CN1122671C - Arbinosyl furanuridine compound and its preparing process - Google Patents
Arbinosyl furanuridine compound and its preparing process Download PDFInfo
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- CN1122671C CN1122671C CN 00118945 CN00118945A CN1122671C CN 1122671 C CN1122671 C CN 1122671C CN 00118945 CN00118945 CN 00118945 CN 00118945 A CN00118945 A CN 00118945A CN 1122671 C CN1122671 C CN 1122671C
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- compound
- uridine
- fmau
- deoxidation
- methyl
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Abstract
The present invention discloses an arabinose furan uridine compound and a synthetic method thereof, particularly 2'-deoxidation-2'-fluorine-3'(4-4'-dialkyl oxygen group-5, 6, 5', 6'-dimethenyldioxy-2'-alkyl group oxygen carbonyl-2-ester group biphenyl)-5-methyl-arabinose furan uridine (alpha-DDB-L-FMAU) as a new compound and a synthetic method thereof. In the method, 2'-deoxidation-2'-fluoro-5-methyl-arabinose furan uridine(L-FMAU) and 4, 4'-dialkyl oxygen group-5, 6, 5', 6'-dimethenyldioxy-2'-alkyl group oxygen carbonyl-2-biphenyl acyl chloride (alpha-DDB) are used as raw materials. By hydroxy protection, esterification connection and deprotecting reaction in sequence, alpha-DDB-L-FMAU is prepared. The compound possibly becomes a new drug for curing hepatitis b by resisting hepatitis b viruses and reducing transaminase and has high application value. The compound has the following structure: R is-CH3,-CH2CH3,-CH(CH3)2,-C(CH3)3,-CH2CH2CH3,-CH2CH2CH2CH3, wherein R1 and R2 represent alkyl groups.
Description
Technical field:
The present invention relates to a kind of arabinofuranosyl adenin uridine compound and synthetic method thereof, relate in particular to a kind of new compound 2 '-deoxidation-2 '-fluoro-3 ' (4,4 '-dialkyl group oxygen base-5,6,5 ', 6 '-secondary methylenedioxy group-2 '-alkyl oxygen carbonyl-2-ester group biphenyl-5-methyl-can sugared furans uridine (α-DDB-L-FMAU) and synthetic method thereof.
Background technology
At present, the treatment hepatitis B can be by reducing people's height serum glutamic pyruvic transminase or reaching curative effect by the activity that suppresses hepatitis B virus.(α-DDB) has through pharmacological screening and falls high serum glutamic pyruvic transminase effect α-Biphenylylmethylcarbinol, is acknowledged as a kind of active drug of transaminase lowering; 2 '-deoxidation-2 '-fluoro-5-methyl-arabinofuranosyl adenin uridine (L-FMAU) also has higher anti-hepatitis B virus activities, preliminary toxicity test to animal shows that toxicity is lower, do not cause deformity, and in to the animal experiment that has chronic viral hepatitis B virus, show biological preferably drug effect yet.These are all in " Acta Pharmaceutica Sinica " (the 17th volume first phase.January nineteen eighty-two) and " Nucleosides δ Nucleotides " (18 (2), 1999) in the report, but possess simultaneously by hepatitis B virus resisting and transaminase lowering reach the treatment hepatitis B novel cpd yet there are no report.
Summary of the invention
The object of the present invention is to provide a kind of new compound, make this compound might become the newtype drug that reaches the treatment hepatitis B simultaneously by hepatitis B virus resisting and transaminase lowering; Another object of the present invention is to provide the synthetic method of this compound.
In order to realize purpose of the present invention, technical scheme is as follows:
This thing of this chemical combination has following structural formula:
Its synthetic route is as shown in the figure:
R＝-CH
3，-CH
2CH
3，-CH(CH
3)
2，-C(CH
3)
3，-CH
2CH
2CH
3，-CH
2CH
2CH
2CH
3
R
1And R
2Represent methylidene.
Tr＝-CPh
3
Step (1) is that 5 ' hydroxyl of 2 '-deoxidation-2 '-fluoro-5-methyl-arabinofuranosyl adenin uridine (L-FMAU) is protected with trityl chloride; step (2) is at N; the N-dimethyl aminopyridine exists down and by esterification the L-FMAU and the α-DDB that have protecting group is combined, and step (3) is to slough blocking group to obtain target compound.
5 ' hydroxyl protection reaction to L-FMAU of the present invention feeds intake with (mol ratio): L-FMAU: trityl chloride=1: 1.5～2.5.
Esterification feed ratio of the present invention (mol ratio): L-FMAU-Tr: α-DDB: DMAP (N.N-dimethyl aminopyridine)=1: 1.4～3: 0.3～0.8, the temperature of reaction is controlled at 10～40 ℃.
Beneficial effect of the present invention is: fall the α-DDB that changes the ammonia ester and have the L-FMAU of anti-hepatitis B virus activities organically to combine having, obtain this new compound, can more effectively treat hepatitis B; And the synthetic method of this compound, highway route design are rationally feasible, and total recovery is more than 20%, and purity is higher, is suitable for industrial production.
Embodiment
The present invention is described in detail below in conjunction with embodiment.
Embodiment 1
Divided for three steps narrated the connection procedure of L-FMAU and α-biphenyl methyl esters acyl ammonia.(1) to the protection of 5 ' hydroxyl of L-FMAU
0.05molL-FMAU (I) 13g, 0.09mol trityl chloride (Ph
3CCl) 25g, in 100ml exsiccant pyridine, room temperature was placed two days, heating two hours (isolated moisture) in boiling water bath then, the pressure reducing and steaming pyridine separates with pillar, and developping agent is CHCl
3: EA: MeOH40: 30: 3, obtain Compound I I (L-FMAU-Tr) (R
1=0.52) 21g (yield 83%).(2) L-FMAU-Tr and α-biphenyl methyl esters acyl chlorides is connected
0.064mol α-biphenyl methyl esters acyl chlorides 27g, 0.012mol N, N-dimethyl aminopyridine (DMAP) 1.3g, in 150ml exsiccant pyridine, stir after one hour, the Compound I I 20g that adds 0.04mol is after stirring four days under 22 ℃, behind the pressure reducing and steaming pyridine, separate with pillar, developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain compound III (R
f=0.75) 14.5g (yield 41%).(3) protecting group is sloughed in the compound III hydrolysis, obtains target compound IV
0.015mol compound III 13.3g, the glacial acetic acid aqueous solution of adding 100ml 80%, stirring at room four hours, reflux one hour, the pressure reducing and steaming solvent separates with pillar, and developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain target compound IV (R
f=0.34) 8.3g (yield 86%).
Attached its high resolution mass spectrum figure.
Embodiment 2
L-FMAU is connected with α-biphenyl ethyl ester acyl chlorides
(1) to the protection of 5 ' hydroxyl of L-FMAU
0.05mol L-FMAU (I) 13g, 0.09mol trityl chloride (Ph
3CCl) 25g, in 100ml exsiccant pyridine, room temperature was placed two days, heating two hours (isolated moisture) in boiling water bath then, the pressure reducing and steaming pyridine separates with pillar, and developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain Compound I I (L-FMAU-Tr) (R
f=0.52) 21g (yield 83%).
(2) Compound I I (L-FMAU-Tr) and α-biphenyl ethyl ester acyl chlorides is connected
0.084mol α-biphenyl ethyl ester acyl chlorides 36.7g, 0.02mol N, N-dimethyl aminopyridine (DMAP) 2.2g, in 150ml exsiccant pyridine, stir after one hour, the Compound I I 20 that adds 0.04mol is after stirring four days under 26 ℃, behind the pressure reducing and steaming pyridine, separate with pillar, developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain compound III (R
f=0.72) 13.7g (yield 38%).
(3) protecting group is sloughed in the compound III hydrolysis, obtains target compound IV
0.015mol compound compound III 13.5g, the glacial acetic acid aqueous solution of adding 100ml 80%, stirring at room four hours, reflux one hour, the pressure reducing and steaming solvent separates with pillar, and developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain target compound IV (R
f=0.32) 8.4g (yield 85%).
Embodiment 3
L-FMAU is connected with α-biphenyl isopropyl ester acyl chlorides
(1) to the protection of 5 ' hydroxyl of L-FMAU
0.05mol L-FMAU (I) 13g, 0.11mol trityl chloride (Ph
3CCl) 30.5g, in 100ml exsiccant pyridine, room temperature was placed two days, heating two hours (isolated moisture) in boiling water bath then, the pressure reducing and steaming pyridine separates with pillar, and developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain Compound I I (L-FMAU-Tr) (R
f=0.52) 21.5g (yield 85%).
(2) compound (L-FMAU-Tr) II and α-biphenyl isopropyl ester acyl chlorides is connected
0.056mol α-biphenyl isopropyl ester acyl chlorides 26g, 0.016mol N, N-dimethyl aminopyridine (DMAP) 1.7g, in 150ml exsiccant pyridine, stir after one hour, the Compound I I 10g that adds 0.02mol is after stirring four days under 33 ℃, behind the pressure reducing and steaming pyridine, separate with pillar, developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain compound III (R
f=0.68) 6.3g (yield 34%).
(3) protecting group is sloughed in the compound III hydrolysis, obtains target compound IV
0.006mol compound compound III 5.6g, the glacial acetic acid aqueous solution of adding 50ml 80%, stirring at room four hours, reflux one hour, the pressure reducing and steaming solvent separates with pillar, and developping agent is CHCl
3: EA: MeOH=40: 30: 3, obtain target compound IV (R
f=0.29) 3.4g (yield 82%).File: C: HPCHEM 1 DATA 0005705.D#100 (2.671min) date: 30May 2000 samples: wy001 MW=646 king is with project number: 99903 conditions: HP5999A mass spectrograph EI 50-400
Shanghai Organic Chemistry Institute, Chinese Academy of Sciences
m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA m/z ％RA41 13.14 79 2.98 107 2.70 135 6.17 177 1.99 229 2.46 280 3.58 341 2.54 400 1.94 550 4.23 646 44.6943 25.34 80 3.28 108 2.26 136 2.02 178 3.22 236 3.22 283 9.66 343 23.15 400 2.67 551 5.20 659 8.0744 16.63 81 5.37 109 4.79 137 2.45 179 5.02 237 2.46 285 7.45 345 5.45 401 2.10 552 2.08 660 14.4645 9.22 82 4.48 110 3.25 139 2.13 180 2.37 239 3.24 297 2.24 353 2.62 404 100.00 552 2.07 688 2.8453 2.37 83 7.93 111 3.17 140 4.69 185 2.29 240 2.81 298 3.68 355 10.31 421 2.23 563 4.3355 13.86 84 5.45 112 2.91 141 2.26 193 4.36 241 3.47 299 5.73 356 2.97 422 2.31 564 2.4856 6.40 85 4.97 115 2.27 149 2.13 199 2.19 242 2.84 300 4.12 357 4.06 423 1.93 565 2.2157 15.76 86 2.46 116 2.54 150 3.55 204 2.98 243 5.97 300 4.28 358 4.89 489 1.96 576 2.1859 3.65 87 7.45 117 2.45 151 2.40 205 3.66 255 5.35 301 3.92 359 5.68 520 47.43 577 3.1460 4.06 91 2.57 121 2.73 152 2.15 206 10.72 256 3.36 313 20.54 359 6.13 521 54.52 578 2.1067 4.14 93 2.24 123 2.68 155 2.53 207 8.48 257 5.42 315 7.15 361 1.97 522 16.41 597 3.0069 9.66 94 2.32 124 1.94 157 1.97 208 3.39 258 1.91 321 2.24 367 3.02 523 6.57 615 2.4270 4.26 95 5.10 125 3.55 162 2.02 211 2.32 268 2.29 325 2.48 368 2.57 524 2.08 615 2.4271 8.37 96 4.53 126 9.87 165 3.46 213 3.14 269 3.11 329 53.13 371 1.91 536 2.43 628 2.4972 2.49 97 5.72 127 4.44 166 2.19 215 2.73 269 3.09 331 3.05 373 6.81 537 2.92 629 2.8473 6.08 98 5.18 128 2.75 167 2.16 225 2.32 270 3.55 339 2.18 374 7.37 538 3.51 629 2.8474 3.32 99 3.74 129 3.93 170 3.71 227 3.85 271 4.20 339 2.31 375 2.61 549 3.17 645 26.0477 2.98 105 2.56 134 2.15 171 3.35 228 2.27 272 2.64 341 2.18 387 27.24 549 4.39 646 44.78
Eight peak values: 404 100.00 521 54.52 329 53.13 520 47.43 646 44.78 387 27.24 5 26.04 43 25.34LIST:200607-1-c1 07-Jun-00 Elapse:06:29.1 30Samp:M646 Start:10:34:04 36Mode:EI+VE+LMR BSCAN (EXP) UP HR NRMOper:Inlet:Limt:(0)..
：(931)C50.H60.F.N2.O14Peak：1000.00 mmu R+D：-2.0＞60.0Data：CMASS：converted
89736 (mmu)
Mass Intensity ％RA Flags Delta R+D Composition283.0226 122669 6.83 F# -1.2 4.5 C7.H8.F.N2.O9
1.7 12.5 C15.H7.O6
-2.3 8.5 C10.H7.N2.O8
2.8 8.5 C12.H8.F.O7
-3.0 17.5 C19.H4.F.O2313.0332 212239 11.83 F# -0.4 22.0 C23.H4.F.N
-1.2 4.5 C8.H10.F.N2.O10
1.6 12.5 C16.H9.O7
-2.4 8.5 C11.H9.N2.O9
2.8 8.5 C13.H10.F.O8314.0409 112407 6.26 # -0.3 21.5 C23.H5.F.N
-1.2 4.0 C8.H11.F.N2.O10
1.7 12.0 C16.H10.O7
-2.3 8.0 C11.H10.N2.O9
2.9 8.0 C13.H11.F.O8327.0490 109856 6.12 # -0.6 22.0 C24.H6.F.N
-1.4 4.5 C9.H12.F.N2.O10
1.5 12.5 C17.H11.O7
-2.6 8.5 C12.H11.N2.O9
2.6 8.5 C14.H12.F.O8328.0578 487415 27.16 F# 0.5 12.0 C17.H12.O7
-1.5 21.5 C24.H7.F.N
1.7 8.0 C14.H13.F.O8
-2.3 4.0 C9.H13.F.N2.O10
2.4 -1.0 C5.H16.N2.O14329.0652 707484 39.42 F# 1.0 11.5 C17.H13.O7
-1.1 21.0 C24.H8.F.N
-1.9 3.5 C9.H14.F.N2.O10
2.1 7.5 C14.H14.F.O8
2.8 -1.5 C5.H17.N2.O14330.0662 142956 7.97 # 1.0 2.5 C9.H16.N.O12
-1.0 12.0 C16.H11.F.N2.O5
1.8 20.0 C24.H10.O2
2.2 -1.5 C6.H17.F.N.O13
-2.2 16.0 C19.H10.N2.O4343.0814 202926 11.31 F# 0.4 11.5 C18.H15.O7
1.5 7.5 C15.H16.F.O8
-1.7 21.0 C25.H10.F.N
2.2 -1.5 C6.H19.N2.O14
-2.5 3.5 C10.H16.F.N2.O10344.0544 103984 5.79 F# -0.1 8.0 C14.H13.F.O9
-1.2 12.0 C17.H12.O8
1.5 16.5 C20.H10.N.O5
2.6 12.5 C17.H11.F.N.O6
-3.3 21.5 C24.H7.F.N.O374.0608 153040 8.53 # 0.1 4.0 C10.H15.F.N2.O12
-0.2 25.5 C28.H8.N.O
0.9 21.5 C25.H9.F.N.O2
-1.0 8.0 C13.H14.N2.O11
-1.7 17.0 C22.H11.F.O5387.0706 294098 16.39 # 1.0 12.5 C19.H15.O9
-1.0 22.0 C26.H10.F.N.O2
-1.9 4.5 C11.H16.F.N2.O12
2.2 8.5 C16.H16.F.O10
-2.2 26.0 C29.H9.N.O388.0744 93425 5.21 # 0.3 17.0 C23.H13.F.O5
-0.8 21.0 C26.H12.O4
1.1 8.0 C14.H16.N2.O11
-1.6 3.5 C11.H18.N.O14
1.9 25.5 C29.H10.N.O404.0742 1047257 58.35 # 0.2 12.0 C19.H16.O10
0.8 26.0 C29.H9.F.N2
1.3 8.0 C16.H17.F.O11
-1.9 21.5 C26.H11.F.N.O3
-2.7 4.0 C11.H17.F.N2.O13405.0777 207671 11.57 # -0.3 16.5 C23.H14.F.O6
0.4 7.5 C14.H17.N2.O12
1.2 25.0 C29.H11.N.O2
-1.4 20.5 C26.H13.O5
1.6 3.5 C11.H18.F.N2.O13520.1038 99832 5.56 # 0.5 18.5 C27.H19.F.N.O9
-0.6 22.5 C30.H18.N.O8
2.1 27.0 C33.H16.N2.O5
-2.1 14.0 C24.H21.F.O12
-2.7 32.0 C37.H13.F.N2.O521.1093 411310 22.92 F# 0.2 13.5 C24.H22.F.O12
-0.3 31.5 C37.H14.F.N2.O
-0.9 17.5 C27.H21.O11
-1.5 35.5 C40.H13.N2
1.7 22.0 C30.H19.N.O8522.1106 103687 5.78 # -0.2 26.0 C34.H18.O6
0.9 22.0 C31.H19.F.O7
1.6 13.0 C22.H22.N2.O13
2.4 30.5 C37.H16.N.O3
2.8 9.0 C19.H23.F.N2.O14646.1430 141947 7.91 # -0.2 30.0 C41.H23.F.O7
0.5 21.0 C32.H26.N2.O13
1.3 38.5 C47.H20.N.O3
-1.4 34.0 C44.H22.O6
1.6 17.0 C29.H27.F.N2.O14
Claims (5)
1, a kind of new compound is characterized in that it has following structure:
R=-CH
3,-CH
2CH
3,-CH (CH
3)
2,-C (CH
3)
3,-CH
2CH
2CH
3,-CH
2CH
2CH
2CH
3, R
1And R
2Represent methylidene.
2, the synthetic method of compound as claimed in claim 1, it is characterized in that it realizes as follows: (1) is protected with trityl chloride the hydroxyl of 2 '-deoxidation-2 '-fluoro-5-methyl-arabinofuranosyl adenin uridine 5 ' position; (2) at N, the N-dimethyl aminopyridine exists following, has 2 ' of protecting group-deoxidation-2 '-fluoro-5-methyl-arabinofuranosyl adenin uridine and 4,4 '-dimethyl oxygen base-5 by the esterification handle, 6,5 ' 6 '-secondary methylenedioxy group-2 '-alkyl oxygen carbonyl-2-dibenzoyl chloropexia is got up; (3) slough blocking group and obtain target compound.
3, the synthetic method of compound as claimed in claim 2 is characterized in that the reactant molar ratio is when carrying out step (1) reaction: 2 '-deoxidation-2 '-fluoro-5-methyl-arabinofuranosyl adenin uridine: trityl chloride=1: 1.5～2.5.
4, the synthetic method of compound as claimed in claim 2, it is characterized in that the reaction molar ratio is when carrying out step (2) esterification: 2 '-deoxidation-2 '-fluoro-5 '-three benzyloxies-5-methyl-arabinofuranosyl adenin uridine: 4,4 '-dimethyl oxygen base--5,6,5 ' 6 '-secondary methylenedioxy group-2 '-alkyl oxygen carbonyl-2-biphenyl acyl chlorides: N, N-dimethyl aminopyridine=1: 1.4～3: 0.3～0.8.
5, the synthetic method of compound as claimed in claim 4 is characterized in that the humidity of esterification is controlled at 10～40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00118945 CN1122671C (en) | 2000-08-11 | 2000-08-11 | Arbinosyl furanuridine compound and its preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00118945 CN1122671C (en) | 2000-08-11 | 2000-08-11 | Arbinosyl furanuridine compound and its preparing process |
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|---|---|
| CN1338461A CN1338461A (en) | 2002-03-06 |
| CN1122671C true CN1122671C (en) | 2003-10-01 |
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ID=4587370
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603836A (en) * | 2012-02-10 | 2012-07-25 | 郑州大学 | Schisandrin C simplifier, schisandrin analogue, preparation method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735294B (en) * | 2005-07-01 | 2013-01-02 | 博瑞生物医药技术(苏州)有限公司 | Prodrug of L-nucleoside |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102603836A (en) * | 2012-02-10 | 2012-07-25 | 郑州大学 | Schisandrin C simplifier, schisandrin analogue, preparation method and applications thereof |
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