Improved Synthesis of 1,4-Diazaspiro[5.5]undecan-3-one

Abstract

The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one and its analogs, which can be used to prepare pharmaceutical compounds including those for treating diseases involving abnormal cell proliferation. Chemical intermediates in the method are also provided.

Description

[0001] Related References

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 722,675, filed Aug. 24, 2018. The entire content of that application is incorporated herein by reference. Technical Field

[0003] The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one and its analogs, which method can be used to prepare certain pharmaceutical compounds including those for treating diseases involving abnormal cell proliferation. Chemical intermediates in the method are also provided. Background Art

[0004] U.S. Pat. Nos. 8,822,683, 8,598,197, 8,598,186, 8,691,830, 8,829,102, 8,822,683, 9,102,682, 9,499,564, 9,481,591, and 9,260,442, filed by Tavares and Strum and assigned to G1 Therapeutics, Inc., describe compounds including a spirocyclic core. Specifically, these patents describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin-dependent kinase inhibitors, including inhibitors of the formula (with variables as defined therein):

[0005]

[0006] U.S. Pat. Nos. 9,464,092, 9,487,530, and 9,527,857, assigned to G1 Therapeutics, Inc., describe the use of such compounds for treating cancer.

[0007] The patents cited above use a multi-step method in which the spirocyclic core is formed by intramolecular cyclization late in the process. The method starts with commercially available tert-butyl (1-(aminomethyl)cyclohexyl)carbamate and uses several protection and deprotection steps to control the selectivity of the two amino groups throughout the synthesis. After cyclization, the desired heteroaryl is added by nucleophilic aromatic substitution. This method is shown in Scheme 1 below.

[0008]

[0009] Scheme 1. Previous Synthesis of N-(Heteroaryl)-Pyrrolo[3,2-d]Pyrimidin-2-Amine Cyclin-Dependent Kinase Inhibitors

[0010] Another method for synthesizing N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin-dependent kinase inhibitors is disclosed in PCT application WO2018 / 005865. This method provides some improvements over previous methods, including the use of 1,4-diazaspiro[5.5]undecan-3-one as an intermediate.

[0011]

[0012] 1,4-diazaspiro[5.5]undecan-3-one

[0013] The '865 application also provides a method for synthesizing 1,4-diazaspiro[5.5]undecan-3-one. This method obtains 1,4-diazaspiro[5.5]undecan-3-one from commercially available cyclohexanone in six steps. This method is summarized in Scheme 2.

[0014]

[0015] Scheme 2. Previous synthesis of 1,4-diazaspiro[5.5]undecan-3-one

[0016] There is still a need for methods to synthesize 1,4-diazaspiro[5.5]undecan-3-one with higher yields, requiring fewer and / or milder chemical reactions and / or having fewer steps. SUMMARY OF THE INVENTION

[0017] It has been found that 1,4-diazaspiro[5.5]undecan-3-one and structurally similar compounds (Formula II and Formula IV below) can be advantageously prepared from cyclohexanone in a two-pot process. In the first pot, cyclohexanone reacts with nitromethane to form 1-(nitromethyl)cyclohex-1-ol, which then loses water to form (nitromethylidene)cyclohexane. Then glycine alkyl ester is added to (nitromethylidene)cyclohexane to form (1-(nitromethyl)cyclohexyl)glycine alkyl ester. Then, in the second pot, the nitro group of (1-(nitromethyl)cyclohexyl)glycine ester is converted to an amino group to form (1-(aminomethyl)cyclohexyl)glycine methyl ester. Then the alkyl group is removed to form (1-(aminomethyl)cyclohexyl)glycine. Then, this compound undergoes internal cyclization to form 1,4-diazaspiro[5.5]undecan-3-one. In one embodiment, the cyclization occurs in the absence of hydrolysis. This synthetic sequence is shown in Scheme 3 below.

[0018]

[0019] Scheme 3. Improved synthetic route for preparing 1,4-diazaspiro[5.5]undecan-3-one

[0020] Advantageously, in one aspect of the present invention, one or more of the mechanistic steps shown in Scheme 3 can be carried out in the same reaction vessel without separation. For example, the Henry reaction, elimination, and Michael addition can all be combined in one reaction. Similarly, the reduction, hydrolysis, and cyclization reactions can also be combined in one reaction. An example of this advantageous embodiment is given in Scheme 4 below.

[0021]

[0022] Scheme 4. Preparation of 1,4-diazaspiro[5.5]undecan-3-one with only two separations

[0023] In another aspect of the present invention, one or more separation steps can be accomplished by recrystallization or filtration after the addition of an acid. For example, in Scheme 5 below, the hydrobromic acid workup allows for the separation of the Michael adduct in high yield by filtration.

[0024]

[0025] Scheme 5. Separation of the Michael addition product using hydrobromic acid

[0026] As described in more detail in the detailed description below, having been taught this reaction, those skilled in the art can select other reagents, reactants, and solvents other than those provided in Schemes 4 and 5 to obtain similar desired results. For example, Scheme 6 provides a more general form of the reaction that still uses only two separation steps.

[0027]

[0028] Scheme 6. General preparation of 1,4-diazaspiro[5.5]undecan-3-one with only two separations

[0029] In another aspect of the present invention, the methods described herein can be used to generate compounds of Formula II.

[0030]

[0031] Scheme 7. General preparation of 1,4-diazaspiro[5.5]undecan-3-one with only two separation steps

[0032] Wherein:

[0033] y is 0, 1, 2, 3, or 4;

[0034] n is 0 or 1;

[0035] R 1 is selected from hydrogen, alkyl, and aryl; and

[0036] R50 Each instance of is independently selected from hydrogen, halogen, and alkyl.

[0037] In another aspect of the invention, the methods described herein can be used to generate compounds of Formula IV.

[0038]

[0039] Scheme 8. General Preparation of Compounds of Formula IV with Only Two Separation Steps

[0040] Wherein:

[0041] y is 0, 1, 2, 3, or 4;

[0042] n is 0 or 1;

[0043] R 1 is selected from hydrogen, alkyl, and aryl;

[0044] R 2 is selected from hydrogen, substituted heteroaryl, and

[0045] R 3 is selected from hydrogen, NR 5 R 6 , OR 7 , SR 7 and halogen;

[0046] R 4 is selected from NR 8 R 9 and OR 10 ;

[0047] R 5 and R 6 are independently selected from hydrogen, alkyl, aryl, -alkyl-aryl, and -C(O)R 11 ;

[0048] R 7 is selected from alkyl, aryl, and -alkyl-aryl;

[0049] R 8 and R 9 are independently selected from hydrogen, alkyl, aryl, and -alkyl-aryl;

[0050] R 10 is selected from alkyl, aryl, and -alkyl-aryl;

[0051] In an alternative embodiment, R 10 is alkenyl;

[0052] R 11 is selected from alkyl and aryl;

[0053] R12 Selected from alkyl, aryl, and -alkyl-aryl;

[0054] R 13 Selected from -S-alkyl and Cl; and

[0055] R 50 Each instance of which is independently selected from hydrogen, halogen, and alkyl.

[0056] In one embodiment of the above invention, y is 0, n is 1, resulting in the following synthesis method:

[0057]

[0058] Scheme 9. Another preparation of the compound of formula IV with only two separation steps

[0059] In another aspect of the present invention, there is provided a useful synthetic intermediate of formula I:

[0060]

[0061] or an acceptable salt, N-oxide, or isotope derivative thereof;

[0062] wherein,

[0063] y is 0, 1, 2, 3, or 4;

[0064] n is 0 or 1;

[0065] R 1 Selected from hydrogen, alkyl, and aryl; and

[0066] R 50 Each instance of which is independently selected from hydrogen, halogen, and alkyl.

[0067] In one embodiment, the compound of formula I is:

[0068]

[0069] or an acceptable salt, oxide, or isotope derivative thereof.

[0070] In another aspect of the present invention, there is provided a useful synthetic intermediate of formula III:

[0071]

[0072] or an acceptable salt, N-oxide, or isotope derivative thereof;

[0073] wherein,

[0074] y is 0, 1, 2, 3, or 4;

[0075] n is 0 or 1;

[0076] R 1 is selected from hydrogen, alkyl, and aryl;

[0077] R 2 is selected from hydrogen, substituted heteroaryl, and

[0078] R 3 is selected from hydrogen, NR 5 R 6 、OR 7 、SR 7 and halogen;

[0079] R 4 is selected from NR 8 R 9 and OR 10 ;

[0080] R 5 and R 6 are independently selected from hydrogen, alkyl, aryl, -alkyl-aryl, and -C(O)R 11 ;

[0081] R 7 is selected from alkyl, aryl, and -alkyl-aryl;

[0082] R 8 and R 9 are independently selected from hydrogen, alkyl, aryl, and -alkyl-aryl;

[0083] R 10 is selected from alkyl, aryl, and -alkyl-aryl;

[0084] In an alternative embodiment, R 10 is alkenyl;

[0085] R 11 is selected from alkyl and aryl;

[0086] R 12 is selected from alkyl, aryl, and -alkyl-aryl;

[0087] R 13 is selected from -S-alkyl and Cl; and

[0088] R 50 Each instance of is independently selected from hydrogen, halogen, and alkyl.

[0089] Non-limiting examples of embodiments of the present invention include the following:

[0090] Method A

[0091] Method A for preparing the spiro compound of the present invention comprises the following steps: 1. Reacting a cycloalkanone with a nitroalkane to obtain a cycloalkyl group substituted with a nitroalkylene group; 2. Reacting the compound of step (1) with a glycine ester to obtain a compound of formula III; 3. Reducing the compound of formula III with a reducing agent; 4. Cyclizing the compound of step (3);

[0092] wherein the cycloalkanone has the following formula:

[0093]

[0094] wherein the nitroalkane has the following formula:

[0095]

[0096] wherein the glycine ester has the following formula:

[0097]

[0098] wherein formula III is:

[0099]

[0100] wherein the spiro compound has the following formula:

[0101]

[0102] wherein

[0103] y is 0, 1, 2, 3 or 4;

[0104] n is 0 or 1;

[0105] R 1 is selected from hydrogen, alkyl and aryl; and

[0106] R 2 is selected from hydrogen, substituted heteroaryl and

[0107] R 3 is selected from hydrogen, NR 5 R 6 、OR 7 、SR 7 and halogen;

[0108] R 4 is selected from NR 8 R 9 and OR 10 ;

[0109] R 5 and R 6 are independently selected from hydrogen, alkyl, aryl, -alkyl-aryl and -C(O)R 11 ;

[0110] R 7 is selected from alkyl, aryl and -alkyl-aryl;

[0111] R 8 and R 9 are independently selected from hydrogen, alkyl, aryl and -alkyl-aryl;

[0112] R 10 is selected from alkyl, aryl and -alkyl-aryl;

[0113] In an alternative embodiment, R 10 is alkenyl;

[0114] R 11 is selected from alkyl and aryl;

[0115] R 12 is selected from alkyl, aryl and -alkyl-aryl;

[0116] R 13 is selected from -S-alkyl and Cl; and

[0117] R 50 each instance of which is independently selected from hydrogen, halogen and alkyl.

[0118] Additional embodiments of Method A include the following:

[0119] (i) The method, wherein R 1 is hydrogen.

[0120] (ii) The method, wherein the nitroalkane is the solvent.

[0121] (iii) The method, wherein the nitroalkane is the only solvent.

[0122] (iv) The method, wherein an organic base or an inorganic base is used in Step 1.

[0123] (v) The method, wherein a carbonate base is used in Step 1.

[0124] (vi) The method, wherein potassium carbonate is used in Step 1.

[0125] (vii) The method, wherein oxalic acid is added after Step 2 to precipitate one or more undesired by-products.

[0126] (viii) The method, wherein hydrobromic acid is added after Step 2 to precipitate the compound of Formula III.

[0127] (ix) The method, wherein the alkyl is methyl.

[0128] (x) The method, wherein the alkyl is ethyl.

[0129] (xi) The method as described above, wherein the alkyl group is isopropyl.

[0130] (xii) The method as described above, wherein the alkyl group is tert-butyl.

[0131] Method B

[0132] Method B for preparing the spiro compound of the present invention comprises the following steps: 1. Reacting a cyclic ketone with a nitroalkane to obtain a cycloalkyl group substituted with a nitroalkylene group; 2. Reacting the compound of step (1) with an alkyl glycinate to obtain a compound of formula I; 3. Reducing the compound of formula I with a reducing agent; 4. Cyclizing the compound of step (3);

[0133] wherein the cyclic ketone has the following formula:

[0134]

[0135] wherein the nitroalkane has the following formula:

[0136]

[0137] wherein the alkyl glycinate has the following formula:

[0138]

[0139] wherein formula I is:

[0140]

[0141] wherein the spiro compound has the following formula:

[0142]

[0143] wherein

[0144] y is 0, 1, 2, 3 or 4, and is usually 0;

[0145] n is 0 or 1;

[0146] R 1 is selected from hydrogen, alkyl and aryl; and

[0147] each instance of R 50 is independently selected from hydrogen, halogen and alkyl.

[0148] Further embodiments of Method B include the following:

[0149] (i) The method as described above, wherein R 1 is hydrogen.

[0150] (ii) The method as described above, wherein the nitroalkane is a solvent.

[0151] (iii) The method, wherein the nitroalkane is the sole solvent.

[0152] (iv) The method, wherein an organic base or an inorganic base is used in step 1.

[0153] (v) The method, wherein a carbonate base is used in step 1.

[0154] (vi) The method, wherein potassium carbonate is used in step 1.

[0155] (vii) The method, wherein oxalic acid is added after step 2 to precipitate one or more undesired by-products.

[0156] (viii) The method, wherein hydrobromic acid is added after step 2 to precipitate the compound of formula I.

[0157] (ix) The method, wherein the alkyl group is methyl.

[0158] (x) The method, wherein the alkyl group is ethyl.

[0159] (xi) The method, wherein the alkyl group is isopropyl.

[0160] (xii) The method, wherein the alkyl group is tert-butyl.

[0161] Method C

[0162] Method C for preparing the spiro compound of the present invention comprises the following steps: 1. reducing the compound of formula I with a reducing agent; 2. cyclizing the compound of step (1);

[0163] wherein formula I is:

[0164]

[0165] wherein the spiro compound has the following formula:

[0166]

[0167] wherein

[0168] y is 0, 1, 2, 3 or 4, usually 0;

[0169] n is 0 or 1;

[0170] R 1 is selected from hydrogen, alkyl and aryl; and

[0171] each instance of R 50 is independently selected from hydrogen, halogen and alkyl.

[0172] Further embodiments of Method A, Method B and Method C include the following:

[0173] (i) The method as described above, wherein the reducing agent is zinc.

[0174] (ii) The method as described above, wherein an acid is added in the reduction step.

[0175] (iii) The method as described above, wherein ammonium chloride is added in the reduction step.

[0176] (iv) The method as described above, wherein the reduction conditions include platinum(IV) oxide and hydrogen.

[0177] (v) The method as described above, wherein the reduction conditions include Raney nickel and hydrogen.

[0178] (vi) The method as described above, wherein the reducing agent is iron.

[0179] (vii) The method as described above, wherein the reducing agent is samarium diiodide.

[0180] (viii) The method as described above, wherein the reduction and cyclization occur in the same reaction vessel.

[0181] (ix) The method as described above, wherein water is the solvent used in the reduction step.

[0182] (x) The method as described above, wherein a mixture of water and acetone is used as the solvent in the reduction step.

[0183] (xi) The method as described above, wherein the reduction and cyclization are carried out at room temperature.

[0184] (xii) The method as described above, wherein the reduction and cyclization are carried out at about 15 °C.

[0185] (xiii) The method as described above, wherein all steps are carried out at room temperature.

[0186] (xiv) The method as described above, wherein all steps are carried out at about 15 °C.

[0187] (xv) The method as described above, wherein an acid is added during the cyclization step.

[0188] (xvi) The method as described above, wherein a base is added during the cyclization step.

[0189] (xvii) The method as described above, wherein neither an acid nor a base is added in the cyclization step.

[0190] (xviii) The method as described above, wherein the alkyl group is methyl.

[0191] (xix) The method as described above, wherein the alkyl group is ethyl.

[0192] (xx) The method as described above, wherein the alkyl group is isopropyl.

[0193] (xxi) The method, wherein the alkyl group is tert-butyl.

[0194] Method D

[0195] Method D for preparing the compound of formula I comprises the following steps: 1. Reacting a cycloalkanone with a nitroalkane to obtain a cycloalkyl group substituted with a nitroalkylene group; 2. Reacting the compound of step (1) with an alkyl glycinate;

[0196] wherein the cycloalkanone has the following formula:

[0197]

[0198] wherein the nitroalkane has the following formula:

[0199]

[0200] wherein the alkyl glycinate has the following formula:

[0201]

[0202] wherein formula I is:

[0203]

[0204] wherein

[0205] y is 0, 1, 2, 3 or 4, usually 0;

[0206] n is 0 or 1;

[0207] R 1 is selected from hydrogen, alkyl and aryl; and

[0208] each instance of R 50 is independently selected from hydrogen, halogen and alkyl.

[0209] Further embodiments of Method D include the following:

[0210] (i) The method, wherein R 1 is hydrogen.

[0211] (ii) The method, wherein the nitroalkane is the solvent.

[0212] (iii) The method, wherein the nitroalkane is the sole solvent.

[0213] (iv) The method, wherein an organic base or an inorganic base is used in step 1.

[0214] (v) The method, wherein a carbonate base is used in step 1.

[0215] (vi) The method, wherein potassium carbonate is used in step 1.

[0216] (vii) The method as described above, wherein oxalic acid is added after step 2 to precipitate one or more undesired by-products.

[0217] (viii) The method as described above, wherein hydrobromic acid is added after step 2 to precipitate the compound of formula I.

[0218] (ix) The method as described above, wherein the alkyl group is methyl.

[0219] (x) The method as described above, wherein the alkyl group is ethyl.

[0220] (xi) The method as described above, wherein the alkyl group is isopropyl.

[0221] (xii) The method as described above, wherein the alkyl group is tert-butyl.

[0222] Method E

[0223] Method E for preparing the spiro compound of the present invention comprises the following steps: 1. Reacting a cyclic ketone with a nitroalkane to obtain a cycloalkyl group substituted by a nitroalkylene group; 2. Reacting the compound of step (1) with a protected glycine ester to obtain a compound of formula I'; 3. Reducing the compound of formula I' with a reducing agent; 4. Cyclizing the compound of step (3);

[0224] wherein the cyclic ketone has the following formula:

[0225]

[0226] wherein the nitroalkane has the following formula:

[0227]

[0228] wherein the protected glycine ester has the following formula:

[0229]

[0230] wherein formula I' is:

[0231]

[0232] wherein the spiro compound has the following formula:

[0233]

[0234] wherein

[0235] y is 0, 1, 2, 3 or 4, usually 0;

[0236] n is 0 or 1;

[0237] R 1 is selected from hydrogen, alkyl and aryl;

[0238] R 4 selected from NR 8 R 9 and OR 10 ;

[0239] R 8 and R 9 are independently selected from hydrogen, alkyl, aryl, cycloalkyl, and -alkyl-aryl;

[0240] R 10 is selected from alkyl, aryl, cycloalkyl, and -alkyl-aryl;

[0241] In an alternative embodiment, R 10 is alkenyl; and

[0242] R 50 each instance of which is independently selected from hydrogen, halogen, and alkyl.

[0243] Additional embodiments of Method E include the following:

[0244] (i) The method wherein R 1 is hydrogen.

[0245] (ii) The method wherein the nitroalkane is the solvent.

[0246] (iii) The method wherein the nitroalkane is the only solvent.

[0247] (iv) The method wherein an organic base or an inorganic base is used in Step 1.

[0248] (v) The method wherein a carbonate base is used in Step 1.

[0249] (vi) The method wherein potassium carbonate is used in Step 1.

[0250] (vii) The method wherein oxalic acid is added after Step 2 to precipitate one or more undesired by-products.

[0251] (viii) The method wherein hydrobromic acid is added after Step 2 to precipitate the compound of Formula I.

[0252] (ix) The method wherein R 4 is OR 10 .

[0253] (x) The method wherein R 4 is NR 8 R 9 .

[0254] (xi) The method wherein the alkyl is methyl.

[0255] (xii) The method as described above, wherein the alkyl group is ethyl.

[0256] (xiii) The method as described above, wherein the alkyl group is isopropyl.

[0257] (xiv) The method as described above, wherein the alkyl group is tert-butyl.

[0258] Method F

[0259] Method F for preparing the compound of formula I' comprises the following steps: 1. Reacting a cycloalkanone with a nitroalkane to obtain a cycloalkyl group substituted by a nitroalkylidene; 2. Reacting the compound of step (1) with an alkyl glycinate;

[0260] wherein the cycloalkanone has the following formula:

[0261]

[0262] wherein the nitroalkane has the following formula:

[0263]

[0264] wherein the protected glycine ester has the following formula:

[0265]

[0266] wherein formula I' is:

[0267]

[0268] wherein

[0269] y is 0, 1, 2, 3 or 4, usually 0;

[0270] n is 0 or 1;

[0271] R 1 is selected from hydrogen, alkyl and aryl;

[0272] R 4 is selected from NR 8 R 9 and OR 10 ;

[0273] R 8 and R 9 are independently selected from hydrogen, alkyl, aryl, cycloalkyl and -alkyl-aryl; and

[0274] R 10 is selected from alkyl, aryl, cycloalkyl and -alkyl-aryl;

[0275] In an alternative embodiment, R 10 is alkenyl; and

[0276] R 50 Each instance of R is independently selected from hydrogen, halogen, and alkyl.

[0277] Additional embodiments of Method F include the following:

[0278] (i) The method, wherein R 1 is hydrogen.

[0279] (ii) The method, wherein the nitroalkane is a solvent.

[0280] (iii) The method, wherein the nitroalkane is the sole solvent.

[0281] (iv) The method, wherein an organic base or an inorganic base is used in Step 1.

[0282] (v) The method, wherein a carbonate base is used in Step 1.

[0283] (vi) The method, wherein potassium carbonate is used in Step 1.

[0284] (vii) The method, wherein oxalic acid is added after Step 2 to precipitate one or more undesired by-products.

[0285] (viii) The method, wherein hydrobromic acid is added after Step 2 to precipitate the compound of Formula I.

[0286] (ix) The method, wherein the alkyl is methyl.

[0287] (x) The method, wherein the alkyl is ethyl.

[0288] (xi) The method, wherein the alkyl is isopropyl.

[0289] (xii) The method, wherein the alkyl is tert-butyl.

[0290] In summary, the above methods use several innovations to achieve improved yields and / or production. Non-limiting examples of these innovations include: (1) using nitromethane as the main solvent and an inorganic base in the first step; (2) nesting the Henry reaction into the Michael addition reaction, which prevents the formation of structural isomers of nitroolefins; (3) optionally using oxalic acid to remove excess glycine methyl ester as the hemioxalate from the first reaction mixture; (4) optionally isolating the key nitro intermediate as the hydrobromide salt, which stabilizes the intermediate and eliminates the need for further purification.

[0291] These improvements offer several advantages over previously reported routes, including: (1) the overall yield can now reach even about 50%, for example, as high as about 20%, 30%, or 40%; (2) the number of isolated intermediates is reduced from 4 - 5 to 1; (3) the overall preparation time is significantly reduced; (4) multiple steps are not required (improving atomic efficiency); (5) some hazardous / difficult-to-handle reagents and the need for cryogenic cooling are eliminated. Description of the Drawings

[0292] Figure 1 is a flow chart for the synthesis of 1,4-diazaspiro[5.5]undecan-3-one as described in Example 5. In a non-limiting exemplary instance, the steps are as follows: 1) Charge water for the method; 2) Charge ammonium chloride; 3) Charge acetone; 4) Charge methyl (1-(nitromethyl)cyclohexyl)glycinate hydrobromide; 5) Charge zinc powder in batches; 6) Charge K2CO3 solution; 7) Charge DCM; 8) Charge the combined organic layer; 9) Charge cyclohexane. In one embodiment, the reactor is degassed between step 5 and step 6, then the material is filtered after step 6, the aqueous layer from step 7 is discarded, the excess solvent from step 8 is distilled off, and then the solid product is filtered after step 9. The box labeled 1 corresponds to a single reactor that is stirred for 1 hour. The box labeled 2 represents steps that are still carried out in the same reactor as 1 while maintaining a temperature between 25°C and 40°C. The box labeled 3 represents steps that still occur in the same reactor at a temperature between 25°C and 40°C with the reaction stirred for 2 hours. The box labeled 4 represents the solid that is removed by filtration and heated under vacuum for drying. Detailed Description

[0293] I. Terms

[0294] Compounds are described using standard terms. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0295] Compounds in any of the formulas described herein include racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers such as rotamers, as if each were specifically described.

[0296] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and / or". Unless otherwise stated, the recitation of numerical ranges is merely intended to be a shorthand method of referring separately to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. All endpoints of a range are included within the range and may be combined independently. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein may be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is merely intended to better illustrate the invention and does not limit the scope of the invention. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0297] In an alternative embodiment of the invention, the compound of formula I or formula III provides at least one isotope substitution of a desired atom in an amount higher than the natural abundance of the isotope, i.e., is enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons.

[0298] As a general example and not a limitation, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H), may be used anywhere in the described structure to obtain the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C, may be used.

[0299] Isotope substitution, such as deuterium substitution, may be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched 90%, 95% or 99% or higher at any position of interest. In a non-limiting embodiment, deuterium is enriched 90%, 95% or 99% at the desired position.

[0300] In a non-limiting embodiment, the replacement of a hydrogen atom by a deuterium atom occurs at a position selected from R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 and R 50within any of the R groups. For example, when any R group is methyl, ethyl, or methoxy or contains methyl, ethyl, or methoxy, for example, by substitution, the alkyl residue can be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.).

[0301] The compounds of the present invention can form solvates with solvents (including water). Thus, in one non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO. Solvates can be in liquid or solid form.

[0302] A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the ketone (C=O) group.

[0303] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In a non-limiting embodiment, the alkyl contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In a non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, the specified ranges indicate that alkyl groups having each member of the range are described as independent species. For example, the term C1-C6 alkyl as used herein means a straight-chain or branched-chain alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as an independent species. For example, the term C1-C4 alkyl as used herein means a straight-chain or branched-chain alkyl having 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of them is described as an independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In an alternative embodiment, the alkyl is optionally substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when using terms including "alkyl", unless the context clearly excludes, "cycloalkyl" or "carbocyclic" can be considered part of the definition. For example but not limited to, terms such as "alkyl", "-O-alkyl", "haloalkyl", etc. can all be considered to include the cyclic form of alkyl, unless the context clearly excludes it.

[0304] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6π, 10π or 14π electrons shared in a cyclic array), which has 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C 6-14 aryl"). In some embodiments, the aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the linking group or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aromatic ring system. One or more fused cycloalkyl or heterocyclic groups can be 4- to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0305] The term "heterocyclic" includes saturated and partially saturated ring groups containing heteroatoms, where the heteroatoms can be selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocycles include 3- to 10-membered monocyclic rings and 5- to 16-membered bicyclic systems (which can include bridged fused and spiro fused bicyclic systems). It does not include rings containing -O-O-, -O-S-, or -S-S- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heterocyclic monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrroline, piperazinyl]; saturated 3- to 6-membered heterocyclic monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [morpholinyl]; saturated 3- to 6-membered heterocyclic monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrroline, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl.

[0306] "Heterocyclic" also includes groups in which the heterocyclic group is fused / condensed with an aryl or carbocyclic group, where the point of attachment is the heterocycle. For example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline, isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0307] The term "heteroaryl" denotes a stable aromatic ring system containing one or more heteroatoms selected from O, N, and S, where ring nitrogen and sulfur atoms are optionally oxidized and nitrogen atoms are optionally quaternized. Examples include, but are not limited to, 5- to 6-membered heterocyclic monocyclic groups containing 1-4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heterocyclic monocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered heterocyclic monocyclic groups containing a sulfur atom, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heterocyclic monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- to 6-membered heterocyclic monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. In one embodiment, the "heteroaryl" group is an 8-, 9-, or 10-membered bicyclic system. Examples of 8-, 9-, or 10-membered bicyclic heteroaryls include benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuryl, indolyl, indazolyl, and benzotriazolyl. As used herein, "substituted heteroaryl" means a heteroaryl substituted with the said substituent.If no substituents are explicitly described, "substituted heteroaryl" means a heteroaryl substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, cyano, hydroxy, -O-alkyl, -SH, -S-alkyl, -COOH, -COO-alkyl, -CO-alkyl, -COH, -CONH2, -CONH-alkyl, -CON(alkyl)2, -OC(O)-alkyl, -NHC(O)-alkyl, -N-alkylC(O)-alkyl, nitro, amino, -NH-alkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocycle, heterocycle, -COO-aryl, -CO-aryl, -CONH-aryl, -CON(alkyl)(aryl), -OC(O)-aryl, -NHC(O)-aryl, -N-alkylC(O)-aryl, -COO-heteroaryl, -CO-heteroaryl, -CON-heteroaryl, -CON(alkyl)(heteroaryl), -OC(O)-heteroaryl, -NHC(O)-heteroaryl, -N-alkylC(O)-heteroaryl, -COO-heterocycle, -CO-heterocycle, -CON-heterocycle, -CON(alkyl)(heterocycle), -OC(O)-heterocycle, -NHC(O)-heterocycle, and -N-alkylC(O)-heterocycle.

[0308] As used herein, "carbocyclic group", "carbocyclic", "carbocycle", or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group in a non-aromatic ring system that contains all carbocyclic atoms, 3 to 14 ring carbon atoms ("C 3-14 cycloalkyl") and zero heteroatoms. In some embodiments, the cycloalkyl has 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 9 ring carbon atoms ("C 3-9 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 7 ring carbon atoms ("C3-7 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, the cycloalkyl has 4 to 6 ring carbon atoms ("C 4-6 cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 10 ring carbon atoms ("C 5-10"cycloalkyl"). Exemplary C3-6 cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 cycloalkyls include, but are not limited to, the above C 3-6 cycloalkyls and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3-10 cycloalkyls include, but are not limited to, the above C 3-8 cycloalkyls and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), etc. As shown in the foregoing examples, in certain embodiments, the cycloalkyl can be saturated or can contain one or more carbon-carbon double bonds.

[0309] II. Embodiments of the present invention

[0310] Embodiments of y and n

[0311] In one embodiment, y is 0.

[0312] In one embodiment, y is 1.

[0313] In one embodiment, y is 2.

[0314] In one embodiment, y is 3.

[0315] In one embodiment, y is 4.

[0316] In one embodiment, n is 0.

[0317] In one embodiment, n is 1.

[0318] In one embodiment, n is 0 and y is 0.

[0319] In one embodiment, n is 0 and y is 1.

[0320] In one embodiment, n is 0 and y is 2.

[0321] In one embodiment, n is 0 and y is 3.

[0322] In one embodiment, n is 0 and y is 4.

[0323] In one embodiment, n is 1 and y is 0.

[0324] In one embodiment, n is 1 and y is 1.

[0325] In one embodiment, n is 1 and y is 2.

[0326] In one embodiment, n is 1 and y is 3.

[0327] In one embodiment, n is 1 and y is 4.

[0328] In one embodiment, n is 1 and y is 5.

[0329] R 1 embodiment of

[0330] In one embodiment, R 1 is hydrogen.

[0331] In one embodiment, R 1 is alkyl.

[0332] R 50 embodiment of

[0333] In one embodiment, at least one R 50 is halogen.

[0334] In one embodiment, at least one R 50 is alkyl.

[0335] In one embodiment, at least one R 50 is methyl.

[0336] embodiment of "alkyl"

[0337] In one embodiment, "alkyl" is C1-C 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl.

[0338] In one embodiment, "alkyl" has one carbon.

[0339] In one embodiment, "alkyl" has two carbons.

[0340] In one embodiment, "alkyl" has three carbons.

[0341] In one embodiment, "alkyl" has four carbons.

[0342] In one embodiment, "alkyl" has five carbons.

[0343] In one embodiment, "alkyl" has six carbons.

[0344] Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0345] Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl.

[0346] Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl.

[0347] Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl.

[0348] Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl.

[0349] In one embodiment, “alkyl” is “substituted alkyl”.

[0350] In one embodiment, “alkenyl” is “substituted alkenyl”.

[0351] In one embodiment, “alkynyl” is “substituted alkynyl”.

[0352] Embodiments of Formula III and Formula IV:

[0353] a. In one embodiment, n is 0.

[0354] b. In another embodiment, n is 1.

[0355] c. Embodiment a or b, wherein R 1 is hydrogen.

[0356] d. Embodiment a or b, wherein R 1 is alkyl.

[0357] e. Embodiment a or b, wherein R 1 is methyl.

[0358] f. Embodiment a or b, wherein R 1 is ethyl.

[0359] g. Embodiment a or b, wherein R 1 is propyl.

[0360] h. Embodiment a or b, wherein R 1 is cyclopropyl.

[0361] i. Any one of embodiments a-h, wherein R 2 is hydrogen.

[0362] j. Any one of embodiments a-h, wherein R 2 is substituted heteroaryl.

[0363] k. Any one of embodiments a - h, wherein R 2 is

[0364] l. Embodiment k, wherein R 12 is alkyl.

[0365] m. Embodiment k, wherein R 12 is methyl.

[0366] n. Embodiment k, wherein R 12 is aryl.

[0367] o. Embodiment k, wherein R 12 is - alkyl - aryl.

[0368] p. Any one of embodiments k - o, wherein R 13 is - S - alkyl.

[0369] q. Any one of embodiments k - o, wherein R 13 is - S - methyl.

[0370] r. Any one of embodiments k - o, wherein R 13 is Cl.

[0371] s. Any one of embodiments a - r, wherein R 3 is hydrogen.

[0372] t. Any one of embodiments a - r, wherein R 3 is halogen.

[0373] u. Any one of embodiments a - r, wherein R 3 is NR 5 R 6 .

[0374] v. Embodiment u, wherein R 5 is hydrogen.

[0375] w. Embodiment u, wherein R 5 is alkyl.

[0376] x. Embodiment u, wherein R 5 is - C(O)R 11 .

[0377] y. Embodiment x, wherein R 11 is alkyl.

[0378] z. Embodiment x, wherein R 11 is aryl.

[0379] aa. Any one of embodiments u - z, wherein R6 is hydrogen.

[0380] bb. Any one of embodiments u - z, wherein R 6 is alkyl.

[0381] cc. Any one of embodiments a - r, wherein R 3 is OR 7 .

[0382] dd. Any one of embodiments a - r, wherein R 3 is SR 7 .

[0383] ee. Embodiment cc or dd, wherein R 7 is alkyl, aryl, and - alkyl - aryl.

[0384] ff. Embodiment cc or dd, wherein R 7 is aryl.

[0385] gg. Embodiment cc or dd, wherein R 7 is - alkyl - aryl.

[0386] hh. Any one of embodiments a - gg, wherein R 4 is NR 8 R 9 .

[0387] ii. Embodiment hh, wherein R 8 is hydrogen.

[0388] jj. Embodiment hh, wherein R 8 is alkyl.

[0389] kk. Embodiment hh, wherein R 8 is alkyl - aryl.

[0390] ll. Any one of embodiments hh - kk, wherein R 9 is hydrogen.

[0391] mm. Any one of embodiments hh - kk, wherein R 9 is alkyl.

[0392] nn. Any one of embodiments hh - kk, wherein R 9 is alkyl - aryl.

[0393] oo. Any one of embodiments a - gg, wherein R 4 is OR 10 .

[0394] pp. Embodiment oo, wherein R 10 is alkyl.

[0395] qq. Embodiment oo, wherein R 10 is aryl.

[0396] rr. Embodiment oo, wherein R 10 is -alkyl-aryl.

[0397] ss. Any one of embodiments a-rr, wherein at least one R 50 is alkyl.

[0398] tt. Any one of embodiments a-rr, wherein at least one R 50 is halogen.

[0399] uu. Any one of embodiments a-rr, wherein y is 0.

[0400] vv. Any one of embodiments a-uu, wherein y is 1.

[0401] ww. Any one of embodiments a-uu, wherein y is 2.

[0402] xx. Any one of embodiments a-uu, wherein y is 3.

[0403] yy. Any one of embodiments a-uu, wherein y is 4.

[0404] zz. Any one of embodiments a-zz, wherein the alkyl is methyl.

[0405] aaa. Any one of embodiments a-zz, wherein the alkyl is ethyl.

[0406] bbb. Any one of embodiments a-zz, wherein the alkyl-aryl is benzyl.

[0407] R 2 Additional embodiments of

[0408] In certain embodiments, "substituted heteroaryl" is a 6-membered heteroaryl substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C(O)OH, C(O)Oalkyl, C(O)NH2, C(O)NHalkyl, C(O)Nalkyl2, -S-alkyl, -S(O)-alkyl, and -SC(O)2-alkyl.

[0409] In certain embodiments, R 2 is

[0410] In certain embodiments, R 2 is

[0411] In certain embodiments, R2 For

[0412] In certain embodiments, R 2 is

[0413] In certain embodiments, R 2 is

[0414] In certain embodiments, R 2 is

[0415] In certain embodiments, R 2 is

[0416] In certain embodiments, R 2 is

[0417] In certain embodiments, R 2 is

[0418] In certain embodiments, R 2 is

[0419] III. Synthesis of Compounds of Formula I and Formula III

[0420]

[0421] Scheme 10. Synthesis of Compounds of Formula I and Formula III

[0422] It has been found that compounds of Formula I and Formula III, such as methyl (1-(nitromethyl)cyclohexyl)glycinate and its analogs, are advantageously prepared by performing a Henry reaction, followed by elimination and Michael addition. This sequence is used to prepare new glycine esters and allows for the synthesis of 1,4-diazaspiro[5.5]undecan-3-one in excellent yields and quantities. These mechanistic steps can be advantageously carried out in one pot to obtain the compounds of Formula I and Formula III in a single synthetic step.

[0423] This synthetic sequence is shown in Scheme 10 above, starting from cyclohexanone and proceeding with nucleophilic addition (Henry reaction), followed by elimination of water and nucleophilic conjugate addition of an alkyl glycinate (Michael addition).

[0424] Step 1

[0425] Typically, Step 1 can be accomplished in a polar aprotic solvent at room temperature in the presence of a base that facilitates the reaction. Any polar aprotic solvent that achieves the desired result can be used. In one embodiment, nitromethane or a substituted nitromethane is used as both the reactant and the solvent. The addition order can be varied in a manner that achieves a suitable result. The order of adding the cyclic ketone, glycine ester, and potassium carbonate to nitromethane or a substituted nitromethane generally does not significantly affect the yield. If desired and advantageous, the addition order of the glycine ester and the cyclic ketone can be changed. In certain embodiments, the solvent used is methyl tert-butyl ether. In certain embodiments, the solvent used is cyclohexane.

[0426] In one embodiment, the concentration of cyclohexanone is at least about 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 1.25 M, 1.5 M, 1.75 M, or 2 M.

[0427] In another embodiment, the cyclic ketone is a substituted cyclohexanone, a substituted cyclopentanone, an unsubstituted cyclohexanone, or an unsubstituted cyclopentanone.

[0428] In another embodiment, the glycine ester is methyl glycinate, ethyl glycinate, isopropyl glycinate, or tert-butyl glycinate. For example, the glycine ester can be methyl glycinate.

[0429] Any suitable base can be used in Step 1 to achieve the desired result. In one embodiment, the base is an inorganic base selected from potassium carbonate, calcium carbonate, magnesium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide.

[0430] In another embodiment, the base is an organic base selected from DIPEA (N,N-diisopropylethylamine), DMAP (4-dimethylaminopyridine), DBU (1,8-diazabicycloundec-7-ene), TEA (triethylamine), pyridine, trimethylamine, tripropylamine, triisopropylamine, dimethylaniline, dimethylbenzylamine, DABCO (1,4-diazabicyclo[2.2.2]octane), 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-dimethylpyridine, morpholine, piperidine, piperazine, proton-sponge, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0431] In a typical embodiment, the glycine ester selected is more nucleophilic than the base used. In one embodiment, the glycine ester is in the form of a salt, such as a hydrochloride salt.

[0432] The temperature can be any temperature that provides the desired yield with minimal undesired by-products within the desired time. In non-limiting embodiments, the temperature can be from about 0 °C to about 50 °C, from about 10 °C to about 50 °C, from about 10 °C to about 40 °C, from about 20 °C to about 40 °C, or from about 20 °C to about 30 °C. In one non-limiting embodiment, the temperature is selected to be room temperature. In another non-limiting embodiment, the temperature is from about 25 °C to about 35 °C.

[0433] The reaction can be carried out for a sufficient time to obtain the desired product yield. In non-limiting embodiments, the reaction can be carried out in Step 1 for about 0.5 hours to about 10 hours, about 0.5 hours to about 8 hours, about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, or about 1 hour to about 3 hours. Those skilled in the art should understand that the time and temperature of the reaction are related. For example, if a higher temperature is appropriate and does not result in an unacceptable level of by-products, a lower reaction time may achieve the desired yield. Alternatively, a lower temperature may require a longer reaction time with fewer by-products.

[0434] The reaction can be carried out for a sufficient time to obtain the desired product yield. In non-limiting embodiments, the reaction can be carried out in Step 1 for less than 14 hours, less than 10 hours, less than 6 hours, less than 4 hours or less than 3 hours.

[0435] The reaction can be carried out for a sufficient time to obtain the desired product yield. In non-limiting embodiments, the reaction can be carried out in Step 1 for about 5 hours to about 24 hours, about 6 hours to about 22 hours, about 7 hours to about 20 hours, about 8 hours to about 19 hours, about 9 hours to about 18 hours, about 10 hours to about 17 hours, about 11 hours to about 16 hours, about 12 hours to about 16 hours, or about 13 hours to about 15 hours.

[0436] In one embodiment, the compound of Formula I or Formula III can be isolated in the form of a salt. In one example, hydrobromic acid or a similar acid can be added at the end of the reaction to collect the compound of Formula I or Formula III in solid form. In another embodiment, oxalic acid or a similar organic acid is added to chemically remove any remaining glycine ester starting material in solid form. These two acidic separation steps can be used together. For example, after work-up, oxalic acid can be added and the excess glycine ester starting material can be removed by filtration. After removing the excess glycine ester, hydrobromic acid can be added to the mixture to precipitate the pure compound of Formula I or Formula III as the hydrobromide salt.

[0437] In some non-limiting examples, an excess of glycine ester is used relative to the cyclohexanone. In this embodiment, at least about 1.2, 1.5, 1.7, 2, 2.2, 2.5, 2.7, or 3 equivalents of glycine ester can be used. In another embodiment, an excess of cyclohexanone is used relative to the glycine ester. In this embodiment, at least about 1.2, 1.5, 1.7, 2, 2.2, 2.5, 2.7, or 3 equivalents of cyclohexanone can be used. In the above embodiments, any equivalent amount of base is used that provides the product in the desired yield and purity. In one embodiment, at least about 1, 1.2, 1.5, 1.7, 2, 2.2, 2.5, 2.7, 3, 3.2, 3.5, 3.7, or 4 equivalents of base are used.

[0438] The reaction can be allowed to proceed for a sufficient time to obtain the desired product yield. For example, in one embodiment, the reaction is allowed to proceed for up to about 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, or 10 hours. Those skilled in the art will understand that the reaction time and temperature are related. For example, if a higher temperature is appropriate and does not result in an unacceptable level of by-products, a lower reaction time may provide the desired yield. Alternatively, a lower temperature may require a longer reaction time with fewer by-products.

[0439] In one embodiment, the conditions described herein are used for the synthesis of methyl (1-(nitromethyl)cyclohexyl)glycinate.

[0440] IV. Synthesis of Compounds of Formula II and Formula IV

[0441]

[0442] Scheme 11. Synthesis of Compounds of Formula II and Formula IV

[0443] It has been found that compounds of Formula II and Formula IV, such as 1,4-diazaspiro[5.5]undecan-3-one and its analogs, are advantageously prepared from compounds of Formula I or Formula III or pharmaceutically acceptable salts thereof. Compounds of Formula I or Formula III or salts thereof can be prepared as described above.

[0444] Advantages of this method include high yields, fewer protection and deprotection requirements, increased atom efficiency, fewer hazardous reagents, fewer steps, and shorter preparation times.

[0445] The synthetic sequence starting from a compound of Formula II or Formula IV and undergoing reduction, hydrolysis, and cyclization is shown in Scheme 11 below. In one embodiment, cyclization and hydrolysis occur simultaneously.

[0446] Stage 2

[0447] Typically, Stage 2 can be completed in a solvent or solvent mixture that promotes the reaction. Various reagents can be added to achieve the appropriate result. In one embodiment, the reducing agent is compatible with the base or amide coupling agent, so all reactants and reagents are added at the start of the reaction. In this embodiment, the entire process starting from the cyclic ketone is two synthetic steps with multiple transformations. In another embodiment, the reducing agent is added first, and then the base or amide coupling agent is added after the desired period of time has passed.

[0448] In one embodiment, the intramolecular cyclization is carried out without adding a base or amide coupling agent. For example, the intramolecular cyclization can be carried out after reducing the nitro group to an amine without additional reagents.

[0449] In certain embodiments, methyl tert-butyl ether is used as the solvent. In certain embodiments, cyclohexane is used as the solvent.

[0450] In one aspect, the initial concentration of the compound of Formula I or Formula III is at least about 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 1.25 M, 1.5 M, 1.75 M, or 2 M. The reducing agent and conditions used in Step 1 can be any reducing agent and conditions that achieve the desired purpose. In one aspect, the reducing agent is zinc activated with a weak acid such as ammonium chloride or acetic acid. In another embodiment, the reducing agent is platinum(IV) oxide in the presence of hydrogen, Raney nickel, iron, or samarium diiodide in the presence of hydrogen. In certain embodiments, the reducing agent is zinc powder.

[0451] In one embodiment, at least about 10, 8, 6, 5, 4, 3, or 2 equivalents of the reducing agent are used. For example, at least about 10, 8, 6, 5, 4, 3, or 2 equivalents of zinc are used. Those skilled in the art will recognize that different equivalents of the reducing agent will affect the reduction rate. For example, the reducing agent can stop at 2 equivalents of zinc, but there is no problem in using 5 equivalents of zinc.

[0452] In certain instances, the base can be an inorganic base selected from potassium carbonate, calcium carbonate, magnesium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide.

[0453] In another embodiment, the base is an organic base selected from DIPEA (N,N-diisopropylethylamine), DMAP (4-dimethylaminopyridine), DBU (1,8-diazabicycloundec-7-ene), TEA (triethylamine), pyridine, trimethylamine, tripropylamine, triisopropylamine, dimethylaniline, dimethylbenzylamine, DABCO (1,4-diazabicyclo[2.2.2]octane), 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-dimethylpyridine, morpholine, piperidine, piperazine, proton sponge, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0454] The temperature can be any temperature that provides the desired yield with a minimum of undesired by-products over the desired time. In non-limiting embodiments, the temperature can be from about 0 °C to about 50 °C, from about 10 °C to about 50 °C, from about 10 °C to about 40 °C, from about 20 °C to about 40 °C, or from about 20 °C to about 30 °C. In one non-limiting embodiment, the temperature is selected to be room temperature.

[0455] The reaction can be allowed to proceed for a sufficient time to obtain the desired product yield. For example, in one embodiment, the reaction is allowed to proceed for up to about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, or 4 hours. One of ordinary skill in the art will understand that the time and temperature of the reaction are related. For example, if a higher temperature is appropriate and does not result in an unacceptable level of by-products, a lower reaction time may achieve the desired yield. Alternatively, a lower temperature may require a longer reaction time with fewer by-products.

[0456] In one embodiment, the conditions described herein are used to synthesize 1,4-diazaspiro[5.5]undecan-3-one from methyl (1-(nitromethyl)cyclohexyl)glycinate.

[0457] V. Compounds of the Invention

[0458] Non-limiting examples of the compounds of the invention include:

[0459]

[0460]

[0461] Additional non-limiting examples of the compounds of the invention include:

[0462]

[0463]

[0464] Additional non-limiting examples of the compounds of the invention include:

[0465]

[0466]

[0467]

[0468] Additional non - limiting examples of the compounds of the present invention include:

[0469]

[0470] Non - limiting examples of compounds that can be synthesized according to the method of the present invention include:

[0471]

[0472] Additional non - limiting examples of compounds that can be synthesized according to the method of the present invention include:

[0473]

[0474] VI. Exemplary Embodiments

[0475] General Method

[0476] The structures of the starting materials, intermediates and final products are confirmed by standard analytical techniques such as NMR spectroscopy and / or mass spectrometry. Unless otherwise specified, reagents and solvents are used as obtained from commercial suppliers. Proton nuclear magnetic resonance spectra are obtained at 300 MHz in chloroform - d. HPLC analysis is performed on a Waters SunFire C18, 150x4.6 mm, 4.6 µm column.

[0477] Example 1. Synthesis of Methyl (1 - (nitromethyl)cyclohexyl)glycinate Hydrobromide

[0478]

[0479] At room temperature, a suspension of cyclohexanone (4 g, 40.8 mmol), glycine methyl ester hydrochloride (12.79 g, 102 mmol, 2.5 equiv.), and potassium carbonate (14.08 g, 102 mmol, 2.5 equiv.) in nitromethane (50 ml) was stirred for 2 h. The reaction mixture was then diluted with dichloromethane and filtered through a sintered funnel. The residue was washed several times with dichloromethane. The combined filtrates were concentrated to dryness, and the remaining oil was dissolved in diethyl ether. A solution of oxalic acid (1.835 g, 20.38 mmol, 0.5 eq.) in 5 mL of methanol was added with stirring, concentrated to dryness, resuspended in diethyl ether, and sonicated for 10 min. The solid was filtered off, washed with diethyl ether, and air-dried. Analysis of this solid confirmed it to be glycine methyl ester hemioxalate (5.5 g). Hydrogen bromide (7.14 ml, 40.8 mmol, 33% in acetic acid, 1 eq.) was added to the filtrate with stirring. The suspension was stirred for 10 min, sonicated for 10 min, and the solid was separated by filtration, washed with diethyl ether, and air-dried to give methyl (1-(nitromethyl)cyclohexyl)glycinate, HBr (11.4 g, 36.6 mmol, 91% yield), as an off-white solid.

[0480] 1 H NMR (300 MHz, chloroform-d) δ 1.52 (q, J = 15.2, 14.1 Hz, 2H), 1.79 (d, J = 13.6 Hz, 6H), 1.98 (d, J = 13.1 Hz, 2H), 3.85 (s, 3H), 4.23 (s, 2H), 5.13 (s, 2H).

[0481] Example 2. Alternative synthesis of methyl (1-(nitromethyl)cyclohexyl)glycinate hydrobromide

[0482]

[0483] At room temperature, a suspension of cyclohexanone (4 g, 40.8 mmol), glycine methyl ester hydrochloride (12.79 g, 102 mmol, 2.5 equiv.), and potassium carbonate (14.08 g, 102 mmol, 2.5 equiv.) in nitromethane (50 ml) was stirred for 2 h. The reaction mixture was then diluted with dichloromethane and filtered through a sintered funnel. The residue was washed several times with dichloromethane. The combined filtrates were concentrated to dryness, and the remaining oil was dissolved in diethyl ether. A solution of hydrogen bromide (7.14 ml, 40.8 mmol, 33% in acetic acid, 1 equiv.) was added with stirring. The suspension was stirred for 10 min, sonicated for 10 min, and the solid was separated by filtration, washed with diethyl ether, and air-dried to give methyl (1-(nitromethyl)cyclohexyl)glycinate, HBr salt.

[0484] Alternatively, the above method can be used to prepare methyl (1-(nitromethyl)cyclohexyl)glycinate as the free base by using an alternative purification method instead of using hydrogen bromide.

[0485] Example 3. Synthesis of 1,4-diazaspiro[5.5]undecan-3-one

[0486]

[0487] To a suspension of methyl (1-(nitromethyl)cyclohexyl)glycinate hydrobromide (2 g, 6.43 mmol) in acetone (30 ml) and water (6.00 ml) was added ammonium chloride (3.44 g, 64.3 mmol, 10 eq.), potassium carbonate (0.888 g, 6.43 mmol, 1 eq.), and zinc (4.2 g, 64.3 mmol, 10 eq.), and the mixture was stirred vigorously for 10 minutes. Volatiles were removed in vacuo, and the residue was treated with saturated K2CO3 solution. The mixture was filtered through a sintered funnel, and the residue was washed several times with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude mixture, which was triturated with isopropyl ether. The solid was separated by filtration and air-dried to give 1,4-diazaspiro[5.5]undecan-3-one (674 mg, 4.01 mmol, 62.3% yield) as an off-white solid.

[0488] 1 1H NMR (300 MHz, chloroform-d) δ 1.41 - 1.62 (m, 10H); 3.16, 3.17 (d, J = 2.6 Hz, 2H), 3.48 (s, 2H), 6.22 (s, 1H).

[0489] Example 4. Alternative synthesis of methyl (1-(nitromethyl)cyclohexyl)glycinate hydrobromide

[0490]

[0491] Nitrogen was applied to the reaction vessel and then evacuated to not less than 450 mm Hg. Nitrogen was applied again, and then the reactor was rinsed with nitromethane. Nitromethane (4 L) was added to the reactor, followed by potassium carbonate (2.5 kg) and glycine methyl ester (3.2 kg). A solution of cyclohexanone (1 kg) in nitromethane (3.5 L) was prepared and added to the reaction. All steps were carried out at about 25 °C.

[0492] Cool the reaction materials to 10 °C and add process water (2.5 L) dropwise over a period of not less than 180 minutes. The addition of water is carried out at 10 °C. Then raise the temperature to 30 °C and stir the reaction at 30 °C for 14 hours or until the cyclohexanone content measured by TLC does not exceed 5%. Next, dilute the reaction mixture with 2 M potassium carbonate (10 L) at 30 °C and stir the reaction materials at 30 °C for 5 minutes, then add methyl tert-butyl ether (10 L) and stir the reaction for an additional 40 minutes at 30 °C.

[0493] Separate the organic layer from the aqueous layer, mix the aqueous layer with methyl tert-butyl ether (10 L), and allow to stir at 30 °C for 30 minutes. Repeat this process twice. Discard the aqueous layer. Combine the three organic layers and add methyl tert-butyl ether (20 L) to further dilute the reaction mixture. Cool the solution to 5 °C and add hydrobromic acid solution (1.9 L, 33% in acetic acid) over a period of not less than 240 minutes. Then stir the mixture at 5 °C for 3 hours. Then filter the reaction materials and wash with methyl tert-butyl ether (0.5 L). Dry the materials at 25 °C until the mother liquor is completely removed and further dry the wet cake in vacuo at 50 °C for 4 - 5 hours.

[0494] Example 5. Alternative synthesis of 1,4-diazaspiro[5.5]undecan-3-one

[0495]

[0496] Charge the reactor with process water (1.9 L), then ammonium chloride (0.60 kg), and then acetone (7.5 kg). Stir the reaction for 10 minutes. Add (1-(nitromethyl)cyclohexyl)glycine methyl ester hydrobromide (1 kg) to the reactor, and then add zinc powder (0.75 kg) in batches over 30 minutes. Stir the reaction at 50 °C for 30 minutes or until the content of (1-(nitromethyl)cyclohexyl)glycine methyl ester hydrobromide does not exceed 0.5%.

[0497] Completely distill off the acetone under vacuum at 55 °C and adjust the pH of the resulting solution to pH 10 - 11 using 2 M potassium carbonate. Stir the solution at 25 °C for 30 minutes. Then filter the reactants through a diatomaceous earth pad and charge the resulting reactants into a 10% MeOH in DCM solution (10 kg) and stir for 30 minutes to separate the organic matter from the aqueous matter. Repeat 6 times. Discard the resulting aqueous layer. Concentrate the organic layer to dryness and triturate with cyclohexane (0.55 kg). Stir the solution at 5 °C for 20 minutes, filter, and wash with cyclohexane (0.20 kg). Then dry the wet material in a vacuum oven at 55 °C to obtain 0.18 kg of the product. In an alternative embodiment, trituration is carried out with methyl tert-butyl ether.

[0498] This specification has been described with reference to embodiments of the present invention. However, those of ordinary skill in the art should understand that various modifications and changes can be made without departing from the scope of the present invention as set forth in the appended claims. Accordingly, this specification should be regarded as illustrative rather than restrictive, and all such modifications are intended to be included within the scope of the present invention.

Claims

1. A method for preparing a spiro compound, comprising: a. Reacting a cyclic ketone with a nitroalkane to obtain a cycloalkyl group substituted with a nitroalkylene group; b. Reacting the compound formed in step (a) with a glycine ester to obtain a compound of formula III; c. Reducing the compound of formula III with a reducing agent; d. Cyclizing the compound formed in step (c); wherein the cyclic ketone has the following formula: wherein the nitroalkane has the following formula: wherein the glycine ester has the following formula: wherein formula III is: wherein the spiro compound has the following formula: wherein y is 0; n is 1; R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; R 4 is OR 10 ; R 10 Selected from C1-C6 alkyl groups.

2. The method according to claim 1, wherein the nitroalkane is also a solvent.

3. The method according to claim 1, wherein a base is used in step (a).

4. The method according to claim 3, wherein the base is an organic base.

5. The method according to claim 3, wherein the base is an inorganic base.

6. The method according to claim 3, wherein the base is a carbonate.

7. The method according to claim 3, wherein the base is potassium carbonate.

8. The method according to any one of claims 1-7, wherein oxalic acid is added after step (b) to precipitate and remove unwanted by-products.

9. The method according to any one of claims 1-7, wherein an acid is added after step (b) to separate the compound as a salt.

10. The method according to claim 9, wherein the acid is hydrobromic acid.

11. The method according to any one of claims 1-7, wherein the reducing agent is iron.

12. The method according to any one of claims 1-7, wherein the reducing agent is samarium diiodide.

13. The method according to any one of claims 1-7, wherein the reduction and cyclization occur in the same reaction vessel.

14. The method according to any one of claims 1-7, wherein water is used as a solvent in the reduction step.

15. The method according to any one of claims 1-7, wherein a mixture of water and acetone is used as a solvent in the reduction step.

16. The method according to any one of claims 1-7, wherein the reduction and cyclization are carried out at 25 °C.

17. The method according to any one of claims 1-7, wherein the reduction and cyclization are carried out at 15 °C.

18. The method according to any one of claims 1-7, wherein the reduction and cyclization are carried out at 35 °C.

19. The method according to any one of claims 1-7, wherein the cyclization is acid-catalyzed.

20. The method according to any one of claims 1-7, wherein the cyclization is base-catalyzed.

21. The method according to any one of claims 1-7, wherein the glycine ester is methyl glycinate.

22. The method according to any one of claims 1-7, wherein the glycine ester is ethyl glycinate.

23. The method according to any one of claims 1-7, wherein the nitroalkane is nitromethane.

24. The method according to any one of claims 1-7, wherein all steps are carried out at 25 °C.

25. The method according to any one of claims 1-7, wherein the C1-C6 alkyl group is methyl or ethyl.

26. A compound of the following formula: or an acceptable salt thereof; wherein y is 0; n is 1; R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; R 4 is OR 10 ; R 10 selected from C1-C6 alkyl groups.

27. The compound according to claim 26, wherein R 4 is -OMe.

28. The compound according to claim 26, wherein R 4 is -OEt.

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