CN102675239A - Method for preparing linezolid crystal form I - Google Patents

Method for preparing linezolid crystal form I Download PDF

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Publication number
CN102675239A
CN102675239A CN2012101835470A CN201210183547A CN102675239A CN 102675239 A CN102675239 A CN 102675239A CN 2012101835470 A CN2012101835470 A CN 2012101835470A CN 201210183547 A CN201210183547 A CN 201210183547A CN 102675239 A CN102675239 A CN 102675239A
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Prior art keywords
linezolid
crystal
solvent
crystal form
crystal formation
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安荣昌
董学军
王伟华
徐全文
庄大浪
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Kaiyuan Hengtai Pharma Co., Ltd.
Zhejiang Anglikang Pharmaceutical Co., Ltd.
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KAIYUAN HENGTAI PHARMA CO Ltd
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Abstract

The invention discloses a method for preparing a linezolid crystal form I, which comprises the following steps: suspending linezolid in a solvent, heating to 100-150 DEG C, presenting a backflow state and completely dissolving the linezolid; distilling the solvent off under constant pressure till a crystal is separated out; cooling to 0-30 DEG C and separating the crystal out; and filtering, washing and drying, thereby obtaining the linezolid crystal form I. The method provided by the invention has the advantages of convenience in operation, high yield, stable crystal, high purity of crystal form and being suitable for large-scale production.

Description

A kind of method for preparing linezolid crystal formation I
Technical field
The present invention relates to a kind of brand-new compound method for preparing linezolid crystal formation I, belong to technical field of medicine synthesis.
Background technology
Linezolid has another name called Linezolid, Lei Naizuoli, and molecular formula is C 16H 20FN 3O 4, CAS:165800-03-3, chemical name: (S)-and N-[[3-(3-fluoro-4-morpholinyl phenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide, have following formula (I) structure.Linezolid is the oxazolidine ketone microbiotic of synthetic, obtains drugs approved by FDA, and is used to treat the coccigenic infection of gram-positive (G+) in 2000.
Figure BDA00001730594700011
Linezolid has multiple crystal habit, mainly comprises following five kinds: document J.Med.Chem.39 (3), and 673 (1996) have reported linezolid crystal formation I; International monopoly WO 0157035 and U.S. Pat 6559305 have been reported the linezolid crystal form II; WO 2005/035530 has reported linezolid crystal form II I, and the while, with this crystal formation called after linezolid form IV, European patent EP 2033960 was reported the linezolid hydrate in patent patent WO 2007/026369; Chinese patent CN 102260222 has reported the linezolid crystal form V.
Document J.Med.Chem.39 (3); 673 (1996) have reported the preparation method of linezolid crystal formation I: the linezolid bullion behind column chromatography purification with ETHYLE ACETATE and normal hexane mixed solvent recrystallization; Obtain white crystal, yield 68.8%, 181.1 ~ 182.5 ℃ of fusing points.The yield of the linezolid crystal formation I that this method obtained is lower, is inappropriate for suitability for industrialized production.
Chinese patent CN 102070548 has reported a kind of evaporative crystallization technique for preparing linezolid crystal formation I, with alcoholic solvent linezolid is dissolved, and steams solvent 70 ~ 100 ℃ of decompressions, and cooling adds the solvent that evaporates, cooling crystallization again.Product yield is up to 90%, but this method need steam solvent earlier, adds solvent after the cooling more again, and operation is comparatively complicated.
Summary of the invention
To above-mentioned defective of the prior art, the invention discloses the novel method of a kind of linezolid crystal formation I.This method is easy and simple to handle, is fit to industrialized production, and product yield is high.
For realizing above-mentioned purpose, the present invention provides following technical scheme:
A kind of method for preparing linezolid crystal formation I comprises the steps:
1) linezolid is suspended in the solvent, is heated to 100 ~ 150 ℃, be reflux state, make its whole dissolvings; Preferably, Heating temperature is 110-120 ℃;
2) steam solvent under the normal pressure, to there being crystal to begin to separate out;
3) be cooled to 0 ~ 30 ℃, separate out crystal;
4) filtration, washing, drying.
Further, above-mentioned steps 1) return time in is 0.5 to 5 hour, preferred 1-3 hour.
Further, above-mentioned linezolid is suspended in the solvent of 3 ~ 12 times of weight, and preferred 4-8 doubly.
Further, above-mentioned solvent is that boiling point is higher than 100 ℃ high boiling solvent, preferred propyl carbinol, isopropylcarbinol and toluene.
Further, above-mentioned steps 4) in the washing employed be normal hexane.
The linezolid that in aforesaid method, uses is linezolid crystal form II, III, IV, V or linezolid mixing crystal formation.
The present invention has easy and simple to handle, and yield is high, crystalchecked, and crystal formation purity is high, is applicable to the advantage of scale operation.
Description of drawings
Fig. 1 is X-Ray powdery diffractometry (XRPD) spectrogram of linezolid crystal form II;
Fig. 2 is X-Ray powdery diffractometry (XRPD) spectrogram of prepared linezolid crystal formation I in the embodiment of the invention 1;
Fig. 3 is X-Ray powdery diffractometry (XRPD) spectrogram of prepared linezolid crystal formation I in the embodiment of the invention 2;
Fig. 4 is X-Ray powdery diffractometry (XRPD) spectrogram of obtained linezolid crystal formation I in the embodiment of the invention 3.
Embodiment
Through embodiment the present invention is done further detailed description below, the purpose of embodiment be the explanation and non-limiting.
The present invention mainly is the linezolid with existing different crystal forms, comprises monocrystalline type (crystal form II, crystal form II I, form IV, crystal form V) and contains the mixing crystal formation of two kinds and two or more crystal formations, changes into linezolid crystal formation I.The linezolid that existing market is sold mainly is a crystal form II, shown in X-Ray powdery diffractometry (XRPD) spectrogram among Fig. 1.Utilize the X-ray 2 θ angles of the linezolid crystal formation I that method provided by the invention obtains to locate to occur the peak at 7.30 ± 0.2 °, 13.14 ± 0.2 °, 17.92 ± 0.2 °, 20.95 ± 0.2 ° and 22.12 ± 0.2 ° at least; Preferably, the peak is also located to occur at 9.25 ± 0.2 °, 14.64 ± 0.2 °, 18.36 ± 0.2 ° and 25.35 ± 0.2 ° in X-ray 2 θ angles.
Embodiment 1:
In 100 milliliters single port bottle, add linezolid crystal form II (10g) and 50mL propyl carbinol, be heated to 120 ℃ to reflux state, be incubated 0.5 hour, air distillation goes out solvent to beginning have crystal to separate out.Stop heating, be cooled to room temperature, have a large amount of crystal to separate out.Filter, filter cake washs with normal hexane, obtains linezolid crystal formation I 9.3g after the drying, yield: 93%, and HPLC purity: 99.98%.X-Ray powdery diffractometry (XRPD) spectrogram is seen accompanying drawing 1.
Wherein, concrete data see table.
2-Theta:2 θ angle intensity: intensity
Figure BDA00001730594700041
spacing (dust) BG: background abbreviation
Hight: peak height I%: relative intensity
Area: peak area FWHM: peak width
# 2-Theta d(A) BG Height I% Area I% FWHM
1 7.284 12.1267 738 8557 15.64 82580 15.70 0.177
2 9.258 9.5442 922 3514 6.42 29729 5.65 0.192
3 13.403 6.6005 1356 28096 51.34 269922 51.33 0.169
4 14.645 6.0437 1403 6331 11.57 63846 12.14 0.217
5 15.278 5.7946 1501 3179 5.81 15873 3.02 0.159
6 16.221 5.4596 1405 2132 3.90 5015 0.95 0.116
7 16.703 5.3034 1364 3196 5.84 17138 3.26 0.157
8 17.903 4.9504 1636 11624 21.24 96258 18.30 0.162
9 18.359 4.8284 1559 5102 9.32 51431 9.78 0.229
10 18.652 4.7533 1758 4520 8.26 39059 7.43 0.223
11 19.757 4.4899 1763 5528 10.10 48406 9.20 0.216
12 20.944 4.2380 2364 18555 33.91 190052 36.14 0.197
13 21.515 4.1267 2636 4664 8.52 32249 6.13 0.267
14 22.107 4.0176 2457 54722 100.00 525907 100.00 0.169
15 25.345 3.5112 2032 17562 32.09 177766 33.80 0.192
16 26.708 3.3350 2036 3291 6.01 16848 3.20 0.225
17 27.613 3.2277 2072 6009 10.98 40294 7.66 0.172
18 28.266 3.1546 1909 5944 10.86 57823 10.99 0.240
19 29.570 3.0184 1759 4064 7.43 32077 6.10 0.233
20 33.044 2.7086 1420 2226 4.07 13175 2.51 0.258
Embodiment 2:
In 100 milliliters single port bottle, add linezolid crystal form II (10g) and 50mL toluene, heat 115 ℃ to reflux state, be incubated 1 hour, distilling off solvent is to beginning have crystal to separate out under the normal pressure.Stop heating, be cooled to room temperature, have a large amount of crystals to separate out.Filter, filter cake washs with normal hexane, obtains linezolid crystal formation I 9.1g after the drying, yield: 91%, and HPLC purity: 99.95%.X-Ray powdery diffractometry (XRPD) spectrogram is seen accompanying drawing 2.
Wherein, concrete data see table.
# 2-Theta d(A) BG Height I% Area I% FWHM
1 7.336 12.0402 768 9723 23.54 101834 21.78 0.191
2 9.296 9.5058 850 4985 12.07 62304 13.33 0.253
3 13.459 6.5731 1290 23111 55.95 296766 63.47 0.228
4 14.649 6.0421 1362 4875 11.80 44419 9.50 0.212
5 15.298 5.7871 1230 3305 8.00 33933 7.26 0.274
6 16.207 5.4644 1081 1889 4.57 9897 2.12 0.206
7 16.721 5.2977 1116 3923 9.50 33092 7.08 0.198
8 17.942 4.9396 1386 14790 35.81 178711 38.22 0.224
9 18.376 4.8240 1356 6945 16.81 94968 20.31 0.268
10 18.653 4.7529 1637 5322 12.88 64518 13.80 0.276
11 19.777 4.4853 1519 3564 8.63 28945 6.19 0.237
12 20.961 4.2346 2323 16813 40.70 195119 41.73 0.226
13 21.537 4.1226 2524 4288 10.38 33723 7.21 0.302
14 22.127 4.0140 2249 41305 100.00 467534 100.00 0.201
15 25.364 3.5086 1351 8810 21.33 116252 24.86 0.261
16 26.768 3.3277 1411 2156 5.22 9367 2.00 0.211
17 27.634 3.2253 1546 4376 10.59 31339 6.70 0.186
18 28.305 3.1503 1316 3686 8.92 41229 8.82 0.292
19 29.685 3.0070 1178 2295 5.56 16759 3.58 0.252
20 30.614 2.9179 1121 1808 4.38 6348 1.36 0.155
21 33.063 2.7071 1021 1896 4.59 14263 3.05 0.273
22 39.379 2.2862 698 1179 2.85 11253 2.41 0.369
Embodiment 3:
In 100 milliliters single port bottle, add linezolid bullion (10g) and 50mL toluene, be heated to 115 ℃ to reflux state, be incubated 1 hour, distilling off solvent is to beginning have crystal to separate out under the normal pressure.Stop heating, be cooled to room temperature, have a large amount of solids to separate out.Filter, filter cake washs with normal hexane, obtains linezolid crystal formation I 9.3g after the drying, yield: 93%, and HPLC purity: 99.97%.X-Ray powdery diffractometry (XRPD) spectrogram is seen accompanying drawing 3.
Wherein, concrete data see table.
# 2-Theta d(A) BG Height I% Area I% FWHM
1 7.302 12.0967 782 9253 27.22 97706 22.58 0.194
2 9.257 9.5454 836 4782 14.07 53231 12.30 0.226
3 13.401 6.6017 1307 27002 79.45 303615 70.17 0.198
4 14.647 6.0429 1379 4223 12.42 43720 10.10 0.258
5 15.220 5.8165 1324 2810 8.27 31342 7.24 0.354
6 16.204 5.4656 1109 2040 6.00 11412 2.64 0.206
7 16.700 5.3043 1153 5289 15.56 42183 9.75 0.171
8 17.901 4.9509 1461 14382 42.31 175969 40.67 0.228
9 18.339 4.8338 1368 8432 24.81 105542 24.39 0.236
10 18.615 4.7628 1671 5028 14.79 91407 21.13 0.430
11 19.683 4.5066 1541 3553 10.45 33994 7.86 0.283
12 20.960 4.2349 2487 18669 54.93 230058 53.17 0.239
13 21.496 4.1305 2608 4384 12.90 42681 9.86 0.379
14 22.125 4.0144 2290 33988 100.00 432671 100.00 0.229
15 25.344 3.5113 1492 9728 28.62 131361 30.36 0.268
16 26.706 3.3352 1502 2250 6.62 9549 2.21 0.214
17 27.577 3.2319 1650 4010 11.80 21809 5.04 0.155
18 28.302 3.1508 1426 4848 14.26 48884 11.30 0.240
19 29.570 3.0184 1280 2738 8.06 19264 4.45 0.222
20 30.557 2.9231 1240 1672 4.92 4707 1.09 0.183
21 32.273 2.7715 1100 1672 4.92 7460 1.72 0.219
22 33.023 2.7102 1122 1981 5.83 16141 3.73 0.315
23 39.415 2.2842 787 1320 3.88 10822 2.50 0.341

Claims (7)

1. the preparation method of a linezolid crystal formation I is characterized in that, comprises the steps:
1) linezolid is suspended in the solvent, is heated to 100 ~ 150 ℃, be reflux state, make its whole dissolvings;
2) steam solvent under the normal pressure, to there being crystal to begin to separate out;
3) be cooled to 0 ~ 30 ℃, separate out crystal;
4) filtration, washing, drying.
2. the method for claim 1 is characterized in that, the described return time of step 1) is 0.5-5 hour.
3. according to claim 1 or claim 2 method is characterized in that said linezolid is suspended in the solvent of 3 ~ 12 times of weight.
4. method as claimed in claim 3 is characterized in that, said solvent is to be higher than 100 ℃ high boiling solvent.
5. method as claimed in claim 4 is characterized in that, said solvent is propyl carbinol, isopropylcarbinol or toluene.
6. the method for claim 1 is characterized in that, what the said washing of step 4) was used is normal hexane.
7. the method for claim 1 is characterized in that, said linezolid is linezolid crystal form II and linezolid mixing crystal formation.
CN2012101835470A 2012-06-06 2012-06-06 Method for preparing linezolid crystal form I Pending CN102675239A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850290A (en) * 2012-10-10 2013-01-02 天津市炜杰科技有限公司 Preparation method of crystal form I linezolid
CN108117527A (en) * 2018-01-12 2018-06-05 上海龙翔生物医药开发有限公司 A kind of I preparation method of linezolid form suitable for industrialized production

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006110155A1 (en) * 2004-06-29 2006-10-19 Teva Pharmaceutical Industries Ltd Solid forms of linezolid and processes for preparation thereof
US20070015753A1 (en) * 2005-07-15 2007-01-18 Glenmark Pharmaceuticals Limited Process for the preparation of a crystalline form of (S)-N [[3-(3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide
CN102070548A (en) * 2011-01-13 2011-05-25 浙江新东港药业股份有限公司 Evaporation crystallization process for linezolid with crystal form I
WO2011077310A1 (en) * 2009-12-26 2011-06-30 Alembic Limited Process for the preparation of linezolid
CN102399200A (en) * 2011-12-14 2012-04-04 浙江新东港药业股份有限公司 Suspension crystallization method for preparing crystal form I of linezolid

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006110155A1 (en) * 2004-06-29 2006-10-19 Teva Pharmaceutical Industries Ltd Solid forms of linezolid and processes for preparation thereof
US20070015753A1 (en) * 2005-07-15 2007-01-18 Glenmark Pharmaceuticals Limited Process for the preparation of a crystalline form of (S)-N [[3-(3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide
WO2011077310A1 (en) * 2009-12-26 2011-06-30 Alembic Limited Process for the preparation of linezolid
CN102070548A (en) * 2011-01-13 2011-05-25 浙江新东港药业股份有限公司 Evaporation crystallization process for linezolid with crystal form I
CN102399200A (en) * 2011-12-14 2012-04-04 浙江新东港药业股份有限公司 Suspension crystallization method for preparing crystal form I of linezolid

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Title
STEVEN J. BRICKNER，等: "Synthesis and Antibacterial Activity of U-100592 and U-100766, Two Oxazolidinone Antibacterial Agents for the Potential Treatment of Multidrug-Resistant Gram-Positive Bacterial Infections", 《J. MED. CHEM.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850290A (en) * 2012-10-10 2013-01-02 天津市炜杰科技有限公司 Preparation method of crystal form I linezolid
CN108117527A (en) * 2018-01-12 2018-06-05 上海龙翔生物医药开发有限公司 A kind of I preparation method of linezolid form suitable for industrialized production

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