WO2006026927A1

WO2006026927A1 - A new polymorph of dolasetron mesylate monohydrate and preparation thereof

Info

Publication number: WO2006026927A1
Application number: PCT/CN2005/001440
Authority: WO
Inventors: Yong Qin; Peiliang Guo; Junguo Xin; Yin Wang
Original assignee: Chengdu Giantech Hi-Technology Development Co., Ltd.
Priority date: 2004-09-10
Filing date: 2005-09-09
Publication date: 2006-03-16
Also published as: CN100390172C; CN1629161A

Abstract

The invention discloses a new polymorph of dolasetron mesylate monohydrate and preparation thereof. As white powdery crystal, the melt point of the polymorph is 160-170°C, peak value of differential thermal analysis is 434-437K, and the peaks are in the range of between 420K and 445K. The polymorph's high stability makes it qualified as formulation material. It could be used in treatment of hemicrania and analogous diseases, and in treatment of vomit that is caused by operation or cytotoxic agents. 1

Description

Technical field

The invention relates to a new crystal form of dolasetron mesylate and a preparation method thereof.

Background technique

Dolasetron mesylate is a synthetic serotonin subtype 5HT ₃ receptor antagonist with high specific activity and high selectivity containing pseudo-phenoline skeleton. It is widely used in clinical treatment. Headaches and similar conditions, as well as treatment of vomiting due to surgery or by cytotoxic drugs (MW Gittos and M. Fatmi, Actual Chim. Ther. 1989, 16, 187; US4906755).

Figure 1. Dorasin mesylate monohydrate

(Dolasetron mesylate monohydrate) The chemical structure of dolasetron mesylate is shown in the above figure, and its chemical name is ( ^p哚-3-carboxylic acid-2 α , 6 α , 8 α , 9 α β ) - octahydro - 3-Oxo-2,6-methylene-dihydro-quinoline-8-ester monohydrate methanesulfonate. The only one monohydrate known to it (dolasetron-methanesulfonic acid-water) is a crystalline form having a melting point of 278 ° C, which has a higher melting point.

Intramuscular metabolic pathway

As indicated above, the ketone group of dolasetron is first reduced in vivo to a hydroxy group by a carbonyl reductase. To be reduced form of dolasetron (J. Dow et al. Chirality 1995, 7, 342; H. Boxenbaum et al. Biopharm. Drug Dispos. 1992, 13, 693; H. Boxenbaum et al. Biopharm. Drug Dispos. 1993, 14, 131). Although the body is directly effective in the reduced form of dolasetron, and in vitro tests have shown that the reduced form of dolasetron is at least 35 times more potent than dolasetron (PH Boeijinga et al. Euro. J. Pharm. 1992:

219, 9), but the possibility of administration of the reduced form of dolasetron is ruled out due to the low absorption rate of the reduced form of dolasetron in the gastrointestinal tract. The existing crystalline form of dolasetron itself has the disadvantages of poor permeability of the gastrointestinal tract and ease of being rapidly eliminated from the liver, which leads to its disadvantage of low bioavailability (J. Dow et al). J. Pharm. Sciences 1996, 85, 685), thus requiring a larger dosage. Preparation of different crystalline forms of dolasetron mesylate may be one of the viable methods to improve the bioavailability of dolasetron. Summary of the invention

The technical problem to be solved by the present invention is to overcome the defects of the existing crystal form of dolastatin mesylate, and provide a new crystal form of dolasetron mesylate, which has high stability and can satisfy all the raw materials as preparation materials. It is required to be clinically useful for the treatment of migraine and the like, as well as for the treatment of vomiting caused by cytotoxic drugs.

In order to solve the above problems, the present invention uses the following technical solutions:

The novel crystalline form of dolasetron mesylate of the present invention is a white powdery crystal having a melting point of 160 - 170 ° C, a differential thermal analysis peak of 434 - 437 K, and a peak range of 420 K to .445 K, molecular The composition is C ₁₉ H ₂ . N ₂ 0 ₃ .CH ₄ 0 ₃ SH ₂ 0, the molecular structure is as follows

Mesal acid dolasetron monohydrate

(Dolasetron mesylate monohydrate)

Preferably, the novel crystalline form of dolasetron mesylate of the present invention has a melting point of from 160 to 165 Torr, more preferably, a melting point of from 162 to 164 °C.

The invention also provides a preparation method of the novel crystal form of dolasetron methanesulfonic acid, which is prepared by the condensation of alcohol with an alcohol and catalyzed by doracin free amine. Compounds, as well as starting from dolastatin ketal compounds, hydrolyzed and reconstituted from water

Hey.

The present invention dolasetron free amine is ^{p-indol-3-carboxylic} acid -2 α, 6 α, 8 α , 9 α β - octahydro _--3 _ Yue alkylene oxide group _2,6- - dihydro - a quinoline-8-ester, the acid being at least one selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid and p-toluenesulfonic acid pyridinium, the alcohol being selected from one to eight carbon atoms At least one of a linear or branched alcohol, a 3- to 8-membered cyclic alcohol, and a vicinal diol having two to eight carbon atoms, the condensation reaction condition being the above-mentioned free amine, the alcohol and the acid heated to 60-150 °C for 1 to 24 hours, the hydrolysis reaction conditions are that the dolastatin ketal product and its mesylate salt are heated to 10 - 100 in the presence of more than 1 equivalent of methanesulfonic acid. C 0.5 to 30 hours, the recrystallization conditions are such that the above hydrolysis reaction solution is concentrated and allowed to stand at room temperature.

The crystal form of the drug molecule is closely related to the stability of the drug and its bioavailability in vivo when administered orally. In the general sense, the crystalline form of the lower melting point of the same drug has a better bioavailability when administered orally than the high melting crystalline form, exhibiting different pharmacokinetics.

The ketone group of dolasetron is first reduced in vivo to a hydroxyl group by a carbonyl reductase to a reduced form of dolasetron (J. Dow et al. Chirality 1995, 7, 342; H. Boxenbaum et al. Biopharm. Drug Dispos. 1992, 13, 693; H. Boxenbaum et al. Biopharm. Drug Dispos. 1993, 14, 131 ). Despite the direct effect of the in vivo form of the reduced form of dolasetron, and in vitro tests have shown that the reduced form of dolasetron is at least 35 times more potent than dolasetron (R H. Boeijinga et al. Euro. J. Pharm. 1992, 219,

9), but due to the low absorption rate of the reduced form of dolasetron in the gastrointestinal tract, the possibility of administration directly to the reduced form of dolasetron is ruled out. Dorstron itself also has the disadvantage of poor permeability of the gastrointestinal tract and its ability to be rapidly eliminated from the liver, resulting in its low bioavailability (J. Dow et al. J. Pharm). Sciences 1996, 85 _:

685), thus requiring a larger dosage. The addition of dorsalazine derivatives with different functional groups, especially to increase their ester solubility and prolong the time of their reduction by carbonyl reductase, may be one of the feasible methods to improve the bioavailability of dolasetron.

The present invention prepares a dolase ketal precursor by a novel synthesis process, and prepares a methanesulfonic acid having a specific crystal form having a melting point of 160 - 170 ° C by using such an ketal precursor. Rastron, this crystal form has the same chemical structure and chemical composition as the melting point of 278 ° C of dolase.

Preparation of Dorasdin Monomethanesulfonate of a Specific Crystal Form with a Melting Point of 162-164 ° C The dolastatin ketal precursor compound has the molecular structure and composition described above. a substituted, unsubstituted cyclic alkyl group wherein R is a linear or branched alkyl group of 3 to 8 carbon atoms or a 3-membered ring; RR is a substituted 5 or 6-membered ring, unsubstituted 2 A ketal fragment. Hydrolysis of the ketal precursor compound of the above-described dolastatin, the hydrolyzate is recrystallized from water to obtain dolasetron monomethanesulfonate, which is an off-white powdery crystal having a melting point of 160 - 170 Specific crystal form of °C. The preparation of dolasetron mesylate by hydrolysis of the dolastatin ketal precursor compound can not only prepare a novel crystal form having a melting point of 160 - 170'C, but also makes the target product easy to be colored with impurities and traces. Separation of matter.

The precursor compound of the dorasagirol ketal can be prepared by refluxing the corresponding anhydrous alcohol with the dolastatin free amine under acid catalysis for high yield. When dorsalazine free amine and anhydrous ethanol are refluxed in the presence of one equivalent of methanesulfonic acid, a diethoxy condensed dolastatin mesylate white crystal having a melting point of 247 ° C is obtained. In contrast, dolasetron free amine and ethanol are directly recrystallized after heating to 60 ° C in the presence of about one equivalent of methanesulfonic acid, but the melting point is 278 ° C. White powdery crystals (US 4,906,755). The melting point obtained by the synthetic preparation method of the ketal precursor compound is 160 -

The 170 Ό specific crystal form of dolaserone monohydrate has the same activity as the crystalline form of dolasetron monohydrate of 278 ° C claimed by the drug manufacturer of dolasetron. Moreover, the crystal form has high stability and a low melting point, and may have good bioavailability, and can better meet all the requirements as a raw material for the preparation. The new crystalline form of the precursor compounds of dolasetron and dolase ketal is a serotonin subtype 5HT3 receptor antagonist, which is clinically useful for the treatment of migraine and similar conditions, as well as treatment. Vomiting due to surgery or by drugs with cytotoxicity.

DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of the novel crystal form of the present invention.

Figure 2 is a differential thermal analysis map (DSC) of the new crystal form of the present invention.

detailed description

Example 1 Preparation of diethoxy condensed dolastron mesylate

Dorazin free amine (80.5 g, 0.25 mol) was dissolved in 480 mL of absolute ethanol, and 10 g of activated carbon and methanesulfonic acid (23.9 g, 0.25 mol) were added. The resulting solution was refluxed for 8 hours under a nitrogen atmosphere. After filtration and cooling to room temperature, it was allowed to stand overnight to precipitate white crystals. The crystals were filtered and dried in vacuo to give 118.5 g (yield: 96.0% yield) of diethoxy condensed dolsulfamide methanesulfonate mp 218-220. C. IR: 3229, 2982, 2579, 1708, 1531, 1442, 1309, 1213, 1160, 1128, 1106, 1060, 1032 cm"¹; ^! H NMR (400 MHz, DMSO-d ₆ ) δ 11.98 (d, lH, J = 2.4 Hz), 9.80 (s, lH, plus D ₂ 0 disappears), 8.04 (q, 2H, J = 2.7 Hz), 7.52 (m, lH), 7.22 (m, 2H), 5.31 (d, lH, 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 ₅ 6H , J = 7.2 Hz) ppm; ¹³ C NMR (400 MHz, 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, 15.14 ppm; ¹³ C NMR (DMSO-d ₆ ) Dept ( 135° ) Up (CH, CH ₃ ): δ 136.69, 122.73, 121.62, 120.23, 112.72, 62.98, 49.49, 40.11, 28.40, 15.14 ppm; Dept (135°), Down (CH ₂ ): 5 58.32, 56.16, 31.97, 23.93 ppm; Dept ( 90., CH ) δ 136.69, 122.73, 121.62, 120.23, 112.70, 62.98, 49.49, 28.40 ppm; Elemental Analysis (C^HMNZO ! ), Calculation: C, 58.24; 6.88; N, 5.66; S, 6.47; Found: C, 58.19; H, 6.86; N, 5.70; S, 6.50; Mass Spectrum (MS 398, FAB) : 397 ( M-l+ ).

Example 2 Preparation of ethylene glycol condensed dolasetron

The reaction was carried out in a similar manner to the diethoxy condensed dolastatin mesylate preparation. Doraskey free amine was dissolved in 5 equivalents of ethylene glycol and heated to 85 with 1 equivalent of methanesulfonic acid. C1 0 hours. The reaction solution was cooled, poured into a 10% sodium carbonate solution, and extracted with ethyl acetate. Drying over anhydrous magnesium sulfate and column chromatography (ethyl acetate as eluent) afforded ethylene glycol condensed dolase. ^ NMR (400MHz, CDC1 ₃ ) δ 8. 85 (s, 1Η) , 8. 27 (m, 1H) , 7. 83 (d, 1H, J=2. 8 Hz) , 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, 7=3. 6Hz) , 2. 07 (m, 4H), 1. 89 (m, 1H). Example 3 Melting point: 162-164 ° C - Doraspirin mesylate (吲哚-3-carboxylic acid-2 α , 6 α , 8 α , 9 α β - octahydro-3-oxo-2,6 -methylene-dihydro-quinoline-8-ester monomethanesulfonate) preparation

100 g (0.21 mol) of diethoxy condensed dolasetron mesylate and 0.2 g of methanesulfonic acid were dissolved in 600 mL of distilled water and heated to 85. C 5 hours, most of the water was removed under reduced pressure until the remaining amount of the solution was about 80 ml. After cooling, the crystals were precipitated and suction filtered. The mother liquor is further concentrated to about 10 mL, and some crystals are precipitated, filtered by suction, combined with crystallization, and naturally dried. 83.6 g (93.0% yield) of white powdery crystals m. C; DSC (differential thermal analysis, 10 degrees/min): 420-445K, peak 434.5Κ» IR: 3363, 2528, 2496, 1754, 1697, 1445, 1421, 1309, 1269, 1193, 1148, 1114, 1097, 1021cm"¹; ^l U MR (400MHz, DMSO-d ₆ ) δ 12.02 (s,lH), 10.40 (s,lH, plus D ₂ 0 disappears), 8.06(m,2H), 7.54(m,lH) , 7.22(m,2H) , 5.41(s,lH) , 4.14(s,2H) , 4.01(d,2H,/=6.4Hz), 2.81(s,lH), 2.62(d,2H, J=14.1Hz ), 2.40 (s, 3H), 2.37 (s, 4H), 2.25 (t, 2H, J = 11.8 Hz) ppm; ¹³ C NMR (400 MHz, 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, 25.28 ppm; ¹³ C 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 ) 5 132.52 , 122.57 , 121.45 , 120.06 , 112.54 , 62.73 , 49.75 , 37.48ppm ; Elemental analysis ( ( ₂₀ Η ₂₆ Ν ₂ ΟΑ ), calculation: C, 54.73; H, 5.93; N, 6.38; S, 7.30; measured: C, 54.92; Η, 5 · 89; Ν,6·46; S, 7.04. Mass spectrometry (MS 324, EI ): 323 ( M-1+ ); X-ray scattering spectra: 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

Rights request

1. A new crystalline form of dolastose mesylate characterized by: it is a white powdery crystal having a melting point of 160 - 170°" The differential thermal analysis peak is 434 - 437K, and the peak range is 420K. To 445K, the molecular composition is C ₁₉ H _{2 .} N ₂ 0 ₃ .CH ₄ 0 ₃ SH ₂ 0, the molecular structure is as follows

Dorasin monohydrate

(Dolasetron mesylate monohydrate)

A novel crystalline form of dolasetron mesylate according to claim 1, which has a melting point of from 160 to 165 °C.

3. The new crystalline form of dolasetron mesylate according to claim 1, which has a melting point of from 162 to 164 °C.

4. A process for preparing a new crystalline form of dolastose mesylate according to any one of claims 1 to 3, characterized in that it is derived from dolasetron free amine under acid catalysis. The alcoholic condensation is used to prepare a dolastatin ketal compound, starting from a dolase ketal compound, hydrolyzed and recrystallized from water.

The process according to claim 4, wherein the dolasetron free amine is indole-3-carboxylic acid-2α,6α,8α,9αβ)-octahydro-3-oxo -2,6-methylene-dihydro-quinoline-8-ester, the acid being at least one selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid and p-toluenesulfonic acid pyridinium. The alcohol is at least one selected from the group consisting of a linear or branched alcohol having one to eight carbon atoms and a vicinal diol having two to eight carbon atoms, and the condensation reaction conditions are referred to as heating of the above-mentioned free amine, alcohol and acid. To 60-150. C 1 to 24 hours, the hydrolysis reaction strip The product is heated to 10 - 100 ° C for 0.5 to 30 hours in the presence of more than 1 equivalent of methanesulfonic acid, and the recrystallization reaction is carried out by concentrating the above hydrolysis reaction liquid. And at rest at room temperature.