CN112778162B - Preparation method of chiral beta- (Boc-amino) -5-hexynoic acid - Google Patents
Preparation method of chiral beta- (Boc-amino) -5-hexynoic acid Download PDFInfo
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- CN112778162B CN112778162B CN202110012849.0A CN202110012849A CN112778162B CN 112778162 B CN112778162 B CN 112778162B CN 202110012849 A CN202110012849 A CN 202110012849A CN 112778162 B CN112778162 B CN 112778162B
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Abstract
The invention provides a preparation method of chiral beta- (Boc-amino) -5-hexynoic acid. The preparation method comprises the following steps: (1) The chiral alpha- (Boc-amino) -4-pentynoic acid and chloroformate undergo a carboxyl activation reaction to obtain a compound shown in a formula I; (2) Carrying out substitution reaction on the compound shown in the formula I and diazomethane obtained in the step (1) to obtain a compound shown in the formula II; (3) Carrying out Wolff rearrangement reaction on the compound shown in the formula II obtained in the step (2) in the presence of an alkaline substance to obtain a compound shown in the formula III; (4) And (3) performing an acidification reaction on the compound shown in the formula III obtained in the step (3) to obtain a target product. The preparation method has the advantages of easily available raw materials, mild reaction conditions and suitability for industrial scale-up production.
Description
Technical Field
The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a preparation method of chiral beta- (Boc-amino) -5-hexynoic acid.
Background
When forming an organic molecule, 4 atoms or groups can form a three-dimensional space structure through 4 covalent bonds. Two molecular structures, called chiral molecules, can be formed due to the difference in the atoms or groups attached. Chiral molecules are mirror symmetrical in chemical structure but cannot be completely overlapped after being arbitrarily rotated, like a left hand and a right hand, so the chiral molecules are also called chiral isomers, and often have differences in drug potency, toxicity and the like, and some of the chiral molecules are even opposite in effect, so that more and more methods are applied to the preparation of chiral molecules.
CN102442981a discloses a resolution method of gamma-dodecalactone chiral molecules. The technology hydrolyzes gamma-dodecalactone into hydroxy acid under alkaline condition, adopts chiral resolution reagent R- (+) -alpha-phenethylamine with optical activity to react with hydroxy acid under the action of catalyst to form hydroxy acid salt complex, then separates and purifies racemic hydroxy acid salt complex by recrystallization method, and then acidizes and cyclizes under the action of catalyst to obtain chiral gamma-dodecalactone. The technology solves the problems of low yield and high resolution cost in the resolution process of gamma-dodecalactone chiral molecules in the prior art, and can be used for producing gamma-dodecalactone chiral molecules in a large scale.
CN108440242a discloses a method for synthesizing high-activity chiral alkynol (S, E) -1, 9-diene-4, 6-diacetylene-3-octadecanol. The technology takes bromooctane as an initial raw material, firstly synthesizes the required alkynol, and then realizes the efficient synthesis of the active molecule (S, E) -1, 9-diene-4, 6-diyne-3-octadecanol through reduction, bromination, coupling reaction, desilication and docking with chiral molecules. The method has the advantages of simple and easily obtained raw materials, mild reaction conditions, simple separation and purification operation, capability of directly obtaining the target compound with higher purity, introduction of chiral centers in the last step and capability of avoiding racemization of the substance in the reaction.
CN109810129a discloses a binaphthyl azobenzene cyclic photosensitive chiral molecule, a preparation method and application thereof. The preparation method of the chiral molecule comprises the following steps: dissolving 6,6 '-dibromo-1, 1' -bi-2-naphthol, potassium carbonate, potassium iodide and 2- (2-chloroethoxy) ethanol in N, N-dimethylformamide to obtain an intermediate 1; dissolving the intermediate 1 and 4-pentoxy biphenyl boric acid in 1, 4-dioxane, and reacting with a potassium carbonate aqueous solution and tetraphenylphosphine palladium to obtain an intermediate 2; then dissolving the intermediate 2 in dichloromethane, adding triethylamine, 4-dimethylaminopyridine and p-toluenesulfonyl chloride, and reacting to obtain an intermediate 3; and mixing the intermediate 3, 2' -dihydroxyazobenzene and dibenzo-18-crown ether-6 under the nitrogen atmosphere, and adding cesium carbonate for reaction to obtain a target product T. The binaphthyl azobenzene photosensitive ring chiral molecule prepared by the technology is easy to synthesize and good in stability, but the preparation process is complex and the production cost is high.
Because chiral molecules have wide application in the fields of biomedicine, photoresponsive materials, molecular recognition and the like, developing a preparation method of chiral molecules with easily available raw materials and simple process route has become a problem to be solved in the field.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of chiral beta- (Boc-amino) -5-hexynoic acid, which takes chiral alpha- (Boc-amino) -4-pentynoic acid as a starting material, and obtains a target product with high yield through carboxyl activation reaction, substitution reaction, wolff rearrangement reaction and acidification reaction; the preparation method has the advantages of easily available raw materials, mild reaction conditions and suitability for industrial scale-up production.
To achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of chiral alpha- (Boc-amino) -4-pentynoic acid, which comprises the following steps:
(1) The chiral alpha- (Boc-amino) -4-pentynoic acid and chloroformate undergo a carboxyl activation reaction to obtain a compound shown in a formula I, wherein the reaction formula is as follows:
(2) Carrying out substitution reaction on the compound shown in the formula I and diazomethane obtained in the step (1) to obtain a compound shown in the formula II, wherein the reaction formula is as follows:
(3) Carrying out Wolff rearrangement reaction on the compound shown in the formula II obtained in the step (2) in the presence of an alkaline substance to obtain a compound shown in the formula III, wherein the reaction formula is as follows:
(4) Acidifying the compound shown in the formula III obtained in the step (3) to obtain chiral beta- (Boc-amino) -5-hexynoic acid, wherein the reaction formula is as follows:
wherein R is 1 Is a C1-C4 linear or branched alkyl group (which may be C1, C2, C3 or C4, for example), M represents a cation in the basic substance described in step (3), and represents the position of a chiral carbon atom.
The preparation method provided by the invention uses chiral alpha- (Boc-amino) -4-pentynoic acid as a starting material, and obtains a target product with high yield through carboxyl activation reaction, substitution reaction, wolff rearrangement reaction and acidification reaction; the preparation method has the advantages of easily available raw materials, mild reaction conditions and suitability for industrial scale-up production.
As a preferred embodiment of the present inventionTechnical scheme, the R 1 Any one selected from methyl, ethyl, isopropyl or isobutyl is preferably ethyl.
Preferably, the molar ratio of chiral alpha- (Boc-amino) -4-pentynoic acid to chloroformate is 1 (1.2-1.4), and may be, for example, 1:1.2, 1:1.22, 1:1.24, 1:1.26, 1:1.28, 1:1.3, 1:1.32, 1:1.34, 1:1.36, 1:1.38, or 1:1.4, etc.
Preferably, the chloroformate is added at a temperature of-5 to 5 ℃, and may be, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃,0 ℃,1 ℃,2 ℃,3 ℃,4 ℃, or 5 ℃.
As a preferred embodiment of the present invention, the carboxyl group activation reaction in the step (1) is performed in the presence of an acid-binding agent.
Preferably, the acid-binding agent is selected from any one or a combination of at least two of triethylamine, N-methylmorpholine or N, N-diisopropylethylamine.
Preferably, the molar ratio of the acid-binding agent to chiral alpha- (Boc-amino) -4-pentynoic acid is (1.1-1.3): 1, and may be, for example, 1.1:1, 1.12:1, 1.14:1, 1.16:1, 1.18:1, 1.2:1, 1.22:1, 1.24:1, 1.26:1, 1.28:1, or 1.3:1, etc.
Preferably, the temperature of the carboxyl group activation reaction is 0 to 5 ℃, and for example, it may be 0 ℃,1 ℃,2 ℃,3 ℃,4 ℃,5 ℃, or the like.
Preferably, the time of the carboxyl activating reaction is 50-70 min, for example, 50min, 52min, 54min, 56min, 58min, 60min, 62min, 64min, 66min, 68min or 70min, etc.
Preferably, the carboxyl activation reaction is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from tetrahydrofuran and/or methyl tert-butyl ether.
Preferably, the carboxyl group activation reaction is carried out in the presence of an inert gas.
Preferably, the inert gas is selected from nitrogen and/or argon.
As a preferable technical scheme of the invention, the diazomethane in the step (2) is a diazomethane solution.
Preferably, the solvent of the diazomethane solution is selected from isopropyl ether and/or methyl tert-butyl ether.
Preferably, the molar concentration of the diazomethane solution is 0.5-1mol/L, and for example, 0.5mol/L, 0.55mol/L, 0.6mol/L, 0.65mol/L, 0.7mol/L, 1.75 mol/L, 0.8mol/L, 0.85mol/L, 0.9mol/L, 0.95mol/L, 1mol/L or the like can be used.
Preferably, the molar ratio of diazomethane to chiral-alpha- (Boc-amino) -4-pentynoic acid is (5-6): 1, and may be, for example, 5:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1, 5.7:1, 5.8:1, 5.9:1, or 6:1, etc.
Preferably, the diazomethane is added at a temperature of-15 to-10 ℃, for example, -15 ℃, -14.5 ℃, -14 ℃, -13.5 ℃, -13 ℃, -12.5 ℃, -12 ℃, -11.5 ℃, -11 ℃, -10.5 ℃ or-10 ℃ and the like.
Preferably, the substitution reaction temperature is-15 to-10 ℃, and may be, for example, -15 ℃, -14.5 ℃, -14 ℃, -13.5 ℃, -13 ℃, -12.5 ℃, -12 ℃, -11.5 ℃, -11 ℃, -10.5 ℃ or-10 ℃ and the like.
Preferably, the time of the substitution reaction is 15 to 25 minutes, for example, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, or the like.
Preferably, the substitution reaction is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one or a combination of at least two of tetrahydrofuran, methyl tertiary butyl ether or isopropyl ether.
As a preferable technical scheme of the invention, the substitution reaction in the step (2) further comprises a post-treatment step after completion.
Preferably, the post-treatment is performed in the presence of an organic acid.
Preferably, the organic acid is selected from acetic acid and/or propionic acid.
Preferably, the molar ratio of the organic acid to chiral alpha- (Boc-amino) -4-pentynoic acid is (5.5-6.5): 1, and may be, for example, 5.5:1, 5.6:1, 5.7:1, 5.8:1, 5.9:1, 6:1, 6.1:1, 6.2:1, 6.3:1, 6.4:1, 6.5:1, or the like.
Preferably, the organic acid is added at a temperature of-5 to 5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃,0 ℃,1 ℃,2 ℃,3 ℃,4 ℃,5 ℃ or the like.
Preferably, the post-treatment temperature is-5 to 5 ℃, and may be, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃,0 ℃,1 ℃,2 ℃,3 ℃,4 ℃, or 5 ℃, etc.
Preferably, the post-treatment time is 25 to 35min, for example, 25min, 26min, 27min, 28min, 29min, 30min, 31min, 32min, 33min, 34min or 35min, etc.
As a preferred embodiment of the present invention, the alkaline substance in the step (3) is an alkaline substance solution.
Preferably, the alkaline substance is selected from any one or a combination of at least two of sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.
Preferably, the solvent of the alkaline substance solution is pure water.
Preferably, the molar ratio of the basic substance to chiral alpha- (Boc-amino) -4-pentynoic acid is (4.5-5.5): 1, and may be, for example, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, or 5.5:1, etc.
Preferably, the Wolff rearrangement reaction is carried out in the presence of a catalyst.
Preferably, the catalyst is selected from silver acetate and/or silver oxide.
Preferably, the molar ratio of the catalyst to chiral alpha- (Boc-amino) -4-pentynoic acid is (0.04-0.06): 1, which may be, for example, 0.04:1, 0.042:1, 0.044:1, 0.046:1, 0.048:1, 0.05, 0.052:1, 0.054:1, 0.056:1, 0.058:1, or 0.06:1, etc.
Preferably, the Wolff rearrangement reaction is carried out in the presence of an organic base.
Preferably, the organic base is selected from any one or a combination of at least two of triethylamine, N-methylmorpholine or N, N-diisopropylethylamine.
Preferably, the molar ratio of the organic base to chiral alpha- (Boc-amino) -4-pentynoic acid is (0.9-1.1): 1, and may be, for example, 0.9:1, 0.92:1, 0.94:1, 0.96:1, 0.98:1, 1:1, 1.02:1, 1.04:1, 1.06:1, 1.08:1, 1.1:1, or the like.
As a preferable embodiment of the present invention, the temperature of the Wolff rearrangement reaction is 30 to 35℃and may be, for example, 30℃30.5℃31℃31.5℃32.5℃32.5℃33℃33.5℃34.5℃34.5℃35 ℃.
Preferably, the Wolff rearrangement reaction is carried out for 1.5 to 2.5 hours, for example, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, or the like.
Preferably, step (3) further comprises mixing the compound of formula II with a basic substance prior to performing the Wolff rearrangement reaction.
Preferably, the temperature of the mixing is-5 to 5 ℃, and may be, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃,0 ℃,1 ℃,2 ℃,3 ℃,4 ℃, or 5 ℃, etc.
Preferably, the mixing time is 25 to 35min, for example, 25min, 26min, 27min, 28min, 29min, 30min, 31min, 32min, 33min, 34min or 35min, etc.
Preferably, the Wolff rearrangement reaction is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from tetrahydrofuran and/or 2-methyltetrahydrofuran.
Preferably, the Wolff rearrangement reaction in the step (3) further comprises a post-treatment step after completion.
Preferably, the post-treatment method comprises the following steps: standing, separating, and retaining water phase.
In a preferred embodiment of the present invention, the pH of the acidification reaction in the step (4) is 2 to 3, and may be, for example, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.
The acidification reaction is preferably carried out at a temperature of 23 to 28℃and may be, for example, 23℃23.5℃24℃24.5℃25℃25.5℃26℃26.5℃27.5℃or 28 ℃.
Preferably, the acidification reaction time is 50-70 min, for example, 50min, 52min, 54min, 56min, 58min, 60min, 62min, 64min, 66min, 68min or 70min, etc.
Preferably, the acidification reaction is carried out in the presence of water.
Preferably, the step (4) further comprises a post-treatment step after the acidification reaction is completed.
Preferably, the post-treatment method comprises the following steps: the organic phase is washed, retained and dried.
As a preferable technical scheme of the invention, the chiral alpha- (Boc-amino) -4-pentynoic acid obtained in the step (1) is (R) -alpha- (Boc-amino) -4-pentynoic acid, and the chiral alpha- (Boc-amino) -4-hexynoic acid obtained in the step (4) is (R) -alpha- (Boc-amino) -4-hexynoic acid, and the reaction process route is as follows:
the chiral alpha- (Boc-amino) -4-pentynoic acid obtained in the step (1) is (S) -alpha- (Boc-amino) -4-pentynoic acid, the chiral alpha- (Boc-amino) -4-hexynoic acid obtained in the step (4) is (S) -alpha- (Boc-amino) -4-hexynoic acid, and the reaction process route is as follows:
as a preferable technical scheme of the invention, the preparation method comprises the following specific steps:
(1) Mixing chiral alpha- (Boc-amino) -4-pentynoic acid, an acid binding agent and an organic solvent, dropwise adding chloroformate into the mixture at the temperature of-5 to 5 ℃ under the condition of inert gas, and heating to the temperature of 0 to 5 ℃ for reacting for 50 to 70 minutes after the dropwise adding to obtain a compound
The molar ratio of the acid binding agent to chiral alpha- (Boc-amino) -4-pentynoic acid is (1.1-1.3) 1, and the molar ratio of the chiral alpha- (Boc-amino) -4-pentynoic acid to chloroformate is (1.2-1.4);
(2) Dripping the molar concentration of the mixture into the reaction liquid obtained in the step (1) at the temperature of between minus 15 ℃ and minus 10 DEG C0.5-1mol/L diazomethane solution, and reacting for 15-20 min at-15 to-10 ℃ to obtain the compound
The molar ratio of the diazomethane to the chiral alpha- (Boc-amino) -4-pentynoic acid is (5-6) 1;
(3) Dropwise adding an alkaline substance solution into the reaction solution obtained in the step (2) at the temperature of minus 5-5 ℃, mixing for 25-35 min, adding a catalyst and optional organic alkali, heating to the temperature of 30-35 ℃ for reacting for 1.5-2.5 h to obtain a compound
Standing, separating liquid, and retaining water phase; the molar ratio of the alkaline substance to the chiral alpha- (Boc-amino) -4-pentynoic acid is (4.5-5.5) 1, the molar ratio of the catalyst to the chiral alpha- (Boc-amino) -4-pentynoic acid is (0.04-0.06) 1, and the molar ratio of the organic base to the chiral alpha- (Boc-amino) -4-pentynoic acid is (0.9-1.1) 1;
(4) Regulating the pH value of the water phase obtained in the step (3) to 2-3, and reacting for 50-70 min at the temperature of 23-28 ℃ to obtain the chiral alpha- (Boc-amino) -4-hexynoic acid
In the structural formula, R 1 And C1-C4 straight chain or branched alkyl, wherein M represents a cation in the alkaline substance in the step (3), and represents the position of chiral carbon atoms.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method provided by the invention uses chiral alpha- (Boc-amino) -4-pentynoic acid as a starting material, and obtains a target product with high yield through carboxyl activation reaction, substitution reaction, wolff rearrangement reaction and acidification reaction, wherein the yield of the target product is more than or equal to 77%, the high-purity and high-yield preparation of the target product is realized, the raw materials in the preparation method are easy to obtain, the reaction condition is mild, and the preparation method is suitable for industrial scale-up production.
Drawings
FIG. 1 is a schematic view of(R) -beta- (Boc-amino) -5-hexynoic acid prepared in example 1 1 H-NMR spectrum.
Detailed Description
The technical scheme of the invention is further described below through the detailed description and the attached drawings. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The preparation method of the (R) -beta- (Boc-amino) -5-hexynoic acid specifically comprises the following steps:
(1)
(R) -alpha- (Boc-amino) -4-pentynoic acid (1.5 g,7.035 mmol) and triethylamine (0.93 g,9.145 mmol) were added to 10mL of tetrahydrofuran, ethyl chloroformate (0.992 g,9.145 mmol) was added dropwise thereto under the protection of nitrogen gas at 0℃and after completion of the addition, the reaction was continued at 0℃for 60 minutes to give the product
The product obtained
Unstable and can be directly used for the next reaction without purification.
(2)
Dropwise adding isopropyl ether solution (38.69 mL) of diazomethane with the molar concentration of 1mol/L into the reaction solution obtained in the step (1) at the temperature of minus 15 ℃, and reacting for 20min at the temperature of minus 15 ℃; heating to 0deg.C, dropwise adding acetic acid solution (21.12 g) with mass percent of 10%, and reacting at 0deg.C for 30min to obtain the final product
The reaction mixture was directly taken to the next step without purification.
(3)
Dropwise adding 7% sodium bicarbonate solution (42.21 g) into the reaction solution obtained in the step (2) at the temperature of minus 5 ℃, stirring for 30min, adding triethylamine (0.712 g,7.035 mmol) and silver acetate (0.059 g,0.352 mmol) into the reaction solution, and heating to the temperature of 30 ℃ for reaction for 2h; standing, separating to obtain liquid, and retaining water phase to obtain the final product
(4)
At room temperature, regulating the pH of the water phase obtained in the step (3) to 2 by using dilute hydrochloric acid with the molar concentration of 3mol/L, and reacting for 60min; extraction 3 times with ethyl acetate, combining the organic phases, concentrating and drying gave the target product (R) -beta- (Boc-amino) -5-hexynoic acid 1.29g total, combined yield 81%.
Detecting a target: 1 H-NMR (400 MHz, D-DMSO): δ11.9 (bis, 1H), 6.83 (d, 1H), 3.81 (m, 1H), 2.78 (s, 1H), 2.42-2.32 (m, 2H), 2.28 (m, 2H), 1.35 (s, 9H), the target product 1 The H-NMR spectrum is shown in FIG. 1.
Example 2
The preparation method of the (S) -beta- (Boc-amino) -5-hexynoic acid specifically comprises the following steps:
(1)
(S) -alpha- (Boc-amino) -4-pentynoic acid (1.8 g,8.441 mmol) and N-methylmorpholine (1.02 g,10.13 mmol) were added to 10mL of methyl tert-butyl ether, ethyl chloroformate (1.099 g,10.13 mmol) was added dropwise thereto at-5℃under the protection of argon, and after completion of the dropwise addition, the temperature was raised to 2℃for reaction for 55min to give the product
Obtained byProduct->
Unstable and can be directly used for the next reaction without purification.
(2)
Dropwise adding methyl tertiary butyl ether solution (63.91 mL) of diazomethane with the molar concentration of 0.7mol/L into the reaction liquid obtained in the step (1) at the temperature of minus 13 ℃, and reacting for 15min at the temperature of minus 13 ℃; heating to-3deg.C, dropwise adding 10% propionic acid solution (33.11 g), and reacting at-3deg.C for 32min to obtain the final product
The reaction mixture was directly taken to the next step without purification.
(3)
Dropwise adding 7 mass percent potassium bicarbonate solution (56.74 g) into the reaction solution obtained in the step (2) at the temperature of minus 3 ℃, stirring for 35min, adding N-methylmorpholine (0.811 g,8.019 mmol) and silver oxide (0.078 g,0.338 mmol) into the mixture, and heating the mixture to the temperature of 33 ℃ for reaction for 1.7h; standing, separating to obtain liquid, and retaining water phase to obtain the final product
(4)
At room temperature, the pH of the water phase obtained in the step (3) is regulated to 2.4 by dilute hydrochloric acid with the molar concentration of 3mol/L, and the reaction is carried out for 65min; extraction 3 times with ethyl acetate, combining the organic phases, concentrating and drying gave the target product (S) -beta- (Boc-amino) -5-hexynoic acid 1.49g total, combined yield 78%.
Example 3
The preparation method of the (R) -beta- (Boc-amino) -5-hexynoic acid specifically comprises the following steps:
(1)
(R) -alpha- (Boc-amino) -4-pentynoic acid (2 g,9.38 mmol) and N, N-diisopropylethylamine (1.33 g,10.32 mmol) were added to 10mL of tetrahydrofuran, ethyl chloroformate (1.272 g,11.72 mmol) was added dropwise thereto at-3℃under nitrogen protection, and after completion of the dropwise addition, the temperature was raised to 4℃for 50 minutes to obtain the product
The product obtained->
Unstable and can be directly used for the next reaction without purification.
(2)
Dropwise adding isopropyl ether solution (52.11 mL) of diazomethane with the molar concentration of 0.9mol/L into the reaction solution obtained in the step (1) at the temperature of minus 12 ℃, and reacting for 18min at the temperature of minus 12 ℃; heating to 5 ℃, dropwise adding acetic acid solution (28.16 g) with the mass percent of 10%, and reacting for 35min at the temperature of 5 ℃ to obtain the product
The reaction mixture was directly taken to the next step without purification.
(3)
Dropwise adding a sodium carbonate solution (73.86 g) with the mass percent of 7% into the reaction liquid obtained in the step (2) at the temperature of 5 ℃, stirring for 28min, adding N, N-diisopropylethylamine (1.091 g,8.442 mmol) and silver acetate (0.07 g,0.422 mmol) into the reaction liquid, and heating to the temperature of 35 ℃ for reaction for 1.5h; standing, separating to obtain liquid, and retaining water phase to obtain the final product
(4)
At room temperature, the pH of the water phase obtained in the step (3) is regulated to 2.8 by dilute hydrochloric acid with the molar concentration of 3mol/L, and the reaction is carried out for 70min; extraction 3 times with ethyl acetate, combining the organic phases, concentrating and drying gave the target product (R) -beta- (Boc-amino) -5-hexynoic acid 1.7g total, combined yield 80%.
Example 4
The preparation method of the (S) -beta- (Boc-amino) -5-hexynoic acid specifically comprises the following steps:
(1)
(S) -alpha- (Boc-amino) -4-pentynoic acid (1.2 g, 5.6278 mmol) and triethylamine (0.71 g,7.035 mmol) were added to 10mL of tetrahydrofuran, ethyl chloroformate (0.855 g,7.879 mmol) was added dropwise thereto under nitrogen protection at 2℃and after completion of the dropwise addition, the reaction was carried out at 1℃for 65 minutes to give the product
The product obtained
Unstable and can be directly used for the next reaction without purification.
(2)
Dropwise adding isopropyl ether solution (67.54 mL) of diazomethane with the molar concentration of 0.5mol/L into the reaction solution obtained in the step (1) at the temperature of minus 10 ℃, and reacting for 25min at the temperature of minus 10 ℃; heating to 2 ℃, dropwise adding acetic acid solution (20.28 g) with the mass percent of 10 percent, and reacting for 27min at the temperature of 2 ℃ to obtain the product
The reaction mixture was directly taken to the next step without purification.
(3)
Dropwise adding 7% by mass of potassium carbonate solution (61 g) into the reaction solution obtained in the step (2) at 2 ℃, stirring for 25min, adding triethylamine (0.598 g,5.909 mmol) and silver oxide (0.078 g,0.338 mmol) into the mixture, and heating the mixture to 30 ℃ for reaction for 2.3h; standing, separating to obtain liquid, and retaining water phase to obtain the final product
(4)
At room temperature, the pH of the water phase obtained in the step (3) is regulated to 3 by dilute hydrochloric acid with the molar concentration of 3mol/L, and the reaction is carried out for 55min; extraction 3 times with ethyl acetate, combining the organic phases, concentrating and drying gave the desired product (S) -beta- (Boc-amino) -5-hexynoic acid in total 0.98g, combined yield 77%.
Example 5
The preparation method of the (R) -beta- (Boc-amino) -5-hexynoic acid specifically comprises the following steps:
(1)
(R) -alpha- (Boc-amino) -4-pentynoic acid (1.3 g,6.096 mmol) and triethylamine (0.71 g,7.01 mmol) were added to 10mL of tetrahydrofuran, ethyl chloroformate (0.893 g,8.23 mmol) was added dropwise thereto under nitrogen protection at 5℃and after completion of the dropwise addition, the reaction was carried out at 5℃for 70 minutes to give the product
The product obtained->
Unstable and can be directly used for the next reaction without purification.
(2)
Dropwise adding isopropyl ether solution (44.2 mL) of diazomethane with the molar concentration of 0.8mol/L into the reaction solution obtained in the step (1) at the temperature of-11 ℃ for reaction for 22min at the temperature of-11 ℃; heating to 0deg.C, dropwise adding acetic acid solution (23.79 g) with mass percent of 10%, and reacting at 0deg.C for 25min to obtain the final product
The reaction mixture was directly taken to the next step without purification.
(3)
To the reaction solution obtained in the step (2) was added dropwise 7% by mass sodium hydrogencarbonate solution (32.86 g) at 0℃and, after stirring for 33 minutes, triethylamine (0.678 g,6.706 mmol) and silver acetate (0.056 g,0.335 mmol) were added thereto, and the mixture was heated to 34℃to react for 2.5 hours; standing, separating to obtain liquid, and retaining water phase to obtain the final product
(4)
At room temperature, the pH of the water phase obtained in the step (3) is regulated to 2.5 by dilute hydrochloric acid with the molar concentration of 3mol/L, and the reaction is carried out for 50min; extraction 3 times with ethyl acetate, combining the organic phases, concentrating and drying gave the target product (R) -beta- (Boc-amino) -5-hexynoic acid 1.07g total, combined yield 77%.
In summary, the chiral beta- (Boc-amino) -5-hexynoic acid of the target product is prepared by taking chiral alpha- (Boc-amino) -4-pentynoic acid as a starting raw material through carboxyl activation reaction, substitution reaction, wolff rearrangement reaction and acidification, the yield of the target product is more than or equal to 77%, the preparation of the target product with high purity and high yield is realized, the raw materials in the preparation method are easy to obtain, the reaction condition is mild, and the preparation method is suitable for industrialized amplified production.
The applicant states that the present invention illustrates a process for the preparation of chiral β - (Boc-amino) -5-hexynoic acid according to the invention by the above examples, but the invention is not limited to, i.e. it does not mean that the invention has to be carried out in dependence of the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (5)
1. A method for preparing (R) -beta- (Boc-amino) -5-hexynoic acid, which is characterized by comprising the following steps:
(1)
1.5g of (R) -alpha- (Boc-amino) -4-pentynoic acid and 0.93g of triethylamine are added into 10mL of tetrahydrofuran, 0.992g of ethyl chloroformate is dropwise added into the mixture under the protection of nitrogen at the temperature of 0 ℃, and after the dropwise addition is finished, the mixture is reacted for 60min at the temperature of 0 ℃, and the obtained reaction liquid is directly subjected to the next reaction without purification;
(2)
dropwise adding 38.69mL of 1mol/L isopropyl ether solution of diazomethane into the reaction solution obtained in the step (1) at the temperature of minus 15 ℃, and reacting for 20min at the temperature of minus 15 ℃; heating to 0 ℃, dropwise adding 21.12g of acetic acid solution with the mass percent of 10%, and reacting for 30min at the temperature of 0 ℃, wherein the obtained reaction solution directly enters the next step without purification;
(3)
dropwise adding 42.21g of 7% sodium bicarbonate solution into the reaction solution obtained in the step (2) at the temperature of minus 5 ℃, stirring for 30min, adding 0.712g of triethylamine and 0.059g of silver acetate into the mixture, and heating to the temperature of 30 ℃ for reaction for 2h; standing, separating liquid, and retaining water phase;
(4)
at room temperature, regulating the pH value of the water phase obtained in the step (3) to be 2 by using 3mol/L dilute hydrochloric acid, and reacting for 60min; ethyl acetate was extracted 3 times, the organic phases were combined, concentrated and dried to give (R) - β - (Boc-amino) -5-hexynoic acid.
2. A method for preparing (S) -beta- (Boc-amino) -5-hexynoic acid, which is characterized by comprising the following steps:
(1)
1.8g of (S) -alpha- (Boc-amino) -4-pentynoic acid and 1.02g N-methylmorpholine are added into 10mL of methyl tertiary butyl ether, 1.099g of ethyl chloroformate is dropwise added into the mixture at the temperature of minus 5 ℃ under the protection of argon, after the dropwise addition is finished, the temperature is raised to 2 ℃ for reaction for 55min, and the reaction liquid obtained by the product is directly subjected to the next reaction without purification;
(2)
dropwise adding 63.91mL of 0.7mol/L methyl tertiary butyl ether solution of diazomethane into the reaction solution obtained in the step (1) at the temperature of minus 13 ℃, and reacting for 15min at the temperature of minus 13 ℃; heating to-3 ℃, dropwise adding 33.11g of 10% propionic acid solution, reacting for 32min at-3 ℃, and directly entering the next step without purifying the obtained reaction liquid;
(3)
dropwise adding 56.74g of 7% potassium bicarbonate solution into the reaction solution obtained in the step (2) at the temperature of minus 3 ℃, stirring for 35min, adding 0.811g N-methylmorpholine and 0.078g of silver oxide into the solution, and heating to the temperature of 33 ℃ for reaction for 1.7h; standing, separating liquid, and retaining water phase;
(4)
at room temperature, regulating the pH value of the water phase obtained in the step (3) to be 2.4 by using 3mol/L dilute hydrochloric acid, and reacting for 65min; ethyl acetate was extracted 3 times, the organic phases were combined, concentrated and dried to give (S) - β - (Boc-amino) -5-hexynoic acid.
3. A method for preparing (R) -beta- (Boc-amino) -5-hexynoic acid, which is characterized by comprising the following steps:
(1)
2g of (R) -alpha- (Boc-amino) -4-pentynoic acid and 1.33g of N, N-diisopropylethylamine are added into 10mL of tetrahydrofuran, 1.272g of ethyl chloroformate is dropwise added into the mixture at the temperature of-3 ℃ under the protection of nitrogen, after the dropwise addition is finished, the mixture is heated to the temperature of 4 ℃ for reaction for 50min, and the obtained reaction liquid is directly subjected to the next reaction without purification;
(2)
dropwise adding 52.11mL of 0.9mol/L isopropyl ether solution of diazomethane into the reaction solution obtained in the step (1) at the temperature of minus 12 ℃, and reacting for 18min at the temperature of minus 12 ℃; heating to 5 ℃, dropwise adding 28.16g of acetic acid solution with the mass percent of 10%, and reacting for 35min at the temperature of 5 ℃, wherein the obtained reaction solution directly enters the next step without purification;
(3)
dropwise adding 73.86g of 7% sodium carbonate solution in mass percent into the reaction solution obtained in the step (2) at the temperature of 5 ℃, stirring for 28min, adding 1.091g of N, N-diisopropylethylamine and 0.07g of silver acetate into the mixture, and heating to the temperature of 35 ℃ for reaction for 1.5h; standing, separating liquid, and retaining water phase;
(4)
at room temperature, regulating the pH value of the water phase obtained in the step (3) to be 2.8 by using 3mol/L dilute hydrochloric acid, and reacting for 70min; ethyl acetate was extracted 3 times, the organic phases were combined, concentrated and dried to give (R) - β - (Boc-amino) -5-hexynoic acid.
4. A method for preparing (S) -beta- (Boc-amino) -5-hexynoic acid, which is characterized by comprising the following steps:
(1)
1.2g of (S) -alpha- (Boc-amino) -4-pentynoic acid and 0.71g of triethylamine are added into 10mL of tetrahydrofuran, 0.855g of ethyl chloroformate is dropwise added into the mixture at the temperature of 2 ℃ under the protection of nitrogen, and after the dropwise addition is finished, the mixture is reacted for 65min at the temperature of 1 ℃, and the obtained reaction liquid is directly subjected to the next reaction without purification;
(2)
dropwise adding 67.54mL of 0.5mol/L isopropyl ether solution of diazomethane into the reaction solution obtained in the step (1) at the temperature of minus 10 ℃, and reacting for 25min at the temperature of minus 10 ℃; heating to 2 ℃, dropwise adding 20.28g of acetic acid solution with the mass percent of 10%, and reacting for 27min at the temperature of 2 ℃, wherein the obtained reaction solution directly enters the next step without purification;
(3)
dropwise adding 61g of 7% potassium carbonate solution in mass percent into the reaction solution obtained in the step (2) at the temperature of 2 ℃, stirring for 25min, adding 0.598g of triethylamine and 0.078g of silver oxide into the solution, and heating to the temperature of 30 ℃ for reaction for 2.3h; standing, separating liquid, and retaining water phase;
(4)
at room temperature, regulating the pH value of the water phase obtained in the step (3) to be 3 by using 3mol/L dilute hydrochloric acid, and reacting for 55min; ethyl acetate was extracted 3 times, the organic phases were combined, concentrated and dried to give (S) - β - (Boc-amino) -5-hexynoic acid.
5. A method for preparing (R) -beta- (Boc-amino) -5-hexynoic acid, which is characterized by comprising the following steps:
(1)
1.3g of (R) -alpha- (Boc-amino) -4-pentynoic acid and 0.71g of triethylamine are added into 10mL of tetrahydrofuran, 0.893g of ethyl chloroformate is dropwise added into the mixture at the temperature of 5 ℃ under the protection of nitrogen, and after the dropwise addition is finished, the mixture is reacted for 70min at the temperature of 5 ℃, and the obtained reaction liquid is directly subjected to the next reaction without purification;
(2)
dropwise adding 44.2mL of isopropyl ether solution of 0.8mol/L diazomethane into the reaction solution obtained in the step (1) at the temperature of-11 ℃, and reacting for 22min at the temperature of-11 ℃; heating to 0 ℃, dropwise adding 23.79g of acetic acid solution with the mass percent of 10%, reacting for 25min at the temperature of 0 ℃, and directly entering the next step without purifying the obtained reaction solution;
(3)
dropwise adding 32.86g of 7% sodium bicarbonate solution into the reaction solution obtained in the step (2) at the temperature of 0 ℃, stirring for 33min, adding 0.678g of triethylamine and 0.056g of silver acetate into the reaction solution, and heating to the temperature of 34 ℃ for reaction for 2.5h; standing, separating liquid, and retaining water phase;
(4)
at room temperature, regulating the pH value of the water phase obtained in the step (3) to be 2.5 by using 3mol/L dilute hydrochloric acid, and reacting for 50min;
ethyl acetate was extracted 3 times, the organic phases were combined, concentrated and dried to give (R) - β - (Boc-amino) -5-hexynoic acid.
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