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RU2365579C1 - Method of obtaining substituted aminobenzhydrols - Google Patents

Method of obtaining substituted aminobenzhydrols Download PDF

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RU2365579C1
RU2365579C1 RU2008103310/04A RU2008103310A RU2365579C1 RU 2365579 C1 RU2365579 C1 RU 2365579C1 RU 2008103310/04 A RU2008103310/04 A RU 2008103310/04A RU 2008103310 A RU2008103310 A RU 2008103310A RU 2365579 C1 RU2365579 C1 RU 2365579C1
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aminobenzhydrols
amino
och
general formula
reduction
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RU2008103310/04A
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Роман Сергеевич Бегунов (RU)
Роман Сергеевич Бегунов
Игорь Игоревич Бродский (RU)
Игорь Игоревич Бродский
Александр Михайлович Кунтасов (RU)
Александр Михайлович Кунтасов
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Государственное образовательное учреждение высшего профессионального образования Ярославский государственный университет им. П.Г. Демидова
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Abstract

FIELD: chemistry.
SUBSTANCE: invention relates to method of obtaining substituted aminobenzhydrols, which can be used as semi-products in synthesis of medications of general formula
Figure 00000033
, where: R1=R3=H, R2=NH2, R4=Cl (1); R1=R3=H, R2=NH2, R4=Br (2); R1=R3=H, R2=NH2, R4=OCH3 (3); R1=R4=H, R2=NH2, R3=Cl (4); R1=H, R2=NH2, R3=Cl, R4=Cl (5); R1=NH2, R2=Cl, R3=R4=H (6); R1=NH2,
Figure 00000034
, R3=R4=H (7); R1=NH2, R2=Cl, R3=H, R4=Cl (8); R1=NH2,
Figure 00000034
, R3=H, R4=Cl (9); R1=NH2, R3=Cl, R2=R4=H (10); R1=NH2,
Figure 00000035
, R2=R4=H (11); R1=NH2, R2=H, R3=Cl, R4=Cl (12); R1=NH2, R2=H,
Figure 00000035
, R4=Cl (13), whish lies in simultaneous reduction of nitro- and carbonyl groups of respective nitrobenzphenones of general formula
Figure 00000036
, where: R1=R3=H, R2=NO2, R4=Cl; R1=R3=H, R2=NO2, R4=Br; R1=R3=H, R2=NO2, R4=OCH3; R1=R4=H, R2=NO2, R3=Cl; R1=H, R2=NO2, R3=Cl, R4=Cl; R,=NO2, R2=Cl, R3=R4=H; R1=NO2,
Figure 00000034
, R3=R4=H; R1=NO2, R2=Cl, R3=H, R4=Cl; R1=NO2,
Figure 00000034
, R3=H, R4=Cl; R1=NO2, R3=Cl, R2=R4=H; R1=NO2,
Figure 00000035
, R2=R4=H; R1=NO2, R2=H, R3=Cl, R4=Cl; R1=NO2, R2=H,
Figure 00000035
, R4=Cl, reducing system Zn-NaBH4 in alcohol with molar ratio of substratum : zinc: sodium tetrahydroborate equal 1 : 3.5 : 0.25.
EFFECT: reduction of synthesis cost, reduction of time and temperature for process carrying out, increase of target products output.
1 cl, 2 tbl, 13 ex

Description

Изобретение относится к способу синтеза ароматических аминосоединений, в частности к получению замещенных аминобензгидролов общей формулыThe invention relates to a method for the synthesis of aromatic amino compounds, in particular to the production of substituted aminobenzhydrols of the general formula

Figure 00000001
Figure 00000001

где R1=R3=H, R2=NH2, R4=Cl (1); R1=R3=H, R2=NH2, R4=Br (2); R1=R3=H, R2=NH2, R4=OCH3 (3); R1=R4=H, R2=NH2, R3=Cl (4); R1=H, R2=NH2, R3=Cl, R4=Cl (5); R1=NH2, R2=Cl, R3=R4=H (6); R1=NH2, where R 1 = R 3 = H, R 2 = NH 2 , R 4 = Cl (1); R 1 = R 3 = H, R 2 = NH 2 , R 4 = Br (2); R 1 = R 3 = H, R 2 = NH 2 , R 4 = OCH 3 (3); R 1 = R 4 = H, R 2 = NH 2 , R 3 = Cl (4); R 1 = H, R 2 = NH 2 , R 3 = Cl, R 4 = Cl (5); R 1 = NH 2 , R 2 = Cl, R 3 = R 4 = H (6); R 1 = NH 2 ,

Figure 00000002
,
Figure 00000002
,

R3=R4=H (7); R1=NH2, R2=Cl, R3=H, R4=Cl (8); R1=NH2, R 3 = R 4 = H (7); R 1 = NH 2 , R 2 = Cl, R 3 = H, R 4 = Cl (8); R 1 = NH 2 ,

Figure 00000002
,
Figure 00000002
,

R3=H, R4=Cl (9); R1=NH2, R3=Cl, R2=R4=H (10); R1=NH2, R 3 = H, R 4 = Cl (9); R 1 = NH 2 , R 3 = Cl, R 2 = R 4 = H (10); R 1 = NH 2 ,

Figure 00000003
,
Figure 00000003
,

R2=R4=H (11); R1=NH2, R2=H, R3=Cl, R4=Cl (12); R1=NH2, R2=H, R 2 = R 4 = H (11); R 1 = NH 2 , R 2 = H, R 3 = Cl, R 4 = Cl (12); R 1 = NH 2 , R 2 = H,

Figure 00000003
,
Figure 00000003
,

R4=Cl (13), которые могут быть использованы в качестве полупродуктов в синтезе лекарственных препаратов (Pei Y., Lilly M., Owen D., D'Sousa L., Tang X., Yu J., Nazarbaghi R., Hunter A., Anderson C., Glasco S., Ede N., James I., Maitra U., Chandrasekaran S., Moos W., Ghoush S.S. // J. Org. Chem., 2003, 68, №1, p.92) и красителей (Пат. 5026634. США, 1991, Michio Ono, Hiroyuki Hirai, Nobutaka Onki, Kouichi Hanaki, Koki Nakamura).R 4 = Cl (13), which can be used as intermediates in the synthesis of drugs (Pei Y., Lilly M., Owen D., D'Sousa L., Tang X., Yu J., Nazarbaghi R., Hunter A., Anderson C., Glasco S., Ede N., James I., Maitra U., Chandrasekaran S., Moos W., Ghoush SS // J. Org. Chem., 2003, 68, No. 1, p. 92) and dyes (Pat. 5026634. USA, 1991, Michio Ono, Hiroyuki Hirai, Nobutaka Onki, Kouichi Hanaki, Koki Nakamura).

К заявляемым соединениям относятся:The claimed compounds include:

4-амино-4'-хлорбензгидрол (1):4-amino-4'-chlorobenzhydrol (1):

Figure 00000004
Figure 00000004

4-амино-4'-бромбензгидрол (2):4-amino-4'-bromobenzhydrol (2):

Figure 00000005
Figure 00000005

4-амино-4'-метоксибензгидрол (3):4-amino-4'-methoxybenzhydrol (3):

Figure 00000006
Figure 00000006

4-амино-2-хлорбензгидрол (4):4-amino-2-chlorobenzhydrol (4):

Figure 00000007
Figure 00000007

4-амино-2,4'-дихлорбензгидрол (5):4-amino-2,4'-dichlorobenzhydrol (5):

Figure 00000008
Figure 00000008

3-амино-4-хлорбензгидрол (6):3-amino-4-chlorobenzhydrol (6):

Figure 00000009
,
Figure 00000009
,

3-амино-4-морфолинобензгидрол (7):3-amino-4-morpholinobenzhydrol (7):

Figure 00000010
Figure 00000010

3-амино-4,4'-дихлорбензгидрол (8):3-amino-4,4'-dichlorobenzhydrol (8):

Figure 00000011
Figure 00000011

3-амино-4-морфолино-4'-хлорбензгидрол (9):3-amino-4-morpholino-4'-chlorobenzhydrol (9):

Figure 00000012
Figure 00000012

5-амино-2-хлорбензгидрол (10):5-amino-2-chlorobenzhydrol (10):

Figure 00000013
Figure 00000013

5-амино-2-морфолинобензгидрол (11):5-amino-2-morpholinobenzhydrol (11):

Figure 00000014
Figure 00000014

5-амино-2,4'-дихлорбензгидрол (12):5-amino-2,4'-dichlorobenzhydrol (12):

Figure 00000015
Figure 00000015

5-амино-2-морфолино-4'-хлорбензгидрол (13):5-amino-2-morpholino-4'-chlorobenzhydrol (13):

Figure 00000016
Figure 00000016

Известен способ получения 2,5-диметокси-3'-аминобензгидрола, основанный на одностадийном восстановлении нитро- и карбонильной групп соответствующего бензофенона, заключающийся в каталитическом гидрировании субстрата при использовании в качестве катализатора 10% Pd/C. Процесс проводят при давлении водорода 100 кг/см2, в этиловом спирте, при температуре 130°С, в течение 8 ч. Выход продукта составляет 53%. (Пат. 5026634. США, 1991, Michio Ono, Hiroyuki Hirai, Nobutaka Onki, Kouichi Hanaki, Koki Nakamura).A known method for producing 2,5-dimethoxy-3'-aminobenzhydrol, based on a one-step reduction of the nitro and carbonyl groups of the corresponding benzophenone, which consists in the catalytic hydrogenation of the substrate using 10% Pd / C as a catalyst. The process is carried out at a hydrogen pressure of 100 kg / cm 2 , in ethyl alcohol, at a temperature of 130 ° C, for 8 hours. The product yield is 53%. (Pat. 5026634. United States, 1991, Michio Ono, Hiroyuki Hirai, Nobutaka Onki, Kouichi Hanaki, Koki Nakamura).

Figure 00000017
Figure 00000017

Недостатками известного способа синтеза замещенных аминобензгидролов является использование дорогостоящего палладия, высокие температура и давление, длительность процесса, а также низкий выход целевого соединения.The disadvantages of the known method for the synthesis of substituted aminobenzhydrols are the use of expensive palladium, high temperature and pressure, the duration of the process, as well as the low yield of the target compound.

Цель изобретения - снижение стоимости синтеза, сокращение времени и температуры проведения процесса, повышение выходов целевых продуктов.The purpose of the invention is to reduce the cost of synthesis, reduce the time and temperature of the process, increase the yields of target products.

Поставленная цель достигается тем, что в качестве восстанавливающего агента используется более дешевая система реагентов цинк - тетрагидридоборат натрия, процесс проводят при атмосферном давлении, температуре 60°С в течение 2 часов и мольном соотношении субстрат: цинк: тетрагидридоборат натрия, равном 1:3.5:0.25, что позволяет снизить температуру реакции с 130°С до 60°С и сократить время процесса с 8 ч до 2 ч, при этом выходы целевых соединений составляют 94.8-98.5%.This goal is achieved by the fact that as a reducing agent, a cheaper system of reagents zinc - sodium tetrahydride borate is used, the process is carried out at atmospheric pressure, a temperature of 60 ° C for 2 hours and a molar ratio of substrate: zinc: sodium tetrahydride borate equal to 1: 3.5: 0.25 that allows you to reduce the reaction temperature from 130 ° C to 60 ° C and reduce the process time from 8 hours to 2 hours, while the yields of target compounds are 94.8-98.5%.

Строение и чистоту целевых аминобензгидролов анализировали методом ПМР, масс-спектроскопии, определением температуры плавления и элементного состава.The structure and purity of the target aminobenzhydrols were analyzed by PMR, mass spectroscopy, determination of the melting temperature and elemental composition.

Изобретение иллюстрируется следующими примерами.The invention is illustrated by the following examples.

Пример 1. 4-амино-4'-хлорбензгидрол (1)Example 1. 4-amino-4'-chlorobenzhydrol (1)

К взвеси 1 г (1 моль) 4-нитро-4'-хлорбензофенона в 20 мл этилового спирта при температуре 20°С вносят 0.86 г (3.5 моль) Zn и 0.03 г (0.25 моль) NaBH4, и ведут процесс в течение 2 ч при температуре 60°С. Отфильтровывают реакционную смесь от окиси Zn и обрабатывают фильтрат раствором НСl концентрацией 0.1 моль/л до pH=7. Выпавший осадок отфильтровывают и промывают 10 мл этилового спирта. Получают 0.86 г (97% от теории) 4-амино-4'-хлорбензгидрола - белый порошок, т.пл. 108-110°С.To a suspension of 1 g (1 mol) of 4-nitro-4'-chlorobenzophenone in 20 ml of ethyl alcohol at a temperature of 20 ° C add 0.86 g (3.5 mol) of Zn and 0.03 g (0.25 mol) of NaBH 4 , and carry out the process for 2 h at a temperature of 60 ° C. Filter the reaction mixture from Zn oxide and treat the filtrate with a HCl solution of 0.1 mol / L concentration to pH = 7. The precipitate formed is filtered off and washed with 10 ml of ethyl alcohol. Obtain 0.86 g (97% of theory) of 4-amino-4'-chlorobenzhydrol - white powder, so pl. 108-110 ° C.

Найдено, %: C 66.84; H 5.14; N 6.02Found,%: C 66.84; H 5.14; N 6.02

Вычислено, %: C 66.81; H 5.17; N 5.99Calculated,%: C 66.81; H 5.17; N 5.99

1Н ПМР (DMSO-d6) δ, мд: 7.51 (d, 2H, H3', H5', J=9.0), 7.30 (d, 2H, H2', H6', J=7.0), 6.96 (d, 2H, H2, H6, J=8.0), 6.52 (d, 2H, H3, H5, J=7.0), 5.65 (m, 1H, CH), 5.49 (m, 1H, OH), 5.05 (s, 2H, NH2). 1 H PMR (DMSO-d6) δ, ppm: 7.51 (d, 2H, H 3 ' , H 5' , J = 9.0), 7.30 (d, 2H, H 2 ' , H 6' , J = 7.0), 6.96 (d, 2H, H 2 , H 6 , J = 8.0), 6.52 (d, 2H, H 3 , H 5 , J = 7.0), 5.65 (m, 1H, CH), 5.49 (m, 1H, OH ), 5.05 (s, 2H, NH 2 ).

Примеры 2-13. Замещенные аминобензгидролы получают аналогично примеру 1.Examples 2-13. Substituted aminobenzhydrols are obtained analogously to example 1.

Физико-химические характеристики аминобензгидролов приведены в таблицах 1 и 2.Physico-chemical characteristics of aminobenzhydrols are given in tables 1 and 2.

Figure 00000018
Figure 00000018

Figure 00000019
Figure 00000019

Claims (1)

Способ получения замещенных аминобензгидролов общей формулы
Figure 00000020

где R1=R3=H, R2=NH2, R4=Cl (1); R1=R3=H, R2=NH2, R4=Br (2); R1=R3=H, R2=NH2, R4=OCH3 (3); R1=R4=H, R2=NH2, R3=Cl (4); R1=H, R2=NH2, R3=Cl, R4=Cl (5); R1=NH2, R2=Cl, R3=R4=H (6); R1=NH2,
Figure 00000021

R3=R4=H (7); R1=NH2, R2=Cl, R3=H, R4=Cl (8); R1=NH2,
Figure 00000022

R3=H, R4=Cl (9); R1=NH2, R3=Н, R2=R4=H (10); R1=NH2,
Figure 00000023

R2=R4=H (11); R1=NH2, R2=H, R3=Cl, R4=Cl (12); R1=NH2, R2=H,
Figure 00000024

R4=Cl (13), заключающийся в одновременном восстановлении нитро- и карбонильной групп соответствующих нитробензофенонов общей формулы
Figure 00000025

где R1=R3=H, R2=NО2, R4=Cl; R1=R3=H, R2=NО2, R4=Br; R1=R3=H, R2=NО2, R4=OCH3; R1=R4=H, R2=NО2, R3=Cl; R1=H, R2=NО2, R3=Cl, R4=Cl; R1=NО2, R2=Cl, R3=R4=H; R1=NО2,
Figure 00000026

R3=R4=H; R1=NО2, R2=Cl, R3=H, R4=Cl; R1=NО2,
Figure 00000027

R3=H, R4=Cl; R1=NО2, R3=Н, R2=R4=H; R1=NО2,
Figure 00000028

R2=R4=H; R1=NО2, R2=H, R3=Cl, R4=Cl; R1=NО2, R2=H,
Figure 00000029

R4=Cl, восстанавливающей системой Zn-NaBH4 в спирте при мольном соотношении субстрат:цинк:тетрагидридоборат натрия, равном 1:3.5:0.25. The method of obtaining substituted aminobenzhydrols of the General formula
Figure 00000020

where R 1 = R 3 = H, R 2 = NH 2 , R 4 = Cl (1); R 1 = R 3 = H, R 2 = NH 2 , R 4 = Br (2); R 1 = R 3 = H, R 2 = NH 2 , R 4 = OCH 3 (3); R 1 = R 4 = H, R 2 = NH 2 , R 3 = Cl (4); R 1 = H, R 2 = NH 2 , R 3 = Cl, R 4 = Cl (5); R 1 = NH 2 , R 2 = Cl, R 3 = R 4 = H (6); R 1 = NH 2 ,
Figure 00000021

R 3 = R 4 = H (7); R 1 = NH 2 , R 2 = Cl, R 3 = H, R 4 = Cl (8); R 1 = NH 2 ,
Figure 00000022

R 3 = H, R 4 = Cl (9); R 1 = NH 2 , R 3 = H, R 2 = R 4 = H (10); R 1 = NH 2 ,
Figure 00000023

R 2 = R 4 = H (11); R 1 = NH 2 , R 2 = H, R 3 = Cl, R 4 = Cl (12); R 1 = NH 2 , R 2 = H,
Figure 00000024

R 4 = Cl (13), which consists in the simultaneous reduction of the nitro and carbonyl groups of the corresponding nitrobenzophenones of the general formula
Figure 00000025

where R 1 = R 3 = H, R 2 = NO 2 , R 4 = Cl; R 1 = R 3 = H, R 2 = NO 2 , R 4 = Br; R 1 = R 3 = H, R 2 = NO 2 , R 4 = OCH 3 ; R 1 = R 4 = H, R 2 = NO 2 , R 3 = Cl; R 1 = H, R 2 = NO 2 , R 3 = Cl, R 4 = Cl; R 1 = NO 2 , R 2 = Cl, R 3 = R 4 = H; R 1 = NO 2 ,
Figure 00000026

R 3 = R 4 = H; R 1 = NO 2 , R 2 = Cl, R 3 = H, R 4 = Cl; R 1 = NO 2 ,
Figure 00000027

R 3 = H, R 4 = Cl; R 1 = NO 2 , R 3 = H, R 2 = R 4 = H; R 1 = NO 2 ,
Figure 00000028

R 2 = R 4 = H; R 1 = NO 2 , R 2 = H, R 3 = Cl, R 4 = Cl; R 1 = NO 2 , R 2 = H,
Figure 00000029

R 4 = Cl, a reducing system of Zn-NaBH 4 in alcohol at a molar ratio of substrate: zinc: sodium tetrahydride borate equal to 1: 3.5: 0.25.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1003907A (en) * 1961-04-04 1965-09-08 Dieter Goerrig Reduction process
SU596159A3 (en) * 1973-08-15 1978-02-28 Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие) Method of preparing a-ethylbenzhydrol derivatives or salts thereof
US5026634A (en) * 1988-07-21 1991-06-25 Fuji Photo Film Co., Ltd. Color light-sensitive material

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1003907A (en) * 1961-04-04 1965-09-08 Dieter Goerrig Reduction process
SU596159A3 (en) * 1973-08-15 1978-02-28 Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие) Method of preparing a-ethylbenzhydrol derivatives or salts thereof
US5026634A (en) * 1988-07-21 1991-06-25 Fuji Photo Film Co., Ltd. Color light-sensitive material

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