CN108299184A - A kind of preparation method of deuterated ginkgoic acid - Google Patents
A kind of preparation method of deuterated ginkgoic acid Download PDFInfo
- Publication number
- CN108299184A CN108299184A CN201810165424.1A CN201810165424A CN108299184A CN 108299184 A CN108299184 A CN 108299184A CN 201810165424 A CN201810165424 A CN 201810165424A CN 108299184 A CN108299184 A CN 108299184A
- Authority
- CN
- China
- Prior art keywords
- deuterated
- acid
- ginkgoic acid
- ginkgoic
- rhodium
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation methods of deuterated ginkgoic acid, include the following steps：1) mixed solution of dichloro (pentamethylcyclopentadiene) rhodium (III) deuterated methanol and heavy water is dissolved；2) ginkgoic acid is first dissolved with heavy water, then adds dichloro (pentamethylcyclopentadiene) rhodium (III) solution of preparation again, stirred, with deuterated sodium hydroxide tune pH value to alkalinity, microwave heating；3) solution that reaction is completed is adjusted to acidity with acid regulator, is repeatedly extracted with ether, combined ether layer, it is dry, deuterated ginkgoic acid is obtained after concentration.The preparation method of the present invention is simple, easy to operate, of low cost；The deuterated ginkgoic acid standard items purity prepared is high, and chemical property is stablized, and preparation is facilitated, and can be used for producing the deuterated internal standard compound used when analysis detection ginkgoic acid, has filled up the market has openings of product.
Description
Technical field
The present invention relates to chemical analysis detection fields, and in particular to a kind of preparation method of deuterated ginkgoic acid.
Background technology
Ginkgo (Ginkgo biloba.L) belongs to the deciduous tree of Ginkgoaceae Ginkgo.Since ancient times, just have will be silver-colored in China
Apricot leaf is used as medicine the record with dietotherapy, such as《This is through meeting source》Described in：" ginkgo leaf is distributed in lung channel, can astringe the lung and relieving asthma, invigorating heart analgesic ".Closely
In decades, domestic and foreign scholars are to the chemistry of active constituent, biology and the progress such as pharmacological activity and clinic and application in ginkgo
Numerous studies, ginkgo biloba extract and its preparation at present have become treatment and prevention Cardial or cerebral vascular diseases generally acknowledged in the world
Autonomic drug, and be expected to become effective medicine of the senile dementias relevant diseases such as treatment alzheimer's disease.Ginkgoic acid is in ginkgo
A kind of main component, be 6- alkyl or the salicylic derivative of 6- alkenyls.Ginkgoic acid is because with sensitization, embryotoxicity, exempting from
The bio-toxicities such as epidemic disease toxicity and cytotoxicity, and be considered as main side effects in ginkgo biloba p.e and its preparation at
Point, and provide that its limitation must not exceed 5ppm, the content of ginkgoic acid oneself through main at one in ginkgo agent quality standard
Con trolling index.
Quality control has external standard method and internal standard method in Pharmaceutical Analysis method.External standard method is exactly that standard is added into blank sample
Product monitoring analysis process and as a result, external standard method require whole operation process is strictly controlled, otherwise cause analytical error；Internal standard method
It is that the method for adding internal standard compound in sample to be tested is monitored, reduces the influence of many objective factors.For internal standard method and
The selection of external standard method, it is considered that：Under conditions of, result precision relatively high for precision requirement will produce significant impact,
Internal standard method is selected first.Because internal standard method can to avoid in Pharmaceutical Analysis due to complicated matrix effect, pre-treatment and mass spectrum inspection
The influences of the factors to analysis method measurement result such as device are surveyed, the generation of false negative especially can be effectively controlled, it can be effectively
The error occurred in bearing calibration significantly improves the rate of recovery and method stability of target compound.And internal standard method is used to carry out
When analysis, to obtain most rigorous, most accurate analysis result, best internal standard compound is the deuterated standard items of each analysis object.
Currently, the deuterated standard items sold on domestic market are to act on behalf of based on external product, it is expensive, and about deuterium
Product for ginkgoic acid is even more blank, and market is in short supply, also has no the research report of related manufacturing processes.
Invention content
To solve the deficiencies in the prior art, a kind of in short supply, work of present invention offer of deuterated ginkgo acid product on the market is provided
Skill reasonable design, operability is strong, and product purity is high, yield it is high, it can be achieved that industrialized production deuterated ginkgoic acid preparation method.
To achieve the goals above, technical scheme is as follows.
A kind of preparation method of deuterated ginkgoic acid, which is characterized in that include the following steps：
1) mixed solution of dichloro (pentamethylcyclopentadiene) rhodium (III) deuterated methanol and heavy water is dissolved, obtains dichloro
(pentamethylcyclopentadiene) rhodium (III) solution；
2) ginkgoic acid is first dissolved with heavy water, then adds dichloro (pentamethylcyclopentadiene) rhodium of step 1) preparation again
(III) solution, stirring, with deuterated sodium hydroxide tune pH value to 10~12, microwave heating, the following institute of the ginkgoic acid structural formula
Show：
3) solution that reaction is completed in step 2) is adjusted to acidity with acid regulator, is extracted 2~5 times with ether, merged
Ether layer, it is dry, deuterated ginkgoic acid is obtained after concentration；
Preferably, the mass fraction of dichloro (pentamethylcyclopentadiene) rhodium (III) solution that prepared by the step 1)
It is 1.6%~3.3%, the volume ratio of deuterated methanol and heavy water is 1: 6~10 in mixed solution；
Preferably, the temperature of the step 2) microwave heating be 160 DEG C~220 DEG C, the reaction time be 18min~
35min。
The common method for preparing compound isotopically labelled, is synthesized with using the reaction substrate of isotope labelling,
There is advantage in terms of the anticipation acquisition of product, but for natural isotope, need to take more time and hold high
Your reagent.It is a kind of more advantageous method containing deuteride to allow target molecule to carry out H/D exchanges to prepare, and this method is more
Soon, more effective and more economical material benefit.This method eliminates the step of purifying below, can be effective and can be pre- but must use
The pattern of survey introduces D-atom.As a kind of synthetic technology, H/D exchanges are a kind of to focus primarily upon the catalysis and gold that pH is relied on
Belong to the reaction process of catalysis.It finds in practice：The soluble rhodium complex of certain mass score as a kind of homogeneous catalyst,
Exchange especially suitable for H/D in compound under alkaline condition, the but if mass fraction of rhodium complex is excessively high, urge
It is too strong to change performance, then ginkgoic acid will be promoted to decompose.In above-mentioned reaction environment, alkalinity is be conducive to ginkgoic acid deuterated anti-
With the increase of deuterated amount of sodium hydroxide when answering, and starting, the deuterated rate of ginkgoic acid is consequently increased, when deuterated sodium hydroxide
When amount is more than certain value, there is time reaction in deuterated reaction, therefore the additive amount of deuterated sodium hydroxide will be controlled strictly.Microwave is auxiliary
It is a kind of common method in organic synthesis to help reaction, it can obtain the product of high yield in a short time.Microwave radiation technology has
Promote the effect of H/D exchange reactions, which, which is the energy of magnetron release, can directly affect salting liquid, and then activate c h bond,
Improve H/D exchange efficiencies.In practice, it has been found that the acid extraction of microwave can produce the effect of H/D exchange reactions
Raw to influence, control is not also easy to produce decomposing phenomenon strictly.
Preferably, in the step 2), in the ginkgoic acid per 2.5mg, the heavy water volume of addition be 1.6mL~
Dichloro (pentamethylcyclopentadiene) rhodium (III) liquor capacity of 3.3mL, addition are 0.1mL~0.7mL.
Preferably, the acid regulator in the step 3) is deuterated hydrochloric acid, deuterated phosphoric acid, deuterated formic acid, deuterium
For one kind in acetic acid, deuterated trifluoroacetic acid.
According to above-mentioned deuterated ginkgoic acid preparation method, which is characterized in that specifically comprise the following steps：
1) weigh dichloro (pentamethylcyclopentadiene) rhodium (III) in test tube with ground stopper, be added mixed solution, mixed solution by
Deuterated methanol and the heavy water composition that volume ratio is 1: 6~8, ultrasonic wave added dissolving obtain two that mass fraction is 1.6%~2.8%
Chlorine (pentamethylcyclopentadiene) rhodium (III) solution；
2) respectively into microwave reaction tank add 2.5mg ginkgoic acid, the heavy water of 1.6mL~2.8mL, 0.2~0.5mL's
Dichloro (pentamethylcyclopentadiene) rhodium (III) solution, with deuterated sodium hydroxide tune pH value to 10~12, mixing, sealing；
3) retort is placed in microwave dissolver, under conditions of temperature is 190 DEG C~210 DEG C, reaction 26min~
31min；
4) after the completion of, reaction solution is transferred in separatory funnel, with deuterated hydrochloric acid tune pH value to 3~6, be added 10mL~
23mL ether extracts, and extracts 3 times repeatedly, and combined ether layer is dried with anhydrous sodium sulfate, and deuterated ginkgoic acid is obtained after concentrated by rotary evaporation.
Description of the drawings
Fig. 1 is the mass spectrogram of ginkgoic acid；
Fig. 2 is the mass spectrogram of deuterated ginkgoic acid；
Fig. 3 is the infrared spectrogram of ginkgoic acid and deuterated ginkgoic acid；
Fig. 4 is that the 1H-NMR of ginkgoic acid schemes；
Fig. 5 is that the 1H-NMR of deuterated ginkgoic acid schemes.
Specific implementation mode
The present invention is described further With reference to embodiment, it is pointed out that following implementation is only
It is the indicative explaination done to the present invention in the form of enumerating, but protection scope of the present invention is not limited to that, Suo Youben
The technical staff in field each falls within protection scope of the present invention with the equivalent replacement that the spirit of the present invention is the present invention.
Embodiment 1
Experiment reagent and instrument：
Ginkgoic acid (13:0, purity：HPLC >=98%) it is purchased from Chengdu Crow agate bio tech ltd；, dichloro (five first
Butylcyclopentadiene) rhodium (III) (purity 99%), heavy water (D2O), deuterated hydrochloric acid (DCl) be purchased from purchased from lark prestige company；
Methanol (CH3OH, chromatographically pure, Oceanpak, Sweden)；1mol/LNaOD/D2O is by sodium and heavy water reaction self-control；Ether, just oneself
Alkane, anhydrous sodium sulfate, hydrochloric acid are purchased from Beijing traditional Chinese medicines reagent group；It is limited that spectroscopic pure potassium bromide is purchased from Aladdin reagent (Shanghai)
Company；Ultra-pure water (>18.2M Ω) it is standby using U.S. Milli-Q ultra-pure water instrument corporations；
Bruker AVANCE-500 superconducting pulse Fourier-transform nuclear magnetic resonance spectrometers (Bruker, Germany), LCQ
Advantage Max mass spectrographs (Fennigan Corp., CA, UK), ETHOS A microwave dissolvers (Italy,
MILESTONE), 101 type of electric drying oven with forced convection (bright Medical Instruments Co., Ltd forever), retort (Binhai County plastics at prime
Factory), ultrasonic cleaner KQ3200E types (Shanghai Shanghai ooze experimental instruments and equipment limited), electronic balance AL204 types (Shanghai Mei Te
Le-support benefit Co., Ltd).
Experimental method：
Paper electrospray mass spectrometry detects：Negative ion mode, paper spray voltage -3.5kV, capillary voltage and capillary temperature difference
It is set as 10V and 250 DEG C.15 μ L of sample size analyze deuterated ginkgoic acid sample methanol solution using methanol as eluent；With mass spectrum, Fu
In the analytical technologies such as leaf transformation infrared spectrum, nuclear magnetic resonance characterize ginkgoic acid (13:0) H is by positions replaced D and deuterated
Rate.
The selection of catalytic pH environmental condition
Claim 250.8mg dichloros (pentamethylcyclopentadiene) rhodium (III) in 25mL test tube with ground stoppers, be added 1mL deuterated methanols and
8.75mL heavy water ultrasonic dissolutions obtain 2.5% dichloro (pentamethylcyclopentadiene) rhodium (III) solution, abbreviation Rh complex solutions.Point
The ginkgoic acid of 2.5mg is added not into multiple microwave reaction tanks, the molar concentration of the heavy water of 2.8mL, 0 μ of μ L~40 L is
The deuterated sodium hydroxide of 1.0mol/L, the deuterated hydrochloric acid that the mass fraction of 0 μ of μ L~10 L is 35%, the mass fraction of 0.2mL are
2.5% dichloro (pentamethylcyclopentadiene) rhodium (III) solution, mixing, sealing；Retort is placed in microwave dissolver, in temperature
Under conditions of degree is 100 DEG C, 30min is reacted；After the completion of reaction, reaction solution is transferred in separatory funnel, is with mass fraction
50% deuterated hydrochloric acid tune pH value is added the extraction of 10mL ether, extracts 3 times repeatedly, combined ether layer, with anhydrous sodium sulfate to 6
It is dry, deuterated ginkgoic acid is obtained after concentrated by rotary evaporation, the results are shown in Table 1-1.
By table 1-1 it is found that Rh complexs do not urge the H/D exchange reactions of ginkgoic acid in the case of not acid adding or alkali
Change performance.Wherein serial number II and III has catalytic performance it is found that acid or alkali is added in Rh complexs to ginkgoic acid H/D exchanges, is added 40
The 1mol/LNaOD/D of μ L2The mass spectrogram of O, ginkgoic acid show that main peak is the peak [M+1], i.e., the d that a H atom is replaced by D1Peak, it is secondary
Peak is original matter d0The d that peak and two H atoms are replaced by D2Peak, d0、d1And d2Three's percentage contents are respectively 23.50%,
54.64%, 21.86%；The DCl of 10 μ L is added in Rh complexes systems, the catalysis ginkgoic acid H/D of Rh complexs exchanges effect not
If alkaline condition is good, mass spectrum shows that main peak is original mass peak d0Peak, only minimal amount of d1Peak.
The selection of table 1-1 catalyst and reaction acid-base property
Note：Molecular weight determines that ratio is determined by mass spectrum percentage contents by paper spray mass spectrum.d0、d1Refer to ginkgoic acid H to be taken by D
The number in generation.
Embodiment 2
The selection of deuterated sodium hydroxide additive amount
The ginkgoic acid of 2.5mg, the heavy water of 2.8mL, mole of 20 μ of μ L~80 L are added into multiple microwave reaction tanks respectively
The deuterated sodium hydroxide of a concentration of 1.0mol/L, dichloro (pentamethylcyclopentadiene) rhodium that the mass fraction of 0.2mL is 2.5%
(III) solution, mixing, sealing；Retort is placed in microwave dissolver, under conditions of temperature is 150 DEG C, reacts 30min；
After the completion of reaction, reaction solution is transferred in separatory funnel, the deuterated hydrochloric acid tune pH value for being 50% with mass fraction is added to 6
10mL ether extracts, and extracts 3 times repeatedly, and combined ether layer is dried with anhydrous sodium sulfate, and deuterated ginkgoic acid is obtained after concentrated by rotary evaporation,
It the results are shown in Table 1-2.
By table 1-2 it is found that the deuterated rate of ginkgoic acid increases, reaction substrate with the increase of deuterated sodium hydroxide additive amount
The content of d0- ginkgoic acids is lower and lower.When deuterated sodium hydroxide additive amount amount adds to 50 μ L, H/D exchange reactions rapidly accelerate and
Acutely, the peak of d0- ginkgoic acids and d1- ginkgoic acids all disappears, and occurs more than the peak of 50%d3- ginkgoic acids, continues growing deuterated hydrogen
The amount of sodium oxide molybdena, the deuterated extent of reaction continue to increase, be added 60 μ L deuterated sodium hydroxide, that is, pH be 11 when, d3- ginkgoic acids at
It is 77.5% for main peak, the d4- ginkgoic acids containing about 1/4, but when deuterated amount of sodium hydroxide is added to 80 μ L, ginkgoic acid H/D is handed over
Reaction is changed to be not so good as to add the effect of 60 μ L NaOD instead, it is deuterated time reaction occur.
Table 1-2NaOD/D2The influence of the amount ginkgoic acid H/D reactions of O
Note：Molecular weight determines that ratio is determined by mass spectrum percentage contents by paper spray mass spectrum.d0-d4Refer to ginkgoic acid H to be taken by D
The number in generation is 0-4.
Embodiment 3
The selection of reaction temperature
The ginkgoic acid of 2.5mg is added into multiple microwave reaction tanks respectively, the molar concentration of the heavy water of 2.8mL, 60 μ L is
When deuterated sodium hydroxide, that is, pH of 1.0mol/L is 11, dichloro (pentamethylcyclopentadiene) that the mass fraction of 0.2mL is 2.5%
Rhodium (III) solution, mixing, sealing；Retort is placed in microwave dissolver, under conditions of temperature is 120 DEG C~200 DEG C, instead
Answer 15min；After the completion of reaction, reaction solution is transferred in separatory funnel, the deuterated hydrochloric acid tune pH value for being 50% with mass fraction
To 6, the extraction of 10mL ether is added, extracts 3 times repeatedly, combined ether layer is dried with anhydrous sodium sulfate, is obtained after concentrated by rotary evaporation deuterated
Ginkgoic acid the results are shown in Table 1-3.
Influence of the table 1-3 temperature to ginkgoic acid H/D exchange reactions
Molecular weight determines that ratio is determined by mass spectrum percentage contents by paper spray mass spectrum.d1-d5The H for referring to ginkgoic acid is taken by D
The number in generation.
By table 1-3 it is found that high temperature is conducive to ginkgoic acid H/D exchange reactions, but add in view of ginkgoic acid too high-temperature decomposes
It is acute.H/D exchanges, d just has occurred in ginkgoic acid microwave reaction 15min at 120 DEG C0Ginkgoic acid accounts for main body, is left 66.23%, secondary peak
For d1Ginkgoic acid, also a small amount of d2Ginkgoic acid.Temperature is increased, deuterated rate obviously increases, d0Peak is reduced rapidly, d1And d2Peak increases
Add, when rising to 180 DEG C, d occurs3Product.It is heated to reaction substrate d at 200 DEG C0Ginkgoic acid only has 5%, and product is mainly d3
And d4Ginkgoic acid has also appeared a small amount of d5Ginkgoic acid, estimation are 3 aromatics of phenyl ring and the methylene 2 of benzyl position
Deuterated reaction has occurred in proton, and decomposes and diastereomerism also unobvious.
Embodiment 4
The selection in reaction time
The ginkgoic acid of 2.5mg is added into multiple microwave reaction tanks respectively, the molar concentration of the heavy water of 2.8mL, 60 μ L is
When deuterated sodium hydroxide, that is, pH of 1.0mol/L is 11, dichloro (pentamethylcyclopentadiene) that the mass fraction of 0.2mL is 2.5%
Rhodium (III) solution, mixing, sealing；Retort is placed in microwave dissolver, under conditions of temperature is 120 DEG C, reacts 5min
~40min；After the completion of reaction, reaction solution is transferred in separatory funnel, the deuterated hydrochloric acid tune pH value for being 50% with mass fraction
To 6, the extraction of 10mL ether is added, extracts 3 times repeatedly, combined ether layer is dried with anhydrous sodium sulfate, is obtained after concentrated by rotary evaporation deuterated
Ginkgoic acid the results are shown in Table 1-4.
Influence of the table 1-4 reaction time to ginkgoic acid H/D exchange reactions
Note：Molecular weight determines that ratio is determined by mass spectrum percentage contents by paper spray mass spectrum.d0-d4Refer to the H of ginkgoic acid by D
Substituted number is 0-5.
By table 1-4 it is found that the deuterated reaction of microwave is faster compared to traditional deuterated reaction of heating, when substantially reducing reaction
Between.Bigger H/D exchange reactions, d just has occurred in reaction 5min ginkgoic acids1Product just account for 30% or more, reaction substrate
Just only 60% or so.The proper extension reaction time is conducive to ginkgoic acid H/D and exchanges, and reaction 30min can't detect substrate d0-
Ginkgoic acid, product are mainly d3Ginkgoic acid, there is also about 22% d4Ginkgoic acid.But lengthen reaction time deuterated rate not
There is raising, but reaction has occurred back, product is with d0Ginkgoic acid and d1Based on ginkgoic acid, and Whole Response value is almost low
An order of magnitude.This illustrates that high temperature can accelerate the H/D exchange rates of ginkgoic acid, but the reaction time is long but also will produce decomposition now
As.
Embodiment 5
Experimental method：
Infrared spectrum detects：Appropriate amount of sample and tabletting after potassium bromide mixing, carry out infrared spectrum qualitative analysis；Nuclear magnetic resonance
Analysis：It is solvent with DMSO-d6, having carried out 1H-NMR and 13C-NMR to sample detects.
The characterization of deuterated ginkgoic acid
Claim 250.8mg dichloros (pentamethylcyclopentadiene) rhodium (III) in 25mL test tube with ground stoppers, be added 1mL deuterated methanols and
8.75mL heavy water ultrasonic dissolutions obtain 2.5% dichloro (pentamethylcyclopentadiene) rhodium (III) solution, abbreviation Rh complex solutions.Point
The ginkgoic acid of 2.5mg is added not into microwave reaction tank, the molar concentration of the heavy water of 2.8mL, 60 μ L is the deuterated of 1.0mol/L
When sodium hydroxide, that is, pH value is 11, dichloro (pentamethylcyclopentadiene) rhodium (III) solution that the mass fraction of 0.2mL is 2.5%,
Mixing, sealing；Retort is placed in microwave dissolver, under conditions of temperature is 200 DEG C, reacts 30min；Reaction is completed
Afterwards, reaction solution is transferred in separatory funnel, 10mL ether is added to 6 in the deuterated hydrochloric acid tune pH value for being 50% with mass fraction
Extraction extracts 3 times repeatedly, and combined ether layer is dried with anhydrous sodium sulfate, deuterated ginkgoic acid is obtained after concentrated by rotary evaporation, and purity is
93.5%, the rate of recovery 88.6%.Respectively by mass spectrum (see Fig. 1 and 2), infrared spectrum (see Fig. 3), nmr spectrum (see
Figure 4 and 5) the deuterated ginkgoic acid prepared by the above method is characterized.
From Fig. 1 and 2：Deuterated product has because of the number difference of the atom containing isotope D after ginkgoic acid H/D exchange reactions
Different molecular masses, therefore mass spectral analysis can be used and differentiate these deuterated products.Fig. 1 and 2 is ginkgoic acid and deuterated ginkgo
The mass spectrogram of acid.Molecular ion peak [M-1] under ginkgoic acid negative ion mode is 319.3.Main peak in Fig. 2 is 322.5 Hes
323.4, it is mainly d3- ginkgoic acids, content 78.17%, also a small amount of d4- ginkgoes to illustrate that the deuterated product of ginkgoic acid is
Acid.Reaction substrate d0- ginkgoic acids and other deuterated products have seldom been less than detection line.D3- ginkgoic acids and original matter d0- ginkgoes
Acid can be completely separable in mass spectrogram, and has been separated with the natural isotopic peak of d0- ginkgoic acids, therefore entirely appropriate makees mass spectrum
Uantitative analytical ginkgo acid content.
As shown in Figure 3：Ginkgoic acid is as the functional group of deuterated ginkgoic acid, so infrared spectrum is almost the same, uniquely not
Same is that c h bond and C-D key stretching vibrations peak position are different, the vibration peak wavelength (2200cm of C-D keys-1Near) to be less than phenyl ring
C h bond (3000cm-1Near).Due to ginkgoic acid (13:0) molecular weight is bigger, and branch C-H groups are long, phenyl ring proton and
Branched alkyl proton H/D exchange does not carry out completely, therefore the infrared spectrum of deuterated ginkgoic acid and the common ginkgoic acid of substrate is very in Fig. 3
It is similar, do not see prodigious variation.Therefore it needs further accurately to characterize the structure of deuterated product with NMR spectrum.
As shown in Figure 4：Fig. 4 is ginkgoic acid GA (13:0)1H-NMR spectrum utilizes GA (13:0) chemistry known to H NMR spectroscopy
Displacement (δ) is that the broad peak at 10.196 is GA (13:0)-COOH proton peaks, 3 phenyl ring chemical shift of proton are as follows：H4(δ
7.15, m, 1H, J4,3=8.5HZ, J4,5=7.5HZ), H3(δ 6.714d, 1H, J=8.5HZ)、H5(δ 6.67, d, 1H, J=
7.5HZ).A broad peak is the moisture peak in ginkgoic acid-OH protons and sample between δ 3~4, and the triplet of δ 2.592 is in phenyl ring
No. 7 connected benzyl methene proton peaks, the multiplet at δ 1.5 are close to No. 8 methene proton peaks of No. 7 methylene, δ
No. 8 methylene and 10 methene proton peaks among No. 9 methyl of the big Bao Fengwei ginkgoic acids branch of 1.23 attachmentes, δ 0.856
Triplet be No. 9 methyl peaks of branch terminals.
The GA (13 known to Figure 4 and 5:0) methyl-CH3H/D exchanges do not occur for proton, therefore do not have when the deuterated rate of calculating
Other internal standards are added, with integrated value and the-CH of other protons33 protons integrated value compared to relatively calculating deuterated rate.Cause
This can be seen that：H4H/D exchange reactions do not have complete, deuterated rate is about 57%；H3And H5H/D exchange substantially completely, deuterium
It is 95% for rate；H7Reaction after integrate and nearly reduce 1, it may thus be appreciated that in 2 protons of benzyl 1 replaced by D, deuterated rate is about
It is 94%.Therefore, 3 proton H/D of 3,5, No. 7 positions have been exchanged substantially completely, and the proton of No. 4 positions alreadys exceed half and taken by D
In generation, this is consistent with mass spectral results.
Claims (4)
1. a kind of preparation method of deuterated ginkgoic acid, which is characterized in that include the following steps：
1) mixed solution of dichloro (pentamethylcyclopentadiene) rhodium (III) deuterated methanol and heavy water is dissolved, obtains dichloro (five first
Butylcyclopentadiene) rhodium (III) solution；
2) ginkgoic acid is first dissolved with heavy water, dichloro (pentamethylcyclopentadiene) rhodium (III) for then adding step 1) preparation again is molten
Liquid, stirring, with deuterated sodium hydroxide tune pH value to 10~12, microwave heating, the ginkgoic acid structural formula is as follows：
3) solution that reaction is completed in step 2) is adjusted to acidity with acid regulator, is extracted 2~5 times with ether, merge ether
Layer, it is dry, deuterated ginkgoic acid is obtained after concentration；
Wherein, the mass fraction of dichloro (pentamethylcyclopentadiene) rhodium (III) solution that prepared by the step 1) is 1.6%~
3.3%, the volume ratio of deuterated methanol and heavy water is 1: 6~10 in mixed solution；
Wherein, the temperature of the step 2) microwave heating is 160 DEG C~220 DEG C, and the reaction time is 18min~35min.
2. the preparation method of deuterated ginkgoic acid according to claim 1, which is characterized in that in step 2), the silver per 2.5mg
In apricot acid, the heavy water volume of addition is 1.6mL~3.3mL, dichloro (pentamethylcyclopentadiene) rhodium (III) liquor capacity of addition
For 0.1mL~0.7mL.
3. the preparation method of deuterated ginkgoic acid according to claim 1, which is characterized in that the acid regulator in step 3)
For one kind in deuterated hydrochloric acid, deuterated phosphoric acid, deuterated formic acid, deuterated acetic acid, deuterated trifluoroacetic acid.
4. according to any deuterated ginkgoic acid preparation method of claims 1 to 3, which is characterized in that include the following steps：
1) dichloro (pentamethylcyclopentadiene) rhodium (III) is weighed in test tube with ground stopper, mixed solution is added, mixed solution is by volume
Than the deuterated methanol and heavy water composition for 1: 6~8, ultrasonic wave added dissolving obtains the dichloro (five that mass fraction is 1.6%~2.8%
Methyl cyclopentadiene) rhodium (III) solution；
2) ginkgoic acid of 2.5mg, the heavy water of 1.6mL~2.8mL, the dichloro of 0.2~0.5mL are added into microwave reaction tank respectively
(pentamethylcyclopentadiene) rhodium (III) solution, with deuterated sodium hydroxide tune pH value to 10~12, mixing, sealing；
3) retort is placed in microwave dissolver, under conditions of temperature is 190 DEG C~210 DEG C, reacts 26min~31min；
4) after the completion of, reaction solution is transferred in separatory funnel, with deuterated hydrochloric acid tune pH value to 3~6,10mL~23mL second is added
Ether extracts, and extracts 3 times repeatedly, and combined ether layer is dried with anhydrous sodium sulfate, and deuterated ginkgoic acid is obtained after concentrated by rotary evaporation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810165424.1A CN108299184B (en) | 2018-02-27 | 2018-02-27 | Preparation method of deuterated ginkgoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810165424.1A CN108299184B (en) | 2018-02-27 | 2018-02-27 | Preparation method of deuterated ginkgoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108299184A true CN108299184A (en) | 2018-07-20 |
| CN108299184B CN108299184B (en) | 2021-01-15 |
Family
ID=62848961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810165424.1A Active CN108299184B (en) | 2018-02-27 | 2018-02-27 | Preparation method of deuterated ginkgoic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108299184B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | The method that a kind of utilization microchannel reaction unit prepares deuterated amino benzenes compounds |
| CN107353176A (en) * | 2017-08-11 | 2017-11-17 | 中国科学院广州生物医药与健康研究院 | A kind of method, the deuterated methyl compound of the aromatic series being prepared and its application that cyano group is catalytically converted into deuterated methyl |
-
2018
- 2018-02-27 CN CN201810165424.1A patent/CN108299184B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | The method that a kind of utilization microchannel reaction unit prepares deuterated amino benzenes compounds |
| CN107353176A (en) * | 2017-08-11 | 2017-11-17 | 中国科学院广州生物医药与健康研究院 | A kind of method, the deuterated methyl compound of the aromatic series being prepared and its application that cyano group is catalytically converted into deuterated methyl |
Non-Patent Citations (6)
| Title |
|---|
| ALYSSA L. GARREAU ET AL: "A Protocol for the Ortho -Deuteration of Acidic Aromatic Compounds", 《ORG. LETT.》 * |
| ANDERS KIRSTEIN PEDERSE ET.AL: "Preparation and analysis of deuterium‐labeled aspirin: Application to pharmacokinetic studies", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| BOLE YU ET AL: "Rhodium-catalyzed C-H activation of hydrazines leads to isoquinolones with tunable aggregation-induced emission properties", 《CHEM. COMMUN》 * |
| CHRISTIAN P. LENGES ET AL.,: "Hydrogen/Deuterium Exchange Reactions and Transfer Hydrogenations Catalyzed by [C5Me5Rh(olefin)2] Complexes:Conversion of Alkoxysilanes to Silyl Enolates", 《J. AM. CHEM. SOC》 * |
| W.J.S. LOCKLEY: "Regioselective deuteration of aromatic and α,β-unsaturated", 《TETRAHEDRON LETTERS》 * |
| 钟冬莲等: "HPLC-MS /MS 法同时测定马尾松松针中水杨酸和茉莉酸", 《分析试验室》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108299184B (en) | 2021-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Breslow | Rapid Deuterium Exchange in Thiazolium Salts1 | |
| Eaton et al. | Kinetic isotope effect on proton tautomerism in tetraarylporphyrins | |
| Bernhard et al. | Direct measurement of a prominent outer-sphere electron self-exchange: kinetic parameters for the hexaaquaruthenium (II)/(III) couple determined by oxygen-17 and ruthenium-99 NMR | |
| CN104530105B (en) | Two boron fluoride complexings two pyrroles's methine derivative organic dyestuff of a kind of diazosulfide or benzene 1,4-Dithiapentalene bridging and preparation method thereof | |
| Miles et al. | Antineoplastic agents. 3. The structure of juncusol. A novel cytotoxic dihydrophenanthrene from the estuarine marsh plant juncus reomerianus | |
| CN104277061A (en) | Boric acid fluorescence molecular probe as well as preparation method and application thereof | |
| Wigfield et al. | Factors influencing stereochemistry in the reduction of conformationally mobile 2-alkylcyclohexanones by sodium borohydride | |
| Robinson et al. | Rapid determination of organic hydroxyl groups with 3, 5,-dinitrobenzoyl chloride | |
| Salunkhe et al. | N, N-Diethylaniline· borane, an efficient reducing agent for reduction of representative functional groups | |
| CN108299184A (en) | A kind of preparation method of deuterated ginkgoic acid | |
| Mazur et al. | Long-distance intramolecular electron transfer in a macrocyclic crown ether, a thermoneutral, nonadiabatic process | |
| Mc Ewen et al. | Hydrogen bonding of hydroxy groups to carbanions in indenide-and fluorenide-derivatized alcohols directly observed by UV, IR, and NMR spectroscopy | |
| Dalzell et al. | Crystal structure of potassium tris (oxalato) rhodate (III) | |
| CN106117197A (en) | A kind of method being prepared 2,3,9,10 4 butoxy protoberberines by Rhizoma Coptidis mixed biologic alkali | |
| Lipkin et al. | Iodination of thymidine. Synthesis of 06, 5'-cyclothymidine | |
| Brufani et al. | The x-ray analysis of the structure of rifamycin Y | |
| Risley et al. | Oxygen-18 isotope effect in carbon-13 nuclear magnetic resonance spectroscopy. 8. Oxygen exchange of 2, 4, 6-trimethylpyrylium cation | |
| Wiberg et al. | Thermochemical studies of carbonyl reactions. 2. Steric effects in acetal and ketal hydrolysis | |
| Bonnet et al. | Spectroscopic and structural characterization of ruthenium (II) carbonyl-porphine complexes | |
| Lunazzi et al. | Conformational studies by dynamic nuclear magnetic resonance. Part 4. Rotational isomers and torsional barriers of pyridinecarbaldehydes | |
| Bellobono et al. | Kinetics of the reaction of 1, 3-dinitrobenzene with methoxide ion in methanol solution | |
| Holzberger et al. | Conformational analysis of mixed oxathia crown ethers and their complexational ability towards Ag (i) and Pd (ii)—an experimental solution NMR and theoretical molecular modelling study | |
| Johlman et al. | Wittig reaction of a boron-stabilized carbanion with carbon dioxide in the gas phase | |
| Frisch et al. | Synthesis and crystal structure analysis of a rhodiacyclopentenedione complex containing a coordinated water ligand | |
| Onda et al. | Structure of carzinophilin. 3. Structure elucidation by nuclear magnetic resonance spectroscopy. 1 |
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 | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20180720 Assignee: Hunan Warburg Pharmaceutical Co.,Ltd. Assignor: HUNAN NORMAL University Contract record no.: X2023980034736 Denomination of invention: A preparation method of deuterated ginkgolic acid Granted publication date: 20210115 License type: Common License Record date: 20230414 |
|
| EE01 | Entry into force of recordation of patent licensing contract |