Process for the preparation of a foxap ligand and use thereof

Abstract

The application discloses a chiral ligand S , S p t A practical synthesis method of Bu-FOXAP is disclosed. By improving the synthesis process in the literature, the production operation is more simple. Compared with the column chromatography purification method used in each step in the literature, the new process does not need column chromatography purification, the product can be purified by beating or recrystallization, the purity of the final product can reach more than 97.0 %, the ee value is greater than 99.0 %, the d.r. value is greater than 20:1, the purification is simple and the cost is greatly reduced. The chiral ligand prepared by the new process can be used as a catalyst for asymmetric hydrogenation reaction after in-situ complexing with ruthenium metal, and can be used for catalytic synthesis of a key intermediate of a best-selling drug, sacubitril / valsartan.​

Description

Technical Field

[0001] This application relates to the practical preparation of chiral ferrocene phosphine nitrogen-phosphorus ligands and their application in the synthesis of sacubitril-valsartan intermediates. Background Technology

[0002] (S)-tert-butyl-[( S p )-2-(diphenylphosphino)ferrocene]-2-oxazoline, abbreviated as S , S p - t Bu-FOXAP ligand is a chiral oxazoline phosphine ligand based on a ferrocene framework, with the following structure:

[0003] .

[0004] This ligand has a wide range of applications and can achieve good results in many types of asymmetric catalysis, including but not limited to asymmetric hydrogenation of alkenes, ketones, imines and heterocyclic compounds, asymmetric hydrogen transfer reactions of ketones, asymmetric hydrogen silylation reactions, asymmetric allyl substitution reactions, asymmetric Heck reactions and cross-coupling reactions, and asymmetric alkylation reactions of glycine derivatives to prepare non-natural amino acids. S, S p - t The asymmetric catalytic reactions involving Bu-FOXAP ligands are summarized below.

[0005] .

[0006] .

[0007] In 2007, Li [ Tetrahedron: Asymmetry , 2007, 18 [629–634] reported the asymmetric hydrogenation of nonfunctionalized olefin 2, in which a chiral catalyst formed by ligand 1 and metallic Ir gave a conversion of 38% and an ee value of 78%. The Merck team in [ Tetrahedron: Asymmetry , 2006, 17 In 2004, Zhou reported the asymmetric hydrogenation of ketone 3 involving chiral oxazoline phosphine ligands. The RuCl2(PPh3)3 / 1 catalyst combination showed good reaction performance, with a yield of product 3a of 92% and an ee value of 96%. [550–553] Adv. Synth. Catal. , 2004, 346 The asymmetric hydrogenation of 2-methylquinoline catalyzed by [Ir(COD)Cl]2 / 1 was reported in [909–912], with the product tetrahydroquinoline 4a achieving an ee value of over 90%. Hou and Dai's research group in [J. Org. Chem. 2002, 67 , 4684–4695] reported the asymmetric allylic alkylation and amination of compound 5 using organopalladium complex of 1 with [Pd(C3H5)Cl]2 as catalyst, with 92.3% ee of product when dimethyl malonate was used as nucleophile and 91.3% ee of product when benzylamine was used as nucleophile. Guiry et al. in [ J. Organomet. Chem. , 2003, 687 , 545–561] realized the intramolecular asymmetric Heck reaction of substrate 6 using Pd2(dba)3dba / 1 as catalyst, with 82% ee of product 6a, which provided a new way for the synthesis of natural product. Recently, ligand 1 has shown high practicability in the catalytic synthesis of unnatural amino acids: in 2023, Yin group reported the asymmetric alkylation catalyzed by Cu(CH3CN)4PF5 / 1 in [ Nature Communications , 2023, 14 , 2187], with diphenylketone-protected tert-butyl glycinate 7 or benzaldehyde-protected methyl glycinate as substrate, chiral unnatural amino acid derivatives were synthesized in one step, and various unnatural amino acids could be obtained by deprotection of the latter.

[0008] Although ligand 1 has a wide range of applications, its synthesis is reported relatively limited. In 1996, Ahn and Park et al. reported the synthesis of ligand 1 in [ J. Org. Chem. 1996, 61 , 4937-4943]: starting from ferrocenecarboxylic acid ethyl ester and S-tert-leucinol, ligand 1 was synthesized through three steps of amine-ester exchange, dehydration ring closure with p-toluenesulfonyl chloride / triethylamine, ortho-directed lithiation-diphenyl phosphine chloride substitution. The influence of different solvents, temperatures, and butyllithium species on the reaction was systematically investigated in the literature. Column chromatography separation was needed for purification in the three steps, and trimethylaluminum used in the first step was a dangerous reagent that was prone to spontaneous combustion, and the solvent ethyl ether used in the third step had low boiling point and was flammable, which were not conducive to production. The synthetic route is as follows:

[0009] .

[0010] In 2017, Richards et al. synthesized ligand 1 in a similar way in [ Organic Letters , 2017, 19, 702 – 705], but the yield of the last step was only 18%, and super-low temperature (-78℃), dangerous solvent ethyl ether, and dangerous reagent sec-butyllithium were used, and column chromatography was also needed for purification, which was also not conducive to production.

[0011] The maximum synthesis scale in the above reports is only gram level, and the limitation is great, so the market price of ligand 1 is very high.

[0012] The high price of ligand 1 seriously restricts its application potential, so it is meaningful to develop a suitable route and process for the large-scale production of ligand 1. We report here a practical route and process for the production of ligand 1, which is simple to operate, beneficial to scale-up production, does not require column chromatography separation throughout the process, and has high purity of the final product. The entire operation process can be continuously produced and the product can be obtained at high purity under mild reaction temperature conditions. Most importantly, due to the improvement of reaction and purification conditions, the cost is greatly reduced compared with the market price, and the synthesis route is as follows:

[0013] . SUMMARY

[0014] The purpose of the present application is to provide a S , S p - t A new preparation process of Bu-FOXAP ligand (compound 1) is provided, and the application of the ligand in the synthesis of a best-selling drug, sacubitril valsartan chiral intermediate, is preliminarily reported.

[0015] The ligand 1 is synthesized by acid-amine condensation, dehydration ring closure and hydrogen abstraction nucleophilic substitution using ferrocene formic acid and S-tert-leucinol as starting materials. The reaction scale can be scaled up to hundreds of grams to kilograms, and the product can be purified by beating or recrystallization without column chromatography.

[0016] In the first step of the present application, the starting materials are ferrocene formic acid and S-tert-leucinol. The ferrocene formic acid can be prepared into acyl chloride and then reacted with S-tert-leucinol under alkaline conditions, or an acid-amine condensation reaction can be directly carried out using a condensing agent. The acyl chloride reagent or condensing agent is at least one of oxalyl chloride, thionyl chloride, DCC, EDCI, HATU and Oxyma. The solvent is at least one of dichloromethane, tetrahydrofuran, dimethyl tetrahydrofuran and toluene. The reaction temperature is -10 ℃ to 30 ℃.

[0017] In the second step of the present application, the dehydration ring closure reagent is at least one of thionyl chloride, p-toluenesulfonyl chloride and Burgess reagent. The solvent is at least one of dichloromethane, tetrahydrofuran, dimethyl tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, toluene, isopropyl acetate and N,N-dimethylformamide. The reaction temperature is 0 ℃ to 80 ℃.

[0018] In the third step implementation of the present application, the lithiation reagent is one of n-butyllithium and sec-butyllithium. The solvent is at least one of tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, n-hexane and n-heptane. The reaction temperature is at least one of -78℃ and 30℃.

[0019] In the first step purification of the present application, the beating-up or crystallization solvent is at least one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, acetonitrile and dichloromethane.

[0020] In the second step purification of the present application, the beating-up or crystallization solvent is at least one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, acetonitrile and dichloromethane.

[0021] In the third step purification of the present application, the beating-up or crystallization solvent is at least one of ethanol, isopropyl alcohol, methanol and acetone.

[0022] In one implementation of the present application, the catalyst is formed in situ by complexing [RuCl2(cymene)]2 or [RuI2(cymene)]2 with ligand 1 in a solvent. p p

[0023] In one implementation of the present application, the catalytic reaction solvent is at least one of methanol, ethanol, isopropyl alcohol, 2,2,2-trifluoroethanol, dichloromethane, toluene, tetrahydrofuran, ethyl acetate, n-hexane and cyclohexane.

[0024] In one implementation of the present application, the catalytic substrate is sacubitril valsartan intermediate (compound 8).

[0025] ,

[0026] The catalytic reaction temperature is 25-80℃, and the reaction time is 6-24 h.

[0027] With the above technical solutions, the present application has the following beneficial effects: the new process of the present application can be used for industrialized production and synthesis of ligand 1, and the product can be purified by beating-up or crystallization without column chromatography. The new process greatly reduces the synthesis difficulty and production cost of ligand 1, and lays a foundation for developing its catalytic potential. In addition, the complex formed by ligand 1 and metal ruthenium is tried to be used for asymmetric hydrogenation of sacubitril valsartan intermediate, and good catalytic effect is obtained, which provides a new scheme for synthesis of the above drug molecule advanced intermediate. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of ligand 1 in the present application, Figure 2 ​​is a nuclear magnetic resonance phosphorus spectrum of Ligand 1. DETAILED DESCRIPTION

[0029] The application will be described in further detail below with specific reference to embodiments illustrated in the accompanying drawings. In the following embodiments, numerous specific details are described in order to provide a more thorough understanding of the application. However, it will be apparent to one of ordinary skill in the art that the application can be practiced without these specific details. In other instances, well-known features have not been described in detail in order to avoid obscuring the application. Thus, the specific details set forth hereinafter are merely exemplary in nature and should not be construed as limiting the scope of the application in any manner.

[0030] In addition, the features, operations, or characteristics described in the specification can be combined in any suitable manner in various embodiments. Also, each of the steps or acts in the method descriptions can be performed in any suitable order, or in parallel, unless otherwise specified. Therefore, the order in which the operations are described is not necessarily the order in which the operations are performed, unless otherwise specified.

[0031] The serial numbers of the structural formulae or groups in the present application, such as "Ligand 1", "Compound 8", etc., are only used to distinguish the described objects, and do not have any order or technical meaning.

[0032] The term "room temperature" in the present application refers to 25±2℃.

[0033] In the present application, Me represents methyl, Et represents ethyl, Ac represents acetyl, and Boc represents tert-butyloxycarbonyl.

[0034] In the present application, Ph represents phenyl.

[0035] Example 1 (Synthesis of Ligand 1)

[0036] The three-step reaction in this example is used to synthesize Ligand 1 as follows:

[0037] In the first step, ferrocenecarboxylic acid 1a reacts with oxalyl chloride in dichloromethane to form ferrocenecarbonyl chloride, which reacts with S-tert-leucinol in the presence of triethylamine to synthesize compound 1b;

[0038] In the second step, compound 1b reacts with p-toluenesulfonyl chloride, triethylamine, and 4-dimethylaminopyridine in dichloromethane to synthesize compound 1c through dehydration and ring closure reaction;

[0039] Thirdly, compound 1c was prepared by the reaction of compound 1b with n-butyllithium in methyl tert-butyl ether, and then the active lithium intermediate was subjected to nucleophilic substitution reaction with diphenyl chlorophosphine to obtain the target product ligand 1.

[0040] The technical route for synthesizing compound 1b is as follows:

[0041] .

[0042] A 2 L three-necked flask was charged with ferrocenecarboxylic acid 1a (100.0 g, 0.435 mol) and dichloromethane (1.0 L, 10 vol), and stirring was started. The reaction system was cooled to 0-10 ℃, and oxalyl chloride (66.3 g, 0.522 mol, 1.2 eq) was added dropwise. The reaction was stirred at room temperature for 1 h. Another 2 L three-necked flask was charged with S-tert-leucinol (56.0 g, 0.465 mol, 1.1 eq) and dichloromethane (100 mL, 1 vol), followed by the addition of triethylamine (88.0 g, 0.870 mol, 2.0 eq). The reaction was controlled at 10-20 ℃, and water (200 mL, 2 vol) was added to quench the reaction. Dichloromethane was removed by concentration, and methyl tert-butyl ether (400 mL, 4 vol) and water (200 mL, 2 vol) were added to the obtained crude product, and the mixture was slurried at room temperature. The solid was collected by filtration, and was dried by air blowing to obtain brown-yellow solid 1a. The weight was 115.0 g, the yield was 80%, and the purity was 99.0%.

[0043] The technical route for synthesizing compound 1c is as follows:

[0044] .

[0045] A 2 L jacketed flask was charged with 1b (100.0 g, 0.304 mol) and dichloromethane (1.0 L, 10 vol), and stirring was started. 4-Dimethylaminopyridine (3.71 g, 0.030 mol, 0.1 eq) and triethylamine (92.2 g, 0.911 mol, 3.0 eq) were added at a temperature of 10-15 ℃, and p-toluenesulfonyl chloride (86.9 g, 0.456 mol, 1.5 eq) was added. The reaction was stirred at 20-30 ℃ for 15 h. After the reaction was completed, 10% sodium carbonate aqueous solution (400 mL, 4 vol) was added to the reaction system to quench the reaction, dichloromethane was removed by concentration, and acetonitrile (400 mL, 4 vol) was added to the mixture to slurry. The filter cake was collected by filtration, and was dried to obtain brown-yellow solid. The weight was 85.0 g, the yield was 90%, and the purity was 99.0%.

[0046] The technical route for synthesizing compound 1 is as follows:

[0047] .

[0048] Add 1c (100.0 g, 0.321 mol) and methyl tert-butyl ether (1.7 L, 17 vol) to a 5 L jacketed flask, cool to 10–15 °C, and slowly add a hexane solution of n-butyllithium (2.5 M, 0.457 mmol, 1.42 eq, 183.0 mL). After the addition is complete, stir at room temperature for 2 h, then cool to 0–10 °C, add diphenylphosphine chloride (99.2 g, 0.449 mol, 1.4 eq), and heat to room temperature and stir for 30 min. The reaction is complete. Quench the reaction with a saturated sodium bicarbonate aqueous solution (5 vol, 500 mL). Filter, and wash the filter cake once with methyl tert-butyl ether (200 mL, 2 vol). Concentrate the organic phase, add isopropanol (200 mL, 2 vol), distill, and then slurry with isopropanol. The solid was collected by filtration and dried to obtain a yellow crystalline solid with a weight of 95.5 g, a yield of 60%, a purity of 97.0%, an ee of 99.5%, and a dr ratio of >20:1.

[0049] Example 2 (Catalytic Reaction Experiment)

[0050] This example uses synthesized ligand 1 and [RuCl2( p -cymene)]2 or [RuI2( p The catalyst formed in situ by [-cymene)]2 is used for the asymmetric hydrogenation reaction of sacubitril / valsartan intermediate 8.

[0051] The technical route for asymmetric hydrogenation is as follows:

[0052] .

[0053] Specific procedures for asymmetric hydrogenation reaction: In a glove box, [RuCl2( p -cymene)]2 or [RuI2( p [-cymene)]2 (0.01 mmol, 0.5 mol%) and ligand 1 (0.02 mmol, 1.0 mol%) were added to a 10 mL reaction flask, along with solvent (10 vol). The mixture was stirred at room temperature for 1 h, and then the substrate (2.0 mmol) was added. The reaction flask was transferred to an autoclave, which was then removed from the glove box. 30 bar of H2 was introduced into the autoclave, and the mixture was stirred at 40 °C for 20 h. After the reaction was complete, the mixture was cooled to room temperature, and the residual pressure in the autoclave was slowly released. Samples were taken to test the conversion rate and the chiral purity of the product.

[0054] The partial data of the asymmetric hydrogenation reaction of Ligand 1 catalyzed by ruthenium in situ are as follows:

[0055] .

[0056] The above further describes the present application in conjunction with specific embodiments, and the specific implementation of the present application cannot be limited to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, some simple deductions or replacements can be made without departing from the concept of the present application.

Claims

1. A t Process for the preparation of the Bu-FOXAP ligand compound IV, The first step reaction: compound I ferrocenecarboxylic acid is activated by oxalyl chloride and condensed with S or R-tert-leucinol in dichloromethane solvent to prepare compound of formula II, The second step reaction: compound of formula II is ring-closed under dehydration condition in dichloromethane solvent to form compound of formula III, The third step reaction: compound of formula III is reacted with n-butyllithium under the condition of methyl-tert-butyl ether as solvent at a reaction temperature of 0~30°C to carry out hydrogen-lithium exchange, and then reacted with diphenylchlorophosphine to obtain compound of formula IV through isopropanol crystallization and purification, ， wherein Compound of formula II, compound of formula III is in R or S configuration, and compound of formula IV is in (R, R) or (S, S) configuration.

2. The preparation method of compound IV according to claim 1, wherein the reaction temperature of the first step reaction is 0~30°C.

3. The preparation method of compound IV according to claim 1, wherein the reaction temperature of the second step reaction is 0~30°C.

4. The preparation method of compound IV according to claim 1, wherein the enantiomeric excess of the product of compound of formula IV obtained by the method is more than 99%, and the ratio of diastereoisomers is more than 20:

1.

5. The preparation method of compound IV according to claim 1, wherein the purity of compound of formula IV obtained by the method is more than 97%.

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