CN107540574B - Preparation method of R-biphenylalaninol - Google Patents
Preparation method of R-biphenylalaninol Download PDFInfo
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Abstract
The invention relates to a preparation method of a shakubiqu intermediate, in particular to a preparation method of R-biphenylalaninol, which comprises the following steps: firstly, reacting D-tyrosine derivative serving as a raw material with sulfonyl chloride (or anhydride) with different substituents to obtain a compound shown in a formula III, and preparing the compound shown in the formula III into R-biphenylalaninol by two routes respectively. Route one: reducing the compound shown in the formula III into a compound shown in a formula II, and coupling to obtain R-biphenylalaninol; and a second route: and (3) coupling the compound shown in the formula III to obtain a compound shown in a formula V, and reducing to obtain the R-biphenylalaninol. The compound R-biphenylalaninol prepared by the method is a key intermediate of Sacubitril (AHU-377) which is one component of a novel antihypertensive drug LCZ696 (Entresto). The method is simple to operate, short in route and suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of a shakubiqu intermediate, in particular to a preparation method of R-biphenylalaninol, belonging to the field of pharmaceutical chemicals.
Background
Sacubitril (AHU-377) has a blocking threat to the mechanism of action of two polypeptides responsible for lowering blood pressure, and is one of the important components of the antihypertensive drug LCZ 696. LCZ696 is a new antihypertensive drug developed by Novartis, a company that has dual action standards for angiotensin ii receptors and enkephalinase, clinically exhibits a unique mode of action, is believed to reduce strain in failing hearts, is superior to the antihypertensive action of standard drugs, and qualifies the U.S. FDA and eu EMEA for rapid access. It is generally accepted in the industry that LCZ696 will bring about an improvement in the treatment of traumatic pain and heart failure.
R-biphenylalaninol is a key intermediate for Sacubitril synthesis, and for example, patents US5217996, WO2008031567, WO2010136474, WO2012025501, US4722810 and EP00590442 report that the Sacubitril is prepared by taking R-biphenylalaninol as a raw material. Therefore, the efficient, low-cost and low-toxicity synthesis of R-biphenylalaninol is very necessary.
The structural formula of the R-biphenylalaninol is as follows:
the left side is biphenyl, and the right side is provided with chiral groups. Currently, there are two strategies for preparing R-biphenylalaninol or similar compounds: one is synthesized by taking a raw material containing a chiral group as a starting raw material and adding benzene; the other is prepared by taking biphenyl-containing raw materials as starting materials and adding chiral groups or splitting.
The first synthetic strategy has been reported only rarely, mainly because the phenyl group is less active and it is difficult to substitute a phenyl group for another phenyl group.
Med. chem. in 1995, a method for synthesizing R-biphenylpropaneurethane from D-tyrosine is reported, wherein trifluoromethanesulfonic anhydride with very strong activity is used for replacing the hydroxyl group on the benzene of D-tyrosine to form a relatively strong-activity intermediate 3, then the intermediate 3 is reacted with phenylboronic acid to obtain a compound 4, and the compound is further reduced to obtain the R-biphenylpropaneurethane.
In the method, trifluoromethanesulfonic anhydride is needed, which is expensive, highly corrosive, flammable, high in operational risk, high in equipment requirement and difficult in industrial application.
Just because the former method is very difficult, the second strategy is almost always adopted for synthesis, such as:
(1) the method comprises the following steps of reacting biphenyl formaldehyde and N-benzoylglycine with acid anhydride, and then carrying out carboxyl methyl esterification, asymmetric hydrogenation, ester reduction, hydrogenolysis and amino protection to generate R-biphenylalaninol (CN103764624), wherein the specific content is shown as the following formula:
the method needs to use a very expensive rhodium catalyst and a phosphine ligand to prepare a chiral intermediate in the reaction process, needs to use a palladium catalyst to catalyze, and has a long whole reaction route, thereby causing very high cost.
(2) Biphenyl formaldehyde and N-acylglycine are used as starting materials, achiral N-acylbiphenylalanine (WO2011035569, CN200810200404) is obtained through Erlenmeyer-Plocl cyclization, hydrolysis and hydrogenolysis, and chiral N-acylbiphenylalanine (WO2010081410) is obtained through chiral amine resolution, and the specific contents are as follows:
the method needs to use the traditional resolution method to synthesize the chiral biphenyl amino acid, and has the advantages of low yield, long route and high cost.
(3) Taking biphenyl formaldehyde and hydantoin as initial raw materials, and obtaining chiral biphenyl alanine (CN200780002319.6) through Schiff base reaction, catalytic hydrogenation and biological enzyme resolution, wherein the specific contents are as follows:
the process is a biological enzyme resolution technology which has high requirements on reaction conditions, needs to strictly control the pH value of the reaction, has low substrate concentration and is difficult to produce in a large scale, and in addition, the bioactive enzyme Alkalase has high price and high cost.
(4) The method comprises the following steps of taking brominated biphenyl as a raw material, firstly carrying out Grignard reaction, then carrying out reaction with chiral propylene oxide, then carrying out ammoniation and amino protection to obtain an analogue of a target compound R-biphenylalaninol (WO2014032627), wherein the specific content is shown as the following formula:
the method needs a Grignard reagent in the reaction, has high activity and high reaction operation requirement, racemization exists in the ammoniation process, and large-scale production is difficult.
It can be seen that the current method using the second strategy still has the defects of high cost, long route or high operation requirement, and the industrial application is limited.
Therefore, there is a need to develop a safer and cheaper process for the preparation of R-biphenylalaninol.
Disclosure of Invention
In order to solve the problems, the invention provides a method for preparing R-biphenylalaninol, which is safe, short in synthetic route, low in cost and simple and convenient to operate.
The invention provides a compound shown in a formula III, which has the following structural formula:
wherein R is1Is an amino protecting group;
R2is H, C1-C12Alkyl, aryl, heteroaryl, C1-C12Alkylaryl or C1-C12The alkyl heteroaryl is optionally substituted with one or more of the following: c1-C12An alkyl group;
R3is H, C1-C20Alkyl, aryl, heteroaryl, aralkyl, C1-C20Alkylaryl group, C1-C20The alkylheteroaryl or silicon group is optionally substituted with one or more of: c1-C12An alkyl group.
Further, the amino protecting group R1Is a protective group containing alkyl, aralkyl and aryl.
Preferably, the amino protecting group R1Is Boc, Cbz, Bn or Fmoc.
The invention provides a method for preparing the compound, which comprises the following steps:
taking a D-tyrosine derivative shown in a formula IV, and reacting a sulfonylation reagent with the D-tyrosine derivative to prepare a compound shown in a formula III; wherein the sulfonylation reagent is R2SO2Cl or (R)2SO2)2O；
In the above reaction formula, R1Is an amino protecting group;
R2is H, C1-C12Alkyl, aryl, heteroaryl, C1-C12Alkylaryl or C1-C12The alkyl heteroaryl is optionally substituted with one or more of the following: c1-C12An alkyl group;
R3is H, C1-C20Alkyl, aryl, heteroaryl, aralkyl, C1-C20Alkylaryl group, C1-C20The alkylheteroaryl or silicon group is optionally substituted with one or more of: c1-C12An alkyl group.
Preferably, the reaction of the sulfonylating agent with the D-tyrosine derivative is: and (3) sequentially adding the D-tyrosine derivative, the sulfonylation reagent and triethylamine into a solvent at 0-5 ℃, evaporating to dryness and purifying after the reaction at 20-25 ℃ to obtain the compound shown in the formula III.
Further, the solvent is anhydrous tetrahydrofuran, methyl tert-butyl ether or 1, 4-dioxane.
Further, the molar volume ratio of the D-tyrosine derivative to the solvent is 1: 1-10 mmol/ml; and/or the molar ratio of the D-tyrosine derivative to triethylamine is 1: 2-4; and/or the molar ratio of the D-tyrosine derivative to the sulfonylation reagent is 1: 1-1.2.
The invention provides a compound shown as a formula II, which has the following structural formula:
wherein R is1Is an amino protecting group; r2Is H, C1-C12Alkyl, aryl, heteroaryl, C1-C12Alkylaryl or C1-C12The alkyl heteroaryl is optionally substituted with one or more of the following: c1-C12An alkyl group.
The invention provides a method for preparing a compound shown in a formula II by using the compound III.
The invention provides a compound shown as a formula V, which has the following structural formula:
wherein R is1Is an amino protecting group; r3Is H, C1-C20Alkyl, aryl, heteroaryl, aralkyl, C1-C20Alkylaryl group, C1-C20Alkyl radicalThe heteroaryl or silicon group is optionally substituted with one or more of the following: c1-C12An alkyl group.
The invention provides a method for preparing a compound shown in a formula V by using the compound III, which comprises the step of coupling the compound III to prepare the compound shown in the formula V.
The use of the above compound III for the preparation of R-biphenylalaninol.
The invention provides a method for preparing R-biphenylalaninol by using the compound III:
taking the compound III, carrying out reduction reaction to obtain a compound shown as a formula II, and carrying out coupling reaction on the compound II to obtain R-biphenylalaninol;
alternatively, the first and second electrodes may be,
and (3) taking the compound III, carrying out coupling reaction to obtain a compound shown as a formula V, and carrying out reduction reaction on the compound V to obtain the R-biphenylalaninol.
Further, the reduction reaction is: sequentially adding the reaction raw material A and lithium aluminum hydride into methyl tert-butyl ether at 0-5 ℃, reacting for 1-3 h at 20-25 ℃, quenching, filtering and purifying to obtain the product; wherein the reaction raw material A is a compound III or a compound V.
Further, the molar volume ratio of the reaction raw material A to the methyl tert-butyl ether is 1: 2-8 mmol/ml; and/or the molar ratio of the reaction raw material A to the lithium aluminum hydride is 1: 3-5.
Furthermore, the lithium aluminum hydride is added for five times within 5-10 min.
Further, the coupling reaction is: adding a reaction raw material B into a solvent, adding a phenyl boride, an alkali, a metal catalyst and/or a ligand L1, and reacting at 30-130 ℃ under an argon environment to obtain R-biphenylalaninol; wherein the reaction raw material B is a compound II or a compound III.
Further, the solvent is dichloromethane, methanol, ethanol, isopropanol, toluene, tetrahydrofuran, dioxane or morpholine.
Further, the phenyl boron compound is phenylboronic acid, methyl phenylboronate, ethyl phenylboronate, isopropyl phenylboronate, pinacol phenylboronate, dimethyl phenylborone or diethyl phenylborone.
Further, the base is potassium carbonate, potassium tert-butoxide, potassium phosphate, potassium hydroxide, cesium carbonate, sodium carbonate or triethylamine.
Further, the weight volume ratio of the reaction raw material B to the solvent is 1: 10-30 g/ml.
Furthermore, the molar ratio of the reaction raw material B to the phenyl boride is 1: 1-6.
Preferably, the molar ratio of the reaction raw material B to the phenyl boride is 1: 2-4.
Further, the molar ratio of the reaction raw material B to the alkali is 1: 1-6.
Preferably, the molar ratio of the reaction raw material B to the alkali is 1: 3-4.
Further, the molar ratio of the reaction raw material B to the metal catalyst is 1: 0.005-0.1.
Preferably, the molar ratio of the reaction raw material B to the metal catalyst is 1: 0.03-0.05.
Further, the temperature of the coupling reaction is 110-130 ℃.
Further, the coupling reaction time is 12-36 h.
Preferably, the coupling reaction time is 24 h.
Further, the metal catalyst is a palladium catalyst or a nickel catalyst.
Further, the nickel catalyst is nickel chloride and hydrates thereof, nickel bromide and hydrates thereof or nickel acetate and hydrates thereof.
Further, the palladium catalyst is palladium acetate, palladium propionate, palladium dichloride, palladium dibromide or a palladium complex.
Preferably, the palladium complex has the general formula PdLaXbScL is ligand, X is halogen, S is pyridine, 3-chloropyridine or propaneAlkenyl or phenylpropenyl, a is 0 to 2, b is 0 to 2, and c is 1 to 4.
Preferably, the ligands L and L1 are independently selected from aryl phosphine, alkyl phosphine, N-heterocarbene and its salt compound, pyridine, 3-chloropyridine, propenyl, phenylpropenyl, cyanophenyl, acetonitrile, 1, 5-cyclooctadiene, acetylacetone or dibenzylidene acetone.
Preferably, the N-heterocarbene ligand is:
wherein R is4，R5Independently selected from C3The above alkyl or aryl groups are optionally substituted with one or more of the following groups: c1Alkyl of the above, -C (Ph)2、C1Alkylamino group or C above1The above alkoxy group.
Preferably, the palladium complex is [ (IMes) Pd (cin) Cl]、[(SIMes)Pd(cin)Cl]、[(IPr)Pd(cin)Cl]、[(SIPr)Pd(cin)Cl]、[(IPr*)Pd(cin)Cl]、[(IPr*OMe)Pd(cin)Cl]、[(IMes)Pd(allyl)Cl]、[(IPr)Pd(allyl)Cl]、[(IMes)Pd(Py)Cl2]、[(SIMes)Pd(Py)Cl2]、[(IPr)Pd(Py)Cl2]、[(SIPr)Pd(Py)Cl2]、[(IPr*)Pd(Py)Cl2]、[(IPr*)Pd(3-Cl-Py)Cl2]、[Pd(AmPhos)2Cl2]、[Pd(Phos)2Cl2]、[Pd(X-Phos)2Cl2]Or [ Pd (PPh)3)4]。
The abbreviations of the invention correspond to the structural formulas:
definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
C1-C12Alkyl means a straight or branched hydrocarbon chain containing from one to twelve carbon atoms, optionally substituted by C1-C12Alkyl substitution;
substitution means that a hydrogen atom in a molecule is replaced by another, different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix (C)a～Cb) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C12The alkyl group means an alkyl group having 1 to 12 carbon atoms.
Halogen is fluorine, chlorine, bromine or iodine.
Aryl represents an aryl carbocyclic group having a single ring, multiple rings or multiple condensed rings, at least one of which is aromatic, which may be substituted by C1-C12Alkyl mono-, di-, tri-substituted.
Heteroaryl denotes one or more 5-, 6-or 7-membered aromatic ring systems containing at least one heteroatom selected from nitrogen, oxygen or sulfur, which may be substituted by C1-C12Alkyl mono-, di-, tri-substituted.
C1-C12Alkylaryl denotes a radical containing C1-C12Is linked to an aryl group, optionally by C1-C12Alkyl substitution.
C1-C12Alkylheteroaryl denotes a compound containing C1-C12Is linked to a heteroaryl group, optionally substituted by C1-C12Alkyl substitution.
"Compound of the invention" means a compound represented by the formula (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
The method adopts a first strategy to prepare the R-biphenylalaninol. The inventor finds that the R-biphenylalaninol can be finally prepared under the condition of the invention by adopting benzenesulfonyl chloride with lower activity to react with the hydroxyl on the benzene of D-tyrosine to obtain an intermediate III.
When the intermediate III is prepared, adopted benzene sulfonyl chloride is non-corrosive and non-flammable, and has the advantages of low cost, low requirement on equipment and simple and convenient operation.
The intermediate III is adopted to prepare the R-biphenylalaninol, and the R-biphenylalaninol can be obtained through two routes. Route one: reducing the formula III into a formula II, and then coupling to obtain R-biphenylalaninol; and a second route: coupling the compound shown in the formula III to obtain a compound shown in the formula V, and reducing the compound to obtain the R-biphenylalaninol. The two methods are only needed to react under the conditions of the catalyst and the like, and the catalyst is short in synthetic route and low in cost.
The invention achieves the following beneficial effects: the method for preparing the key intermediate R-biphenylalaninol of Sacubitril (AHU-377) which is one component of the novel antihypertensive drug LCZ696(Entresto) provided by the invention does not need to introduce chiral groups, has the advantages of short route, simple operation, safe, stable and reliable production, high yield, high optical purity of products and low cost, and is suitable for industrial production.
The present invention is described in further detail with reference to the following embodiments, but the present invention is not limited thereto, and various other modifications, substitutions and alterations can be made without departing from the basic technical idea of the present invention based on the above-mentioned contents of the present invention and common technical knowledge and conventional means in the art.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and commercially available products.
EXAMPLE 1 Synthesis of Compound III
20g of D-Boc tyrosine methyl ester was weighed into a reaction flask, and a solvent of 60mL of anhydrous tetrahydrofuran was added thereto, and 21.6mL of triethylamine was added thereto under ice bath, followed by slowly dropping 12.7g of benzenesulfonyl chloride into the reaction flask, and a large amount of white solid was generated immediately. After the addition, the ice bath was removed and the reaction was carried out at room temperature for 5 hours. The solvent was evaporated to dryness, 80mL of ethyl acetate was added thereto, and the organic phase was washed successively with a saturated aqueous sodium carbonate solution, a saturated aqueous ammonium chloride solution and a saturated saline solution. Drying, evaporating to dryness to obtain 29.3g of yellow oily compound III (4-benzenesulfonyl-D-Boc tyrosine methyl ester) with yield of 99.4%.
Example 2 Synthesis of Compound II from Compound III
Weighing 10g of compound III (4-benzenesulfonyl-D-Boc tyrosine methyl ester) in a reaction bottle, adding 50mL of methyl tert-butyl ether to dissolve the compound III, slowly adding 3.49g of lithium aluminum hydride in ice bath, removing the ice bath after the addition is finished, and reacting for 1h at room temperature. Slowly adding ethanol dropwise for quenching, and filtering. After spin-drying the filtrate, 50mL of ethyl acetate was added, the organic phase was washed with a saturated aqueous ammonium chloride solution, water and a saturated common salt solution in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and column chromatography (PE: EA ═ 5:1) was performed to obtain 8.5g of a yellow oily compound ii (4-benzenesulfonyl-D-Boc phenylalaninol) with a yield of 90.8%.
Example 3 Synthesis of Compound I from Compound II
A reaction flask was charged with 50mg, 0.123mmol of Compound II (4-benzenesulfonyl-D-Boc phenylalaninol), phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol) and [ (IMes) Pd (Py) Cl2](5 mol%) adding solvent morpholine 1mL, reacting at 120 ℃ for 24h under argon atmosphere to obtain R biphenyl alaninol. The yield is 62.5%, the e.e. value is more than 99%, and the alpha value is]D25＝+21.9(c＝0.01g/mL,CHCl3)。
Example 4 Synthesis of Compound I from Compound II
50mg, 0.123mmol of Compound II (4-benzenesulfonyl-D-Boc phenylalaninol), phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol) and [ (SIMes) Pd (Py) Cl2](5 mol%) is added with 1mL of solvent morpholine, and the mixture reacts for 24h at 120 ℃ under the argon atmosphere to obtain the R-biphenylalaninol. The yield is 55.4 percent, and the e.e. value is more than 99 percent.
EXAMPLE 5 Synthesis of Compound I from Compound II
Into a reaction flask, compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (50mg, 0.123mmol), phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol) and [ (C.) (0.491 mmol)IPr)Pd(Py)Cl2](5 mol%) adding solvent morpholine 1mL, reacting at 120 deg.C for 24h under argon atmosphere to obtain R-biphenylalaninol. The yield is 57.6 percent, and the e.e. value is more than 99 percent.
Example 6 Synthesis of Compound I from Compound II
Into a reaction flask, compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (50mg, 0.123mmol), phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol) and [ (IPr) Pd (acac) Cl2](5 mol%) adding 1mL of 1, 4-dioxane solvent, and reacting at 120 ℃ for 24h under argon atmosphere to obtain R-biphenylalaninol. The yield is 48.9 percent, and the e.e. value is more than 99 percent.
Example 7 Synthesis of Compound I from Compound II
Adding compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (50mg, 0.123mmol), phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol), [ (IPr x) Pd (cin) Cl ] (5 mol%) and solvent dioxane 1mL into a reaction bottle, and reacting at 120 ℃ for 24h under an argon atmosphere to obtain R-biphenylalaninol. The yield is 46.0 percent, and the e.e. value is more than 99 percent.
Example 8 Synthesis of Compound I from Compound II
Into a reaction flask, compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (50mg, 0.123mmol), phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol) and [ (IMes) Pd (Py) Cl2](5 mol%) adding solvent morpholine 1mL, reacting at 130 deg.C for 24h under argon atmosphere to obtain R-biphenylalaninol. The yield is 56.0 percent, and the e.e. value is more than 99 percent.
Example 9 Synthesis of Compound I from Compound II
Into a reaction flask, compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (50mg, 0.123mmol), phenylboronic acid (30mg, 0.246mmol), potassium carbonate (51mg, 0.368mmol) and [ (IMes) Pd (Py) Cl2](5 mol%) adding solvent morpholine 1mL, reacting at 120 deg.C for 24h under argon atmosphere to obtain R-biphenylalaninol. The yield is 48.0 percent, and the e.e. value is more than 99 percent.
EXAMPLE 10 Synthesis of Compound I from Compound II
Into a reaction flask, compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (50mg, 0.123mmol), phenylboronic acid (30mg, 0.246mmol), and carbonPotassium (51mg, 0.368mmol) and [ (IMes) Pd (Py) Cl2](10 mol%) adding solvent morpholine 1mL, reacting at 120 ℃ for 24h under argon atmosphere to obtain R-biphenylalaninol. The yield is 47.5 percent, and the e.e. value is more than 99 percent.
EXAMPLE 11 Synthesis of Compound I from Compound II
Into a reaction flask, compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (200mg, 0.49mmol), phenylboronic acid (239mg, 1.96mmol), potassium carbonate (271mg, 1.96mmol) [ (IMes) Pd (Py) Cl2](5 mol%) and 4mL of solvent morpholine, reacting for 24h at 120 ℃ under the argon atmosphere to obtain the R-biphenylalaninol. Yield: 63.3%, and e.e. value > 99%.
EXAMPLE 12 Synthesis of Compound I from Compound II
The reaction flask was charged with compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (2.0g, 4.9mmol), phenylboronic acid (2.39g, 19.6mmol), potassium carbonate (2.71g, 19.6mmol), [ (IMes) Pd (Py) Cl2](5 mol%) and 40mL of solvent morpholine, and reacting for 24h at 120 ℃ under the argon atmosphere to obtain the R-biphenylalaninol. Yield: 65.3%, and e.e. value > 99%.
EXAMPLE 13 Synthesis of Compound I from Compound II
And (3) putting the compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (2.0g, 4.9mmol), phenylboronic acid (2.39g, 19.6mmol), potassium carbonate (2.71g, 19.6mmol), palladium acetate (5 mol%) and 40mL of solvent morpholine into a reaction bottle, and reacting at 120 ℃ for 24 hours under an argon atmosphere to obtain R-biphenylalaninol. Yield: 74.5%, and e.e. value > 99%.
EXAMPLE 14 Synthesis of Compound I from Compound II
And (3) putting the compound II (4-benzenesulfonyl-D-Boc phenylalaninol) (2.0g, 4.9mmol), phenylboronic acid (2.39g, 19.6mmol), potassium carbonate (2.71g, 19.6mmol), nickel chloride (5 mol%) and 40mL of morpholine serving as a solvent into a reaction bottle, and reacting at 120 ℃ for 24 hours under an argon environment to obtain R-biphenylalaninol. Yield: 48.2%, e.e. value > 99%.
EXAMPLE 15 Synthesis of Compound V from Compound III
The reaction flask was charged with compound III (4-benzenesulfonyl-D-Boc tyrosine methyl ester) (2.1g, 4.8mmol), phenylboronic acid (2.39g, 19.6mmol), potassium carbonate (2.71g, 19.6mmol), [ (IPr x) Pd (cin) Cl ] (5 mol%), and morpholine (40 mL) as a solvent, and reacted at 120 ℃ for 24 hours under argon atmosphere to obtain 3-biphenyl-D-Boc alanine methyl ester. Yield: 53.7%, e.e. value > 99%.
EXAMPLE 16 Synthesis of Compound I from Compound V
The compound V (3-biphenyl-D-Boc alanine methyl ester) (2.0g, 5.6mmol) was charged into a reaction flask, 10mL of methyl tert-butyl ether was added thereto and dissolved, 0.85g of lithium aluminum hydride was slowly added under ice bath, and after completion of the addition, the ice bath was removed and the reaction was carried out at room temperature for 1 hour. Slowly adding ethanol dropwise for quenching, and filtering. And (3) spin-drying the filtrate, adding 20mL of ethyl acetate, washing an organic phase by using a saturated ammonium chloride aqueous solution, water and a saturated saline solution in sequence, drying the organic phase by using anhydrous sodium sulfate, then evaporating the solvent under reduced pressure, and carrying out column chromatography (PE: EA is 5:1) to obtain the R-biphenylalaninol, wherein the yield is 89.3%, and the e.e. value is more than 99%.
According to examples 1 to 16, it is understood that the target product R-biphenylalaninol can be prepared by using the compound III, and the prepared product has high purity and high yield.
In conclusion, the invention provides an intermediate compound III, which can be used for effectively synthesizing R-biphenylalaninol without introducing chiral groups, and has the advantages of short route, simple operation, safe, stable and reliable production, low cost, high yield, high optical purity of products and good industrial application prospect.
Claims (4)
1. A method for preparing R-biphenylalaninol, characterized in that:
taking a compound III, carrying out reduction reaction to obtain a compound shown as a formula II, and carrying out coupling reaction on the compound II to obtain R-biphenylalaninol;
wherein R is1Is Boc, Cbz, Bn or Fmoc; r2Is phenyl; r3Is H, C1-C20An alkyl group;
the coupling reaction is as follows: adding a reaction raw material B into a solvent, adding phenyl boride, alkali and a metal catalyst into the solvent, and reacting at the temperature of between 30 and 130 ℃ under an argon environment to obtain the catalyst; wherein the reaction raw material B is a compound II;
the metal catalyst is a palladium catalyst, and the palladium catalyst is palladium acetate.
2. The method of claim 1, wherein: the solvent is dichloromethane, methanol, ethanol, isopropanol, toluene, tetrahydrofuran, dioxane or morpholine.
3. The method of claim 1, wherein: the phenyl boron compound is phenylboronic acid, methyl phenylboronate, ethyl phenylboronate, isopropyl phenylboronate, pinacol ester phenylboronate, dimethyl phenylborone or diethyl phenylborone.
4. The method of claim 1, wherein: the base is potassium carbonate, potassium tert-butoxide, potassium phosphate, potassium hydroxide, cesium carbonate, sodium carbonate or triethylamine.
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| CN111205204A (en) * | 2020-01-16 | 2020-05-29 | 南京红杉生物科技有限公司 | Sacubitril intermediate and synthetic method and application thereof |
| CN111253425B (en) * | 2020-02-21 | 2022-04-29 | 常州南京大学高新技术研究院 | Synthesis method of 1, 3-bis [2- (3, 4-epoxycyclohexyl) ethyl ] tetramethyldisiloxane |
| CN115745841B (en) * | 2021-09-03 | 2024-04-16 | 凯特立斯（深圳）科技有限公司 | Preparation method of sakubi-qu intermediate |
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