BACKGROUND OF THE INVENTION Processes for the preparation of spirocyclic lactams have previously been described. In particular radical cyclizations are reported in (a) Nagushima, H. et al., J.C.S. Chem. Commun.. 1985, 518, (b) Jolly,

R.S. et al., J. Am. Chem. Soc. 1988, HQ, 7536 and (c) Cossy, J. et al.,

Tetrahedron Lett.. 1989, 4531. None of the above references, however, describe the preparation of spirocyclic lactams N-substituted with a tertiary amine substituent.

Additionally, U.S. Patent No. 4,963,557 describes the formation of cyclic- 1-carboxy-l-acetic acid anhydrides via the dehydration of cyclic- 1- carboxy-1-acetic acid compounds. As used therein subsequent amidation of the anhydride followed by reduction of the spiroimides thus obtained yields pharmaceutically active azaspiranes N-substituted with a tertiary amine substituent.

The above disclosures require numerous reaction steps and difficult isolation procedures resulting in low overall yields. Thus, there is a need in the art for a safe, economical and reliable method to prepare spirocyclic lactams N-substituted with a tertiaryamine substituent. This invention relates to the novel use of α, co-diiodides as

.^functional electrophiles in the spiroalkylation of lactams N-substituted with a tertiary amine group. The invented process is advantageous in that it shortens the number of overall steps, utilizes a convergent synthetic scheme, ehminates the need for chromatography and increases overall yield.

This discovery is particularly surprising in view of corresponding research which concluded that chlorides, bromides, tosylates and mesylates fail when substituted for iodine in the invented process.

SUMMARY OF THE INVENTION This invention relates to an improved process for the preparation of spirocyclic lactams which utilizes α, ω-diiodides in the spiroalkylation of lactams N-substituted with a tertiary amine group. This invention relates to an improved process for the preparation of 2-azaspiro [4.5] decane ring systems.

This invention specifically relates to an improved process for the preparation of

N, N-dimethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; N, N-diethyl-8, 8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; and 2-(3-piperidinopropyl)-8,8-dipropyl-2-azaspiro [4.5] decane.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term N,N-dimethyl-8, 8-dipropyl-2- azaspiro[4.5]decane-2-propanamine refers to a compound of Formula I where n is 3, ^ and ^ are each methyl and R* and R^ are each propyl.

As used herein, the term N,N-diethyl-8,8-dipropyl-2-azaspiro [4.5]decane-2-propanamine refers to a compound of Formula I where n is 3, R ³ and R ⁴ are -CH2 -CH3 and R ¹ and R ² are each propyl. As used herein, the term 2-(3-piperidinopropyl)-8,8-dipropyl-2- azaspiro [4.5] decane refers to a compound of Formula I where n is 3, R ³ and R are joined together to form a cyclic alkyl group containing 5 carbon atoms and R- and R ² are each propyl.

By the term "appropriate solvent" as used herein is meant a solvent such as tetrahydrofuran, hexane, or diethyl ether.

By the term "organic solvent" as used herein is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'- propylene urea, N-methyl-2-pyrrolidinone, methanol, isopropyl alcohol, dimethylformamide (DMF), pyridine, quinoline or ethanol.

By the term "reduced temperature" as used herein is meant below

25°C, preferably at 0°C when a salt of hexamethyldisilane (as described

herein) is used, preferably at-78°C when an alkyllithium reagent (as described herein) is used.

By the term "appropriate reducing agent" as used herein is meant a compound capable of reductively removing an oxo substituent, such as lithium aluminum hydride or, preferably, NaBH4/BF3-Et2θ.

By the term "active base" as used herein is meant (i) an alkyllithium reagent; preferably, n-butyllithium. sec-butyllithium or igrt-butyllithium in conjunction with an appropriate alkylamine base, preferably diisopropylamine or (ii) salts of hexamethyldisilane, such as sodium-, lithium- or, preferably, potassium-hexamethyldisilyazide.

Pharmaceutically acceptable salts, hydrates and solvates of Formula (I) compounds are formed where appropriate by methods well known to those of skill in the art.

The present invention provides a process for the preparation of a compound of Formula (I).

in which: n is 1-7

Rl and R ² are the same or different and are selected from straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained by Rl and R ² when taken together is 4-10; or l and R2 are joined together to form a cyclic alkyl group containing 3-7 carbon atoms; 3 and R ⁴ are the same or different straight chain alkyl groups of 1-3 carbons; or B and R- are joined together to form a cyclic alkyl group containing 4-7 carbon atoms; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises: a) reacting, in an appropriate solvent and at a reduced temperature, a compound of Formula (II)

wherein n, R ³ and ⁴ are as defined above, in the presence of an active base with a compound of the Formula (III)

wherein R- and ² are as defined above to form a compound of Formula (IV)

wherein n, R-> R ² , R3 and R ⁴ are as defined above and

b) subsequently, in an appropriate solvent and in the presence of an appropriate reducing agent, reducing the oxo substituent to form a compound of Formula I and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IVA)

and converting the same into the following compound of structure (IA)

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IVB)

and converting the same into the following compound of structure (IB)

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IVC)

and converting the same into the following compound of structure (IC)

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Also, prepared in utilizing the presently invented process are novel intermediates of

wherein Ε.- and ² are as defined in Formula I.

Novel intermediates of Formula (III) of the present invention can be prepared by methods outlined in Schemes 1-3 below and in the Examples from known and readily available ethyl cyanoacetate

and from known and readily available cyanoacetamide

Scheme I

(2)

(c)

(g)

Scheme I outlines formation of novel intermediates of Formula (HI). As used in Scheme I compounds of Formula (b) are prepared by reacting compound (a) a compound of formula (z), acetic acid and NH4OAC in cyclohexane at reflux with constant water removal.

A compound of Formula (b), sodium and cyanoacetamide are reacted in absolute ethanol, followed by the addition of concentrated HCl to yield compounds of Formula (c).

Acidification of compounds (c) yields compounds (d) which are subsequently reduced to yield compounds (e).

Compounds (e) are reacted with mesyl chloride and triethylamine preferably in diethyl ether, preferably at 0°C to yield compounds of Formula (f).

Reaction of compounds (f) with Nal, preferably in acetone, preferably at room temperature yields compounds of Formula (g).

As used in Scheme I, compounds of Formula (z) are known and readily available or can be prepared from known and readily available materials by methods well known to those of skill in the art.

Scheme II

< ^e > (g)

Scheme II outlines formation of novel intermediates of Formula

(III). The starting material in Scheme II are formula (b) compounds prepared as described in Scheme I.

As used in Scheme II, formula (b) compounds are treated with an allyl Grignard reagent, preferably allyl magnesium chloride, in an appropriate solvent, preferably tetrahydrofuran or diethyl ether, preferably at reflux temperature to yield formula (h) compounds. Alternatively, a halogen copper reagent, preferably copper iodide, is added to the allyl Grignard reagent in tetrahydrofuran, preferably at - 78°C, to form an allyl copper halo reagent. Said allyl copper reagent is reacted with a formula (b) compound, preferably at 0°C to yield formula (h) compounds.

Formula (h) compounds and a base, preferably potassium hydroxide, in an organic solvent, preferably ethylene glycol is reacted, preferably at reflux to yield formula (i) compounds.

Formula (i) compounds are reduced, preferably with lithium aluminum hydride, in an organic solvent, preferably diethyl ether, to yield formula (j) compounds.

Formula (j) compounds in an organic solvent, preferably methanol, preferably at -78°C are reacted with methylsulfide in the presence of ozone, followed by the addition of a base, preferably sodium borohydride, preferably at 0°C to yield Formula (e) compounds.

Formula (e) compounds are reacted as in Scheme I to yield Formula (g) compounds in two steps.

Scheme III

(I) (m)

Scheme III outlines formation of novel intermediates of Formula (HI). The starting materials in Scheme III are Formula (b) compounds prepared as described in Scheme I.

As used in Scheme HI, compounds of Formula (b) are treated with a Grignard reagent, preferably vinyl magnesium bromide, in an appropriate solvent, preferably tetrahydrofuran or diethyl ether, preferably at reflux temperature to yield compounds of Formula (k). Alternatively, a halogen copper reagent, preferably copper iodide, in tetrahydofuran is added to the Grignard reagent, preferably at -78°C, to form a vinyl copper halo reagent. Said vinyl copper halo reagent is reacted with compounds (b), preferably at 0°C to yield compounds (k).

Compounds (k) and a base, preferably potassium hydroxide, in an organic solvent, preferably ethylene glycol, are reacted preferably at reflux to yield compounds (1).

Compounds (1) are reduced, preferably with lithium aluminum hydride, in an organic solvent, preferably diethyl ether, to yield compounds (m).

Compounds (m) in an organic solvent preferably tetrahydrofuran, at -78°C are reacted with BH3, followed by H2O2 to yield compounds (e).

Compounds (e) are reacted as in Scheme I to yield compounds (g) in two steps.

Also, prepared in utilizing the presently invented process are novel intermediates of Formula II

wherein n, R ³ and R ⁴ are as defined in Formula I.

Novel intermediates of Formula II of the present invention can be prepared by methods outlined in Scheme IV below and in the examples from known and readily available butyrolactone

Scheme IV

Scheme IV outlines the formation of novel intermediates of Formula (II).

As used in Scheme IV, compound (n) is reacted with a Formula (y) compound at reflux with constant water removal to yield Formula (o) compounds.

As used in Scheme IV compounds of Formula (y) are known and readily available or can be prepared from known and readily available materials by methods well known to those of skill in the art.

Example 1-Corresponding to Scheme I 3.3-Dipropvl-1.5-diiodopentane (i) Ethyl α-cyano-α-(4-heptylidene)acetate

In a 100 mL round-bottom flask was dissolved 4-heptanone (11.4 g, 0.10 mmole) and ethyl cyanoacetate (11.30 g, 0.100 mole) in cyclohexane (25 mL). Acetic acid (1.0 mL) and NH4OAC (2.0 g) were added. The solution was magnetically stirred and heated to reflux with a Dean-Stark trap in place overnight under N2. The reaction was cooled to ambient, diluted with ethyl acetate (100 mL) washed with H2O (2 x 50 mL) and brine (25 mL). The organic extracts were dried (Na2SO4, filtered and concentrated under vacuum to give an oil that was distilled (bp. 135-137° C, 20 mmHg) to give Ethyl α-cyano-α-(4- heptylidene)acetate (16.65 g, 0.080 mole, 80%). IR (neat film) 2950, 2910, 2860, 2200, 1725, 1570, 1235, 1085 cm' ¹ ; -Η. NMR (400 MHz, CDCI3 δ 4.15 (q, J = 9 Hz, 2H), 2.60 (t, J= 10 Hz, 2H), 2.38 (t, J = 10 Hz, 2H), 1.25 (t, J = 9 Hz, 2H), 1.40 (sextet, J = 9 Hz, 2H), 1.25 (t, J = 9 Hz,

3H), 0.88 (m, 6H); 13 c NMR (100 MHz, CDC1 ₃ ) δ 181.2, 161.5, 115.5, 104.6, 61.4, 40.2, 35.2, 21.9, 21.4, 14.1, 13.8 (one carbon not observed due to overlap); MS (CI) m/e 211 (14.5), 210 (100), 209 (3.59), 182 (3.5), 164 (2.8); HRMS (CI) calcd for C12H20NO2 (M + H) m/e 210.1484, found 210.1491.

(ii) 3,5-Dicyano-4,4-dipropylcyclohexyUmide In a 100 mL round-bottom flask equipped with a drying tube and magnetic stir bar was added sodium (0.795 g, 34.6 mmole) to absolute ethanol (50 mL). To the room temperature solution was added cyanoacetamide (2.91 g, 34.6 mmole) as a solid to give a white suspension. After 2-3 min, ethyl α-cyano-α-(4-heptylidene)acetate (7.22 g, 34.6 mmole) was added rapidly and the mixture stirred at room temperature 2 h to give a clear solution. Water (50 mL) then concentrated HCl (8.75 mL) was added. After standing in the freezer overnight, the precipitate was collected by filtration, washed with ethanol and allowed to air dry to give 3,5-Dicyano-4,4- dipropylcyclohexylimide (7.40 g, 29.9 mmole, 87%). mp. 218-219° C. Mixture of two isomers by capillary GC.RT = 7.86 min, 51%, RT = 7.94 min, 43%; IR (FTIR in KBr) 3600-3000, 3008, 1752, 1710, 1234 cm" ¹ ; -H NMR (400 MHz, CDCI3) δ 8.38 (br, 1H); 3.81 (s, 2H), 1.8-1.3 (m, 6H), 1.09 (t, J = Hz, 2H), 0.90 (m, 6H); 13C NMR (100 MHz, dβ, DMSO) 165.3, 114.3, 43.3, 41.6, 38.8, 38.1, 17.0, 15.9, 14.5, 14.1; MS m/e (CI) 249 (16.5), 248 (70.8); Anal. Calcd for CnHi7N0 ₂ * 1/2 H ₂ 0 (256.306: C, 60.92; H, 7.08; N, 16.39. Found: C, 60.96; H, 6.84; N, 16.56.

(iii) 3,3-Dipropylpentandioic acid

In a 100 mL round-bottom flask equipped with a magnetic stir bar was dissolved 3,5-Dicyano-4,4-dipropylcyclohexyUmide (350 mg, 1.42 mmole) in glacial acetic acid (10 mL). Concentrated HCl (10 mL) and H2O (10 mL) were added. The solution was refluxed 12 h then concentrated to 10 mL by simple distillation. The solution was extracted with CH2CI2 (3 x 10 mL). The combined extracts were washed with H2O and brine, dried (Na2Sθ4), filtered and concentrated. The residue was crystallized from 30% ethyl acetate-hexanes to give 3,3- Dipropylpentandioic acid (280 mg, 1.30 mmole, 91%). mp. 107° C, d; IR (KBr) 3500-2500, 3000-2800, 1726, 1698, 1303, 1207, 915 cm"l; iH NMR

(400 MHz, d ⁶ -DMSO) δ 11.9 (br s, 2H), 2.35 (s, 9H), 1.35 (m, 4H0, 1.20 (m, 4H), 1.20 (m, 4H), 0.79 (t, J = 9 Hz, 6H); 13c NMR (100 MHz, d ⁶ - DMSO) δ 173.0, 40.2, 38.8, 37.1, 15.9, 14.7; MS 9e intensity) 217 (M+, 3), 216 (0.5), 200 (13), 199 (100), 198 (28), 157 (2); Anal. Calcd for C11H2OO4: C, 61.09; H, 9.32. Found: C, 61.10; H, 9.16.

(iv) 3,3-Dipropyl-l,5-diiodopentane

3,3-Dipropylpentandioic acid was converted to the corresponding diol, in quantitative yield, by reaction with lithium aluminum hydride in diethyl ether.

In a 500 mL round-bottom flask equipped with a magnetic stir bar was dissolved the diol (6.40 g, 34.04 mmole) in ether (150 mL). The solution was cooled to 0° C and triethylamine (14.18 g, 140.16 mmole) followed by mesyl chloride (9.75 g, 85.1 mmole) were added. The reaction was stirred 5 min then quenched with saturated NaHC03 (100 mL) and diluted with ether (100 mL). The organic layer was washed with H2O (100 mL) and brine (2 x 50 mL), dried (Na2SO4) filtered, and concentrated to yield the dimesylate as an oil (11.53 g, 33.5 mmole, 98.4%). Rf (silica gel, 1:1 hexane:ethyl acetate) = 0.82. The dimesylate was immediately dissolved in acetone (500 mL) and stirred under N2 in a 1 L round-bottom flask as Nal (102 g, 680 mmole) was added as a solid. After stirring for 5 days in the dark at room temperature, the reaction was diluted with ether (100 mL) and washed with saturated NH4CI, 25% Na2S2θs and brine. The organic layer was dried (Na2S04), filtered, and concentrated to a white solid. The residue was filtered through silica gel eluting with 10% ethyl acetate-hexane to give, after concentration, 3,3-dipropropyl-l,5- diiodopentane (12.60 g, 30.88 mmole, 91% for the two steps), mp 60-62° C. IR (FTIR in KBr) 3000-2800, 1451, 1465, 1178, 1195, 600, 300 cm" ¹ ; lH NMR (400 MHz, CDCI3) δ 3.19 (m, 4H), 1.9 (m, 4H), 1.30 (m, 8H), 0.95 (t, J = 10 Hz, 6H); ¹³ C NMR (100 MHz, CDCI3 δ 43.7, 41.8, 38.1, 16.2, 14.8, 0.2; MS m/e (CI) 408 (1.14), 282 (11.47), 281 (100), 253 (2.3), 233 (2.1), 225 (5.73), 211 (6.0), 185 (9.7), 169 (24.5), 153 (6.7); Anal. Calcd for C11H22I2: C, 32.37; H, 5.43; I, 62.19. Found: C, 32.60; H, 5.43; I, 61.85.

Example 2 - Corresponding to Scheme IV N-(Dimethylaminopropyl) butyrolactam Butyrolactone (86.09 g, 1.00 mole) and N,N- Dimethylaminopropylamine (102.18 g, 1.00 mole) were combined in a 500 mL round-bottom flask equipped with a magnetic stir bar and Dean- Stark trap. The mixture was heated at reflux. After 1 eq. of H2O was collected (8-10 h) the reaction was cooled to room temperature. The Dean-Stark trap was replaced with a fractionating column and the product was distilled under vacuum to yield to N-(Dimethylaminopropyl) butyrolactam £145 g, 0.85 mole, 85%). bp 79-84° C, 0.25 mmHG; IR (neat film) 2920, 2750, 1780, 1650, 1450, 1430, 1260, 1280 cm" ¹ ; iH NMR (400 MHz, CDCI3) δ 3.15 (m, 2H), 3.05 (m, 2H), 2.07 (m, 2H), 2.02 (m, 2H), 2.0 (s, 6H), 1.75 (m, 2H), 1.42 (m, 2H); 13C NMR (100 MHz, CDC1 ³ ) δ 174.2, 56.5, 46.7, 45.0 (double intensity), 40.1, 30.5, 25.1, 17.4; MS m/e (CI) 172 (17.2), 171 (100), 170 (5.3), 169 (11.9), 127 (1.3), 126 (15.5); HRMS (CI) calcd for C9H19N2O (MH) m/e 171.1497, found 171.1503; Anal Calcd for C ₉ H ₁₈ N ₂ 0: C, 63.49; H, 10.66; N, 16.45. Found: C, 63.12; H, 10.68; N, 16.17.

Example 3

N-(3-(Dimethylamino)propyl)-8.8-dipropyl-2-azaspiro T4.51decane (i) N-(3-(Dimethylamino)propyl)-8 ,8-dipropyl-2-azaspiro [4.5]decane-l-one

In a dry 250 mL round-bottom flask under N2 was dissolved diisopropylamine (5.06 g, 50.0 mmole) in THF (35 mL). The solution was cooled to -25° C. With magnetic stirring, n-BuLi (2.5 M, 20 mL, 50 mmole) was added over 10 min. After stirring an additional 30 min., the solution was cooled to -78° C. N-(Dimethylaminopropyl)butrolactam (3.40 g. 20.0 mmole) was added via syringe as a THF (5 ml) solution over 10 min. The solution was stirred an additional 1.5 h. 3,3-Dipropyl-l,5- diiodopentane was added as a THF (5 mL) solution over 10 min. The reaction was stirred 4 h at -78° C then warmed to room temperature and allowed to stir 48 h. Saturated NH4CI (20 mL) was added and the mixture concentrated under reduced pressure. The residue was diluted with CH2CI2 (100 mL). The organic layer was washed with H2O (2 x 25 mL) then dried (K2CO3), filtered and concentrated at reduced pressure. The oil was dissolved in ether (200 mL) and treated with 6N HCl (200

mL). The aqueous layer was washed with ether (2 x 75 mL), basified with 50% NaOH (with cooling in an ice bath) and extracted with ether (3 x 50 mL). The organic extracts were washed with brine, dried (K2CO3), filtered, and concentrated. The resultant oil was filtered through silica gel eluting with 15% Ne-3-EtOAc to remove some base line impurities to give N-(3-(Dimethylamino)propyl)-8 ,8-dipropyl-2-azasprio[4.5]decane- 1- one (3.75 g, 18.4 mmole, 92%). IR (neat film) 2950, 2920, 2860, 1735, 1685, 1450, 1260, 1240 cm"!; iH NMR (400 MHz, CDCI3) δ 3.25 (m, 4H), 2.25 (m, 2H), 2.20 (s, 6H), 1.82 1, J = 6 Hz, 2H), 1.79 (m, 2H), 1.63 (m, 2H), 1.45 (br, 2H), 1.30 (m, 2H), 1.2-0.9 (m, 10H), 0.87 (m, 6H); 1 ³ C NMR (100 MHz, CDCI3) δ 179.2, 56.9, 45.4 (double intensity), 45.0, 44.8, 43.8, 38.4, 34.3, 34.0, 31.5 (double intensity), 29.5, 27.9 (double intensity), 25.5, 16.2, 16.0, 14.9, 14.8; MS m/e (CI) 325 (18.8), 324 (22.5), 323 (100), 322 (11.6), 321 (21.7), 307 (1.21), 279 (8.5); HRMS (CI) calcd for C20H39N2O (M + H) m/e 323.3062, found 323.3050.

(ii) N-(3-(Dimethylamino)propyl)-8,8-dipropyl-2- azasprio[4.5]decane

In a 50 mL round-bottom flask lithium aluminum hydride (11.8 mg, 0.311 mmole) was suspended in ether (5 mL) by means of a magnetic stir bar. N-(3-(Dimethylamino)propyl)-8,8-dipropyl-2- azasprio[4,5]decane-l-one (100 mg, 0.311 mmole) was added as an ether (5 mL) solution over 15 min. The reaction was stirred an additional 30 min then quenched saturated Na2SO4, filtered and concentrated under reduced pressure to give N-(3-(Dimethylamino)propyl)-8,8-dipropyl-2- azasprio[4.5]decane as an oil (88 mg, 0.285 mmole, 92%).

Example 4 N-(3-(Dimethylamino)propyl)-8.8-dipropyl-2-azaspiror4.51deca ne-l-one In a dry 12 L flask under N2 was dissolved potassium hexamethyldisilyazide (1139 g, 5.7 mole) in hexanes (2 L). The solution was cooled to 0°C. With stirring, a solution of N-

(Dimethylaminopropyl)butrolactam (387.1 g, 2.28 mole) and 3,3-Dipropl- 1,5-diiodopetane (845 g, 2.07 mole) in hexanes (2 L) was added over a period of 1.5 hours. The reaction was stirred over night at 0°C.

Saturated NH4CI (1.2 L) was added. The aqueous layer was separated and extracted with hexanes (2 L). The combined hexanes layers were

washed with saturated NaCl (2 L), dried with Na2SO4 and concentrated to yield the title compound as a dark brown oil (71%, 1.62 moles).

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its ftdlest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.