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Crystalline form of 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione intermediates

IP.com Disclosure Number: IPCOM000234107D
Publication Date: 2014-Jan-13
Document File: 7 page(s) / 228K

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The IP.com Prior Art Database

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 Crystalline form of 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6- dione intermediates

Described herein after are intermediates in the synthesis of 8-[(3R)-3- aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2- yl)methyl]-3,7-dihydro-1H-purine-2,6-dione.

("compound I")

Methylxanthine

-

3

-

Bromo

-

8

Crystalline

Figure 1: a powder XRD pattern of compound I

CPS

Main XRD peaks of compound I are: 10.3, 12.6, 14.4, 19.8, 20.4, 21.6, 22.0,


22.5, 23.2, 25.7, 26.5, 27.2, 28.7, 29.0, 29.5, 30.9, 32.1, 33.2, 35.6, 36.0, 37.6 and 38.6 ± 0.2 degrees 2-theta.

Figure 2: FTIR spectrum of compound I

degrees 2-theta


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Example 1: Preparation of crystalline form of compound I

O O N

O O N

HN

HN Br2
NaOAc / AcOH HN

HN

Br

N

N

Glacial acetic acid, sodium acetate and 3-Methylxanthine were mixed together. Bromine was added slowly at ambient temperature for 1 hr. The reaction mixture was heated slowly to about 65°C and stirred for 3 hours. After the reaction completion, the mixture was cooled and stirred for another 2 hrs. The precipitate was filtered, washed with acetic acid and water. The white solid was dried in oven to afford compound I (yield - 82%; purity - 99.9%).

("compound II")

methylxanthine

-

3

-

yl)

-

1

-

yn

-

2

-

(but

-

7

-

Bromo

-

8

Crystalline

Figure 3: a powder XRD pattern of compound II

CPS

degrees 2-theta

Main XRD peaks of compound II are: 11.7, 12.3, 15.4, 17.4, 18.3, 19.4, 20.2,


22.1, 23.0, 24.4, 25.2, 25.7, 26.4, 27.0, 28.1, 28.8, 30.8, 31.6, 32.6, 34.2, 35.1,


35.6, 37.2 and 39.2 ± 0.2 degrees 2-theta.


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Figure 4: FTIR spectrum of compound II

Example 2: Preparation of crystalline form of compund II

O O N

O O N

HN

N

HN

DiPEA

HN

Br

+

Br

N

Br

   NMP MeOH / Toluene

N

Compound I, N-Methyl-2-pyrrolidone (NMP) and diisopropyl ethyl amine (DiPEA) were mixed together. 1-Bromo-2-butyne was added slowly to the obtained mixture by keeping the temperature below 30°C. The resulting mixture was heated to about 105°C and stirred for 9 hrs. Methanol was added to the cooled reaction mixture and stirred for 2 hrs. The resulting suspension was filtered and washed with methanol and toluene. The filtered cake was dried under reduced pressure to afford compound II (yield - 98%; purity - 99.8%).

Crystalline 2-(Chloromethyl)-4-methylquinazoline ("compound III")

Figure 5: a powder XRD pattern of compound III


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CPS

Main XRD peaks of compound III are: 8.2, 9.1, 12.0, 12.3, 16.1, 17.9, 18.3,


18.6, 19.5, 22.4, 23.5, 23.8, 24.2, 25.2, 25.6,...