CN107619377A - A kind of novel crystal forms of fortimicin intermediate and application thereof - Google Patents
A kind of novel crystal forms of fortimicin intermediate and application thereof Download PDFInfo
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- CN107619377A CN107619377A CN201610555492.XA CN201610555492A CN107619377A CN 107619377 A CN107619377 A CN 107619377A CN 201610555492 A CN201610555492 A CN 201610555492A CN 107619377 A CN107619377 A CN 107619377A
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- crystal formation
- methine
- chloro
- terramycin
- crystal
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- 239000013078 crystal Substances 0.000 title claims abstract description 62
- 229930195503 Fortimicin Natural products 0.000 title claims abstract description 16
- BIDUPMYXGFNAEJ-APGVDKLISA-N astromicin Chemical compound O[C@@H]1[C@H](N(C)C(=O)CN)[C@@H](OC)[C@@H](O)[C@H](N)[C@H]1O[C@@H]1[C@H](N)CC[C@@H]([C@H](C)N)O1 BIDUPMYXGFNAEJ-APGVDKLISA-N 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 47
- 229940063650 terramycin Drugs 0.000 claims abstract description 28
- KIPLYOUQVMMOHB-MXWBXKMOSA-L [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O Chemical compound [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O KIPLYOUQVMMOHB-MXWBXKMOSA-L 0.000 claims abstract description 27
- 229950004288 tosilate Drugs 0.000 claims abstract description 18
- 238000005755 formation reaction Methods 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000002329 infrared spectrum Methods 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 238000002076 thermal analysis method Methods 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000012452 mother liquor Substances 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910002483 Cu Ka Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
Abstract
The invention discloses a kind of novel crystal forms A of the methine terramycin tosilate of 11 α chlorine 6.The novel crystal forms A of the present invention solves the problems, such as solid block in existing crystal formation, can be achieved with the separation of solid and mother liquor with conventional rejection filter centrifuge, and obtained solid is loose, it is easier to baking material and directly progress next step reaction.Therefore, by the preparation of crystal formation of the present invention, fortimicin more can easily be prepared, be more suitable for the industrialized production of fortimicin, be with a wide range of applications.
Description
Technical field
The present invention relates to pharmaceutical intermediate field, and in particular to 11- α-chloro- 6- methine terramycin tosilate
A kind of novel crystal forms.
Background technology
Fortimicin is tetracycline antibiotics medicine, and antibacterial effect is more stronger than natural product, and purposes scope is wider, drug resistance
Small, its dosage in pig, chicken and toy is big.
Fortimicin also known as doxycycline, it is semi-synthetic tetracycline medication, and its synthetic route is as follows：
The raw material 11- α of the reaction-chloro- 6- methine terramycin tosilate is the key intermediate of fortimicin.
However, in current actual production process, the 11- α-chloro- 6- methines terramycin being prepared is to toluene sulphur
Hydrochlorate is a kind of sticky and caking crystal (being temporarily referred to as crystal formation B).This product state is frequently run onto in chemical synthesis
Situation, those skilled in the art are made to feel intractable deeply, it brings very big difficulty to the separation of post processing especially product..
For the sticky crystal of 11- α-chloro- 6- methine terramycin tosilate, consolidating for crystallization is mainly reflected in
Body parcel mother liquor lumps and makes material be difficult to flow, so as to need a large amount of manpowers to pass through manual mode blowing in amplification production.
Also, because that obtain is crystal formation B, the good separation of solid and mother liquor can not be realized with conventional rejection filter centrifuge, must not
Plate and frame filter press is not used to filter, obtained solid block and hardness is big could be carried out after also needing to mechanical crushing after drying
React in next step, be extremely unfavorable for fortimicin industrialized production.
Therefore, need to need badly at present to seek a kind of new mode, particularly a kind of novel crystal forms prevented from caking so that strength
The large-scale production process of mycin more can be carried out smoothly.
The content of the invention
To solve the above problems, the invention provides a kind of 11- α-chloro- 6- methine terramycin tosilate crystal formations
A, in the X-ray powder diffraction of the crystal formation, 2 θ angle of diffraction are 8.79 ± 0.20,9.79 ± 0.20,10.76 ± 0.20,11.67
There is feature at ± 0.20,14.67 ± 0.20,15.69 ± 0.20,18.93 ± 0.20,23.69 ± 0.20,24.68 ± 0.20 degree
Peak.
Further, in the crystal formation X-ray powder diffraction, 2 θ angle of diffraction are also 6.54 ± 0.20,13.41 ± 0.20,
14.67±0.20、15.69±0.20、18.93±0.20、19.23±0.20、9.90±0.20、20.35±0.20、21.70
±0.20、21.97±0.20、22.31±0.20、23.07(±0.20、24.06±0.20、25.48±0.20、27.37±
0.20、27.94±0.20、28.49±0.20、30.19±0.20、31.23±0.20、33.79±0.20、35.20±0.20、
36.01±0.20、36.63±0.20、37.47±0.20、38.67±0.20、39.18±0.20、41.80±0.20、43.60
There is characteristic peak at ± 0.20,44.64 ± 0.20,46.72 ± 0.20 degree.
Further, in the crystal formation X-ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is：
Further, the crystal formation has X-ray powder diffraction pattern substantially as shown in Figure 1.
Further, in the differential scanning calorimetric analysis curve of the crystal formation, melt initiation temperature degree is 205 ± 3 DEG C, and peak value is most
The temperature of general goal is 216 ± 2 DEG C.
Further, the crystal formation has differential scanning calorimetric analysis curve substantially as shown in Figure 2.
Further, the infrared spectrum of the crystal formation 3362.3,3247.3,3137.9,1678.5,1645.1,1620.8,
753.4、732.9、645.9、628.9、605.5567.0、532.2、531.3、458.0、429.2cm-1There is characteristic absorption peak at place.
Determined by KBr tablettings.
Further, the crystal formation has following characteristics infrared absorption peak：
Wherein, s represents strong, and m represents medium, and w represents weak, and vw represents extremely weak.
Present invention also offers the method for the crystal formation A, it is characterised in that：It comprises the following steps：
(1) in ethanol, 11- α-chloro- 6- methine terramycin crude products and p-methyl benzenesulfonic acid are reacted；
(2) more than 60 DEG C are heated to, is naturally cooling to 20~30 DEG C of crystallizations；
(3) crystal is isolated, is drying to obtain.
Present invention also offers a kind of method for preparing fortimicin, methods described is mould with 11- α-chloro- 6- methine soil
Plain mesylate crystals are raw material, the method that fortimicin is prepared；Wherein, 11- α-chloro- 6- methine terramycin methanesulfonic acids
Salt is prepared by preceding method.
The novel crystal forms A of the present invention solves the problems, such as solid block in existing crystal formation, with conventional rejection filter centrifuge with regard to energy
The separation of solid and mother liquor is realized, and obtained solid is loose, it is easier to baking material and directly progress next step reaction.Therefore, lead to
Crystal formation A of the present invention preparation is crossed, fortimicin more can easily be prepared, the industrialization for being more suitable for fortimicin is raw greatly
Production, is with a wide range of applications.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Brief description of the drawings
Fig. 1 is radiates using Cu-Ka, 11- α of the present invention-chloro- 6- methine terramycin tosilate crystal formations A X
Ray powder diffraction.
Fig. 2 is 11- α of the present invention-chloro- 6- methine terramycin tosilate crystal formations A DSC collection of illustrative plates.
Fig. 3 is 11- α of the present invention-chloro- 6- methine terramycin tosilate crystal formations A TGA collection of illustrative plates.
Fig. 4 is 11- α of the present invention-chloro- 6- methine terramycin tosilate crystal formations A infrared spectrogram.
Fig. 5 is radiates using Cu-Ka, 11- α-chloro- 6- methine terramycin tosilate crystal formations B x-ray powder
Diffracting spectrum.
Fig. 6 is 11- α-chloro- 6- methine terramycin tosilate crystal formations B DSC collection of illustrative plates.
Fig. 7 is 11- α-chloro- 6- methine terramycin tosilate crystal formations B TGA collection of illustrative plates.
Fig. 8 is 11- α-chloro- 6- methine terramycin tosilate crystal formations B infrared spectrogram.
Embodiment
11- α-chloro- 6- methine terramycin crude products reaction solution used obtains for single step reaction thereon in following embodiments
The ethanol solution arrived, its HPLC purity is between 70%~80%, and maximum single miscellaneous HPLC purity is between 5%~8%.
The 11- α of the present invention of embodiment 1-chloro- 6- methine terramycin tosilate crystal formations A preparation
Crude product reaction solution containing 300g 11- α-chloro- 6- methine terramycin is added in 3L reaction bulbs 1.Will
97.5g p-methyl benzenesulfonic acid is added in 500mL reaction bulb 2, and the ethanol for adding 100mL stirs to form solution.
Under stirring, by the crude product in solution of the 11- α in reaction bulb 1-chloro- 6- methine terramycin, reaction bulb 2 is added
In p-methyl benzenesulfonic acid solution, solution is heated to more than 60 DEG C, 20~30 DEG C is naturally cooling to until solid precipitation, continues to stir
Separate out completely to most of solid within 4~6 hours.Gained solid is filtered, crystalline product 345.2g is obtained after drying.Yield
84.5%, HPLC purity 96.18%.Solid is analyzed and identified as 11- α-chloro- 6- methine terramycin through XRD, TGA, DSC and IR
Tosilate crystal formation A, measurement result is as Figure 1-4.
In actual production, the separation of crystal formation and mother liquor can be achieved with using conventional rejection filter centrifuge, and what is obtained consolidates
Body is loose, it is easier to baking material and directly progress next step reaction.
The 11- α of comparative example 1-chloro- 6- methine terramycin tosilate crystal formations B preparation
97.5g g p-methyl benzenesulfonic acid is added in 3L reaction bulb 2, the ethanol for adding 100mL stirs to form solution.
Under stirring, the crude product reaction solution containing 300g 11- α-chloro- 6- methine terramycin is added to pair of reaction bulb 2
In toluenesulfonic acid solution, until solid separates out, stopping stirring, system forms rapidly a monoblock, stands crystallization 4~6 hours.Will be whole
Block solid is smashed to pieces, obtains thick paste, filtering, and crystalline product 337.1g is obtained after drying.Yield 82.6%, HPLC purity
94.54%.Solid is analyzed and identified as 11- α-chloro- 6- methine terramycin tosilate crystalline substance through XRD, TGA, DSC and IR
Type B, measurement result is as viewed in figures 5-8.
In actual production, whole reactor forms one piece, it is necessary to manually smash to pieces and feed liquid is manually imported into plate compression
Machine, whole process needs to expend huge muscle power, and feed liquid discharges sour gas during smashing to pieces, and smell is pungent.Gained is consolidated
Body caking is serious, needs that after mechanical crushing next step reaction could be carried out after drying.
In summary, novel crystal forms A of the invention solves the problems, such as solid block in existing crystal formation, with conventional rejection filter from
Scheming can be achieved with the separation of solid and mother liquor, and obtained solid is loose, it is easier to baking material and directly progress next step reaction.
Therefore, by the preparation of crystal formation of the present invention, fortimicin more can easily be prepared, be more suitable for the industry of fortimicin
Change big production, be with a wide range of applications.
Claims (10)
- A kind of 1. 11- α-chloro- 6- methine terramycin tosilate crystal formations A, it is characterised in that：The X ray powder of the crystal formation In last diffraction, 2 θ angle of diffraction 8.79 ± 0.20,9.79 ± 0.20,10.76 ± 0.20,11.67 ± 0.20,14.67 ± 0.20th, there is characteristic peak at 15.69 ± 0.20,18.93 ± 0.20,23.69 ± 0.20,24.68 ± 0.20 degree.
- 2. crystal formation A according to claim 1, it is characterised in that：In the crystal formation X-ray powder diffraction, 2 θ angle of diffraction are also 6.54 ± 0.20,13.41 ± 0.20,14.67 ± 0.20,15.69 ± 0.20,18.93 ± 0.20,19.23 ± 0.20,9.90 ±0.20、20.35±0.20、21.70±0.20、21.97±0.20、22.31±0.20、23.07(±0.20、24.06± 0.20、25.48±0.20、27.37±0.20、27.94±0.20、28.49±0.20、30.19±0.20、31.23±0.20、 33.79±0.20、35.20±0.20、36.01±0.20、36.63±0.20、37.47±0.20、38.67±0.20、39.18 There is characteristic peak at ± 0.20,41.80 ± 0.20,43.60 ± 0.20,44.64 ± 0.20,46.72 ± 0.20 degree.
- 3. crystal formation A according to claim 2, it is characterised in that：In the crystal formation X-ray powder diffraction, 2 θ angle of diffraction are special Sign peak relative intensity value be：
- 4. crystal formation A according to claim 1, it is characterised in that：The crystal formation has x-ray powder substantially as shown in Figure 1 Diffracting spectrum.
- 5. crystal formation A according to claim 1, it is characterised in that：In the differential scanning calorimetric analysis curve of the crystal formation, melting Initial temperature is 205 ± 3 DEG C, and the temperature of peak value maximum is 216 ± 2 DEG C.
- 6. crystal formation A according to claim 5, it is characterised in that：The crystal formation has differential scanning amount substantially as shown in Figure 2 Thermal analysis curve.
- 7. crystal formation A according to claim 1, it is characterised in that：The infrared spectrum of the crystal formation is 3362.3,3247.3, 3137.9、1678.5、1645.1、1620.8、753.4、732.9、645.9、628.9、605.5567.0、532.2、531.3、 458.0、429.2cm-1There is characteristic absorption peak at place.
- 8. crystal formation A according to claim 7, it is characterised in that：The crystal formation has following characteristics infrared absorption peak：Wherein, s represents strong, and m represents medium, and w represents weak, and vw represents extremely weak.
- A kind of 9. method for preparing any one of the claim 1-8 crystal formation A, it is characterised in that：It comprises the following steps：(1) in ethanol, 11- α-chloro- 6- methine terramycin crude products and p-methyl benzenesulfonic acid are reacted；(2) more than 60 DEG C are heated to, is naturally cooling to 20~30 DEG C of crystallizations；(3) crystal is isolated, is drying to obtain.
- A kind of 10. method for preparing fortimicin, it is characterised in that：It comprises the following steps：(1) the 11- α being prepared in accordance with the method for claim 9-chloro- 6- methine terramycin mesylate crystals；(2) using 11- α-chloro- 6- methine terramycin mesylate crystals as raw material, fortimicin is prepared.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686634A (en) * | 1994-07-01 | 1997-11-11 | Pfizer, Inc. | Process for producing 5-hydroxy-6-demethyl-6-desoxy-6-methylene-11A-chlorotetracycline |
| CN103467336A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline |
| CN105152961A (en) * | 2015-08-31 | 2015-12-16 | 河南师范大学 | Doxycycline midbody 6-methenyl oxytetracycline synthesis method |
-
2016
- 2016-07-14 CN CN201610555492.XA patent/CN107619377A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686634A (en) * | 1994-07-01 | 1997-11-11 | Pfizer, Inc. | Process for producing 5-hydroxy-6-demethyl-6-desoxy-6-methylene-11A-chlorotetracycline |
| CN103467336A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline |
| CN105152961A (en) * | 2015-08-31 | 2015-12-16 | 河南师范大学 | Doxycycline midbody 6-methenyl oxytetracycline synthesis method |
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Application publication date: 20180123 |