CN114853689A - Preparation method of high-purity lithium butoxide complex - Google Patents
Preparation method of high-purity lithium butoxide complex Download PDFInfo
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- CN114853689A CN114853689A CN202110152019.8A CN202110152019A CN114853689A CN 114853689 A CN114853689 A CN 114853689A CN 202110152019 A CN202110152019 A CN 202110152019A CN 114853689 A CN114853689 A CN 114853689A
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a high-purity lithium butoxide complex. The preparation method comprises the following steps: (1) activating 9-fluorenone and trimethyl orthoformate to obtain ketal under the activation of iron p-toluenesulfonate, exchanging the ketal and 1, 4-cis-butene diol to obtain cyclic ketal, and oxidizing the cyclic ketal to obtain epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ]; (2) performing epoxy ring-opening preparation reaction on cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in an organic solvent under the action of lithium salt to generate an intermediate I; (3) carrying out nitrogen alkylation on the intermediate I and the alpha-substituted acetate in an organic solvent to generate an intermediate II; (4) hydrolyzing the ester group of the intermediate II under an alkaline condition to obtain an intermediate III; (5) and removing ketal from the intermediate III under an acidic condition to obtain the lithium butoxide complex.
Description
The technical field is as follows:
the invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a high-purity lithium butoxide complex.
Background art:
gadobutrol was developed by bayer and was first marketed in switzerland in 1998, and has now been approved in over 100 countries. The health food is approved by the Food and Drug Administration (FDA) to be marketed at 14 days 3 and 14 months in 2011, approved by the Chinese Food and Drug Administration (CFDA) at 13 days 7 and 13 months 2014, approved by the Japanese pharmaceutical and medical device integration agency (PMDA) at 26 days 3 and 2015, and marketed by Bayer, and sold under the trade names Gadavist, Gagleam and Gadovist respectively.
Gadobutrol is a non-ionic gadolinium chelate, has the characteristic of paramagnetism, and is used as a magnetic resonance contrast agent. It is mainly distributed in the extracellular fluid, but not through the blood-brain barrier, and is only for intravenous administration, for imaging of CNS, kidney and liver and for magnetic resonance angiography in diagnosis. Gadobutrol is one of the 3 low risk gadolinium contrast agents recommended by european guidelines and is the only gadolinium contrast agent available for neonates to which FDA approval is granted.
The mesocultural 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; english chemical name 10- [ (1SR, 2RS) -2, 3-dihydroxy-1-hydroxymethypropylphosphate]-1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid, gadolinium complex; molecular formula C 18 H 31 Gd N 4 O 9 (ii) a Molecular weight 604.72; CAS registry number 138071-82-6
The structural formula is as follows:
because gadobutrol is important in image diagnosis, particularly in MRI diagnosis, a plurality of documents are available for researching the synthesis method of gadobutrol, gadobutrol is mainly prepared by complexing gadobutrol and gadolinium oxide, and the preparation of gadobutrol is the most critical. Three routes are specifically disclosed in inorg. chem.1997,36,6086-6093: route 1 has fewer side reactions, but the intermediate has poor physicochemical properties and does not have strong uv absorption (not conducive to quality control), and requires purification using resin; the route 2 has more side reactions, low yield, poor purity and high purification difficulty; route 3 uses flammable and explosive reagents, is suitable for laboratory preparation, and is not suitable for industrial amplification. The patent CN109293592A improves the scheme 1, and adopts recrystallization to purify the intermediate, thereby eliminating column chromatography or ion exchange resin, but not changing the ultraviolet absorption problem of the intermediate; the patent CN107001294B improves the scheme 2, and adopts resin purification and recrystallization methods to purify the intermediate, but does not change the quality detection (ultraviolet absorption) problem of the intermediate; patent CN1229357C, patent CN10354757B and patent CN106543094A develop a method for complexing metal lithium and cyclen, solve the problem of selectivity, prepare gadobutrol key intermediate butol lithium complex, but do not solve the difficult problems of intermediate separation and purification and intermediate control, therefore, a new preparation method needs to be developed, the preparation steps are short, the intermediate can be conveniently purified by recrystallization and quality control, and the production process of gadobutrol key intermediate butol lithium complex has high yield and high quality and is suitable for industrial amplification.
The invention content is as follows:
the invention aims to provide a preparation method of a high-purity lithium butoxide complex. According to the invention, by optimizing the epoxy side chain, the regioselectivity of the reaction and the crystallinity of the intermediate are increased, the operation is simplified, the quality of the intermediate is improved, and a novel method for preparing the high-purity lithium butoxide complex with high yield and high quality is invented.
The invention relates to a preparation method of a high-purity lithium butoxide complex, which comprises the following specific reaction steps:
wherein:
r is C 1 ～C 6 A linear or branched alkyl group;
x is halogen or sulfonate;
m is lithium, sodium, potassium or hydrogen.
The preparation method I is to prepare the lithium butoxide complex through the intermediate III.
The method comprises the following steps:
(1) activating 9-fluorenone and trimethyl orthoformate to obtain ketal under the activation of iron p-toluenesulfonate, exchanging the ketal and 1, 4-cis-butene diol to obtain cyclic ketal, and oxidizing the cyclic ketal to obtain epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ];
(2) the preparation method comprises the following steps of carrying out epoxy ring-opening preparation reaction on cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in an organic solvent under the action of lithium salt to generate an intermediate I:
the lithium salt is selected from lithium chloride, lithium bromide, lithium iodide, lithium methanesulfonate, lithium benzenesulfonate, and lithium p-toluenesulfonate. The organic solvent is selected from C 4 ～C 11 Ether solvent, C 1 ～C 4 Alcohol solvent, C 1 ～C 4 The nitrile solvent, preferably an organic solvent, is selected from tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, etc., but is not limited thereto.
The epoxy ring-opening reaction temperature is from room temperature to reflux, and the reaction is preferably carried out under reflux, but not limited thereto.
And (3) crystallizing and purifying the intermediate I, cooling to separate out a crude intermediate I after the epoxy ring opening reaction is finished, and crystallizing and purifying the crude intermediate I by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, nitrile, ester or a mixture of the alcohol, the ether, the chlorohydrocarbon, the alkane, the nitrile and the ester, and the mixture of the alcohol and the ester is preferred, but not limited to the above.
(3) The intermediate I and the alpha-substituted acetate are subjected to nitrogen alkylation (i.e. carboxymethylation) in an organic solvent to form an intermediate II:
the nitrogen alkylation (i.e., carboxymethylation) of intermediate i and the α -substituted acetate is typically carried out in the presence of an organic solvent which may be a mixture of water and an ether or a nitrile, preferably tetrahydrofuran as the ether and acetonitrile as the nitrile, but is not limited thereto.
The nitrogen alkylation (i.e. carboxymethylation) reaction may be carried out in the presence of a base, in particular in the presence of an inorganic base. Preferably, the base is an inorganic base, such as lithium carbonate, lithium hydroxide or a mixture thereof, but is not limited thereto.
The temperature of the nitrogen alkylation (i.e., carboxymethylation) reaction is from room temperature to reflux, preferably from 50 ℃ to reflux, but is not limited thereto.
And (3) crystallizing and purifying the intermediate II, namely adding an organic solvent after the nitrogen alkylation (namely carboxymethylation) reaction is finished, washing with water to remove inorganic salts, concentrating an organic phase to obtain a crude intermediate II, and crystallizing and purifying the crude intermediate II by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, ester, amide, nitrile, water or a mixture of the alcohol, the ether, the chlorohydrocarbon, alkane, ester, amide, nitrile and water, preferably a mixture of methyl tert-butyl ether and ethyl acetate, but is not limited to the above.
(4) And hydrolyzing the ester group of the intermediate II under the alkaline condition to obtain an intermediate III:
the hydrolysis of the ester group of the intermediate II under basic conditions is usually carried out in the presence of an organic solvent which may be an ether, a halogenated hydrocarbon, an alcohol or a mixed solvent of water and an alcohol, and the preferred alcohol is methanol, but is not limited thereto.
The base required to hydrolyze the ester group is an inorganic base. Preferably, the alkali is strong alkali, such as sodium hydroxide, potassium hydroxide, lithium hydroxide;
the reaction temperature for hydrolyzing the ester group is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited thereto.
Crystallization and purification of intermediate III: after the ester group hydrolysis is finished, cooling to room temperature, filtering to obtain a crude product of the intermediate III, and crystallizing and purifying the crude product of the intermediate III by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether or a mixture of the alcohol and the ether, and preferably a mixture of methanol and methyl tert-butyl ether.
(5) Removing ketal from the intermediate III under acidic condition to obtain a lithium butoxide complex:
the acidic ketal removal from the intermediate III is usually carried out in the presence of an organic solvent such as ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof, preferably water and methyl t-butyl ether, but not limited thereto.
The acid required for removing ketal is organic acid and inorganic acid. Preferably, the inorganic acid is hydrochloric acid, and the organic acid is acetic acid or trifluoroacetic acid, but not limited thereto.
The reaction temperature for removing ketal is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited thereto. Crystallizing and purifying the lithium butoxylate complex, after the ketal removal reaction is finished, removing an organic phase, recovering 9-fluorenone, adjusting the pH of a water phase adjusting system to be 3-4, adding alcohol for crystallization after concentration, separating out a lithium butoxylate complex crude product, crystallizing and purifying the lithium butoxylate complex crude product by adopting a crystallization solvent, wherein the crystallization solvent can be alcohol, ketone, water or a mixture of the alcohol, the ketone and the water, preferably the mixture of the methanol and the water, and after crystallization and purification, the purity of the lithium butoxylate complex obtained is more than 99%, and the single impurity is less than 0.10%, but not limited to the above.
The preparation of the intermediate III can be directly prepared from the intermediate I as well as the intermediate II.
Wherein, the intermediate III is obtained by nitrogen alkylation (namely carboxymethylation) of the intermediate I and alpha-substituted acetic acid or salt in an organic solvent:
the alpha-substituted acetate is selected from lithium, sodium, potassium salts, preferably lithium salts, but not limited to the above.
The nitrogen alkylation (i.e., carboxymethylation) of intermediate i and the α -substituted acetate salt is generally carried out in the presence of an organic solvent which may be a mixed solvent of water and an alcohol, an ether or a nitrile, with methanol being a preferred alcohol, but is not limited thereto.
The nitrogen alkylation (i.e. carboxymethylation) reaction may be carried out in the presence of a base, in particular in the presence of an inorganic base. Preferably, the base is an inorganic base, such as lithium carbonate, lithium hydroxide or a mixture thereof, but is not limited thereto.
The temperature of the nitrogen alkylation (i.e., carboxymethylation) reaction is from room temperature to reflux, preferably from 50 ℃ to reflux, but is not limited thereto.
Crystallization and purification of intermediate III: after the nitrogen alkylation (namely carboxymethylation) is finished, alcohol is added after concentration, the mixture is cooled to room temperature, and the crude product of the intermediate III is filtered to obtain crude product of the intermediate III, the crude product of the intermediate III is crystallized and purified by adopting a crystallization solvent, wherein the crystallization solvent can be alcohol, ether or a mixture of the alcohol and the ether, and preferably a mixture of methanol and methyl tert-butyl ether.
And the preparation method II is used for preparing the lithium butoxide complex through the intermediate II.
(1) Activating 9-fluorenone and trimethyl orthoformate to obtain ketal under the activation of iron p-toluenesulfonate, exchanging the ketal and 1, 4-cis-butene diol to obtain cyclic ketal, and oxidizing the cyclic ketal to obtain epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ];
(2) the preparation method comprises the following steps of carrying out epoxy ring-opening preparation reaction on cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in an organic solvent under the action of lithium salt to generate an intermediate I:
the lithium salt is selected from lithium chloride, lithium bromide, lithium iodide, lithium methanesulfonate, lithium benzenesulfonate, and lithium p-toluenesulfonate.
The organic solvent is selected from C 4 ～C 11 Ether solvent, C 1 ～C 4 Alcohol solvent, C 1 ～C 4 The nitrile solvent, preferably an organic solvent, is selected from tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, etc., but is not limited thereto.
The epoxy ring-opening reaction temperature is from room temperature to reflux, and the reaction is preferably carried out under reflux, but not limited thereto.
And (3) crystallizing and purifying the intermediate I, cooling to separate out a crude intermediate I after the epoxy ring opening reaction is finished, and crystallizing and purifying the crude intermediate I by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, nitrile, ester or a mixture of the alcohol, the ether, the chlorohydrocarbon, the alkane, the nitrile and the ester, and the mixture of the alcohol and the ester is preferred, but not limited to the above.
(3) The intermediate I and the alpha-substituted acetate are subjected to nitrogen alkylation (i.e. carboxymethylation) in an organic solvent to form an intermediate II:
the nitrogen alkylation (i.e., carboxymethylation) of intermediate i and the α -substituted acetate is typically carried out in the presence of an organic solvent which may be a mixture of water and an ether or a nitrile, preferably tetrahydrofuran as the ether and acetonitrile as the nitrile, but is not limited thereto.
The nitrogen alkylation (i.e. carboxymethylation) reaction may be carried out in the presence of a base, in particular in the presence of an inorganic base. Preferably, the base is an inorganic base, such as lithium carbonate, lithium hydroxide or a mixture thereof, but is not limited thereto.
The temperature of the nitrogen alkylation (i.e., carboxymethylation) reaction is from room temperature to reflux, preferably from 50 ℃ to reflux, but is not limited thereto.
And (3) crystallizing and purifying the intermediate II, namely adding an organic solvent after the nitrogen alkylation (namely carboxymethylation) reaction is finished, washing with water to remove inorganic salts, concentrating an organic phase to obtain a crude intermediate II, and crystallizing and purifying the crude intermediate II by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, ester, amide, nitrile, water or a mixture of the alcohol, the ether, the chlorohydrocarbon, alkane, ester, amide, nitrile and water, preferably a mixture of methyl tert-butyl ether and ethyl acetate, but is not limited to the above.
(4) And hydrolyzing an ester group and removing ketal under the acidic condition of the intermediate II to obtain the lithium butoxide complex.
And hydrolyzing ester group and removing ketal under the acidic condition of the intermediate II to obtain a lithium butoxide complex:
the acidic ketal removal from the intermediate II is usually carried out in the presence of an organic solvent such as ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof, preferably water and methyl t-butyl ether, but not limited thereto.
The acid required for removing ketal is organic acid and inorganic acid. Preferably, the inorganic acid is hydrochloric acid, and the organic acid is acetic acid or trifluoroacetic acid, but not limited thereto.
The reaction temperature for removing ketal is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited thereto.
Crystallizing and purifying the lithium butoxylate complex, after the ketal removal reaction is finished, removing an organic phase, recovering 9-fluorenone, adjusting the pH of a water phase adjusting system to be 3-4, adding alcohol for crystallization after concentration, separating out a lithium butoxylate complex crude product, crystallizing and purifying the lithium butoxylate complex crude product by adopting a crystallization solvent, wherein the crystallization solvent can be alcohol, ketone, water or a mixture of the alcohol, the ketone and the water, preferably the mixture of the methanol and the water, and after crystallization and purification, the purity of the lithium butoxylate complex obtained is more than 99%, and the single impurity is less than 0.10%, but not limited to the above.
The invention provides the epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ], the intermediate I, the intermediate II, the intermediate III and the lithium butoxyl complex which are convenient to prepare and easy to control the quality, the regioselectivity is high in the preparation process, the crystallinity of the intermediate is good, the quality control is convenient, the side chain protecting group (9-fluorenone) is convenient to recover, and the prepared lithium butoxyl complex has high quality (the purity is more than 99.0 percent, and the single impurity is less than 0.10 percent), and has good industrial prospect.
Preferably, the preparation method of the invention is as follows:
according to one of the embodiments, the preparation method of the present invention comprises the steps of:
(1)3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ]
Adding 9-fluorenone, trimethyl orthoformate, ferric p-toluenesulfonate and methanol into a reaction bottle, dissolving all materials, reacting at room temperature, separating out solids in the system, tracking the reaction process by TLC (thin layer chromatography), filtering after the reaction is finished, and drying to obtain 9, 9-dimethoxy-9H-fluorene;
adding 9, 9-dimethoxy-9H-fluorene, iron p-toluenesulfonate, maleic-1, 4-diol and dichloromethane into a reaction bottle, completely dissolving the materials, reacting at room temperature, tracking the reaction process by TLC, adding saturated sodium carbonate aqueous solution after the reaction is finished, separating, drying an organic phase, and concentrating to obtain 4',7' -dihydrospiro [ fluorene-9, 2' - [1,3] dioxepane ];
adding 4',7' -dihydrospiro [ fluorene-9, 2'- [1,3] dioxepane ], disodium hydrogen phosphate and dichloromethane into a reaction bottle, adding m-chloroperoxybenzoic acid in batches, reacting at room temperature, tracking the reaction process by TLC, filtering after the reaction is finished, adding a sodium carbonate aqueous solution and a saturated sodium sulfite aqueous solution into a filtrate, separating, drying an organic phase, concentrating to obtain a crude product, adding ethyl acetate for recrystallization, filtering and drying to obtain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ].
(2) Under the protection of nitrogen, mixing cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in acetonitrile, adding lithium chloride, stirring, heating to reflux, tracking the reaction process by HPLC, stopping heating after the reaction is finished, cooling to room temperature, performing suction filtration, washing, drying to obtain a crude product, adding a methanol methyl tert-butyl ether system, and recrystallizing to obtain an intermediate I
(3) Adding the intermediate I and acetonitrile into a three-neck flask, stirring, adding lithium carbonate and tert-butyl chloroacetate, heating the system to 50-55 ℃ for reaction, tracking the reaction process by HPLC (high performance liquid chromatography), cooling after the reaction is finished, adding ethyl acetate and purified water into the reaction liquid, separating liquid, washing an organic phase with water, concentrating, and recrystallizing residual liquid with a methyl tert-butyl ether ethyl acetate system to obtain an intermediate II.
(4) Adding the intermediate II and methanol into a three-neck flask, adding lithium hydroxide, stirring, heating the lower body system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, adding methyl tert-butyl ether after the reaction is finished, cooling to room temperature, filtering to obtain a filter cake, namely an intermediate III crude product, and purifying the intermediate III crude product by adopting a methanol methyl tert-butyl ether system to obtain an intermediate III.
(5) Adding a compound III, water and methyl tert-butyl ether into a three-necked bottle, adding hydrochloric acid to adjust the pH value of a system to be 1-2, heating the system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, separating liquid after the reaction is finished, recovering 9-fluorenone from an organic phase, adjusting the pH value of the system to be 3-4 in an aqueous phase, concentrating the aqueous phase under reduced pressure, adding ethanol for crystallization, filtering and drying to obtain a lithium butoxide complex crude product, recrystallizing the lithium butoxide complex crude product by using ethanol water, and drying to obtain the lithium butoxide complex (the purity is more than 99.0% and the single impurity is less than 0.10%).
Alternatively, the intermediate III can be prepared by the following method:
adding the intermediate I, chloroacetic acid, methanol and water into a three-neck flask, stirring, adding lithium hydroxide, heating the system to 50-55 ℃ for reaction, adjusting the pH of the system to 9-10 by using the lithium hydroxide, tracking the reaction process by HPLC, evaporating the solvent under reduced pressure after the reaction is finished, carrying the residual liquid by using methanol for three times, adding the methanol and methyl tert-butyl ether, pulping, filtering a filter cake to obtain a crude product of the intermediate III, and purifying the crude product of the intermediate III by using a methanol methyl tert-butyl ether system to obtain the intermediate III.
Alternatively, the lithium butoxide complex can also be prepared by the following method:
adding a compound II, water and methyl tert-butyl ether into a three-necked bottle, adding hydrochloric acid to adjust the pH value of the system to 1-2, heating the system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, separating liquid after the reaction is finished, recovering 9-fluorenone from an organic phase, adding lithium chloride, adjusting the pH value of the system to 3-4 in an aqueous phase, concentrating the aqueous phase under reduced pressure, adding ethanol for crystallization, filtering, drying to obtain a lithium butoxide complex crude product, recrystallizing the lithium butoxide complex crude product with ethanol water, and drying to obtain the lithium butoxide complex (the purity is more than 99.0% and the single impurity is less than 0.10%).
The preparation method is simpler and more convenient, has low cost and controllable quality, and the product has the characteristics of high purity, high yield, less impurities and the like.
The specific implementation mode is as follows:
the present invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention thereto.
The reaction equation is as follows:
preparation of epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ]:
9, 9-dimethoxy-9H-fluorene
9-fluorenone (22g), trimethyl orthoformate (26g), iron p-toluenesulfonate (1.4g) and methanol (150g) were added to a reaction flask, and the materials were all dissolved to react at room temperature, and a solid precipitated in the system, followed by reaction progress by TLC, and after completion of the reaction, filtration and drying were carried out to obtain 9, 9-dimethoxy-9H-fluorene (white solid, 24.8g, yield: 89.8%, HPLC: 98.93%). 1 H 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) + ].
4',7' -dihydrospiro [ fluorene-9, 2' - [1,3] dioxepane ]
Adding 9, 9-dimethoxy-9H-fluorene (20g), ferric p-toluenesulfonate (0.5g), maleic-1, 4-diol (10g) and dichloromethane (100g) into a reaction bottle, completely dissolving the materials, reacting at room temperature, tracking the reaction process by TLC, adding saturated sodium carbonate aqueous solution (30g) after the reaction is finished, separating, drying an organic phase, and concentrating to obtain 4',7' -dihydrospiro [ fluorene-9, 2' - [1 ] fluorene,3]Dioxepane (II)](off-white solid, 22g, yield 99.1%, HPLC: 92.80%, MS: M/e 251.1[ (M + H) + ].), was not purified and was directly subjected to epoxidation.
3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ]
Adding 4',7' -dihydrospiro [ fluorene-9, 2' - [1,3] into a reaction bottle]Dioxepane (II)](21.5g), disodium hydrogen phosphate (13g) and dichloromethane (200g), adding m-chloroperoxybenzoic acid (20g) in batches, reacting at room temperature, tracking the reaction process by TLC, filtering after the reaction is finished, adding a sodium carbonate aqueous solution and a saturated sodium sulfite aqueous solution into filtrate, separating, drying an organic phase, concentrating to obtain a crude product (22g), adding ethyl acetate (50g), recrystallizing, filtering and drying to obtain the 3,5, 8-trioxaspiro [ bicyclo [5.1.0]]Octane-4, 9' -fluorene](white solid, 20g, yield 87.5%) 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/e 267.1[(M+H) + ].
Preparation of intermediate I
Under the protection of nitrogen, cycleanine (21g) and 3,5, 8-trioxaspiro [ bicyclo [5.1.0]]Octane-4, 9' -fluorenes](22g) And lithium chloride (5.2g) are mixed in ethanol (100mL), stirred and heated to reflux, HPLC tracks the reaction process, heating is stopped after the reaction is finished, the temperature is reduced to room temperature, and the mixture is subjected to suction filtration, washing and drying to obtain a crude product of 37g, and a methanol methyl tert-butyl ether system is added for recrystallization to obtain a product: 32.5g, yield: 81.8% and HPLC 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 percent
Preparation of intermediate II
Adding the intermediate I (20g) and acetonitrile (300mL) into a three-neck flask, stirring, adding lithium carbonate (25.2g) and tert-butyl chloroacetate (24g), heating the system to 50-55 ℃ for reaction, tracking the reaction process by HPLC (high performance liquid chromatography), finishing the reaction, cooling, adding purified water and acetonitrile into the reaction solution, adding purified water into the reaction solution, adding acetonitrile into the reaction solution, stirring, adding sodium chloride, sodium chloride and sodium chloride, stirring, adding sodium chloride, sodium chloride and the likeSeparating the solution from ethyl acetate, washing the filtrate with water, concentrating, and recrystallizing the residual solution with a methyl tert-butyl ether ethyl acetate system to obtain a white solid compound II: 28.9g, yield: 89.0 percent and 99.4 percent of HPLC. 1 H NMR(400MHz,Chloroform-d)δ7.67–7.51(m,4H),7.42–7.20(m,4H),5.33(d,J＝10.5Hz,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) + ].
Preparation of Compound III
Adding an intermediate I (10g), methanol (60mL), chloroacetic acid (16g) and water (30g) into a three-necked bottle, stirring, adding a lithium hydroxide aqueous solution to adjust the pH value of a system to 9-10, heating the system to 50-55 ℃ for reaction, adjusting the pH value of the system to 9-10 by using lithium hydroxide, tracking the reaction process by HPLC (high performance liquid chromatography), concentrating a reaction solution after the reaction is finished, adding methanol into concentrated residual liquid for entrainment, adding methanol and methyl tert-butyl ether for recrystallization, performing suction filtration, and drying to obtain a filter cake as an intermediate III: 17.5g (product contains lithium chloroacetate), HPLC: 99.2%. MS: m/e 615.6[ intermediate III Carboxylic acid (M + H) + ]
Adding a compound II (10g) and methanol (100mL) into a three-neck flask, stirring, adding lithium hydroxide (2.5g), heating the system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, adding methyl tert-butyl ether (100mL) after the reaction is finished, filtering to obtain a filter cake, namely a crude product of an intermediate III, recrystallizing the intermediate III by using methanol and methyl tert-butyl ether, performing suction filtration, drying, and obtaining the filter cake as an intermediate III, wherein the yield is 7.8 g: 93.1%, HPLC: 99.5%. 1 H NMR (400MHz, Deuterium Oxide) δ 7.41(t, J ═ 8.1Hz,4H),7.23(ddt, J ═ 19.4,12.6,7.0Hz,6H),3.78(dd, J ═ 17.9,10.5Hz,2H),3.54 to 3.26(m,4H),3.12 to 2.25(m,22H), IC method determination: the lithium content was 4.3%.
Preparation of lithium bronopol complexes
Adding the intermediate II (5g) and 1, 4-dioxane (50mL) into a three-necked bottle, stirring, adding 1N 1, 4-dioxane solution of hydrogen chloride (50mL), heating the system to reflux reaction, tracking the reaction process by HPLC (high performance liquid chromatography), finishing the reaction, concentrating, adding residual liquid into water, extracting by methyl tert-butyl ether, adding lithium chloride (1g), adjusting the pH value of an aqueous phase system to 3-4, concentrating, adding ethanol for crystallization, filtering, and drying to obtain a white crude product (2.9 g). The crude product was recrystallized from ethanol water, and dried to give a lithium butoxylate complex (white solid 2.6g, yield: 74.9%, HPLC: 99.6%, maximum single impurity 0.06%), water: 9.8%, IC method determination: the lithium content was 2.65% and the chlorine content was 6.85%.
Adding the intermediate III (5g), purified water (50ml) and methyl tert-butyl ether (50ml) into a three-necked bottle, adjusting the pH of the system to 1-2 by using hydrochloric acid, tracking the reaction process by using HPLC, separating liquid after the reaction is finished, adjusting the pH of the water phase to 3-4 by using lithium hydroxide, then carrying out reduced pressure concentration, adding methanol for crystallization, filtering and drying to obtain a white crude product (3.9 g). The crude product was recrystallized from ethanol water, and dried to give a lithium butoxylate complex (white solid, 3.5g, yield: 82.9%, HPLC: 99.8%, maximum single impurity 0.05%), water: 9.7%, IC method determination: the lithium content was 2.68% and the chlorine content was 6.91%.
Example 2 comparative experiment TW450965, CN1229357C
Preparation of 1- (6-hydroxy-2, 2-dimethyl-1, 3-dioxepan-5-yl) -1,4,7, 10-tetraazacyclododecane lithium chloride complex
Under the protection of nitrogen, mixing cyclen (20g), 4-dimethyl-3, 5, 8-trioxabicyclo [5.1.0] octane (19.2g) and lithium chloride (4.85g) in isopropanol (40g), stirring, heating to reflux, tracking the reaction process by HPLC, stopping heating after the reaction is finished, reducing pressure, concentrating to remove isopropanol, adding methyl tert-butyl ether for crystallization, performing suction filtration, washing and drying to obtain a crude product of 40g, adding a methyl tert-butyl ether system for recrystallization, and obtaining a product: 32g, yield: 76.8%, HPLC 90.17%.
Preparation of lithium bronopol complexes
Adding 1- (6-hydroxy-2, 2-dimethyl-1, 3-dioxepan-5-yl) -1,4,7, 10-tetraazacyclododecane lithium chloride complex (30g) and water (150mL) into a three-necked bottle, stirring, adding chloroacetic acid (60g), heating the system to 60-65 ℃ for reaction, adjusting the pH of the system to 10-11 by using lithium hydroxide, tracking the reaction process by HPLC (high performance liquid chromatography), acidifying the system to 1.5 by using hydrochloric acid after the reaction is finished, concentrating the reaction liquid, adding methanol (500mL) for dissolving, filtering to remove salt, concentrating the filtrate, adding residual liquid into water, adjusting the pH of the system to 3-4 by using lithium hydroxide, decompressing and concentrating the aqueous phase, adding ethanol for crystallization, filtering and drying to obtain a white crude product (38 g). The crude product was recrystallized from ethanol water and dried to give a lithium butoxylate complex (white solid, 23.2g, yield: 61.5%, HPLC: 99.3%, single impurity < 0.10%).
In order to better illustrate the advantages of the patent, the cyclen is used as a raw material to prepare the lithium butoxide complex, and the reaction steps, the total yield and the quality are compared, and the specific results are as follows:
the above list shows that the present invention has high yield, excellent quality and excellent intermediate quality.
Claims (9)
1. The preparation method of the lithium butoxide complex is characterized by comprising the following steps:
wherein:
r is C 1 ～C 6 A linear or branched alkyl group;
x is halogen or sulfonate;
m is lithium, sodium, potassium or hydrogen.
2. The production method according to claim 1,
the method comprises the following steps:
(1) activating 9-fluorenone and trimethyl orthoformate to obtain ketal under the activation of iron p-toluenesulfonate, exchanging the ketal and 1, 4-cis-butene diol to obtain cyclic ketal, and oxidizing the cyclic ketal to obtain epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ];
(2) performing epoxy ring-opening preparation reaction on cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in an organic solvent under the action of lithium salt to generate an intermediate I;
(3) carrying out nitrogen alkylation on the intermediate I and the alpha-substituted acetate in an organic solvent to generate an intermediate II;
(4) hydrolyzing the ester group of the intermediate II under an alkaline condition to obtain an intermediate III;
(5) and removing ketal from the intermediate III under an acidic condition to obtain the lithium butoxide complex.
3. The production method according to claim 1,
wherein, the intermediate III is obtained by nitrogen alkylation of the intermediate I and alpha-substituted acetic acid or salt in an organic solvent:
the alpha-substituted acetate is selected from the group consisting of lithium, sodium, potassium, preferably lithium, but not limited to,
the nitrogen alkylation reaction of intermediate i with the α -substituted acetate is generally carried out in the presence of an organic solvent which may be a mixed solvent of water and an alcohol, ether or nitrile, with the preferred alcohol being methanol, but is not limited thereto,
the nitrogen alkylation reaction may be carried out in the presence of a base, particularly an inorganic base, preferably an inorganic base such as lithium carbonate, lithium hydroxide or a mixture thereof, but not limited thereto, and the nitrogen alkylation reaction temperature is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited thereto.
4. The method of claim 1, comprising the steps of:
(1) activating 9-fluorenone and trimethyl orthoformate to obtain ketal under the activation of iron p-toluenesulfonate, exchanging the ketal and 1, 4-cis-butene diol to obtain cyclic ketal, and oxidizing the cyclic ketal to obtain epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ];
(2) the preparation method comprises the following steps of carrying out epoxy ring-opening preparation reaction on cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in an organic solvent under the action of lithium salt to generate an 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 C 4 ～C 11 Ether solvent, C 1 ～C 4 Alcohol solvent, C 1 ～C 4 Nitrile solvents, preferred organic solvents are selected from tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, and the like, but are not limited to the above,
the epoxy ring-opening reaction temperature is from room temperature to reflux, and the reaction is preferably carried out under reflux, but not limited to the above,
crystallizing and purifying the intermediate I, cooling after the epoxy ring opening reaction is finished to separate out crude intermediate I, crystallizing and purifying the crude intermediate I by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, nitrile, ester or a mixture of the alcohol, the ether, the chlorohydrocarbon, the alkane, the nitrile and the ester, preferably the mixture of the alcohol and the ester, but is not limited to the above,
(3) the intermediate I and the alpha-substituted acetate are subjected to nitrogen alkylation (i.e. carboxymethylation) in an organic solvent to form an intermediate II:
the nitrogen alkylation (i.e., carboxymethylation) of intermediate i and the α -substituted acetate is typically carried out in the presence of an organic solvent which may be a mixture of water and an ether or a nitrile, preferably tetrahydrofuran as the ether and acetonitrile as the nitrile, but is not limited to the above,
the nitrogen alkylation (i.e., carboxymethylation) reaction may be carried out in the presence of a base, particularly an inorganic base, preferably an inorganic base such as lithium carbonate, lithium hydroxide or mixtures thereof, but is not limited to,
the temperature of the nitrogen alkylation (i.e., carboxymethylation) reaction is from room temperature to reflux, preferably from 50 ℃ to reflux, but is not limited to,
crystallization and purification of the intermediate II, after the nitrogen alkylation (namely carboxymethylation) reaction is finished, adding an organic solvent, washing with water to remove inorganic salts, concentrating an organic phase to obtain a crude intermediate II, and performing crystallization and purification on the crude intermediate II by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, ester, amide, nitrile, water or a mixture of the alcohol, the ether, the chlorohydrocarbon, alkane, ester, amide, nitrile and water, preferably a mixture of methyl tert-butyl ether and ethyl acetate, but is not limited to the above,
(4) and hydrolyzing the ester group of the intermediate II under the alkaline condition to obtain an intermediate III:
the hydrolysis of the ester group under basic conditions of the intermediate II is usually carried out in the presence of an organic solvent which may be an ether, a halogenated hydrocarbon, an alcohol or a mixed solvent of water and an alcohol, the preferred alcohol being methanol, but is not limited thereto,
the alkali required for hydrolyzing the ester group is inorganic alkali, preferably, the alkali is strong alkali, such as sodium hydroxide, potassium hydroxide and lithium hydroxide;
the reaction temperature for hydrolyzing the ester group is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited to the above, crystallization purification of intermediate iii: after the ester group hydrolysis is finished, cooling to room temperature, filtering to obtain a crude product of an intermediate III, crystallizing and purifying the crude product of the intermediate III by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether or a mixture of the alcohol and the ether, preferably a mixture of methanol and methyl tert-butyl ether,
(5) removing ketal from the intermediate III under acidic condition to obtain a lithium butoxide complex:
the acidic removal of the ketal from the intermediate III is usually carried out in the presence of an organic solvent such as ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof, preferably water and methyl t-butyl ether, but not limited thereto,
the acid needed for removing ketal is organic acid and inorganic acid, preferably, the inorganic acid is hydrochloric acid, the organic acid is acetic acid, trifluoroacetic acid, but is not limited to the above,
the ketal removal reaction temperature is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited to the above, the crystallization purification of the lithium butoxide complex, after the ketal removal reaction is finished, separating an organic phase, recovering 9-fluorenone, adjusting the pH of a water phase system to 3-4, concentrating, adding alcohol for crystallization, and separating out a lithium butoxide complex crude product, wherein the lithium butoxide complex crude product is crystallized and purified by adopting a crystallization solvent, the crystallization solvent can be alcohol, ketone, water or a mixture thereof, preferably a mixture of methanol and water, and after the crystallization purification, the purity of the obtained lithium butoxide complex is more than 99%, and the single impurity is less than 0.10%, but not limited to the above.
5. The production method according to claim 1,
the second method comprises the following steps:
(1) activating 9-fluorenone and trimethyl orthoformate to obtain ketal under the activation of ferric p-toluenesulfonate, exchanging the ketal and cis-butene-1, 4-diol to obtain cyclic ketal, and oxidizing the cyclic ketal to obtain an epoxy side chain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ];
(2) the preparation method comprises the following steps of carrying out epoxy ring-opening preparation reaction on cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in an organic solvent under the action of lithium salt to generate an 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 C 4 ～C 11 Ether solvent, C 1 ～C 4 Alcohol solvent, C 1 ～C 4 Nitrile solvents, preferably organic solvents selected from tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, and the like, but not limited thereto,
the epoxy ring-opening reaction temperature is from room temperature to reflux, and the reaction is preferably carried out under reflux, but not limited to the above,
crystallizing and purifying the intermediate I, cooling after the epoxy ring opening reaction is finished to separate out crude intermediate I, crystallizing and purifying the crude intermediate I by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, nitrile, ester or a mixture of the alcohol, the ether, the chlorohydrocarbon, the alkane, the nitrile and the ester, preferably the mixture of the alcohol and the ester, but is not limited to the above,
(3) and (3) carrying out nitrogen alkylation on the intermediate I and the alpha-substituted acetate in an organic solvent to generate an intermediate II:
the nitrogen alkylation reaction of intermediate i with the α -substituted acetate is generally carried out in the presence of an organic solvent which may be a mixed solvent of water and an ether or a nitrile, preferably tetrahydrofuran as an ether and acetonitrile as a nitrile, but is not limited thereto,
the nitrogen alkylation reaction may be carried out in the presence of a base, particularly an inorganic base, preferably an inorganic base such as lithium carbonate, lithium hydroxide or a mixture thereof, but not limited thereto, at a temperature ranging from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited thereto,
crystallizing and purifying the intermediate II, adding an organic solvent after the nitrogen alkylation reaction is finished, washing with water to remove inorganic salts, concentrating an organic phase to obtain a crude intermediate II, crystallizing and purifying the crude intermediate II by using a crystallization solvent, wherein the crystallization solvent can be alcohol, ether, chlorohydrocarbon, alkane, ester, amide, nitrile, water or a mixture of the alcohol, the ether, the chlorohydrocarbon, the alkane, the ester, the amide, the nitrile and the water, preferably a mixture of methyl tert-butyl ether and ethyl acetate, but is not limited to the above,
(4) hydrolyzing ester group and removing ketal under the acidic condition of the intermediate II to obtain the lithium butoxide complex,
and hydrolyzing ester group and removing ketal under the acidic condition of the intermediate II to obtain a lithium butoxide complex:
the acidic ketal removal from the intermediate II is usually carried out in the presence of an organic solvent such as ether, halogenated hydrocarbon, alcohol, water or a mixed solvent thereof, preferably water and methyl t-butyl ether, but not limited thereto,
the acid needed for removing ketal is organic acid and inorganic acid, preferably, the inorganic acid is hydrochloric acid, the organic acid is acetic acid, trifluoroacetic acid, but is not limited to the above,
the reaction temperature for removing ketal is from room temperature to reflux, preferably from 50 ℃ to reflux, but not limited thereto.
6. The method of claim 1, comprising the steps of:
7. the method of claim 6, comprising the steps of:
(1)3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ]
Adding 9-fluorenone, trimethyl orthoformate, ferric p-toluenesulfonate and methanol into a reaction bottle, dissolving all materials, reacting at room temperature, separating out solids in the system, tracking the reaction process by TLC (thin layer chromatography), and filtering and drying after the reaction is finished to obtain 9, 9-dimethoxy-9H-fluorene;
adding 9, 9-dimethoxy-9H-fluorene, iron p-toluenesulfonate, maleic-1, 4-diol and dichloromethane into a reaction bottle, completely dissolving the materials, reacting at room temperature, tracking the reaction process by TLC, adding saturated sodium carbonate aqueous solution after the reaction is finished, separating, drying an organic phase, and concentrating to obtain 4',7' -dihydrospiro [ fluorene-9, 2' - [1,3] dioxepane ];
adding 4',7' -dihydrospiro [ fluorene-9, 2'- [1,3] dioxepane ], disodium hydrogen phosphate and dichloromethane into a reaction bottle, adding m-chloroperoxybenzoic acid in batches, reacting at room temperature, tracking the reaction process by TLC, filtering after the reaction is finished, adding a sodium carbonate aqueous solution and a saturated sodium sulfite aqueous solution into a filtrate, separating, drying an organic phase, concentrating to obtain a crude product, adding ethyl acetate for recrystallization, filtering and drying to obtain 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ].
(2) Under the protection of nitrogen, mixing cyclen and 3,5, 8-trioxaspiro [ bicyclo [5.1.0] octane-4, 9' -fluorene ] in acetonitrile, adding lithium chloride, stirring, heating to reflux, tracking the reaction process by HPLC, stopping heating after the reaction is finished, cooling to room temperature, performing suction filtration, washing, drying to obtain a crude product, adding a methanol methyl tert-butyl ether system, and recrystallizing to obtain an intermediate I
(3) Adding the intermediate I and acetonitrile into a three-neck flask, stirring, adding lithium carbonate and tert-butyl chloroacetate, heating the system to 50-55 ℃ for reaction, tracking the reaction process by HPLC (high performance liquid chromatography), cooling after the reaction is finished, adding ethyl acetate and purified water into the reaction liquid, separating liquid, washing an organic phase with water, concentrating, and recrystallizing residual liquid with a methyl tert-butyl ether ethyl acetate system to obtain an intermediate II.
(4) Adding the intermediate II and methanol into a three-neck flask, adding lithium hydroxide, stirring, heating the lower body system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, adding methyl tert-butyl ether after the reaction is finished, cooling to room temperature, filtering to obtain a filter cake, namely an intermediate III crude product, and purifying the intermediate III crude product by adopting a methanol methyl tert-butyl ether system to obtain an intermediate III.
(5) Adding a compound III, water and methyl tert-butyl ether into a three-necked bottle, adding hydrochloric acid to adjust the pH value of a system to 1-2, heating the system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, separating liquid after the reaction is finished, recovering 9-fluorenone from an organic phase, adjusting the pH value of the system to 3-4 in an aqueous phase, concentrating the aqueous phase under reduced pressure, adding ethanol for crystallization, filtering and drying to obtain a lithium butoxide complex crude product, recrystallizing the lithium butoxide complex crude product with ethanol water, and drying to obtain the lithium butoxide complex.
8. The process according to claim 7, wherein intermediate III is further prepared by:
adding the intermediate I, chloroacetic acid, methanol and water into a three-neck flask, stirring, adding lithium hydroxide, heating the system to 50-55 ℃ for reaction, adjusting the pH of the system to 9-10 by using the lithium hydroxide, tracking the reaction process by HPLC, evaporating the solvent under reduced pressure after the reaction is finished, carrying the residual liquid by using methanol for three times, adding the methanol and methyl tert-butyl ether, pulping, filtering a filter cake to obtain a crude product of the intermediate III, and purifying the crude product of the intermediate III by using a methanol methyl tert-butyl ether system to obtain the intermediate III.
9. The method according to claim 6, wherein the lithium butoxide complex is also prepared by:
adding a compound II, water and methyl tert-butyl ether into a three-necked bottle, adding hydrochloric acid to adjust the pH value of the system to 1-2, heating the system to 50-60 ℃ for reaction, tracking the reaction process by HPLC, separating liquid after the reaction is finished, recovering 9-fluorenone from an organic phase, adding lithium chloride, adjusting the pH value of the system to 3-4 in an aqueous phase, concentrating the aqueous phase under reduced pressure, adding ethanol for crystallization, filtering, drying to obtain a lithium butoxide complex crude product, recrystallizing the lithium butoxide complex crude product with ethanol water, and drying to obtain the lithium butoxide complex.
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