CN101704846B - 9-(2-phosphatidyl methoxy ethyl)-adenine crystal and preparation method thereof - Google Patents
9-(2-phosphatidyl methoxy ethyl)-adenine crystal and preparation method thereof Download PDFInfo
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- CN101704846B CN101704846B CN2009101998476A CN200910199847A CN101704846B CN 101704846 B CN101704846 B CN 101704846B CN 2009101998476 A CN2009101998476 A CN 2009101998476A CN 200910199847 A CN200910199847 A CN 200910199847A CN 101704846 B CN101704846 B CN 101704846B
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Abstract
The invention relates to a 9-(2-phosphatidyl methoxy ethyl)-adenine (PMEA) crystal and a preparation method thereof. The X-ray diffraction spectra data of the PMEA crystal are respectively 14.740, 18.640, 20.720, 23.420, 24.420, 25.560, 26.880 and 29.880, wherein Cu-Ka radiation is used and the diffraction angle is shown as 2Theta. The PMEA crystal is beneficial to preparing an antiviral drug, i.e. 9-[2-[di (pivoxil) phosphatidyl methoxy] ethyl]-adenine (adefovir dipivoxil).
Description
Technical field
The present invention relates to xln of a kind of 9-(2-phosphatidyl methoxy ethyl)-VITAMIN B4 and preparation method thereof.
Background technology
9-(2-phosphatidyl methoxy ethyl)-VITAMIN B4 { 9-[2-(phosphonomethoxy) ethyl] adenine; Being called for short PMEA} is preparation antiviral 9-[2-[two (pivaloyl oxygen methyl) phosphatidyl methoxy] ethyl] VITAMIN B4 (adefovir dipivoxil; Write a Chinese character in simplified form AD) key intermediate (US 4724233, US4808716 and EP481214 etc.).
In existing document, do not see the crystal formation and its report that in preparation AD, concerns between the reactivity worth that disclose PMEA.And contriver of the present invention finds: the reactivity worth of the PMEA of different crystal forms in preparation AD greatly differs from each other.Therefore, a kind of PMEA xln that helps preparing AD being provided is the technical issues that need to address of the present invention.
Summary of the invention
One of the object of the invention is, a kind of PMEA xln that helps preparing AD is provided;
Two of the object of the invention is, a kind of method for preparing above-mentioned PMEA xln is provided.
(brief note: crystal 1), its X-ray diffraction data see that table 1, x-ray diffraction pattern see Fig. 1 to the PMEA xln that helps preparing AD of the present invention
Table 1
Remarks: use Cu-K α radiation.
PMEA of the present invention is according to John E.Starrett, and institute's reported method in J.Med.Chem.37:1857-1864 (1994) such as Jr. makes.To be crystal 2 according to the prepared PMEA xln brief note of prior art (John E.Starrett, described method such as Jr.).
Description of drawings
Fig. 1 is the x-ray diffraction pattern of crystal 1;
Fig. 2 is the x-ray diffraction pattern of crystal 2.
Embodiment
A kind of method for preparing crystal 1 of the present invention, its key step is: crystal 2 (adopt John E.Starrett, the prepared PMEA xln of described method such as Jr., its X-ray diffraction data see that table 2, x-ray diffraction pattern see Fig. 2) is placed reactor drum; The deionized water that in this reactor drum, adds 90 ℃～100 ℃ makes the crystal 2 dissolving, adds gac again; Stir the back filtered while hot, stir gained filtrating, make it be cooled to 0 ℃～5 ℃ rapidly; And, stop to stir, under 0 ℃～5 ℃ conditions this temperature insulation at least 3 hours; Left standstill at least 5 hours, and filtered, the gained solid is target compound (crystal 1) after drying.
Table 2
Through embodiment the present invention is done further elaboration below:
In an embodiment, it is as follows to prepare the equation of AD by PMEA:
Embodiment 1
A, the preparation of 1-chlorine methoxyl group-2-monochloroethane
In the 500ml round-bottomed flask, and the adding Paraformaldehyde 96 (94g, 3.13mol), ethylene chlorhydrin (250g, 3.12mol); Logical HCl gas, controlled temperature dissolves until solid at 22 ℃ fully, stops logical HCl, leaves standstill 1 hour; Tell lower floor's feed liquid, add Calcium Chloride Powder Anhydrous (50g), feed nitrogen until HCl gas being caught up with to the greatest extent underpressure distillation; Collect 78～84 ℃/0.09MPa cut, get 281g, yield 70%, the GC detection level is greater than 97%.
B, the preparation of 2-chloroethoxy methyl acid phosphate diethyl ester
In the 500ml round-bottomed flask, and adding 1-chlorine methoxyl group-2-monochloroethane (152g, 1.17mol); Be warming up to 90 ℃, and the dropping triethyl-phosphite (232g, 1.39mol); Maintain the temperature at 125 ℃, reacted underpressure distillation 3 hours; Collect the cut of 148-151 ℃/0.09MPa, get little yellow liquid (246g), the GC detection level is greater than 98%.
C, the preparation of PMEA
In the 2L reaction flask, add DMF (800ml), stir down, the adding VITAMIN B4 (25g, 0.185mol), Anhydrous potassium carbonate (52g; 0.377mol), be warming up to 60 ℃, stirred 0.5 hour, under protection of nitrogen gas, add 2-chloroethoxy methyl acid phosphate diethyl ester (43g; 0.186mol), be warming up to 78 ℃, to react 24 hours, decompression steams DMF (500ml), is cooled to room temperature; (180g 1.176mol), drips and finishes, and constant temperature stirred 12 hours, filtered to drip bromotrimethylsilane; Filtrate decompression is concentrated into dried, adds entry (50ml), standing demix, and water layer is regulated pH=3 with 40% sodium hydroxide, cooling; Leave standstill to crystal and separate out fully, filter, filter cake gets white solid (20g) at 100 ℃ of dry 12h, and the HPLC detection level is greater than 99%.This is crystal 2 (its X-ray diffraction data see table 2, x-ray diffraction pattern see Fig. 2).
D, the adjustment of PMEA crystal formation
(20g) joins in the 2L there-necked flask with crystal 2, adds entry (1L) and gac (0.8g), is heated to backflow, dissolves fully until solid; Filtered while hot is transferred to another 2L flask with the filtrating of heat, and flask is placed ice/water-bath (0 ℃～5 ℃), stirs; The adularescent solid is separated out after 1 hour, continues to stir 2 hours, then flask is put into refrigerator (0 ℃～5 ℃); Left standstill 5 hours, and filtered, filter cake is in 100 ℃ of dryings; White powder solid (18.5g), this is crystal 1 (its X-ray diffraction data see table 1, x-ray diffraction pattern see Fig. 1), yield 93%.
E, the preparation of adefovir ester (AD)
Add DMF (90ml) in the 500ml reaction flask, and PMEA (crystal 1,20g, 0.073mol), triethylamine (11.1g; 0.109mol), N, (42.8g 0.146mol), stirs and drips chloromethyl pivalate (55.0g down N-dicyclohexyl-4-morpholine amidine; 0.365mol), being warming up to 58 ℃, insulation reaction 4 hours is cooled to 30 ℃; Add ETHYLE ACETATE (300ml), stirred 1 hour, separate out a large amount of white solids this moment, filter; Filter cake is with ETHYLE ACETATE (90ml) washing, and merging filtrate and washings with water washing (35mlx3), merge water and wash with ETHYLE ACETATE (30mlx3).Merge organic phase,, merge water, with cold saturated K with 2mol/L HCl (50mlx3) washing
2CO
3Solution is regulated pH=7, and have a large amount of white solids to separate out this moment, filters, and filter cake is used the small amount of cold water washing, and 50 ℃ of vacuum-dryings get white solid (16g), yield 50%, and the HPLC detection level is greater than 97%.
1H-NMR (CDCl
3) δ ppm:8.34 (s, 1H, aromatic ring 8-H), 7.95 (s, 1H, aromatic ring 2-H), 5.91 (s, 2H, NH
2), 5.66 (m, 4H, CH
2OP), 4.40 (t, 2H, J=5.0Hz, CH
2N), 3.94 (t, 2H, J=5.0Hz, CH
2O), 3.85 (d, J=7.8Hz, 2H, OCH
2P), 1.21 (s, 18H, CH
3).
Reference examples 1
The preparation process of a-c obtains the PMEA crystal 2 with example 1
In the 500ml reaction flask, add DMF (90ml), and the PMEA crystal 2 (20g, 0.073mol), triethylamine (11.1g; 0.109mol), N, and N-dicyclohexyl-4-morpholine amidine (42.8g, 0.146mol); Stir down, (55.0g 0.365mol), is warming up to 60 ℃ to drip chloromethyl pivalate; Insulation reaction 5 hours, TLC detection reaction almost do not take place, and continue reaction 24 hours, find that reaction does not take place yet.
The preparation process of a-d obtains PMEA crystal 1 with example 1
PMEA crystal 1 (2.73g 0.01mol) is suspended among the DMF (35ml), and the adding triethylamine (2ml, 0.013mol); N, N-dicyclohexyl-4-morpholine amidine (5.68g, 0.02mol) and chloromethyl pivalate (7.5g, 0.05mol); Stirring at room 24 hours, the elimination insolubles is evaporated to dried; Use extracted in toluene, get yellow oil (2.0g), yield 38.4% behind the evaporate to dryness toluene.
1H-NMR (CDCl
3) δ ppm:8.32 (s, 1H, aromatic ring 8-H), 7.91 (s, 1H, aromatic ring 2-H), 5.77 (s, 2H, NH
2), 5.63 (m, 4H, CH
2OP), 4.37 (t, 2H, J=5.0Hz, CH
2N), 3.92 (t, 2H, J=5.0Hz, CH
2O), 3.82 (d, J=7.7Hz, 2H, OCH
2P), 1.18 (s, 18H, CH
3).
The preparation process of a-d obtains PMEA crystal 1 with example 1
N
2Under the protection, DMF (310ml), PMEA crystal 1 (46.8g, 0.17mol), triethylamine (160ml; 1.10mol), chloromethyl pivalate (127.5g, 0.85mol), 40 ℃ were reacted 30 hours; Add ETHYLE ACETATE (460ml), reaction is 1 hour under the room temperature, filters, and filtrate water, saturated nacl aqueous solution respectively wash three times; Anhydrous sodium sulfate drying filters, and is evaporated to driedly, and residue is with silica gel column chromatography (eluent: ethanol/methylene=1/1) must little yellow oil (30.5g); Add methylene dichloride (160ml), heating for dissolving adds gac (5.0g), filtered while hot after 30 minutes; Filtrate decompression is concentrated into dried, and with sherwood oil (60-90 ℃) washing, vacuum-drying gets off-white powder adefovir ester (29.0g), yield 33.7%.
1H-NMR (CDCl
3) δ ppm:8.36 (s, 1H, aromatic ring 8-H), 7.94 (s, 1H, aromatic ring 2-H), 5.92 (s, 2H, NH
2), 5.66 (m, 4H, CH
2OP), 4.41 (t, 2H, J=5.0Hz, CH
2N), 3.94 (t, 2H, J=5.0Hz, CH
2O), 3.85 (d, J=7.8Hz, 2H, OCH
2P), 1.21 (s, 18H, CH
3).
Embodiment 4
A, the preparation of 1-chlorine methoxyl group-2-monochloroethane
In the 500L reaction kettle, (94kg, 3.13kmol), (250kg 3.12kmol), leads to HCl gas to ethylene chlorhydrin, and controlled temperature dissolves until solid at 22 ℃ fully, becomes clear liquor at last to add Paraformaldehyde 96.Stop logical HCl, left standstill 1 hour, tell lower floor's feed liquid, add Calcium Chloride Powder Anhydrous (50kg); Feed nitrogen until HCl gas being caught up with to the greatest extent, 78～84 ℃/0.09MPa cut is collected in underpressure distillation; Get 258～263kg, yield about 65%, the GC detection level is greater than 97%.
B, the preparation of 2-chloroethoxy methyl acid phosphate diethyl ester
In the 500L reaction kettle, methoxyl group-(152kg 1.17kmol), is warming up to 90 ℃ to 2-monochloroethane to add 1-chlorine; (232kg 1.39kmol), maintains the temperature at 125 ℃ to drip triethyl-phosphite; React and got little yellow liquid in 4 hours, underpressure distillation, 148-151 ℃/0.09MPa of collection cut; Get 255-261kg, yield about 96%, the GC detection level is greater than 98%.
C, the preparation of PMEA
In the 2000L reaction kettle, add DMF (800kg), stir down, the adding VITAMIN B4 (25kg, 0.185kmol); (52kg 0.377kmol), is warming up to 60 ℃ to Anhydrous potassium carbonate, stirs 0.5 hour, under nitrogen protection; (43kg 0.186kmol), is warming up to 78 ℃, reacts concentrating under reduced pressure 24 hours to add 2-chloroethoxy methyl acid phosphate diethyl ester; Boil off DMF (500L), be cooled to room temperature, (180kg 1.176kmol), drips and finishes to drip bromotrimethylsilane; Reacted 16 hours, and be evaporated to driedly, add entry (50kg), leave standstill, water layer is regulated pH=3 with 40% sodium hydroxide; The crystal of separating out is filtered in cooling, and 100 ℃ of dryings of filter cake 12 hours get white powder solid (20kg), and the HPLC detection level is greater than 99%.This is crystal 2 (its X-ray diffraction data see table 2, x-ray diffraction pattern see Fig. 2).
D, the adjustment of PMEA crystal formation
Crystal 2 (10kg) is joined in the 1000L reaction kettle, add entry (500L) again, be heated to backflow, dissolve fully until solid; Add gac (0.4kg) after the cooling, reheat stirs 1h, filtered while hot to refluxing; The filtrating of heat is transferred in another reaction kettle (is cooled to 0 ℃～5 ℃ with chilled brine in advance), stirred 3 hours, stop to stir, 0 ℃～5 ℃ left standstill 8 hours; Filter, filter cake gets white powder solid (9.4kg), yield 94% in 100 ℃ of dry 12h.This is crystal 1 (its X-ray diffraction data see table 1, x-ray diffraction pattern see Fig. 1).
E, the preparation of adefovir ester (AD)
In the 500L reaction kettle, add DMF (89.5kg), and PMEA (crystal 1,20kg, 0.073kmol), triethylamine (10.25kg; 0.109kmol), N, (41.6kg 0.146kmol), stirs and drips chloromethyl pivalate (55kg down N-dicyclohexyl-4-morpholine amidine; 0.365kmol), being warming up to 60 ℃, insulation reaction 4 hours is cooled to 30 ℃; Add ETHYLE ACETATE (600kg), stirred 1 hour, separate out a large amount of white solids, filter; Filter cake discards after washing with ETHYLE ACETATE (90kg), merging filtrate and washings, and water (50kgx3) washing merges water and washs with ETHYLE ACETATE (30kgx3); Merge all organic phases,, merge water, with cold saturated K with 2mol/LHCl (50kgx3) washing
2CO
3Solution is regulated pH=7, and have a large amount of white solids to separate out this moment, filters, and filter cake use the small amount of cold water washing, and 50 ℃ of vacuum-drying 24 hours must white solid (15kg), yield 46.8%, and the HPLC detection level is greater than 97%.
1H-NMR (CDCl
3) δ ppm:8.36 (s, 1H, heterocycle 8-H), 7.94 (s, 1H, heterocycle 2-H), 5.92 (s, 2H, NH
2), 5.66 (m, 4H, CH
2OP), 4.41 (t, 2H, J=5.0Hz, CH
2N), 3.94 (t, 2H, J=5.0Hz, CH
2O), 3.85 (d, J=7.8Hz, 2H, OCH
2P), 1.21 (s, 18H, CH
3).
Claims (1)
1. the crystal 1 of a 9-(2-phosphatidyl methoxy ethyl)-VITAMIN B4 is characterized in that, the X-ray diffraction spectroscopic data of said crystal 1 is to use Cu-K α radiation; 2 θ represent with diffraction angle, 14.740,18.640,20.720; 23.420,24.420,25.560,26.880 and 29.880;
Wherein, said crystal 1 is made by key step method as follows:
The crystal 2 of 9-(2-phosphatidyl methoxy ethyl)-VITAMIN B4 is placed reactor drum, in this reactor drum, add 90 ℃～100 ℃ deionized water, make the crystal 2 dissolving, add gac again; Stir the back filtered while hot, stir gained filtrating, make it be cooled to 0 ℃～5 ℃ rapidly; And, stop to stir, under 0 ℃～5 ℃ conditions this temperature insulation at least 3 hours; Left standstill at least 5 hours, and filtered, the gained solid is target compound after drying;
The X-ray diffraction spectroscopic data of wherein said crystal 2 does, uses Cu-K α radiation, and 2 θ represent with diffraction angle, 13.879,15.079,18.400,22.701,24.121,25.120,25.841 and 42.200.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396170A (en) * | 2002-07-08 | 2003-02-12 | 江苏正大天晴药业股份有限公司 | Crystal form of Pifuadefuwei |
| CN1900091A (en) * | 1997-07-25 | 2007-01-24 | 吉尔利德科学股份有限公司 | Nucleotide analog compositions |
| CN1935818A (en) * | 2006-09-22 | 2007-03-28 | 闫敬武 | Adefovir dipivoxil novel crystallinestate, crystalline state composition, and itspreparing method and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900091A (en) * | 1997-07-25 | 2007-01-24 | 吉尔利德科学股份有限公司 | Nucleotide analog compositions |
| CN1396170A (en) * | 2002-07-08 | 2003-02-12 | 江苏正大天晴药业股份有限公司 | Crystal form of Pifuadefuwei |
| CN1935818A (en) * | 2006-09-22 | 2007-03-28 | 闫敬武 | Adefovir dipivoxil novel crystallinestate, crystalline state composition, and itspreparing method and use |
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