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Preparation method of (R,S)-2-[[5-(9-fluorenemethoxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid

A technology of fluorenylmethoxycarbonylamino and methoxyphenethyl, applied in (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptyl The field of preparation of alkane-2-yl]oxy]acetic acid can solve the problems of long steps, many wastes, troublesome post-processing, etc., and achieve the effects of improving the post-processing method, increasing the overall yield, and reducing production costs

Active Publication Date: 2015-07-08
江苏吉泰肽业科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems of long steps in the original synthesis method, troublesome post-processing, many wastes and high cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1, a method for preparing (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid, Include the following steps:

[0045] A. Mix 500g o-carboxybenzaldehyde and 553g m-methoxyphenylacetic acid, add 600g sodium acetate, stir in a 5L three-necked flask, heat up to 200°C and react for 9 hours. The temperature was lowered, the reactant was acidified by dissolving 5% HCl in water, extracted with ethyl acetate, the solvent was evaporated under negative pressure, the reactant was dissolved in 2.5L of methanol, 35g of Pd-C was added, hydrogen was passed, stirred at 30°C for 2 hours, suction filtered, and the The solvent was evaporated to dryness under pressure, dissolved in 1L of ethyl acetate, recrystallized by adding 2L of petroleum ether, and 645g of (R-1) was obtained by suction filtration, with a yield of 77%, melting point of 140-143°C, and HPLC of 98.91%;

[0046] B. Mix 100g (R-1) with SOCl 2 232 g was reacted at 60°C for 3 hou...

Embodiment 2

[0050] Example 2, a preparation method of (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid, Include the following steps:

[0051] A. Mix 500g o-carboxybenzaldehyde with 553g m-methoxyphenylacetic acid, add 50g sodium acetate, stir and heat up to 230°C for 8 hours, cool down, dissolve with dioxane, add 35g Raney nickel, pass through H 2 Keep the reaction at 34°C for 1.5 hours, filter it out with suction, evaporate the solution to dryness, dissolve it with 1 ethyl acetate, add 2.2L petroleum ether for recrystallization, and obtain 630g of the target product (R-1), with a yield of 74% and a melting point of 140-144°C , HPLC 98.44%;

[0052] B. Mix 100g (R-1) with POCl 3 260 g was reacted at 70°C for 3 hours, and the excess SOCl was evaporated to dryness under negative pressure 2 , the residue was dissolved in 400mL of benzene, and added dropwise in a solution containing 165g of anhydrous AlCl 3 1200mL of anhydrous benzene solution, re...

Embodiment 3

[0056] Example 3, a method for preparing (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid, Include the following steps:

[0057] A. Mix 500g of o-carboxybenzaldehyde and 553g of m-methoxyphenylacetic acid, add 50g of anhydrous sodium acetate, stir and heat up to 195°C, react for 11 hours, cool down, dissolve the reactant in THF, add 35g of Pd-C to pass H 2 Stir, react at 24°C for 2 hours, filter with suction, evaporate the solvent to dryness, dissolve with 1L ethyl acetate, add 2.3L petroleum ether for recrystallization, and obtain 640g of the target product (R-1), with a yield of 75% and a melting point of 140-144°C , HPLC 98.76%;

[0058] B. Mix 100g (R-1) with SOCl 2 230 g was reacted at 60°C for 3 hours, and the excess SOCl was evaporated to dryness under negative pressure 2 , the residue was dissolved in 400mL of benzene, and added dropwise in a solution containing 158g of anhydrous AlCl 3 1200mL of anhydrous toluene solution...

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Abstract

The invention relates to a preparation method of Ramage linker and mainly solves problems of long processes, complex post-treatment, much waste water, waste gas and solid waste, and high cost in a conventional synthetic method. The preparation method includes following steps: (A) carrying out a reaction to 2-carboxybenzaldehyde and m-methoxyphenylacetic acid to obtain an intermediate 2-(3-methoxylstyryl)benzoic acid, dissolving the intermediate with a solvent, performing hydrogenation reduction, and performing post-treatment crystallization to obtain a compound R-1; (B) carrying out a reaction to the R-1 with SOCl2 or POCl3 to obtain 2-methoxyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-one, performing negative-pressure evaporation to remove the SOCl2 or the POCl3, dissolving the 2-methoxyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-one in benzene, methylbenzene or 1,2-dichloroethane, performing a catalytic reaction with anhydrous AlCl3 and performing post-treatment crystallization to obtain a compound R-2; (C) carrying out a reaction to the R-2 with benzyl bromoacetate in DMF or an acetone / K2CO3 solution to obtain a compound R-3; (D) performing hydrogenation reduction to the R-3 to obtain a compound R-4; and (E) adding a catalyic amount of PTS to the R-4 in DMF and carrying out a reaction to the R-4 with Fmoc-NH2 to obtain the Ramage linker, which is an effective C-terminal linker in solid-phase synthesis.

Description

technical field [0001] The present invention relates to linking agent (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid (Ramage linker) Preparation. Background technique [0002] (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid (Ramage linker) is an effective solid The C-terminal linker is synthesized in phase, and the cleavage conditions are mild compared to other polypeptide links. The synthesis method of Ramage linker, the current method is the following 8 steps [0003] 1. O-carboxybenzaldehyde and m-methoxyphenylacetic acid are post-reacted under the catalysis of anhydrous sodium acetate to obtain R-a; [0004] 2. After the hydrogenation reduction reaction of R-a is processed to obtain R-1; [0005] 3. R-1 is post-reacted under the catalysis of polyphosphoric acid to obtain R-b; [0006] 4. R-b was dissolved in 1,2-dichloroethane, and dissolved in anhydrous AlCl 3 The post-processing ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/24
Inventor 付等良徐红岩涂雨龙
Owner 江苏吉泰肽业科技有限公司
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