1. A process for the manufacture of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid in HX salt form of formula I
wherein R1 and R2 independently denote C1-3-alkyl groups and X\u2212 denotes an acid anion, comprising the following synthesis steps:
a) step 1:
wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H (p-toluenesulfonic acid) and CF3CO2H, the base denotes a strong base, and solvent denotes water, a water miscible organic solvent, and the mixtures thereof, and
b) step 2:
wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid, and solvent denotes a suitable solvent.
2. The process of claim 1 for the manufacture of (E)-4-N,N-dimethylamino crotonic acid in HX salt form wherein
R1 and R2 denote methyl groups,
R3 independently denote C1-3-alkyl groups,
in step 1 HX denotes HCl, the base denotes NaOH, and the solvent denotes pure water or a mixture of water with MeOH or EtOH, and
in step 2 HX denotes HCl and the solvent denotes ethyl acetate.
3. The process of claim 1, wherein HX in both steps denotes HCl, and further comprising converting (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid hydrochloride salt of compound I\u2032 according to
c) step 3:
wherein R1 and R2 independently denote C1-3-alkyl groups, with a chlorinating agent selected from thionylchloride, POCl3, PCl.
4. The process according to claim 3, wherein R1 and R2 denote methyl groups, and the chlorinating agent is thionyl chloride.
5. A process for the manufacture of formula (III)
wherein X denotes a methine group substituted by a cyano group or a nitrogen atom,
Ra denotes a 3-chloro-4-fluorophenyl group, a 3-chloro-4-(pyridin-2-yl-methoxy)-phenyl group, or a 3-chloro-4-(3-fluoro-phenylmethoxy)-phenyl group,
Rc denotes a methoxy, ethoxy or tetrahydrofuran-3-yl-oxy group, and
R1 and R2 independently denote C1-3-alkyl groups,
comprising:
a) step 1:
wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, and HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H and CF3CO2H, the base denotes a strong base, and solvent denotes water, a water miscible organic solvent, and the mixtures thereof,
b) step 2:
wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, and solvent denotes selected from ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane,
c) step 3:
subsequent conversion of (E)-4-N,N-dialkylamino crotonic acid hydrochloride salt of compound I\u2032 into the activated derivative II
wherein R1 and R2 independently denote C1-3-alkyl groups, with a chlorinating agent selected from thionylchloride, POCl3, PCl5, and
e) step 4:
wherein X denotes a methine group substituted by a cyano group or a nitrogen atom,
Ra denotes a 3-chloro-4-fluorophenyl group, a 3-chloro-4-(pyridin-2-yl-methoxy)-phenyl group, or a 3-chloro-4-(3-fluoro-phenylmethoxy)-phenyl group,
Rc denotes a methoxy, ethoxy or tetrahydrofuran-3-yl-oxy group, and
R1 and R2 independently denote C1-3-alkyl groups.
6. The process of claim 5, wherein
wherein X denotes a nitrogen atom,
Ra denotes a 3-chloro-4-fluorophenyl group,
Rc denotes a tetrahydrofuran-3-yl-oxy group, and
R1 and R2 both denote methyl groups,
comprising the following synthesis steps:
a) step 1:
wherein R1 and R2 both denote methyl groups, R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes HCl, the base denotes an alkali hydroxide, and solvent denotes water, a water miscible organic solvent,
b) step 2:
wherein R1 and R2 both denote methyl groups, OBut denotes a tert-butyloxy group, and solvent denotes a solvent selected from such as ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane,
c) step 3:
subsequent conversion of (E)-4-N,N-dimethylamino crotonic acid hydrochloride salt I\u2032 into the activated derivative II
wherein R1 and R2 both denote methyl groups, with thionylchloride as the chlorinating agent,
and
e) step 4:
wherein X denotes a nitrogen atom,
Ra denotes the 3-chloro-4-fluorophenyl group,
Rc denotes a tetrahydrofuran-3-yl-oxy group, and R1 and R2 both denote methyl groups.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A surgical blade assembly comprising:
a scalpel blade;
a body operatively connected to said scalpel blade; and
a guard attached to said body and movable between an open position and a closed position wherein said closed position at least partially covers said scalpel blade.
2. A surgical blade as set forth in claim 1 wherein said guard is resiliently biased towards said closed position.
3. The surgical blade assembly of claim 2 wherein said guard pivots relative to said scalpel blade between said open position and said closed position.
4. The surgical blade assembly of claim 3 wherein a spring resiliently biases said guard towards said closed position.
5. The surgical blade assembly of claim 4 wherein said spring is positioned in said handle to extend at an angle relative to a top surface of said handle and such that said hood is caused to pivot about a pivot point.
6. The surgical blade assembly of claim 5 wherein said spring is spaced relative to said hinge point to be on an opposed side of said hinge point relative to said blade.
7. The surgical blade assembly of claim 1 wherein said guard has a thinner portion and a thicker portion, with said thicker portion being spaced from a forward end of said scalpel blade, and said thinner portion being positioned adjacent said forward end of said scalpel blade to minimize the obstruction of a surgeon’s view.
8. The surgical blade assembly of claim 1 wherein said guard is formed of a generally transparent plastic.
9. A surgical blade assembly comprising:
a scalpel blade;
a body operatively connected to said scalpel blade;
a guard attached to said body and pivotally movable between an open position and a closed position wherein said closed position at least partially covers said scalpel blade; and
a spring resiliently biasing said guard towards said closed position.
10. A surgical blade assembly as set forth in claim 9 wherein said guard is resiliently biased towards said closed position.
11. The surgical blade assembly of claim 10 wherein said guard pivots relative to said scalpel blade between said open position and said closed position.
12. The surgical blade assembly of claim 9 wherein said guard has a thinner portion and a thicker portion, with said thicker portion being spaced from a forward end of said scalpel blade, and said thinner portion being positioned adjacent said forward end of said scalpel blade to minimize the obstruction of a surgeon’s view.
13. The surgical blade assembly of claim 9 wherein said guard is formed of a generally transparent plastic.