Method for synthesizing chiral dorzolamide hydrochloride

A synthesis method and compound technology, applied in the field of synthesis of chiral dulzolamide hydrochloride, can solve the problems of only 10% weight yield, low chiral resolution efficiency, easy racemization, etc., and achieve high optical purity , Avoid racemization, easy to operate

Inactive Publication Date: 2010-06-16
FUJIAN SOUTH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The main disadvantage of the first route is: the efficiency of chiral resolution is extremely low, and the weight yield is only about 10%
The main disadvantage of the second route is: the substitution reaction of mercaptothiophene and 3-p-toluenesulfonyloxybutyric acid methyl ester is prone to racemization, and the stability of the reaction is relatively poor

Method used

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  • Method for synthesizing chiral dorzolamide hydrochloride
  • Method for synthesizing chiral dorzolamide hydrochloride
  • Method for synthesizing chiral dorzolamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of (R)-N-crotonyl-4-benzyl oxazolidinone (compound represented by general formula 2)

[0037] According to the literature Synlett. (2003, 2351), 177 g (1 mol) of chiral prosthetic oxazolidinone and 172 g (2 mol) of crotonic acid were dissolved in dichloromethane, and 412 g (2 mol) of dicyclohexylcarbonimide was added, The reaction was carried out at 25°C for 24 hours, followed by conventional post-treatment to obtain 240 g of solid, namely (R)-N-crotonyl-4-benzyloxazolidinone, which was directly used in the next reaction.

[0038]

[0039] C 14 h 15 NO 3 C 18 h 19 NO 3 S 2

[0040] Mol.Wt.: 245.27 Mol.Wt.: 361.48

[0041] In a 500ml dry four-neck flask, add 250ml of dichloromethane, 24.5g (0.1mol) of the solid (R)-N-crotonyl-4-benzyl oxazolidinone obtained above and 17.3g of titanium tetrachloride, and stir After dissolving, it was cooled to 0°C, and 20ml (0.13mol) of tetramethylethylenediamine and 12g (0.1mol) of 2-mercaptothiophene were...

Embodiment 2

[0043]

[0044] C 18 h 19 NO 3 S 2 C 8 h 8 OS 2

[0045] Mol.Wt.: 361.48 Mol.Wt.: 184.28

[0046] Dissolve the solid obtained in Example 1, that is, 29 g (0.08 mol) of the compound represented by general formula 1 in 300 ml of anhydrous tetrahydrofuran, add 50 ml of n-butyllithium (1.6M) dropwise at -78 ° C, and stir for 24 hours after the addition , adding ice water, conventional post-treatment to obtain 12g of solid product, i.e. the compound shown in general formula 3, its spectral data are as follows:

[0047] 1H NMR (500M, CDCl3) δ: 7.40(d, J=5.4Hz, 1H), 7.00(d, J=5.5Hz, 1H), 3.80(m, 1H), 2.89(dd, J=3.0, 16.5Hz , 1H), 2.65(dd, J=11.0, 16.4Hz, 1H), 1.50(d, J=7.0Hz, 3H).

Embodiment 3

[0049] Synthesis of (R)-N-crotonyl-4-isopropylthioxazolidinone (compound represented by general formula 2)

[0050] According to the document Synlett. (2003, 2351), 145g (1mol) of chiral prosthetic group-thioxazolidinone and 172g (2mol) of crotonic acid were dissolved in dichloromethane, and 412g (2mol) of dicyclohexylcarbonimide was added ), reacted at 25°C for 24 hours, and performed conventional post-treatment to obtain 200 g of solid, ie (R)-N-crotonyl-4-isopropylthiooxazolidinone, which was directly used in the next reaction.

[0051]

[0052] C 10 h 15 NO 2 S C 14 h 19 NO 2 S 3

[0053] Mol.Wt.: 213.30 Mol.Wt.: 329.50

[0054] In a 500ml dry four-necked flask, add 100ml of dichloromethane, 22.0g (0.1mol) of the solid (R)-N-crotonyl-4-isopropylthiooxazolidinone obtained above and trifluoromethanesulfonic acid 2.2g of titanium was stirred and dissolved and then cooled to -78°C, and 167ml (1mol) of tetramethylpropylenediamine and 24g (0.2mol) of 2-mercaptothiophen...

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Abstract

The invention discloses a compound represented by a general formula 1 and a preparation method thereof. In the structural formula, X=Y=O, or X=S, Y=O, or X=Y=S; and R represents phenyl, benzyl or isopropyl. The invention also discloses a method for synthesizing a compound represented by a general formula 3, and a method for synthesizing chiral dorzolamide hydrochloride, which are formed by carrying out one step reaction and multi-step reaction on the compound represented by the general formula 1. The compound synthesizes the chiral dorzolamide hydrochloride used for treating glaucoma by adopting a classical chiral prosthetic group induction method, and has the advantages of good yield, no racemization and high optical purity.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a synthesis method of chiral dulzamide hydrochloride. Background technique [0002] Chiral dorzolamide hydrochloride (dorzolamide hydrochloride, dorzolamide) is a product of Merck for the treatment of glaucoma. [0003] The chemical name of chiral duxolamide hydrochloride is: (2S,4S)-2-ethylamino-4-methyl-5,5-dioxo-5,7-dithiobicyclo[4.3.0]nonane -8,10-diene-8-sulfonamide hydrochloride, the structural formula is as follows: [0004] [0005] The synthetic route of chiral duxolamide hydrochloride can basically be summarized into two. Route 1 Condensation of mercaptothiophene and crotonic acid, followed by cyclization to obtain thienothiopyran, and then through sulfonation, amination, reduction, oxidation, Ritter reaction, reduction to obtain racemized dolcetamide, and then diphenylmethyl tartrate The acyl ester was resolved with a resolving reagent to obtain chiral dulzamide ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D495/04C07B53/00
Inventor 沈鑫林复兴何晓杨继东詹华杏
Owner FUJIAN SOUTH PHARMA CO LTD
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