Preparation method and application of FOXAP ligand

Abstract

The invention discloses a practical synthesis method of a chiral ligand S, Sp-tBu-FOXAP (S, Sp-tBu-FOXAP). By improving the synthesis process in the literature, the production operation is simpler. Compared with a column chromatography purification mode used in each step in the literature, the novel process does not need column chromatography purification, the product can be purified through pulping or recrystallization, the purity of the final product can reach 97.0% or above, the ee value is larger than 99.0%, the d.r. Value is larger than 20: 1, 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 complexation with ruthenium metal, and can be used for catalytic synthesis of a key intermediate of savobabatrivalsartan which is a savobabatrivalsartan which is a marketable medicine.

Description

Technical Field

[0001] The present application relates to the practical preparation of chiral ferrocenylphosphine nitrogen-phosphorus ligands and the application of the ligands in the synthesis of sacubitril-valsartan intermediates. Background Art

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

[0003] This ligand has a wide range of uses and can achieve good results in many types of asymmetric catalysis fields, including but not limited to asymmetric hydrogenation reactions of olefins, ketones, imines and heterocyclic compounds, asymmetric hydrogen transfer reactions of ketones, asymmetric hydrosilylation reactions, asymmetric allylic 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 ligand are summarized below.

[0004] .

[0005] .

[0006] In 2007, Li Tetrahedron: Asymmetry , 2007, 18 , 629–634] reported the asymmetric hydrogenation of non-functionalized olefins 2, where the chiral catalyst formed by ligand 1 and metal Ir gave 38% conversion and 78% ee. The Merck team reported in [ Tetrahedron: Asymmetry , 2006, 17 , 550–553] reported the asymmetric hydrogenation of ketone 3 with the participation of chiral oxazoline phosphine ligands. The RuCl2(PPh3)3 / 1 catalyst combination had a good reaction effect, with the yield of product 3a being 92% and the ee value being 96%. In 2004, Zhou et al. Adv. Synth. Catal. , 2004, 346 , 909–912] reported the asymmetric hydrogenation of 2-methylquinoline catalyzed by [Ir(COD)Cl]2 / 1, and the ee value of the product tetrahydroquinoline 4a can reach more than 90%. J. Org. Chem.2002, 67 , 4684–4695] reported the asymmetric allylic alkylation and amination of compound 5, using an organopalladium complex of 1 and [Pd(C3H5)Cl]2 as the catalyst. The product ee value was 92.3% when dimethyl malonate was used as the nucleophile, and the product ee value was 91.3% when benzylamine was used as the nucleophile. Guiry et al. J. Organomet. Chem. , 2003, 687 , 545–561], the intramolecular asymmetric Heck reaction of substrate 6 was achieved with Pd2(dba)3dba / 1 as catalyst, and the ee value of product 6a can reach 82%, providing a new idea for the synthesis of natural products. Recently, ligand 1 has shown high practicality in the catalytic synthesis of unnatural amino acids: in 2023, Yin's group [ Nature Communications , 2023, 14 , 2187] reported a Cu(CH3CN)4PF5 / 1-catalyzed asymmetric alkylation reaction using benzophenone-protected glycine tert-butyl ester 7 or benzaldehyde-protected glycine methyl ester as substrates to synthesize chiral non-natural amino acid derivatives in one step. The latter can be deprotected to obtain various non-natural amino acids.

[0007] Although ligand 1 has a wide range of uses, its synthesis reports are relatively limited. In 1996, Ahn and Park et al. J. Org. Chem. 1996, 61 , 4937-4943] reported the synthesis method of ligand 1: using ethyl ferrocenecarboxylate and S-tert-leucine alcohol as starting materials, ligand 1 was synthesized through three steps of amine ester exchange, p-toluenesulfonyl chloride / triethylamine dehydration ring closure, and ortho-directed lithiation-diphenylphosphine chloride substitution. The literature systematically investigated the effects of different solvents, temperatures, and types of butyl lithium on the reaction. Column chromatography separation is required for purification of the three steps. Trimethylaluminum used in the first step is a dangerous reagent that is prone to spontaneous combustion. The solvent ether in the third step has a low boiling point and is flammable, which is not conducive to production. The synthesis route is as follows: .

[0008] In 2017, Richards et al. Organic Letters , 2017, 19, 702 – 705] used a similar method to synthesize ligand 1, but the yield of the last step was only 18%, and ultra-low temperature (-78°C), dangerous solvent ether, and sec-butyl lithium, a dangerous reagent that is prone to spontaneous combustion, were used, and purification required column chromatography. This is also not conducive to production.

[0009] The maximum synthesis scale in the above reports is only at the gram level and has large limitations, so the market price of ligand 1 is very expensive.

[0010] The high price of ligand 1 severely restricts its application potential, so it is of great significance 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 and conducive 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 a mild reaction temperature. Most importantly, due to the improvement of reaction and purification conditions, the cost is greatly reduced compared to the market quotation. The synthetic route is as follows: . Summary of the invention

[0011] The purpose of this application is to provide a S , S p - t A new preparation process for Bu-FOXAP ligand (compound 1) was reported, and its application in the synthesis of chiral intermediates of the blockbuster drug sacubitril-valsartan was preliminarily reported.

[0012] Using ferrocenecarboxylic acid and S-tert-leucine alcohol as starting materials, ligand 1 was synthesized in three steps via acid-amine condensation, dehydration ring closure and hydrogen extraction nucleophilic substitution. The reaction scale can be scaled up to 100 grams to kilograms, and the product can be purified by slurrying or recrystallization without column chromatography.

[0013] In the first implementation of the present application, the starting materials are ferrocenecarboxylic acid and S-tert-leucine alcohol. Ferrocenecarboxylic acid can be prepared into an acyl chloride and then reacted with S-tert-leucine alcohol under alkaline conditions, or a condensing agent can be directly used for an acid-amine condensation reaction. 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, dimethyltetrahydrofuran, and toluene. The reaction temperature is -10 ° C ~ 30 ° C.

[0014] In the implementation method of the second step of the present application, the dehydration ring-closing reagent is at least one of thionyl chloride, p-toluenesulfonyl chloride, and Burgess reagent. The solvent is at least one of dichloromethane, tetrahydrofuran, dimethyltetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, toluene, isopropyl acetate, and N,N-dimethylformamide. The reaction temperature is 0°C to 80°C.

[0015] In the implementation of the third step of the present application, the lithiation reagent is one of n-butyl lithium and sec-butyl lithium. 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°C to 30°C.

[0016] In the first step of purification of the present application, the pulping or crystallization solvent is at least one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, acetonitrile, and dichloromethane.

[0017] In the second step purification method of the present application, the pulping or crystallization solvent is at least one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, acetonitrile, and dichloromethane.

[0018] In the third step of purification of the present application, the pulping or crystallization solvent is at least one of ethanol, isopropanol, methanol, and acetone.

[0019] In one implementation of the present application, the catalyst is [RuCl2( p -cymene)]2 or [RuI2( p -cymene)]2 is formed by in situ complexation with ligand 1 in the solvent.

[0020] In one implementation of the present application, the catalytic reaction solvent is at least one of methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, dichloromethane, toluene, tetrahydrofuran, ethyl acetate, n-hexane, and cyclohexane.

[0021] In one implementation of the present application, the catalytic substrate is a sacubitril-valsartan intermediate (Compound 8); , The catalytic reaction temperature is 25-80 °C and the reaction time is 6-24 h.

[0022] Due to the adoption of the above technical scheme, the beneficial effect of the present application is that the new process of the present application can be used for the industrial production and synthesis of ligand 1, and the product can be purified by slurrying or crystallization without column chromatography. The new process greatly reduces the difficulty of synthesis and production cost of ligand 1, laying the foundation for the development of its catalytic potential. In addition, the complex formed by ligand 1 and metal ruthenium was tried for the asymmetric hydrogenation reaction of sacubitril-valsartan intermediates, and a good catalytic effect was achieved, providing a new scheme for the synthesis of the above drug molecule advanced intermediates. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of ligand 1 in the embodiment of the present application, Figure 2 is the NMR phosphorus spectrum of ligand 1. DETAILED DESCRIPTION

[0024] The present invention is further described in detail below by specific embodiments in conjunction with the accompanying drawings. In the following embodiments, many detailed descriptions are intended to enable the present application to be better understood. However, those skilled in the art can easily recognize that some of the features can be omitted in different situations, or can be replaced by other materials and methods. In some cases, some operations related to the present application are not shown or described in the specification, in order to avoid the core part of the present application being overwhelmed by too much description, and for those skilled in the art, it is not necessary to describe these related operations in detail, and the related operations can be fully understood according to the description in the specification and the general technical knowledge in the art.

[0025] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various implementations. At the same time, the steps or actions in the method description can also be interchanged or adjusted in a manner that is obvious to those skilled in the art. Therefore, the various sequences in the specification and the drawings are only for the purpose of clearly describing a certain embodiment and are not meant to be a required sequence, unless otherwise specified that a certain sequence must be followed.

[0026] The serial numbers assigned to the structural formulas or groups in this application, such as "ligand 1", "compound 8", etc., are only used to distinguish the objects described and do not have any order or technical meaning.

[0027] Terminology explanation: "Room temperature" in this application refers to 25±2°C.

[0028] In the present application, Me represents a methyl group, Et represents an ethyl group, Ac represents an acetyl group, and Boc represents a tert-butyloxycarbonyl group.

[0029] In the present application, Ph represents a phenyl group.

[0030] Example 1 (Synthesis of Ligand 1) The three-step reaction in this example uses the following methods to synthesize ligand 1: In the first step, ferrocenecarboxylic acid 1a reacts with oxalyl chloride in dichloromethane to generate ferrocenecarboxylic acid chloride, which reacts with S-tert-leucine alcohol in the presence of triethylamine to synthesize compound 1b; In the second step, compound 1b reacts with p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine in dichloromethane to undergo a dehydration ring-closure reaction to synthesize compound 1c; In the third step, compound 1c first undergoes a directed hydrogenation-lithiation reaction with n-butyl lithium in methyl tert-butyl ether, and then the generated active lithium intermediate undergoes a nucleophilic substitution reaction with diphenylphosphine chloride to generate the target product ligand 1.

[0031] The technical route for the synthesis of compound 1b is: .

[0032] Add ferrocenecarboxylic acid 1a (100.0 g, 0.435 mol) and dichloromethane (1.0 L, 10 vol) to a 2 L three-necked flask and start stirring. Cool down to 0-10 ℃, add oxalyl chloride (66.3 g, 0.522 mol, 1.2eq) dropwise to the reaction system and stir at room temperature for 1 h. Add S-tert-leucine alcohol (56.0 g, 0.465 mol, 1.1eq) and dichloromethane (100 mL, 1 vol) to another 2 L three-necked flask, followed by triethylamine (88.0 g, 0.870 mol, 2.0 eq). Control the temperature at 10-20 ℃ and add water (200 mL, 2 vol) to quench the reaction. The dichloromethane was removed by concentration, and methyl tert-butyl ether (400 mL, 4 vol) and water (200 mL, 2 vol) were added to the crude product, and the mixture was slurried at room temperature. The solid was collected by filtration and air-dried to obtain a brown solid 1a. The weight was 115.0 g, the yield was 80%, and the purity was 99.0%.

[0033] The technical route for the synthesis of compound 1c is: .

[0034] Add 1b (100.0 g, 0.304 mol) and dichloromethane (1.0 L, 10 vol) to a 2 L jacketed bottle and start stirring. Add 4-dimethylaminopyridine (3.71 g, 0.030 mol, 0.1 eq) and triethylamine (92.2 g, 0.911 mol, 3.0 eq) at a temperature of 10-15 °C, and add p-toluenesulfonyl chloride (86.9 g, 0.456mol, 1.5 eq). The reaction was stirred at 20-30 °C 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, and the dichloromethane was removed by concentration. Acetonitrile (400 mL, 4 vol) was added to slurry. The filter cake was collected by filtration and dried to obtain a brown-yellow solid with a weight of 85.0 g, a yield of 90%, and a purity of 99.0%.

[0035] The technical route for the synthesis of compound 1 is: .

[0036] Add 1c (100.0 g, 0.321 mol) and methyl tert-butyl ether (1.7 L, 17 vol) to a 5 L jacketed bottle, cool to 10-15 ℃, and slowly add n-butyl lithium in n-hexane solution (2.5 M, 0.457 mmol, 1.42 eq, 183.0mL). After the addition, stir at room temperature for 2 h, cool to 0-10 ℃, add diphenylphosphine chloride (99.2 g, 0.449 mol, 1.4 eq), heat to room temperature and stir for 30 min. The reaction is complete. Quench the reaction with 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 (200mL, 2 vol), evaporate, and then use isopropanol and beat. 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%, ee 99.5%, and dr >20:1.

[0037] Example 2 (Catalytic reaction test) In this example, the synthesized ligand 1 and [RuCl2( p -cymene)]2 or [RuI2( p -cymene)]2 is an in situ formed catalyst for the asymmetric hydrogenation of sacubitril-valsartan intermediate 8.

[0038] The technical route of asymmetric hydrogenation reaction is as follows: .

[0039] Asymmetric hydrogenation reaction specific operation: 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 bottle, and solvent (10 vol) was added. Stir at room temperature for 1 h, and then substrate (2.0 mmol) was added. The above reaction bottle was transferred to an autoclave and the autoclave was removed from the glove box. 30 bar H2 was filled into the autoclave and stirred at 40 °C for 20 h. After the reaction, it was cooled to room temperature, the residual pressure in the autoclave was slowly released, and samples were taken to test the conversion rate and chiral purity of the product.

[0040] Part of the data of the asymmetric hydrogenation reaction of ligand 1 and ruthenium in situ catalysis in this example is as follows: .

[0041] The above contents are further detailed descriptions of the present application in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present application is limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A t The preparation method of Bu-FOXAP ligand compound IV, The first step is to activate compound I, ferrocenecarboxylic acid, with oxalyl chloride and condense with S or R-tert-leucine alcohol in dichloromethane solvent to prepare compound II. The second step reaction: the compound of formula II is cyclized in dichloromethane solvent under dehydration conditions to form the compound of formula III, The third step reaction: the compound of formula III is subjected to hydrogen-lithium exchange at a reaction temperature of 0-30°C under the condition of n-butyl lithium in methyl tert-butyl ether as a solvent, and then reacted with diphenylphosphine chloride, and purified by crystallization with isopropanol to obtain the compound of formula IV. ， in, The compounds of formula II and formula III are in R or S configuration, and the compound of formula IV is in (R, R) or (S, S) configuration.

2. The first step of reaction as claimed in claim 1, wherein the reaction temperature is 0 to 30°C.

3. The second step reaction according to claim 1, wherein the reaction temperature is 0-30°C.

4. The (R,R) or (S,S) configuration product of the compound of formula IV as claimed in claim 1 has an enantiomeric excess of more than 99% and a diastereoisomer ratio of more than 20:

1.

5. The purity of the compound of formula IV as claimed in claim 1 is above 97%.

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