CN112500303A - Preparation method of beta-fluoro chiral unnatural amino acid - Google Patents

Preparation method of beta-fluoro chiral unnatural amino acid Download PDF

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CN112500303A
CN112500303A CN202011463840.3A CN202011463840A CN112500303A CN 112500303 A CN112500303 A CN 112500303A CN 202011463840 A CN202011463840 A CN 202011463840A CN 112500303 A CN112500303 A CN 112500303A
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chiral
fluoro
amino acid
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欧阳建梅
唐青林
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Shenzhen Turier Biotech Co ltd
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Abstract

The invention discloses a preparation method of beta-fluoro chiral unnatural amino acid. The method takes N-Boc protected aziridine and pyridine hydrogen fluoride as raw materials, adds chiral ligand, reacts under the action of a transition metal catalyst, and removes Boc group from a reaction product by using a reagent to obtain beta-fluoro chiral unnatural amino acid. The method has the advantages of mild reaction conditions, lower cost, high stereoselectivity of the product, and better yield and optical purity.

Description

Preparation method of beta-fluoro chiral unnatural amino acid
Technical Field
The invention belongs to the technical field of transition metal catalyzed organic chemistry, and particularly relates to a preparation method for obtaining beta-fluoro chiral unnatural amino acid by taking N-Boc protected aziridine and pyridine hydrogen fluoride as basic raw materials and adding a chiral ligand under the catalytic action of transition metal.
Background
From the pharmaceutical perspective, introduction of fluorine atoms can enhance the metabolic stability and bioavailability of drug molecules, and therefore, how to efficiently introduce fluorine atoms into potential drug small molecules is an important research direction in the field of pharmaceutical chemistry. Although the synthesis forms of the fluoro compounds are more and more diversified (J.Am.chem.Soc.2005,127(7): 2050-2051; Angew.chem.int.Ed.2008,47(44): 8404-8406; org.Lett.2009,11(21):5050-5053.), and the application directions are more and more extensive, based on the important application value of the fluoro compounds in the field of medicines, we still need to continuously develop more mild and efficient methods for synthesizing the fluoro compounds, especially for constructing the fluoro compounds with stereoselectivity, which is crucial for the research of novel medicines.
In the existing drug molecules, more than 90% of drugs contain nitrogen atom structures, and fluorine atoms are introduced into amine compounds, so that the metabolic stability and lipophilicity of the drugs can be increased, and the bioavailability of the drug molecules can be improved and the blood brain barrier permeability can be enhanced by reducing the pKa value of the amine (chem.Med.chem.2007,2(8): 1100-. The study of fluorinated amine compounds has also become an important aspect in pharmaceutical Chemistry, as fluorinated amine compounds are important structural moieties in anti-inflammatory drugs, anti-tumor drugs and therapeutic beta-polypeptides (Fluorine in biological Chemistry, Wiley, New York, 1991; Science 2007,317(5846): 1881-.
Currently, the strategy adopted for the synthesis of most fluoroalkane compounds is through the use of reagents with nucleophilic capacity (e.g. Selectfluor, AgF, NFSI, XeF)2、Et3N.HF, etc.) as a fluorine source, and fluorination of an alkane compound is carried out under the action of a transition metal (J.Am.chem.Soc.2010,132(49): 17402-17404; J.am.chem.Soc.2014,136(11): 4101-; J.am.chem.Soc.2015,137(22) 7067-7070; j.am.chem.soc.2015,137(25):8219-8226). Although these reactions can well fluorinate alkane, there are some problems, such as high reaction temperature, large amount of catalyst (5-20 mol%), and the need of using mixed solvent due to the solubility problem of the fluorinating agent, and even the need of adding a large amount of auxiliary agent in the reaction system to ensure the reaction, and the commonly used auxiliary agent such as sodium bicarbonate, lithium carbonate, potassium tert-butoxide, etc., all of which increase the production cost to some extent, so that the industrial application of these reactions is greatly limited.
The aziridine can be attacked by nucleophilic reagents containing atoms such as C, N, O, S, X (X ═ F, Cl, Br, I) and the like under the condition of no activating reagent or mild reaction due to the larger ring tension effect of the aziridine, so that a corresponding ring-opening product is obtained. The use of tetrabutylammonium fluoride, potassium fluoride, boron trifluoride etherate, NiF has been reported2The aziridine structure may be subjected to a ring-opening reaction by XtalFluor-E, DMPU-HF or the like to obtain a β -fluoroalkane compound (J.Am.chem.Soc.2010,132(10): 3268-3269; Eur.J.Org.chem.2010,2010(25): 4920-4931; Org.Lett.2015,17(5): 1074-1077). However, these reactions also exhibit disadvantages such as a narrow range of substrates for the reaction, poor regioselectivity, high reaction temperature, and the like.
In summary, the existing methods for synthesizing beta-fluorinated chiral unnatural amino acids have some problems, such as: high reaction temperature, large catalyst consumption, expensive fluoro reagent, long reaction time, low optical purity and the like. The preparation method of the beta-fluoro chiral unnatural amino acid is mild in condition, low in production cost and capable of obtaining high optical purity.
Disclosure of Invention
The invention aims to provide a preparation method of beta-fluoro chiral unnatural amino acid, which has mild reaction conditions, small catalyst dosage and low pyridine hydrogen fluoride price, greatly reduces the production cost, and greatly shortens the reaction time, thereby improving the production efficiency; in addition, the method has excellent product stereoselectivity, and the prepared beta-fluoro chiral unnatural amino acid has high yield and high optical purity.
In order to achieve the purpose, the invention provides a preparation method of beta-fluoro chiral unnatural amino acid, which takes N-Boc protected aziridine and pyridine hydrogen fluoride as raw materials, adds a chiral ligand, reacts under the action of a transition metal catalyst, and removes Boc groups from a reaction product by using a reagent to obtain the beta-fluoro chiral unnatural amino acid; the reaction formula of the preparation method is as follows:
Figure BDA0002829974520000031
wherein R is1is-H (hydrogen), -Me (methyl), -Et (ethyl), -Pr (propyl), -iPr (isopropyl), -Bu (butyl), -tBu (tert-butyl), -PhCOOCH2(methylene benzyl ester group), -Ph (phenyl), -COOH (carboxyl), -F (fluorine), -Cl (chlorine), -Br (bromine) or-AcO (acetoxy).
In the preparation method, the metal in the transition metal catalyst is at least one of copper, palladium and rhodium; preferred transition metal catalysts are copper fluoride, copper trifluoromethanesulfonate, cuprous iodide, palladium acetate, palladium trifluoromethanesulfonate, rhodium acetate.
In the preparation method, the addition amount of the transition metal catalyst is 1-10 mol% of the mole amount of the N-Boc protected aziridine.
In the preparation method, the addition amount of pyridine hydrogen fluoride is 3-7 times of the molar amount of aziridine protected by N-Boc.
In the preparation method, the chiral ligand is at least one of oxazoline ligand (L1), chiral diphosphine ligand (L2), chiral ferrocene ligand (L3) and chiral amino amide (L4); the structural formula of the chiral ligand is shown as follows:
Figure BDA0002829974520000032
wherein R is2＝R3And are-H (hydrogen), -Me (methyl), -iPr (isopropyl), -tBu (tert-butyl), -Ph (phenyl), -napthyl (naphthyl and naphthyl with various substituents).
In the preparation method of the invention, the addition amount of the chiral ligand is 1-10% mol% of the molar amount of the transition metal catalyst.
In the preparation method of the invention, the reaction temperature is 20-30 ℃ and the reaction time is 5-12 hours.
In the preparation method, the reagent is trifluoroacetic acid.
In the preparation method, a solvent is also added, and the solvent is dichloromethane, tetrahydrofuran or toluene.
In the preparation method for synthesizing the beta-fluoro chiral unnatural amino acid with high optical purity by asymmetric stereoselectivity catalyzed by the transition metal, an aziridine compound protected by N-Boc and pyridine hydrogen fluoride are subjected to ring-opening fluoro reaction under the combined action of the transition metal and a chiral ligand. The experimental results show that: the preparation method of the invention shows excellent product stereoselectivity in the reaction process, the main product is N-Boc-beta-fluoro structure, simultaneously, under the action of the transition metal catalyst and the chiral ligand, the enantioselectivity of the product is improved, the yield can reach 64 percent, and the enantioselectivity reaches more than 90 percent; the obtained N-Boc-beta-fluoro product has high optical purity after removing Boc group by using reagent trifluoroacetic acid to obtain beta-fluoro chiral unnatural amino acid.
Compared with the prior art, the invention has the following beneficial effects:
1) the preparation method has mild reaction conditions, can carry out reaction at room temperature, greatly shortens the reaction time (5-12 hours), saves the production cost and improves the production efficiency.
2) In the preparation method, no additional additive or auxiliary agent is needed to be added except for the reaction raw materials, the transition metal catalyst and the chiral ligand, and the dosage of the catalyst is small, so that the production cost is saved to a certain extent.
3) The preparation method of the invention uses pyridine hydrogen fluoride as fluorine reagent, does not need complicated synthesis steps, has low price and further reduces the production cost.
4) In the preparation method, the stereoselectivity to the product is realized, the obtained product does not generate side products of isomers, and the prepared beta-fluoro chiral unnatural amino acid has high optical purity.
5) In the preparation method, the reagent trifluoroacetic acid is used in the process of removing the Boc protective group, the reagent does not cause great influence on the yield and the optical activity of the product, and the high optical purity of the final product beta-fluoro chiral unnatural amino acid is ensured.
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Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a high performance liquid chromatogram of a β -fluoro chiral unnatural amino acid obtained by the preparation method of example 2 of the present invention.
FIG. 2 is a high performance liquid chromatogram of a β -fluoro chiral unnatural amino acid obtained by the preparation method of example 3 of the present invention.
FIG. 3 is a high performance liquid chromatogram of a β -fluoro chiral unnatural amino acid obtained by the preparation method of example 4 of the present invention.
FIG. 4 is a high performance liquid chromatogram of a β -fluoro chiral unnatural amino acid obtained by the preparation method of example 5 of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. Unless otherwise indicated, reagents or equipment used are commercially available.
The preparation method of the beta-fluoro chiral non-natural amino acid takes N-Boc protected aziridine and pyridine hydrogen fluoride as raw materials, chiral ligands are added to react under the action of a transition metal catalyst, and a reaction product is subjected to Boc group removal by using a reagent to obtain the beta-fluoro chiral non-natural amino acid; the reaction formula of the preparation method is as follows:
Figure BDA0002829974520000051
wherein R is1is-H (hydrogen), -Me (methyl), -Et (ethyl), -Pr (propyl), -iPr (isopropyl), -Bu (butyl), -tBu (tert-butyl), -PhCOOCH2(methylene benzyl ester group), -Ph (phenyl), -COOH (carboxyl), -F (fluorine), -Cl (chlorine), -Br (bromine) or-AcO (acetoxy).
The metal in the transition metal catalyst used in the invention is at least one of copper, palladium and rhodium; preferred transition metal catalysts are copper fluoride, copper trifluoromethanesulfonate, cuprous iodide, palladium acetate, palladium trifluoromethanesulfonate, rhodium acetate. The addition amount of the transition metal catalyst is 1-10 mol% of the mole amount of the N-Boc protected aziridine.
The addition amount of pyridine hydrogen fluoride is 3-7 times of the mol amount of aziridine protected by N-Boc.
The chiral ligand is at least one of oxazoline ligand (L1), chiral diphosphine ligand (L2), chiral ferrocene ligand (L3) and chiral amino amide (L4); the structural formula of the chiral ligand is shown as follows:
Figure BDA0002829974520000061
wherein R is2＝R3And are-H (hydrogen), -Me (methyl), -iPr (isopropyl), -tBu (tert-butyl), -Ph (phenyl), -napthyl (naphthyl and naphthyl with various substituents). The addition amount of the chiral ligand is 1-10 mol% of the molar amount of the transition metal catalyst.
The reaction temperature of the invention is 25-30 ℃, and the reaction time is 5-12 hours.
The reagent of the invention is trifluoroacetic acid.
In the preparation process, a solvent is also added, wherein the solvent is dichloromethane, tetrahydrofuran or toluene; the present invention is not particularly limited in the amount of solvent added, which does not affect the properties of the final product of the present invention.
The experimental materials and instruments used in the following examples were:
cinnamic acid and its derivatives (available from Beijing Yinaoka technologies, Inc.), tert-butyl carbamate (available from Beijing Yinaoka technologies, Inc.), iodosobenzene (available from Beijing carbofuran), pyridine hydrogen fluoride (available from Beijing carbofuran), 10L reactor, heating stirrer, thermometer.
Example 1
Preparing the raw material aziridine.
1481g of cinnamic acid is added to a reaction vessel containing 10L of acetonitrile, 2340g of tert-butyl carbamate and 190g of cuprous iodide are added and stirred for 30 minutes. Then 3080g iodosobenzene was slowly added, and after reaction at room temperature for 24 hours, suction filtration was carried out, the filtrate was concentrated under reduced pressure to obtain a crude product, which was recrystallized to obtain aziridine (1- (tert-butoxycarbonyl) -3-phenylaziridine-2-carboxylic acid), which was a raw material.
Example 2
263g of aziridine of example 1 was taken and added to a reaction vessel containing 1L of methylene chloride, followed by addition of 25.3g of copper methane sulfonate and 0.1 mole of oxazoline ligand L1, followed by reaction with stirring of a slowly added solution of pyridine hydrogen fluoride (3 moles, based on hydrogen fluoride) at 25 ℃ for 5 hours, followed by removal of Boc group with trifluoroacetic acid to give a β -fluoro chiral unnatural amino acid with a yield of 48%.
The optical purity of the obtained product was measured by high performance liquid chromatography, the results are shown in fig. 1, and the retention time, peak area, peak height, and relative peak area of each peak in the high performance liquid chromatography of fig. 1 were analyzed as shown in table 1 below:
TABLE 1
Figure BDA0002829974520000071
The product of this example was analyzed to have an optical purity (ee value) of 90%.
Example 3
263g of aziridine from example 1 was taken and added to a reaction vessel containing 1L of dichloromethane, followed by addition of 22.4g of palladium acetate and 0.1 mol of chiral bisphosphine ligand L2, followed by slow addition of a pyridine hydrogen fluoride solution (3 mol, based on hydrogen fluoride) with stirring, and after 7 hours of reaction at 25 ℃ the Boc group was removed using trifluoroacetic acid to give a β -fluoro chiral unnatural amino acid with a yield of 64%.
The optical purity of the obtained product was measured by high performance liquid chromatography, the results are shown in fig. 2, and the retention time, peak area, peak height, and relative peak area of each peak in the high performance liquid chromatography of fig. 2 were analyzed as shown in table 2 below:
TABLE 2
Figure BDA0002829974520000072
The product of this example was analyzed to have an optical purity (ee value) of 96%.
Example 4
263g of aziridine from example 1 was added to a reaction vessel containing 1L of dichloromethane, followed by addition of 22.4g of palladium acetate and 0.1 mol of chiral ferrocene ligand L3, stirring with a slowly added solution of pyridine in hydrogen fluoride (3 mol, based on hydrogen fluoride), and after 10 hours at 25 ℃ reaction, Boc group was removed using trifluoroacetic acid to give a β -fluoro chiral unnatural amino acid with a yield of 62%.
The optical purity of the obtained product was measured by high performance liquid chromatography, the results are shown in fig. 3, and the retention time, peak area, peak height, and relative peak area of each peak in the high performance liquid chromatography of fig. 3 were analyzed as shown in table 3 below:
TABLE 3
Figure BDA0002829974520000081
The product of this example was analyzed to have an optical purity (ee value) of 93%.
Example 5
263g of aziridine from example 1 were taken and charged into a reaction vessel containing 1L of methylene chloride, followed by addition of 28.0g of rhodium acetate and 0.1 mol of chiral aminoamide L4, and after reaction with stirring of a slowly added solution of pyridine in hydrogen fluoride (3 mol, based on hydrogen fluoride) at 25 ℃ for 12 hours, the Boc group was removed using trifluoroacetic acid to give a β -fluoro chiral unnatural amino acid in 58% yield.
The optical purity of the obtained product was measured by high performance liquid chromatography, the results are shown in fig. 4, and the retention time, peak area, peak height, and relative peak area of each peak in the high performance liquid chromatography of fig. 4 were analyzed as shown in table 4 below:
TABLE 4
Figure BDA0002829974520000082
The product of this example was analyzed to have an optical purity (ee value) of 97%.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it is therefore intended that all such changes and modifications as fall within the true spirit and scope of the invention as defined by the appended claims be interpreted in accordance with the breadth to which they are fairly, if not explicitly recited herein.

Claims (9)

1. A preparation method of beta-fluoro chiral unnatural amino acid is characterized in that: taking N-Boc protected aziridine and pyridine hydrogen fluoride as raw materials, adding a chiral ligand, reacting under the action of a transition metal catalyst, and removing a Boc group from a reaction product by using a reagent to obtain beta-fluoro chiral unnatural amino acid; the reaction formula of the preparation method is as follows:
Figure FDA0002829974510000011
wherein R is1Is hydrogen radical, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, methylene benzyl ester group, phenyl, carboxyl, fluorine, chlorine, bromine or acetoxy.
2. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the metal in the transition metal catalyst is at least one of copper, palladium and rhodium; the transition metal catalyst is at least one of copper fluoride, copper trifluoromethanesulfonate, cuprous iodide, palladium acetate, palladium trifluoromethanesulfonate and rhodium acetate.
3. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the addition amount of the transition metal catalyst is 1-10 mol% of the mole amount of the N-Boc protected aziridine.
4. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the addition amount of the pyridine hydrogen fluoride is 3-7 times of the mol amount of the aziridine protected by the N-Boc.
5. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the chiral ligand is at least one of an oxazoline ligand, a chiral diphosphine ligand, a chiral ferrocene ligand and a chiral amino amide ligand; the structural formula of the chiral ligand is shown as follows:
Figure FDA0002829974510000021
wherein R is2＝R3And is hydrogen radical, methyl, isopropyl, tertiary butyl, phenyl, naphthyl or naphthyl with substituent group.
6. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the addition amount of the chiral ligand is 1-10 mol% of the molar amount of the transition metal catalyst.
7. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the reaction temperature is 20-30 ℃, and the reaction time is 5-12 hours.
8. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the reagent is trifluoroacetic acid.
9. The method for producing a β -fluoro chiral unnatural amino acid according to claim 1, which comprises: the preparation method also comprises the step of adding a solvent, wherein the solvent is dichloromethane, tetrahydrofuran or toluene.
CN202011463840.3A 2020-12-11 2020-12-11 Preparation method of beta-fluoro chiral unnatural amino acid Pending CN112500303A (en)

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Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHANG-HUA DING ET AL.: "An Efficient and Highly Regioselective Fluorination of Aziridines Using BF3·OEt2 as Fluorine Source", 《SYNLETT》 *
JULIA A. KALOW ET AL.: "Synthesis of β -Fluoroamines by Lewis Base Catalyzed Hydro fluorination of Aziridines", 《J. ORG. CHEM.》 *
JULIA A. KALOW, ABIGAIL G. DOYLE: "Enantioselective fluoride ring opening of aziridines enabled by cooperative Lewis acid catalysis", 《TETRAHEDRON》 *
LIPING ZHU ET AL.: "Highly efficient regio-selective ring-opening nucleophilic fluorination of aziridines and azetidines: access to β- or γ- fluorinated amino acid derivatives", 《ORG. BIOMOL. CHEM.》 *
MATTHEW H. KATCHER AND ABIGAIL G. DOYLE: "Palladium-Catalyzed Asymmetric Synthesis of Allylic Fluorides", 《J. AM. CHEM. SOC.》 *
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