Improved method for the production of lysergic acid diethylamide (lsd) and novel derivatives thereof

A method for the production of a lysergic acid diethylamide (LSD) derivative of the following formula II

• wherein:
• RN is selected from —NH—(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —NH—(C1-5 haloalkyl), —N(C1-5 alkyl)(C1-5 haloalkyl), —N(C1-5 haloalkyl)(C1-5 haloalkyl), —NH—(C1-5 alkylene)-O—(C1-5 alkyl), —N(C1-5 alkyl)[—(C1-5 alkylene)-O—(C1-5 alkyl)], —N[—(C1-5 alkylene)-O—(C1-5 alkyl)]-(C1-5 alkylene)-O—(C1-5 alkyl), —N(C1-5 haloalkyl)[—(C1-5 alkylene)-O—(C1-5 alkyl)], —N(C3-7 cycloalkyl)(C3-7 cycloalkyl), an N-containing polycyclic heterocyclyl, 1,3-oxazolidin-3-yl, 3-methylpyrrolidin-1-yl, and an N-containing monocyclic heterocyclyl which is substituted with one or more halogens,
• wherein any alkyl groups and/or any alkylene groups comprised in said —NH—(C1-5 alkylene)-O—(C1-5 alkyl), in said —N(C1-5 alkyl)[—(C1-5 alkylene)-O—(C1-5 alkyl)] or in said —N[—(C1-5 alkylene)-O—(C1-5 alkyl)]-(C1-5 alkylene)-O—(C1-5 alkyl) are each optionally substituted with one or more halogens, wherein said N-containing polycyclic heterocyclyl or said N-containing monocyclic heterocyclyl comprises at least one nitrogen ring atom and is attached to the remainder of the compound via said nitrogen ring atom, wherein said N-containing polycyclic heterocyclyl is not indolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or 3-azabicyclo[3.2.2]nonan-3-yl, wherein said N-containing polycyclic heterocyclyl, said 1,3-oxazolidin-3-yl, said N-containing monocyclic heterocyclyl, and the cycloalkyl groups comprised in said —N(C3-7 cycloalkyl)(C3-7 cycloalkyl) are each optionally substituted with one or more groups R4, and further wherein RN is not —N(CH2CH3)—CH2CH3;
• and
• each R4 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-O(C1-5 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—OH, —(C0-3 alkylene)-N(C1-5 alkyl)-OH, —(C0-3 alkylene)-NH—O(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-O(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-NO2, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—O—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—NH—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—N(C1-5 alkyl)-(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO2—(C1-5 alkyl), and —(C0-3 alkylene)-SO—(C1-5 alkyl);
• wherein the method comprises the steps of:
• a. preparing a suspension of lysergic acid hydrate in ethyl acetate;
• b. addition of an amine compound of the formula RN—H, wherein RN has the same meaning as in formula II, under protective gas atmosphere;
• c. addition of propane-phosphonic acid anhydride solution (T3P) in ethyl acetate;
• d. stirring of the mixture under protective gas atmosphere for at least 4 hours;
• e. stopping the reaction by dilution with ethyl acetate;
• f. extraction with water;
• g. drying of the organic phase over a desiccant at 20-60° C. and under vacuum;
• h. obtaining a crude product containing the LSD derivative of formula II.

A compound which is a lysergic acid diethylamide (LSD) derivative according to the general formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is selected from —NH—(C1-5 haloalkyl), —N(C1-5 alkyl)(C1-5 haloalkyl), —N(C1-5 haloalkyl)(C1-5 haloalkyl), —NH—CH2—O—(C1-5 alkyl), —NH—(CH2)3-5—O—(C1-5 alkyl), —N(C1-5 alkyl)[—(C1-5 alkylene)-O—(C1-5 alkyl)], —N[—(C1-5 alkylene)-O—(C1-5 alkyl)]-(C1-5 alkylene)-O—(C1-5 alkyl), —N(C1-5 haloalkyl)[—(C1-5 alkylene)-O—(C1-5 alkyl)], —N(C3-7 cycloalkyl)(C3-7 cycloalkyl), an N-containing polycyclic heterocyclyl, 1,3-oxazolidin-3-yl, 3-methylpyrrolidin-1-yl, and an N-containing monocyclic heterocyclyl which is substituted with one or more halogens,
• wherein said —NH—(C1-5 haloalkyl) is not —NH—CH2CH2—Cl or —NH—CH(—CH2CH3)—CH2—Cl, wherein any alkyl groups and/or any alkylene groups comprised in said —NH—CH2—O—(C1-5 alkyl), in said —NH—(CH2)3-5—O—(C1-5 alkyl), in said —N(C1-5 alkyl)[—(C1-5 alkylene)-O—(C1-5 alkyl)] or in said —N[—(C1-5 alkylene)-O—(C1-5 alkyl)]-(C1-5 alkylene)-O—(C1-5 alkyl) are each optionally substituted with one or more halogens, wherein said N-containing polycyclic heterocyclyl or said N-containing monocyclic heterocyclyl comprises at least one nitrogen ring atom and is attached to the remainder of the compound of formula I via said nitrogen ring atom, wherein said N-containing polycyclic heterocyclyl is not indolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or 3-azabicyclo[3.2.2]nonan-3-yl, and further wherein said N-containing polycyclic heterocyclyl, said 1,3-oxazolidin-3-yl, said N-containing monocyclic heterocyclyl, and the cycloalkyl groups comprised in said —N(C3-7 cycloalkyl)(C3-7 cycloalkyl) are each optionally substituted with one or more groups R4, and
• R2 is selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C1-5 haloalkyl;
• or alternatively R1 is —NH—(C1-5 alkyl) or —N(C1-5 alkyl)(C1-5 alkyl), and
• R2 is C1-5 haloalkyl;
• R3 is selected from hydrogen, C1-5 alkyl, —CO—(C1-5 alkyl), —CO—(C3-6 cycloalkyl), and an amino acid, wherein said amino acid is attached via a —CO— group formed from a carboxylic acid group of the amino acid, and further wherein said C1-5 alkyl, the alkyl group comprised in said —CO—(C1-5 alkyl), the cycloalkyl group comprised in said —CO—(C3-6 cycloalkyl) and any alkyl group comprised in said amino acid are each optionally substituted with one or more halogens;
• and
• each R4 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-O(C1-5 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—OH, —(C0-3 alkylene)-N(C1-5 alkyl)-OH, —(C0-3 alkylene)-NH—O(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-O(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-NO2, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—O—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—NH—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—N(C1-5 alkyl)-(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO2—(C1-5 alkyl), and —(C0-3 alkylene)-SO—(C1-5 alkyl).