CN113943269A - Synthesis method of Texitasai C-13 side chain - Google Patents

Synthesis method of Texitasai C-13 side chain Download PDF

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CN113943269A
CN113943269A CN202111364944.3A CN202111364944A CN113943269A CN 113943269 A CN113943269 A CN 113943269A CN 202111364944 A CN202111364944 A CN 202111364944A CN 113943269 A CN113943269 A CN 113943269A
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曾永明
毕思峰
李楠
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CHANGJI UNIVERSITY
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Abstract

A method for synthesizing a Texitasai C-13 side chain. 3-fluoropyridine-2-aldehyde and p-anisidine are used as initial raw materials, Schiff base is synthesized through condensation reaction, and then Staudinger reaction is carried out between the Schiff base and acetoxyl acetyl chloride to synthesize the alpha-acetoxyl substituted beta-lactam. And then, removing the p-methoxyphenyl protecting group on the nitrogen atom of the beta-lactam, hydrolyzing and splitting by using bovine liver enzyme to obtain an optically pure chiral product, and finally protecting the nitrogen atom by using a tert-butyloxycarbonyl protecting group to obtain the C-13 side chain precursor of the tenuisticide.

Description

Synthesis method of Texitasai C-13 side chain
Technical Field
The invention relates to a synthesis method of a Texitasai C-13 side chain, belonging to the technical field of organic chemistry.
Background
Paclitaxel is a natural product anticancer drug, is extracted from Taxus x western bark for the first time in 1966 by Ware and Warner of U.S. chemists, and has good therapeutic effect on malignant tumors of ovarian cancer, lung cancer and breast cancer. Paclitaxel, docetaxel and cabazitaxel are the most typical drug preparations in the compounds, however, patients have adverse drug reactions after being injected with paclitaxel drugs and docetaxel drugs, particularly, patients have nervousness reactions to the drugs, and even occasionally die, and the drugs can cause leucopenia, nerve function damage and other adverse reactions.
The texitasai is a novel orally-taken taxane anticancer drug, has high anticancer activity, is taken as an oral capsule, avoids side reaction of a patient to drug injection, and improves the convenience of administration of the patient. The dosage of the tesetaxel can be changed when the tesetaxel can be used alone or in combination with other drugs, so that the treatment period of a patient can be flexibly adjusted. The U.S. food and drug administration approved tacetaxel as an oral agent of taxanes for the treatment of advanced melanoma by Genta in 2008, and is currently undergoing a third phase clinical study. The existing tesetaxel compounds are prepared by docking a tesetaxel mother ring with a baccatin structure with its corresponding side chain, and it is therefore important to find a route suitable for the feasible synthesis of tesetaxel (tesetaxel). Therefore, a route for efficiently synthesizing the C-13 side chain of the tesetaxel is developed, and the method has important significance for the synthesis and scale preparation of the tesetaxel.
The existing main synthesis method of the tesetaxel side chain comprises the following steps:
the side chain synthesis route in the Texitasai semisynthetic route reported in 2002 by Tsunehiko Soga, Kouichi Uoto and Yasuyuki Takeda, first pharmaceutical Co., Ltd., Japan. Taking 3-fluoropyridine-2-aldehyde as raw material and CH3COCH2The COCl is subjected to Staudinger reaction to synthesize beta-lactam, protecting groups on hydroxyl and nitrogen are treated, and an optically pure tersitaxel side chain precursor in the form of the beta-lactam is obtained through chiral column resolution.
Figure BDA0003360269580000021
A side chain synthetic route among Tectasai semisynthetic routes was reported in EP 1375495B 1 by Sato Kouji, Yagi Tsutomu and Kitagawa Yutaka of first pharmaceutical Co., Ltd., Japan in 2006. Synthesizing beta-lactam by using 3-fluoropyridine-2-aldehyde as a raw material, hydrolyzing and resolving by using lipase to obtain the required optically pure beta-lactam, and treating hydroxyl and nitrogen protecting groups to obtain a target product texitasai side chain precursor.
Figure BDA0003360269580000022
The side chain synthetic route in the tesetasai semisynthetic route in US 2012/0220634a1 patent reported in 2012 by the real he company John k.
Figure BDA0003360269580000023
Disclosure of Invention
The invention provides a method for synthesizing a beta-lactam side chain precursor with short synthetic route and high efficiency, and then obtaining an optically pure tesetaxel side chain precursor by lipase resolution, thereby saving two steps of removing a protecting group from a hydroxyl group and adding a protecting group, and shortening the route steps.
The technical scheme of the invention is as follows: a method for synthesizing a Texitasai C-13 side chain. The method is characterized by comprising the following steps:
(1) taking 3-fluoropyridine-2-aldehyde and p-anisidine as initial raw materials, and synthesizing Schiff base through a condensation reaction.
(2) Staudinger reaction is carried out between Schiff base and acetoxyacetyl chloride to synthesize the beta-lactam with alpha-acetoxyl substitution.
(3) Removing the p-methoxyphenyl protecting group on the nitrogen atom of the beta-lactam by using a ceric ammonium nitrate reagent.
(4) Hydrolyzing and splitting the beta-lactam with the protective group removed by bovine liver enzyme to obtain the chiral beta-lactam with optical purity.
(5) With tert-butyl dicarbonate (Boc)2O) reacts under the catalytic amount of 4-dimethylamino pyridine to protect the nitrogen atom on the chiral beta-lactam, and the C-13 side chain precursor of the superfine tatsai is obtained.
The synthesis method specifically comprises the following steps:
(1) dissolving hydroxyacetic acid in 1, 4-dioxane, adding acetyl chloride, heating to 90-100 deg.c to react for 3-5 hr until no gas is produced, heating to 115 deg.c and 130 deg.c to evaporate unreacted acetyl chloride and 1, 4-dioxane solvent to obtain acetoxy acetic acid, adding oxalyl chloride and small amount of DMF, reacting at room temperature for 1-3 hr, adding oxalyl chloride, and further reacting for 1-3 hr until no gas is produced to obtain acetoxy acetyl chloride.
Figure BDA0003360269580000031
(2) Dissolving 3-fluoropyridine-2-formaldehyde and p-anisidine in benzene, adding anhydrous sodium sulfate, stirring at normal temperature for 0.5-2 hr, filtering, spin drying, and vacuum drying for 2-4 hr; dissolving the obtained product in dichloromethane under the protection of anhydrous oxygen-free argon, adding triethylamine at-80 to-70 ℃, slowly dropwise adding acetoxyacetyl chloride, adding water at room temperature to quench reaction, extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude product of beta-lactam, and recrystallizing with dichloromethane-petroleum ether to obtain the high-purity beta-lactam.
Figure BDA0003360269580000041
(3) Dissolving beta-lactam in acetonitrile, slowly adding ammonium ceric nitrate at-15-0 ℃, reacting for 20-50 minutes, and quenching the reaction by using a saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin-drying, and separating to obtain racemic beta-lactam without PMP protecting group.
Figure BDA0003360269580000042
(4) Dissolving racemic beta-lactam in a proper amount of ether, adding a beef liver enzyme solution at a certain temperature, detecting the reaction by TLC, and adding acetone to quench the reaction after the reaction is finished. Extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, spin drying, and separating by column chromatography to obtain chiral beta-lactam.
Figure BDA0003360269580000043
(5) Chiral beta-lactam is dissolved in dichloromethane and Boc is added2O and DMAP react for 20-50 minutes, and the C-13 side chain precursor is obtained by direct column chromatography separation.
Figure BDA0003360269580000044
The specific implementation mode is as follows:
the present invention is further illustrated by the following examples, but is not limited thereto.
Example 1
(1) Dissolving 90g of glycolic acid in 600mL of 1, 4-dioxane, adding 80mL of acetyl chloride, heating to 90 ℃, reacting for 3 hours until no gas is generated, heating to 120 ℃ to evaporate unreacted acetyl chloride and 1, 4-dioxane solvent to obtain acetoxyacetic acid, dissolving acetoxyacetic acid in 500mL of benzene, adding 170mL of oxalyl chloride and a few drops of DMF, reacting for 1 hour at room temperature, adding 84mL of oxalyl chloride, and continuing to react for 1.5 hours until no gas is generated to obtain acetoxyacetyl chloride.
(2) Dissolving 15g of 3-fluoropyridine-2-formaldehyde and 14.8g of p-anisidine in 200mL of benzene, adding 15g of anhydrous sodium sulfate, stirring at normal temperature for 0.5 hour, filtering, spin-drying, and vacuum-drying for about 2.5 hours; dissolving the obtained product in 100mL of dichloromethane under the protection of anhydrous oxygen-free argon, adding 66mL of triethylamine at-80 ℃, slowly dropwise adding 65g of acetoxyacetyl chloride, adding water at room temperature to quench the reaction, extracting with 200mL of ethyl acetate for three times, washing with a saturated NaCl solution twice, drying with anhydrous sodium sulfate, filtering, spin-drying, and recrystallizing the obtained crude product with dichloromethane-petroleum ether to obtain the high-purity beta-lactam.
(3) 10g of beta-lactam was dissolved in acetonitrile, and 60g of ammonium ceric nitrate was slowly added thereto at-15 ℃ to react for 20 minutes. The reaction was quenched with saturated sodium bicarbonate solution. Extracted five times with 300mL ethyl acetate, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, spin dried, and separated by column chromatography. Obtaining the racemic beta-lactam yield after the PMP protective group is removed.
(4)30g of beef liver minced by a meat grinder, and 100mL of a beef liver solution was prepared by adding a buffer solution of potassium hydrogenphosphate and potassium dihydrogenphosphate having a pH of 8. Dissolving racemic beta-lactam in a proper amount of ether, adding a beef liver enzyme solution at a certain temperature, detecting the reaction by TLC, and adding acetone to quench the reaction after the reaction is finished. Extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, spin drying, and separating by column chromatography to obtain chiral beta-lactam.
(5) The chiral beta-lactam was dissolved in dichloromethane and 1 equivalent of Boc was added2O, 0.2 equivalent of DMAP, reacted for 20 minutes, and directly applied to a column for column chromatography to separate the C-13 side chain precursor.
Example 2
(1) Dissolving 90g of glycolic acid in 600mL of 1, 4-dioxane, adding 80mL of acetyl chloride, heating to 90 ℃, reacting for 3.5 hours until no gas is generated, heating to 120 ℃, evaporating unreacted acetyl chloride and 1, 4-dioxane solvent to obtain acetoxyacetic acid, dissolving acetoxyacetic acid in 500mL of benzene, adding 170mL of oxalyl chloride and a few drops of DMF, reacting for 1.5 hours at room temperature, adding 80mL of oxalyl chloride, and continuing to react for 1.5 hours until no gas is generated to obtain acetoxyacetyl chloride.
(2) Dissolving 10g of 3-fluoropyridine-2-formaldehyde and 13g of p-anisidine in 200mL of benzene, adding 15g of anhydrous sodium sulfate, stirring at normal temperature for 0.5 hour, filtering, spin-drying, and vacuum-drying for about 2.5 hours; dissolving the obtained product in 100mL of dichloromethane under the protection of anhydrous oxygen-free argon, adding 66mL of triethylamine at-80 ℃, slowly dropwise adding 60g of acetoxyacetyl chloride, adding water at room temperature to quench the reaction, extracting with 200mL of ethyl acetate for three times, washing with a saturated NaCl solution twice, drying with anhydrous sodium sulfate, filtering, spin-drying, and recrystallizing the obtained crude product with dichloromethane-petroleum ether to obtain the high-purity beta-lactam.
(3) 10g of beta-lactam was dissolved in acetonitrile, and 60g of ammonium ceric nitrate was slowly added thereto at-15 ℃ to react for 20 minutes. The reaction was quenched with saturated sodium bicarbonate solution. Extracting with ethyl acetate for five times, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin drying, and separating by column chromatography. Obtaining the racemic beta-lactam yield after the PMP protective group is removed.
(4)40g of beef liver minced by a meat grinder was added with a buffer solution of potassium hydrogenphosphate and potassium dihydrogenphosphate having a pH of 8 to prepare 100mL of a beef liver solution. Dissolving racemic beta-lactam in a proper amount of ether, adding a beef liver enzyme solution at a certain temperature, detecting the reaction by TLC, and adding acetone to quench the reaction after the reaction is finished. Extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, spin drying, and separating by column chromatography to obtain chiral beta-lactam.
(5) The chiral beta-lactam was dissolved in dichloromethane and 1 equivalent of Boc was added2O, 0.2 equivalent of DMAP, reacted for 20 minutes, and directly applied to a column for column chromatography to separate the C-13 side chain precursor.
Example 3
(1)70g of glycolic acid is dissolved in 300mL of 1, 4-dioxane, 80mL of acetyl chloride is added, the temperature is raised to 97 ℃ for reaction for 3.5 hours until no gas is generated, then the temperature is raised to 120 ℃ for evaporation of unreacted acetyl chloride and 1, 4-dioxane solvent to obtain acetoxyacetic acid, the acetoxyacetic acid is dissolved in 500mL of benzene, 170mL of oxalyl chloride and a few drops of DMF are added, the mixture is reacted for 1.5 hours at room temperature, 80mL of oxalyl chloride is added, and the reaction is continued for 2 hours until no gas is generated, so that acetoxyacetyl chloride is obtained.
(2) Dissolving 10g of 3-fluoropyridine-2-formaldehyde and 13g of p-anisidine in 200mL of benzene, adding 15g of anhydrous sodium sulfate, stirring at normal temperature for 0.5 hour, filtering, spin-drying, and vacuum-drying for about 2.5 hours; dissolving the obtained product in 100mL of dichloromethane under the protection of anhydrous oxygen-free argon, adding 66mL of triethylamine at-80 ℃, slowly dropwise adding 47g of acetoxyacetyl chloride, adding water at room temperature to quench the reaction, extracting with 200mL of ethyl acetate, washing with a saturated NaCl solution, drying with anhydrous sodium sulfate, filtering, spin-drying, and recrystallizing the obtained crude product with dichloromethane-petroleum ether to obtain the high-purity beta-lactam.
(3) 10g of beta-lactam was dissolved in acetonitrile, and 60g of ammonium ceric nitrate was slowly added thereto at-10 ℃ to react for 20 minutes. The reaction was quenched with saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin drying, and separating by column chromatography. Obtaining the racemic beta-lactam without PMP protecting group.
(4)20g of beef liver minced by a meat grinder was added with a buffer solution of potassium hydrogenphosphate and potassium dihydrogenphosphate having a pH of 8 to prepare 100mL of a beef liver solution. Dissolving racemic beta-lactam in a proper amount of ether, adding a beef liver enzyme solution at a certain temperature, detecting the reaction by TLC, and adding acetone to quench the reaction after the reaction is finished. Extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, spin drying, and separating by column chromatography to obtain chiral beta-lactam.
(5) The chiral beta-lactam was dissolved in dichloromethane and 1 equivalent of Boc was added2O, 0.2 equivalent of DMAP, reacted for 20 minutes, and directly applied to a column for column chromatography to separate the C-13 side chain precursor.

Claims (2)

1. A synthetic method of a Texitasai C-13 side chain is characterized by comprising the following steps:
(1) synthesizing Schiff base by using 3-fluoropyridine-2-aldehyde and p-anisidine as initial raw materials through a condensation reaction;
(2) staudinger reaction is carried out between Schiff base and acetoxyl acetyl chloride to synthesize alpha-acetoxyl substituted beta-lactam;
(3) removing the p-methoxyphenyl protecting group on the nitrogen atom of the beta-lactam by using a ceric ammonium nitrate reagent;
(4) hydrolyzing and splitting the beta-lactam with the protective group removed by bovine liver enzyme to obtain chiral beta-lactam with optical purity;
(5) with tert-butyl dicarbonate (Boc)2O) reacts under the catalytic amount of 4-dimethylamino pyridine to protect the nitrogen atom on the chiral beta-lactam, and the C-13 side chain precursor of the superfine tatsai is obtained.
2. The method of claim 1, wherein the method comprises the following steps:
(1) dissolving glycolic acid in 1, 4-dioxane, adding acetyl chloride, heating to 80-120 ℃, reacting for 3-5 hours until no gas is generated, heating to 115-130 ℃, evaporating unreacted acetyl chloride and 1, 4-dioxane solvent to obtain acetoxyacetic acid, adding oxalyl chloride and a small amount of DMF, reacting for 1-3 hours at room temperature, adding oxalyl chloride, and continuing to react for 1-3 hours until no gas is generated to obtain acetoxyacetyl chloride;
(2) dissolving 3-fluoropyridine-2-formaldehyde and p-anisidine in benzene, adding anhydrous sodium sulfate, stirring at normal temperature for 0.5-2 hr, filtering, spin drying, and vacuum drying for 2-4 hr; dissolving the obtained product in dichloromethane under the protection of anhydrous oxygen-free argon, adding triethylamine at-80 to-70 ℃, slowly dropwise adding acetoxyacetyl chloride, adding water at room temperature for quenching reaction, extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude product of beta-lactam, and recrystallizing with dichloromethane-petroleum ether to obtain high-purity beta-lactam;
(3) dissolving beta-lactam in acetonitrile, slowly adding ammonium ceric nitrate at the temperature of-15-0 ℃, and reacting for 20-50 minutes; quenching the reaction with saturated sodium bicarbonate solution; extracting with ethyl acetate, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, spin-drying, and separating to obtain racemic beta-lactam without PMP protecting group;
(4) dissolving racemic beta-lactam in a proper amount of diethyl ether, adding a beef liver enzyme solution at a certain temperature, detecting the reaction by TLC, and adding acetone to quench the reaction after the reaction is finished; extracting with ethyl acetate, washing with saturated NaCl solution, drying with anhydrous sodium sulfate, spin-drying, and separating by column chromatography to obtain chiral beta-lactam;
(5) chiral beta-lactam is dissolved in dichloromethane and Boc is added2And (3) reacting O and DMAP for 20-50min, and directly performing column chromatography separation to obtain a C-13 side chain precursor.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020143178A1 (en) * 1999-10-15 2002-10-03 Daiichi Pharmaceutical Co., Ltd. Pentacyclic taxan compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020143178A1 (en) * 1999-10-15 2002-10-03 Daiichi Pharmaceutical Co., Ltd. Pentacyclic taxan compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
岳琴等: "紫杉醇的半合成", 《药学学报》, vol. 31, no. 12, pages 911 - 917 *
阎家麒: "牛肝酯酶催化紫杉醇侧链手性合成的研究", 《药物生物技术》, vol. 12, no. 2, pages 90 - 92 *

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