Method for preparing phosphocholine chloride calcium salt tetrahydrate

Abstract

The invention discloses a method for preparing phosphocholine chloride calcium salt tetrahydrate, which comprises the steps of (1) subjecting a choline chloride crude product and a phosphorylating agent to phosphorylation reaction to obtain a phosphocholine chloride mixture; (2) subjecting the phosphocholine chloride mixture and a calcium-source aqueous solution to replacement reaction to obtain a metathetical mixture; (3) subjecting the metathetical mixture to reduced pressure distillation to separate out solids and obtain a solid-liquid mixture; (4) crystallizing, filtering and drying the solid-liquid mixture at -10 to -1 DEG C to obtain phosphocholine chloride calcium salt tetrahydrate. The phosphorylating agent is selected from phosphoric acid and / or polyphosphoric acid. The calcium-source aqueous solution is one or more selected from calcium chloride aqueous solution, calcium carbonate aqueous solution, calcium hydroxide aqueous solution and calcium bicarbonate aqueous solution. The method is mild in environment condition, high in yield and high in product purity.

Description

technical field

[0001] The invention relates to a preparation method of phosphorylcholine chloride calcium salt tetrahydrate. Background technique

[0002] Phosphoryl Choline Chloride Calcicam Salt (English full name: Phosphoryl Choline Chloride Calcicam Salt) is an important component of phospholipids and lecithin in organisms, and is the core raw material for the preparation of cytosine diphosphocholine (abbreviated as CDPC). The structural formula is as follows:

[0003]

[0004] According to the difference of crystal water, there are three structures, one does not contain crystal water, one contains one molecule of crystal water, and one contains four molecules of crystal water; usually, it is used for pharmaceutical raw materials and intermediates. Phosphorylcholine chloride calcium salt with tetramolecular water of crystallization. The quality specifications of phosphorylcholine chloride calcium salt tetrahydrate products are generally shown in the table below: ...

Examples

preparation example Construction

[0018] The invention provides a preparation method of phosphorylcholine chloride calcium salt tetrahydrate, the preparation method comprising:

[0019] 1) Phosphorylating the crude choline chloride product with a phosphorylating reagent to obtain a phosphorylcholine chloride mixture;

[0020] 2) performing a metathesis reaction on the phosphorylcholine chloride mixture and the calcium source aqueous solution to obtain a metathesis mixture;

[0021] 3) The metathesis mixture is subjected to vacuum distillation to separate out a solid to obtain a solid-liquid mixture;

[0022] 4) crystallizing, filtering and drying the solid-liquid mixture at -10°C to -1°C to obtain phosphorylcholine chloride calcium salt tetrahydrate;

[0023] Wherein, the phosphorylation reagent is selected from phosphoric acid and / or polyphosphoric acid; the calcium source aqueous solution is selected from one or more of calcium chloride aqueous solution, calcium carbonate aqueous solution, calcium hydroxide...

Embodiment 1

[0037] 1) At 25°C and -0.09MPa, slowly add 140g of phosphoric acid dropwise (the drop rate is 10 drops / s) to 100g of choline chloride crude product (containing 70% choline chloride), after the dropwise addition is completed The temperature was raised to 70°C for vacuum distillation until there was no distilled water, then the temperature was raised to 120°C and the pressure was controlled at -0.09MPa to react for 6h, and then 50g of water was added to terminate the reaction to obtain a phosphorylcholine chloride mixture;

[0038] 2) At 25° C., mix 100 g of the above-mentioned phosphorylcholine chloride mixture with 3000 g of calcium hydroxide aqueous solution (the mass fraction of calcium hydroxide is 15%) for 40 min until the pH of the system reaches 8 to obtain a metathesis mixture;

[0039] 3) At 25°C and 35Pa, the above-mentioned metathesis mixture was subjected to vacuum distillation until the solid was precipitated to obtain a solid-liquid mixture;

[0040] 4) Cool the a...

Embodiment 2

[0044] Carry out according to the method for implementing 1, change phosphoric acid into polyphosphoric acid when different.

[0045] The parameters of the infrared spectrum of the phosphorylcholine chloride calcium salt tetrahydrate are consistent with the standard infrared spectrum of the phosphorylcholine chloride calcium salt tetrahydrate; the elemental analysis results are consistent with the theoretical value.

[0046] In the present embodiment, the productive rate is 68%; wherein, step 4) obtains 100.2g phosphorylcholine chloride calcium salt tetrahydrate (purity is 100%); step 5) obtains 9.8g phosphorylcholine chloride calcium salt Salt tetrahydrate (99.5% pure).

technical field

[0001] The invention relates to a preparation method of phosphorylcholine chloride calcium salt tetrahydrate. Background technique

[0002] Phosphoryl Choline Chloride Calcicam Salt (English full name: Phosphoryl Choline Chloride Calcicam Salt) is an important component of phospholipids and lecithin in organisms, and is the core raw material for the preparation of cytosine diphosphocholine (abbreviated as CDPC). The structural formula is as follows:

[0003]

[0004] According to the difference of crystal water, there are three structures, one does not contain crystal water, one contains one molecule of crystal water, and one contains four molecules of crystal water; usually, it is used for pharmaceutical raw materials and intermediates. Phosphorylcholine chloride calcium salt with tetramolecular water of crystallization. The quality specifications of phosphorylcholine chloride calcium salt tetrahydrate products are generally shown in the table below: ...

Examples

preparation example Construction

[0018] The invention provides a preparation method of phosphorylcholine chloride calcium salt tetrahydrate, the preparation method comprising:

[0019] 1) Phosphorylating the crude choline chloride product with a phosphorylating reagent to obtain a phosphorylcholine chloride mixture;

[0020] 2) performing a metathesis reaction on the phosphorylcholine chloride mixture and the calcium source aqueous solution to obtain a metathesis mixture;

[0021] 3) The metathesis mixture is subjected to vacuum distillation to separate out a solid to obtain a solid-liquid mixture;

[0022] 4) crystallizing, filtering and drying the solid-liquid mixture at -10°C to -1°C to obtain phosphorylcholine chloride calcium salt tetrahydrate;

[0023] Wherein, the phosphorylation reagent is selected from phosphoric acid and / or polyphosphoric acid; the calcium source aqueous solution is selected from one or more of calcium chloride aqueous solution, calcium carbonate aqueous solution, calcium hydroxide...

Embodiment 1

[0037] 1) At 25°C and -0.09MPa, slowly add 140g of phosphoric acid dropwise (the drop rate is 10 drops / s) to 100g of choline chloride crude product (containing 70% choline chloride), after the dropwise addition is completed The temperature was raised to 70°C for vacuum distillation until there was no distilled water, then the temperature was raised to 120°C and the pressure was controlled at -0.09MPa to react for 6h, and then 50g of water was added to terminate the reaction to obtain a phosphorylcholine chloride mixture;

[0038] 2) At 25° C., mix 100 g of the above-mentioned phosphorylcholine chloride mixture with 3000 g of calcium hydroxide aqueous solution (the mass fraction of calcium hydroxide is 15%) for 40 min until the pH of the system reaches 8 to obtain a metathesis mixture;

[0039] 3) At 25°C and 35Pa, the above-mentioned metathesis mixture was subjected to vacuum distillation until the solid was precipitated to obtain a solid-liquid mixture;

[0040] 4) Cool the a...

Embodiment 2

[0044] Carry out according to the method for implementing 1, change phosphoric acid into polyphosphoric acid when different.

[0045] The parameters of the infrared spectrum of the phosphorylcholine chloride calcium salt tetrahydrate are consistent with the standard infrared spectrum of the phosphorylcholine chloride calcium salt tetrahydrate; the elemental analysis results are consistent with the theoretical value.

[0046] In the present embodiment, the productive rate is 68%; wherein, step 4) obtains 100.2g phosphorylcholine chloride calcium salt tetrahydrate (purity is 100%); step 5) obtains 9.8g phosphorylcholine chloride calcium salt Salt tetrahydrate (99.5% pure).

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