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Details for Patent: 7,790,899

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Details for Patent: 7,790,899

Title:Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl)carbamide and its tartrate salt and crystalline forms
Abstract: Disclosed herein are methods for synthesizing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl)carbamide. Also disclosed herein is the hemi-tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)-p- henylmethyl)carbamide and methods for obtaining the salt. Further disclosed are various crystalline forms of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl)carbamide and its hemi-tartrate salt including various polymorphs and solvates.
Inventor(s): Tolf; Bo-Ragnar (Malmo, SE), Schlienger; Nathalie (Frederiksberg, DK), Thygesen; Mikkel Boas (Copenhagen, DK)
Assignee: ACADIA Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:May 15, 2007
Application Number:11/749,115
Claims:1. A method of synthesizing N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide, comprising: reacting 4-hydroxybenzaldehyde with isobutylbromide in the presence of dimethylformamide, potassium iodide and potassium carbonate to produce 4-isobutoxybenzaldehyde; reacting the 4-isobutoxybenzaldehyde with about 1.5 equivalents of NH.sub.2OH to produce 4-isobutoxybenzoxime; reacting the 4-isobutoxybenzoxime with H.sub.2 in the presence of Raney-Ni and from about 13 to about 16 equivalents of NH.sub.3 to produce (4-isobutoxyphenyl)methanamine; adding acetic acid to produce (4-isobutoxyphenyl)methanamine acetate; treating the (4-isobutoxyphenyl)methanamine acetate with about 30% NaOH and extracting with toluene to produce (4-isobutoxyphenyl)methanamine; reacting the (4-isobutoxyphenyl)methanamine with HCl and COCl.sub.2 in the presence of toluene to produce 1-isobutoxy-4-(isocyanatomethyl)benzene; and reacting a solution of the 1-isobutoxy-4-(isocyanatomethyl)benzene in toluene with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to produce N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide.

2. The method of claim 1, further comprising forming a tartrate salt of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide, and seeding the formed N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide tartrate with crystalline Form C of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide tartrate to produce crystalline Form C of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide tartrate.

3. The method of claim 2, wherein the product of the method comprises less than about 0.2% by weight of Impurity 1: ##STR00034##

4. The method of claim 2, wherein the product of the method comprises less than about 0.1% by weight of Impurity 2: ##STR00035##

5. The method of claim 2, wherein the product of the method comprises substantially no Impurity 2.

6. The method of claim 2, wherein the crystalline Form C of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide tartrate is present in amounts of at least about 90%.

7. The method of claim 6, wherein the crystalline Form C of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide tartrate is present in amounts of at least about 95%.

8. The method of claim 6, wherein the crystalline Form C of N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl- oxy)phenylmethyl)carbamide tartrate is present in amounts of at least about 98%.

9. The method of claim 2, wherein the product of the method comprises substantially no Impurity 1.
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