WO1994027985A1 - Process for the preparation of substituted 3-halomethyl-benzothiophenes, benzofurans and -indoles and intermediates thereof - Google Patents
Process for the preparation of substituted 3-halomethyl-benzothiophenes, benzofurans and -indoles and intermediates thereof Download PDFInfo
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- WO1994027985A1 WO1994027985A1 PCT/US1994/005929 US9405929W WO9427985A1 WO 1994027985 A1 WO1994027985 A1 WO 1994027985A1 US 9405929 W US9405929 W US 9405929W WO 9427985 A1 WO9427985 A1 WO 9427985A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Definitions
- 4,959,360, 4,963,547, 4,978,660, and 5,006,521 may be prepared from C 1-2 alkyl
- this invention is a process for preparing compounds of formula (I):
- X 1 , X 2 , and X 3 independently are any accessible combination of H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR2, CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SC 1-4 alkyl, S(CH 2 ) 0-6 phenyl or SCF 3 ;
- Y is Br or Cl
- A is S, O, or NH
- each R 2 independently is C 1-6 alkyl or (CH 2 ) 0-6 phenyl;
- each R 3 independently is H, C 1-6 alkyl, COR 2 , or SO 2 R 2 ;
- R 4 is H or C 1-6 alkyl
- R 5 is C 1-6 alkyl,C 3-5 alkenyl, or (CH 2 ) 0-6 Phenyl; which comprises reacting a compound of the formula (II):
- X 1 , X 2 , X 3 , A and R 1 are as defined above for formula (I),
- a feature of this invention is novel intermediate compounds of the formula (VI):
- X 1 is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 2 , CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SC 1-4 alkyl, S(CH 2 ) 0-6 phenyl or SCF 3 ;
- Y is Br or Cl
- A is S, O, or NH.
- the present invention discloses useful intermediates and a process for the preparation of compounds of formula (I):
- X 1 , X 2 , and X 3 independently are any accessible combination of H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 2 , CO 2 R 2 , CONR 2 R 2 CN, NO 2 , NR 3 R 4 , OR 3 ,
- SC 1-4 alkyl S(CH 2 ) 0-6 phenyl or SCF 3 ;
- Y is Br or Cl
- A is S, O, or NH
- each R 2 independently is C 1-6 alkyl or (CH 2 ) 0-6 phenyl;
- each R 3 independently is H, C 1-6 alkyl, COR 2 , or SO 2 R 2 ;
- R 4 is H or C 1-6 alkyl; and R 5 is C 1-6 alkyl,C 3-5 alkenyl, or (CH 2 ) 0-6 phenyl; which comprises reacting a compound of the formula (II):
- X 1 , X 2 , X 3 , A and R 1 are as defined above for formula (I), with a halomethylating agent, in the presence of a phase-transfer catalyst.
- alkyl and alkenyl mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term.
- the process can be used to prepare compounds according to formula (III):
- A, Y and R 1 are as defined above for formula (I);
- X 1 is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 2 , CO 2 R 2 , CONR 2 R 2 , CN,
- a and R 1 are as defined in formula (I);
- X 2 is defined in formula (III).
- the process can be used to prepare compounds of formula (III) in which X 1 is Cl, Br, F, or I, A is S or O, and R 1 is C 1-6 alkyl.
- the process can be used to prepare formula (III) compounds in which X 1 is Cl, A is S, R 1 ethyl and Y is Br, which is 2-ethyl-3-bromomethyl-5-chlorobenzo[b]thiophene.
- the reaction is carried out on compounds of formula (II) in which X 1 , X 2 , X 3 , A and R 1 are as required in the formula (I) product.
- the process is conducted with formula (IN) compounds.
- phase-transfer catalyst used in the present invention is a quaternary salt of the formula (N): (R') 4 M + U- (V) wherein:
- M is nitrogen, arsenic, phosphorous, antimony, or bisbuth
- each R' independently is C 1-25 alkyl, with the total carbon content of (R') 4 being greater than 16 carbon atoms, but not greater than 50 carbon atoms.
- M is a pentavalent ion
- R 1 is an organic portion of the salt molecule bonded to M by four covalent linkages
- U- is an anion.
- the preferred halide quaternary salts are those wherein M is nitrogen and U is Cl or Br.
- Suitable quaternary salts are cetyltrimethylammonium bromide, myristyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetyldimethylethylammonium bromide, cetyltrihexylammonium bromide, trioctylethylammonium bromide, tridecylmethylammonium chloride,
- the preferred quaternary salts are cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
- the halomethylating agent used in the present invention is generated from formaldehyde, or an equivalent thereof, and aqueous hydrobromic or hydrochloric acid.
- the halomethylating agent is generated from formaldehyde, formalin or 1, 3, 5-trioxane, preferably 1, 3, 5-trioxane, and 48% hydrobromic acid in glacial acetic acid.
- the process is carried out by reacting a 2-substituted- benzo[b]thiophene, -benzo[b]furan, or -indole, preferably 2-ethyl-5-chlorobenzo[b]thiophene, with a halomethylating agent, preferably generated from 1, 3, 5-trioxane and 48% hydrobromic acid in glacial acetic acid, in the presence of a phase-transfer catalyst, such as a quaternary salt, preferably
- cetyltrimethylammonium bromide or myristyltrimethylammonium bromide are examples of cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
- novel intermediates of formula (VI) are prepared by reacting a
- a phase-transfer catalyst for example cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
- the formula (II) and (IV) compounds are prepared from the appropriately substituted phenol, thiophenol or aniline starting materials, such as 4-chlorothiophenol, in a reaction with ⁇ -bromobutyraldehyde diethyl acetal, followed by acid-catalyzed cyclization.
- the flask was then allowed to warm to room temperature, and sodium iodide (67.6 g, 0.451 mol) and ⁇ -bromobutyraldehyde diethyl acetal (1015.33 g, 4.51 mol) were added bulkwise over 15 min.
- the reaction was heated to reflux for 18 hr. and then checked by GC [120°(1)/15° min/275° (5); DB-1, 15 meter column] for the disappearance of the starting materials.
- the reaction was allowed to heat under reflux 2 hr. more and then allowed to cool to room temperature.
- the reaction solution was partitioned between ethyl acetate and water (3.0 L each).
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Abstract
This invention relates to novel intermediates and processes for preparing useful intermediates of formula (I) which are useful in the synthesis of pharmaceutically active agents.
Description
Process for the preparation of substituted 3-halomethyl-benzothiophenes, benzofurans and -indoles and intermediates thereof.
Field of the Invention This invention relates to novel intermediates and processes for preparing
useful intermediates in the synthesis of pharmaceutically active agents.
Background of the Invention 3-Halomethyl-benzo[b]thiophenes, -benzo[b]furans, and -indoles are useful intermediates for preparing pharmaceutically active compounds. For example,
certain α-adrenoceptor blocking 3,4,5,6-tetrahydrothieno[4,3,2-ef][3]benzazepines and 3,4,5,6-tetrahydrofuro [4,3,2-ef][3]benzazepines disclosed in U.S. Patent Nos.
4,959,360, 4,963,547, 4,978,660, and 5,006,521 may be prepared from C1-2alkyl
3-bromomethylbenzo[b]thiophene-2-carboxylates and C1-2alkyl 3- bromomethylbenzo[b]furan-2-carboxylates, respectively. These intermediates are prepared by methyl bromination of the corresponding C1-2alkyl 3- methylbenzo[b]thiopene-2-carboxylates or the corresponding C1-2alkyl 3- methylbenzo[b]furan-2-carboxylates. Surprisingly, it has been found that 2- substituted-benzo[b]thiophenes, -benzo[b]furans, and -indoles can be
halomethylated directly in the 3-position. The efficiency of the process and the
quality and yields of the intermediates are particularly important when preparing compounds on a large scale for therapeutic use. Summary of the Invention
It is an object of this invention to provide a new and efficient process for the preparation of compounds of formula (I). Accordingly, this invention is a process for preparing compounds of formula (I):
X1, X2, and X3 independently are any accessible combination of H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2, CN, NO2, NR3R4, OR3, SC1-4alkyl, S(CH2)0-6phenyl or SCF3;
Y is Br or Cl;
A is S, O, or NH;
R1 is C1-6alkyl, Cl, Br, F, I, CF3, (CH2)0-6phenyl,COR2, CO2R2, CN, NO2, CONR2R2, -CH=CHCO2R2, or SR5;
each R2 independently is C1-6alkyl or (CH2)0-6phenyl;
each R3 independently is H, C1-6alkyl, COR2, or SO2R2;
R4 is H or C1-6alkyl; and
R5 is C1-6alkyl,C3-5alkenyl, or (CH2)0-6Phenyl; which comprises reacting a compound of the formula (II):
wherein:
X1, X2, X3, A and R1 are as defined above for formula (I),
with a halomethylating agent, in the presence of a phase-transfer catalyst.
A feature of this invention is novel intermediate compounds of the formula (VI):
wherein:
X1 is H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2, CN, NO2, NR3R4, OR3, SC1-4alkyl, S(CH2)0-6phenyl or SCF3;
Y is Br or Cl; and
A is S, O, or NH.
Detailed Description of the Invention
The present invention discloses useful intermediates and a process for the preparation of compounds of formula (I):
wherein:
X1, X2, and X3 independently are any accessible combination of H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2 CN, NO2, NR3R4, OR3,
SC1-4alkyl, S(CH2)0-6phenyl or SCF3;
Y is Br or Cl;
A is S, O, or NH;
R1 is C1-6alkyl, Cl, Br, F, I, CF3, (CH2)0-6Phenyl,COR2, CO2R2, CN, NO2, CONR2R2, -CH=CHCO2R2, or SR5;
each R2 independently is C1-6alkyl or (CH2)0-6phenyl;
each R3 independently is H, C1-6alkyl, COR2, or SO2R2;
R4 is H or C1-6alkyl; and
R5 is C1-6alkyl,C3-5alkenyl, or (CH2)0-6phenyl; which comprises reacting a compound of the formula (II):
wherein:
X1, X2, X3, A and R1 are as defined above for formula (I), with a halomethylating agent, in the presence of a phase-transfer catalyst.
It should be noted that, as used herein, the terms alkyl and alkenyl mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term.
Preferably, the process can be used to prepare compounds according to formula (III):
A, Y and R1 are as defined above for formula (I); and
X1 is H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2, CN,
NO2, NR3R4, OR3, SC1-6alkyl, S(CH2)0-6phenyl or SCF3;
which comprises reacting a compound of the formula (IV):
wherein:
A and R1 are as defined in formula (I); and
X2 is defined in formula (III).
with a halomethylating agent, in the presence of a phase-transfer catalyst.
In particular, the process can be used to prepare compounds of formula (III) in which X1 is Cl, Br, F, or I, A is S or O, and R1 is C1-6alkyl. Most particularly, the process can be used to prepare formula (III) compounds in which X1 is Cl, A is S, R1 ethyl and Y is Br, which is 2-ethyl-3-bromomethyl-5-chlorobenzo[b]thiophene.
Suitably, the reaction is carried out on compounds of formula (II) in which X 1, X2, X3, A and R1 are as required in the formula (I) product. Preferably, the process is conducted with formula (IN) compounds.
The phase-transfer catalyst used in the present invention is a quaternary salt of the formula (N): (R')4M+U- (V) wherein:
M is nitrogen, arsenic, phosphorous, antimony, or bisbuth;
U is Cl, Br, F, or I: and
each R' independently is C1-25alkyl, with the total carbon content of (R')4 being greater than 16 carbon atoms, but not greater than 50 carbon atoms.
In formula (V) compounds, M is a pentavalent ion, R1 is an organic portion of the salt molecule bonded to M by four covalent linkages, and U- is an anion. The preferred halide quaternary salts are those wherein M is nitrogen and U is Cl or Br.
Examples of suitable quaternary salts are cetyltrimethylammonium bromide, myristyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetyldimethylethylammonium bromide, cetyltrihexylammonium bromide,
trioctylethylammonium bromide, tridecylmethylammonium chloride,
didoceyldimethylammonium chloride, or dioctadecyldimethylammonium chloride.
The preferred quaternary salts are cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
The halomethylating agent used in the present invention is generated from formaldehyde, or an equivalent thereof, and aqueous hydrobromic or hydrochloric acid. Suitably, the halomethylating agent is generated from formaldehyde, formalin or 1, 3, 5-trioxane, preferably 1, 3, 5-trioxane, and 48% hydrobromic acid in glacial acetic acid.
Suitably, the process is carried out by reacting a 2-substituted- benzo[b]thiophene, -benzo[b]furan, or -indole, preferably 2-ethyl-5-chlorobenzo[b]thiophene, with a halomethylating agent, preferably generated from 1, 3, 5-trioxane and 48% hydrobromic acid in glacial acetic acid, in the presence of a phase-transfer catalyst, such as a quaternary salt, preferably
cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
The novel intermediates of formula (VI) are prepared by reacting a
2-C1-6alkyl-benzo[b]thiophene, -benzo[b]furan, or -indole, such as 2-ethyl-5-chlorobenzo[b]thiophene, with a halomethylating agent generated from aqueous hydrobromic or hydrochloric acid, preferably 48% hydrobromic acid, and 1,3,5-trioxane, in glacial acetic acid, in the presence of a phase-transfer catalyst, for example cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
The formula (II) and (IV) compounds are prepared from the appropriately substituted phenol, thiophenol or aniline starting materials, such as 4-chlorothiophenol, in a reaction with α-bromobutyraldehyde diethyl acetal, followed by acid-catalyzed cyclization.
The invention is illustrated by the following example. The example is not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelow.
EXAMPLE 1
Preparation of 2-Ethyl-3-bromomethylbenzo[b]thiophene i). α-Bromobutyraldehyde diethylacetal
[Ref. H. Esterbauer and W. Wager, Monatsh. Chem. 98 (5) 1884-91 (1967)]
In a 5 L, 3-necked flask with a mechanical stirrer attached was dissolved
442.25 g (6.13 mol) of butyraldehyde in 375 mL of chloroform. The solution was cooled to -30°C by an acetonitrile/dry ice bath. To this solution was added 800 g
(5.0 mol) of bromine in 500 mL of chloroform, and the solution was allowed to stir at -30°C for 6 hr. and then allowed to warm to room temperature overnight. The resulting orange solution was cooled to -10°C, and 1.0 L of absolute ethanol was added slowly at -10°C. The flask was allowed to warm after ethanol addition to room temperature and stirred for 24 hr. The reaction was then quenched by pouring it into a separatory funnel containing an aqueous solution of 5 moles of sodium acetate. The aqueous layer was basified with solid sodium carbonate to pH 8-9 and extracted with chloroform. The organic solution was dried over magnesium sulfate, then concentrated, and finally fractionally distilled twice with an 18" Nigreux column to yield 428.8 g (2.02 mol, 40.4% yield) of product: [bp ~88°C (10 mm)]. ii). 2-(4-Chlorophenylthio)butyraldehyde diethyl acetal
In a 12 L, 3-necked flask with a mechanical stirrer, thermometer, and reflux condenser attached, was added 3.15 L of ethanol. Sodium metal (103.73 g, 4.51 mol) was added carefully to the ice-water cooled flask, and the reaction temperature was kept below 45°C throughout the addition. 4-Chlorothiophenol (652.22 g, 4.51 mol) was added neat, and the solution was heated to reflux (88°C) for 2 hrs. The flask was then allowed to warm to room temperature, and sodium iodide (67.6 g, 0.451 mol) and α-bromobutyraldehyde diethyl acetal (1015.33 g, 4.51 mol) were added bulkwise over 15 min. The reaction was heated to reflux for 18 hr. and then checked by GC [120°(1)/15° min/275° (5); DB-1, 15 meter column] for the disappearance of the starting materials. The reaction was allowed to heat under reflux 2 hr. more and then allowed to cool to room temperature. The reaction solution was partitioned between ethyl acetate and water (3.0 L each).
The organic layer was washed with 2.4 L of water and 1.5 L of brine, then dried over magnesium sulfate. The solvent was removed under vacuum to yield 1114.7 g of crude material that could not be distilled. However, a previous 5 L run yielded distillable material: bp 112°C (0.05 torr); oil bath 150°C. GC analysis of both runs were comparable so the material obtained in this latter run was used directly after removal of all volatiles (130°C/10 mm). iii). 2-Ethylbenzo[b]thiophene
In a 12 L, round-bottomed, 3-necked flask under nitrogen flow, equipped with a mechanical stirrer, reflux condenser, and thermometer, was added 4 kg of PPA, and the suspension was heated to 90-95°C. The thioacetal prepared above (1114.7 g, 4.27 mol) was added dropwise over a 5 minute period. Then the
suspension (very dark) was heated to reflux for 1 hr (~135°C) and checked by GC to show primarily the desired product. The heat was removed, and the solution was allowed to cool to 80°C. At this point, 3.5 L of water was carefully added with stirring. The organic layer was separated, and the aqueous layer was extracted with toluene. The organic extracts were combined and washed with 3.5 L of 5% sodium bicarbonate solution, 3.5 L of water and 2 L of brine. The organic solution was dried (magnesium sulfate) then concentrated to yield after distillation: (bp 95-105°C/0.5 mm); 562.2 g (2.858 mol, 67% yield) of product. iv). 2-Ethyl-3-bromomethylbenzo[b]thiophene
In a 12 L, round-bottomed, 3-necked flask equipped with a mechanical stirrer under nitrogen flow, was added 2.25 L of 48% hydrobromic acid and 0.26 L of acetic acid. The 5-Chlorobenzo[b]thiophene (534.0 g, 2.715 mol) was dissolved in 0.26 L of acetic acid and was added to the 12 L reaction flask bulkwise. To this suspension was added bulkwise 1,3,5-trioxane (437.5 g, 4.86 mol) and
myristyltrimethylammonium bromide. The suspension was allowed to stir 36 hours after which time TLC (100% hexanes) showed predominantly the desired product with very little of the starting material remaining. Water (2 L) was added and the suspension was filtered and washed with water to yield 750.4 gm of solid product after vacuum drying (2.58 mol, 95% yield); mp 97-99°C (crude); recrystallized mp 103-105°C.
Claims
1. A process for preparing a compound of the formula (I):
wherein:
X1, X2, and X3 independently are any accessible combination of H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2, CN, NO2, NR3R4 OR3, SC1-4alkyl, S(CH2)0-6phenyl or SCF3;
Y is Br or Cl;
A is S, O, or NH;
R1 is C1-6alkyl, Cl, Br, F, I, CF3, (CH2)0-6Phenyl,COR2, CO2R2, CN, NO2, CONR2R2, -CH=CHCO2R2, or SR6;
exach R2 independently is C1-6alkyl or (CH2)0-6Phenyl;
each R3 independently is H, C1 -6alkyl, COR2, or SO2R2;
R4 is H or C1-6alkyl; and
R5 is C1-6alkyl, C3-5alkenyl, or (CR2)0-6phenyl; which comprises reacting a compound of the formula (II):
wherein:
X1, X2, X3, A and R1 are as defined above for formula (I),
with a halomethylating agent, in the presence of a phase-transfer catalyst.
2. The process according to claim 1 for preparing a compound of the formula (III):
wherein:
A, Y and R I are as defined above for formula (I); and
X1 is H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2, CN,
NO2, NR3R4, OR3, S C1-6alkyl, S(CH2)0-6Phenyl or SCF3; which comprises reacting a compound of the formula (IV):
% v
wherein:
A and R1 are as defined in formula (I); and
X1 is as defined in formula (III),
with a halomethylating agent, in the presence of a phase-transfer catalyst.
3. The process according to claim 2 in which:
X1 is Cl, Br, F, or I;
A is S or O; and
R1 is C1-6alkyl.
4. The process according to claim 3 in which X1 is Cl, A is S, and R1 is ethyl.
5. The process according to claim 2 in which the phase-transfer catalyst is a quaternary salt of the formula (V):
(R')4M+U- (V) wherein:
M is nitrogen, arsenic, phosphorous, antimony, or bisbuth;
U is Cl, Br, F, or I: and
each R' independently is C1-25alkyl, with the total carbon content of (R')4 being greater than 16 carbon atoms, but not greater than 50 carbon atoms.
6. The process according to claim 5 wherein M is nitrogen and U is Cl or Br.
7. The process according to claim 6 wherein the quaternary salt is cetyltrimethylammonium bromide, myristyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetyldimethylethylammonium bromide, cetyltrihexylammonium bromide, trioctylethylammonium bromide,
tridecylmethylammonium chloride, didoceyldimethylammonium chloride, or dioctadecyldimethylammonium chloride.
8. The process according to claim 7 wherein the quaternary salt is cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
9. The process according to claim 2 wherein the halomethylating agent is generated from 1,3,5-trioxane and 48% hydrobromic acid in glacial acetic acid.
10. The process according to claim 2 wherein the formula (III) compound is 2-ethyl-3-bromomethyl-5-chlorobenzo[b]thiophene.
11. The process according to claim 2 wherein 2-ethyl-5-chlorobenzo[b]thiophene is reacted with 1,3,5-trioxane and 48% hydrobromic acid in glacial acetic acid, in the presence of cetyltrimethylammonium bromide.
12. The process according to claim 2 wherein 2-ethyl-5-chlorobenzo[b]thiophene is reacted with 1,3,5-trioxane and 48% hydrobromic acid in glacial acetic acid, in the presence of myristyltrimethylammonium bromide.
13. A compound of the formula (VI):
wherein:
X1 is H, Cl, Br, F, I, CF3, C1-6alkyl, COR2, CO2R2, CONR2R2, CN, NO2, NR3R4, OR3, SC1-4alkyl, S(CH2)0-6Phenyl or SCF3;
Y is Br or Cl; and
A is S, O, or NH.
14. The compound according to claim 14 in which:
X 1 is Cl, Br, F, or l;
Y is Br, and
A is S or O.
15. The compound according to claim 15 in which X1 is Cl and A is S.
16. The compound according to claim 16 which is 2-ethyl-3-bromomethyl-5-chlorobenzo[b]thiophene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6891493A | 1993-05-28 | 1993-05-28 | |
| US08/068,914 | 1993-05-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994027985A1 true WO1994027985A1 (en) | 1994-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1994/005929 Ceased WO1994027985A1 (en) | 1993-05-28 | 1994-05-26 | Process for the preparation of substituted 3-halomethyl-benzothiophenes, benzofurans and -indoles and intermediates thereof |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1994027985A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0919552A4 (en) * | 1996-07-24 | 1999-09-15 | Teikoku Hormone Mfg Co Ltd | METHOD FOR PRODUCING 2,6-DISUBSTITUTED BENZOTHIOPHENE COMPOUNDS |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2553495A (en) * | 1950-05-04 | 1951-05-15 | Nat Drug Co | N-(3-benzothenyl)-n-ethyl-betachloroethylamine adrenolytic |
| US3331854A (en) * | 1964-12-14 | 1967-07-18 | American Cyanamid Co | Novel furan and thiophene compounds |
| US5196429A (en) * | 1986-12-31 | 1993-03-23 | Hoechst-Roussel Pharmaceuticals Inc. | Method of inhibiting the activity of leukocyte derived cytokines |
-
1994
- 1994-05-26 WO PCT/US1994/005929 patent/WO1994027985A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2553495A (en) * | 1950-05-04 | 1951-05-15 | Nat Drug Co | N-(3-benzothenyl)-n-ethyl-betachloroethylamine adrenolytic |
| US3331854A (en) * | 1964-12-14 | 1967-07-18 | American Cyanamid Co | Novel furan and thiophene compounds |
| US5196429A (en) * | 1986-12-31 | 1993-03-23 | Hoechst-Roussel Pharmaceuticals Inc. | Method of inhibiting the activity of leukocyte derived cytokines |
Non-Patent Citations (10)
| Title |
|---|
| CHEMCIAL ABSTRACTS, Volume 87, issued 1977, ARESCHKA et al., "Studies on the Benzofuran Series", Abstract No. 102105. * |
| CHEMICAL ABSTRACTS, Volume 77, issued 1972, ARESCHKA et al., "Benzofurans. Benzofurarylmethylimidazolines", Abstract No. 164591. * |
| CHEMICAL ABSTRACTS, Volume 77, issued 1972, BINON et al., "2-Ä (2-Alkylbenzofuran)MethylÜ-2-Imidazolones", Abstract No. 140068. * |
| CHEMICAL ABSTRACTS, Volume 80, issued 1973, DESCAMPS et al., "Antihypertensive Acetamidine Derivatives", Abstract No. 96017. * |
| CHEMICAL ABSTRACTS, Volume 80, issued 1973, KHILYA et al., "Synthesis and Properties of Heterocyclic Analogs of Isoflavones", Abstract No. 59825. * |
| CHEMICAL ABSTRACTS, Volume 85, issued 1976, ARESCHKA et al., "New Piperazine Amidines and Related Compounds", Abstract No. 160029. * |
| CHEMICAL ABSTRACTS, Volume 85, issued 1976, WITIAK et al., "Synthesis and Antilipidemic Properties of Cis-7-Chloro-3a,8b-Dihydro.....Benzofuran", Abstract No. 116536. * |
| CHEMICAL ABSTRACTS, Volume 99, issued 1983, CROSS et al., "Thromboxane Synthetase Inhibitors and Pharmaceutical Compositions Comprising Them", Abstract No. 105247. * |
| J. MARCH, "Advanced Organic Chemistry", 4th Edition, Published 1992, by WILEY-INTERSCIENCE (N.Y.), see pages 362-363. * |
| J. MCMURRY, "Organic Chemistry", 2nd Edition, Published 1988, by BROOKS/COLE (CA), see pages 1039-1040. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0919552A4 (en) * | 1996-07-24 | 1999-09-15 | Teikoku Hormone Mfg Co Ltd | METHOD FOR PRODUCING 2,6-DISUBSTITUTED BENZOTHIOPHENE COMPOUNDS |
| US6020531A (en) * | 1996-07-24 | 2000-02-01 | Teikoku Hormone Mfg. Co., Ltd. | Process for the preparation of 2,6-disubstituted benzothiophene compounds |
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