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Methods for making 4-tetrazolyl-4-phenylpiperidine compounds

A kind of technology of compound and composition, applied in the field of preparing 4-tetrazolyl-4-phenylpiperidine compound, can solve the problems such as compound synthesis without description of tetrazole part

Inactive Publication Date: 2007-02-14
EURO-CELTIQUE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the '282 patent does not describe the synthesis of any compounds containing tetrazole moieties

Method used

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  • Methods for making 4-tetrazolyl-4-phenylpiperidine compounds
  • Methods for making 4-tetrazolyl-4-phenylpiperidine compounds
  • Methods for making 4-tetrazolyl-4-phenylpiperidine compounds

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preparation example Construction

[0566] 4.2.7. The preparation method of compound (9)

[0567] In another embodiment, the present invention relates to a process for the preparation of compound (9) (4-phenyl-4-(2H-tetrazol-5-yl)-piperidine), comprising making compound (8) (4-cyano Base-4-phenyl-piperidinium chloride) is reacted with sodium azide in the presence of a suitable zinc salt as shown in Scheme 7 below:

[0568] Option 7

[0569]

[0570] In certain embodiments, the phenyl moiety attached to the 4-position of the piperidine ring according to compound (8) (commercially available) and other compounds formed therefrom is substituted with one or more R 2 group, where R 2 defined above.

[0571] The reaction of Scheme 7 is carried out in a solvent containing a polar aprotic solvent. Examples of suitable polar aprotic solvents for use in the reaction of Scheme 7 include, but are not limited to, dioxane, N-methylpyrrolidone, dimethylformamide, dimethylacetamide or dimethyls...

Embodiment 1

[0775] 5.1. Example 1: Synthesis of compound (2) (1-benzyl-4-phenyl-4-(2H-tetrazol-5-yl)-piperidine)

[0776] To well stirred 125.77 g of 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride (the hydrochloride salt of compound (1)) (Aldrich Chemical Co., Milwaukee, Wisconsin) in 1.0 L of chloroform Add 500mL Na to the solution 2 CO 3 saturated aqueous solution. Separate the layers and recover the chloroform layer. The aqueous layer was extracted with about 200 ml of chloroform. The chloroform layers recovered twice were combined, extracted with about 500 mL of deionized water, dried over anhydrous sodium sulfate and evaporated to constant weight to obtain 109.7 g of compound (1) as a free amine, (1-benzyl-4-cyano base-4-piperidine).

[0777] The free amine compound (1) (109.7 g) was dissolved in 500 mL of 1-methyl-2-pyrrolidone and divided into two parts, and the following steps were performed in parallel on the two parts using the same flask.

[0778] A portion of compound...

Embodiment 2

[0780] 5.2. Example 2: Synthetic compound (4) (2-[5-(1-benzyl-4-phenylpiperidin-4-yl)-tetrazol-2-yl]-acetamide)

[0781]

[0782] Equipped with magnetic stirrer, temperature controller, condenser and N 2 Add compound (2) (1-benzyl-4-phenyl-4-(2H-tetrazol-5-yl)-piperidine) (234.57g, 0734mol) to an imported 3-liter round bottom flask, dimethyl Formamide (2.0 L), potassium carbonate (121.8 g, 0.881 mol) and 2-bromoacetamide (101.32 g, 0.734 mol) (Aldrich Chemical Co., Milwaukee, Wisconsin). The reaction mixture was heated to 50 °C under N 2 Incubate overnight. Analysis of a reaction sample by LC / MS indicated the reaction was complete.

[0783] The reaction mixture was cooled to room temperature and poured into 4.5 L of rapidly stirring deionized water. Ethyl acetate (2.5 L) was added and the resulting precipitate was collected by vacuum filtration and dissolved in about 6 L of ethyl acetate. The resulting layers were separated and the ethyl acetate layer was recovered, dr...

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Abstract

Methods, composition, and intermediates are disclosed that are useful for making 4-Tetrazolyl-4-phenylpiperidine Compounds according to Formula (I), where Ar<1> is -C3-C8 cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or -(5-7-membered) heteroaryl, each being unsubstituted or substituted with one or more R<2> groups; Ar<2> is phenyl, naphthyl, anthryl, phenanthryl or -(5-7-membered) heteroaryl, each being unsubstituted or substituted with one or more R<2> groups; Z<1> and Z<2> are each independently a -(C1-C4 alkyl) group; R<1> is -(CH2)nC(O)N(R<3>)(R<4>) where R<3> and R<4> are each independently H or -(C1-C4 alkyl); R<2> is halogen, -C1-C3 alkyl, -O-(C1-C3 alkyl), -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2; n is an integer ranging from 1 to 4; m is an integer ranging from 0 to 4; and, in certain embodiments, the phenyl moiety attached to the 4-position of the piperidine ring of a compound according to formula (I) can be optionally substituted with one or mor R<2> groups.

Description

technical field [0001] The present invention relates to compositions, intermediates and methods for the preparation of 4-tetrazolyl-4-phenylpiperidine compounds. Background technique [0002] Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. Acute pain is usually self-limited, whereas chronic pain can last three months or more and result in significant changes in the patient's personality, lifestyle, functional capacity, or overall quality of life (K.M. Foley, Pain, in Cecil Textbook of Medicine 100 -107, J.C. Bennett and E. Plum eds., 20 th ed.1996). [0003] Typically, by administering nonopioid analgesics such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen, Or pain control by administering opioid pain relievers such as morphine, hydromorphone, methadone, oxymethorphan, fentanyl, oxycodone, and oxymorphone. [0004] 4-tetrazolyl-...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D211/64C07D257/04C07D307/22C07C237/20
Inventor 凯文·布朗蒂莫西·J·多伊尔约翰·W·F·怀特黑德
Owner EURO-CELTIQUE SA