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CN1629161A - Methane sulfonic acid dolasetron crystallographic form and its preparation method - Google Patents

Methane sulfonic acid dolasetron crystallographic form and its preparation method Download PDF

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CN1629161A
CN1629161A CN 200410074654 CN200410074654A CN1629161A CN 1629161 A CN1629161 A CN 1629161A CN 200410074654 CN200410074654 CN 200410074654 CN 200410074654 A CN200410074654 A CN 200410074654A CN 1629161 A CN1629161 A CN 1629161A
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dolasetron
acid
sulfonic acid
methane sulfonic
alcohol
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CN100390172C (en
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秦勇
郭陪良
辛军国
王印
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Haisike Pharmaceutical Meishan Co ltd
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CHENGDU XINJIE HI-TECH DEVELOPMENT Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

The invention discloses a methane sulfonic acid dolasetron crystallographic form and its preparation method, which is a white powder form crystallization with a melting point of 160-170 deg. C, differential thermal analysis peak of 434-437K, peak range of 420K-445K. The invention can be applied for treating antimigraine and vomit caused by surgery or medicament having cell toxicity.

Description

A kind of methane sulfonic acid dolasetron crystallographic form and preparation method thereof
Technical field
The present invention relates to a kind of methane sulfonic acid dolasetron crystallographic form and preparation method thereof.
Background technology
Dolasetron mesilate (dolasetron mesylate) is containing of the synthetic serotonin hypotype 5HT pseudopelletierine skeleton, that have high specific activity and highly selective 3Receptor antagonist is widely used in treatment migraine and similar conditions clinically, and treatment is owing to operation or by having the caused vomiting of Cytotoxic medicine (M.W.Gittos and M.Fatmi, Actual.Chim.Ther.1989,16,187; US4906755).
Figure A20041007465400041
Figure one, dolasetron mesilate-hydrate
Dolasetron?mesylate?monohydrate)
The chemical structure of dolasetron mesilate as shown above, its chemistry (indole-3-carboxylic acid-2 α, 6 α, 8 α, 9 α β)-octahydro-3-oxygen-2 by name, 6-methylene radical-dihydro-quinoline-8-ester one water beetle sulfonate.At present known its unique a kind of monohydrate (dolasetron-methylsulfonic acid-water) is that to have fusing point be a kind of crystal formation of 278 ℃, and the fusing point of this crystal formation is higher.
Dolasetron internal metabolism approach
As implied above, the ketone group of dolasetron at first is reduced to dolasetron (the J.Dow et al.Chirality 1995,7,342 that hydroxyl becomes the reduction form by carbonyl reductase in vivo; H.Boxenbaum et al.Biopharm.Drug Dispos.1992,13,693; H.Boxenbaumet al.Biopharm.Drug Dispos.1993,14,131).Although that directly plays drug effect in the body is the dolasetron of reduction form, and the dolasetron activity that in vitro tests shows the reduction form is at least than strong (the P.H.Boeijinga et al.Euro.J.Pharm.1992 more than 35 times of dolasetron, 219,9), but owing to the dolasetron of reduction form GI low specific absorption got rid of directly with the dolasetron administration of reduction form may.There is gi tract perviousness difference in the dolasetron of existing crystal formation itself and is easy to be reduced at the liver position and is removed external shortcoming fast, cause its shortcoming that also has lower bioavailability (J.Dow et al.J.Pharm.Sciences 1996,85,685), thereby need bigger dosage.The dolasetron mesilate of preparation different crystal forms perhaps is one of feasible method that improves the dolasetron bioavailability.
Summary of the invention
The technical issues that need to address of the present invention just are to overcome the defective of existing dolasetron mesilate crystal formation, a kind of methane sulfonic acid dolasetron crystallographic form is provided, its stability is high, can satisfy all requirements as preparation raw material, can be used for treating migraine and similar conditions clinically, and treatment is by having the caused vomiting of Cytotoxic medicine.
For addressing the above problem, the present invention adopts following technical scheme:
Methane sulfonic acid dolasetron crystallographic form of the present invention, it is a kind of white powdery crystallization, and having fusing point is 160-170 ℃, and the differential thermal analysis peak value is 434-437K, and going out the peak value scope is 420K to 445K, molecular composition is C 19H 20N 2O 3.CH 4O 3S.H 2O, molecular structure is as follows
Figure A20041007465400051
Dolasetron mesilate-hydrate
(Dolasetron?mesylate?monohydrate)
Preferably, methane sulfonic acid dolasetron crystallographic form fusing point of the present invention is 160-165 ℃, and more preferably, fusing point is 162-164 ℃
The present invention also provides a kind of preparation method of described methane sulfonic acid dolasetron crystallographic form, it is to be set out by the free amine of dolasetron, under the acid catalysis effect,, and set out hydrolysis and recrystallization from water by dolasetron alcohol ketal compound with pure condensation prepared dolasetron alcohol ketal compound.
The free amine of dolasetron of the present invention is indole-3-carboxylic acid-2 α, 6 α, 8 α, 9 α β-octahydros-3-oxygen-2,6-methylene radical-dihydro-quinoline-8-ester, described acid comprises methylsulfonic acid, tosic acid, tosic acid and tosic acid pyridinium salt, described alcohol is the straight or branched alcohol of one to eight carbon atom, the alcohol of 3 to 8 yuan of rings, and the adjacent glycol of two to eight carbon atoms, described condensation reaction condition is meant above-mentioned free amine, pure and mild acid be heated to 60-150 ℃ 1 to 24 hour, described hydrolysis reaction condition to be dolasetron alcohol ketal product and mesylate thereof be heated in the presence of greater than 1 normal methylsulfonic acid 10-100 ℃ 0.5 to 30 hour, described recrystallization condition is that the said hydrolyzed reaction solution is concentrated and static in room temperature.
Its bioavailability in vivo is closely related when the crystal formation of drug molecule and stability of drug and oral administration.On the ordinary meaning, have better bioavailability than dystectic crystal formation during the low-melting crystal formation oral administration of same medicine, show different pharmacokineticss.
The ketone group of dolasetron at first is reduced to dolasetron (the J.Dow et al.Chirality 1995,7,342 that hydroxyl becomes the reduction form by carbonyl reductase in vivo; H.Boxenbaum etal.Biopharm.Drug Dispos.1992,13,693; H.Boxenbaum et al.Biopharm.Drug Dispos.1993,14,131).Although that directly plays drug effect in the body is the dolasetron of reduction form, and the dolasetron activity that in vitro tests shows the reduction form is at least than strong (the P.H.Boeijinga et al.Euro.J.Pharm.1992 more than 35 times of dolasetron, 219,9), but owing to the dolasetron of reduction form GI low specific absorption got rid of directly with the dolasetron administration of reduction form may.Also there is gi tract perviousness difference in dolasetron itself and is easy to be reduced at the liver position and is removed external shortcoming fast, cause its shortcoming that also has lower bioavailability (J.Dow et al.J.Pharm.Sciences 1996,85,685), thereby need bigger dosage.The dolasetron derivative that contains different functional groups especially can increase its ester dissolubility and can prolong it by the carbonyl reductase reductive time, perhaps is one of feasible method that improves the dolasetron bioavailability.
The present invention prepares dolasetron alcohol ketal precursor by a new building-up process, and by a so pure ketal precursor preparation to have fusing point be that fusing point is the dolasetron mesilate of 160-170 ℃ specific crystal formation, it is 278 ℃ of chemical structure and chemical constitutions that dolasetron mesilate is identical that this crystal formation has with fusing point.
Figure A20041007465400071
Fusing point is the preparation of dolasetron one water beetle sulfonate of 162-164 ℃ specific crystal formation
Dolasetron alcohol ketal precursor compound has above-mentioned molecular structure and composition.Wherein R is that straight chain, the branched-chain alkyl or 3 of 1 to 8 carbon atom causes the replacement of 8 yuan of rings, the cyclic alkyl of non-replacement; What R-R linked to each other is the glycol ketal segment of the replacement of 5,6 yuan of rings, non-replacement.The pure ketal precursor compound of the dolasetron shown in hydrolysis is above-mentioned, hydrolysate water recrystallization obtain a water beetle sulfonic acid dolasetron, are the crystallization of off-white color powdery, have fusing point and be 160-170 ℃ specific crystal formation.Prepare dolasetron mesilate by the hydrolysis of dolasetron alcohol ketal precursor compound, can not only prepare fusing point is that fusing point is 160-170 ℃ a novel crystal formation, and this method makes target product be easy to separate with micro-coloring matter with impurity.
The precursor compound of dolasetron alcohol ketal can be by corresponding absolute alcohol and the high yield preparation of the free amine of dolasetron reflux dewatering under the katalysis of acid.The reflux dewatering in the presence of the monovalent methylsulfonic acid when free amine of dolasetron and dehydrated alcohol, getting fusing point is the dolasetron mesilate white crystals of 247 ℃ diethoxy condensation.And different therewith be that what free amine of dolasetron and ethanol were heated in the presence of about monovalent methylsulfonic acid after 60 ℃ that direct recrystallization obtains but is that fusing point is 278 ℃ of dolasetron mesilate off-white color powdery crystallizations (US4906755).
By the resulting fusing point of the synthesis preparation method of pure ketal precursor compound is that a water beetle sulfonic acid dolasetron of 160-170 ℃ of specific crystal formation has the identical activity of a water beetle sulfonic acid dolasetron that the fusing point of being declared with dolasetron drug development merchant is 278 ℃ a crystal formation.And this stable crystal form height, fusing point is lower, may have bioavailability preferably, can satisfy all requirements as preparation raw material better.The precursor compound of the dolasetron mesilate of new crystal and dolasetron alcohol ketal is serotonin hypotype 5HT 3Receptor antagonist can be used for treating migraine and similar conditions clinically, and treatment is owing to operation or by having the caused vomiting of Cytotoxic medicine.
Description of drawings
Fig. 1 is the X light powder diffraction collection of illustrative plates of new crystal of the present invention.
Fig. 2 is the differential thermal analysis collection of illustrative plates (DSC) of new crystal of the present invention.
Embodiment
The dolasetron mesilate preparation of embodiment 1 diethoxy condensation
With the free amine of dolasetron (80.58,0.25mol) be dissolved in the 480mL dehydrated alcohol, and add 10g gac and methylsulfonic acid (23.9g, 0.25mol).Gained solution refluxed 8 hours under nitrogen protection.Filter, be cooled to standing over night after the room temperature, separate out white crystals.Crystallization is filtered, and natural air drying obtains the dolasetron mesilate of 118.5g (96.0% productive rate) diethoxy condensation, fusing point 218-220 ℃.IR:3229,2982,2579,1708,1531,1442,1309,1213,1160,1128,1106,1060,1032cm -1 1H NMR (400MHz, DMSO-d 6) (J=2.4Hz), 9.80 (s, 1H add D to δ 11.98 for d, 1H 2O disappears), 8.04 (q, 2H, J=2.7Hz), 7.52 (m, 1H), 7.22 (m, 2H), 5.31 (d, 1H, J=2.4Hz), 3.74 (d, 2H, J=4.4Hz), 3.44 (m, 4H), 3.38 (s, 2H), 2.33 (s, 3H), 2.16 (m, 8H), 1.15 (t, 6H, J=7.2Hz) ppm; 13C NMR (400MHz, DMSO-d 6) δ 163.22,136.69,132.63,126.07,122.73,121.62,120.23,112.72,106.16,97.72,62.98,58.32,56.16,49.49,40.11,31.97,28.40,23.93,15.14ppm; 13C NMR (DMSO-d 6) Dept (135 °) Up (CH, CH3): δ 136.69,122.73,121.62,120.23,112.72,62.98,49.49,40.11,28.40,15.14ppm; Dept (135 °), Down (CH 2): δ 58.32,56.16,31.97,23.93ppm; Dept (90 °, CH) δ 136.69,122.73,121.62,120.23,112.70,62.98,49.49,28.40ppm; Ultimate analysis (C 24H 34N 2O 7S 1), calculate: C, 58.24; H, 6.88; N, 5.66; S, 6.47; Actual measurement: C, 58.19; H, 6.86; N, 5.70; S, 6.50; (MS 398, FAB): 397 (M-1 for mass spectrum +).
The dolasetron preparation of embodiment 2 ethylene glycol condensations
Figure A20041007465400101
It is similar that reaction process and the dolasetron mesilate of diethoxy condensation prepare, the free amine of dolasetron is dissolved in the 5 normal ethylene glycol, and add 1 normal methylsulfonic acid heating to 85 ℃ 10 hours.To pour 10% sodium carbonate solution into, ethyl acetate extraction after the reaction solution cooling.Anhydrous magnesium sulfate drying, column chromatography for separation (ethyl acetate is an eluent) gets the dolasetron of ethylene glycol condensation. 1H?NMR(400MHz，CDCl 3)δ8.85(s，1H)，8.27(m，1H)，7.83(d，1H，J＝2.8Hz)，7.43(m，1H)，7.29(m，2H)，5.41(m，1H)，3.96(m，2H)，3.90(m，2H)，3.14(m，2H)，3.08(s，2H)，2.13(d，4H，J＝3.6Hz)，2.07(m，4H)，1.89(m，1H)。
Embodiment 3 fusing points are a 162-164 ℃ of water beetle sulfonic acid dolasetron (indole-3-carboxylic acid-2 α, 6 α, 8 α, 9 α β-octahydros-3-oxygen-2,6-methylene radical-dihydro-quinoline-8-ester one water beetle sulfonate) preparation
Figure A20041007465400102
The dolasetron mesilate and the 0.2g methylsulfonic acid of the condensation of 100g (0.21mol) diethoxy are dissolved in 600mL distilled water, be heated to 85 ℃ 5 hours, to take out most of water be about 80ml up to the solution residual content in decompression, separates out crystallization, suction filtration after cooling is left standstill.Mother liquor further is concentrated into about 10mL, has partial crystallization to separate out again, and suction filtration merges crystallization, and natural air drying gets 83.6g (93.0% productive rate) white powder crystallization, fusing point 161-164 ℃; DSC (differential thermal analysis, 10 degree/minute): 420-445K, peak value 434.5K.IR:3363,2528,2496,1754,1697,1445,1421,1309,1269,1193,1148,1114,1097,1021cm -1 1H NMR (400MHz, DMSO-d 6) (s, 1H), 10.40 (s, 1H add D to δ 12.02 2O disappears), 8.06 (m, 2H), 7.54 (m, 1H), 7.22 (m, 2H), 5.41 (s, 1H), 4.14 (s, 2H), 4.01 (d, 2H, J=6.4Hz), 2.81 (s, 1H), 2.62 (d, 2H, J=14.1Hz), 2.40 (s, 3H), 2.37 (s, 4H), 2.25 (t, 2H, J=11.8Hz) ppm; 13C NMR (400MHz, DMSO-d 6) δ 204.27,162.96,136.52,132.52,125.96,122.57,121.45,120.06,112.54,105.89,62.73,59.03,49.75,39.70,37.47,31.73,25.28ppm; 13C NMR (DMSO-d 6) Dept (135 °) Up (CH, CH 3): δ 132.52,122.57,121.45,120.06,112.54,62.73,49.75,39.70,37.48ppm; Dept (135 °) Down (CH 2): 59.03,31.73,25.28ppm; Dept (90 °, CH) δ 132.52,122.57,121.45,120.06,112.54,62.73,49.75,37.48ppm; Ultimate analysis (C 20H 26N 2O 7S 1), calculate: C, 54.73; H, 5.93; N, 6.38; S, 7.30; Actual measurement: C, 54.92; H, 5.89; N, 6.46; S, 7.04.(MS 324, EI): 323 (M-1 for mass spectrum +); X-ray scattering spectrum: 12.429,9.181,8.629,7.667,6.938,5.874,5.238,4.917,4.708,4.541,4.246,3.991,3.812,3.616,3.431,3.373,3.301,3.204,3.115,3.008,2.842,2.741,2.543,2.457,2.394,2.342,2.227,2.117,2.087,1.985,1.960,1.856.

Claims (5)

1, a kind of methane sulfonic acid dolasetron crystallographic form is characterized in that: it is a kind of white powdery crystallization, and having fusing point is 160-170 ℃, and the differential thermal analysis peak value is 434-437K, and going out the peak value scope is 420K to 445K, and molecular composition is C 19H 20N 2O 3.CH 4O 3S.H 2O, molecular structure is as follows
Figure A2004100746540002C1
Dolasetron mesilate-hydrate
(Dolasetron?mesylate?monohydrate)
2, the described methane sulfonic acid dolasetron crystallographic form of claim 1 is characterized in that: its fusing point is 160-165 ℃.
3, the described methane sulfonic acid dolasetron crystallographic form of claim 1 is characterized in that: its fusing point is 162-164 ℃.
4, the preparation method of arbitrary described methane sulfonic acid dolasetron crystallographic form of a kind of claim 1-3, it is characterized in that: it is to be set out by the free amine of dolasetron, under the acid catalysis effect with pure condensation prepared dolasetron alcohol ketal compound, and set out hydrolysis and recrystallization from water by dolasetron alcohol ketal compound.
5, the described preparation method of claim 4, it is characterized in that the free amine of described dolasetron is indole-3-carboxylic acid-2 α, 6 α, 8 α, 9 α β)-octahydro-3-oxygen-2,6-methylene radical-dihydro-quinoline-8-ester, described acid comprises methylsulfonic acid, tosic acid, tosic acid and tosic acid pyridinium salt, described alcohol is the straight or branched alcohol of one to eight carbon atom, and the adjacent glycol of two to eight carbon atoms, described condensation reaction condition is meant above-mentioned free amine, pure and mild acid be heated to 60-150 ℃ 1 to 24 hour, described hydrolysis reaction condition to be dolasetron alcohol ketal product and mesylate thereof be heated in the presence of greater than 1 normal methylsulfonic acid 10-100 ℃ 0.5 to 30 hour, described recrystallization condition is that the said hydrolyzed reaction solution is concentrated and static in room temperature.
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CN109503580A (en) * 2019-01-15 2019-03-22 南京恩泰医药科技有限公司 A kind of dolasetron mesilate crystal form and preparation method

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WO2007072506A2 (en) * 2005-12-23 2007-06-28 Usv Limited Polymorphic forms of dolasetron mesylate and processes thereof
EP1874767A2 (en) * 2006-01-05 2008-01-09 Teva Gyogyszergyár Zártköruen Muködo Részvenytarsaság Production of dolasetron

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FR2531083B1 (en) * 1982-06-29 1986-11-28 Sandoz Sa NOVEL PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICINES
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ZA878096B (en) * 1986-11-03 1988-04-26 Merrell Dow Pharmaceuticals Inc. Esters of hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one and related compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109503580A (en) * 2019-01-15 2019-03-22 南京恩泰医药科技有限公司 A kind of dolasetron mesilate crystal form and preparation method

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