Title of Invention

PROCESS FOR THE PREPARATION OF CCR-2 ANTAGONIST.

Abstract The present invention provides an efficient synthesis for the preparation of ((lR,3S)-3-isopropyl- 3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3- methoxytetrahydro-2H-pyran-4-yl]amine  and  its  succinate  salt  by  a  process  comprising hydrogenating (3S,4S)-N-((lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine to yield ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine. The succinate salt is prepared by further contacting ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine with succinic acid to yield ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl} cyclopentyl)[(3 S,4S)-3 -methoxytetrahydro-2H-pyran-4-yl]amine succinate. The present invention additionally provides an efficient syntheses for the preparation of ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine and its  succinate salt  wherein  the  intermediates  (3R)-3-methoxytetrahydro-4H-pyran-4-one;  (1S,4S)-4-(2,5- dimethyl-1H-pyrrol-1-  yl)-l-isopropylcyclopent-2-ene-l-carboxylic acid; and 3- (trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine are prepared by processes and also for the preparation of the precursor (3S,4S)-N-((1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine. The invention additionally resides in the superior properties of the succinate salt of ((lR,3S)-3- isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine.
Full Text FIELD OF INVENTION
The present invention provides a process for preparing CCR 2 antagonist ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine of formula I.
BACKGROUND OF THE INVENTION
International patent applications US03/12929, filed April 25, 2003, and US03/13042, filed April 25, 2003, disclose tetrahydropyranyl cyclopentyl tetrahydropyridopyndine compounds. These compounds are useful for the treatment of diseases or conditions of humans or other species which can be treated with inhibitors, modulators or promoters of chemokine receptor function. Such diseases or conditions include those mentioned in the referenced applications.
((lR,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1:
(Formula Removed)
is a potent CCR-2 inhibitor. The laboratory preparation of compound 1, including the laboratory preparation of certain intermediates and precursors employed to in the synthesis of compound 1 is described in International patent applications US03/12929 and US03/13042.
Prior techniques for synthesizing compound 1 were inefficient and time consuming, and thus expensive from the standpoint of production. The synthesis of the naphthyridine building block, for example, comprised nine separate steps and required the use of several expensive reagents, hampering the efficiency of the overall synthetic process. Similarly, the synthesis of the cyclopentene building block resulted in a high proportion of undesirable stereoisomers. Other aspects of the synthesis were likewise inefficient, expensive, and/or not amenable to commercial production. Previously synthesized hydrochloride salts of compound 1, moreover, displayed less than ideal solubility, handling (e.g., hydroscopicity) and other properties. Thus, there remains a need for an improved synthetic route to compound 1 that is amenable to large scale production formulation, storage and distribution. There also remains a need to develop improved salt forms of compound 1.

SUMMARY OF THE INVENTION
The present invention provides an efficient synthesis for the preparation of ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yI]amine and its succinate salt. The present invention additionally provides an efficient syntheses for the preparation of intermediates (3R)-3-methoxytetrahydro-4H-pyran-4-one; (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)l-isopropylcyclopent-2-ene-l-carboxylic acid; and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine; and for the preparation of the precursor (3S.4S)-N-((lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,S-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine. The invention additionally resides in the superior properties of the succinate salt of ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yljamine.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of (3S,4S)-N-((lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine, 2:

(Figure Removed)
comprising the steps of:
(1) reacting (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-ene-l-
carboxylic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine to form 6-{[(lS,4S)-4-
(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-en-l-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-
tetrahydro-1,6-naphthyridine;
(2) treating the 6-{[(lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-
2-en-l-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine with hydroxylamine to
form(lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin'6(5H)-yl]carbonyl) cycIopent-2-en-1 -amine; and
(3) coupling the (lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-amine with(3R)-3-methoxytetrahydro-4H-pyran-4-one via reductive amination.
In a further aspect, the present invention provides a process for the preparation of ((IR,3S)-3-isopropyl-3-{[3-(trifIuoromethyI)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1:

(Figure Removed)
comprising the further step of:
(4) hydrogenating(3S,4S)-N-((lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetraliydro-2H-pyran-4-amine.
In another aspect of the invention, discussed in greater detail below, the hydrogenation step is accomplished prior to the formation of compound 2.
The syntheses of (3S,4S)-N-((lS,4S)-4-isopropyI-4-{ [3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine, 2, and ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1, are depicted in Scheme
(Figure Removed)
N-((lR,3S)-3-isopropyI-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)-N-[(cis-3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1, is synthesized by sequentially coupling three building block compounds 4, 5 and 6 (Schemes 3, 4 and 5, below). An amidation reaction between 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine, 5, and (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)l-isopropylcyclopent-2-ene-l-carboxylic acid, 4, is carried out in the presence of methanesulfonyl chloride to afford 6-{[(15,45)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-en-l-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine. Deprotection of the pyrrole group was carried out at this stage using hydroxylamine as a through process to provide an amine salt. The amine salt and (3R)-3-methoxytetrahydro-4H-pyran-4-one, 6, are coupled through reductive amination, in the presence of a tributylamine buffer, and with NaBH(OAc)3 to afford
(3S)4S)-N-((lS,4S)-4-isopropyI-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine, 2. The cyclopentene moiety of compound 2 was then hydrogenated to form free base compound 1.
In another aspect the invention provides a process for the preparation of ((1R,3S)-3-isopropyl-3-{[3-(trifluorometJiyl)-7>8-dihydro-l,6-naphthyridin-6(5H)-ylJcarboJiyUcyclopentyl)f(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate, 3:
(Figure Removed)
comprising the further step of:
(5) contacting ((lR,3S)-3-isopropyl-3-{[ naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1 with succinic acid.
Optionally, prior to step (5) compound 1 may be purified employing crystallization, either as a succinate salt or other salt such as a benzenesulfonate salt, followed by a salt break. Purification in this manner is described in the examples which follow.
The synthesis of compound 3, the succinate salt, is depicted in Scheme 2
(Formula Removed)



In another aspect, the invention provides a process for the preparation of the intermediate (1 S,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-ene-l-carboxylic acid, 4, comprising the steps of:
(1) reacting (lR,4S)-4-aminocyclopenten-2-ene-l-carboxylic acid with MeOH in the presence thionyl chloride to form methyl (lR,4S)-4-aminocyclopent-2-ene-l-carboxylate;
(2) reacting said methyl (1 R,4S)-4-aminocyclopent-2-ene-1 -carboxylate with acetonyl acetone to form methyl (lR,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)cyclopent-2-ene-l-carboxylate;
(3) reacting said methyl (lR,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)cyclopent-2-ene-l-carboxylate with 2-iodopropane to form methyl (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-1 -isopropylcyclopent-2-ene-1 -carboxylate; and
(4) reacting said methyl (1 S,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-ene-l-carboxylate with NaOH and MeOH to form (lS,4S)-4-(2,5-dimethyl-1 H-pyrrol-1 -y 1)-1 -isopropylcyclopent-2-ene-1 -carboxylie acid.
The syntheses of (1 S,4S)-4-(2,5-dimethyl-1 H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-ene-l-carboxylic acid , 4, is depicted in Scheme 3:

Scheme 3
(Formula Removed)


Here, (lR,4S)-4-aminocyclopent-2-ene-l-carboxylic acid is converted into the corresponding methyl ester by treatment with thionyl chloride in methanol. Methyl (1R,45)-4-(2,5-dimethyl-lH-pyrrol-l-yl)cyclopent-2-ene-l-carboxylate is then synthesized by reacting the (lR,4S)-4-aminocyclopent-2-ene-l-carboxylate methyl ester with acetonyl acetone in the presence of DIEA. The following alkylation of methyl (1R,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)cyclopent-2-ene-l-carboxylate with iodopropane is carried out using lithium bis-(trimethylsilyl)amide as a base. The resulting alkylated product is then hydrolyzed to form the (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-ene-l-carboxylic acid 4.
While the above discussion assumes that the cyclopentene moiety will be hydrogenated in a later step to afford the cyclopentane, in fact many of the compounds depicted in Scheme 1 and 3 may be hydrogenated in an intervening step to produce a cyclopentane analog. (Because a pyrrole protecting group, if present, would also be reduced to a pyrrolidine during this process, an alternate protecting group could be employed.)



Moreover, in another feature of this aspect of the invention, intermediates may be synthesized having protecting groups other than 2,5-dimethyl-lH-pyrrol-l-yl. Thus, skilled chemists would pursue intermediate compounds of the general formula:
(Figure Removed)
wherein the protecting group 'PG1" includes but is not limited to tert-butoxycarbonyl, benzyloxycarbonyl, alkyloxycarbonyl, allyloxycarbonyl, benzoyl, formyl, acetyl, trifluoroacetyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyI, benzyl, triphenylmethyl, imines (such as diphenylmethylene) and other protecting groups known in the art, as exemplified in Greene, T; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., New York, NY 1999.
In another aspect the invention provides a process for the preparation of the intermediate 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine, 5, comprising the steps of:
(1) reacting 3,3,3-trifluoropropanoic acid with POC13, DMF, NaPF6 and a base to
formN-[3-(dimethylarmno)-2-(trifluoromethyl)prop-2-enylidene]-N-methylmethanamium
hexafluorophosphate (CF3DT);
(2) reacting CF3DT with the protected piperidone to form - N-(protecting group)-3-
(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine (for example, reacting CF3DT with BOC-
piperidone to form - N-(tert-butoxycarbony])-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine);
and
(3) reacting said - N-(protecting group)-3-(trifluoromethyl)-5,6)7,8-tetrahydro-l,6-
naphthyridinene (for example, N-(tert-butoxycarbonyl)-3-(trif]uoromethyl)-5,6,7,8-tetrahydro-l,6-
naphthyridine) in the presence of HC1 and methanol to form - 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-
naphthyridine.
The syntheses of 3-(trifluoromethyl)-5,6,7,S-tetrahydro-l,6-naphthyridine, 5, is depicted in Scheme 4A and 4B, below:
(Figure Removed)
Phosphorous oxychloride (POC13) is added to chilled DMF at a rate such that the temperature remained below 10 °C (approx. 1 h). The reaction mixture is warmed to RT and then 3,3,3-trifluoropropanoic acid is added (exotherm to approx. 45 °C). The reaction mixture is warmed to 50°C and held at this temperature for approx 4 h. Upon completion of the vinamidinium formation the reaction mixture is allowed to cool to RT. The reaction mixture is then added concurrently with 5 N NaOH to a solution of NaPFe in water cooled to 0°C. The rates of addition of the two solutions are controlled such that the temperature of the aqueous slurry remains below 10 °C and the pH is between 3 and 4 (addition time takes about 2 h). Upon completion of the additions the resulting yellow slurry is aged for one hour at 0 °C then filtered to collect solids. The filtercake is slurry washed with ice cold water (2 times) and the cake dried with nitrogen/vacuum. Typical yield 85 %.
A solution of the protected piperidone, for instance the BOC protected piperidone, in THF is then added to a cooled (-20 °C) solution of lithium hexamethyldisilylamide (LiN(TMS)2) in THF, keeping the temperature below 10°C, to form the lithium enolate (approx 45 min). After warming to RT the enolate solution is transferred to a chilled (-20 °C) slurry of the CF3DT in THF at a rate such that the internal temperature remains below -10 °C (approx 45 min). This mixture is aged for 2 h at -20 °C then acetic acid is added and the mixture warmed to room temperature over 30 minutes. Ammonium acetate is then added and the mixture heated to 65 °C. After two hours at 65 °C the reaction mixture is cooled to RT. Water and heptane are then added and the layers separated. The organic layer is washed with 2 M aqueous citric acid and then assayed for the BOC naphthyridine. Typical yield 65%.
Next, the organic layer from the naphthyridine formation is concentrated and solvent switched to methanol. HC1 in IPA is then added and the mixture heated at 60 °C until the deprotection is complete (about 1 h). After cooling to room temperature water is added and the pH adjusted to appox 10.5. IP Ac is added and the layers separated. The aqueous layer is back extracted with IPAc two additional times. The combined organic layers are concentrated and solvent switched to PA. This IPA solution is filtered to remove inorganic salts, the filtercake washed with IPA and the combined filtrate and washes reconcentrated to a total volume of about 5 mL/g. After the free base/IPA solution to 60 °C HC1 in IPA is added over 30 minutes. Solids are evident at about 50% addition. After completion of the HC1/IPA addition heptane is added to complete the crystallization and the slurry cooled to room temperature. The solids are isolated by filtration and washed with IP A/heptane (3 times 1 mL/g) then dried. Typical yield 75% from BOC naphthyridine.
As noted above, piperidones having protecting groups ("PG2") other than tert-
butoxycarbonyl may also be used. Other protecting groups useful in the synthesis of the naphthiridine include, but are not limited to benzyloxycarbonyl, alkyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, formyl, trifluoroacetyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, N-benzyl, triphenylmethyl, and other protecting groups known in the art, as exemplified in Greene, T; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., New York, NY 1999.
In another aspect the invention provides a process for the preparation of the intermediate (3R)-3-methoxytetrahydro-4H-pyran-4-one, 6, comprising the steps of:
(1) reacting tetrahyro-4H-pyran-4-one with tripropylorthoformate and chlorobenzene
to form 4-propoxytetrahydro-2H-pyran-ethene;
(2) reacting said 4-propoxytetrahydro-2H-pyran-ethene in the presence of acetone,
water, hydroquinidine-l,4-phthalazinediyl diether (DHQD2PHAI), potassium osmate dehydrate, and 4-
methylmorpholine N-oxide monohydrate (NMO) to form 3,4-dihydroxytetrahydro-2H-pyran-4-sulfonic
acid, sodium salt;
(3) reacting said 3,4-dihydroxytetrahydro-2H-pyran-4-sulfonic acid, sodium salt
with methanol and trimethylorthoformate in the presence of an acid to form 4,4-dimethoxytetrahydro-2H-
pyran-3-ol; and
(4) reacting said 4,4-dimethoxytetrahydro-2H-pyran-3-ol in the presence of THF,
NaOt-Bu, Me2SO4, and an acid to form (3R)-3-methoxytetrahydro-4H-pyran-4-one.
The syntheses of (3R)-3-methoxytetrahydro-4H-pyran-4-one, 6, is depicted in the Scheme 5:
(Figure Removed)
The starting pyranone is converted to its dipropyl ketal by treatment with
tripropylorthoformate in the presence of an acid catalyst. The crude ketal is then heated in the presence of chlorobenzene. Under these conditions, elimination of propanol provides the propyl enol ether. The
reaction is driven by the removal of propanol by distillation during the reaction sequence. The crude enol ether is then oxidized under modified Sharpless asymmetric dihydroxylation conditions. In this reaction N-methylmorpholine oxide is used as the stoichiometric oxidant. The reaction typically gives the product a-hydroxyketone in about 80 to 85 % ee. The a-hydroxyketone is not isolated directly but an aqueous solution of Na2S2O5 is added to form the bisulfite adduct of the ketone . From the acetone water mixture, racemic bisulfite adduct crystallizes. The racemate is removed by filtration and the resulting mother liquor is typically 95 to 99 % enantiomeric excess (ee). The acetone is removed in vacuo and isopropanol is added to give the crystalline bisulfite adduct with high enantiomeric excess. This is treated with HC1 and methanol with trimethylorthoformate as a water scavenger, to provide the dimethylketal. The hydroxyl group is then methylated using NaOt-Bu and Me2SO4. Adding water and HC1 to the reaction mixture provides the target cc-methoxypyranone in about 96% ee.
Several abbreviations, acronyms and other shorthand is presented herein. Although these terms are known to those skilled in the art, presented below is a table summarizing these terms:

MSCI
DffiA
IPAc
IPA
i-Prl
LHMDS
THF
DMF
P.O.
BOC
NMO
TFPA

methanesulfonyl chloride
diisopropyl ethylamine
isopropylacetate
ispropanol
2-iodopropane
lithium hexamethyldisilazide
tetrahydrofuran
dimethylformamide
protecting group
/ert-butyloxycarbonyl
N-methylmorphaline oxide
trifluoropropionic acid

Example 1
((lR,3S)-3-Isopropyl-3-{t3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yI]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine

Step 1 - 6~{[(lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-en-l-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l, 6-naphthyridine
(Figure Removed)
The pyrrole cyclopentene acid (730 g, 90.4wt%, 2.67 mmol) and diisopropylethylamine (0.93 L, 5.34 mol) were mixed in THF (6.6 L). The resulting dark solution (KF = 195 mg/mL) was cooled to 0 °C, then methanesulfonyl chloride (228 mL, 2.94 mol) was added over 1 min whereupon the internal temperature increased to 13 °C over a few min. The cooling bath was removed and the mixture was aged at room temperature for 4 h. The reaction solution was cooled to -15 °C and tetrahydronaphthyridine-HC1 salt (670 g, 73.2wt% as free base equivalent, 2.42 mol) was added. The temperature was increased to 23 °C and another portion of diisopropylethylamine (0.93 L, 5.34 mol) was added with cooling at -25 °C over 15 min. The mixture was aged for >1 h and was then diluted with 5% NaHCO3 (16 L). The product was extracted with ethyl acetate (EtOAc) (16 L). The organic phase was washed with water (10 L) and concentrated under vacuum with displacement of the EtOAc with methanol to a volume of 10 L. The assay yield of the amide was quantitative (1.055 kg, 2.45 mol).
Step 2 -(lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8'dihydro-J,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-amine
(Figure Removed)
The amide (1.055 kg, 2.45 mol) in methanol (10 L) was added to hydroxylamine-HCl (1 kg, 14.4 mol), 50% hydroxylamine in water (1 L, 16.3 mol) and water (5 L). The resulting slurry was heated to reflux (71 °C) and maintained at this temperature for 6 h. The reaction solution was cooled to room temperature and the pH was adjusted to 11.0 with 10 N NaOH. The reaction solution was diluted with water (12 L) and the product was extracted with chlorobenzene three times (14 L, 13L, and 13L). Each organic layer was washed once with the same water (10 L). The organic layers containing product (0.79 assay kg, 2.24 mol, 92% yield) were combined and concentrated. The solvent was switched to isopropanol (8 L). Anhydrous HC1 in IPA (4.3 N, 1.4 L, 6.0 mol) was added. This mixture was concentrated to ~2 L. The resulting slurry was heated to 70 °C and n-heptane (8 L) was added slowly. The slurry was cooled and aged at room temperature overnight (16 h). The solids were filtered, washed with of 20% IP A/heptane (1.5 L) and dried under nitrogen to yield 1.12 kg of the HC1 salt (0.76 kg of free base equivalent) in 91% overall yield.
Step3-(3S,4S)-N-((lS,4S)-4-isopropyl-4-{[3-(trifliwwmethyl)-7,8-dihydro-l,6-naphthyridm-6(5H^ yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro~2H-pyran-4-amine
(Figure Removed)
The amine dihydrochloride salt (777 g, 552 g as free base, 1.56 mol) was slurried in IPAc (3 L). The mixture was cooled in an ice bath and n-Bu3N (860 mL, 3.61 mol) was added followed by isopropanol (260 mL, 3.40 mol). Sodium triacetoxyborohydride (724 g, 3.42 mol) was added at 5 °C. After 1 h, a solution of the methoxypyranone in IPAc (1.76 L of a 160 g/L solution, 2.17 mol) was added to the batch at 1 °C. After 6 h, the mixture was partitioned between saturated aq. NaHCO3 (3 L), water (8 L), and EtOAc (10 L). The aqueous phase was further extracted with EtOAc (15 L). The combined organic phases were extracted with sat'd NaHCO3 (4 L), dried over MgSO4(600 g), then concentrated. The resulting oil was dissolved in CH3CN (15 L) and extracted with heptane (3 x 4 L). The acetonitrile phase contained 654 g (1.4 mol, 90%) (3S,4S)-N-((lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine. The solvent was removed in vacuo to provide an oil that was used in the final hydrogenation step.
Step 4-((lR,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine
(Figure Removed)
The crude coupled cyclopentene of Step 3 (640 g) was diluted with methanol (3.2 L) and the solution was concentrated to an oil. Dilution with methanol (3.2 L) and concentration were repeated two additional times. After the final concentration the oil was diluted with methanol (6.4 L) and charged to an autoclave. The catalyst 5% Pd/C (256 g) was charged to the autoclave as a slurry in methanol (1.4 L). The hydrogenation (40 psi) was run overnight (18 h) at 25 °C. The batch was filtered through solka floe (-1.5 in depth) in an 8 L sintered-glass funnel. The autoclave was rinsed with methanol (5.0 L) and this rinse was used to wash the filter cake. The cake was washed again with methanol (1.3 L). The sequential rinsing was repeated four additional times. By LC assay the combined filtrate and washes (total wt = 17.1 kg) contained 633 assay g (98.5 % yield) of the free base. The filtrate and washes were concentrated to an oil (770 assay g, 1.634 mol). The oil was dissolved in IPA (3.1 L) and the solution was concentrated to a brown oil. Dilution with IPA (3.1 L) and concentration was repeated two additional times.
Example 2

((lR,3S)-34soproyl)\l-3-{f3-(trinuorometh\l)-7,8-dih\dro-l,6-naphthyridm-6(5H)-yl]carbonvl}cyclopentyl)f(3S,4S)-3-methoxvtetrahydro-2H-pyran-4-yl]amine succinate
Synthesis 1:
Purification from Benzenesulfonate Salt: The resulting oil from the Example 1 was dissolved in IPA (1.54 L) and transferred to crystallization flask. An IPA (2 X 385 mL) rinse was added to the batch. The solution was warmed to 56 °C at which point benzenesulfonic acid (283 g, 1.79 mol) was added which resulted in an increase in temperature to 71°C. The solution was cooled to 60 °C and benzenesulfonate salt seed (1 g) was added. The thin slurry was aged for 30 min to develop a thick seed bed after which heptane (4.62 L) was added over 50 min. After aging at 55 to 65 °C for 2 h the slurry was cooled to ambient temperature overnight. The slurry was filtered and the wet cake was washed with 2:1 heptane/IPA (2 X 2.3 L). The off-white solid was dried under Ni/vacuum to give the benzenesulfonate salt (875 g, 98.3 wt%) as a tan solid (84% adjusted yield). Water (11.1 L), IPAc (32 L), and ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine benzenesulfonate salt (1.645 kg) were added to a solution of K2CO3 (6.58 kg) in water (18.3 L). The mixture was aged 15 min. The layers were separated and the organic layer was washed with water (16 L). The IPAc solution of ((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyI}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine free base (60.5 kg containing 1.16 kg free base) was concentrated to an oil. The resulting oil was diluted with ethanol (3.785 L) and reconcentrated to an oil. The dilution and concentration were repeated three more times.
Synthesis of the Succinic Acid Salt: After the final concentration the oil was diluted with ethanol (4.055 L). The ethanol solution was then heated to 65 °C. Succinic acid (294 g, 2.48 mol) was added in one portion followed by addition of heptane (530 mL) over 10 min. The solution was then seeded with ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-rnethoxytetrahydro-2H-pyran-4-yl]amine succinate (5.8 g) as a slurry in heptane (50 mL). The resulting slurry was aged for 1 h at 65 °C during which time it noticeably thickened. At the end of the seed bed age, heptane (7.54 L) was added over 1.5 h. The slurry was aged for 2 h at 65 °C, then allowed to cool to room temperature overnight (~9 h). The solids were filtered,
washed with 2:1 heptane/ethanol (2 X 2.3 L, 2 mL/g free base), and dried under vacuum with a N2 stream for 2 h. The filtercake was broken up and further dried with N2/vacuum for -48 h to afford 1.328 kg of the succinate salt (91.6 %). The dried batch of ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate (1.328 g) was passed through a Comil using a 460 µm screen affording 1.313 g.
Synthesis 2
Formation of Succinate Salt: The free base (3034.2 g) was charged via a lµm inline filter to a 72 L flask equipped with a thermocouple, overhead stirrer, N2/vacuum inlet, and batch concentrator, flask had been marked at 11.2 L. The combined concentrates were further concentrated to ~7 L and solvent switched to FtOH at constant volume using 17 L EtOH. The solution was diluted with EtOH to the 11.2 L mark on the flask. Vacuum was released and batch concentrator was replaced with an addition funnel. 839 g succinic acid was added and batch was warmed to 65°C. Heptane (1.4 L) was added over 7min. 5 g seed was dissolved in 100 mL heptane and added to the batch. The thin slurry was aged 60 min to develop a thick seed bed after which 34.9 L heptane was added over 120 min. After aging at 65°C for 2h the slurry was cooled to ambient temp overnight. LC assay of the mother liquors showed a loss of 6.5 mg/mL. The slurry was filtered and wet cake slurry washed with 2 X 8 L 3/1 heptane/EtOH, followed by a 4L displacement wash with 3/1 heptane/EtOH. The off white solid was dried under No/vacuum on the filter pot to give 3404 g tan solid 96.7wt%, 86% adjusted yield with 10.3% assay loss.
Recrystallization of Succinate Salt (Optional): 12.1 L EtOH was charged to a visually clean SOL flask equipped with No/vacuum inlet, mechanical stirrer, thermocouple, and inlet adaptor. Succinate salt was added and rinsed in with 4.7 L EtOH. Slurry was warmed to 65°C at which point the solution was transferred to a 72 L flask under static vacuum via a 1 urn inline filter. When transfer was complete 50 L flask was rinsed with 1 L EtOH, rinse was transferred via inline filter to batch in 72 L flask. The filtered EtOH solution was concentrated at 38-44°C with 25in Hg to through it with vacuum for 3 h then the filtercake was broken up and further dried with N2/vacuum for approximately 48 h. After completion of drying the bulk drug was stored in a doubled polybag within a fiber drum to await milling. A total of 3.018 kg of the succinate salt (93.9 % yield) was obtained.
Example 3 (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-ene-l-carboxylic acid
Step 1 - Methyl (lR,4S)-4-aminocyclopent-2-ene-l-carboxylate
(Formula Removed)
Solid (lR,4S)-4-aminocyclopenten-2-ene-l-carboxylic acid (1.0 kg, 7.72 mol) was dissolved in MeOH (3.0 L). The slurry was cooled to 0-5 °C. Thionyl chloride (0.576 L, 7.92 mol) was added dropwise over 2 h maintaining a temperature Step 2 - Methyl (lR,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)cyclopent-2-ene-l-carboxylate
(Formula Removed)

The solid aminocyclopentene methyl ester salt (1.076 kg, 6.059 mol) was dissolved in MeOH (3 L, 2M) at 20 °C under nitrogen. Diisopropylethylamine (DIEA, 0.78 kg, 6.059 mol) was added followed by acetonyl acetone (0.711 kg, 6.241 mol). The batch had an exotherm increasing the temperature to 32-35 °C. The reaction mixture was then aged at 25 °C for 16 h. The batch was diluted with IPAc (9-10 L) and washed with 10% NH4C1 (2 x 3 L) and 5% brine (2x3 L). The IPAc batch was dried over sodium sulfate, filtered, and concentrated to an oil. THF (3 L) was used as a flush and the batch was again concentrated to an oil. The air-sensitive pyrrole-protected aminocyclopentene carboxylate (1189 g, 92% yield) was stored at 5-7 °C under nitrogen until the alkylation step was run.

Step 3 - Methyl (lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-isopropylcyclopent-2-ene-l-carboxylate

(Figure Removed)
The pyrrole methyl ester (1189 g) dissolved in THF (1.2 L) was added dropwise over 40 min to 1 M lithium hexamethyldisilazide (LHMDS) in THF (8.65 L, 8.650 mol) at -20 °C. The batch was aged for 30 min and 2-iodopropane was added over 1 h. The batch was aged for 1 h, then allowed to warm to 20 °C over 2 h and aged at 20 °C for 1-2 h until complete by HPLC ( (Figure Removed)
The alkylated pyrrole methyl ester (1.38 kg, 5.197 mol) was dissolved in MeOH (7.7 L). DI water (2.5 L) was added followed by ION NaOH (2.08 L, 20.786 mol). The batch was then heated to 65 °C for 16 h. The batch was cooled to 10 °C. The product was crystallized by adjusting the pH to 4.5 with coned HCI. The slurry was aged for 1 h and DI water (15 L) was charged to the batch. The slurry was aged 18 h at 20-25 °C. The solids were filtered, washed with 10% MeOH/DI water and dried in a vacuum oven (40-50 °C, 25-26" Hg) to provide the alkylated pyrrole cyclopentene acid (1223 g, 95% yield).
Example 4 3-(trifluoromethvl)-5.6,7,8-tetrahydro-l,6-naphthyridine
Step 1 - N-[3-(Dimethylamino)-2-(trifluoromethyl)prop-2-enylidene]-N-inethyhnethanamiuin hexqfluorophosphate (CF3DT)
(Figure Removed)
Phosphorous oxychloride (1.1 L, 11.8 mol) was added to dimethylformamide (2.6 L) at 4 °C over 1 h and the reaction mixture was allowed to warm to 20 °C. 3,3,3-Trifluoropropionic acid (TFPA ) (771 g, 6.02 mol) was added over 6 min. The reaction mixture was then aged at 50 to 60 °C for 4 h and then allowed to cool to room temperature. The TFPA/POCls/DMF reaction mixture was charged to a 5 L addition funnel. The reaction flask was rinsed with DMF, 3 x 75 mL, and the rinses also transferred to the 5 L addition funnel. Hexafluorophosphoric acid (980 mL, 60 wt% aqueous) was added to water (7.1 L) with cooling at 4 °C. Sodium hydroxide (5 N, 2.0 L) was added slowly keeping the internal temperature below 15 °C. The solution was then cooled to 0 °C. Sodium hydroxide (5 N) was charged to a 2 L addition funnel and added concurrently with the TFPA/POC13/DMF reaction mixture at a rate such that the internal temperature remained below 5 °C and the pH varied from 3.05 to 3.6 (approx. 3.2 during most of the addition). The resulting yellow slurry was then aged for 60 min at ~0 °C. The solids were filtered, slurry-washed with ice-cold water (2 x 4.0 L) then dried with a stream of N2 under vacuum. A total of 1.785 kg (87%) of the CF3DT (vinamidinium salt) was obtained.
Step 2 - N-(tert-Butoxycarbonyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine
(Figure Removed)
N-BOC-4-piperidone (672 g) in THF (2.72 L) was charged to a solution of lithium bis(trimethylsilyl) amide (LHMDS) (3.55 L, 1.0 M solution in THF) in THF (3.7 L) at -12 °C over 45 min. The reaction mixture was allowed to warm to room temperature. This mixture was added over 30 min to a slurry of CF3DT (1.17 kg) in THF (5.45 L) cooled to -24 °C. The reaction mixture was then aged for 2 h at ~ -20 °C. Acetic acid (295 mL) was added over 3 min. The reaction mixture was warmed to 20 °C over 1 h 15 min and ammonium acetate (741 g) was added in one portion. The reaction mixture was warmed to 64 °C and aged for 2 h at this temperature. The reaction mixture was cooled to room temperature then diluted with water (15.4 L) and methylcyclohexane (15.4 L). The mixture was agitated, the stirring stopped, and the layers were allowed to settle. The lower aqueous layer was removed and the organic layer was washed with 2 M aqueous citric acid (6.2 L). After agitation and separation of layers LC assay of the organic layer (total weight = 19.8 kg) gave an assay yield of 617 g (64%) of the BOC naphthyridine.
(Figure Removed)
The organic layer from the naphthyridine formation containing N-(tert-butoxycarbonyl)-3-(trifluorometliyl)-5,6,7,8-tetrahydro-l,6-naphthyridine (34.2 kg total weight containing 989 g of BOC naphthyridine) was concentrated to an oil. The residue was diluted with methanol (6 L) and the solution was concentrated to an oil. Methanol (6 L) was added to the residue and this solution was concentrated to 2.3 L. The solution was diluted with methanol to a volume of 7.3 L and 4.58 M HCI in IPA (3.6 L) was added. The solution was heated to 55 °C and aged for 1 h. After cooling to room temperature water (5 L) was added. A solution of K2CO3 (2.28 kg) in water (5 L) was then carefully added (pH = 10). The mixture was extracted with IP Ac (3 X 10 L). The organic extractions contained 601 g (91%) of deprotected naphthyridine. The combined organic layers were concentrated and the residue was diluted with IPA (6 L) and reconcentrated. The resulting oil was diluted with IPA (6 L) and the solution was concentrated to a total volume of ~2 L. The solution was filtered through a sintered glass funnel, which
was washed with IPA (3x1 L). The combined filtrate and rinses were concentrated to -0.5 L and then diluted with IPA (1.95 L). The solution was heated to 60 °C and HC1 in IPA (790 mL, 4.33 M by titration) was added over 40 min. During the addition the formation of solids became evident. Heptane (2.75 L) was added over 30 min after which heating was discontinued and the slurry was allowed to cool to room temperature overnight. Additional HC1/IPA (80 mL) and heptane (2 X 1.38 L) were added. The solids were filtered, washed with 2:1 heptane/IPA (3 x 550 mL), and dried under vacuum with a nitrogen stream to afford 678.8 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine in 75 % yield from BOC naphthyridine (497 g, 73.2 weight percent as free base).
Example 5 (3R)-3-Methoxvtetrahvdro-4H-pvran-4-oae
Step 1- tetrahyro-4H-pyran-4'One: A 22 L round-bottomed-flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with tetrahydro-4H-pyran-4-one (3.00 kg, 30.0 mol) and tripropylorthoformate (5.70 kg, 30.0 mol). The pump used for the transfer was flushed with chlorobenzene (300 mL) and the flush was added to the batch. The resulting solution was cooled in an ice bath to 5 °C. Amberlyst-15 (60 g), previously washed with DI water then propanol and dried, was added in one portion. The mixture was stirred at ambient temperature for 16 h. This provides a solution of 2 (GC). The mixture was concentrated under vacuum (75 mm Hg). The solids were removed by filtration through a pad of solka floe and the filter pad was rinsed with MTBE (2 L). The filtrate was diluted with MTBE (26 L) and extracted with saturated aqueous NaHCO3 (24 L) then water (2x16 L). The organic phase was concentrated under vacuum (500 mm Hg) to remove the MTBE. When the internal temperature reached 44 °C, chlorobenzene (3 L) was added. The distillation was continued using a packed column at a rate that maintained a vapor temperature of about 85 to 90 °C. Chlorobenzene was added periodically to maintain a constant volume. A total of 15 L was used. The batch temperature was maintained between 122 and 125 °C during the distillation. After 16 h, GC assay indicated > 9:1 conversion. The vacuum was increased to 50 mm Hg and the reaction was distilled to provide a 53 wt% solution of 3 (3.13 kg, 73 % yield) and chlorobenzene.
Step 2- 3,4-dihydroxy-tetrahydro-2-H-pyran-4-sulfonic acid, sodium salt: A 50 L round-bottomed-flask equipped with a mechanical stirrer, nitrogen inlet and thermocouple was charged with acetone (12.7 L) and water (1.28 L). Hydroquinidine-l,4-phthalazinediyl diether (DHQD2PHAL, 54.8 g, 0.070 mol),
potassium osmate dihydrate (12.95 g, 0.035 mol), and 4-methylmorpholine N-oxide monohydrate (NMO, 1.078 kg, 7.74 mol) were added sequentially to the solvent and the resulting solution was cooled to 0 °C. The propylenol ether (1.85 kg of a 54 wt % solution, 7.03 mol) was added over 7 h while maintaining a reaction temperature of about 0 °C. A freshly prepared solution of Na2S2O5 (802 g, 4.22 mol) and water (5.63 L) was added followed by glacial acetic acid (1.2 L). After aging 16 h at it, the solids were removed by filtration and the filtrate was concentrated in vacuo to remove the acetone. Isopropanol (28 L) was added over 3.5 h to provide a colorless slurry. The solids were collected on a frit, rinsed with isopropanol (6 L) and dried in a vacuum oven to provide 958 g of 92 wt% (57 % isolated yield) product that was 97.2 % ee.
Step 3 - 4,4-dimethoxytetrahydro-2H-pyran-3-ol: A 22 L round bottomed flask equipped with a mechanical stirrer, 5 L dropping funnel, nitrogen inlet and thermocouple was charged with bisulfite adduct (893 g of a 92 wt% solid, 4.06 mol)MeOH (8.1 L) and trimethylorthoformate (948 g, 8.93 mol). The resulting slurry was warmed to 50 °C and a 1.89 M solution of HC1 in MeOH (2.48 L, 4.69 mol) was added via dropping funnel over 40 min. The slurry was cooled to 7 °C and 50 wt% NaOH (340 mL) was added as a slow stream. The solids were collected on a frit and the filtrate was solvent switched to toluene using a total of 12 L toluene. The batch was concentrated to about 3 L then the solids were removed by filtration and the cake was rinsed with THF (2 L). A solution containing 577 g of product (3.56 mol in 5.33 L, 88% yield, 97.5% ee) results.
Step 4 - (3R)-3-Methoxytetrahydro-4H-pyran-4-one: A 22 L round-bottomed-flask equipped with a thermocouple, nitrogen inlet and dropping funnel was charged with a solution of 6 (3.56 mol in 5.33 L) and THF (5.8 L). KF of the solution indicates 1.11 mol water is present. NaOt-Bu (494 g, 5.14 mol) was added in one portion to provide a clear yellow solution. The flask was immersed in an ice bath and Me2SO4(737 g, 5.84 mol) was added over 20 min maintaining an internal temp of below 36 °C. The cold bath was removed and the reaction mixture was aged for 4 h to provide a crude solution. Water (1.5 L) was added followed by 2N HC1 (840 mL). The apparent pH of the two phase mixture was 0.6. After 20 h at RT, NaHCO3 (497 g) was added and the mixture was extracted with IPAc (4x5 L). The combined organic phases were concentrated and the residual solids removed with a frit to provide a solution of the product (429 g in 2.635 kg of solution, d = 0.914, 149 g/L, 93% yield, 97.2 % ee).
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes,
modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.






We claim:
l.:A process for preparing ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-
dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-
pyran-4-yl]amine, or succinate salt thereof, comprising:
(i) hydrogenating (3S,4S)-N-((1 S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-amine to yield ((lR,3S)-3-isopropyl-3-{ [3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine; and (ii) optionally contacting ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine with succinic acid to yield ((lR,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yI]carbonyl }cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate.
2. The process as claimed in claim 1, wherein (3S,4S)-N-((1S,4S)-4-isopropyl-4-
{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-
methoxytetrahydro-2H-pyran-4-amine is prepared by a process comprising:
coupling (1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-
naphthyridin-6(5H)-yl]carbonyl}cyelopent-2-en-1-amine with (3R)-3 -
methoxytetrahydro-4H-pyran-4-one to yield (3S,4S)-N-((1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4-arnine.
3. The process as claimed in claim 2, wherein (1S,4S)-4-isopropyl-4-{[3-
(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1 -
amine is prepared by a process comprising
treating 6-{ [(1S ,4S)-4-(2,5-dimethyl-1 H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-en-l-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-
naphthyridine with hydroxylamine to yield (lS,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-l-amine.
4. The process as claimed in claim 3, wherein 6-{[(lS,4S)-4-(2,5-
dimethyl-1 H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-en-1 -yl]carbonyl} -3 -(trifluoromethyl)-
5,6,7,8-tetrahydro-l,6-naphthyridine is prepared by a process comprising
reacting (1 S,4S)-4-(2,5-dimethy 1-1 H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-ene-1-carboxylic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydronaphthyridine to yield 6-{ [(1 S,4S)-4-(2,5-dimethyl-1 H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-en-1 -yl]carbonyl} -3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine.
5. The process as claimed in claim 1, for preparing ((lR,3S)-3-isopropyl-
3-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-
yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine or
succinate salt thereof, wherein said hydrogenating step is preceded by a process comprising:
(i) reacting (1 S,4S)-4-(2,5-dimethyl-1H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-ene-1-carboxylic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydronaphthyridine to yield 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1 -yl)-1 -isopropylcyclopent-2-en-1 -yl] carbonyl} -3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine;
(ii) treating 6-{[(lS,4S)-4-(2,5-dimethyl-lH-pyrrol-l-yl)-l-
isopropylcyclopent-2-en-l-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine with hydroxylamine to yield (1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1-amine; and
(iii) coupling (1S,4.S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1 -amine with (3R)-3-methoxytetrahydro-4H-pyran-4-one to yield (3S,4S)-N-((1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]carbonyl}cyclopent-2-en-l-yl)-3-methoxytetrahydro-2H-pyran-4- amine.

Documents:

2137-DELNP-2006-Abstract (19-01-2010).pdf

2137-DELNP-2006-Abstract-(10-01-2011).pdf

2137-DELNP-2006-Abstract-(11-05-2009).pdf

2137-delnp-2006-abstract.pdf

2137-DELNP-2006-Assignment (19-01-2010).pdf

2137-delnp-2006-assignment.pdf

2137-DELNP-2006-Claims (19-01-2010).pdf

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2137-DELNP-2006-Claims-(11-05-2009).pdf

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2137-DELNP-2006-Correspondence Others-(13-10-2011).pdf

2137-DELNP-2006-Correspondence-Others (17-02-2010).pdf

2137-DELNP-2006-Correspondence-Others (19-01-2010).pdf

2137-DELNP-2006-Correspondence-Others-(10-01-2011).pdf

2137-DELNP-2006-Correspondence-Others-(11-05-2009).pdf

2137-DELNP-2006-Correspondence-Others-(23-12-2010).pdf

2137-DELNP-2006-Correspondence-Others-(29-12-2010).pdf

2137-delnp-2006-Correspondence-Others-(30-12-2009).pdf

2137-delnp-2006-correspondence-others-1.pdf

2137-delnp-2006-correspondence-others.pdf

2137-DELNP-2006-Description (Complete)-(11-05-2009).pdf

2137-delnp-2006-description (complete).pdf

2137-DELNP-2006-Form-1-(17-02-2010).pdf

2137-delnp-2006-form-1.pdf

2137-delnp-2006-form-18.pdf

2137-DELNP-2006-Form-2-(11-05-2009).pdf

2137-DELNP-2006-Form-2-(17-02-2010).pdf

2137-delnp-2006-form-2.pdf

2137-DELNP-2006-Form-3 (19-01-2010).pdf

2137-DELNP-2006-Form-3-(11-05-2009).pdf

2137-DELNP-2006-Form-3-(23-12-2010).pdf

2137-delnp-2006-form-3.pdf

2137-DELNP-2006-Form-5-(17-02-2010).pdf

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2137-DELNP-2006-GPA-(11-05-2009).pdf

2137-DELNP-2006-GPA-(13-10-2011).pdf

2137-DELNP-2006-GPA-(17-02-2010).pdf

2137-DELNP-2006-GPA-(29-12-2010).pdf

2137-delnp-2006-gpa.pdf

2137-DELNP-2006-Others-Document-(11-05-2009).pdf

2137-delnp-2006-pct-210.pdf

2137-delnp-2006-pct-220.pdf

2137-delnp-2006-pct-237.pdf

2137-delnp-2006-pct-304.pdf

2137-delnp-2006-pct-311.pdf

2137-delnp-2006-pct-326.pdf

2137-delnp-2006-pct-373.pdf


Patent Number 245945
Indian Patent Application Number 2137/DELNP/2006
PG Journal Number 06/2011
Publication Date 11-Feb-2011
Grant Date 07-Feb-2011
Date of Filing 19-Apr-2006
Name of Patentee MERCK SHARP & DOHME CORP.,
Applicant Address 126 EAST LINCION AVENUE, RAHWAY, NJ 07065-0907 USA.
Inventors:
# Inventor's Name Inventor's Address
1 CAI, DONGWEI 126 EAST LINCION AVENUE, RAHWAY, NJ 07065-0907 UNITED STATES OF AMERICA.
2 FLEITZ,FRED 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
3 GE, MIN 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
4 HOERRNER,SCOTT 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
5 JAVADI, GARY 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
6 JENSEN, MARK 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
7 LARSEN, ROBERT 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
8 LI.WENJIE 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
9 NELSON,DORIAN 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
10 SZUMIGALA, ELIZABETH 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
11 YANG, LIHU 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
12 ZHOU, CHANGYOU 126 EAST LINCION AVENUE, RAHWAY, NEW JERSEY 07065-0907 UNITED STATES OF AMERICA.
PCT International Classification Number C07D 207/327
PCT International Application Number PCT/US2004035294
PCT International Filing date 2004-10-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/514,754 2003-10-27 U.S.A.