JP2002511441A - Oxidation method using periodic acid - Google Patents

Abstract

  (57) [Summary] The present invention relates to the oxidation of a primary or secondary alcohol of formula (II) to a acid or ketone of formula (I) using periodic acid and a catalytic amount of a chromium reagent.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Oxidation is one of the most fundamental transformations in organic synthesis, and numerous methods have been reported in the literature. (Oxidation by Hudricky, M.
s in Organic Chemistry "ACS Monograph
186, 1990). However, the direct conversion of primary alcohols to the corresponding carboxylic acids is still a challenge, especially in the presence of other functional groups. There are only a few commonly used methods for this conversion, such as CrO ₃ / H ₂ SO ₄ (Bowd
J. En., Heilbron, Jones, Weedon. Chem. So
c. 1946, 39; Bowers, H .; Jones, L .; J. Che
m. Soc. , 1953, 2548; Millar, J .; G. FIG. , Oehlsch
lager, A .; C. Wong, J .; W. J. Org. Chem. 19
83,48,4404), and _{RuCl 3 / H 5 IO 6 (} Carlsen, P
. H. J. , Katsuki, T .; Martin, V .; S. , Sharple
ss, K .; B. J. Org. Chem. 1981, 46, 3936), and TEMPO / NaClO (Nooy, AEJ de, Besemer).
, A. C. Bekkum, H .; v. Synthesis, 1996, 1
153, Annelli, P .; L. Biffi, C .; , Montanari, F
. Quici, S .; J. Org. Chem. 1987, 52, 2559
Miyazawa, T .; Endo, T .; Shiihashi, S .; , Ok
awara, M .; J. Org. Chem. 1985, 50, 1332). Swern oxidation (Mancus
o, A. J. Huang, SL. Swern, D .; J. Org. C
hem. 1978, 43, 2480, Mancuso, A .; J. , Brownf
an, D.S. S. Swern, D .; J. Org. Chem. 1979, 4
4,4148, Ireland, R.A. Norbeck, D .; J. Org
. Chem. 1985, 50, 2198).
Oxidation with 10 ₂ (Lindgren, BO, Nilsson,
T. Acta Chem. Scand. 1973, 27, 888, Dal
canale, E .; Montanari, F .; J. Org. Chem.
1986, 51, 567) is another option. But,
All of these procedures have limitations and disadvantages, and new methods for the oxidation of primary alcohols to carboxylic acids are still desired (Schrode).
r, M. Griffith, W .; P. J. Chem. Soc. Chem
. Comm. 1979, 58, and Paquette, L .; A. , Dress
el, J. et al. Pansegrou, P .; D. Tetrahedron L by
ett. 1987, 28, 4965).

A very simple oxidation of primary alcohols to carboxylic acids has been described using only catalytic CrO ₃ and periodate (H ₅ IO ₆ ) as stoichiometric oxidants. Chromium-catalyzed oxidation of secondary alcohols is known (Muzart, J. et al.
Chem. Review 1992, 92, 113-140, and Mu
zart, J.M. Piva, O .; Tetrahedron Lett. 1
988, 29, 2321-2324), no similar method for the oxidation of primary alcohols to their acids has been reported. This chromium-catalyzed oxidation process avoids chromium waste associated with the typical Jones oxidation reaction, reduces isomerization of any α-chiral centers, and provides secondary yields in quantitative yield. It oxidizes the alcohol to the corresponding ketone and is a one-step procedure. The reaction is mild and rapid, with high yield and with a CrO ₃ of 1-2 mo.
Only 1% is needed.

The present invention provides the following formula I:

[0004]

Embedded image Discloses a process for preparing a compound of the formula II in a solvent comprising:

[0005]

Embedded image Is reacted with periodate and a catalytic amount of a chromium reagent to oxidize to a compound of formula I.

SUMMARY OF THE INVENTION The present invention provides a compound of formula I:

[0007]

Embedded image(Where R¹Are: a) OH, b) H, c) C₁~ C₈Alkyl, d) C₁~ C₈Alkoxyl, e) C₃~ C₇Cycloalkyl, f) aryl, g) heteroaryl, or h) heterocyclyl, wherein C₁~ C₈Alkoxy, C₁~ C₈Alkyl or C₃~ C₈Cyclo
Alkyl is unsubstituted or OH, CO₂R⁴, Br, Cl, F, I, C
F₃, N (R⁵)₂, C₁~ C₈Alkoxy, C₃~ C₈Cycloalkyl, ant
, Heteroaryl, heterocyclyl, CO (CH₂)_nCH₃, And CO
(CH₂)_nCH₂N (R⁵)₂One, two or three selected from the group consisting of
Substituted with substituents, aryl is defined as phenyl or naphthyl, which is unsubstituted
Or OH, CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁ ~ C₈Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (C
H₂)_nCH₃, CO (CH₂)_nCH₂N (R⁵)₂Selected from the group consisting of
Substituted on one, two or three substituents, or on an adjacent carbon
When an aryl is substituted, one, two or three heterologs selected from O, N and S
A 5- or 6-membered fused ring having a terrorist atom can be formed, wherein the ring is unsubstituted
OH, CO on carbon or nitrogen₂R⁴, Br, Cl, F, I, CF ₃ , N (R⁷)₂, C₁~ C₈Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Shi
Chloroalkyl, CO (CH₂)_nCH₃, And CO (CH₂)_nCH₂N (R ⁵ )₂Wherein one, two or three substituents selected from the group consisting of are substituted;
Is defined as a 5- or 6-membered aromatic ring containing atoms, the aromatic ring being unsubstituted
Or OH, CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~ C ₈ Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH₂ )_nCH₃, CO (CH₂)_nCH₂N (R⁵)₂1 selected from the group consisting of
And the 5- or 6-membered aromatic ring is benzo
Can be condensed, unsubstituted or as described above with one, two or three
Heterocyclyl is substituted with one or more substituents, wherein the heterocyclyl is 1, 2 or 3 hetero atoms selected from O, N and S;
Is defined as a 5- or 6-membered non-aromatic ring containing one or two atoms.
And the non-aromatic ring is unsubstituted or OH,
CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~ C₈Alkoki
Si, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH₂)_nCH₃ , CO (CH₂)_nCH₂N (R⁵)₂1, 2 or selected from the group consisting of
Substituted with three substituents, and the 5- or 6-membered ring is benzo-fused
And can be unsubstituted or substituted with one, two or three substituents as described above.
R²Is a) C₁~ C₈Alkyl, b) C₃~ C₇Cycloalkyl, c) aryl, d) heteroaryl, or e) heterocyclyl, n is 0-5, t is 0, 1 or 2;⁴Is H or C₁~ C₈Alkyl or R⁵Is H or C₁~ C₈Alkyl or aryl;⁷Is H, C₁~ C₈Alkyl, aryl, two R⁷Substituents are the same
When on nitrogen, they can combine to form a ring having 3 to 6 atoms.
A process for the preparation of a compound of the formula II comprises the following formula II in a solvent:
:

[0008]

Embedded image Is reacted with a solution of periodic acid and a catalytic amount of a chromium reagent in a solvent to oxidize to a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula I:

[0010]

Embedded image(Where R¹Are: a) OH, b) H, c) C₁~ C₈Alkyl, d) C₁~ C₈Alkoxyl, e) C₃~ C₇Cycloalkyl, f) aryl, g) heteroaryl, or h) heterocyclyl, wherein C₁~ C₈Alkoxy, C₁~ C₈Alkyl or C₃~ C₈Cyclo
Alkyl is unsubstituted or OH, CO₂R⁴, Br, Cl, F, I, C
F₃, N (R⁵)₂, C₁~ C₈Alkoxy, C₃~ C₈Cycloalkyl, ant
, Heteroaryl, heterocyclyl, CO (CH₂)_nCH₃, And CO
(CH₂)_nCH₂N (R⁵)₂One, two or three selected from the group consisting of
Aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted
Or OH, CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~
C₈Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH ₂ )_nCH₃, CO (CH₂)_nCH₂N (R⁵)₂Selected from the group consisting of
Substituted with one, two or three substituents, or
When the reel is replaced, one, two or three heads selected from O, N and S
A 5- or 6-membered fused ring having two atoms, wherein the ring is unsubstituted.
OH, CO on carbon or nitrogen₂R⁴, Br, Cl, F, I, CF₃ , N (R⁷)₂, C₁~ C₈Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Shiku
Loalkyl, CO (CH₂)_nCH₃, And CO (CH₂)_nCH₂N (R⁵ )₂Wherein one, two or three substituents selected from the group consisting of are substituted;
Is defined as a 5- or 6-membered aromatic ring containing atoms, the aromatic ring being unsubstituted
Or OH, CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~ C ₈ Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH₂ )_nCH₃, CO (CH₂)_nCH₂N (R⁵)₂1 selected from the group consisting of
And the 5- or 6-membered aromatic ring is benzo
Can be condensed, unsubstituted or as described above with one, two or three
Heterocyclyl is substituted with one or more substituents, wherein the heterocyclyl is 1, 2 or 3 hetero atoms selected from O, N and S;
Is defined as a 5- or 6-membered non-aromatic ring containing one or two atoms.
And the non-aromatic ring is unsubstituted or OH,
CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~ C₈Alkoki
Si, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH₂)_nCH₃ , CO (CH₂)_nCH₂N (R⁵)₂1, 2 or selected from the group consisting of
Substituted with three substituents, and the 5- or 6-membered ring is benzo-fused
And can be unsubstituted or substituted with one, two or three substituents as described above.
R²Is a) C₁~ C₈Alkyl, b) C₃~ C₇Cycloalkyl, c) aryl, d) heteroaryl, or e) heterocyclyl, n is 0-5, t is 0, 1 or 2;⁴Is H or C₁~ C₈Alkyl or R⁵Is H or C₁~ C₈Alkyl or aryl;⁷Is H, C₁~ C₈Alkyl, aryl, two R⁷Substituents are the same
When on nitrogen, they can combine to form a ring having 3 to 6 atoms.
A process for the preparation of a compound of the formula II comprises the following formula II in a solvent:
:

[0011]

Embedded image A compound obtained by dissolving periodic acid and a catalytic amount of a chromium reagent in a solvent is added to a solution of about -20.
Reacting at a temperature in the range of from about C to about -40 C for about 15 minutes to about 24 hours to oxidize to the compound of Formula I.

The solvent is acetonitrile, tetrahydrofuran, diethyl ether, MTBE (
Methyl t-butyl ether), DME (dimethoxyethane), DIGLYME (
The above method selected from the group consisting of 2-methoxyethyl ether), TRIGLYME (triethylene glycol dimethyl ether), dioxane, or a mixture of said solvents, including a mixture of said solvent and water.

The periodic acid (H ₅ IO ₆ ) is present in an amount of about 2.0 to about 4.0 equivalents, preferably about 2.5 equivalents.
The above method used in equivalent amounts. A minimum of 2 equivalents of periodic acid is required to effect oxidation of the primary alcohol to the carboxylic acid. Further, if the compound of Formula II contains any basic functional groups, additional periodic acid equivalents for each basic functional group are required to effect oxidation.

The chromium reagent is from CrO ₃ , Na ₂ Cr ₂ O ₇ , K ₂ Cr ₂ O ₇ , CrX ₃ (where X is Cl, Br, F, NO ₂ , OAc, or ClO ₄ ) The above method selected from the group consisting of: From about 0.1 to about 10 mole percent of the chromium reagent;
The above-described method, preferably used at about 1.0 to about 2.0 mole percent.

[0015] Such a method, wherein the temperature range is from about -20 ° C to about 30 ° C, preferably from about -10 ° C to about 0 ° C. The reaction time is about 15 minutes to about 24 hours, preferably about 45 minutes and about 1.
A method as described above, which is for 5 hours.

It is further understood that the substituents described above include the definitions set out below.

The alkyl substituents described above may be methyl, ethyl, isopropyl, isobutyl, t-
Shows straight and branched chain hydrocarbons of defined length, such as butyl, neopentyl, isopentyl and the like.

Alkenyl substituents may each be a carbon- such as vinyl, allyl and 2-butenyl.
The above alkyl group is modified to include a carbon double bond.

Cycloalkyl denotes a ring composed of 3 to 8 methylene groups, each substituted or unsubstituted with other hydrocarbon substituents, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 4 -Methylcyclohexyl.

Alkoxy substituents represent an alkyl group as described above attached through an oxygen bridge.

Aryl substituents represent phenyl and 1-naphthyl or 2-naphthyl;
Includes aryl substituted with 5- or 6-membered fused rings such as unsubstituted and substituted methylenedioxy, oxazolyl, imidazolyl or thiazolyl rings.

Heteroaryl substituents include carbazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl,
Represents thiazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl and purinyl.

Heterocyclyl substituents represent oxazolidinyl, thiazolidinyl, imidazolidinyl, thiazolidinyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl.

Each of the above substituents (alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclyl) is either unsubstituted or substituted as defined herein. I can do it.

Reaction Scheme I

[0026]

Embedded image Primary alcohols have, in aqueous acetonitrile (v / v to _1/1), it was found to be be oxidized to the acid using H 5 IO ₆ and 5 mol% CrO _3. A conversion of 72% height was observed, but the reaction could not be completed by the addition of H ₅ IO ₆ . Further, the reaction mixture is composed of Cr (II
I) The color gradually changed to a greenish color indicating seed formation, but it could not return to Cr (VI). But nevertheless, these experiments have proven that the catalytic process is feasible. H ₂ SO ₄ was added to the reaction mixture because strong acids increase the oxidizing potential of CrO ₃ . This seemed to improve oxidation only slightly. On the other hand, water had a dramatic effect on the reaction rate. By removing water from the system, complete reaction took place in less than 15 minutes at room temperature. We have subsequently found that the presence of small amounts of water weakens the oxidative strength of the system, leading to a more complete reaction. Therefore, H ₅ IO ₆ / Cr in wet MeCN (0.75% by weight of water)
O ₃ solution (2.5 eq /1.1Molpasento) by adding to the alcohol at 0 to 5 ° C., can be obtained best yield. The reaction was typically completed within one hour.

Table 1 summarizes the results of the oxidation of various alcohols as represented by the following reaction formulas.

Oxidation of (R ² ) (R ¹ ) CHOH → (R ² ) (R ¹ ) C ＝ O 12 phenetanol (1a) yielded phenylacetic acid (2a) in 96% yield (described). Matters 1). Similarly, substrates with electron-rich aromatic rings such as 1b and 1c were converted to carboxylic acids 2b and 2c in excellent yields (entries 2, 3). Most notably, chiral alcohol 1d was brilliantly oxidized (95%) to 2d without evidence of racemization based on chiral HPLC assay (entry 4). This was probably due to the very short life of the aldehyde intermediate under the reaction conditions. In all cases tested, no more than 5% of the aldehyde intermediate was observed during the reaction (HPLC). The cyclopropyl group in alcohol 1e was not impaired under the reaction conditions, yielding 2e in 90% yield (entry 5). The amide acetal in 1f also remains, and the yield is 73
% Yielded the desired product 2f (entry 6). 1 g of Cbz-protected amino alcohol was oxidized in high yield to 2 g of Cbz-protected amino acid without racemization (83%, entry 7). In this case, the reaction was performed at room temperature due to the low solubility of the substrate at 0 ° C. The adjacent diol, i.e., 1-phenyl-1,2
-With respect to ethanediol (1h), carbon-carbon bond cleavage occurs and the yield is 7
7% gave benzoic acid (entry 8). Surprisingly, benzyl alcohol,
Oxidation of benzylic alcohols such as 4-methoxybenzyl alcohol and furfuryl alcohol did not produce satisfactory results. Interestingly, electron deficient 4-nitrobenzyl alcohol (1i) yielded a quantitative yield of 4-nitrobenzoic acid (entry 9). Substrates with highly electron rich aromatic groups, such as 2,4,6-trimethoxybenzyl alcohol and 2- (3 ', 4'-dimethoxyphenyl) ethanol, resulted in complex reaction mixtures. No reaction was observed with cinnamon alcohol and 3-phenyl-2-propyn-1-ol. As expected, the secondary alcohols, s-phenetanol (1j) and 1-phenyl-2-propanol (1k), were oxidized in quantitative yield to acetophenone and phenylacetone, respectively (entries 10, 11). . In these cases, only 1.25 equivalents of periodic acid and 0.6 mol% of CrO ₃ were required.

[0029]

[Table 1]

[0030]

[Table 2]

The present invention can be further understood by the following examples, which do not limit the invention.

(Summary) All substrates except 1d (the production of this primary alcohol is described in Examples 2-5
Commercially available and used without purification. The product was identified by comparing the ¹ H and ¹³ C NMR spectra of the product, except for 2d and 2f, with the spectra of commercial materials. Yields are based on Zorbax S
B-phenyl or YMC ODS-AM column and MeCN as mobile phase
/0.1% H ₃ PO ₄ Determined by reverse phase HPLC.

Example 1 Oxidation of Primary Alcohol-Periodic Acid and Chromium Trioxide

[0034]

Embedded image Stock solutions of H ₅ IO ₆ / CrO _{3 dissolves H 5 IO 6 (11.4g, 50mmol} ) and _CrO 3 (23 mg, 1.2 mol%) in wet MeCN (water content 0.75 vol%), volume Made by making 114 mL (typically required 1-2 hours for complete dissolution). Thereafter, alcohol 1 (2.0 mmol) was added to wet acetonitrile (10 mL, water 0
. In solution in 75 _{volume%), H 5 IO 6 /} CrO 3 solution (11.4 mL)
Was added for 30-60 minutes. The mixture was aged for 0.5 hours at 0 ° C. and the completion of the reaction was confirmed by HPLC assay. NaHPO ₄ aqueous solution (H ₂ O 10 mL
The reaction was quenched by adding 0.6 g). Toluene (15 mL) was added and the organic layer was separated and washed with a 1/1 brine / water mixture (2 × 10 mL), followed by aqueous NaHSO ₃ (0.22 in 5 mL of water) and brine (5 mL).
). Thereafter, the organic phase was concentrated to yield crude carboxylic acid 2. Most of this crude product was very pure based on ¹ H NMR analysis and HPLC assay.

2g: The enantiomeric excess of Cbz-phenylalanine (2g) is
Determined by HPLC after removal of the bz protecting group (H ₂ / Pd in MeOH). H
PLC conditions: Crown Pack (CROWNPAK) CR (+) column, pH = 2
. 0 aqueous HClO ₄ mobile phase (0.80 mL / min), UV at 220 nm
Detection and residence time: D-phenylalanine 9.3 minutes, L-phenylalanine
6 minutes.

2f: ¹ H NMR (CDCl ₃ ) δ: 9.0 to 8.0 (broad, 1H),
7.47 to 7.30 (m, 5H), 5.71 (d, J = 7.7 Hz, 1H), 4
. 43 (d, J = 7.7 Hz, 1H) 2.70 to 2.40 (m, 2H), 2.3
3 to 2.27 (m, 1H), 2.17 to 1.80 (m, 3H), 1.58 (s,
3H).

¹³ C NMR (CDCl ₃ ) δ: 172.04, 169.48, 137.5
2, 128.73, 126.16, 94.66, 77.05, 64.34, 34
. 52, 29.91, 23.45, 17.28.

Example 2 Preparation of 2-bromo-5-methoxybenzyl alcohol

[0039]

Embedded image Slurry sodium borohydride (8.6 g) in THF (150 mL, KF = 150 μg / mL) in a round bottom flask equipped with a thermocouple, addition funnel, nitrogen inlet, stirrer and cooling bath. 2-bromo-5-methoxybenzoic acid (5
0 g) was dissolved in THF (100 mL, KF = 150 μg / mL).
Add to the sodium borohydride slurry over 45 minutes while maintaining the temperature at ２５25 ° C. The reaction must be controlled by carefully monitoring the rate of addition with intermittent cooling. The mixture is aged for 30 minutes at 20-25 ° C. Boron trifluoride etherate (36.9 g) is added over 30 minutes at 30-35 ° C.

[0040] The addition of boron trifluoride etherate causes delayed exotherm and should be added slowly to control the reaction temperature. The obtained white slurry is 30 to 35
Aged at <RTIgt; 1 C </ RTI> for 1 hour before sampling for HPLC assay. The peak at RT = 8.7 minutes is an impurity related to the starting material. Acid is the peak at RT = 9.1 minutes.

The reaction mixture is cooled to 15 ° C. and quenched carefully into a cold saturated ammonium chloride solution (10 ° C., 150 mL) while maintaining the temperature at <25 ° C.

Ethyl acetate (500 mL) and separate layers. The organic layer was washed with water (100 mL
) And then transferred to a 1 L round bottom flask equipped for distillation. The solution was concentrated and charged with fresh ethyl acetate. A 200 mL solution has a KF <20
This is repeated until it has 0 μg / mL. Then, the solvent was changed to DMF and K
Obtain a final volume of 200 mL with F <200 μg / mL.

Example 3 Preparation of 2-bromo-5-methoxybenzyl chloride

[0044]

Embedded image DMF solution of benzyl alcohol (91.3 g in 400 mL, KF = 300 μg / mL) in a 2 L flask equipped with stirrer, thermocouple, N ₂ inlet and cooling bath
). The solution was cooled to 0-5 ° C and the addition funnel was charged with thionyl chloride (55
. 0 g). Thionyl chloride is added over 45 minutes while maintaining the temperature at 5-10 ° C. The mixture is aged at 5 ° C. for 1 hour and assayed by HPLC.

Fill the addition funnel with water (400 mL) and maintain it at a temperature <15 ° C.
Add dropwise to the reaction mixture over 30 minutes. Temperature is controlled by monitoring cooling and addition rates. The initial addition of water is accompanied by a large exotherm. The use of a large excess of thionyl chloride can further reduce heat generation. If you do not control this heat generation stop temperature,
Benzyl chloride can be hydrolyzed back to alcohol.

The resulting thick white slurry is aged at 0-5 ° C. for 1 hour. The benzyl chloride is isolated by filtration. The cake is washed with (1: 1) DMF: H ₂ O (100 mL) followed by water (200 mL). Dry the solid in vacuo to obtain 93 g of benzyl chloride (94% yield, 96A%).

HPLC Assay: Column: Waters Symmetry
try) C8, 4.6 × 250 mm, UV detection: 220 nm, column temperature: 25
° C, flow rate: 1 mL / min, eluent: CH ₃ CN: H ₂ O: 0.1% H ₃ PO ₄ (7
0:30), RT (benzyl alcohol) = 3.9 minutes, RT (benzyl chloride) =
7.3 min, and RT (DMF) = 2.6 min.

Example 4 Preparation of acetonide of N-propanoyl (1R, 2S) -cis-aminoindano

[0049]

Embedded image Stirrer, N ₂ inlet port, thermocouple probe, three-necked round bottom flask 5L equipped with a heating mantle and addition funnel, (1R, 2S) - cis - aminoindanol (
100 g), tetrahydrofuran (1.2 L, KF = 120 mg / mL), and triethylamine (96 mL, KF = 500 μg / mL). The resulting slurry is heated to 40-45 C under a nitrogen atmosphere to give a yellow solution. Propionyl chloride (59 mL) is charged to the addition funnel and added to the solution while maintaining a temperature of 45-50 ° C.

The temperature is controlled by the rate of propionyl chloride addition and the cooling bath. HPLC
The assay shows> 99% of the resulting amide. Add methanesulfonic acid (3 mL) to the reaction slurry. Charge 2-methoxypropene (140 mL) to the addition funnel and add at 50 ° C. over 30 minutes.

The addition of 2-methoxypropene is accompanied by a mild exotherm. Maintain temperature by addition rate and heating mantle. The reactant remains a slurry but becomes less concentrated.

The reaction slurry is aged at 50 ° C. for 1-2 hours. HPLC assay at this point shows <0.5 A% residual amide. The amide is not isolated and removed because it is important to complete the reaction. Cool the reaction slurry to 0-5 ° C and quench by adding 5% aqueous sodium carbonate (1 L) and heptane (1 L). Stir the layers, separate and wash the organic layer with water (300 mL).

An HPLC assay at this point shows acetonide in> 98 A%, yield> 90%. The acetonide / THF / heptane solution is filtered into a 2 L round bottom flask and the solution is distilled to a final volume of 700 mL. Heptane (1 L) is added and the solution is distilled to a final volume of 700 mL. Distillation is performed at 〜50 ° C. under partial vacuum. NMR assay at this point shows <2 mol% THF. The solution is allowed to cool and seeded with acetonide at 35-40 ° C. The thick slurry is aged for 1 hour at ambient temperature, then cooled to 0-5 ° C and aged for 1 hour. The slurry is filtered and the cake is washed with cold heptane (200 mL) and air dried to give acetonide as a crystalline white solid (141.1 g, 85% yield, 99.%).
6A%).

Example 5 Alkylation of acetonide using 2-bromo-5-methoxybenzyl chloride

[0055]

Embedded image A solution of acetonide (252 g) and benzyl chloride (255 g) in THF (2 L)
, KF <200 μg / mL) to −10 ° C. Lithium bis (trimethylsilyl) amide (1.45 L) is added dropwise at 0-2 ° C over 5 hours. The mixture is then aged for 1.5 hours and assayed by HPLC.

The reaction is quenched by adding a saturated aqueous solution of ammonium chloride (1 L).
The initial addition of ammonium chloride should be done slowly to reduce foaming. When the frothing subsides, the rate of addition can be increased.

The quenched reactants are then transferred into a mixture of aqueous ammonium chloride (1.5 L), water (0.5 L), and ethyl acetate (3 L). Thereafter, the mixture is stirred for 15 minutes and the layers are separated. Wash the organic layer with water (1 L) and brine (0.5 L). Concentrate the ethyl acetate solution to low volume and change the solvent to 1,4-dioxane. The dioxane solution is adjusted to a final volume of 1.8 L.

A solution of the conjugated product in dioxane is charged to a 12 L round bottom flask and charged with 6 M HCl (1.5 L). The mixture is heated to reflux and monitored by HPLC.

Cool the mixture to 20 ° C. and add MTBE (3 L). The mixture is stirred for 15 minutes and the layers are separated. Wash the organic layer with (1 L) water. The MTBE solution of the crude acid is extracted with 0.6 M sodium hydroxide (2 L). An aqueous solution of the sodium salt of the acid is mixed with MTBE (2.5 L) and cooled to 10 ° C.

The biphasic mixture is acidified with 5.4 molar sulfuric acid (250 mL), stirred for 15 minutes, allowed to settle, and the phases are separated. Wash the acid MTBE solution with water (0.5 L). The MTBE solution of the acid is dried by distillation, after which the solvent is changed to THF.
The final volume of THF is 2 L with KF <250 μg / mL.

HPLC Assay: Column: Waters Symmetry
try), eluent: acetonitrile: water: phosphoric acid (70: 30: 0.1), flow rate: 1 mL / min, RT (acetonide) = 4.5 minutes, RT (benzyl chloride) = 7.5
Min, RT (conjugated product) = 11.5 minutes, RT (aminodanol) = 1.7 minutes,
RT (hydroxyamide) = 1.7 minutes, RT (acid) = 4.5 minutes.

Example 6 Production of 3- (2-bromo-5-methoxyphenyl) -2-methylpropanol

[0063]

Embedded image Slurry sodium borohydride (33 g) in THF (0.5 L, KF = 200 μg / mL) in a round bottom flask. The THF solution of the acid (2 L) is added to the sodium borohydride slurry over 1 hour while maintaining the temperature at 20-25 ° C.

The reaction is controlled by carefully monitoring the rate of addition using a cooling bath. It is also important to flush nitrogen and properly discharge hydrogen.

The mixture is aged at 20-25 ° C. for 30 minutes. Boron trifluoride etherate (152 g) is added over 1 hour at 30-35 ° C. This addition causes a delayed exotherm and should be carefully monitored to control the reaction temperature. The resulting milky slurry is aged at 30 ° C. for 1 hour and sampled for HPLC assay.

The reaction mixture is cooled to 15 ° C. and carefully stopped in a cold ammonium chloride solution (10 ° C., 1.5 L) while maintaining the temperature at 25 ° C. The rate of hydrogen evolution is controlled by the rate at which the mixture is added to ammonium chloride. The quenched mixture is distilled in vacuo to remove the THF. Extract the aqueous layer with MTBE (1.5 L) and dry the organic layer by washing with additional MTBE. After that, MTB
For the E solution, the solvent is changed to hexane, the volume is adjusted to 350 mL, and the seeds are added. The slurry is aged at 20 ° C. for 2 hours, then cooled to 0-5 ° C., aged for 1 hour, and filtered. Wash the cake with cold hexane (200 mL). The solid is dried under a stream of nitrogen. The isolated solid (164 g) is> 99 A% by HPLC and> 99% ee.

HPLC: Column: Waters Symmetry
y) C8, solvent: acetonitrile: water: phosphoric acid (50: 50: 0.1), flow rate:
1 mL / min, detection: 220 nm, RT (acid) = 10.2 min, RT (alcohol)
= 10.7 minutes.

Chiral HPLC: Column: Chiracel OD-H: Hexane: 2-propanol (97: 3), flow rate: 1 mL / min, detection: 220 nm, R
T (minor isomer) = 21 minutes, RT (major isomer) = 23 minutes.

Example 7 Preparation of 3- (2-bromo-5-methoxyphenyl) -2-methylpropanol

[0070]

Embedded image The alcohol was prepared according to the general procedure listed in Example 1. Product (2d)
The enantiomeric purity of was reduced to alcohol (1d) using BH ₃ THF,
Measured by chiral HPLC.

HPLC conditions: Column: CHIRALCEL OD-H: Hexane / i-PrOH (97/3, 100 mL / min), UV detection at 220 nm. Residence time: (R) -isomer, 23.6 minutes, (S) -isomer, 29.2 minutes.

2d: ¹ H NMR (CDCl ₃ ) δ: 7.44 (d, J = 8.7 Hz, 1H
), 6.78 (d, J = 3.1 Hz, 1H), 6.66 (dd, J = 8.7, 3
. 1 Hz, 1 H), 3.75 (s, 3 H), 3.13 (dd, J = 13.1, 6)
. 8Hz, 1H), 2.98 to 2.84 (m, 1H), 2.77 (dd, J = 1
3.1, 7.4 Hz, 1H), 1.23 (d, J = 6.9 Hz, 3H).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 57/46 C07C 57/46 59/64 59/64 63/06 63/06 201/12 201/12 205 / 57 205/57 269/06 269/06 271/22 271/22 C07D 498/04 105 C07D 498/04 105 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM) , AE, AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR , LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA, US, UZ, VN, YU, ZA (72) Inventor Chien, David M. United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Son, Chiguo United States, New Jersey 07065, Lowway, East・ Lincoln Avenue 126 (72) Inventor Chiao, Mantu USA, New Jersey 07065, Lowway, East Lincoln Avenue 126F Terms (Reference) 4C072 AA01 BB02 CC01 CC11 EE03 FF07 GG07 GG09 HH02 JJ01 4H006 AA02 AC44 AC46 BA02 BA14 BA30 BA32 BA34 BA37 BB15 BB21 BB25 BB31 BC10 BC14 BC19 BC31 BC34 BE05 BJ50 BM30 BM73 BP30 BS10 BS10

Claims (10)

[Claims] 1. A compound of the formula I:(Where R¹Are: a) OH, b) H, c) C₁~ C₈Alkyl, d) C₁~ C₈Alkoxyl, e) C₃~ C₇Cycloalkyl, f) aryl, g) heteroaryl, or h) heterocyclyl, wherein C₁~ C₈Alkoxy, C₁~ C₈Alkyl or C₃~ C₈Cyclo
Alkyl is unsubstituted or OH, CO₂R⁴, Br, Cl, F, I, C
F₃, N (R⁵)₂, C₁~ C₈Alkoxy, C₃~ C₈Cycloalkyl, ant
, Heteroaryl, heterocyclyl, CO (CH₂)_nCH₃, And CO
(CH₂)_nCH₂N (R⁵)₂One, two or three selected from the group consisting of
Aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted
Or OH, CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~
C₈Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH ₂ )_nCH₃, CO (CH₂)_nCH₂N (R⁵)₂Selected from the group consisting of
Substituted with one, two or three substituents, or
When the reel is replaced, one, two or three heads selected from O, N and S
A 5- or 6-membered fused ring having two atoms, wherein the ring is unsubstituted.
OH, CO on carbon or nitrogen₂R⁴, Br, Cl, F, I, CF₃ , N (R⁷)₂, C₁~ C₈Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Shiku
Loalkyl, CO (CH₂)_nCH₃, And CO (CH₂)_nCH₂N (R⁵ )₂Heteroaryl is substituted with one, two or three substituents selected from the group consisting of:
Is defined as a 5- or 6-membered aromatic ring containing atoms, the aromatic ring being unsubstituted
Or OH, CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~ C ₈ Alkoxy, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH₂ )_nCH₃, CO (CH₂)_nCH₂N (R⁵)₂1 selected from the group consisting of
And the 5- or 6-membered aromatic ring is benzo
Can be condensed, unsubstituted or as described above with one, two or three
Heterocyclyl is substituted with one or more substituents, wherein the heterocyclyl is 1, 2 or 3 hetero atoms selected from O, N and S;
Is defined as a 5- or 6-membered non-aromatic ring containing one or two atoms.
And the non-aromatic ring is unsubstituted or OH,
CO₂R⁴, Br, Cl, F, I, CF₃, N (R⁵)₂, C₁~ C₈Alkoki
Si, C₁~ C₈Alkyl, C₃~ C₈Cycloalkyl, CO (CH₂)_nCH₃ , CO (CH₂)_nCH₂N (R⁵)₂1, 2 or selected from the group consisting of
Substituted with three substituents, and the 5- or 6-membered ring is benzo-fused
And can be unsubstituted or substituted with one, two or three substituents as described above.
R²Is a) C₁~ C₈Alkyl, b) C₃~ C₇Cycloalkyl, c) aryl, d) heteroaryl, or e) heterocyclyl, n is 0-5, t is 0, 1 or 2;⁴Is H or C₁~ C₈Alkyl or R⁵Is H or C₁~ C₈Alkyl or aryl;⁷Is H, C₁~ C₈Alkyl, aryl, two R⁷Substituents are the same
When on nitrogen, they can combine to form a ring having 3 to 6 atoms.
A process for the preparation of a compound of the formula II comprising the steps of:A solution of periodic acid, a catalytic amount of a chromium reagent in a solvent from about -20 ° C.
A method comprising reacting in a temperature range of about -40 ° C for about 15 minutes to about 24 hours. 2. The solvent is acetonitrile, tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), DME (dimethoxyethane).
The method of claim 1, wherein the solvent is selected from the group consisting of: DIGLYME (2-methoxyethyl ether), TRIGLYME (triethylene glycol dimethyl ether), dioxane, or a mixture of the solvents, including a mixture of the solvent and water. 3. The method of claim 2, wherein periodate (H ₅ IO ₆ ) is used in about 2.0 to about 4.0 equivalents. 4. The method according to claim 1, wherein the chromium reagent is CrO₃, Na₂Cr₂O₇, K₂Cr₂O ₇ , CrX₃(Where X is Cl, Br, F, NO₂, OAc, or ClO₄ 4. The method of claim 3, wherein the method is selected from the group consisting of: 5. The method of claim 4, wherein the chromium reagent is used at about 0.1 to about 10 mole percent. 6. The method of claim 5, wherein the temperature range is from about −10 ° C. to about 30 ° C. 7. The method according to claim 6, wherein periodate (H ₅ IO ₆ ) is used in about 2.5 equivalents. 8. The method of claim 7, wherein chromium trioxide (CrO ₃ ) is used at about 1.0 to about 2.0 mole percent. 9. The method according to claim 8, wherein the temperature range is from about −10 ° C. to about 0 ° C. 10. The method of claim 9, wherein the reaction time is from about 45 minutes to about 1.5 hours.