A preparation method of N-Boc-N-[2-(2-chloro-5-pyrimidinyl)ethyl]amine
Through a series of specific chemical response steps, N-BOC-N- [2-chloro-5-piomididine) ethyl] can be prepared to solve the problem of lack of large-scale preparation methods in the existing technology. Realize the possibility of high income and industrialization applications.
Patent Information
- Application Number
- CN202010581989.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2020-06-23
- Publication Date
- 2025-01-24
- Estimated Expiration
- 2040-06-23
AI Technical Summary
There is a lack of an effective synthesis method for N-Boc-N-[2-(2-chloro-5-pyrimidinyl)ethyl]amine suitable for large-scale preparation in the prior art.
Through a series of steps, including the reaction of the compound II and the compound III, the reaction between the compound IV and the alkali 2, and finally the reaction of the compound V and the compound VI to prepare N-BOC-N- [2 2 -(2-chloro-5-pyrimimyl) ethyl] amine.
This method provides a reliable synthetic route. The response conditions are simple, the raw materials are easy to obtain, the operation is convenient, and the total income is high, which can reach 58.13%, which has the prospects of industrialized applications.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of drug intermediate synthesis, and in particular to a method for preparing N-Boc-N-[2-(2-chloro-5-pyrimidinyl)ethyl]amine. Background Art
[0002] Aromatic ethylamine compounds are endogenous neurotransmitters, natural products, and intermediates for a series of drugs. The disclosed literature does not provide a method for preparing the N-Boc-N-[2-(2-chloro-5-pyrimidinyl)ethyl]amine (Compound I) of the present invention.
[0003] The document Journal of the American Chemical Society, 2019, vol. 141, #9, p. 4147-4153] discloses the preparation method of analogs:
[0004]
[0005] Reagents and conditions: HCOONa, 5 mol% 10-phenylphenothiazine (PTH), 5 mol% cyclohexanethiol (CySH), 5% H2O / DMSO, blue light (blue LED), 23°C, yield 70%. Not suitable for large-scale preparation. Summary of the invention
[0006] Purpose of the invention: The present invention provides a new method for preparing N-Boc-N-[2-(2-chloro-5-pyrimidinyl)ethyl]amine, which has a reliable synthetic route, is easy to scale up, and is easy to operate.
[0007] The present invention provides a method for preparing compound I, comprising:
[0008]
[0009] In the step of preparing compound IV from compound II and compound III, base 1 is added, and base 1 is selected from triethylamine or N,N-diisopropylethylamine. The molar ratio of compound II, compound III and base 1 is in the range of 1:1-1.1:1.5-3.
[0010] In the step of preparing compound V from compound IV, base 2 is added, and base 2 is selected from sodium tert-butoxide and potassium tert-butoxide. The molar ratio of compound IV to base 2 is in the range of 1:1-3.
[0011] In the step of preparing compound I from compound V and compound VI, compound VI is first reacted with isopropyl magnesium chloride, and then catalyst boron trifluoride etherate and compound V are added, the reaction temperature is -78 to -65°C, and the reaction is continued to obtain compound I. In the step of preparing compound I from compound V and compound VI, the molar ratio of compound VI, isopropyl magnesium chloride, compound V and catalyst is in the range of 1:1.0 to 2.0:0.9 to 1.1:1.5 to 3.
[0012] Compound II (N-Boc-N-hydroxyethylamine) reacts with compound III (p-toluenesulfonyl chloride) under the action of a base to obtain compound IV; then under the action of a base, compound V is obtained; compound VI first reacts with isopropylmagnesium chloride, and then catalyst boron trifluoride etherate and compound V are added, the reaction temperature is -78 to -65°C, and the reaction is continued to obtain compound I.
[0013] Beneficial Effects
[0014] The N-Boc-N-[2-(2-chloro-5-pyrimidinyl)ethyl]amine of the present invention is obtained by a new and simple synthesis route. The method has a reliable synthesis route, cheap and readily available raw materials, simple reaction conditions, easy reaction amplification, convenient operation, industrial application prospects, and a high overall yield of up to 58.13%.
[0015] The abbreviations of the reaction reagents involved in the instructions are as follows:
[0016] Boc: tert-butoxycarbonyl;
[0017] THF: tetrahydrofuran;
[0018] TEA: triethylamine;
[0019] DIPEA: N,N-diisopropylethylamine;
[0020] DCM: dichloromethane;
[0021] MTBE: methyl tert-butyl ether;
[0022] EA: ethyl acetate. DETAILED DESCRIPTION
[0023] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.
[0024] Example 1
[0025]
[0026] Preparation of compound IV:
[0027] Compound II (50.00 g, 310.18 mmol, 1 eq.) was dissolved in DCM (400 mL), and TEA (47.08 g, 465.26 mmol, 1.5 eq.) and p-toluenesulfonyl chloride (59.13 g, 310.18 mmol, 1.0 eq.) were added at 0°C. After the addition, the mixture was stirred at room temperature for 17 hours. TLC showed that the raw materials had reacted completely. The reaction solution was concentrated under reduced pressure to obtain 88.04 g of compound IV with a yield of 90.0%.
[0028] Preparation of Compound V:
[0029] Compound IV (50.00 g, 143.18 mmol, 1 eq.) was dissolved in THF (600 mL), and potassium tert-butoxide (17.79 g, 143.18 mmol, 1 eq.) was added in batches. After the addition was complete, the mixture was stirred at room temperature for 2 hours. TLC showed that the raw materials had reacted completely. 400 mL of water was slowly added to the reaction solution, and after stirring for 15 minutes, 300 mL of MTBE was added. The organic phases were combined and concentrated under reduced pressure to remove the solvent to obtain 36.3 g of compound V with a yield of 80.50%.
[0030] Preparation of Compound I:
[0031] Compound VI (30.22 g, 125.70 mmol, 1 eq.) was added to toluene (300 mL), and the mixture was cooled to about -78°C. Isopropylmagnesium chloride (94.3 mL, 188.55 mmol, 1.5 eq., 2M THF solution) was added dropwise, and the reaction was detected by HPLC. After the reaction was completed, boron trifluoride etherate (26.76 g, 188.55 mmol, 1.5 eq.) was added dropwise at -78°C to -65°C, and a toluene (300 mL) solution of compound V (18.00 g, 125.70 mmol, 1 eq.) was added. The mixture was reacted at about -78°C for 5 hours. After the reaction was completed, 20% NH4Cl (100 mL) was added, and the mixture was extracted with MTBE. The organic phases were combined, dried, and concentrated under reduced pressure to obtain 24.46 g of compound I as a white solid with a yield of 75.5%.
[0032] Example 2
[0033]
[0034] Preparation of compound IV:
[0035] Compound II (50.00 g, 310.18 mmol, 1 eq.) was dissolved in DCM (400 mL). N,N-diisopropylethylamine (64.15 g, 496.28 mmol, 1.6 eq.) and p-toluenesulfonyl chloride (65.04 g, 341.2 mmol, 1.1 eq.) were added at 0°C. After addition, the mixture was stirred at room temperature for 10 hours. TLC showed that the raw materials had reacted completely. The reaction solution was concentrated under reduced pressure to obtain 90.00 g of compound IV with a yield of 92.0%.
[0036] Preparation of Compound V:
[0037] Compound IV (50.00 g, 143.18 mmol, 1 eq.) was dissolved in THF (500 mL), and sodium tert-butoxide (41.28 g, 429.54 mmol, 3 eq.) was added in batches. After the addition was complete, the mixture was stirred at room temperature for 2 hours. TLC showed that the raw materials had reacted completely. 400 mL of water was slowly added to the reaction solution, and after stirring for 20 minutes, 300 mL of MTBE was added. The liquids were separated, the organic phases were combined, and the solvent was removed by concentration under reduced pressure to obtain 35.4 g of compound V with a yield of 78.50%.
[0038] Preparation of Compound I:
[0039] Compound VI (30.22 g, 125.70 mmol, 1 eq.) was added to THF (300 mL), and the mixture was cooled to about -78°C. Isopropyl magnesium chloride (62.8 mL, 125.70 mmol, 1 eq., 2M THF solution) was added dropwise, and the reaction was detected by HPLC. After the reaction was completed, boron trifluoride etherate (53.52 g, 377.10 mmol, 3 eq.) was added dropwise at -78°C to -65°C, and a solution of compound V (19.80 g, 138.27 mmol, 1.1 eq.) in THF (300 mL) was added. The mixture was reacted at about -78°C for 8 hours. After the reaction was completed, 20% NH4Cl (100 mL) was added, and the mixture was extracted with MTBE. The organic phases were combined, dried, and concentrated under reduced pressure to obtain 26.08 g of compound I as a white solid with a yield of 80.5%.
Claims
1. A method for preparing compound I, characterized in that: In the step of preparing compound IV from compound II and compound III, base 1 is added; in the step of preparing compound V from compound IV, base 2 is added; in the step of preparing compound I from compound V and compound VI, compound VI is first reacted with isopropylmagnesium chloride, and then catalyst boron trifluoride etherate and compound V are added, and the reaction is continued to obtain compound I.
2. The method for preparing compound I according to claim 1, characterized in that: In the step of preparing compound IV from compound II and compound III, base 1 is selected from triethylamine or N,N-diisopropylethylamine.
3. The method for preparing compound I according to claim 1 or claim 2, characterized in that: In the step of preparing compound IV from compound II and compound III, the molar ratio of compound II, compound III and base 1 is in the range of 1:1-1.1:1.5-3.
4. The preparation method according to claim 1, characterized in that: In the step of preparing compound V from compound IV, base 2 is selected from sodium tert-butoxide and potassium tert-butoxide.
5. The preparation method according to claim 1 or claim 4, characterized in that: In the step of preparing compound V from compound IV, the molar ratio of compound IV to base 2 is in the range of 1:1-3.
6. The preparation method according to claim 1, characterized in that: In the step of preparing compound I from compound V and compound VI, the molar ratio of compound VI, isopropylmagnesium chloride, compound V and catalyst is in the range of 1:1.0-2.0:0.9-1.1:1.5-3.
7. The preparation method according to claim 1 or claim 6, characterized in that: In the step of preparing compound I from compound V and compound VI, the reaction temperature is -78 to -65°C.