JPS61171479A - Novel benzothiophene and benzofuran - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides
The present invention provides combustible compounds, methods for their combustible synthesis, selected intermediates, medicinal compositions and the use of combustible compounds, especially as anti-allergic agents. Additionally, the compounds of the present invention block the release of mediators, including histamine and leukotrienes, from basophils and mast cells and block respiratory breakdown in neutrophils, resulting in cardiovascular and anti-inflammatory, anti-inflammatory properties. Provides useful activity in habit and anti-migraine therapy. These compounds act as inhibitors of cell activation.

5science Vol. 220, p. 568 (1983), No. 1
0 icotriens: a mediator of immediate hypersensitivity reactions and inflammation”, Trends in Pharma
colOgical 5sciences75 and 77
P, J, Piper's 10 Ikotriens 1 and 01rcu'1ation 67 Vol. 10 in p. C19B5)
See J. L., Romun et al., J., L., Romun et al., 1 Reducing the extent of ischemic myocardial injury due to neutrophil deficiency in dogs, p. 16 (1983).

European Patent Application (xp) 0146243 discloses a series of benzofuran and benzothiophene compounds. However, the benzothiophene of the present invention is Jlip01
46245 and the present invention cannot be prepared by the method disclosed in EPO 146243.

European Patent Application 69.521 discloses benzothiophene derivatives. However, one sinterable compound of the present invention has an IP69,5
It has a different tetrazole and carboxamide substitution than the No. 21 compound. Furthermore, US patent 3
, 452,039 discloses benzothiophene derivatives. However, the substituents of one compound of the invention are not shown.

Furthermore, the anti-inflammatory effect found for the sinterable compound of the present invention is IP 69.5□1.
It is not within the scope of the teachings of benzothiophene compounds disclosed by US Pat. No. 5,452,059.

The present invention relates to compounds of formula 5 (tl) and pharmaceutically acceptable salts thereof.

In the above formula, h (1) * R' * R' and R5 are independently H% alkyl of 1 to 12 carbons, alkoxy of 1 to 12 carbons, hydroxy, aryl, 2 R1
Twice bonded R1 . with each R1 on adjacent carbons such that together are methylenedioxy. Nitro, amino, substituted amino, mercapto, furkylthio of 1 to 4 carbons, alkylsulfinyl of 1 to 4 carbons, alkylsulfonyl of 1 to 411!1 carbons, arylthio.

Arylsulfinyl, arylsulfonyl or halogen, (2) R2 is H, 1-121 carbon alkyl, 1-12 if! ! carbon alkoxy, arylmethoxy, amino, & substituted amino, mercapto,
1-4i- oxygen alkylthio% 1-%-4 carbon alkylsulfinyl, 1 to 4 carbon alkylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl and (+) R1 is A or B Ash (however.

(if R6 is B then R2 must not be H or alkyl of 1 to 12 carbons) and (4) or oxygen or 5(0)q (where q is 0, 1 or 2) It is.

Furthermore, the present invention provides a compound of formula (II) (wherein R1 and R2 are as defined above) to obtain a compound of formula (1) as shown in Scheme 1. )(
The method includes a method for producing a compound of the formula (wherein R1, R4, R5, R2 and R3 are as described above).

Scheme I In addition, the present invention provides a method of formula a in the presence of a coupling agent.
ID or Cm,) (wherein R6 are the same or different carbons and hydrogen, alkyl or protecting group of carbons from 1 to 611m, provided that R6 are not both hydrogen), a compound of the formula ( R5 of formula (1) is a moiety represented by A by treatment with a compound of formula (11
) Compound wt- The scheme consisting of obtaining the method t- includes.

Suitable coupling reagents for the transformation of compounds of scheme ■ or formula (2) or formula <ms are 1,1-carbonylbis(IH-
imidazole), 1. ．． 5-dicyclohexylcarbodiimide, 1-ethoxycarbonyl-2-ethoxy-1,
2-dihydroquinoline (l[)Q) and the like. (NCR' in ①) The two groups are then treated to remove the holding @ group, if necessary.

Compounds of formula (B) are known or can be easily prepared from compounds known in the literature. For example, compounds of formula (2) in which R2 is amino or substituted amino
The compound of James, R.

Beck (J, Org, Ohem, Volume 37, No. 21, 522
4-6 (1972)]. Beck discloses compounds in which X is sulfur and the substituent R2 is 7 mino. Substituted amino groups can be prepared from amino compounds by standard methods. Compounds of formula (flD) in which X is oxygen and R2 is amino or substituted amino are prepared by the round blade method as shown in formula 1 using conditions similar to those known in the literature. be able to.

Diagram 2 ■ In particular, the formula (■su, (III) and (R6) of the diagram ■
Selected compounds with
, Prakt, Ohem, vol. 315, p. 779 (19
), F, A.

Trophy sled etc. (C!hem, Het, oomp, 1
1, p. 1129 (1975)] and S. B. Mahayan and Y. S. Agassimundin (J. Incl. Ch.
Em, 8oc, Vol. 54, p. 965 (1977)]. Scheme ■ indicates the use of an acetyl protecting group. Other known protecting groups can be used as described below.

Compounds (substituted at position 81 of IID (not described by Beck) can be obtained by other known methods.

For example, for compounds of formula (1) where X is oxygen, R2 is alkoxy or arylmethoxy, and R5 is OOOH or A, the preparation of the precursor is shown in Scheme V.

Scheme V (wherein R4 is argyl, arylmethyl of 1 to 12 carbon atoms) (wherein R2 is OR4-) Alkylating reagents suitable for the conversion of (1112) to (1[11) is an alkyl halide, an alkyl sulfonate,
0-alkyl-N, N'-dialkyl isourea and the like. In particular, compounds of formula (R2)% (R1) and (2) where X is oxygen have been described by J. D. Brewer et al.
.

J, Chem, vol. 24, p. 1883 (1971), by I, O, Schroeder J, Org, Oh
em, vol. 27, p. 586 (1962), and V.
, Chew by Auer.

Ber, Vol. 61, p. 408 (1928) K.

Compounds of formula (2) in which R2 is mercapto or alkyl or arylmercapto within the scope of the invention are described in Examples IA-In, 2A-Il! below. or by procedures similar to those shown for producing mercapto-containing compounds in 6A-11i or other known methods. Similarly, the formula (Ig
) can be prepared by known methods suitable for preparing such compounds from mercapto by alkylation or arylation followed by oxidation.

A method of processing a compound of formula (2) to obtain a compound of formula (I) in which R5 is the moiety represented by B is a method known in the art. A similar method was used to prepare a tin salt of the formula (R1 and R
2 is the above-mentioned formula), [for example, Oh
em, Pharm, Bull, Volume 32(7), 1256
0-4 (1984) and also for the compound of formula (■) in which X is oxygen, M. Beck and Shorenick, UK, published May 26, 1971. Patent 1.255268 [J, Ch
R in em, Soc, J 2361 (1965).

Prianto and Tori, L., Haslam's description and rIn
d, J, c! hem, Jl 4B6886 page (1976
S, S, Sangapure and Y, 8. See the description of Agosim/Zin] The compound of formula CM) is then treated in a manner analogous to that described in the aforementioned US Pat. No. 5,452,059. (See Scheme ■) Scheme ■ 1:+5 The antiallergic activity of the compound having the formula (1) of the present invention is described, for example, by N. Zhang et al. The method of making the surzutale of the public or by the hexheimer
'-J, Phyaiol, J (London) Volume 117 2
9 as measured by the in vivo antiallergy test published in 1952.

This anti-allergic activity makes compounds of Formula 91 useful in the treatment of allergic hypersensitivity reactions (AHR) with a wide range of symptoms. For example, the symptoms may include dermatitis, lacrimation, nasal drainage, cough, sneezing, nausea, vomiting, laxatives, difficulty breathing, pain, inflammation and, in severe cases, anaphylactic shock, circulatory shock and even death. . Ah
R is for bronchial asthma, hay fever (e.g. hay fever),
It is found in humans and other animals suffering from allergic rhinitis, allergic rhinitis, allergic conjunctivitis, food allergies, and allergic reactions.

In AHR, antibodies (reagin in humans) react with antigens, impacting the cell membranes of mast cells and causing hypertrophy.
4 induces a reaction within the cell, which ultimately leads to bradykinin, a slow reactant of anaphylaxis (SR8-A)
*Causes the release of mediators (active compounds) such as histamine, serotonin (5HT), possibly some prostaglandins or other unknown substances.

The mediator is released from the mast cell, which then engages the appropriate receptor site (eg, smooth muscle), resulting in the AHR attack pathology. Various methods have been used to alleviate the symptoms of AHR. However, it is not known what mechanism is responsible for the antiallergic use of the compounds having formula (1) of the present invention.

Pharmaceutical compositions of the present invention are prepared using an inert pharmaceutical carrier.
It can be produced from the compound of 1) and its salt.

The composition may be either solid or liquid.

An ordinarily skilled physician or veterinarian can readily determine which patients exhibit AER symptoms. Regardless of the method of administration chosen, the compounds of the invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical arts.

The compounds can be administered in oral unit dosage forms such as tablets, capsules, pills, powders or fists. The compound is also. It can also be administered rectally or vaginally in the form of suppositories or puggies. The compound is also. # Parenterally (subcutaneously) using the forms known in pharmaceutical technology.

It can also be administered (intravenously or intramuscularly). The compound is also. 4 people directly affected by the disease (for example in the form of eye drops or by inhalation). For the treatment of erythematous AHR fatty diseases, the compounds of the present invention can also be administered topically in the form of soft IF, creams, gels, and the like. Generally, the preferred method of administration is oral.

An effective and non-toxic amount of the compound is used in therapy. An ordinarily skilled physician or veterinarian can readily determine and prescribe an effective amount of an anti-AHR agent to prevent or arrest the progression of the disease. In such cases, the physician or veterinarian may initially use a relatively low dose and then increase the dose until the best response is obtained.

The initial dosage of a compound of the invention having formula (1) is usually from 10 g Ig to 2 P per day, preferably from 1 to 2 P per day, orally.
The dosage ranges from 10 to 500 q/dose, given 4 times orally as needed. When using other dosage forms, corresponding dosages are used.

Compounds of the present invention also include sNaOH%KOJ Mg(C
I()2゜0a(OH)2. Administered as pharmaceutically acceptable salts, such as can be readily prepared using inorganic and organic bases such as NH4OH, substituted nine ammonium moieties, L-fulginine, choline, N-methylglucamine, etc. You can also do it.

Compounds having the formula (1) t- are referred to as benzothiophene or benzofuran wfj4 because of the sulfur- or oxygen-containing polycyclic five-membered ring fused to the phenyl ring. The fused ring is 1 as shown in the ring system of formula (1').
The numbers are numbered counterclockwise starting from the sulfur or oxygen atom in position.

Compounds within the range of formula (1) as described above are preferred. Preferred compounds of formula (1) are those in which R6 is substituent A, ie carboxamidonato dizole. Also, preferred compounds are those in which R1 is methoxy, especially in the 5- or 6-position. The most preferred are the following compounds. (1) 5-methoxy-6-(1-methylethoxy)-N-1H-tetrazol-5-yl-penzolothiophene-2-carboxamide, (2N,5-dimethoxy-N-IH-nato2zole-5- Irubenzo (6)
Thio7en-2-carboxamide, (3) -(1-methylethoxy)-N-l
H-tetrazol-5-yl-ninzothio7ene-2-
Carboxamide, (5) 5-methoxy-3-((1-methylethyl)-thio)-N-IH-tetrazole-5-
yl-benzo(t)-thiophene-2-carboxamide and (6) 6-medoxy6-(phenylmethoxy)
-N-IH-nato2zol-5-yl-2-benzofurancarboxamide.

Among the compounds mentioned above, the most suitable compound is (
1), (3) and (5).

Alkyl of 1 to 4 carbons is methyl, ethyl.

°Propyl, butyl or its isomeric forms.

Alkyl of 1 to 12 carbons is methyl, ethyl.

Propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc. and includes isomeric forms of alkyl of 1 to 6 carbons.

Alkyl of 1 to 6 carbons is preferred.

Alkoxy of 1 to 12 carbons is methoxy, ethoxy,
It includes isomeric forms of propoxy, butoxy and alkoxy of 1 to 6 carbons. 1~6114ft
carbon alkoxy is preferred.

Substituted amino is mono- or di-alkylamino (
Alkyl, alone or together, is the same or different alkyl having 1 to 6 carbons).

Halogen is chlorine% fluorine, iodine or trifluoromethyl.

Aryl is substituted with one or two substituents such as phenyl or halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, hydroxy, nitro, amino, substituted 9-amino, etc. It is phenyl.

In general, a compound having formula (1) (wherein R1 and R2 are the same as previously described and R5 is a substituent A) is a compound of formula (10) (wherein R' and R2 are as previously described). ) can be prepared by treating the compound by either of two methods.

The first method, shown below, which is preferred, involves treating compound CB' with 5-aminotetrazole in the presence of a coupling agent and triethylamine. Compound (2) 1
Approximately a 20% excess of 5-aminotetrazole, coupling agent and triethylamine compared to the sample is preferred. The coupling agent is 1,1'-carbonyl (IH-imidazole), dicyclohexylcarbodiimide%1,6
- may include diituprovir carbodiimide and the like. Solvents for the process include one or more of tetrahydrofuran, dimethylformamide, acetonitrile, and the like, with the preferred solvent being acetonitrile. The mixture is refluxed for about 4-24 hours.
The second method, generally shown as the scheme 1, is to prepare the formula (
110 and 5-7 minotetrazole (all in equal amounts).

In general, the coupling reaction shown in Scheme 1 is as follows.

Contains variables known to those skilled in the art.

The above compounds of the formula (1) can be separated and purified by conventional methods or used in crude form.

Under certain circumstances it may be necessary to protect the N or 0 of the intermediates in the above process with known suitable protective groups. The introduction and removal of such appropriate oxygen and nitrogen protecting groups is well known in the art of organic chemistry. For example, (1) "Proteotive Group" by J. F. W. Matsukuomie (New York, 1973).
s in Organic OhemiatryJ46
ft, 95ff pages, (2) Advances in Organic Chemistry, Volume 3, 191
T., F., W. Matsukuomie's description in ~281 pages (1963), (5) Advances in Organic Chemistry, Vol. 5, 159-1.
90 Sada (1965) and the description of R.A. Bolsonas and (4) Chem, &l Ind, 606
See J. F. W. Matsukuomie, P. (1979).

Examples of suitable oxygen-sparing groups include benzyl, t-butyldimethylsilyl, methyl, isopropyl, ethyl, tert-butyl, ethoxyethyl, and the like. Protection of N--H containing moieties is necessary for some of the methods described for the preparation of compounds of the invention. A suitable nitrogen protecting group is benzyl.

Triphenylmethyl, trialkylsilyl, trichloroethyl carbamate, trichloroethoxycarbonyl,
vinyloxy carbamate, etc.

Under some circumstances, two groups may be protected by dissimilar protecting groups, such that one can be selectively removed and the other retained.
It is necessary to protect 11 different oxygens. Benzyl and t-butyldimethylsilyl groups are used in this method. In this case, either one can be removed in the presence of the other. Benzyl is removed by catalytic hydrogenolysis and t-butyldimethylsilyl is removed, e.g.
- removed by reaction with butylammonium fluoride.

In the method described for the preparation of the compounds of the invention,
The need for protecting groups is generally well recognized in the art of organic chemistry, and therefore the use of suitable protecting groups is included in the schematic method, although not explicitly indicated.

The products of the nine reactions described herein are isolated by conventional means such as extraction, distillation, tin salt chromatography, and the like.

O by a suitable intermediate step to convert the mercapto'1-so2-alkyl substituent, a suitable intermediate step to convert the nitrile to a carboxylic acid substituent, or a suitable group as described above.
Variations on the methods described above, including the protection of N-containing substituents, are possible with the present invention.

The salt of the compound of formula (1) described above can be prepared by reacting a suitable base with a chemical equivalent of a basic thiophene or benzofuran compound of formula (1) to form a pharmaceutically acceptable salt thereof. be done.

Compounds of the invention also include. It can exist in hydrated or solvated forms.

The method of the invention is further illustrated by the following representative examples.

Example 1(A) Methyl 4-methoxysalicylate [Glebe and Maltum nn, 340.215 (1909). boiling point 235
~240°C] A mixture of 4-methoxysalicylic acid (Aldrich) (17aIP, 1.06 mmol), sodium bicarbonate C89t, 1.06 mol) and dimethyl sulfate (1316F 11.06 mol) in acetone (2 t) was heated under nitrogen. 20 in
Stir and reflux for an hour. The mixture is cooled, filtered and the acetone removed in vacuo to give an oily residue. This residue was dissolved in ether (1,8t) and toluene (Cl1L501).
)/C take. The extract is washed with sodium bicarbonate solution, water, dried over sodium sulfate and concentrated to give a syrup (19 (L9f)) which is recrystallized from hexane to give an analytically pure solid 172.7F (89, 596), melting point 49-50°C.

Example 1(B) 4-Methoxy-2((:)methylaminocothioquinemethoxy]-benzoic acid methyl ester) (171,7t% 0.94 mole) and 1,4-
diazabicyclo(2,2,2)octane (23599,
To a solution of 2.02 mol) dimethylthiocarbamoyl chloride (25 (1,2,02 mol)) is rapidly added while stirring under nitrogen. The resulting mixture is heated to 1.75 mol at room temperature.
hours, then stirred at 50'' for 18 hours. The mixture was cooled, poured into ice water (~51) and toluene (~51).
, 51) twice. The combined toluene extracts are washed successively with dilute hydrochloric acid, water, cold bicarbonate solution, and water. Dry the extract over sodium sulfate. The solvent was removed under reduced pressure to obtain the crude product, which was recrystallized twice from methanol to give analytically pure product 1q2.6
Obtain tC76) with a melting point of 126-7°C.

Example 1(C) 4-Methoxy-2[(dimethylamino)carbonylnotio]-benzoic acid methyl ester diphenyl ether (1
4-methoxy-2[(dimethylaminocthioxomethoxy]-benzoic acid methyl ester C188 in 1402)
? ) (D solution H under nitrogen atmosphere at 237-255°C for 14
Heat for an hour. After cooling to room temperature, the contents of the flask were poured into hexane (~2.5 t) and incubated at ~1oC for 30
Stir for a minute. The crystalline precipitate that formed was collected and recrystallized from methanol to give 1 sq., 1 sq.
tc74%). Melting point 74-5°C 0 Example 1(D) 4-methoxy-thiosalicylic acid [Leonkat et al.: U.S. Pat. No. 2,767.173 (1956). 0A51 volume 67
046 pages (1957). Melting point 240 @ (produced by diazo with 4-methoxy-anthranilic acid).]]4
-Methoxy2-(:)methylamino)carbonyl)thio]-benzoic acid methyl ester (122,8P1046
A mixture of sodium hydroxide (47.4f, 1.15mol), methanol (940m) and water (470m) is stirred and refluxed under nitrogen for 13 hours. Most of the methanol is removed at 50° C. under water aspirator pressure. The solution is cooled, diluted to a volume of ~3 t with ice water and carefully acidified with aqueous hydrochloric acid, maintaining the temperature below 15°C. The solids were collected, washed with water and dried to give an analytically pure product. (9a5%) is obtained. Melting point: 237°C.

Example 1 (B) ″“−“′?″″′″9fV-) (L', ty).

Kak et al.: J, Org, Chew, 18 volumes, 138
Pages 0-1402 (1953). Yield of 88 yen and general esterification method (acid + CH30H-)-HO2 (g)
→Give Estherf. However, no other data are available. ]]4-Methoxythiosalicylic acid 9A15f% [1,
45 mol), methanol (2 t) and concentrated sulfuric acid (92 m
) is stirred and refluxed under nitrogen for 17.75 hours.

Most of the methanol is removed under water aspirator pressure at 40°. The reaction mixture is cooled, poured into ice water and extracted with ether. The ethereal extract is washed with cold sodium bicarbonate solution, water and dried over sodium sulfate. After evaporation of the solvent in vacuo, the crude oil (82,82) was distilled under high vacuum to give an analytically pure solid 77.3PC86.9%)
get. Melting point: 38-9°C.

Example 1(F) 3-Hydroxy-6-medoxybenzo(b) thiophene-2-carboxylic acid methyl ester methyl 4-methoxythiosalicylate (76,4t% CL + 9 mol) in dimethyl sulfoxide (500rl) and potassium t −
A mixture of butoxide (45t 5ICL4 moles) was added to methyl chloroacetate (41,
8t% a, 39 mol) was added dropwise while maintaining the temperature at 20-30@. Stirring is continued for 10 minutes at room temperature and the mixture is then heated on a steam bath for 50 minutes. The solution is cooled to 50°C and more potassium tert-butoxide (<45t) is added. The mixture is heated on a steam bath for 4.5 hours and left overnight at room temperature. The mixture is then poured into ice water (~4 t) and carefully acidified with dilute hydrochloric acid. The precipitate is collected F, washed with water and dried to obtain solid 100F. Melting point 122-3@.

Analytically pure product 75? recrystallized from acetone (decolorized with charcoal)-methanol and then methylene chloride-methanol. (81,89J) is obtained. Melting point 124-5O Example 1 (G) 6-Medoxy 3-(1-methylethoxynobenzo
b] Thiophene-2-carboxylic acid (A) 3-hydroxy-6-medoxybenzoIJI thio7ene-2-carboxylic acid methyl ester C25,8t%Q, 1 mol) and N,N',O in acetonitrile (400m) −)
Liisoprobil pseudourea [Erich Schmidt and Frino Muthmuller: RANN, J597, pp. 235-40 (1955)] (774, 5M0.4
The mixture of mol) is stirred at reflux for 23 hours under nitrogen and then cooled. [ik1 (N,N-diisopropylurea)] is removed. The solvent and volatiles are removed under vacuum and then under high vacuum. The residue is dissolved in ether and
Filter and discard solids. After evaporating the solvent under vacuum, the residue was dissolved in methylene chloride and silica gel C2
20f) 6-Medoxy 3-(1-
Methyl ethoxynobenzo[1))thiophene-2-carbo/acid methyl ester 27.4f (97,89k)
get. This is used directly in the next step.

φ) Crude ester C27,4f from the above process in potassium hydroxide (11,8F) and methanol (30
The mixture of 〇-) is stirred and refluxed for 2.75 hours under nitrogen.

Most of the methanol is then removed under reduced pressure at 45''.

The residue is dissolved in water (~750 d) and decolorized with activated carbon. After cooling, the solution is carefully acidified with dilute hydrochloric acid while maintaining the temperature below 15°. The crystalline precipitate is filtered, washed with water and dried to yield 24.09t of solid.

melting point 159'C decomposition). Recrystallized from acetonitrile to give analytical K U # rj ″″′″85? (8°
""~°11 points 159-160°C (decomposition).

Example 1(H) 6-medoxy3-(1-methylethoxy)-N-IH
-tetrazol-5-yl-benzo[b]thio7ene-2-carboxamide acetonitrile (6-medoxy-3-( in 200 ml)
1-methylethoxynobenzo(t)) thiophene-
2-carboxylic acid (1α412, 0.039 mol) and 1,11-carbonyldiimidazole (7,61?, 0
．． 047 mol) is stirred and refluxed for 80 minutes under nitrogen. A solution of 5-aminotetrazole C5,99f, (LO47 mol) and triethylamine (4,75F% 0.047 mol) in acetonitrile (100 sd) is added dropwise. The mixture is heated to reflux for 21.5 hours, then most of the acetonitrile is removed under water suction pressure at 40°.

The residue is treated with cold water (~700 mg) and then acidified with acetic acid (14,51').

The resulting solid is separated by filtration, washed with water then ether and dried to yield 12.1t of solid. Analytically pure product recrystallized from methanol 11.
Obtain 06F (84.9%), melting point 237-9'C (decomposition).

Example 2(A) Methyl 5-methoxysalicylate 5 in acetone (1,5t) by the method of Example 1(A)
-methoxysalicylic acid (Aldrich X151.6f,
09 mol) to sodium bicarbonate C75,74F%0.9
mol) and dimethyl sulfate (11A7f1 (L9 mol)
149t (917%) of analytically pure oil are obtained. Boiling point Q8@/CLO5■.

Example 2(B) Methyl 5-methoxysalicylate (149f, α82 mol) in dimethylformamide (1t) by the method of 5-methoxy-2-[(dimethylaminocothioxomethoxy]-benzoic acid methyl ester Example 10) and 1.4
-diazabicyclo[2,2,2)octane (257,3
Treatment of 2.22 mmol of P% with dimethylthiocarbamoyl chloride (2759°2.22%) gives the product. Recrystallization twice from methanol gives analytically pure product 157.9f (71.7%). Melting point 102
~3℃.

Example 2(C) 5-Methoxy-2[(dimethylamino)carbonyl'thio]-benzoic acid methyl ester Example 1(C) Treatment of oxomethoxytwobenzoic acid methyl ester (150f) gives the product.

Recrystallization from methylene chloride-hexane gives analytically pure product 92.9F (61,91).

Melting point: 70-2°C.

Example 2 (D) 5-methoxythiosalicylic acid CF, sactor and P,
Stutz: rMonatsh, ChemieJ
Vol. 98, p. 1962 (1967). Melting point: 300-1°C.
(170-3).

0, Francis Bennett et al; [Organic Pr
epa-ration and procedures
Eng. nt, J6(6), pp. 287-293 (1974)
. Melting point 175-6°C. Manufactured by different methods. ] Example 1 5-methoxy-2-[(dimethylamino)carbonyl)thiocoubenzoic acid methyl ester (9α7F, α34 mol) was dissolved in sodium hydroxide (55
9), methanol (700 m6,1 and water (350 d
) to produce pure product 6CL9fc9t7.6%]
get. Melting point: 170-2°C.

Example 2 (E) 3-hydroxy-5-methoxy-benzo(1)) f”
7"y-2-7"bore acid 'chi'"8te" 1G
) Methyl-5- in dimethyl sulfoxide (250m)
Methoxythiosalicylate [0, Francis Bennet etc. rorganic Preparation and
Procedures Eng. J 6 (6) Vol. 28
7-293 pages (1974) 0 boiling point 105-610.3
A mixture of sw+,
f, (126 mol) is added dropwise, maintaining the temperature between 10 and 30@. After the introduction is complete, stirring is continued for 10 min at room temperature. The resulting mixture is heated on a steam bath for 1.75 h. From now on, the reaction Add ice water (~1.7t) to the mixture.1.
Extract with -f le (241t). The combined extracts are washed with water and dried over sulfuric acid. The solvent is removed in vacuo to yield 67.5 f of a semi-solid residue. This was recrystallized twice from methanol to yield the product 9.4P (15
, 3chi]. Melting point: 153-4°C. Concentrate solution F to obtain methyl 2-(carbomethoxymethylthio)-5-methoxybenzony) 41.3r (in two yields), melting point 55-7°C. This is used directly in the next step.

03) A solution of sodium methoxide (sodium metal, 545F (0,15 mol) and methanol 400
-) without stirring the diester (41f, [1
15 moles] (from the previous step) are added rapidly. Stirring is continued for 20 minutes at room temperature and the mixture is then refluxed on a steam bath for 4 hours. After cooling to room temperature, the reaction mixture was dissolved in water (
~41) and filter through Supercell Hyflo and Gluco G60 Mat. The resulting solution is cooled and carefully acidified with dilute hydrochloric acid. The resulting lettuce solid (27.5?) was filtered and recrystallized from methylene chloride-methanol to give analytically pure product 26.8f.
C74%). Melting point 133-154 Co combined yield 59% Example 2 (F) 5-methoxy-3-(1-methylethoxy)-benzo(
1) 3thiophene-2-carboxylic acid (A) 3-hydroxy-5 in dimethyl sulfoxide (150 mg)
-Methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (10F.

0,042 mol) and 2-bromopropane (11,3
Potassium t-butoxide (5,4f, α048 mol) is added to the mixture of 0.091 mol of F, 0.091 mol]. The mixture is then heated at 100 @ with stirring under nitrogen for 7 hours and left overnight. The resulting mixture is then poured into ice water and extracted with ether. The organic phase was washed with cold potassium carbonate solution 1 and water, dried over sodium sulfate and concentrated to a dark oil, 5-methoxy-3-(1-methylmethoxy)-benzoC1))thiophene-2 -Carboxylic acid methyl ester 111L36t is obtained. This is used directly in the next step.

ψ) Crude ester from the previous step (1[L36t), potassium hydroxide (i8f) and methanol (100-)
The mixture is treated according to the procedure of Example 1 (GB).

7.24 t (65%) of product are obtained. Melting point 1
33-4''. This is recrystallized from acetonitrile to give analytically pure product 6.0tC55,B).

Melting point: 153-4°C.

Example 2 (G) (4) 5-methoxy-3-(1-methylethoxy)-
N-IH-tetrazol-5-yl-benzo[b)thiophene-2-carboxamide complex with 1H-imidazole (1:1) 5-methoxy-5-(1-methylethoxy )-benzo0]thio7ene-2-carboxylic acid <5.35t, α02
The mixture of C126t, [102-Enyl)O and 1,1'-carbonyldiimidazole is stirred under nitrogen for 2 hours. To this solution was added 5-aminotetrazole (1,71?, (102 mol)) and the resulting mixture was stirred at room temperature for 17 hours and then refluxed for 2 hours. The mixture was filtered and Part F was concentrated under reduced pressure. A solid is obtained which is washed with ether.

Analytically pure product Z recrystallized from methanol
, 2fC27,4chi) are obtained. Melting point: 187-9°C.

03) 5-methoxy-3-(1-methylethoxy)-N
-IH-tetrazol-5-ylbenzoTo]thiophene-2-carboxamide acetonitrile (300d)
5-methoxy-3-(1-methylethoxy)-benzo(1))thiophene-2-carboxylic acid (1[1L41
2% 0.039 mol), 1,1'-carbonyldiimidazole (7,6411% Q, 047 mol), 5-aminotetrazo-/L' (599f, 0.047 mol) and triethylamine (4,75? , 0.047 mol) is treated according to the procedure of Example 1@.Product 11
．． 65F is obtained.

Melting point 214-6°C (decomposition). Analytically pure product recrystallized from methanol 9.25? (71%)
get. Melting point 214-6°C (decomposition).

(C) 5-methoxy-3-(1-methylethoxy)-N
-I H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide sodium salt 5-methoxy-3-(1-
methylethoxy)-N-I H-tetrazol-5-ylbenzo(b) Thiophene-2-carboxamide (6
, 99F, [LO21 mole] was added water (40
Add a solution of sodium hydroxide ((L86t1α021 mol) in m). The reaction mixture is stirred at room temperature until a clear solution is obtained and then the solvent is removed under water suction pressure below 60°C. Methanol (~150sd
) and ethanol (350 m) and remove the solvent.

This procedure is repeated two more times, then the residue is dissolved in a minimum amount of methanol and ether is added. The resulting solid is collected, washed with ether and dried to give an analytically pure product (5.5tC69,7H). Melting point 190
~210℃.

Example 3 (A) 3.5-dimethoxy-benzo[b]thiophene-2-carboxylic acid methyl ester 3-hydroxy-5-methoxy-benzo(b) thio7ene-2-carboxylic acid methyl ester in acetone (300+d) (7,81% 1033 mol), carbonffi potassium (4,5f% 1033 mol) and dimethyl sulfate (4
, 7f, 0.037 mol] under nitrogen.
．． Stir and reflux for 5 hours. The mixture is cooled, filtered and the acetone removed under water suction pressure at 45". The residue is treated with water and extracted with nityl. The ether extract is washed with water and dried over sodium sulfate. The solvent is then removed to obtain a solid 7.fJ f, melting point 102-3
℃. Recrystallization from methylene chloride-methanol gives analytically pure product 7.47r (92.5 qb).

Melting point 102-3C.

Example 3(B) 5,5-dimethoxy-benzo[b]thio7ene-2-carboxylic acid 3,5-dimethoxy-benzo(1+3thiophene-2-carboxylic acid methyl ester (
6,76? , α027 mol) with methanolic potassium hydroxide yields the analytically pure product a5.
Obtain 5f (87,3%). Melting point 190℃ (decomposition) (from methanol). Example 1 3 (C
) 3,5-Dimethoxy-N-IH-tetrazol-5-yl-benzo(b) thiophene-2-carboxamit 3,5-dimethoxy-benzo(b) thiophene-2-carboxylic acid (b) in tetrahydrofuran (250d) 4,5
A mixture of 8t, 0.019 mol), 1,1'-carbonyldiimidazole (51721 [1019 mol)] and 5-aminotetrazole (1,64f% (LO 19 mol)) was prepared by the procedure of Example 2(G). Process.Solid5.
8f is obtained. Analytically pure solid 2 recrystallized from methanol-tetrahydrofuran-acetonitrile
．． We get 5r (47,8ts). Melting point 213-5°C (decomposition).

Example 4 (A) 3-Hydroxy-5 in 3-ethoxy-5-methoxy-benzo[su]thiophene-2-carboxylic acid) acetone<5OoWIt)
-methoxy-benzo[b)thiophene-2-carboxylic acid methyl ester (10f, α042 mol) Potassium carbonate (15,8t, α042 mol) and diethyl sulfate C7
, 52t, 0L047 mol) under nitrogen at 24
Stir and reflux for an hour. Then evaporate the acetone. The residue is treated with potassium carbonate (5,8F), diethyl sulfate (Cat)s and dimethyl sulfoxide (150d). The mixture is heated on a steam bath for 24 hours, cooled, poured into ice water and extracted with ether. 10 ether extract
Wash with potassium chloride solution, water and dry over sodium sulfate. Removal of the solvent under vacuum left a dark oil, 3-ethoxy-5-methoxy-pen'/' [, b]
Thiophene-2-carboxylic acid methyl ester is obtained. This is used in the direct process.

ii) The mixture of crude ester (a4f), potassium hydroxide (5,4f) and methanol (150d) from the previous step is treated according to the procedure of Example 1 (GB). Analytically pure product 6.1 after recrystallization from acetonitrile! Obtain M (58%). Melting point 162-3°C (decomposed).

Example 4(B) 3-Ethoxy-5-methoxy-N-IH-tetrazol-5-yl-benzo[b] 3-ethoxy-5-methoxy-benzo[b] in thiophene-2-carboxamide acetonitrile (200 m) Thio7ay-2-carboxylic acid C5
, 54f, 0.021 mol), 1.1'-carbonyldiimidazole (4,12fl [LD 25 mol), 5
-aminotetrazole (2,16f%0.025 mol) and triethylamine (2,57f1α025 mol)
The mixture is treated according to the procedure of Example 1 (Transition). 6.7 t of product are obtained. Melting point: 225-7°C. Analytically pure product 6.55f recrystallized from methanol
(96.9%) is obtained. Melting point: 225-7℃ (decomposition)
.

Example 5(A) 7-medoxy5-(1-methylethoxy)-pen'/
(b) Thio-7ene-2-carboxylic acid Example 2
-Midoxybenzo[b]thiophene-2-carboxylic acid-methyl ester [Siems R, Beck: rJ,
0r(z, Chem, J38(23) Volume 4086-7
Page (1973). Melting point 118~9＠] (14,051
% (LO59 mol), 2-bromopropane (15,5f
sα130 mol) and potassium t-butoxide (7,
A dark oil, 7-medoxy 3-(1-methylethoxyfluorinzo('b)thiophene-2-carboxylic acid methyl ester) is obtained by treating 28f11065 mol), which is used directly in the next step. .

A mixture of the crude ester (a4 t ) from the previous step, potassium hydroxide (5t) and methanol (200m) is treated according to the procedure of Example 1 (GB).

Product 4.68f is obtained. This was recrystallized from acetonitrile to give analytically pure product 3.4f (21
, 7%). Melting point 14S2-3°C.

Example 5(B) 7-medoxy5-(1-methylethoxy)-N-I
H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamitotitrahydrofuran (200 m
) 7-medoxy 3-(1-methylethoxy)-benzo[b]thiophene-2-carboxylic acid c2.96f%
1011 mol), 1.1'-carbonyldiimidazole (1,El.

0.011 mol) and 5-aminotetrazole (α9
A mixture of 4f, [11 moles of LO] is treated according to the procedure of Example 2 (GA). Solid 18f is obtained. This is recrystallized from methanol to give analytically pure product t,6F (43%). Melting point 228-250°C (decomposition).

Example 6 (A) Methyl 5-methylsalicylate [Prederman, Pike: rBer, J6, p. 324 (1873) Boiling point 23
6-7°] Example 1) 5-Methylsalicylic acid (Aldritsupi) (304,3t 12 mol), sodium bicarbonate (168f 12 mol) in acetone (2 t) were dissolved in dimethyl sulfate (252,26r, 2 mol) by the method of Example 1). An analytically pure oil 296.2 P (89%) is obtained by treatment with . Boiling point 105''/6&Example 6(B) 5-Methyl-2[(dimethylamino)thioxomethoxybenzoic acid methyl ester Dimethylformamide (1,
2t) in methyl 5-methylsalicylate 25a79.
1.50 mol) and 1,4-diazabicyclo[2,2
, 2) Octane<574F%523 mol) to dimethylthiocarbamoyl chloride (400f.

5.23 mol] to obtain the product. Analytically pure product 246.6 recrystallized twice from methanol
fC64,9ch) is obtained. Melting point 102-3°C.

Example 6(C) 5-Methyl-2[(:)methylamino)carbonyl)thio-benzoic acid methyl ester diphenyl ether C225 by the method of Example 1(C)
5-Methyl-2-[(dimethylamino)thioxomethoxytwobenzoic acid methyl ester C2614f in 49)
) to obtain a mixture.

Dissolve this in hexane and use silica gel (789?)
Chromatography above. Elution first with hexane and then diphenyl ether followed by methylene chloride gave a viscous oil, 16a2t. Further elution with chloroform gives analytically pure oil 1[L5f. Total yield 17 CL7 tc67.4'l).

Example 6 (D) 5-Methylthiosalicylic acid (F, Knorrpfeiffer et al.: rchem, Ber, J vol. 59, p. 1668)
(1925).

5-Methyl-2[(dimethylamino]carbonylthio]benzoic acid methyl ester (
170.2f%a, 67 mol) of sodium hydroxide A (
Analytically pure product 107.1f (94.4%) is obtained by hydrolysis of 7CL2f (17 mol), methanol (940-n) and water (470+wj), melting point 155-7°C.

99 6(E)
1-methyl 5-methylthiosalicylate [Frederick (
), ffn, etc.: “J, Chem, 8oc, J 7
47 pages (j951). Boiling point 85-7/α5■. Melting point 6
1-2@(different methods)] 5-Methylthiosalicylic acid (
106,6F, (163 mol) in methanol (2,2t
) and sulfuric acid (128m). The solid was dissolved in ether, washed with water and dried to give analytically pure product IO6,3f (92%).
get. Melting point 56-8°C.

Example 6(F) Methyl 5-hydroxy-5-methyl-benzo[su]]thiophene-2-carboxylic acid methyl ester in dimethyl sulfoxide (600m) by the method of Example 1F).
Methylthiosalicylic acid) (1o5.6t, 0.58
The product is obtained by treating 1.2 mol) with potassium t-butoxide (135F, 1.2 mol) and methyl chloroacetate (62.9f, α58 mol). Analytically pure product 91.62 (
71.1%). Melting point 93-4°C.

Example 6(G) 5-Methyl-5-(1-methylethoxy)-benzo[b
) Thio-7ene-2-carboxylic acid (A) Example 1 (GA)
3-Hydroxy-5-methyl-benzo(b)thiophene-2-carboxylic acid methyl ester (15F% α067
mol) with O,N,N'-triisopropyl pseudourea (5Q, 3f, Q, 27 mol) to give a dark oil, 5-methyl-3-(1-methylethoxy)-benzo(1). ) Thio-7ene-2-carboxylic acid methyl ester 1
Obtain Z51f. This is used directly in the next step.

(B) Crude ester from the above step (17,51F
), potassium hydroxide (7,9t) and methanol (
The mixture of 2001 ml) is processed according to the procedure of Example 1 (GB) to give product 15.15f. Melting point 160
~1°C (decomposition).

Recrystallization from acetonitrile gives 12.97t (76.8%) of analytically pure product. Melting point 161-2
°C (decomposition).

Example 6 (H) 3-(1-methylethoxy)-5-methyl-N-1H-
Tetrazol-5-yl-benzo[b)thiophene-2
-5-methyl-5-( in carboxamide acetonitrile (300 mg)
1-methylethoxy)-benzo[b]thio7enecarboxylic acid (a!M, [LO34 mol), 1,1'-carbonyldiimidazole (462f, 1041 mol), 5-aminotetrazole (547f% 1041 mol) ) and triethylamine (4,1!, CLO41 so) are treated by the procedure of Example 1(b). Product 1
α32f is obtained. Melting point 247-9°C (decomposition). Analytically pure product recrystallized from methanol &17
Obtain F (80,8%). Melting point 247-9°C (decomposition).

Example 7 [A] 6-chloro-3-(1-methylethoxy)-ben'/
(1:+)thiophene-2-carboxylic acid (A) Example 2
Dimethyl sulfoxide (25
6-chloro-benzo(b)thiophene-2- in 0 mJ
Carboxylic acid methyl ester [JEAS R, Beck: r
L Org, Chem, J38, 4086-7 (1
973): 1 (24,3f% (L1 mol), 2-bromofuropane (26,32f1CL21 mol) and potassium t-butoxide (12,91F, α011 mol-9
to give 6-chloro-3-(1-methylethoxy)-
benzo(1)]]thiophene-2-carboxylic acid methyl
Obtain puruester 1412 (56,5 cup).Melting point 7
2-31° (B) Ester from the above step <15. st), potassium hydride (6,5f) and methanol (160
mg) is treated according to the procedure of Example 1 (GB).

Product 12.8F is obtained. This was recrystallized from acetonitrile to give analytically pure product 9,469.
(S 4.9) is obtained. Melting point 185-6°C (decomposition) Example 7 (B) 6-chloro-3-(1-methylethoxy)-N-1H-
Tetrazol-5-yl-benzo[b]thiophene-2
-6-chloro-3-(1- in carboxamide acetonitrile (20M))
Methyl ethoxy)benzo('b)thiophene-2-carboxylic acid (ao5f%cLOS mo#), 1.1'
-Carbonyldiimidazole C5,79t, (LO36
mol), 5-aminotetrazole (504f1α036
mol) and triethylamine C5,6 mg% (LO3
6 mol) of the mixture were prepared according to the procedure of Example 1@. Product 9.82 is obtained. Melting point 250-1°C (decomposition). Recrystallization from dimethylformamide-methanol gives analytically pure product a4F (841). Melting point 249-251°C (decomposed).

Example 8(A) 3-(1-Methylethoxy)-benzo[b]thiophene-2-carboxylic acid) Benzo[b]thiophene-2-carboxylic acid in dimethylsulfoxide (200m) by the method of Example 2(FA) Acid methyl ester [Friedlander: rAnn,
J Vol. 35.1, p. 390 (1907)) (25f,
0.12 mol], 2-bromopropane C32,5f,
0.26 mol] and potassium t-butoxide (15,
5t, 0.14 mol) to give a dark oil i.e. 3
-(1-methylethoxy)benzo[1))thiophene-
2-carboxylic acid methyl ester 1a61 is obtained.

■) The crude ester (1a63F) from the previous step, potassium hydroxide (a5 t ) and methanol (180d
) is processed according to the procedure of Example 1 (GB). Product 159f is obtained. Analytically pure product 1α was obtained by recrystallization from acetonitrile. t6
Obtain f (36,5 嗟). Melting point 135-7°C O Example 8(B) 3-(1-methylethoxy)-N-I H-tetrazol-5-yl-benzo('fi)thio7ene-2-carboxamide 1H-imidazole (1:1) Complex 3-(1-methylethoxy)-benzo(b)thiophene-24-carboxylic acid (1α3f, (1044 mol) and 1,1'-carbonyldiimidazole (7,1?, () in tetrahydrofuran (300 m)) A mixture of 1044 mol) was stirred at room temperature under nitrogen for 100 minutes and then heated to 49°C.
Stir for 3 hours. Add 5-7 minotetraso-
5721. [LO44 morn is added and the resulting mixture is heated at 48°C for 3 hours and then stirred at room temperature overnight. The resulting solid (IA38f) is filtered and prepared from methanol-tetra and dolofuran. Recrystallization gives analytically pure product 11.31 (69.8%), melting point 171-5°C. Example 8(C) 3-Methoxy-N-IH-tetrazol-5-yl-benzo0] Thiophene-2-carboxami 3-methoxy'''' in totetrahydrofuran (250sd)
"ゝy'(bl?j"7"'-2"""5'.i
2 years). Melting point 171-173℃) (15f% (1072
mol), 1.1'-carbonyldiimidazole (11,
9f, (1072 mol) and 5-aminotetrazole (6,12f.

0.072 mol] is treated according to the procedure of Example 2 (GA). 19.1 t of product are obtained. Analytically pure product recrystallized from dimethylformamide-methanol6. Obtain ar(3xal). Melting point 2
14°C (decomposition).

Example 8(D) 3-(1,1-dimethylethoxy)-benzo(1+)
Thiophene-2-carboxylic acid (A) 3-Hydroxy-benzo(b) thiophene in acetonitrile (4ooWIt) by the method of Example 11G) (other than washing the crude reaction mixture containing unreacted ester with dilute potassium carbonate solution) 7ene-2-carboxylic acid methyl ester (IQ, 4F.

105 mo#) to N,N'-diisopropyA/-0
-Tertiary butyl pseudourea [Nieschschmidt and Fritzmosmiet-:rmnn, J 597
Volume 235-40 (1955)) (40t, (LO2
Treatment with e) gives a dark oil, 5-(1,1-dimethylethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester &57t. This is used directly in the next step.

A mixture of the crude ester from the previous step, potassium hydroxide (S, B7t) and methanol (150m) was treated by the procedure of Example 1 (GB) to give the product 4.
Get 43f. Analytically pure product recrystallized from acetonitrile 2.35? (1a8L) is obtained. Melting point: 129-131°C.

Example 9(B) 5-10 rho 3-(1-methylethoxy)-benzo(1
)) Thiophene-2-carboxylic acid 5-chlorothiosalicylic acid as described by Leon Katz et al., rJ, Org, Chsm
, J Vol. 18, p. 1380 (1953). It is then esterified with methanol-sulfuric acid to give methyl 5-chlorothiosalicylate according to the procedure of Example 1(K).

The desired 5-chloro-3-hydroxy-benzo
b] Thiophene-2-carboxylic acid-methyl ester [Neto T. Heide/l/: r, 7.0Fg,
Chem, J 52, 267B (1967). Melting point: 154-5°C. A yield of 71.4111 is obtained.

(A) Example 1 5-chloro-
3-hydrobenzo(1))thiophene-2-carboxylic acid methyl ester (24,27f% 11 mol) 0
, N, N'-) lyisoprobil pseudourea (74,4
5-chloro-3-(1-methylethoxy)-benzo[b]thiophene-2-carboxylic acid methyl ester 25tC8B%) after recrystallization from methanol. get. Melting point 65-7°003) Ester from the above process (25 25t% a0
82 mol), potassium hydroxide (14.04f) and methanol (3so-) is treated by the procedure of Example 1 (GB) to give the product 21.4F. Melting point 1
93° (decomposition). Recrystallization from acetonitrile gives analytically pure product 17.5F (7a 9%).

Melting point: 193-5°C [decomposition].

Example 9(C) 3-(1-methylethoxy)-5-chloro-N-IH-
5-chloro-31-(tetrazol-5-yl-benzo(1)]]thio7ene-2-carboxamidocetonitrile (500 m)
1-methylethoxy)benzo(1))thio7ene-2-
Carboxylic acid (a311% (1031 mol), 1.1'-
Carbonyldiimidazole (422f% CL038 mol), 5-aminotetrazole (526f% 1038 mol) and triethylamine 088f% (L038 mol)
A mixture of is treated according to the procedure of Example 1@. The product 1α2t is obtained. Melting point 237-9 (decomposition). Analytically pure product recrystallized from methanol7.
6tC71554) with a melting point of 238-240°C (decomposition).

Example 10(B) 5-methoxy-3-(1,1-dimethylethoxy)-benzo[b]thiophene-2-carboxylic acid The method of Example 10) (the crude reaction mixture containing unreacted ester was dissolved in dilute potassium carbonate solution) 5-Methoxy-benzo(1))thiophene-2-
Carboxylic acid methyl ester to N,N'-diisopropyl-〇-tert-butyl pseudourea (see Example 1 (GA))
181 to form a dark oily substance, 5-methoxy-3-(
1,1-dimethylethoxy)-benzo[b]thio7ene-2-carboxylic acid methyl ester 7, Of is obtained. Example 1
Hydrolysis with methanolic potassium hydroxide according to the procedure of (GB) gives the analytically pure product 37f (35.6 k) after recrystallization from acetonitrile. Melting point 145-7°C (decomposition).

Example 10 (C) S -(1,1-dimethylethoxy-5-methoxy-
N-1) 1-tetrazol-5-yl-benzo [1)]
]thiophene-2-carboxamitotitrahydrofuran IOM) 5-methoxy-3-(1,1-dimethylethoxy)benzo('b]thiophene-2-carboxylic acid C
2,8F%0.01 mol], 5-aminotetrazole (
A solution of 1,3-diisopropylcarbodiimide (1,3t, 1 mol ao) in tetrahydrofuran (10 m) is added dropwise at θ° under nitrogen atmosphere to a mixture of Stir for 2 hours then at room temperature for 17 hours. The solvent is removed under reduced pressure <30@ and the residue is recrystallized from methanol to give analytically pure product a8t. Melting point 246-8° C. (decomposition). .

Example 11 (B) 5-nitro-3-(1-methylethoxy)-benz(b
) Thiophene-2-carboxylic acid (4) 3- in acetonitrile (600 m) by the method of Example 1 (GA)
Hydroxy-5-nitro-benzo(1))thiophene-
2-Carboxylic acid methyl ester [Michael Leow
Tominet; U.S. Patent 4954.748 (1976)
)lcL25t.

(108 mol) with O,N,N'-)liisoprobil pseudourea (s9.6r; (132 mol) to give analytically pure 5- after recrystallization from methylene chloride-methanol. Nitro-6-(1-methylethoxy)-benzo(
t)) Thiophene-2-carboxylic acid methyl ester IA
Obtain 64f (57,8qb).

Melting point: 175-7°C.

ψ) Noester (12,57t1cL0
43 mol), potassium hydroxide (7,4f) and methanol (180m) is treated by the procedure of Example 1 (GB) to give the product 11.82f. Melting point 22
8-250” (decomposition). Analytically pure product IQ recrystallized from tetrahydrofuran-acetonitrile,
95? (91, Section 5) is obtained. Melting point 228-230℃ (
Disassembly).

Example 11 (C) 3″″ (1-methyl-1-toxy)″5″= ) o −
Ng-IH-tetrazol-5-yl-benzo(b)thiophene-2-carboxamide 5-nitro-3-(1) in acetonitrile (500 m)
-methylethoxy)benzo[b]thiophene-2-carboxylic acid (IOF, (LO36 mol), 1,1'-carbonyldiimidazole (7,2?, Q, 044 mol), 5
-A mixture of aminotetrazole (578t% [LO44 mol) and triethylamine (4,49f, α044 mol] is treated according to the procedure of Example 1 (6). The product 12.5f is obtained. Melting point 211-3 @(Disassembly)
. Recrystallization from dimethylformamide-methanol gives analytically pure product. Melting point 211-3°C (decomposed).

Example 12 (A) 3-chloro-N-IH-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide acetonitrile (100d)-tetrahydro7rane (1
00rn1. 5-aminotetrazole (&51P) in J
, CL1molno and triethylamine (1(11f,
A solution of 0.1 mol) in acetonitrile (10
0ad, Beni/so(b)-5-offene-2-carbonylchloride-3-ri in l-tetrahydrofuran (100d) (W, B, Wright Jr. et al.: rJ,
Hatero-cycle Chem, 41971 8
[5), pp. 711-14] (231f% 0.1 mol) dropwise. The mixture is further stirred at room temperature for 18 hours and the precipitate is separated by filtration. The solid is dissolved in water (~
Suspend for 700 d, 1 m, heat on a steam bath and then cool.

The solid is isolated by filtration, washed thoroughly with water then ether and dried to give product 249. Melting point 277
°C (decomposition). Recrystallized from dimethylformamide-methanol to give analytically pure product 21.84fC7
9.3%). Melting point 275°C (decomposed).

Example 13 (At 5-methoxy-3-(1-methylethoxy)-pen:/
(1)) A mixture of thiophene-2-cardexamide 5-methoxy-6-(1-methylethoxy)benzo[b]thiophene-2-carzenic acid (10t, r: 1.057 mol) and thionyl chloride (2517) The thionyl chloride is removed by heating at 50° C. for 30 minutes on a water bath and then concentrating in vacuo.

The residue is dissolved in methylene chloride (~35 Qiu) and added to a stirred mixture of concentrated aqueous ammonium (25011 J) and methylene chloride (2501 mg) at 5-7°C. After 20 minutes at this temperature, the reaction mixture is stirred at room temperature for 75 minutes. The organic layer was separated, washed with water (2x1.3), then diluted with ice water and acidified with acetic acid. Washing with methylene chloride solution Rt water and brine and drying gives a solid a3 ft-. Analytically pure 5-methoxy-3-(1-methylethoxy
Benzo(b)thiophene-2-carboxamide & 3El
(64 chi) is obtained. Melting point: 155-7°C.

Example 15(B) 5-methoxy-3-(1-methylethoxy)-benzo[
b] Thiophene-2-cal 2-nitrile acetonitrile (
5-Methoxy-3-(1-methylethoxy)benzo(b,lthiophene-2-carboxamide (525f,Q,12mopv))
The mixture was stirred for so minutes at room temperature. Allyl bromide (1
1,8f, 0.098 mol) and reaction mixture 7
Heat to reflux for 12 hours.

Most of the volatiles were removed at ambient pressure and the resulting residue was dissolved in ether and washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water. Extract gt-sulfuric acid) Dry over IJum and remove the solvent to obtain an oily residue A2ft.

This oil is purified by chromatography on silica gel (110?). Elution with methylene chloride gave solid AO1? (100%) f: Obtain. Melting point: 80-1°C. Recrystallization from hexane gives analytically pure 5-methoxy-3-(1-methylethoxy)benzo(b)thiophene-2-carbonitrile 2.79f (92%) IP.

Melting point 80-1°C Example 13(C) 5-[5-Methoxy-6-(1-methylethoxy), benzo(b)cheno-2-yl]-1H-tetrazole 5-methoxy in dimethylformamide (250m) −
3-(1-methylethoxy)-benzo(b)thiophene-2-carbonitrile (6,2flα025 mol), sodium azide (5,39F.

α080 mol) and ammonium chloride f) J-, (4,5
t.

(L080 mol) on a wax bath at 120 to 1
Heat to 35°C for 24 hours. The reaction mixture is then cooled and
Filter and remove dimethylformamide under reduced pressure at 60°C. The whole residue was treated with ice-water (700 R7) and then acidified with vinegar.The resulting solids were separated by filtration, washed with water and then with ether and dried to give 5 solids.
．． Get 8ft. Analytically pure 5-[5-methoxy-3-(1-methylethoxy)benzo(1))cheso-2-yl]-1■-tetrazole 4.8? recrystallized from acetonitrile (6&6chi) t-get. Melting point 191
~6℃.

Example 14 3-(1-methylethoxy)-benzo(b)thiophene-2-carboxamide 3-(1-methylethoxy)-benzo(b)thiophene-2-carmen@(32,1?, 0.13 mol) ).

Polyphos 7ate ester (PPE) (357f)
(Kana talent, Yuwichi, etc.: r Chem, Pha
rm, Bull, J 13(9) Vol. 1065-10
72 (1965)] and purified chloroform (1301d) is cooled in a dry ice-acetone bath and sparged with ammonia (~100d). <
After stirring at 00 for 5 hours and at room temperature for 26 hours,
The reaction mixture is refluxed for 7 hours, then cooled and treated with 25% aqueous sodium carbonate. Extract the product with chloroform. Organic layer? Rinse with water, salt water and dry. Chloroform was removed under reduced pressure leaving a residue of 19.7
f t-get. Chromatography on basic alumina (4272) using methylene chloride and then chloroform as eluents followed by recrystallization from methanol gave the analytically pure product, 3-(1-methylethoxy)-benzo[b ] Thio-7ene-2-calgexamide 7.3tk is obtained. Melting point 162-4°C.

Example 14 (B1 3-(1-methylethoxy)-benzo[b]thiophene-2-cal-2-nitrile 5-(1-methylethoxy)-benzo(b)thiophene-2-calzexamide (5,95t, 0.025 mole), 1.1'-carbonylneuimigusol (a2t
, (LO51 mol) and allyl bromide (24,5f.

0.2 mol) is processed according to the procedure of Example 13B. An oily residue of 5.6 f is obtained.

Dissolve this in hexane and use silica gel (120?)
Chromatography above. Elution with methylene chloride yielded 3-(1-methylethoxy)-benzo(t) as an oil.
)) Thio7ene-2-carnitrile 5.45f (99
, 3 h) t-obtain. This will be used directly in the next factory.

Example 14 (C1 5-(3-(1-methylethoxy)benzo[b]thien-2-ylk 6-(1-methylethoxy)benzo(b) from the previous step in 1H-tetrazoltzmethylformamide (ioam) Thiophene-2-caronitrile (5,26t, α024 mol), sodium azide (2
, 14t, 0.035 mol) and ammonium chloride (
1,8P, α0!1! l -Tnyl) mixture t1 Example 1
Process by method 3C. Solid 47f is obtained.

Melting point: 185-7°C.

Analytically pure 5-(3
-(1-methylethoxy)benzo(1))cheno-2-
yl]-1H-tetrazole 4.2f (66.8%) is obtained. Melting point: 185-7°C.

Example 15 (^ 3-((dimethylamino)thioxomethoxy-2-5-methoxy-benzo(b)thiophene-2-carbonyl methyl ester dimethylthiocarbamoyl chloride (a15?, 0.066 mol) in acetonitrile (1001M) A solution of benzo(b)thio7ene-2-carginic acid-3-hydroxy-5-methoxy-methyl ester (15,151,
[LO64 mol) and potassium carbonate (9,1?, 0.
Add 0.06 (S moles) to the stirred mixture.

The reaction mixture is then refluxed for t-18 hours, cooled, filtered and the solvent is removed under reduced pressure on a rotary evaporator at 50°C. The whole residue was dissolved in ether and the solution was washed sequentially with water and cooled at 8F.
Wash with dihydrochloric acid, water, cold sodium bicarbonate solution and water. The organic phase is dried and concentrated to form a solid 2cLyt't:
obtain. Analytically pure 6 recrystallized from methanol
-[(dimethylamino)thioxomethoxy-5-methoxy-benzo(b)thiophene-2-carboxylic methyl ester 16.4f (79.3qb) is obtained. Melting point 13
6-8℃.

Example 15(B) 3-((dimethylamino)carzenyl)thio-5-methoxy-benzo(b) 6-[(dimethylamino)thioxomethoxy-5- in thiophene-2-carboxylic acid methyl ester diphenyl ether (2409) Methoxy-benzo (
b) Thiophene-2-carboxylic acid methyl ester (14
, 49t) t-Heating at 2!10-247°C for 21 hours on a wax bath under a nitrogen atmosphere. After cooling, the mixture was dissolved in hexane and chromatographed on silica gel (430 t). The column was sequentially eluted with hexane, methylene chloride, and chloroform. Chloroform gold was removed under reduced pressure to obtain 12.48 ft of solid. Analytically pure 6-[((dimethylamino)carzenyl)thio-5-methoxy-benzo[
b] Thiophene-2-carboxylic acid methyl ester 9.9
59 (69,1%) k obtained.

Melting point 105-7°C.

Example 15 (C1 3-mercapto-5-methoxybenzo(b)thiophene-2-carboxylic acid 5-(((dimethylamino)carzenyl)thio2-5-
A mixture of methoxy-benzo(b)thiophene-2-carboxylic acid methyl ester (9,35P, Q, 029 mol), sodium hydroxide (2,99), water (4ON) and methanol (40m) under total nitrogen Stir and reflux for 6 hours.

Most of the methanol is then removed under reduced pressure at 50°C. The residue is dissolved in water (250 g) and decolorized with activated carbon. After cooling, the solution is carefully acidified with dilute hydrochloric acid and extracted with ether while maintaining the temperature below 1-15°C.

The extract was washed with water and brine, dried and concentrated to a residue 6. get ot'. Recrystallize from acetonitrile to obtain monomercapto-5-methoxybenzo(k))thiophene-2-carboxylic acid! A.4? We get (49,3chi). Melting point: 148-150°C (decomposition).

This is used in the direct process.

Example 15 (DJ 1-Methylethyl 5-methoxy-3-((1-methylethyl)thio]benzo(1))thiophene-2-carloxylate 6-mercapto-5-methoxybenzo in acetonitrile (200111j) [b] Thiophene-2-kaky
)r Phosphoric acid (121, CLOl 3 moy) >LbinN
, N',0-triisopropyl pseudourea (20,4
A mixture of f, (111 mol) is stirred and refluxed under nitrogen for 20 hours. The solvent and volatiles are removed under vacuum and then under high vacuum. The residue was dissolved in methylene chloride and applied on a silica gel column (115f) to 1-methylethyl 5-methoxy-! 1-((1-methylethyl)thio]benzo(b)thiophene-2-calyl key/L/
-To 1579 (7a4%) '141-like product. This is used in the direct process.

Example 15 (El 5-methoxy-3-((1-methylethyl)thiocoubenz[b]thiophene-2-carmenic acid 5-methoxy-
3-((1-methylethyl)thio-benzo(b)thiophene-2-carboxylic acid 71 f A/ ! f py
Esthetics A/ (i 37 f, Q, 01 Mok
), potassium hydroxide (5t) and methanol (80
The mixture of M) is refluxed for 3 hours under total nitrogen. Most of the methanol is removed under reduced pressure at 45°C. The residue was soaked in hot water (~s
oomz) and decolorized with activated carbon. After cooling,
Carefully acidify the basic solution with dilute hydrochloric acid. The crystalline precipitate is filtered, washed with water, then dissolved in ether and dried over sulfuric acid. The solvent was removed under reduced pressure to give 5-methoxy-3-((1-methylethyl)thio]-
Henso[b]thiophene-2-cal&nic acid 2.659
(90,1)'! i- get. Melting point: 151-2°C. This is used in the direct process.

Example 15 (Fl 5-methoxy-3-((1-methylethyl)thio-N-
IH-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide acetonitrile (15017
) in 5-methoxy-3-((1-methylethyl)thio]-benzo(b,1thiophene-2-carzenic acid (2,
5f, 0.0085 mol) Okobi 1,1/-Cal 2
A mixture of nylneumidazole (1,72t, (LOl 1 mol) is stirred and refluxed under nitrogen for 100 min. 5-aminotetrazole (α9
r, [LO11 mol) and triethylamine (1,0
7f, 0.011 mol) is added dropwise. Mixture ke 1
Heat to reflux for 7 hours and then remove most of the acetonitrile under water vacuum pressure at 40°C. Dip the residue in cold water (~5
001J), acidified with acetic acid (54m) and stirred. The resulting nine solids were separated by filtration, washed with water and then with ether, and dried to give 2.49 f solids.
obtain. Analytically pure 5 recrystallized from methanol
-methoxy-3-((1-methylethyl)thio-N-1
) 1-tetrazol-5-yl-benzo (b) thiophene-2-carboxamide 1.7 t (55%) ?
obtain.

Melting point 266°C (decomposition) Example 16 Example 16 (A-F) was prepared by the method of Example 15 (A-F).
One was prepared and shown in Table 1.

Table 1 Chill 16 (DI C02CH--8CH(CHx)2Ba
3 Oil (CH3)2 16 (odor C02H-8CH(CH5)2 70
140-1 Acetonitrile Example 16 (Fl Benzo(b)thiophene-2-carboxamide, 3-((1-
methylethyl)thio)-N-IH-tetrazole-5-
5-Methoxy-2-(2-methoxy-2-oxoethoxy)benzoic acid methyl ester N,N-dimethylformamide 2-hydroxy-5-methoxybenzoic acid methyl ester 5α0f(
(L27 mol), anhydrous potassium carbonate 8aOP ((16
4 mol) and methyl bromoacetate 25.4aj (46-
A mixture of 4i (130 mol) is stirred at room temperature for 24 hours. The reaction mixture is added to 1100 tons of ice/water, stirred for 1 hour and the precipitated crude product is filtered and washed with water. 54.7 t (78% yield) of analytically pure 5-methoxy-2-(2-methoxy-2-oxoethoxy)benzoic acid methyl ester were obtained by recrystallization from aqueous methanol. Melting point 82-85°C.

The following compounds are prepared in a similar manner to Procedure A above using the corresponding starting materials.

2-(2-methoxy-2-oxoethoxy)-5-phenylbenzoic acid methyl ester, melting point 66-6a5℃ 2-(2-methoxy-2-oxoethoxy)-3-phenylbenzoic acid methyl ester, melting point 60 4-Methoxy-2-(2-methoxy-2-oxoethoxy)benzoic acid methyl ester, melting point 74-77°C. [See above-mentioned J, D, Preware et al.] 6-Medoxy 2-(2-methoxy-2-oxoethoxy)benzoic acid methyl ester, melting point 73-74°C.

3-(2-methoxy-2-oxoethoxy)-2-naphthalenecarboxylic acid methyl ester, melting point 70-72°C Procedure B 6-methoxybenzoic acid methyl ester in 2-cyanomethane N,N-trimethylformamide 260M 2-hydroxy-3-methoxybenzoic acid methyl ester of 57.1f
(0.31 mol), anhydrous potassium carbonate 95.5? (0
, 69 mol) and chloroacetonitrile (2a5?,
The mixture of (38 mol L) is heated on a whole steam bath for 6 hours. The mixture is cooled, added to ice/water 17002, stirred for 1 hour and the precipitated crude product kW is washed with water. 2-cyanomethoxy-5-methoxybenzoic acid methyl ester recrystallized from aqueous methanol 52.5
? (Yield of 77 pieces) Good life. Melting point 77-78°C. [See U.S. Pat. No. 4,42Q, 476 t. Melting point 74~
75℃]. The following compounds are prepared in a similar manner to Procedure B using the corresponding starting materials.

2-cyanomethoxy-5-methoxybenzoic acid methyl ester, melting point 58-59.5°C 2-cyanomethoxy-4-
Methoxybenzoic acid methyl ester, melting point 59 DEG -64 DEG C. The following compounds are prepared using the method described by S.

2-cyanomethoxybenzoic acid ethyl ester, melting point 54
~56°C 2-cyanomethoxybenzonitrile, melting point 64-66°C Melting points of these compounds Its K, Gewand and I
(-J, Yanshi: z: J, Prakt, Che
This corresponds to the melting point reported for the compound in Vol. 315, p. 779 (1973).

Procedure C 3-hydroxynaphtho(2,3-1:+)furan-2-
Carboxylic acid methyl ester under nitrogen atmosphere) IJium metal 5.69 (CL2
A total solution of sodium methoxide is prepared by adding 4 mol) in small portions to methanol 650-. 5-(
2-Methoxy-2-oxoethoxy)-2-naphthalenecarboxylic acid methyl ester 47.0f ((117 mol)
Add 150 ml of methanol to the solution 1, stir and then add 150 ml of methanol.
TILE f.

The mixture was stirred at reflux for t-4.5 hours, cooled and added to 1.0 U of ice/water. The crude furan product is precipitated by acidification with glacial acetic acid, which is then washed with water. Analytically pure 6-hydroxynaphtho(2,3-b)furan-2-carboxylic acid methyl ester recrystallized from ethanol 26.9? (yield of 65%) is obtained. Melting point 15
8-160℃.

The following compounds are prepared in a similar manner to Procedure C above using the corresponding starting materials.

6-Hydroxy-5-phenylbenzofuran-2-carzenic acid methyl ester, melting point 167-169°C.

6-Hydroxy7-phenyl-2-penzofurancarzenic acid methyl ester, melting point 158-160°C.

3-Hydroxy-5-methoxy-2-penzofurancarzenic acid methyl ester, melting point 181-184°C.

3-Hydroxy-7-medoxy 2-penzofurancarzenic acid methyl ester, melting point 116-115°C.

Procedure D 6-Hyroxy 6-methoxy 2-penzofurancargenic acid methyl ester Force in toluene 175d under nitrogen atmosphere, lithium tert-butoxide 10.4? ((1093 mol) cD The mixture is stirred and cooled in a cold water bath. 4-Methoxy-2-(
A solution of 2-methoxy-2-oxoethoxy)benzoic acid methyl ester 1a1r (1071 mol) is added over t-80 minutes. The mixture is stirred and heated on a steam bath for 6 hours, then cooled and added to 600 t of ice/water.

The organic layer is completely separated, washed with water (2×1001111/) and combined with the original aqueous layer. The combined aqueous layers are washed with dichloromethane (2x25om) and then treated with F. Cooling in Ffik ice and acidification with glacial acetic acid precipitates the crude product, which is filtered and washed with water. Recrystallized from aqueous methanol to give 6-bitroxy-6-methoxy-2- The benzofurancardic acid methyl ester product a5f (54% yield) is obtained, melting point 93-95°C (melting points of 80-85°C are reported in the previously cited publications of T, P, F Reuwer et al.).

The following compounds are prepared in a similar manner to the procedure described above using the corresponding starting materials.

6-Hydroxy-5-methoxy-2-pene! Furancarzenitrile, melting point 166°C (decomposed).

The melting point of this compound is as described above in British Patent No. 1,233.2+.
In 58, the temperature is 184°C.

3-Hydroxy-6-medoxy 2-benzo7rancarmenitrile, melting point 160-161°C.

3-Hydroxy-7-medoxy 2-penzofurancarnitrile, melting point 181-182°C. J, P mentioned above
rakt, Chem, vol. 515, p. 779 (1975
A melting point of 176-178° C. was reported by Gewandt H, J. and Jansch in 2000).

Furthermore, the following compounds are produced.

5-7mi/-2-pen! 7-rancarzenic acid ethyl ester, melting point 76-78°C. (K, Geguant work H-J
, Jansch J., Prakt, Cheln, 515
Vol. 779, p. 1973 (1973). Agasi Munnon Ind, J, Chem, 14B 688
6 (1976)].

3-amino/-2-benzofurancardanitrile, melting point 1
59-161.5℃ [The above-mentioned S, S, and Sun are manufactured by the method reported by Pure Y, and 8.7 is manufactured by the method reported by Simunnon, where a melting point of 149℃ was reported. There is]

Procedure E 6-Medoxynaphtho(2,3-b)furan-2-carmenic acid methyl ester acetone 6-hydroxynaphtho(2+
5-b) 7 Run-2-Force/I/g 7@l f
” - A mixture of 2aOf (1110 mol), anhydrous potassium carbonate 15.1 (0.11 mol) and 10.6 g (14.1?, 0.11 mol) of dimethyl sulfate was
Stir under reflux for 4 hours. The mixture is cooled, filtered and the filter cake is washed several times with fresh acetone.

The combined F liquids were evaporated in total vacuum and the residue was recrystallized from methanol to give analytically pure 6-methoxynaphtho(
2,3-1:+)furan-2-carzenic acid methyl ester 2[L3F (77% yield) t-obtained. Melting point 121~
124℃.

By replacing methyl sulfate with diethyl t-m acid in the above procedure, etoyac ester is obtained.

The following additional alkoxy-esters are also prepared from the corresponding hydroxy-esters using this procedure.

5-Methoxy-5-phenyl-2-benzofurancarboxylic acid methyl ester 6-nitoxy-5-phenyl-2-penz7rancarzenate methyl ester 3-methoxy-7-phenyl-2-penz7rancarzenate methyl ester 5-ethoxy- 7-Phenyl-2-benzofurancarboxylic acid methyl ester These compounds are used as oils in the conversion to the corresponding calgenic acids without undue purification.

The following compounds are prepared in the same manner as Procedure E using the corresponding appropriate starting materials.

5.5-Dimethoxy-2-benzofurancarboxylic acid methyl ester, melting point 108-110°C6.6-Simethoxy-2-benzofurancarboxylic acid methyl ester, melting point 7
1 to 74°C [A melting point of 63 to 65°C has been reported for this compound by the aforementioned J, D, Preware et al.].

3.7-Simethoxy 2-benzofuran cargenic acid methyl ester, melting point 71-76°C.

Procedure F 5-methoyac-3-(1-methylethoxy)-2-benzofurancal dimethyl ester A solution of 1 L5 t (11 mol CL) of potassium tert-butoxide in 100 a dimethyl sulfoxide in a cold water bath under a nitrogen atmosphere. After cooling, 6-hydroxy-5-methoyac-2-penzofurancarzenic acid methyl ester 16.6f ((LO7
5 mol) solution. The mixture was stirred for 45 minutes after the addition was complete and 2-promoglopane 7,0IILl
(9,2f, (1075 mol) k Add at once.

After stirring at room temperature for 24 hours, the reaction mixture was diluted with ice/water 1.5
Add to k19 and stir for an additional hour. The precipitated product is treated with kW and washed with water. The gross yield is 9. O?
(46% yield). A sample recrystallized from aqueous methanol gives analytically pure 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid methyl ester. Melting point 66-68°C.

Replacing 2-promogloyne in the procedure described above with other alkylating agents (eg dimethyl sulfate) allows the preparation of the corresponding alkoxy-esters.

Additionally, the following additional alkoxy-esters are also prepared from the appropriate hydroxy-esters by this procedure.

3-(1-Methylethoxy)-5-phenyl-2-benzofurancarboxylic acid methyl ester 3-(1-methylethoxy)-7-phenyl-2-benzofurancarboxylic acid methyl ester 7-medoxy 3-(nonyloxy)
-2-benzofurancarboxylic acid methyl ester 6-medoxy 6-(1-methylethoxy)-2-benzofurancarmene methyl ester These compounds are used as oils for conversion to the corresponding carboxylic acids without undue purification. .

Additionally, the following compounds are prepared using the above procedure FK using the appropriate corresponding starting materials.

7-Medoxy 6-(1-methylethoxy)-2-benzofurancarmene methyl ester, melting point 53-55°C
.

3.5-dimethoxy-2-benzofurancarbonitrile, melting point 118-120°C.

3.6-Simethoxy-2-benzofurancarbonitrile, melting point 139-140°C.

6.7-Simethoxy-2-benzofurancarbonitrile, melting point 106-109°C.

Procedure G 5-methoxy-3-(phenylmethoxy)-2-penzofurancargenic acid methyl ester acetonitrile 200
3-hydroxy-5-methoxy-2-benzofurancarmene methyl ester aof (0,036 mol) in d
〇-PhenylmethΦC N, N'-diisopropylisourea (L, J, Matthias: 5ynthesis
561 (1979)] 1αot ([L043 mol)] is stirred and refluxed for 22 hours under a total nitrogen atmosphere. The mixture is cooled and filtered to remove the by-product 1,3-silylable pylurea. The insoluble material is washed with hexane and the combined P solution is evaporated in vacuo.

The residue was treated with 250M diethyl ether and the mixture was diluted again and evaporated. The crude oily residue was used as an eluent in dichloromethane/dichloromethane (2:1).
-C&IJ kake~□1. 1. 5-methoxy-3-(phenylmethoxy)-2-benzo7rancarzene powder methyl ester 7.2t (yield: 64 cs) was obtained as an oily product by treatment with 1-madography. The ester is saponified without further purification.

Also, 6-medoxy 3-(phenylmethoxy)-2-benzofurancar dimethyl ester is produced by the above operating method. Melting point: 81-84°C.

Procedure H 6-(acetylamino)-2-benzofurancarbonitrile A solution of 5.86 f (α024 mol) of 6-amino-2-benzofuran carbonitrile in pyridine 501 is cooled in water and dissolved over 15 minutes in acetyl chloride 2. (11
4 (2,21f, 0.028 mol). The mixture is stirred in water for a further 2 hours and added to 250 f ice/water. The precipitated crude product is filtered, washed with water and recrystallized from aqueous methanol to give 2.8f (857% yield) of 6-(acetylamino)-2-benzofurancarbonitrile. A sample recrystallized twice in the manner described above gives analytically pure product.

Melting point 187-189°C.

Furthermore, using the appropriate corresponding starting materials, the procedure HV
The following compound is produced by c and c.

3-(acetylamino)-2-benzofurancarmenic acid ethyl ester, melting point 164-167°C [S above mentioned,
B. Manojan and Y. S. Agassimundin reported a melting point of 166° C. for this compound].

Procedure 3. 10.6 f(0,
045 mol) mixture? 1. Treat with 75 ml of ON aqueous sodium hydroxide solution. The new mixture is stirred at reflux for 45 minutes, cooled and added to 750 t of ice/water. After extraction with dichloromethane (3×300 m), the aqueous layer is cooled in water and acidified with glacial acetic acid to precipitate the crude product. The precipitate was filtered off and washed with water to give 9.69 g of 3,5-dimethoxy-2-benzofurancarboxylic acid (crudeness 88%). A sample recrystallized from ethyl acetate gives analytically pure product. Melting point: 168°C (decomposed).

Additionally, the following compounds are prepared by engineering using the appropriate corresponding starting materials.

5-/) xy-5-phenyl-2-benzfurancarboxylic acid, melting point 190-191°C 3-ethyasi-5-phenyl-2-benzfurancarmen, melting point 168-170
°C 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxylic acid, melting point 170-17 (L5 °C 3-methoxy-7-7enyl-2-benzofurancarboxylic acid, melting point 175-178 °C 6-nitoxy7 - Phenyl-2-benzo7rancarin, melting point 165-166
°C3-(1-,)'thylethoxy)-7-phenyl-2
``''Benzofurancarboxylic acid, melting point 180-182°C 3-(1-methylethoxy)-5-methoxy-2-benzofurancarboxylic acid, melting point 136-138°C 5-methoxy-3-phenylmethoxy-2-benzofurancarboxylic acid Acid, melting point 176°C (decomposed) 3.6-dimethoxy-2-penzofurancargenic acid, melting point 145°C (decomposed) 3-(1-methylethoxy)-6-medoxy 2-benzofurancal $711.8 points 120°C (decomposition) 3.7-dimethoxy-2-benzofurancarboxylic acid,
Melting point 189-190°C 3-(methylethoxy)-7-medoxy-2-benzofurancarboxylic acid, melting point 128-129°C 3-acetylamino-2-benzo7rancarzenic acid, melting point 208°C (decomposition) [F, A mentioned above .

Trofimov et al. reported a melting point of 210'C (decomposition) for this compound].

6-Methoxynaphtho(2,3-'b)furan-2-cardoic acid, melting point 220°C (decomposed) 6-Medoxy 3-7enylmethoxy-2-benzofurancarboxylic acid, melting point 140°C (decomposed) Procedure J 7-Medoxy 3-(Nonyloxy)-2-benzofurancarmenic acid A mixture of 1.54 F (0,012 mol) of potassium 6-ptoxide in 501 methyl sulfoxide under a nitrogen atmosphere was converted into crude 7-medoxy 3-(nonyloxy)-2-
Benzofurancarboxylic acid methyl ester 2.5 ? (
(10066 mol).

After stirring for 6 hours at room temperature, the mixture is added to 400 t of gold ice/water. Add the new mixture to dichloromethane (5X25011
j) and cooled the aqueous layer in water and 4. O
Make it acidic by dispersing NN. The semi-solid precipitate that forms is removed by extraction with dichloromethane (3×150d). The combined extracts were backwashed with water (2X200111J), dried (anhydrous sodium sulfate), and odor-evaporated to give 7-medoxy-3-(nonyloxy)-2-benzofurancarmenic acid (0,71, 32%) as a t-oil. This crude oil is converted to the corresponding 2-benzofurancarbamoyltetrazole without further purification.

The procedure included 6-medoxy 5-phenyl-2-benzofurancardoic acid α902 (α003
4 morn and 1,1-carbonylbis(1H-imif
y-le) 0.5! A mixture of M' ((LOO 34 mol) is stirred and refluxed for t-1 hour. Anhydrous 5-aminotetrazole cL29t (00034 mol) is added to this mixture and the new mixture is stirred and refluxed for a further 16 hours. Cooled to room temperature and refluxed for 6 hours. A precipitate of medoxy-5-phenyl-N-IB-tetrazol-5-yl-2-benzo7rancarmexamide is formed. This precipitate is filtered and recrystallized from methanol to give an analytically pure Tetrazole [1911 (yield: 80%) was obtained.

Melting point: 260-262°C.

The following compounds are prepared in a similar manner as in Procedure K using the appropriate corresponding starting materials fit-.

6-nitoxy5-722-N-IB-tetrazol-5-yl-2-benzofurancarboxamide, melting point 2
63-266℃.

3-(1-methylethoxy)-5-722-N-IH
-Tetrazol-5-yl-2-benzofurancarboxamide, melting point 255-254°C.

3-Methoxy-7-phenyl-N-IB-tetrazol-5-yl-2-benzo7rancarmexamide (1:1-11 combination with imidazole), □j melting point 2
14-215°C.

3-Ethoxy-7-phenyl-N-1H-tetrazol-5-yl-2-benzoheptacarmexamide (1:1 complex with imidazole), mp 214-216<0>C.

3-(1-methylethoxy)-7-7enyl-N-IB
-tetrazol-5-yl-2-benzofurancal 2xamide (1=1 complex with imidazole), melting point 224
~227℃.

Procedure L 3.6-Nomethoxy N-IH-tetrazol-5-yl-2-benzofurancarboxamide N, 3.6-Simethoxy 2-benzofurancarboxylic acid aof ((1,023 mol) and 1.1-carbonylbis(II(-imidazole) a
clt<1049 mol) tr) The mixture is stirred and warmed for 20 minutes on a steam bath. The mixture is cooled to room temperature, 5-aminotetrazole-hydrate ZSt (α024 mol)'t-is added and the new mixture is heated again for 20 minutes. The reaction mixture is cooled, added to 650 tons of ice/water and acidified with 4,ON hydrochloric acid to precipitate the tetrazole product. The precipitate was filtered, washed with 50% aqueous ethanol and recrystallized from aqueous N,N-methylformamide to give analytically pure 6,6-simethoxy N-
2.8 t (yield 43%) of IH-tetrazol-5-yl-2-benzofurancarboxamide are obtained. Melting point 23
8°C (decomposition).

The following compounds are prepared in a similar manner to the procedure using the appropriate corresponding starting materials.

3.5-dimethoxy-N-11(-tetrazole-5-
yl-2-benzofurancarboxamide, melting point 243°C
(Decomposition) 6.6-Simethoxy N-1)! -tetrazole-5-
Ilu 2-benzofurancargyxamide, melting point 238°C
(Decomposition) 3.7-Simethoxy N-1) 1-tetrazole-5-
yl-2-benzo7rancarzexamide, melting point 255~
238°C 6-tunyloxy-7-methoxy N-IH-tetrazol-5-yl-2-benzofurancarboxamide, melting point 207-209°C 6-acetylamino-N-IH-tetrazol-5-yl-2-benzofurancarboxamide, melting point 275 ℃(
decomposition) 6-methoxy N-(1H-tetrazol-5-yl)
nuts (2,3-b, l-furan-2-carboxamide,
Melting point 250°C (decomposition) Operating method M 5-methoxy-3-(1-methylethoxy)-N-IH
-tetrazol-5-yl-2-benzofurancarboxamide 5-methoxy-3-(
1-methylethoxy)-2-benzofurancarboxylic acid 5
．． 7t (α025 mol) 1,1-carginylbis(1H-imidazole) 4.29 (α026 mol)
The mixture is stirred and refluxed for t-1 hour.

Cool the mixture and add anhydrous 5-aminotetrazole Z,5
? (1027 mol) and triethylamine y7.7rt
d (5,6t, cL055 mol) and heated to reflux for a further 5 hours. The cooled reaction mixture is added to 1.5 kg of ice/water and acidified with glacial acetic acid to precipitate the tetrazole product. The precipitate was filtered, washed with water and recrystallized from aqueous acetonitrile to give analytically pure 5-methoxy-3-tetrazol-5-yl-2-benzofurancarboxamide &O2 (yield 82 cs). Melting point 241-245°C.
The following compounds are prepared in a manner analogous to that described in Procedure M using the appropriate corresponding starting materials.

N-1H-tetrazol-5-yl-2-benzofurancarboxamide in 5-methoxy-3-phenylmeth, melting point 205°C (decomposition) 2-Benzofurancarboxamide, mp 210°C (decomposed) 6-medoxy 3-(1-methoxyethoxy)-NIB-tetrazol-5-yl-2-benzofurancarboxamide, mp 231°C (decomposed) 7-medoxy 3-( 1-methylethoxy)-N-IH-tetrazol-5-yl-2
-Benzo7rancarzexamide, melting point 188-190°C
Procedure N 6-amino-N-1) 1-tetrazol-5-yl-2
-Penzofurancarboxamide ether/-/I'5 om ozbin (12,0M) [3-(acetylamino)-N-IH-tetrasol-5-yl-2-benzofurancarboxamide 5 in acid 50g
．． A mixture of 3f (0,019 mol)? Stir and reflux for 2 hours. The reaction mixture was cooled in water to give 3-amino-N-IH.
-Tetrazol-5-yl-2-benzofurancarboxamide is precipitated. The precipitate was filtered, washed with 50 g of aqueous ethanol and recrystallized from aqueous 2-methoxyethanol to give analytically pure 3-amino-N-
IH-tetrazol-5-yl-2-benzofurancarboxamide 2.4f (yield 53%) is obtained. Melting point 275
°C (decomposition).

The following compounds are prepared in a similar manner as described in Procedure N using the appropriate corresponding starting materials.

5-(3-Amino-benzofuranyl)-1H-tetrazole Melting point 185°C (decomposition) Procedure 0 5-(5,6-Simethoxy2-benzofuranyl)-
1) 3,6-Simethoxy 2-benzofurancarzenitrile A8 in 1-tetrazole N,N-dimethylformamide 40d? ((1
A mixture of sodium azide 54f (Q, 052 mol) and ammonium chloride 2.8f (0,052 mol) is stirred and heated on a steam bath for 4 hours under a nitrogen atmosphere. The mixture was cooled, added to 400 t of ice/water and acidified with glacial vinegar to give 5-(3,6--/methoxy 2
-benzofuranyl)-1B-tetrazole is precipitated. The precipitate was filtered, washed with water and recrystallized from ethyl acetate to give analytically pure tetrazole product2. O
f (yield 4396) t- obtained. Melting point: 182-184°C.

The following compounds are prepared in a similar manner as described in Procedure 0 using the appropriate corresponding starting materials.

5-(3,5-dimethoxy-2-benzofuranyl)-
1H-tetrazole, melting point 216°C (decomposition) 5- (5
, 2-pentufuranyl)-1H-tetrazole in ,7-diphth, mp 206-205°C5-(6-acetylamino-2-benzofuranyl)-1H-tetrazole, mp 267°C (decomposition).

Patent applicant Warner-Lampert Kompany□
1,; 2 other people

Claims (1)

[Scope of Claims] 1) A compound having the formula ▲A mathematical formula, a chemical formula, a table, etc.▼(I) and a pharmaceutically acceptable salt thereof. In the above formula, (1) R^1, R^4 and R^5 are H, 1
~12 carbon alkyl, 1-12 carbon alkoxy, hydroxy, aryl, each R^1 on adjacent carbons such that the two R^1s together are methylenedioxy having twice bonded R^1, nitro,
amino, substituted amino, mercapto, alkylthio of 1 to 4 carbons, alkylsulfinyl of 1 to 4 carbons, alkylsulfonyl of 1 to 4 carbons, arylthio, arylsulfinyl, arylsulfonyl or halogen; (2) R^2 is H, alkyl of 1 to 12 carbons, alkoxy of 1 to 12 carbons, arylmethoxy, amino, substituted amino, mercapto,
alkylthio of 1 to 4 carbons, alkylsulfinyl of 1 to 4 carbons, alkylsulfonyl of 1 to 4 carbons, arylthio, arylsulfinyl or arylsulfonyl, (3) R^3 is A ▲ formula, There are chemical formulas, tables, etc.▼A or B ▲There are mathematical formulas, chemical formulas, tables, etc.▼B (However, if R^3 is B, R^2 is H or an alkyl of 1 to 12 carbons) (4) X is oxygen or S(O)_q (where q is 0, 1
or 2). 2) A compound according to claim 1, wherein X is sulfur. 3) The compound according to claim 1, wherein X is oxygen. 4) The compound according to claim 2, wherein R^3 is A as described in claim 1. 5) The compound according to claim 2, wherein R^3 is B as described in claim 1. 6) The compound is 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]
5. A compound according to claim 4 which is a thiophene-2-carboxamide. 7) The compound according to claim 6, wherein the compound is an arginine salt. 8) The compound according to claim 6, wherein the compound is a sodium salt. 9) The compound is 3-ethoxy-5-methoxy-N-1H-
Tetrazol-5-yl-benzo[b]thiophene-2
- A compound according to claim 4 which is a carboxamide. 10) The compound is 7-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b
] The compound according to claim 4, which is thiophene-2-carboxamide. 11) The compound is 3-(1-methylethoxy)-5-methyl-N-1H-tetrazol-5-yl-benzo[b]
5. A compound according to claim 4 which is a thiophene-2-carboxamide. 12) The compound is 6-chloro-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]
5. A compound according to claim 4 which is a thiophene-2-carboxamide. 13) The compound according to claim 4, wherein the compound is 3-methoxy-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide. 14) The compound is 5-chloro-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]
5. A compound according to claim 4 which is a thiophene-2-carboxamide. 15) The compound is 3-(1,1-ditylethoxy)-5-
5. A compound according to claim 4 which is methoxy-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide. 16) The compound is 3-(1-methylethoxy)-5-nitro-N-1H-tetrazol-5-yl-benzo[b]
5. A compound according to claim 4 which is a thiophene-2-carboxamide. 17) The compound according to claim 4, wherein the compound is 3,5-dimethoxy-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide. 18) The compound is 6-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b
] The compound according to claim 4, which is thiophene-2-carboxamide. 19) The compound is 3-(1-methylethoxy)-N-1H
-Tetrazol-5-yl-benzo[b]thiophene-
5. A compound according to claim 4 which is a 2-carboxamide. 20) The compound is 3-chloro-N-1H-tetrazole-
5. A compound according to claim 4 which is 5-yl-benzo[b]thiophene-2-carboxamide. 21) The compound according to claim 4, wherein the compound is 5-methoxy-3-[(1-methylethyl)thio]-N-1H-tetrazol-5-yl-benzothiophene-2-carboxamide. 22) The compound is 3-[(1-methylethyl)thio]-N
5. The compound according to claim 4, which is -1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide. 23) The compound is 5-[5-methoxy-3-(1-methylethoxy)-benzo[b]thien-2-yl]-1H-
6. A compound according to claim 5 which is a tetrazole. 24) The compound according to claim 5, wherein the compound is 5-[3-(1-methylethoxy)benzo[b]-thien-2-yl]-1H-tetrazole. 25) A compound according to claim 3, wherein R^3 is A as described in claim 1. 26) A compound according to claim 3, wherein R^3 is B as described in claim 1. 27) The compound is 3-methoxy-5-phenyl-N-1H
-Tetrazol-5-yl-2-benzofurancarboxamide. 28) The compound is 3-ethoxy-5-phenyl-N-1H
-Tetrazol-5-yl-2-benzofurancarboxamide. 29) Claim 25, wherein the compound is 3-(1-methylethoxy)-5-phenyl-N-1H-tetrazol-5-yl-2-benzofurancarboxamide.
Compounds described in Section. 30) The compound is 3-methoxy-7-phenyl-N-1H
-Tetrazol-5-yl-2-benzofurancarboxamide. 31) The compound is 3-ethoxy-7-phenyl-N-1H
-Tetrazol-5-yl-2-benzofurancarboxamide. 32) Claim 25, wherein the compound is 3-(1-methylethoxy)-7-phenyl-N-1H-tetrazol-5-yl-2-benzofurancarboxamide.
Compounds described in Section. 33) The compound according to claim 25, wherein the compound is 3,6-dimethoxy-N-1H-tetrazol-5-yl-2-benzofurancarboxamide. 34) The compound according to claim 25, wherein the compound is 3,5-dimethoxy-N-1H-tetrazol-5-yl-2-benzofurancarboxamide. 35) The compound is 6-methoxy-3-phenylmethoxy-
26. The compound of claim 25 which is N-1H-tetrazol-5-yl-2-benzofurancarboxamide. 36) The compound according to claim 25, wherein the compound is 3,7-dimethoxy-N-1H-tetrazol-5-yl-2-benzofurancarboxamide. 37) The compound is 3-nonyloxy-7-methoxy-N-
26. The compound according to claim 25, which is 1H-tetrazol-5-yl-2-benzofurancarboxamide. 38) The compound according to claim 25, wherein the compound is 3-acetylamino-N-1H-tetrazol-5-yl-2-benzofurancarboxamide. 39) The compound according to claim 25, wherein the compound is 3-methoxy-N-(1H-tetrazol-5-yl)-naphtho[2,6-b]furan-2-carboxamide. 40) Claim 25, wherein the compound is 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-2-benzofurancarboxamide
Compounds described in Section. 41) The compound is 5-methoxy-3-phenylmethoxy-
26. The compound of claim 25 which is N-1H-tetrazol-5-yl-2-benzofurancarboxamide. 42) The compound according to claim 25, wherein the compound is 6-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzofurancarboxamide. 43) The compound according to claim 25, wherein the compound is 7-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzofurancarboxamide. 44) The compound is 3-amino-N-1H-tetrazole-
26. A compound according to claim 25 which is 5-yl-2-benzofurancarboxamide. 45) The second claim wherein the compound is 5-(3-amino-2-benzofuranyl)-1H-tetrazole
Compound according to item 6. 46) The compound according to claim 26, wherein the compound is 5-(3,6-dimethoxy-2-benzofuranyl)-1H-tetrazole. 47) The compound according to claim 26, wherein the compound is 5-(3,5-dimethoxy-2-benzofuranyl)-1H-tetrazole. 48) The compound according to claim 26, wherein the compound is 5-(3,7-dimethoxy-2-benzofuranyl)-1H-tetrazole. 49) The compound according to claim 26, wherein the compound is 5-(3-acetylamino-2-benzofuranyl)-1H-tetrazole. 50) A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier. 51) A method for treating allergies in a mammal, which comprises administering an effective amount of the pharmaceutical compound according to claim 1 to a mammal in need of such treatment.