CN1139597C - Prepn of 9 [2-[[[di (trimethylacetoxyl) methyl] phosphoros]-methoxy-ethyl] adenine - Google Patents
Prepn of 9 [2-[[[di (trimethylacetoxyl) methyl] phosphoros]-methoxy-ethyl] adenine Download PDFInfo
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- CN1139597C CN1139597C CNB021510318A CN02151031A CN1139597C CN 1139597 C CN1139597 C CN 1139597C CN B021510318 A CNB021510318 A CN B021510318A CN 02151031 A CN02151031 A CN 02151031A CN 1139597 C CN1139597 C CN 1139597C
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Abstract
The present invention relates to a method for preparing formless 9-[2-[[[bi(trimethyl acetoxyl)methyl]phosphoroso]methoxy]-ethyl]adenine. Because the present invention uses low cost Me3SiCl reagents to replace import reagents of Me3SiBr in the prior art and adds catalysts A and/or catalysts B, the synthetic cost of 9-[2-[[[double(trimethyl acetoxyl)methyl]phosphoroso]methoxy]-ethyl]adenine is greatly reduced.
Description
Technical field
The present invention relates to two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] preparation method of VITAMIN B4.
Background technology
Adefovir ester (Adefovir Dipivoxil, abbreviation AD) chemical structural formula is two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4, it all has stronger extracorporeal antivirus effect activity to HIV, HBV, people CMV, HSV-1 and HSV-2, and can suppress duplicating of human herpes virus 6 (HHV-6) in the HSB-2 cell, therefore can suppress cytopathic effect and HHV-6-specific antigen that HHV-6-causes and express.Behind the vivo medicine-feeding, this compound can also delay tumour formation and death of mouse and the splenomegaly that the obvious FLV-of inhibition causes that MSV-brings out significantly.
Clinical study is found, two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 can treat the patient that HIV infects effectively, and its toxicity is lower.In addition, two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 also can be used as the preliminary treatment of chronic hepatitis B (HBV) or combines medication with other anti-HBV medicine.
Based on two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] the above-mentioned widespread use of VITAMIN B4, people are sought after low cost, two (pivalyl oxygen) methyl of the 9-[2-[[[that use properties is good] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4.
United States Patent (USP) 4,724,233 and 4,808,716, EP481,214, J.Med.Chem such as Starrett (1994) 37:1857-1864 etc. has disclosed two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 and preparation method thereof, what it was prepared all is amorphous form, its physicals is unfavorable for follow-up use, has indefinite fusing point, mobile poor, the low preparation difficulty that reaches of purity.
WO99/04774 (PCT/US98/15304) has disclosed and has contained AD crystalline composition and application thereof, and it has also related to the method for synthetic AD.Be initiator with the VITAMIN B4 in this documents, by using NSC 11801, the bromo trimethyl silane, chloro methyl pivalate, reaction reagents such as second cyanogen and toluene, the synthetic mixed solution that obtains containing AD, and then with being selected from acetone, the mixed solution of di-n-butyl ether, the mixed solution of ethyl acetate and di ether, the mixed solution of the trimethyl carbinol and di-n-butyl ether, the mixed solution of methylene dichloride and di-n-butyl ether, the mixed solution of ether and di ether, the mixed solution of tetrahydrofuran (THF) and di-n-butyl ether, the mixed solution of ethyl acetate and di-n-butyl ether, the mixed solution of tetrahydropyrans and di-n-butyl ether, the mixed solution of ethyl acetate and ether, t-butyl methyl ether, ether, di-n-butyl ether, the trimethyl carbinol, toluene, the solvent of isopropyl acetate or ethyl acetate carries out crystallization, obtains the AD crystal, and crystallization yield is lower than 50%.Total recovery is lower than 10%.
Above-mentioned part reagent and recrystallisation solvent or depend on external import; or its cost costliness; thereby improved two (pivalyl oxygen) methyl of 9-[2-[[[greatly] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystalline production cost; be unfavorable for two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] use of VITAMIN B4; yield is low; solvent-oil ratio is big, and partial solvent toxicity height is unfavorable for environment protection.
The present technique field is devoted to develop two (pivalyl oxygen) methyl of the low 9-[2-[[[of production cost for a long time always] phosphoroso-] methoxyl group]-ethyl] preparation method of VITAMIN B4.
Summary of the invention
An object of the present invention is to provide two (pivalyl oxygen) methyl of described 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 crystalline preparation method.
Design of the present invention is implemented by following technical proposal:
Two (pivalyl oxygen) methyl of a kind of down formula V 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] preparation method of VITAMIN B4,
This method comprises: make following formula (III) compound
React in the presence of catalyst A and/or catalyst B with methylene dichloride, chloro trimethyl silane, get 9-[2-(phosphate methoxy) ethyl] and the VITAMIN B4 product (IV, PMEA);
Two (pivalyl oxygen) methyl of the 9-[2-[[[that makes compound (IV) and Chloro methyl pivalate, NMP and triethylamine in the presence of catalyst A and/or catalyst B, react requiredly then] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V).
Described catalyst A is bromated mineral compound or bromated organic compound, preferably is selected from Sodium Bromide, Potassium Bromide, brometo de amonio, (R
1R
2R
3) NBr, wherein R
1, R
2And R
3Can be identical or different, be selected from C independently of one another
1-16The straight or branched alkyl.Described catalyst B is the organic compound that contains the mineral compound of iodine or contain iodine, preferably is selected from sodium iodide, potassiumiodide, ammonium iodide or (R
1R
2R
3) NI, wherein R
1, R
2And R
3Definition the same.
Described catalyst A and catalyst B can be used separately or composition uses, and its blending ratio is not particularly limited.
Two (pivalyl oxygen) methyl of described amorphous 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 makes by following reaction process:
a.Et
3N，b.TsCl，c.KOH/NaOH，d.DMF，e.CH
3ONa/DMF/CH
2Cl
2
F.Me
3SiCl/CH
2Cl
2/ H
2O/ catalyst A and/or B, g.NMP/ catalyst A and/or B
Embodiment
In one embodiment of the invention, two (pivalyl oxygen) methyl of described amorphous 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 prepares according to the following step:
(1) in reaction vessel, add diethyl phosphite, Paraformaldehyde 96, add SULPHURYL CHLORIDE below 0 ℃, triethylamine, reaction is finished, and obtains reaction product (I);
(2) in reaction vessel, add by diethyl carbonate, ethylene glycol and N, after the mixed solution reaction that dinethylformamide (DMF) is formed, add sodium hydroxide and VITAMIN B4 again, until VITAMIN B4 content≤0.3%.Add Iso Butyl Acetate, obtain reaction product (II);
(3) add reaction product (II), DMF, the CH that step (2) obtains successively
3ONa stirs the back and adds the mixed solution that the reaction product (I) that obtained by step (1) and DMF form, stirs the back and adds methylene dichloride, reflux, and stirring at normal temperature again, getting light brown solid (III) is 9-[2-(diethyl phosphate methoxy) ethyl] VITAMIN B4;
(4) in reaction vessel, add (III) successively, methylene dichloride, the chloro trimethyl silane adds catalyst A and/or catalyst B, is stirred to react completely, and transfers pH3.0～3.5 to get 9-[2-(phosphate methoxy) ethyl] the VITAMIN B4 product (IV, PMEA);
(5) in (IV), add Chloro methyl pivalate, NMP and triethylamine, add catalyst A and/or catalyst B, be stirred to and react completely, add Iso Butyl Acetate again and stir back filtering solid, boil off solvent, add acetone and n-butyl ether, stir two (pivalyl oxygen) methyl of crude product 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V).
Set forth two (pivalyl oxygen) methyl of 9-[2-[[[of the present invention below in conjunction with specific embodiment] phosphoroso-] methoxyl group]-ethyl] preparation method of VITAMIN B4.
Embodiment 1
Synthesizing of diethyl sulfonic acid oxygen METHAPHOSPHORIC ACID ester (I)
In the reactor of N2 protection, add diethyl phosphite (available from the good magnificent chemical industry in Lanxi, Zhejiang company limited) 1.0Kg (7.24 moles), Paraformaldehyde 96 successively (available from Shanghai solvent factory; ACS:3525-89-4) 0.28kg (8.77 moles); stirring reaction 2 hours; add SULPHURYL CHLORIDE 1.25kg (6.57 moles) below 0 ℃; triethylamine 1kg (9.88 moles); stirring at room reaction 8～10 hours, the TLC detection reaction is finished.Filter, with solvent 2 * 250ml washing, merging filtrate washing, decolorizing with activated carbon drying, underpressure distillation remove to solvent less than 1% (GC), oily matter, be syrupy shape after the cooling, (I).Yield 75～80%, content: 〉=85% (HPLC).
Embodiment 2
Synthesizing of 9-(2-hydroxyethyl) VITAMIN B4 (II):
Dry reaction still N
2Protection; drop into diethyl carbonate (available from Shanghai reagent head factory) 0.75kg (6.35 moles) successively; ethylene glycol (available from the Shanghai reagent head factory) 0.4Kg (mixed solution that 6.45 moles and DMF 1kg form; insulated and stirred to reaction is finished; drop into (0.125 mole of sodium hydroxide 0.005kg; fine ground); VITAMIN B4 (available from Zhejiang Cheng Yi Pharmaceutical Co., Ltd) 1kg (USP24) (7.40 moles); insulated and stirred HPLC monitoring VITAMIN B4 content≤0.3%, reaction finishes, and adds the 4.0kg Iso Butyl Acetate and stirs 2 hours; leach solid; with the Iso Butyl Acetate washing, vacuum-drying gets pulverulent solids (II); yield 90%～95%, content 〉=90% (HPLC).
Embodiment 3
9-[2-(diethyl phosphate methoxy) ethyl] VITAMIN B4 (III) synthetic
Dry reaction still N
2Protection adds (II) 1.0kg (5.58 moles), DMF4.8kg, CH successively
3ONa1.0kg, (I) 2.25kg (6.98 moles), stirred 8～10 hours, the HPLC monitoring reaction is finished, and adds methylene dichloride 16kg with in the Glacial acetic acid and back and stirs, and leaches solid, with 2 * 1.5kg washed with dichloromethane, merging filtrate, water 2 * 0.8kg washing, methylene dichloride 2 * 1.5kg extracts water, merge organic phase, add hexanaphthene 3kg after reclaiming methylene dichloride, stir solid, vacuum-drying 2 days, get light brown solid (III), yield 50～65%, content 〉=90% (HPLC), mp136～138 ℃.
Embodiment 4
9-[2-(phosphate methoxy) ethyl] VITAMIN B4 (IV, PMEA) synthetic
Dry reaction still N
2Protection adds (III) 1.0kg (3.03 moles) successively, methylene dichloride 5kg, and chloro trimethyl silane 1.65kg (15.20 moles), stirring reaction 2 days, the product spot is not seen in the thin plate monitoring.
Embodiment 5
9-[2-(phosphate methoxy) ethyl] VITAMIN B4 (IV, PMEA) synthetic
Dry reaction still N
2Protection adds (III) 1.0kg (3.03 moles), methylene dichloride 5kg successively; bromo trimethyl silane 1.65kg (10.78 moles) is stirred to reaction and finishes, and steams to add entry 3kg behind the methylene dichloride and filter; elimination removes insolubles after being dissolved in alkali; the filtrate acidifying gets solid, and vacuum-drying 2 days is pulverized; get white solid (IV); yield 50～55%, content 〉=96% (HPLC), mp 〉=260 ℃ (vaporization).
Embodiment 6
9-[2-(phosphate methoxy) ethyl] VITAMIN B4 (IV, PMEA) synthetic
Dry reaction still N
2Protection adds (III) 1.0kg (3.03 moles), methylene dichloride 5kg, chloro trimethyl silane 1.65kg (15.20 moles) successively; catalyst B (NaI, 2 moles of % are with respect to III); stirred 3～5 hours, TLC detects (III) and reacts completely, and adds entry 3kg after steaming methylene dichloride; filter, be dissolved in alkali after elimination remove insolubles, the filtrate acidifying gets solid; vacuum-drying 2 days is pulverized, and gets white solid (IV); yield 85～90%, content 〉=98% (HPLC), mp 〉=278 ℃ (vaporization).
Embodiment 7
Two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V) synthetic
Dry reaction still N
2Protection adds (IV) 1.0kg (3.66 moles), chloromethyl pivalate 2.5kg (16.60 moles) successively; NMP4kg, triethylamine 1kg (9.88 moles) stirred 6～10 hours; add Iso Butyl Acetate 12kg; stir filtering solid, organic phase pressure reducing and steaming solvent; add acetone 1kg and normal hexane 6kg in the residual oily matter; stir solid, vacuum-drying, crude product (V).Yield 40～50%, content 〉=97% (HPLC).
Embodiment 8
Two (pivalyl oxygen) methyl of 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V) synthetic
Dry reaction still N
2Protection adds (IV) 1.0kg (3.66 moles), chloromethyl pivalate 2.5kg (16.60 moles), NMP4kg, triethylamine 1kg (9.88 moles), catalyst A (NH successively
4Br, 2 moles of % are with respect to IV), stirred 2～3 hours, add Iso Butyl Acetate 12kg, stir the filtering solid, organic phase pressure reducing and steaming solvent adds acetone 1kg and normal hexane 6kg in the residual oily matter, stir filter solid, vacuum-drying, crude product (V).Yield 70～75%, content 〉=97% (HPLC).
Ultimate analysis (C
2OH
32N
5O
8P): calculated value %C47.90; H6.43; N13.97; P6.18.
Measured value %C48.01; H6.45; N13.86; P6.12.
IR(KBr，cm
-1)：3367.16，3275.97，3122.44，2981.10，2935.17，2875.39，1759.15，1683.62，1605.43，1573.65，1480.43，1263.00，1137.26，1029.64，967.08。
1H?NMR(CDCl
3)δ：8.332(s，1H)，7.943(s，1H)，6.552(brs，2H)，5.709-5.653(m，4H)，4.407(t，J＝5.2Hz，2H)，3.964(t，J＝5.2Hz，2H)，3.877(d，J＝7.6Hz，2H)，1.212(s，18H)。
13C NMR (CDCl
3) δ: 152.739 (1 CH), 149.713 (1 quaternary carbon), 119.245 (1 quaternary carbon), (155.734 1 quaternary carbon), 141.079 (1 CH) 43.166 (1 CH2), 71.217 (d, J=9.5Hz, 1 CH2) 65.392 (d, J=165.7Hz, 1 CH2), (81.545 d, J=6.4Hz, 2 CH2) 176.570 (2 quaternary carbons), (38.525 2 quaternary carbons), 26.641 (6 CH3)
31P NMR (CDCl
3) δ: 21.745 (1 P).
MS(EI，M+)501；MS(ESI)，[M+1]+502，[M+K]+540，[2M+1]+1003，[2M+Na]+1025，[2M+K]+1041。
The above results proof embodiment 8 synthetic really two (pivalyl oxygen) methyl of 9-[2-[[[that obtained formula V] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4.
The present invention is owing to adopted Me cheaply
3SiCl reagent substitutes import reagent Me of the prior art
3So SiBr, and add catalyst A and/or catalyst B is 9-[2-[[[pair of (pivalyl oxygen) methyl] phosphoroso-] methoxyl group]-ethyl] the synthetic cost of VITAMIN B4 greatly descends.
Claims (3)
1. one kind prepares two (pivalyl oxygen) methyl of amorphous down formula V 9-[2-[[[] phosphoroso-] methoxyl group]-ethyl] method of VITAMIN B4,
Comprise and make following formula (III) compound
React in the presence of catalyst A and/or catalyst B with methylene dichloride, chloro trimethyl silane, get 9-[2-(phosphate methoxy) ethyl] VITAMIN B4 product (IV);
Two (pivalyl oxygen) methyl of the 9-[2-[[[that makes compound (IV) and Chloro methyl pivalate, NMP and triethylamine in the presence of catalyst A and/or catalyst B, react requiredly then] phosphoroso-] methoxyl group]-ethyl] VITAMIN B4 (V),
Described catalyst A is bromated mineral compound or bromated organic compound, and described catalyst B is the organic compound that contains the mineral compound of iodine or contain iodine.
2. preparation method according to claim 1, wherein said catalyst A is selected from Sodium Bromide, Potassium Bromide, brometo de amonio, (R
1R
2R
3) NBr, wherein R
1, R
2And R
3Can be identical or different, be selected from C independently of one another
1-16The straight or branched alkyl.
3. preparation method according to claim 1, wherein said catalyst B is selected from sodium iodide, potassiumiodide, ammonium iodide or (R
1R
2R
3) NI, wherein R
1, R
2And R
3Can be identical or different, be selected from C independently of one another
1-16The straight or branched alkyl.
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