CN110204505A - (S) preparation process of -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione - Google Patents
(S) preparation process of -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione Download PDFInfo
- Publication number
- CN110204505A CN110204505A CN201910466728.6A CN201910466728A CN110204505A CN 110204505 A CN110204505 A CN 110204505A CN 201910466728 A CN201910466728 A CN 201910466728A CN 110204505 A CN110204505 A CN 110204505A
- Authority
- CN
- China
- Prior art keywords
- reaction
- valine
- preparation process
- benzyloxycarbonyl group
- oxazolidinedione
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
- C07D263/44—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention provides (S) -3- benzyloxycarbonyl group -4- isopropyls -2, the preparation process of 5- oxazolidinedione, (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione can be used as valganciclovir hydrochloride intermediate, it includes following operation: taking Valine starting material to react with benzyl chloroformate, generates N- benzyloxy-oxo-L-valine；Again with N, N- carbonyl dimidazoles (CDI) react N- benzyloxy-oxo-L-valine, generate (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione.This process of preparing is easy, is easy to purify, process stabilizing is quality controllable, and product yield increases substantially, and does not cause environmental pollution, is suitable for industrial mass production.
Description
Technical field
The present invention relates to the preparation processes of (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione, belong to chemical conjunction
At with production field.
Background technique
Valganciclovir hydrochloride (valganciclovir hydrochloride) (formula 4) is one kind by Roche Holding Ag, Switzerland
The oral anti-cytomegalovirus infection medicine of research and development, paper " the hydrochloric acid figured silk fabrics that Zhao Shikui et al. is delivered in Chinese Journal of Pharmaceuticals
The synthesis of Ganciclovir " describes Ganciclovir derivative N, O- bis- (trityl) Ganciclovir (formula under triethylamine effect
5) a hydroxyl and (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione (formula 3) is condensed, then 2,2,2- tri-
Trityl-protecting group is removed through trifluoroacetic acid in fluoroethanol, then acidified, hydro-reduction obtains valganciclovir hydrochloride.
Currently, the preparation of (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione (formula 3) is divided to two by reaction route 2
Step carries out, step 1: Valine (formula 7) and phosgene or triphosgene obtain (S) -4- isopropyl oxazole -2,5- diketone (formula
6), step 2: (S) -4- isopropyl oxazole -2,5- diketone (formula 6) reacts under alkaline environment with benzyl chloroformate (formula 8) again
To (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione (formula 3).Wherein first step raw material phosgene is high toxicity gas,
And triphosgene also has phosgene generation during the reaction, be easy to cause environmental pollution；The condensation reaction of second step must utilize
In Alkali absorption reaction the hydrogen chloride that generates could driving a reaction carry out, but (S) -4- isopropyl oxazole -2,5- diketone (formula 6) and
(S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione (formula 3) all unstable (S) -3- benzyl that can allow under alkaline environment
Oxygen carbonyl -4- isopropyl -2,5- oxazolidinedione (formula 3) open loop, in reaction in order to reduce the decomposition of raw material and product need -
25 DEG C or less are reacted and can only do acid binding agent using N-methylmorpholine.The report yield of this method can only achieve 50%.Cause this
It is more to walk reaction waste, hardly possible purifying, disadvantage at high cost.
Reaction route:
US 5359086 uses N, and N- carbonyl dimidazoles (formula 9) are cyclizing agent, with N- [1- (S)-carbethoxyl group -3- phenylpropyl alcohol
Base]-l-Alanine be raw material, at reaction temperature -5~0 DEG C prepare N- [1- (S)-ethoxycarbonyl-3-phenylpropyl] third ammonia of-L-
Acid-N- carboxy acid anhydride.
CN106831630A uses N, and N- carbonyl dimidazoles (formula 9) are cyclizing agent, with L- alanine (formula 10), L- junket ammonia
Acid, Pidolidone-γ-Bian ester or L- ε-trifluoroacetyl group-lysine are raw material, generate the third ammonia of L- respectively in a heated condition
Acid-N- ring inner-acid anhydride (formula 11), 5- Bian ester-N- carboxyanhydrides, N- (4- (2,5- dioxo -4- oxazolidinyl) butyl) -
2,2,2- trifluoroacetamide or (4S) -4- [(4- hydroxy phenyl) methyl] -2,5- oxazolidinedione.
But currently, yet there are no above-mentioned reaction for valganciclovir hydrochloride intermediate (S) -3- benzyloxycarbonyl group -4- isopropyl -
The preparation of 2,5- oxazolidinedione (formula 3).
The present invention has found in preliminary experiment early period, if directly using the reaction process of following hypothesis, can not obtain target production
Object.
It is found after carrying out test of many times to experiment condition etc., it is necessary to which heating under neutral alkaline environment on the weak side just can solve
The problem, but (S) -4- isopropyl oxazole -2,5- diketone (formula 6) easy open loop under alkaline environment, and the combination of solvent and weak base
Mode influences yield very big.
Summary of the invention
In order to overcome disadvantage existing in the prior art, the object of the present invention is to provide (S) -3- benzyloxycarbonyl group -4-
The preparation process of isopropyl -2,5- oxazolidinedione reacts the benzyl chloroformate that must just can be carried out under alkaline environment first
It carries out, then allows to alkali labile (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione in neutral alkaline environment on the weak side
Lower preparation.With high security, environmental pollution is small for the program, and operation is easy, and product yield is high, lower production costs, fits
The characteristics of together in industrialized production.
The present invention provides the preparation processes of (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione, it includes such as
Lower operation:
S1. it takes Valine and benzyl chloroformate to react under alkaline condition and generates N- benzyloxy-oxo-L-valine,
Synthetic method includes that Valine is dissolved in sodium hydroxide solution, and Carbobenzoxy Chloride is added dropwise during the reaction or contains chloro-carbonic acid
Isosorbide-5-Nitrae-dioxane solution of Bian ester is reacted under room temperature；
S2. extraction and separation discard organic phase, retain aqueous, adjust aqueous pH value to acidity, reuse reaction dissolvent extraction
It takes, takes organic phase to be transferred in kettle under nitrogen protection environment and mix and cool down with alkaline accelerator, then be added dropwise containing N, N- carbonyl two
The reaction dissolvent of imidazoles reacts 6~14h under neutral alkaline environment on the weak side and reaction temperature, generates and contain (S) -3- benzyloxycarbonyl group -
The reaction dissolvent of 4- isopropyl -2,5- oxazolidinedione.
Neutrality alkaline environment on the weak side of the present invention be relative to solution for calibrated pH meter measures pH=7, when
Reaction solution measurement pH is greater than 7 and had both met neutrality alkaline environment on the weak side of the present invention.
In a specific embodiment of the invention, pH value of solution used in step S2 is 7.3~9.0.
In a specific embodiment of the invention, reaction dissolvent is selected from methylene chloride, tetrahydrofuran, N, N- bis- in step S2
One of methylformamide, formamide, 1,4- dioxane, acetonitrile or two kinds and combination of the above.
In a specific embodiment of the invention, it is preferable that reaction dissolvent is selected from methylene chloride and tetrahydro furan in step S2
It mutters, the combination of N,N-dimethylformamide or the combination of methylene chloride and acetonitrile, N,N-dimethylformamide.
In a specific embodiment of the invention, further, reaction dissolvent selects methylene chloride and tetrahydro in step S2
Furans, n,N-Dimethylformamide combination when, reaction temperature be 0~25 DEG C.
In a specific embodiment of the invention, further, in step S2 reaction dissolvent select methylene chloride and acetonitrile,
When the combination of n,N-Dimethylformamide, reaction temperature is 0~40 DEG C.
In a specific embodiment of the invention, it is preferable that step S3 neutral and alkali promotor be selected from 4-dimethylaminopyridine,
At least one of pyridine, piperidines.
In a specific embodiment of the invention, further, step S3 neutral and alkali promotor selects 4- dimethylamino pyrrole
Pyridine.
In a specific embodiment of the invention, it is preferable that step S3 neutral and alkali promotor and N- benzyloxycarbonyl group-L- figured silk fabrics
The mole dosage ratio of propylhomoserin is (0.05~0.2): 1.
In a specific embodiment of the invention, it is preferable that N- benzyloxycarbonyl group-L- valine and N in step S3, N- carbonyl
The mole dosage ratio of base diimidazole is 1:(1~2).
Preferably, step S2 further includes purification step after completion of the reaction:
Hydrogen chloride tetrahydro furan is added dropwise to the reaction dissolvent of -4- isopropyl -2,5- oxazolidinedione Han (S) -3- benzyloxycarbonyl group
It mutters and solution or Hydrochloride/ethyl acetate or is passed through dry hydrogen chloride gas with the alkaline matter in neutralization reaction liquid,
It allows in whole system last handling process and is maintained in acidic environment, protect product；
It is filtered to remove instead using good solvent is first added into (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
Answer the salt of middle generation, filtrate adds after poor solvent is filtered to remove impurity, precipitates under liquid freezing；
The poor solvent is selected from least one of methyl tertiary butyl ether(MTBE), toluene, n-hexane, petroleum ether；
The good solvent is selected from least one of methylene chloride, ethyl acetate；
The impurity refers to the impure ingredient being mingled in target compound, including but not limited to reacts the by-product of generation
The reaction mass of imidazoles and not fully reacting.
Preferably, step S2 further includes N- benzyloxycarbonyl group-L- valine purification step before using reaction dissolvent extraction:
Aqueous is extracted with reaction dissolvent, it is dry extract layer is taken, then be evaporated under reduced pressure reaction dissolvent, obtains N- benzyloxy-oxo-L-valine；
Or keep aqueous tune acid out brilliant, and it is dry, obtain N- benzyloxy-oxo-L-valine.
Preferably, step S2 further includes organic phase removal step: being washed with saturated common salt after using reaction dissolvent extraction
It after washing, then is dried, filtered with anhydrous sodium sulfate, obtains anhydrous salt-free organic phase.
Based on above-mentioned same principle, the present invention also provides using a-amino acid as Material synthesis N- benzyloxycarbonyl group-alpha-amido
The method of acid-NCA, which is characterized in that it includes the following steps
A-amino acid shown in modus ponens 10,12 compound of the production that reacts under alkaline condition with benzyl chloroformate,
12 compound of separate type again turns to be dissolved in reaction dissolvent in acid condition, merge with alkaline accelerator, with N, N- carbonyl dimidazoles
Reacted under neutral alkaline environment on the weak side and reaction temperature, can 13 compound of production, the a-amino acid includes: sweet ammonia
Acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, serine, tyrosine, cysteine, egg ammonia
Acid, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine.
Of the invention has following technical effect that
Using any in methylene chloride, tetrahydrofuran, N,N-dimethylformamide, formamide, 1,4- dioxane, acetonitrile
When a kind of conduct reaction dissolvent, methylene chloride and tetrahydrofuran, the combination of n,N-Dimethylformamide or methylene chloride and second
The combination of nitrile, n,N-Dimethylformamide, the yield highest of target compound.
When using pyridine or piperidines as alkaline accelerator, the yield of target compound is lower than 4-dimethylaminopyridine
As alkaline accelerator.
The mole dosage ratio of alkaline accelerator and N- benzyloxy-oxo-L-valine is (0.05~0.2): target chemical combination when 1
The yield of object is higher.With the increase of alkaline accelerator dosage, the yield of target product is not improved, when mole dosage is than super
0.2 is crossed, the yield of target product declines instead.
This preparation process first carries out the benzyl chloroformate that must just can be carried out under alkaline environment reaction, then allows to alkali not
Stable (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione is prepared under neutral alkaline environment on the weak side, and technique is whole
Upper highly-safe, environmental pollution is small, and operation is easy, avoids (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidine two
The characteristics of ketone open loop under alkaline environment, product yield is high, lower production costs, is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic spectrum for the white solid that the embodiment of the present invention 1 obtains；
Fig. 2 is the nuclear magnetic spectrum for the white powdery solids that the embodiment of the present invention 2 obtains.
Specific embodiment
Below by way of the form of specific embodiment, above content of the invention is described in further details again.But it does not answer
This is interpreted as to the scope of the above subject matter of the present invention is limited to the following embodiments.It is all to be realized based on above content of the present invention
Technology all belongs to the scope of the present invention.
The synthesis of 1 N- benzyloxy-oxo-L-valine of embodiment
Sodium hydroxide solution 5L, 1.06Kg (10mol) sodium carbonate of Valine 1.17Kg (10mol), 2mol/L is taken to add
Enter in 20L reaction kettle, open stirring, after Valine dissolution completely, solution temperature is down to 0 DEG C hereinafter, instilling containing chloromethane
The Isosorbide-5-Nitrae of acid benzyl ester 2.05Kg (12mol)-dioxane solution 5L, dropwise addition Process liquor temperature are maintained at 20 DEG C and finish hereinafter, dripping,
8h is reacted at room temperature.Reaction is finished, and reaction solution is extracted with methylene chloride 2.5L, discards organic phase, and water phase is cooled to 10 DEG C hereinafter, drop
Enter concentrated hydrochloric acid until pH=2, stir 30min at 10 DEG C, a large amount of white solids are precipitated, filter, filter residue is washed with water, will
White solid is put into vacuum oven dry, obtains white N- benzyloxy-oxo-L-valine 2.35Kg, yield 93.7%,
Purity 99.6% (HPLC), optical value are -4.1 ° (C=2, glacial acetic acid, T=20 DEG C)；Nuclear magnetic spectrum testing result is carried out as schemed
1,1H NMR (400MHz, DMSO) δ 12.59 (s, 1H), 7.50 (d, J=8.5Hz, 1H), 7.41-7.27 (m, 5H), 5.04
(s, 2H), 3.88 (dd, J=8.5,6.0Hz, 1H), 2.05 (dq, J=13.4,6.7Hz, 1H), 0.89 (t, J=6.8Hz,
6H)。
The advantages of the present embodiment method: Isosorbide-5-Nitrae-dioxane, which is added, can allow reaction more complete, reduce benzyl chloroformate
Consumption；It can dry to be directly used in using the product for adjusting acid out to go out after methylene chloride extracting impurities and react in next step, without weighing again
Crystallization purifying.It is directly used in without further purification after adjusting the product being precipitated after acid that drying can directly be extracted with dichloromethane anti-in next step
It answers.
The synthesis of embodiment 2 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
Sodium hydroxide solution 5L, 1.06Kg (10mol) sodium carbonate of Valine 1.17Kg (10mol), 2mol/L is taken to add
Enter in 20L reaction kettle, open stirring, after Valine dissolution completely, solution temperature is down to 0 DEG C hereinafter, instilling containing chloromethane
The Isosorbide-5-Nitrae of acid benzyl ester 2.05Kg (12mol)-dioxane solution 5L, dropwise addition Process liquor temperature are maintained at 20 DEG C and finish hereinafter, dripping,
8h is reacted at room temperature.Reaction is finished, and reaction solution is extracted with methylene chloride 2.5L, discards organic phase, and water phase is cooled to 10 DEG C hereinafter, drop
Enter concentrated hydrochloric acid until pH=2, mixed liquor is extracted 3 times with 3L methylene chloride, merges organic phase, and organic phase is washed with 3L saturated common salt
The dry 12h of rear anhydrous sodium sulfate, filtering are washed, filtrate is transferred in the 20L kettle with nitrogen protection, and 4-dimethylaminopyridine 122g is added
(1mol) after n,N-Dimethylformamide 2L stirs 30min at room temperature, solution temperature is down under 0~5, N is slowly added dropwise, N- carbonyl
Base diimidazole 1.78Kg (11mol) is dissolved in the solution of 4L tetrahydrofuran, be added dropwise Process liquor temperature be maintained at 20 DEG C hereinafter,
Drop finishes, and solution is maintained at 40 DEG C of reaction 5h, and reaction is complete, instill after the hydrogen chloride tetrahydrofuran solution 1L of 10mol/L recycle it is molten
4L methylene chloride is added into residue, is heated to reflux 30min, filters while hot for liquid, and after 15L toluene is added in filtrate, room temperature is stirred
It is filtered after mixing 30min, filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated, and filters, and filter residue is washed with cold toluene,
Vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione 2.39Kg, yield
It is 86.4%, purity 99.3% (HPLC), optical value is+60.4 ° (C=1, tetrahydrofuran, T=25 DEG C)；Carry out nuclear magnetic spectrum
Testing result such as Fig. 2,1H NMR (400MHz, DMSO) δ 7.51-7.32 (m, 5H), 5.40-5.28 (m, 2H), 4.72 (d, J
=3.6Hz, 1H), 2.47-2.37 (m, 1H), 1.07 (d, J=7.1Hz, 3H), 0.85 (d, J=6.9Hz, 3H).
The synthesis of embodiment 3 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
Sodium hydroxide solution 5L, 1.06Kg (10mol) sodium carbonate of Valine 1.17Kg (10mol), 2mol/L is taken to add
Enter in 20L reaction kettle, open stirring, after Valine dissolution completely, solution temperature is down to 0 DEG C hereinafter, instilling containing chloromethane
The Isosorbide-5-Nitrae of acid benzyl ester 2.05Kg (12mol)-dioxane solution 5L, dropwise addition Process liquor temperature are maintained at 20 DEG C and finish hereinafter, dripping,
8h is reacted at room temperature.Reaction is finished, and reaction solution is extracted with methylene chloride 2.5L, discards organic phase, and water phase is cooled to 10 DEG C hereinafter, drop
Enter concentrated hydrochloric acid until pH=2, mixed liquor is extracted 3 times with 3L methylene chloride, merges organic phase, and organic phase is washed with 3L saturated common salt
The dry 12h of rear anhydrous sodium sulfate, filtering are washed, filtrate is transferred in the 20L kettle with nitrogen protection, and 4-dimethylaminopyridine 122g is added
(1mol) after n,N-Dimethylformamide 2L stirs 30min at room temperature, solution temperature is down under 0~5, N is slowly added dropwise, N- carbonyl
Base diimidazole 1.78Kg (11mol) is dissolved in the solution of 4L acetonitrile, and dropwise addition Process liquor temperature is maintained at 20 DEG C and finishes hereinafter, dripping,
Solution is maintained at 40 DEG C of reaction 5h, reaction is finished, solution is recycled after instilling the hydrogen chloride tetrahydrofuran solution 1L of 10mol/L, to
4L methylene chloride is added in residue, is heated to reflux 30min, filters while hot, after 20L methyl tertiary butyl ether(MTBE) is added in filtrate, room
It is filtered after temperature stirring 30min, filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated, and filters, the cold methyl of filter residue
Tertbutyl ether washing, vacuum drying obtain white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
2.36Kg, yield 85.1%, purity 99.2% (HPLC), optical value are+59.8 ° (C=1, tetrahydrofuran, T=25 DEG C)；
The synthesis of embodiment 4 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), N,N-dimethylformamide 1L, tetrahydrofuran 4L, 4- bis-
Methylamino pyridine 31g (0.25mol) is added in the 20L kettle with nitrogen protection, and after stirring 30min at room temperature, solution temperature is dropped
N is slowly added dropwise under to 0~5, N- carbonyl dimidazoles 891g (5.5mol) is dissolved in the solution of 2L tetrahydrofuran, and it is molten that process is added dropwise
Liquid temperature is maintained at 20 DEG C and finishes hereinafter, dripping, and solution is maintained at 20~25 DEG C of reaction 6h, and reaction is finished, and the chlorination of 10mol/L is instilled
Solution is recycled after hydrogen tetrahydrofuran solution 500ml, 2L methylene chloride is added into residue, is heated to reflux 30min, while hot mistake
It filters, after 5L n-hexane is added in filtrate, is filtered after 30min is stirred at room temperature, filtrate is cooled to -10 DEG C and stirs 2h, is precipitated a large amount of
White solid filters, and filter residue is washed with cold methyl tertiary butyl ether(MTBE), and vacuum drying obtains white powdery solids (S) -3- benzyloxy carbonyl
Base -4- isopropyl -2,5- oxazolidinedione 1.22Kg, yield 88.3%, purity 99.5% (HPLC), optical value be+
60.1 ° (C=1, tetrahydrofuran, T=25 DEG C)；
The synthesis of embodiment 5 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), N,N-dimethylformamide 1L, tetrahydrofuran 4L, 4- bis-
Methylamino pyridine 122g (1mol) is added in the 20L kettle with nitrogen protection, and after stirring 30min at room temperature, solution temperature is down to
N is slowly added dropwise under 0~5, N- carbonyl dimidazoles 891g (5.5mol) is dissolved in the solution of 2L tetrahydrofuran, and Process liquor is added dropwise
Temperature is maintained at 20 DEG C and finishes hereinafter, dripping, and solution is maintained at 20~25 DEG C of reaction 6h, and reaction is finished, and the hydrogen chloride of 10mol/L is instilled
Solution is recycled after tetrahydrofuran solution 500ml, 2L ethyl acetate is added into residue, is heated to reflux 30min, filters while hot,
It after 5L petroleum ether is added in filtrate, is filtered after 30min is stirred at room temperature, filtrate is cooled to -10 DEG C and stirs 2h, is precipitated a large amount of white
Color solid filters, and filter residue is washed with cold methyl tertiary butyl ether(MTBE), and vacuum drying obtains white powdery solids (S) -3- benzyloxy carbonyl
Base -4- isopropyl -2,5- oxazolidinedione 1.19Kg, yield 85.9%, purity 99.2% (HPLC), optical value be+
60.3 ° (C=1, tetrahydrofuran, T=25 DEG C)
The synthesis of embodiment 6 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), N,N-dimethylformamide 1L, tetrahydrofuran 4L, 4- bis-
Methylamino pyridine 153g (1.25mol) is added in the 20L kettle with nitrogen protection, after stirring 30min at room temperature, by solution temperature
N is slowly added dropwise under being down to 0~5, N- carbonyl dimidazoles 891g (5.5mol) is dissolved in the solution of 2L tetrahydrofuran, and process is added dropwise
Solution temperature is maintained at 20 DEG C and finishes hereinafter, dripping, and solution is maintained at 20~25 DEG C of reaction 6h, and reaction is finished, and the chlorine of 10mol/L is instilled
Solution is recycled after changing hydrogen tetrahydrofuran solution 500ml, 2L methylene chloride is added into residue, is heated to reflux 30min, while hot mistake
It filters, after 7.5L toluene is added in filtrate, is filtered after 30min is stirred at room temperature, filtrate is cooled to -10 DEG C and stirs 2h, is precipitated a large amount of
White solid filters, and filter residue is washed with cold toluene, and it is different that vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4-
Propyl -2,5- oxazolidinedione 809g, yield 58.4%, purity 98.3% (HPLC), optical value be+62.0 ° (C=1, four
Hydrogen furans, T=25 DEG C)
The synthesis of embodiment 7 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), N,N-dimethylformamide 1L, tetrahydrofuran 4L, pyridine
79g (1mol) is added in the 20L kettle with nitrogen protection, and after stirring 30min at room temperature, solution temperature is down to 0~5 lower slowly drop
Add N, N- carbonyl dimidazoles 1.62Kg (10mol) to be dissolved in the solution of 2L tetrahydrofuran, Process liquor temperature is added dropwise and is maintained at 20
DEG C hereinafter, drop finishes, solution is maintained at 30~40 DEG C of reaction 12h, reaction is complete, and the hydrogen chloride ethyl acetate for instilling 10mol/L is molten
Solution is recycled after liquid 500ml, 2L methylene chloride is added into residue, is heated to reflux 30min, filters while hot, be added in filtrate
It after 10L methyl tertiary butyl ether(MTBE), is filtered after 30min is stirred at room temperature, filtrate is cooled to -10 DEG C and stirs 2h, and it is solid that a large amount of whites are precipitated
Body filters, and filter residue is washed with cold methyl tertiary butyl ether(MTBE), and vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4-
Isopropyl -2,5- oxazolidinedione 0.93Kg, yield 71.7%, purity 99.2% (HPLC), optical value are+61.1 ° of (C=
1, tetrahydrofuran, T=25 DEG C).
The synthesis of embodiment 8 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), N,N-dimethylformamide 1L, tetrahydrofuran 4L, piperidines
85g (1mol) is added in the 20L kettle with nitrogen protection, and after stirring 30min at room temperature, solution temperature is down to 0~5 lower slowly drop
Add N, N- carbonyl dimidazoles 1.22Kg (7.5mol) to be dissolved in the solution of 2L tetrahydrofuran, Process liquor temperature is added dropwise and is maintained at
20 DEG C are finished hereinafter, dripping, and solution is maintained at 40 DEG C of reaction 10h, and reaction is finished, and the hydrogen chloride tetrahydrofuran solution of 10mol/L is instilled
Solution is recycled after 500ml, and 2L methylene chloride is added into residue, is heated to reflux 30min, filters while hot, be added in filtrate
10L methyl tertiary butyl ether(MTBE) filters after 30min is stirred at room temperature, and filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated,
It filters, filter residue is washed with cold methyl tertiary butyl ether(MTBE), and vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl
Base -2,5- oxazolidinedione 1.02Kg, yield 73.5%, purity 98.8% (HPLC), optical value be+59.8 ° (C=1, four
Hydrogen furans, T=25 DEG C).
The synthesis of embodiment 9 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), N,N-dimethylformamide 1L, acetonitrile 4L, 4- diformazan ammonia
Yl pyridines 92g (0.75mol) is added in the 20L kettle with nitrogen protection, after stirring 30min at room temperature, solution temperature is down to 0~
N is slowly added dropwise under 5, N- carbonyl dimidazoles 891g (5.5mol) is dissolved in the solution of 2L acetonitrile, and Process liquor temperature is added dropwise and keeps
At 20 DEG C hereinafter, drop finishes, solution is maintained at 40 DEG C of reaction 8h, reaction is finished, and the hydrogen chloride tetrahydrofuran solution of 10mol/L is instilled
Solution is recycled after 500ml, and 2L methylene chloride is added into residue, is heated to reflux 30min, filters while hot, 10L is added in filtrate
Methyl tertiary butyl ether(MTBE) filters after 30min is stirred at room temperature, and filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated, and takes out
Filter, filter residue are washed with cold methyl tertiary butyl ether(MTBE), and vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl
Base -2,5- oxazolidinedione 1.2Kg, yield 86%, purity 99% (HPLC), optical value are+60.5 ° of (C=1, tetrahydro furans
It mutters, T=25 DEG C).
The synthesis of embodiment 10 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), tetrahydrofuran 8L, 4-dimethylaminopyridine 92g
(0.75mol) is added in the 20L kettle with nitrogen protection, and after stirring 30min at room temperature, it is lower slow that solution temperature is down to 0~5
N is added dropwise, N- carbonyl dimidazoles 1.22Kg (7.5mol) is dissolved in the solution of 2L tetrahydrofuran, and Process liquor temperature is added dropwise and keeps
At 20 DEG C hereinafter, drop finishes, solution is maintained at 40 DEG C of reaction 14h, reaction is finished, recycled after being passed through dry hydrogen chloride gas 5min
2L methylene chloride is added into residue, is heated to reflux 30min, filters while hot for solution, and 10L methyl tertbutyl is added in filtrate
Ether filters after 30min is stirred at room temperature, and filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated, and filters, and filter residue is used
Cold methyl tertiary butyl ether(MTBE) washing, vacuum drying obtain white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazole
Alkane diketone 0.75Kg, yield 53.8%, purity 98.5% (HPLC), optical value are+62.1 ° of (C=1, tetrahydrofuran, T=
25℃)。
The synthesis of embodiment 11 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), 1,4- dioxane 8L, 4- dimethylamino naphthyridine 92g
(0.75mol) is added in the 20L kettle with nitrogen protection, and after stirring 30min at room temperature, solution temperature is down to 0~5 lower slowly drop
Add N, N- carbonyl dimidazoles 1.22Kg (7.5mol) to be dissolved in the solution of 2L tetrahydrofuran, Process liquor temperature is added dropwise and is maintained at
20 DEG C are finished hereinafter, dripping, and solution is maintained at 40 DEG C of reaction 14h, and reaction is finished, and the hydrogen chloride tetrahydrofuran solution of 10mol/L is instilled
Solution is recycled after 500ml, and 2L methylene chloride is added into residue, is heated to reflux 30min, filters while hot, be added in filtrate
10L methyl tertiary butyl ether(MTBE) filters after 30min is stirred at room temperature, and filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated,
It filters, filter residue is washed with cold methyl tertiary butyl ether(MTBE), and vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl
Base -2,5- oxazolidinedione 632g, yield 45.6%, purity 98.0% (HPLC), optical value are+62.9 ° of (C=1, tetrahydros
Furans, T=25 DEG C).
The synthesis of embodiment 12 (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione
By N- benzyloxy-oxo-L-valine 1.25Kg (5mol), formamide 8L, 4-dimethylaminopyridine 92g (0.75mol)
It is added in the 20L kettle with nitrogen protection, after stirring 30min at room temperature, solution temperature is down under 0~5, N is slowly added dropwise, N- carbonyl
Base diimidazole 1.22Kg (7.5mol) is dissolved in the solution of 2L tetrahydrofuran, be added dropwise Process liquor temperature be maintained at 20 DEG C hereinafter,
Drop finishes, and solution is maintained at 40 DEG C of reaction 14h, and reaction is finished, and is returned after instilling the hydrogen chloride tetrahydrofuran solution 500ml of 10mol/L
Solution is received, 2L methylene chloride is added into residue, is heated to reflux 30min, filters while hot, 10L methyl- tert fourth is added in filtrate
Base ether filters after 30min is stirred at room temperature, and filtrate is cooled to -10 DEG C and stirs 2h, and a large amount of white solids are precipitated, and filters, filter residue
It is washed with cold methyl tertiary butyl ether(MTBE), vacuum drying obtains white powdery solids (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5-
Oxazolidinedione 838g, yield 60.5%, purity 98.0% (HPLC), optical value are+62.9 ° of (C=1, tetrahydrofuran, T
=25 DEG C).
Claims (14)
- The preparation process of (1. S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione, which is characterized in that it includes as follows Operation:S1. it takes Valine and benzyl chloroformate to react under alkaline condition and generates N- benzyloxy-oxo-L-valine, synthesize Method includes that Valine is dissolved in sodium hydroxide solution, and Carbobenzoxy Chloride or the ester of Bian containing chloro-carbonic acid are added dropwise during the reaction Isosorbide-5-Nitrae-dioxane solution, react under room temperature；S2. extraction and separation discard organic phase, retain aqueous, adjust aqueous pH value to acidity, reuse reaction dissolvent extraction, take Organic phase is transferred in kettle under nitrogen protection environment and mixes and cool down with alkaline accelerator, then is added dropwise containing N, N- carbonyl dimidazoles Reaction dissolvent reacts 6~14h under neutral alkaline environment on the weak side and reaction temperature, generates the benzyloxycarbonyl group -4- isopropyl containing (S) -3- The reaction dissolvent of base -2,5- oxazolidinedione.
- 2. preparation process according to claim 1, it is characterised in that: the pH of the neutrality alkaline environment on the weak side be 7.3~ 9.0。
- 3. preparation process according to claim 1, it is characterised in that: reaction dissolvent is selected from methylene chloride, four in step S3 One of hydrogen furans, N,N-dimethylformamide, formamide, 1,4- dioxane, acetonitrile or two kinds and combination of the above.
- 4. preparation process according to claim 1, it is characterised in that: reaction dissolvent is selected from methylene chloride and four in step S3 Hydrogen furans, the combination of N,N-dimethylformamide or the combination of methylene chloride and acetonitrile, N,N-dimethylformamide.
- 5. preparation process according to claim 1, it is characterised in that: reaction dissolvent selects methylene chloride and four in step S3 Hydrogen furans, n,N-Dimethylformamide combination when, reaction temperature be 0~25 DEG C.
- 6. preparation process according to claim 1, it is characterised in that: reaction dissolvent selects methylene chloride and second in step S3 Nitrile, n,N-Dimethylformamide combination when, reaction temperature be 0~40 DEG C.
- 7. preparation process according to claim 1, it is characterised in that: step S3 neutral and alkali promotor is selected from 4- dimethylamino At least one of pyridine, pyridine, piperidines.
- 8. preparation process according to claim 1, it is characterised in that: step S3 neutral and alkali promotor selects 4- dimethylamino Pyridine.
- 9. preparation process according to claim 1, it is characterised in that: step S3 neutral and alkali promotor and N- benzyloxycarbonyl group- The mole dosage ratio of Valine is (0.05~0.2): 1.
- 10. preparation process according to claim 1, it is characterised in that: N- benzyloxy-oxo-L-valine and N in step S3, The mole dosage ratio of N- carbonyl dimidazoles is 1:(1~2).
- 11. described in any item preparation processes according to claim 1~10, it is characterised in that: step S3 after completion of the reaction, is also wrapped Include purification step:It is molten that hydrogen chloride tetrahydrofuran is added dropwise to the reaction dissolvent of -4- isopropyl -2,5- oxazolidinedione Han (S) -3- benzyloxycarbonyl group Liquid or Hydrochloride/ethyl acetate are passed through dry hydrogen chloride gas with the alkaline matter in neutralization reaction liquid, allow whole It is maintained in acidic environment in a system last handling process, protects product；Good solvent filtering and impurity removing is first added using into (S) -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione, filtrate is again The lower precipitating of poor solvent freezing is added；The poor solvent is selected from least one of methyl tertiary butyl ether(MTBE), toluene, n-hexane, petroleum ether；The good solvent is selected from least one of methylene chloride, ethyl acetate；The impurity refers to the impure ingredient being mingled in target compound, including but not limited to reacts the by-product imidazoles of generation The not reaction mass of fully reacting.
- 12. preparation process according to claim 1, which is characterized in that step S2 is also wrapped before using reaction dissolvent extraction It includes N- benzyloxy-oxo-L-valine purification step: extracting aqueous with reaction dissolvent, it is dry to take extract layer, then be evaporated under reduced pressure reaction Solvent obtains N- benzyloxy-oxo-L-valine；Or keep aqueous tune acid out brilliant, and it is dry, obtain N- benzyloxy-oxo-L-valine.
- 13. preparation process according to claim 1, which is characterized in that step S2 is also wrapped after using reaction dissolvent extraction It includes organic phase removal step: drying, filtering, obtain anhydrous salt-free organic with after saturated common salt water washing, then with anhydrous sodium sulfate Phase.
- 14. using a-amino acid as Material synthesis N- benzyloxycarbonyl group-a-amino acid-NCA method, which is characterized in that it include with Lower stepA-amino acid shown in modus ponens 10,12 compound of the production that reacts under alkaline condition with benzyl chloroformate, then divide From 12 compound of formula, turn to be dissolved in reaction dissolvent in acid condition, merge with alkaline accelerator, with N, N- carbonyl dimidazoles are in Reacted under property alkaline environment on the weak side and reaction temperature, can 13 compound of production, the a-amino acid includes: glycine, third Propylhomoserin, valine, leucine, isoleucine, phenylalanine, tryptophan, serine, tyrosine, cysteine, methionine, day Winter amide, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910466728.6A CN110204505B (en) | 2019-05-31 | 2019-05-31 | Preparation process of (S) -3-benzyloxycarbonyl-4-isopropyl-2, 5-oxazolidinedione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910466728.6A CN110204505B (en) | 2019-05-31 | 2019-05-31 | Preparation process of (S) -3-benzyloxycarbonyl-4-isopropyl-2, 5-oxazolidinedione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110204505A true CN110204505A (en) | 2019-09-06 |
| CN110204505B CN110204505B (en) | 2023-02-03 |
Family
ID=67789815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910466728.6A Active CN110204505B (en) | 2019-05-31 | 2019-05-31 | Preparation process of (S) -3-benzyloxycarbonyl-4-isopropyl-2, 5-oxazolidinedione |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110204505B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110988246A (en) * | 2019-11-29 | 2020-04-10 | 荆门医药工业技术研究院 | Method for detecting contents of Z-L-valine and intermediate (S) -4-isopropyloxazole-2, 5-diketone thereof |
| CN112010780A (en) * | 2020-09-18 | 2020-12-01 | 浙江天瑞化学有限公司 | Preparation method of CBZ-L-valine |
| CN115286632A (en) * | 2022-09-16 | 2022-11-04 | 河北医科大学 | Preparation process of valganciclovir hydrochloride |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992016501A1 (en) * | 1991-03-20 | 1992-10-01 | Vertex Pharmaceuticals Incorporated | Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease |
| WO1993022299A1 (en) * | 1992-04-24 | 1993-11-11 | E.I. Du Pont De Nemours And Company | Fungicidal oxazolidinones |
| US5359086A (en) * | 1992-09-16 | 1994-10-25 | Krka, Pharmaceutical & Chemical Works | Process for preparing alkyl-L-alanyl-L-proline derivatives |
| WO1999058151A2 (en) * | 1998-05-07 | 1999-11-18 | Universiteit Gent | Synthetic polyaminoacid complexes for delivery of nucleic acids to target cells |
| US20020151744A1 (en) * | 2000-07-31 | 2002-10-17 | Li Deng | Kinetic resolutions of chiral 2-and-3-substituted carboxylic acids |
| CN1388804A (en) * | 2000-07-04 | 2003-01-01 | 三井化学株式会社 | Amino acid-N-carboxy anhydrides having substitent at nitrogen |
| WO2003011799A1 (en) * | 2000-07-31 | 2003-02-13 | Brandeis University | Kinetic resolutions of chirat 3- and 3-substituted carboxylic acids |
| CN1903854A (en) * | 2006-08-09 | 2007-01-31 | 丽珠医药集团股份有限公司 | Method of synthesizing valaciclovir hydrochloride |
| CN101821235A (en) * | 2007-08-07 | 2010-09-01 | 武田药品工业株式会社 | Pyrrolidin-2 -one derivatives as androgen receptor modulator |
| CN106831630A (en) * | 2017-03-02 | 2017-06-13 | 成都永泰诺科技有限公司 | The preparation technology of acetic acid copaxone intermediate |
-
2019
- 2019-05-31 CN CN201910466728.6A patent/CN110204505B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992016501A1 (en) * | 1991-03-20 | 1992-10-01 | Vertex Pharmaceuticals Incorporated | Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease |
| WO1993022299A1 (en) * | 1992-04-24 | 1993-11-11 | E.I. Du Pont De Nemours And Company | Fungicidal oxazolidinones |
| US5359086A (en) * | 1992-09-16 | 1994-10-25 | Krka, Pharmaceutical & Chemical Works | Process for preparing alkyl-L-alanyl-L-proline derivatives |
| WO1999058151A2 (en) * | 1998-05-07 | 1999-11-18 | Universiteit Gent | Synthetic polyaminoacid complexes for delivery of nucleic acids to target cells |
| CN1388804A (en) * | 2000-07-04 | 2003-01-01 | 三井化学株式会社 | Amino acid-N-carboxy anhydrides having substitent at nitrogen |
| US20020151744A1 (en) * | 2000-07-31 | 2002-10-17 | Li Deng | Kinetic resolutions of chiral 2-and-3-substituted carboxylic acids |
| WO2003011799A1 (en) * | 2000-07-31 | 2003-02-13 | Brandeis University | Kinetic resolutions of chirat 3- and 3-substituted carboxylic acids |
| CN1903854A (en) * | 2006-08-09 | 2007-01-31 | 丽珠医药集团股份有限公司 | Method of synthesizing valaciclovir hydrochloride |
| CN101821235A (en) * | 2007-08-07 | 2010-09-01 | 武田药品工业株式会社 | Pyrrolidin-2 -one derivatives as androgen receptor modulator |
| CN106831630A (en) * | 2017-03-02 | 2017-06-13 | 成都永泰诺科技有限公司 | The preparation technology of acetic acid copaxone intermediate |
Non-Patent Citations (4)
| Title |
|---|
| JIANFENG HANG ET AL.: ""Asymmetric Synthesis of α-Amino Acids via Cinchona Alkaloid-Catalyzed Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides"", 《J. AM. CHEM. SOC.》 * |
| VITALI LIPIK ET AL.: ""Synthesis of biomimetic co-polypeptides with tunable degrees of phosphorylation"", 《POLYMER CHEMISTRY》 * |
| 张华 等: ""α-氨基酸-N-羧基内酸酐(NCAs)合成工艺研究进展"", 《浙江化工》 * |
| 马英改 等: ""α-氨基酸-N-羧基内酸酐合成的研究进展"", 《石油化工》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110988246A (en) * | 2019-11-29 | 2020-04-10 | 荆门医药工业技术研究院 | Method for detecting contents of Z-L-valine and intermediate (S) -4-isopropyloxazole-2, 5-diketone thereof |
| CN112010780A (en) * | 2020-09-18 | 2020-12-01 | 浙江天瑞化学有限公司 | Preparation method of CBZ-L-valine |
| CN115286632A (en) * | 2022-09-16 | 2022-11-04 | 河北医科大学 | Preparation process of valganciclovir hydrochloride |
| CN115286632B (en) * | 2022-09-16 | 2023-05-09 | 河北医科大学 | Preparation process of valganciclovir hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110204505B (en) | 2023-02-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110204505A (en) | (S) preparation process of -3- benzyloxycarbonyl group -4- isopropyl -2,5- oxazolidinedione | |
| CN105503878A (en) | Synthesis method of anagliptin | |
| CN108997187A (en) | A kind of preparation method of N (π)-methyl-L-histidine derivative and its application in synthesis whale carnosine | |
| CN105254649B (en) | A kind of preparation method of Method of cefcapene pivoxil hydrochloride | |
| CN106518694A (en) | Novel preparation method of L-alanine isopropyl ester hydrochloride | |
| CN108727269A (en) | A kind of preparation method of N (τ)-methyl-L-histidine derivative and its application in synthesizing anserine | |
| CN107674062B (en) | Anti-hepatitis C drug intermediate, preparation method and application | |
| CN114369139B (en) | Preparation method of snake venom tripeptide | |
| CN109678887A (en) | A kind of preparation method of Method of cefcapene pivoxil hydrochloride intermediate B CN | |
| TW202140457A (en) | Process for preparing a phthalazinone derivative and intermediates thereof | |
| CN107074858A (en) | The method for preparing the carboxylic acid sodium of (2S, 5R) 6 (benzyloxy) 7 oxo 1,6 diazabicylo [3.2.1] octane 2 | |
| CN106699604A (en) | Sacubitril and preparation method of midbody of sacubitril | |
| CN110183391A (en) | The method that one kettle way prepares D-Cycloserine | |
| CN106831630B (en) | The preparation process of acetic acid copaxone intermediate | |
| CN111138335B (en) | Preparation method of optically active 2-methylproline | |
| CN110981879B (en) | Method for preparing NS5A inhibitor-wipatasvir | |
| CN104030958A (en) | Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile | |
| CN107501154B (en) | Synthesis method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile | |
| US20220235044A1 (en) | Method for synthesizing 1,7-naphthyridine derivatives | |
| CN107698589B (en) | A kind of preparation method of Adprin | |
| CN109280050B (en) | Preparation method of medical compound avanafil | |
| CN108658961A (en) | A kind of preparation method of Azilsartan | |
| CN104151299B (en) | Compound, crystal-form compound and preparation method thereof | |
| CN108640912A (en) | A kind of industrially scalable preparation method of Pidotimod | |
| CN103951661B (en) | A kind of preparation method of razaxaban |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |