CN103086906B - Droxidopa crystal and preparation method thereof - Google Patents
Droxidopa crystal and preparation method thereof Download PDFInfo
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- CN103086906B CN103086906B CN201110342702.4A CN201110342702A CN103086906B CN 103086906 B CN103086906 B CN 103086906B CN 201110342702 A CN201110342702 A CN 201110342702A CN 103086906 B CN103086906 B CN 103086906B
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Abstract
The invention relates to a crystal A of droxidopa and its preparation method. The results of X-ray powder diffraction, infrared scanning and differential scanning calorimetry define a unique space structure of the droxidopa crystal A. The method for preparation of the droxidopa crystal A has the characteristics of simple process, low cost, short cycle, and can prepare the droxidopa crystal A with high purity, thus providing more forms of bulk drugs convenient for preparation production for the pharmaceutical preparation field.
Description
Technical field
Crystal form A that the present invention relates to Droxidopa and preparation method thereof.
Background technology
Droxidopa, English name Droxidopa, chemical name (-)-(2S, 3R)-2-amino-3-hydroxyl-3-(3,4-dihydroxy phenyl) propionic acid, chemical formula is as follows:
It is a kind of amino acid precursor of synthesis (-)-norepinephrine, be norepinephrine by intestinal absorption and metabolism, be mainly used in improving the stiff and positional vertigo of parkinsonism patient gait, and be used for the treatment of the medicine of postural hypotension.
JP 09-031038 discloses the preparation method of Droxidopa, and preparation flow is as follows:
Namely structural formula I obtains structural formula II under copper catalyst exists, then open loop, cancellation R and X group obtain the Droxidopa of structural formula III.
Also provide a kind of preparation method of Droxidopa in JP05 – 239025, preparation flow is as follows.
A kind of method preparing Droxidopa optically active body is disclosed: racemic Droxidopa is heated formation saturated solution soluble in water in JP 59-055861, after first time cooling, optically active Droxidopa of access control amount is as crystal seed, is incubated crystallization after second time cooling.A kind of purification process of Droxidopa is disclosed: be dissolved in by crude product Droxidopa in the alcoholic solvent of moisture and mineral acid, and then neutralize with organic or inorganic alkali, crystallization and obtain purifying in JP 64-022849.JP 59-055861 claims and can obtain optically active Droxidopa by the method, and JP 64-022849 then thinks that its purge process heats, and can avoid because heating the Droxidopa degraded caused.
Through the inquiry to pertinent literatures such as the preparation of Droxidopa or purification process, all there are no the report of Droxidopa crystal formation.According to the general knowledge of crystal, same molecular may have different crystalline forms, different crystal formations has unique and different physical propertiess, as fusing point, X-ray powder diffraction, IR collection of illustrative plates and solubleness etc., and then have direct impact to the ability of processing and/or useful in preparing drug formulations, as mobility, and solubleness, bioavailability and stability etc., so the different crystal exploring same molecular has its Practical significance.
For existing crystal characterization means, the constitutional features showing crystal that the particular crystal only reaching certain purity could repeat, and the formation of specific high-purity crystals affects by crystallization solvent, crystallization speed, temperature, crystal seed etc. are many-sided.Disclosed Droxidopa preparation or purification process are not specialized in its crystal before this, due to the not strict factors considering preparation high-purity crystals, even if the Droxidopa obtained has the existence of crystalline form to be also mixed crystal, because single crystalline form can not reach certain amount, and do not possess the value of crystal.
Summary of the invention
In view of the foregoing, Droxidopa crystal formation that the invention provides called after crystal form A and preparation method thereof, defines the space structure of this crystal uniqueness by X-ray powder diffraction, infrared scan and means of differential scanning calorimetry result.
Droxidopa crystal form A is that the X-ray powder diffraction of 18.9 °, 20.1 °, 21.0 °, 22.6 °, 24.0 °, 26.0 °, 30.0 °, 32.6 °, 35.2 ° is described by comprising 2 θ angles, wherein the 2 θ angles of peak relative intensity row front 2 are followed successively by 20.1 °, 24.0 °, have the X-ray powder diffraction pattern consistent with Fig. 1.The general precision of 2 θ values is in the scope of ± 0.2 °.
This Droxidopa crystal form A has at 3441cm
-1, 1660cm
-1, 1591cm
-1, 1522cm
-1, 1451cm
-1, 1405cm
-1, 1351cm
-1, 1288cm
-1, 1228cm
-1, 1117cm
-1wave number comprises the infared spectrum of absorption band, has the infrared scan figure consistent with Fig. 2.The general precision of wave number value is at ± 2cm
-1scope in.
This Droxidopa crystal form A, when differential scanning calorimetric analysis, has endotherm(ic)peak at 461 ± 1K and 496 ± 1K place respectively, has the differential scanning calorimetric thermogram consistent with Fig. 3.
Droxidopa crystal form A is prepared by following steps:
Step 1: Droxidopa crude product is placed in water, adds hydrochloric acid at room temperature clearly molten.
The feed ratio of Droxidopa crude product, water, hydrochloric acid is quality (g): volume (ml): quality (g)=1:4-6:05-0.6, preferably stirring and dissolving at 20-25 DEG C.The Droxidopa crude product dropped into can be prepared according to the method for document JP05 – 239025, or presses following formula preparation.
Step 2:
Add organic solvent to above solution, be cooled to 5-10 DEG C, maintain stirring 2 hours.One in organic solvent particular methanol herein, ethanol, acetone, tetrahydrofuran (THF), the feed ratio of Droxidopa crude product and organic solvent is quality (g): volume (ml)=1:4-6.
Step 3: regulate pH to be 4-5 with inorganic alkali solution again, can add the crystal seed of Droxidopa crystal form A when needing, mineral alkali herein can be the one in sodium carbonate, sodium bicarbonate, sodium hydroxide, salt of wormwood, saleratus, potassium hydroxide.Maintain stirring 2 hours, its crystallization is fully separated out, filter, gained solid must carry out washing (homogeneity that washing process can have influence on the crystal of acquisition) with appropriate organic solvent in (2).The stroke impact of the speed that alkaline solution adds on crystallization is little, but in order to obtain more homogeneous crystal formation, recommends N-process slowly.
Step 4: gained solid is in 40-50 DEG C of drying under reduced pressure 5-10 hour, and preferred 6-8 hour, obtains Droxidopa.Avoid overtemperature dry time dry, to prevent the transformation of crystal formation.
The Droxidopa that present method obtains is carried out X-ray powder diffraction, infrared scan and differential scanning calorimetric analysis, the result obtained and above-mentioned data consistent.Separately tested by specific optical rotation, the specific optical rotation recorded is at-38 °---and in the scope of 41 ° (JP15 specifies that qualified Droxidopa specific rotation scope is-38 °---43 °) and, confirm the highly purified target product crystal form A of acquisition that can be repeated by preparation method of the present invention further.
The analytical procedure that the present invention uses:
(1) X-ray powder diffraction analysis
Being placed in by sample has in the retainer of cavity, presses sample powder to guarantee irregular surface and correct height of specimen (if sample particle is excessive be unfavorable for sample preparation, being prepared after caning be passed through grinding) by slide glass or Equivalent.Use Cu (40KV, 30mA) as x-ray source, 1 ° of scatter slit, 0.30mm light intercepting slit, graphite secondary monochromator and scintillation counter with wide-angle goniometer, under 2 θ continuous sweep patterns, with the sweep velocity of 4.0 °/min, in the scope of 5 ° ~ 50 ° with the scanning step data acquisition of 0.02 °.
(2) infrared scan analysis
Sample thief 1-1.5mg puts in agate mortar with dry Potassium Bromide fine powder about 200 ~ 300mg and fully grinds well, and puts compression mold film-making, and obtained slice, thin piece answers transparent shape, and sample dispersion is even, there is no obvious particulate state sample.At 4000-400cm
-1inside carry out infrared scan.
(3) differential scanning calorimetric analysis
Sample 5 ~ 10mg is placed in platinum crucible, with the heating rate of 10K/min under drying nitrogen, image data in 320-560K.
(4) angle-of-rotation measuring
Get dry sample 0.25g, put in 50ml volumetric flask, add 0.1mol/L hydrochloric acid soln and make dissolving in right amount, and be diluted to scale, shake up, put in polarization tube that length is 1dm, measure specific rotation with the D line (589.3nm) of sodium spectrum, measuring temperature is 20 DEG C.Specific optical rotation is calculated by right formula:
In formula: α is the specific rotation recorded; L is the length of polarization tube, 1dm; C is the amount containing measured matter in 100ml solution, g (in dry product).
Compared with the method that the present invention and JP 59-05586 prepare Droxidopa optically active body, reaction conditions is gentle, it also avoid because heating the Droxidopa degraded caused.Compared with the purification process of JP 64-022849 Droxidopa, the stricter temperature controlling dissolving crude product, have adjusted scope and the consumption of solvent, the temperature and time of the alkali used when specify that crystallization and required pH condition and drying, this is all that repeatably to obtain high purity Droxidopa crystal A necessary.
Droxidopa crystal form A of the present invention, preparation technology is simple, cost is low, the cycle is short, can obtain high purity Droxidopa crystal form A, thus for field of pharmaceutical preparations provide be convenient to preparation produce bulk drug form.
The invention will be further described by the following examples, but except following examples, the various replacement made according to ordinary skill knowledge and customary means or change, include within the scope of the invention.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction pattern of Droxidopa crystal form A;
Fig. 2: Droxidopa crystal form A infrared scan figure;
Fig. 3: Droxidopa crystal form A differential scanning calorimetric thermogram.
Embodiment
Embodiment 1
L-revives-3-(3, 4-dihydroxy phenyl) preparation method 1 of Serine: successively by the methyl alcohol of 300kg and L-N-carbonylbenzyloxy-3-(3, 4-benzyloxy phenenyl) Serine 30kg adds in the hydrogenation reaction cauldron of 500L, the hydrochloric acid dripping 3mol/L makes dissolution of solid, add 5% palladium carbon 8kg, pass into hydrogen, pressure remains on 0.02Mpa, temperature of reaction controls at 40 ± 5 DEG C, react after 6 hours, exhaust, add concentrated hydrochloric acid 7kg and 0.3kg gac, stir 20 minutes, suction filtration, filtrate is 6-7 with the NaOH aqueous solution adjust pH of 30%, crystallization filters for 2 hours, obtain (reaction formula is as follows).
The preparation method 2 of L-Soviet Union-3-(3,4-dihydroxy phenyl) Serine:
Add dehydrated alcohol 100kg in a kettle., L-Soviet Union-3-(3 is added under stirring, 4-dihydroxy phenyl)-3-hydroxyl-2-adjacent benzene di-imidogen propionic acid, stirring at room temperature is clearly molten to solid, hydrazine hydrate liquid is dripped at 40-45 DEG C, after adding hydrazine hydrate, back flow reaction, after 16 hours, is cooled to less than 30 DEG C, drips concentrated hydrochloric acid 30kg, stir 1 hour at maintaining 30 DEG C, rejection filter, filter cake hydrochloric acid water washs once, and filtrate adjusts pH to be 6-7 with the NaOH aqueous solution of 30%, crystallization filters for 2 hours, obtains (reaction formula is as follows).
Embodiment 2
In the 250ml there-necked flask of cleaning, the Droxidopa crude product 5g that in Example 1, method 1 obtains, adds water 20ml, add hydrochloric acid 2.5g, 20-25 DEG C is stirred 0.5 hour, makes it complete clearly molten, add solvent acetone 24ml again, be cooled to 5-10 DEG C, maintain stirring 2 hours, regulate pH to be 4-5 with 20% sodium hydroxide solution again, maintain stirring 2 hours, its crystallization is fully separated out, filter, gained solid acetone 5ml washs, and 50 DEG C of dryings 5 hours of reducing pressure, obtain product 4.7g.
The product of acquisition is carried out specific rotation test, records specific rotation and be-39.2 °, in the acceptability limit that JP15 specifies.Carry out X-ray powder diffraction further, obtain the diffracting spectrum shown in Fig. 1, be that 18.9 °, 20.1 °, 21.0 °, 22.6 °, 24.0 °, 26.0 °, 30.0 °, 32.6 °, 35.2 ° places have diffraction peak at 2 θ angles, wherein the 2 θ angles of peak relative intensity row front 3 are followed successively by 20.1 °, 24.0 °, 21.0 °.Carry out infrared scan analysis, obtain the infrared scan figure shown in Fig. 2, at 3441cm
-1, 1660cm
-1, 1591cm
-1, 1522cm
-1, 1451cm
-1, 1405cm
-1, 1351cm
-1, 1288cm
-1, 1228cm
-1, 1117cm
-1wave number comprises absorption band.Carry out differential scanning calorimetric analysis, have endotherm(ic)peak at 461K and 496K place respectively, obtain the differential scanning calorimetric thermogram shown in Fig. 3.Such analysis confirms the Droxidopa crystal form A being obtained the present invention's name by this preparation process.
Embodiment 3
In the 250ml there-necked flask of cleaning, the Droxidopa crude product 5g that in Example 1, method 1 obtains, add water 20ml, add hydrochloric acid 3.0g, 20-25 DEG C is stirred 0.5 hour, makes it complete clearly molten, then add solvent methanol 24ml, be cooled to 5-10 DEG C, maintain stirring 2 hours, then regulate pH to be 4-5 with 50% sodium carbonate solution, add the crystal seed 0.1g of Droxidopa crystal form A, maintain stirring 2 hours, its crystallization is fully separated out, and filter, gained solids with methanol 5ml washs, to reduce pressure 45 DEG C of dryings 10 hours, obtain product 4.8g.
The product of acquisition is carried out specific rotation test, records specific rotation and be-40.1 °, in the acceptability limit that JP15 specifies.Carry out X-ray powder diffraction further, in the scope of general precision ± 0.2 of 2 θ values °, obtain the diffracting spectrum consistent with Fig. 1.Carry out infrared scan analysis, at the general precision ± 2cm of wave number value
-1scope in, obtain the infrared scan figure consistent with Fig. 2.Carry out differential scanning calorimetric analysis, in the scope of the general precision ± 1K of temperature, obtain the differential scanning calorimetric thermogram consistent with Fig. 3.Such analysis confirms the Droxidopa crystal form A being obtained the present invention's name by this preparation process.
Embodiment 4
In the 250ml there-necked flask of cleaning, the Droxidopa crude product 5g that in Example 1, method 2 obtains, add water 22ml, add hydrochloric acid 2.7g, 15-20 DEG C is stirred 0.5 hour, makes it complete clearly molten, then add etoh solvent 22ml, be cooled to 5-10 DEG C, maintain stirring 2 hours, then regulate pH to be 4-5 with 20% potassium hydroxide solution, add the crystal seed 0.1g of Droxidopa crystal form A, maintain stirring 2 hours, its crystallization is fully separated out, and filter, gained solid ethanol 5ml washs, to reduce pressure 50 DEG C of dryings 6 hours, obtain product 4.7g.
The product of acquisition is carried out specific rotation test, records specific rotation and be-39.5 °, in the acceptability limit that JP15 specifies.Carry out X-ray powder diffraction, infrared scan, differential scanning calorimetric analysis further, confirm the Droxidopa crystal form A being obtained the present invention's name by this preparation process.
Embodiment 5
In the 250ml there-necked flask of cleaning, the Droxidopa crude product 5g that in Example 1, method 2 obtains, add water 20ml, add hydrochloric acid 2.5g, stirring at room temperature 0.5 hour, makes it complete clearly molten, then adds solvents tetrahydrofurane 20ml, be cooled to 5-10 DEG C, maintain stirring 2 hours, then regulate pH to be 4-5 with 50% potassium bicarbonate solution, add the crystal seed 0.05g of Droxidopa crystal form A, maintain stirring 2 hours, its crystallization is fully separated out, and filter, gained solid tetrahydrofuran (THF) 5ml washs, to reduce pressure 47 DEG C of dryings 8 hours, obtain product 4.6g.
The product of acquisition is carried out specific rotation test, records specific rotation and be-38.5 °, in the acceptability limit that JP15 specifies.Carry out X-ray powder diffraction, infrared scan, differential scanning calorimetric analysis further, confirm the Droxidopa crystal form A being obtained the present invention's name by this preparation process.
Claims (5)
1. Droxidopa crystal form A, it has the X-ray powder diffraction comprising peak at the 2 θ angles of 18.9 ± 0.2 °, 20.1 ± 0.2 °, 21.0 ± 0.2 °, 22.6 ± 0.2 °, 24.0 ± 0.2 °, 26.0 ± 0.2 °, 30.0 ± 0.2 °, 32.6 ± 0.2 °, 35.2 ± 0.2 °.
2. Droxidopa crystal form A as claimed in claim 1, the 2 θ angles that wherein the X-ray powder diffraction of crystal form A comprises peak relative intensity row front 2 are followed successively by 20.1 ± 0.2 °, 24.0 ± 0.2 °.
3. Droxidopa crystal form A as claimed in claim 1, wherein crystal form A has at 3441 ± 2cm
-1, 1660 ± 2cm
-1, 1591 ± 2cm
-1, 1522 ± 2cm
-1, 1451 ± 2cm
-1, 1405 ± 2cm
-1, 1351 ± 2cm
-1, 1288 ± 2cm
-1, 1228 ± 2cm
-1, 1117 ± 2cm
-1wave number comprises the infared spectrum of absorption band.
4. Droxidopa crystal form A as claimed in claim 1, wherein crystal form A has endotherm(ic)peak at 461 ± 1K and 496 ± 1K place respectively when differential scanning calorimetric analysis.
5. Droxidopa crystal form A as claimed in claim 1, wherein crystal form A is prepared by following steps:
1': Droxidopa crude product is placed in water, add hydrochloric acid stirs clearly molten at 20-25 DEG C, and the consumption of Qi Zhongshui, hydrochloric acid is in Droxidopa crude product quality (g): volume of water (ml): the ratio of hydrochloric acid quality (g)=1:4-6:0.5-0.6 feeds intake;
2': add methyl alcohol, ethanol, acetone or tetrahydrofuran solvent to above solution, the consumption of organic solvent is in Droxidopa crude product quality (g): the ratio of organic solvent volume (ml)=1:4-6 feeds intake, be cooled to 5-10 DEG C, maintain stirring 2 hours;
3': regulate pH to be 4-5 with inorganic alkali solution again, can add the crystal seed of Droxidopa crystal form A when needing, maintain stirring 2 hours, its crystallization is fully separated out, filter, the solvent in gained solid 2' washs; Wherein said mineral alkali is the one in sodium carbonate, sodium bicarbonate, sodium hydroxide, salt of wormwood, saleratus, potassium hydroxide.
4': gained solid, in 40-50 DEG C of drying under reduced pressure 5-10 hour, obtains target product Droxidopa crystal form A.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0141613A2 (en) * | 1983-11-04 | 1985-05-15 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | A process for producing an optically active 3-(3,4-dihydroxphenyl) serine and a proteced derivative thereof |
| WO2005085178A1 (en) * | 2004-03-05 | 2005-09-15 | Estechpharma Co., Ltd. | Method of preparing optically active serine derivative |
| WO2006123678A1 (en) * | 2005-05-18 | 2006-11-23 | Dainippon Sumitomo Pharma Co., Ltd. | Stable tablet containing droxidopa |
| CN101657193A (en) * | 2007-03-09 | 2010-02-24 | 切尔西治疗公司 | The droxidopa and the pharmaceutical composition thereof that are used for the treatment of fibromyalgia |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60160895A (en) * | 1984-01-31 | 1985-08-22 | Sumitomo Chem Co Ltd | Preparation of optically active-threo-3-(3,4- dihydroxyphenyl)serine |
| JPH0796537B2 (en) * | 1987-07-16 | 1995-10-18 | 住友製薬株式会社 | Method for purifying 3- (3,4-dihydroxyphenyl) serine |
-
2011
- 2011-11-03 CN CN201110342702.4A patent/CN103086906B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0141613A2 (en) * | 1983-11-04 | 1985-05-15 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | A process for producing an optically active 3-(3,4-dihydroxphenyl) serine and a proteced derivative thereof |
| WO2005085178A1 (en) * | 2004-03-05 | 2005-09-15 | Estechpharma Co., Ltd. | Method of preparing optically active serine derivative |
| WO2006123678A1 (en) * | 2005-05-18 | 2006-11-23 | Dainippon Sumitomo Pharma Co., Ltd. | Stable tablet containing droxidopa |
| CN101657193A (en) * | 2007-03-09 | 2010-02-24 | 切尔西治疗公司 | The droxidopa and the pharmaceutical composition thereof that are used for the treatment of fibromyalgia |
Non-Patent Citations (1)
| Title |
|---|
| 屈昔多巴的合成;李鸿波等;《合成化学》;20101231;第18卷(第1期);124-127页 * |
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