CN102020521A - Preparation mode and application of deuterium substituted Chinese herbal monomer - Google Patents
Preparation mode and application of deuterium substituted Chinese herbal monomer Download PDFInfo
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Abstract
The invention relates to a preparation mode and application of a deuterium substituted Chinese herbal monomer. The Chinese herbal monomer is a chemical compound extracted and separated from Chinese herbs, a hydrocarbon structure (C: H) is one of the essential structures in the chemical molecular structure of the Chinese herbal monomer, and a formed carbon-hydrogen bond is an essential chemical bond. The preparation method and the application of the deuterium substituted Chinese herbal monomer which can change the bond energy of the chemical bond and a hydrogen bond of the Chinese herbal monomer chemical compound are disclosed. In the preparation method, deuterium atom (D) which is an isotopic nuclide of hydrogen is used for substituting hydrogen atom (H) in the molecular structure of the Chinese herbal monomer chemical compound to change the chemical molecular structure and the bond energy of the replaced Chinese herbal monomer so as to form a novel deuterium substituted Chinese herbal monomer. The deuterium substituted Chinese herbal monomer can be used for studying Chinese herbal pharmacokinetics, obviously enhancing the functions of Chinese herbal monomer on disease prevention and treatment, and reducing the toxic and side effects of the Chinese herbal monomer.
Description
Technical field
The invention belongs to the medical medicine technical field, relate in particular to preparation method and the application of deuterium for traditional Chinese medicine monomer.
Background technology
Chemicals new drug development difficulty is big, the cycle is long, expense is high, makes the exploitation of plant milk extract become new selection.Purified traditional Chinese medicine monomer compound, its structure is clear, the pharmaceutical research data is comprehensive, all belongs to this type of as rutin, Potenlini, taxol etc.Plant monomer compound drug effect is clear and definite, as the Artemisinin developed from the Chinese medicine sweet wormwood and the preparation of derivative thereof, is to treat the best medicine of malaria at present; The coixenolide that extracts from the Chinese medicine Semen Coicis can be antitumor, but enhancing immunity again, to put, chemotherapy can play synergism and attenuation; Particularly Artemisinin has international organization's volumn of purchase of 1,500,000,000～4,000,000,000 dollars every year at least, has become international cookle formula medicine.But, the normal two big shortcomings that exist of many monomeric compounds: the one, easily by liver P450 drug degradation enzyme system degraded in the body, a little less than the effect; The 2nd, there is poison, pays effect.
Carbon in the traditional Chinese medicine monomer molecular structure of compounds: hydrogen structure (C:H) is the most basic structure, the C-H (C-H) that forms also is the most basic chemical bond, hydrogen bond is represented with X-H...Y, and distance between the X-Y is decided to be the bond distance of hydrogen bond, hydrogen bond has bond energy, and structure of hydrogen bonds parameter such as bond distance, bond angle, asking property of side can change in quite on a large scale, influence bond energy, the bond distance is short more, and hydrogen bond is strong more.Though the bond energy of hydrogen bond is little, very big to the influence of physical property, reason has two: 1. form maximum hydrogen bond principles, material inside becomes to asking in as far as possible hydrogen bonds that generate to reduce the energy of system more.2. because hydrogen bond energy is little, its formation and to destroy required activation energy also little, between the material interior molecules and under the continuous motion change condition of intramolecularly, hydrogen bond constantly ruptures and forms, the hydrogen bonded of maintenance some amount in material.The formation of hydrogen bond all can have deep effect to the various physicochemical property of material, also plays crucial effect [((structural chemistry basis)), the 4th edition, 322 pages in human and vegeto-animal physiology, biological process.Zhou Gongdu writes, the BJ University Press].
Therefore, change monomeric compound chemical bond and hydrogen bond energy, can change monomeric chemistry, pharmaceutical properties.
But the technological approaches and the means that change monomeric compound chemical bond and hydrogen bond energy are very difficult.
Summary of the invention
In view of this, problem to be solved by this invention is: invented can change traditional Chinese medicine monomer compound chemistry key and hydrogen bond energy deuterium for traditional Chinese medicine monomer preparation method and application.For full and accurate explanation technical scheme of the present invention, need set forth accordingly principle of the present invention:
Hydrogen has three kinds of isotropic substances: nucleidic mass is 1 protium (common name hydrogen is stable isotropic substance for Hydrogen, symbol of element H); Nucleidic mass be 2 deuterium (Deuterium, symbol of element D or
2H, the hydrogen of also weighing is stable isotropic substance) and nucleidic mass be 3 tritium (symbol of element T, a kind of radio isotope).
Deuterium is as a kind of stable form isotropic substance of hydrogen, and its nucleus is made up of a proton and a neutron.Than the many neutrons (D atom amount=2, microcrith=1) of hydrogen nuclei, cause the C-D chemical bond than stable (fast 6 times of the c h bond breakdown rates of c h bond than C-D key; Consult 1,＜＜Nature News home, Published online 16March 2009|Nature|doi:10.1038/458269a; 2,＜＜Chemistry﹠amp; , Industry〉〉 2009.March.9; Page 24-26).As monomeric compound chemical structure methyl C-H
3Key is by C-D
3Replace, the hydrogen bond energy grow, strengthened the stability of individual molecule, though it is very small with regard to the individual molecule bond energy, but hundreds of millions molecules are combined in and form material simultaneously, again at kinetic isotope effect Kinetic Isotope Effect) effect under, finally change monomeric chemistry, pharmacology pharmacokinetics character significantly.Obtain beyond thought effect, the monomer that significantly slows down is a degradation rate by liver P450 enzyme, optimizes the monomer pharmacokinetics, obviously strengthens the monomer drug effect, increases the monomer new indication.The drug effect enhancing causes reducing the monomer dosage, reduces this monomer meta-bolites, reduces the monomer poison, pays effect.Form the novel isotropic substance substituted monomer of a class: be called deuterium for traditional Chinese medicine monomer.
In order to reach above-mentioned target, need the technology of preparation deuterium for traditional Chinese medicine monomer.Existing preparation deuterium generation technique is to adopt the multistep synthesis method, and the step complexity, equipment is many, efficient is low.
Synthetic deuterium has two main paties for traditional Chinese medicine monomer: the one, with heavy water (deuterium gas) suitable traditional Chinese medicine monomer is carried out catalytic reduction; Another is that heavy water uses (deuterium gas) that the Lu Shi element of traditional Chinese medicine monomer is carried out catalysis halogen-deuterium exchange.
In order to solve above technical problem, provide a kind of technology for preparing deuterium for traditional Chinese medicine monomer in the specific embodiments of the present invention.Adopt heavy water, effective catalyst, synthetic with the traditional Chinese medicine monomer compound replacement with suitable chemical structure, the preparation deuterium is for traditional Chinese medicine monomer, and its feature comprises:
(1) heavy water (D
2O), deuterium gas (D
2), deuterium is for ethanol, deuterated methanol; Concentration: 1-99.6%;
(2) purity is greater than 90% traditional Chinese medicine monomer compound;
(3) palladium carbon, platinum carbon, ruthenium C catalyst; Content 5-10%;
(4) microwave chemical reactor;
(5) liquid column chromatography separation system;
As a kind of preferred implementation, of the present invention be the preparation scheme that specifically provided in the embodiment, comprise as lower section or full technical characterictic:
(1) described D derives from heavy water (D
2O), deuterium gas (D
2), deuterium is for ethanol, deuterated methanol, concentration: 1-99.6%, for water-soluble traditional Chinese medicine monomer, preferred heavy water; For fat-soluble traditional Chinese medicine monomer, preferred deuterium is for organic solvent;
(2) traditional Chinese medicine monomer is meant that the purity that obtains from single medicinal material is greater than 90% monomeric compound;
(3) palladium carbon, platinum carbon, ruthenium C catalyst; Content 5-10%; Preferred palladium-carbon catalyst;
(4) reaction system is used: ph:7-12, preferred 10; Temperature: 20～200 ℃, preferred 160 ℃; Normal pressure, reaction times: 1-24 hour, preferred 20 hours;
When (5) using microwave chemical reaction, the reaction times only needs: 30-60 minute;
Entire reaction general formula process is:
When (6) chemical structure of monomeric compound had one or more heterocycle structures, the H in the heterocycle was replaced by D, reaction conditions; 10% palladium-carbon catalyst, pH:10, temperature: 60-180 ℃, normal pressure, 20 hours;
When (7) chemical structure of monomeric compound has one or more methyl, methyl (CH
3) in H replaced reaction conditions by D; 5% palladium-carbon catalyst, pH:7, temperature: 60-180 ℃, normal pressure, 10 hours;
(8) deuterium is for the solution-air chemical exchange: for increasing deuterium for rate, the traditional Chinese medicine monomer compound is carried out pre-process; Raw material: a. catalytic exchange post b. deuterium gas, the fat-soluble traditional Chinese medicine monomer of c..In the catalytic exchange post, carry out the counter current contact reaction, realize the exchange of deuterium from the gas phase to the liquid phase;
(9) liquid column chromatography separation system, liquid chromatography separation and purification deuterium is for product, and recrystallization obtains deuterium for traditional Chinese medicine monomer.
According to above-mentioned preparation method, can prepare deuterium for monomer, it is characterized by:
(1) H of C:H has at least more than one and is replaced by D in the chemical structure of monomeric compound, forms the C:D structure.In the chemical formula :-CH ,-CH
2,-CH
3,-CH
n, change-CD-CD into
2,-CD
3,-CDn;
(2) deuterium has for traditional Chinese medicine monomer: be used for traditional Chinese medicine monomer medicines structure, metabolism, acceptor, pharmacology, toxicologic research as tracer; On drug effect, obtain beyond thought effect, promptly strengthen the application of traditional Chinese medicine monomer in preparation prevention, treatment disease drug effect; Reduce poison, pair effect of traditional Chinese medicine monomer to human body.
Description of drawings:
D contrast H structure and chemical bond energy synoptic diagram among Fig. 1, the present invention.
Fig. 2, monomeric compound selagine chemical structure.
Fig. 3, D replace H synoptic diagram in the selagine chemical structure.
Fig. 4, monomeric compound Tanshinone II A chemical structure.
Fig. 5, D replace H synoptic diagram in the Tanshinone II A chemical structure.
Embodiment
One, deuterium prepares for selagine:
The traditional Chinese medicine monomer selagine easily sees through hemato encephalic barrier, can anti-acetylcholinesterase, and be a kind of reversible inhibitor of acetylcholinesterase, obviously improve levels of acetylcholine in the brain, hypermnesis and regulate nerve excitability.Obvious promotion study, memory process are arranged or obviously improve amnemonic effect, and selectivity is distributed in cortex hippocampus etc. and study, the relevant brain district of memory, (Alzeheimers Disease AD) has good efficacy to be used for the treatment of optimum aging amnesia (Beniga Senescent Forgetfulners BSF) and old stupid disease.But this medicine and acetylcholinesterase receptors bind are insecure, and metabolism is fast, and need administration 4 times every day, have limited this medicine and have used.
Chinese: selagine;
Plant origin: a kind of alkaloid that extracts in the Huperziaceae plant Herba Lycopodii serrati [Huperzinaserrata (Thumb.) Trev]);
English name: Huperzine A;
CAS：102518-79-6；
Chemical name: (5R, 9R, 11E)-and 5-amino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is (b) pyridine-2 (1H) ketone also;
Molecular formula: C
15H
18N
2O;
Molecular weight: 242.32;
Structural formula: see Fig. 2;
Preparation raw material: 99.5% deuterated methanol, heavy water (U.S. Cambridge isotropic substance company), 99% (HPLC) selagine (Xi'an Chu Kang bio tech ltd), 5% palladium carbon catalyst (DuPont).
Reaction: in flask, add selagine 242mg (1mmol), be dissolved in 99.5% deuterated methanol 40ml, contain 5% palladium carbon catalyst 30mg, add heavy water 40ml in the dropping funnel, in flask, slowly drip pH=10, normal pressure, temperature: 60 ℃, reacted 6 hours, reaction is carried out.Cooling, stopped reaction promptly gets crude product, the filter paper separating catalyst, collect filtrate, the multistage liquid column chromatography separates [column chromatography silica gel (200～300 order) Haiyang Chemical Plant, Qingdao], collects parting liquid, the acetone recrystallization drying, obtain deuterium for selagine, yield 83%, deuterium is seen Fig. 3 for rate 96.8%.
Compound is confirmed:
Physical properties: dark white powder, fusing point: 214 ℃ (the micro-fusing point test of X4 type contains instrument), solvability: be soluble in methyl alcohol, ethanol, be slightly soluble in water.
Qualitative analysis: silica gel thin-layer chromatography GF254 silica gel thin-layer plate, selagine standard substance, deuterium are put on same plate chloroform for selagine solution: methyl alcohol (95: 5) launches, and with the iodine vapor colour developing, the Rf value is consistent.
Nuclear-magnetism spectrum: 1H-NMR (600MHz, CDCl
3, nuclear magnetic resonance spectrometer Bruker DRX-600 type), the selagine standard substance show: δ H 6.45 (1H, d, J=9.4, H-2), 7.92 (1H, d, J=9.4, H-3)], δ 5.53 (1H, q, J=6.7, H-11), 5.45 (1H, d, J=4.8, H-8)], 1 bimodal methyl [δ 1.72 (3H, d, J=6.7, Hz, and unimodal methyl [δ 1.56 (3H, s, J=6.1, H-16)] H-10)].After the reaction, methyl δ peak disappears in the hydrogen spectrum, uses deuterium spectrum (2H) instead, and methyl δ peak reproduces, 2H-NMR (61MHz, CH
2Cl
2), δ 2.16 (br s), δ 1.89 (br s).
13C-NMR(150MHz，CDCl3)：δC?165.6(C-1)，117.7(C-2)，140.3(C-3)，124.5(C-4)，141.6(C-5)，36.1(C-6)，33.6(C-7)，125.1(C-8)，135.0(C-9)，12.6(C-10)，113.4(C-11).144.6(C-12)，55.2(C-13)，49.3(C-14)，22.6(C-15).
Molecular formula: C
15H
12D
6N
2O.
Molecular weight: 248.32;
Preliminary drug effect detects
Test method: deuterium for selagine to rat cerebral tissue's acetylcholine esterase active influence 24 of male SD rats, be divided into 4 groups (6 every group) at random.The normal control group: not modeling, only irritate stomach to physiological saline; Model control group: modeling, only irritate stomach to physiological saline; Deuterium gives 0.5mg/kg respectively for selagine, selagine, irritates stomach every day 1 time, totally 2 weeks; After time administration, 1 modeling of abdominal injection scopolamine (2mg/kg) is not put to death animal, is separated the cortical area cerebral tissue, detects acetylcholine esterase active;
Acetylcholine esterase active is measured: put to death animal in 30 minutes after the modeling, separate brain cortical area tissue immediately, weigh, add damping fluid make tissue homogenate at 1: 9,4 ℃, 3,000 rev/mins, centrifugal 15 minutes, get supernatant, reference reagent box specification sheets is surveyed acetylcholine esterase active;
Table 1: rat brain cortex acetylcholine esterase active:
Annotate: deuterium is for selagine group inhibiting rate 40.6%, apparently higher than selagine group 51.2% (P＜05); In sum, adopt the deuterium generation technique to prepare deuterium, replace selagine CH with D for selagine
3On H, obtain beyond thought effect, the selagine effect can be increased about 20%.
The result: the deuterium that has prepared the effect increase is for selagine.
Two, deuterium is for Tanshinone I I
APreparation:
The botanical herbs red sage root is that cardiovascular disease is treated in important smelting, and TANSHINONES is its effective monomer, Tanshinone II A (Tanshinone IIA, C
19H
18O
3) be the monomer major ingredient, [other comprise Tanshinone I (TanshinoneI, C
18H
12O
3),, Tanshinone I I
B(Tanshinone II
B, C
19H
18O
4), Cryptotanshinone (Cryptotanshinone, C
19H
20O
3), hydroxyl Tanshinone I I
A(Hydr-oxytanshinone II)].But the action temperature of Tanshinone I I A and.By deuterate, the H with on the CH of D replacement R group can increase vasodilation.
Chinese: Tanshinone II A;
Source: be the dry root and rhizome of labiate red sage root Salvia miltiorrhiza Bge.;
English name: TanshinoneIIA;
Another name: red sage root quinone II, red sage root quinone IIA;
Chemical name: Phenanthro[1,2-b] furan-10,11-dione, 6,7,8,9-tetrahydro-1,6,6-trimethyl;
Molecular formula: C
19H
18O
3
Molecular weight: 294.33;
CAS number: 568-72-9;
Structural formula: see Fig. 4;
(1) deuterium replaces pre-process for solution-air:
Raw material: catalytic exchange post, deuterium gas (D
2), contain the liquid of fat-soluble traditional Chinese medicine monomer Tanshinone II A.By the bidirectional adverse current contact, in the catalytic exchange post, react, realize the exchange of D atom from the gas phase to the liquid phase, obtain the part deuterium for Tanshinone II A.
(2 meters long for the catalytic exchange post, 5 centimeters of diameters, catalyzer and hydrophilic filler load in mixture), concentration 99.6% deuterium gas preheating enters at the bottom of the catalytic exchange post, with top-down traditional Chinese medicine monomer Tanshinone II A solution counter current contact, in 45-65 ℃ of scope, adjustments of gas flow 0.5-2.0m3/h, liquid flow rate 100-400ml/h, in the catalytic exchange post, react, realize the exchange of deuterium from the gas phase to the liquid phase.Thief hole collected specimens at the bottom of capital and the post adopts Delta gas mass spectrograph to measure the concentration of deuterium respectively, calculates the transformation efficiency of deuterium, regulates the gas/liquid ratio according to transformation efficiency.When 45 ℃ of liquid flow rate 4mol/h, temperature of reaction, change gas flow, the result shows: along with the increase of gas flow, the D transformation efficiency all obviously descends.At gas flow is that 8mol/h, temperature of reaction are under 45 ℃ the condition, changes liquid flow rate, and the result shows: along with liquid flow rate increases, i.e. and the reduction of gas/liquid ratio, the D transformation efficiency is in rising trend, however this trend is littler to the influence of D transformation efficiency than gas flow.
(2) deuterium replaces synthetic for the Tanshinone II A chemistry:
Raw material: 99.5% deuterated methanol (U.S. Cambridge isotropic substance company), 95.5% Tanshinone II A (Sichuan Tian Yang company), 5% palladium carbon catalyst (DuPont).Tanshinone II A 2 grams in part deuterium generation in the sixth of the twelve Earthly Branches, 10 milliliters of 99.5% deuterated methanols contain 5% palladium carbon catalyst 200mg, pH=10, normal pressure, temperature: 60 ℃, reacted 20 hours.Stopped reaction, filtration catalizer is collected filtrate, and liquid column chromatography separates, and the acetone recrystallization drying obtains complete deuterium for Tanshinone II A, yield 78.4%, deuterium is seen Fig. 5 for rate 98.1%.
Compound is confirmed:
Physical properties: tangerine look needle crystal, molten point: 210 ℃ (X4 type micro melting point apparatus), solvability:
Be dissolved in ethanol, acetone and other organic solvent is slightly soluble in water.
Qualitative analysis: silica gel thin-layer chromatography GF254 silica gel thin-layer plate, Tanshinone II A standard substance, deuterium are put on same plate chloroform for Tanshinone II A solution: methyl alcohol (95: 5) launches, and with the iodine vapor colour developing, the Rf value is consistent.
Nuclear-magnetism spectrum: 1H-NMR (600MHz, CDCl 3, nuclear magnetic resonance spectrometer is a Bruker DRX-600 type) and the demonstration of Tanshinone II A standard substance: δ H 3.21 (2H, t, J=6.4Hz, H-1), 1.82 (2H, m, H-2), 1.68 (2H, m, H-3), 7.65 (1H, d, J=8.1Hz, H-6), 7.57 (1H, d, J=8.1Hz, H-7), 7.24 (1H, s, H-16), unimodal methyl [δ 2.28 (3H, a s, H-17), 2 bimodal methyl [δ 1.33 (6H, s, H-18and H-19)]; After the reaction, methyl δ peak disappears in the hydrogen spectrum, uses deuterium spectrum (2H) instead, and methyl δ peak reproduces, and 2H-NMR (61MHz, CH2C12), δ 2.56 (br s), δ 1.67 (br s).
13C-NMR(150MHz，CDCl3)：δC?29.9(C-1)，19.1(C-2)，37.8(C-3)，35.0(C-4)，150.1(C-5)，133.5(C-6)，120.2(C-7)，127.5(C-8)，126.5(C-9)，144.5(C-10)，183.7(C-11)，175.8(C-12)，121.2(C-13)，161.7(C-14)，120.2(C-15)，141.3(C-16)，8.8(C-17)，31.8(C-18and?C-19)。
Molecular formula should be: C
19H
9D
9O
3
Molecular weight should be: 303.33;
Preliminary drug effect detects
Tanshinone II A has the synthetic and release vaso-excitor material that suppresses ADP induced platelet aggregation, inhibition platelet T XA2 and promotes the fibrin degradation effect.Can reduce the whole blood and the plasma viscosity of coronary heart disease, cerebral ischemia apoplexy and infraction, reduce pcv, the effect by the anti-freezing viscosity reduction makes blood samples of patients rheology index recover normal.
Test method: deuterium is for the effect of Tanshinone II A to the rabbit platelet aggregation
Laboratory animal and main agents rabbit, 4 weeks of age week, below the body weight 800g, male.Aspirin tablet.
Experiment grouping (1) normal control group (Normal); (2) model control group (Control); (3) Tanshinone II A treatment group (TanIIA): TanIIA 5mg/kgd-1, iv; (4) deuterium is for Tanshinone II A treatment group: deuterium is for Tanshinone II A 5mg/kgd-1, iv; 4. aspirin for treatment group (Aspirin): (be equivalent to people 30～50mg/kgd-1), irritate stomach, change 10mg/kgd-1 behind the 7d, qd (is equivalent to people 3～5mg/kgd-1), finishes to experiment acetylsalicylic acid effervescent tablet 100mg/kgd-1.Normal and model control group gives physiological saline, 10 every group.
The detection cardiac puncture blood sampling 2ml of platelet aggregation, 3.8% Sodium Citrate anti-freezing, the ratio of antithrombotics and blood is 1: 9.At room temperature centrifugal immediately after the blood sampling with 800r/min * 10min, obtain being rich in thrombocyte blood plasma (platelet rich plasma, PRP); And then centrifugal 3000r/min * 15min, obtain platelet poor plasma (platelet poor plasma, PPP).Regulate the thrombocyte scope at 100～600 * 109/L.Adopt the BornShi turbidimetry, TYXN 96 intelligent blood agglutometers are measured platelet aggregation.Platelet aggregation inductor ADP final concentration is 2 μ mol/L, and with the automatic record aggregate curve of registering instrument, wave mode, (maximum aggregation rate MAR) is degree, writing speed 10mm/min, average record 5min with the record MA.Above-mentioned experimental implementation is finished in 2h.
Assemble inhibiting rate (%)=(control group MAR-administration group MAR)/control group MAR * 100%.The variation model control group thrombocyte MA of platelet aggregation is 39.6 ± 12.4%, compares with 21.4 ± 9.2% of normal control group, and difference has statistical significance (P＜0.05).Aspirin for treatment is the anticoagulant rate obviously, and inhibiting rate is 60.5%, compares with model group, and difference has statistical significance (P＜0.01).Tanshinone II A treatment back platelet aggregation rate also suppresses to some extent, is 26.3%, but compares no difference of science of statistics with model group.A little less than pointing out the effect of Tanshinone II A anticoagulant than acetylsalicylic acid.Deuterium has obvious inhibition for Tanshinone II A treatment back platelet aggregation rate, is 42.7%, compares with model group, and difference has statistical significance (P＜0.01), also than the Tanshinone II A group obvious inhibition is arranged.Result: obtain beyond thought effect, prepared the obvious deuterium that increases of effect for Tanshinone II A.
Claims (3)
1. a chemical structure hydrogen atom (H) that is used for the traditional Chinese medicine monomer compound is stabilized isotropic substance D atom (D, also title
2H) preparation method of Qu Daiing is characterized in that comprising:
(1) described D derives from heavy water (D
2O), deuterium gas (D
2), deuterium is for ethanol, deuterated methanol, concentration: 1-99.6%;
(2) traditional Chinese medicine monomer; Be meant that the purity that obtains from single medicinal material is greater than 90% monomeric compound;
(3) palladium carbon, platinum carbon, ruthenium C catalyst; Content 5-10%;
(4) microwave chemical reactor;
(5) liquid column chromatography separation system;
2. H be is characterized in that comprising by the preparation method that D replaces in the traditional Chinese medicine monomer compound structure according to claim 1:
(1) reaction system; Ph:7-12; Temperature: 20～200 ℃; Normal pressure, reaction times: 1-24 hour; During microwave chemical reaction, 30-60 minute;
The entire reaction general formula:
When (2) chemical structure of monomeric compound had one or more heterocycle structures, the H in the heterocycle was replaced by D, reaction conditions: 10% palladium-carbon catalyst, pH:10, temperature: 60-180 ℃, normal pressure, 20 hours;
When (3) chemical structure of monomeric compound has one or more methyl, methyl (CH
3) in H replaced reaction conditions by D; 5% palladium-carbon catalyst, pH:7, temperature: 60-180 ℃, normal pressure, 10 hours;
(4) for water-soluble traditional Chinese medicine monomer compound, preferred heavy water; For fat-soluble traditional Chinese medicine monomer compound, preferred deuterium is for organic solvent;
(5) deuterium is for the solution-air chemical exchange: for increasing deuterium for rate, can carry out pre-process to the traditional Chinese medicine monomer compound; In containing the exchange column of catalyzer, carry out the reaction of deuterium gas and traditional Chinese medicine monomer compound counter current contact, realize the exchange of deuterium from the gas phase to the liquid phase.
(6) liquid column chromatography separation system, filtering separation catalyzer and reaction product, liquid column chromatography separation of deuterium are for product, and recrystallization obtains the solid deuterium for monomeric compound.
3. preparation method according to claim 1 can prepare deuterium for monomeric compound, it is characterized by:
(1) H of C:H has at least more than one and is replaced by D in the chemical structure of monomeric compound,
Form the C:D structure.In the chemical formula :-CH ,-CH
2,-CH
3,-CH
n, change-CD-CD into
2,-CD
3,-CDn;
(2) deuterium has for the traditional Chinese medicine monomer compound: be used for traditional Chinese medicine monomer compound medicine structure, metabolism, acceptor, pharmacology, toxicologic research as tracer; On drug effect, obtain beyond thought effect, promptly strengthen of the application of traditional Chinese medicine monomer compound in preparation prevention, treatment disease drug effect; Reduce of poison, pair effect of traditional Chinese medicine monomer compound to human body.
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| US20080234488A1 (en) * | 2004-01-23 | 2008-09-25 | Wako Pure Chemical Industries, Ltd. | Method of Deuteration Using Mixed Catalyst |
| DE102005056856A1 (en) * | 2005-11-28 | 2007-05-31 | Sanofi-Aventis Deutschland Gmbh | Deuteriation of organic compounds, useful in research centers, comprises dissolving/suspending a compound in deuterium oxide and exposing the compound in catalyst mixture comprising transition metal and deuteride and/or hydride |
| US20070276042A1 (en) * | 2006-05-26 | 2007-11-29 | Auspex Pharmaceuticals, Inc. | Preparation and utility of substituted carboxylic acid compounds |
| WO2008066158A1 (en) * | 2006-12-01 | 2008-06-05 | Wako Pure Chemical Industries, Ltd. | Method for deuterating alkane |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631649A (en) * | 2016-12-01 | 2017-05-10 | 深圳大学 | Method for preparing deuterated chemicals and deuterated chemicals |
| WO2018099271A1 (en) * | 2016-12-01 | 2018-06-07 | 深圳大学 | Method for preparing deuterated chemicals, and deuterated chemicals |
| CN106631649B (en) * | 2016-12-01 | 2020-02-18 | 深圳大学 | Method for preparing deuterated chemical and deuterated chemical |
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