GB2036017A - Selective Process for the Preparation of 7-hydroxycoumarin Derivatives - Google Patents
Selective Process for the Preparation of 7-hydroxycoumarin Derivatives Download PDFInfo
- Publication number
- GB2036017A GB2036017A GB7938197A GB7938197A GB2036017A GB 2036017 A GB2036017 A GB 2036017A GB 7938197 A GB7938197 A GB 7938197A GB 7938197 A GB7938197 A GB 7938197A GB 2036017 A GB2036017 A GB 2036017A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- compound
- reacting
- produce
- haloresorcinol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical class C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 title description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 7
- 235000015320 potassium carbonate Nutrition 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims abstract description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract 2
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- -1 1 -ethoxycarbonylmethoxy Chemical class 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KLOIYEQEVSIOOO-UHFFFAOYSA-N carbocromen Chemical class CC1=C(CCN(CC)CC)C(=O)OC2=CC(OCC(=O)OCC)=CC=C21 KLOIYEQEVSIOOO-UHFFFAOYSA-N 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
A selective process for the preparation of substantially pure 8- halo-3-( beta -diethylaminoethyl)-4- methyl-7-ethoxycarbonylmethoxy coumarin comprises a) reacting a 2- haloresorcinol with alpha -acetyl- gamma - butyrolactone in the presence of KBr and acetic acid, b) reacting the resulting 3-( beta -bromoethyl)-4-methyl- 7-hydroxy-8-halocoumarin with ethyl chloroacetate and reacting the product with diethylamine in the presence of anhydrous K2CO3 to obtain the desired final product. Steps a) and b) may be reversed. Acid addition salts of the final product are disclosed.
Description
SPECIFICATION
Selective Process for the Preparation of 7-hydroxycoumarin Derivatives
The present invention relates to the preparation of derivatives of 7-hydroxycoumarin.
In ourcopending U.K. Patent Application No. 43690/78, (Publication No. 2008109 A) there is disclosed a new method for the preparation of basic coumarin derivatives of the general formula IA and of their acid addition salts with organic and inorganic acids:
where
R1 is an alkyl group having thereon a basic substituent;
R2 is H, alkyl or aryl;
R3 is an alkyl group having thereon a basic substituent, or an alkenyl, carboxyalkyl or alkoxycarboxy-alkyl group; and
X is halogen.
The compounds of formula IA may be considered as derivatives of carbochromene, i.e., 3-(p- diethylam inoethyl)-4-methyl-7-ethoxycarbonyl methoxycoumarin chlorohydrate, which is known in the literature and used as coronary dilator. Compared with carbochromane, the main characteristic of the compounds of formula IA is the presence of a halogen atom in the 8-position and a particular feature of the method disclosed in the previous application, is that the 8-halo derivatives are obtained in substantially pure state, i.e. without the presence of other halogen-derivated isomers or dihalogen derivatives or other impurities.
The present invention provides an alternative selective method for the preparation of 8-halo-3-(p- diethylaminoethyl)-4-methyl-7-ethoxycarbonylmethoxy coumarin and in particular the 8-chloro derivative, i.e. compounds of the formula IB
According to the present invention the compounds of formula IB, particularly the 8-chloro compound, and their acid addition salts, are prepared in isomerically pure form by
a) reacting a 2-haloresorcinol of the formula II with cg-acetyl-y-butyrolactone in the presence of
KBr and acetic acid to produce a compound of formula Ill;
where
X is as defined above;
b) reacting the compound of formula Ill with ethyl chloroacetate to produce a compound of the formula IV::
and,
c) reacting the compound of formula IV with diethylamine to produce the compound of formula
IB. Alternatively steps a) and b) can be reversed, i.e. the 2-halo-resorcinol may first be reacted with the ethylchloroacetate and then with the a-acetyl-y-butyrolactone. The characteristic step of the present invention is the reaction of the 8-halo-resorcinol, or its 1 -ethoxycarbonylmethoxy derivative, with the a-acetyl-y-butyrolactone in the presence of KBr and acetic acid.
The full reaction scheme is as follows:
Step a) is preferably carried out under reflux conditions.
Step b) is preferably carried out in the presence of a solvent, e.g. acetone and in the presence of
KI and K2CO3, and is preferably followed by recrystallisation of the compound of formula IV, e.g. from aqueous acetone.
Step c) is preferably carried out in a suitable solvent such as benzene and a hydrogen bromide acceptor, preferably anhydrous K2CO3.
Following step c), the product compound may be converted into an acid addition salt in known manner, and preferably the hydrochloride by reaction in solution in CH2Cl2 with HCI.
The selective process according to the present invention will be better understood from the following working examples of the various phases of the process.
Example 1 3-(,B-bromoethyl)-4-methyl-7-hydroxy-8-chlorocoumarin (Ill) To a solution of 34 g of HBr in 116 ml of acetic acid there are added 9.2 g of 2-chlororesorcine and then, at 0 C, there are added dropwise 6.9 g of a-acetyl-y-butyrolactone. The reaction mixture is refluxed for 2 hours and then cooled to room temperature.
Upon addition, with stirring, of 350 ml of H2O an oily mass separates. The oily residue, on recrystal lisation from MetOH, gives the 3-(p-bromoethyl)-4-methyl-7-hydroxy-8-chlorocoumarin; m.p.
192-1 940C.
Example 2 3-(t\-brornoethyl)-4-rnethyl-7-ethoxycarbonyl-methoxy-8-chlorocoumarin ( IV)
To a solution of 2.6 g of 3-(}ss-bromoethyl)-4-methyl-7-hydroxy-8-chlorocoumarin in 16 ml of acetone there are added 2.36 g of K2CO3 and the mixture is refluxed for 1 5 minutes. There are then added 4 mg of KI and 2 g of ethyl chloroacetate, keeping the mixture at the boiling point for an additional 1 5 minutes. After cooling to room temperature, there are added 70 ml of H2O and the mixture is stirred overnight. There precipitates therefrom a crystalline product which is removed by filtration and washed with water to a neutral pH.The residue, after recrystallization from acetonewater, gives the 3-(-bromoethyl)-4-methyl-7-ethoxycarbonyl methoxy-8-chlorocou marin; m.p. 1 61 - 1620C.
Example 3 3-(p-diethylaminoethyl)-4-methyl-7-ethoxy-carbonyl methoxy-8-chlorocoumarin Chlorohydrate (IB)
To a solution of 1 g of 3-(A-bromoethyl)-4-methyl-7-ethoxywarbonylmethoxy-8-chloro-coumarin in 5 ml of benzene there are added 0.6 g of anhydrous K2CO3 and 0.45 g of diethylamine. The mixture is refiuxed for 5 hours and is then cooled to room temperature. The organic phase is washed with water and then dried over Na2SO4. After evaporation of the solvent, there is obtained a residue which is then dissolved in CH2CI2. The resulting solution is treated with HCI and then evaporated. The residue, after recrystallization from absolute EtOH, gives the 3-(,B-diethylaminoethyl)-4-methyl-7-ethoxywarbonyl- methoxy-8-chlorocoumarin chlorohydrate; m.p. 219--2200C.
Claims (10)
1. A method for the preparation of 8-halo-3-(p-diethylaminoethyl)-4-methyl-7- ethoxycarbonylmethoxy coumarin of the formula IB
where X is halogen, which comprises a) reacting a 2-haloresorcinol of the formula Il with a-acetyl-y-butyrolactone in the presence of KBr and acetic acid to produce a compound of the formula Ill;
where X is as defined above;
b) reacting the compound of formula Ill with ethyl chloroacetate to produce a compound of the formula IV:
and
c) reacting the compound of formula IV with diethylamine to produce the compound of formula
IB.
-
2. A method according to claim 1, where X is chlorine.
3. A method according to claim 1 or 2, wherein step b) is carried out in the presence of K2CO3 and
KI.
4. A method according to claim 1, 2 or 3, wherein step c) is carried out in the presence of anhydrous K2CO3.
5. A method according to any one of claims 1-4, wherein following step b) and before step c) the compound of formula IV is recrystallised from solution in aqueous acetone.
6. A method according to any one of the preceding claims, modified in that step a) comprises reacting the 2-haloresorcinol with ethyl chloracetate to produce a 1 -ethoxycarbonylmethoxy-2- haloresorcinol, and step b) comprises reacting the 1 -ethoxycarbonylmethoxy-2-haloresorcinol with said -acetyl-y-butyrolactone in the presence of said KBr and acetic acid to produce said compound of formula IV.
7. A method according to any one of claims 1-6, including the additional step of converting the product compound of formula IB to an acid addition salt.
8. A method according to claim 7, wherein said salt is the hydrochloride.
9. A method according to claim 1, substantially as hereinbefore described in Examples 1-3.
10. A compound of formula IB as defined in claim 1 when prepared by a method claimed in any one of claims 1-5, 8 or 9.
1 An acid addition salt of a compound of formula IB as defined in claim 1, when prepared by a method claimed in claim 6 or 7.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT29466/78A IT1100069B (en) | 1978-11-06 | 1978-11-06 | SELECTIVE PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 7-HYDROXICUMARINE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2036017A true GB2036017A (en) | 1980-06-25 |
| GB2036017B GB2036017B (en) | 1983-03-23 |
Family
ID=11227039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7938197A Expired GB2036017B (en) | 1978-11-06 | 1979-11-05 | Selective process for the preparation of 7-hydroxycoumarin derivatives |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5569575A (en) |
| AT (1) | AT372380B (en) |
| BE (1) | BE879821A (en) |
| CA (1) | CA1113948A (en) |
| CH (1) | CH641796A5 (en) |
| DE (1) | DE2944376A1 (en) |
| ES (1) | ES485745A1 (en) |
| FI (1) | FI793400A7 (en) |
| FR (1) | FR2440948A1 (en) |
| GB (1) | GB2036017B (en) |
| GR (1) | GR68055B (en) |
| IT (1) | IT1100069B (en) |
| NL (1) | NL7907983A (en) |
| PT (1) | PT70412A (en) |
| YU (1) | YU40580B (en) |
| ZA (1) | ZA795805B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5482975A (en) * | 1991-10-22 | 1996-01-09 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents |
| US5484951A (en) * | 1990-10-19 | 1996-01-16 | Octamer, Incorporated | 5-iodo-6-amino-6-nitroso-1,2-benzopyrones useful as cytostatic and antiviral agents |
| US5783599A (en) * | 1993-02-24 | 1998-07-21 | Octamer Inc | Methods of treating cancer and viral infections with 5-iodo-6-amino-and 5-iodo-6-nitroso-1 2-benzopyrones |
| US5877185A (en) * | 1991-10-22 | 1999-03-02 | Octamer, Inc. | Synergistic compositions useful as anti-tumor agents |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2361M (en) * | 1961-08-12 | 1964-02-24 | Cassella Farbwerke Mainkur Ag | Coronary dilator drug containing a derivative of 7-hydroxy-coumarin. |
| DE2039867A1 (en) * | 1970-08-11 | 1972-02-17 | Troponwerke Dinklage & Co | Amino-hydroxypropyl-coumarins - with coronary dilating activity |
| IT1088554B (en) * | 1977-11-17 | 1985-06-10 | F I D I A Spa | SELLECTIVE PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 7-INDROSSI CUMARINA |
-
1978
- 1978-11-06 IT IT29466/78A patent/IT1100069B/en active
-
1979
- 1979-10-30 ZA ZA00795805A patent/ZA795805B/en unknown
- 1979-10-31 CH CH975079A patent/CH641796A5/en not_active IP Right Cessation
- 1979-10-31 NL NL7907983A patent/NL7907983A/en not_active Application Discontinuation
- 1979-10-31 FI FI793400A patent/FI793400A7/en not_active Application Discontinuation
- 1979-11-02 DE DE19792944376 patent/DE2944376A1/en not_active Withdrawn
- 1979-11-05 BE BE0/197963A patent/BE879821A/en not_active IP Right Cessation
- 1979-11-05 YU YU2696/79A patent/YU40580B/en unknown
- 1979-11-05 CA CA339,137A patent/CA1113948A/en not_active Expired
- 1979-11-05 GR GR60422A patent/GR68055B/el unknown
- 1979-11-05 PT PT70412A patent/PT70412A/en unknown
- 1979-11-05 JP JP14376579A patent/JPS5569575A/en active Pending
- 1979-11-05 GB GB7938197A patent/GB2036017B/en not_active Expired
- 1979-11-06 FR FR7927350A patent/FR2440948A1/en active Granted
- 1979-11-06 ES ES485745A patent/ES485745A1/en not_active Expired
- 1979-11-06 AT AT0712979A patent/AT372380B/en not_active IP Right Cessation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5484951A (en) * | 1990-10-19 | 1996-01-16 | Octamer, Incorporated | 5-iodo-6-amino-6-nitroso-1,2-benzopyrones useful as cytostatic and antiviral agents |
| US5519053A (en) * | 1990-10-19 | 1996-05-21 | Octamer, Inc. | 5-Iodo-6-amino-1,2-Benzopyrones and their metabolites useful as cytostatic agents |
| US5482975A (en) * | 1991-10-22 | 1996-01-09 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents |
| US5877185A (en) * | 1991-10-22 | 1999-03-02 | Octamer, Inc. | Synergistic compositions useful as anti-tumor agents |
| US5783599A (en) * | 1993-02-24 | 1998-07-21 | Octamer Inc | Methods of treating cancer and viral infections with 5-iodo-6-amino-and 5-iodo-6-nitroso-1 2-benzopyrones |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2440948A1 (en) | 1980-06-06 |
| NL7907983A (en) | 1980-05-08 |
| GR68055B (en) | 1981-10-29 |
| ATA712979A (en) | 1983-02-15 |
| CA1113948A (en) | 1981-12-08 |
| YU40580B (en) | 1986-02-28 |
| DE2944376A1 (en) | 1980-05-14 |
| AT372380B (en) | 1983-09-26 |
| PT70412A (en) | 1979-12-01 |
| GB2036017B (en) | 1983-03-23 |
| ES485745A1 (en) | 1980-07-01 |
| BE879821A (en) | 1980-03-03 |
| CH641796A5 (en) | 1984-03-15 |
| IT7829466A0 (en) | 1978-11-06 |
| IT1100069B (en) | 1985-09-28 |
| ZA795805B (en) | 1980-10-29 |
| JPS5569575A (en) | 1980-05-26 |
| FI793400A7 (en) | 1981-01-01 |
| YU269679A (en) | 1983-01-21 |
| FR2440948B1 (en) | 1983-06-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19941105 |