For synthesis of 6-hydroxyalkyl-2,3- dimethoxy-5-methyl-1,4-benzoquinone

专利摘要:
A method for producing a compound of the formula: <CHEM> [wherein R<1> and R<2> each stand for a lower alkyl group; n denotes an integer of 0 to 21; X stands for hydrogen atom or an optionally protected hydroxyl group; and Y stands for an optionally protected hydroxyl group], which comprises by reducing an ester compound of the formula: <CHEM> [wherein R<1>, R<2>, n, X and Y are of the same meaning as defined above, and R<3> stands for a lower alkyl group] with a mixture of sodium borohydride and aluminum chloride, gives the desired compound in a high yield, and is advantageous from the industrial point of view.
公开号:SU1768029A3
申请号:SU4356640
申请日:1988-09-19
公开日:1992-10-07
发明作者:Окада Таиити；Абе Ясуаки
申请人:Такеда Кемикал Индастриз, Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to an improved process for the preparation of 6-hydroxyalkyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone, which is used as an intermediate compound for medicinal preparations.
A method of producing 6-hydroxy-alkyl-2,3-dimethoxy-6-methyl-1,4-benzoquinone is known, which consists in that 9- / 3,4-dimethoxy-2-hydroxy-6 -methyl-benzoyl / nonanoate is subjected to Clemmensene or Wolfe-Kisner reduction or in the presence of a catalyst in an environment at a temperature of 0-140 ° C (20-70) of an organic solvent to obtain 10- (3,4-dimethoxy-2-hydroxy -6-methylphenyl) decanoate, which is reduced to sodium bis (2-methoxyethoxy) aluminum hydride in organic solvent 1-140 ° C (10-40) ° C. To obtain 10- (2-hydroxy-3,4 -dimethoxy-6-methylphenyl) de can-1-ol, which th oxidized in the presence of various oxidants such as chloride, Fe (III) .oksid silver nitrozodisulfon to 6 oksial keel-2,3-dimethoxy-5-methyl-1,4-baa nzohinona.
A disadvantage of the known method is the use of flammable sodium bis (2-methoxyethoxy) aluminum hydride in the reduction stage, since it reacts with air moisture to produce hydrogen, and this reduction agent is rather difficult to remove.
The aim of the invention is to forgive the process by improving the recovery stage.
Xi
About 00
eight
Yu

Ca
This goal is achieved by the method of obtaining 6-hydroxyalkyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone of the general formula I:
ABOUT
R g plj
H / 1 I V. X.X Vx J
CHvO V CrVrrCrbOri
ABOUT
where n 4-20,
that a compound of the general formula II:
X
H3COjiyCH3
nzso (schdgsoon,
where p - has the above meaning,
X - H, hydroxy group
RI is lower alkyl,
subjected to reduction with sodium borohydride in a mixture with aluminum chloride, preferably taken in an amount of 3 mol per 1 mol and 1.63-3.6 mol, calculated on the starting ester of formula II, and in the presence of water, which is taken, preferably in an amount of 0, 93-1.67 mol per 1 mol of aluminum chloride.
The resulting 3,4-dimethoxy-5-methylphenylalkanol of the general formula III
X
° ЈСНз
(CH2) h- CH2OH
where n, X - are as defined above, oxidized, preferably with a dibasic alkali metal salt of nitrosodisulfonic acid, obtained by electrochemical reduction of an aqueous solution of a dibasic alkali metal hydroxylamine disulfonic acid
The invention is illustrated by the examples below.
Example 1 881 g (2.5 mol) of methyl 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) -deconate are dissolved in 1.8 l of tetrahydrofuran. A suspension of 340 g (9 mol) of sodium borohydride in 10.7 L of tetrahydrofuran is added to the resulting solution and the mixture is stirred. To the prepared suspension, 75 ml (4.16 mol) of water are added. A solution of 400 g (3 mol) of aluminum chloride in 6.0 l of tetrahydrofuran and the resulting solution is added dropwise at a predetermined rate over 90 minutes to the previously prepared suspension. During this time, the temperature of the reaction mixture is maintained at 25 ± 2 ° C. The reaction mixture is stirred at this temperature for another 30 minutes, then it is cooled to 15 ° C and 2 l of water is added dropwise to it,
to cause decomposition, and then drop by drop 2.7 liters of hydrochloric acid. Thereafter, the reaction mixture is twice subjected to extraction with toluene, in portions of 9 l each. The toluene phases are combined and washed.
First, 4.4 L of a 5% aqueous solution of sodium bicarbonate, and then 4.4 L of water. Thereafter, it is concentrated under reduced pressure to obtain 805 g (2.48 mol, 99.2% yield) of 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) -decan-1-ol as oily liquid.
IR spectrum: Ayaktsy about 3400 (OH).
NMR spectrum 5Ј% C | h: 1.10-1.80 (16H, multiplet, - (CH2) s-), 2.22 (ZN, singlet, CH3), 2.40-2.75 (2H, multiplet, СН2), 8.50-8.70 (2H, multiplet, С№), 3.80 (ЗН, singlet, ОНЗз), 8.84 (ЗН, singlet, ОНзз), 6.25 (1Н, singlet ring H).
Example 2. In this example, studied
the influence of the amount of added water on the yield of 10- (2-ethoxy-3,4-dimethoxy-6-methylphenyl) -decan-1-ol In 17.3 g of tetrahydrofuran dissolved to 17.3 g ) methyl 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) -decanoate (methyldecanoate) and the resulting solution is added to a suspension of 5.8 g (80 mmol) of sodium borohydride in 214.5 ml of tetrahydrofuran . The mixture is stirred. Accurately measure the specified volume of water (see Table 1) and add it to the prepared suspension. 8.0 g (60 mmol) of chloride are dissolved in 142 ml of tetrahydrofuran.
aluminum and the prepared solution is added dropwise to the above suspension over 90-120 minutes, maintaining the temperature of the suspension equal to 25 ± 2 ° C. The reaction mixture is stirred for 30 minutes at this temperature and then cooled to 15 ± 2 ° C and 446 ml of water is added dropwise, and then also dropwise, gradually, so that the temperature of the reaction mixture does not exceed 20 ° C 53.5 ml of hydrochloric acid. The reaction mixture is then twice subjected to toluene extraction in 178.5 ml portions, the toluene phases are combined and washed twice with water (89.5 ml). Toluene phase
concentrate under reduced pressure to obtain 10- (2-hydroxy-3.4-dimethoxy-6-methylphenyl) -decan-1-ol as an oily liquid. Table 1 presents the data on the effect of the amount of water added on the yield of the target product (decanol) and the by-product di-OH-derivative.
Example 3. Synthesis of an aqueous solution of the hydroxylamide disulfonic acid disodium salt to produce an oxidizing agent.
1875 g of sodium nitrate is dissolved in 7.5 l of water and 11.5 l of a 35% w / w aqueous solution of sodium hydrosulfite is added dropwise to the resulting solution, maintaining the solution temperature at 0 ° C or below. Thereafter, 2860 ml of acetic acid is added dropwise to the mixture at a temperature not higher than 5 ° C and stirred at this or lower temperature for 90 minutes. Then, 3125 ml of a 30% (wt.%) Aqueous solution of caustic soda at a temperature of 10 ° C or lower are added dropwise to it, and then 20 l of a 25% (wt.%) Aqueous solution is added dropwise. sodium carbonate solution to produce an aqueous solution of the hydroxylamine disulfonic acid disodium salt required for electrochemical oxidation. Salt yield is about 84%.
Example 4. Synthesis of an aqueous solution of a nitrosodisulfonic acid disodium salt by electrochemical oxidation.
A two-chamber monopolar electrolyzer of filter-press construction (active electrode surface 4.5 dm) electrolyzer x 2 electrolyzer loads 6-8 l of an aqueous solution of disodium salt hydroxylamine disulfonic acid as anolyte and 6-8 l of 10% (wt.%) sodium carbonate solution as catholyte. The electrolyte is circulated by a pump. When an electric current is passed through the electrolyzer for 2-3 hours under given conditions (current density 8 A / dm2, linear circulation rate 10.4 cm / s, temperature 15 ° C), an aqueous solution of disodium nitrodisulfonate is obtained with a yield of 90% .
Examples 5-8. 271 g of 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) -decan-1-ol are dissolved in 5.4 l of methanol and 6.7 l (concentration 0.359 mol / l) is added to the resulting solution an aqueous solution of disodium nitrosodisulfonate obtained by diluting an aqueous solution of this salt, synthesized by electrochemical oxidation. The mixture is stirred for 2 hours, maintaining its temperature at 50 ± 2 ° C. After making sure that all starting material had reacted with thin layer chromatography, 8.6 L of water was added to the reaction mixture.
five
and then extract it twice with toluene, in portions of 5.5 and 2.7 l. The toluene phases are combined, washed with water and concentrated under reduced pressure. AT
288 g (content 94.8%, yield 96.9%) of the crude product, 6- (10-oxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone are obtained. 20 g of the crude product are recrystallized from a mixture of 60 ml of toluene and
0 180 ml of n-hexane. The resulting crystals are dissolved in 60 ml of toluene and the solution is passed through a layer of 30 g of precoated activated alumina. The filtrate is concentrated under reduced pressure.
5 and the concentrate is recrystallized again from a mixture of 55 ml of toluene and 165 ml of n-hexane. The crystals obtained are then recrystallized from 108 ml of 50% ethanol and dried. As a result, 16.2 g of 6- (10-oxydecyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone as orange-green crystals are taken into account. M.p. 54.0 ° C.
IR spectrum Yamakssm 1: 3550 (OH), 1660. 1650, 1610 (1,4-benzoquinone).
NMR spectrum: 1.1-1.8 (6H, multiplet- (CHa) 8-), 2.00 (3N, singlet CH3), 2.43 (2H, triplet, J 7 Hz CHa). 3.63 (2H, triplet, J 6 Hz, SNAOH), 3.97 (6H, singlet,
0 OSSN) Other examples using
As a starting material of an aqueous solution of disodium nitrosodisulfonate synthesized by electrochemical oxidation, is given in Table 2.
PRI me R s 9-11. 6.84 kg of 10- (2-hydroxy-3,4-dimethoxy-6-methylphenyl) -decan-1-ol is dissolved in 110 l of methanol and 27.4 kg of acetate is added to the resulting solution
Q sodium and 110 liters of water. 23.5 kg (concentration 69.9%) of dipotassium nitrosodisulfonate are then added to the mixture and stirred for 3 hours at 50 ± 3 ° C. After using thin layer chromatography
5 make sure that all the starting material has reacted, 550 l of water is added to the mixture and stirred for 30 minutes or longer at 10 ° C or lower temperature. Drop-out crystals separate Q by centrifuging. The wet crystals are dissolved in 40 liters of ethyl acetate and washed with 25 ml of water. The ethyl acetate phase is 6.70 kg (yield 93.9%) of the crude product, 6- (10-oxydecyl) -2,3-dimethoxy-5-methyl-1,
5 4-benzoquinone. Comparative examples using dipotassium nitrodisulfonate (Fremy salt) described in Table 3.
Thus, the proposed method is carried out in 2 stages (instead of 3 by a known method) without the use of hard-to-reach and highly flammable reducing agents, with the final product
get with a yield of up to 99.2%.

权利要求:
Claims (4)
[1]
1. The method of obtaining 6-oxyalkyl-2,3-dimethoxy-5-methyl-1, 4-benzoquinone total
Formula I
ABOUT
 P I PJ.J U I 1 j J xXS / Fri.
(SN21P-SK2ON
about
where n 4-20,
reduction of the alkyl ester, 3,4-dimethoxy-6-methylphenyl-alkylcarboxylic acid in an organic solvent to obtain the corresponding 3,4-dimethoxy-6-methylphenylalkanol, which is subjected to oxidation, in order to simplify , as the ester of the general formula I use the compound of formula II
sn,
he
(CH2) n-COOR1
where n has the specified value; X is hydrogen, hydroxy group;
RI is lower alkyl,
the reduction is carried out with sodium borohydride in a mixture with aluminum chloride in the presence of water to obtain 3,4-dimethoxy-6-methylphenylalkanol of general formula III
ten
H3CO H3SO
JH (CH2) n-CH2OH
where n, X have the indicated meanings.
[2]
2. Method as claimed in Claim 1, characterized in that sodium borohydride is used in an amount of preferably 3 mol per mol and in an amount of 1.63-3.6 mol, calculated on the starting ester of general formula II.
[3]
3. A process according to claim 1, characterized in that water is used in an amount of 0.93-1.67 mol per 1 mol of aluminum chloride.
[4]
4. A method according to claim 1, characterized in that the oxidation is carried out by a dibasic alkali metal salt of nitrosodisulfonic acid, obtained by electrolytic oxidation of an aqueous solution of a dibasic alkali metal salt of hydroxylamine disulfonic acid,
Priority points: 04/27/87 according to claim 1-3; 04/29/87 on item 4.
Table 1
The effect of the amount of added water on the yield of decanol and di-OH-derivative
oh oh
0.8 0.8 M 1.0 1.5 1.5 1.8 1.8 1.8 2.0 2.0 2.0 2.5 2.5
0.0 0.0 O, 7 O, 7k
0.93 0.93 1.39 1.39 1.67 1.67 1.86 1.85 2.31 2.31
molar ratio
pD9V§Ia peak di; OH; n9 eivodvodny peak area decanols
-exit of the di-OH-derivative f-r .- -frr: - -0--1-- x 100; di-OH-derivative: 10- (2, 3-dioxy-β-methoxy-b-methyphenyl) -lecan-1-ol

9.2 6.9 3.3
2.8 1.8 2.7 0.6
1.4 1.2 1.7 0.5 0.0 0.0 0.0 0.0
 water added the number of moles of aluminum chloride
pD9V§Ia peak di; OH; n9 eivodvodny peak area decanols
f-r .- -frr: - -0--1-- x dioxy--methoxy-b-methyphenyl) -lec
6lit2
Oxidation of a compound of formula I with an aqueous solution of disodium nitrosodisulfonate prepared by
electrochemical oxidation Q HzCO-CH3 CM303 # 02 (3),
HjCO-V CH OH CH3OH-H20
he
(CH2) 10OH
Oxidation of compound I using dipotassium nitroso disulfonate (in the form of crystals)
H3CO
NiTvgҐ
sn.
 ONCS03K) 2 (iO
NZSOTCHSN UNO SNZON-H2O
he CH3co2Na
 The amount of the loaded substance, the amount of the source material x concentration ,.
40
and Q,
(CH2) 10OH
Table3
n with
ABOUT
uYVCHj
n3soLg1sn2) 10on o

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JPH0115492B2|1980-04-15|1989-03-17|Takeda Chemical Industries Ltd|JP2838126B2|1989-02-06|1998-12-16|東ソー株式会社|Method for producing orthoquinones|

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NZ513547A|2001-08-13|2002-09-27|Antipodean Biotechnology Ltd|Synthesis of triphenylphosphonium quinolsand/or quinones |

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US7888334B2|2003-08-22|2011-02-15|Antipodean Pharmaceuticals, Inc.|Mitoquinone derivatives used as mitochondrially targeted antioxidants|

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US7160578B2|2004-03-10|2007-01-09|Pilkington North America|Method for depositing aluminum oxide coatings on flat glass|

法律状态:
2005-01-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20030427 |

优先权:

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申请号 | 申请日 | 专利标题

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JP10579587|1987-04-27|

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JP10574487|1987-04-29|

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