A substituted ferrocene-based diphosphine homogeneous catalyst ligand

Abstract

This application provides a substituted ferrocene-based diphosphine homogeneous catalyst ligand of formula I. Furthermore, compound I is a metal complex ligand for a homogeneous hydrogenation catalyst. The catalyst ligand is simple to synthesize, easy to post-process, and readily suitable for industrial production. Using this catalyst, very high activity, productivity, and enantioselectivity can be achieved.

Description

Technical Field

[0001] This application relates to the field of drug synthesis, specifically to a substituted ferrocene-based diphosphine homogeneous catalyst, its synthesis, and its application. Background Technology

[0002] The first report on ferrocene-based diphosphine homogeneous catalysts was published by French scientist Paul Knochel in Chem. Eur. J. 4 (1998) 950-968 and Tetrahedron: Asymmetry 10 (1999) 1839-1842. In collaboration with Degussa-Hills AG, a patent for the relevant catalyst compound, US6284925B, was filed in 1999. The general formula of its catalyst structure is as follows:

[0003] .

[0004] As research into this ligand deepened, YUMIKORON AG opted to optimize the aromatic ring of the diarylphosphine branched chain and filed a patent application (CN100410263C) for the related compound in 2004. The general formula of the catalyst ligand for which they are seeking protection is as follows:

[0005] .

[0006] Following a subsequent collaboration between Yumicol AG and Solvias AG, a class of ligands with the following specific structure was named Mandyphos and has been applied in numerous fields, as reported in articles such as Solvia's summary article Tetrahedron: Asymmetry 15 (2004) 2299–2306; and Novartis' patent CN101516831B. The general formula for Mandyphos is described as follows:

[0007] .

[0008] Mandyphos acts as a catalytic hydrogenation ligand in the synthesis of intermediate IV in Novartis's new heart failure drug Entresto (sacubitril / valsartan sodium tablets). Novartis reported in patent CN101516831B a method for constructing a chiral N-Boc biphenyl γ-amino acid (CAS No.: 1012341-50-2; chemical name: ((2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid) using the ligand Mandyphos SL-M004-1 (also known as (R)-(S)-NMe2-P(3,5-Me-4-MeOPh)2-Mandyphos) provided by Solvias, with the chemical structure shown in compound IV.

[0009] .

[0010] More specifically, the ligand Mandyphos SL-M004-1 used by Novartis has the structure shown in compound II below:

[0011] .

[0012] The preparation of this ligand requires the synthesis and purification of a highly active, high-boiling-point compound, bis(3,5-dimethyl-4-methoxyphenyl)phosphine chloride. Production is difficult, requiring specialized equipment and processes, which is detrimental to industrial-scale production. According to Example 8 of Chirotech Technology Co., Ltd.'s patent WO1998054193, the synthesis of bis(3,5-dimethyl-4-methoxyphenyl)phosphine chloride is subject to harsh conditions, with a final distillation purification temperature and vacuum pressure of 210°C and 0.2 mbar, respectively, and a low yield of only 25%. Because the purity of bis(3,5-dimethyl-4-methoxyphenyl)phosphine chloride is directly related to the purity of the ligand, and the purity of the ligand has a significant impact on the results of asymmetric catalytic hydrogenation, including yield and chiral selectivity, the difficulty in synthesizing bis(3,5-dimethyl-4-methoxyphenyl)phosphine chloride greatly increases the manufacturing cost of this catalyst, making industrial-scale production impractical and resulting in high catalyst costs and limited application scope.

[0013] Besides novel ligands like Mandyphos, which are obtained by modifying the substitution positions of diarylphosphine, the literature Chem. Eur. J. 4 (1998) 950-968 and Tetrahedron: Asymmetry 10 (1999) 375–384 also disclosed the use of commercially inexpensive and readily available diphenylphosphine as the phosphine group, while modifying ligands at other positions of ferrocene, as shown in formulas IA, IB, IC, and ID. However, the modification of these ligands did not result in good catalytic hydrogenation performance, and therefore, they have not been widely used.

[0014] Summary of the Invention

[0015] The purpose of this application is to provide a substituted ferrocene-based diphosphine homogeneous catalyst ligand, wherein the structure of the ligand is shown in Formula I:

[0016]

[0017] Wherein, the Ar group is 4-methylphenyl or 3,5-dimethylphenyl, and the absolute configuration of the chiral center at the Ar group is simultaneously (R) or simultaneously (S).

[0018] When studying a new class of diphenylphosphine as a phosphine group and modifying ligands at other positions of ferrocene, we first used the known ligands IA, IB, IC and ID from the literature as the baseline reaction to evaluate the ligand reactivity. We found that ligands IA, IB, IC and ID did not give good results, as shown in Table 1.

[0019]

[0020] Table 1:

[0021] ligands Chiral HPLC IA 89.44% IB 64.76% IC 81.02% ID 51.01%

[0022] Although ligands IA, IB, IC, and ID did not yield satisfactory results, we further modified the methyl groups at positions 3, 4, and 5 to analyze the catalyst's effect. Unexpectedly, we found that modification with ligand IE significantly improved both catalytic activity and selectivity. Specific results are shown in Table 2.

[0023]

[0024] Table 2

[0025] ligands Chiral HPLC IE 96.13%

[0026] In the subsequent scale-up synthesis stage of the catalyst, we further discovered that ligands IF and IE do not require time-consuming and industrially unscalable purification methods such as column chromatography as other known substituted ferrocene diphosphine ligands reported in the literature. Instead, they can be purified into crystalline products with high efficiency and purity using solvents such as methyl tert-butyl ether.

[0027] In summary, we found that:

[0028] 1) Although most ligands using diphenylphosphine as the phosphine group and modifying other positions of the ferrocene ligands did not yield good results for our target reaction, the ligand IE unexpectedly exhibited better catalytic activity and selectivity. The resulting product could be purified to obtain very high purity and chiral purity.

[0029] 2) IE has very high catalytic activity. Through further research, we found that its TON value can reach 10,000 or even higher.

[0030] 3) The synthesis of IE catalysts uses commercially available and inexpensive diphenylphosphine as the phosphine group, eliminating the need for bis(3,5-dimethyl-4-methoxyphenyl)phosphine chloride, which greatly reduces the difficulty and cost of preparation;

[0031] 4) Unlike other known substituted ferrocene diphosphine ligands reported in the literature, IE does not require time-consuming and industrially unscalable purification methods such as column chromatography. Instead, it can be purified into crystallized products with high efficiency and purity using solvents such as methyl tert-butyl ether, which further reduces the difficulty of its industrial production and expands the scope of its potential industrial applications.

[0032] 5) Because ligand IE can be purified by a stable and reproducible recrystallization method, its quality is more stable, which is beneficial for obtaining more stable reaction results in the asymmetric catalytic hydrogenation reaction of ligand IE. Detailed Implementation

[0033] The embodiments of this application are described below. Those skilled in the art should recognize that these specific embodiments are merely illustrative of the implementation techniques chosen to achieve the objectives of this application and are not intended to limit the technical solutions. Based on the teachings of this application, improvements to the technical solutions of this application, combined with existing technologies, are obvious and all fall within the scope of protection of this application.

[0034] The implementation conditions used in the examples can be further adjusted according to specific requirements. Implementation conditions not specified are usually those in routine experiments.

[0035] In the specific ligand research examples, the asymmetric catalytic hydrogenation method used is to react with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal catalyst is a ruthenium catalyst.

[0036] Example 1 Preparation of compound IE

[0037]

[0038] Aluminum trichloride (8.06 g, 2.5 eq) was added to dichloromethane (59 mL, 13 vol), and p-methylbenzoyl chloride (10.5 g, 2.8 eq) was added dropwise at 0–10 °C. Ferrocene (4.5 g, 1.0 eq) was then added. After the reaction was complete, the reaction solution was added to 100 mL of water, stirred, and separated into layers. The aqueous phase was extracted once with dichloromethane, the organic phases were combined, evaporated to dryness, and ethyl acetate was added and distilled. 70 mL of ethyl acetate was added, and the mixture was heated until dissolved. 140 mL of n-heptane was added dropwise, the mixture was cooled to room temperature, stirred for 2 h, filtered, and the filter cake was dried at 50 °C to obtain compound A.

[0039] Add S-2-methyl-CBS-oxazolium borane (6.3 g, 0.6 eq) and 200 mL tetrahydrofuran to a reactor, cool to -15 °C, and simultaneously add a tetrahydrofuran solution of borane dimethyl sulfide (37.9 mL, 2.0 eq) and compound A (16.0 g, 1.0 eq) in 40 mL at -15 to -10 °C. After the addition is complete, continue the reaction at -15 to -10 °C. After the reaction is complete, quench with 50 mL methanol, stir for 1 h, evaporate to dryness, add dichloromethane and distill, add 200 mL dichloromethane and 200 mL ammonium chloride solution, separate the liquid to obtain the organic phase, wash with 200 mL sodium bicarbonate solution and 200 mL water, evaporate to dryness, distill once with methyl tert-butyl ether, add 80 mL methyl tert-butyl ether, heat until dissolved, add 80 mL n-heptane, precipitate a solid, cool to 0-10 °C, filter, and the filter cake is 50 mL. The material was dried at °C to obtain compound B.

[0040] Compound B (10 g, 1.0 eq) was added to the reactor, followed by pyridine (60 mL, 6 vol). Acetic anhydride (20 mL, 2 vol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was allowed to return to room temperature. The reaction mixture was then evaporated to dryness by rotary evaporation. Tetrahydrofuran (80 mL, 8 vol) was added, followed by dimethylamine aqueous solution (80 mL, 8 vol). The reaction was carried out at 50 °C. After the reaction was complete, the mixture was concentrated. Ethyl acetate was evaporated once, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined and concentrated. Methyl tert-butyl ether was evaporated twice. The mixture was cooled to 0 °C, and tert-butyllithium (45 mL, 3.0 eq) was added dropwise. The reaction was carried out for 2 h after the addition was complete. Diphenylphosphine chloride (18.9 g, 3.6 eq) was added dropwise, and the reaction was carried out for 1 h. The reaction was quenched with 1 N hydrochloric acid, and the pH was adjusted to 7–8 with 20% potassium carbonate. 100% potassium carbonate solution was added. Extracted with 1 mL of dichloromethane, the organic phase was washed twice with ammonium chloride and water, concentrated, and distilled once with methyl tert-butyl ether. 50 mL of methyl tert-butyl ether was added, and the mixture was heated until dissolved. The mixture was cooled to room temperature, and a solid precipitated. The solid was filtered to give a yellow solid compound IE.

[0041] The NMR data for compound IE are as follows: 1 H NMR (400MHz, CDCl3): δ6.98~7.35 (m, 28 H), 4.51 (s, 2H), 4.37 (s, 2H), 3.33 (s, 2 H), 3.15 (s, 2 H), 2.4 (s, 6 H), 1.51 (s, 12H);

[0042] 31 P NMR (162 MHz, CDCl3): δ24.9.

[0043] Example 2 Preparation of compound IF

[0044]

[0045] Aluminum trichloride (8.04 g, 2.5 eq) was added to dichloromethane (59 mL, 13 vol). 3,5-Dimethylbenzoyl chloride (11.4 g, 2.8 eq) was added dropwise at 0–10 °C. Ferrocene (4.5 g, 1.0 eq) was added. After the reaction was complete, the reaction solution was added to 100 mL of water. The mixture was stirred to separate the layers, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, evaporated to dryness, and ethyl acetate was added and distilled. 70 mL of ethyl acetate was added, and the mixture was heated until dissolved. 140 mL of n-heptane was added dropwise, and the mixture was cooled to room temperature and stirred for 2 h. The mixture was filtered to obtain a filter cake, which was dried at 50 °C to obtain compound C.

[0046] Add S-2-methyl-CBS-oxazolium borane (5.91 g, 0.6 eq) and 200 mL tetrahydrofuran to a reactor, cool to -15 °C, and simultaneously add borane dimethyl sulfide (35.6 mL, 2.0 eq) and a tetrahydrofuran (40 mL) solution of compound C (16.0 g, 1.0 eq) dropwise at -15 to -10 °C. After the addition is complete, continue the reaction at -15 to -10 °C. After the reaction is complete, quench with 50 mL methanol, stir for 1 h, evaporate to dryness, add dichloromethane and distill, add 200 mL dichloromethane and 200 mL ammonium chloride solution, separate the liquid to obtain the organic phase, wash with 200 mL sodium bicarbonate solution and 200 mL water, evaporate to dryness, distill once with methyl tert-butyl ether, add 80 mL methyl tert-butyl ether, heat until dissolved, add 80 mL n-heptane dropwise, precipitate the solid, cool to 0-10 °C. °C, filter, dry the filter cake at 50 °C to obtain compound D.

[0047] Compound D (10 g, 1.0 eq) was added to the reactor, followed by pyridine (60 mL, 6 vol). Acetic anhydride (20 mL, 2 vol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was allowed to return to room temperature. The reaction mixture was then evaporated to dryness by rotary evaporation. Tetrahydrofuran (80 mL, 8 vol) was added, followed by dimethylamine aqueous solution (80 mL, 8 vol). The reaction was carried out at 50 °C. After the reaction was complete, the mixture was concentrated. Ethyl acetate was evaporated once, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined and concentrated. Methyl tert-butyl ether was evaporated twice. The mixture was cooled to 0 °C, and tert-butyllithium (42 mL, 3.0 eq) was added dropwise. The reaction was allowed to proceed for 2 h after the addition was complete. Diphenylphosphine chloride (17.7 g, 3.6 eq) was added dropwise. The reaction was allowed to proceed for 1 h. The reaction was quenched with 1 N hydrochloric acid, and the pH was adjusted to 7–8 with 20% potassium carbonate. 100% potassium carbonate solution was added. Extracted with 1 mL of dichloromethane, the organic phase was washed twice with ammonium chloride and water, concentrated, and distilled once with methyl tert-butyl ether. 50 mL of methyl tert-butyl ether was added, heated until dissolved, cooled to room temperature, and the solid precipitated. The solid was filtered to give a yellow solid compound IF.

[0048] The NMR data for compound IF are as follows: 31 P NMR (162 MHz, CDCl3): δ25.2.

[0049] Example 3: Screening of compounds III to IV by hydrogenation of various ligands

[0050] Compound III (10 g, 1.0 eq), [RuI2(p-cymene)]2 (25.7 mg, 0.1% eq) and ligand (0.22% eq) were added to a hydrogenation reactor. The reactor was purged with nitrogen three times, and then degassed ethanol (50 ml, 5 vol) was added. The reactor was then purged with hydrogen three times and purged with hydrogen to 6 MPa. The temperature inside the hydrogenation reactor was set to 50-60 °C to start the reaction. After the reaction was completed, compound IV was obtained.

[0051]

[0052]

[0053] Example 3: Scale-up preparation of compound IV with high TON

[0054] Compound III (1.0 kg, 1.0 eq), [RuI2(p-cymene)]2 (128 mg, 0.005% eq), and ligand IE (223 mg, 0.01% eq) were added to a hydrogenation reactor. The reactor was purged with nitrogen three times, and degassed ethanol (5 L, 5 vol) was added. The reactor was then purged with hydrogen three times and purged with hydrogen to 6 MPa. The temperature inside the hydrogenation reactor was set to 50–60 °C to start the reaction. After the reaction was completed, the mixture was concentrated to dryness. Isopropyl acetate (3 L, 3 vol) and n-heptane (3 L, 3 vol) were added, and the mixture was heated until dissolved. The mixture was then cooled to 20–25 °C to crystallize. The crystals were centrifuged, and the filter cake was dried at 50 °C to obtain compound IV, with a purity greater than 99.5% and a chiral purity greater than 99.9%.

[0055] This application includes, but is not limited to, the above embodiments. Any equivalent substitutions or partial improvements made under the spirit and principles of this application shall be deemed to be within the scope of protection of this application.

Claims

1. A method for preparing a compound of formula IV, comprising the following steps: in an alcohol solvent, in the presence of a compound of formula I, a ruthenium metal compound, and hydrogen, reducing compound III to obtain compound IV. ， Where R1 and R1′ are independently hydrogen or amine protecting groups. This represents a covalent bond, wherein the stereochemistry of the bond is determined to be (S) or (R) configuration with respect to the chiral center, and the structure of the compound of formula I is as follows: ， The Ar group is 4-methylphenyl, and the absolute configuration of the chiral centers at the two Ar groups in Formula I is either (R) or (S).

2. As described in claim 1, the alcohol solvent is methanol or ethanol.

3. As described in claim 1, R1 is tert-butoxycarbonyl (Boc).

4. As claimed in claim 1, R1 is tert-butoxycarbonyl (Boc) and R1′ is hydrogen.

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