SA96170395B1 - Processes and intermediates for the preparation of 1-benzy-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine 1-benzy1-4-((5,6-dimethoxy -1-Indanone)-2-y1)methy1piperidine - Google Patents

Abstract

Abstract: The present invention relates to a process for preparing a compound of formula (I), where R l is -(R2O(C=O) or -(R2,R3(C=O) is C1-C4)alkyl), and R3 is Cl- C4)alkyl) or optionally substituted phenyl with one to three separately selected substituents of - (C1 halo, (Cl-C4)alkoxy, C4)alkyl or trifluoromethyl, comprising: (a) a compound reaction of the formula,( III) where R l is -(R2O(C=O) or -(R2,R3(C=O) is R3 and (Cl-C4)alkyl , is an alkyl(C1-C4) or optionally substituted phenyl with one to three substituents separately selected from Cl-, (C1-C4)alkyl)halo, C4)alkoxy or trifluoromethyl, with a methenylation agent to form a compound of formula (II), where Rl is -(R2O(C-O) or -(R2 R3(C=O is Cl-C4)alkyl), and R3 is an optionally substituted (Cl-(Cl-C4)C4)alkyl or phenyl with one to three individually selected substituents of (Cl - (Cl-C4)alkyl halo C4) alkoxy or ifluoromethyl and (b) the reaction of said compound of formula (II), thus formed, with a strong acid. The present invention also includes an additional step of reacting the compound of formula (I) with a hydroxide to form the compound of formula ( VI), and said compound of formula (VI) thus formed reacted with benzyl halide and base to form compound of formula (VII). The present invention also relates to novel intermediates of formula (II), (I), and (III).

Description

1-Dimethoxy-1-Indanone (-?-yl)=O)benzyl-;-1 Processes and intermediates for the preparation of methylpiperidin 1-Benzyl-4-((5,6-Dimethoxy-1) -Indanon)-2-YIl) Methylpiperidine Full Description BACKGROUND The invention relates to a new 070058 process for the preparation of: 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl) methylpiperidine (E2020), new for use in coli 711 intermediates and intermediates of the compound form of the said process. © to Jan 14460 YY US Patent 8,554467; 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine are useful intermediates; Methods and drug combinations for the treatment of diseases caused by the activity of dementia. Thus incorporated herein as a full reference is the patent Jie cacetylcholinesterase

NAA Jan YY US 6845441; Issued at 0° General Description of the Invention The present invention relates to a compound of formula: 8

N

1

OMe m (Ci-Ca)alkyl mr -(220)0-0 sqm R' wherein the present invention also relates to a compound of the formula: - 0 º OMe

I

Ad v (Ci-Cq)alkyl hr R?5R*O(C=0)- is R' where is The present invention also relates to a compound of the formula: 0 rN OMe 1 .methyl s Ra R*0O(C=0)- is R' where: The present invention also relates to a process for preparing a compound of formula 5 0 rN OMe 1 is -(220)0-0 Ra is Owlad(Et -,©); They include: R' where is a complex reaction of the formula: (i) 1c \ N 0 OMe 1 is -(20)0-0 rt is enulose-0); with a methenylation agent R' where is 0 to form a compound of the formula: methenylation agent 0 ©6661 OMe ri Cre OMe 1 (mer allolorine-) and R?5 R?0(C=0)- is R' Cua formed in this way is with a strong acid JI (b) the reaction of the said compound of the formula p50008. acid m m

¢ It is preferable that the aforementioned demethylation agent be tetramethyldiaminomethane in acetic anhydride. It is more preferable that acetic ahydride 5 tetramethyldiaminomethane be added in excess. It is more preferable that said tetramethyldiaminomethane comprise 7 gram-molecular equivalents (with respect to the amount of the compound of formula (ITT) and said acetic anhydride shall include; The most preferred is the sulfuric acid The sulfuric acid is the concentrated sulfuric acid The most preferred is the said concentrated sulfuric acid comprises 5 gram molecular equivalent (in relation to the amount of said compound of the formula TT). The present invention by any of the above processes which also include the additional 0 step Jeli compound of formula dd where R' is (2820)0-0 and 1832 is “(Ci-Cy)alkyl with hydroxide (It is preferred (potassium hydroxide) to form a compound of formula: 0 OMe not 0 VI and the reaction of the mentioned compound of formula VI formed in this way with benzyl halide and a base to form a compound of formula: 0 OMe Jude © vi yo : Said benzyl halide preferably benzyl bromide Preferably base No A more favorable embodiment of the above invention relates to a process whereby said compound of Formula 1 is isolated prior to its conversion to the compound of Formula VI The compound of formula 1 can be isolated by adding the strong acid solution Yee containing the compound of formula ] to ice/water and then extraction with an organic solvent and removal of the organic solvent. The present invention also relates to a process for preparing a compound of the formula: aaa o 8

N

ome0

ome. 11 includes a complex reaction of the formula:

ome

Iv with a compound of the formula:

R'—N

Ci 0

Vv ° in aluminum trichloride as Lewis (Lewis) in the presence of acid .methylene chloride fis (reaction inert solvent) Detailed description of the invention 2c (R' and 1711 and the following VI groups. unless Specify otherwise; the compounds of formulas [8] 1, 111 _ 0 and 8 in the following reaction and explanation programs are as specified above.

ad

0 1 OMe CL software. +mo,

ome cl 0

Iv no R 1 \ i Me

OMe 111 0

LCL Me

NCH

: 2 OMe 11 0 1 Me 1 A One

I

Av9

No program Y 0 OMe i ] 2> 2 RY OMe I 0 i Me ° A - OMe safe VI 0 OMe Cl 0 : Me VII Program 1 indicates a process for preparing a compound of formula ]; which can be converted to a compound of formula VII 52020; By methods of Program 7.° with reference to Program 1; compound of Formula 7 is commercially available]. Formula V compounds are also commercially available or may be prepared by methods well known to those skilled in the art. The compound of formula [IT] can be prepared from the compound of formula TV by reacting said compound of formula TV with the compound of formula 7; where a18 is -(820)6-0 and 18 is ((Cr-Cylalkyl) in the presence of Lewis acid in an inert solvent. Preferably a7 is R?O(C=0)- and 12 is Obedience is how much

A

Suitable 5 acids 70, titanium tetrachloride “aluminium trichloride (yea) or boron trichloride preferably an acetylene trichloride. Suitable inert solvents for the reaction include methylene chloride or “dichloroethane” preferably methylene chloride The reaction is generally carried out at a temperature of A temperature from about 0°C to about ghee preferably about 07" seminal. 0 The compound of formula [1] can be prepared from the compound of formula TTT by reacting the said compound of formula 11 with a methenylation agent preferably R'. Mo -"ruhra with Ra" is methyl. Suitable methenylation agents include tetramethyldiaminomethane in formaldehyde acetic anhydride (about 7717 by weight in water) in formaldehyde “diethylamine” (about 771 by weight in water). Water) in piperidine N-methylthiomethylpiperidine 0 Preferably the methenylation agent is tetramethyldiaminomethane in Laie .866106 anhydride The methenylation agent is tetramethyldiaminomethane in acetic anhydride It is preferable to carry out the reaction with an increase of anhydride s tetramethyldiaminomethane mint. most preferred to be interacted with; Equivalents of acetic anhydride (in relation to the amount of the formula compound (IT) and equivalents of tetramethyldiaminomethane (eve) (in relation to the amount of the formula compound (IIT) when a methenylation agent other than tetramethyldiaminomethane in the acetic anhydride is permitted. Use a solvent to facilitate the reaction Suitable solvents include ethers “acetic anhydride” acetic acid “methanol” (tetrahydrofuran s diethyl ether Mi) or “dioxane” preferably acetic anhydride The reaction takes place at a temperature of about zero Celsius to about Gest x Preferably at about 6°C Reaction time may vary from about + hours to about Ve hours Preferably reaction time is about 11 hours A compound of formula 1 can be prepared from a compound of formula IT by reaction Compound of formula [1] mentioned with a strong acid in an inert solvent. Suitable strong acids include concentrated aluminum trichloride sulfuric acid or concentrated hydrochloric acid; concentrated sulfuric acid is preferred. When ve is aluminum trichloride is the acid add solvent Use suitable solvents include “dichloroethane methylene chloride” carbon disulfide Preferably Ad q. Preferably at about #5 sperm. VII compound of formula (E2020 ? program indicates conversion of compounds of formula 1 to reactant VI with reference to program; compound of formula 1 can be converted to compound of formula is reactant In the presence of a solvent Preferably the substrate is 507008 base with a strong base 0 A suitable base (methyl) is methyl R75 820(0-0)- compound of formula [; where L18 is -potassium hydroxide is preferred ¢sodium hydroxide s potassium hydroxide includes water or mixtures thereof preferably a 1:7 mixture of water/lower alcohols suitable solvents including The reaction takes place at a temperature of about #9 7 Preferably 100°C to about 100°C methanol hr; YE to about 1°C preferably at approx 100°C Reaction time may vary from about 0 hr. The best is to convert the formula VI compound to the formula compound acidic solution by decanting the acidic solution IT isolate the formula VI compound converting it to the formula compound containing the formula 1 compound over an ice/water mixture and extract the aqueous phase with an organic solvent It is preferable to use dichloroethane or ethyl acetate «methylene chloride (Pasa) as suitable solvents. The organic layer can be concentrated and then suitable for treatment with a strong chloride base VI By reacting the compound of formula VI with the compound of formula VII a suitable compound of formula including halides can be prepared in an inert solvent in the reaction. The said halide 56021 with suitable inert solvents includes bromide and O10010; cbromide «chloride | 0 The reaction takes place at isopropyl ether preferably ctetrahydrofuran “isopropyl ether” diethyl ether. Ionm* 70 temperature from about 0C to about 17”C; Preferably about acceptable acid addition salts to VII acid addition salts The compound of the formula can be converted pharmacologically from the compound of formula [1. The acids used in the preparation of pharmacologically acceptable adsorbents from a compound of formula [171] are those that form non-vo hydrochloride additive salts, pharmacologically acceptable Jie salts, anions, toxic Sia-containing salts; or phosphate “bisulfate 4 sulfate” nitrate < hydroiodide < hydrobromide

AA

Yo: bitartrate J tartrate “acid citrate i citrate” lactate cacetate “acid phosphate methanesulfonate (benzoate “saccharate” gluconate “fumarate” maleate “succinate .[1,1'-methylene-bis-(2-hydroxy-3-naphthoate)” |pamoate 5 The compound of formula [71] is basic in nature and is therefore capable of forming a wide variety of different salts with various inorganic and organic acids. Although these salts must be pharmacologically acceptable 0 for administration to animals, it is often desirable In practice we initially isolate from the reaction mixture as a pharmacologically unacceptable salt and then simply convert the latter back into the formula VII compound and then calkaline reagent by treatment with a free base alkaline reagent. Acidification salts from the base compounds of this invention are easily prepared by treating the base compound with a substantially equivalent amount of the chosen organic or mineral acid 0 methanol in an aqueous solvent medium or in a suitable organic solvent such as When carefully evaporating the solvent, we obtain the desired solid salt. ,

NA YY American Invention 589857841; issued in 1 in particular; US Patent 4,840,841 states that in vitro activity of acetylcholinesterase 1-benzyl-4-((5,6-diethoxy-1-indanon)-2-y)methylpiperidine, E2020, or a Pharmaceutical Acceptable Salt thereof may be determined According to the method:

Ellman et al. Biochem. Pharmacol., 7, 88-95 (1961). Y. From: acetylcholinesterase Inhibitory Activity for 1-benzyl-4-((5,6-diethoxy-1-indanon)-2-yl)methylpiperidine, He (ICs) Inhibitory Concentration of 750 and others; Expressed by the Ellman term defined according to the micromolecular Grammy method. 6 Other methods for determining activity are: vo 1-benzyl-4-((5,6-diethoxy- 1-indanon)-2-yl)methylpiperidine .9968 JAN YY Issued in EAGOAEY (Described in US Patent

11 dialled] fie 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine if prevented; mitigation; to improve; etc; various types of dementia; Specifically, dementia due to aging from diseases of the cerebral arteries associated with a stroke; For example, cerebral hemorrhage or infarction in Alzheimer's type, etc.; poor attention; slurred speech; shawl oul brain; cerebral arteriosclerosis; Injury to incomplete children; emotional changes a disturbance in recent memory; schizophrenia; oo behavioral changes; etc; associated encephalitis; Mental retardation; etc. 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine In addition, ld is strong and highly selective; What makes the compound also useful as a cholinesterase drug has an anticholinesterase effect that depends on this method of effect. 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methyl-piperidine especially; The Diay 1 and Late Pick Disequilibrium Huntington's disease is effective for; For example. tremor disease

Alzheimer's or delayed involuntary movements other than dementia due to aging of the type as a drug 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine when using a coin used non-intestically in closes form of these diseases; It can be taken enterally or non-intestically. As an intravenous injection; Under the skin; and intramuscularly; Sublingual suppositories or tablets. Dosage ve varies according to symptoms; Age; sex » weight; patients' sensitivity; method of administration; time and intervals of discharge; And the type of pharmaceutical preparations, so there is no specific limit regarding (al sally) abuse 001 to 1 mg; preferably 7000 to 1.1 per dose. Usually the compound is given in a dose of about mg; daily For an adult, usually in one to four batches. Sublingual tablets chalet cia eg Re ja Pharmaceutical preparations in the form of 7 tablets and capsules are prepared according to methods generally accepted in the art. In the preparation of injections, the ingredient is mixed Active; when necessary; with an agent to adjust the pH; a solubilizing agent a suspending agent to adjust the pH a suspension agent a preservative agent a preservative a ctonicity agent a reinforcing agent a slabilizer agent a stabilizing agent etc., followed by preparing an injection into the vein, under the skin, or intramuscularly, according to a normal method. In this case, ve when necessary, it is possible to dry these preparations by cooling according to a normal method.

VY

“Polysorbate 80° “methylcellulos” on suspensions includes a Bd “sodium carboxymethylcellulose “powdered tragacanth” acacis<hydroxyethylcellulose “polyoxyethylene sorbitan monolaurate s” polyoxyethylene hydrogenated castor oil. polyoxyethylene sorbitan monolaurate “nicotinamid” Polysorbate 80° 0 castor oil fatty acid from ethyl esters “ether 5” sodium metasulfite “sodium sulfite Examples of a stabilizer include “ethyl p-hydroxybenozate methyl p-hydroxybenzoate and examples of Preservative containing .chlorocresol 5 “cresol “phenol” sorbic acid E2020 depicting examples (400) preparation of compounds of the present invention and preparation of commercial reagents without further purification. Melting points are not corrected. It is recorded from deuterium solvent in parts per million and refers to the deuterium closing signal. NMR data of Bashir deuterium oxide. 0.0 refers to Bruker 300 MHz. The sample is obtained from a “chromatography” device. The analysis indicates Chromatography .deuterochloroform to CDCly silica gel Specify otherwise; to column chromatography using 17-77 µm vo and carried out under nitrogen pressure conditions (flashing chromatography). Thin layer chromatography (TLC) refers to thin layer chromatography (TLC) and filtered with the indicated solvent. The analysis is done (E. Merck, Kiesel Gel 60 F254) silica gel on a high pressure liquid chromatography (HPLC) (Thermo Separation Products Co.) LDC Analytical constaMetric® 3200 HPLC device. ¥-

A 0001” 1 ag fu al 01 Zorbax® C8 ag ac used and filtered for HPLC analysis (Mac-Mod Analytical, Inc., Chadds Ford, PA 19317) (FABMS) Fast Atom Bombardment Mass Spectrometry with the indicated solvent. On a mass spectroscopic analysis instrument, it indicates mass spectroscopic analysis (chemical ionization of a microparticle beam). Hewlett-Packard 5989 Mass Spectrometer ve ?

YY

3-Pyridin-4-vlpropen-2-oic acid (mol) at 1.37 mol (+ +) pyridin-4-ylcarboxaldehyde to a solution of mol) at 97 a= V+ +) malonic acid in milliliters) add 100 (pyridine) methanol dilute the reaction slurry with “(CO,) carbon dioxide metabolite. After emission stabilization (V + g yield AY) the title compound is isolated as a white solid by filtration 0 'H NMR (HOAc-dy) 811.70(s,1H), 8.85(d,2H), 7.95(d,2H), 7.80(d,1H), 6.90(d,1H).

Y preparation 3-Piperidin-4-ylpropanoic acid

Y hydrochloric mole) in an acid (+, YY can TY) 1. The product from a preparation is dissolved on carbon 758 under an atmosphere of rhodium with a weight of 701 milliliters) and treated with (151 N (0) hydrogen ( Press 0 psi) until the absorption of hydrogen gas stops. The catalyst is filtered and the resulting solution of the title compound is carried directly to the next step. 'H NMR (D;0) 3.25(m,211), 2.80( m,2H), 2.25(t,2H), 1.75(m,2H), 1.50-1.10 (m,5H). FABMS (M+1)" = 157. Preparation? ve 3-[N-(Methoxycarbonyl) )-piperidin-4-yl]propionic acid potassium hydroxide with 11 The product solution of the preparation?; reaches pH in gram molecules) after +, YY in milliliters; (YY) methyl chlorofomate aqueous. Add to this 1 N hydrochloric solution with 1 acid 1 h; the solution is brought to pH and replaced with sodium sulfate the organic layer is dried with dichloromethane with sali, 0

YA) Al1500:007. The title compound is isolated as a solid by filtration. 2H), 2.35(t,2H), 1.80-1.10 (m,7H).FABMS (M+1)" = 216. Yo 1 Ex. 4-(2-Chlorocarbonyl-ethyl)-piperidine-1-carboxylic acid methyl ester

AeA

1 mol) in 151 to a solution of the product from a preparation of © (54 g ml; 0.07 equiv.) 71 (dimethylformamide ml) is added © + dichloromethane (mol). After gas emission stabilizes, the formation of 077 “bile YY) oxalyl chlorides, the title compound, is complete. The solution of the title compound is carried directly to the next step. 1 Example ° 4-[3-(3,4-Dimethoxy-phenyl)-3-oxo-propyl]-piperidine- 1 -carboxylic acid methyl ester molecule +, Ye milliliters; Y0,0) at room temperature 1 is added to the product solution from eg

V+ +) aluminum trichloride then added in batches 1,2-dimethoxybenzene (gram) of one molecule). The reaction mixture was stirred for; hours at room temperature. VO a total of 0 shows that the reaction has completed. HPLC (high pressure liquid chromatography) reaction quenching (mL). The materials (© + XY) methylene chloride were washed carefully and then extracted with cle by adding mL); Then 1 N (Yo) brine sodium hydroxide combined organic extract with the solution was filtered and sodium sulfate removed. The organic layer was dried over pal of 1 ml. You) g; quantitative raw weight). Thin Layer Chromatography (TY) solvent by vacuum for oil 1 indicates that the product is of sufficient purity to proceed HPLC and TLC directly to the next step. Using HPLC 5 TLC systems The progress and purity of these reactions is monitored by both analysis of the reaction product (Ry) shown (t). Ascites acetate hexane time 1:40 (Na = Ry called: gel) TLC Y.

Yot (Zorbax Cg) 1.3 min is (HPLC) pressure Je liquid chromatography acetic acid [triethylamine [acetonitrile] ele 0:7: 40 vr To ml/min;1 nm; -4.20(m,2H), 3.92(s,3H), 3.91(s,3H), 3.65(s,3H), 2.93(t,2H,J=7.3Hz), 2.64-2.78(m,2H), 1.61-1.76(m,4H), 1.40-1.55(m, 1H), 1.06-1.21(m,2H).FABMS Yo

CisHasNOs(M+1)" = 336.

A]

Vo 4-[2-(3.,4-Dimethoxy-benzovl)-allyl]-piperidine- 1 -carboxylic acid methyl ester gram molecule) 170 is added to a solution of the product, for example? (13 g ot) tetramethyldiaminomethane (mol) then + A + milliliters (VT) acetic anhydride (mol). The reaction is heated externally to 10" seminal. After heating is complete, 045 milliliter; for three hours, then left to stir overnight at 4550s external temperature; the reaction is heated at room temperature. Cool. Extract hydrochloric milliliter) from the reaction vessel and treated with acid (1) an aqueous amount is removed. Then the treated bicarbonate layer is dried with Lol methylene chloride solution with HPLC showing organic matter consumption and decomposed by high-temperature liquid chromatography Compression initiating.< crude reaction directly to the next step. sale based on the purity of the crude reaction mixture; tolerance (t) degradation). silica gel) TLC

Yot (Zorbax Cg) hr 10.4 min (HPLC) HPLC (acetic acid [triethylamine [acetonitrile] water/VY: 00500 Adds mL/1 nM; '"H NMR (CDCl) 8 7.35-7.40(m,2H), 6.83(d,1H,J=8.8Hz), 5.68(s, 1H), 5.54(s,1H), m 3.94-4.14(m, 2H), 3.89 (s,3H), 3.88(s,3H), 3.62(s,3H), 2.59-2.75(m,2H), 2.32-2.41 (m,2H), 1.55-1.74(m, 3H) , 1.00-1.21(m,2H).FABMS C5HsNOs (M+1)" = 348. Ex: 4-(5,6-Dimethoxy-1-ox0-indan-2-ylmethyl)-piperidine-1-carboxylic acid methyl ester 7 001 (sulfuric concentrate) Treat the crude reaction mixture of example © (+ 070 mol) with acid and leave the reaction to stir overnight at room temperature; Male mL) at 0*C. to completion of the reaction. HPLC pressure quenching Me then liquid chromatography indicates o++xY) methylene chloride as a kg of ice; The aqueous phase was extracted with 1 reaction by pouring in a silla of 5000 ml). The combined organic extracts were washed with +0 mL water; Yo’ sodium sulfate mL brine; The difference of 500 N; 1 sodium hydroxide 00 mL was dried, and the volatile substances were removed by vacuum. Then the oily solid is crushed with mm

cisopropyl ether and the product was filtered to yield £7.0 g ZA) of JAA «dimethoxybenzene per step] from the title compound as a yellow solid. Ry :(silica gel) TLC = nebulization (40 (ethyl acetate /hexane) 1 sequestration time (t) Je pressure liquid chromatography (HPLC) is 1100 min Yot (Zorbax) Cg) © nm; 1 milliliter/min; 0:5600 0:37:40 water/ (acetic acid [triethylamine [acetonitrile (s,1H), 6.85(s, 1H), -4.08 4.23(m,2H), 3.95(s,3H), 3.89(s, 7.15 8 (bl02) “I NMR 3H), 3.67(s,3H), 3.24(dd,1H,J=17.8, 8.3Hz), 2.62-2.82(m,4H), 1.84-1.95(m,1H), 1.62-1.80(m,3H), 1.25-1.39(m,1H), 1.08-1.33(m,2H) .FABMS C5HysNOs (M+1)* .348 = .3 ° 5.6-Dimethoxy-2-piperidin-4-ylmethyl-indan-1-one to a solution of product from eg? (© 15,5 com mmol (min in methanol (£1 mL) add potassium hydroxide (0.9 g; AY mmol) dissolved in 80 mL water. The mixture is then heated under nitrogen atmosphere for J Then HPLC ae - high pressure liquid chromatography (HPLC) reports consumption of the starting material. The aqueous phase is extracted with (+x¥) methylene chloride © milliliters); the combined organic layers are dried with “sodium sulfate” and the volatiles are removed. by aspiration to provide 0.7 g (AVA) of the title compound as a solid. This material is used without additional purification. The retention time of (,a) HPLC baal is 7.15 min. Zorbax Cg) v: 754 nm 1 mL/min 00300 1:73:46 [acetonitrile [sles]. (acetic acid [triethylamine I NMR (CDCly) 8 7.12(s,1H), 6.82(s, 1H), 3.91(s,3H), 3.86(s,3H), 3.20(dd, 1H,J= 17.7,8.2Hz), 3.00-3.13(m,2H), 2.52-2.77(m,4H), 1.70-1.94(m,1H), 1.51-1.80(m, 3H), 1.02-1.35 (m,3H).FABMS C;7H33NO;3 (M+1)" = 290. Yo Ex. 1 2-(1-Benzyl-piperidin-4-ylmethyl)-5,6-dimethoxy-indan- 1-one AQ

and" to a slurry of the title compound of eg 0 (VAY; 1.7 mmol) in T+ (isopropyl ether) mL add Ve) benzylbromide + ml; 3.7 mmol) 5 triethanolamine (464 mg; Ale LY µm). The slurry was stirred overnight; at 0'a resting place; then HPLC indicates that most of the starting material has been consumed. The reaction mixture was then filtered to remove the precipitated triethanolamine hydrobromide. To the remaining solution ether saturated with VY «allll 1 (hydrochloric acid (Ale mole)] was added; the solvent was removed by vacuum. The residue was dissolved in 1 milliliter of hot Yo isopropanol and allowed to cool to room temperature The precipitated solid was filtered off to yield 1.6 g (AY) of the title compound as a white solid (silica gel) TLC Ve = 1 + (0 /methylene chloride 01: cutoff); HPLC = 1.01 min Yet Zorbax Cs) nm” filtered with 0:500 0:73:40 water/(acetic acid [triethylamine [acetonitrile] NMR (of the free base, DMSO-dg) 5 7.06(s, 1H), 7.03(s, 1H), 3.84(s,311), 3.77(s, 1.1 3H), 3.41(s.2H), 3.19 (dd , 1H,J=17.8,8.2Hz), 2.71-2.86(m,2H), 2.58-2.71(m,2H), 1.82-1.96(m,2H), 1.52-1.78(m,3H), 1.31 -1.50(m,1H), 1.08-1.30(m,3H). FABMS vo (M+1)" = 380. Wu Laumtaben Ald

Claims (1)

YA Protectants of formula: compound BKRM-1 1 R! \ N 0 OMe 111 7 Ra Mer Alolalazine-). Y (C1-Cyalkyl Mer R?5R*O(C=0)- Mo R' where v is of the formula: compound oS =F 1 0 RY N OMe 1 Y .methyl Ra Mer R?0(C=0)- bitter R' where r is for the preparation of a compound of the formula: process 001 0 rN OMe I Y process including: oCp-Cy)alkyl bitter R* 5 R*FO(C=0)- hr R' where r is a complex reaction of the formula: ( ) N 2s ome ome 11 where a is R’O(C=0)- and 1832 is (C-Coalkyl) with methenylation agent 7 to form a compound of the formula: 0 Asim Cr OMe I A 9 where R' hr is R?5R*O(C=0)-Fu((C1-Cqalkyl 5 ¢ 0) (b) The reaction of said compound of formula I] formed in this way; With a strong acid ~~ methenylation agent for the protectant, where the methenylating agent is Wh process ©#-01 .acetic anhydride process in the mentioned tetramethyldiaminomethane s Y tetramethyldiaminomethane for the protectant © where Wha is added process shine-1 1 in excess acetic ahydride 5 Y process shine-1” 1 according to claim 7 wherein said tetramethyldiaminomethane Y includes 1 equivalent and said acetic anhydride includes ; EQ. process Ae = A 0 according to any one of the claims; to 1 where strong acid 7 is p0150116? Sulfuric acid is a sulfuric acid that is Cua A according to the protection element process 4 - process 1 concentrate. -01-1 Wa process of claim 9 wherein said concentrated sulfuric acid comprises Y 4 equivalent. AA Yo. also includes Additional Step 01 under any one of the claims; To β process -11 0 is the alpha(-0) with R*5 220(0-0)- is R' where oJ is for the reaction of the compound of the formula to form a compound of the formula: base r 0 OMe because VI. The said compound of formula VI formed in this way reacted with benzylhalide to form 1 compound of formula: 0 QL N OMe v 71 . —VY 1 The Wh process of claim 11 where said benzyl halide is .benzyl bromide ¥ process Adee —VY 1 of claim 11 or claim VY where said base 7 is hydroxide Wh process Adee —VE of claim 11 or claim VY wherein said base Y is triethanolamine process Ale-1#0 according to any one of claims 11 through 16 where said compound of formula Y 1 is isolates By adding a strongly acidic solution to ela/ice then Y extraction with an organic solvent and removal of the organic solvent ¢ before treating the formula 1 compound with base 1 - process process to prepare a compound of the formula: N 2s ome ome 10 . Involving the reaction of a compound of formula: (C-Cylalkyl is -(820)0-0 and is R' where r is OMe QL... Iv ¢ ° with a compound of formula: r" v Cl 0 v " in an inert solvent in the Lewis reaction as specified above; In the presence of an acid RY where the reaction inert solvent ~~ A mentioned is Lewis where the acid is OT according to the protection element process 17-1 the aforementioned reaction inert solvent and the inert solvent in the reaction ‎ aluminum trichloride Y .methylene chloride sa v 4-[3-(3,4-dimethoxy-phenyl)-3-oxo-propyl]-piperidine-1-carboxylic acid ester =A substantially as described herein with reference to Any one of the examples. Y substantially 4-[2-(3,4-Dimethoxy-benzoyl)-allyl]-piperidine-1-carboxylic acid ester =Y3 as described herein before with reference to any one of the examples 4-(5,6-Dimethoxy-1-oxo-indan-2-ylmethyl)-piperidine-1-carboxylic acid ester 100 substantially as described herein by reference to any one of the examples. To prepare process —YY 1 4-(5,6-Dimethoxy-1-oxo-indan-2-yimethyl)-piperidine-1-carboxylic acid ester, v AQ YY is substantially as described here before with reference to any one of the examples. piperidine- 1 -carboxylic acid ester, Y substantially as described herein before with reference to any one of the examples. 4-(5,6-Dimethoxy-1-oxo-indan-2-ylmethyl)-piperidine-1-carboxylic acid ester —= Y¥ 0 .71 or 14 prepared by the process from any one of the claims; to Y 4-[3-(3,4-dimethoxy-phenyl)-3-oxo-propyl]-piperidine--carboxylic acid ester derivative —V 1 1 .71 or 11 ve prepared by the process from Any one of the claims Y AQ