CA2611572A1 - Preparations containing amino acids and orotic acid - Google Patents
Preparations containing amino acids and orotic acid Download PDFInfo
- Publication number
- CA2611572A1 CA2611572A1 CA002611572A CA2611572A CA2611572A1 CA 2611572 A1 CA2611572 A1 CA 2611572A1 CA 002611572 A CA002611572 A CA 002611572A CA 2611572 A CA2611572 A CA 2611572A CA 2611572 A1 CA2611572 A1 CA 2611572A1
- Authority
- CA
- Canada
- Prior art keywords
- amino acid
- amide
- orotate
- group
- benzyl protected
- 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
- 150000001413 amino acids Chemical class 0.000 title claims abstract 15
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title claims abstract 12
- 229960005010 orotic acid Drugs 0.000 title claims abstract 5
- 238000002360 preparation method Methods 0.000 title 1
- -1 amino acid orotate compounds Chemical class 0.000 claims abstract 23
- 238000000034 method Methods 0.000 claims abstract 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract 6
- 150000001266 acyl halides Chemical class 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract 4
- 239000003054 catalyst Substances 0.000 claims abstract 2
- 229940024606 amino acid Drugs 0.000 claims 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 14
- 238000001914 filtration Methods 0.000 claims 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 3
- 238000003818 flash chromatography Methods 0.000 claims 3
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims 3
- 239000000741 silica gel Substances 0.000 claims 3
- 229910002027 silica gel Inorganic materials 0.000 claims 3
- 239000004475 Arginine Substances 0.000 claims 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 229960000310 isoleucine Drugs 0.000 claims 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 2
- 239000004474 valine Substances 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- HTJDVAQGUYGUON-UHFFFAOYSA-N benzyl n,n'-di(propan-2-yl)carbamimidate Chemical compound CC(C)NC(=NC(C)C)OCC1=CC=CC=C1 HTJDVAQGUYGUON-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 abstract 1
- 150000001408 amides Chemical class 0.000 abstract 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention describes compounds produced from an orotic acid molecule and an amino acid molecule. The compounds being in the form of amino acid orotate compounds bound by an amide linkage and produced by one of two disclosed methods; 1) reacting orotic acid or derivatives thereof with a thionyl halide, and then combining the acyl halide with an amino acid in the presence of dichloromethane and a DMAP catalyst; or 2) protecting the carboxylic acid of an amino acid and then combining the amino acid with a DCC
activated orotic acid, followed by removal of the carboxylic acid protecting group.
The resulting amino acid orotate amide has an enhanced stability in solution as compared to a related ester. In addition, specific benefits are conferred by the particular amino acid used to form the compounds in addition to, and separate from, the orotate substituent.
activated orotic acid, followed by removal of the carboxylic acid protecting group.
The resulting amino acid orotate amide has an enhanced stability in solution as compared to a related ester. In addition, specific benefits are conferred by the particular amino acid used to form the compounds in addition to, and separate from, the orotate substituent.
Claims (22)
1. A compound having the general structure:
wherein R is selected from the group consisting of (CH3)2CHCH2-;
(CH3)2CH-; CH3CH2CH(CH3)-; H2NC(=NH)NH(CH2)3-; and C6H5CH2-.
wherein R is selected from the group consisting of (CH3)2CHCH2-;
(CH3)2CH-; CH3CH2CH(CH3)-; H2NC(=NH)NH(CH2)3-; and C6H5CH2-.
2. A method for producing amino acid orotate amides comprising at least the steps of:
mixing at least equivalent molar amounts of a thionyl halide with orotic acid to form an acyl halide;
said acyl halide then being added to a dichloromethane suspension of an amino acid in the presence of a 4-dimethyl-aminopyridine;
and isolating and purifying the resulting amino acid orotate amide.
mixing at least equivalent molar amounts of a thionyl halide with orotic acid to form an acyl halide;
said acyl halide then being added to a dichloromethane suspension of an amino acid in the presence of a 4-dimethyl-aminopyridine;
and isolating and purifying the resulting amino acid orotate amide.
3. The method of claim 2 wherein the halide of the thionyl halide is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
4. The method of claim 2 wherein the amino acid is selected from the group consisting of; Leucine, Valine, Isoleucine, Arginine and Phenylalanine.
5. The method of claim 2 wherein the 4-dimethyl-aminopyridine is present in catalytic amounts.
6. The method of claim 2 wherein the acyl halide is produced at temperatures from between about 30°C to about 55°C.
7. The method of claim 2 wherein the acyl halide and the amino acid suspended in dichloromethane are reacted at temperatures from between about -15°C to room temperature.
8. The method of claim 2 wherein the amino acid orotate amide is isolated by filtration and then concentrated in vacuo.
9. The method of claim 2 wherein the amino acid orotate amide is purified by flash chromatography using a silica gel packed column.
10.The method of claim 2 wherein the amino acid orotate amide has the general structure of:
wherein R is selected from the group consisting of (CH3)2CHCH2-;
(CH3)2CH-; CH3CH2CH(CH3)-; H2NC(=NH)NH(CH2)3-; and C6H5CH2-.
wherein R is selected from the group consisting of (CH3)2CHCH2-;
(CH3)2CH-; CH3CH2CH(CH3)-; H2NC(=NH)NH(CH2)3-; and C6H5CH2-.
11. A method for producing amino acid orotate amides comprising at least the steps of:
reacting an amino acid with N,N' diisopropyl-O-benzylisourea to form a benzyl protected amino acid;
isolating said benzyl protected amino acid;
reacting an activated orotic acid with the benzyl protected amino acid to form a benzyl protected amino acid orotate amide;
isolating and purifying said benzyl protected amino acid orotate amide;
removing the benzyl protecting group from said benzyl protected amino acid orotate amide; and isolating and purifying the deprotected amino acid orotate amide.
reacting an amino acid with N,N' diisopropyl-O-benzylisourea to form a benzyl protected amino acid;
isolating said benzyl protected amino acid;
reacting an activated orotic acid with the benzyl protected amino acid to form a benzyl protected amino acid orotate amide;
isolating and purifying said benzyl protected amino acid orotate amide;
removing the benzyl protecting group from said benzyl protected amino acid orotate amide; and isolating and purifying the deprotected amino acid orotate amide.
12.The method of claim 11 wherein the amino acid is selected from the group consisting of; Leucine, Valine, Isoleucine, Arginine and Phenylalanine.
13.The method of claim 11 wherein the benzyl protected amino acid is isolated by filtration.
14. The method of claim 11 wherein the orotic acid is activated in situ by dicyclohexylcarbodiimine.
15. The method of claim 11 wherein the benzyl protected amino acid orotate amide is produced at temperatures from between about 0°C to about room temperature.
16. The method of claim 11 wherein the benzyl protected amino acid orotate amide is isolated by filtration through and then concentrated under reduced pressure.
17. The method of claim 11 wherein the benzyl protected amino acid orotate amide is purified by flash chromatography using a silica gel packed column.
18. The method of claim 11 wherein the benzyl protected amino acid orotate amide is deprotected by the removal of the benzyl group from the carboxylic acid.
19.The method of claim 18 wherein the benzyl group from the carboxylic acid is removed via hydrogenation using a palladium on carbon catalyst.
20. The method of claim 11 wherein the deprotected amino acid orotate amide is isolated by filtration and then concentrated under reduced pressure.
21. The method of claim 11 wherein the deprotected amino acid orotate amide is purified by flash chromatography using a silica gel packed column.
22.The method of claim 11 wherein the deprotected amino acid orotate amide has the general structure of:
wherein R is selected from the group consisting of (CH3)2CHCH2-;
(CH3)2CH-; CH3CH2CH(CH3)-; H2NC(=NH)NH(CH2)3-; and C6H5CH2-.
wherein R is selected from the group consisting of (CH3)2CHCH2-;
(CH3)2CH-; CH3CH2CH(CH3)-; H2NC(=NH)NH(CH2)3-; and C6H5CH2-.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2611572A CA2611572C (en) | 2007-12-18 | 2007-12-18 | Preparations containing amino acids and orotic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2611572A CA2611572C (en) | 2007-12-18 | 2007-12-18 | Preparations containing amino acids and orotic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2611572A1 true CA2611572A1 (en) | 2008-03-04 |
| CA2611572C CA2611572C (en) | 2010-11-16 |
Family
ID=39153750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2611572A Expired - Fee Related CA2611572C (en) | 2007-12-18 | 2007-12-18 | Preparations containing amino acids and orotic acid |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2611572C (en) |
-
2007
- 2007-12-18 CA CA2611572A patent/CA2611572C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2611572C (en) | 2010-11-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20211220 |
|
| MKLA | Lapsed |
Effective date: 20211220 |