CN102432484B - Crystallization method for preparing L-phenylalanine monohydrate - Google Patents

Abstract

The invention discloses a crystallization method for preparing L-phenylalanine monohydrate, belonging to the technical field of purification and separation of compounds. The method comprises the following steps of: (A) quickly cooling an L-phenylalanine saturated solution to 5 DEG C at certain temperature, and growing grains by adopting a temperature circulating technology for 12 hours; and (B) performing reduced-pressure suction filtration, acetone washing, vacuum drying and room temperature storage at the temperature lower than the phase transition point. A crystal product obtained with the method is determined as L-phenylalanine monohydrate and an anhydrous compound not containing L-phenylalanine monohydrate by adopting methods such as X-ray powder diffraction, infrared spectrography, thermogravimetric analysis, differential scanning calorimetry and the like.

Description

A kind of crystallization method of preparing a hydration L-Phe

Technical field

The present invention relates to the preparation method of a hydration L-Phe, more particularly, the present invention relates to control L-Phe monohydrate to the transformation of crystal of its anhydrous type, prepare the novel method of a hydration L-Phe of high crystal formation purity, belong to separating and purifying technology field.

Background technology

" pseudo-polymorphic " (also referred to as solvate or hydrate), mainly refers to that solvent molecule and solute molecule are combined in lattice by certain stoichiometric ratio and the molecular complex that forms.In pseudo-polymorphic structure, solvent molecule directly affects solute molecule in intracrystalline spatial disposition.When solute when crystallization, due to solvent instrumentality, can become another kind of crystal formation from a kind of crystal conversion from solvent, or be transformed into a certain specific crystal formation by amorphous.

Solvate has a very wide range of applications in medicine and chemical industry.In European Pharmacopoeia, 58% medicine can form polymorphic form, and 57% can form hydrate, and 20% can form other solvate.For the amino acid that has pseudo-polymorphic phenomenon, the research of the formation condition of its different crystal forms, mode of appearance and phase co-conversion, has important directive significance to its crystallization production process.

L-Phe has two kinds of crystal formations, is respectively its anhydride and monohydrate.L-Phe anhydride crystal is rhombic system, and outward appearance in the form of sheets; L-Phe monohydrate crystal is oblique system, and outward appearance is needle-like.Through measuring, we have obtained it, and to turn brilliant temperature be 37 ℃.At present only there is JP2009079014 about the patent of preparing L-Phe monohydrate, it discloses a kind of L-Phe anhydride brilliant in magma transfer is the method for monohydrate crystal: at 25 ℃, stir L-Phe anhydride magma, to its ultrasonic 45 min, turn crystalline substance as monohydrate to accelerate L-Phe anhydride with ultrasonic generator (wavelength is 20 kHz); After for some time, sampling, carries out microscopic examination to determine that whether turn crystalline substance complete.The method is ultrasonic due to L-Phe anhydride magma is carried out, and turning brilliant time shorten is 2 hours, but product yield is very low, is not enough to carry out suitability for industrialized production.

Summary of the invention

Main purpose of the present invention is to solve the technical deficiency of an existing hydration L-Phe crystallization production process, and the novel method of the high crystal formation purity of a kind of efficient preparation L-Phe monohydrate is provided.

In order to solve the problems of the technologies described above, the present invention is achieved by the following technical solutions:

(1), accurately weigh a certain amount of L-Phe dissolving crude product in the deionized water of 70 ℃, the thick product ︰ of L-Phe deionized water quality ratio is controlled at 1 ︰ 16.3-16.5, filtered while hot after dissolving completely;

(2), step (1) gained filtrate is transferred in the crystallizer of a cleaning, be warming up to a little more than temperature of saturation constant temperature 30 min;

(3) growing the grain 4 h, add fast another homo(io)thermism in the crystallizer of 5 ℃ the solution of step (2), and at this temperature;

(4), with the speed of 0.05 ℃/min, by the magma of step (3), be warming up to 8 ℃, growing the grain 2 h;

(5), with the speed of 0.05 ℃/min, by the magma of step (4), be cooled to 5 ℃, growing the grain 4 h;

(6), by step (5) gained magma decompress filter, with vacuum tightness 50 mbar vacuum-drying 24 h at washing with acetone, 30 ℃, obtain a hydration L-Phe crystal product.

Above-mentioned quench crystallization adopts high starting point concentration, and the concentration control in deionized water of 70 ℃ of L-Phes is 6.08-6.14 g/100 g water, its pH=7.2.

In described step (2), steady temperature, a little more than temperature of saturation, is eliminated the tiny nucleus producing in filtration and transfer process.

The Tc of above-mentioned quench crystallization is 5 ℃.

After above-mentioned quench crystallization, adopt temperature cycle method to eliminate thin crystalline substance, increase product granularity.

The said products drying temperature should be lower than 37 ℃ of the brilliant temperature of turning of a hydration L-Phe.

Beneficial effect of the present invention: the present invention adopts quench crystallization method and temperature cycle growing the grain method efficiently to prepare the L-Phe monohydrate of high crystal formation purity.Compared with prior art, the present invention has the following advantages: technique is simply efficient, and energy-conservation, environmental friendliness can be implemented immediately on large-scale industrial production device, has obvious economic benefit.

Accompanying drawing explanation

The microphotograph of Fig. 1 the inventive method example 1 one hydration L-Phe products.

The X-ray powder diffraction of Fig. 2 the inventive method example 1 one hydration L-Phe products.

The DSC figure of Fig. 3 the inventive method example 1 one hydration L-Phe products.

The TGA figure of Fig. 4 the inventive method example 1 one hydration L-Phe products.

The X-ray powder diffraction of Fig. 5 L-Phe anhydride crystal product.

Embodiment

By specific embodiment, the present invention is further described: accurately weigh in the deionized water that a certain amount of L-Phe anhydride is dissolved in 70 ℃, after dissolving completely, filtered while hot is to remove solid impurity; L-Phe solution after filtering is warming up to a little more than temperature of saturation, and constant temperature 30 min, until solution clarifies completely, without tiny nucleus; Settled solution is placed in the crystallizer of 5 ℃, quench crystallization, after temperature cycle method growing the grain 12 h, decompress filter, with washing with acetone 2 ~ 3 times, vacuum-drying 24 h at 30 ℃, obtain a hydration L-Phe product, under room temperature, store.

Embodiment 1:

Accurately take 5.131 g L-Phes and be dissolved in 84 g deionized waters, it is 70 ℃ that super constant temperature circulating actuator temperature is set, and filtered while hot after solute dissolves completely, removes solid impurity in solution.L-Phe solution after filtering is warming up to a little more than temperature of saturation, constant temperature 30 min, until solution clarification, tiny nucleus completely dissolve.Add fast another homo(io)thermism in the crystallizer of 5 ℃ settled solution, quench crystallization, and at this temperature growing the grain 4 h.Subsequently, with the speed of 0.05 ℃/min, be warming up to 8 ℃, growing the grain 2 h; Be cooled to 5 ℃ with the speed of 0.05 ℃/min again, growing the grain 4 h.Decompress filter, uses washing with acetone 2 ~ 3 times, and vacuum-drying at 30 ℃ (vacuum tightness 50 mbar) 24 h, obtain 3.641 g needle-like L-Phe monohydrate crystal products, and yield is 64.0%.DSC figure shows that the initial dehydration temperaturre of product is 70.73 ℃, and peak value is 87.87 ℃, and PXRD verifies as sterling.

Embodiment 2:

Accurately take 10.178 g L-Phes and be dissolved in 166 g deionized waters, it is 70 ℃ that super constant temperature circulating actuator temperature is set, and filtered while hot after solute dissolves completely, removes solid impurity in solution.L-Phe solution after filtering is warming up to a little more than temperature of saturation, constant temperature 30 min, until solution clarification, tiny nucleus completely dissolve.Add fast another homo(io)thermism in the crystallizer of 5 ℃ settled solution, quench crystallization, and at this temperature growing the grain 4 h.Subsequently, with the speed of 0.05 ℃/min, be warming up to 8 ℃, growing the grain 2 h; Be cooled to 5 ℃ with the speed of 0.05 ℃/min again, growing the grain 4 h.Decompress filter, uses washing with acetone 2 ~ 3 times, and vacuum-drying at 30 ℃ (vacuum tightness 50 mbar) 24 h, obtain 7.221 g needle-like L-Phe monohydrate crystal products, and yield is 64.0%.DSC figure shows that the initial dehydration temperaturre of product is 75.15 ℃, and peak value is 90.16 ℃, and PXRD verifies as sterling.

Embodiment 3:

Accurately take 9.796 g L-Phes and be dissolved in 161 g deionized waters, it is 70 ℃ that super constant temperature circulating actuator temperature is set, and filtered while hot after solute dissolves completely, removes solid impurity in solution.L-Phe solution after filtering is warming up to a little more than temperature of saturation, constant temperature 30 min, until solution clarification, tiny nucleus completely dissolve.Add fast another homo(io)thermism in the crystallizer of 5 ℃ settled solution, quench crystallization, and at this temperature growing the grain 4 h.Subsequently, with the speed of 0.05 ℃/min, be warming up to 8 ℃, growing the grain 2 h; Be cooled to 5 ℃ with the speed of 0.05 ℃/min again, growing the grain 4 h.Decompress filter, uses washing with acetone 2 ~ 3 times, and vacuum-drying at 30 ℃ (vacuum tightness 50 mbar) 24 h, obtain 7.214 g needle-like L-Phe monohydrate crystal products, and yield is 66.4%.DSC figure shows that the initial dehydration temperaturre of product is 73.89 ℃, and peak value is 88.45 ℃, and PXRD verifies as sterling.

Embodiment 4:

Accurately take 3.536 g L-Phes and be dissolved in 58 g deionized waters, it is 70 ℃ that super constant temperature circulating actuator temperature is set, and filtered while hot after solute dissolves completely, removes solid impurity in solution.L-Phe solution after filtering is warming up to a little more than temperature of saturation, constant temperature 30 min, until solution clarification, tiny nucleus completely dissolve.Add fast another homo(io)thermism in the crystallizer of 5 oC settled solution, quench crystallization, and at this temperature growing the grain 4 h.Subsequently, with the speed of 0.05 ℃/min, be warming up to 8 ℃, growing the grain 2 h; Be cooled to 5 ℃ with the speed of 0.05 ℃/min again, growing the grain 4 h.Decompress filter, uses washing with acetone 2 ~ 3 times, and vacuum-drying at 30 ℃ (vacuum tightness 50 mbar) 24 h, obtain 2.604 g needle-like L-Phe monohydrate crystal products, and yield is 66.4%.DSC figure shows that the initial dehydration temperaturre of product is 69.58 ℃, and peak value is 86.47 ℃, and PXRD verifies as sterling.

Above said content is only the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.

Claims (1)

1. prepare a crystallization method for a hydration L-Phe, it is characterized in that the method comprises the following steps:

(1), accurately weigh a certain amount of L-Phe dissolving crude product in the deionized water of 70 ℃, the concentration of L-Phe in deionized water is 6.08-6.14g/100g water, its pH=7.2, filtered while hot after dissolving completely;

(2), step (1) gained filtrate is transferred in the crystallizer of a cleaning, be warming up to a little more than temperature of saturation constant temperature 30 min;

(3) growing the grain 4 h, add fast another homo(io)thermism in the crystallizer of 5 ℃ the solution of step (2), and at this temperature;

(4), with the speed of 0.05 ℃/min, by the magma of step (3), be warming up to 8 ℃, growing the grain 2 h;

(5), with the speed of 0.05 ℃/min, by the magma of step (4), be cooled to 5 ℃, growing the grain 4 h;

(6), by step (5) gained magma decompress filter, with vacuum tightness 50 mbar vacuum-drying 24 h at washing with acetone, 30 ℃, obtain a hydration L-Phe crystal product.

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