A method for preparing high-purity lithium butoxide complex

Abstract

The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a high-purity butrol lithium complex. The preparation method of the present invention comprises the following steps: (1) 9-fluorenone and trimethyl orthoformate are activated by iron p-toluenesulfonate to obtain a ketal, the ketal and cis-1,4-diol are exchanged to obtain a cyclic ketal, and the cyclic ketal is oxidized to obtain an epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]; (2) cyclocyclohexane and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] are subjected to an epoxy ring-opening reaction in an organic solvent under the action of a lithium salt to generate an intermediate I; (3) the intermediate I and an α-substituted acetate are subjected to nitrogen alkylation in an organic solvent to generate an intermediate II; (4) the ester group of the intermediate II is hydrolyzed under alkaline conditions to obtain an intermediate III; and (5) the ketal is removed from the intermediate III under acidic conditions to obtain a butrol lithium complex.

Description

Technical field:

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a high-purity butrol lithium complex. Background technology:

[0002] Gadobutrol, developed by Bayer and first marketed in Switzerland in 1998, has now been approved in over 100 countries. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on March 14, 2011, by the China Food and Drug Administration (CFDA) on July 13, 2014, and by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on March 26, 2015. Bayer markets it under the trade names Gadavist, Galexin, and Gadovist.

[0003] Gadobutrol is a nonionic gadolinium chelate with paramagnetic properties used as a magnetic resonance imaging contrast agent. It is primarily distributed in the extracellular fluid but does not cross the blood-brain barrier. It is administered intravenously and is used diagnostically for imaging the central nervous system, kidneys, and liver, as well as for magnetic resonance angiography. Gadobutrol is one of three low-risk gadolinium contrast agents recommended by European guidelines and is the only gadolinium contrast agent approved by the FDA for use in neonates.

[0004] The Chinese chemical name of gadobutrol is: 10-[(1SR, 2RS)-2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid gadolinium complex; the English chemical name is: 10-[(1SR, 2RS)-2,3-dihydroxy-1-hydroxymethylpropyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, gadolinium complex; the molecular formula is: C 18 H 31 Gd N4O9; molecular weight: 604.72; CAS registration number: 138071-82-6

[0005] The structural formula is as follows:

[0006]

[0007] Due to the importance of gadobutrol in diagnostic imaging, particularly MRI, its synthesis has been extensively researched. Gadobutrol is primarily prepared by complexing butrol with gadolinium oxide, making its preparation crucial. Inorg. Chem. 1997, 36, 6086–6093 discloses three specific routes: Route 1 offers fewer side reactions, but the intermediates exhibit poor physicochemical properties and lack strong UV absorption (impeding quality control), and require resin purification. Route 2 exhibits numerous side reactions, resulting in low yield and purity, making purification difficult. Route 3 utilizes flammable and explosive reagents, making it suitable for laboratory preparation but unsuitable for industrial scale-up. Patent CN109293592A improves Route 1 by using recrystallization to purify the intermediate, eliminating column chromatography or ion exchange resins. However, this does not address the ultraviolet absorption problem of the intermediate. Patent CN107001294B improves Route 2 by using resin purification and recrystallization to purify the intermediate. However, this does not address the quality control (ultraviolet absorption) problem of the intermediate. Patent CN1229357C, Patent CN10354757B, and CN106543094A develop a method for complexing metallic lithium with cyclamenine, which addresses the selectivity issue and prepares the key intermediate of gadobutrol, the lithium butoxide complex. However, this does not address the challenges of intermediate separation, purification, and control. Therefore, a new preparation method is needed that shortens the preparation process, allows for convenient recrystallization purification and quality control of the intermediate, and provides a high-yield, high-quality production process for the key intermediate of gadobutrol, the lithium butoxide complex, suitable for industrial scale-up. Summary of the invention:

[0008] The present invention aims to provide a method for preparing a high-purity lithium butoxide complex. By optimizing the epoxy side chain, the present invention increases the regioselectivity of the reaction and the crystallinity of the intermediate, simplifies the operation, and improves the quality of the intermediate. This invention provides a new method for preparing high-purity lithium butoxide complexes with high yield and quality.

[0009] The preparation method of the high-purity butoxide lithium complex described in the present invention comprises the following specific reaction steps:

[0010]

[0011] in:

[0012] R is a C1-C6 straight or branched chain alkyl group;

[0013] X is halogen or sulfonate;

[0014] M is lithium, sodium, potassium or hydrogen.

[0015] Preparation method 1: prepare butoxide lithium complex through intermediate III.

[0016] The following steps are involved:

[0017] (1) 9-Fluorenone and trimethyl orthoformate are activated by iron p-toluenesulfonate to obtain a ketal. The ketal and cis-1,4-diol undergo exchange to obtain a cyclic ketal. The cyclic ketal is then oxidized to obtain the epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene];

[0018] (2) Cyclotrimethylenetetramine and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] undergo epoxy ring-opening reaction in an organic solvent under the action of lithium salt to generate intermediate I:

[0019] The lithium salt is selected from lithium chloride, lithium bromide, lithium iodide, lithium methanesulfonate, lithium benzenesulfonate, lithium p-toluenesulfonate. The organic solvent is selected from C4~C 11 Ether solvents, C1-C4 alcohol solvents, C1-C4 nitrile solvents, preferably organic solvents are selected from tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, etc., but not limited to the above.

[0020] The epoxy ring-opening reaction temperature is from room temperature to reflux, more preferably under reflux, but not limited to the above.

[0021] Crystallization purification of intermediate I: After the epoxy ring-opening reaction is completed, the crude intermediate I is cooled and precipitated. The crude intermediate I is crystallized and purified using a crystallization solvent. The crystallization solvent can be alcohol, ether, chlorinated hydrocarbon, alkane, nitrile, ester or a mixture thereof, preferably a mixture of alcohol and ester, but is not limited to the above.

[0022] (3) Intermediate I and α-substituted acetate undergo nitrogen alkylation (i.e., carboxymethylation) in an organic solvent to generate intermediate II:

[0023] The nitrogen alkylation (i.e., carboxymethylation) reaction of intermediate I with α-substituted acetate is usually carried out in the presence of an organic solvent, which can be a mixed solvent of water and ether or nitrile. The preferred ether is tetrahydrofuran and the nitrile is acetonitrile, but are not limited to the above.

[0024] The nitrogen alkylation (i.e., carboxymethylation) reaction can be carried out in the presence of a base, specifically an inorganic base. Preferably, the base is an inorganic base, such as lithium carbonate, lithium hydroxide, or a mixture thereof, but not limited thereto.

[0025] The nitrogen alkylation (ie, carboxymethylation) reaction temperature is from room temperature to reflux, preferably from 50° C. to reflux, but is not limited thereto.

[0026] Crystallization purification of intermediate II: After the nitrogen alkylation (i.e., carboxymethylation) reaction is completed, an organic solvent is added, and the inorganic salts are washed with water. The organic phase is concentrated to obtain a crude intermediate II. The crude intermediate II is crystallized and purified using a crystallization solvent. The crystallization solvent can be alcohol, ether, chlorinated hydrocarbon, alkane, ester, amide, nitrile, water, or a mixture thereof, preferably a mixture of methyl tert-butyl ether and ethyl acetate, but is not limited to the above.

[0027] (4) Intermediate II is hydrolyzed under alkaline conditions to obtain intermediate III:

[0028] The hydrolysis of the ester group of intermediate II under alkaline conditions is usually carried out in the presence of an organic solvent. The organic solvent can be ether, halogenated hydrocarbon, alcohol or a mixed solvent of water and alcohol. The preferred alcohol is methanol, but it is not limited to the above.

[0029] The base required for hydrolyzing the ester group is an inorganic base. Preferably, the base is a strong base, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide;

[0030] The reaction temperature for hydrolyzing the ester group is from room temperature to reflux, preferably from 50° C. to reflux, but not limited thereto.

[0031] Crystallization purification of intermediate III: After the hydrolysis of the ester group is completed, the mixture is cooled to room temperature and filtered to obtain a crude intermediate III. The crude intermediate III is crystallized and purified using a crystallization solvent. The crystallization solvent can be an alcohol, an ether, or a mixture thereof, preferably a mixture of methanol and methyl tert-butyl ether.

[0032] (5) After removing the ketal from the intermediate III under acidic conditions, a lithium butoxide complex is obtained:

[0033] The removal of ketal from intermediate III under acidic conditions is usually carried out in the presence of an organic solvent, which can be ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof, preferably water and methyl tert-butyl ether, but not limited to the above.

[0034] The acid required for removing the ketal is an organic acid and an inorganic acid. Preferably, the inorganic acid is hydrochloric acid, and the organic acid is acetic acid or trifluoroacetic acid, but is not limited to the above.

[0035] The reaction temperature for removing the ketal is from room temperature to reflux, preferably from 50°C to reflux, but is not limited to the above. Crystallization purification of the butoxide lithium complex: After the ketal removal reaction is completed, the organic phase is separated and the 9-fluorenone is recovered. The aqueous phase is adjusted to a pH of 3-4, concentrated, and then alcohol is added for crystallization to precipitate a crude butoxide lithium complex. The crude butoxide lithium complex is crystallized and purified using a crystallization solvent. The crystallization solvent can be an alcohol, a ketone, water, or a mixture thereof, preferably a mixture of methanol and water. After crystallization and purification, the obtained butoxide lithium complex has a purity greater than 99% and a single impurity of less than 0.10%, but is not limited to the above.

[0036] Among them, the preparation of intermediate III can be obtained not only through intermediate II, but also directly through intermediate I.

[0037] Among them, intermediate III is obtained by nitrogen alkylation (i.e., carboxymethylation) of intermediate I and α-substituted acetic acid or salt in an organic solvent:

[0038] The α-substituted acetate is selected from lithium salt, sodium salt, potassium salt, preferably lithium salt, but is not limited to the above.

[0039] The nitrogen alkylation (i.e., carboxymethylation) reaction of intermediate I with α-substituted acetate is usually carried out in the presence of an organic solvent, which can be a mixed solvent of water and alcohol, ether or nitrile. The preferred alcohol is methanol, but is not limited to the above.

[0040] The nitrogen alkylation (i.e., carboxymethylation) reaction can be carried out in the presence of a base, specifically an inorganic base. Preferably, the base is an inorganic base, such as lithium carbonate, lithium hydroxide, or a mixture thereof, but not limited thereto.

[0041] The nitrogen alkylation (ie, carboxymethylation) reaction temperature is from room temperature to reflux, preferably from 50° C. to reflux, but is not limited thereto.

[0042] Crystallization purification of intermediate III: After nitrogen alkylation (i.e., carboxymethylation) is completed, alcohol is added after concentration, and the mixture is cooled to room temperature. Filtering is to obtain a crude intermediate III. The crude intermediate III is crystallized and purified using a crystallization solvent. The crystallization solvent can be an alcohol, an ether, or a mixture thereof, preferably a mixture of methanol and methyl tert-butyl ether.

[0043] Preparation method 2: prepare butoxide lithium complex through intermediate II.

[0044] (1) 9-Fluorenone and trimethyl orthoformate are activated by iron p-toluenesulfonate to obtain a ketal. The ketal and cis-1,4-diol undergo exchange to obtain a cyclic ketal. The cyclic ketal is then oxidized to obtain the epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene];

[0045] (2) Cyclotrimethylenetetramine and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] undergo epoxy ring-opening reaction in an organic solvent under the action of lithium salt to generate intermediate I:

[0046] The lithium salt is selected from lithium chloride, lithium bromide, lithium iodide, lithium methanesulfonate, lithium benzenesulfonate, and lithium p-toluenesulfonate.

[0047] The organic solvent is selected from C4~C 11Ether solvents, C1-C4 alcohol solvents, C1-C4 nitrile solvents, preferably organic solvents are selected from tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, etc., but not limited to the above.

[0048] The epoxy ring-opening reaction temperature is from room temperature to reflux, more preferably under reflux, but not limited to the above.

[0049] Crystallization purification of intermediate I: After the epoxy ring-opening reaction is completed, the crude intermediate I is cooled and precipitated. The crude intermediate I is crystallized and purified using a crystallization solvent. The crystallization solvent can be alcohol, ether, chlorinated hydrocarbon, alkane, nitrile, ester or a mixture thereof, preferably a mixture of alcohol and ester, but is not limited to the above.

[0050] (3) Intermediate I and α-substituted acetate undergo nitrogen alkylation (i.e., carboxymethylation) in an organic solvent to generate intermediate II:

[0051] The nitrogen alkylation (i.e., carboxymethylation) reaction of intermediate I with α-substituted acetate is usually carried out in the presence of an organic solvent, which can be a mixed solvent of water and ether or nitrile. The preferred ether is tetrahydrofuran and the nitrile is acetonitrile, but are not limited to the above.

[0052] The nitrogen alkylation (i.e., carboxymethylation) reaction can be carried out in the presence of a base, specifically an inorganic base. Preferably, the base is an inorganic base, such as lithium carbonate, lithium hydroxide, or a mixture thereof, but not limited thereto.

[0053] The nitrogen alkylation (ie, carboxymethylation) reaction temperature is from room temperature to reflux, preferably from 50° C. to reflux, but is not limited thereto.

[0054] Crystallization purification of intermediate II: After the nitrogen alkylation (i.e., carboxymethylation) reaction is completed, an organic solvent is added, and the inorganic salts are washed with water. The organic phase is concentrated to obtain a crude intermediate II. The crude intermediate II is crystallized and purified using a crystallization solvent. The crystallization solvent can be alcohol, ether, chlorinated hydrocarbon, alkane, ester, amide, nitrile, water, or a mixture thereof, preferably a mixture of methyl tert-butyl ether and ethyl acetate, but is not limited to the above.

[0055] (4) The ester group of intermediate II is hydrolyzed under acidic conditions and the ketal is removed to obtain a lithium butoxide complex.

[0056] Intermediate II is hydrolyzed under acidic conditions and the ester group is removed to obtain a lithium butoxide complex:

[0057] The removal of ketal from intermediate II under acidic conditions is usually carried out in the presence of an organic solvent, which can be ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof, preferably water and methyl tert-butyl ether, but not limited to the above.

[0058] The acid required for removing the ketal is an organic acid and an inorganic acid. Preferably, the inorganic acid is hydrochloric acid, and the organic acid is acetic acid or trifluoroacetic acid, but is not limited to the above.

[0059] The reaction temperature for removing ketal is from room temperature to reflux, preferably from 50° C. to reflux, but not limited thereto.

[0060] Crystallization purification of the butoxide lithium complex: After the ketal removal reaction is completed, the organic phase is separated and 9-fluorenone is recovered. The aqueous phase is adjusted to a pH of 3-4, concentrated, and then alcohol is added for crystallization to precipitate a crude butoxide lithium complex. The crude butoxide lithium complex is crystallized and purified using a crystallization solvent. The crystallization solvent can be an alcohol, a ketone, water, or a mixture thereof, preferably a mixture of methanol and water. After crystallization and purification, the obtained butoxide lithium complex has a purity greater than 99% and a single impurity less than 0.10%, but is not limited to the above.

[0061] The present invention provides convenient preparation and easily quality-controlled epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene], intermediate I, intermediate II, intermediate III, and a butrol lithium complex for preparing butrol. The preparation process has high regioselectivity, good intermediate crystallinity, convenient quality control, and convenient recovery of the side chain protecting group (9-fluorenone). The prepared butrol lithium complex is of high quality (purity >99.0%, single impurity <0.10%) and has good industrial prospects.

[0062] Preferably, the preparation method of the present invention is as follows:

[0063]

[0064] According to one embodiment, the preparation method of the present invention comprises the following steps:

[0065] (1) 3,5,8-Trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]

[0066] 9-Fluorenone, trimethyl orthoformate, ferric p-toluenesulfonate, and methanol were added to the reaction flask until all the materials were dissolved and reacted at room temperature. Solids precipitated from the system. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered and dried to obtain 9,9-dimethoxy-9H-fluorene.

[0067] 9,9-dimethoxy-9H-fluorene, iron p-toluenesulfonate, cis-1,4-diol, and dichloromethane were added to the reaction flask until all the materials were dissolved and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, saturated aqueous sodium carbonate solution was added, the liquids were separated, and the organic phase was dried and concentrated to obtain 4',7'-dihydrospiro[fluorene-9,2'-[1,3]dioxepane];

[0068] 4',7'-dihydrospiro[fluorene-9,2'-[1,3]dioxepane], disodium hydrogen phosphate and dichloromethane were added to the reaction flask, and m-chloroperbenzoic acid was added in batches. The reaction was allowed to react at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was filtered, and aqueous sodium carbonate solution and saturated aqueous sodium sulfite solution were added to the filtrate. The layers were separated, and the organic phase was dried and concentrated to obtain a crude product. Ethyl acetate was added for recrystallization, and the product was filtered and dried to obtain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene].

[0069] (2) Under nitrogen protection, cyclopentane and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] were mixed in acetonitrile, lithium chloride was added, stirred, heated to reflux, and the reaction progress was monitored by HPLC. After the reaction was completed, heating was stopped, the temperature was lowered to room temperature, filtered, washed, and dried to obtain a crude product, which was then recrystallized by adding methanol and methyl tert-butyl ether system to obtain intermediate I.

[0070] (3) Add intermediate I and acetonitrile to a three-necked flask and stir. Then add lithium carbonate and tert-butyl chloroacetate. Heat the system to 50-55°C for reaction. Follow the reaction progress with HPLC. After the reaction is complete, cool the system and add ethyl acetate and purified water to the reaction solution. Separate the liquids. Wash the organic phase with water and concentrate. Recrystallize the residual liquid from methyl tert-butyl ether and ethyl acetate to obtain intermediate II.

[0071] (4) Add intermediate II and methanol to a three-necked flask, add lithium hydroxide, and heat the system to 50-60°C with stirring to react. The reaction progress is monitored by HPLC. After the reaction is completed, methyl tert-butyl ether is added, cooled to room temperature, and filtered. The filter cake is the crude intermediate III. The crude intermediate III is purified using a methanol methyl tert-butyl ether system to obtain intermediate III.

[0072] (5) Compound III, water and methyl tert-butyl ether were added to a three-necked flask, and hydrochloric acid was added to adjust the pH of the system to 1-2. The system was heated to 50-60°C for reaction, and the reaction progress was tracked by HPLC. After the reaction was completed, the liquids were separated, and 9-fluorenone was recovered from the organic phase. The pH of the aqueous phase was adjusted to 3-4, and the aqueous phase was concentrated under reduced pressure. Ethanol was added for crystallization, filtered, and dried to obtain a crude butrol lithium complex. The crude butrol lithium complex was recrystallized from ethanol and water, and dried to obtain a butrol lithium complex (purity>99.0%, single impurity<0.10%).

[0073] Alternatively, intermediate III can also be prepared by the following method:

[0074] Intermediate I, chloroacetic acid, methanol and water were added to a three-necked flask and stirred. Lithium hydroxide was added and the system was heated to 50-55°C for reaction. The pH of the system was adjusted to 9-10 with lithium hydroxide. The reaction progress was tracked by HPLC. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residual liquid was entrained with methanol three times. Methanol and methyl tert-butyl ether were added and the mixture was slurried. The filter cake was filtered to obtain the crude intermediate III. The crude intermediate III was purified using a methanol and methyl tert-butyl ether system to obtain intermediate III.

[0075] Alternatively, the butoxide lithium complex can also be prepared by the following method:

[0076] Compound II, water, and methyl tert-butyl ether were added to a three-necked flask, hydrochloric acid was added to adjust the pH of the system to 1-2, the system was heated to 50-60°C for reaction, and the reaction progress was monitored by HPLC. After the reaction was completed, the liquids were separated, 9-fluorenone was recovered from the organic phase, and lithium chloride was added to adjust the pH of the aqueous phase to 3-4. The aqueous phase was concentrated under reduced pressure, ethanol was added for crystallization, filtered, and dried to obtain a crude butrol lithium complex. The crude butrol lithium complex was recrystallized from ethanol and water, and dried to obtain a butrol lithium complex (purity>99.0%, single impurity<0.10%).

[0077] The preparation method of the present invention is simpler, has low cost, and is quality-controllable. The product has the characteristics of high purity, high yield, and few impurities. Specific implementation method:

[0078] The present invention is further illustrated by the following specific examples, but is not intended to be limiting of the present invention.

[0079] The reaction equation is as follows:

[0080]

[0081] Preparation of epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]:

[0082] 9,9-Dimethoxy-9H-fluorene

[0083] 9-Fluorenone (22 g), trimethyl orthoformate (26 g), ferric p-toluenesulfonate (1.4 g), and methanol (150 g) were added to a reaction flask. All materials dissolved and reacted at room temperature. Solid precipitated, and the reaction progress was monitored by TLC. After completion of the reaction, the mixture was filtered and dried to obtain 9,9-dimethoxy-9H-fluorene (white solid, 24.8 g, yield: 89.8%, HPLC: 98.93%). 1H NMR(400MHz,Chloroform-d)δ7.62(dt,J=7.5,1.0Hz,2H),7.54(dt,J=7.4,1.0Hz,2H ),7.43–7.38(dd,J=7.4,1.1Hz,2H),7.32(dd,J=7.4,1.1Hz,2H),3.35(s,6H).MS:m / e 227.1[(M+H) + ].

[0084] 4',7'-Dihydrospiro[fluorene-9,2'-[1,3]dioxepane]

[0085] 9,9-dimethoxy-9H-fluorene (20 g), iron p-toluenesulfonate (0.5 g), cis-1,4-diol (10 g) and dichloromethane (100 g) were added to the reaction flask. All the materials were dissolved and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, saturated aqueous sodium carbonate solution (30 g) was added, the liquid was separated, and the organic phase was dried and concentrated to obtain 4',7'-dihydrospiro[fluorene-9,2'-[1,3]dioxepane] (off-white solid, 22 g, yield 99.1%, HPLC: 92.80%, MS: m / e 251.1 [(M+H) + ].) was directly subjected to epoxidation without purification.

[0086] 3,5,8-Trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]

[0087] 4',7'-dihydrospiro[fluorene-9,2'-[1,3]dioxepane] (21.5 g), disodium hydrogen phosphate (13 g) and dichloromethane (200 g) were added to the reaction flask, and m-chloroperbenzoic acid (20 g) was added in batches. The reaction was reacted at room temperature and the reaction progress was tracked by TLC. After the reaction was completed, it was filtered, and an aqueous sodium carbonate solution and a saturated aqueous sodium sulfite solution were added to the filtrate. The organic phase was dried and concentrated to obtain a crude product (22 g). Ethyl acetate (50 g) was added for recrystallization. After filtration and drying, 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] (white solid, 20 g, yield 87.5%) was obtained. 1 H NMR(400MHz,Chloroform-d)δ7.65(d,J=7.5Hz,1H),7.63–7.56(ddd,J=7.5Hz,3H),7.43–7.36(dtd,J=8.7, 7.5,1.0Hz,2H),7.32–7.25(dd,J=7.5Hz,2H),4.57–4.46(m,4H),3.47(t,J=1.4Hz,2H).MS:m / e267.1[(M+H) + ].

[0088] Preparation of intermediate Ⅰ

[0089] Under nitrogen protection, cyclopentane (21 g) was mixed with 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] (22 g) and lithium chloride (5.2 g) in ethanol (100 mL), stirred, and heated to reflux. The reaction progress was monitored by HPLC. After the reaction was completed, heating was stopped, the temperature was lowered to room temperature, filtered, washed, and dried to obtain 37 g of a crude product, which was recrystallized by adding methanol and methyl tert-butyl ether to obtain 32.5 g of the product with a yield of 81.8% and an HPLC rate of 98.4%. 1 H NMR(400MHz,Chloroform-d)δ7.67(d,J=7.6Hz,1H),7.57(dd,J=7.5,1.9Hz,3H),7.40–7.35(m,2H) ,7.28(dd,J=7.6,1.1Hz,1H),7.24(d,J=7.7Hz,1H),4.44–3.88(m,6H),2.99–2.54(m,16H).MS:m / e 439.3[(M+H) + Titration method: Chlorine content: 8.5%

[0090] Preparation of Intermediate II

[0091] Intermediate I (20 g) and acetonitrile (300 mL) were added to a three-necked flask and stirred. Lithium carbonate (25.2 g) and tert-butyl chloroacetate (24 g) were added and the system was heated to 50-55° C. for reaction. The reaction progress was tracked by HPLC. After the reaction was completed, the temperature was lowered and the reaction solution was added to purified water and ethyl acetate. The liquids were separated and the filtrate was washed with water and concentrated. The residual liquid was recrystallized from methyl tert-butyl ether and ethyl acetate to obtain 28.9 g of white solid Compound II with a yield of 89.0% and an HPLC yield of 99.4%. 1 H NMR(400MHz,Chloroform-d)δ7.67–7.51(m,4H),7.42–7.20(m,4H),5.33(d,J=1 0.5Hz,1H),4.70–3.34(m,14H),3.18–2.05(m,14H),1.60–1.40(m,27H).MS:m / e 781.5[(M+H) + ].

[0092] Preparation of compound III

[0093] Intermediate I (10 g), methanol (60 mL), chloroacetic acid (16 g), and water (30 g) were added to a three-necked flask and stirred. A lithium hydroxide aqueous solution was added to adjust the pH of the system to 9-10. The system was heated to 50-55°C for reaction. Lithium hydroxide was used to adjust the pH of the system to 9-10. The reaction progress was monitored by HPLC. After the reaction was completed, the reaction solution was concentrated, methanol was added to the concentrated residue, and then methanol and methyl tert-butyl ether were added for recrystallization. The residue was filtered and dried. The filter cake contained 17.5 g of Intermediate III (the product contained lithium chloroacetate). HPLC: 99.2%. MS: m / e 615.6 [Intermediate III carboxylic acid (M+H) + ]

[0094] Compound II (10 g) and methanol (100 mL) were added to a three-necked flask and stirred. Lithium hydroxide (2.5 g) was added and the system was heated to 50-60° C. for reaction. The reaction progress was tracked by HPLC. After the reaction was completed, methyl tert-butyl ether (100 ml) was added and filtered. The filter cake was the crude intermediate III. Intermediate III was recrystallized from methanol and methyl tert-butyl ether, filtered with suction, and dried. The filter cake was 7.8 g of intermediate III, with a yield of 93.1% and an HPLC yield of 99.5%. 1 H NMR (400 MHz, Deuterium Oxide) δ7.41 (t, J=8.1 Hz, 4H), 7.23 (ddt, J=19.4, 12.6, 7.0 Hz, 6H), 3.78 (dd, J=17.9, 10.5 Hz, 2H), 3.54–3.26 (m, 4H), 3.12–2.25 (m, 22H). IC determination: lithium content: 4.3%.

[0095] Preparation of butoxide lithium complex

[0096] Intermediate II (5 g) and 1,4-dioxane (50 mL) were added to a three-necked flask and stirred. A 1N solution of hydrogen chloride in 1,4-dioxane (50 mL) was added and the system was heated to reflux. The reaction progress was monitored by HPLC. Upon completion of the reaction, the system was concentrated, and the residual liquid was added to water. The solution was extracted with methyl tert-butyl ether, and lithium chloride (1 g) was added. The pH of the aqueous phase was adjusted to 3-4. The system was concentrated, and ethanol was added for crystallization. The solution was filtered and dried to obtain a white crude product (2.9 g). The crude product was recrystallized from ethanol and water, and dried to obtain a lithium butoxide complex (2.6 g white solid, yield: 74.9%, HPLC: 99.6%, maximum single impurity 0.06%). The water content was 9.8%. IC analysis showed a lithium content of 2.65% and a chloride content of 6.85%.

[0097] Intermediate III (5 g), purified water (50 ml), and methyl tert-butyl ether (50 ml) were added to a three-necked flask. The pH of the system was adjusted to 1-2 with hydrochloric acid. The reaction progress was monitored by HPLC. After the reaction was completed, the liquid phase was separated. The aqueous phase was adjusted to pH 3-4 with lithium hydroxide and then concentrated under reduced pressure. Methanol was added for crystallization, filtered, and dried to obtain a white crude product (3.9 g). The crude product was recrystallized from ethanol and water and dried to obtain a lithium butoxide complex (white solid, 3.5 g, yield: 82.9%, HPLC: 99.8%, maximum single impurity 0.05%). The water content was 9.7%. IC analysis showed a lithium content of 2.68% and a chloride content of 6.91%.

[0098] Example 2, comparative experiment: TW450965, CN1229357C

[0099]

[0100] Preparation of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1,4,7,10-tetraazacyclododecane lithium chloride complex

[0101] Under nitrogen protection, cyclopentane (20 g), 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (19.2 g) and lithium chloride (4.85 g) were mixed in isopropanol (40 g), stirred, and heated to reflux. The reaction progress was monitored by HPLC. After the reaction was completed, heating was stopped, and the isopropanol was removed by concentration under reduced pressure. After crystallization, methyl tert-butyl ether was added, the mixture was filtered, washed, and dried to obtain 40 g of a crude product, which was recrystallized by adding methyl tert-butyl ether to obtain 32 g of the product. The yield was 76.8%, HPLC: 90.17%.

[0102] Preparation of butoxide lithium complex

[0103] A three-necked flask was charged with 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1,4,7,10-tetraazacyclododecane lithium chloride complex (30 g) and water (150 mL). The mixture was stirred and chloroacetic acid (60 g) was added. The reaction mixture was heated to 60-65°C for reaction. The pH of the reaction mixture was adjusted to 10-11 with lithium hydroxide. The reaction progress was monitored by HPLC. After the reaction was completed, the reaction mixture was acidified to a pH of 1.5 with hydrochloric acid. The reaction mixture was concentrated and dissolved in methanol (500 ml). The salt was removed by filtration and the filtrate was concentrated. The residual solution was added to water and the pH of the reaction mixture was adjusted to 3-4 with lithium hydroxide. The aqueous phase was concentrated under reduced pressure and crystallized by adding ethanol. The mixture was filtered and dried to obtain a white crude product (38 g). The crude product was recrystallized from ethanol and water and dried to obtain the butoxide lithium complex (white solid, 23.2 g, yield: 61.5%, HPLC: 99.3%, single impurity <0.10%).

[0104] In order to better illustrate the advantages of this patent, butoxide lithium complex was prepared using cyclopentane as raw material, and the reaction steps, total yield and quality were compared. The specific results are as follows:

[0105]

[0106]

[0107] It can be seen from the above table that the present invention has high yield, excellent quality, and excellent quality of the intermediates.

Claims

1. A method for preparing a butoxide lithium complex, characterized in that: The following steps are involved: in: R is a C1-C6 straight or branched chain alkyl group; X is halogen or sulfonate; M is lithium, sodium or potassium.

2. The preparation method according to claim 1, characterized in that Method 1: (1) 9-Fluorenone and trimethyl orthoformate are activated by iron p-toluenesulfonate to obtain a ketal. The ketal and cis-1,4-diol undergo exchange to obtain a cyclic ketal. The cyclic ketal is then oxidized to obtain the epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]; (2) Cyclotrimethylenetetramine and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] undergo an epoxy ring-opening reaction in an organic solvent under the action of lithium salt to produce intermediate I; (3) Intermediate I and α-substituted acetate undergo nitrogen alkylation in an organic solvent to generate intermediate II; (4) The ester group of intermediate II is hydrolyzed under alkaline conditions to obtain intermediate III; (5) After the intermediate III is deacetalized under acidic conditions, a lithium butoxide complex is obtained.

3. The preparation method according to claim 1, characterized in that in, Intermediate III is obtained by nitrogen alkylation of intermediate I and α-substituted acetic acid or salt in an organic solvent: α-substituted acetate is selected from lithium salt, sodium salt, potassium salt, The nitrogen alkylation reaction between the intermediate I and the α-substituted acetate is carried out in the presence of an organic solvent, wherein the organic solvent is selected from a mixed solvent of water and an alcohol, an ether or a nitrile, wherein the alcohol is methanol, The nitrogen alkylation reaction is carried out in the presence of an inorganic base, which is selected from lithium carbonate, lithium hydroxide or a mixture thereof. The nitrogen alkylation reaction temperature is from room temperature to reflux.

4. The preparation method according to claim 1, characterized in that The following steps are involved: (1) 9-Fluorenone and trimethyl orthoformate are activated by iron p-toluenesulfonate to obtain a ketal. The ketal and cis-1,4-diol undergo exchange to obtain a cyclic ketal. The cyclic ketal is then oxidized to obtain the epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]; (2) Cyclotrimethylenetetramine and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] undergo epoxy ring-opening reaction in an organic solvent under the action of lithium salt to generate intermediate I: The lithium salt is selected from lithium chloride, lithium bromide, lithium iodide, lithium methanesulfonate, lithium benzenesulfonate, lithium p-toluenesulfonate, The organic solvent is selected from C4~C 11 Ether solvents, C1-C4 alcohol solvents, C1-C4 nitrile solvents, the epoxy ring-opening reaction temperature is room temperature to reflux, Crystallization purification of intermediate I: after the epoxy ring-opening reaction is completed, the crude intermediate I is cooled and precipitated, and the crude intermediate I is crystallized and purified using a crystallization solvent selected from alcohol, ether, chlorinated hydrocarbon, alkane, nitrile, ester or a mixture thereof; (3) Intermediate I and α-substituted acetate undergo nitrogen alkylation in an organic solvent to generate intermediate II: The nitrogen alkylation reaction between the intermediate I and the α-substituted acetic acid ester is carried out in the presence of an organic solvent, which is a mixed solvent of water and ether or nitrile. The nitrogen alkylation reaction is carried out in the presence of an inorganic base, which is selected from lithium carbonate, lithium hydroxide or a mixture thereof. The nitrogen alkylation reaction temperature is from room temperature to reflux, Crystallization purification of intermediate II: after the nitrogen alkylation reaction is completed, an organic solvent is added, the inorganic salt is washed with water, and the organic phase is concentrated to obtain a crude intermediate II. The crude intermediate II is crystallized and purified using a crystallization solvent selected from alcohol, ether, chlorinated hydrocarbon, alkane, ester, amide, nitrile, water or a mixture thereof; (4) Intermediate II is hydrolyzed under alkaline conditions to obtain intermediate III: The hydrolysis of the ester group of intermediate II under alkaline conditions is carried out in the presence of an organic solvent, wherein the organic solvent is selected from ether, halogenated hydrocarbon, alcohol or a mixed solvent of water and alcohol. The base required for the hydrolysis of the ester group is an inorganic base, and the reaction temperature for the hydrolysis of the ester group is from room temperature to reflux. Crystallization purification of intermediate III: After the hydrolysis of the ester group is completed, the mixture is cooled to room temperature and filtered to obtain a crude intermediate III. The crude intermediate III is crystallized and purified using a crystallization solvent selected from alcohol, ether or a mixture thereof; (5) After removing the ketal from the intermediate III under acidic conditions, a lithium butoxide complex is obtained: The removal of ketal from intermediate III under acidic conditions is carried out in the presence of an organic solvent selected from ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof. The acid required for removing the ketal is an organic acid and an inorganic acid. The reaction temperature for removing ketal is from room temperature to reflux. The butoxide lithium complex is crystallized and purified. After the ketal removal reaction is completed, the organic phase is separated and 9-fluorenone is recovered. The aqueous phase is adjusted to a pH of 3-4, concentrated, and then alcohol is added for crystallization to precipitate a crude butoxide lithium complex. The crude butoxide lithium complex is crystallized and purified using a crystallization solvent selected from alcohol, ketone, water, or a mixture thereof. The obtained butoxide lithium complex has a purity greater than 99% and a single impurity less than 0.10%.

5. The preparation method according to claim 1, characterized in that Method 2: (1) 9-Fluorenone and trimethyl orthoformate are activated by iron p-toluenesulfonate to obtain a ketal. The ketal and cis-1,4-diol undergo exchange to obtain a cyclic ketal. The cyclic ketal is then oxidized to obtain the epoxy side chain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]; (2) Cyclotrimethylenetetramine and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] undergo epoxy ring-opening reaction in an organic solvent under the action of lithium salt to generate intermediate I: The lithium salt is selected from lithium chloride, lithium bromide, lithium iodide, lithium methanesulfonate, lithium benzenesulfonate, lithium p-toluenesulfonate, The organic solvent is selected from C4~C 11 Ether solvents, C1~C4 alcohol solvents, C1~C4 nitrile solvents, The epoxy ring-opening reaction temperature is from room temperature to reflux, Crystallization purification of intermediate I: after the epoxy ring-opening reaction is completed, the crude intermediate I is cooled and precipitated, and the crude intermediate I is crystallized and purified using a crystallization solvent selected from alcohol, ether, chlorinated hydrocarbon, alkane, nitrile, ester or a mixture thereof; (3) Intermediate I and α-substituted acetate undergo nitrogen alkylation in an organic solvent to generate intermediate II: The nitrogen alkylation reaction between the intermediate I and the α-substituted acetic acid ester is carried out in the presence of an organic solvent, which is a mixed solvent of water and ether or nitrile. The nitrogen alkylation reaction is carried out in the presence of an inorganic base, which is selected from lithium carbonate, lithium hydroxide or a mixture thereof. The nitrogen alkylation reaction temperature is room temperature to reflux, and the intermediate II is crystallized and purified. After the nitrogen alkylation reaction is completed, an organic solvent is added, and the inorganic salt is washed with water to remove the inorganic salt. The organic phase is concentrated to obtain a crude intermediate II. The crude intermediate II is purified by crystallization using a crystallization solvent selected from alcohol, ether, chlorinated hydrocarbon, alkane, ester, amide, nitrile, water or a mixture thereof; (4) Intermediate II is hydrolyzed under acidic conditions and the ester group is removed to obtain a lithium butoxide complex. The removal of ketal from intermediate II under acidic conditions is carried out in the presence of an organic solvent, wherein the organic solvent is ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof. The acid required for removing the ketal is an organic acid and an inorganic acid, the inorganic acid is hydrochloric acid, and the organic acid is acetic acid and trifluoroacetic acid. The reaction temperature for removing the ketal is from room temperature to reflux.

6. The preparation method according to claim 1, characterized in that The following steps are involved:

7. The preparation method according to claim 6, characterized in that The following steps are involved: (1) 3,5,8-Trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] 9-Fluorenone, trimethyl orthoformate, ferric p-toluenesulfonate, and methanol were added to the reaction flask until all the materials were dissolved and reacted at room temperature. Solids precipitated from the system. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered and dried to obtain 9,9-dimethoxy-9H-fluorene. 9,9-dimethoxy-9H-fluorene, iron p-toluenesulfonate, cis-1,4-diol, and dichloromethane were added to the reaction flask until all the materials were dissolved. The reaction was carried out at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, saturated aqueous sodium carbonate solution was added, the liquids were separated, and the organic phase was dried and concentrated to obtain 4',7'-dihydrospiro[fluorene-9,2'-[1,3]dioxepane]; 4',7'-dihydrospiro[fluorene-9,2'-[1,3]dioxepane], disodium hydrogen phosphate and dichloromethane were added to the reaction flask, and m-chloroperbenzoic acid was added in batches. The reaction was allowed to react at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was filtered, and an aqueous sodium carbonate solution and a saturated aqueous sodium sulfite solution were added to the filtrate. The filtrate was separated, and the organic phase was dried and concentrated to obtain a crude product. Ethyl acetate was added for recrystallization, and the product was filtered and dried to obtain 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene]. (2) Under nitrogen protection, cyclopentane and 3,5,8-trioxaspiro[bicyclo[5.1.0]octane-4,9'-fluorene] were mixed in acetonitrile, lithium chloride was added, stirred, and heated to reflux. The reaction progress was monitored by HPLC. After the reaction was completed, heating was stopped, the temperature was lowered to room temperature, filtered, washed, and dried to obtain a crude product, which was then recrystallized by adding methanol and methyl tert-butyl ether to obtain intermediate I. (3) Add intermediate I and acetonitrile to a three-necked flask, stir, add lithium carbonate and tert-butyl chloroacetate, heat the system to 50-55°C for reaction, and monitor the reaction progress with HPLC. After the reaction is complete, cool the reaction solution, add ethyl acetate and purified water, separate the liquids, wash the organic phase with water, concentrate, and recrystallize the residual liquid from methyl tert-butyl ether / ethyl acetate to obtain intermediate II. (4) Add intermediate II and methanol to a three-necked flask, add lithium hydroxide, and heat the system to 50-60°C with stirring to react. The reaction progress is monitored by HPLC. After the reaction is completed, add methyl tert-butyl ether, cool to room temperature, and filter. The filter cake is the crude intermediate III. The crude intermediate III is purified using a methanol methyl tert-butyl ether system to obtain intermediate III. (5) Compound III, water and methyl tert-butyl ether were added to a three-necked flask, and hydrochloric acid was added to adjust the pH of the system to 1-2. The system was heated to 50-60°C for reaction, and the reaction progress was tracked by HPLC. After the reaction was completed, the liquids were separated, and 9-fluorenone was recovered from the organic phase. The pH of the aqueous phase was adjusted to 3-4, and the aqueous phase was concentrated under reduced pressure. Ethanol was added for crystallization, filtered, and dried to obtain a crude butoxide lithium complex. The crude butoxide lithium complex was recrystallized from ethanol and water, and dried to obtain a butoxide lithium complex.

8. The preparation method according to claim 7, characterized in that Intermediate III was prepared by the following method: Intermediate I, chloroacetic acid, methanol and water were added to a three-necked flask and stirred. Lithium hydroxide was added and the system was heated to 50-55°C for reaction. The pH of the system was adjusted to 9-10 with lithium hydroxide. The reaction progress was tracked by HPLC. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residual liquid was entrained with methanol three times. Methanol and methyl tert-butyl ether were added and the mixture was slurried. The filter cake was filtered to obtain the crude intermediate III. The crude intermediate III was purified using a methanol and methyl tert-butyl ether system to obtain intermediate III.

9. The preparation method according to claim 6, characterized in that The butoxide lithium complex was prepared by the following method: Compound II, water, and methyl tert-butyl ether were added to a three-necked flask, and hydrochloric acid was added to adjust the pH of the system to 1-2. The system was heated to 50-60°C for reaction, and the reaction progress was tracked by HPLC. After the reaction was completed, the liquids were separated, and 9-fluorenone was recovered from the organic phase. After lithium chloride was added, the pH of the aqueous phase was adjusted to 3-4. The aqueous phase was concentrated under reduced pressure, and ethanol was added for crystallization. The mixture was filtered and dried to obtain a crude butrol lithium complex. The crude butrol lithium complex was recrystallized from ethanol and water, and dried to obtain a butrol lithium complex.

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