CN101613351A - Methanol solvate compound of S-4661 intermediate and preparation method thereof - Google Patents
Methanol solvate compound of S-4661 intermediate and preparation method thereof Download PDFInfo
- Publication number
- CN101613351A CN101613351A CN200810039426A CN200810039426A CN101613351A CN 101613351 A CN101613351 A CN 101613351A CN 200810039426 A CN200810039426 A CN 200810039426A CN 200810039426 A CN200810039426 A CN 200810039426A CN 101613351 A CN101613351 A CN 101613351A
- Authority
- CN
- China
- Prior art keywords
- compound
- methanol solvate
- preparation
- solvate compound
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses methanol solvate compound of S-4661 intermediate shown in the formula I and preparation method thereof, the PNB representative is to nitrobenzyl in the intermediate compound I, and PNZ represents the nitro carbobenzoxy-(Cbz).Methanol solvate compound purity height of the present invention, good stability, easy handling and preservation; And the preparation method is simple and reliable, suitable industrial enforcement.
Description
Technical field
The present invention relates to methanol solvate compound of a kind of S-4661 intermediate and preparation method thereof.
Background technology
Pyrrolidine sulfsulopenem derivative, popular name S-4661 (Compound I I) are a kind of known Broad spectrum antibioticss.Compound I is the synthetic intermediate of Compound I I, and in the document of in the past reporting, this compound is unformed, does not isolate a kind of specific crystallized form as yet.But refining, the purifying of this amorphous compound, preserve and be used for next step deprotection base and obtain high-purity compound II and all have many difficulties.As everyone knows, in chemical synthesis process, especially in industrially preparing process, be preferably the compound of producing with a certain method and all have high purity or can separate and refiningly become a kind of maneuverable crystallized form.
The PNB representative is to nitrobenzyl in the Compound I, and PNZ represents the nitro carbobenzoxy-(Cbz).
Summary of the invention
Technical problem to be solved by this invention is to have overcome that existing formula I compound---the S-4661 intermediate is all amorphous compound, it is refining, the defective of purifying, preservation difficulty, a kind of methanol solvate compound of S-4661 intermediate is provided, it is the crystallinity compound, easily preserves, easy to operate, good stability, purity height; And its preparation method is simple and reliable, suitable industrial enforcement.
The chemical structural formula of S-4661 intermediate compound I is as follows:
Wherein: PNB represents nitrobenzyl, and PNZ represents the nitro carbobenzoxy-(Cbz).
Among the present invention, what the methanol content of described methanol solvate compound was preferable is the 0.1-2mol/mol Compound I; Better is the 1.5mol/mol Compound I.
In the preferred embodiment of the present invention, the methanol solvate compound of described formula I compound S-4661 intermediate is in its x-ray diffractogram of powder, in diffraction angle 2 θ=5.63,7.99,11.30,11.60,12.65,13.32,13.73,14.86,15.88,16.54,17.90,18.99,19.83,20.88,21.91 there is main peak at 23.43,25.49 and 26.48 degree places; 2 θ value limit of error are ± 0.2.
The preparation method of methanol solvate compound of the present invention is: Compound I is dissolved in the suitable solvents, to wherein adding methyl alcohol, stirs, separate out described methanol solvate compound.
Wherein, suitable solvents refers to all organic solvents of energy dissolved compound I, and preferable is ethyl acetate, methylene dichloride, dimethyl formamide (DMF), acetonitrile, acetone or chloroform; That better is ethyl acetate, methylene dichloride or DMF; Variation to some extent is as the criterion so that Compound I is dissolved the consumption of described suitable solvents with its solvability to Compound I is different; The consumption of described methyl alcohol changes to some extent with the difference of the suitable solvents of using, so that separating out, the methanol solvate compound is as the criterion, common consumption is 2～10 times of suitable solvents volume, 2～6 times of preferable is suitable solvents volume, 2～3 times of best is suitable solvents volume; What the temperature of described stirring was preferable is 0～35 ℃, and better is 5～25 ℃, and best is 5～10 ℃; What churning time was preferable is 1 hour～48 hours, and better is 8 hours～24 hours, and best is 8 hours～12 hours.
Preferable, also the methanol solvate compound of separating out can be carried out recrystallization again, operation is with aforementioned.
All reagent of the present invention are all commercially available to be got.
Positive progressive effect of the present invention is to provide first a kind of methanol solvate compound of S-4661 intermediate compound I, and it is the crystallinity compound, easily preserves, easy to operate, good stability, purity height; And its preparation method is simple and reliable, suitable industrial enforcement.
Description of drawings
Fig. 1 is the powder x-ray diffraction figure of the methanol solvate compound of embodiment 4, adopts Bruker D8ADVANCE instrument to measure.Condition determination is as follows: CuKa 40Kv 40mA is a light source, 0.02 ° of step-length, and sweep velocity: 8 °/min, sweep limit: 3 °～80 °, room temperature.
Fig. 2 is the infrared absorption figure of the methanol solvate compound of embodiment 4, and infrared absorption spectrum adopts the America NI COLET 670FI-IR of company spectrophotometer, pressing potassium bromide troche, sweep limit 400～4000cm
-1
Fig. 3 is thermogravimetic analysis (TGA) (TGA) figure of the methanol solvate compound of embodiment 4, thermogravimetic analysis (TGA) adopts NETZSCH TG 209F1 to measure, condition determination is as follows: use alumina crucible, with the temperature rise rate of 10 ℃/min, scan 250 ℃ from 20 ℃ under nitrogen purging.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
The condition for preparing the methanol solvate compound with different suitable solvents and methyl alcohol is listed in the table 1, concrete operations are as follows: amorphous powder 0.1 gram of Compound I are dissolved in the suitable solvents, and after this solution dissolving, to wherein adding methyl alcohol continuously, stir, separate out the methanol solvate compound.Embodiment 13 carries out the condition of recrystallization again for the methanol solvate compound that embodiment 12 is made.
Table 1
| ??No | Suitable solvents | Consumption/ml | Soluble solvent | Consumption/ml | Whipping temp/℃ | Churning time/h | Purity (%) |
| ??1 | Ethyl acetate | ??0.1 | Methyl alcohol | ??0.2 | ??15 | ??12 | ??99.1 |
| ??2 | Methylene dichloride | ??0.1 | Methyl alcohol | ??0.2 | ??15 | ??12 | ??99.3 |
| ??3 | ??DMF | ??0.2 | Methyl alcohol | ??0.4 | ??15 | ??12 | ??98.1 |
| ??4 | Ethyl acetate | ??0.2 | Methyl alcohol | ??0.6 | ??10 | ??8 | ??99.6 |
| ??5 | Methylene dichloride | ??0.2 | Methyl alcohol | ??0.6 | ??10 | ??8 | ??99.1 |
| ??6 | Acetonitrile | ??0.2 | Methyl alcohol | ??0.6 | ??10 | ??8 | ??98.8 |
| ??7 | Acetone | ??0.2 | Methyl alcohol | ??0.6 | ??10 | ??8 | ??98.7 |
| ??8 | Chloroform | ??0.3 | Methyl alcohol | ??0.9 | ??5 | ??15 | ??92.7 |
| ??9 | ??DMF | ??0.5 | Methyl alcohol | ??1.5 | ??5 | ??15 | ??99.3 |
| ??10 | Ethyl acetate | ??0.2 | Methyl alcohol | ??0.6 | ??0 | ??1 | ??99.5 |
| ??11 | Ethyl acetate | ??0.2 | Methyl alcohol | ??1.2 | ??25 | ??24 | ??99.4 |
| ??12 | Ethyl acetate | ??0.2 | Methyl alcohol | ??2 | ??35 | ??48 | ??98.7 |
| ??13 | Ethyl acetate | ??0.2 | Methyl alcohol | ??2 | ??35 | ??48 | ??99.6 |
Illustrate: the table moderate purity adopts high performance liquid chromatography (HPLC) to measure, and chromatographic condition is as follows: phenomenex C
18ODS-H, moving phase: acetonitrile: water=25: 75, detect wavelength; 245nm, column temperature: 40 ℃.
Wherein, among the embodiment 4 X ray test of methanol solvate compound the results are shown in Table 2.
Table 2
When measuring crystallization of the present invention, sometimes because the instrument of measuring or the condition of mensuration can have error at measurment slightly for measured peak with the X-diffraction.Specifically, for example, the error at measurment of 2 θ values is approximately ± 0.2 sometimes, even when using very accurate equipment, also can produce error approximately ± 0.1 sometimes.Therefore, when determining every kind of crystalline texture, this error should be taken into account.
The character of the methanol solvate compound that table 3 obtains for embodiment 1,2,4,5,6,7,8,9.The fusing point of solvate is measured by DSC.Methanol content adopts vapor-phase chromatography (GC) and the comparative study of thermogravimetry (TGA) condition to measure, and is as the criterion with thermogravimetry.
Table 3
| ??No | Separate out the solvate quality | Fusing point (℃) | Methanol content (%) | Methanol content (mol/mol Compound I) |
| ??1 | ??56mg | ??100-102 | ??5.98 | ??1.5/1 |
| ??2 | ??49mg | ??99-101 | ??6.15 | ??1.5/1 |
| ??4 | ??93mg | ??100-103 | ??6.14 | ??1.5/1 |
| ??5 | ??88mg | ??99-101 | ??6.10 | ??1.5/1 |
| ??6 | ??56mg | ??89-92 | ??7.89 | ??2/1 |
| ??7 | ??42mg | ??99-100.5 | ??4.1 | ??1/1 |
| ??8 | ??19mg | ??155-165 | ??0.5 | ??0.1/1 |
| ??9 | ??23mg | ??99-103 | ??5.88 | ??1.5/1 |
The comparative example
According to reference (Practical Large-Scale Synthesis of Doripenem:A Novel
Antibiotic, Organic Process Research ﹠amp; Development, 2003,7:
) method described: prepare oily matter 35 grams of Compound I by condensation reaction, be dissolved among the ethyl acetate 150ml, under the whipped state, splash into toluene 300ml in the 30min, yellow mercury oxide production is arranged, suction filtration obtains amorphous products 30 grams of Compound I.Fusing point: 160-180 ℃.HPLC method (actual conditions is seen description among the embodiment 1～13) is measured the purity 91.5% of amorphous compound I.
Repeat above-mentioned preparation experiment: will prepare oily matter 35 grams of Compound I by condensation reaction, and be dissolved among the ethyl acetate 150ml, and under the whipped state, splash into toluene 300ml in the 30min, thick yellow oily deposits yields is arranged.Getting this oily matter and measure its purity with the HPLC method, is 90.5%.
From above-mentioned experiment as can be seen, the purity of unformed product is relatively poor, and the circulation ratio of preparation process is also relatively poor.
Claims (10)
1, the methanol solvate compound of S-4661 intermediate shown in a kind of formula I,
The PNB representative is to nitrobenzyl among the formula I, and PNZ represents the nitro carbobenzoxy-(Cbz).
2, methanol solvate compound as claimed in claim 1 is characterized in that: in its x-ray diffractogram of powder, in diffraction angle 2 θ=5.63,7.99,11.30,11.60,12.65,13.32,13.73,14.86,15.88,16.54,17.90,18.99,19.83,20.88,21.91 there is main peak at 23.43,25.49 and 26.48 degree places; 2 θ value limit of error are ± 0.2.
3, methanol solvate compound as claimed in claim 1 is characterized in that: wherein the content of methyl alcohol is 0.1-2mol/mol formula I compound.
4, methanol solvate compound as claimed in claim 3 is characterized in that: wherein the content of methyl alcohol is 1.5mol/mol formula I compound.
5, as the preparation method of each described methanol solvate compound in the claim 1～4: Compound I is dissolved in the suitable solvents,, stirs, separate out the methanol solvate compound to wherein adding methyl alcohol.
6, preparation method as claimed in claim 5 is characterized in that: described suitable solvents is selected from one or more in ethyl acetate, methylene dichloride, dimethyl formamide, acetonitrile, acetone and the chloroform.
7, preparation method as claimed in claim 5 is characterized in that: described methanol usage is 2～10 times of suitable solvents volume, is more preferred from 2～6 times, and the best is 2～3 times.
8, preparation method as claimed in claim 5 is characterized in that: described whipping temp is 0～35 ℃, is more preferred from 5～25 ℃, and the best is 5～10 ℃.
9, preparation method as claimed in claim 5 is characterized in that: described churning time is 1 hour～48 hours, is more preferred from 8 hours～24 hours, and the best is 8 hours～12 hours.
10, preparation method as claimed in claim 5 is characterized in that: the methanol solvate compound of separating out is carried out recrystallization again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100394262A CN101613351B (en) | 2008-06-24 | 2008-06-24 | Methanol solvate of doripenem intermediate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100394262A CN101613351B (en) | 2008-06-24 | 2008-06-24 | Methanol solvate of doripenem intermediate and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101613351A true CN101613351A (en) | 2009-12-30 |
| CN101613351B CN101613351B (en) | 2011-10-19 |
Family
ID=41493257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100394262A Active CN101613351B (en) | 2008-06-24 | 2008-06-24 | Methanol solvate of doripenem intermediate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101613351B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702201A (en) * | 2012-03-26 | 2012-10-03 | 深圳市海滨制药有限公司 | Doripenem intermediate compound, preparation method and application of doripenem intermediate compound and preparation method for doripenem |
| CN103130805A (en) * | 2011-12-01 | 2013-06-05 | 石药集团中奇制药技术（石家庄）有限公司 | Doripenem intermediate solvate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4274739B2 (en) * | 2001-05-10 | 2009-06-10 | 塩野義製薬株式会社 | Method for producing acetylthiopyrrolidine derivatives |
| JP2008303143A (en) * | 2005-08-19 | 2008-12-18 | Shionogi & Co Ltd | Method for producing carbapenem derivative by continuous reaction |
-
2008
- 2008-06-24 CN CN2008100394262A patent/CN101613351B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130805A (en) * | 2011-12-01 | 2013-06-05 | 石药集团中奇制药技术（石家庄）有限公司 | Doripenem intermediate solvate |
| CN103130805B (en) * | 2011-12-01 | 2016-08-17 | 石药集团中奇制药技术（石家庄）有限公司 | Doripenem intermediate solvate |
| CN102702201A (en) * | 2012-03-26 | 2012-10-03 | 深圳市海滨制药有限公司 | Doripenem intermediate compound, preparation method and application of doripenem intermediate compound and preparation method for doripenem |
| WO2013143266A1 (en) * | 2012-03-26 | 2013-10-03 | 深圳市海滨制药有限公司 | Doripenem intermediate compound, preparation process therefor and use thereof, and preparation process for doripenem |
| CN102702201B (en) * | 2012-03-26 | 2013-12-25 | 深圳市海滨制药有限公司 | Doripenem intermediate compound, preparation method and application of doripenem intermediate compound and preparation method for doripenem |
| US9169258B2 (en) | 2012-03-26 | 2015-10-27 | Shenzhen Haibin Pharmaceutical Co., Ltd. | Doripenem intermediate compound, preparation process therefor and use thereof, and preparation process for doripenem |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101613351B (en) | 2011-10-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103360391B (en) | Novel apixaban crystal form and preparation method thereof | |
| CN101613351B (en) | Methanol solvate of doripenem intermediate and preparation method thereof | |
| CN105017176B (en) | A kind of hydrobromic acid Vortioxetine crystal and preparation method thereof | |
| CN115233243A (en) | Preparation method of 2,4, 5-trisubstituted oxazole derivative under electrocatalysis | |
| CN114685485B (en) | Synthesis method of pyridoimidazole thiopropionic acid anti-gout compound | |
| CN103509031A (en) | Preparation method of Darunavir amorphous matter | |
| CN1189822A (en) | Process for the prepn. of ropivacaine hydrochloride monohydrate | |
| CN115124551B (en) | Preparation method of high-purity midostaurin | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| CN114105872B (en) | Intermediate for preparing procaterol hydrochloride and preparation method thereof | |
| CN111533747B (en) | Method for preparing pyrrolo [2,1-F ] [1,2,4] triazine-4-amine by one-pot method | |
| CN104910099B (en) | The preparation method for western spit of fland crystal irrigated by a kind of hydrobromic acid | |
| CN110981831B (en) | Preparation method of 3-morpholine propanesulfonic acid | |
| CN109851599B (en) | Preparation method of 2-aminobenzofuran compound | |
| CN106316937A (en) | Preparation method of fluazinam | |
| CN103130805B (en) | Doripenem intermediate solvate | |
| CN102516114B (en) | R-(-)-2-amino-3-methoxyl-N-benzyl propionamide-D-tartrate and preparation method thereof | |
| CN113121492A (en) | Vilandiolo intermediate, preparation method and application thereof | |
| CN105566429B (en) | Preparation method of obeticholic acid type 1 | |
| CN104650074A (en) | Apixaban compound | |
| CN115010624B (en) | Preparation method of deuterium-labeled sibutrol | |
| CN113105385B (en) | Preparation method of levobupivacaine | |
| EP4345093A1 (en) | A process method for synthesizing quinolones intermediates by use of a microreactor | |
| CN106008315A (en) | Apremilast crystal form S and preparing method thereof | |
| CN107641085B (en) | Synthesis method of diphenylenone and derivatives thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160523 Address after: 200040 Beijing West Road, Shanghai, No. 1320 Patentee after: Shanghai Institute of pharmaceutical industry Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |