The present disclosure discloses a method for safely preparing pimavanserin and tartrate thereof by using triphosgene. The synthesis route includes:

##STR00001##

Raw materials used in the method of the present disclosure are safe and inexpensive, thereby effectively reducing the production costs. The method of the present disclosure has mild reaction conditions, and avoids using phosgene, which is highly toxic and difficult to handle is avoided. Thus, the method is readily implemented industrially.

The present disclosure discloses a method for safely preparing pimavanserin and tartrate thereof by using triphosgene. The synthesis route includes:

##STR00001##

Raw materials used in the method of the present disclosure are safe and inexpensive, thereby effectively reducing the production costs. The method of the present disclosure has mild reaction conditions, and avoids using phosgene, which is highly toxic and difficult to handle is avoided. Thus, the method is readily implemented industrially.

A new intermediate for synthesizing 1-substituted-4-[phenyl(propanoyl)amino]piperidine-4-carbonitrile derivatives is laid open. Specifically set out is a method for use of this intermediate in the preparation of remifentanil. The enclosed shorter process offers a greater yield of products with higher purity as compared to methods reported in the prior art.

A new intermediate for synthesizing 1-substituted-4-[phenyl(propanoyl)amino]piperidine-4-carbonitrile derivatives is laid open. Specifically set out is a method for use of this intermediate in the preparation of remifentanil. The enclosed shorter process offers a greater yield of products with higher purity as compared to methods reported in the prior art.

The present disclosure is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises: (a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The disclosure is also related to novel intermediates: ##STR00001##
wherein R, R and X are as described in the specification.

The present disclosure is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises: (a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The disclosure is also related to novel intermediates: ##STR00001##
wherein R, R and X are as described in the specification.

Provided herein are piperidine dione compounds having the following structure:

##STR00001## wherein R.sup.N, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, L, V, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.

Provided herein are piperidine dione compounds having the following structure:

##STR00001## wherein R.sup.N, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, L, V, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.

Disclosed herein are methods for obtaining N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N-(4-(2-methylpropyloxy)phenylmethyl) carbamide (pimavanserin) comprising the step of contacting an intermediate according to Formula (A) or a salt thereof, with an intermediate Formula B, or a salt thereof, to produce pimavanserin or a salt thereof wherein Y is OR.sub.i or NR.sub.2aR.sub.2b; R.sub.3 is hydrogen or substituted or unsubstituted heteroalicyclyl, R.sub.4 is substituted or unsubstituted aralkyl; X is OR.sub.22 or NR.sub.23R.sub.24; (wherein R.sub.22 is hydrogen or substituted or unsubstituted C.sub.1-6alkyl and one of R.sub.23 and R.sub.24 is hydrogen and the other is hydrogen or N-methylpiperidin-4-yl); and R.sub.21 is OCH.sub.2CH(CH.sub.3).sub.2 or F; Also disclosed herein is the tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N-(4-(2-methylpropyloxy)phenylmethyl) carbamide and methods for obtaining the salt.

##STR00001##

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.