US2473484A - Method for the preparation of aminophthalidylalkanes - Google Patents
Method for the preparation of aminophthalidylalkanes Download PDFInfo
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- US2473484A US2473484A US696619A US69661946A US2473484A US 2473484 A US2473484 A US 2473484A US 696619 A US696619 A US 696619A US 69661946 A US69661946 A US 69661946A US 2473484 A US2473484 A US 2473484A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- 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
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- This invention relates to a method for the (4) preparation of new compositions of matter and, more particularly, for the preparation of compounds having the following structure:
- X is a single or multiple fiveor six-mem- (5) O bered ring system which may be saturated or unsaturated, isocyclic or heterocyclic, and substituted or unsubstituted;
- R. is, for example, I C CER hydrogen, alkyl containing not over 10 carbon l IHaHY atoms, aryl, aralkyl;
- R" and R may be hydro- (6) gen, halogen, alkoxyl, aralkyl, or alkyl of less than six carbon atoms, and when one is hydrogen, the other may also be hydroxyl and aryl;
- O is, for example, I C CER hydrogen, alkyl containing not over 10 carbon l IHaHY atoms, aryl, aralkyl;
- R" and R may be hydro- (6) gen, halogen, alkoxyl, aralkyl, or alkyl of less than six carbon atoms, and when one is hydrogen, the other may also
- HY is a strong mineral acid radical, for l example, hydrochloric, hydrobromic, sulfuric, NHLHY or the like. (7)
- the method in accordance with this invention is contemplated for the production of compounds having the above structure where the two groups C0 and CH are attached to the ring on adjacent positions (8) C O or occupy the carbon atoms adjacent to the point of fusion of two rings in a multiple sys- 3O tem, such as, for example, the 1, 8 positions of J naphthalene and it will be further understood that the ring structure may be mono-substituted N by, for example, alkyl of less than 6 carbon (9) 00 atoms, alkoxyl, halogen, aryl and aralkyl groups,
- ring structure may be dior poly-substi- O tuted by, for example, alkyl, alkoxyl or halogen C-OH-R groups.
- compounds having NH HY the above structure may be exemplified by compounds having the following structures: 0 (10) C Allin-HY NH2.HY
- R is an alkyl, aryl or an aralkyl group.
- ester II is then treated with an alkyl nitrite, as, for example, ethyl nitrite, amyl nitrite, propyl nitrite, or the like, and hydrogen chloride or nitrosyl chloride in a suitable solvent, for example, ether, methylene chloride, or the like; and preferably chilled to a temperature of, for example, 0 C.5 0., though the treatment may be carried out at a temperature within about the range of, for example, -5 C. to room temperature.
- an alkyl nitrite as, for example, ethyl nitrite, amyl nitrite, propyl nitrite, or the like
- hydrogen chloride or nitrosyl chloride in a suitable solvent, for example, ether, methylene chloride, or the like; and preferably chilled to a temperature of, for example, 0 C.5 0., though the treatment may be carried out at a temperature within about the range of, for example, -5
- the compound having the above structure III is reduced in solution with hydrogen in the presence of a noble metal catalyst such as platinum, palladium, or the like, and a strong mineral acid, such as sulfuric, hydrobromic, hydrochloric, or thelike.
- a noble metal catalyst such as platinum, palladium, or the like
- a strong mineral acid such as sulfuric, hydrobromic, hydrochloric, or thelike.
- An amino alcohol having the structure III (amino alcohol) COOR in which R, R", R' and HY are as above may be formed as anintermediate, and which spontaneously loses alcohol to form the end product.
- the catalyst may, if desired, be supported on an inert carrier, such as kieselguhr, carbon, or the like.
- the reduction. will be carried out at hydrogen pressure above atmosphere, preferably, for example, 25-1000 pounds gauge pressure, and while the reduction may be carried out at room temperature, it will preferably be carried. out at a temperature of, for example, 50-80? C.
- the final product may bereadily isolated by removing the catalyst by filtration. and evaporating the reaction. solution to dryness. Purification. of' the product may be accomplished; for example, byv washing with. acetone and crystallizing from a. suitable solvent, such as alcohol.
- the temperature may rise to about 36 C. during the first 60 minutes and return again to about C. during the next minutes.
- One-half of the methylene chloride solvent is then removed by distillation.
- the remaining reaction mixture is cooled, and the solid crystalline product, methyl a-isonitrosobutyrophenoneo-carboxylate, is isolated by filtration. After recrystallization from 99% isopropanol, the product melts at 150-151 C.
- R is a member of the group consisting of H, alkyl not in excess of 10 carbon atoms, aryl and aralkyl the alkyl portion of which has less than 6 carbon atoms;
- R" and R are members of the group consisting of H, alkoxyl the alkyl portion of which has less than 6 carbon atoms, aralkyl the alkyl portion of which has less than 6 carbon atoms, alkyl of less than 6 carbon atoms;
- Y is a strong mineral acid radical, which comprises esterifying.
- R is a member of the group consisting of alkyl, aryl and aralkyl groups; treating the last mentioned compound with a reagent from the group consisting of an alkyl nitrite-hydrogen chloride and nitrosyl chloride to produce a compound having the structure:
- R, R" and R' are as specified above and R is a member of the group consisting of alkyl, aryl and aralkyl groups; treating the last mentioned compound with a reagent from the group consisting of an alkyl nitrite-hydrogen chloride and nitrosyl chloride to produce a compound having the structure:
Description
Patented June 14, 1949 UNITED STATES ATENT OFFICE METHOD FOR THE PREPARATION OF AMINOPHTHALIDYLALKANES Glenn E. Ullyot, Philadelphia, Pa., assignor to Smith, Kline & French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania No Drawing. Application September 12, 1946, Serial No. 696,619
2 Claims. (Cl. 260-344.6)
1 2 This invention relates to a method for the (4) preparation of new compositions of matter and, more particularly, for the preparation of compounds having the following structure:
where X is a single or multiple fiveor six-mem- (5) O bered ring system which may be saturated or unsaturated, isocyclic or heterocyclic, and substituted or unsubstituted; R. is, for example, I C CER hydrogen, alkyl containing not over 10 carbon l IHaHY atoms, aryl, aralkyl; R" and R may be hydro- (6) gen, halogen, alkoxyl, aralkyl, or alkyl of less than six carbon atoms, and when one is hydrogen, the other may also be hydroxyl and aryl; O
and HY is a strong mineral acid radical, for l example, hydrochloric, hydrobromic, sulfuric, NHLHY or the like. (7)
It will be understood that the method in accordance with this invention is contemplated for the production of compounds having the above structure where the two groups C0 and CH are attached to the ring on adjacent positions (8) C O or occupy the carbon atoms adjacent to the point of fusion of two rings in a multiple sys- 3O tem, such as, for example, the 1, 8 positions of J naphthalene and it will be further understood that the ring structure may be mono-substituted N by, for example, alkyl of less than 6 carbon (9) 00 atoms, alkoxyl, halogen, aryl and aralkyl groups,
or the ring structure may be dior poly-substi- O tuted by, for example, alkyl, alkoxyl or halogen C-OH-R groups. By way of example, compounds having NH HY the above structure may be exemplified by compounds having the following structures: 0 (10) C Allin-HY NH2.HY
(11) C OO (2) C 0 Compounds produced by the method in accordance with this invention will have variously physiological or therapeutic capacity and variously will be useful as intermediates for the production of compounds having physiological or therapeutic capacity.
Generally speaking, in proceeding in accordance with the method embodying this invention for the production of the compounds indicated, a compound having the following structure:
COOH
EL 0 on fU -C 0 011,4.
where X, R, R" and. R' areas above indicated and R is an alkyl, aryl or an aralkyl group.
The above ester II is then treated with an alkyl nitrite, as, for example, ethyl nitrite, amyl nitrite, propyl nitrite, or the like, and hydrogen chloride or nitrosyl chloride in a suitable solvent, for example, ether, methylene chloride, or the like; and preferably chilled to a temperature of, for example, 0 C.5 0., though the treatment may be carried out at a temperature within about the range of, for example, -5 C. to room temperature.
The treatment will effect the production of a compound having the following structure:
ll NOH where X, R, R, R" and R are as. indicated above.
Now for the production of the final product, the compound having the above structure III is reduced in solution with hydrogen in the presence of a noble metal catalyst such as platinum, palladium, or the like, and a strong mineral acid, such as sulfuric, hydrobromic, hydrochloric, or thelike. An amino alcohol having the structure III (amino alcohol) COOR in which R, R", R' and HY are as above may be formed as anintermediate, and which spontaneously loses alcohol to form the end product.
The catalyst may, if desired, be supported on an inert carrier, such as kieselguhr, carbon, or the like.
The reduction. will be carried out at hydrogen pressure above atmosphere, preferably, for example, 25-1000 pounds gauge pressure, and while the reduction may be carried out at room temperature, it will preferably be carried. out at a temperature of, for example, 50-80? C.
The final product may bereadily isolated by removing the catalyst by filtration. and evaporating the reaction. solution to dryness. Purification. of' the product may be accomplished; for example, byv washing with. acetone and crystallizing from a. suitable solvent, such as alcohol.
As more specifically illustrating procedure in accordance with the method of this invention and from which the procedure for the production of any of the various compounds, indicated with selection of the starting compound with reference to the compound desired will be made apparent, for example, the compound l-aminol-phthalidylpropane hydrochloride will be prepared as follows:
640 grams of butyrophenone-o-carboxylic acid (a known compound) dissolved in 1200 cc. of methanol are placed in a suitable flask equipped With a sealed stirrer and a reflux condenser. 133.5 grams of sodium hydroxide dissolved in 200 cc. of water is added and, while stirring, 422 g. of dimethy1 sulfate is added at a steady rate over a period of minutes. After an additional onehalf hour of stirring, a solution of 26.7 g. of sodium hydroxide in 40 cc. of water and 84.2 g. of dimethyl sulfate are added simultaneously over a period of 30 minutes The solution is stirred an additional one-half hour and then about 600 cc. of alcohol are removed by distillation in vacuo at about 60 C. The residue is cooled and the product is isolated by ether extraction. The ether extract is thoroughly washed with sodium bicarbonate solution, then with saturated sodium chloride solution, and dried over sodium sulfate. After removal of the drying agent by filtration and the ether by distillation, the product, methyl butyrophenone-o-carboxylate, is distilled at l35-l52 (1/4 mm.
412 grams of methyl butyrophenone-ocarboxylate is dissolved in 1 liter of methylene chloride and placed in a suitable reaction flask equipped with a reflux condenser, a hydrogen chloride inlet tube, an ethyl nitrite inlet tube (both inlet tubes extend to the bottom of the flask), and a sealed stirrer. The reaction flask is cooled in an ice bath in order to maintain the solution at 0-5 C. Three molar equivalents of ethyl nitrite is then passed into the cold, stirred methylene chloride solution over a period of 60 minutes, after three molar equivalents of dry hydrogen chloride is passed in over a period of 90 minutes. During the addition of the hydrogen chloride, the temperature may rise to about 36 C. during the first 60 minutes and return again to about C. during the next minutes. One-half of the methylene chloride solvent is then removed by distillation. The remaining reaction mixture is cooled, and the solid crystalline product, methyl a-isonitrosobutyrophenoneo-carboxylate, is isolated by filtration. After recrystallization from 99% isopropanol, the product melts at 150-151 C.
grams of methyl oziSOHitIOSObUtYIOPhBIlOHB- o-carboxylate is reduced by dissolving it in 400 cc. of 95% alcohol, adding 38 cc. of concentrated hydrochloric acid and carrying out the reduction in a suitable autoclave over a period of 4-8 hours, using a 10% palladium on charcoal catalyst at an initial hydrogen pressure of 500 lb./sq. in. above atmosphere. Reduction may be carried out at between room temperature and 80 C. After removal of the catalyst from the reduced solution, the solvent is removed by distillation in vacuo and the residue is collected and washed thoroughly with acetone. Recrystallization from 95% ethanol or propanol gives l-amino-lphthalidylpropane hydrochloride, which decomposes between 264 and 270 C. and consists of the desired amine hydrochloride.
What I claim and desire to protect by Letters Patent is:
1. The method for preparing compounds as exemplified by the structure wherein R is a member of the group consisting of H, alkyl not in excess of 10 carbon atoms, aryl and aralkyl the alkyl portion of which has less than 6 carbon atoms; R" and R are members of the group consisting of H, alkoxyl the alkyl portion of which has less than 6 carbon atoms, aralkyl the alkyl portion of which has less than 6 carbon atoms, alkyl of less than 6 carbon atoms; and Y is a strong mineral acid radical, which comprises esterifying. a compoundv having the structure:
where R, R" and R are as specified above, to produce a compound having the following struc-- ture:
m R COCHz-R where R, R" and R' are as specified above and R is a member of the group consisting of alkyl, aryl and aralkyl groups; treating the last mentioned compound with a reagent from the group consisting of an alkyl nitrite-hydrogen chloride and nitrosyl chloride to produce a compound having the structure:
in which R, R, R" and R' are as specified above and reducing the last mentioned compound with hydrogen under pressure in the presence of a catalyst.
2. The method for preparing compounds as exemplified by the structure R I". O
where R, R" and R' are as specified above, to produce a compound having the following structure:
where R, R" and R' are as specified above and R is a member of the group consisting of alkyl, aryl and aralkyl groups; treating the last mentioned compound with a reagent from the group consisting of an alkyl nitrite-hydrogen chloride and nitrosyl chloride to produce a compound having the structure:
in which R, R, R" and R' are as specified above and. reducing the last mentioned. com;- pound with hydrogen under pressure in the presence of a catalyst.
GLENN E. ULLYOT.
REFERENCES CITED The followingv referenices are of record in the. file of this patent:
UNITED STATES PATENTS bllnfnber Name Date Re.22,264= Loewe Feb. 9, 1943 2,390,526 Elderfield et a1 Dec. 11, 1945 2391628 Snyder Apr. 2, 1946
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US696619A US2473484A (en) | 1946-09-12 | 1946-09-12 | Method for the preparation of aminophthalidylalkanes |
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US696619A US2473484A (en) | 1946-09-12 | 1946-09-12 | Method for the preparation of aminophthalidylalkanes |
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US2473484A true US2473484A (en) | 1949-06-14 |
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US696619A Expired - Lifetime US2473484A (en) | 1946-09-12 | 1946-09-12 | Method for the preparation of aminophthalidylalkanes |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3993666A (en) * | 1971-12-17 | 1976-11-23 | Bayer Aktiengesellschaft | Coumaranedione-3-monoximes |
US3993665A (en) * | 1971-12-17 | 1976-11-23 | Bayer Aktiengesellschaft | 3-Amidocoumaranones |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE22264E (en) * | 1943-02-09 | Secondary and tertiary j-amino | ||
US2390526A (en) * | 1943-09-11 | 1945-12-11 | Lilly Co Eli | Butyrolactones and methods of preparing them |
US2397628A (en) * | 1942-08-21 | 1946-04-02 | Merck & Co Inc | Synthesis of amino acids |
-
1946
- 1946-09-12 US US696619A patent/US2473484A/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE22264E (en) * | 1943-02-09 | Secondary and tertiary j-amino | ||
US2397628A (en) * | 1942-08-21 | 1946-04-02 | Merck & Co Inc | Synthesis of amino acids |
US2390526A (en) * | 1943-09-11 | 1945-12-11 | Lilly Co Eli | Butyrolactones and methods of preparing them |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3993666A (en) * | 1971-12-17 | 1976-11-23 | Bayer Aktiengesellschaft | Coumaranedione-3-monoximes |
US3993665A (en) * | 1971-12-17 | 1976-11-23 | Bayer Aktiengesellschaft | 3-Amidocoumaranones |
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