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KR-102962306-B1 - Improved synthesis of 1,4-diazaspiro[5.5]undecan-3-one

KR102962306B1KR 102962306 B1KR102962306 B1KR 102962306B1KR-102962306-B1

Abstract

The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one and analogs thereof, which are useful for the manufacture of pharmaceutical compounds for the treatment of disorders accompanied by abnormal cell proliferation. A chemical intermediate in the method is also provided.

Inventors

  • 슈나이더, 스티븐
  • 화이트, 한나
  • 페싸드, 토마스
  • 벨다, 사가

Assignees

  • 쥐원 쎄라퓨틱스, 인크.

Dates

Publication Date
20260508
Application Date
20190823
Priority Date
20180824

Claims (20)

  1. a. A step of reacting a cyclic ketone with a nitroalkane to obtain a cycloalkyl group substituted with a nitroalkylene; b. A step of reacting the compound of step (a) with glycinate to obtain a compound of formula III; c. A step of reducing a compound of Formula III with a reducing agent; and d. Step of cyclizing the compound of step (c) A method for preparing a spirocyclic compound comprising; Here, the chemical formula for cyclic ketones is: having; Here, the chemical formula for nitroalkanes is: having; Here, glycinate has the chemical formula: having; Here, chemical formula III is And; Here, the chemical formula of the spirocyclic compound is: having; Here y is 0 and; n is 1 and; R1 is hydrogen and; R2 is hydrogen and Selected from; R₃ is hydrogen; R 4 is selected from NR 8, R 9 , and OR 10 ; R 8 and R 9 are independently selected from hydrogen, alkyl, aryl, and -alkyl-aryl; R 10 is selected from alkyl, aryl, and -alkyl-aryl; R 12 is selected from alkyl, aryl, and -alkyl-aryl; R 13 is selected from -S-alkyl and Cl method.
  2. A method according to claim 1 in which the nitroalkane is also a solvent.
  3. A method according to claim 1, wherein a base is used in step (a).
  4. In paragraph 3, the method in which the base is an organic base.
  5. In paragraph 3, the method in which the base is an inorganic base.
  6. In paragraph 3, the method in which the base is carbonate.
  7. In paragraph 3, the method in which the base is potassium carbonate.
  8. A method according to any one of claims 1 to 7, wherein oxalic acid is added after step (b) to precipitate and remove undesirable by-products.
  9. A method according to any one of claims 1 to 7, wherein an acid is added after step (b) to isolate the compound as a salt.
  10. In paragraph 9, the method in which the acid is hydrobromide.
  11. A method in which the reducing agent is iron in any one of paragraphs 1 to 7.
  12. A method according to any one of claims 1 to 7, wherein the reducing agent is samarium diiodide.
  13. A method according to any one of claims 1 to 7, wherein reduction and cyclization occur in the same reaction vessel.
  14. A method in which water is used as a solvent in the reduction step in any one of claims 1 to 7.
  15. A method according to any one of claims 1 to 7, wherein a mixture of water and acetone is used as a solvent in the reduction step.
  16. A method according to any one of claims 1 to 7, wherein reduction and cyclization are performed at 25°C.
  17. A method according to any one of claims 1 to 7, wherein reduction and cyclization are performed at 15°C.
  18. A method according to any one of claims 1 to 7, wherein reduction and cyclization are performed at 35°C.
  19. A method in which, in any one of claims 1 to 7, cyclization is an acid catalyst.
  20. A method in which, in any one of claims 1 to 7, cyclization is catalyzed by a base.

Description

Improved synthesis of 1,4-diazaspiro[5.5]undecan-3-one Related applications This application claims the benefit of U.S. Provisional Application No. 62/722,675 filed on August 24, 2018. The full text of this application is incorporated by reference. Field of invention The present invention provides a method for preparing 1,4-diazaspiro[5.5]undecan-3-one and analogs thereof, which are useful for the preparation of specific pharmaceutical compounds for the treatment of disorders accompanied by abnormal cell proliferation. A chemical intermediate in the method is also provided. U.S. Patent 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, describe compounds comprising a spirocyclic core. Specifically, these patents describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine cycline-dependent kinase inhibitors comprising compounds of the following chemical formula (variable groups as defined herein): Additionally, U.S. patents No. 9,464,092; 9,487,530; and 9,527,857, assigned to G.W. Therapeutics, describe the use of these compounds to treat cancer. The aforementioned patent utilizes a multi-step method in which a spirocycle core is formed later in a method by intramolecular cyclization. The method is initiated by the 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 group is added by a nucleophilic aromatic substitution reaction. This method is presented in Reaction Scheme 1 below. Reaction Scheme 1. Conventional synthesis of an N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine cycline-dependent kinase inhibitor. Another method for synthesizing N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine cycline-dependent kinase inhibitors is disclosed in PCT application WO 2018/005865. This method provides several improvements over conventional methods, including the use of 1,4-diazaspiro[5.5]undecan-3-one as an intermediate. Application '865 also provides a method for synthesizing 1,4-diazaspiro[5.5]undecan-3-one. By this method, 1,4-diazaspiro[5.5]undecan-3-one is obtained from commercially available cyclohexanone in six steps. This method is summarized below in Reaction Scheme 2. Reaction Scheme 2. Conventional synthesis of 1,4-diazaspiro[5.5]undecane-3-one. There remains a need for a method that has a higher yield, requires fewer and/or milder chemical reactions, or has fewer steps to synthesize 1,4-diazaspiro[5.5]undecan-3-one. It has been found that 1,4-diazaspiro[5.5]undecan-3-one and structural analogs (Formula II and Formula IV below) can advantageously be prepared from cyclohexanone by a two-port process. In the first port, cyclohexanone is reacted with nitromethane to produce 1-(nitromethyl)cyclohexan-1-ol, and then water is lost to produce (nitromethylene)cyclohexane. Then, an alkyl glycinate is added to (nitromethylene)cyclohexane to produce alkyl (1-(nitromethyl)cyclohexyl)glycinate. Then, in the second port, the nitro group of (1-(nitromethyl)cyclohexyl)glycinate is converted to an amino group to produce methyl (1-(aminomethyl)cyclohexyl)glycinate. Then, the alkyl group is removed to produce (1-(aminomethyl)cyclohexyl)glycine. Next, this compound is internally cyclized to produce 1,4-diazaspiro[5.5]undecane-3-one. In one embodiment, cyclization occurs in the absence of hydrolysis. This synthesis sequence is presented in Reaction Scheme 3 below. Reaction Scheme 3. Improved synthetic route for preparing 1,4-diazaspiro[5.5]undecan-3-one. Advantageously, in one aspect of the invention, one or more mechanistic steps presented in Reaction Scheme 3 can be carried out in the same reaction vessel without isolation. For example, the Henry reaction, removal, and Michael addition can all be combined in a single reaction. Similarly, the reduction, hydrolysis, and cyclization reactions can also be combined in a single reaction. An example of such an advantageous embodiment is presented in Reaction Scheme 4 below. Reaction Scheme 4. Preparation of 1,4-diazaspiro[5.5]undecan-3-one by only two isolation steps. In another aspect of the present invention, one or more isolation steps can be achieved by recrystallization or filtration after the addition of acid. For example, in Reaction Scheme 5 below, post-treatment with hydrobromide enables high-yield isolation of Michael adducts by filtration. Reaction Scheme 5. Use of hydrobromide for isolating Michael addition products. As described in more detail in the following detailed explanation and as instructed by this reaction, a skilled operator may achieve similar intended results by selecting alternative reagents, reactants, and solvents other than those presented in Reaction Schemes 4 and 5. For example, Reaction Scheme 6 provides a more generalized version