CN102206187A - New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and its analogues - Google Patents
New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and its analogues Download PDFInfo
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Abstract
The invention relates to a new synthetic method for a compound which is represented by the general formula (IV), n thereof is 1, 2 or 3, R1 is selected from phenyl, naphthyl, cyclopentyl and cyclohexyl, R2 is selected from C1 to C4 alkyl, vinyl and formoxyl, and R3 is selected from methyl, vinyl, cyclohexyl and phenyl. The invention provides the new synthetic method which treats isopropyl cyclomalonate as a raw material. The method has the advantages of easily obtained raw materials and reagents and simple operation, and allows multi sites to be reconstructed simultaneously and easily, a large selection space in new drug molecule designation to be achieved and the officinal possibility of such compound to be increased.
Description
Technical field:
The present invention relates to a kind of preparation method of active constituents of medicine, a kind of preparation method with the active compound 6-benzyl of anti-HIV-1 type acquired immune deficiency syndrome (AIDS)-1-ethoxymethyl-5 sec.-propyl uridylic (Emivirine) and analogue thereof more specifically says so.
Background technology:
Emivirine is a kind of non-nucleoside reverse transcriptase inhibitor, produce the noncompetitive inhibition with the reversed transcriptive enzyme of HIV-1 C-type virus C, has potent external HIV (human immunodeficiency virus)-resistant activity, with AZT (zidovudine), the main drug combination of d4T (Si Tafuding) and 3TC many anti-HIV-1s such as (lamivudines) can produce synergy, and does not produce crossing drug resistant between the efabirenz.There is drug-fast virus strain still can fully keep susceptibility to AZT and 3TC to this medicine.Toxicology characteristic good before this medicine is clinical.The zoology test result shows that this medicine can not produce long-term or cumulative toxicity, to not obviously influence of fertility.This medicine once entered the test of II phase Linchuan in the U.S..
The synthetic route of existing Emivirine mainly contains two.Article one, be to be raw material with 5-sec.-propyl uridylic, after the N-1 position replaces, under the highly basic condition with phenyl aldehyde generation nucleophilic substitution reaction, at last hydrogenation after the glycoloylization is removed, get final product (Masanori B etc., Nucleosides, Nucleotides Nucleic Acids.1995,14:575-583; Ubasawa etc., 1996, JP 08003143; Cazaux etc., 1999, FR 2779722; Otani, Hiroshi etc., 2001, JP2001114767), route is shown in Scheme 1.
a.1)(Me
3Si)
2NH,(NH
4)
2SO
4,CH
2Cl
2;2)KI,EtOCH
2OEt.b.1)NaOH,PhMe;2)BuLi,THF/hexane,PhCHO.c.AcOH,4-DMAP(cat.)d.H
2,Et
3N,Pd,Me
2CHOH.
Another is with 4; 5-two bromo-2; the 6-dimethoxypyridin is a raw material, after its halogen of 5,6 with the sec.-propyl Grignard reagent Ge Shi permutoid reaction takes place respectively; react with acetone and bromotoluene respectively again; wherein with after the acetone reaction need dehydroxylation, remove protecting group at last and obtain final product (Paul K etc., Organic Letters.2006; 8:3737-3740), route is shown in Scheme 2.With 6-chloro-5-sec.-propyl uracil is raw material, utilizes similar method, has not also obtained final product (9:1639-1641), route is shown in Scheme 3 for PaulK etc., Organic Letters.2007 but do not need protection.
a.1)i-PrMgCl·LiCl,THF,rt.2)LaCl
3·2LiCl,Me
2CO,THF,0℃.b.1)Et
3N,TFA,CH
2Cl
2,rt.2)H
21bar,PtO
2,EtOH.
c.1)i-PrMgCl·LiCl,THF,rt.2)PhCH
2Br,rt.d.HCl?conc.MeOH,reflux.e.1)BSA,MeCN.2)TMS?triflates,CH
2(OEt)
2.
a.POCl
3,H
3PO
4,reflux.b.NaI,HI,rt.c.1)MeMgCl·LiCl,-30℃.2)i-PrMgCl·LiCl,-30℃.d.1)CuI,BnBr,-30℃.e.1)BSA,MeCN.2)TMS?triflates,CH
2(OEt)
2.
In addition, it is key intermediate that Emivirine analogue synthetic can prepare Compound I I earlier, pieces together ring then, and the N-1 position replaces and obtains final product.Wherein, Compound I I is by two kinds of approach preparations (Erik B.P etc. 1995,8:934-936; NielsenC etc., 1996,39:2427-2431; Nielsen C etc., 2002,45:5721-5726), route is shown in Scheme 4.
a.Zn,THF,reflux.b.1)Et
3N,MgCl
2?2)HCl?c.1)NaOEt,EtOH,reflux.2)aq.ClCH
2COOH,reflux.d.BSA,LiI,MeCN.
Use in the above synthetic route be not be simple and easy to most raw material, and related to organometallic reaction, reaction conditions is required relatively harsher, as anhydrous, anaerobic, low temperature etc.In grignard reaction, used transition element and cuprous salt to be catalyzer, poisoned bigger.Auspicious Buddhist MAERSK reaction (Reformastky Reaction) needs excessive greatly zinc powder, and to the strictness of zinc powder specification of quality.Therefore, still need a kind of easier, more economical, and synthetic route that can easier acquisition homologue.
Summary of the invention:
The invention provides the method for the enough simple feedstock production formulas of a kind of energy (IV) compound.
In the formula, n is 1,2 or 3; R
1Be phenyl, naphthyl, cyclopentyl, cyclohexyl;
R
2Be C1-C4 alkyl, vinyl, formyl radical;
R
3Be methyl, vinyl, cyclohexyl, phenyl;
The present invention implements by following reaction scheme:
Step (1) be propanedioic acid ring isopropyl ester (Meldrum ' s Acid) with carboxylic acid halides in the presence of organic bases, in reaction solvent, carry out the nucleophilic substitution reaction of a few hours under the certain temperature, the backflow alcoholysis obtains formula (I) compound in ethanol again.More particularly, nucleophilic substitution reaction is to adopt organic bases (for example triethylamine, tri-n-butylamine, pyridine, tripropylamine) to be the disacidify agent, in reaction solvent (for example tetrahydrofuran (THF), dioxane, acetone, methylene dichloride, chloroform, acetonitrile) ,-10~30 ℃ temperature range internal reactions 1~6 hour.After reaction finished, the pressure reducing and steaming solvent directly refluxed in dehydrated alcohol 2~8 hours, and alcohol solves formula (I) compound, wherein R
1Identical with the compound of general formula (IV).
Step (2) be formula (I) compound and halogenide in the presence of organic bases or mineral alkali, in non-protonic solvent, carry out the nucleophilic substitution reaction of a few hours under the certain temperature, obtain formula (II) compound.More particularly, nucleophilic substitution reaction is to adopt organic bases (for example sodium alkoxide, triethylamine, tri-n-butylamine, pyridine, tripropylamine) or mineral alkali (for example NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH), Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, CsCO
3) be the disacidify agent, in non-protonic solvent (for example DMF, DMSO, tetrahydrofuran (THF), acetone, dioxane, pyrrolidinone compounds),, obtain formula (II) compound 20~160 ℃ of reactions 2~10 hours, wherein, R
1, R
2Identical with the compound of general formula (IV).
Step (3) is that formula (II) compound and thiocarbamide carry out cyclization reaction under sodium ethylate/ethanol condition, again in the chloroacetic aqueous solution under the reflux conditions hydrolysis obtain formula (III) compound.
Step (4) be formula (III) compound under the catalysis of silicon etherifying reagent and Lewis alkali with alkyl chloride methyl ether generation nucleophilic substitution, obtain final product (IV), wherein, R
1, R
2, R
3Identical with the compound of general formula (IV).Work as R
1Be phenyl, R
2Be sec.-propyl, R
3During for phenyl, final product is 1-ethoxymethyl-5-sec.-propyl-6 benzyluracils (Emivirine).
The invention has the advantages that: 1, this route is a raw material with propanedioic acid ring isopropyl ester (Meldrum ' s Acid), through synthetic 1-ethoxymethyl of four steps-5-sec.-propyl-6-benzyluracils or its analogue.Raw materials used and reagent is all cheap and easy to get, and the reaction pair condition do not have harsh requirement, and is easy and simple to handle, is easy to a large amount of preparations.2, by this route can be easy the derivative transformed simultaneously of three important sites of acquisition, finish the accumulation of library of compounds, for the structure activity relationship and the efficient anti-HIV-1 type AIDS-treating medicine of exploitation of further probing into this compounds lays the first stone.
Annotate: propanedioic acid ring isopropyl ester can obtain from the commercial channel, also can with propanedioic acid more cheap and easy to get through a step make (David D etc., J.Am.Chem.Soc.1948,70:3426-3428).
Embodiment:
The invention will be further described below in conjunction with embodiment, but do not limit this explanation.
The preparation (formula I compound) of embodiment 1 3-oxo-4-phenylbutyrate
With propanedioic acid ring isopropyl ester (23.75g, 0.165mol) and anhydrous pyridine (32.5mL 0.4mol) is dissolved in methylene dichloride 100mL, under 0 ℃, slowly splash into phenyllacetyl chloride (25.50g then, 0.165mol), continue 0 ℃ of reaction 1 hour, room temperature reaction 1 hour.Reaction solution adds 100mL 2N hydrochloric acid with 50mL methylene dichloride dilution back, separates organic phase, and water layer merges organic phase with methylene dichloride (50mL) extracting twice, and the pressure reducing and steaming solvent gets the light orange solid.Small amount of ethanol drip washing can get white crystals, directly refluxes 2.5 hours in the 250mL dehydrated alcohol behind the suction filtration, obtains light yellow liquid behind the pressure reducing and steaming solvent, can not purifiedly be used for the next step.Get light yellow liquid 33.05g by silica gel chromatography (50: 1 petrol ether/ethyl acetate), yield is 98.8%.
ESI-MS:m/z=207.1[M+H]
+
1H?NMR(300MHz,CDCl
3)δ:7.31~7.15(5H,m,ArH),5.20(2H,s,COCH
2CO),4.52(2H,s,CH
2Ph),3.61~3.56(2H,q,OCH
2CH
3),1.16~1.14(3H,t,OCH
2CH
3).
The preparation (formula I compound) of embodiment 2 3-oxo-4-cyclohexyl ethyl butyrate
With propanedioic acid ring isopropyl ester (23.75g, 0.165mol) and anhydrous pyridine (32.5mL 0.4mol) is dissolved in methylene dichloride 100mL, under 0 ℃, slowly splash into cyclohexyl Acetyl Chloride 98Min. (26.40g then, 0.165mol), continue 0 ℃ of reaction 1 hour, room temperature reaction 1 hour.Reaction solution adds 100mL 2N hydrochloric acid with 50mL methylene dichloride dilution back, separates organic phase, and water layer merges organic phase with methylene dichloride (50mL) extracting twice, and the pressure reducing and steaming solvent gets the light orange solid.Directly in the 250mL dehydrated alcohol, refluxed 2.5 hours behind the suction filtration, obtain light yellow liquid behind the pressure reducing and steaming solvent, can not purifiedly be used for the next step.Get light yellow liquid 30.74g by silica gel chromatography (50: 1 petrol ether/ethyl acetate), yield is 88.3%.
ESI-MS:m/z=212.2[M+H]
+
1H?NMR(300MHz,CDCl
3)δ:4.20(2H,s,COCH
2CO),3.58~3.45(2H,q,OCH
2CH
3),2.61(2H,s,CH
2),1.15~1.12(3H,t,OCH
2CH
3).
The preparation (formula II compound) of embodiment 3 2-sec.-propyl-3-oxygen-4 phenylbutyrate
(16.5g, 0.080mol), (11.8g, 0.096mol), (26.2g 0.24mol) mixes stirring at room 12 hours with dry DMF (25mL) to Anhydrous potassium carbonate to the 2-N-PROPYLE BROMIDE with 3-oxo-4-phenylbutyrate.Add ethyl acetate (50mL) dilution, wash with water,, use dried over sodium sulfate with the saturated common salt washing.The pressure reducing and steaming solvent, silica gel chromatography (80: 1 petrol ether/ethyl acetate) gets light yellow liquid 14.2g, yield 71.3%.
ESI-MS:m/z=249.1[M+H]
+
1H?NMR(300MHz,CDCl
3)δ:7.38~7.22(5H,m,ArH),5.07(1H,s,COCHCO),4.42~4.36(1H,m,CHMe
2),4.21~4.16(2H,q,OCH
2CH
3),4.11(2H,s,CH
2Ph),1.32~1.29(3H,t,OCH
2CH
3)1.26~1.24(6H,d,CHMe
2).
13C?NMR(75MHz,CDCl
3)δ:172.01(C-3),167.84(C-1),138.14,129.18,128.14,126.20(C-aryl),91.69(CO
CHCO),70.23(
CH
2Ph),59.37(O
CH
2CH
3),37.81(
CHMe
2),21.35(CH
Me 2),14.43(OCH
2 CH
3)
The preparation (formula III compound) of embodiment 4 5-sec.-propyl-6-benzyluracils
With sodium Metal 99.5 (2.2g 96mmol) is dissolved among the absolute ethanol 200ml, add thiocarbamide (4.96g, 64mmol) and 2-sec.-propyl-3-oxygen-4 phenylbutyrate (6.56g, 32mmol), reaction mixture reflux 6 hours.Be threaded near doing 40~50 ℃ of decompressions, in the residuum water-soluble (50ml).Transfer pH to 4 with 2N hydrochloric acid, filter out precipitation 6.12g, with Mono Chloro Acetic Acid (200ml) reflux of this precipitation and 20% 8 hours with suction funnel.Be cooled to room temperature, separate out white crystal, suction filtration, with cold ethanol and cold diethyl ether washing, drying obtains 5-sec.-propyl-6-benzyluracils 5.48g, productive rate 66.1%, 224~226 ℃ of mp at last successively.
ESI-MS:m/z=245.4[M+H]
+
1H?NMR(300MHz,CDCl
3)δ:10.97~10.94(2H,br?s,2NH),7.33~7.16(5H,m,ArH),3.90(2H,s,CH
2Ph),2.95~2.88(1H,m,CHMe
2),1.20~1.18(6H,d,CHMe
2).
13C?NMR(75MHz,CDCl
3)δ:163.77(C-4),150.94(C-2),148.45,136.99,128.46,127.88(C-aryl),113.79(C-5),35.21(
CH
2Ph),26.29(
CHMe
2),19.99(CH
Me 2)
Embodiment 5 6-benzyl-1-ethoxymethyl-5-sec.-propyl uridylic (formula IV compound, Emivirine)
With 5-sec.-propyl-6-benzyluracils (1.2g, 5.0mmol) be dissolved in the methylene dichloride (30ml), add N, O-two trimethyl silicane yl acetamide (BSA) (3.2ml, 11.0mmol) afterreaction liquid change clarification, stirring at room adds chloromethyl ethyl ether after 40 minutes (0.57g, 6.0mmol) with catalytic amount LiI, stirring at room adds saturated Na after 3 hours
2CO
3The solution stopped reaction, dichloromethane extraction, dried over sodium sulfate, the pressure reducing and steaming solvent, silica gel chromatography (3: 1 petrol ether/ethyl acetate), at last 1-ethoxymethyl-5-sec.-propyl-6-benzyluracils 1.38g, productive rate 91.5%, mp.105~108 ℃.
HRESI-MS?m/z:calcd?for?C
17H
22N
2O
3,303.17090[M+H]
+;found?303.17032.
1H?NMR(300MHz,CDCl
3)δ:8.97(1H,br?s,NH),7.36~7.11(5H,m,ArH),5.13(2H,s,NCH
2O),4.18(2H,s,CH
2Ph),3.65~3.60(2H,q,OCH
2Me),2.90~2.82(1H,m,CHMe
2),1.29~1.27(6H,d,CHMe
2),1.20~1.17(3H,t,OCH
2Me)
13C?NMR(75MHz,CDCl
3)δ:162.23(C-4),151.82(C-2),148.46(C-6),135.44,129.19,127.26,127.22(C-aryl),119.71(C-5),72.91(N
CH
2O),65.00(O
CH
2CH
3),33.50(
CH
2Ph),28.34(
CHMe
2),20.39(CH
Me 2),15.03(OCH
2 CH
3)
Embodiment 6 6-benzyl-1-benzyloxymethyl-5-sec.-propyl uridylic (formula IV compound)
With 5-sec.-propyl-6-benzyluracils (1.2g, 5.0mmol) be dissolved in the methylene dichloride (30ml), add N, O-two trimethyl silicane yl acetamide (BSA) (3.2ml, 11.0mmol) afterreaction liquid change clarification, stirring at room adds the chloromethyl benzylic ether after 40 minutes (0.94g, 6.0mmol) with catalytic amount LiI, stirring at room adds saturated Na after 3 hours
2CO
3The solution stopped reaction, dichloromethane extraction, dried over sodium sulfate, the pressure reducing and steaming solvent, silica gel chromatography (3: 1 petrol ether/ethyl acetate), at last 1-benzyloxymethyl-5-sec.-propyl-6-benzyluracils 1.57g, productive rate 86.5%, mp.105~108 ℃.
HRESI-MS?m/z:calcd?for?C
22H
24N
2O
3,365.18536[M+H]
+;found?365.18597.
1H?NMR(300MHz,CDCl
3)δ:8.87(1H,br?s,NH),7.33~7.25(8H,m,ArH),7.06~7.04(2H,d,ArH),5.21(2H,s,NCH
2O),4.65(2H,s,OCH
2Ph),4.16(2H,s,CH
2Ph),2.88~2.81(1H,m,CHMe
2),1.27~1.25(6H,d,CHMe
2)
13C?NMR(75MHz,CDCl
3)δ:162.09(C-4),151.79(C-2),148.37(C-6),137.33,135.29,129.21,128.48,128.00,127.78,127.27(C-aryl),119.79(C-5),72.96(N
CH
2O),71.81(O
CH
2Ph),33.48(
CH
2Ph),28.32(
CHMe
2),20.40(CH
Me 2)
Claims (11)
1. the new preparation process of general formula (IV):
In the formula, n is 1,2 or 3; R
1Be phenyl, naphthyl, cyclopentyl, cyclohexyl;
R
2Be C1-C4 alkyl, vinyl, formyl radical;
R
3Be methyl, vinyl, cyclohexyl, phenyl;
The preparation method of logical formula V is made up of the following step:
(1) by propanedioic acid ring isopropyl ester (Meldrum ' sAcid) and carboxylic acid halides generation nucleophilic substitution reaction, alcoholysis obtains formula I compound in ethanol again;
(2) formula I compound and halogenide generation nucleophilic substitution reaction obtain formula II compound;
(3) formula II compound and thiocarbamide carry out ring-closure reaction, and hydrolysis obtains the formula III compound in the chloroacetic aqueous solution again;
(4) the formula III compound under the catalysis of silicon etherifying reagent and Lewis alkali with monochloromethyl-ether generation nucleophilic substitution, obtain final product (IV).
2. according to the described synthetic method of claim 1, it is characterized in that synthetic 6-benzyl-1-ethoxymethyl-5-sec.-propyl uridylic (Emirivine), promptly n is 1, R
1Be phenyl, R
2Be sec.-propyl, R
3Be ethyl.
3. according to the described synthetic method of claim 1, it is characterized in that step (1): key intermediate (I) by propanedioic acid ring isopropyl ester and carboxylic acid halides in the presence of organic bases, in reaction solvent, carry out the generation nucleophilic substitution reaction of a few hours under the certain temperature, the backflow alcoholysis obtains in ethanol again, wherein R
1Identical with the compound of general formula (IV).
4. it is characterized in that according to the described synthetic method of claim 3 nucleophilic substitution reaction of step (1) is the disacidify agent with the organic bases, organic bases is selected from triethylamine, tri-n-butylamine, pyridine, tripropylamine.
5. it is characterized in that according to the described synthetic method of claim 3 solvent of step (1) is selected from tetrahydrofuran (THF), dioxane, acetone, methylene dichloride, chloroform, acetonitrile.
6. it is characterized in that according to the described synthetic method of claim 3 temperature of reaction of step (1) is-10 ℃~30 ℃, the reaction times is 1~6 hour.
7. according to the described synthetic method of claim 1, it is characterized in that step (2): in the presence of organic bases or mineral alkali, in reaction solvent, the nucleophilic substitution reaction that carries out a few hours under the certain temperature obtains key intermediate (II) by formula I compound and halogenide, wherein, R
1, R
2Identical with the compound of general formula (IV).
8. it is characterized in that according to the described synthetic method of claim 7 nucleophilic substitution reaction of step (2) is the disacidify agent with the organic bases, organic bases is selected from sodium alkoxide, triethylamine, tri-n-butylamine, tripropylamine.
9. it is characterized in that according to the described synthetic method of claim 7 step (2) is the disacidify agent with the mineral alkali, mineral alkali is selected from NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH), Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, CsCO
3..
10. it is characterized in that according to the described synthetic method of claim 7 solvent of step (2) is selected from DMF, DMSO, tetrahydrofuran (THF), dioxane, pyrrolidinone compounds.
11. it is characterized in that according to the described synthetic method of claim 7 temperature of reaction of step (2) is 20 ℃~160 ℃, the reaction times is 2~10 hours.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102295608A (en) * | 2010-06-24 | 2011-12-28 | 北京大学 | Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor |
CN102634546A (en) * | 2012-03-16 | 2012-08-15 | 苏州汉酶生物技术有限公司 | Enzymatic synthesis method of chiral beta-hydroxyl ester compound |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1352637A (en) * | 1999-04-13 | 2002-06-05 | 三角药物公司 | Process for preparing MKC-442 |
CN1539827A (en) * | 2003-10-31 | 2004-10-27 | 中国科学院上海有机化学研究所 | 6-substitution-5-fluorin-4-hydroxy miazines compound and intermediate, synthetic method and usage |
WO2008051942A2 (en) * | 2006-10-24 | 2008-05-02 | Smithkline Beecham Corporation | Farnesoid x receptor agonists |
EP2039689A1 (en) * | 2006-05-26 | 2009-03-25 | Kaneka Corporation | Process for production of optically active 3-amino-2 -hydroxypropionic cyclopropylamide derivatives and salts thereof |
-
2010
- 2010-03-31 CN CN 201010136763 patent/CN102206187B/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1352637A (en) * | 1999-04-13 | 2002-06-05 | 三角药物公司 | Process for preparing MKC-442 |
CN1539827A (en) * | 2003-10-31 | 2004-10-27 | 中国科学院上海有机化学研究所 | 6-substitution-5-fluorin-4-hydroxy miazines compound and intermediate, synthetic method and usage |
EP2039689A1 (en) * | 2006-05-26 | 2009-03-25 | Kaneka Corporation | Process for production of optically active 3-amino-2 -hydroxypropionic cyclopropylamide derivatives and salts thereof |
WO2008051942A2 (en) * | 2006-10-24 | 2008-05-02 | Smithkline Beecham Corporation | Farnesoid x receptor agonists |
Non-Patent Citations (1)
Title |
---|
田辉凯等: "含香豆素基团的二氯丙烯类衍生物的合成及杀虫活性", 《农药学学报》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102295608A (en) * | 2010-06-24 | 2011-12-28 | 北京大学 | Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor |
CN102295608B (en) * | 2010-06-24 | 2014-09-24 | 北京大学 | Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor |
CN102634546A (en) * | 2012-03-16 | 2012-08-15 | 苏州汉酶生物技术有限公司 | Enzymatic synthesis method of chiral beta-hydroxyl ester compound |
CN102634546B (en) * | 2012-03-16 | 2013-10-16 | 苏州汉酶生物技术有限公司 | Enzymatic synthesis method of chiral beta-hydroxyl ester compound |
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