HCID 59507518, compound → HCID 178494244, compound

HRID 1043820Notes

Reaction equation

HRID 1043820 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:3]=1.O1CC[N:31]([C:34]2[N:39]=[C:38](C3C=NC(N)=NC=3)[CH:37]=[C:36]([O:47][C:48]3C=NC=CC=3)[N:35]=2)CC1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:48][O:47][CH:36]1[NH:35][C:34]([NH2:31])=[N:39][CH:38]=[C:37]1[C:2]1[CH:3]=[C:4]([O:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[N:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:7]=1

Participants

6

Reactant 2

HCID 59507518HCID 59507518, compoundHCID 59507577HCID 59507577, compound

Product 1

HCID 178494244HCID 178494244, compoundYield 94.6%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4-yloxy)piperidine-1-carboxylate (500 mg, 1.26 mmol), 4-methoxy-2-aminopyrimidyl boronate ester (prepared as in Method 8, 630 mg, 2.51 mmol) and Pd(dppf)Cl2—CH2Cl2 (51 mg, 0.063 mmol) in dimethoxyethane and 2 M Na2CO3 (3:1, 12 mL) was heated under microwave irradiation for 15 minutes at 120° C. The reaction mixture was partitioned between EtOAc (200 mL) and Na2CO3(sat.) (50 mL), the organic layer was separated and washed with brine (50 mL). The combined aqueous layers were extracted further with EtOAc (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated. To this material was added 4 M HCl/dioxane (20 mL) to remove the Boc group. After standing for 12 hours, the volatiles were removed in vacuo, and the residue was partitioned between CH2Cl2 (200 mL) and 1N NaOH (50 mL). Upon separating, the aqueous layer was extracted further with CH2Cl2 (200 mL) and then CHCl3 (2×150 mL). The combined organic layers were concentrated yielding 1,6-dihydro-6-methoxy-5-(2-morpholino-6-(piperidin-4-yloxy)pyrimidin-4-yl)pyrimidin-2-amine (464 mg). The crude compound and morpholine (0.9 mL, 10.45 mmol) in NMP (10 mL) were heated under microwave irradiation for 15 minutes at 200° C. to convert the methoxy pyrimidine to the pyrimidone. Additional morpholine (0.9 mL, 10.45 mmol) was added and the solution was heated under microwave irradiation for 15 minutes and than 10 minutes at 200° C. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the bis TFA salt of the 2-amino-5-(2-morpholino-6-(piperidin-4-yloxy)pyrimidin-4-yl)pyrimidin-4(3H)-one was isolated as an off-white solid (325 mg, 45%). LCMS (m/z): 374.1 (MH+). The title compound was prepared by acylation of the secondary amino group as shown in Example 19, step 4. LCMS (m/z): 416.0 (MH+), Rt 1.67.

Workup

  1. customThe reaction mixture was partitioned between EtOAc (200 mL) and Na2CO3(sat.) (50 mL)
  2. customthe organic layer was separated
  3. washwashed with brine (50 mL)
  4. extractionThe combined aqueous layers were extracted further with EtOAc (2×100 mL)
  5. dry with materialthe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. additionTo this material was added 4 M HCl/dioxane (20 mL)
  9. customto remove the Boc group
  10. customthe volatiles were removed in vacuo
  11. customthe residue was partitioned between CH2Cl2 (200 mL) and 1N NaOH (50 mL)
  12. customUpon separating
  13. extractionthe aqueous layer was extracted further with CH2Cl2 (200 mL)
  14. concentrationThe combined organic layers were concentrated

Sources & evidence

ORD record
ord-68d790c6bfa444929bc4a67596534636
Source dataset
uspto-grants-2013_10
Patent number
US08563549B2

Reaction notes

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