US3652651A - Synthesis of novel guanidino fatty acid esters - Google Patents
Synthesis of novel guanidino fatty acid esters Download PDFInfo
- Publication number
- US3652651A US3652651A US770072A US3652651DA US3652651A US 3652651 A US3652651 A US 3652651A US 770072 A US770072 A US 770072A US 3652651D A US3652651D A US 3652651DA US 3652651 A US3652651 A US 3652651A
- Authority
- US
- United States
- Prior art keywords
- fatty acid
- acid esters
- synthesis
- acid ester
- amino
- 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.)
- Expired - Lifetime
Links
- 235000014113 dietary fatty acids Nutrition 0.000 title abstract description 21
- 229930195729 fatty acid Natural products 0.000 title abstract description 21
- 239000000194 fatty acid Substances 0.000 title abstract description 21
- -1 guanidino fatty acid esters Chemical class 0.000 title abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000288 anti-kallikrein effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
Definitions
- n and R are as defined above, with S-methyl thiourea or cyanamide.
- This invention relates to the production of w-guanidino fatty acid esters.
- the fatty acids as used in the present invention are those fatty acid having 4 to 6 carbon atoms.
- the ester of such fatty acid is an alkyl (1-7 carbon atoms), arylalkyl or aryl ester wherein the arylalkyl is a benzyl group and the aryl is a phenyl group either of which may have or may not have in the aromatic ring such substituent as, for example, a methylol, methoxy, halogen, carboxyl or nitro group.
- N32 CNNH r (IS-CH NH; H2N(CH2)nCOOR H NFNHUJHQDCOOR wherein nis 3 to and R is an alkyl, arylalkyl, arylalkyl or aryl group having 1 to 7 carbon atoms and which may be substituted as mentioned before.
- guanidino fatty acid esters of the present invention are basic and therefore are preferable to be separated after converting the same into a salt with an acid which can form a salt with a guanidino base.
- acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or carbonic acid, and organic acids such as oxalic acid, tartaric acid or p-toluene sulfonic acid.
- the w-guanidino fatty acid esters obtained by the present invention are novel compounds and have action to strongly inhibit the hydrolysis of alginine ester by kallikrein as shown in my concurrently filed patent application Ser. No. 769,815 and therefore are useful for a medicine as an antikallikrein agent.
- An amino fatty acid ester which is the starting material in the process of the present invention may be prepared as follows. Thus, 0.2 mol of w-amino acid, ml. of a corresponding aliphatic alcohol or aromatic alcohol and 150 ml. of benzene are mixed together. The mixture is heated and refluxed while introducing a dry hydrochloric acid gas. The esterification reaction is conducted for 4 to 5 hours. Then the reaction product is concentrated under a reduced pressure and the residue is recrystallized from water, alcohol or acetone to obtain an w-amino fatty acid ester hydrochloride, the ester being an alkyl or arylalkyl ester.
- 0.2 mol of an w-amino acid having had the amino group carbobenzyloxylated to be protected -by a known conventional process 0.2 mol of oor p-substituted phenol, 1 liter of tetrahydrofuran and 0.2 mol of phosphorus oxychloride are mixed together under cooling at l5 C. Then 32 ml. of pyridine are dropwise added thereto under this condition. The mixture is returned to the normal or room temperature after 30 minutes and is left to stand for 1 hour. Then the solution is separated under cooling, and the upper layer is concentrated under a reduced pressure. Then the protected group is removed by the treatment with glacial acetic acid and hydrobromic acid or by palladium reduction to obtain an w-amino fatty acid ester or its hydrobromate.
- the w-amino fatty acid ester thus prepared is then dissolved in 200 to 300 ml. of water. To this solution is added 0.1 mol of S-methyl thiourea, and the mixture is allowed to react at 20 to 30 C. for 5 hours. Then the mixture is left to stand at the normal temperature and is ice-cooled after about 20 hours. The precipitated crystals are recovered by filtration and recrystallized from water.
- the w-amino fatty acid ester is mixed into an aqueous solution of 1 to 10% ammonia in the presence of 10 to 20% cyanamide. The mixture is allowed to react until the final amino ester concentration becomes 30 to 40%. The solution is left to stand at the normal or room temperature or concentrated under a reduced pressure. The crystals formed are recovered and recrystallized from water.
- n and R are as defined above, with S-methyl 45 thiourea or cyanamide.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP42068693A JPS502494B1 (enrdf_load_stackoverflow) | 1967-10-24 | 1967-10-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3652651A true US3652651A (en) | 1972-03-28 |
Family
ID=13381078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US770072A Expired - Lifetime US3652651A (en) | 1967-10-24 | 1968-10-23 | Synthesis of novel guanidino fatty acid esters |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US3652651A (enrdf_load_stackoverflow) |
| JP (1) | JPS502494B1 (enrdf_load_stackoverflow) |
| BE (1) | BE722520A (enrdf_load_stackoverflow) |
| CH (1) | CH527800A (enrdf_load_stackoverflow) |
| DE (1) | DE1804998A1 (enrdf_load_stackoverflow) |
| FR (1) | FR1597579A (enrdf_load_stackoverflow) |
| SE (1) | SE337367B (enrdf_load_stackoverflow) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6388122B1 (en) | 1996-04-10 | 2002-05-14 | Ono Pharmaceutical Co., Ltd. | Tryptase inhibitor and novel guanidino derivatives |
-
1967
- 1967-10-24 JP JP42068693A patent/JPS502494B1/ja active Pending
-
1968
- 1968-10-18 BE BE722520D patent/BE722520A/xx unknown
- 1968-10-18 SE SE14147/68A patent/SE337367B/xx unknown
- 1968-10-23 FR FR1597579D patent/FR1597579A/fr not_active Expired
- 1968-10-23 CH CH1583468A patent/CH527800A/de not_active IP Right Cessation
- 1968-10-23 US US770072A patent/US3652651A/en not_active Expired - Lifetime
- 1968-10-24 DE DE19681804998 patent/DE1804998A1/de active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6388122B1 (en) | 1996-04-10 | 2002-05-14 | Ono Pharmaceutical Co., Ltd. | Tryptase inhibitor and novel guanidino derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CH527800A (de) | 1972-09-15 |
| FR1597579A (enrdf_load_stackoverflow) | 1970-06-29 |
| DE1804998A1 (de) | 1969-06-19 |
| SE337367B (enrdf_load_stackoverflow) | 1971-08-09 |
| JPS502494B1 (enrdf_load_stackoverflow) | 1975-01-27 |
| BE722520A (enrdf_load_stackoverflow) | 1969-04-18 |
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