CN108948001A - The synthetic route of 1R, 3S-1- methyl tetrahydro-beta-carboline -3- carboxylic acid, anti-thrombus activity and application - Google Patents
The synthetic route of 1R, 3S-1- methyl tetrahydro-beta-carboline -3- carboxylic acid, anti-thrombus activity and application Download PDFInfo
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- CN108948001A CN108948001A CN201710351711.7A CN201710351711A CN108948001A CN 108948001 A CN108948001 A CN 108948001A CN 201710351711 A CN201710351711 A CN 201710351711A CN 108948001 A CN108948001 A CN 108948001A
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- carboline
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- 0 OC(*C(C1)NCc2c1c(C#CCC=C1)c1[n]2)=O Chemical compound OC(*C(C1)NCc2c1c(C#CCC=C1)c1[n]2)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses following formula 1R, 3S-1- methyl-1 is prepared, the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid discloses its antithrombotic acitivity, and discloses it and preparing the application in antithrombotic reagent.
Description
Technical field
The present invention relates to preparation 1R, 3S-1- methyl-1, the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid is related to
Its antithrombotic acitivity, and be related to it and preparing the application in antithrombotic reagent.The invention belongs to biomedicine fields.
Background technique
Inventor's prediction, with 1S, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acids compare 1R, 3S-1- methyl -
The antithrombotic acitivity of 1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid is stronger.For this purpose, inventor explores always 1S, 3S-1- methyl-1,
The synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid.It is original with L-Trp under Pictet-Spengle condensation condition
Material is reacted with acetaldehyde produces 1R, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid and 1S, 3S-1- methyl-1, and 2,
3,4- tetrahydro-beta-carboline -3- carboxylic acid.Although the relative scale of the former and the latter are 1 to 16 in HPLC spectrum, it is difficult from this
The former is separated in the mixture of sample.So, also it is difficult to obtain the 1R of sufficient amount, 3S-1- methyl-1,2,3,4- tetra-
Hydrogen-B-carboline -3- carboxylic acid sterling completes antithrombotic acitivity research.
Inventor tested by 6 years, and hair, which is reacted using L-Trp benzyl ester as raw material with acetaldehyde, can make 1R, 3S-1- methyl-1,
2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate and 1S, 3S-1- methyl-1, the phase of 2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate
Comparative example is increased to 1 to 1.2 from known 1 to 16.1R, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic can thus be made
Acid and 1S, 3S-1- methyl-1, the relative scale of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid are increased to 1 ratio from known 1 to 16
1.2.According to this discovery, the present invention is inventors herein proposed.
Summary of the invention
First content of the invention is to provide the 1R for preparing following formula, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3-
The synthetic route of carboxylic acid.
1R, 3S-1- methyl-1, the cyclization reaction of the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid is by L-Trp-
OBzl and acetaldehyde cyclization, 1R, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates and 1S, 3S-1- methyl-1,2,
The relative scale of 3,4- tetrahydro-beta-carboline -3- benzyl carboxylate is 1 to 1.2.
1R, 3S-1- methyl-1, the cyclization reaction of the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acids, by L-Trp-
OBzl and acetaldehyde are in 20 DEG C, 40 DEG C and 60 DEG C cyclizations, most preferably in 60 DEG C of cyclizations, 1R, 3S-1- methyl-1,2,3,4- tetrahydro-β-click
Quinoline -3- benzyl carboxylate and 1S, 3S-1- methyl-1, the relative scale of 2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate are 1 to 1.2.
The antithrombotic acitivity of the 1R obtained as the result is shown, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid is significantly stronger than 1S,
3S-1- methyl-1, the antithrombotic acitivity of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid.
Second content of the invention is to evaluate 1R, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid and 1S,
3S-1- methyl-1, the antithrombotic acitivity of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid.
Detailed description of the invention
Fig. 1 1S, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid and 1R, 3S-1- methyl-1,2,3,4- tetra-
Hydrogen-B-carboline -3- carboxylic acid synthetic route .i) 60 DEG C, distilled water, sulfuric acid；Ii) dimethylformamide, Boc2O, triethylamine, pH
12；iii)Pd/C,H2, the ethyl acetate solution (4M) of hydrogen chloride.
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares 1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate (1)
The concentrated sulfuric acid that 1mL concentration is 98% is added dropwise into 800mL distilled water in 60 DEG C, after mixing evenly by 10.0g
(34mmol) L-Trp-OBzl is added thereto in three times.Stirring five minutes, makes L-Trp-OBzl sufficiently be suspended with aqueous sulfuric acid.
Later, 10mL concentration is added dropwise into floating suspension is 40% acetaldehyde solution.Prior to 60 DEG C stirring 12h of compound of reaction, then
3mL concentrated ammonia liquor tune reaction solution pH to 8 is added dropwise inward.Compound of reaction stands 1h, is sufficiently precipitated to product.Solid is filtered out, is done
It is dry, 9.84g (90%) faint yellow solid is obtained, is 1R- methyl-1,2,3,4- tetrahydro-beta-carboline -3S- benzyl carboxylates and 1S- first
The mixture of base -1,2,3,4- tetrahydro-beta-carboline -3S- benzyl carboxylate.ESI-MS(m/e):321[M+H]+。
Embodiment 2 prepares N-Boc-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate (2a and 2b)
9.84g (30.8mmol) 1- methyl-1 that embodiment 1 is obtained, 2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate are used
20mLN, dinethylformamide (DMF) dissolution.Add 6.98g (32.0mmol) Boc into solution in 0 DEG C2O.Obtained solution
PH 12 is adjusted with triethylamine, 48h is stirred at room temperature.Reaction mixture is concentrated under reduced pressure, and removes DMF.Residue 100mL acetic acid second
Ester dissolution.Obtained ethyl acetate solution successively washes (50mL × 3) and saturated sodium-chloride water solution with 5% aqueous potassium hydrogen sulfate
Wash (50mL × 3).The isolated ethyl acetate layer dry 12h of anhydrous sodium sulfate, filtering, the oily that filtrate decompression is concentrated to get
Object.The grease obtains 5.02g (38%) N-Boc-1R- methyl-1 with silica gel post separation (methylene chloride/methanol, 100/1),
2,3,4- tetrahydro-beta-carboline -3S- benzyl carboxylate (2a) and 6.00g (47%) N-Boc-1S- methyl-1,2,3,4- tetrahydro-β-click
Quinoline -3S- benzyl carboxylate (2b).It is colourless powder.
2a:ESI-MS(m/e):421[M+H]+。1H NMR (DMSO-d6,800MHz) δ/ppm=7.457 (d, J=
8.0Hz,1H)；7.314 (d, J=8.0Hz, 1H)；7.239 (m, 5H), 7.080 (t, J=7.2Hz, 1H)；7.000 (t, J=
7.2Hz,1H)；5.377(m,1H)；5.095(m,2H)；0.499(m,1H)；3.421(m,1H)；2.906(m,1H)；1.454
(m,12H)。
2b:ESI-MS(m/e):421[M+H]+。1H NMR (DMSO-d6,800MHz) δ/ppm=7.434 (d, J=
7.2Hz,1H)；7.313(m,1H)；7.214(s,1H)；7.158(m,2H)；7.063(m,3H)；6.990(m,1H)；5.066
(m,1H)；5.020(m,2H)；4.890(m,1H)；3.275(m,1H)；3.074(m,1H)；1.495(s,3H),1.438(s,
3H)；1.331(m,6H).
Embodiment 3 prepares 1R, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid (3a)
Toward 1g (2.38mmol) N-Boc-1R- methyl-1,2,3,4- tetrahydro-beta-carboline -3S- benzyl carboxylate (2a) and 40mL
In the solution of anhydrous tetrahydro furan plus 100mg Pd/C, stirring become uniform suspension.It depressurizes in extraction system
Air is passed through hydrogen, and 10h is stirred at room temperature, and TLC (methylene chloride/methanol, 100/1) shows that 2a is completely disappeared.It is filtered to remove Pd/
C, filtrate decompression concentration, the ESI-MS (m/e) of obtained colourless powder are 329 [M-H]-.By the colourless powder be dissolved in 10mL without
Water ethyl acetate under ice bath inward plus 10mL hydrogen chloride/ethyl acetate solution (4M) stirs 2h under ice bath.Reaction solution decompression is dense
It is reduced to dry, residue adds 10mL anhydrous ethyl acetate to dissolve, then is concentrated to dryness.The operation is repeated 3 times.Residue adds 10mL
Anhydrous ether, solution are concentrated to dryness.The operation is repeated 3 times.Obtain target compound.ESI-MS(m/e):231[M+H]+。
Embodiment 4 prepares 1S, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid (3b)
According to the method for embodiment 3, from 1g (2.38mmol) N-Boc-1S- methyl-1,2,3,4- tetrahydro-beta-carboline -3S-
Benzyl carboxylate (2b) obtains.
The antithrombotic acitivity of the evaluation of experimental example 1 compound 3a
It is random to be grouped by male SD rat (200 ± 20g), it every group 8, raises 1 day, stops feeding and stay overnight.Stomach-filling is given
(dosage is 1 μm of ol/ to the normal saline solution of the normal saline solution (dosage is 1 μm of ol/kg) of compound 3a or compound 3b
) or physiological saline (dosage 10mL/kg) kg.The normal saline solution anesthesia of 20% Ethylurethanm of rat, receives after 30min
Operation.The silk thread of correct amount is placed in bypass intubation by the right carotid and left neck vein for separating rat, and one end of pipe is inserted into left
Vein, another end pipe is inserted into right artrial and to inject 0.2mL heparin sodium anticoagulant.So that blood flow flows through bypass intubation from right artrial
Into left side vein, the silk thread with thrombus is taken out after 15min and is weighed, the weight of silk thread before and after blood circulation is calculated.It obtains
Wet weight of thrombus represent antithrombotic acitivity, make t inspection.Table 1 statistics indicate that, although oral 1 μm of ol/kg compound 3a and 3b are
Thrombosis can be effectively inhibited, but the activity of 3a is significantly stronger than 3b.These results explanation, synthetic route of the invention have
Specific application prospect.
Antithrombotic acitivity of the table 1 in 1 μm of ol/kg dosages for Compound 3a
And physiological saline ratio p < 0.01, a) with 3b ratio p < 0.05；And physiological saline ratio p < 0.05 b)；N=8.
Claims (5)
1. the 1R of following formula, 3S-1- methyl-1, the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acids,
2. the 1R of claim 1,3S-1- methyl-1, the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acids, it is characterised in that
Cyclization reaction is by L-Trp-OBzl and acetaldehyde cyclization, 1R, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates with
1S, 3S-1- methyl-1, the relative scale of 2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate are 1 to 1.2.
3. the 1R of claim 2,3S-1- methyl-1, the cyclization reaction of the synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acids,
It is characterized in that by L-Trp-OBzl and acetaldehyde in 20 DEG C, 40 DEG C and 60 DEG C cyclizations, most preferably in 60 DEG C of cyclizations, 1R, 3S-1- first
Base -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate and 1S, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylate
The relative scale of ester is 1 to 1.2.
4. the 1R of claim 1,3S-1- methyl-1, the synthetic route synthetic route of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acids,
The antithrombotic acitivity of the 1R being characterized in that, 3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid is significantly stronger than 1S,
3S-1- methyl-1, the antithrombotic acitivity of 2,3,4- tetrahydro-beta-carboline -3- carboxylic acid.
5. the 1R of claim 1,3S-1- methyl-1,2,3,4- tetrahydro-beta-carboline -3- carboxylic acid is in preparing antithrombotic reagent
Using.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116804040A (en) * | 2023-05-26 | 2023-09-26 | 首都医科大学 | Carboline oral small molecule anti-inflammatory medicament and preparation method and application thereof |
| CN117204433A (en) * | 2023-08-03 | 2023-12-12 | 山东蓬勃生物科技有限公司 | Application and preparation method of compound 1-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid |
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| CN1743327A (en) * | 2004-09-03 | 2006-03-08 | 首都医科大学 | Indole alkaloid derivative, and its preparing method and use |
| CN102234277A (en) * | 2010-05-07 | 2011-11-09 | 首都医科大学 | Amino-acid-modified 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acids, and synthesis method and application thereof |
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| CN1743327A (en) * | 2004-09-03 | 2006-03-08 | 首都医科大学 | Indole alkaloid derivative, and its preparing method and use |
| CN102234277A (en) * | 2010-05-07 | 2011-11-09 | 首都医科大学 | Amino-acid-modified 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acids, and synthesis method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116804040A (en) * | 2023-05-26 | 2023-09-26 | 首都医科大学 | Carboline oral small molecule anti-inflammatory medicament and preparation method and application thereof |
| CN117204433A (en) * | 2023-08-03 | 2023-12-12 | 山东蓬勃生物科技有限公司 | Application and preparation method of compound 1-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid |
| CN117204433B (en) * | 2023-08-03 | 2024-04-02 | 山东蓬勃生物科技有限公司 | Application and preparation method of compound 1-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid |
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