57280-22-5

Usage

Uses

Used in Chemical Synthesis:
4,4-Dimethyl-3,5,8-trioxabicyclooctane is used as a key intermediate in the CO2-mediated formation of chiral carbamates from meso-epoxides. This process is significant because it allows for the creation of a wide range of CO2-based carbamate scaffolds with excellent yields and 99% enantiomeric excess, which is crucial for the development of various pharmaceuticals and specialty chemicals.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, 4,4-Dimethyl-3,5,8-trioxabicyclooctane is used as a crucial component in the synthesis of chiral carbamates. These carbamates are essential for the development of new drugs with improved efficacy and selectivity, as they can be used to create a variety of biologically active molecules with potential applications in medicine.
Used in Specialty Chemicals:
4,4-Dimethyl-3,5,8-trioxabicyclooctane is also used in the specialty chemicals industry for the production of various high-value compounds. The ability to create CO2-based carbamate scaffolds with high enantiomeric excess makes it a valuable tool for the synthesis of enantiomerically pure compounds, which are essential for various applications, including agrochemicals, fragrances, and other specialty products.

Synthetic route

2,2-dimethyl-4,7-dihydro-1,3-dioxepin (1003-83-4) → 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5)

Conditions	Yield
With disodium hydrogenphosphate; dihydrogen peroxide; sodium hydroxide In methanol; water; acetonitrile at 60 - 80℃; pH=7 - 9.5; Large scale; Green chemistry;	85.2%
With disodium hydrogenphosphate; 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 18h; Inert atmosphere;	85%
With disodium hydrogenphosphate; dihydrogen peroxide; Hexafluoroacetone In 1,2-dichloro-ethane for 24h; Heating;	83%

2,2-dimethoxy-propane (77-76-9) → 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / dichloromethane / 3 h / 20 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid; disodium hydrogenphosphate / dichloromethane / 18 h / 20 °C / Inert atmosphere View Scheme

C7H13BrO3 → 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5)

Conditions	Yield
With potassium carbonate In methanol at 20℃; for 16h;	19 g

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + Trimethylenediamine (109-76-2) → C17H34N2O6

Conditions	Yield
In ethanol epoxide:amine=2:1;	100%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + benzylamine (100-46-9) → trans-6-benzylamino-2,2'-dimethyl-1,3-dioxocycloheptan-5-ol (1036765-71-5)

Conditions	Yield
Stage #1: benzylamine With titanium(IV) isopropylate; (R)-1,1'-Bi-2-naphthol; (R)-6,6'-dibromo-1,1'-binaphth-2-ol In toluene at 20℃; for 0.5h; Stage #2: 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane With water In toluene at 40℃; for 12h; optical yield given as %ee;	99%
With titanium(IV) isopropylate; (R)-1,1'-Bi-2-naphthol In toluene enantioselective reaction;	78%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + benzylamine (100-46-9) → (5R,6S)-6-(benzylamino)-2,2-dimethyl-1,3-dioxepan-5-ol

Conditions	Yield
With C92H72N2O6*2Ti*2O In water; toluene at 40℃; for 18h; Reagent/catalyst; Inert atmosphere; Green chemistry;	99%
Stage #1: benzylamine With titanium(IV) isopropylate; C20H24O2; (R)-3,3'-diiodo-2,2'-dihydroxy-1,1'-binaphthyl In toluene at 20℃; for 0.5h; Stage #2: 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane With water In toluene at 40℃; for 12h; optical yield given as %ee;	27%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + 1,4,7-tris-tert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclododecane (122555-91-3) → 1,4,7-tris(tert-butoxycarbonylmethyl)10-(6-hydroxy-2,2-dimethyl-1,3-dioxepane-5yl)-1,4,7,10-tetraazacyclododecane

Conditions	Yield
With potassium carbonate In isopropyl alcohol at 60℃; for 12h; Reagent/catalyst; Temperature;	99%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + ethylenediamine (107-15-3) → 6-(2-Amino-ethylamino)-2,2-dimethyl-[1,3]dioxepan-5-ol

Conditions	Yield
In ethanol epoxide:amine=1:1; addition of epoxide to amine dropwise over 1 h;	98%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + thiophenol (108-98-5) → (2R*,3R*)-1,4-di-O-isopropylidene-3-phenylthio-1,2,4-butanetriol

Conditions	Yield
With sodium hydride In tetrahydrofuran 0 deg C, 30 min, reflux, 1 h;	96.9%

bis(3-aminopropyl)amine (56-18-8) + 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → 6-[3-(3-Amino-propylamino)-propylamino]-2,2-dimethyl-[1,3]dioxepan-5-ol

Conditions	Yield
In ethanol epoxide:amine=1:1; addition of epoxide to amine dropwise over 1 h;	92%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + isopropylamine (75-31-0) → 6-(isopropylamino)-2,2-dimethyl-1,3-dioxepan-5-ol (1036765-73-7)

Conditions	Yield
Stage #1: isopropylamine With titanium(IV) isopropylate; (R)-1,1'-Bi-2-naphthol In toluene at 20℃; Stage #2: 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane With water In toluene at 40℃; for 12h; optical yield given as %ee;	91%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → (5S,6S)-6-Iodo-2,2-dimethyl-[1,3]dioxepan-5-ol

Conditions	Yield
With lithium iodide for 15h; Ambient temperature;	90%
With silica gel; lithium iodide for 0.25h; Ambient temperature;	90%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → trans-2,2-Dimethyl-6-hydroxy-5-amino-1,3-dioxepane (188923-20-8)

Conditions	Yield
With ammonia In water	87%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + tert-butylamine (75-64-9) → 6-(tert-butylamino)-2,2-dimethyl-1,3-dioxepan-5-ol (1036765-74-8)

Conditions	Yield
Stage #1: tert-butylamine With titanium(IV) isopropylate; (R)-1,1'-Bi-2-naphthol In toluene at 20℃; Stage #2: 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane With water In toluene at 40℃; for 48h; optical yield given as %ee;	85%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + 1,4,7-tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane (175854-39-4) → C12H28N4O3

Conditions	Yield
Stage #1: 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane; 1,4,7-tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane With lithium chloride In isopropyl alcohol for 20h; Reflux; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 60℃; for 2h;	85%

bromobenzene (108-86-1) + 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → (5S,6R)-2,2-dimethyl-6-phenyl-1,3-dioxepan-5-ol

Conditions	Yield
With [2,2]bipyridinyl; manganese; (1,2-dimethoxyethane)dichloronickel(II); bis(η5((1R,2S,5R)-5-methyl-2-[prop-2-yl]-cyclohex-1-yl)cyclopentadienyl)-titanium dichloride; triethylamine hydrochloride at 20℃; for 12h; Inert atmosphere; Glovebox; Autoclave; enantioselective reaction;	82%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → (5S,6S)-6-Bromo-2,2-dimethyl-[1,3]dioxepan-5-ol

Conditions	Yield
With lithium bromide for 8h; Ambient temperature;	80%
With silica gel; lithium bromide for 8h; Ambient temperature;	80%

1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid trisodium salt + 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → 2,2',2"-(10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (138168-36-2)

Conditions	Yield
Stage #1: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid trisodium salt; 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane In isopropyl alcohol for 10h; Inert atmosphere; Reflux; Industrial scale; Stage #2: With hydrogenchloride In water for 1h; Solvent; Industrial scale;	80%

1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid trisodium salt + gadolinium(III) chloride + 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → gadolinium complex of 10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

Conditions	Yield
Stage #1: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid trisodium salt; 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane With hydrogenchloride In water at 40 - 80℃; for 12h; Stage #2: gadolinium(III) chloride In water at 50℃; for 1h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;	79.1%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + lithium cyanide (2408-36-8) → (+/-)-trans-6-hydroxy-2,2-dimethyl-1,3-dioxepane-5-carbonitrile (141077-78-3)

Conditions	Yield
In tetrahydrofuran for 3h; Heating;	79%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + trimethylsilan (993-07-7) + carbon monoxide (201230-82-2) → 2,2-Dimethyl-5-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-[1,3]dioxepane

Conditions	Yield
dicobalt octacarbonyl In toluene at 25℃; under 760 Torr; for 20h;	77%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → (5S,6S)-6-Chloro-2,2-dimethyl-[1,3]dioxepan-5-ol

Conditions	Yield
With water; silica gel; lithium chloride for 96h; Ambient temperature;	76%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + 1,4,7,10-tetraazacyclododecan (294-90-6) → 3-(1,4,7,10-tetraazacyclododecane-1-yl)butane-1,2,4-triol tetrahydrochloride

Conditions	Yield
Stage #1: 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane; 1,4,7,10-tetraazacyclododecan With lithium chloride In isopropyl alcohol at 85 - 95℃; Large scale; Stage #2: With hydrogenchloride In methanol for 3h; Reflux; Large scale;	73.4%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) → 4,4-dimethyl-3,5-dioxacycloheptanol (141509-49-1)

Conditions	Yield
With lithium aluminium tetrahydride In diethyl ether for 24h; Ambient temperature;	68%

4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane (57280-22-5) + 1,5-diamino-3-azapentane (111-40-0) → 6-[2-(2-Amino-ethylamino)-ethylamino]-2,2-dimethyl-[1,3]dioxepan-5-ol

Conditions	Yield
In ethanol epoxide:amine=1:1; addition of epoxide to amine dropwise over 1 h;	67%

Upstream product

• 1003-83-4 2,2-dimethyl-4,7-dihydro-1,3-dioxepin 
• 77-76-9 2,2-dimethoxy-propane 

Downstream Products

• 72791-80-1 2-(3-Methoxy-2-methoxymethoxy-5-methyl-phenyl)-propan-2-ol 
• 72791-81-2 3-Hydroxy-4-(3-methoxy-2-methoxymethoxy-5-methyl-phenyl)-butan-2-one 
• 72791-82-3 4-Hydroxy-3-(3-methoxy-2-methoxymethoxy-5-methyl-phenyl)-butan-2-one 
• 1010702-30-3 (5R,6S)-2,2-dimethyl-6-<(S)-1-phenylmethylamino>-1,3-dioxepan-5-ol 
• 174691-31-7 (2S,3S)-(-)-1,4-di-O-isopropylidene-3-phenylthio-1,2,4-butanetriol 
• 174691-32-8 (2R,3R)-(+)-2-acetoxy-1,4-di-O-isopropylidene-3-phenylthio-1,4-butanediol 
• 1036765-71-5 trans-6-benzylamino-2,2'-dimethyl-1,3-dioxocycloheptan-5-ol 
• 1234692-91-1 C₇H₁₄O₄ 

Relevant academic research and scientific papers

Divergent approach to the synthesis of (-)-balanol heterocycle and cis-3-hydroxypipecolic acid based on chiral 2-aminoalkanol equivalent

Enantioselective synthesis of the hexahydroazepine core of (?)-balanol and formal synthesis of cis-3-hydroxypipecolic acid from a common intermediate have been accomplished by a divergent path. The common intermediate was accessed from a favorably protected enantiomerically pure 2-amino-1,3,4-butanetriol (ABT) equivalent via oxidation and Wittig olefination. The synthesis of (?)-balanol heterocycle featured tandem reduction/acetal-deprotection/γ-lactonization reaction and a one-pot azide reduction followed by seven membered aza-heterocycle formation while the route to cis-3-hydroxypipecolic acid highlighted the base induced piperidine ring formation and regioselective benzylidine-acetal cleavage.

Method for efficiently preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane

The invention discloses a method for efficiently preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane. According to the method, 4,7-dihydro-2,2-dimethyl-1,3-dioxep-5-ene is used as a raw material and is subjected to a reaction in the presence of a catalyst and hydrogen peroxide so as to produce 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane, wherein the catalyst is selected from the group consisting of phosphomolybdic acid, phosphotungstic acid, sodium tungstate and vanadyl acetylacetonate. The method of the invention can significantly reduce reaction temperature, avoid the generation of a large amount of waste, and greatly increase the purity of the product 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane.

Preparation process method of gadobutrol epoxy side chain intermediate

The invention disclose a 4,4-dimethyl 3,5,8-trioxabic [5,1,0]ycloctane and particularly relates to a preparation process method of a gadobutrol epoxy side chain intermediate. According to the preparation process method disclosed by the invention, by adjusting the weight ratio of feeding materials, optimizing reaction conditions and improving post treatment and purification methods, the impurity content of an obtained gadobutrol epoxy side chain intermediate product is low; the quality of the intermediate product is greatly improved while the yield is increased, so that the difficulty of process control of the gadobutrol crude drugs during the production process is reduced, and the quality and the qualification rate of the gadobutrol crude drugs are improved. The preparation process method disclosed by the invention has the advantages of simple operation methods in all process steps, safe and feasible solvent and technological conditions, realization of green and environmental-friendly production and wide application prospect.

The synthesis of the 2, 3-difluorobutan-1, 4-diol diastereomers

The diastereoselective synthesis of fluorinated building blocks that contain chiral fluorine substituents is of interest. Here we describe optimisation efforts in the synthesis of anti-2, 3-difluorobutane-1, 4-diol, as well as the synthesis of the corresponding syn-diastereomer. Both targets were synthesised using an epoxide opening strategy.

Production method of optically active amino alcohols

A method for producing an optically active amino alcohol compound of the formula [3], an enantiomer thereof or a salt thereof, comprising reacting a mesoepoxide compound of the formula [1] with a compound of the formula [2] in the presence of a mixed catalyst comprising a Lewis acid and a proton donor: wherein R1, R2and R3are each H, an optionally substituted lower alky, and the like, or R1and R1or R2and R3may form an optionally substituted ring; and R4and R5are each H, an optionally substituted lower alkyl, and the like, or R4and R5may form an optionally substituted ring together with the adjacent N, or an imide group or azide group together with the adjacent N, and R6is H or a silyl group. The present invention enables stereoselective production of a desired intermediate compound, which is an HIV protease inhibitor, extremely efficiently as compared to conventional methods. The method of the present invention is a very useful method which can be used not only for the production of said intermediate compound but also for the production of various other compounds.

Process for producing amide derivatives and intermediates therefor

PCT No. PCT/JP96/02756 Sec. 371 Date Apr. 14, 1998 Sec. 102(e) Date Apr. 14, 1998 PCT Filed Sep. 24, 1996 PCT Pub. No. WO97/11937 PCT Pub. Date Apr. 3, 1997A method for producing an amide derivative of the formula [XV] wherein each symbol is as defined in the specification, and an enantiomer thereof, a novel intermediate useful for producing said compound and a production method thereof. The production method of the present invention is extremely easy and simple as compared to the conventional methods, and enables effective production of compound [XV] at high yields, which includes compound [XVI] having an HIV protease inhibitory action. In addition, the novel intermediates of the present invention are extremely useful as intermediates for producing not only the aforementioned compound [XVI] but also compounds useful as X-ray contrast media.

Production of amide derivatives and intermediate compounds therefor

A method for producing an amide derivative of the formula ?XV! STR1 wherein each symbol is as defined in the specification, and an enantiomer thereof, a novel intermediate useful for producing said compound and a production method thereof. The production method of the present invention is extremely easy and simple as compared to the conventional methods, and enables effective production of compound ?XV! at high yields, which includes compound ?XVI! having an HIV protease inhibitory action. In addition, the novel intermediates of the present invention are extremely useful as intermediates for producing not only the aforementioned compound ?XVI! but also compounds useful as X-ray contrast media.

Novel amino-dioxepane intermediates for the synthesis of new non-ionic contrast media

Novel intermediates for non-ionic polyiodo amino-substituted benzenepolyamides having polyol substituents on the amide nitrogens are provided which are 5-amino-6-hydroxy-1,3-dioxepanes. The compounds provide an economic and efficient route to novel contrast media having excellent chemical and physiological properties. Also provided are methods for preparing the subject compounds.