CN115974746A - Synthetic method of tosufloxacin tosylate intermediate - Google Patents
Synthetic method of tosufloxacin tosylate intermediate Download PDFInfo
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Abstract
The invention discloses a tosufloxacin tosylate intermediate and a synthesis method thereof, which comprises the following steps: reacting glycine ethyl ester or hydrochloride thereof with di-tert-butyl dicarbonate to obtain N-tert-butoxycarbonyl-glycine ethyl ester; reacting the N-tert-butyloxycarbonyl-glycine ethyl ester with ethyl acrylate to obtain N-tert-butyloxycarbonyl-4-oxo-3-pyrrolidine ethyl formate; carrying out deesterification reaction on the N-tert-butyloxycarbonyl-4-oxo-3-pyrrolidine ethyl formate to obtain 3-pyrrolidone hydrochloride; 3-pyrrolidone hydrochloride reacts with di-tert-butyl dicarbonate to obtain N-tert-butoxycarbonyl-3-pyrrolidone; reacting N-tert-butyloxycarbonyl-3-pyrrolidone with an amine source to obtain N-tert-butyloxycarbonyl-3-aminopyrrolidine; and carrying out deprotection reaction on the N-tert-butyloxycarbonyl-3-aminopyrrolidine to obtain the tosufloxacin tosylate intermediate. The synthesis method of the tosufloxacin tosylate intermediate is short in preparation, simple and convenient to operate, easy to purify the intermediate quality, and suitable for large-scale production.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthesis method of a tosufloxacin tosylate intermediate. In addition, the invention also relates to a tosufloxacin tosylate intermediate obtained by the synthesis method.
Background
The tosufloxacin tosylate intermediate 3-aminopyrrolidine is an important organic synthesis intermediate, is widely applied to the synthesis of fine chemicals, and various derivatives thereof are also widely applied to the synthesis of pesticides and medicines. At present, the synthesis routes of the compounds mainly comprise the following routes:
pfizer company is exploring the use of optically active 3-aminopyrrolidine and its derivatives in the synthesis of vinylpyrrolidone cephalosporins and discloses a process for the synthesis of 3-aminopyrrolidine using N-benzyl-3-hydroxypyrrolidine as the starting material and explosive sodium azide as the amination reagent. The process route is as follows:
US4785119 discloses: amination of 1,2, 4-tribromobutane produces 3-aminopyrrolidine. It is noteworthy that the use of this process in drug synthesis is limited due to the genotoxicity of 1,2, 4-tribromobutane. The process route is as follows:
EP1188744 discloses: a process for preparing 3-aminopyrrolidine by using aspartic acid as a raw material. The method starts from aspartic acid as a raw material, obtains (S) -3-aminopyrrolidine containing a chiral center through 6 steps of reaction, and has complex reaction and expensive raw material price. The process route is as follows:
CN201810649466, discloses a process for preparing 3-aminopyrrolidine by hydrogenation reduction after pyrrole nitration. This process can convert pyrrole to 3-aminopyrrolidine in only two steps, but its use in industry is limited due to the use of nitric acid. The process route is as follows:
in summary, most of the existing routes require hydrogenation to synthesize 3-aminopyrrolidine and derivatives thereof, while hydrogenation usually requires high-pressure equipment, hydrogen is flammable and explosive, and is greatly limited in industrial production, and meanwhile, some of the routes use raw materials which are genotoxic or flammable and explosive, and have low reaction efficiency.
Disclosure of Invention
The invention provides a tosufloxacin tosylate intermediate and a preparation method thereof, which aim to solve the technical problems that the existing synthesis of 3-aminopyrrolidine and derivatives adopts a hydrogenation method, high-pressure equipment is needed, the preparation method is complex, the cost of raw materials is high, and the industrial production is difficult to realize.
The technical scheme adopted by the invention is as follows:
a synthetic method of tosufloxacin tosylate intermediate comprises the following steps:
s1, reacting glycine ethyl ester or hydrochloride thereof with di-tert-butyl dicarbonate under an alkaline condition to obtain N-tert-butoxycarbonylglycine ethyl ester;
s2, reacting the N-tert-butyloxycarbonyl glycine ethyl ester with ethyl acrylate under an alkaline condition to obtain N-tert-butyloxycarbonyl-4-oxo-3-pyrrolidine ethyl formate;
s3, carrying out a de-esterification reaction on the ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate to obtain N-tert-butoxycarbonyl-3-pyrrolidone;
s4, reacting N-tert-butyloxycarbonyl-3-pyrrolidone with an amine source to obtain N-tert-butyloxycarbonyl-3-aminopyrrolidine;
and S5, under an acidic condition, carrying out deprotection reaction on N-tert-butyloxycarbonyl-3-aminopyrrolidine to obtain a tosufloxacin tosylate intermediate. The overall reaction equation is as follows:
further, the specific step of reacting glycine ethyl ester or hydrochloride thereof with di-tert-butyl dicarbonate in step S1 comprises:
dissolving glycine ethyl ester or hydrochloride thereof and di-tert-butyl dicarbonate in a solvent, adding alkali to enable a reaction system to form an alkaline condition, reacting the glycine ethyl ester or hydrochloride thereof with the di-tert-butyl dicarbonate, adding an organic solvent to mix after the reaction is finished, extracting, collecting an organic phase, drying, filtering and concentrating to obtain the N-tert-butoxycarbonyl-glycine ethyl ester.
In the step S1, the glycine ethyl ester hydrochloride has low cost, the reaction of the glycine ethyl ester hydrochloride and the di-tert-butyl dicarbonate is easy to occur, and the synthesis rate is high. The tert-butyloxycarbonyl group is used as a protecting group, the reaction is easy to carry out, and the obtained product is also easy to remove the protection.
Preferably, the reaction temperature is 50-100 ℃, the reaction time is 6-24 h, and the molar ratio of the di-tert-butyl dicarbonate to the glycine ethyl ester or the hydrochloride thereof is 0.5-5; the molar ratio of the alkali to the glycine ethyl ester or the hydrochloride thereof is 0.1-5.
More preferably, the reaction temperature is 75-85 ℃, the reaction time is 11-13 h, and the molar ratio of the di-tert-butyl dicarbonate to the glycine ethyl ester or the hydrochloride thereof is 1-2; the molar ratio of the alkali to the glycine ethyl ester or the hydrochloride thereof is 2-4. So that the glycine ethyl ester hydrochloride and the di-tert-butyl dicarbonate react fully, the reaction yield is improved, and the conversion rate of the glycine ethyl ester hydrochloride is improved.
Further, the specific step of reacting N-tert-butoxycarbonyl-glycine ethyl ester with ethyl acrylate in step S2 includes:
dissolving N-tert-butyloxycarbonyl-glycine ethyl ester and ethyl acrylate in a solvent, adding an alkali to enable a reaction system to form an alkaline condition, reacting the N-tert-butyloxycarbonyl-glycine ethyl ester with the ethyl acrylate, adding an organic solvent after the reaction is finished, mixing, extracting, collecting an organic phase, drying, filtering and concentrating to obtain the N-tert-butyloxycarbonyl-4-oxo-3-pyrrolidine ethyl formate.
Preferably, the reaction temperature is 0-60 ℃, the reaction time is 6-24 h, and the molar ratio of the ethyl acrylate to the N-tert-butoxycarbonyl-glycine ethyl ester is 0.5-5; the molar ratio of the alkali to the N-tert-butyloxycarbonyl-glycine ethyl ester is 0.1-5.
More preferably, the reaction temperature is 20-30 ℃, the reaction time is 6-12 h, and the molar ratio of the ethyl acrylate to the N-tert-butoxycarbonyl-glycine ethyl ester is 1-2; the molar ratio of the base to the N-tert-butyloxycarbonyl-glycine ethyl ester is 2-4.
Further, the step S3 of performing a de-esterification reaction on ethyl N-t-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate includes the following specific steps:
dissolving the ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate in a solvent B to perform a de-esterification reaction, adding an organic solvent after the reaction is finished, mixing, extracting, collecting an organic phase, drying, filtering and concentrating to obtain the N-tert-butoxycarbonyl-3-pyrrolidone.
In the step S3, it is considered that the t-butyloxycarbonyl group and-COOEt are in different positions, and the-COOEt is in the α position of the carbonyl group and is easily separated during the reaction, and the α -carbanion generated after the removal of the-COOEt is easily bonded to hydrogen, however, the t-butyloxycarbonyl group is stably bonded to ammonia, and thus, no reaction occurs at this stage. This was also confirmed by experiments.
Compared with the prior art that the protecting group on N and the ester group on the pyrrole ring can be removed simultaneously by removing the group, only 3-ethyl formate on the pyridine ring is removed in the step S3, and the tert-butyloxycarbonyl group on N cannot be removed, so that the step that a protecting group needs to be added on N for protecting the N group on the pyrrole ring before the reduction reaction in the subsequent step S4 is omitted.
Preferably, the organic solvent is ethyl acetate; toluene was used as solvent B.
Preferably, the reaction temperature is 100-150 ℃, and the reaction time is 15-20 h.
More preferably, the temperature of the reaction is from 110 ℃ to 150 ℃. The reaction time is 18-20 h.
Further, in the step S4, two synthesis methods of N-tert-butoxycarbonyl-3-pyrrolidone and an amine source are adopted, and the specific steps include:
the method comprises the following steps:
dissolving N-tert-butyloxycarbonyl-3-pyrrolidone, a catalyst and an amine source in a solvent A for reaction, adding an organic solvent after the reaction is finished, mixing, extracting, collecting an organic phase, drying, filtering and concentrating to obtain the N-tert-butyloxycarbonyl-3-aminopyrrolidine.
In the first method in step S4, the carbonyl group first generates an imine-like intermediate in the reaction process, and the imine-like intermediate is reduced to amine under the catalytic condition (palladium on carbon hydrogenation or palladium on carbon ammonium formate). The reaction time is shortened as the reaction temperature is increased. The catalyst changes the reaction rate through catalysis, and generally is not consumed in the reaction, so the dosage is low.
Preferably, the catalyst is a palladium catalyst; and/or, the amine source adopts methanolamine or ammonium formate; and/or the solvent A is a mixed solution of ethanol and water in a certain volume ratio; and/or the organic solvent adopts ethyl acetate.
More preferably, the volume ratio of ethanol to water in the solvent A is 5-15: 1.
Preferably, the reaction temperature is 0-60 ℃, and the reaction time is 12-24 h; the mol ratio of the amine source to the N-tert-butyloxycarbonyl-3-pyrrolidone is 0.5-10: 1; the molar ratio of the catalyst to the N-tert-butyloxycarbonyl-3-pyrrolidone is 0.01-1.
More preferably, the reaction temperature is 40-50 ℃, and the reaction time is 20-24 h; the molar ratio of the amine source to the N-tert-butyloxycarbonyl-3-pyrrolidone is 2-3; the molar ratio of the catalyst to the N-tert-butyloxycarbonyl-3-pyrrolidone is 0.05-0.2.
The second method comprises the following steps:
dissolving N-tert-butoxycarbonyl-3-pyrrolidone, a catalyst of tetraisopropyl titanate and an amine source in a solvent A for reaction, adding a reducing agent for continuous reaction, adding water after the reaction is finished to stop the reaction, adding an organic solvent for mixing, extracting, collecting an organic phase, drying, filtering and concentrating to obtain the N-tert-butoxycarbonyl-3-aminopyrrolidine.
Preferably, the reducing agent is sodium borohydride; and/or, the amine source adopts ammonia methanol solution or ammonium formate and/or, the solvent A adopts mixed solution of ethanol and water according to a certain volume ratio; and/or the organic solvent adopts ethyl acetate.
More preferably, the volume ratio of ethanol to water in the solvent A is 5-15: 1.
In the second method in step S4, tetraisopropyl titanate is first coordinated with carbonyl to generate a transition state that is easily aminated with ammonia, and then hydrogenated and substituted under the action of reducing agent sodium borohydride to obtain the target product. If tetraisopropyl titanate is not added during the reaction, the system does not react, tetraisopropyl titanate is added to react, and tetraisopropyl titanate coordinates with a carbonyl group to form an intermediate which is easily aminated. In this process, the reaction time is inversely related to the range of reaction temperature.
Preferably, the reaction temperature is 0-60 ℃, the reaction time is 8-24 h, and the continuous reaction time is 2-10 h.
More preferably, the reaction temperature is 40-50 ℃, and the reaction time is 20-24 h; the continuous reaction time is 3-6 h.
Preferably, the molar ratio of the tetraisopropyl titanate, the N-tert-butoxycarbonyl-3-pyrrolidone and the amine source is 0.2-2: 1:0.5 to 10; the mol ratio of the reducing agent to the N-tert-butyloxycarbonyl-3-pyrrolidone is 1.1-2: 1.
when the molar ratio of tetraisopropyl titanate, N-tert-butyloxycarbonyl-3-pyrrolidone and the amine source is 0.2-2: 1: when the molar ratio of tetraisopropyl titanate to amine source is further increased, the reaction polarity can be effectively accelerated and the reaction conversion rate can be improved, but the cost is increased by further increasing the molar ratio of tetraisopropyl titanate to amine source.
More preferably, the molar ratio of tetraisopropyl titanate, N-t-butoxycarbonyl-3-pyrrolidone, and amine source is 0.6: 1: 2.
Further, the specific step of the N-tert-butoxycarbonyl-3-aminopyrrolidine undergoing a deprotection reaction in step S5 includes:
dissolving N-tert-butyloxycarbonyl-3-aminopyrrolidine in a solvent, adding an acid solution to enable a reaction system to form an acidic condition, carrying out deprotection reaction on the N-tert-butyloxycarbonyl-3-aminopyrrolidine, adding an organic solvent after the reaction is finished, mixing, extracting, collecting an organic phase, recrystallizing and drying to obtain the tosufloxacin tosylate intermediate.
Preferably, the reaction temperature is 0-60 ℃, and the reaction time is 12-24 h; the molar ratio of the acid solution to the N-tert-butyloxycarbonyl-3-aminopyrrolidine is 0.5-2: 1; the acid solution is hydrochloric acid ethanol solution.
More preferably, the acid solution is prepared by adding 5.4mol of HCl to 1L of ethanol. Wherein, the HCl can be hydrogen chloride gas, and can also be hydrochloric acid ethanol solution or hydrochloric acid ethyl acetate solution.
According to another aspect of the invention, the invention also provides a tosufloxacin tosylate intermediate which is prepared by adopting the synthesis method of the tosufacin tosylate intermediate.
Compared with the existing synthesis method, the synthesis method of the tosufloxacin tosylate intermediate has the following beneficial effects:
1. the glycine ethyl ester or the hydrochloride thereof serving as the starting raw material has wide source and low price, and is synthesized by adopting sodium borohydride and tetraisopropyl titanate with relatively low price to replace an expensive palladium-carbon reduction hydrogenation method, the yield is slightly high, and the cost is saved.
2. Each synthesis step is short, the operation is simple and convenient, the reaction condition is mild, the operation and the control are easy, and the conventional reaction equipment is adopted; the overall process yield is high, the total yield can reach more than 60 percent, and the total yield under the optimized condition can reach 89 percent.
3. Few byproducts are produced in the synthesis process, each intermediate is easy to purify, and the product purity is high.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification. In the drawings:
FIG. 1 is a hydrogen spectrum of N-t-butoxycarbonylglycine ethyl ester of example 1 of the present invention;
FIG. 2 is a hydrogen spectrum of ethyl N-t-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate of example 1 of the present invention;
FIG. 3 is a chart showing hydrogen spectra of N-t-butoxycarbonyl-3-pyrrolidone of example 1 of the present invention;
FIG. 4 is a hydrogen spectrum of N-t-butoxycarbonyl-3-aminopyrrolidine of example 1 of the present invention;
FIG. 5 is a 3-aminopyrrolidine HPLC-MS chromatogram of example 1 of the present invention;
FIG. 6 is a 3-aminopyrrolidine HPLC-MS mass spectrum of example 1 of the present invention;
FIG. 7 is a 3-aminopyrrolidine HPLC-MS chromatogram of example 2 of the present invention;
FIG. 8 is a 3-aminopyrrolidine HPLC-MS mass spectrum of example 2 of the present invention.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
The crude yield in the examples is indicated as the product containing a small amount of solvent without purification after the reaction is completed, i.e. the crude yield may exceed one hundred percent.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
S1, synthesis of intermediate ethyl N-tert-butoxycarbonylglycinate (2)
Glycine ethyl ester hydrochloride (30.0g, 214.9mmol, 1.0equiv) and di-tert-butyl dicarbonate (54.5g, 249.3mmol, 1.2equiv) are weighed and added into a 500mL single-port bottle, triethylamine (59.6g, 588.9mmol, 2.7equiv) and ethanol (100 mL) are added and stirred uniformly, the mixture is reacted at 80 ℃ for 12 hours, after the reaction is finished, the reaction system is concentrated, ethyl acetate (100 mL) is added for extraction for three times, an organic phase is collected, and the organic phase is dried, filtered and concentrated to obtain a crude intermediate 2N-tert-butoxycarbonylglycine ethyl ester (45.3 g, wherein the crude yield is more than or equal to 99%).
As shown in figure 1, hydrogen spectrum detection of N-tert-butyloxycarbonyl glycine ethyl ester: 1 H NMR(400MHz,CDCl 3 )δ5.19(s,1H)，4.15(q,J＝7.1Hz,2H)，3.83(d,J＝5.5Hz,2H)，1.40(s,9H)，1.22(t,J＝7.1Hz,3H)。
s2, synthesis of intermediate ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate (3)
Adding the intermediate 2N-tert-butoxycarbonyl glycine ethyl ester crude product (45.3 g) and ethyl acrylate (54.5g, 249.3mmol, 1.1equiv) into a 500mL single-neck flask, adding triethylamine (59.6 g,588.9mmol, 2.7equiv) and ethanol (100 mL), stirring uniformly after adding, reacting at 25 ℃ for 11h, concentrating the reaction system after finishing the reaction, adding ethyl acetate (100 mL), extracting for three times, collecting an organic phase, drying, filtering and concentrating to obtain the intermediate 3N-tert-butoxycarbonyl-4-oxo-3-pyrrolidine ethyl ester crude product (58.2 g, the crude yield is more than or equal to 99%).
As shown in FIG. 2, the hydrogen spectrum of ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate was measured: 1 H NMR(400MHz,CDCl 3 )δ4.34～4.12(m,7H)，1.49(d,J＝2.8Hz,9H)，1.32(q,J＝7.2Hz,3H)。
s3, synthesis of intermediate N-tert-butyloxycarbonyl-3-pyrrolidone (4)
Adding the intermediate crude product (58.2 g) of ethyl 3N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate into a 500mL single-neck bottle, adding toluene (100 mL) and ethanol (100 mL), stirring uniformly after the addition, reacting at 110 ℃ for 18h, after the reaction is finished, concentrating the reaction system, adding ethyl acetate (100 mL) for extraction three times, collecting an organic phase, drying, filtering and concentrating to obtain the intermediate crude product (43.3 g, the crude yield is more than or equal to 99%) of ethyl 4N-tert-butoxycarbonyl-3-pyrrolidone.
As shown in FIG. 3, the hydrogen spectrum of N-tert-butoxycarbonyl-3-pyrrolidone was measured by: 1 H NMR(400MHz,CDCl 3 )δ3.83～3.69(m,4H)，2.60(q,J＝7.7Hz,2H)，1.49(s,9H)。
s4, synthesis of intermediate N-tert-butyloxycarbonyl-3-aminopyrrolidine (5)
Adding tetraisopropyl titanate (39.88g, 11.9mmol and 0.6equiv) into crude intermediate 4N-tert-butoxycarbonyl-3-pyrrolidone (43.3 g), adding methanol ammonia (66.8mL, 467.8mmol and 2.0equiv) and ethanol (100 mL), stirring uniformly, reacting at the reaction temperature of 50 ℃ for 24 hours, adding sodium borohydride (13.2g, 350.8mmol and 1.5equiv), reacting for 3 hours, adding 10mL of water, quenching, concentrating, adding ethyl acetate (100 mL), extracting for three times, collecting an organic phase, drying, filtering and concentrating to obtain crude intermediate 5N-tert-butoxycarbonyl-3-aminopyrrolidine (49.9 g, wherein the crude yield is more than or equal to 99%).
As shown in FIG. 4, the hydrogen spectrum of N-tert-butoxycarbonyl-3-aminopyrrolidine was examined: 1 H NMR(400MHz,CDCl 3 )δ3.58(s,1H)，3.45(d,J＝16.0Hz,1H)，3.39～3.26(m,2H)，3.12～2.95(m,1H)，2.07(dd,J＝11.5,6.0Hz,1H)，1.77～1.52(m,2H)，1.46(s,9H)。
s5, synthesis of tosufloxacin tosylate intermediate (6)
Adding hydrochloric acid ethanol solution (199.5 mL,1076.4mmol and 4.0 equiv) into an intermediate 5N-tert-butoxycarbonyl-3-pyrrolidone crude product (49.9 g), adding ethanol (50 mL), uniformly stirring, reacting for 24 hours at the reaction temperature of 50 ℃, concentrating a reaction system after the reaction is finished, adding ethyl acetate (100 mL) for extraction for three times, collecting an organic phase, recrystallizing (ethanol is a non-benign solvent and water is a benign solvent), filtering and drying to obtain a product 6-aminopyrrolidine dihydrochloride, namely a tosufloxacin tosylate intermediate (30.4 g, and the total yield of the molar weight relative to glycine ethyl ester is 89%).
FIGS. 5 and 6 are a chromatogram and a mass spectrum of 3-aminopyrrolidine, respectively.
Elemental analysis: the real theoretical value is: c,30.21%, H,7.60%, N,17.61%; measuring: c,30.23%, H,7.63%, N,17.59%, corresponds to the theoretical value.
Example 2
The feeding of S1, S2 and S3 in the embodiment 2 is the same as the embodiment 1, and the difference from the embodiment 1 is only the S4 step.
S4, synthesis of intermediate N-tert-butyloxycarbonyl-3-aminopyrrolidine (5)
Adding a palladium carbon catalyst (the palladium content is 10 percent, 13.98g,11.9mmol and 0.05equiv) and ammonium formate (29.4g, 467.8mmol and 2.0equiv) into the intermediate 4N-tert-butoxycarbonyl-3-pyrrolidone, adding ethanol (200 mL) and water (20 mL), uniformly stirring, reacting at the reaction temperature of 50 ℃ for 24 hours, concentrating the reaction system after the reaction is finished, adding ethyl acetate (100 mL) for extraction for three times, collecting an organic phase, drying, filtering and concentrating to obtain the intermediate 5N-tert-butoxycarbonyl-3-aminopyrrolidine.
According to the synthesis conditions of the S5 step in example 1, the product 6-aminopyrrolidine dihydrochloride, i.e., tosufloxacin tosylate intermediate, was obtained (25.3 g, total yield 74% relative to the molar amount of glycine ethyl ester).
FIGS. 7 and 8 are a chromatogram and a mass spectrum of 3-aminopyrrolidine, respectively.
Example 3
S1, synthesis of intermediate ethyl N-tert-butoxycarbonylglycinate (2)
Glycine ethyl ester hydrochloride (30.0g, 214.9mmol, 1.0equiv) and di-tert-butyl dicarbonate (54.5g, 249.3mmol, 1.2equiv) are weighed into a single-port bottle with the volume of 500mL, triethylamine (59.6 g,588.9mmol, 2.7equiv) and ethanol (100 mL) are added, the mixture is uniformly stirred after the addition, the mixture is reacted at the temperature of 50 ℃ for 10 hours, after the reaction is finished, the reaction system is concentrated, ethyl acetate (100 mL) is added for extraction for three times, an organic phase is collected, and the intermediate 2N-tert-butoxycarbonylglycine ethyl ester is obtained after drying, filtering and concentrating.
S2, synthesis of intermediate ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate (3)
Adding the intermediate 2N-tert-butoxycarbonylglycine ethyl ester and ethyl acrylate (54.5g, 249.3mmol and 1.1equiv) into a 500mL single-neck bottle, adding triethylamine (59.6 g,588.9mmol and 2.7equiv) and ethanol (100 mL), stirring uniformly after the addition, reacting at 50 ℃ for 24 hours, concentrating the reaction system after the reaction is finished, adding ethyl acetate (100 mL) for extraction for three times, collecting an organic phase, drying, filtering and concentrating to obtain the intermediate 3N-tert-butoxycarbonyl-4-oxo-3-pyrrolidine carboxylic acid ethyl ester.
As shown in FIG. 2, the hydrogen spectrum of ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate was measured: 1 H NMR(400MHz,CDCl 3 )δ4.34～4.12(m,7H)，1.49(d,J＝2.8Hz,9H)，1.32(q,J＝7.2Hz,3H)。
s3, synthesis of intermediate N-tert-butyloxycarbonyl-3-pyrrolidone (4)
Adding the intermediate 3N-tert-butoxycarbonyl-4-oxo-3-pyrrolidine ethyl formate into a 500mL single-neck bottle, adding toluene (100 mL) and ethanol (100 mL), stirring uniformly after adding, reacting at 100 ℃ for 18h, after the reaction is finished, concentrating the reaction system, adding ethyl acetate (100 mL) for extraction three times, collecting an organic phase, and drying, filtering and concentrating to obtain the intermediate 4N-tert-butoxycarbonyl-3-pyrrolidone.
As shown in FIG. 3, the hydrogen spectrum of N-tert-butoxycarbonyl-3-pyrrolidone was measured by: 1 H NMR(400MHz,CDCl 3 )δ3.83～3.69(m,4H)，2.60(q,J＝7.7Hz,2H)，1.49(s,9H)。
s4, synthesis of intermediate N-tert-butyloxycarbonyl-3-aminopyrrolidine (5)
Weighing intermediate 4N-tert-butoxycarbonyl-3-pyrrolidone, adding tetraisopropyl titanate (39.88g, 11.9mmol, 0.6equiv), methanolic ammonia (66.8mL, 467.8mmol, 2.0equiv), ethanol (100 mL), stirring uniformly, reacting for 10h at the reaction temperature of 35 ℃, adding sodium borohydride (13.2g, 350.8mmol, 1.5equiv), reacting for 3h, adding 10mL of water, quenching, reacting, concentrating, adding ethyl acetate (100 mL), extracting for three times, collecting an organic phase, drying, filtering, and concentrating to obtain intermediate 5N-tert-butoxycarbonyl-3-aminopyrrolidine.
As shown in FIG. 4, the hydrogen spectrum of N-tert-butoxycarbonyl-3-aminopyrrolidine was examined: 1 H NMR(400MHz,CDCl 3 )δ3.58(s,1H)，3.45(d,J＝16.0Hz,1H)，3.39～3.26(m,2H)，3.12～2.95(m,1H)，2.07(dd,J＝11.5,6.0Hz,1H)，1.77～1.52(m,2H)，1.46(s,9H)。
s5, synthesis of tosufloxacin tosylate intermediate (6)
Weighing an intermediate 5N-tert-butoxycarbonyl-3-pyrrolidone, adding an ethanol solution of hydrochloric acid (190.0 mL,1025.2mmol and 4.0 equiv) (5.4 mol of HCl gas is added into 1L of ethanol), adding ethanol (50 mL), uniformly stirring, reacting for 20 hours at the reaction temperature of 40 ℃, concentrating the reaction system after the reaction is finished, adding ethyl acetate (100 mL) for extraction for three times, collecting an organic phase, recrystallizing (ethanol is a non-benign solvent and water is a benign solvent), filtering and drying to obtain a product 6-aminopyrrolidine dihydrochloride, namely a tosufloxacin intermediate tosylate (27.6 g, and the total yield of molar weight relative to glycine ethyl ester is 81%).
Comparative example 1
The feeding of S1, S2, S3 in comparative example 1 is identical to example 1, differing from example 1 only by the amine source in step S4.
Intermediate 4N-t-butoxycarbonyl-3-pyrrolidone (43.3 g,233.9mmol, 1.0equiv) was weighed, tetraisopropyl titanate (39.88g, 11.9mmol, 0.6equiv) was added, ammonium formate (73.6gmL, 1169.5mmol, 5.0equiv) was added, ethanol (100 mL) was added, the mixture was stirred uniformly, and reacted at 50 ℃ for 24 hours, sodium borohydride (13.2g, 350.8mmol, 1.5equiv) was added, the reaction was carried out for 3 hours, 10mL of water was added to quench the reaction, the reaction was concentrated, ethyl acetate (100 mL) was added to extract three times, the organic phase was collected, and the intermediate 5N-t-butoxycarbonyl-3-aminopyrrolidine was produced after drying, filtration and concentration, but no detection was made. That is, when the ammonia source was ammonium formate, the formation of the intermediate 5N-t-butoxycarbonyl-3-aminopyrrolidine was not detected.
Comparative example 2
The only difference from example 1 is the addition amount of the intermediate 4N-t-butoxycarbonyl-3-pyrrolidone, tetraisopropyl titanate, methanolic ammonia, sodium borohydride in the S4 step. The feed ratio and yield are shown in table 1 below:
TABLE 1
| n Tetra-isopropyl titanate ：n Intermediate 4 ：n Methanol ammonia | n Intermediate 4 ：n Sodium borohydride | Crude yield of intermediate 5 | |
| |
0:1:2 | 1:1.5 | 0 |
| |
0.3:1:2 | 1:1.5 | 0.65 |
| |
0.6:1:2 | 1:1.5 | >0.99 |
| Test 4 | 1:1:2 | 1:1.5 | >0.99 |
| |
0.6:1:2 | 1:1.3 | 0.89 |
| |
0.6:1:2 | 1:2 | >0.99 |
| |
0.6:1:1.5 | 1:1.5 | 0.77 |
| |
0.6:1:2.5 | 1:1.5 | >0.99 |
As can be seen from the above table 1,
test 1: when tetraisopropyl titanate is not added in the reaction system, the intermediate 4 does not react with methanolic ammonia and sodium borohydride;
runs 2-4: when the molar ratio of tetraisopropyl titanate to intermediate 4N-tert-butoxycarbonyl-3-pyrrolidone is less than 0.6, the crude yield of the product is gradually increased with the increase of the addition amount of tetraisopropyl titanate; however, when the molar ratio is more than 0.6, the crude yield of the product is substantially maintained;
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of tosufloxacin tosylate intermediate is characterized by comprising the following steps:
s4, reacting the N-tert-butyloxycarbonyl-3-pyrrolidone, a catalyst of tetraisopropyl titanate and an amine source to obtain N-tert-butyloxycarbonyl-3-aminopyrrolidine;
and S5, under an acidic condition, carrying out deprotection reaction on the N-tert-butyloxycarbonyl-3-aminopyrrolidine to obtain a tosufloxacin tosylate intermediate.
2. The method for synthesizing tosufloxacin tosylate intermediate according to claim 1, wherein the specific steps of reacting N-t-butoxycarbonyl-3-pyrrolidone, tetraisopropyl titanate and an amine source in step S4 comprise:
dissolving the N-tert-butoxycarbonyl-3-pyrrolidone, the tetraisopropyl titanate and an amine source in a solvent A for reaction, adding a reducing agent for continuous reaction, adding water after the reaction is finished to stop the reaction, adding an organic solvent for mixing, extracting, collecting an organic phase, drying, filtering and concentrating to obtain the N-tert-butoxycarbonyl-3-aminopyrrolidine.
3. The method for synthesizing tosufloxacin tosylate intermediate according to claim 2, characterized in that,
the reducing agent in the step S4 is sodium borohydride;
and/or the amine source adopts ammonium methanol solution or ammonium formate;
the solvent A is a mixed solution of ethanol and water in a certain volume ratio; and/or
The organic solvent adopts ethyl acetate.
4. The method for synthesizing tosufloxacin tosylate intermediate according to claim 2, wherein the molar ratio of the reducing agent to N-t-butoxycarbonyl-3-pyrrolidone in the step S4 is 1.1 to 2:1.
5. the method for synthesizing tosufloxacin tosylate intermediate according to claim 1, wherein the molar ratio of tetraisopropyl titanate, N-t-butoxycarbonyl-3-pyrrolidone and amine source in step S4 is 0.2 to 2:1:0.5 to 10.
6. The method for synthesizing tosufloxacin tosylate intermediate according to claim 1, wherein the temperature of the reaction in step S4 is 0 ℃ to 60 ℃; the reaction time is 8-24 h, and the continuous reaction time is 2-10 h.
7. The method for synthesizing tosufloxacin tosylate intermediate according to any of claims 1 to 6, wherein the specific step of deprotection reaction of N-tert-butoxycarbonyl-3-aminopyrrolidine in step S5 comprises:
dissolving the N-tert-butyloxycarbonyl-3-aminopyrrolidine in a solvent, adding acid, after the reaction is finished, adding an organic solvent, mixing, extracting, collecting an organic phase, recrystallizing and drying to obtain a tosufloxacin tosylate intermediate;
the reaction temperature is 0-60 ℃, and the reaction time is 12-24 h;
the molar ratio of the acid solution to the N-tert-butoxycarbonyl-3-aminopyrrolidine is 0.5-2;
the acid solution is hydrochloric acid ethanol solution.
8. The method for synthesizing tosufloxacin tosylate intermediate according to claim 7, further comprising the steps of:
s1, reacting glycine ethyl ester or hydrochloride thereof with di-tert-butyl dicarbonate under an alkaline condition to obtain N-tert-butoxycarbonylglycine ethyl ester;
s2, reacting the N-tert-butyloxycarbonyl glycine ethyl ester with ethyl acrylate under an alkaline condition to obtain N-tert-butyloxycarbonyl-4-oxo-3-pyrrolidine ethyl formate;
s3, carrying out a de-esterification reaction on the ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate to obtain the N-tert-butoxycarbonyl-3-pyrrolidone.
9. The method for synthesizing tosufloxacin tosylate intermediate according to claim 8, wherein the specific step of de-esterification reaction of ethyl N-t-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate in the step S3 comprises:
dissolving the ethyl N-tert-butoxycarbonyl-4-oxo-3-pyrrolidinecarboxylate in a solvent B, adding an organic solvent after the reaction is finished, mixing, extracting, collecting an organic phase, drying, filtering and concentrating to obtain N-tert-butoxycarbonyl-3-pyrrolidone;
the reaction temperature in the step S3 is 100-150 ℃, and the reaction time is 15-20 h;
the organic solvent in the step S3 is ethyl acetate;
in the step S3, toluene is used as the solvent B.
10. An intermediate of tosufloxacin tosylate, which is prepared by the method for synthesizing the tosufloxacin tosylate intermediate of any one of claims 1 to 9.
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