CN108101942A - Half fumaric acid tenofovir Chinese mugwort draws the synthetic method of potential impurity in the production of phenol amine - Google Patents
Half fumaric acid tenofovir Chinese mugwort draws the synthetic method of potential impurity in the production of phenol amine Download PDFInfo
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
It ends the invention discloses half fumaric acid tenofovir and draws the preparation method of potential impurity and degradation impurity in phenol amine production technology.The impurity spectrogram that half fumaric acid tenofovir Chinese mugwort draws phenol amine is listed, directive function is played to improving production technology, improving product internal control quality.
Description
Technical field
It ends the present invention relates to a kind of half fumaric acid tenofovir and draws the synthetic method of potential impurity in the production of phenol amine.
Background technology
Tenofovir Chinese mugwort draws the DNA that phenol amine (tenofovir alafenamide, TAF, GS-7340) is RNA dependences
Poly enzyme inhibitor is the oral prodrugs of tenofovir (tenofovir, TFV).Similar to tenofovir disoproxil, TAF is in the cell
TFV is converted into, is currently used primarily in treatment AIDS, and good Anti-HBV activity curative effect is shown in III clinical trial phase.Because of it
Clinical administration dosage is far below TDF, reduces serious adverse reaction caused by long-term use of TDF significantly, can improve renal function
It with bone security parameter, and is had an optimistic view of extensively, the prospect of long-term or even lifelong AntiHIV1 RT activity should not be underestimated.
According to Birkus et al., 2016.Intracellular Activation of Tenofovir
Alafenamide and the Effect of Viral and Host Protease Inhibitors.Antimicrob
Agents Chemother 60:316-322 and A.S.RAY ET AL., 2016.Tenofovir alafenamide:A
novel prodrug of tenofovir for the treatment of Human Immunodeficiency
Virus.Antiviral Research 125:The intracellular generation for reporting tenofovir Chinese mugwort and drawing phenol amine of two documents of 63-70
It apologizes for having done sth. wrong journey.Tenofovir Chinese mugwort draws the endocellular metabolism procedure chart of phenol amine as shown in Figure 1.
Two documents elaborate the mechanism of action of TAF, and correlative study shows in peripheral blood mononuclear cells (PBMCs),
The high expression of lysosomal protein enzyme A (CatA), catalysis TAF are converted into TFV-Ala, and TAF is in resting stage PBMCs than activation
Conversion process is faster in PBMCs.And in liver cell, TAF is converted into the process of TFV-Ala, is driven by carboxy-lesterase 1 (CES 1)
It is dynamic.TFV-Ala is hydrolyzed into TFV under lysosomal acid environment.Then, TFV is in the effect of adenosine acid kinase (AMP kinases)
Under, phosphoric acid turns to TFVp.Finally under the action of ndp kinase, continue phosphoric acid and turn to TFVpp (TFV-DP), TAF is entirely transformed
Journey is shown in Fig. 1.TAF metabolic process generations in the cell TAF-impurity A, TAF-impurity C and TAF- in document
Tri- metabolism impurity of impurity F, have not yet to see document report so far to the degradation pathway and preparation method of its impurity at present.
It is ended according to tenofovir and the chemical structural formula of phenol amine is drawn to derive degradation process (see Fig. 2).Tenofovir Chinese mugwort draws phenol amine
Building-up process in generate side reaction impurity spectrogram (see Fig. 3).
Fumaric acid tenofovir Chinese mugwort is reported in CN201510943798 and draws phenol three impurity of amine：Tenofovir Chinese mugwort draws phenol amine
Isopropyl ester impurity (TAF-impurity H), tenofovir Chinese mugwort draws phenol amine diphenyl ester impurity (TAF-impurity I), for promise good fortune
The synthetic method of Wei Aila phenol amine diamides impurity (TAF-impurity J), but to TAF-impurity A~F impurity
Route of synthesis and preparation method have not yet to see document report so far.
The content of the invention
It ends the object of the present invention is to provide half fumaric acid tenofovir and draws potential impurity in phenol amine production technology and degrade miscellaneous
The preparation method of matter.The present invention has listed the impurity spectrogram that half fumaric acid tenofovir Chinese mugwort draws phenol amine, to improving production technology, carrying
High product internal control quality plays directive function.
The preparation method of TAF-impurity A shown in formula A provided by the invention, comprises the following steps：
In alkaline conditions, make Formulas I compound represented that reaction be hydrolyzed, obtain formula A compounds represented.
In Formulas I, R be selected from it is following any one：Methyl, ethyl, isopropyl, tertiary butyl, to nitrobenzyloxycarbonyl, benzyloxy carbonyl
Base and t-Butyldimethylsilyl, preferably tertiary butyl.
Wherein, it is described reaction carry out in a solvent, the solvent be selected from it is following any one：Methanol, ethyl alcohol, acetic acid second
Ester, tetrahydrofuran, dichloromethane and acetonitrile etc., preferably tetrahydrofuran.
The alkaline condition is provided by base reagent, and the base reagent is selected from inorganic base or organic base, and the inorganic base is selected from
Lower at least one：Sodium hydroxide, potassium hydroxide and lithium hydroxide etc., the organic metal alkali are selected from lower at least one：Sodium methoxide,
Sodium ethoxide, potassium tert-butoxide, n-BuLi and two (trimethyl silicon substrate) Sodamides etc., the base reagent preferably two (trimethyl silicon substrate)
Sodamide.
The preparation method of TAF-impurity B shown in formula B provided by the invention, comprises the following steps：
1) Formula II compound represented is made first to carry out acylation reaction with acylating agent, then again by obtained chloro thing and formula
III compounds represented carry out esterification, obtain IV compound represented of formula；
Wherein, R is selected from any one following group in formula III：TMS (trim,ethylchlorosilane), TBS (fert-butyidimethylsilyls
Silane), Cbz (benzyloxycarbonyl group), Boc (tertbutyloxycarbonyl), PNZ (formic acid is to p-Nitrobenzyl), Fmoc (tablet held before the breast by officials methoxycarbonyl group) etc.,
It is preferred that Cbz；R2Selected from any one following group：Methyl, ethyl, isopropyl, tertiary butyl and TBS etc.；
The same formula III of the definition of R in formula IV；
2) hydrogenation is carried out to IV compound represented of formula, obtains formula B compounds represented.
Wherein, acylating agent described in step 1) may be selected from it is following any one：Thionyl chloride, phosphorus trichloride, tosyl
Chlorine and Cyanuric Chloride.
The Formula II compound represented and the molar ratio of acylating agent are 1：1-4.
The reaction condition of the acylation reaction is：When 60~90 DEG C of reaction 12-48 are small.
The molar ratio of the chloro thing and compound shown in formula III is 1：1-3.
DBU (11 carbon -7- alkene of 1,8- diazabicylos) is additionally added in the esterification.
The catalyst of hydrogenation described in step 2) is palladium charcoal, and the reaction condition of the hydrogenation is：Reaction temperature
For room temperature (15-25 DEG C), when reaction time 1-4 is small, reaction pressure 1-10Mpa Hydrogen Vapor Pressures, preferably 4Mpa.
The hydrogenation carries out in a solvent, the solvent be selected from it is following any one：Ethyl acetate, tetrahydrofuran,
Dichloromethane and acetonitrile etc., preferably tetrahydrofuran.
The preparation method of TAF-impurity C shown in formula C provided by the invention, comprises the following steps：
(R) -9- (2- phosphate methoxies propyl)-adenine (tenofovir) shown in Formula V is made to be acylated with acylating agent
Then amide reaction occurs with l-Alanine isopropyl ester, obtains the TAF-impurity C shown in formula C, i.e. 9- again for reaction
[(R) -2- [[[[1- (isopropoxy carbonyl) ethyl] amino] phosphoric acid] methoxyl group] propyl] adenine.
Wherein, the acylating agent be selected from it is following any one：Thionyl chloride, thionyl chloride, phosphorus trichloride, tosyl
Chlorine, Cyanuric Chloride etc..The reaction condition of the acylation reaction is：When 60~90 DEG C of reaction 12-48 are small.
The Formula V compound represented and the molar ratio of acylating agent are 1：1-4.
The acylation reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane, tetrahydrochysene
Furans etc., preferably toluene.
The amide reaction carries out in alkaline conditions, and the alkaline condition is supplied by any one following alkali carries：Triethylamine,
DIPEA, diethylamine etc., preferably triethylamine.The reaction condition of amide reaction is：When -15~5 DEG C of reaction 2-10 are small.It is described
Amide reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane, tetrahydrofuran etc., preferably first
Benzene.
The preparation method of TAF-impurity D shown in formula D provided by the invention, comprises the following steps：
TAF-impurity C shown in formula C occur with formula III compound represented (i.e. protecting group aminopropan urethane)
Esterification obtains VI compound represented of formula, and then deprotection obtains the TAF-impurity D shown in formula D, i.e. 9-
[(R) -2- [[(S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] [(amino-ethyl) carbonyl] phosphinyl] methoxyl group] third
Base] adenine；
Wherein, the R group in formula VI is selected from any one following group：TMS (trim,ethylchlorosilane), TBS (tertiary butyl two
Methyl-monosilane), Cbz (benzyloxycarbonyl group), Boc (tertbutyloxycarbonyl), PNZ (formic acid is to p-Nitrobenzyl), Fmoc (tablet held before the breast by officials methoxy carbonyl
Base), AOC (allyloxycarbonyl) etc., preferably Cbz.
The preparation method of TAF-impurity E shown in formula E provided by the invention, comprises the following steps：
In alkaline conditions, hydrolysis occurs for the TAF-impurity D shown in formula D, obtains the TAF- shown in formula E
Impurity E, i.e. 9- [(R) -2- [[(S)-[[(S) -1- propionic acid] amino] [(amino-ethyl) carbonyl] phosphinyl] methoxyl group]
Propyl] adenine.
The hydrolysis carries out in a solvent, the solvent be selected from it is following any one：Acetonitrile, methanol, ethyl alcohol, tetrahydrochysene
Furans, dichloromethane, ethyl acetate, toluene etc., preferably acetonitrile.
The alkaline condition is provided by base reagent, and the base reagent is selected from inorganic base or organic base, and the inorganic base is selected from
Lower at least one：Sodium hydroxide, potassium hydroxide and lithium hydroxide etc., the organic metal alkali are selected from lower at least one：Sodium methoxide,
Sodium ethoxide, potassium tert-butoxide, n-BuLi and two (trimethyl silicon substrate) Sodamides etc., the preferred sodium hydroxide of base reagent.
The preparation method of TAF-impurity F shown in formula F provided by the invention, comprises the following steps：
TAF-impurity C shown in formula C are reacted with trifluoroacetic acid, obtain the TAF-impurity shown in formula F
F。
The reaction carries out in a solvent, the solvent be selected from it is following any one：Methanol, ethyl alcohol, tetrahydrofuran, dichloro
Methane, ethyl acetate, toluene etc., preferably methanol.
The reaction condition of the reaction is：When room temperature reaction 2-10 is small.
The present invention has been successfully prepared out purer half fumaric acid tenofovir Chinese mugwort and has drawn potential impurity in phenol amine production technology
And degradation impurity.The impurity spectrogram that half fumaric acid tenofovir Chinese mugwort draws phenol amine is listed, to improving production technology, improving product internal control
Quality plays directive function.
Description of the drawings
Fig. 1 is the endocellular metabolism procedure chart that background section tenofovir Chinese mugwort draws phenol amine.
Fig. 2 is to be ended that the chemical structural formula of phenol amine is drawn to derive degradation process figure according to tenofovir.
Fig. 3 is to generate side reaction impurity spectrogram in the building-up process of tenofovir Chinese mugwort drawing phenol amine.
Fig. 4 is the reacting flow chart that the present invention prepares TAF-impurity A.
Fig. 5 is the reacting flow chart that the present invention prepares TAF-impurity B.
Fig. 6 prepares TAF-impurity C, TAF-impurity D, the reaction process of TAF-impurity E for the present invention
Figure.
Fig. 7 is the reacting flow chart that the present invention prepares TAF-impurity F.
Fig. 8 is the related substance spectrogram that tenofovir Chinese mugwort draws phenol amine；Peak sequence：1. fumaric acid；2. tenofovir；
3.TAF-impurity F；4.TAF-impurity E；5.TAF-impurity A；6.9- [(R) -2- [[(phenoxy group phosphine oxides
Base) methoxyl group] propyl]] adenine；7.TAF-impurity C；8.TAF-impurity D；9.TAF-impurity B；
10.TAF。
Fig. 9 is TAF-impurity A-F mass spectrograms.
Specific embodiment
The method of the present invention is illustrated below by specific embodiment, but the present invention is not limited thereto, it is all at this
All any modification, equivalent and improvement done within the spirit and principle of invention etc., should be included in the protection model of the present invention
Within enclosing.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Embodiment 1, synthesis TAF-impurity A
Tetrahydrofuran 120ml is added in into 500ml reaction bulbs, adds in 9- [(R) -2- [[(S)-[[(S) -1- (tertiary butyl oxygen
Base carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine 10g, it is added dropwise to bis- (trimethyl silicanes of 2mol/L
Base) Sodamide tetrahydrofuran solution, TLC monitoring reactions complete, and reaction is quenched in acetic acid.Be concentrated under reduced pressure tetrahydrofuran, with V bis-
Chloromethanes：V methanol is 2:1 column chromatography purifies, and obtains white solid impurity 9- [(R) -2- [[(S)-[[(S) -1- propionic acid] ammonia
Base] phenoxy group phosphinyl] methoxyl group] propyl] adenine (TAF-impurity A) 6.0g, yield 68%, purity is more than
98%.
Structural identification data：
TAF-impurity A mass spectrometric datas：m/z M+1:435.2[C18H23N6O5P+].
Nuclear magnetic data：H NMR(400MHz,d6-DMSO)
δ10.92(brs,1H),δ8.22(s,1H),δ8.16(s,1H),δ7.36-7.32(t,4H),δ7.18-7.16(t,
1H),
δ7.09-7.07(d,2H),δ4.82(t,1H),δ4.42-4.38(dd,1H),δ4.28-4.23(dd,1H),δ
3.98(m,1H),
δ3.24-3.20(m,2H),δ3.12(t,1H),δ1.14(d,3H),δ1.06(d,3H)
Embodiment 2, synthesis TAF-impurity B
500ml toluene is added in the reaction bulb of 1L, adds in 50g 9- [(R) -2- [[(phenoxy group phosphinyl) methoxies
Base] propyl] adenine is warming up to 90 DEG C of reflux water-dividings until go out without apparent moisture, and it is slowly added dropwise into 30g thionyl chlorides, adds
It when 80 DEG C of reactions 20 of heat preservation are small, is concentrated under reduced pressure until going out without apparent fraction, nitrogen protection, which declines, warms to room temperature addition dichloromethane
200ml, is dispersed with stirring that be transferred to dropping funel for use.
2000ml dichloromethane is added in the reaction bulb of 5L, adds in 100g N- carbobenzyloxy-L-alanine-N- hydroxyls
Base succinimide ester is cooled to -15 DEG C under nitrogen protection, chloro thing is slowly added dropwise, DBU is added dropwise, it is small to add room temperature reaction 20
When.10% biphosphate sodium water solution is added in, saturated nacl aqueous solution stratification, be concentrated under reduced pressure dichloromethane, adds in four
Hydrogen furans and water, 10% palladium charcoal are hydrogenated with 4MPa after completion of the reaction, V n-hexanes：V ethyl acetate=1:2 column chromatography is foamed
Object 9- [(R) -2- [[(S)-[[(S)-(amino-ethyl) carbonyl] phenoxy group phosphinyl] methoxyl group] propyl] adenine (TAF-
Impurity B) 5.5g, yield 10%, purity is more than 95%.
Structural identification data：
TAF-impurity B mass spectrometric datas：m/z M+1:435.2[C18H23N6O5P+].
Nuclear magnetic data：H NMR(400MHz,d6-DMSO)
δ8.26(s,1H),δ8.18(s,1H),δ7.38-7.33(t,4H),δ7.19-7.17(t,1H),δ7.10-7.08
(d,2H),δ 4.86(t,1H),δ4.43-4.39(dd,1H),δ4.29-4.25(dd,1H),δ3.26-3.22(m,2H),δ
3.15(t,1H),δ 3.00-2.95(m,2H),δ1.14(d,3H),δ1.06(d,3H)
Embodiment 3, synthesis TAF-impurity C, TAF-impurity D, TAF-impurity E
500ml toluene is added in the reaction bulb of 1L, 50g tenofovirs is added in and is warming up to 90 DEG C of reflux water-dividings until nothing
Apparent moisture goes out, and is slowly added dropwise into 30g thionyl chlorides, add 80 DEG C of reactions 20 of heat preservation it is small when, be concentrated under reduced pressure until without substantially evaporating
It separates, nitrogen protection, which declines to warm to room temperature, adds in dichloromethane 200ml, is dispersed with stirring for use.
500ml dichloromethane is added in the reaction bulb of 3L, adds in 32g l-Alanine isopropyl ester hydrochlorides and 40g
Saleratus, add in anhydrous sodium sulfate 50g room temperatures dissociate 4 it is small when, filtering is drained, nitrogen protection under be cooled to -15 DEG C, slowly plus
Enter triethylamine and above-mentioned chloro thing, add insulation reaction, TLC monitoring reactions are completed.10% biphosphate sodium water solution is added in,
Saturated nacl aqueous solution stratification, organic phase are dried with 200g anhydrous sodium sulfates, and filtering, 35 DEG C of mother liquor is concentrated under reduced pressure to obtain oily
Object, V dichloromethane：V methanol=2:1 column chromatography obtains faint yellow solid TAF-impurity C, 56.1g, and yield is
80%, purity is more than 98%.
The reaction solution of chloro thing reaction generation TAF-impurity C is taken, adds in 80g N- carbobenzyloxy-L-alanines-N-
Hydroxysuccinimide eater, adds 40 DEG C of insulation reactions, and TLC monitoring reactions are completed.10% biphosphate sodium water solution is added in,
Saturated nacl aqueous solution stratification, organic phase are dried with 50g anhydrous sodium sulfates, and filtering, 35 DEG C of mother liquor is concentrated under reduced pressure to obtain oily
Object crystallizes to obtain white solid with ethyl acetate and normal heptane.Solid adds in tetrahydrofuran and water, 10% palladium charcoal hydrogenation 4MPa
After completion of the reaction, V n-hexanes：V ethyl acetate=1:2 column chromatography obtains foamed TAF-impurity D, 19.5g, yield
For 30%, purity is more than 95%.
TAF-impurity D are added in into acetonitrile dissolving completely, 2N sodium hydroxide hydrolysis, TLC monitoring reactions are completed, and use second
Acetoacetic ester extracts, and abandons ethyl acetate layer.It is extracted in 2N hydrochloric acid with water layer, dichloromethane, V n-hexanes after being concentrated under reduced pressure：V second
Acetoacetic ester=1:2 column chromatography purifying, obtains foamed TAF-impurity E, 10.0g, yield 57%, purity is more than
95%.
Structural identification data：
TAF-impurity C mass spectrometric datas：m/z M+1:401.8[C15H25N6O5P+].
Nuclear magnetic data：H NMR(400MHz,d6-DMSO)
δ11.33(brs,1H),δ8.26(s,1H),δ8.15(s,1H),δ7.09-7.07(d,2H),δ5.88(t,1H),δ
4.82(t,1H),
δ4.42-4.39(dd,1H),δ4.29-4.23(dd,1H),δ3.97(m,1H),δ3.24-3.20(m,2H),δ
3.12(m,1H),
δ1.13(d,9H),δ1.06(d,3H)
TAF-impurity D mass spectrometric datas：m/z M+1:472.3[C18H30N7O6P+].
Nuclear magnetic data：H NMR(400MHz,d6-DMSO)
δ8.26(s,1H),δ8.16(s,1H),δ7.09-7.07(d,2H),δ6.06(t,1H),δ4.90-4.82(m,
2H),
δ4.43-4.35(dd,1H),δ4.31-4.26(dd,1H),δ3.88(m,1H),δ3.26-3.21(m,2H),δ
3.15(t,1H),
δ3.00-2.95(m,2H),δ1.13(d,12H),δ1.06(d,3H)
TAF-impurity E mass spectrometric datas：m/z M+1:430.3[C15H24N7O6P+].
Nuclear magnetic data：H NMR(400MHz,d6-DMSO)
δ11.15(brs,1H),δ8.27(s,1H),δ8.15(s,1H),δ7.10-7.08(d,2H),δ4.85-4.79(m,
2H),
δ4.35-4.31(dd,1H),δ4.30-4.26(dd,1H),δ3.91-3.88(m,1H),δ3.26-3.20(m,
2H),δ 3.16(t,1H),δ3.00-2.95(m,2H),δ1.15(d,6H),δ1.06(d,3H)
Embodiment 4, synthesis TAF-impurity F
TAF-impurity C 10g are added in into methanol and trifluoroacetic acid, when stirring 4 is small after TCL monitoring reactions complete.Three
Reaction is quenched in ethamine, and V dichloromethane is used after being concentrated under reduced pressure：V methanol=1:1 column chromatography purifies, and column chromatography purifies to obtain off-white color
Solid 9- (R) -2- [(1- propionic acid) amino] phosphinyl] methoxyl group] propyl] adenine (TAF-impurity F), 8.1g, production
Rate is 90%, and purity is more than 99%.
Structural identification data：
TAF-impurity F mass spectrometric datas：m/z M+1:359.3[C12H19N6O5P+].
Nuclear magnetic data：H NMR(400MHz,d6-DMSO)
δ11.21(brs,2H),δ8.28(s,1H),δ8.16(s,1H),δ7.11-7.09(d,2H),δ4.90(t,1H),δ
4.42-4.39(dd,1H),δ4.36-4.30(dd,1H),δ3.88(m,1H),δ3.24-3.20(m,2H),δ3.01(m,1H),δ
1.14(d,3H),δ1.06(d,3H)。
Claims (10)
1. the method for the TAF-impurity E shown in formula E, comprises the following steps：
1) make Formula V compound represented that acylation reaction first occur with acylating agent, amide then occurs with l-Alanine isopropyl ester again
Reaction, obtains the TAF-impurity C shown in formula C；
2) with formula III compound represented esterification occurs for the TAF-impurity C shown in formula C, obtains shown in formula VI
Compound, then deprotection obtain the TAF-impurity D shown in formula D；
Wherein, R is selected from any one following group in formula III：Trim,ethylchlorosilane, t-butyldimethyl silane, benzyloxycarbonyl group,
Tertbutyloxycarbonyl, formic acid is to p-Nitrobenzyl, tablet held before the breast by officials methoxycarbonyl group；R in formula III2Selected from any one following group methyl, ethyl,
Isopropyl, tertiary butyl, t-butyldimethyl silane；
The same formula III of the definition of R in formula VI；
3) in alkaline conditions, hydrolysis occurs for the TAF-impurity D shown in formula D, obtains the TAF- shown in formula E
impurity E。
2. according to the method described in claim 1, it is characterized in that：
Acylating agent described in the step 1) be selected from it is following any one：Thionyl chloride, thionyl chloride, phosphorus trichloride, toluene sulphur
Acyl chlorides and Cyanuric Chloride；
The Formula V compound represented and the molar ratio of acylating agent are 1：1-4；
The reaction condition of the acylation reaction is：When 60~90 DEG C of reaction 12-48 are small；
The acylation reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane, tetrahydrofuran,
It is preferred that toluene.
3. method according to claim 1 or 2, it is characterised in that：In the step 1), the amide reaction is in alkaline item
It is carried out under part, the alkaline condition is supplied by any one following alkali carries：Triethylamine, DIPEA, diethylamine, preferably triethylamine；
The reaction condition of amide reaction is：When -15~5 DEG C of reaction 2-10 are small；
Amide reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane and tetrahydrochysene furan
It mutters, preferably toluene.
4. method according to any one of claim 1-3, it is characterised in that：
In the step 3), the hydrolysis carries out in a solvent, the solvent be selected from it is following any one：Acetonitrile, methanol,
Ethyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and toluene, preferably acetonitrile；
The alkaline condition is provided by base reagent, the base reagent be selected from inorganic base or organic base, the inorganic base be selected from down toward
Few one kind：Sodium hydroxide, potassium hydroxide and lithium hydroxide, the organic metal alkali are selected from lower at least one：Sodium methoxide, ethyl alcohol
Sodium, potassium tert-butoxide, n-BuLi and two (trimethyl silicon substrate) Sodamides；The preferred sodium hydroxide of base reagent.
5. the method for the TAF-impurity D shown in formula D, comprises the following steps：
1) make Formula V compound represented that acylation reaction first occur with acylating agent, it is then anti-with L-Ala isopropyl ester generation amide again
Should, obtain the TAF-impurity C shown in formula C；
2) with formula III compound represented esterification occurs for the TAF-impurity C shown in formula C, obtains shown in formula VI
Compound, then deprotection obtain the TAF-impurity D shown in formula D；
Wherein, R is selected from any one following group in formula III：Trim,ethylchlorosilane, t-butyldimethyl silane, benzyloxycarbonyl group,
Tertbutyloxycarbonyl, formic acid is to p-Nitrobenzyl, tablet held before the breast by officials methoxycarbonyl group；R2Selected from any one following group methyl, ethyl, isopropyl,
Tertiary butyl, t-butyldimethyl silane；
The same formula III of the definition of R in formula VI.
6. according to the method described in claim 5, it is characterized in that：In the step 1), the acylating agent is selected from following arbitrary
It is a kind of：Thionyl chloride, thionyl chloride, phosphorus trichloride, toluene sulfochloride and Cyanuric Chloride；
The Formula V compound represented and the molar ratio of acylating agent are 1：1-4；
The reaction condition of the acylation reaction is：When 60~90 DEG C of reaction 12-48 are small；
The acylation reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane, tetrahydrofuran,
It is preferred that toluene.
7. method according to claim 5 or 6, it is characterised in that：In the step 1), the amide reaction is in alkaline item
It is carried out under part, the alkaline condition is supplied by any one following alkali carries：Triethylamine, DIPEA, diethylamine, preferably triethylamine；
The reaction condition of amide reaction is：When -15~5 DEG C of reaction 2-10 are small；
Amide reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane and tetrahydrochysene furan
It mutters, preferably toluene.
8. the method for the TAF-impurity C shown in formula C, comprises the following steps：
Make Formula V compound represented that acylation reaction first occur with acylating agent, it is then anti-with l-Alanine isopropyl ester generation amide again
Should, obtain the TAF-impurity C shown in formula C；
9. according to the method described in claim 8, it is characterized in that：The acylating agent be selected from it is following any one：Thionyl chloride,
Thionyl chloride, phosphorus trichloride, toluene sulfochloride and Cyanuric Chloride；
The Formula V compound represented and the molar ratio of acylating agent are 1：1-4；
The reaction condition of the acylation reaction is：When 60~90 DEG C of reaction 12-48 are small；
The acylation reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane, tetrahydrofuran,
It is preferred that toluene.
10. method according to claim 8 or claim 9, it is characterised in that：The amide reaction carries out in alkaline conditions, institute
Alkaline condition is stated to be supplied by any one following alkali carries：Triethylamine, DIPEA, diethylamine, preferably triethylamine；
The reaction condition of amide reaction is：When -15~5 DEG C of reaction 2-10 are small；
Amide reaction carries out in a solvent, the solvent be selected from it is following any one：Toluene, dichloromethane and tetrahydrochysene furan
It mutters, preferably toluene.
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