CN115010703A - Ritasol morpholine salt and preparation method and application thereof - Google Patents

Ritasol morpholine salt and preparation method and application thereof Download PDF

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Publication number
CN115010703A
CN115010703A CN202210744975.XA CN202210744975A CN115010703A CN 115010703 A CN115010703 A CN 115010703A CN 202210744975 A CN202210744975 A CN 202210744975A CN 115010703 A CN115010703 A CN 115010703A
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salt
sitagliptin
sitafloxacin
morpholine
water
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陈金萍
牛国志
刘叶
王莎
赵军旭
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Hebei Zhiheng Pharmaceutical Technology Co ltd
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Hebei Zhiheng Pharmaceutical Technology Co ltd
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Publication of CN115010703A publication Critical patent/CN115010703A/en
Priority to CN202310417304.7A priority patent/CN116425729A/en
Priority to PCT/CN2023/102344 priority patent/WO2024001995A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

The invention relates to the technical field of drug synthesis, and particularly relates to a sitagliptin salt, and a preparation method and application thereof. The provided salt of sitagliptin can be dissociated in trace acidic water to remove morpholine, so that high-purity sitagliptin is obtained, the yield is high, the operation is simple, and the generation of waste solvent and waste water in the process of purifying the sitagliptin can be greatly reduced. The preparation method of the sitagliptin morpholine salt provided by the invention is easy to implement, and the prepared sitagliptin morpholine salt has high yield and high purity. In the process of purifying the sitagliptin, the crude product of the sitagliptin is firstly prepared into the sitagliptin morpholine salt, and then the simple acid hydrolysis separation is carried out, so that the process of purifying the sitagliptin can be greatly simplified, the generation of waste solvents and waste water is reduced, the reaction continuity is strong, and the process is safe and controllable.

Description

Ritasol morpholine salt and preparation method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a sitagliptin salt, and a preparation method and application thereof.
Background
The sitagliptin is a lymphocyte function-associated antigen 1(LFA-1) antagonist drug for treating dry eye diseases.
The preparation process of the sitagliptin relates to purification, but related documents are less reported at present, and two methods are mainly used at present. The method is that the sitagliptin is directly refined in a certain solvent, such as acetonitrile or butanone, but because of the unique physicochemical property of the sitagliptin, the method is easy to form viscous solid in the crystallization process, and the industrialized production cannot be realized; if a dust separation mode is adopted, the solid state is better, but the purification effect is poor, and multiple times of crystallization are needed. The second method is to form dicyclohexylamine salt of the sitafloxacin and refine the salt, although the purity of the sitafloxacin salt is high, the post treatment is very complex when the sitafloxacin salt is dissociated: the hydrochloride of the dicyclohexylamine is insoluble in water and cannot be separated and purified; if phosphoric acid, sulfuric acid, formic acid, acetic acid and trifluoroacetic acid are used as acidic media to dissociate the salts, as dicyclohexylamine salts of the acids have certain solubility in a solvent, even if the dicyclohexylamine salts are extracted for a plurality of times with large dose, some dicyclohexylamine still remains in the obtained products; if the salt is hydrolyzed under alkaline conditions, a large amount of solvent is used for extraction and removal of dicyclohexylamine, and then acid is adjusted to precipitate the sitaxel, so that the burning residues of the obtained product exceed the standard. Therefore, if raw material medicines with qualified ignition residues, dicyclohexylamine residues and solvent residues are obtained, the post-treatment is very complicated, and a large amount of waste acid aqueous solution and waste organic solvent are generated in the whole process, so that the amplification production is not facilitated.
Disclosure of Invention
Aiming at the technical problems, the invention provides a sitagliptin morpholine salt, a preparation method and application thereof. The sitagliptin morpholine salt can be dissociated into the sitagliptin in trace acid water, so that the generation of waste solvents and waste water in the process of purifying the sitagliptin can be greatly reduced, and the operation is simple and convenient. The preparation method of the salt of the sitafloxacin morpholine provided by the invention is easy to implement, and the salt of the sitafloxacin morpholine with high purity can be prepared. The salt of sitagliptin and the preparation method thereof can be used for industrially purifying a crude product of sitagliptin.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
in a first aspect, the present invention provides a salt of sitafloxacin, having the structural formula shown in formula I:
Figure BDA0003716614980000021
the sitagliptin morpholine salt has simple post-treatment, can remove morpholine in trace acid water to dissociate the sitagliptin, does not need to use large-capacity organic solvent, and is more suitable for industrial production. In the process of purifying the sitagliptin, the crude product of the sitagliptin is firstly prepared into the sitagliptin morpholine salt, and then acid-water dissociation is carried out, so that the process of purifying the sitagliptin can be greatly simplified, and the high-purity sitagliptin which meets the pharmaceutical grade can be obtained.
In a second aspect, the invention provides a preparation method of the sitafloxacin salt, which specifically comprises the following operations: dissolving the crude product of the sitagliptin in a mixed solution of an organic solvent and water or the organic solvent, adding morpholine, separating out solid, and carrying out solid-liquid separation to obtain the sitagliptin morpholine salt.
The method is simple and convenient to operate, and the obtained crude product of the sitafloxacin salt has high purity and high yield. The method is used for preparing and purifying the sitagliptin, can greatly reduce the using amount of the solvent, simplifies the operation and shortens the production period.
Optionally, a small amount of the sitesporpholine salt may be added after morpholine addition as seed crystals to speed up the precipitation of the sitesporpholine salt in the reaction.
With reference to the second aspect, the solvent comprises at least one of isopropanol, ethanol, methanol, tetrahydrofuran, butanone, methyl butyl ketone, acetone, acetonitrile, isopropyl acetate, and N, N-dimethylformamide.
Preferably, the ratio of the volume of the organic solvent and water mixed solution or the organic solvent to the mass of the crude product of the sitagliptin is 4-30: 1 (ml: g).
Preferably, in the mixed solution of the organic solvent and water, the mass of the water is not more than 3 times of the mass of the crude product of the sitagliptin.
In combination with the second aspect, the ratio of the molar amount of morpholine to the molar amount of crude sitaxetil is 0.5-10: 1. which contains the molar mass of crude sitaxel ═ sitaxel mass ÷ sitaxel molecular mass.
In combination with the second aspect, the preparation method further comprises further purifying the product obtained by solid-liquid separation to further improve the purity of the product.
Preferably, the purification method comprises the steps of dissolving the crude product of the salt of the sitafloxacin morpholine in an organic solvent, heating to 55-65 ℃, and stirring for reaction for 30-60 min; cooling to room temperature, and filtering to obtain refined product of the salt of lithospermate.
In a third aspect, the invention provides the use of the above-mentioned salt of sitagliptin or the preparation method thereof in the purification of a crude product of sitagliptin.
With reference to the third aspect, the application specifically includes the following operations: dissolving the sitafloxacin salt in water, adding acid to adjust the pH of the solution to 2-6, and separating solid from liquid after the solid is separated out to obtain a refined sitafloxacin product.
The high-purity sitagliptin refined product can be obtained by utilizing the sitagliptin morpholine salt under the dissociation condition, the reaction continuity is strong, the process is safe and controllable, the HPLC purity of the obtained sitagliptin refined product is more than 99.7 percent, the requirement of medicinal grade is met, and the yield is higher and is more than 80 percent.
Optionally, the acid used to adjust the pH of the solution comprises at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, and formic acid.
In combination with the third aspect, the method further comprises adding an organic solvent prior to adjusting the pH of the solution. The addition of the organic solvent helps to change the solid state of the sitagliptin and can reduce the water content in the finished product of the sitagliptin.
Preferably, the organic solvent is at least one of methanol, ethanol, acetone, butanone and acetonitrile.
Preferably, the mass ratio of the volume of the organic solvent to the salt of lithospermate is 1-5: 1 (ml: g).
With reference to the third aspect, the applying may further specifically include: dissolving the sitagliptin morpholine salt in water, adding dichloromethane, adding acid to adjust the pH value of the solution to 2-6, stirring and reacting for 10-40 min, separating and extracting, discarding the water phase, concentrating the organic layer, adding an organic solvent to dissolve, adding the obtained solution into water, continuing stirring and reacting for 20-40 min, and carrying out solid-liquid separation to obtain the sitagliptin.
Optionally, the organic solvent is at least one of methanol, ethanol, acetone, butanone and acetonitrile, and the amount of the organic solvent is determined by the dissolution of the solid in the concentrated organic layer, so that the solid in the concentrated organic layer is dissolved.
In a fourth aspect, the embodiment of the invention provides an application of the sitagliptin salt or the preparation method thereof in preparing a crude sitagliptin product, wherein the crude sitagliptin product is prepared into the sitagliptin salt in the preparation process of the sitagliptin product, and the refined sitagliptin product is prepared through dissociation.
The invention has the beneficial effects that: the preparation method of the high-purity sitagliptin morpholine salt provided by the invention can be used for preparing the high-purity sitagliptin morpholine salt, is high in yield, simple in post-treatment and suitable for industrial production; compared with the process for generating the sitagliptin dicyclohexylamine salt, the process has the advantages that a large amount of solvent is not needed for extracting and washing free alkali in the post-treatment process, water is directly added for regulating acid to separate out, and the organic alkali morpholine can be removed completely, so that the sitagliptin refined product which meets the medicinal grade is obtained.
Drawings
FIG. 1 is a NMR spectrum of a salt of lithotriptolide in example 1 of the present invention;
FIG. 2 is a mass spectrum of a salt of lithotriptolide in example 1 of the present invention;
FIG. 3 is an HPLC chromatogram of a salt of lithotriptolide in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The purification process of sitagliptin is mainly divided into two types at present: recrystallizing in solvent, or refining after preparing dicyclohexylamine salt. The former is easy to form viscous solid in the crystallization process, and is not beneficial to industrial production. Although the latter can obtain the high-purity sitagliptin dicyclohexylamine salt, the post-treatment of dissociating the sitagliptin dicyclohexylamine salt is very complicated, if raw material medicines with qualified burning residues, dicyclohexylamine residues and solvent residues are obtained, the post-treatment is complicated, and the whole process generates a large amount of waste acid aqueous solution and waste solvent, so that the scale-up production is not facilitated. Therefore, the importance of developing a simple, convenient and economic method for purifying the sitaxel, which is suitable for large-scale production, is particularly remarkable.
According to the invention, a crystallization mode suitable for sitaxel is obtained through a large amount of experimental research and condition screening, high-purity sitaxel morpholine salt (I) can be obtained through the crystallization mode, the salt can be dissociated into the sitaxel after being added with trace acid water, the generation of waste solvents and waste water in the process of purifying the sitaxel can be greatly reduced, the synthesis of the sitaxel is more beneficial to industrial production, the operation is simpler and more convenient, and the preparation of the medical-grade sitaxel is more beneficial.
Example 1
This example provides a method for preparing a salt of sitafloxacin.
And adding 5g of the crude product of the sitagliptin into 50mL of butanone, stirring and dissolving at the room temperature of 25 +/-5 ℃, then adding 1.4g of morpholine, stirring for 0.5h, then separating out a small amount of solid, continuing to react at the room temperature for 16h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of butanone, and drying at the temperature of 50 +/-5 ℃ to obtain 4.7g of the sitagliptin morpholine salt, wherein the yield is 82.05%.
The structure of the obtained sitagliptin morpholine salt is analyzed, the nuclear magnetic resonance hydrogen spectrum is shown in figure 1, the mass spectrum is shown in figure 2, and the structure can be determined to be shown in formula I.
Figure BDA0003716614980000051
The HPLC spectrum of the obtained sitagliptin morpholine salt is shown in figure 3, and the HPLC purity is 99.82%.
Example 2
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 40mL of butanone, stirring and dissolving at the room temperature of 25 +/-5 ℃, adding 3.5g of morpholine, stirring and reacting for 1h, adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 18h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of butanone, and drying at the temperature of 50 +/-5 ℃ to obtain 5.0g of the sitagliptin morpholine salt with the yield of 87.61%; HPLC purity 99.79%.
Example 3
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of crude sitafloxacin into 135mL of isopropanol, heating to 60 +/-5 ℃, stirring for dissolving, adding 2.1g of morpholine and 15g of water, stirring for reacting for 1 hour, adding 0.05g of seed crystal, cooling to room temperature, reacting for 24 hours, separating out a large amount of solid, filtering, washing a filter cake with 10mL of isopropanol, and drying at 50 +/-5 ℃ to obtain 5.2g of sitafloxacin salt, wherein the yield is 91.12%; HPLC purity 99.27%.
Example 4
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitafloxacin into 120mL of ethanol and 10mL of methanol, heating to 60 +/-5 ℃, stirring for dissolving, adding 5g of morpholine, stirring for reacting for 1h, adding 0.05g of seed crystal, cooling to room temperature, reacting overnight for 14h, precipitating a large amount of solid, filtering, washing a filter cake with 10mL of ethanol, and drying at 50 +/-5 ℃ to obtain 5.2g of the sitafloxacin salt, wherein the yield is 91.12%; HPLC purity 98.82%.
Example 5
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 20mL of methanol and 40mL of isopropanol, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 2.1 morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, cooling to 0 +/-5 ℃, reacting overnight for 16h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of isopropanol, and drying at the temperature of 50 +/-5 ℃ to obtain 4.4g of the sitagliptin morpholine salt, wherein the yield is 77.19%; HPLC purity 98.92%.
Example 6
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 50mL of tetrahydrofuran, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 0.5g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 16h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of tetrahydrofuran, and drying at the temperature of 50 +/-5 ℃ to obtain 4.8g of the salt of the sitagliptin with the yield of 70.21%; HPLC purity 99.74%.
Example 7
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of crude sitafloxacin into 60mL of methyl butyl ketone and acetonitrile, stirring and dissolving at the room temperature of 30 +/-5 ℃, adding 5.6g of morpholine, stirring and reacting for 1 hour, adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 14 hours, separating out a large amount of solid, filtering, washing a filter cake with 10mL of methyl butyl ketone, and drying at the temperature of 50 +/-5 ℃ to obtain 4.5g of sitafloxacin morpholine salt, wherein the yield is 78.95%; HPLC purity 99.26%.
Example 8
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 50mL of acetone, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 1.0g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 16h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of acetone, and drying at the temperature of 50 +/-5 ℃ to obtain 5.0g of the sitagliptin salt, wherein the yield is 87.72%; HPLC purity 98.72%.
Dissolving 5.0g of the sitafloxacin salt in 50mL of acetone, heating to 60 +/-5 ℃, and stirring for reacting for 30 min; cooling to room temperature, and filtering to obtain 4.8g of sitafloxacin salt. The yield is 96.00%; HPLC purity 99.72%.
Example 9
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 70mL of acetonitrile, stirring and dissolving at the room temperature of 30 +/-5 ℃, adding 1.4g of morpholine, stirring and reacting for 1h, adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 16h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of acetonitrile, and drying at the temperature of 50 +/-5 ℃ to obtain 5.3g of the sitagliptin salt with the yield of 92.87%; HPLC purity 99.82%.
Example 10
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 20mL of N, N-dimethylformamide and butanone at room temperature of 30 +/-5 ℃, stirring and dissolving, then adding 3.6g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing the overnight reaction for 18h at room temperature, separating out a large amount of solid, filtering, washing a filter cake with 10mL of butanone, and drying at 50 +/-5 ℃ to obtain 4.8g of the sitagliptin morpholine salt, wherein the yield is 84.11%; HPLC purity 98.69%.
Example 11
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 20mL of acetonitrile and 2mL of water, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 2.1g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing to react for 24h at the room temperature, separating out a large amount of solid, filtering, washing a filter cake with 10mL of acetonitrile, and drying at the temperature of 50 +/-5 ℃ to obtain 5.1g of the salt of the sitagliptin with the yield of 89.48%; HPLC purity 99.72%.
Example 12
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 40mL of butanone and 20mL of isopropanol, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 4.2g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 18h, separating out a large amount of solid, filtering, washing a filter cake with 8mL of butanone and 4mL of isopropanol, and drying at the temperature of 50 +/-5 ℃ to obtain 5.3g of the sitagliptin morpholine salt, wherein the yield is 92.87%; HPLC purity 99.39%.
Example 13
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 20mL of acetonitrile and 80mL of butanone, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 2.1g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 18h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of acetonitrile, and drying at the temperature of 50 +/-5 ℃ to obtain 5.0g of the sitagliptin morpholine salt, wherein the yield is 87.62%; HPLC purity 99.73%.
Example 14
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 50mL of tetrahydrofuran and 10mL of isopropyl acetate, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 1.7g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing the overnight reaction at the room temperature for 18h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of tetrahydrofuran and 2mL of isopropyl acetate, drying at the temperature of 50 +/-5 ℃, and obtaining 4.7g of the sitagliptin morpholine salt with the yield of 82.46%; HPLC purity 99.42%.
Example 15
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 60mL of acetonitrile and 5mL of water, stirring and dissolving at the room temperature of 30 +/-5 ℃, then adding 3.4g of morpholine, stirring and reacting for 1h, then adding 0.05g of seed crystal, continuing to react for 48h at the room temperature, separating out a large amount of solid, filtering, washing a filter cake with 10mL of acetonitrile, and drying at the temperature of 50 +/-5 ℃ to obtain 4.9g of the salt of the sitagliptin with the yield of 85.97%; HPLC purity 99.76%.
Example 16
This example provides a method for preparing a salt of sitafloxacin.
Adding 5g of the crude product of the sitagliptin into 40mL of acetone and 1mL of water, stirring at room temperature of 30 +/-5 ℃ for dissolving, adding 2.6g of morpholine, stirring for reacting for 1h, adding 0.05g of seed crystal, continuing the overnight reaction at room temperature for 16h, separating out a large amount of solid, filtering, washing a filter cake with 10mL of acetone, and drying at 50 +/-5 ℃ to obtain 4.9g of the sitagliptin morpholine salt with the yield of 85.70%; HPLC purity 99.83%.
Example 17
This example provides a method for preparing a salt of sitafloxacin.
Adding 100g of the crude product of the sitafloxacin into 800mL of butanone and 50mL of water, stirring at room temperature of 30 +/-5 ℃ for dissolving, adding 28.3g of morpholine, stirring for reacting for 4 hours, separating out a large amount of solids, filtering, washing a filter cake with 100mL of butanone, and drying at 50 +/-5 ℃ to obtain 100g of the sitafloxacin salt, wherein the yield is 87.77%; HPLC purity 99.86%.
Example 18
This example provides a method for preparing a salt of sitafloxacin.
Adding 100g of the crude product of the sitafloxacin into 600mL of butanone and 100mL of acetonitrile, stirring at room temperature of 30 +/-5 ℃ for dissolving, adding 25.7g of morpholine, stirring for reacting for 8 hours, separating out a large amount of solid, filtering, washing a filter cake with 120mL of butanone, and drying at 50 +/-5 ℃ to obtain 106g of the sitafloxacin salt, wherein the yield is 92.98%; HPLC purity 99.75%.
Example 19
This example provides a process for preparing sitagliptin as a sitagliptin morpholine salt.
Taking 10g of the sitafloxacin salt obtained in the example 17, adding 100mL of water, stirring and dissolving, slowly adding dilute hydrochloric acid at 20 +/-10 ℃ to adjust the pH value to be between 4 and 6 (10 min for use), and separating out a large amount of solid; continuously stirring and reacting for 30 min; filtering to obtain sitaxetil, and vacuum drying at 40 deg.C to obtain white solid 8.3g, with yield of 95.04% and HPLC purity of 99.89%; chiral HPLC purity 100%; the morpholine content is less than or equal to 0.1 percent.
Example 20
This example provides a process for preparing sitagliptin as a sitagliptin morpholine salt.
Taking 10g of the sitafloxacin salt obtained in the example 17, adding 150mL of water, stirring for dissolving, adding 30mL of acetone, slowly adding dilute hydrochloric acid at the temperature of 20 +/-10 ℃ to adjust the pH value to be between 2 and 4 (the time for use is 10min), and separating out a large amount of solid; continuously stirring and reacting for 30 min; filtering to obtain sitaxetil, and vacuum drying at 40 deg.C to obtain white solid 7.9g, with yield of 90.18% and HPLC purity of 99.88%; chiral HPLC purity 100%; the morpholine content is less than or equal to 0.1 percent.
Example 21
This example provides a process for preparing sitagliptin as a sitagliptin morpholine salt.
Taking 10g of the sitafloxacin salt obtained in the example 17, adding 150mL of water, stirring for dissolving, adding 30mL of methanol, slowly adding diluted hydrochloric acid at the temperature of 20 +/-10 ℃ to adjust the pH value to be between 5 and 6 (10 min in use), and separating out a large amount of solid; continuously stirring and reacting for 30 min; filtering to obtain sitaxetil, and vacuum drying at 40 deg.C to obtain white solid 7.0g, with yield of 80.00% and HPLC purity of 99.86%; chiral HPLC purity 100%; the morpholine content is less than or equal to 0.1 percent.
Example 22
This example provides a process for preparing sitagliptin as a sitagliptin morpholine salt.
Taking 10g of the sitafloxacin salt obtained in the example 17, adding 150mL of water, stirring and dissolving, slowly adding dilute sulphuric acid at 20 +/-10 ℃ to adjust the pH value to 3-4 (10 min for use), and separating out a large amount of solid; continuously stirring and reacting for 30 min; filtering to obtain sitaxetil, and vacuum drying at 40 deg.C to obtain white solid 7.8g, with yield of 89.04% and HPLC purity of 99.83%; chiral HPLC purity 100%; the morpholine content is less than or equal to 0.1 percent.
Example 23
This example provides a process for preparing sitagliptin as a sitagliptin morpholine salt.
Taking 10g of the sitafloxacin salt obtained in the example 17, adding 150mL of water, stirring and dissolving, slowly adding dilute sulphuric acid at 20 +/-10 ℃ to adjust the pH value to between 2 and 3 (10 min for use), and separating out a large amount of solid; continuously stirring and reacting for 30 min; filtering to obtain sitaxetil, and vacuum drying at 40 deg.C to obtain white solid 8.0g, with yield of 91.32% and HPLC purity of 99.86%; chiral HPLC purity 100%; the morpholine content is less than or equal to 0.1 percent.
Example 24
This example provides a process for the preparation of sitafloxacin from a sitafloxacin morpholine salt.
Taking 10g of the sitafloxacin salt obtained in the example 17, adding 150mL of water, stirring and dissolving, adding 100mL of dichloromethane for extraction, slowly adding dilute hydrochloric acid at 20 +/-10 ℃ to adjust the pH value to be between 4 and 5 (10 min when the use is carried out), and continuing stirring and reacting for 20min after the dropwise addition is finished; separating and extracting, discarding the water phase, concentrating the dichloromethane organic layer until no obvious liquid flows out, stopping concentrating, adding 30mL of methanol, stirring for dissolving, slowly adding into 150mL of water (for 10min), and separating out a large amount of solid; continuously stirring and reacting for 30 min; filtering to obtain sitaxetil, and vacuum drying at 40 ℃ to obtain 8.1g of white solid, wherein the yield is 93.10%, and the HPLC purity is as follows: 99.89%; chiral HPLC purity 100%; the morpholine content is less than or equal to 0.1 percent.
Comparative example 1
This comparative example provides another method of purifying sitaxel.
50g of the crude sitaxel is added into 400mL of acetone and 50mL of water, stirred at room temperature of 30 +/-5 ℃ and dissolved, 22.07g of dicyclohexylamine (used for 10min) is slowly added, stirring is carried out overnight, a large amount of solid is separated out, filtering is carried out, and 100mL of acetone is added into the obtained solid to wash a filter cake. Drying at 50 +/-5 ℃ to obtain 45g of sitaxetil dicyclohexylamine salt, wherein the yield is 69.54%; HPLC purity 99.68%.
Taking 10g of the prepared sitagliptin dicyclohexylamine salt, adding 100mL of dichloromethane, adding 100mL of water, stirring, dissolving the solid, slowly adding 10% phosphoric acid water solution under stirring until the pH value of the water phase is between 3 and 5 (10 min for use), and continuously stirring for 30 min; extracting and layering, and discarding a water phase; adding 100mL of water into the organic phase, adding 10% phosphoric acid aqueous solution under stirring until the pH value of the water phase is between 3 and 5, and continuously stirring for 30 min; extracting and layering, and discarding a water phase; after TLC plate checking, the dichloromethane layer still has free dicyclohexylamine which is not removed; repeating the extraction once again; concentrating dichloromethane phase, adding ethyl acetate to replace residual dichloromethane, separating out solid, filtering, adding 20mL ethyl acetate into filter cake, washing, and vacuum drying at 40 ℃ to obtain 6.5g of a sitafloxacin refined product, with the yield: 85 percent; HPLC purity: 99.59 percent; chiral HPLC purity 99.9%; the content of dicyclohexylamine is 0.32 percent, and the pharmaceutical standard is not met.
Comparative example 2
Taking 10g of the sitafloxacin dicyclohexylamine salt obtained in the comparison 1; adding 100mL of methyl tert-butyl ether and 150mL of water, slowly adding 10% sodium hydroxide aqueous solution under stirring until the pH of the water phase is 10-11 (10 min for use), and continuing stirring for 30min after all the solid is dissolved; extracting and layering, and discarding a tert-butyl methyl ether phase; adding 60mL of methyl tert-butyl ether into the water phase, and washing once; extracting and layering, and discarding an organic phase; TLC spot plate is visible, dicyclohexylamine is removed; slowly adding dilute hydrochloric acid into the obtained water phase to adjust the pH value to 3-6 (the time for use is 5min), separating out a large amount of solids, stirring to react for 30min, filtering, adding 100mL of water into a filter cake to wash, and drying in vacuum at 40 ℃ to obtain 7.0g of a sitafloxacin refined product, wherein the yield is as follows: 90.9 percent; HPLC purity: 99.61 percent; chiral HPLC purity 99.9%; dicyclohexylamine was not detected; residue: 0.31%, and does not meet the medicinal standard.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (10)

1. A salt of sitafloxacin, characterized in that the structural formula is shown in formula I:
Figure FDA0003716614970000011
2. a method for preparing a salt of lithospermate morpholine according to claim 1, comprising the following steps: dissolving the crude product of the sitagliptin in a mixed solution of an organic solvent and water or the organic solvent, adding morpholine, separating out solid, and carrying out solid-liquid separation to obtain the sitagliptin morpholine salt.
3. The process for preparing a salt of rituximab of claim 2 wherein the solvent comprises at least one of isopropanol, ethanol, methanol, tetrahydrofuran, butanone, methyl butyl ketone, acetone, acetonitrile, isopropyl acetate and N, N-dimethylformamide.
4. The method for preparing a salt of sitagliptin morpholine according to claim 2, characterized in that the ratio of the volume of the mixed solution of the organic solvent and water or the organic solvent to the mass of the crude product of sitagliptin is 4-30: 1 (ml: g).
5. The method for preparing a salt of sitafloxacin according to claim 4, wherein the mass of water in the mixed solution of the organic solvent and water is not more than 3 times the mass of the crude product of sitafloxacin.
6. A process for the preparation of a salt of sitafloxacin according to any one of claims 2 to 5, wherein the molar amount of morpholine to the crude sitafloxacin is from 0.5 to 10: 1.
7. use of a process for the preparation of a salt of sitafloxacin according to claim 1 or a salt of sitafloxacin according to any one of claims 2 to 6 for the purification of a crude product of sitafloxacin.
8. The use according to claim 7, characterized in that it comprises in particular the following operations: dissolving the sitafloxacin salt in water, adding acid to adjust the pH of the solution to 2-6, and separating solid from liquid after the solid is separated out to obtain a refined sitafloxacin product.
9. The use according to claim 7, characterized in that it comprises in particular the following operations: dissolving the sitagliptin morpholine salt in water, adding dichloromethane, adding acid to adjust the pH value of the solution to 2-6, stirring and reacting for 10-40 min, separating and extracting, discarding the water phase, concentrating the organic layer, adding an organic solvent to dissolve, adding the obtained solution into water, continuing stirring and reacting for 20-40 min, and carrying out solid-liquid separation to obtain the sitagliptin.
10. Use of the sitafloxacin morpholine salt according to claim 1 or the method for the preparation of a sitafloxacin morpholine salt according to any one of claims 2 to 6 for the purification of a crude sitafloxacin salt, characterized in that the crude sitafloxacin salt is prepared into the sitafloxacin morpholine salt during the preparation of the sitafloxacin salt, and further dissociated to obtain the refined sitafloxacin salt.
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