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Method for synthesizing substitution N-phenylmorpholine compounds

A technology of phenylmorpholine and synthesis method, which is applied in the field of cyclic chiral amino compounds can be enlarged, can solve the problems of high cost, low yield, complicated operation and the like, and achieve the effects of cost reduction and high yield

Active Publication Date: 2017-07-07
ACCELA CHEMBIO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the Buchwald-Hartwig reaction is mainly used in the technology, which uses an expensive catalyst, which has high cost, and requires column chromatography to separate and purify, and the operation is complicated (Organic Letters, 2012, 14, 16, 4182~4185; Journal of Organic Chemistry ,2015,vol.80,#15p.7666~73), and the yield is very low (only about 2% to 10%)
[0003] In addition, there is an aniline and 2-chloroethyl ether ring-closing reaction (US2009 / 48320A1; WO2012 / 139775A1; Org.Biomol.Chem.2008, 6, 24, 4634~42), which requires the use of solvents such as DMF that are difficult to recover, and the use of inorganic Alkali reaction, some reactions also use microwave reaction, the purification yield is low (15-30%)

Method used

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  • Method for synthesizing substitution N-phenylmorpholine compounds
  • Method for synthesizing substitution N-phenylmorpholine compounds
  • Method for synthesizing substitution N-phenylmorpholine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Synthesis of 4-(2-fluoro-4-bromophenyl)morpholine

[0025]

[0026] Compound 1 (50g, 0.263mol), 500mL 2-chloroethyl ether, and triethylamine (53.3g, 0.526mol) were mixed, heated to 150°C and reacted for 24 hours. After the reaction was detected by TLC, the recovered solvent 2 was distilled off under reduced pressure. -Chloroethyl ether, cooled and poured into 1L of water, added EA (300ml×2) for extraction, dried with 20g of anhydrous sodium sulfate, decolorized with 5g of activated carbon, filtered and concentrated to obtain a off-white solid and spin-dried to obtain compound 2 (55g, yield: 80.4%)().

[0027] 1 H NMR (300MHz, CDCl 3 ): 7.20-7.23(m,2H), 6.80-6.84(t,1H), 3.87-4.0(t,4H), 3.06-3.09(t,4H).

Embodiment 2

[0028] Example 2 Synthesis of 2-methyl-3-(4-morpholinyl) methyl benzoate

[0029]

[0030] Compound 3 (148.7g, 0.900mol), 700mL 2-chloroethyl ether, and triethylamine (228g, 2.25mol) were mixed and heated to 150°C for 4 hours. After the reaction was detected by TLC, the recovered solvent 2 was distilled off under reduced pressure. -Chloroethyl ether, cooled and poured into 1L water, added EA (500ml×2) for extraction, dried with 50g of anhydrous sodium sulfate, decolorized with 15g of activated carbon, filtered and concentrated to give off-white solid spin-dried to give compound 4 (140.4g, yield : 66.3%).

[0031] 1 H NMR (300MHz, CDCl 3 ):7.55-7.59 (d, 1H), 7.21-7.25 (m, 2H), 3.86-3.91 (m, 7H), 2.90-2.939 (t, 4H), 2.53 (s, 3H).

Embodiment 3

[0032] Example 3 Synthesis of 4-(2-methyl-4-bromophenyl)morpholine

[0033]

[0034] Compound 5 (100g, 0.537mol), 600mL 2-chloroethyl ether, and triethylamine (108.3g, 1.074mol) were mixed, and heated to 150°C for 24 hours. After the reaction was detected by TLC, the recovered solvent 2 was distilled off under reduced pressure. -Chloroethyl ether, cooled and poured into 1L of water, added EA (500ml×2) for extraction, dried with 50g of anhydrous sodium sulfate, decolorized with 15g of activated carbon, filtered and concentrated to give an off-white solid and spin-dried to obtain compound 6 (85g, yield: 61.7%).

[0035] 1 H NMR (300MHz, CDCl 3 ):7.30-7.32(m,2H),6.87-6.90(d,1H),7.61(m,2H),3.83-3.87(t,4H),2.85-2.89(t,4H),2.29(s,3H ).

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Abstract

The invention discloses a method for synthesizing substitution N-phenylmorpholine compounds. Substituted aniline and 2-chloroethyl ether are heated under the effect of alkali and then are subjected to ring closure to obtain the N-phenylmorpholine compounds. The method has the inexpensive advantages that the inexpensive aniline and the excessive2-chloroethyl ether are directly heated under the effect of the alkali and then are subjected to ring closure to obtain products, reaction is carried out without solvents, accordingly, N-phenylmorpholine of phenylmorpholine with steric hindrance can be synthesized from the aniline steric hindrance by the aid of simple and effective processes, and the cost can be lowered to a great extent; the organic alkali is used, and the method is high in yield.

Description

technical field [0001] The invention relates to a method for synthesizing morpholine compounds, in particular to a cyclic chiral amino compound containing a urea group, which can be scaled up and is easy for industrial production. Background technique [0002] The N-phenylmorpholine that has sterically hindered phenylmorpholine has important purposes in pharmaceutical industry, is the important intermediate (J.Med.Chem. 2005, 48, 8261-8269; J. Med. Chem. 2003, 46, 284-302). At present, the Buchwald-Hartwig reaction is mainly used in the technology, which uses an expensive catalyst, which has high cost, and requires column chromatography to separate and purify, and the operation is complicated (Organic Letters, 2012, 14, 16, 4182~4185; Journal of Organic Chemistry , 2015, vol.80, #15p.7666~73), and the yield is very low (only about 2% to 10%). [0003] In addition, there is an aniline and 2-chloroethyl ether ring-closing reaction (US2009 / 48320A1; WO2012 / 139775A1; Org.Biomol...

Claims

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Application Information

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IPC IPC(8): C07D295/073C07D295/155
CPCC07D295/073C07D295/155
Inventor 郭涛吴勇
Owner ACCELA CHEMBIO CO LTD
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