((1R,2S,3R,5R,6S)-3-(aminomethyl)tricyclic [4.2.1.0]) 2,5 Preparation of non-7-en-3-yl)acetic acid benzenesulfonate

[0243] 10.0 g of compound 07 was dissolved in 50 mL of dichloromethane, and 10 mL of trifluoroacetic acid was slowly added dropwise. The reaction was carried out at room temperature for 5-6 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a brown oily substance (compound of formula I). ​​100 mL of sodium bicarbonate aqueous solution was added to the reaction system and stirred for 2-3 h. The mixture was filtered, and the solid obtained was dissolved in 100 mL of THF. 13 g of benzenesulfonic acid was added to the reaction system at room temperature, and the temperature was raised to reflux. The reaction was carried out for 10 h, and TLC showed that the reaction was complete. The reaction system was brought back to room temperature, filtered, and the filter cake was dried to obtain the target compound sample of formula III, a white solid of 8.05 g, with a yield of 59.0%.

[0244] Experimental Example 1: Study on the physicochemical properties (melting point, hygroscopicity, solubility, etc.) of different salt forms of the compound shown in Formula I.

[0245] The melting point, hygroscopicity, and solubility of the salt samples of the compounds shown in Formula I of this application (benzene sulfonate sample, hydrochloride sample, methane sulfonate sample, and p-toluene sulfonate sample of the compounds shown in Formula I) were tested respectively.

[0246] Table 3 shows the melting point, hygroscopicity, and solubility of salt samples of the compounds represented by Exemplary Formula I in this application.

[0247] In Table 3, the benzenesulfonate sample (the compound sample shown in Formula III) was prepared according to Example 1 of this application, the p-toluenesulfonate sample was prepared according to Example 8 of patent CN202211372369.6, the hydrochloride sample was prepared according to Example 7 of this application, and the methanesulfonate sample was prepared according to Example 8 of this application.

[0248] Experimental results show that, compared with the hydrochloride, methanesulfonate, and p-toluenesulfonate of the compound shown in Formula I, the benzenesulfonate of Formula I (the compound shown in Formula III) has a higher melting point and lower hygroscopicity. Surprisingly, the benzenesulfonate of the compound shown in Formula I also exhibits high solubility while maintaining a high melting point and low hygroscopicity. These superior physicochemical properties make the benzenesulfonate of the compound shown in Formula I more suitable for large-scale production, formulation development, and clinical trials.

[0249] Experimental Example 2: In vitro binding of the compound to human recombinant calcium ion channel Cav2.2α2δ-1

[0250] Objective: To evaluate the binding characteristics of the benzenesulfonate sample of the compound of exemplary formula I of this application to the human recombinant calcium channel Cav2.2 using a radioligand binding assay, with pregabalin as a control drug.

[0251] Methods: The experimental system was derived from human recombinant CHO cells. The test compounds were incubated with the experimental system for 2 hours (25°C) in 10 mM HEPES / KOH buffer (pH 7.4) using 1.0% DMSO as the solvent. In the binding assay, 5.0 nM [3H]Gabapentin was used as the specific ligand, and 10.0 μM unlabeled Gabapentin was used to determine nonspecific binding. Specific binding accounted for approximately 90% of the total binding. Binding parameters were obtained through radioligand binding assays. The dissociation constant (K2) of [3H]Gabapentin with Cav2.2 was... d The maximum binding amount (B) is 20.0 nM. max The protein content was 7.20 pmole / mg. Data were processed using standard radioligand binding analysis, with ≥50% maximum stimulation or inhibition as the criterion for statistical significance. Based on this, the binding activity differences between the benzenesulfonate of the compound shown in Formula I and pregabalin were compared to evaluate the target binding ability of the benzenesulfonate of the compound shown in Formula I.

[0252] The test results are shown in Table 4 below:

[0253] Table 4

[0254] In Table 4, the benzenesulfonate sample (the compound sample shown in Formula III) was prepared according to Example 1 of this application.

[0255] Result: In competitive [ 3 In the H]Gabapentin binding experiment, both benzenesulfonate and pregabalin, compounds shown in Formula I, could inhibit [H]Gabapentin in a dose-dependent manner. 3 The binding of H]Gabapentin to the VGCC α2δ subunit. The IC50 of the benzenesulfonate of the compound shown in Formula I. 50 It is 8.44 nM, K i =6.75 nM. The IC50 of pregabalin. 50 250 nM, K i =200 nM. Compared with pregabalin, the binding affinity of the benzenesulfonate compound shown in Formula I is significantly enhanced, approximately 30 times. Therefore, the benzenesulfonate compound shown in Formula I has a voltage-gated calcium ion channel α2δ binding effect and can be used as an active ingredient in the preparation of drugs for the treatment of chronic neuropathic pain, epilepsy, and anxiety.

[0256] Experimental Example 3: Pharmacokinetic Study

[0257] Beagle PK experiments were conducted using salt samples of the compounds shown in Formula I (benzenesulfonate samples and p-toluenesulfonate samples of the compounds shown in Formula I).

[0258] Experimental objective: To compare the pharmacokinetic characteristics of benzenesulfonate and p-toluenesulfonate of compound I in beagle dogs.

[0259] Experimental protocol: Healthy male beagle dogs were selected and administered a single oral gavage dose of 5 mg / kg (based on free base). Samples were prepared as a 0.5% CMC-Na suspension. Whole blood was collected before administration and at 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Plasma was obtained after centrifugation. The concentration of the drug in the beagle dog plasma samples was quantitatively determined using LC-MS / MS. Pharmacokinetic parameters were calculated using the non-compartmental model method with WinNonlin software. The main pharmacokinetic parameters are shown in Table 5 below.

[0260] Table 5. Pharmacokinetic parameters of salt samples of the compounds of exemplary formula I of this application.

[0261] In Table 5, the benzenesulfonate sample (the compound sample shown in Formula III) was prepared according to Example 1 of this application, and the p-toluenesulfonate sample was prepared according to Example 8 of patent CN202211372369.6.

[0262] Experimental results show that the benzenesulfonate of the compound shown in Formula I is more effective than other salts of the compound shown in Formula I. max It is superior, has a faster onset of action, and lower body exposure (C). max (and AUC) are higher.

[0263] Experiment Example 4: Stability Investigation Experiment of Influencing Factors

[0264] The crystal form of the compound sample shown in Formula III of this application (prepared according to Example 1) was investigated after being placed under high temperature (60°C), high humidity (RH 92.5%) and light (4500 lx ± 500 lx) for 10 days, 20 days, and 30 days.

[0265] Table 6 shows the stability study of the compound samples of exemplary formula III of this application.

[0266] The experimental results show that the crystal form of the compound shown in Formula III remains unchanged under different influencing factors, exhibiting excellent crystal form stability. This ensures the quality stability of the drug during storage and prevents the crystal form from changing due to factors such as pressure, heating, solvents, moisture (or humidity), excipients, and mechanical force during drug formulation, thereby affecting the efficacy and safety of the drug.

[0267] Those skilled in the art will recognize that the scope of this application is not limited to the various specific embodiments and examples described above, but rather that various modifications and changes can be made to the crystal form of the compound and its preparation method without departing from the spirit of this application. Therefore, the scope of protection of this application covers various modifications and changes made to this application, as long as such modifications or changes are within the scope covered by the claims and their equivalents.

Claims

1. A pharmaceutically acceptable salt of the compound shown in Formula I, wherein, The salt is an acidic salt, zwitterionic salt (internal salt), or quaternary ammonium salt formed with organic and / or inorganic acids; 2. The pharmaceutically acceptable salt according to claim 1, wherein, The pharmaceutically acceptable salt is the compound shown in Formula II; The HA is an organic acid or an inorganic acid; Preferably, the pharmaceutically acceptable salt is a benzenesulfonate, acetate, benzoate, propionate, oxalate, 4-aminosalicylate, ascorbate, p-toluenesulfonate, phthalate, butyrate, camphorsulfonate, camphorate, cinnamate, 2,2-dichloroacetate, formate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, citrate, fumarate, hydrochloride, hippurate, glycolate, hydrobromide, hydroiodate, lactate, maleate, malonate, glutamate, nitrate, phosphate, salicylate, perchlorate, trifluoroacetate, sulfate, glutamate, aspartate, citrate, malate, succinate, gluconate, succinate, or tartrate.

3. The pharmaceutically acceptable salt according to claim 1 or 2, wherein, The pharmaceutically acceptable salt is the compound shown in Formula III:

4. A method for preparing a compound of Formula III, comprising: (1) The compound shown in Formula IX reacts with benzenesulfonic acid to obtain the compound shown in Formula III; in, R3 is selected from C1-C6 alkyl, phenyl, and benzyl groups; preferably, R3 is selected from -C(CH3)3; or (2) The compound shown in Formula I reacts with benzenesulfonic acid to obtain the compound shown in Formula III; 5. The preparation method according to claim 4, wherein, The method further includes: hydrolyzing the compound represented by formula IX to obtain the compound represented by formula I; in, R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups; Preferably, the compound represented by Formula IX is hydrolyzed under alkaline or acidic conditions; Preferably, the R3 is selected from -C(CH3)3.

6. The preparation method according to claim 4 or 5, wherein, The method further includes: purifying the compound shown in Formula VIII to obtain the compound shown in Formula IX; in, X is the resolving reagent; Preferably, the resolving agent is selected from chiral acids; more preferably, the resolving agent is selected from (S)-(+)-O-acetylmandelic acid, (S)-(+)mandelic acid, Boc-D-phenylglycine or a combination thereof; Preferably, the compound shown in Formula VIII is released under alkaline conditions to obtain the compound shown in Formula IX.

7. The preparation method according to any one of claims 4-6, wherein, The method includes: 1) Preparation of the compound shown in formula (±)V: Compound (±)01 reacts with the compound shown in Formula IV to give the compound shown in Formula (±)V; 2) Preparation of the compound shown in formula (±)VI: The compound shown in formula (±)V reacts with nitromethane to give the compound shown in formula (±)VI; 3) Preparation of the compound shown in Formula VIII: The compound shown in formula (±)VI of L-1 undergoes a reduction reaction and then reacts with a resolving agent to obtain the compound shown in formula VIII. or After the compound shown in formula (±)VI undergoes a reduction reaction, it reacts with HB to form a salt, yielding the compound shown in formula (±)VII. The compound shown in formula (±) VII, after being released, undergoes a resolution reaction with a resolving agent to obtain the compound shown in formula VIII; 4) Preparation of the compound shown in Formula IX: The compound shown in formula VIII was released to obtain the compound shown in formula IX; 5) Preparation of the compound shown in Formula III: The compound of formula IX (M-1) reacts with benzenesulfonic acid to give the compound of formula III; or Hydrolysis of the compound shown in Formula IX (M-2) yields the compound shown in Formula I. The compound of Formula I reacts with benzenesulfonic acid to give the compound of Formula III. in, R1 and R2 are each independently selected from C1 to C6 alkyl groups; R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups; HB is the acidic reagent mentioned above; X is the resolving reagent; Preferably, R1 is -CH3; and / or R2 is -CH3; and / or R3 is -C(CH3)3.

8. A compound as follows: in, R3 is selected from C1 to C6 alkyl, phenyl, and benzyl groups; HB is an acidic reagent, and HB does not include p-toluenesulfonic acid; X is a resolving agent, which does not include (S)-(+)-mandelate; Preferably, the compound represented by formula (±)VII is compound (±)05; The compound represented by Formula IX is compound 07: or The compound shown in Formula VIII is compound 06:

9. A method for preparing the compound of claim 8, comprising: (1) After the compound shown in formula (±)VI undergoes a reduction reaction, it reacts with HB to form a salt, thereby obtaining the compound shown in formula (±)VII. (2) The compound shown in formula VIII is released to obtain the compound shown in formula IX; in, X is the resolving reagent; (3) The compound shown in formula (±)VI undergoes a reduction reaction and then reacts with the resolving reagent X to obtain the compound shown in formula VIII; Alternatively, after the compound shown in formula (±) VII is freed, it undergoes a resolution reaction with the resolving agent X to obtain the compound shown in formula VIII; in, HB is an acidic reagent.

10. A crystal form of the compound shown in Formula III, 11. The crystal form according to claim 18, wherein, Its X-ray powder diffraction pattern shows characteristic peaks at one or more locations between 2θ angles of 6.0±0.2° and 23.8±0.2°; or The X-ray powder diffraction pattern of the crystal form has characteristic peaks at one or more of the following locations at a 2θ angle: 6.0±0.2°, 11.9±0.2°, and 23.8±0.2°; or The X-ray powder diffraction pattern of the crystal form also shows characteristic peaks at one or more locations with 2θ angles of 29.9±0.2° and 36.0±0.2°; or The X-ray powder diffraction pattern of the crystal form also shows characteristic peaks at one or more of the following 2θ angles: 17.8±0.2°, 28.0±0.2°, 29.9±0.2°, 31.6±0.2°, 32.9±0.2°, 33.4±0.2°, 35.2±0.2°, and 36.0±0.2°; or The X-ray powder diffraction pattern of the crystal form is basically shown in Figure 1.

12. The crystal form according to claim 19 or 20, wherein, The TGA spectrum of the crystal form shows a weight loss of approximately 0.10% in the temperature range of 30℃ to 105℃. Preferably, the TGA spectrum of the crystal form is substantially as shown in Figure 2; and / or The DSC spectrum of the crystal form has an endothermic peak near 206.46℃. Preferably, the DSC spectrum of the crystal form is basically as shown in Figure 3.

13. A method for preparing the crystal form according to any one of claims 10-12, comprising: (1) Mix and suspend the compound shown in Formula III with solvent I; or (2) Dissolve the compound shown in Formula III in solvent II, and after it is dissolved, mix it with solvent III to crystallize.

14. The preparation method according to claim 13, wherein, Solvent I is one or more selected from acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyl carbonate, ethyl formate, methyl tert-butyl ether, petroleum ether, anisole, ethylene glycol dimethyl ether, dichloromethane, cyclohexane, n-heptane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene; or Solvent II is selected from one or more of ethanol, trifluoroethanol, isopropanol, dimethyl sulfoxide, hexafluoroisopropanol, and ethylene glycol methyl ether; or Solvent III is selected from one or more of acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dimethyl carbonate, ethyl formate, methyl tert-butyl ether, anisole, ethylene glycol dimethyl ether, dichloromethane, cyclohexane, n-heptane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and toluene.

15. The preparation method according to claim 13, wherein, The suspension is a room temperature stirred suspension; or The dissolution is ultrasonic dissolution; or The crystallization was carried out by stirring at room temperature.

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