Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/30—Oxygen atoms, e.g. delta-lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
  • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• Ri and R 2 are identical, R 1( R 2 and R 3 are benzyl or silyl protecting groups, and R 5 is lower alkyl or phenyl which is substituted, most preferably monosubstituted, by lower alkyl.
• Ri and R 2 and R 3 are all tert-butyl dimethylsilyl, R 4 is phenyl which is unsubstituted or monosubstituted by methoxy and R 5 is methyl or phenyl which is monosubstituted by lower alkyl.
• Ph denotes phenyl and R' and R 2 are independently of each other a silyl protecting group, hydrogen or benzyl which is unsubstituted or mono- or disubstituted by lower alkoxy under the proviso that one of both radicals R' and R 2 is a silyl protecting group.
• the invention relates to a ⁇ -valerolactol of the formula X
• the invention relates to a process for preparing an ether of formula XXVI
• Ri is benzyl which is mono- or disubstituted by alkoxy
• R 2 represents a protecting group for a hydroxy group or hydrogen
• R 10 is N-oxazolidinyl which is unsubstituted or substituted by alkyl, benzyl or phenyl
• OR e wherein R ⁇ is alkyl or benzyl, or N(R a ) 2 wherein R a is alkyl or benzyl, in which process a compound of formula XXVII,
• a protecting group for a hydroxy group as defined herein is a protecting group that can be detached under basic or neutral conditions, i.e. in a medium having a pH > 7, and is especially benzyl which is unsubstituted or mono-or disubstituted by alkoxy, in particular lower alkoxy, preferably methoxy, or, more particular, a silyl protecting group.
• a silyl protecting group is a group consisting of a silicium atom having a free valence and bearing three groups selected from aryl, alkyl and arylalkyl.
• Alkoxy is preferably lower alkoxy, e.g. ethoxy or terf-butoxy, and very preferably methoxy.
• Arylalkyl is in particular benzyl.
• Halogen is preferably fluorine, chlorine, bromine or iodine. Any reference to other documents or publications within this application means that the respective document or publication is included by reference into the present disclosure.
• a compound of formula III wherein Ri and R 2 are protecting groups for a hydroxy group which protecting groups can be identical or different, R 3 is hydrogen and R 6 is alkyl or arylalkyl, and R 4 is phenyl which is unsubstituted or mono-or disubstituted by alkoxy, can also be reacted to a compound of formula I wherein Ri, R 2 and R 4 have the same meaning as in the compound of formula III and R 3 is a protecting group for a hydroxy group in a one- flask synthesis, i.e. without isolating the intermediates described herein.
• a compound of formula VII, wherein R 3 is hydrogen, R is phenyl which is unsubstituted or mono-or disubstituted by alkoxy, and R 6 is alkyl or arylalkyl is obtained, e.g., by reacting an aldehyde of formula XII
• the lacton of formula XX wherein R 2 is a protecting group for a hydroxy group is the product of the reaction of a compound of formula VIII wherein R is hydrogen and R 2 is a protecting group for a hydroxy group with a catalytic amount of a potassium alcoholate, e.g. potassium tert-butanolate, in a suitable solvent, e.g. tetrahydrofurane, at a temperature between about -10 °C and + 10 °C, e.g. 0 °C
• Ri and R 2 are as defined above for a compound of formula XI and R 7 is alkyl or arylalkyl.
• the reaction is preferably accomplished in tetrahydrofurane in the presence of the base potassium hexamethyldisilazane and 18-crown-6.
• stage 3.1 (1.00g, 3.87 mmol) is dissolved in 40 mL of toluene and 3.10 mL (4.65 mmol) of DIBAH (1.5 M in toluene) is added over 10 min at -78 °C. After 30 min at -78 °C, the reaction mixture is quenched by addition of 2 mL of MeOH. The resulting mixture is poured on aqu. sat. NH 4 CI and the two layers are separated. The aqu. layer is extracted (3 times) with EtOAc. The combined organic phases are washed successively with 10% aqu. H 2 SO , sat. aqu. NaHCO 3 and sat. aqu.
• Stage 3.1 A solution of the alcohol from Example 2 (43 mg, 0.1 mmol) in 1.5 mL of THF/H 2 O (3:1) is treated with 40 ⁇ l (0.4 mmol, 4.0 eq.) of H 2 O 2 (30%) followed by 8 mg (0.2 mmol, 2.0 eq.) of LiOH monohydrate at 0 °C. After stirring for 40 min, 0.3mL of a 1.5 M aqu. solution of Na 2 SO 3 is added. The reaction is quenched with sat. aqu. NaHCO 3 and extracted with TBME. The ether layer is washed with sat. aqu. NaHCO 3 solution twice. The combined aqu.
• Stage 4.1 A solution of 14.9 mL (87 mmol, 1.45 eq.) of diisoproylethylamine in 30 mL of CH 2 CI 2 under an atmosphere of argon is treated sequentially at -5 °C over 10 min with a 1.0 M solution (78 mL, 78 mmol, 1.3 eq.) of Bu 2 BOTf in CH 2 CI 2 and at -78 °C over 15 min with a solution of ( ?)-4-isopropyl-5,5-diphenylpropionyloxazolidin-2-one (20.2 g, 60 mmol; prepared according to T. Deutschenmann, D. Seebach, Helv. Chim.
• Phosphate buffer pH 7.0 60 mL
• MeOH 180 mL
• MeOH/35% H 2 O 2 2:1 v/v, 180 mL
• the mixture is recooled to 0 °C and treated with 40% aqu. NaHSO 3 (80 mL).
• the volatiles are removed in vacuo and the aqu. phase is extracted with toluene (3 x 200 mL).
• the combined organic layers are washed with 1 N HCL (60 mL), sat. aqu. NaHCO 3 (60 mL) and sat. aqu.
• Stage 4.2 The crude alcohol of stage 4.1 (13.9 g) is dissolved in 50 mL of CH 2 CI 2 under argon and cooled to 0 °C. 2,6-Lutidine (4.9 mL, 42 mmol) is added followed by dropwise addition over 10 min of TBSOTf (7.1 mL, 31 mmol). The reaction mixture is stirred for 30 min at 0 °C, after which 100 mL of hexane and 45 mL of 1N HCL are added sequentially. The aqu. layer is extracted (2 times) with hexane. The combined organic layers are washed with 1 N HCI (2 times), sat. aqu. NaHCO 3 and sat. aqu.
• Stage 5.1 A solution of (/ c ?)-4-isopropyl-5,5-diphenylpropionyloxazolidin-2-one (see stage 4.1 ; 1.00g, 2.96 mmol) in 7.5 mL of dichloromethane is treated with a 1.0 M solution (3.55 mL, 3.55 mmol) of Bu 2 BOTf at 0 °C under an atmosphere of argon. To the resulting brown- red mixture 0.66 mL (3.85 mmol) of diisoproylethylamine is added to give a colorless, clear solution, which is stirred a 0 °C for 1 h.
• Stage 5.2 The alcohol from stage 5.1 (96 mg, 0.18 mmol) is dissolved in 5 mL of CH 2 CI 2 under argon and cooled to 0 °C.2,6-Lutidine (31 ⁇ L, 0.27 mmol) is added followed by dropwise addition of TBSOTf (50 ⁇ L, 0.22 mmol). The reaction mixture is stirred for 45 min at 0 °C, poured onto ice water and extracted with TBME (3 times). The combined organic layers are washed with 1 N HCI, sat. aqu. NaHCO 3 and sat. aqu. NaCI, then dried over MgSO 4 and concentrated in vacuo to give the desired product as a colorless oil.
• Example 6 The alcohol of Example 6 (1.10 g, 2.04 mmol) is dissolved in 20 mL of CH 2 CI 2 under an atmosphere of argon and cooled to 0 °C.2,6-Lutidine (0.28 mL, 2.45 mmol, 1.20 eq.) is added followed by dropwise addition of TBSOTf (0.49 mL, 2.14 mmol, 1.05 eq.). The reaction mixture is stirred for 60 min, poured onto 1 N HCI and extracted with heptane (3 times). The organic layer is washed with sat. aqu. NaHCO 3 and sat. aqu. NaCI, then dried over MgSO and concentrated in vacuo to give the title compound as a colorless oil which crystallizes upon conservation at 4 °C providing a solid with a m.p. of 104-105 °C.
• a 2.0 M solution of LiBH (6.55 mL, 13.10 mmol) in THF is added to a solution of the bis- TBDMS ether of Example 7 (5.36 g, 8.19 mmol) in 130 mL of diethylether and 234 ⁇ L (13.02 mmol) of water at 0 °C over a period of 10 min.
• the mixture is allowed to warm to ambient temperature over night.
• the chiral auxiliary forms a white crystalline precipitate.
• Another 73 ⁇ L (4.06 mmol) water and 2.05 mL (4.09 mmol) of a 2 M LiBH 4 solution are added at 23 °C.
• Stage 8.1 A solution of 0.455 mL (5.30 mmol) oxalylchloride in 20 mL CH 2 CI 2 is treated with a solution of 0.75 mL (10.6 mmol) DMSO in 1.0 mL CH 2 CI 2 at -78 °C. After 15 min a solution of the title compound (1.0 g, 2.65 mmol) in 8 mL CH 2 CI 2 is added dropwise over a period of 30 min. Et 3 N (2.3 mL, 15.9 mmol) is added over 12 min and the reaction mixture is allowed to warm to room temperature. After additional stirring for 30 min 40 mL TBME and 50 mL of a sat. NH CI solution are added. The aqu.
• Stage 8.2 A solution of 2-[bis-(2,2,2-trifluoroethyl)]-phosphono propionic acid ethyl ester (0.948g, 2.74 mmol, prepared analog to the procedure described in Synthesis 1986, 16(11) 1285-1295) and 18-crown-6 (2.0 g, 10.0 mmol) in 20 ml THF is treated with 5.5 mL (2.74 mmol) of a 0.5 M solution of KHMDS in toluene at -78 °C. After 5 min a solution of the aldehyde of stage 8.1 (1.029 g, 2.74 mmol) in 8 ml THF is added dropwise over 15 min.
• Example 10 To a solution of the alcohol of Example 10 (54 mg, 0.10 mmol) in 1.0 mL of CH 2 CI 2 at 0 °C under an atmosphere of argon, 4 A molecular sieve (55 mg) and DDQ (30 mg, 0,13 mmol, 1.3 eq.) are added sequentially in one portion. The resulting deep green reaction mixture is stirred at 0 °C for 15 h. A precipitate is formed. After removal of the precipitate by filtration, concentration in vacuo and PTLC (SiO 2 , 10x20 cm plate, heptane/AcOEt 2:1), the title compound is obtained as a colorless oil.
• PTLC SiO 2 , 10x20 cm plate, heptane/AcOEt 2:1
• Stage 13.1 To a solution of 12.62 g of the crude acetal of Example 11 in 60 mL of THF at - 78 °C under an atmosphere of argon is added over a period of 30 min 62 mL of a 1 M solution of LiAIH 4 in THF (62 mmol). After 3 h of stirring at -78 °C, the reaction mixture is warmed to 0 °C and treated sequentially with 2.4 mL of water, 2.4 mL of 15% aqu. NaOH, and 7.1 mL of water. The resulting precipitate is removed by filtration and washed with THF (2 x 10 mL). The filtrate is collected and concentrated in vacuo to half of its initial volume.
• Stage 13.2 A solution of 3.10 g of oxalyl chloride (24 mmol) in 40 mL of CH 2 CI 2 at -78 °C under an atmosphere of argon is treated sequentially by dropwise addition of a solution of 4.22 g of DMSO (54 mmol) in 16 mL of CH 2 CI and a solution of the crude alcohol of stage 13.1 (6.20 g) in 30 mL of CH 2 CI 2 . The resulting reaction mixture is stirred at -78 °C for 30 min.
• Stage 15.1 To a stirred solution of the crude product of Example 14 (400 mg, 0.51 mmol) in CH 2 CI 2 (10 mL) at -78°C Et 3 N (714 ⁇ L, 5.13 mmol) is added, followed by addition of TBDMSOTf (586 ⁇ L, 2.55 mmol). The reaction mixture is allowed to warm to RT and stirred for 4 h. The reaction mixture is then partitioned between NaHCO 3 (20 mL) and CH 2 CI 2 (3 x 50 mL). The combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo. Filtration over SiO 2 (5% EtOAc/Hexanes) gives the crude product as a colourless oil; MS (El) m/z 915 (100, [M + Na] + ).
• Stage 15.3 To a stirred solution of the crude product of stage 15.2 (400 mg, 0.49 mmol) in CH 2 CI 2 (10 mL) at RT is added Et 3 N (338 ⁇ L, 2.43 mmol) and methanesulfonylchloride (58 ⁇ L, 0.74 mmol). After 20 h the mixture is partitioned between NaHCO 3 (15 mL) and CH 2 CI 2 (3 x 20 mL). The combined organic extracts are dried (Na 2 SO 4 ) and concentrated in vacuo. Filtration over SiO 2 (10-20% EtOAc/Hexanes) gives the crude product as a colourless oil; MS (El) m/z 891 (100, [M + Na] + ).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Steroid Compounds (AREA)
• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Pyrane Compounds (AREA)
• Polyoxymethylene Polymers And Polymers With Carbon-To-Carbon Bonds (AREA)
• Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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