CN110317132B - Preparation method of sodium phenylbutyrate - Google Patents
Preparation method of sodium phenylbutyrate Download PDFInfo
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- CN110317132B CN110317132B CN201910681637.4A CN201910681637A CN110317132B CN 110317132 B CN110317132 B CN 110317132B CN 201910681637 A CN201910681637 A CN 201910681637A CN 110317132 B CN110317132 B CN 110317132B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
Abstract
The invention discloses a preparation method of sodium phenylbutyrate. Adding the materials and anhydrous 2, 3-butanediol into a reaction container under inert atmosphere and uniformly mixing; the relevant materials include allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, N- (octaaminoquinoline) but-3-enamide, lithium acetate, bromobenzene, cyanoacetic acid and water; placing the reaction container in an oil bath at 125-135 ℃ and violently stirring for reaction for 12 hours, and purifying a reaction product through a silica gel column to obtain a compound with a guide group; adding the compound into an ethanol solvent containing sodium hydroxide, heating the mixture to 130-140 ℃, carrying out reflux reaction for 12 hours, and carrying out reduced pressure distillation on the reaction product to remove the solvent, extraction, water layer collection and water removal, thus obtaining the sodium phenylbutyrate preparation. The method has the characteristics of high reaction area selectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of sodium phenylbutyrate.
Background
Sodium phenylbutyrate is a prodrug that is rapidly metabolized to phenylacetate. It can combine with glutamic acid and ammonia to produce phenylacetylglutamine, which is excreted by the kidney as yet another route for the excretion of nitrogenous wastes. Administration of sodium phenylbutyrate results in excessive blood ammonia and blood glutamate levels being reduced to form phenylacetylglutamine which increases the excretion of nitrogenous wastes. Is suitable for all the patients with enzyme deficiency of newborn (complete enzyme deficiency in 28 days after birth) and delayed enzyme deficiency with family history of high blood ammonia encephalopathy (partial enzyme deficiency after the first month of birth).
However, the existing synthetic method of sodium phenylbutyrate generally has the problems of more synthetic steps, poor reaction region selectivity, low product yield, mild reaction conditions, complex reaction and post-treatment purification processes and the like.
Disclosure of Invention
The invention aims to provide a preparation method of sodium phenylbutyrate, and aims to overcome the defects in the prior art.
The invention is realized in such a way that a preparation method of sodium phenylbutyrate comprises the following steps:
(1) under an inert atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: 1mL of the solution is added into a reaction container and mixed evenly; wherein the related materials comprise a molar ratio of 1: (1-3): (0.01-0.1): (0.02-0.2): (1-5): (1-3): (1-100) N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water;
(2) placing the reaction container in an oil bath at 125-135 ℃ and violently stirring for reaction for 12 hours, and purifying a reaction product through a silica gel column to obtain a compound with a guide group;
(3) adding the compound into an ethanol solvent containing sodium hydroxide, and heating the mixture to 130-140 ℃ for reflux reaction for 12 hours; wherein the molar ratio of the compound to the sodium hydroxide to the ethanol is 1: (1.5-4): (5-50); and (3) distilling the reaction product under reduced pressure to remove the solvent, extracting, collecting a water layer, and distilling under reduced pressure to remove water to obtain the sodium phenylbutyrate preparation.
Preferably, in step (1), the inert gas used in the inert atmosphere is argon.
Preferably, in step (2), the silica gel column purification is a 1:20 petroleum ether to ethyl acetate wash chromatography silica gel column.
Preferably, in the step (3), the pressure of the reduced pressure distillation is within 100mbar, and the temperature is more than 80 ℃; the extraction was by addition of dichloromethane.
In order to overcome the defects and steps in the prior art, the invention discloses a preparation method of sodium phenylbutyrate. In the invention, the material and anhydrous 2, 3-butanediol are mixed in an inert atmosphere according to a molar volume ratio of 0.1 mmol: 1mL of the solution is added into a reaction container and mixed evenly; wherein the relevant materials include allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, N- (octaaminoquinoline) but-3-enamide, lithium acetate, 4-bromobiphenyl, cyanoacetic acid, and water; and (3) placing the reaction container in an oil bath at 125-135 ℃ to violently stir for reaction for 12 hours, and purifying the reaction product by a silica gel column to obtain the compound 4-phenyl-N- (quinoline-8-yl) butyramide with the guide group.
The compound can be used for synthesizing sodium phenylbutyrate, and the synthesis reaction process of the sodium phenylbutyrate is as follows:
compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: according to the invention, through reduction HECK reaction, the octaaminoquinoline is designed as a compound of a guide group to control the region and chemical selectivity in the reaction, so that the problem of excessive steps in the existing sodium phenylbutyrate synthesis process is effectively solved; in addition, the method has the characteristics of high reaction area selectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
(1) Under an argon atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: 0.1mL of the solution is added into a reaction vessel and mixed evenly; wherein the related materials comprise a molar ratio of 1: 3: 0.01: 0.2: 5: 3: 100 of N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water;
(2) placing the reaction vessel in an oil bath at 125 ℃ and vigorously stirring for reacting for 12 hours, purifying the reaction product by a silica gel column (washing the silica gel column by using petroleum ether and ethyl acetate in a ratio of 1: 20) to obtain a compound with a guide group, and determining that the compound is 4-phenyl-N- (quinoline-8-yl) butyramide by detection.
Example 2
This embodiment is substantially the same as embodiment 1, with the difference that:
in step (1), the molar ratio of N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water is 1: 1: 0.1: 0.02: 1: 1: 1;
in step (2), the oil bath temperature was 130 ℃.
Example 3
This embodiment is substantially the same as embodiment 1, with the difference that:
in step (1), the molar ratio of N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water is 1: 2: 0.05: 0.1: 3: 2: 50;
in step (2), the oil bath temperature was 135 ℃.
Example 4
(1) Adding the 4-phenyl-N- (quinoline-8-yl) butanamide prepared in the example 2 into an ethanol solvent containing sodium hydroxide, and heating the mixture to 130-140 ℃ for reflux reaction for 12 hours; wherein the mol ratio of the 4-phenyl-N- (quinoline-8-yl) butyramide to the sodium hydroxide to the ethanol is 1: 4: 50;
(2) and (2) removing the solvent from the reflux reaction product in the step (1) by reduced pressure distillation (the pressure is within 100mbar and the temperature is more than 80 ℃), adding dichloromethane for extraction for 3 times, collecting a water layer, and removing the reaction solvent (mainly water) in the reaction product by a reduced pressure distillation method (the pressure is within 100mbar and the temperature is more than 80 ℃), thus obtaining the sodium phenylbutyrate preparation 1.
Example 5
This example is essentially the same as example 1, yielding sodium phenylbutyrate formulation 2, with the following differences: in the step (1), the molar ratio of the 4-phenyl-N- (quinoline-8-yl) butanamide to the sodium hydroxide to the ethanol is 1: 1.5: 5.
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (4)
1. The preparation method of sodium phenylbutyrate is characterized by comprising the following steps:
(1) under an inert atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: 1mL of the solution is added into a reaction container and mixed evenly; wherein the material comprises a molar ratio of 1: (1-3): (0.01-0.1): (0.02-0.2): (1-5): (1-3): (1-100) N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water;
(2) placing the reaction container in an oil bath at 125-135 ℃ and violently stirring for reaction for 12 hours, and purifying a reaction product through a silica gel column to obtain a compound with a guide group;
(3) adding the compound into an ethanol solvent containing sodium hydroxide, and heating the mixture to 130-140 ℃ for reflux reaction for 12 hours; wherein the molar ratio of the compound to the sodium hydroxide to the ethanol is 1: (1.5-4): (5-50); and (3) distilling the reaction product under reduced pressure to remove the solvent, extracting, collecting a water layer, and distilling under reduced pressure to remove water to obtain the sodium phenylbutyrate preparation.
2. The method for preparing sodium phenylbutyrate according to claim 1, wherein in step (1), the inert gas used in the inert atmosphere is argon.
3. The method for producing sodium phenylbutyrate according to claim 1, wherein in step (2), the silica gel column is purified by washing a chromatography silica gel column with petroleum ether and ethyl acetate at a ratio of 1: 20.
4. The method for producing sodium phenylbutyrate according to claim 1, wherein in step (3), the reduced pressure distillation is performed at a pressure of 100mbar or less and at a temperature of 80 ℃ or higher; the extraction was by addition of dichloromethane.
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| CN1511133A (en) * | 2001-05-21 | 2004-07-07 | R������˹�� ˹̹��˹�� | Synthesis of 4-Phenylbutyric acid |
| CN1791606A (en) * | 2003-05-16 | 2006-06-21 | 德古萨股份公司 | Nitrogen-containing monodentate phosphines and their use in catalysis |
| CN108658857A (en) * | 2018-06-14 | 2018-10-16 | 南京工业大学 | A kind of method of synthesis of carboxylic acid derivative |
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| CN1511133A (en) * | 2001-05-21 | 2004-07-07 | R������˹�� ˹̹��˹�� | Synthesis of 4-Phenylbutyric acid |
| CN1791606A (en) * | 2003-05-16 | 2006-06-21 | 德古萨股份公司 | Nitrogen-containing monodentate phosphines and their use in catalysis |
| CN108658857A (en) * | 2018-06-14 | 2018-10-16 | 南京工业大学 | A kind of method of synthesis of carboxylic acid derivative |
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| Nickel(0)-catalyzed linear-selective hydroarylation of unactivated alkenes and styrenes with aryl boronic acids;Honggui Lv;《Chem. Sci.》;20180718;第9卷;第6839-6843页 * |
| Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling;Joseph Derosa et al.;《J. Am. Chem. Soc.》;20170724;第139卷;第10657-10660页 * |
| Palladium-Catalyzed Regiocontrollable Reductive Heck Reaction of Unactivated Aliphatic Alkenes;Chengdong Wang et al.;《J. Am. Chem. Soc.》;20180620;第140卷;第9332-9336页 * |
| Three-component vicinal-diarylation of alkenes via direct transmetalation of arylboronic acids;Yun Zhang et al.;《Chem. Sci.》;20190703;第10卷;第7952-7957页 * |
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