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Preparation method of cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride

A technology of hydroxyprolyl and amino acid esters, applied in the field of drug preparation, can solve problems such as unsuitability for large-scale production, difficulty in separating intermediates, and low product purity, and achieve easy control of the reaction process, optimization of the production process, and simplification of operations The effect of steps

Active Publication Date: 2022-02-01
SHANGHAI GAOZHUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Yet this method has more impurity when generating the condensation reaction of compound shown in chemical formula 4 and compound shown in chemical formula 6, and product is less, and yield is low, and impurity and product are close in position on thin-layer chromatogram, are difficult to separate and obtain purer Intermediates, resulting in lower purity final products, not suitable for large-scale production

Method used

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  • Preparation method of cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride
  • Preparation method of cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride
  • Preparation method of cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1. step a: the synthesis of the compound shown in chemical formula 2

[0044] Dissolve Fmoc-Hyp(t-Bu)-OH (i.e. the compound shown in Chemical Formula 1, 50g, 1.0eq) in DMF (250mL), add sodium carbonate (20.25g) and stir for 10min, then add benzyl bromide (i.e. Chemical Formula 8 The shown compound, 25.06g), was reacted at room temperature for 16h, and filtered with diatomaceous earth after the reaction was completed. The filtrate was concentrated and separated by column chromatography to obtain the compound shown in Chemical Formula 2 with a yield of 100%.

[0045] 2. Step b: Synthesis of the compound shown in Chemical Formula 3

[0046] The compound shown in Chemical Formula 2 (61g, 1.0eq) was dissolved in DCM solution (5v / w) containing 25% ethylenediamine, and reacted at room temperature for 3h. After the reaction was detected by TLC, the solvent was removed, and ethyl acetate and water were added. Extracted three times, extracted once with saturated sodium bicarbon...

Embodiment 2

[0056] 7. Step a: Synthesis of the compound shown in Chemical Formula 2

[0057] Dissolve Fmoc-Hyp(t-Bu)-OH (50g, 1.0eq) in DMF (250mL), add sodium bicarbonate (25.36g) and stir for 10min, then add benzyl bromide (25.06g), react at room temperature for 16h, After the reaction was completed, it was filtered with diatomaceous earth. The filtrate was concentrated and separated by column chromatography to obtain the compound shown in Chemical Formula 2 with a yield of 100%.

[0058] 8. Step b: Synthesis of the compound shown in Chemical Formula 3

[0059] The compound shown in Chemical Formula 2 (61g, 1.0eq) was dissolved in a tetrahydrofuran solution (5v / w) containing 25% ethylenediamine, and reacted at room temperature for 3h. After the reaction was detected by TLC, the solvent was removed, and ethyl acetate and water were added. Extracted three times, extracted once with saturated sodium bicarbonate solution, extracted once with saturated saline, dried and filtered the organi...

Embodiment 3

[0069] 13. Step a: Synthesis of the compound shown in Chemical Formula 2

[0070] Dissolve Fmoc-Hyp(t-Bu)-OH (50g, 1.0eq) in acetonitrile (250mL), add sodium carbonate (20.25g) and stir for 10min, then add benzyl bromide (27.58g), react at room temperature for 16h, and react After the end, filter with celite. The filtrate was concentrated and separated by column chromatography to obtain the compound shown in Chemical Formula 2 with a yield of 100%.

[0071] 14. Step b: Synthesis of the compound shown in Chemical Formula 3

[0072] The compound shown in Chemical Formula 2 (61g, 1.0eq) was dissolved in a tetrahydrofuran solution (5v / w) containing 25% ethylenediamine, and reacted at room temperature for 3h. After the reaction was detected by TLC, the solvent was removed, and ethyl acetate and water were added. Extracted three times, extracted once with saturated sodium bicarbonate solution, extracted once with saturated saline, dried and filtered the organic phase, concentrated...

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Abstract

The invention discloses a preparation method of cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride, the preparation method comprises the following steps: step f, in the process of generating a compound as shown in a chemical formula 7 by reacting a compound as shown in a chemical formula 6, adopting a hydrochloric acid organic solution as a deprotection agent; the compound as shown in the chemical formula 7 is the cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride; the hydrochloric acid organic solution is selected from one or more of a hydrochloric acid isopropanol solution, a hydrochloric acid methanol solution, a hydrochloric acid ethanol solution, a hydrochloric acid ethyl acetate solution and a hydrochloric acid acetone solution. The yield and the quality of the whole process can be improved, the material cost is saved, the production process of the process is optimized, a better mass production method is provided for the trans-4-L-hydroxyprolyl-L-serine-O-amino-acid ester hydrochloride, and the method can be well applied to industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular to a preparation method of cyclo-trans-4-L-hydroxyprolyl-L-serine-O-amino acid ester hydrochloride. Background technique [0002] Cholestatic hepatitis (intrahepatic cholestasis, IC) is a disease of the hepatobiliary system that results in metabolic and dysfunctional disorders of bile production, secretion, and excretion. It mainly has the following characteristics: (1) Jaundice: caused by bilirubin metabolism disorders Increased serum bilirubin concentration, hyperbilirubinemia can lead to liver failure and even death; (2) Liver damage: cholestasis can cause damage to liver cells, prompting an increase in the concentration of transaminases in serum, such as alanine amino transferase (ALT), aspartate aminotransferase (AST), etc. Therefore, clinically, the severity of the disease is evaluated by measuring indicators such as total bilirubin and liver function enzymes. At present,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/07Y02A50/30
Inventor 华岳庭李维华王江淮
Owner SHANGHAI GAOZHUN PHARMA CO LTD
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