CN107337613A - A kind of extensive method for preparing high-purity amides compound B crystal form - Google Patents
A kind of extensive method for preparing high-purity amides compound B crystal form Download PDFInfo
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- CN107337613A CN107337613A CN201610283006.3A CN201610283006A CN107337613A CN 107337613 A CN107337613 A CN 107337613A CN 201610283006 A CN201610283006 A CN 201610283006A CN 107337613 A CN107337613 A CN 107337613A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
High-purity, B crystal form are prepared the present invention relates to a kind of extensive, 5（2,5 dimethyl phenoxies）‑N‑（2‑（4 hydroxy phenyls）2 oxoethyls）2,2 dimethyl-penten acid amides（Shown in Formulas I）Method.Gained sample HPLC>99%, it is maximum single miscellaneous<0.05%.
Description
Technical field
The present invention relates to a kind of extensive preparation high-purity 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）The method of -2,2- dimethyl-penten acid amides B crystal forms.
Background technology
WO2012175049 reports a kind of amides compound for playing regulation blood fat in vivo, preventing and treating gall stone effect.Such compound can not only reduce the level of triglycerides in high blood lipid model animal, but also have the function that good reduction cholesterol and low-density lipoprotein.Caused in gold suslik on stone model, there is the effect of preventing and treating gall stone.Wherein compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides（Shown in Formulas I）T-CHOL and triglycerides can be reduced simultaneously, Small side effects, can treat the cardiovascular and cerebrovascular diseases such as hyperlipemia, atherosclerosis and gall stone, and toxicity is smaller, has the good prospect of marketing.
Patent CN103833588 reports compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides have two kinds of crystal formations of A, B, and crystal formation A is semihydrate, the dehydration at 108 ± 5 DEG C, is converted into B.B crystal form is anhydrous crystal forms, is had good stability.In patent, by by compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides are added in dichloromethane at 40 DEG C, concussion dissolving, are concentrated under reduced pressure, and solvent is removed in 10min and prepares B crystal form compound.This method is industrially difficult to realize, and is not used to prepare a large amount of samples, and in addition, this method can not also purify sample.
To sum up, compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides have the application of the cardiovascular and cerebrovascular diseases such as treatment hyperlipemia, atherosclerosis and gall stone, have wide DEVELOPMENT PROSPECT.B crystal form has stability good, the advantages of being adapted to do API crystal formations.But ensure to obtain high-purity, B crystal form 5- currently without suitable route（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）The method of -2,2- dimethyl-penten acid amides, the method for objectively needing to find a suitable preparation of industrialization B crystal form bulk drug.
The content of the invention
To solve the defects of prior art is present, the invention provides a kind of extensive preparation high-purity, B crystal form, 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides（Shown in Formulas I）Method.
A kind of extensive preparation high-purity, B crystal form, 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides（Shown in Formulas I）Method.It is characterized in that：By 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-pentens crude amide, organic solvent（Absolute ethyl alcohol, toluene, acetonitrile, isopropanol, acetone or its mixed solvent）By certain volume mass ratio（3~39mL/g）It is added in reaction vessel, in proper temperature（50-150℃）Dissolving, 1-10h is stirred, be cooled to 45-65 DEG C, add crystal seed, continue to be cooled to 0 DEG C, be incubated 0.5 ~ 3h, filtering, filtration cakes torrefaction, obtain finished product.
High-purity：HPLC>99%, it is maximum single it is miscellaneous≤0.1%.
B crystal form is in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, θ=5.14 of characteristic diffraction angles 2,10.27,15.43,17.23,23.02, and 2 θ values error ranges are ± 0.2.
Further, organic solvent is toluene, acetonitrile or ethanol；Solvent and sample volume mass ratio are 5 ~ 15 mL/g；Solution temperature is 70 ~ 110 DEG C, and mixing time is 3 ~ 5h；Drying temperature is 30 ~ 40 DEG C；It is 50 ~ 60 DEG C of temperature to add seeding temperature.
Further, organic solvent is toluene, ethanol；Solvent and sample volume mass ratio are 5 ~ 10 mL/g；Solution temperature is 70 ~ 110 DEG C；Mixing time is 3 ~ 5h.
Further, organic solvent is toluene, and solvent and sample volume mass ratio are 7 ~ 8 mL/g；Solution temperature is 110 ± 5 DEG C；Mixing time is 3 ~ 5h；Drying temperature is 30 ~ 40 DEG C, and it is 50 ~ 60 DEG C of temperature to add seeding temperature.
Specific embodiment
The present invention is described in more detail below by way of the citing of embodiment.Implementation below is provided to illustrate the technical purpose of the present invention and beneficial effect, is not intended to and is limit the invention in any way.The record that those skilled in the art pass through claims of the present invention and the specification content of the invention; it will readily appreciate that; can be by changing or improveing various non-key parameters; to obtain the result of substantially the same technical scheme, these results will also fall into the protection domain of claims of the present invention.
Embodiment 1：
By Formulas I compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten crude amides（A+B mixed crystal, HPLC>99%, maximum single miscellaneous 0.1% ~ 0.15%）395g, toluene 3L are added in 5L there-necked flasks, stirring, are warming up to backflow.Divide water, stir 3h, be naturally cooling to 54 DEG C, add B crystal seed 0.1g, continue to be cooled to 0 DEG C, be incubated 0.5h, filtering, filter cake is dried in vacuo at 40 DEG C, obtains B crystal form sample 379g, HPLC：99.83%, it is maximum single miscellaneous<0.05%.
Embodiment 2：
By Formulas I compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten crude amides（A mixed crystal, HPLC>99%, maximum single miscellaneous 0.1% ~ 0.15%）98g, toluene 500mL are added in 1L there-necked flasks, stirring, are warming up to backflow.Divide water, stir 5h, be naturally cooling to 60 DEG C, add B crystal seed 0.1g, continue to be cooled to 0 DEG C, be incubated 3h, filtering, filter cake is dried in vacuo at 30 DEG C, obtains B crystal form sample 95g, HPLC：99.78%, it is maximum single miscellaneous<0.05%.
Embodiment 3：
By Formulas I compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten crude amides（A+B mixed crystal, HPLC>99%, maximum single miscellaneous 0.1% ~ 0.15%）87g, acetonitrile 1300mL are added in 5L there-necked flasks, stirring, are warming up to 70 DEG C.4h is stirred, is naturally cooling to 60 DEG C, adds B crystal seed 0.1g, continues to be cooled to 0 DEG C, is incubated 5h, filtering, filter cake is dried in vacuo at 40 DEG C, obtains B crystal form sample 69g, HPLC：99.64%, it is maximum single miscellaneous<0.05%.
Embodiment 4：
By Formulas I compound 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten crude amides（A+B mixed crystal, HPLC>99%, maximum single miscellaneous 0.1% ~ 0.15%）75g, ethanol 1500mL are added in 5L there-necked flasks, stirring, are warming up to backflow.3h is stirred, is naturally cooling to 40 DEG C, adds B crystal seed 0.1g, continues to be cooled to 0 DEG C, is incubated 4h, filtering, filter cake is dried in vacuo at 30 DEG C, obtains B crystal form sample 45g, HPLC：99.51%, it is maximum single miscellaneous<0.05%.
Claims (8)
1. a kind of extensive preparation high-purity, B crystal form, 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-penten acid amides（Shown in Formulas I）Method；It is characterized in that：By 5-（2,5- dimethyl phenoxies）-N-（2-（4- hydroxy phenyls）- 2- oxoethyls）- 2,2- dimethyl-pentens crude amide, organic solvent（Absolute ethyl alcohol, toluene, acetonitrile, isopropanol, acetone or its mixed solvent）By certain volume mass ratio（3~39mL/g）It is added in reaction vessel, in proper temperature（50-150℃）Dissolving, 1-10h is stirred, be cooled to 45-65 DEG C, add crystal seed, continue to be cooled to 0 DEG C, be incubated 0.5 ~ 3h, filtering, filtration cakes torrefaction, obtain finished product；
High-purity：HPLC>99%, it is maximum single it is miscellaneous≤0.1%；
B crystal form is in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, θ=5.14 of characteristic diffraction angles 2,10.27,15.43,17.23,23.02, and 2 θ values error ranges are ± 0.2.
2. as claimed in claim 1, organic solvent is toluene, acetonitrile or ethanol.
3. as claimed in claim 1, solvent and sample volume mass ratio are 5 ~ 20 mL/g.
4. as claimed in claim 1, solution temperature is 70 ~ 110 DEG C, mixing time is 3 ~ 5h.
5. as claimed in claim 1, drying temperature is 30 ~ 40 DEG C.
6. it is 40 ~ 60 DEG C as claimed in claim 1, to add seeding temperature.
7. according to preparation method described in claim 1-4, organic solvent is toluene, ethanol；Solvent and sample volume mass ratio are 5 ~ 10
mL/g ；Solution temperature is 70 ~ 110 DEG C；Mixing time is 3 ~ 5h.
8. according to preparation method described in claim 1-7, organic solvent is toluene, and solvent and sample volume mass ratio are 7 ~ 8 mL/g；Solution temperature is 110 ± 5 DEG C；Mixing time is 3 ~ 5h；Drying temperature is 30 ~ 40 DEG C, and it is 50 ~ 60 DEG C of temperature to add seeding temperature.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838505A (en) * | 2011-06-24 | 2012-12-26 | 上海医药工业研究院 | Amide compound and preparation method as well as application thereof |
| CN103087009A (en) * | 2012-12-17 | 2013-05-08 | 上海现代制药股份有限公司 | Carboxylic acid derivative compound and preparation method and application thereof |
| CN103724221A (en) * | 2012-10-10 | 2014-04-16 | 上海医药工业研究院 | Preparation methods of amide-type compound and intermediate thereof as well as intermediate thereof |
| CN103833588A (en) * | 2012-11-16 | 2014-06-04 | 上海医药工业研究院 | Two crystal forms of amide compound, preparation methods and applications thereof |
-
2016
- 2016-05-03 CN CN201610283006.3A patent/CN107337613A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838505A (en) * | 2011-06-24 | 2012-12-26 | 上海医药工业研究院 | Amide compound and preparation method as well as application thereof |
| CN103724221A (en) * | 2012-10-10 | 2014-04-16 | 上海医药工业研究院 | Preparation methods of amide-type compound and intermediate thereof as well as intermediate thereof |
| CN103833588A (en) * | 2012-11-16 | 2014-06-04 | 上海医药工业研究院 | Two crystal forms of amide compound, preparation methods and applications thereof |
| CN103087009A (en) * | 2012-12-17 | 2013-05-08 | 上海现代制药股份有限公司 | Carboxylic acid derivative compound and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| SIYUN NIAN等: "Discovery and Synthesis of a Novel Series of Liver X Receptor", 《CHEM. PHARM. BULL.》 * |
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Application publication date: 20171110 |