CN114933551B - Synthesis method of chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid - Google Patents
Synthesis method of chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid Download PDFInfo
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- CN114933551B CN114933551B CN202210738737.8A CN202210738737A CN114933551B CN 114933551 B CN114933551 B CN 114933551B CN 202210738737 A CN202210738737 A CN 202210738737A CN 114933551 B CN114933551 B CN 114933551B
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention relates to a chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid synthesis method. Mainly solves the technical problems of long steps and great difficulty of the existing synthesis method. The synthesis method comprises the following steps: the triethyl phosphonoacetate and formaldehyde aqueous solution are reacted under the action of potassium carbonate to generate a compound 1, and the product is purified by column chromatography; reacting the compound 1 with phenethylamine in ethanol to obtain a compound 2 without purification; introducing isobutene into a dichloromethane and concentrated sulfuric acid solution of the compound 2 to generate a compound 3, and purifying the product by column chromatography; the compound 3 is subjected to palladium-carbon catalytic hydrogenation to obtain a compound 4 without purification; the compound 4 is hydrolyzed by lithium hydroxide, fmoc is carried out, and the obtained racemization product is prepared and separated by chiral HPLC to obtain the target product.
Description
Technical Field
The invention relates to the field of synthesis of unnatural amino acid, in particular to a synthesis method of chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid.
Background
Homologous β -amino acids have received great attention in terms of their ability to form secondary structures that are more stable than the natural counterparts and also mimic the biological activity of natural peptides. (S) -Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid (CAS: 865152-44-9) and (R) -Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid (CAS: 847153-42-8) can be widely used as homoserine counterparts in polypeptide drug screening. The routes reported in the literature for these two compounds are: (1) The target product (Helvetica Chimica Acta, 2004, vol. 87, # 12, p.3131-3159) is prepared in 9 steps by taking beta-alanine as a starting material reported by Lelais et al, the key of the route is that chiral hydroxymethyl is introduced by Evans prosthetic group, the disadvantage is long route, low total yield, complex operation and low chiral selectivity. (2) The asymmetric synthetic route reported by Meyer et al, european organic chemistry journal (European Journal of Organic Chemistry, 2015, vol. 2015, # 22, p. 4883-4891), which is 6 steps in total, has high chiral selectivity, but the 3-tertiary methoxy-propionaldehyde starting material is not sold in the market and is not easy to prepare, so the reference significance is not great.
Disclosure of Invention
The invention aims to provide a simple and rapid method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid, which mainly solves the technical problems of long reaction steps, complex operation and high cost of the existing synthesis method.
The technical scheme of the invention is as follows: a synthesis method of chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid comprises the following steps:
(1) The triethyl phosphonoacetate and formaldehyde aqueous solution are reacted under the action of potassium carbonate to generate a compound 1, and the product is purified by column chromatography;
(2) Reacting the compound 1 with phenethylamine in ethanol to obtain a compound 2 without purification;
(3) Introducing isobutene into a dichloromethane and concentrated sulfuric acid solution of the compound 2 to generate a compound 3, and purifying the product by column chromatography;
(4) The compound 3 is hydrogenated under pressure under the action of palladium-carbon to obtain a compound 4 without purification;
(5) Hydrolyzing the lithium hydroxide of the compound 4, adding Fmoc, and preparing and separating the obtained racemization product by chiral HPLC to obtain a target product; the synthetic route is as follows:
in the above reaction, step 1, an aqueous potassium carbonate solution is added dropwise at room temperature, and after the addition, the mixture is stirred at room temperature for 1 to 3 hours, preferably for 2 hours. And 2, reacting for 12-48 hours at 20-40 ℃, preferably at 30 ℃, and preferably at 24 hours. And 3, introducing isobutene for 0.5-2 hours, preferably for 1 hour, and reacting for 12-48 hours at room temperature, preferably for 24 hours. Step 4, the reaction temperature is 30-70 ℃, preferably 50 ℃, and the pressure of the introduced hydrogen is 1.5-3 MPa, preferably 2 MPa. Step 5, hydrolysis reaction temperature is 30-60 ℃, preferably 40 ℃, reaction time is 1-4 hours, preferably 2 hours, then Fmoc room temperature reaction is carried out for 6-18 hours, preferably 12 hours.
The beneficial effects of the invention are as follows: the synthesis of the product of the invention has only 5 steps, the reaction is simple, the raw materials are cheap and easy to operate, and the second step and the fourth step are crude products which are directly used in the next step. The method is very suitable for a laboratory to quickly obtain gram-grade target products for research.
Drawings
FIG. 1 is a mass spectrum of the S-configuration product of the present invention.
FIG. 2 is a mass spectrum of the R-configuration product of the present invention.
FIG. 3 is a nuclear magnetic pattern of the S-configuration product of the present invention.
FIG. 4 is a nuclear magnetic pattern of the R-configuration product of the present invention.
FIG. 5 is a chiral liquid chromatogram of the S-configuration product of the present invention.
FIG. 6 is a chiral liquid chromatogram of an R-configuration product of the present invention.
Detailed Description
Example 1: (S) -Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid and (R) -Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid.
Step 1:
triethyl phosphonoacetate (44.8 g, 0.2 mol) was added to an aqueous formaldehyde solution (37-38% by mass, 60 ml) with stirring, and a solution of potassium carbonate (48.4 g, 0.35 mol) in water (150 ml) was slowly added dropwise thereto. The reaction mixture was stirred at room temperature for 2 hours after the completion of the addition. Water (500 ml) was added for dilution and extraction with ethyl acetate (300 ml x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 1 (19.4 g, 75% yield) as a colorless liquid.
Step 2:
compound 1 (19.4 g, 0.15 mol) and S-phenethylamine (18.2 g, 0.15 mol) were dissolved in ethanol (300 ml), and the reaction solution was stirred at 30 ℃ for 24 hours. The reaction solution was concentrated to dryness under reduced pressure. The residue, compound 2, was used directly in the next step without purification.
Step 3:
compound 2 (37.6 g, 0.15 mol) obtained in the above step was dissolved in methylene chloride (800 ml), concentrated sulfuric acid (9.4 ml) was added under an ice-water bath, and then isobutylene gas was slowly introduced thereinto. After 1 hour, the reaction mixture was slowly warmed to room temperature and stirred for 24 hours. To the reaction solution was added a saturated aqueous sodium hydrogencarbonate solution (500 ml), followed by stirring and separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 3 (15.2 g, 33% two-step yield) as a colorless liquid.
Step 4:
compound 3 (15.2 g, 49.4 mmol) was dissolved in ethanol (300 ml) and placed in an autoclave, 10% palladium on charcoal (2 g) was added, and hydrogen gas at 2MPa pressure was introduced into the autoclave and reacted overnight at 50 ℃. Cooled to room temperature, palladium on charcoal was filtered off, the filtrate was concentrated to dryness and the residue, compound 4, was used directly in the next step without purification.
Step 5:
compound 4 (10 g, 49.4 mmol) obtained in the above step was dissolved in tetrahydrofuran (90 ml), and a solution of sodium hydroxide (4 g, 0.1 mol) in water (90 ml) was added thereto. The reaction solution was stirred at 40 degrees celsius for 2 hours. Cooled to room temperature, the pH was adjusted to neutral with hydrochloric acid, and sodium bicarbonate (12.6 g, 0.15 mol) and FmocOSu (16.6 g, 49.4 mmol) were added thereto. The reaction solution was stirred at room temperature for 12 hours. Petroleum ether (100 ml) was added, stirred and separated. The aqueous phase was adjusted to pH 2-3 with 2M hydrochloric acid and extracted with ethyl acetate (200 ml). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and reducedConcentrating under pressure. Purification of the residue by column chromatography gave racemate (7.6 g), which was prepared by chiral liquid chromatography (AD-H, hex/EtOH/DEA) to give (S) -Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid (3.1 g, 100% e.e, yield 15.8%), MS (ESI) M/Z: 398.19 [ M+H) + ]。 1 H NMR (400 MHz, CDCl 3 ) : δ 7.75-7.77 (m,2H), 7.57-7.59 (m, 2H), 7.29-7.42 (m, 4H), 5.46-5.49 (m, 1H), 4.38 (d, J=7.2 Hz, 2H), 4.19-4.23 (M, 1H), 3.46-3.75 (M, 4H), 2.80-2.83 (M, 1H), 1.24 (s, 9H); (R) -Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid (3.3 g, 99% e.e, 16.7% yield), MS (ESI) M/Z: 398.12 [ m+h + ]。 1 H NMR (400 MHz, CDCl 3 ) : δ 7.75-7.77 (m,2H), 7.57-7.59 (m, 2H), 7.29-7.40 (m, 4H), 5.46-5.49 (m, 1H), 4.38 (d, J=7.2 Hz, 2H), 4.19-4.23 (m, 1H), 3.46-3.75 (m, 4H), 2.80-2.83 (m, 1H), 1.24 (s, 9H). Mass spectra, nuclear magnetic resonance spectra and chiral HPLC figures refer to figures 1, 2, 3, 4, 5, 6.
Example 2, step 1 reaction time 1 hour; the reaction temperature in the step 2 is 40 ℃ and the reaction time is 12 hours; step 3, introducing isobutene for 0.5 hour, and reacting for 48 hours at room temperature; the reaction temperature in the step 4 is 70 ℃, and the pressure of the introduced hydrogen is 1.5MPa; step 5, the hydrolysis reaction temperature is 60 ℃, the reaction time is 1 hour, and the Fmoc reaction time is 6 hours; the procedure is as in example 1.
Example 3, step 1 reaction time 3 hours; the reaction temperature in the step 2 is 20 ℃ and the reaction time is 48 hours; step 3, introducing isobutene for 2 hours, and finishing room temperature reaction for 12 hours; step 4, the reaction temperature is 30 ℃, and the pressure of the introduced hydrogen is 3MPa; step 5, the hydrolysis reaction temperature is 30 ℃, the reaction time is 4 hours, and the Fmoc reaction time is 18 hours; the procedure is as in example 1.
Claims (11)
1. A method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid is characterized by comprising the following steps: the method comprises the following steps:
(1) The triethyl phosphonoacetate and formaldehyde aqueous solution are reacted under the action of potassium carbonate to generate a compound 1, and the product is purified by column chromatography;
(2) The compound 1 reacts with S-phenethylamine in ethanol to obtain a compound 2 without purification;
(3) Introducing isobutene into a dichloromethane and concentrated sulfuric acid solution of the compound 2 to generate a compound 3, and purifying the product by column chromatography;
(4) The compound 3 is hydrogenated under pressure under the action of palladium-carbon to obtain the compound 4 without purification
(5) Hydrolyzing the lithium hydroxide of the compound 4, adding Fmoc, and preparing and separating the obtained racemization product by chiral HPLC to obtain a target product; the synthetic route is as follows:
2. the method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 1, wherein the method comprises the following steps: and in the first step, dropwise adding the aqueous solution of potassium carbonate at room temperature, and stirring at room temperature for 1-3 hours after the addition is finished.
3. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 2, wherein the method comprises the following steps: the reaction was carried out for 2 hours.
4. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 1, wherein the method comprises the following steps: and in the second step, the reaction temperature is 20-40 ℃ and the reaction time is 12-48 hours.
5. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 4, wherein the method comprises the following steps: the second step, the reaction temperature is 30 ℃, and the reaction is carried out for 24 hours.
6. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 1, wherein the method comprises the following steps: and thirdly, introducing isobutene for 0.5-2 hours, and finishing room temperature reaction for 12-48 hours.
7. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 6, wherein the method comprises the following steps: and thirdly, introducing isobutene for 1 hour, and finishing the reaction at room temperature for 24 hours.
8. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 1, wherein the method comprises the following steps: the fourth step, the reaction temperature is 30-70 ℃ and the hydrogen pressure is 1.5-3 MPa.
9. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 8, wherein the method comprises the following steps: and in the fourth step, the reaction temperature is 50 ℃, and the hydrogen pressure is 2 MPa.
10. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 1, wherein the method comprises the following steps: and step five, the hydrolysis reaction temperature is 30-60 ℃, the reaction time is 1-4 hours, and then Fmoc room temperature reaction is carried out for 6-18 hours.
11. The method for synthesizing chiral Fmoc-3-amino-2- (tert-butoxymethyl) propionic acid according to claim 10, wherein: the fifth step, the hydrolysis reaction temperature is 40 ℃, the reaction time is 2 hours, and then Fmoc is carried out at room temperature for 12 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5821251A (en) * | 1994-02-10 | 1998-10-13 | John Wyeth & Brother Limited | Nitrogen heterocycles |
| WO2018108954A1 (en) * | 2016-12-12 | 2018-06-21 | F. Hoffmann-La Roche Ag | Process for the preparation of 2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5821251A (en) * | 1994-02-10 | 1998-10-13 | John Wyeth & Brother Limited | Nitrogen heterocycles |
| WO2018108954A1 (en) * | 2016-12-12 | 2018-06-21 | F. Hoffmann-La Roche Ag | Process for the preparation of 2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol |
Non-Patent Citations (2)
| Title |
|---|
| Scalable Enantioselective Synthesis of Fmoc- β 2 -Serine and Fmoc- β 2 -Threonine by an Organocatalytic Mannich Reaction;Daniel Meyer等;《Eur. J. Org. Chem.》;4883-4891 * |
| Synthesis of Nonproteinogenic Amino Acids To Probe Lantibiotic Biosynthesis;Xingang Zhang等;《J. Org. Chem.》;6685-6692 * |
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