CN110627768B

CN110627768B - Preparation method of moxifloxacin degradation impurity J

Info

Publication number: CN110627768B
Application number: CN201810651252.9A
Authority: CN
Inventors: 朱晶; 徐浩宇; 蔡伟; 鲍鹤龄; 曹兵; 申新程; 石莹; 董志奎
Original assignee: Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2018-06-22
Filing date: 2018-06-22
Publication date: 2021-11-09
Anticipated expiration: 2038-06-22
Also published as: CN110627768A

Abstract

The invention discloses a preparation method of moxifloxacin degradation impurity J, which comprises the following steps: pyrrole-3-formaldehyde is used as a raw material, and subjected to Wittig reaction, reduction reaction and amino protection reaction to prepare a side chain of the moxifloxacin degradation impurity J protected by amino, and subjected to substitution reaction with 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid to prepare the moxifloxacin degradation impurity J protected by amino, and then a protecting group is removed to finally prepare the moxifloxacin degradation impurity J. The impurity J obtained by the method has high purity and high yield.

Description

Preparation method of moxifloxacin degradation impurity J

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of moxifloxacin degradation impurity J.

Background

Moxifloxacin Hydrochloride (Moxifloxacin Hydrochloride) with chemical name of 1-cyclopropyl-7- { (S, S) -2, 8-diazo-bicyclo [4.3.0]Nonan-8-yl } -6-fluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is a fourth-generation fluoroquinolone broad-spectrum antibacterial agent developed by Bayer (Bayer) in Germany. The hydrochloride salt of moxifloxacin was first marketed in germany in 6 months 1999 under the trade name

In the same year, 12 months, us FDA approval was obtained. Moxifloxacin hydrochloride tablets (specification: 0.4g) are imported in China in 2002 and are imported to market in 2005, and the trade name of the moxifloxacin hydrochloride sodium chloride injection is

Moxifloxacin hydrochloride is an 8-methoxy fluoroquinolone antibacterial drug with broad-spectrum antibacterial activity and strong bactericidal effect. The product has antibacterial activity against gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, acid-fast bacteria, and atypical microorganisms such as mycoplasma, chlamydia, and legionella. Its bactericidal mechanism is interference with topoisomerase II and IV, which are key enzymes controlling DNA topology, replication, repair and transcription. The moxifloxacin hydrochloride has bactericidal activity in a concentration dependence manner, and the lowest bactericidal concentration and the lowest bacteriostatic concentration are basically consistent. Moxifloxacin hydrochloride is still effective against beta-lactam and macrolide resistant bacteria. The structural formula is as follows:

during the stability experiment, moxifloxacin hydrochloride is easy to undergo photodegradation reaction, and an impurity shown in the following structure is generated, namely moxifloxacin impurity J:

at present, no synthesis method for degrading impurities J by moxifloxacin is reported in the literature; although the document AAPS PharmSciTech,2018, vol.19, #3, p.1182-1190 reports an isolation method, it is difficult to provide a sample as a control.

Disclosure of Invention

The inventor develops a preparation method which takes pyrrole-3-formaldehyde as a raw material, prepares amino-protected 3-propylamine-pyrrole through Wittig reaction, reduction reaction and amino protection, and then carries out nucleophilic substitution and amino deprotection on the pyrrole-3-formaldehyde and 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid to obtain moxifloxacin degradation impurity J; the method not only can obtain the impurity J with high purity, but also has high yield.

The invention is realized by the following technical scheme, and provides a preparation method of moxifloxacin impurity J, wherein the moxifloxacin degradation impurity J, namely compound I, is as follows:

the preparation method comprises the following steps:

(1) pyrrole-3-formaldehyde, i.e. compound II, and triphenyl acetonitrile based quaternary phosphonium salt, i.e. XPh₃PCH₂CN is subjected to Wittig reaction in a reaction solvent under an alkaline condition to prepare pyrrole-3-acrylonitrile, namely a compound III;

(2) carrying out reduction reaction on the compound III to obtain 3-propylamine-pyrrole, namely a compound IV;

(3) protecting amino in the compound IV to prepare 3-propylamine-pyrrole protected by amino, namely a compound V;

(4) carrying out substitution reaction on the compound V and 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid, namely a compound VI to prepare an amino-protected moxifloxacin degradation impurity J, namely a compound VII;

(5) removing a protecting group of amino in the compound VII to prepare a moxifloxacin degradation impurity J;

in the above-mentioned compound V and compound VII, Q is an amino-protecting group.

In an embodiment of the present invention, the present invention provides a method for preparing moxifloxacin degradation impurity J, wherein, in step (1):

the triphenyl acetonitrile based quaternary phosphonium salt is XPh₃PCH₂The anion X in CN is selected from F^-、 Cl^-、Br^-、I^-、OH^-、SCN^-、(CO₃ ^2-)_0.5、HCO₃ ^-、BF₄ ^-、PF₆ ^-、(HPO₄ ^-)_0.5、 H₂PO₄ ^-、(SO₄ ^2-)_0.5、HSO₄ ^-、C₁-C₆Preferably Cl^-、Br^-、I^-、OH^-、BF₄ ^-、PF₆ ^-One or more of them, more preferably, Cl^-、Br^-、I^-、BF₄ ^-One of (1); optionally, the ratio of the number of equivalents of said triphenylacetonitrile-based quaternary phosphonium salt to the number of equivalents of compound II is selected from 0.8 to 10.0, preferably 1.1 to 2.0;

optionally, the reaction solvent is a chain ether with 3-10 carbon atoms (selected from but not limited to one or more of methyl ethyl ether, diethyl ether, dibutyl ether, etc.), a cyclic ether with 3-10 carbon atoms (selected from but not limited to one or more of tetrahydrofuran, 1, 4-dioxane, etc.), an ester with 3-8 total carbon atoms formed by alkanoic acid and alkanol, C₁-C₆A monohalogenated hydrocarbon orPolyhalogenated hydrocarbons (selected from but not limited to one or more of dichloromethane, trichloromethane, or 1, 2-dichloroethane, etc.), C₂-C₄Alkyl nitrile (selected from but not limited to one or more of acetonitrile, propionitrile, or butyronitrile, etc.), C₁-C₅An alkanol (selected from but not limited to one or more of methanol, ethanol, isopropanol, N-butanol, tert-butanol, and the like), benzene or alkyl substituted benzene, an amide solvent (selected from but not limited to one or more of N, N-dimethylformamide, N-methylpyrrolidone, or N, N-dimethylacetamide, and the like), and one or more of dimethylsulfoxide; preferably, the solvent is one or a mixture of more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethyl acetate, dichloromethane, methanol, ethanol and toluene, and more preferably, the solvent is toluene; optionally, the ratio of the volume of the reaction solvent added (in mL) to the weight of compound II (in g) is selected from 2.0 to 30.0, preferably 11.0 to 13.0; the reaction temperature is 0-120 ℃, and 80-90 ℃ is preferred;

optionally, the alkaline condition is the addition of an inorganic base, or an organic base, or a mixture of the two; here, the inorganic base is selected from MH, MR1, MOH, MOR2, M₂CO₃、M₃PO₄、 M₂HPO₄、MHCO₃One or more of MH, MR1, MOH, MOR2, and M₂CO₃One or a mixture of several of them; wherein MH, MR1, MOH, MOR2, M₂CO₃、 M₃PO₄、M₂HPO₄、MHCO₃M in (1) is selected from Li, Na, K, Rb, Cs and Mg_1/2、Ca_1/2、 Sr_1/2、Ba_1/2One or a mixture of several of them; r1 in MR1 is selected from C₁-C₄One or two of alkyl and phenyl; r2 in MOR2 is selected from C₁-C₅Alkyl groups of (a); the inorganic base is preferably one or more of sodium hydride, lithium hydride, butyl lithium, phenyl lithium, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and cesium carbonate, more preferably sodium hydride, lithium hydride, sodium methoxide, sodium ethoxide and tert-butanolOne of potassium; the organic base is selected from guanidine (one or more selected from but not limited to tetramethyl guanidine, tetraethyl guanidine, etc.), amidine (selected from but not limited to 1, 5-diazabicyclo [4.3.0 ]]Non-5-ene, or 1, 8-diazabicyclo [5.4.0]One or more of undec-7-ene, etc.), one or more of tetraalkylammonium hydroxide with the total number of carbon atoms of 4-24; the organic base is preferably tetramethylguanidine, 1, 8-diazabicyclo [5.4.0 ]]One of undec-7-ene and tetrabutylammonium hydroxide; optionally, the ratio of the equivalents of base added to the equivalents of compound II is selected from 1.0 to 10.0, preferably 1.1 to 1.5.

In an embodiment of the present invention, the present invention provides a method for preparing moxifloxacin degradation impurity J, wherein, in step (2):

a reduction reaction of the compound III, wherein the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond are carried out either in "fractional steps" or in "one-pot", preferably in "fractional steps"; when the reduction is carried out in a stepwise manner, the C ═ C double bond may be reduced first, the C ≡ N triple bond may be reduced first, and the C ≡ C double bond is preferably reduced first. When the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond in compound III are carried out in steps, the reduction of the C ≡ C double bond is by transition metal-catalyzed hydrogenation of hydrogen or transfer hydrogenation with the addition of a "hydrogen source" using a transition metal catalyst selected from the group consisting of metal Pd, metal Pt, metal Ru, metal Ni, PtO₂One or more of compounds of 0-2 valence metal Pd and 0-3 valence metal Ru or their supported forms (such as activated carbon supported or alumina supported), preferably Pd/C, Raney Ni, PtO₂、Pd(OH)₂/C、[Ru(PPh₃)₄]Cl₃One of (1); the hydrogen source used for transfer hydrogenation is one or a mixture of several of formic acid, formate, cyclohexene and 1, 4-cyclohexadiene; optionally, the reaction solvent used for the reduction of the C ═ C double bond is selected from chain ethers having 3 to 10 carbon atoms (one or more selected from but not limited to methyl ethyl ether, diethyl ether, dibutyl ether, and the like), cyclic ethers having 3 to 10 carbon atoms (one or more selected from tetrahydrofuran, 1, 4-dioxane, and the like), the total number of carbon atoms formed by alkanoic acids and alkanolsIs an ester of 3 to 8, C₁-C₆A monohalogenated hydrocarbon or a polyhalogenated hydrocarbon (one or more selected from dichloromethane, trichloromethane, 1, 2-dichloroethane, etc.), C₂-C₄Alkyl nitrile (one or more selected from acetonitrile, propionitrile, butyronitrile, etc.), C₁-C₅The alkanol (can be selected from one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol and the like), one or more of benzene or alkyl substituted benzene, preferably one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethyl acetate, dichloromethane, methanol, ethanol and toluene, and more preferably methanol; optionally, the reaction temperature used for the reduction of the C ═ C double bond is selected from 0 to 60 ℃, preferably 25 ± 5 ℃; optionally, the ratio of the volume of solvent used (in ml) for the reduction of the C ═ C double bond to the mass of compound III (in g) is from 3.0 to 20.0, preferably from 6.0 to 8.0; optionally, when the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond in compound III are carried out separately, the combination of reduction conditions for the C ≡ N triple bond is selected from metal hydrides, non-metal hydrides, raney nickel/H triple bonds₂、Pt/H₂、PtO₂/H₂Or Ru/H₂One or a combination of several of (1), preferably using a metal hydride, or a non-metal hydride alone; the metal hydride herein is selected from MBH₄Or MALH₄One or a mixture of several, MBH₄、MAlH₄M in (1) is selected from Li, Na or K, and the metal hydride is preferably LiAlH₄、LiBH₄、NaBH₄One of (1); the non-metal hydride is borane, alkyl incompletely substituted borane (one or more selected from but not limited to methyl borane, dimethyl borane and the like), preferably borane; optionally, the reaction solvent used for the reduction of the triple bond of C.ident.N is selected from one or more of chain ether(s) with 3-10 carbon atoms (which may be selected from but not limited to one or more of methyl ethyl ether, dibutyl ether, etc.), cyclic ether(s) with 3-10 carbon atoms (which may be selected from but not limited to one or more of tetrahydrofuran, 1, 4-dioxane, etc.), benzene or alkyl substituted benzene, preferably diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, etc,One or more of toluene, more preferably one of diethyl ether, tetrahydrofuran and toluene; optionally, the reaction temperature used for the reduction of the C.ident.N triple bond is selected from 0-65 ℃, preferably 65. + -. 5 ℃; optionally, the ratio of the volume of solvent used (in ml) for the reduction of the C.ident.N triple bond to the mass of compound III (in g) is from 5.0 to 30.0, preferably from 15.0 to 18.0; optionally, when the reduction of the C ≡ C double bond and the C ≡ N triple bond "one-pot" process in compound III is carried out, the reduction method used is a transition metal catalyzed high pressure hydrogen hydrogenation reaction, the transition metal catalyst being as defined for the step-wise C ≡ C double bond reduction method; optionally, the reaction solvent used is selected from chain ether with 3-10 carbon atoms (one or more selected from but not limited to methyl ethyl ether, dibutyl ether, etc.), cyclic ether with 3-10 carbon atoms (selected from but not limited to tetrahydrofuran, or 1, 4-dioxane, etc.), C₁-C₅A mixture of one or more of alkanol (such as one or more of methanol, ethanol, isopropanol, N-butanol, tert-butanol, etc.), amide solvent (which can be selected from but not limited to one or more of N, N-dimethylformamide, N-methylpyrrolidone, or N, N-dimethylacetamide, etc.), preferably one of methanol, ethanol, and tetrahydrofuran; the ratio of the volume of the reaction solvent added (in mL) to the weight of compound III (in g) is 4.0 to 15.0, preferably 6.0 to 10.0; optionally, the pressure of said high pressure hydrogen is from 2 to 70 atmospheres, preferably from 5 to 20 atmospheres; optionally, the reaction temperature is from 0 to 120 deg.C, preferably from 80 to 90 deg.C.

In the embodiment of the invention, the invention provides a preparation method of moxifloxacin degradation impurity J, wherein in the step (3), the amino protecting group Q is selected from R₃-O-C(O)-、C₁-C₆Alkanoyl (which can be selected from but not limited to one of formyl, acetyl, n-propionyl, trifluoroacetyl or n-butyryl, etc.), benzyl (which can be selected from but not limited to one of benzyl, p-methoxybenzyl, benzhydryl, trityl, or2, 4-dimethoxybenzyl, etc.); wherein R is₃R in-O-C (O) -₃Is selected from C₁-C₆Alkyl (e.g., methyl, ethyl, propyl),Or t-butyl), aryl, benzyl, trimethylsiloxyethyl, fluorenylmethyl, or the like.

In the embodiment of the invention, the invention provides a preparation method of moxifloxacin degradation impurity J, wherein in the step (4), the base is selected from MOH, MOR4 and M₂CO₃MH, guanidine (one or more selected from but not limited to tetramethylguanidine, or tetraethylguanidine, etc.), amidine (selected from but not limited to 1, 5-diazabicyclo [4.3.0 ]]Non-5-ene, or 1, 8-diazabicyclo [5.4.0]One or more of undec-7-ene, etc.), one or more of tetraalkylammonium hydroxide with total carbon number of 4-24; MOH, MOR4, M₂CO₃、M₃PO₄、M₂HPO₄M in (1) is selected from Li, Na, K, Rb, Cs and Mg_1/2、Ca_1/2、Sr_1/2、Ba_1/2(ii) a R4 in MOR4 is selected from C₁-C₅Alkyl groups of (a); more preferably, the alkali is NaOH or Na₂CO₃Sodium methoxide, sodium ethoxide, potassium tert-butoxide, NaH, tetrabutylammonium hydroxide, tetramethylguanidine, or 1, 8-diazabicyclo [5.4.0 ]]-one of undec-7-ene; optionally, the solvent is selected from one or more of DMF (dimethylformamide), DMAC (dimethylacetamide), DMSO (dimethylsulfoxide), etc.; optionally, the reaction temperature is selected from 0-100 ℃.

In an embodiment of the present invention, the present invention provides a method for preparing moxifloxacin degradation impurity J, wherein in step (5), the method for removing the protecting group is selected from: if the protecting group is alkoxycarbonyl, the deprotection method comprises the following steps: catalytic hydrogenolysis, e.g. palladium on charcoal/H₂Palladium on carbon/formic acid, palladium on carbon/ammonium formate, Pd (OH)₂-C/H₂、H₂/PdCl₂、Pd(OAc)₂/H₂、Pd(PPh₃)₄Formic acid, platinum/H₂rhodium/H₂Or nickel/H₂Etc.; (II) acid hydrolysis cracking (HX, wherein X is F, Cl, Br, I or trifluoroacetic acid); if the protecting group is fluorenylmethoxycarbonyl, the deprotection method is aminolysis (ammonia, C1-C6 alkylamine or alcohol amine, piperidine, cyclohexylamine, morpholine, pyrrolidone, DBU (1, 8-diazadim)Cyclo [5.4.0]-undec-7-ene), etc.); if the protecting group is alkanoyl, the deprotection method is hydrazinolysis and NaBH₄、 KBH₄Etc.; (II) acid hydrolysis cracking (HX, wherein X is F, Cl, Br, I or trifluoroacetic acid); ③ Na/NH₃(liquid) reduction; fourthly, alkaline hydrolysis, wherein the alkali is selected from MOH, MOR5 and M₂CO₃、M₃PO₄、 M₂HPO₄One or a mixture of more of trialkylamine with the total number of carbon atoms of 6-24, tetramethylguanidine, amidine and tetraalkylammonium hydroxide with the total number of carbon atoms of 4-24; MOH, MOR5, M₂CO₃、 M₃PO₄、M₂HPO₄M in (1) is selected from Li, Na, K, Rb, Cs and Mg_1/2、Ca_1/2、Sr_1/2、 Ba_1/2(ii) a R5 in MOR5 is selected from C1-C5 alkyl; more preferably, the alkali is NaOH or Na₂CO₃、NaOCH₃Potassium tert-butoxide, N-diisopropylethylamine, tetrabutylammonium hydroxide, tetramethylguanidine, DBU; if the protecting group is alkyl, the deprotection method comprises the following steps: catalytic hydrogenolysis, e.g. palladium on charcoal/H₂Palladium on carbon/formic acid, palladium on carbon/ammonium formate, Pd (OH)₂-C/H₂、H₂/PdCl₂、Pd(OAc)₂/H₂、 Pd(PPh₃)₄Formic acid, platinum/H₂rhodium/H₂Ni/H₂Etc.; (iii) acid hydrolysis cracking, such as HX, where X is F, Cl, Br, I or trifluoroacetic acid, or an organic acid having 1 to 6 carbon atoms; ③ alkaline hydrolysis, the alkali is selected from MOH, MOR5, M₂CO₃、M₃PO₄、M₂HPO₄One or a mixture of more of trialkylamine with the total number of carbon atoms of 6-24, tetramethylguanidine, amidine and tetraalkylammonium hydroxide with the total number of carbon atoms of 4-24; MOH, MOR5, M₂CO₃、M₃PO₄、M₂HPO₄M in (1) is selected from Li, Na, K, Rb, Cs and Mg_1/2、Ca_1/2、Sr_1/2、Ba_1/2(ii) a R5 in MOR5 is selected from C1-C5 alkyl; more preferably, the alkali is NaOH or Na₂CO₃、NaOCH₃Potassium tert-butoxide, N-diisopropylethylAmine, tetrabutylammonium hydroxide, tetramethylguanidine, or DBU.

The invention provides a safe and effective preparation method of moxifloxacin degradation impurity J, which comprises the following steps: the reaction time of each step is short, the reaction temperature is low, no dangerous operation is caused, the purity of the impurity J exceeds 99 percent, and an HPLC detection method is disclosed to be used as a reference substance in the detection process of the moxifloxacin hydrochloride impurity, so that the change condition of the moxifloxacin hydrochloride impurity can be directly and effectively monitored. The implementation of the invention is beneficial to improving the quality standard of moxifloxacin hydrochloride, thereby better controlling the product quality of moxifloxacin hydrochloride, and having important significance for safe medication of people.

Drawings

FIG. 1 shows the preparation of Compound (I) in example 13¹³A CNMR map.

Detailed Description

The present invention is further described with reference to the following examples, which are illustrative and are not to be construed as limiting the scope of the invention.

NMR conditions:

the instrument model is as follows: BRUKERAV-400 model NMR spectrometer

Solvent: DMSO-d6

Temperature: 303K

Internal standard: TMS

MS conditions:

the instrument model is as follows: waters Q-TOF micro mass spectrometer

Solvent: methanol

An ionization mode: ESI (+), 120V;

example 1 preparation of starting Material pyrrole-3-Formaldehyde (Compound II)

Sodium hydride (60g) was added to anhydrous tetrahydrofuran (1500mL), the reaction was cooled to-10 deg.C, then pyrrole (100g) was slowly added dropwise over 1 h. After the addition, the reaction was stirred for a further 30min at-10 ℃ and TIPSCl (triisopropylchlorosilane) (370g) was then added dropwise slowly over a period of about 1.5 h. After the addition, the reaction was slowly warmed to room temperature and stirred overnight, then saturated brine (1000mL) was added to separate layers, and the organic phase was washed once with saturated brine (1000mL) and dried to give a brown oil (300 g). Used in the next step without purification.

Oxalyl chloride (106g) was added to anhydrous DCM (dichloromethane) (1500mL), the reaction was cooled to-10 ℃ and anhydrous DMF (66g) was added slowly dropwise over 2 h. After the addition was complete, the reaction was stirred for a further 30min at-10 ℃ and the brown oil (150g) was then added dropwise slowly over a period of about 1.5 h. After the addition, the reaction was refluxed for 1h, cooled, filtered, the filter cake washed with diethyl ether (300mL), then transferred to a 2L bottle, then 2N sodium hydroxide solution (1000mL) was added slowly to prevent the exotherm from rising violently, and after the addition, stirring was continued at room temperature for 4 h. MTBE (methyl tert-butyl ether) (500mL) was added to extract the layers, the aqueous phase was extracted 3 more times with MTBE, the organic phases were combined, dried and spun dry, and column chromatography was performed to give compound II (25g) as a brown oil. The reaction mixture was used in the next reaction without further purification.

EXAMPLE 2 preparation of pyrrole-3-propenenitrile (Compound III)

1000ml of toluene and 84g of the compound II obtained in example 1 were put in a 2L three-necked flask, and 408g of the mixture was added under stirring

After the triphenylacetonitrile is brominated by salt, 174g of DBU is quickly dripped, after the dripping is finished, the temperature is increased to reflux, the reflux reaction is carried out for 1h, the sampling TLC detection is carried out until the compound II is completely reacted, the concentration is carried out till the compound II is dried, then methyl tert-butyl ether is added, the mixture is pulped for 3 times at the temperature of 0 ℃, and most of triphenylphosphine oxide is removed. Column chromatography separation gave 65g of compound III as a white solid for the next reaction.

EXAMPLE 3 preparation of pyrrole-3-propenenitrile (Compound III)

1000ml of toluene and 84g of the compound II obtained in example 1 were put in a 1L three-necked flask, and 360g of the mixture was added thereto with stirring

Salt chlorinated triphenyl acetonitrile group

After the addition is finished, the reaction kettle is used for adding,and (3) rapidly dropwise adding 174g of DBU, heating to reflux after the dropwise adding is finished, carrying out reflux reaction for 1h, carrying out sample TLC detection until the reaction of the compound II is finished, concentrating to dry, adding methyl tert-butyl ether, pulping for 3 times at 0 ℃, and removing most of triphenylphosphine oxide. Column chromatography gave 67g of compound III as a white solid for the next reaction.

EXAMPLE 4 preparation of 3-propylamine-pyrrole (Compound IV)

65g of the compound III prepared in example 2 and 500ml of methanol were placed in a 1L three-necked flask, and then 8g of 10% wet palladium on charcoal was added, and the mixture was subjected to nitrogen substitution 3 times and hydrogen substitution 3 times, followed by hydrogenation at room temperature and normal pressure for 10 hours until HPLC showed that the reaction of the starting materials was completed. Suction filtration is carried out, and the filtrate is concentrated to be dry, so as to obtain 60g of oily matter which is temporarily stored for later use.

1L of anhydrous tetrahydrofuran is added into a 3L three-necked bottle, 60g of lithium aluminum hydride is added, stirring is started, the temperature is reduced to be below 0 ℃, and the tetrahydrofuran solution of the oily substance (60g of the oily substance is dissolved in 200ml of tetrahydrofuran) is slowly dripped for about 30 min. After dripping, slowly heating to reflux, carrying out heat preservation and reflux for 5h, then sampling, carrying out TLC detection, cooling to below-15 ℃ after the reaction of the raw materials is finished, then respectively and slowly dripping 60g of water, 60ml of 15% sodium hydroxide solution and 180g of water, heating to room temperature after the dripping is finished, stirring at room temperature for 1h, carrying out suction filtration, and concentrating the filtrate to dryness to obtain a compound IV which is directly used for the next reaction (61g of oily substance).

Example 5 preparation of 3-propylamine-pyrrole (Compound IV)

A1L three-necked flask was charged with 65g of the compound III prepared in example 2 and 500ml of methanol, followed by 8g of 10% wet palladium on charcoal, 208g of ammonium formate in portions, and then hydrogenated at room temperature and normal pressure for 10 hours until HPLC showed the reaction of the starting materials was completed. Suction filtration is carried out, and the filtrate is concentrated to be dry, so as to obtain 60g of oily matter which is temporarily stored for later use.

Example 6 preparation of 3-propylamine-pyrrole (Compound IV)

1L of anhydrous methanol is added into a 3L three-necked bottle, 60g of Raney Ni is added, stirring is started, the temperature is reduced to be below 0 ℃, and the methanol solution of the compound III prepared in the example 3 (60g of the compound III is dissolved in 200ml of tetrahydrofuran) is slowly dripped for about 30 min. After the dripping is finished, slowly heating to reflux, carrying out heat preservation and reflux for 5h, then sampling, carrying out TLC detection, carrying out suction filtration when the reaction of the raw materials is finished, and concentrating the filtrate to dryness to obtain a compound IV which is directly used for the next reaction (60g, oily substance).

Example 7 preparation of amino protected 3-propylamine-pyrrole (Compound V, Q is BOC)

600ml of anhydrous tetrahydrofuran, 60g of the compound IV obtained in example 4 are placed in a 2L three-necked flask, stirring is switched on and 126.5g of (BOC) are slowly added at room temperature₂O, about 1h is added completely. After the addition, the reaction is continued for 1.5h at room temperature, TLC detection is carried out until the raw material reaction is finished, 300ml of saturated saline solution is added, stirring and washing are carried out for 15min, liquid separation is carried out, a water phase and an organic phase are respectively collected, the water phase is extracted for 1 time by 200ml of ethyl acetate, the organic phases are combined, after drying by anhydrous sodium sulfate, concentration is carried out till dryness, and column chromatography separation is carried out, so that a clear oily compound V (88.6g, the yield is 82.1%) is obtained and is kept for standby.

Example 8 preparation of amino protected 3-propylamine-pyrrole (Compound V where Q is p-toluenesulfonyl)

600ml of anhydrous methanol, 60g of the compound IV obtained in example 5 and 76.5g of pyridine are placed in a 2L three-necked flask, stirring is switched on, 112g of p-toluenesulfonyl chloride are slowly added at room temperature over about 1 h. After the addition, the reaction is continued for 1.5h at room temperature, TLC detection is carried out until the raw material reaction is finished, 300ml of saturated saline solution is added, stirring and washing are carried out for 15min, liquid separation is carried out, a water phase and an organic phase are respectively collected, the water phase is extracted for 1 time by 200ml of ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate, concentrated to be dry, and separated by column chromatography to obtain an oily compound V (107.6g, the yield is 80.0 percent) which is kept for standby.

Example 9 preparation of amino protected 3-propylamine-pyrrole (Compound V where Q is trityl)

600ml of methylene chloride, 60g of the compound IV obtained in example 6 and 97.8g of triethylamine are placed in a 2L three-necked flask, stirring is switched on and 202g of triphenylchloromethane are added slowly over about 1h at room temperature. After the addition, the reaction is continued for 2.5h at room temperature, TLC detection is carried out until the raw material reaction is finished, 300ml of saturated saline solution is added, stirring and washing are carried out for 15min, liquid separation is carried out, a water phase and an organic phase are respectively collected, the water phase is extracted for 1 time by 200ml of ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate, concentrated to be dry, and separated by column chromatography to obtain an oily compound V (150.6g, the yield is 85.0 percent) which is kept for standby.

Example 10 preparation of amino protected impurity J (Compound VII)

600ml of anhydrous DMF was added to a 2L three-necked flask, stirring was started, 45.6g of the compound V obtained in example 7 was added to the system, then 60.8g of potassium tert-butoxide was added in portions at room temperature, after the addition, 40g of the compound VI was added in one portion, and the mixture was heated to raise the temperature and reacted at 80. + -. 5 ℃ for 3 hours with heat preservation. Sampling HPLC till the compound VI finishes the reaction (sampling once every 1 h), cooling to room temperature, transferring the reaction liquid to a 5L three-necked bottle, adding 1.6L of purified water into the system, adjusting the pH to 4 by using 1N hydrochloric acid, adding 1.6L of a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol 10:1) for extraction, collecting an organic phase, extracting an aqueous phase for 2 times and 1.6L times by using a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol 10:1), combining the organic phases, drying by using anhydrous sodium sulfate, and concentrating to be dry to obtain a crude compound VII. The crude compound VII thus obtained was put into a 1L three-necked flask, followed by addition of 600ml of ethyl acetate, heating and refluxing for 1 hour, cooling to room temperature, and suction filtration to obtain compound VII (off-white solid, 55.2g, yield 81.5%).

Example 11 preparation of amino protected impurity J (Compound VII)

600ml of anhydrous DMF was added to a 2L three-necked flask, stirring was started, 56.6g of the compound V obtained in example 8 was added to the system, then 60.8g of potassium tert-butoxide was added in portions at room temperature, after the addition, 40g of the compound VI was added in one portion, and the mixture was heated to raise the temperature and reacted at 80. + -. 5 ℃ for 3 hours with heat preservation. Sampling HPLC till the compound VI finishes the reaction (sampling once every 1 h), cooling to room temperature, transferring the reaction liquid to a 5L three-necked bottle, adding 1.6L of purified water into the system, adjusting the pH to 4 by using 1N hydrochloric acid, adding 1.6L of a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol 10:1) for extraction, collecting an organic phase, extracting an aqueous phase for 2 times and 1.6L times by using a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol 10:1), combining the organic phases, drying by using anhydrous sodium sulfate, and concentrating to be dry to obtain a crude compound VII. The crude compound VII thus obtained was put into a 1L three-necked flask, followed by addition of 600ml of ethyl acetate, heating and refluxing for 1 hour, cooling to room temperature, and suction filtration to obtain compound VII (off-white solid, 61.7g, yield 82.3%).

Example 12 preparation of amino protected impurity J (Compound VII)

600ml of anhydrous DMF was added to a 2L three-necked flask, stirring was started, 74.5g of the compound V obtained in example 9 was added to the system, then 60.8g of potassium tert-butoxide was added in portions at room temperature, after the addition, 40g of the compound VI was added in one portion, and the mixture was heated to raise the temperature and reacted at 80. + -. 5 ℃ for 3 hours with heat preservation. Sampling HPLC till the compound VI finishes the reaction (sampling once every 1 h), cooling to room temperature, transferring the reaction liquid to a 5L three-necked bottle, adding 1.6L of purified water into the system, adjusting the pH to 4 by using 1N hydrochloric acid, adding 1.6L of a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol 10:1) for extraction, collecting an organic phase, extracting an aqueous phase for 2 times and 1.6L times by using a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol 10:1), combining the organic phases, drying by using anhydrous sodium sulfate, and concentrating to be dry to obtain a crude compound VII. The crude compound VII thus obtained was put into a 1L three-necked flask, followed by addition of 600ml of ethyl acetate, heating and refluxing for 1 hour, cooling to room temperature, and suction filtration to obtain compound VII (off-white solid, 71.1g, yield 81.8%).

Example 13 preparation of impurity J (Compound I)

40g of the compound VII prepared in example 10 and 300ml of 6N hydrochloric acid were put into a 1L three-necked flask and stirred at room temperature overnight. Concentrating to dryness to obtain crude product. The crude product was recrystallized from 400 aqueous methanol (methanol: water ═ 1:1) to give 20g of the final product in 62.5% yield.¹H-NMR(DMSO-d₆,400 MHz)δ14.54(1H，s)，δ8.77(1H，s)，δ7.92/7.94(4H，m)，7.02(1H， s)，δ6.91(1H，s)，6.30(1H，s)，δ4.20/4.23(1H，m)δ3.35(3H，s)，δ2.84/2.87(2H，m)、2.56/2.60(2H，m)，1.84/1.92(2H，m)，1.18/1.20 (4H，m)；m/z：400.3。

Example 14 preparation of impurity J (Compound I)

44.3g of the compound VII produced in example 11, 300ml of 40% hydrobromic acid and 20g of phenol were charged in a 1L three-necked flask and stirred at room temperature overnight. Concentrating to dryness to obtain crude product. The crude product was recrystallized from 400 aqueous methanol (methanol: water ═ 1:1) to give 21g of the final product in 65.7% yield.¹H-NMR (DMSO-d₆,400MHz)δ14.54(1H，s)，δ8.77(1H，s)，δ7.92/7.94(4H， m)，7.02(1H，s)，δ6.91(1H，s)，6.30(1H，s)，δ4.20/4.23(1H，m) δ3.35(3H，s)，δ2.84/2.87(2H，m)、2.56/2.60(2H，m)，1.84/1.92(2H， m)，1.18/1.20(4H，m)；m/z：400.3。

Example 15 preparation of impurity J (Compound I)

51.3g of the compound VII prepared in example 12 and 300ml of glacial acetic acid were introduced into a 1L three-necked flask and refluxed for 1 h. Cooling to room temperature, crystallizing overnight, filtering, discarding filter cake, and concentrating the filtrate to dryness to obtain crude product. The crude product was recrystallized from 400 aqueous ethanol (ethanol: water ═ 1:1) to give 20.5g of final product in 64.2% yield.¹H-NMR(DMSO-d₆,400MHz)δ14.54(1H，s)，δ8.77 (1H，s)，δ7.92/7.94(4H，m)，7.02(1H，s)，δ6.91(1H，s)，6.30(1H， s)，δ4.20/4.23(1H，m)δ3.35(3H，s)，δ2.84/2.87(2H，m)、2.56/2.60 (2H，m)，1.84/1.92(2H，m)，1.18/1.20(4H，m)；m/z：400.3。

Example 16 application of Moxifloxacin degradation impurity J as impurity reference substance in detecting Moxifloxacin hydrochloride related substances

The instrument equipment comprises: an Agilent high performance liquid chromatograph, a chromatographic column: shimadzu Inertsil Ph column (4.6 mm. times.250 mm. times.5 μm).

Chromatographic conditions are as follows: mobile phase A- - -buffer salt [ taking 0.50g tetrabutylammonium hydrogen sulfate and 1.0g potassium dihydrogen phosphate, adding 2ml phosphoric acid, adding water, stirring for dissolving and diluting to 1000ml ]; mobile phase B — methanol; gradient elution is adopted; detection wavelength: 293 nm; column temperature: 40 ℃; flow rate: 1.0 ml/min; sample introduction amount: 10 ul.

Preparing a diluent: dissolving 0.50g of tetrabutylammonium hydrogen sulfate and 1.0g of potassium dihydrogen phosphate in 500ml of water, adding 2ml of phosphoric acid and 0.050g of anhydrous sodium sulfite, stirring for dissolving, adding water for diluting to 1000ml, and filtering with a 0.45um membrane.

Elution procedure:

the experimental method comprises the following steps: moxifloxacin dihydrochloride photodegradation impurity J (i.e., the product prepared in example 13) was dissolved in the diluent to prepare a solution containing 0.1mg per 1ml, which was used as a control solution, and analyzed by sample injection under the above conditions, and a chromatogram was recorded (retention time of impurity J was 32.580min, relative peak area was 99.57%).

Dissolving moxifloxacin hydrochloride in a diluent to prepare a solution containing 1mg per 1ml, taking the solution as a test solution, carrying out sample injection analysis according to the conditions, and recording a chromatogram (the retention time of the impurity J is 32.601min, the relative peak area is 0.02%, the retention time of the moxifloxacin hydrochloride is 18.337min, and the relative peak area is 99.85%).

And (3) test results: the moxifloxacin hydrochloride impurity J prepared in example 13 is a main impurity in a moxifloxacin hydrochloride photodegradation product, and under the liquid phase condition, a main peak and each impurity peak can be completely separated, so that the method is an optimal condition for detecting moxifloxacin hydrochloride photodegradation impurities.

Comparative example 1

1) Adding compound VIII (1eq), compound V (3eq) and TEA (4eq) to DMF;

2) the reaction is heated to 60 ℃ and is carried out overnight, and HPLC shows that most of the compound is compound VIII;

note: no product was formed when the solvents were acetonitrile and DMF and the bases were TEA, DBU and potassium carbonate.

Comparative example 2

1) Firstly, synthesizing a compound IX, then adding a compound V (3eq) into DMF, adding NaH (3eq) in batches at room temperature, and then continuing stirring for 20 min;

2) adding a compound IX (1eq), heating to 80 ℃ for reaction, and treating by HPLC to obtain a compound X after the reaction of the raw materials is finished;

3) the compound X was added to 5N sodium hydroxide and the reaction was warmed to reflux, HPLC showed that the reaction was very complex and difficult to separate.

Claims

1. A preparation method of moxifloxacin hydrochloride degradation impurity J comprises the following steps:

(1) pyrrole-3-formaldehyde, i.e. compound II, and triphenyl acetonitrile based quaternary phosphonium salt, i.e. XPh₃PCH₂CN is subjected to Wittig reaction in a reaction solvent under an alkaline condition to prepare pyrrole-3-acrylonitrile, namely a compound III, and the triphenyl acetonitrile based quaternary phosphonium salt, namely XPh₃PCH₂The anion X in CN is selected from F^-、Cl^-、Br^-、I^-、OH^-、SCN^-、(CO₃ ^2-)_0.5、HCO₃ ^-、BF₄ ^-、PF₆ ^-、(HPO₄ ^2-)_0.5、H₂PO₄ ^-、(SO₄ ^2-)_0.5、HSO₄ ^-、C₁-C₆One or a mixture of more of the alkanoic acid anions;

2. The process according to claim 1, wherein in the step (1), XPh is the triphenylacetonitrile-based quaternary phosphonium salt₃PCH₂The anion X in CN is Cl^-、Br^-、I^-、OH^-、BF₄ ^-、PF₆ ^-One or a mixture of several.

3. The process according to claim 2, wherein in the step (1), XPh is the triphenylacetonitrile-based quaternary phosphonium salt₃PCH₂The anion X in CN is Cl^-、Br^-、I^-、BF₄ ^-One kind of (1).

4. The production method according to claim 1, wherein, in the step (1),

the reaction solvent is chain ether with 3-10 carbon atoms, cyclic ether with 3-10 carbon atoms, ester with total carbon atoms of 3-8 formed by alkanoic acid and alkanol, and C₁-C₆A monohalogenated or polyhalogenated hydrocarbon of C₂-C₄Alkyl nitriles of₁-C₅One or a mixture of more of alkanol, benzene or toluene, amide solvents and dimethyl sulfoxide; the amide solvent is selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone or N, N-dimethylacetamide.

5. The method according to claim 4, wherein the reaction solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethyl acetate, dichloromethane, methanol, ethanol, and toluene.

6. The process according to claim 5, wherein the reaction solvent is toluene.

7. The method according to claim 4, wherein the ratio of the volume of the reaction solvent added to the weight of the compound II is 2.0 to 30.0 mL/g.

8. The method according to claim 7, wherein the ratio of the volume of the reaction solvent added to the weight of the compound II is 11.0 to 13.0 mL/g.

9. The process according to claim 4, wherein the reaction temperature is 0 to 120 ℃.

10. The process according to claim 9, wherein the reaction temperature is 80 to 90 ℃.

11. The production method according to claim 1, wherein, in the step (1),

the alkaline condition is to add inorganic base, organic base or the mixture of the inorganic base and the organic base; the inorganic base is selected from MH, MR1, MOH, MOR2, M₂CO₃、M₃PO₄、M₂HPO₄、MHCO₃One or a mixture of several of them; wherein MH, MR1, MOH, MOR2, M₂CO₃、M₃PO₄、M₂HPO₄、MHCO₃M in (1) is selected from Li, Na, K, Rb, Cs and Mg_1/2、Ca_1/2、Sr_1/2、Ba_1/2One or a mixture of several of them; r1 in MR1 is selected from C₁-C₄One or a mixture of more of alkyl and phenyl; r2 in MOR2 is selected from C₁-C₅Alkyl groups of (a); the organic alkali is selected from one or a mixture of more of guanidine, amidine and tetraalkylammonium hydroxide with the total number of carbon atoms of 4-24; the guanidine is selected from one or more of tetramethyl guanidine or tetraethyl guanidine; the amidines are selected from 1, 5-diazabicyclo [4.3.0]Non-5-ene or 1, 8-diazabicyclo [5.4.0]One or more of undec-7-enes.

12. The process according to claim 11, wherein the inorganic base is selected from MH, MR1, MOH, MOR2, M₂CO₃。

13. The process according to claim 11, wherein the inorganic base is selected from the group consisting of sodium hydride, lithium hydride, butyllithium, phenyllithium, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, and cesium carbonate.

14. The method according to claim 13, wherein the inorganic base is selected from the group consisting of sodium hydride, lithium hydride, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.

15. The method of claim 11, wherein the organic base is selected from tetramethylguanidine, DBU, tetrabutylammonium hydroxide.

16. The production method according to claim 1, wherein, in the step (2),

the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond in compound III is carried out either in a "step-wise process" or in a "one-pot process"; when the process is carried out in a stepwise manner, the C ≡ C double bond may be reduced first, or the C ≡ N triple bond may be reduced first.

17. The process according to claim 16, wherein in step (2), the reduction of the C ═ C double bond and the reduction of the C ≡ N triple bond in compound III are carried out in "stepwise manner".

18. The process according to claim 16, wherein in step (2), when the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond in the compound III are carried out in a stepwise manner, the C ≡ C double bond is reduced first.

19. The production method according to claim 16, wherein in the step (2),

when the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond in compound III are carried out in steps, the reduction of the C ≡ C double bond is by transition metal-catalyzed hydrogenation of hydrogen or transfer hydrogenation with the addition of a "hydrogen source" using a transition metal catalyst selected from the group consisting of metal Pd, metal Pt, metal Ru, metal Ni, PtO₂One or a mixture of more of compounds of 0-2 valence metal Pd and compounds of 0-3 valence metal Ru or a supported form thereof; the hydrogen source used for transfer hydrogenation is one or a mixture of several of formic acid, formate, cyclohexene and 1, 4-cyclohexadiene.

20. The process according to claim 19, wherein the transition metal catalyst is selected from the group consisting of Pd/C, Raney Ni, PtO₂、Pd(OH)₂/C、[Ru(PPh₃)₄]Cl₃One kind of (1).

21. The production process according to claim 19, wherein the reaction solvent used for the reduction of the C ═ C double bond is selected from the group consisting of chain ethers having 3 to 10 carbon atoms, cyclic ethers having 3 to 10 carbon atoms, esters having 3 to 8 carbon atoms in total formed from alkanoic acids and alkanols, C ═ C double bonds, and C₁-C₆A monohalogenated or polyhalogenated hydrocarbon of C₂-C₄Alkyl nitriles of₁-C₅One or a mixture of more of alkanol, benzene or toluene.

22. The preparation method according to claim 21, wherein the reaction solvent used for the reduction of the C ═ C double bond is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethyl acetate, dichloromethane, methanol, ethanol and toluene.

23. The production method according to claim 22, wherein a reaction solvent used for the reduction of the C ═ C double bond is methanol.

24. The production method according to claim 19, wherein the temperature of the reduction reaction of the C ═ C double bond is 0 to 60 ℃.

25. The production method according to claim 24, wherein the temperature of the reduction reaction of the C ═ C double bond is 25 ± 5 ℃.

26. The production method according to claim 19, wherein the reduction of the C ═ C double bond is carried out in a solvent, and the mass ratio of the volume of the solvent used to the compound III is 3.0 to 20.0 mL/g.

27. The preparation process as claimed in claim 26, wherein the ratio of the volume of the solvent used to the mass of the compound III is 6.0 to 8.0 mL/g.

28. The production method according to claim 16, wherein, in the step (2),

when the compound isIn III, the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond are carried out step by step, and the reduction condition of the C ≡ N triple bond is selected from metal hydride, nonmetal hydride and Raney nickel/H₂、Pt/H₂、PtO₂/H₂Or Ru/H₂One or a combination of several of (a); the metal hydride is selected from MBH₄Or MALH₄One or a mixture of several, MBH₄、MAlH₄M in (1) is selected from Li, Na or K; the non-metal hydride is borane or borane with incompletely substituted alkyl; the alkyl incompletely substituted borane is selected from one or more of methyl borane, dimethyl borane and the like.

29. The production process as claimed in claim 28, wherein, in the step (2), when the reduction of the C ≡ C double bond and the reduction of the C ≡ N triple bond in the compound III are carried out stepwise, the reduction conditions of the C ≡ N triple bond are separately using a metal hydride or a non-metal hydride.

30. The method of claim 28, wherein the metal hydride is selected from the group consisting of LiAlH₄、LiBH₄、NaBH₄One kind of (1).

31. The method of claim 28, wherein the non-metal hydride is borane.

32. The process as claimed in claim 28, wherein the reduction of the triple bond of C.ident.N is carried out in a reaction solvent selected from one or more of a chain ether having 3 to 10 carbon atoms, a cyclic ether having 3 to 10 carbon atoms, benzene or an alkyl-substituted benzene.

33. The process of claim 32, wherein the solvent is selected from the group consisting of ethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, and toluene.

34. The process of claim 33, wherein the reaction solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, and toluene.

35. The production process as claimed in claim 28, wherein the temperature of the reduction reaction of the C.ident.N triple bond is 0 to 65 ℃.

36. The production process as claimed in claim 35, wherein the temperature of the reduction reaction of the C.ident.N triple bond is 65. + -. 5 ℃.

37. The production process as claimed in claim 28, wherein the mass ratio of the volume of the solvent used for the reduction reaction of the C.ident.N triple bond to the compound III is 5.0 to 30.0 mL/g.

38. The production process as claimed in claim 37, wherein the mass ratio of the volume of the solvent used for the reduction reaction of the C.ident.N triple bond to the compound III is 15.0 to 18.0 mL/g.

39. The production method according to claim 16, wherein, in the step (2),

when the reduction of the C ≡ C double bond and the C ≡ N triple bond "one-pot" in compound III is carried out, the reduction method used is a high-pressure hydrogen hydrogenation reaction catalyzed by a transition metal selected from the group consisting of metal Pd, metal Pt, metal Ru, metal Ni, PtO, and the like₂One or a mixture of more of compounds of 0-2 valence metal Pd and compounds of 0-3 valence metal Ru or a supported form thereof.

40. The method of claim 39, wherein the transition metal catalyst is selected from the group consisting of Pd/C, Raney Ni, PtO₂、Pd(OH)₂/C、[Ru(PPh₃)₄]Cl₃One kind of (1).

41. The process according to claim 39, wherein the reduction is carried out in a solvent selected from the group consisting of a chain ether having 3 to 10 carbon atoms and a carbon atomCyclic ethers having a sub-number of 3-10, C₁-C₅One or a mixture of more of alkanol and amide solvents; the amide solvent is selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone or N, N-dimethylacetamide.

42. The method according to claim 41, wherein the solvent is one selected from methanol, ethanol and tetrahydrofuran.

43. The method of claim 39, wherein the ratio of the volume of solvent added to the weight of compound III is 4.0-15.0 mL/g.

44. The method of claim 43, wherein the ratio of the volume of solvent added to the weight of compound III is 6.0-10.0 mL/g.

45. The method according to claim 39, wherein the pressure of the high-pressure hydrogen gas is 2 to 70 atmospheres.

46. The method according to claim 45, wherein the pressure of the high-pressure hydrogen gas is 5 to 20 atmospheres.

47. The production method according to claim 39, wherein the temperature of the reduction reaction is 0 to 120 ℃.

48. The production method according to claim 47, wherein the temperature of the reduction reaction is 80 to 90 ℃.

49. The production method according to any one of claims 1 to 48, wherein the amino-protecting group Q in step (3) is selected from R₃-O-C(O)-、C₁-C₆Alkanoyl and benzyl; wherein R is₃R in-O-C (O) -₃Is selected from C₁-C₆Alkyl groups of (a); the benzyl is selected from benzyl, p-methoxybenzyl, benzhydryl, trityl or2, 4-dimethoxylOne of the benzylic groups.

50. The method of claim 49, wherein the base in step (4) is selected from the group consisting of MOH, MOR4, M₂CO₃MH, guanidine, amidine, one or more of tetraalkyl ammonium hydroxide with 4-24 carbon atoms in total; MOH, MOR4, M₂CO₃、M₃PO₄、M₂HPO₄M in (1) is selected from Li, Na, K, Rb, Cs and Mg_1/2、Ca_1/2、Sr_1/2、Ba_1/2(ii) a R4 in MOR4 is selected from C₁-C₅Alkyl groups of (a); the guanidine is selected from one or more of tetramethyl guanidine or tetraethyl guanidine; the amidines are selected from 1, 5-diazabicyclo [4.3.0]Non-5-ene or 1, 8-diazabicyclo [5.4.0]One or more of undec-7-enes.

51. The method of claim 50, wherein the base is NaOH or Na₂CO₃Sodium methoxide, sodium ethoxide, potassium tert-butoxide, NaH, tetrabutylammonium hydroxide, tetramethylguanidine or DBU.

52. The method of claim 50, wherein step (4) is performed in a reaction solvent selected from one or more of DMF, DMAC, DMSO.

53. The process according to claim 50, wherein the reaction temperature is selected from the range of 0 to 100 ℃.

54. The process according to claim 50, wherein the protecting group removing means in the step (5) is selected from the group consisting of catalytic hydrogenolysis, acidolysis or alkaline hydrolysis.