110567-22-1

Basic information

• Product Name: (1S,2R,3S,5R)-3-(Phenymethyloxy)-2-(phenylmethoxy)methyl-6-oxabicyclo[3.1.0]hexane
• Synonyms: (1S,2R,3S,5R)-3-(Phenymethyloxy)-2-(phenylmethoxy)methyl-6-oxabicyclo[3.1.0]hexane;(1S,2R,3S,5R)-3-(Phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane;[1S-(1a,2a,3,5a)]-3-(Phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane;6-Oxabicyclo[3.1.0]hexane, 3-(phenylmethoxy)-2-[(phenylmethoxy)methyl]-, (1S, 2R, 3S, 5R);(1S,2R,3S,5R)-3-(Benzyloxymethyl)-6-oxabicyclo[3.1.0]hexane;[1S-(1α,2α,3β,5α)]-3-(Phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane;(1S,2R,3S,5R)-3-(Phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane ,90%;1R,2R-2-[(Phenylmethoxy)methyl]-3-cyclo penten-1-ol
• CAS NO: 110567-22-1
• Molecular Formula: C₂₀H₂₂O₃
• Molecular Weight: 310.38688
• EINECS: 1592732-453-0
• Product Categories: Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 110567-22-1.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 427.928 °C at 760 mmHg
• Flash Point: 145.852 °C
• Appearance: /
• Density: 1.17
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.593
• Storage Temp.: Refrigerator
• Solubility: Benzene, Chloroform, DMSO, Methanol
• CAS DataBase Reference: (1S,2R,3S,5R)-3-(Phenymethyloxy)-2-(phenylmethoxy)methyl-6-oxabicyclo[3.1.0]hexane(CAS DataBase Reference)
• NIST Chemistry Reference: (1S,2R,3S,5R)-3-(Phenymethyloxy)-2-(phenylmethoxy)methyl-6-oxabicyclo[3.1.0]hexane(110567-22-1)
• EPA Substance Registry System: (1S,2R,3S,5R)-3-(Phenymethyloxy)-2-(phenylmethoxy)methyl-6-oxabicyclo[3.1.0]hexane(110567-22-1)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 110567-22-1(Hazardous Substances Data)

Usage

Chemical Properties

Colorless Oil

Uses

Different sources of media describe the Uses of 110567-22-1 differently. You can refer to the following data:
1. Entecavir intermediate.
2. Entecavir intermediate

InChI:InChI=1/C20H22O3/c1-3-7-15(8-4-1)12-21-14-17-18(11-19-20(17)23-19)22-13-16-9-5-2-6-10-16/h1-10,17-20H,11-14H2/t17-,18+,19-,20+/m1/s1

Synthetic route

benzyl bromide (100-39-0) + (2R,3S)-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexan-3-ol (117641-39-1) → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions	Yield
Stage #1: (2R,3S)-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexan-3-ol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 12h;	86%
With tetra-(n-butyl)ammonium iodide; sodium hydride 1.) THF, 2 h; 1.) THF, 2.5 h; Yield given. Multistep reaction;
With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide Yield given;
With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide; mineral oil at -50℃; for 18h;
With sodium hydride In tetrahydrofuran; water at 20℃; Large scale;	4.4 kg

Benzyloxymethyl chloride (3587-60-8) → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: NaH / tetrahydrofuran / 1 h / 0 °C 1.2: tetrahydrofuran / 2 h / -40 °C 2.1: (-)-diisopinocamphenylborane / tetrahydrofuran / 17 h / -60 - 0 °C 2.2: 8.20 g / aq. NaOH; H2O2 / diethyl ether; tetrahydrofuran / 12 h / 0 °C 3.1: 82 percent / Mo(CO)6; t-BuOOH / benzene; decane / 3 h / 80 °C 4.1: NaH / tetrahydrofuran / 1 h / 20 °C 4.2: 86 percent / tetrabutylammonium iodide / tetrahydrofuran / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: tetrahydrofuran / -78 - -65 °C 2: 1.) diisopinylcampheylborane (prepared from (+)-α-pinene), 2.) aq. NaOH, H2O2 / 1.) THF, -65 to -78 deg C 3: VO(acac)2, t-BuOOH / CH2Cl2 4: NaH, Bu4NI / dimethylformamide View Scheme
Multi-step reaction with 4 steps 1: 1.) Na / 1.) THF, -5 deg C, 1.5 h; 2.) THF, -45 deg C, 1 h 2: 15.8 g / (-)-diisopinan-3-ylborane / tetrahydrofuran / 1.) -60 deg C, 1 h; 2.) 5 deg C, 18 h 3: 12.0 g / t-butyl hydroperoxide, vanadium(V)acetylacetonate / 1,2-dichloro-ethane / 2.75 h / 30 °C 4: 1.) NaH; 2.) tetrabutylammonium iodide / 1.) THF, 2 h; 1.) THF, 2.5 h View Scheme

5-(benzyloxymethyl)cyclopentadiene (39939-07-6) → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (-)-diisopinocamphenylborane / tetrahydrofuran / 17 h / -60 - 0 °C 1.2: 8.20 g / aq. NaOH; H2O2 / diethyl ether; tetrahydrofuran / 12 h / 0 °C 2.1: 82 percent / Mo(CO)6; t-BuOOH / benzene; decane / 3 h / 80 °C 3.1: NaH / tetrahydrofuran / 1 h / 20 °C 3.2: 86 percent / tetrabutylammonium iodide / tetrahydrofuran / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: 1.) diisopinylcampheylborane (prepared from (+)-α-pinene), 2.) aq. NaOH, H2O2 / 1.) THF, -65 to -78 deg C 2: VO(acac)2, t-BuOOH / CH2Cl2 3: NaH, Bu4NI / dimethylformamide View Scheme
Multi-step reaction with 3 steps 1: 15.8 g / (-)-diisopinan-3-ylborane / tetrahydrofuran / 1.) -60 deg C, 1 h; 2.) 5 deg C, 18 h 2: 12.0 g / t-butyl hydroperoxide, vanadium(V)acetylacetonate / 1,2-dichloro-ethane / 2.75 h / 30 °C 3: 1.) NaH; 2.) tetrabutylammonium iodide / 1.) THF, 2 h; 1.) THF, 2.5 h View Scheme

cyclopenta-1,3-diene (542-92-7) + (AsCF3)4.5 → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: NaH / tetrahydrofuran / 1 h / 0 °C 1.2: tetrahydrofuran / 2 h / -40 °C 2.1: (-)-diisopinocamphenylborane / tetrahydrofuran / 17 h / -60 - 0 °C 2.2: 8.20 g / aq. NaOH; H2O2 / diethyl ether; tetrahydrofuran / 12 h / 0 °C 3.1: 82 percent / Mo(CO)6; t-BuOOH / benzene; decane / 3 h / 80 °C 4.1: NaH / tetrahydrofuran / 1 h / 20 °C 4.2: 86 percent / tetrabutylammonium iodide / tetrahydrofuran / 12 h / 20 °C View Scheme

(1S,2R)-2-(benzyloxymethyl)-1-hydroxy-3-cyclopentene (110567-21-0) → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 82 percent / Mo(CO)6; t-BuOOH / benzene; decane / 3 h / 80 °C 2.1: NaH / tetrahydrofuran / 1 h / 20 °C 2.2: 86 percent / tetrabutylammonium iodide / tetrahydrofuran / 12 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: VO(acac)2, t-BuOOH / CH2Cl2 2: NaH, Bu4NI / dimethylformamide View Scheme
Multi-step reaction with 2 steps 1: 12.0 g / t-butyl hydroperoxide, vanadium(V)acetylacetonate / 1,2-dichloro-ethane / 2.75 h / 30 °C 2: 1.) NaH; 2.) tetrabutylammonium iodide / 1.) THF, 2 h; 1.) THF, 2.5 h View Scheme
Multi-step reaction with 2 steps 1.1: tert.-butylhydroperoxide; bis(acetylacetonate)oxovanadium / dichloromethane / 16 h / 20 °C / Large scale 1.2: 1 h / 20 °C / Large scale 2.1: sodium hydride / water; tetrahydrofuran / 20 °C / Large scale View Scheme

sodium cyclopentadienylide (4984-82-1) → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrahydrofuran / -78 - -65 °C 2: 1.) diisopinylcampheylborane (prepared from (+)-α-pinene), 2.) aq. NaOH, H2O2 / 1.) THF, -65 to -78 deg C 3: VO(acac)2, t-BuOOH / CH2Cl2 4: NaH, Bu4NI / dimethylformamide View Scheme

cyclopenta-1,3-diene (542-92-7) → (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) Na / 1.) THF, -5 deg C, 1.5 h; 2.) THF, -45 deg C, 1 h 2: 15.8 g / (-)-diisopinan-3-ylborane / tetrahydrofuran / 1.) -60 deg C, 1 h; 2.) 5 deg C, 18 h 3: 12.0 g / t-butyl hydroperoxide, vanadium(V)acetylacetonate / 1,2-dichloro-ethane / 2.75 h / 30 °C 4: 1.) NaH; 2.) tetrabutylammonium iodide / 1.) THF, 2 h; 1.) THF, 2.5 h View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,2R,3S,5R)-2-Hydroxymethyl-6-oxa-bicyclo[3.1.0]hexan-3-ol (117641-42-6)

Conditions	Yield
With hydrogen; palladium on activated charcoal	100%

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,2S,3S,5S)-5-azido-3-(benzyloxy)-2-(benzyloxymethyl)cyclopentanol (110567-23-2)

Conditions	Yield
With sodium azide; ammonium chloride In ethanol at 85℃; for 22h;	99%
With sodium azide; ammonium chloride In ethanol at 85℃; for 22h;

C17H19N5O3 (1351691-90-1) + (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → C37H41N5O6

Conditions	Yield
Stage #1: C17H19N5O3 With lithium hydride In N,N-dimethyl-formamide at 60℃; for 0.25h; Stage #2: (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane In N,N-dimethyl-formamide at 125℃; for 2.5h;	83%

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + potassium cyanide (151-50-8) → (1S,2R,3R,4R)-1-Benzyloxy-2-benzyloxymethyl-4-cyano-3-hydroxycyclopentane (160860-62-8)

Conditions	Yield
With lithium perchlorate In acetonitrile at 70℃; for 96h;	77.5%
With lithium perchlorate In acetonitrile at 70℃; for 24h;	75%

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + 2,4-dihydroxy-5-methylpyrimidine (65-71-4) → 1-(3',5'-di-O-benzyl-2'-deoxy-6'-hydroxy-6'-carba-β-D-ribofuranosyl)thymine (114071-49-7)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 140℃;	70%

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + thymin (65-71-4) → 1-(3',5'-di-O-benzyl-2'-deoxy-6'-hydroxy-6'-carba-β-D-ribofuranosyl)thymine (114071-49-7)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 140℃;	70%
With lithium hydride In N,N-dimethyl-formamide at 140℃;	64%
Stage #1: thymin With triethylaluminum In tetrahydrofuran; hexane at 20℃; for 1h; Stage #2: (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane In tetrahydrofuran; hexane at 20℃; for 48h; ultrasound;	46%
In N-methyl-acetamide; methanol; dichloromethane; acetic acid; toluene; mineral oil

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + adenine (66224-66-6, 66224-67-7, 66224-68-8, 66224-69-9, 134434-48-3, 134434-49-4, 134454-76-5, 134461-75-9) → [1S-(1α,2β,3α,5β)]-5-(6-amino-9H-purin-9-yl)-3-(phenylmethoxy)-2-[(phenylmethoxy)methyl]cyclopentanol (142217-96-7)

Conditions	Yield
With lithium hydride In N,N-dimethyl-formamide at 120℃;	70%

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + uracil (66-22-8) → [1S-(1α,2β,3α,4β)]-1-[2-Hydroxy-4-(phenyl-methoxy)-3-[(phenylmethoxy)methyl]cyclopentyl]-2,4(1H,3H)-pyrimidinedione (114071-48-6)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 130℃;	65%
With sodium hydride In N,N-dimethyl-formamide at 140℃;	63%
With acetic acid In N-methyl-acetamide; methanol; dichloromethane; mineral oil

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + 2-Amino-6-benzyloxypurine (19916-73-5) → [1S-(1α,2β,3α,5β)]-5-(2-amino-6-benzyloxy-9H-purin-9-yl)-3-benzyloxy-2-(benzyloxy)methyl-cyclopentanol (142217-77-4)

Conditions	Yield
With lithium hydride In N,N-dimethyl-formamide at 125℃; for 2h;	60%
Stage #1: 2-Amino-6-benzyloxypurine With lithium hydride In N,N-dimethyl-formamide at 20 - 60℃; for 0.416667h; Stage #2: (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane In N,N-dimethyl-formamide at 60 - 125℃; for 2.25h;	51.18%
With acetic acid In N-methyl-acetamide; methanol; ethanol; dichloromethane; chloroform
With tetrabutylammomium bromide; potassium hydroxide In toluene at 80℃; for 6h; Temperature; Reagent/catalyst;	6 g

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + 2-[(triphenylmethyl)amino]-6-benzyloxy-9H-purine → (1S,2S,3S,5S)-3-(benzyloxy)-5-[6-(benzyloxy)-2-[(triphenylmethyl)amino]-9H-purin-9-yl]-2-[(benzyloxy)methyl]cyclopentan-1-ol

Conditions	Yield
Stage #1: 2-[(triphenylmethyl)amino]-6-benzyloxy-9H-purine With lithium hydride In N,N-dimethyl-formamide at 58 - 62℃; for 0.5h; Stage #2: (2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane In N,N-dimethyl-formamide at 60 - 120℃; for 0.5h;	58.5%

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) + 2-amino-6-methoxyethoxypurine → (1S,2S,3S,5S)-5-[2-Amino-6-(2-methoxy-ethoxy)-purin-9-yl]-3-benzyloxy-2-benzyloxymethyl-cyclopentanol (114071-50-0)

Conditions	Yield
lithium hydride In N,N-dimethyl-formamide at 145℃;

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,2S,3S,5S)-5-azido-3-(benzyloxy)-2-(benzyloxymethyl)cyclopentanol (110567-23-2) + (1R,2R,3R,4S)-2-Azido-4-benzyloxy-3-benzyloxymethyl-cyclopentanol

Conditions	Yield
With sodium azide; ammonium chloride In ethanol; water for 22h; Heating;	A 3.3 g B 0.2 g

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → 5'-O-[1-(2'-deoxy-6'-carba-β-D-ribofuranosyl)thymidinyl]monophosphate

Conditions

Yield

Multi-step reaction with 7 steps 1.1: Et3Al / hexane; tetrahydrofuran / 1 h / 20 °C 1.2: 46 percent / hexane; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: DMAP / acetonitrile / 16 h / 20 °C 3.1: 398 mg / AIBN; n-Bu3SnH / toluene / 3.5 h / 75 °C 4.1: 90 percent / BCl3 / CH2Cl2 / 5 h / -78 °C 5.1: i-Pr2NEt / acetonitrile; dimethylformamide / 2 h / -40 - 0 °C 6.1: 107 mg / t-BuOOH / acetonitrile; dimethylformamide / 2 h / -40 - 20 °C 7.1: 76 percent / Et3N; H2O / acetonitrile / 18 h / 20 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → 1-((1R,3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclopentyl)-5-methylpyrimidine-2,4(1H,3H)-dione (114884-15-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Et3Al / hexane; tetrahydrofuran / 1 h / 20 °C 1.2: 46 percent / hexane; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: DMAP / acetonitrile / 16 h / 20 °C 3.1: 398 mg / AIBN; n-Bu3SnH / toluene / 3.5 h / 75 °C 4.1: 90 percent / BCl3 / CH2Cl2 / 5 h / -78 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → 1-(3',5'-di-O-benzyl-2'-deoxy-6'-carba-β-D-ribofuranosyl)thymine (648414-58-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: Et3Al / hexane; tetrahydrofuran / 1 h / 20 °C 1.2: 46 percent / hexane; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: DMAP / acetonitrile / 16 h / 20 °C 3.1: 398 mg / AIBN; n-Bu3SnH / toluene / 3.5 h / 75 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → 1-{(3S,1R,4R)-3-hydroxy-4-(8-methyl-2-oxo(4H-benzo[d]1,3,2-dioxaphosphan-2-yloxy)methylcyclopentyl)}-5-methyl-1,3-dihydropyrimidine-2,4(1H,3H)-dione

Conditions	Yield
Multi-step reaction with 5 steps 1.1: Et3Al / hexane; tetrahydrofuran / 1 h / 20 °C 1.2: 46 percent / hexane; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: DMAP / acetonitrile / 16 h / 20 °C 3.1: 398 mg / AIBN; n-Bu3SnH / toluene / 3.5 h / 75 °C 4.1: 90 percent / BCl3 / CH2Cl2 / 5 h / -78 °C 5.1: i-Pr2NEt / acetonitrile; dimethylformamide / 2 h / -40 - 0 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → 3-methyl-cyclosaligenyl-5'-O-[1-(2'-deoxy-6'-carba-β-D-ribofuranosyl)thymidinyl]-phosphate (648414-62-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: Et3Al / hexane; tetrahydrofuran / 1 h / 20 °C 1.2: 46 percent / hexane; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: DMAP / acetonitrile / 16 h / 20 °C 3.1: 398 mg / AIBN; n-Bu3SnH / toluene / 3.5 h / 75 °C 4.1: 90 percent / BCl3 / CH2Cl2 / 5 h / -78 °C 5.1: i-Pr2NEt / acetonitrile; dimethylformamide / 2 h / -40 - 0 °C 6.1: 107 mg / t-BuOOH / acetonitrile; dimethylformamide / 2 h / -40 - 20 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → thiocarbonic acid O-[3-benzyloxy-2-benzyloxymethyl-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-cyclopentyl] ester O-phenyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1.1: Et3Al / hexane; tetrahydrofuran / 1 h / 20 °C 1.2: 46 percent / hexane; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: DMAP / acetonitrile / 16 h / 20 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (S)-Methanocarba-Thymidine (156044-00-7)

Conditions

Yield

Multi-step reaction with 11 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min 3: 96.5 percent / CHCl3; diethyl ether / 72 h / 0 °C 4: benzophenone / benzene; acetonitrile / 2 h / Irradiation 5: 25percent aq. NaOH / methanol / 24 h / Heating 6: Et3N, DPPA / toluene / 1.) r.t., 2 h, 2.) 80 deg C, 2 h 7: toluene / 1.) 80 deg C, 2 h, 2.) r.t., overnight 8: 99 percent / Bu4NF / acetonitrile; tetrahydrofuran / 4 h / 70 °C 9: 85.5 percent / CH2Cl2 / 24 h / Ambient temperature 10: 2 M HCl / ethanol / 30 h / Heating 11: 87.72 percent / HCOOH / Pd / methanol / 2 h / 40 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,3S,4R,5S)-3-Benzyloxy-4-benzyloxymethyl-1-aminobicyclo<3.1.0>hexane (170453-02-8)

Conditions

Yield

Multi-step reaction with 8 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min 3: 96.5 percent / CHCl3; diethyl ether / 72 h / 0 °C 4: benzophenone / benzene; acetonitrile / 2 h / Irradiation 5: 25percent aq. NaOH / methanol / 24 h / Heating 6: Et3N, DPPA / toluene / 1.) r.t., 2 h, 2.) 80 deg C, 2 h 7: toluene / 1.) 80 deg C, 2 h, 2.) r.t., overnight 8: 99 percent / Bu4NF / acetonitrile; tetrahydrofuran / 4 h / 70 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (3R,4S)-1-Cyano-4-benzyloxy-3-benzyloxymethylcyclopentene (170452-98-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,3S,4R,5S)-3-Benzyloxy-4-benzyloxymethyl-1-cyanobicyclo<3.1.0>hexane (170453-00-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min 3: 96.5 percent / CHCl3; diethyl ether / 72 h / 0 °C 4: benzophenone / benzene; acetonitrile / 2 h / Irradiation View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,3S,4R,5S)-3-Benzyloxy-4-benzyloxymethylbicyclo<3.1.0>hexane-1-carboxylic acid (190195-74-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min 3: 96.5 percent / CHCl3; diethyl ether / 72 h / 0 °C 4: benzophenone / benzene; acetonitrile / 2 h / Irradiation 5: 25percent aq. NaOH / methanol / 24 h / Heating View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (3aR,4R,5S,6aR)-4-Benzyloxymethyl-5-benzyloxy-6a-cyano-3,3a,4,5,6,6a-hexahydrocyclopentapyrazole (170452-99-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min 3: 96.5 percent / CHCl3; diethyl ether / 72 h / 0 °C View Scheme

(2R,3S)-benzyloxy-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexane (110567-22-1) → (1S,3S,4R,5S)-3-Benzyloxy-4-benzyloxymethyl-1-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)bicyclo<3.1.0>hexane (190195-79-0)

Conditions

Yield

Multi-step reaction with 10 steps 1: 77.5 percent / LiClO4 / acetonitrile / 96 h / 70 °C 2: 98 percent / 1,1'-thiocarbonyldiimidazole, DMAP / dimethylformamide / 1.) r.t., 3 h, 2.) 70 deg C, 30 min 3: 96.5 percent / CHCl3; diethyl ether / 72 h / 0 °C 4: benzophenone / benzene; acetonitrile / 2 h / Irradiation 5: 25percent aq. NaOH / methanol / 24 h / Heating 6: Et3N, DPPA / toluene / 1.) r.t., 2 h, 2.) 80 deg C, 2 h 7: toluene / 1.) 80 deg C, 2 h, 2.) r.t., overnight 8: 99 percent / Bu4NF / acetonitrile; tetrahydrofuran / 4 h / 70 °C 9: 85.5 percent / CH2Cl2 / 24 h / Ambient temperature 10: 2 M HCl / ethanol / 30 h / Heating View Scheme

Upstream product

• 191480-69-0 (3R,4S)-4-(phenylmethoxy)-3-[(phenylmethoxy)methyl]cyclopent-1-ene 
• 542-92-7 cyclopenta-1,3-diene 
• 39939-07-6 5-(benzyloxymethyl)cyclopentadiene 
• 3587-60-8 Benzyloxymethyl chloride 
• 100-39-0 benzyl bromide 
• 117641-39-1 (2R,3S)-2-benzyloxymethyl-6-oxabicyclo<3.1.0>hexan-3-ol 
• 110567-21-0 (1S,2R)-2-(benzyloxymethyl)-1-hydroxy-3-cyclopentene 
• 4984-82-1 sodium cyclopentadienylide 

Downstream Products

• 117641-41-5 (1S,8S,9R,11S)-10-(2,4-dinitroanilino)-3,3,5,5-tetraisopropyl-2,4,6-trioxa-10-aza-3,5-disilatricyclo<6.4.0.0^9,11>dodecane 
• 117660-78-3 (1S,8R,9S,10S)-10-(2,4-dinitroanilino)-3,3,5,5-tetraisopropyl-2,4,6-trioxa-3,5-disilabicyclo<6.3.0>undecan-9-ol 
• 1425925-92-3 (1S,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentanol 
• 1425925-93-4 (1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentanol 
• 1425925-94-5 4-((1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentyloxy)-6-chloropyrimidine 
• 1425925-91-2 ((1R,4S)-4-(benzyloxy)-3-(benzyioxymethyl)cyclopent-2-enyloxy)trimethylsilane 
• 114071-49-7 1-((1S,2R,3S,4S)-4-Benzyloxy-3-benzyloxymethyl-2-hydroxy-cyclopentyl)-5-methyl-1H-pyrimidine-2,4-dione 
• 129436-50-6 1-((3R,4S)-4-Benzyloxy-3-benzyloxymethyl-cyclopent-1-enyl)-5-methyl-1H-pyrimidine-2,4-dione 
• 129436-49-3 1-((1S,4S)-4-Benzyloxy-3-benzyloxymethyl-cyclopent-2-enyl)-5-methyl-1H-pyrimidine-2,4-dione 
• 129436-48-2 (5aS,7S,8R,8aR)-7-Benzyloxy-8-benzyloxymethyl-3-methyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]oxazolo[3,2-a]pyrimidin-2-one 
• 142217-81-0 2-amino-1,9-dihydro-9-[(1S,3R,4S)-2-methylene-4-(phenylmethoxy)-3-[(phenylmethoxy)methyl]cyclopentyl]-6H-purin-6-one 
• 142217-69-4 entecavir 
• 142217-79-6 (2R,3S,5S)-5-[2-[[(4-methoxyphenyl)diphenylmethyl]amino]-6-benzyloxy-9H-fluoren-9-yl]-3-benzyloxy-2-[(benzyloxy)methyl]cyclopentanone 

Relevant articles and documents

A New Route for the Synthesis of Entecavir

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Preparation method of entecavir intermediate

The invention provides a preparation method of an entecavir intermediate, and particularly relates to a preparation method of (1S-(1[alpha], 2[alpha], 3[beta], 5[alpha])-2-((benzyloxy) methyl)-6-oxabicyclo [3.1. 0] hexyl-3-alcohol and an oxabicyclo compound (NT02). The invention provides a brand new preparation route and reaction process conditions, and has the advantages of high operation safety, simple method, low cost and high yield. The product yield is obviously improved, and the method is very suitable for industrial production and application.

New convergent synthesis of carbocyclic nucleoside analogues

Two convergent approaches towards the synthesis of carbocyclic nucleoside analogs will be described. Both approaches start from the stereochemically pure cyclopentenol 8 that has been prepared enantioselectively from an alkylated cyclopentadiene. Using these approaches, carbocyclic analogues of dT, FdU and BVdU have been prepared. Moreover, the conversion into the cycloSalpronucleotide and the corresponding nucleotide will be presented for one example.