Synthesis method of chiral N-Boc homocysteine derivative

Abstract

The invention provides a synthesis method for synthesizing a chiral N-Boc homocysteine derivative through a low-cost reaction. The synthesis method has the advantages of simple flow, convenient post-treatment, easy recovery of the resolution reagent and the enantiomer, cheap and easily available starting materials, and easy industrial production. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical intermediates and non-natural amino acid synthesis, and in particular, to a method for synthesizing chiral non-natural amino acid derivatives. Background Art

[0002] Chiral non-natural amino acids play an increasingly important role in the synthesis of drugs and peptide molecules due to their different metabolism in the body from natural amino acids. Although homocysteine, as a non-natural amino acid, has begun to show its application value, there are few existing reports on the synthesis of its related compounds and derivatives. The main synthetic ideas are as follows.

[0003] 1) 《化学学会志·珀金 Transactions I》 ,1984, 5,1091 - 1097 reported the following synthetic route: .

[0004] This synthetic route uses natural L-methionine or non-natural D-methionine as the starting material and reduces it under ultra-low temperature conditions under active metallic sodium and liquid ammonia to obtain L- or D-homocysteine ​​with a separation yield of 79%. However, the ultra-low temperature reaction and the use of liquid ammonia require demanding production equipment and high energy consumption. Metallic sodium has strong activity and also has high requirements for the production environment and facility safety.

[0005] 2) 《美国化学会志》 ,2011, 133, 379 – 386 reported the following synthesis strategy: .

[0006] This synthetic route uses non-natural L / D-homoserine as the starting material to prepare L / D-homocysteine ​​through acetyl protection and enzyme-catalyzed thiolation reaction. However, the high price of the starting material limits the practical value of this route.

[0007] 3) 《美国化学会志》 , 2005, 127, 2372 – 2373 reported the following synthesis method: .

[0008] The literature reports that the starting material L-homocysteine ​​thiolactone hydrochloride 1 mmol (153 mg) can be reacted in 1 mL 5 mol / L sodium hydroxide solution at 37°C for 5 min to obtain the product with a yield of 96%, but the literature does not report the chiral selectivity of the relevant product. The applicant subsequently found in the attempt to gradually scale up the reaction that with the increase in feed amount and the extension of reaction time, the racemization of the product is difficult to be effectively controlled.

[0009] 4) 《日本化学会公报》 The following synthesis method was reported in 1993, 66, 536 – 540: .

[0010] The literature uses DL-homocysteine ​​thiolactone hydrochloride as the starting material for ring opening, and the two-step cyclization yields 62.4%, and the tartaric acid dynamic kinetic resolution yields 90.2%. Finally, hydroxylamine hydrochloride is used for ring opening to obtain the target product L-homocysteine ​​with a yield of 91.9%. However, the overall route is long, with more processes and chemical reactions, and a large amount of acetic acid is used in the resolution step, which is not very friendly to the production environment.

[0011] Therefore, exploring a low-cost, high-efficiency, and industrially convenient method for synthesizing related compounds has practical scientific significance and economic value. Summary of the invention

[0012] The purpose of this application is to provide a method for preparing compounds of formula IV-a and IV-b: , (1) reacting the compound of formula I with di-tert-butyl dicarbonate to obtain the compound of formula II; (2) the compound of formula II is subjected to ring opening under alkaline conditions to obtain the compound of formula III; (3) The compound of formula III is resolved by chiral amine to obtain chiral ammonium salts of compounds of formula IV-a and IV-b; (4) The ammonium salts corresponding to the compounds of formula IV-a and IV-b are liberated under acidic conditions to obtain the compounds of formula IV-a or IV-b; Among them, the chiral amine is preferably (S)-phenethylamine, (R)-phenethylamine. The alkaline condition is preferably sodium hydroxide or potassium hydroxide. The enantioselectivity of the obtained product can be controlled by changing different phenethylamine resolution reagents. The ammonium salt obtained by resolution can be freed under acidic conditions to obtain the product, and the phenethylamine resolution reagent used can be recovered and reused by conventional reduced pressure distillation, further reducing costs.

[0013] Another object of the present application is to provide a method for preparing compound I by deprotecting and racemizing compounds of formula IV-a and IV-b: , The compound of formula IV-a or IV-b is reacted under heating conditions with hydrochloric acid to prepare the compound of formula I; when the target product produced is only Boc-homocysteine ​​of a single configuration, the other part of the cysteine ​​compound obtained by splitting can be effectively recovered under acidic conditions, thereby avoiding unnecessary waste generation, further enhancing atom economy and reducing raw material costs.

[0014] Another object of the present application is to provide two ammonium salt compounds, wherein the compounds have the structures of formula Va and Vb: , The two types of ammonium salts play an important role in the resolution of N-Boc homocysteine, and each has its own advantages: the phenylethylamine salt has a strong binding, low solubility, low cost, and can obtain the target product in high yield.

[0015] Compared with the prior art, the method for synthesizing N-Boc homocysteine ​​compounds IV-a and IV-b of the present application has the following benefits: (1) The homocysteine ​​product with a protective group can be obtained from cheap starting materials through three steps of reaction, and the step cost is low; (2) Enantiomers can be effectively recovered as raw materials; (3) The reaction conditions of the entire process route are mild, and there are no high-energy-consuming conditions such as low temperature and high pressure, which is conducive to the selection and deployment of production equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This application involves the route flow of compound conversion, Figure 2 is the hydrogen nuclear magnetic resonance spectrum of compound Va obtained in Example 1. DETAILED DESCRIPTION

[0017] The following examples are used to describe the implementation methods of the present application. Those skilled in the art should recognize that these specific examples only illustrate the implementation technical solutions selected to achieve the purpose of the present application, and are not limitations on the technical solutions. According to the teachings of the present application, it is obvious to improve the technical solutions of the present application in combination with the prior art, and all of them belong to the scope of protection of the present application.

[0018] The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in routine experiments.

[0019] Example 1 .

[0020] Add compound I (1.0 eq, 1000 g), water (6 vol), tetrahydrofuran (3 vol) and Boc anhydride (1.0 eq) to the reaction flask, add sodium bicarbonate (1.5 eq) in batches, and keep warm (20~35℃) for 2-3 hours. After the reaction is complete, cool to 10~20℃, add 1 N sodium hydroxide solution (3.0 eq) dropwise, and keep warm (10~20℃) for 3~5 hours. After the reaction is complete, 6N hydrochloric acid is added dropwise to adjust the pH to 3-4. Methyl tert-butyl ether (5 vol) is then added for extraction, and then concentrated at 40°C until no more drops are added; the concentrate (compound I, 350 g) is added with IPAC (15 vol), S-phenylethylamine (1.0 eq), and 0.5 wt% of seed crystals are added under stirring at 15-25°C, and crystallization and stirring are continued for 2 h. Filter; an off-white solid is obtained, which is dried at 50°C; 172 g of compound Va is obtained, with a total yield of 21.2%, a purity of 99.0%, and a chiral purity of 99.8%.

[0021] 1 H-NMR (CD3OD, 400 M): 7.42, m, 5H; 4.95, brs, 5H; 4.43, q, 1H; 4.05,m, 1H; 2.50, t, J=7.6Hz, 1H; 2.02, m, 1H; 1.89, m, 1H; 1.62, d, J=7.2 Hz, 3H;1.43, s, 9H. (HNMR spectrum is Figure 2 ).

[0022] Add the above prepared compound Va (100 g) into a reaction bottle, add methyl tert-butyl ether (5 vol), water (3 vol), add 2N hydrochloric acid (~0.5 vol) dropwise at 15~25°C with stirring to adjust the pH to 3~4. Separate and concentrate to obtain 66 g of compound IV-b as a colorless oil with a purity of 99% and a yield of 100%.

[0023] Example 2 .

[0024] Compound II-a (30.00 g, 1.0 eq), tetrahydrofuran (3 vol), water (5 vol), and lithium hydroxide monohydrate (11.59 g, 2.0 eq) were added to the reaction flask and stirred at 10-20°C. After the reaction was complete, 6N hydrochloric acid was added dropwise at 10-20°C with stirring to adjust the pH to 3-4. MTBE (5 vol) was then added, and the liquid was separated and concentrated to obtain 32 g of compound III as a colorless oil with a yield of 100% and a chiral purity of 52%.

[0025] Example 3 .

[0026] Compound II (20.03 g, 1.0 eq) was added to the reaction flask, followed by tetrahydrofuran (1 vol) and water (3 vol), and the temperature was lowered to 10-20°C. Sodium hydroxide (11.03 g, 3.0 eq) was weighed separately, and water (2 vol) was added for standby use. The temperature was controlled at 10-20°C, and the prepared sodium hydroxide solution was added dropwise, and the mixture was stirred at 10-20°C. After the reaction was complete, concentrated hydrochloric acid (2 vol) was added, and the mixture was stirred at 55-65°C for 3 h. The reaction solution was concentrated under reduced pressure at 65°C until no liquid flowed out, and ethanol (4 vol) was added for pulping. The mixture was filtered to obtain 7.53 g of an off-white solid of compound I with a yield of 53% and a purity of 80%.

[0027] The present application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement made under the spirit and principle of the present application shall be deemed to be within the protection scope of the present application.

Claims

1. A method for preparing a compound of formula IV-a or IV-b, (1) reacting the compound of formula I with di-tert-butyl dicarbonate to obtain a compound of formula II; (2) the compound of formula II is subjected to ring opening under alkaline conditions to obtain the compound of formula III; (3) The compound of formula III is resolved by chiral amine to obtain chiral ammonium salts of compounds of formula IV-a and IV-b; (4) the ammonium salts corresponding to the compounds of formula IV-a and IV-b are liberated under acidic conditions to obtain the compounds of formula IV-a or IV-b; 。 2. As claimed in claim 1, the chiral amine is (S)-phenethylamine or (R)-phenethylamine.

3. as claimed in claim 1, alkaline condition is sodium hydroxide or potassium hydroxide.

4. As described in claim 1, the compound of formula IV-a or IV-b is obtained in a free form, and its diastereomeric excess is above 90%.

5. Two ammonium salt compounds, said compounds having the structure of formula Va, Vb: 。

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