CN111100125A - Preparation method of moxifloxacin intermediate - Google Patents
Preparation method of moxifloxacin intermediate Download PDFInfo
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- CN111100125A CN111100125A CN201911420721.7A CN201911420721A CN111100125A CN 111100125 A CN111100125 A CN 111100125A CN 201911420721 A CN201911420721 A CN 201911420721A CN 111100125 A CN111100125 A CN 111100125A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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Abstract
The invention discloses a preparation method of a moxifloxacin intermediate. The invention provides a preparation method of a compound shown as a formula III, which comprises the following steps: in a solvent, in the presence of alkali, carrying out a cyclization reaction shown as the following on a compound shown as a formula II to obtain a compound shown as a formula III. The method has the advantages of simple operation, high chiral selectivity, simple process, high yield and high purity.
Description
Technical Field
The invention relates to a preparation method of a moxifloxacin intermediate.
Background
Moxifloxacin belongs to fourth-generation quinolone antibacterial drugs, and is a new-generation antibiotic with wide antibacterial spectrum. The product has strong antibacterial activity against common respiratory tract bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and part of Staphylococcus aureus, and especially against Streptococcus pneumoniae. The traditional Chinese medicine composition is clinically used for treating acute sinusitis, acute attack of chronic bronchitis, community-acquired pneumonia, and skin infection and skin soft tissue infection without complications. Moxifloxacin is characterized by almost no photosensitive reaction, good tissue penetrating power, high concentration in lung tissue and good effect of treating respiratory tract infection.
(S, S) -2, 8-diazabicyclo [4,3,0] nonane is an intermediate of moxifloxacin, 2, 3-pyridinedicarboxylic acid is taken as a raw material in the current industrialized route (Chinese medicine industry 2004, 35, 129), imide is reduced and resolved by high-pressure pyridine hydrogenation and lithium aluminum hydride, the process flow is complex, and racemization and reutilization of isomers also show that the route is not economical and environment-friendly.
Patent US5703244 reports the construction of chiral centers by sharpless asymmetric epoxidation followed by a two-step reaction to give pyrrole rings, followed by a series of transformations followed by 12-step reactions to give (S, S) -2, 8-diazabicyclo [4,3,0] nonane. The route is too long and the industrial value is not high.
Chinese patent CN201110312411 reports another chiral synthesis route, which uses 4-substituted-3-pyrrolidone as a raw material, and obtains (S, S) -2, 8-diazabicyclo [4,3,0] nonane through chiral phenethylamine induction to construct a chiral center and then through conversion. The synthesis of the initial raw material of the route is not easy, the effect of chiral induction is not good, and further purification such as subsequent crystallization is needed.
Disclosure of Invention
The invention provides a novel preparation method of moxifloxacin intermediate, aiming at overcoming the defects of low chiral selection, complex process flow and low yield of the existing preparation method of moxifloxacin intermediate. The preparation method of the moxifloxacin intermediate has the advantages of simple operation, high chiral selectivity, simple process, higher yield and higher purity.
The invention provides a preparation method of a compound shown as a formula III, which comprises the following steps: in a solvent, in the presence of alkali, carrying out a cyclization reaction shown as the following on a compound shown as a formula II to obtain a compound shown as a formula III;
in the cyclization reaction, the solvent can be a conventional solvent for the cyclization reaction in the field, and preferably, the solvent is an ether solvent (such as tetrahydrofuran).
In the cyclization reaction, the base can be an alkali metal salt of an organic amine, the organic amine in the alkali metal salt of the organic amine can be dimethylamine, diethylamine or diisopropylamine, and the alkali metal can be lithium, sodium or potassium; preferably, the base is lithium diisopropylamide.
In the cyclization reaction, the molar ratio of the base to the compound shown in the formula II can be a conventional molar ratio of the cyclization reaction in the field, and preferably, the molar ratio of the base to the compound shown in the formula II is 1: 1-1.5: 1 (for example, 1: 1).
In one embodiment, in the ring closure reaction, it comprises the following steps: adding the base into the solvent and the compound shown in the formula II; the alkali can be added into the solvent and the compound as shown in the formula II in a dropwise manner; said base is soluble in an ethereal solvent (e.g., tetrahydrofuran) and is added to said solvent and said compound of formula II; the temperature of the base added to the solvent and the compound of formula II can be from-60 ℃ to-80 ℃ (e.g., -70 ℃).
In the cyclization reaction, the temperature of the cyclization reaction can be the conventional temperature of the cyclization reaction in the field, and preferably, the reaction temperature is-80 ℃ to 30 ℃.
In the cyclization reaction, the concentration of the compound shown in the formula I in the solvent can be the conventional concentration in the cyclization reaction in the field, and preferably, the concentration of the compound shown in the formula I in the solvent is 5-10mL/g (for example, 5.2 mL/g).
In one embodiment, in the cyclization reaction, the raw materials of the cyclization reaction only comprise the solvent, the compound shown in the formula II and the base.
In one embodiment, the preparation method further comprises a post-treatment, and the post-treatment comprises the following steps: and after the cyclization reaction is finished, adding water for quenching, concentrating, extracting and concentrating to obtain the compound shown in the formula III.
The preparation method of the compound shown in the formula III can further comprise the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on a compound shown as a formula I and dibromopropane as shown in the specification to obtain a compound shown as a formula II;
in the substitution reaction, the solvent may be a solvent conventional in the art for such substitution reactions, and preferably, the solvent is an amide-based solvent (e.g., dimethylformamide).
In the substitution reaction, the base may be a conventional base for such substitution reactions in the art, and preferably, the base is an alkali metal hydride (e.g., NaH).
In the substitution reaction, the molar ratio of the dibromopropane to the compound shown in the formula I can be a conventional ratio of the substitution reaction in the field, and preferably, the molar ratio of the dibromopropane to the compound shown in the formula I is 1.5: 1-3: 1 (for example, 2: 1).
In the substitution reaction, the molar ratio of the base to the compound shown in the formula I can be a conventional ratio of the substitution reaction in the field, and preferably, the molar ratio of the base to the compound shown in the formula I is 1: 1-2: 1 (for example, 1: 1).
In the substitution reaction, the reaction temperature can be the conventional temperature in the substitution reaction in the field, and preferably, the reaction temperature is room temperature (10 ℃ to 30 ℃).
In one embodiment, in the substitution reaction, the starting materials for the substitution reaction include only the solvent, the compound of formula I, the dibromopropane, and the base.
In one embodiment, in the substitution reaction, it comprises the steps of: and sequentially adding the compound shown in the formula I, the base and the dibromopropane into the solvent.
In one embodiment, the preparation method further comprises a post-treatment, and the post-treatment comprises the following steps: and after the substitution reaction is finished, adding water for quenching, extracting and concentrating to obtain the compound shown as the formula II.
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps:
(1) obtaining the compound shown in the formula III by adopting the preparation method of the compound shown in the formula III;
(2) in water, in the presence of acid, carrying out Boc removal reaction on the compound shown as the formula III to obtain a compound shown as the formula IV;
in the de-Boc reaction, the acid may be an acid conventional in such de-Boc reactions in the art, and preferably, the acid is HCl or trifluoroacetic acid (e.g., HCl).
In the de-Boc reaction, the concentration of the acid in the water can be the conventional concentration in the de-Boc reaction in the field, and preferably, the concentration of the acid in the water is 3 mol/L.
In the Boc removal reaction, the molar ratio of the acid to the compound shown in the formula III may be a conventional molar ratio in the Boc removal reaction in the field, and preferably, the molar ratio of the hydrochloric acid to the compound shown in the formula III is 1:1 to 2:1 (e.g., 1: 1).
In the de-Boc reaction, the reaction temperature may be a temperature conventional in such de-Boc reactions in the art, and preferably, the reaction temperature is from 40 ℃ to 60 ℃ (e.g., 50 ℃).
In one embodiment, in the de-Boc reaction, the raw materials for the de-Boc reaction only comprise the water, the compound represented by formula III, and the acid.
In one embodiment, said step (2) further comprises a post-treatment, said post-treatment comprising the steps of: and after the Boc removal reaction is finished, extracting and concentrating to obtain the compound shown as the formula IV.
The invention also provides a preparation method of the compound shown as the formula V, which comprises the following steps:
(1) obtaining the compound shown in the formula IV by adopting the preparation method of the compound shown in the formula IV;
(2) in a solvent, in the presence of a reducing agent, carrying out a reduction reaction shown as the following on the compound shown as the formula IV to obtain a compound shown as the formula V;
in the reduction reaction, the solvent may be a solvent conventional in the art for such reduction reactions, and preferably, the solvent is an ethereal solvent (e.g., tetrahydrofuran).
In the reduction reaction, the reducing agent can be a conventional reducing agent in the reduction reaction in the field, and preferably, the reducing agent is lithium aluminum hydride or red aluminum (such as lithium aluminum hydride).
In the reduction reaction, the molar ratio of the reducing agent to the compound shown in the formula IV may be a conventional molar ratio in the field of the reduction reaction, and preferably, the molar ratio of the reducing agent to the compound shown in the formula IV is 1:1 to 1.5:1 (for example, 1.2: 1).
In the reduction reaction, the reaction temperature may be a temperature conventional in the art for such reduction reactions, and preferably, the reaction temperature is 50 ℃ to 80 ℃ (e.g., 66 ℃ to 70 ℃).
In the reduction reaction, the concentration of the compound shown in formula IV in the solvent may be a concentration conventional in the reduction reaction in the art, and preferably, the concentration of the compound shown in formula IV in the solvent is 0.6mol/L to 0.9mol/L (e.g. 0.75 mol/L).
In one embodiment, in the reduction reaction, the raw materials for the reduction reaction only comprise the solvent, the compound represented by formula IV and the reducing agent.
In one embodiment, said step (2) further comprises a post-treatment, said post-treatment comprising the steps of: and after the reduction reaction is finished, sequentially adding an ester solvent and an alkali aqueous solution, concentrating and extracting to obtain the compound shown as the formula IV.
In the post-treatment step of the reduction reaction, the ester solvent may be an ester solvent (e.g., ethyl acetate) conventional in the art.
In the post-treatment step of the reduction reaction, the aqueous solution of the base may be an aqueous solution of a base conventional in the art, preferably, the base is an alkali metal hydroxide (e.g., sodium hydroxide); preferably, the concentration of the alkali aqueous solution is 4 mol/L.
The invention also provides a preparation method of the compound shown in the formula VI, which comprises the following steps:
(1) obtaining the compound shown in the formula V by adopting the preparation method of the compound shown in the formula V;
(2) in a solvent, in the presence of hydrogen and a catalyst, the compound shown as the formula V is subjected to debenzylation reaction shown as the following formula V to obtain a compound shown as the formula VI;
in the debenzylation, the solvent may be a solvent conventional in debenzylation in the art, and preferably, the solvent is an alcohol solvent (e.g., methanol).
In the debenzylation, the catalyst may be a catalyst conventional in the debenzylation in this type of the art, and preferably, the catalyst is palladium on carbon or Raney nickel (e.g., palladium on carbon).
In the debenzylation, the reaction pressure may be a pressure conventional in such dehydrogenation reactions in the art, and preferably, the reaction pressure is 40 to 70 atmospheres (e.g., 50 to 60 atmospheres).
In the debenzylation, the reaction temperature may be a temperature conventional in such dehydrogenation reactions in the art, and preferably, the reaction temperature is 90 ℃ to 110 ℃ (e.g., 100 ℃).
In one embodiment, the starting material for the debenzylation reaction comprises only the solvent, the catalyst and the compound represented by formula V.
In one embodiment, said step (2) further comprises a post-treatment, said post-treatment comprising the steps of: and after the debenzylation reaction is finished, filtering and rectifying to obtain the compound shown as the formula VI.
The invention provides a preparation method of a compound shown as a formula II, which comprises the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on a compound shown as a formula I and dibromopropane as shown in the specification to obtain a compound shown as a formula II;
the reaction conditions and operation of the compound of formula II are as described above.
The invention also provides a compound shown as a formula II, which has the following structure:
on the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention provides a preparation method of a moxifloxacin intermediate, which is simple to operate, high in chiral selectivity, simple in process, high in yield and high in purity.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
The starting N-Boc-aspartic acid benzylimide can be synthesized according to the literature Tetrahedron Letters 2004, 3603.
Dissolving 304 g of raw material N-Boc-aspartic acid benzyl imide in 2L of dimethylformamide, adding 40g of sodium hydride in batches at room temperature, stirring for one hour after the addition is finished, slowly dropwise adding 404 g of dibromopropane, stirring until the TLC detection reaction is finished after the addition is finished, adding water to quench the reaction, extracting with dichloromethane, drying and concentrating to obtain 350g of an intermediate (a compound shown in a formula II), wherein the yield is 82.3%, and the content is more than 97%.
1H NMR(400MHz,CDCl3)δ:7.40-7.28(5H,m),4.90-4.83(1H,m),4.80(2H,s),3.52(2H,t,J＝6.5Hz),3.09(1H,dd,J＝3.5,8.9Hz),2.98(2H,t,J＝6.5Hz),2.79(1H,dd,J＝3.5,8.9Hz),2.10-2.00(2H,m),1.45(9H,s).
And (3) dissolving 350g of the intermediate obtained in the last step in 1400mL of anhydrous tetrahydrofuran, cooling to about-70 ℃, dropwise adding 420 mL (2M) of lithium diisopropylamide tetrahydrofuran solution, and slowly heating to room temperature for reaction after the addition is finished. After the reaction is finished, adding water to quench the reaction, concentrating to remove THF, adding water and ethyl acetate to extract residues, drying and concentrating to obtain 260g of a ring-closing product (a compound shown in a formula III), wherein the yield is as follows: 91.8 percent.
1H NMR(400MHz,CDCl3)δ:7.35-7.22(5H,m),4.78(2H,s),4.73-4.69(1H,m),3.60-3.45(2H,m),3.25-3.20(1H,m),1.95-1.90(1H,m),1.75-1.55(3H,m),1.42(9H,s).
260g of ring-closing product is heated to 50 ℃ by 1000mL of 3N diluted hydrochloric acid and stirred until the reaction is completed, dichloromethane is used for extraction, and concentration and drying are carried out, so that 185g of deprotected product (compound shown as formula IV) is obtained, and the yield is 100%.
1H NMR(400MHz,CDCl3)δ:7.38-7.26(5H,m),4.69(s,2H),3.84(1H,d,J＝6.9Hz),2.90-2.80(2H,m),2.70-2.62(1H,m),2.10(1H,brs),2.05-1.98(1H,m),1.75-1.50(3H,m).
185g of product without Boc protection is dissolved in 500 ml of anhydrous tetrahydrofuran, the solution is slowly dripped into 500 ml of tetrahydrofuran solution containing 35 g of lithium aluminum hydride under reflux, heating reflux is carried out continuously at the reflux temperature of the tetrahydrofuran after the addition is finished, the reaction is completed, cooling is carried out, ethyl acetate is added for quenching reaction, 200 ml of 4N sodium hydroxide solution is added, THF is concentrated, water and dichloromethane are added for extraction, 140g of reduction product (compound shown as formula V) is obtained after concentration, and the yield is 86.5%.
1H NMR(400MHz,CDCl3)δ:7.38-7.26(5H,m),3.69(s,2H),2.98-2.78(4H,m),2.69(1H,d,J＝11.0Hz),2.62-2.52(1H,m),1.96(1H,dd,J＝4.4,8.0Hz),1.77(s,2H),1.62(2H,J＝4.0Hz),1.49-1.42(1H,m),1.32(1H,dd,J＝3.5,9.8Hz).
Dissolving 140g of reduction product in 500 ml of methanol, adding 14g of 10% palladium carbon, introducing hydrogen, pressurizing to 50-60 atmospheric pressure, heating to 100 ℃ for reaction until the reaction is finished, cooling, filtering out the palladium carbon, concentrating the remainder to remove the methanol, and rectifying to obtain 78 g of (S, S) -2, 8-diazabicyclo [4,3,0] nonane (the compound shown in the formula VI), wherein the yield is 95.5% and the chiral purity is 99.5%.
1H NMR(400MHz,CDCl3)δ:3.05(1H,s),2.96-2.75(4H,m),2.68(1H,d,J＝11.0Hz),2.60-2.50(1H,m),1.97(1H,dd,J＝4.4,8.0Hz),1.75(s,2H),1.60(2H,J＝4.0Hz),1.48-1.43(1H,m),1.30(1H,dd,J＝3.5,9.8Hz).
Example 2
Dissolving 304 kg of raw material N-Boc-aspartic acid benzyl imide in 2000L of dimethylformamide, adding 40kg of sodium hydride in batches, stirring for one hour after the addition is finished, slowly dropwise adding 404 kg of dibromopropane, stirring until the reaction is finished after the addition is finished, adding water to quench the reaction, extracting with dichloromethane, drying and concentrating to obtain 350kg of an intermediate, wherein the yield is 82.3%.
350kg of the intermediate is dissolved in 1400L of anhydrous tetrahydrofuran, the temperature is reduced to about-70 ℃, 420L (2M) of lithium diisopropylamide tetrahydrofuran solution is dropwise added, and the temperature is slowly raised to room temperature for reaction after the addition is finished. And (3) after the reaction is finished, adding water to quench the reaction, concentrating to remove THF, adding water and ethyl acetate to the residue for extraction, drying and concentrating to obtain 260kg of a ring-closing product, wherein the yield is as follows: 91.8 percent.
260kg of ring-closing product is heated to 50 ℃ by 1000 liters of 3N diluted hydrochloric acid and stirred until the reaction is completed, dichloromethane is used for extraction, and concentration and drying are carried out to obtain 185kg of deprotected product (the compound shown in the formula IV) with the yield of 100 percent.
185kg of product without Boc protection is dissolved in 500L of anhydrous tetrahydrofuran, slowly dropped into 500L of tetrahydrofuran solution which is refluxed and contains 35 kg of lithium aluminum hydride, after the addition, the reaction is continuously heated until the reaction is complete, the reaction is cooled, ethyl acetate is added to quench the reaction, 200L of 4N sodium hydroxide solution is added, THF is concentrated, water and dichloromethane are added for extraction, and 140kg of reduction product is obtained by concentration, and the yield is 86.5%.
Dissolving 140kg of reduction product in 500L of methanol, adding 14 kg of 10% palladium carbon, introducing hydrogen, pressurizing to 50-60 atmospheric pressure, heating to 100 ℃ for reaction until the reaction is finished, cooling, filtering out the palladium carbon, concentrating the remainder to remove the methanol, and rectifying to obtain 78 kg of (S, S) -2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 95.5% and the chiral purity is 99.7%. The spectral data are consistent with the literature.
Claims (12)
1. A preparation method of a compound shown as a formula III is characterized by comprising the following steps: in a solvent, in the presence of alkali, carrying out a cyclization reaction shown as the following on a compound shown as a formula II to obtain a compound shown as a formula III;
2. the process according to claim 1, wherein the solvent is an ethereal solvent, such as tetrahydrofuran;
and/or, in the cyclization reaction, the base is an alkali metal salt of organic amine, the organic amine in the alkali metal salt of organic amine can be dimethylamine, diethylamine or diisopropylamine, and the alkali metal can be lithium, sodium or potassium; preferably, the base is lithium diisopropylamide;
and/or in the cyclization reaction, the molar ratio of the alkali to the compound shown as the formula II is 1: 1-1.5: 1, such as 1: 1;
and/or, in said ring closure reaction, it comprises the following steps: adding the base into the solvent and the compound shown in the formula II; the alkali can be added into the solvent and the compound as shown in the formula II in a dropwise manner; the alkali can be dissolved in an ether solvent and added into the solvent and the compound shown in the formula II, for example, dissolved in tetrahydrofuran and added into the solvent and the compound shown in the formula II; the temperature of the alkali added into the solvent and the compound as shown in the formula II can be-60 ℃ to-80 ℃, for example-70 ℃;
and/or, in the cyclization reaction, the reaction temperature is-80-30 ℃;
and/or, in the cyclization reaction, the concentration of the compound shown in the formula I in the solvent is 5-10mL/g, such as 5.2 mL/g;
and/or, in the cyclization reaction, the raw material of the cyclization reaction only comprises the solvent, the compound shown in the formula II and the alkali;
and/or, the preparation method also comprises post-treatment, and the post-treatment comprises the following steps: and after the cyclization reaction is finished, adding water for quenching, concentrating, extracting and concentrating to obtain the compound shown in the formula III.
3. The process of claim 1 or 2 for the preparation of a compound of formula III, further comprising the steps of: in a solvent, in the presence of alkali, carrying out substitution reaction on a compound shown as a formula I and dibromopropane as shown in the specification to obtain a compound shown as a formula II;
4. a process for the preparation of a compound of formula III according to claim 3, wherein in the substitution reaction, the solvent is an amide solvent such as dimethylformamide;
and/or, in the substitution reaction, the base is an alkali metal hydride, such as sodium hydride;
and/or in the substitution reaction, the molar ratio of the dibromopropane to the compound shown in the formula I is 1.5: 1-3: 1, such as 2: 1;
and/or, in the substitution reaction, the molar ratio of the base to the compound shown in the formula I is 1: 1-2: 1, such as 1: 1;
and/or, in the substitution reaction, the reaction temperature is room temperature;
and/or, in the substitution reaction, the raw materials of the substitution reaction only comprise the solvent, the compound shown in the formula I, the dibromopropane and the base;
and/or, in said substitution reaction, it comprises the following steps: sequentially adding the compound shown in the formula I, the alkali and the dibromopropane into the solvent;
and/or, the preparation method also comprises post-treatment, and the post-treatment comprises the following steps: and after the substitution reaction is finished, adding water for quenching, extracting and concentrating to obtain the compound shown as the formula II.
5. A preparation method of a compound shown as a formula IV is characterized by comprising the following steps:
(1) obtaining the compound shown in the formula III by adopting the preparation method of the compound shown in the formula III as claimed in any one of claims 1 to 4;
(2) in water, in the presence of acid, carrying out Boc removal reaction on the compound shown as the formula III to obtain a compound shown as the formula IV;
6. the process of claim 5, wherein in said de-Boc reaction, said acid is HCl or trifluoroacetic acid, such as HCl;
and/or, in the de-Boc reaction, the concentration of the acid in the water is 3 mol/L;
and/or in the Boc removal reaction, the molar ratio of the acid to the compound shown as the formula III is 1: 1-2: 1, such as 1: 1;
and/or, in the de-Boc reaction, the reaction temperature is 40-60 ℃, for example 50 ℃;
and/or, in the de-Boc reaction, the raw materials of the de-Boc reaction only comprise the water, the compound shown in the formula III and the acid;
and/or, the step (2) further comprises post-treatment, and the post-treatment comprises the following steps: and after the Boc removal reaction is finished, extracting and concentrating to obtain the compound shown as the formula IV.
7. A preparation method of a compound shown as a formula V is characterized by comprising the following steps:
(1) obtaining the compound shown in the formula IV by adopting the preparation method of the compound shown in the formula IV as claimed in claim 5 or 6;
(2) in a solvent, in the presence of a reducing agent, carrying out a reduction reaction shown as the following on the compound shown as the formula IV to obtain a compound shown as the formula V;
8. the method according to claim 7, wherein the solvent is an ethereal solvent such as tetrahydrofuran;
and/or, in the reduction reaction, the reducing agent is lithium aluminum hydride or red aluminum, such as lithium aluminum hydride;
and/or in the reduction reaction, the molar ratio of the reducing agent to the compound shown as the formula IV is 1: 1-1.5: 1, such as 1.2: 1;
and/or, in the reduction reaction, the reaction temperature is 50 ℃ to 80 ℃, such as 66 ℃ to 70 ℃;
and/or, in the reduction reaction, the concentration of the compound shown in the formula IV in the solvent is 0.6 mol/L-0.9 mol/L, such as 0.75 mol/L;
and/or, in the reduction reaction, the raw materials of the reduction reaction only comprise the solvent, the compound shown in the formula IV and the reducing agent;
and/or, the step (2) further comprises post-treatment, and the post-treatment comprises the following steps: after the reduction reaction is finished, sequentially adding an ester solvent and an aqueous solution of alkali, concentrating and extracting to obtain the compound shown as the formula IV; the ester solvent can be ethyl acetate; the aqueous base solution may be an alkali metal hydroxide, such as sodium hydroxide; the concentration of the aqueous alkali solution can be 4 mol/L.
9. A preparation method of a compound shown as a formula VI is characterized by comprising the following steps:
(1) obtaining the compound shown in the formula V by adopting the preparation method of the compound shown in the formula V as claimed in claim 7 or 8;
(2) in a solvent, in the presence of hydrogen and a catalyst, the compound shown as the formula V is subjected to debenzylation reaction shown as the following formula V to obtain a compound shown as the formula VI;
10. the process of claim 9, wherein in the debenzylation, the solvent is an alcoholic solvent, such as methanol;
and/or, in the debenzylation reaction, the catalyst is palladium carbon or Raney nickel, such as palladium carbon;
and/or, in said debenzylation reaction, said reaction pressure is from 40 to 70 atmospheres, such as from 50 to 60 atmospheres;
and/or, in the debenzylation reaction, the reaction temperature is 90 ℃ to 110 ℃, such as 100 ℃;
and/or, in the debenzylation reaction, the raw material of the debenzylation reaction only comprises the solvent, the catalyst and the compound shown in the formula V;
and/or, the step (2) further comprises post-treatment, and the post-treatment comprises the following steps: and after the debenzylation reaction is finished, filtering and rectifying to obtain the compound shown as the formula VI.
11. A preparation method of a compound shown as a formula II is characterized by comprising the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on a compound shown as a formula I and dibromopropane as shown in the specification to obtain a compound shown as a formula II;
the reaction conditions and operation of the process for the preparation of the compound of formula II are as defined in claims 3 or 4.
12. A compound of formula II, having the structure:
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| CN114085219A (en) * | 2020-08-25 | 2022-02-25 | 武汉理工大学 | Synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane |
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| CN105503864A (en) * | 2015-12-17 | 2016-04-20 | 江苏阿尔法药业有限公司 | Preparing method for moxifloxacin intermediate |
| CN110183445A (en) * | 2019-06-28 | 2019-08-30 | 昆明学院 | The synthetic method of Moxifloxacin and its derivative |
| CN110183446A (en) * | 2019-06-28 | 2019-08-30 | 昆明学院 | A kind of new impurity of Moxifloxacin and its preparation method and use |
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| WO2010100215A1 (en) * | 2009-03-06 | 2010-09-10 | F.I.S. Fabbrica Italiana Sintetici S.P.A. | SYNTHESIS OF (4aS,7aS)-OCTAHYDRO-1H-PYRROLO[3,4-b]PYRIDINE |
| CN105503864A (en) * | 2015-12-17 | 2016-04-20 | 江苏阿尔法药业有限公司 | Preparing method for moxifloxacin intermediate |
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| CN114085219A (en) * | 2020-08-25 | 2022-02-25 | 武汉理工大学 | Synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane |
| CN114085219B (en) * | 2020-08-25 | 2023-08-01 | 武汉理工大学 | Synthesis of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane |
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