CN103910673A - Crystallization methods for 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride - Google Patents
Crystallization methods for 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride Download PDFInfo
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- CN103910673A CN103910673A CN201410069812.1A CN201410069812A CN103910673A CN 103910673 A CN103910673 A CN 103910673A CN 201410069812 A CN201410069812 A CN 201410069812A CN 103910673 A CN103910673 A CN 103910673A
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- chloromethyl
- dimethyl
- methoxypyridine hydrochloride
- acetone
- ethanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses crystallization methods for 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, which belongs to the technical field of synthesis of drug intermediates. A monocrystalline crystallization method comprises the following steps: dissolving a crude 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride product with a mixed solution of ethanol and acetone and then carrying out dilution; and carrying out filtering so as to remove impurities, placing an obtained filtrate in room temperature and carrying out slow volatilization and crystallization for 48 h so as to obtain monocrystalline 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride. A polycrystalline crystallization method comprises the following steps: subjecting the crude 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride product to heating reflux with a mixed solution of ethanol and acetone until the crude product is completely dissolved; and carrying out filtering as the dissolved crude product is still hot so as to remove impurities and then carrying out slow cooling so as to obtain polycrystalline 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride. The methods provided by the invention are simple and convenient, enable yield to be stable and facilitate development and preparation of high-purity monocrystalline/polycrystalline omeprazole.
Description
Invention field
The invention belongs to pharmaceutical intermediate synthesis technical field, be specifically related to 2-chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride.
Background technology
Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is the important intermediate of synthetic omeprazole and esomeprazole, up to the present, omeprazole has been found to have three kinds of crystal formations: A type, Type B and C type, Type B omeprazole the earliest by people such as Ohishi H at Acta Crystallography, 1989, C45, sets forth in 1921-1923; Patent WO 99/08500 discloses preparation method and the characterization data of A type omeprazole subsequently, and has compared in detail the difference of itself and Type B; And then patent WO 2002/085889 has found again C type omeprazole, and its preparation method is simpler than A type and Type B, and yield is higher.Three kinds of crystal formations obtain with different post processing modes respectively, and due to the unstable of omeprazole, qualitative change easily occurs in too much aftertreatment.
Summary of the invention
The invention provides 2-chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, object is to obtain 2-chloromethyl-3 of monocrystalline state and polycrystalline state, and 5-dimethyl-4-methoxypyridine hydrochloride, for the synthesis of the omeprazole pyridine intermediate of different shape.
2-provided by the present invention chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride is specific as follows:
By 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride crude product dissolves and dilutes with the mixing solutions of ethanol and acetone, after elimination impurity, be statically placed in the crystallization that slowly volatilizees under room temperature, after 48h, obtain 2-chloromethyl-3 of monocrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride.The volume ratio of described ethanol and acetone is (0.5 ~ 2): 1, and preferably 1:1; The consumption of described ethanol and acetone mixed solution is every gram of described 2-chloromethyl-3 of 20 ~ 10 mL/, 5-dimethyl-4-methoxypyridine hydrochloride crude product, preferably 15 mL.
Another kind of 2-provided by the present invention chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride is specific as follows:
By 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride crude product is complete to dissolving by the mixing solutions reflux of ethanol and acetone, after elimination impurity, Slow cooling has solid to separate out for ten minutes while hot, obtains 2-chloromethyl-3 of polycrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride.The volume ratio of described ethanol and acetone is (0.5 ~ 2): 1, and preferably 1:1; The consumption of described ethanol and acetone mixed solution is every gram of described 2-chloromethyl-3 of 3 ~ 10 mL/, 5-dimethyl-4-methoxypyridine hydrochloride crude product, preferably 5 mL.
2-chloromethyl-3 prepared by the inventive method, 5-dimethyl-4-methoxypyridine hydrochloride has monocrystalline state and two kinds of forms of polycrystalline state, while synthesizing omeprazole respectively by these two kinds of forms, the form of product is also different: during with the synthetic omeprazole of monocrystalline state intermediate, the omeprazole of formation has single form; And during with the synthetic omeprazole of polycrystalline state, what be easy to form is the form that A type, Type B and C type three mix.
The present invention prepares two kinds of form 2-chloromethyl-3, and the method for 5-dimethyl-4-methoxypyridine hydrochloride is simple and convenient, and stable yield is conducive to the omeprazole that the single crystalline state of high purity is prepared in exploitation.
Brief description of the drawings
Fig. 1 is single 2-chloromethyl-3, and 5-dimethyl-4-methoxypyridine hydrochloride molecule passes through
hydrogen bond form a dimeric structure schematic diagram;
Fig. 2 is 2-chloromethyl-3, the unit cell packed structures schematic diagram that 5-dimethyl-4-methoxypyridine hydrochloride two dimeric molecules form.
Fig. 3 is 2-chloromethyl-3 of polycrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride X-ray diffraction (XRD) collection of illustrative plates.
Embodiment
Get 1.00 g 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, complete with the equal-volume mixed solution dissolving of 15 mL ethanol and acetone, elimination impurity, being statically placed in particular room slowly volatilizees, after 48 h, obtain 2-chloromethyl-3 of monocrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride 0.43g, yield 43%.The crystal of crystallization is oblique system, and spacer is
p2
1/
c, the cell parameter of crystal:
a=6.074 (11),
b=19.88 (4),
c=9.230 (16),
=99.67 (4)
,
v=1098 (3)
3,
z=4,
m r =221.10,
d c =1.343 g/cm
3,
(Mo
k )=0.553 mm
,
f(000)=464,
s=0.988.Individual molecule passes through
hydrogen bond form a dimeric structure, as Fig. 1, Fig. 2 be two dimeric molecules form unit cell accumulation graph.
Table 1
Get 1.00 g 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, complete with the ethanol of 5 mL heat and the dissolving of the equal-volume mixed solution of acetone, elimination impurity while hot, cooling 2-chloromethyl-3 of separating out polycrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride 0.92g, yield 92%, Fig. 3 is shown in by X-ray diffraction (XRD) collection of illustrative plates.From x-ray diffraction pattern, extract peak (the d-value and the peak intensity that calculate by Bragg formula are identified), these peaks are as shown in table 1, and with following definition to replace the concrete numerical value of relative intensity: the very strong vs of 25-100(); 10-25(is strong s); In 5-10(strong m); 1-5(is weak w).
Claims (6)
1.2-chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, it is characterized in that the method is specific as follows: by 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride crude product dissolves and dilutes with the mixing solutions of ethanol and acetone, after elimination impurity, be statically placed in the crystallization that slowly volatilizees under room temperature, after 48h, obtain 2-chloromethyl-3 of monocrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride; The volume ratio of described ethanol and acetone is (0.5 ~ 2): 1; The consumption of described ethanol and acetone mixed solution is every gram of described 2-chloromethyl-3 of 20 ~ 10 mL/, 5-dimethyl-4-methoxypyridine hydrochloride crude product.
2. 2-according to claim 1 chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, the volume ratio that it is characterized in that described ethanol and acetone is 1:1.
3. 2-according to claim 1 chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, the consumption that it is characterized in that described ethanol and acetone mixed solution is every gram of described 2-chloromethyl-3 of 15 mL/, 5-dimethyl-4-methoxypyridine hydrochloride crude product.
4.2-chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, it is characterized in that the method is specific as follows: by 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride crude product is complete to dissolving by the mixing solutions reflux of ethanol and acetone, after elimination impurity, Slow cooling has solid to separate out for ten minutes while hot, obtain 2-chloromethyl-3 of polycrystalline state, 5-dimethyl-4-methoxypyridine hydrochloride; The volume ratio of described ethanol and acetone is (0.5 ~ 2): 1; The consumption of described ethanol and acetone mixed solution is every gram of described 2-chloromethyl-3 of 3 ~ 10 mL/, 5-dimethyl-4-methoxypyridine hydrochloride crude product.
5. 2-according to claim 4 chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, the volume ratio that it is characterized in that described ethanol and acetone is 1:1.
6. 2-according to claim 4 chloromethyl-3, the crystallization treatment process of 5-dimethyl-4-methoxypyridine hydrochloride, the consumption that it is characterized in that described ethanol and acetone mixed solution is every gram of described 2-chloromethyl-3 of 5 mL/, 5-dimethyl-4-methoxypyridine hydrochloride crude product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101648907A (en) * | 2009-09-14 | 2010-02-17 | 南京第一农药集团有限公司 | Purifying method of 2-chloromethyl-4-methoxyl-3,5-dimethylpyridine chloride |
| CN101875629A (en) * | 2010-03-31 | 2010-11-03 | 南京元华科技咨询有限公司 | Industrial preparation method of pantoprazole intermediate pyridine hydrochloride |
-
2014
- 2014-05-08 CN CN201410069812.1A patent/CN103910673A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101648907A (en) * | 2009-09-14 | 2010-02-17 | 南京第一农药集团有限公司 | Purifying method of 2-chloromethyl-4-methoxyl-3,5-dimethylpyridine chloride |
| CN101875629A (en) * | 2010-03-31 | 2010-11-03 | 南京元华科技咨询有限公司 | Industrial preparation method of pantoprazole intermediate pyridine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 徐宝财等: "2-氯甲基-4-甲氧基-3,5-二甲基吡啶盐酸盐的合成", 《精细化工》, vol. 21, no. 1, 31 December 2004 (2004-12-31), pages 67 - 69 * |
| 戴桂元等: "2-氯甲基-4-甲氧基-3,5-二甲基吡啶盐酸盐的制备", 《中国医药工业杂志》, vol. 35, no. 5, 31 December 2004 (2004-12-31), pages 261 - 262 * |
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