CN105254580B - The preparation method of linezolid form - Google Patents
The preparation method of linezolid form Download PDFInfo
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- CN105254580B CN105254580B CN201410164535.2A CN201410164535A CN105254580B CN 105254580 B CN105254580 B CN 105254580B CN 201410164535 A CN201410164535 A CN 201410164535A CN 105254580 B CN105254580 B CN 105254580B
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Abstract
The invention discloses a kind of preparation method of linezolid form.Specifically, the present invention relates to the preparation method that formula (1) compound (S) N [[the oxazole alkyl of 3 (3 fluorine 4 (4 morpholinyl) phenyl) 2 oxo 5] methyl] acetamide crystal formation III is linezolid form III, methods described includes Linezolid adding crystallization in double solvents, dry, obtain target crystal formation.Stable, the favorable repeatability by the property of crystal formation III produced by the present invention, is adapted to drug development.
Description
Technical field
The present invention relates to Linezolid (S)-N- [[3- (the fluoro- 4- of 3- (4- morpholinyls) phenyl) -2- oxo -5- oxazolidines
Base] methyl] acetamide crystal formation III preparation method.
Background technology
Linezolid (1inezolid, trade name Zyvox) be by Pharmacia ＆ Upjohn companies of the U.S. (after by brightness
Auspicious corporate buyout) development and production novel oxazolidinone class synthetic antibacterial drug, U.S. FDA ratifies the medicine on April 18th, 2000
Listing.This product is that the U.S. is approved for treating the medicine that methicillin resistance staphylococcus aureus infects for first over 40 years.
Patent report at present, Linezolid have 14 kinds of crystal formations.Pharmacia＆Upjohn exists in 1998-10-13
CN101353313A open Linezolid crystallizations for the first time, crystal formation I；CN1221547C (Pharmacia ＆ Upjohn) is reported
Crystal formation II；WO2005035530A1 (SYMED LABS LIMRRED) reports crystal formation III；WO2006110155A (Teva) is reported
Crystal formation V is to crystal formation XVIII, and amorphous crystal formation.
Wherein crystal formation II (crystal formation is declared by Yuan Yan companies) and crystal formation III possess preparation technology simple, crystal formation dissolubility and steady
It is qualitative good, it is well suited as pharmaceutical developments crystal formation.
The preparation method of the linezolid form III of document patent report often by the use of higher boiling reagent toluene as solvent, due to
Toluene is two class solvents, so toluene prepares solvent used as crystal formation in pharmaceutical developments certain risk.It is in addition, existing
Reaction process is complicated when having in technology that also to have using ethyl acetate be crystallization solvent, but preparing crystal formation III with the solvent, and needs
There are rigors to reaction conditions such as temperature, it is difficult to industrial applications.
The content of the invention
It is an object of the invention to solve above-mentioned technical problem, there is provided structure is the system of the linezolid form III of formula (1)
Preparation Method, including Linezolid is added into crystallization in double solvents, dry, obtain target crystal formation.
Preferably, the double solvents is selected from ethyl acetate, butyl acetate or isopropyl acetate and normal heptane, n-hexane,
The combination of isohexane, hexamethylene, isopentane, normal octane or isooctane.
It is further preferred that the double solvents is selected from following combination：Ethyl acetate/normal heptane, ethyl acetate/just oneself
Alkane, ethyl acetate/normal octane or ethyl acetate/isooctane.
Preferably, the volume ratio of each solvent is 1 in the double solvents:0.5~1：10.
It is furthermore preferred that the volume ratio of each solvent is 1 in the double solvents:1~1:5.
It is further preferred that the volume ratio of each solvent is 1 in the double solvents:1~1:3, particularly preferred 1:1.
Preferably, the temperature of crystallization is room temperature to 80 DEG C in the preparation method.
It is furthermore preferred that recrystallization temperature is 30~60 DEG C.
It is further preferred that recrystallization temperature is 40~55 DEG C, particularly preferred 50 DEG C.
Applicant is through many experiments it has surprisingly been found that preparing crystal formation III by double solvents and can obtain and make us unexpected
Technique effect, gained crystal formation III has very big improvement on product yield and purity, greatly reduces production cost,
And the quality of production of bulk drug is improved, moreover, production technology enormously simplify by double solvents, and need not be especially low
Cooling or higher reaction temperature so that the preparation technology of the invention is more suitable for industrialized production and application.In addition, hair
A person of good sense is investigated, and the properties such as dissolubility, the stability of crystal formation are made by the inventive method, as a result show, are made by the present invention
The property of crystal formation III obtained is stable, favorable repeatability, is adapted to drug development.
Brief description of the drawings
Fig. 1 is the x-ray diffraction pattern of formula (1) compound linezolid form III.
Embodiment
Present disclosure will be specifically described by drawings and examples below, but the protection content of the present invention not limits
Due to specific embodiment.
Embodiment 1 prepares the crystal formation III of Linezolid using ethyl acetate/normal heptane
Compound 1 (500g, 1.48mol) is added in ethyl acetate (15L), dissolves by heating, then pours into solution just
Cooling and stirring 1h crystallizations in heptane (15L).Filter, be dried under reduced pressure at 50 DEG C of gained solid to constant weight.Target product (468g,
Off-white powder), yield 93.6%, HPLC:99.8%.After testing, its XRPD collection of illustrative plates is as shown in Figure 1.
The linezolid form III preparation condition screening tests of embodiment 2
Inventor has carried out conditional filtering experiment further directed to crystal formation III optimum preparating condition, except solvent in following table
Species is distinct outer, and remaining experimental condition is same as Example 1, after the completion of experiment, crystal formation III yield and product purity
As a result it is as shown in the table：
| Solvent | Yield/% | HPLC/% |
| Ethyl acetate/normal heptane | 93.6 | 99.8 |
| Ethyl acetate/n-hexane | 89.4 | 99.5 |
| Ethyl acetate/isohexane | 88.6 | 99.3 |
| Ethyl acetate/hexamethylene | 84.8 | 95.9 |
| Ethyl acetate/pentane | 88.1 | 98.7 |
| Ethyl acetate/isopentane | 87.4 | 98.2 |
| Ethyl acetate/normal octane | 91.5 | 99.0 |
| Ethyl acetate/isooctane | 90.2 | 99.1 |
| Isopropyl acetate/normal heptane | 86.6 | 97.7 |
| Butyl acetate/normal heptane | 88.4 | 97.1 |
| Ethyl acetate | 74.9 | 77.1 |
| Toluene | 67.2 | 88.6 |
From preparation condition screening as can be seen that double solvents is superior to single solvent crystallization on product yield and purity.
The stability experiment of experimental example 1
INSTRUMENT MODEL：D/Max-RA Japan RigakuX- ray powder diffractometers
Ray：Monochromatic Cu-K alpha rays
Scan mode：The θ of θ/2, scanning range：3-45 °
Temperature range：294K voltages：40KV
X-ray diffraction data comparison is shown in Table 1.
The X-ray diffraction data comparison table of the accelerated stability laboratory sample of table 1
Experiment conclusion：After 6 months Acceleration studies, x-ray diffraction pattern is consistent with primary data, does not occur to turn brilliant existing
As showing that stability of crystal form provided by the present invention is good.
The stability experiment of experimental example 2
Table 2
Experiment conclusion：Stability of crystal form provided by the present invention is good.
Claims (1)
1. a kind of method of formula (1) compound crystal form III,
Including Linezolid is added into crystallization in double solvents, dry, obtain target crystal formation, it is characterised in that the double solvents
The volume ratio of combination selected from ethyl acetate and normal heptane, ethyl acetate and normal heptane is 1:1, recrystallization temperature is 40~55 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410164535.2A CN105254580B (en) | 2014-04-22 | 2014-04-22 | The preparation method of linezolid form |
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| CN201410164535.2A CN105254580B (en) | 2014-04-22 | 2014-04-22 | The preparation method of linezolid form |
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| CN105254580A CN105254580A (en) | 2016-01-20 |
| CN105254580B true CN105254580B (en) | 2018-01-02 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005035530A1 (en) * | 2003-10-16 | 2005-04-21 | Symed Labs Limited | A novel crystalline form of linezolid |
| CN101948442A (en) * | 2009-07-10 | 2011-01-19 | 符健 | Preparation method of linezolid and preparation thereof |
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2014
- 2014-04-22 CN CN201410164535.2A patent/CN105254580B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005035530A1 (en) * | 2003-10-16 | 2005-04-21 | Symed Labs Limited | A novel crystalline form of linezolid |
| CN101948442A (en) * | 2009-07-10 | 2011-01-19 | 符健 | Preparation method of linezolid and preparation thereof |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20160323 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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