CN109796329A - It is a kind of13The synthetic method of C flag butyrine - Google Patents
It is a kind of13The synthetic method of C flag butyrine Download PDFInfo
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Abstract
The present invention relates to one kind13The synthetic method of C flag butyrine, with n-butyric acie -1- (13COOH) it is raw material, carries out acylation reaction with chlorination reagent and intermediate n-butyryl chloride-is made13C, by n-butyryl chloride-13C carries out bromo-reaction and intermediate 2- bromo-butyric acid acyl chlorides-is made13C carries out aminating reaction and obtains intermediate 2-amino butyramide-13C, hydrolysis obtain colorless solid butyrine-(13COOH).Compared with prior art, the present invention has many advantages, such as that reaction process is simple, last handling process is easy, overall yield of reaction >=72% (with butyric acid -1- (13COOH) count), chemical purity >=99%, isotope abundance >=98atom%13C。
Description
Technical field
The present invention relates to the preparation methods of the organic compound of stable isotope labeling, more particularly, to one kind13C stablizes same
Position element label butyrine-(13COOH methodology of organic synthesis).
Background technique
As a kind of unique emerging science, application field almost spreads institute for stable isotope and its labeled compound
There is high-technology field, especially in modern medical diagnosis application field by great concern.Butyrine is to inhibit human body mind
Through information transmit natural amino acid, be important industrial chemicals and medicine intermediate, it has also become a variety of chiral drugs it is important
Chiral intermediate is widely used in pharmaceutical synthesis, such as butyrine is the master of synthesizing new antiepileptic Levetiracetam
Want raw materials for production, and the crucial chiral precursor of the antibacterial anti-tubercular drug ethambutol hydrochloride of synthesis.
Isotope tracer technique uses stable isotope labeling raw material, has the characteristics that on-radiation, non-destructive, is curing
Important function is played in the metabolism group research such as medicine, agricultural.Stable isotope labeling butyrine stablizes same position as one
Plain tracer, the synthesis of high-quality product are the basis in metabolism group tracer technique, stable isotope labeling butyrine
Use, to drug it is accurate treatment and drug metabolism study have positive effect.
The preparation method of butyrine has chemical method and biological method, and chemical synthesis has Jeffery E A (Jefery
E A, Meisters A.Electrochemical synthesis of amino acids by reductive
Amination of keto acids.I.Reduction at mercury electrodes [J] .Aust J Chem,
1978,31 (1): 79-84.) etc. using mercury electrode, electro-catalysis restores its corresponding keto-acid amino in ammonium hydroxide or ammonium chloride solution
The method of sour (or sodium salt of amino acid), is prepared for butyrine, and yield is only 48%, and has the generation of by-product glutamic acid；
Babievskii K K (Babievskii K K, Belikov V M, Tikhonova N A.Amino
acids.Communication 1.synthesis of DL-threonine and DL-2-aminobutyric acid
Based on condensations of nitroacetic ester [J] .Russian Chemical Bulletin,
1965,14 (1): 76-81.) etc. nitro ethyl ester, acetaldehyde and isobutyric reaction product are prepared for alpha-amido after catalytic hydrogenation
Butyric acid, yield is still lower, also there is the generation of by-product threonine.In addition traditional biological enzyme catalysis method is because high-efficient, specificity is strong
And it is widely used.In the technique of Production by Enzymes butyrine, transaminase report at most, however turns ammonia process and is
State balance, the maximum conversion of reaction are 50%.The conversion ratio of reaction can be improved after process modification, but can introduce and product
The similar by-product of butyrine property, influences being further purified for product, therefore be unfavorable for industrialized production.And biology
Synthetic method can not selectivity synthesis carboxyl13C flag object can only carry out whole C13C isotope labelling, greatly increase raw material at
This.Carboxyl13The butyrine of C flag can not be prepared with biological enzyme, can only be just able to achieve by the method for organic synthesis.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide one kind overcome it is above-mentioned existing
Defect existing for technology and provide that a kind of reaction process is simple, last handling process is easy13C stable isotope marks alpha-amido
Butyric acid-(13COOH methodology of organic synthesis), while in order to which scientificlly and effectively research offer can be carried out to the metabolism group of drug
Reliable basis.
The purpose of the present invention can be achieved through the following technical solutions:
13The synthetic method of C flag butyrine, with n-butyric acie -1- (13COOH it is) raw material, carries out acyl with chlorination reagent
Change to react and intermediate (1) n-butyryl chloride-is made13C is carried out bromo-reaction and intermediate (2) 2- bromo-butyric acid acyl chlorides-is made13C,
Aminating reaction is carried out again obtains intermediate (3) 2- amino-butanamide-13C, final hydrolysis obtain colorless solid butyrine-
(13COOH), detailed process is as follows:
Take a certain amount of n-butyric acie -1- (13COOH it) is dissolved in solvent, chlorination reagent is added at low temperature -20~0 DEG C, certain temperature
It is stirred to react under degree, until being released without HCl gas.Reaction solution rotation removes solvent, obtains intermediate (1) n-butyryl chloride-13C。
By intermediate (1) n-butyryl chloride-13C is dissolved in solvent, is slowly added dropwise under heating stirring into dry bromine, stirring
Reaction.Reactant is cooled to room temperature after reaction.Rotation removes solvent, and 150 DEG C of faint yellow oily fractions are collected in vacuum distillation
Intermediate (2) 2- bromo-butyric acid acyl chlorides-13C。
Methenamine is dissolved in solvent, is stirred.Dry ammonia is at room temperature passed through to pH value of solution alkalinity, is added dropwise to
Mesosome (2) 2- bromo-butyric acid acyl chlorides-13The organic solution of C, TLC monitoring reaction to raw material fully reacting.Colorless solid is obtained by filtration,
It is recrystallized with the mixed solution of methanol and petroleum ether, obtains colourless powder solid intermediate (3) 2- amino-butanamide-13C。
By intermediate (3) 2- amino-butanamide-13C is hydrolyzed using acid, obtains product through active carbon decoloring, with water and
The mixed solution of ethyl alcohol is recrystallized, be obtained by filtration colourless powder solid butyrine-(13COOH), yield can achieve
72%.
Reaction route is as follows:
The first step reaction in n-butyric acie -1- (13It COOH is) 1:(1~5 with the molar ratio of chlorination reagent)；Reaction temperature is 0
It~100 DEG C, is preferred with 40~60 DEG C；Reaction time is 2~12h, is preferred with 6~8h；Solvent for use is 1,2- dichloroethanes, two
One or more of chloromethanes, benzene or toluene；Chlorination reagent used is one in thionyl chloride, oxalyl chloride or phosphorus trichloride
Kind is several；
Intermediate therefor (1) n-butyryl chloride-in second step reaction13The molar ratio of C and bromine is 1:(1~5)；Reaction time
For 2~12h, it is preferred with 6~8h；Reaction temperature is 30~120 DEG C, is preferred with 70~90 DEG C；Solvent used is 1,2- dichloro
One or more of ethane, methylene chloride, chloroform or 1,4- dioxane；
Intermediate (2) 2- bromo-butyric acid acyl chlorides-in third step reaction13Molar ratio 1:(1~5 of C and methenamine)；When reaction
Between be 1~8h, be preferred with 3~4h；Solvent for use is one or more of methanol, ethyl alcohol or isopropanol；Reaction solution pH range
Between 8~12, to be preferred between 9~10；
Acid solution used in four-step reaction is one or more of hydrochloric acid, sulfuric acid or hydrobromic acid, concentration is 1~
6mol/l；Reaction temperature is 50~100 DEG C, is preferred with 70~80 DEG C；Reaction time be 6~for 24 hours.
Butyric acid is not prepared into acyl chlorides first with thionyl chloride in the prior art, directly bromo-reaction is carried out with bromine, leads to bromine
Alpha position can be not only substituted onto, the position β and γ can be also substituted onto, by-product separation is difficult, and continuation is reacted down just has β-ammonia
The impurity of base butyric acid and γ-aminobutyric acid, compared with prior art, the present invention is by first preparing acyl with thionyl chloride for butyric acid
Chlorine, it is possible to prevente effectively from the generation of by-product beta-aminobutyric acid and γ-aminobutyric acid, and it is easy to operate, process flow is short, by-product
Object is few.Overall yield of reaction >=72% (with butyric acid -1- (13COOH it) counts).
The prior art using mercury electrode electro-catalysis in ammonium hydroxide or ammonium chloride solution restore its corresponding keto-acid amino acid (or
The sodium salt of amino acid) method be prepared for butyrine, it is entirely different with synthetic route of the invention.It is passed through in route of the present invention
Acylation, bromo, amination, hydrolysis are crossed, every step reaction is all popular response, and easy to operate, yield is higher, thus than existing skill
The 48% of art has greatly improved.
Isotope labelling raw material butyric acid is in carboxyl site in the application13C flag marks in reaction13There is no join for C atom
With react, also do not carry out isotope with other materials and exchange, therefore final products chemical purity >=99%, isotope abundance >=
98atom%13C (measurement of Agilent 7890B-7000C gas chromatograph-mass spectrometer).The method marks stable isotope butyrine-
(13COOH) high income, process flow is short, easy to operate, and by-product is few, and isotope abundance is not diluted, is suitble to Laboratory Production
The stable isotope product has good economy and practical application value.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection scope.
13The synthetic method of C flag butyrine, with n-butyric acie -1- (13COOH it is) raw material, carries out acyl with chlorination reagent
Change to react and intermediate (1) n-butyryl chloride-is made13C is carried out bromo-reaction and intermediate (2) 2- bromo-butyric acid acyl chlorides-is made13C,
Aminating reaction is carried out again obtains intermediate (3) 2- amino-butanamide-13C, final hydrolysis obtain colorless solid butyrine-
(13COOH), reaction route is as follows:
Detailed process is as follows for above-mentioned reaction:
(1) take n-butyric acie -1- (13COOH) it is dissolved in solvent (one of 1,2- dichloroethanes, methylene chloride, benzene or toluene
Or several) in, chlorination reagent (one or more of thionyl chloride, oxalyl chloride or phosphorus trichloride) is added at -20~0 DEG C, just
Butyric acid -1- (13COOH it is) 1:(1~5 with the molar ratio of chlorination reagent), controlled at 0~100 DEG C of 2~12h of reaction, with 40
~60 DEG C, the reaction time, 6~8h was preferred, and is stirred to react to no HCl gas and is released.Reaction solution rotation removes solvent, obtains centre
Body (1) n-butyryl chloride-13C。
(2) by intermediate (1) n-butyryl chloride-13C is dissolved in solvent (1,2- dichloroethanes, methylene chloride, chloroform or 1,4- bis-
One or more of six ring of oxygen) in, it is slowly added dropwise under heating stirring into dry bromine, n-butyryl chloride-13C and bromine are rubbed
You are than being 1:(1~5), it is stirred to react 2~12h controlled at 30~120 DEG C, is preferred with 70~90 DEG C of 6~8h of reaction, is reacted
After reactant is cooled to room temperature.Rotation removes solvent, and 150 DEG C of faint yellow oily fraction intermediates (2) are collected in vacuum distillation
2- bromo-butyric acid acyl chlorides-13C。
(3) methenamine is dissolved in solvent (one or more of methanol, ethyl alcohol or isopropanol), is stirred.Room
It is passed through dry ammonia under temperature to pH value of solution alkalinity (between 8~12, to be preferred between 9~10), is added dropwise to intermediate (2) 2- bromine fourth
Isoxazolecarboxylic acid-13The organic solution of C, intermediate (2) 2- bromo-butyric acid acyl chlorides-13Molar ratio 1:(1~5 of C and methenamine), reaction 1
~8h, is preferred with 3~4h, utilizes TLC monitoring reaction to raw material fully reacting.Colorless solid is obtained by filtration, with methanol and petroleum
The mixed solution of ether is recrystallized, and colourless powder solid intermediate (3) 2- amino-butanamide-is obtained13C。
(4) by intermediate (3) 2- amino-butanamide-13C use acid (one or more of hydrochloric acid, sulfuric acid or hydrobromic acid,
Its concentration is 1~6mol/l) it is hydrolyzed, control reaction temperature is 50~100 DEG C, is preferred with 70~80 DEG C；Reaction 6~for 24 hours,
Product is obtained through active carbon decoloring, is recrystallized with the mixed solution of water and ethyl alcohol, colourless powder solid α-ammonia is obtained by filtration
Base butyric acid-(13COOH)。
More detailed case study on implementation below, by following case study on implementation further illustrate technical solution of the present invention with
And the technical effect that can be obtained.
Embodiment 1
13The synthetic method of C flag butyrine, using following methods:
By 5g n-butyric acie -1- (13COOH it) is dissolved in 50ml 1, in 2- dichloroethanes, 6.68g thionyl chloride is added at 0 DEG C,
It is stirred to react 6h at 0 DEG C, until releasing without HCl gas.Reaction solution rotation removes solvent, obtains Intermediates Intermediate (1) n-butyryl chloride
-13C 5.70g。
By 5.70g intermediate (1) n-butyryl chloride-13C is dissolved in methylene chloride, is heated to 80 DEG C, be slowly added dropwise under stirring into
Dry bromine 42.50g, persistently stirs 12h.Reactant is cooled to room temperature after reaction.Rotation removes solvent, and decompression is steamed
It evaporates, collects 150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyl chlorides-13C 8.90g。
33.42g methenamine is dissolved in 100ml ethyl alcohol, is stirred.Be passed through at room temperature dry ammonia to pH value of solution=
9, it is added dropwise to 8.90g intermediate (2) 2- bromo-butyric acid acyl chlorides-13The ethanol solution of C, reaction time 1h.It is obtained by filtration colourless solid
Body is recrystallized with the mixed solution of methanol and petroleum ether, obtains colorless solid intermediate (3) 2- amino-butanamide-13C
4.67g。
By 4.67g intermediate (3) 2- amino-butanamide-13C is added in 25ml 6mol/l aqueous hydrochloric acid solution, 70 DEG C of heating
Stirring is for 24 hours.It is spin-dried for obtaining product through active carbon decoloring, is recrystallized with the mixed solution of water and ethyl alcohol, it is colourless to obtain 4.24g
Powder solid butyrine-(13COOH), overall yield of reaction be 72.6% (with butyric acid -1- (13COOH) count), chemical purity >=
99%, isotope abundance >=98atom%13C (measurement of Agilent 7890B-7000C gas chromatograph-mass spectrometer).
Embodiment 2
13The synthetic method of C flag butyrine, using following methods:
By 5g n-butyric acie -1- (13COOH it) is dissolved in 50ml methylene chloride, 20.00g thionyl chloride is added at -20 DEG C,
It is stirred to react 8h at 60 DEG C, until releasing without HCl gas.Reaction solution rotation removes solvent, obtains Intermediates Intermediate (1) n-butyryl chloride-13C 5.72g。
By 5.72g intermediate (1) n-butyryl chloride-13C is dissolved in 1,2- dichloroethanes, is heated to 30 DEG C, stirs lower slowly drop
Dry bromine 8.50g is added, persistently stirs 8h.Reactant is cooled to room temperature after reaction.Rotation removes solvent, and decompression is steamed
It evaporates, collects 150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyl chlorides-13C 8.92g。
6.68g methenamine is dissolved in 100ml methanol, is stirred.Be passed through at room temperature dry ammonia to pH value of solution=
8, it is added dropwise to 8.92g intermediate (2) 2- bromo-butyric acid acyl chlorides-13The methanol solution of C, reaction time 4h.It is obtained by filtration colourless solid
Body is recrystallized with the mixed solution of methanol and petroleum ether, obtains colorless solid intermediate (3) 2- amino-butanamide-13C
4.65g。
By 4.65g intermediate (3) 2- amino-butanamide-13C is added in 25ml 3mol/l aqueous sulfuric acid, and 100 DEG C add
Thermal agitation 6h.Be spin-dried for obtaining product through active carbon decoloring, recrystallized with the mixed solution of water and ethyl alcohol, obtain 4.27g without
Color powder solid butyrine-(13COOH), overall yield of reaction be 73.2% (with butyric acid -1- (13COOH) count), chemical purity
>=99%, isotope abundance >=98atom%13C (measurement of Agilent 7890B-7000C gas chromatograph-mass spectrometer).
Embodiment 3
13The synthetic method of C flag butyrine, using following methods:
By 5g n-butyric acie -1- (13COOH it) is dissolved in 50ml benzene, 32.10g oxalyl chloride is added at -20 DEG C, at 100 DEG C
It is stirred to react 2h, until releasing without HCl gas.Reaction solution rotation removes solvent, obtains Intermediates Intermediate (1) n-butyryl chloride-13C
5.74g。
By 5.74g intermediate (1) n-butyryl chloride-13C is dissolved in chloroform, is heated to 60 DEG C, is slowly added dropwise under stirring into drying
Bromine 20.50g, persistently stir 2h.Reactant is cooled to room temperature after reaction.Rotation removes solvent, is evaporated under reduced pressure, and collects
150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyl chlorides-13C8.91g。
15.50g methenamine is dissolved in 100ml isopropanol, is stirred.It is passed through dry ammonia at room temperature to pH value of solution
=12, it is added dropwise to 8.91g intermediate (2) 2- bromo-butyric acid acyl chlorides-13The aqueous isopropanol of C, reaction time 3h.Nothing is obtained by filtration
Color solid is recrystallized with the mixed solution of methanol and petroleum ether, obtains colorless solid intermediate (3) 2- amino-butanamide-13C 4.68g。
By 4.68g intermediate (3) 2- amino-butanamide-13C is added in 75ml 2mol/l hydrobromic acid aqueous solution, and 50 DEG C add
Thermal agitation 12h.Be spin-dried for obtaining product through active carbon decoloring, recrystallized with the mixed solution of water and ethyl alcohol, obtain 4.26g without
Color powder solid butyrine-(13COOH), overall yield of reaction be 73.0% (with butyric acid -1- (13COOH) count), chemical purity
>=99%, isotope abundance >=98atom%13C (measurement of Agilent 7890B-7000C gas chromatograph-mass spectrometer).
Embodiment 4
13The synthetic method of C flag butyrine, using following methods:
By 5g n-butyric acie -1- (13COOH it) is dissolved in 25ml benzene and 25ml toluene mixed solution, 38.40g is added at 0 DEG C
Phosphorus trichloride is stirred to react 12h at 80 DEG C, until releasing without HCl gas.Reaction solution rotation removes solvent, obtains Intermediates Intermediate
(1) n-butyryl chloride-13C 5.75g。
By 5.75g intermediate (1) n-butyryl chloride-13C is dissolved in Isosorbide-5-Nitrae-dioxane, is heated to 120 DEG C, slow under stirring
It is added dropwise to dry bromine 31.50g, persistently stirs 6h.Reactant is cooled to room temperature after reaction.Rotation removes solvent, subtracts
Pressure distillation, collects 150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyl chlorides-13C 8.93g。
25.80g methenamine is dissolved in 50ml methanol and 50ml ethyl alcohol, is stirred.It is passed through dry ammonia at room temperature
To pH value of solution=10, it is added dropwise to 8.93g intermediate (2) 2- bromo-butyric acid acyl chlorides-13The methanol and alcohol mixed solution of C, reaction time
For 8h.Colorless solid is obtained by filtration, is recrystallized with the mixed solution of methanol and petroleum ether, colorless solid intermediate is obtained
(3) 2- amino-butanamide-13C 4.69g。
By 4.69g intermediate (3) 2- amino-butanamide-13C is added in 150ml 1mol/l aqueous hydrochloric acid solution, and 80 DEG C add
Thermal agitation 8h.Be spin-dried for obtaining product through active carbon decoloring, recrystallized with the mixed solution of water and ethyl alcohol, obtain 4.25g without
Color powder solid butyrine-(13COOH), overall yield of reaction be 72.8% (with butyric acid -1- (13COOH) count), chemical purity
>=99%, isotope abundance >=98atom%13C (measurement of Agilent 7890B-7000C gas chromatograph-mass spectrometer).
Embodiment 5
13The synthetic method of C flag butyrine, using following methods:
Take n-butyric acie -1- (13COOH it) is dissolved in 1,2- dichloroethanes, thionyl chloride, n-butyric acie -1- is added at 0 DEG C of low temperature
(13COOH it is) 1:1 with the molar ratio of thionyl chloride, is stirred to react 12h controlled at 0 DEG C and releases to no HCl gas.Reaction solution
Rotation removes solvent, obtains intermediate (1) n-butyryl chloride-13C。
By intermediate (1) n-butyryl chloride-13C is dissolved in 1,2- dichloroethanes, is slowly added dropwise under heating stirring into dry liquid
Bromine, n-butyryl chloride-13The molar ratio of C and bromine is 1:1, is stirred to react 12h controlled at 30 DEG C, after reaction will reaction
Object is cooled to room temperature.Rotation removes solvent, and 150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyls are collected in vacuum distillation
It is chloro-13C。
Methenamine is dissolved in methanol, is stirred.Being passed through dry ammonia to solution ph at room temperature is 8, is added dropwise to
Intermediate (2) 2- bromo-butyric acid acyl chlorides-13The organic solution of C, intermediate (2) 2- bromo-butyric acid acyl chlorides-13Mole of C and methenamine
Than 1:1,1h is reacted, utilizes TLC monitoring reaction to raw material fully reacting.Colorless solid is obtained by filtration, with methanol and petroleum ether
Mixed solution is recrystallized, and colourless powder solid intermediate (3) 2- amino-butanamide-is obtained13C。
By intermediate (3) 2- amino-butanamide-13C is hydrolyzed using the hydrochloric acid that concentration is 1mol/l, controls reaction temperature
For 24 hours for 50 DEG C of reactions, product is obtained through active carbon decoloring, is recrystallized with the mixed solution of water and ethyl alcohol, nothing is obtained by filtration
Color powder solid butyrine-(13COOH)。
Embodiment 6
13The synthetic method of C flag butyrine, using following methods:
Take n-butyric acie -1- (13COOH it) is dissolved in the in the mixed solvent of benzene and toluene, oxalyl chloride, positive fourth are added at 0 DEG C of low temperature
Acid -1- (13COOH it is) 1:2 with the molar ratio of oxalyl chloride, is stirred to react 8h controlled at 40 DEG C and releases to no HCl gas.Instead
It answers liquid rotation except solvent, obtains intermediate (1) n-butyryl chloride-13C。
By intermediate (1) n-butyryl chloride-13C is dissolved in methylene chloride, is slowly added dropwise under heating stirring into dry bromine,
N-butyryl chloride-13The molar ratio of C and bromine is 1:2, is stirred to react 8h controlled at 70 DEG C, after reaction that reactant is cold
But to room temperature.Rotation removes solvent, and 150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyl chlorides-are collected in vacuum distillation13C。
Methenamine is dissolved in isopropanol, is stirred.Being passed through dry ammonia to solution ph at room temperature is 9, is added dropwise
Enter intermediate (2) 2- bromo-butyric acid acyl chlorides-13The organic solution of C, intermediate (2) 2- bromo-butyric acid acyl chlorides-13C and methenamine rub
You react 3h than 1:2, utilize TLC monitoring reaction to raw material fully reacting.Colorless solid is obtained by filtration, with methanol and petroleum ether
Mixed solution recrystallized, obtain colourless powder solid intermediate (3) 2- amino-butanamide-13C。
By intermediate (3) 2- amino-butanamide-13C is hydrolyzed using the sulfuric acid that concentration is 3mol/l, controls reaction temperature
For 70 DEG C of reaction 12h, product is obtained through active carbon decoloring, is recrystallized with the mixed solution of water and ethyl alcohol, nothing is obtained by filtration
Color powder solid butyrine-(13COOH)。
Embodiment 7
13The synthetic method of C flag butyrine, using following methods:
Take n-butyric acie -1- (13COOH it) is dissolved in methylene chloride, phosphorus trichloride, n-butyric acie -1- is added at 0 DEG C of low temperature
(13COOH it is) 1:5 with the molar ratio of phosphorus trichloride, is stirred to react 6h controlled at 60 DEG C and releases to no HCl gas.Reaction solution
Rotation removes solvent, obtains intermediate (1) n-butyryl chloride-13C。
By intermediate (1) n-butyryl chloride-13C is dissolved in chloroform and Isosorbide-5-Nitrae-dioxane in the mixed solvent, delays under heating stirring
Slowly dry bromine, n-butyryl chloride-are added dropwise to13The molar ratio of C and bromine is 1:4, is stirred to react 6h controlled at 90 DEG C, instead
Reactant is cooled to room temperature after answering.Rotation removes solvent, and 150 DEG C of faint yellow oily fraction intermediates are collected in vacuum distillation
(2) 2- bromo-butyric acid acyl chlorides-13C。
Methenamine is dissolved in the in the mixed solvent of methanol and ethyl alcohol, is stirred.It is passed through dry ammonia at room temperature to molten
Liquid pH value is 10, is added dropwise to intermediate (2) 2- bromo-butyric acid acyl chlorides-13The organic solution of C, intermediate (2) 2- bromo-butyric acid acyl chlorides-13C
With the molar ratio 1:4 of methenamine, 4h is reacted, utilizes TLC monitoring reaction to raw material fully reacting.Colorless solid is obtained by filtration,
It is recrystallized with the mixed solution of methanol and petroleum ether, obtains colourless powder solid intermediate (3) 2- amino-butanamide-13C。
By intermediate (3) 2- amino-butanamide-13C is hydrolyzed using the hydrobromic acid that concentration is 6mol/l, control reaction temperature
Degree is 80 DEG C of reaction 10h, obtains product through active carbon decoloring, is recrystallized, be obtained by filtration with the mixed solution of water and ethyl alcohol
Colourless powder solid butyrine-(13COOH)。
Embodiment 8
13The synthetic method of C flag butyrine, using following methods:
Take n-butyric acie -1- (13COOH it) is dissolved in toluene, is added oxalyl chloride at 0 DEG C of low temperature, n-butyric acie -1- (13COOH) with
The molar ratio of oxalyl chloride is 1:4, is stirred to react 2h controlled at 100 DEG C and releases to no HCl gas.Reaction solution rotation removes solvent,
Obtain intermediate (1) n-butyryl chloride-13C。
By intermediate (1) n-butyryl chloride-13C is dissolved in methylene chloride, is slowly added dropwise under heating stirring into dry liquid
Bromine, n-butyryl chloride-13The molar ratio of C and bromine is 1:5, is stirred to react 2h controlled at 120 DEG C, after reaction will reaction
Object is cooled to room temperature.Rotation removes solvent, and 150 DEG C of faint yellow oily fraction intermediate (2) 2- bromo-butyric acid acyls are collected in vacuum distillation
It is chloro-13C。
Methenamine is dissolved in etoh solvent, is stirred.Being passed through dry ammonia to solution ph at room temperature is 11, drop
Intermediate (2) 2- bromo-butyric acid acyl chlorides-is added13The organic solution of C, intermediate (2) 2- bromo-butyric acid acyl chlorides-13C and methenamine
Molar ratio 1:4 reacts 8h, utilizes TLC monitoring reaction to raw material fully reacting.Colorless solid is obtained by filtration, with methanol and petroleum
The mixed solution of ether is recrystallized, and colourless powder solid intermediate (3) 2- amino-butanamide-is obtained13C。
By intermediate (3) 2- amino-butanamide-13C is hydrolyzed using the sulfuric acid that concentration is 4mol/l, controls reaction temperature
For 100 DEG C of reaction 6h, product is obtained through active carbon decoloring, is recrystallized with the mixed solution of water and ethyl alcohol, nothing is obtained by filtration
Color powder solid butyrine-(13COOH)。
The above description of the embodiments is intended to facilitate ordinary skill in the art to understand and use the invention.
Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein general
Principle is applied in other embodiments without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, ability
Field technique personnel announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be of the invention
Within protection scope.
Claims (9)
1. a kind of13The synthetic method of C flag butyrine, which is characterized in that this method comprises:
With n-butyric acie -1- (13COOH) it is raw material, carries out acylation reaction with chlorination reagent and intermediate n-butyryl chloride-is made13C,
By n-butyryl chloride-13C carries out bromo-reaction and intermediate 2- bromo-butyric acid acyl chlorides-is made13C,
It carries out aminating reaction and obtains intermediate 2-amino butyramide-13C,
Hydrolysis obtain colorless solid butyrine-(13COOH)。
2. one kind according to claim 113The synthetic method of C flag butyrine, which is characterized in that by n-butyric acie-
1-(13COOH it) is dissolved in solvent, chlorination reagent is added under low temperature, be stirred to react to no HCl gas and release, reaction solution rotation is except molten
Agent obtains intermediate n-butyryl chloride-13C。
3. one kind according to claim 213The synthetic method of C flag butyrine, which is characterized in that n-butyric acie -1-
(13It COOH is) 1:1~5 with the molar ratio of chlorination reagent；The temperature that chlorination reagent is added is -20~0 DEG C, the temperature being stirred to react
It is 0~100 DEG C, preferably 40~60 DEG C, being stirred to react the time is 2~12h, preferably 6~8h；The solvent is bis- chloroethene of 1,2-
One or more of alkane, methylene chloride, benzene or toluene；The chlorination reagent is in thionyl chloride, oxalyl chloride or phosphorus trichloride
One or more.
4. one kind according to claim 113The synthetic method of C flag butyrine, which is characterized in that just by intermediate
Butyryl is chloro-13C is dissolved in solvent, is slowly added dropwise under heating stirring into dry bromine, is stirred to react, after reaction will reaction
Object is cooled to room temperature, and rotation removes solvent, and 150 DEG C of faint yellow oily fraction intermediate 2- bromo-butyric acid acyl chlorides-are collected in vacuum distillation13C。
5. one kind according to claim 413The synthetic method of C flag butyrine, which is characterized in that the positive fourth of intermediate
Acyl chlorides-13The molar ratio of C and bromine is 1:1~5；Being stirred to react the time is 2~12h, preferably 6~8h；Being stirred to react temperature is 30
~120 DEG C, preferably 70~90 DEG C；The solvent is one in 1,2- dichloroethanes, methylene chloride, chloroform or 1,4- dioxane
Kind is several.
6. one kind according to claim 113The synthetic method of C flag butyrine, which is characterized in that by methenamine
It is dissolved in solvent, is stirred, being passed through dry ammonia to solution ph at room temperature is alkalinity, is added dropwise to intermediate 2- bromo-butyric acid acyl
It is chloro-13The organic solution of C is obtained by filtration colorless solid, is tied again with the mixed solution of methanol and petroleum ether to fully reacting
Crystalline substance obtains colourless powder solid intermediate 2- amino-butanamide-13C。
7. one kind according to claim 613The synthetic method of C flag butyrine, which is characterized in that intermediate 2- bromine
Butyric acid acyl chlorides-13Molar ratio 1:1~5 of C and methenamine；Reaction time be 1~8h, preferably 3~4h, the solvent be methanol,
One or more of ethyl alcohol or isopropanol；Solution ph is between 8~12, between preferably 9~10.
8. one kind according to claim 113The synthetic method of C flag butyrine, which is characterized in that by intermediate 2-
Amino-butanamide-13C is hydrolyzed using acid, is obtained product through active carbon decoloring, is tied again with the mixed solution of water and ethyl alcohol
Crystalline substance, be obtained by filtration colourless powder solid butyrine-(13COOH)。
9. one kind according to claim 813The synthetic method of C flag butyrine, which is characterized in that acid used is
One or more of hydrochloric acid, sulfuric acid or hydrobromic acid of 1~6mol/L of concentration；The reaction temperature of hydrolysis is 50~100 DEG C,
Preferably 70~80 DEG C；Reaction time be 6~for 24 hours.
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Cited By (1)
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| CN115850216A (en) * | 2022-11-29 | 2023-03-28 | 上海化工研究院有限公司 | Stable isotope labeled 2, 5-furandicarboxylic acid-2- 13 Method for synthesizing COOH |
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