Quaternary cycloalkylated quaternary carbon beta amino acid derivative and preparation method thereof

Abstract

The invention discloses a quaternary cycloalkanated quaternary carbon beta amino acid derivative compound E, an intermediate compound and a preparation method of the quaternary cycloalkanated quaternary carbon beta amino acid derivative compound E. The structural general formula of the quaternary carbon beta amino acid derivative is # imgabs0 #, R1 is alkyl, R2 is amino protecting group, and R3 is hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl, methoxyl and methyl. The chiral beta amino acid derivative can be obtained by adopting a cobalt chloride catalytic reduction method, so that the reaction time is shortened, the production cost is reduced, the reaction yield is improved, and the blank of a beta amino acid derivative synthesis method is filled.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a quaternary carbon beta amino acid derivative and a preparation method thereof. Background Art

[0002] Studies have shown that β-amino acids are an important class of organic compounds. They not only exist in many natural products, but are also the main raw materials for new antibiotics. Therefore, how to prepare β-amino acids quickly and efficiently is very important. We have proposed a method for preparing β-chiral amino acid derivatives to solve the problems of long reaction time and low yield in the current chemical synthesis method for preparing chiral β-amino acids. In addition, quaternary carbon β-amino acid derivatives based on four-membered ring alkane have not been reported yet, so they have great application prospects.

[0003] Most of the current synthetic routes for β-amino acids have limitations and are not suitable for large-scale industrial production. For example, the synthetic method reported in the Chinese patent (CN201610539344) directly uses a halogenated hydrocarbon and a methylene group connected to a cyano group to react to obtain chiral carbon, which is purified by distillation, with a low yield and time-consuming and labor-intensive. The latter step uses catalytic hydrogenation to reduce the cyano group to the amino group, which requires the use of a high-risk autoclave and hydrogen, increasing the process cost and the difficulty of synthesis. The reaction process requires a lot of equipment and high cost, and further optimization is needed to reduce costs and simplify the reaction.

[0004]

[0005] A method for preparing chiral β-amino acid derivatives was reported in a Chinese patent (CN202111651687.1). The authors used two different palladium catalysts to synthesize phthalimide into chiral β-amino acid derivatives. Although the reaction conditions were simplified, the expensive palladium catalyst restricted the large-scale application of the reaction. Therefore, finding a cheap and efficient synthesis route became a top priority.

[0006]

[0007] The patent (CN200480007313.4) published by Merck also adopts catalytic hydrogenation to obtain β-amino acid derivatives. How to avoid transition metal catalysts to reduce costs has become a pain point in the preparation of β-amino acid derivatives.

[0008]

[0009] The article published by the University of Liverpool (DOI: 10.1038 / s41557-024-01473-5) used an iridium catalyst and reacted at 130°C for 1-4 days to obtain chiral amino acids. The more expensive catalysts, higher temperatures and longer reaction times restrict industrial production.

[0010] Summary of the invention

[0011] The technical problem to be solved by the technology of the present invention is to provide a simple, efficient and low-cost synthesis route of chiral β-amino acid derivatives.

[0012] To achieve the above object, the technical solution of the present invention is:

[0013] First, the present invention provides a novel four-membered cycloalkane-based quaternary carbon β-amino acid derivative compound E, the structural formula of which is as follows:

[0014]

[0015] Among them, R 1 is an alkyl group, R 2 is an amino protecting group, R 3 It is a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group or a methyl group.

[0016] The preferred R 1 It is methyl or phenyl.

[0017] The present invention provides an intermediate compound D, the structural formula of which is as follows:

[0018]

[0019] Among them, R 1 , R 3 Same as above definition.

[0020] The present invention provides an intermediate compound C, the structural formula of which is as follows:

[0021]

[0022] Among them, R 1 , R 3 Same as above definition.

[0023] The present invention provides a method for preparing a four-membered cycloalkane-based quaternary carbon β-amino acid derivative compound E, which is prepared by subjecting compound D to the above protection reaction.

[0024]

[0025] The reagent for the amino protection reaction can be di-tert-butyl dicarbonate, benzyl chloroformate, p-toluenesulfonyl chloride; preferably di-tert-butyl dicarbonate.

[0026] The molar ratio of compound D to reagent in the amino protection reaction can be in the range of 1:1.0-1.5.

[0027] The solvent for the amino protection reaction can be dichloromethane, tetrahydrofuran, or N,N-dimethylformamide; preferably dichloromethane.

[0028] The present invention provides a method for preparing compound D, which is prepared by reducing compound C.

[0029]

[0030] The reducing agent of the reduction reaction is a metal salt such as cobalt chloride.

[0031] The molar ratio of compound C to reducing agent in the reduction reaction can be in the range of 1:2.0-10.0.

[0032] The solvent for the reduction reaction can be an alcohol solvent, such as methanol, ethanol, isopropanol, and methanol is more preferred.

[0033] The present invention also provides a method for preparing compound C, which is prepared by a substitution reaction between compound A and compound B.

[0034]

[0035] The molar ratio of compound A to compound B in the substitution reaction may be in the range of 1:1.2-5.0.

[0036] The solvent for the substitution reaction can be toluene, xylene, or N,N-dimethylformamide; preferably toluene.

[0037] The present invention uses DMAP catalysis as low as 5% equivalent to form a compound with a four-membered cycloalkane structure, which reduces the reaction speed, reduces the reaction cost and improves the reaction efficiency. On this basis, a metal salt reducing agent such as cobalt chloride is used for catalytic reduction to obtain a chiral β-amino acid derivative, which shortens the reaction time, reduces the production cost, improves the reaction yield and has a bright application prospect. The β-amino acid derivative prepared by the present invention is a quaternary carbon β-amino acid derivative of a four-membered cycloalkane, which fills the blank of the synthesis method of such compounds.

[0038] The present invention provides a technical solution for preparing a quaternary carbon β-amino acid derivative based on four-membered cycloalkane, which adopts a cobalt chloride catalytic reduction method to obtain a chiral β-amino acid derivative, shortens the reaction time, reduces the production cost, improves the reaction yield, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Attached Figure 1 This is the H-NMR spectrum of compound C prepared in Example 1.

[0040] Attached Figure 2 This is the C-NMR spectrum of compound C prepared in Example 1.

[0041] Attached Figure 3 This is the H-NMR spectrum of compound E prepared in Example 2.

[0042] Attached Figure 4 This is the C-NMR spectrum of compound E prepared in Example 2.

[0043] Attached Figure 5 This is the H-NMR spectrum of compound C' prepared in Example 3.

[0044] Attached Figure 6 This is the C-NMR spectrum of compound C' prepared in Example 3. DETAILED DESCRIPTION

[0045] In order to further understand the present invention, a four-membered cycloalkane quaternary carbon β-amino acid derivative provided by the present invention and its preparation method are described in detail below in conjunction with the examples. It should be understood that these examples are only for further describing the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0046] Embodiment 1:

[0047]

[0048] A (1.55 g, 8 mmol, 1.0 eq.), B (3.05 g, 24 mmol, 3.0 eq.), 80 mL of toluene and DMAP (48.87 mg, 0.4 mmol, 0.05 eq.) were added to a dry 250 mL sealed tube in sequence; the sealed tube was evacuated and replaced with nitrogen, and the cycle was repeated three times; the sealed tube was placed in a 110 ° C oil bath for 16 h; after 16 h, it was cooled to room temperature and monitored by TLC (n-Hexane:EA=2:1, Rf=0.3, 254 nm), and the reaction was complete; the reaction solution was transferred to a 250 mL single-mouth bottle and silica gel was added, and the reaction was concentrated under reduced pressure and separated by column chromatography; n-Hexane:EA=5:1 was used as the eluent, and the desired eluent was collected and dried to obtain 2.0 g of a colorless viscous liquid (C, trans / cis>1:20 by Crude 1 HNMR 2.0g,78%yelid,Colourless oil) 1H NMR (400 MHz, CDCl 3 )δ7.88(d,J=7.6Hz,2H),7.67(t,J=7.2Hz,1H),7.57(t,J=7.6Hz,2H),4.31–4.23(m,2H),3.69–3.62 (m,1H),2.70–2.62(m,1H),2.59–2.49(m,2H),2.35–2.23(m,2H),1.50(s,3H),1.32(t,J=7.2Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ167.9,137.6,134.1,129.5,128.6,118.1,63.3,52.1,46.6,35.7,26.3,25.8,20.0,14.2.HRMS(ESI)m / z:[M+Na] + Calculated for C 16 H 19 NNaO 4 S 344.0927; Found 344.0924.

[0049] Embodiment 2:

[0050]

[0051] Take C (1.51 g, 4.7 mmol, 1.0 eq) and add it to a 250 mL single-mouth bottle; add cobalt chloride (1.22 g, 9.4 mmol, 2.0 eq); add 50 mL of methanol and stir to cool down, the solution turns purple and starts to cool down; after it drops to 0°C, start to add sodium borohydride (890.0 mg, 23.5 mmol, 5.0 eq) in batches, a large number of bubbles are generated, and the solution turns black; stir at 0°C for 2 h and remove the ice bath; add 20 mL of 2N hydrochloric acid, the solution turns red, pH = 1-2; add 20 mL 2N NaOH solution, the solution turns purple, a large amount of purple solid precipitates, pH = 9-10; filter to obtain a colorless filtrate; the colorless filtrate is extracted with 100mL*3 ethyl acetate; the ethyl acetate phase is combined and dried with 20g anhydrous sodium sulfate; the ethyl acetate phase is concentrated to obtain a light yellow oily liquid D, add 20mL DCM and stir; add triethylamine (1000mg, 9.9mmol, 2.1eq) and then add boc anhydride (1.0g, 1.5eq) and stir for 16h; after stopping stirring, wash three times with 10mL*3 water, and then dry with 20g anhydrous sodium sulfate; filter, concentrate, and dry to obtain 1.6g of white solid. (E, 1.6g, 80% yelid) 1 H NMR (400 MHz, CDCl 3)δ7.81(d,J=7.2Hz,2H),7.60(t,J=7.6Hz,1H),7.51(t,J=7.6Hz,2H),4.91(br,1H),4.18–4.12(m,2H),3.59–3.51 (m,1H),3.19–3.11(m,2H),2.49–2.39(m,3H),2.13–2.07(m,2H),1.37(s,9H),1.27(t,J=7.2Hz,3H),1.09(s,3H). 13 CNMR (101MHz, CDCl 3 )δ175.2,156.1,138.2,133.7,129.3,128.2,79.3,61.2,52.6,48.5,45.6,34.6,28.4,25.5,24.7,16.9,14.3.HRMS(ESI)m / z:[M+Na] + Calculated for C 21 H 31 NaO 6 S 448.1764; Found 448.1764.

[0052] Embodiment 3:

[0053]

[0054] A (97.0 mg, 0.5 mmol, 1.0 eq.), B' (283.8 mg, 1.5 mmol, 3.0 eq.), 5 mL of toluene and DMAP (3.05 mg, 0.025 mmol, 0.05 eq.) were added to a dry 250 mL sealed tube in sequence; the sealed tube was evacuated and replaced with nitrogen, and the cycle was repeated three times; the sealed tube was placed in a 110 ° C oil bath for 16 h; after 16 h, it was cooled to room temperature and monitored by TLC (n-Hexane: EA = 2: 1, Rf = 0.3, 254 nm), and the reaction was complete; the reaction solution was transferred to a 250 mL single-mouth bottle and silica gel was added, and the reaction was concentrated under reduced pressure and then separated by column chromatography; n-Hexane: EA = 5: 1 was used as the eluent, and the desired eluent was collected and dried to obtain 130.4 mg of white solid C', (trans / cis = 1: 11 by Crude 1 H NMR, 134.4 mg, 68% yelid, Solid) 1 H NMR (400 MHz, CDCl 3)δ7.86(d,J=7.2Hz,2H),7.64(t,J=7.2Hz,1H),7.54(t,J=7.6Hz,2H),7.44–7.41(m,2H),7.41–7.35(m,3H),4.28–4.15(m,2H),3.68–3.59(m,1H),3.22–3.13(m,1H),2.69–2.61(m,1H),2.46–2.35(m,2H),2.00–1.92(m,1H),1.23(t,J=7.2Hz,3H). 13 CNMR(101MHz,CDCl3)δ165.5,136.6,133.0,131.5,128.5,128.4,128.3,127.6,125.1,115.3,62.6,57.0,51.6,35.0,26.6,25.2,12.9.HRMS(ESI)m / z:[M+Na] + Calculated forC 21 H 21 NNaO 4 S 406.1083;Found 406.1051。

Claims

1. A four-membered cycloalkane-based quaternary carbon β-amino acid derivative compound E and its intermediate compound, the structural formula of which is: in, R1 is an alkyl group, R2 is an amino protecting group, and R3 is a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methoxy group or a methyl group.

2. A method for preparing a four-membered ring alkane quaternary carbon β-amino acid derivative compound E, characterized in that: Prepared by amino protection reaction of compound D, Wherein, R1, R2, and R3 are the same as those defined in claim 1.

3. The preparation method according to claim 2, characterized in that: The reaction reagent of the amino protection reaction is di-tert-butyl dicarbonate, benzyl chloroformate or p-toluenesulfonyl chloride.

4. The preparation method according to claim 2, characterized in that: The molar ratio of compound D to protecting agent in the amino protection reaction is in the range of 1:1.0-1.

5.

5. The preparation method according to claim 2, characterized in that: The solvent for the amino protection reaction is dichloromethane, tetrahydrofuran or N,N-dimethylformamide.

6. A method for preparing compound D, characterized in that: Prepared by reduction reaction of compound C, Wherein, R1 and R3 are the same as defined in claim 1.

7. The preparation method according to claim 6, characterized in that: The reducing agent of the reduction reaction is a metal salt.

8. The preparation method according to claim 6, characterized in that: The molar ratio of compound C to reducing agent in the reduction reaction is in the range of 1:2.0-10.

0.

9. The preparation method according to claim 6, characterized in that: The solvent for the reduction reaction is an alcohol solvent.

10. A method for preparing compound C, characterized in that: Prepared by substitution reaction of compound A and compound B, Wherein, R1 and R3 are the same as defined in claim 1.

11. The preparation method according to claim 10, characterized in that: The molar ratio of compound A to compound B in the substitution reaction is in the range of 1:1.2-5.0.

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