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5, 7-dichlorotetrahydroisoquinoline acetal amine compound as well as preparation method and application thereof

A compound, C3-C20 technology, applied in the field of 5,7-dichlorotetrahydroisoquinoline aminals, its preparation, and the synthesis of key intermediates of ritazast, which can solve the problem of increasing recovery and processing Issues such as the cost of three wastes, great environmental hazards, and reduced production efficiency

Pending Publication Date: 2021-02-26
TOPHARMAN TANCHENG CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The main weak point of this route is: (1) the atom economy of trityl (Tr) protecting group is poor, has reduced production efficiency; product, which not only increases the cost of recycling and treating the three wastes, but also tends to leave trityl alcohol in the product, which increases the difficulty of purifying the product
[0012] The main disadvantages of this route are: (1) the sulfonyl chloride used is a toxic reagent, which is harmful to the environment; the price of trifluoromethanesulfonic anhydride is relatively high; (2) expensive metals are used in the key reaction of introducing methyl ester Palladium catalysts and ligands are difficult to recycle, resulting in higher production costs; (3) the reaction of introducing methyl esters needs to be heated and pressurized in a carbon monoxide atmosphere, and there are serious safety hazards in operation, which is not conducive to industrial production
[0013] In view of the above-mentioned disclosed methods for preparing intermediates IV-1 and IV-2, there are many deficiencies, so the development of a short synthesis route, high atom economy, low production cost and easy industrial production has great practical significance.

Method used

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  • 5, 7-dichlorotetrahydroisoquinoline acetal amine compound as well as preparation method and application thereof
  • 5, 7-dichlorotetrahydroisoquinoline acetal amine compound as well as preparation method and application thereof
  • 5, 7-dichlorotetrahydroisoquinoline acetal amine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Synthesis of two (5,7-dichloro-3,4-dihydroisoquinolin-2 (1H)-yl) methane (I-1) of embodiment 1

[0079]

[0080] At room temperature, 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (II-1) (4 g, 16.77 mmol) was added to 80 mL of water, and then added to the suspension 37% formaldehyde aqueous solution (0.680g, 8.38mmol) was stirred for 30 minutes, then sodium hydroxide (0.771g, 19.28mmol) aqueous solution (8mL) was added in portions, and the addition was completed in about 40 minutes. After the addition, the reaction solution was stirred at room temperature for 3 hours, then filtered, the filter cake was washed with water, and dried to obtain bis(5,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)methane (I-1), white solid 3.278g, yield: 94%. 1 H NMR (400MHz, CDCl 3 ): δ7.23(d, J=1.8Hz, 2H), 6.96(s, 2H), 3.70(s, 4H), 3.28(s, 2H), 2.90~2.86(m, 4H), 2.84~2.81( m, 4H). 13 C NMR (400MHz, CDCl 3 ): δ138.3, 134.9, 131.6, 126.7, 125.7, 79.4, 53.9, 48.5, 26.7.

Embodiment 2

[0081] Example 2 Synthesis of (5,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)methane (I-1)

[0082]

[0083] At room temperature, 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.5 g, 2.10 mmol) was added to 10 mL of water, and then paraformaldehyde ( 0.031g, 1.05mmol), and stirred for 30 minutes. The prepared aqueous sodium hydroxide solution (0.096 g of sodium hydroxide dissolved in 1 mL of water) was added to the suspension in batches, and the addition was completed in about 20 minutes. After the addition, the reaction solution was stirred at room temperature for 5 hours, then the reaction solution was filtered, the filter cake was washed with water, and dried to obtain bis(5,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl) Methane (I-1), white solid 0.38g. Yield: 87%. 1 H NMR (400MHz, CDCl 3 ): δ7.23(d,J=1.8Hz,2H),6.96(s,2H),3.70(s,4H),3.28(s,2H),2.90~2.86(m,4H),2.84~2.81( m, 4H). 13 C NMR (400MHz, CDCl 3 ): δ138.3, 134.9, 131.6, 126.7, 125.7, 79.4, 53.9, 4...

Embodiment 3

[0084] Example 3 Synthesis of two (5,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)methane (I-1)

[0085]

[0086] At room temperature, 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.5 g, 2.10 mmol) was added to 10 mL of water, and then paraformaldehyde ( 0.031g, 1.05mmol), and stirred for 30 minutes. The prepared potassium carbonate aqueous solution (0.333g potassium carbonate dissolved in 2mL water) was added to the above suspension in batches, and the addition was completed in about 20 minutes. After the addition, the reaction solution was stirred at room temperature for 5 hours, then the reaction solution was filtered, the filter cake was washed with water, and dried to obtain bis(57-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)methane (I-1), 0.35 g of white solid. Yield: 80%. 1 H NMR (400 MHz, CDCl 3 ): δ7.23(d,J=1.8Hz,2H),6.96(s,2H),3.70(s,4H),3.28(s,2H),2.90~2.86(m,4H),2.84~2.81( m, 4H). 13 C NMR (400MHz, CDCl 3 ): δ138.3, 134.9, 131.6, 126.7, 125.7, 79...

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Abstract

The invention provides a 5, 7-dichlorotetrahydroisoquinoline acetal amine compound as shown in a formula III, and a preparation method and an application thereof. The 5, 7-dichlorotetrahydroisoquinoline compound as shown in the formula III can be used for synthesizing a key intermediate of the rotinostat. The method has the advantages of high atom economy, few byproducts and the like, conforms tothe concept of green chemistry, and is suitable for being developed into an industrial production process.

Description

technical field [0001] The invention relates to the field of chemical synthesis of medicines, in particular to a 5,7-dichlorotetrahydroisoquinoline aminal compound, a preparation method thereof, and a synthesis method for preparing a key intermediate of ritaglast by using the compound. Background technique [0002] Litahast (Lifitegrast), the chemical name is (S)-2-[2-(benzofuryl-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquine Phyloline-6-carboxamido]-3-(3-methylsulfonylphenyl)-propionic acid, the specific structural formula is as follows: [0003] [0004] On July 11, 2016, the U.S. Food and Drug Administration (FDA) approved the marketing application for the British pharmaceutical company Shire's Litamiast eye drops, which is the first drug approved by the FDA for the treatment and improvement of dry eye. New drugs for eye diseases. Dry eye syndrome is a type of disease that causes ocular discomfort and visual dysfunction due to tear film instability or (and) ocul...

Claims

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Application Information

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IPC IPC(8): C07D217/02
CPCC07D217/02
Inventor 朱富强雷生辉孙长亮沈敬山
Owner TOPHARMAN TANCHENG CO LTD
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