Preparation process of fosfomycin calcium salt

Abstract

The invention provides a fosfomycin calcium salt preparation process, and particularly relates to the field of medicines. The preparation method comprises the following steps: mixing water and ethanol to obtain a mixed solution, adding 200-220g of a fosfomycin intermediate into the mixed solution, adding 3-4g of talcum powder, heating to 80-85 DEG C, filtering to obtain a filter cake, washing the filter cake by using 20mL of ice ethanol, heating to 85 DEG C, and drying for 2 hours to obtain DL-salt; uniformly mixing 20-25g of sodium hydroxide and 70mL of purified water, adding 65-70g of DL-salt, heating to 60 DEG C, uniformly mixing, cooling to 45-50 DEG C, and standing for 1.5-2 hours to obtain a lower-layer separation solution; the preparation method comprises the following steps: uniformly mixing 35-40g of calcium chloride and 100mL of purified water, adding 3-4g of talcum powder, standing for 30 minutes, filtering, and adjusting the pH value to 4.8-5 to obtain a calcium chloride solution; and adding 600-650ml of purified water into the lower-layer separation liquid, heating to 65-70 DEG C, adding a calcium chloride solution, filtering, washing with distilled water until no washing liquid drips, and drying at 60-65 DEG C for 1 hour to obtain a finished product. The method is high in yield, simple in step and beneficial to improvement of production efficiency and reduction of production cost.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medicine, and particularly relates to a fosfomycin calcium salt preparation process. BACKGROUND

[0002] Fosfomycin calcium salt is generally prepared by taking levofosfomycin salt and dextrofosfomycin salt as starting materials, then preparing levofosfomycin calcium and dextrofosfomycin calcium respectively, and then mixing the two according to a specific ratio to obtain the target product.

[0003] Application No. CN201610425651.4 discloses a fosfomycin calcium preparation method, which comprises the following steps: (1) generating mixed spin fosfomycin; (2) pretreatment: mixing the mixed spin fosfomycin with benzeneethylamine salt, adding ethanol, stirring and heating to 90 DEG C, and then filtering to obtain a filter cake; drying the filter cake to obtain fine mixed spin fosfomycin benzeneethylamine salt; (3) adding sodium hydroxide aqueous solution, heating to 50 DEG C, and keeping the temperature for half an hour; allowing the mixture to stand to separate into two layers, the upper layer is benzeneethylamine solution, and the lower layer is mixed spin fosfomycin sodium salt solution; removing the benzeneethylamine solution, and reserving the mixed spin fosfomycin sodium salt solution; (4) adding calcium chloride aqueous solution, heating to 70 DEG C, and keeping the temperature for one hour; (5) washing and drying with pure water to obtain mixed spin fosfomycin calcium semi-finished product; and (6) additionally adding levofosfomycin calcium to mix the levofosfomycin calcium and dextrofosfomycin calcium to obtain fosfomycin calcium. This method still has the problem of complicated preparation process, because the target product is obtained by mixing levofosfomycin calcium and dextrofosfomycin calcium according to a specific ratio. SUMMARY

[0004] The application aims to provide a fosfomycin calcium salt preparation process, which has high yield, simple steps, and is beneficial to improving production efficiency and reducing production cost.

[0005] The application provides the following technical scheme:

[0006] A fosfomycin calcium salt preparation process, which comprises the following steps:

[0007] S1, mixing water and ethanol at a ratio of 1:9 and heating to 40-45 DEG C to obtain a mixed solution, adding 200-220 g of fosfomycin intermediate into the mixed solution, adding 3-4 g of talc, and heating to 80-85 DEG C to obtain a filter cake; when there is no mother liquor, rinsing the filter cake with 20 mL of ice ethanol until no washing liquid drops, and then heating to 85 DEG C and drying for 2 hours to obtain a mixed spin salt;

[0008] S2, mix 20-25g of sodium hydroxide with 70ml of purified water, add 65-70g of mixed salt, heat to 60°C and mix evenly, then cool to 45-50°C and stand for 1.5-2h, separate the lower layer solution, add 3-4g of talcum powder to the lower layer solution, stand for 30min, then filter to obtain the lower layer separated solution;

[0009] S3, mix 35-40g of calcium chloride with 100ml of purified water, add 3-4g of talcum powder, stand for 30min, filter, and adjust the pH to 4.8-5 to obtain a calcium chloride solution;

[0010] S4, add 600-650ml of purified water to the lower layer separated solution, heat to 65-70°C, add the calcium chloride solution at a uniform speed while stirring, after adding, stir for 10-15min, then stand for 30min, filter, wash with distilled water until no washing solution drops, and dry at 60-65°C for 1h to obtain the finished product.

[0011] Preferably, in the S1 step, mix 1000ml of water and ethanol 1:9 and heat to 43°C to obtain a mixed solution, add 210g of fosfomycin intermediate to the mixed solution, add 3.5g of talcum powder, and heat to 83°C.

[0012] Preferably, in the S2 step, mix 23g of sodium hydroxide with 70ml of purified water, add 68g of mixed salt, heat to 60°C and mix evenly, then cool to 48°C and stand for 1.8h, separate the lower layer solution, and add 3.5g of talcum powder to the lower layer solution.

[0013] Preferably, in the S3 step, mix 38g of calcium chloride with 100ml of purified water, add 3.5g of talcum powder, stand for 30min, filter, and adjust the pH to 4.9 to obtain a calcium chloride solution.

[0014] Preferably, in the S4 step, add 625ml of purified water to the lower layer separated solution, heat to 68°C, add the calcium chloride solution at a uniform speed while stirring, after adding, stir for 13min, then stand for 30min, filter, wash with distilled water until no washing solution drops, and dry at 63°C for 1h.

[0015] Preferably, the filtration is performed using a Buchner funnel.

[0016] Preferably, the drying is performed using ultrasonic drying.

[0017] Preferably, the stirring is performed using a magnetic stirrer.

[0018] Preferably, the stirring speed of the stirrer is 160rpm.

[0019] The beneficial effects of the present application are:

[0020] The application improves the yield of the calcium phosphomycin by controlling the pH and cooperating with other reaction conditions, and the calcium phosphomycin is obtained without mixing the left-handed calcium phosphomycin and the right-handed calcium phosphomycin in a specific ratio, thereby simplifying the process and reducing the production cost. DETAILED DESCRIPTION

[0021] Example 1

[0022] S1, 1000ml of water and ethanol were mixed in a ratio of 1:9 and heated to 40℃ to obtain a mixed solution, 200g of phosphomycin intermediate was added into the mixed solution, 3g of talcum powder was added, and heated to 80℃, filtered through a Buchner funnel to obtain a filter cake, when there was no mother liquor, the filter cake was washed with 20ml of ice ethanol until no washing liquid dropped, and then heated to 85℃ and dried by ultrasonic wave for 2 hours to obtain 179.1g of mixed salt;

[0023] S2, 20g of sodium hydroxide was uniformly mixed with 70ml of purified water, 65g of mixed salt was added, heated to 60℃ and uniformly mixed, then cooled to 45℃ and stood for 1.5h, the lower layer solution was separated, 3g of talcum powder was added to the lower layer solution, stood for 30 minutes, and then filtered through a Buchner funnel to obtain the lower layer separation solution;

[0024] S3, 35g of calcium chloride was uniformly mixed with 100ml of purified water, 3g of talcum powder was added, stood for 30 minutes, filtered through a Buchner funnel, and the pH was adjusted to 4.8 to obtain a calcium chloride solution;

[0025] S4, 600ml of purified water was added to the lower layer separation solution, heated to 65℃, and the calcium chloride solution was added at a uniform speed while stirring at a speed of 160r / min, after the addition was completed, the stirring was continued for 10 minutes, then stood for 30 minutes, filtered through a Buchner funnel, washed with distilled water until no washing liquid dropped, and dried by ultrasonic wave at 60℃ for 1h to obtain 48.3g of finished product with a HPLC of 98%.

[0026] Example 2

[0027] S1, 1000ml of water and ethanol were mixed in a ratio of 1:9 and heated to 43℃ to obtain a mixed solution, 210g of phosphomycin intermediate was added into the mixed solution, 3.5g of talcum powder was added, and heated to 83℃, filtered through a Buchner funnel to obtain a filter cake, when there was no mother liquor, the filter cake was washed with 20ml of ice ethanol until no washing liquid dropped, and then heated to 85℃ and dried by ultrasonic wave for 2 hours to obtain 190.1g of mixed salt;

[0028] S2, 23g of sodium hydroxide was uniformly mixed with 70ml of purified water, 68g of mixed salt was added, heated to 60℃ and uniformly mixed, then cooled to 48℃ and stood for 1.8h, the lower layer solution was separated, 3.5g of talcum powder was added to the lower layer solution, stood for 30 minutes, and then filtered through a Buchner funnel to obtain the lower layer separation solution;

[0029] S3, calcium chloride 38g is mixed with 100mL purified water, talcum powder 3.5g is added, and it is left to stand for 30 minutes, then filtered, and the pH is adjusted to 4.9 to obtain a calcium chloride solution;

[0030] S4, the lower layer separation solution is added with 625mL purified water, heated to 68℃, and the calcium chloride solution is added at a uniform speed while stirring, the magnetic stirrer is rotated at 160r / min, after the addition is completed, it is stirred for 13 minutes, then left to stand for 30 minutes, filtered through a Buchner funnel, washed with distilled water until no washing liquid drops, dried at 63℃ for 1h, and 50.2g of finished product is obtained, HPLC is 99%.

[0031] Example 3:

[0032] S1, 1000mL of water and ethanol 1:9 is mixed and heated to 45℃ to obtain a mixed solution, 220g of fosfomycin intermediate is added into the mixed solution, 4g of talcum powder is added, and heated to 85℃, filtered through a Buchner funnel to obtain a filter cake, when there is no mother liquor, the filter cake is washed with 20mL of ice ethanol until no washing liquid drops, and then heated to 85℃ and ultrasonic dried for 2h to obtain 197.9g of mixed salt;

[0033] S2, 25g of sodium hydroxide is mixed with 70mL of purified water, 70g of mixed salt is added, heated to 60℃ and mixed uniformly, then cooled to 50℃ and left to stand for 2h, the lower layer solution is separated, 4g of talcum powder is added to the lower layer solution, left to stand for 30 minutes, then filtered through a Buchner funnel to obtain the lower layer separation solution;

[0034] S3, 40g of calcium chloride is mixed with 100mL of purified water, 4g of talcum powder is added, left to stand for 30 minutes, filtered through a Buchner funnel, and the pH is adjusted to 5 to obtain a calcium chloride solution;

[0035] S4, the lower layer separation solution is added with 650mL of purified water, heated to 70℃, and the calcium chloride solution is added at a uniform speed while stirring, the magnetic stirrer is rotated at 160r / min, after the addition is completed, it is stirred for 15 minutes, then left to stand for 30 minutes, filtered through a Buchner funnel, washed with distilled water until no washing liquid drops, ultrasonic dried at 65℃ for 1h, and 49.1g of finished product is obtained, HPLC is 99%.

[0036] The above is only a preferred embodiment of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments or make equivalent replacements to some technical features. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of fosfomycin calcium salt, characterized by, The steps are as follows: S1, mix water and ethanol 1:9 to obtain a mixed solution, heat to 40-45℃, add phosphomycin intermediate 200-220g to the mixed solution, add talcum powder 3-4g, heat to 80-85℃, filter to obtain a filter cake, when there is no mother liquor, rinse the filter cake with 20mL ice ethanol until no washing liquid drops, then heat to 85℃ and dry for 2 hours to obtain a mixed salt; S2, mix sodium hydroxide 20-25g with 70mL purified water, add the mixed salt 65-70g, heat to 60℃ and mix uniformly, then cool to 45-50℃ and stand for 1.5-2h, separate the lower layer solution, add talcum powder 3-4g to the lower layer solution, stand for 30 minutes, then filter to obtain the lower layer separated solution; S3, mix calcium chloride 35-40g with 100mL purified water, add talcum powder 3-4g, stand for 30 minutes, filter, and adjust the pH to 4.8-5 to obtain a calcium chloride solution; S4, add purified water 600-650mL to the lower layer separated solution, heat to 65-70℃, add the calcium chloride solution at a uniform speed while stirring, after adding, stir for 10-15 minutes, then stand for 30 minutes, filter, wash with distilled water until no washing liquid drops, and dry at 60-65℃ for 1h to obtain the finished product.

2. The process for the preparation of fosfomycin calcium salt according to claim 1, characterized by the fact that: In S1 step, mix water and ethanol 1:9 to obtain a mixed solution, heat to 43℃, add phosphomycin intermediate 210g to the mixed solution, add talcum powder 3.5g, and heat to 83℃.

3. The process for the preparation of fosfomycin calcium salt according to claim 1, characterized by the fact that: In S2 step, mix sodium hydroxide 23g with 70mL purified water, add the mixed salt 68g, heat to 60℃ and mix uniformly, then cool to 48℃ and stand for 1.8h, separate the lower layer solution, add talcum powder 3.5g to the lower layer solution.

4. The process for preparing fosfomycin calcium salt according to claim 1, characterized by the fact that: In S3 step, mix calcium chloride 38g with 100mL purified water, add talcum powder 3.5g, stand for 30 minutes, filter, and adjust the pH to 4.9 to obtain a calcium chloride solution.

5. The process for the preparation of fosfomycin calcium salt according to claim 1, characterized by the fact that: In S4 step, add purified water 625mL to the lower layer separated solution, heat to 68℃, add the calcium chloride solution at a uniform speed while stirring, after adding, stir for 13 minutes, then stand for 30 minutes, filter, wash with distilled water until no washing liquid drops, and dry at 63℃ for 1h.

6. A process for the preparation of fosfomycin calcium salt according to any one of claims 1, 4, 5, characterized by: Filtering uses a Buchner funnel.

7. A process for the preparation of fosfomycin calcium salt according to any one of claims 1, 5, characterized by the fact that: Drying uses ultrasonic drying.

8. The process for the preparation of fosfomycin calcium salt according to claim 1, characterized by the fact that: Stirring uses a magnetic stirrer.

9. The process for the preparation of fosfomycin calcium salt according to claim 8, characterized by the fact that: The stirring speed of the stirrer is 160rpm.