CN105061323A - Refining method of ornidazole compound - Google Patents

Refining method of ornidazole compound Download PDF

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Publication number
CN105061323A
CN105061323A CN201510458320.6A CN201510458320A CN105061323A CN 105061323 A CN105061323 A CN 105061323A CN 201510458320 A CN201510458320 A CN 201510458320A CN 105061323 A CN105061323 A CN 105061323A
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China
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deg
ornidazole
impurity
characterized
hydrochloric acid
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CN201510458320.6A
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Chinese (zh)
Inventor
张在富
吴浩山
许馨文
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珠海亿邦制药股份有限公司
亿邦国创药物研究院(北京)有限公司
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Priority to CN201510458320.6A priority Critical patent/CN105061323A/en
Publication of CN105061323A publication Critical patent/CN105061323A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91Nitro radicals
    • C07D233/92Nitro radicals attached in position 4 or 5
    • C07D233/94Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members

Abstract

The invention discloses a refining method of an ornidazole compound. The refining method is characterized by comprising the following steps: dissolving ornidazole into ethanol, wherein the ratio of ornidazole mass to ethanol volume is 1:1-3 g/mL; adding a proper amount of hydrochloric acid, wherein the mole ratio of hydrochloric acid to ornidazole is 0.25-1:100; heating to a temperature of 40 to 85 DEG C to dissolve ornidazole, carrying out ring-opening reactions for 15 minutes to 18 hours to remove impurity (3), cooling to a temperature of -15 to -5 DEG C to dissolve out crystals, filtering, and drying the crystals at a temperature of 25 to 45 DEG C so as to obtain refined product of ornidazole.

Description

A kind of process for purification of ornidazole compound

Technical field

The invention belongs to medical art, be specifically related to the process for purification of ornidazole compound.

Background technology

Ornidazole (ornidazole, CAS16773-42-5) be after metronidazole and tinidazole, in 1977 by Roche Holding Ag of Switzerland first Germany go on the market anerobe and anti-trichomonal medicine, it plays mechanism of anti-microbial effect: in oxygen-free environment, be reduced into amino by the nitro in its molecule or interacted by the formation of free radical and cellular constituent, thus causing the death of microorganism; Ornidazole is used for the treatment of and bites the multi-infection disease of knitting caused by the dimension responsive anerobe such as bacterium, gum genera bacillus by bacteroides fragilis, bacteroides disiens, ovum garden bacterioide, multirow bacterioide, bacteroides vulgatus, clostridium, Eubacterium, dyspepsiacoccus and peptostreptococcus, helicobacter pylori, bacaeroides melaninogenicus, fusobacterium, co2 clinically.

In " research of nitroimidazoles medicine impurity " of people's works such as document He Jiajia, the impurity mentioned in ornidazole raw material commercially available at present mainly contains 3 kinds, and ornidazole and impurity structure are respectively:

Ornidazole: 1-(the chloro-2-hydroxypropyl of 3-)-2-methyl-5-nitre imidazoles, structural formula is shown in formula I;

Impurity 1:2-5-nitro imidazole, structural formula is shown in formula II;

Impurity 2:3-(2-5-nitro imidazole-1-base)-1,2-PD, structural formula is shown in formula III;

Impurity 3:1-(2,3-epoxypropyl)-2-methyl-5-nitre imidazoles, structural formula is shown in formula IV.

Mention epoxy construction in " caution structure of genetoxic impurity " of " Chinese new drug impurity " the 23rd volume the 18th phase report in 2014 and there is potential genetoxic.Though ornidazole impurity 3 is not mentioned in standards of pharmacopoeia, because it has epoxy construction, there is potential genetoxic, caused now great attention in the industry.

In prior art, usual toluene or re-crystallizing in ethyl acetate carry out refining ornidazole compound, although the content of impurity 1,2 meets standards of pharmacopoeia in ornidazole sterling obtained by the method, the content of impurity 3 is not well controlled.Relative to common impurities, the safe threshold of legacy toxic impurities is lower, namely may produce carcinogenic risk at very low concentrations, therefore stricter to its control overflow.Therefore be necessary the process for purification inventing a kind of ornidazole compound, the content of ornidazole impurity 1 and impurity 2 can control within pharmacopoeial requirements by the method, ornidazole impurity 3 can also be carried out stricter control simultaneously.

Summary of the invention

In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of process for purification of ornidazole compound, the method is simple, and product purity is high, and yield is high, and key the content of ornidazole impurity 3 can be controlled within 1ppm.

Process for purification provided by the invention for ornidazole be ornidazole crude product obtained by known at present synthetic method or commercially available ornidazole bulk drug, be below referred to as the ornidazole crude product that the present invention adopts.

Specifically, for realizing object of the present invention, following technical scheme is adopted:

The process for purification of ornidazole, it comprises the following steps: be dissolved in by ornidazole in polyvalent alcohol, adds appropriate halogenated acid, heating for dissolving, impurity 3 open loop is reacted, cooling crystallization after reaction, filters, dry ornidazole highly finished product,

Wherein impurity 3 ring-opening reaction is specially:

Preferred process for purification is further: be dissolved in by ornidazole in ethanol, the mass volume ratio of ornidazole and ethanol is 1: 1 ~ 3g/ml, add appropriate hydrochloric acid, wherein the mol ratio of hydrochloric acid and ornidazole is: 0.25 ~ 1: 100, heats 40 DEG C ~ 85 DEG C dissolvings, impurity 3 open loop is reacted, reaction times is 15 minutes to 18 hours,-15 DEG C ~-5 DEG C cooling crystallizations, filter, 25 DEG C ~ 50 DEG C dry ornidazole highly finished product.

Preferred process for purification is: be dissolved in by ornidazole in ethanol, the mass volume ratio of ornidazole and ethanol is 1: 2g/ml, add appropriate hydrochloric acid, the wherein mol ratio of hydrochloric acid and ornidazole: 0.5: 100, heats 80 DEG C ~ 85 DEG C dissolvings, impurity 3 open loop is reacted, react 6 hours,-10 DEG C ~-8 DEG C cooling crystallizations, filter, 25 DEG C ~ 35 DEG C dry ornidazole highly finished product.

Beneficial effect of the present invention is:

The present invention is adding appropriate hydrochloric acid with in the process of ethyl alcohol recrystallization, and hydrochloric acid can make impurity 3 open loop obtain ornidazole, obviously can reduce the content of impurity 3.The present invention simultaneously, by controlling the usage quantity of recrystallization solvent, obviously can reduce the content of impurity 1.

The present invention also has applicable industrialized mass, simple to operate, quality controllable, low cost and other advantages.

Embodiment

The following examples will be explained more specifically to the present invention, but the present invention is not limited only to these embodiments, and these embodiments do not limit the present invention in any way yet equally.

Embodiment 1

In 250ml four-hole bottle, add 100ml Virahol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.10ml (11.8N, 0.94 × 10 -3mol, 4.14 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain ornidazole 46.2g, yield 92.4%.

Embodiment 2

In 250ml four-hole bottle, add 50ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.10ml (11.8N, 1.18 × 10 -3mol, 5.18 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-8 ~-10 DEG C of crystallizations, filter, 35 DEG C of dryings, obtain ornidazole 45.8g, yield 91.6%.

Embodiment 3

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mo1), add concentrated hydrochloric acid 0.10ml (11.8N, 1.18 × 10 -3mol, 5.18 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain ornidazole 47.1g, yield 94.2%.

Embodiment 4

In 250ml four-hole bottle, add 150ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.10ml (11.8N, 1.18 × 10 -3mol, 5.18 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain ornidazole 45.4g, yield 90.8%.

Embodiment 5

In 500ml four-hole bottle, add 200ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.10ml (11.8N, 1.18 × 10 -3mol, 5.18 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain ornidazole 45.0g, yield 90.0%.

Embodiment 6

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.05ml (11.8N, 0.59 × 10 -3mol, 2.59 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-8 ~-10 DEG C of crystallizations, filter, 35 DEG C of dryings, obtain ornidazole 46.5g, yield 93.0%.

Embodiment 7

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.1ml (11.8N, 1.18 × 10 -3mol, 5.18 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 46.3g, yield 92.6%.

Embodiment 8

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.15ml (11.8N, 1.77 × 10 -3mol, 7.67 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 47.2g, yield 94.4%.

Embodiment 9

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.20ml (11.8N, 2.36 × 10 -3mol, 10.35 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 46.7g, yield 93.4%.

Embodiment 10

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), add concentrated hydrochloric acid 0.25ml (11.8N, 2.95 × 10 -3mol, 12.94 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 44.8g, yield 89.6%.

Embodiment 11

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 300ppm, 0.228mol), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 45.8g, yield 91.6%.

Embodiment 12

In 250ml four-hole bottle, add 100ml dehydrated alcohol, add 50.0g ornidazole crude product (epoxy: 650ppm, 0.228mol), add concentrated hydrochloric acid 0.10ml (11.8N, 1.18 × 10 -3mol, 5.18 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 46.1g, yield 92.2%.

Embodiment 13

In 5L four-hole bottle, add 2L dehydrated alcohol, add 1Kg ornidazole crude product (epoxy: 650ppm, 4.566mol), add concentrated hydrochloric acid 2.0ml (11.8N, 2.36 × 10 -2mol, 5.17 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 DEG C ~-8 DEG C crystallizations, filter, 35 DEG C of dryings, obtain 0.936Kg, yield 93.6%.

Table 1: embodiment 1 ~ 12 ornidazole refines rear impurity 1 and impurity 3 comparision contents

Embodiment 14

In 5L four-hole bottle, add 2L dehydrated alcohol, add 1Kg ornidazole crude product (epoxy: 650ppm, 4.566mol), add concentrated hydrochloric acid 2.0ml (11.8N, 2.36 × 10 -2mol, 5.17 × 10 -3eq), be heated to 80 DEG C, react 6 hours, be cooled to-10 ~-8 DEG C of crystallizations, filter, obtain 1.26Kg and to wet product.

By some for production sharing parts, carry out drying experiment.

Table 2: ornidazole refines rear wet product drying temperature and time to the impact (forced air drying) of impurity 3

Table 3: ornidazole refines rear wet product drying temperature and time to the impact (vacuum-drying) of impurity 3

Note: from the data of table 2 and table 3, when drying temperature is 60 DEG C, when time of drying is more than 24h, the content of epoxy impurity 3 can more than 1ppm; When drying temperature is 50 DEG C, if when time of drying is more than 48h, the content of impurity 3 has the risk more than 1ppm.

Claims (7)

1. a process for purification for ornidazole compound, is characterized in that: be dissolved in by ornidazole in polyvalent alcohol, adds appropriate halogenated acid, heating for dissolving, impurity 3 open loop is reacted, cooling crystallization after reaction, filters, dry ornidazole highly finished product,
Wherein impurity 3 ring-opening reaction is specially:
2. process for purification according to claim 1, it is characterized in that: ornidazole is dissolved in ethanol, the mass volume ratio of ornidazole and ethanol is 1: 1 ~ 3g/ml, adds appropriate hydrochloric acid, and wherein the mol ratio of hydrochloric acid and ornidazole is: 0.25 ~ 1: 100, heat 40 DEG C ~ 85 DEG C dissolvings, impurity 3 open loop reacted, the reaction times is 15 minutes to 18 hours ,-15 DEG C ~-5 DEG C cooling crystallizations, filter, 25 DEG C ~ 50 DEG C dry ornidazole highly finished product.
3. method according to claim 2, is characterized in that the mass volume ratio of described ornidazole and ethanol is: 1: 2g/ml.
4. method according to claim 2, is characterized in that the mol ratio of described hydrochloric acid and ornidazole is: 0.5: 100.
5. method according to claim 2, is characterized in that described heating for dissolving temperature is 80 DEG C ~ 85 DEG C.
6. method according to claim 2, is characterized in that the temperature of described cooling crystallization is-10 DEG C ~-8 DEG C.
7. method according to claim 2, is characterized in that described drying temperature is 25 DEG C ~ 35 DEG C.
CN201510458320.6A 2015-07-31 2015-07-31 Refining method of ornidazole compound CN105061323A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435049A (en) * 1965-05-19 1969-03-25 Hoffmann La Roche Nitroimidazole derivatives
US3519637A (en) * 1966-12-06 1970-07-07 Hoffmann La Roche 1-(4-thiazolylmethyl)nitroimidazole derivatives
CN102643238A (en) * 2012-04-06 2012-08-22 陕西合成药业有限公司 Preparation and purification method for new ornidazole optical antimer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435049A (en) * 1965-05-19 1969-03-25 Hoffmann La Roche Nitroimidazole derivatives
US3519637A (en) * 1966-12-06 1970-07-07 Hoffmann La Roche 1-(4-thiazolylmethyl)nitroimidazole derivatives
CN102643238A (en) * 2012-04-06 2012-08-22 陕西合成药业有限公司 Preparation and purification method for new ornidazole optical antimer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
何佳佳: "硝基咪唑类药物杂质研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 *

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