CN103242291A - Mass production process of polycrystalline high-content benzoic acid alogliptin - Google Patents
Mass production process of polycrystalline high-content benzoic acid alogliptin Download PDFInfo
- Publication number
- CN103242291A CN103242291A CN 201310195299 CN201310195299A CN103242291A CN 103242291 A CN103242291 A CN 103242291A CN 201310195299 CN201310195299 CN 201310195299 CN 201310195299 A CN201310195299 A CN 201310195299A CN 103242291 A CN103242291 A CN 103242291A
- Authority
- CN
- China
- Prior art keywords
- phenylformic acid
- content
- egelieting
- hours
- benzoic acid
- 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.)
- Pending
Links
- 0 C1CC*CC1 Chemical compound C1CC*CC1 0.000 description 1
Images
Abstract
The invention relates to a mass production process of polycrystalline high-content benzoic acid alogliptin. According to the process, the products do not need to be refined and the qualified products conforming to the pharmaceutical production demand can be obtained directly. The process comprises the following steps: putting 5kg of the benzoic acid into a 200L reaction kettle; adding 100L of pure water; stirring, heating and refluxing for 1 hour; centrifuging after the reaction liquid is decreased to 50 to 60 DEG C; filtering into a filter cake in a pressing manner by using a plate-and-frame filter press and performing the forced air drying at the temperature of 60 to 65 DEG C for 10 to 12 hours, thereby obtaining 2.41kg of a white needle-shaped crystal benzoic acid refined product; putting 3.11kg of alogliptin and 1.13kg of the white needle-shaped crystal benzoic acid refined product into the reaction kettle; adding 15L of a solvent; heating and dissolving; heating until refluxing for 2 to 3 hours; stopping the heating until separating out white solids; naturally cooling to the room temperature; stirring and separating out a crystal for 10 to 12 hours; centrifuging; washing the obtained solid by using 1L of the solvent; and performing the forced air drying for 8 to 10 hours at the temperature of 40 to 45 DEG C, thereby obtaining 3.82kg of the finished polycrystalline high-content benzoic acid alogliptin product.
Description
[technical field]
The present invention relates to a kind of mass production processes of polymorphic high-content phenylformic acid Egelieting, product need not to re-refine, and can directly obtain meeting the salable product of pharmaceutical production demand.
[background technology]
Egelieting is serine protease DPP IV (DPP IV) inhibitor optionally, by control glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic polypeptide (GIP, be also referred to as gastric inhibitory polypeptide) the incretin activity, effectively keep blood sugar homeostasis (glucose stable state, glucose homeostasis).Therefore, it is suggested the potent drug as the treatment diabetes B.The benzoate of Egelieting (SYR-322) has shown challenging anti-glycosuria effect.
The Egelieting chemical name is 2-[6-[3 (R)-amino piperidine-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] cyanobenzene, represented by following chemical structure:
The compound of new form has the physical properties that is different from and is better than those other crystallized forms or amorphous form.These comprise, packaging character such as molecular volume, density and water absorbability; Thermomechanical property such as melt temperature, vapor pressure and solvability; Dynamic performance is as the dissolution rate under different storage conditions and stability; Surface property such as surface-area, wettability, interfacial tension and shape; Mechanical property such as hardness, tensile strength, compactibility (plasticity), handling property, mobile and mixed performance; And filtering feature.In these performances any one variation all can influence the chemistry of compound and pharmaceutical technology with and bioavailability and the new form that presents be conducive to medical use usually.
WO2007/035372 (US2007/0066635) discloses two kinds of polymorphs of phenylformic acid Egelieting, a kind of amorphous polycrystalline shape of a kind of crystallization polymorph thing, called after form A and form 1 respectively.Crystallized form is characterised in that the X-ray diffraction peak of locating distinct property at 9.44,10.84,17.82,18.75,25.87 and 28.522 θ °.Amorphous form is characterised in that no characteristic peak exists in the X-ray powder diffraction pattern, and demonstrates wide halation.Amorphous form be further characterized in that 809,868,1119,1599 and the 1703cm-1 place comprise the IR spectrum at unique peak; 805,1280 and the 1703cm-1 position have the FT-Raman spectrum at unique peak; Differential scanning calorimetric (circulation DSC) spectrum with Tg=70 ℃ (beginning (initial)), 132 ℃ of (maximum value) heat releases and 183 ℃ of (beginning temperature (starting temperature)) heat absorptions; And the data presentation of its thermogravimetric analysis is from 25 ℃ to 151 ℃, weight loss 4%.
Document J.Med.Chem.2007,50.2297-2300 is starting raw material with the 6-chlorouracil, be substituted reaction with 2-cyano-benzyl bromide, methyl iodide after, with (3R)-3-amino piperidine piperidines dihydrochloride reaction, get the phenylformic acid Egelieting with the phenylformic acid salify.Synthetic route is as follows:
There is following shortcoming in this preparation method:
When starting raw material 6-chlorouracil and the reaction of 2-cyano-benzyl bromide, introduce 2-cyano group benzyl simultaneously in 1,3 meeting of 6-chlorouracil and generate by product
This by product be difficult for to be removed, and in subsequent reactions can with (3R)-3-amino piperidine piperidines dihydrochloride generation substitution reaction, in finished product, generate impurity
And be difficult for removing.
In addition, when introducing (R)-3-amino piperidine substituted radical, use (R)-3-amino piperidine dihydrochloride as raw material, thus the product that the inevitable generation of this step reaction part 3-bit amino is replaced
And be difficult to remove, finally have influence on the purity of finished product.
Document US 2009/0275750 is starting raw material with 6-chloro-3-6-Methyl Uracil, be substituted reaction with the 2-cyano-benzyl bromide after, with (3R)-3-amino piperidine piperidines dihydrochloride reaction, get the phenylformic acid Egelieting with the phenylformic acid salify.Synthetic route is as follows:
There is following shortcoming in this preparation method:
Be starting raw material with 6-chloro-3-6-Methyl Uracil, though avoided impurity
Generation, but when introducing (R)-3-amino piperidine substituted radical, also use (R)-3-amino piperidine dihydrochloride as raw material, thereby make the same inevitable product that produces the replacement of part 3-bit amino of this step reaction
And be difficult to remove, finally have influence on the purity of finished product.
[summary of the invention]
The preparation technology of para Toluic Acid's Egelieting of the present invention improves, and a kind of mass production processes of polymorphic high-content phenylformic acid Egelieting is provided, to solve the existing in prior technology technical problem.
The present invention solves the problems of the technologies described above the technical scheme that adopts to be: a kind of mass production processes of polymorphic high-content phenylformic acid Egelieting may further comprise the steps:
1) benzoic refining:
Get phenylformic acid 5kg, put 200 liters of reactors, add 100 liters of pure water, stirred temperature rising reflux 1 hour.Reacting liquid temperature is centrifugal after being down to 55～60 ℃, becomes filter cake and 60～65 ℃ of forced air dryings 10～12 hours, gets 2.41 kilograms of white needles crystal formation phenylformic acid highly finished product with the plate-and-frame filter press press filtration;
2) preparation of phenylformic acid Egelieting:
Get 3.11kg Egelieting (HPLC:99.6%) and the above-mentioned white needles crystal formation of 1.13kg phenylformic acid highly finished product, place reactor, add the 15L solvent, heating for dissolving is heated to and refluxed 2～3 hours, when separating out, the adularescent solid stops heating, naturally cool to room temperature, stirring and crystallizing 10～12 hours, centrifugal, the gained solid obtains 3.82 kilograms of polymorphic phenylformic acid Egelieting finished products with 1 liter of described solvent wash and 40～45 ℃ of forced air dryings 8～10 hours.
Synthetic method of the present invention is starting raw material with 6-chloro-3-6-Methyl Uracil; react with the 2-cyano-benzyl bromide; get 2-((6-chloro-2; 4-dioxy-3; 4-dihydro-2H-pyrimidine-1-yl) cyanobenzene methyl); again with tertbutyloxycarbonyl-(3R)-3-amino piperidine reaction; get N-(3-(2-cyano group benzyl)-1-methyl-2; 6-dioxy-1,2,3; 6-tetrahydropyrimidine-4-yl) piperidines-(3R)-3-t-butyl carbamate; through the trifluoroacetic acid deprotection, with the phenylformic acid salify, get the phenylformic acid Egelieting again.
Synthetic route is as follows:
Further, benzoic acid content 〉=99.9% of the crystal formation of white needles described in step 1) phenylformic acid highly finished product, the preferred pure water of its crystallization solvent for use.
Further, the described solvent step 2) is one or more mixture of tetrahydrofuran (THF), ethyl acetate, acetonitrile, methyl alcohol.Described solvent is preferably dehydrated alcohol.In described Egelieting and the benzoic salt-forming reaction, adding the analytical pure phenylformic acid need make with extra care, and salt-forming reaction is made solvent with dehydrated alcohol, environmental protection more, and dehydrated alcohol low price, and dehydrated alcohol simultaneously is easier of the impurity that produces in the dereaction.
Further, the characteristic peak that the IR spectrum of described polymorphic high-content phenylformic acid Egelieting has is included in 711.7,1211.2, and 1364.8,1446.9,1615.3,1697.8,2229.9,3085.3 places.
Beneficial effect: preparation technology's operation of the present invention is simple, and it is higher to obtain the product productive rate, and product purity is higher.Salt-forming reaction is made solvent with dehydrated alcohol, environmental protection more, and dehydrated alcohol low price, and dehydrated alcohol simultaneously is easier of the impurity that produces in the dereaction.
[description of drawings]
The invention will be further described in conjunction with the embodiments with reference to the accompanying drawings.
Fig. 1 is the X-ray powder diffraction figure of phenylformic acid Egelieting finished product of the present invention,
Fig. 2 is the IR spectrum of phenylformic acid Egelieting finished product of the present invention,
Fig. 3 is the differential scanning thermography of phenylformic acid Egelieting finished product of the present invention.
[embodiment]
Egelieting can be provided the preparation of method by CN101360723A, and phenylformic acid is from the commercially available analytical pure of Shanghai Su Yi chemical reagent company limited.
Get phenylformic acid 5kg, put 200 liters of reactors, add 100 liters of pure water, stirred temperature rising reflux 1 hour.Reacting liquid temperature is centrifugal after being down to 55～60 ℃, and filter cake and 60～65 ℃ of forced air dryings 10～12 hours gets 2.41 kilograms of white needles crystal formation phenylformic acid highly finished product (HPLC:99.9%); Yield: 48.2%.
The preparation of 2 phenylformic acid Egelietings:
Get 3.11kg Egelieting (HPLC:99.6%) and 1.13kg phenylformic acid highly finished product, put in 50 liters of reactors.Add 15L ethanol, heating for dissolving is heated to and refluxed 2～3 hours, and the adularescent solid is separated out.Stop heating, naturally cool to room temperature, stirring and crystallizing 10～12 hours.Centrifugal, solid was with 1 liter of washing with alcohol and 40～45 ℃ of forced air dryings 8～10 hours.Get polymorphic phenylformic acid Egelieting finished product (white crystalline powder) about 3.82 kilograms (HPLC:99.9%), yield: 90.3%.
The physical properties of gained polymorphic phenylformic acid Egelieting:
X-ray powder diffraction figure, its feature diffracted ray be as shown in Figure 1:
| Position (° 2 θ) | 9.42 | 15.2 | 18.72 | 20.9 | 27.6 |
| Relative intensity | 55 | 31 | 100 | 84 | 21 |
IR spectrum, as shown in Figure 2, it is included in
711.7,1211.2,1364.8,1446.9,1615.3, the absorption peak at 1697.8,2229.9,3085.3 places.
The differential scanning thermography, it has at 184 ℃ to about 195 ℃ absorption region, 186.2 ℃ at its peak (as shown in Figure 3).
The preparation of high-content Egelieting requires:
1. owing to contain acidic impurities such as phthalic acid in the phenylformic acid, can generate impurity with the Egelieting reaction and be difficult to remove, so require benzoic acid content 〉=99.9% of white needles crystal formation phenylformic acid highly finished product, the preferred pure water of its crystallization solvent for use.
2. content 〉=the 99.5%. of Egelieting
3. solvent can be used tetrahydrofuran (THF), ethyl acetate, acetonitrile, methyl alcohol etc., preferred alcohol solvent.
The present invention relates to the production in enormous quantities technology of the phenylformic acid Egelieting of polymorphic high-content, benzoic content 〉=99.9%, the content of Egelieting 〉=99.5% o'clock; The phenylformic acid Egelieting of prepared in reaction need not to make with extra care in alcohol solvent, content 〉=99.9%, and always assorted content＜0.1% meets the medicinal raw material requirement.
Although illustrated and described embodiments of the invention, for the ordinary skill in the art, be appreciated that without departing from the principles and spirit of the present invention and can carry out multiple variation, modification, replacement and modification to these embodiment, scope of the present invention is limited by claims and equivalent thereof.
Claims (5)
1. the mass production processes of a polymorphic high-content phenylformic acid Egelieting is characterized in that may further comprise the steps:
1) benzoic refining:
Get phenylformic acid 5kg, put 200 liters of reactors, add 100 liters of pure water, stirred temperature rising reflux 1 hour.Reacting liquid temperature is centrifugal after being down to 55～60 ℃, becomes filter cake and 60～65 ℃ of forced air dryings 10～12 hours, gets 2.41 kilograms of white needles crystal formation phenylformic acid highly finished product with the plate-and-frame filter press press filtration;
2) preparation of phenylformic acid Egelieting:
Get the above-mentioned white needles crystal formation of 3.11kg Egelieting and 1.13kg phenylformic acid highly finished product, place reactor, add the 15L solvent, heating for dissolving is heated to and refluxed 2～3 hours, when separating out, the adularescent solid stops heating, naturally cool to room temperature, stirring and crystallizing 10～12 hours, centrifugal, the gained solid obtains 3.82 kilograms of polymorphic phenylformic acid Egelieting finished products with 1 liter of described solvent wash and 40～45 ℃ of forced air dryings 8～10 hours.
2. according to the mass production processes of the described a kind of polymorphic high-content phenylformic acid Egelieting of claim 1, it is characterized in that: benzoic acid content 〉=99.9% of the crystal formation of white needles described in step 1) phenylformic acid highly finished product, the preferred pure water of its crystallization solvent for use.
3. according to the described mass production processes according to the described a kind of polymorphic high-content phenylformic acid Egelieting of claim 1 of claim 1, it is characterized in that: step 2) in described solvent be one or more mixture of tetrahydrofuran (THF), ethyl acetate, acetonitrile, methyl alcohol.
4. according to the described mass production processes according to the described a kind of polymorphic high-content phenylformic acid Egelieting of claim 1 of claim 3, it is characterized in that: described solvent is dehydrated alcohol.
5. according to the polymorphic high-content phenylformic acid Egelieting of weighing 1 described mass production processes preparation, it is characterized in that: the characteristic peak that the IR spectrum of described polymorphic high-content phenylformic acid Egelieting has is included in 711.7,1211.2,1364.8,1446.9,1615.3,1697.8,2229.9,3085.3 places.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310195299 CN103242291A (en) | 2013-05-23 | 2013-05-23 | Mass production process of polycrystalline high-content benzoic acid alogliptin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310195299 CN103242291A (en) | 2013-05-23 | 2013-05-23 | Mass production process of polycrystalline high-content benzoic acid alogliptin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103242291A true CN103242291A (en) | 2013-08-14 |
Family
ID=48922196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201310195299 Pending CN103242291A (en) | 2013-05-23 | 2013-05-23 | Mass production process of polycrystalline high-content benzoic acid alogliptin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103242291A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923063A (en) * | 2014-04-11 | 2014-07-16 | 浙江永宁药业股份有限公司 | Novel crystal form of alogliptin benzoate and preparation method thereof |
| CN105820153A (en) * | 2016-03-15 | 2016-08-03 | 威海迪素制药有限公司 | Novel crystal form of alogliptin benzoate |
| CN106632242A (en) * | 2017-02-14 | 2017-05-10 | 杭州百诚医药科技股份有限公司 | Preparation and after-treatment method for high-purity alogliptin benzoate |
-
2013
- 2013-05-23 CN CN 201310195299 patent/CN103242291A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923063A (en) * | 2014-04-11 | 2014-07-16 | 浙江永宁药业股份有限公司 | Novel crystal form of alogliptin benzoate and preparation method thereof |
| CN103923063B (en) * | 2014-04-11 | 2016-05-11 | 浙江永宁药业股份有限公司 | Crystal formation of a kind of SYR-322 and preparation method thereof |
| CN105820153A (en) * | 2016-03-15 | 2016-08-03 | 威海迪素制药有限公司 | Novel crystal form of alogliptin benzoate |
| CN106632242A (en) * | 2017-02-14 | 2017-05-10 | 杭州百诚医药科技股份有限公司 | Preparation and after-treatment method for high-purity alogliptin benzoate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103974949B (en) | A kind of I type crystallization of 2-maleate of tyrosine kinase inhibitor and preparation method | |
| KR20140075703A (en) | Polymorphic form of pridopidine hydrochloride | |
| EP2927226A1 (en) | Monohydrate crystal of fimasartan potassium salt, method for preparing same, and pharmacological composition comprising same | |
| CN103242291A (en) | Mass production process of polycrystalline high-content benzoic acid alogliptin | |
| CN102584693B (en) | Preparation method for high purity 2-chlorine-3-aminopyridine hydrochloride | |
| CN103864690B (en) | S crystal formation, its preparation method and the pharmaceutical composition of Ivabradine hydrochloride | |
| CN107531744A (en) | A kind of new crystalline form of shellfish cholic acid difficult to understand and preparation method thereof | |
| CN112028896A (en) | Novel crystal form of acatinib and preparation method thereof | |
| CN103980249A (en) | Method for refining alogliptin benzoate | |
| CN102070650B (en) | Preparation method for levofloxacin-N-oxide | |
| CN113582880A (en) | Preparation method of (3-aminobicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester | |
| CN102875397B (en) | Meclofenoxatum preparation method | |
| CN111349075A (en) | Preparation method of trelagliptin succinate | |
| CN104487437A (en) | Emtricitabine sylicylate and crystalline, preparing methods and uses thereof | |
| CN103804265B (en) | The synthesis of a kind of Sulpiride or its optical isomer and post-processing approach | |
| CN109369757B (en) | Method for preparing Sofosbuvir crystal form 6 | |
| CN113980012A (en) | Purification method of emtricitabine | |
| JP2022520629A (en) | FGFR inhibitor compound in solid form and method for producing the same | |
| CN108863946B (en) | Preparation method of dibazole impurity reference substance | |
| CN110734393A (en) | Preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride | |
| CN105566429B (en) | Preparation method of obeticholic acid type 1 | |
| CN103880747B (en) | The preparation method of amorphous tolvaptan | |
| CN102206185A (en) | Process for refining bendazac lysine and analogs thereof | |
| CN112608286B (en) | Preparation method of high-purity pramipexole | |
| CN102382041A (en) | Preparation method of amlodipine maleate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130814 |