Nipecotic Acid → (S)-1-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-piperidine-3-carboxylic acid

HRID 1771936Notes

Reaction equation

HRID 1771936 reaction equation
Cl[C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.Cl.[NH:26]1[CH2:34][CH2:33][CH2:32][C@H:28]([C:29]([OH:31])=[O:30])[CH2:27]1.C(N(C(C)C)CC)(C)C.N1CCCC(C(O)=O)C1.[OH-].[Na+]>O>[C:11]1([C:10]2[C:5]3[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[N:3][C:2]([N:26]4[CH2:34][CH2:33][CH2:32][C@H:28]([C:29]([OH:31])=[O:30])[CH2:27]4)=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

7

Reactant 5

HCID 4498Nipecotic AcidHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 24820453(3S)-piperidine-3-carboxylic acid hydrochlorideHCID 865963692-chloro-5-phenyl-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine

Product 1

HCID 68386813(S)-1-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-piperidine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine (5.9 kg, 16.7 mol) and (S)-nipecotic acid hydrochloride (4.15 kg, 25.1 mol) were dissolved in butyrolnitrile (13.9 kg). An excess of diisopropylethylamine (8.6 kg, 66.9 mol) was added and the mixture heated to 110° C. for 24 to 48 hours to complete reaction. With coupling complete (<2% nipecotic acid remaining), the reaction was cooled to room temperature and water (29 kg) was charged. The mixture pH was adjusted to ˜10 with 25% aqueous sodium hydroxide (4.5 L) and the layers separated. The product aqueous layer was extracted twice with ethyl acetate (15.9 L) then methylene chloride (23.5 kg) was added to the aqueous layer and the pH adjusted to ˜2.5 with concentrated hydrochloric acid (6.3 kg). The layers were separated and the aqueous layer re-extracted with methylene chloride (2×15.7 kg). The methylene chloride layers were combined and washed with water (18 kg) then dried over sodium sulfate (5.9 kg) and product solution was held for processing in next step (Example 16).

Workup

  1. customthe layers separated
  2. extractionThe product aqueous layer was extracted twice with ethyl acetate (15.9 L)
  3. additionmethylene chloride (23.5 kg) was added to the aqueous layer
  4. customThe layers were separated
  5. extractionthe aqueous layer re-extracted with methylene chloride (2×15.7 kg)
  6. washwashed with water (18 kg)
  7. dry with materialthen dried over sodium sulfate (5.9 kg) and product solution

Sources & evidence

ORD record
ord-4f35881f6da24751b8e5798da81c1325
Source dataset
uspto-grants-2016_02
Patent number
US09249155B2

Reaction notes

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