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Chemical Structure| 308348-93-8
Chemical Structure| 308348-93-8
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Product Details of [ 308348-93-8 ]

CAS No. :308348-93-8 MDL No. :MFCD08275693
Formula : C6H7N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :JVHBXKOTWYZYDF-UHFFFAOYSA-N
M.W : 153.14 Pubchem ID :9793866
Synonyms :

Calculated chemistry of [ 308348-93-8 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 37.72
TPSA : 78.1 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.27
Log Po/w (XLOGP3) : -0.32
Log Po/w (WLOGP) : -0.15
Log Po/w (MLOGP) : -0.63
Log Po/w (SILICOS-IT) : 0.02
Consensus Log Po/w : 0.04

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.86
Solubility : 21.2 mg/ml ; 0.138 mol/l
Class : Very soluble
Log S (Ali) : -0.86
Solubility : 21.2 mg/ml ; 0.138 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.35
Solubility : 6.78 mg/ml ; 0.0443 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.41

Safety of [ 308348-93-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 308348-93-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 308348-93-8 ]
  • Downstream synthetic route of [ 308348-93-8 ]

[ 308348-93-8 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 308348-93-8 ]
  • [ 3167-50-8 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: at 60℃;
Stage #2: With hydrogenchloride; water In methanol
Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 ml_) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60 0C overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCI. 2- Aminopyrimidine-5-carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90percent): 1H NMR (DMSO-c/6) δ: 12.73 (1 H, br s), 8.63 (2H, s), 7.44 (2H, br s).
90%
Stage #1: With water; lithium hydroxide In methanol at 60℃;
Stage #2: With hydrogenchloride In water
Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCI. 2-Aminopyrimidine-5- carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90percent): 1 H NMR (DMSO-cfe) δ: 12.73 (1 H, br s), 8.63 (2H, s), 7.44 (2H, br s).
90%
Stage #1: With water; lithium hydroxide In methanol at 60℃;
Stage #2: With hydrogenchloride In water
Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCI. 2-Aminopyrimidine-5- carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90percent): 1 H NMR (DMSO-d6) δ: 12.73 (1 H, br s), 8.63 (2H, s), 7.44 (2H, br s).
Reference: [1] Patent: WO2008/70150, 2008, A1, . Location in patent: Page/Page column 59
[2] Patent: WO2012/62743, 2012, A1, . Location in patent: Page/Page column 57
[3] Patent: WO2012/62745, 2012, A1, . Location in patent: Page/Page column 58
[4] ChemMedChem, 2016, p. 1517 - 1530
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2692 - 2703
  • 2
  • [ 308348-93-8 ]
  • [ 120747-84-4 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With water; lithium hydroxide In methanol at 60℃;
Stage #2: With hydrogenchloride In methanol; water
Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCI. 2- Aminopyrimidine-5-carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90percent): 1 H NMR (DMSO-cfe) δ: 12.73 (1 H, br s), 8.63 (2H, s), 7.44 (2H, br s).
Reference: [1] Patent: WO2012/62748, 2012, A1, . Location in patent: Page/Page column 53-54
  • 3
  • [ 308348-93-8 ]
  • [ 287714-35-6 ]
YieldReaction ConditionsOperation in experiment
44.4%
Stage #1: With hydrogenchloride; zinc(II) chloride In dichloromethane at 5 - 20℃; for 0.5 h;
Stage #2: at 5 - 10℃; for 2 h;
Step 3a. 2-Chloro-pyrimidine-5-carboxylic acid methyl ester (compound 1001-7) The above intermediate (7 g, 0.046 mol) was added to a mixture of concentrated hydrochloric acid (15.2 mL) and CH2Cl2(60 mL). After cooling, ZnCl2 (18.6 g, 0.138 mol) was added at 15-20° C. The mixture was stirred at 15-20° C. for 0.5 h and cooled to 5-10° C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internal temperature 5-10° C. The reaction was continued for 2 h. The reaction mixture was poured into ice-water (50 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×2). The combined organic extracts were concentrated to afford crude product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60° C. for 30 minutes and filtered. The filtrate was concentrated to afford the titled compound 1001-7 (3.5 g, 44.4percent) as an off-white solid. LCMS: m/z 214.1 [M+42]+. 1HNMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 9.15 (s, 2H
44.4%
Stage #1: With hydrogenchloride; zinc(II) chloride In dichloromethane; water at 15 - 20℃; for 0.5 h; Cooling
Stage #2: With sodium nitrite In dichloromethane; water at 5 - 10℃; for 2 h;
Step g:
Methyl 2-chloropyrimidine-5-carboxylate (Compound R-2-2)
Compound 207 (7 g, 0.046 mol) was added to a mixture of concentrated hydrochloric acid (15.2 mL) and CH2Cl2 (60 mL).
After cooling, ZnCl2 (18.6 g, 0.138 mol) was added at 15-20° C.
The mixture was stirred at 15-20° C. for 0.5 h and cooled to 5-10° C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internal temperature 5-10° C.
The reaction was continued for ˜2 h.
The reaction mixture was poured into ice-water (50 mL).
The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL*2).
The combined organic extracts were concentrated to afford crude product (4.2 g).
The crude compound was suspended in hexane (20 mL), heated at 60° C. for 30 minutes and filtered.
The filtrate was concentrated to afford the title compound R-2-2 (3.5 g, 44.4percent) as an off-white solid. LCMS (m/z): 214.1[M+42]+. 1HNMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 9.15 (s, 2H).
44.4%
Stage #1: With hydrogenchloride; zinc(II) chloride In dichloromethane; water at 15 - 20℃; for 0.5 h;
Stage #2: With sodium nitrite In dichloromethane at 5 - 10℃; for 2 h;
Compound 207 (7 g, 0.046 mol) was added to a mixture of concentratedhydrochloric acid (15.2 mL) and CH2C12(60 mL). After cooling, ZnC12 (18.6 g, 0.138mol) was added at 15-20 °C. The mixture was stirred at 15-20 °C for 0.5 h and cooled to 5-10 °C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internaltemperature 5-10 °C. The reaction was continued for 2 h. The reaction mixture was poured into ice-water (50 mL). The organic layer was separated and the aqueous phase was extracted with CH2C12 (30 nL*2) The combined organic extracts were concentrated to afford cmde product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60 °C for 30 minutes and filtered. The filtrate was concentrated to afford the title compound R-2-2 (3.5 g, 44.4 percent) as an off-white solid. LCMS (m/z): 214.1[M+42f. ‘H1’MR (400 MHz, CDC13): ö 4.00 (s, 3H), 9.15 (s, 2H).
Reference: [1] Patent: US2014/18368, 2014, A1, . Location in patent: Paragraph 0162; 0179
[2] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 35
[3] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 28; 29
  • 4
  • [ 67-56-1 ]
  • [ 7752-82-1 ]
  • [ 201230-82-2 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
71% With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 120℃; To a solution of 2-amino pyridine (30 g, 0.31 mol) in DME (120 mL) was added chloro acetone (40.5 mL, 0.47 mol) at room temperature. The reaction mixture was heated to reflux, and then stirred for 48 hours. The volatiles were concentrated under reduced pressure. Then the residue was purified by column chromatography eluting with 1percent MeOH/DCM to afford Int-2 (20 g, 48percent) as a liquid. Mass (m/z): 133 [M++1]. 1H NMR (200 MHz, dmso-d6): δ8.05 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 7.1 (t, J=6.8 Hz, 1H), 6.7 (t, J=6.8 Hz, 1H), 6.5 (d, J=8.2 Hz, 1H), 2.45 (s, 3H). To a solution of Int-2 (10 g, 76.7 mmol) in acetonitrile (50 mL) was added N-iodo succinamide (20.4 g, 80 mmol) portion wise at room temperature and then stirred for 48 hours. The precipitated solid was filtered off. The crude material was re-crystallized from ethyl acetate/water to afford Int-3 (9 g, 49percent) as solid. Mass (m/z): 259 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 8.22 (d, J=8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.29 (t, J=7.0 Hz, 1H), 2.35 (s, 3H). To a solution of Int-3 (6.0 g, 29.2 mmol) in IPA-H2O (75 mL, 2:1) was added PdCl2(dppf).DCM (4.7 g, 5.8 mmol), followed by the addition of tert-butyl amine (3.1 g, 43.8 mmol) at room temperature and the resulting reaction mixture was degassed for 15 minutes. Then Int-4 (2.9 g, 18.6 mmol) was added to the reaction mixture at room temperature. The reaction mixture was heated to 100° C. and then stirred for 16 hours. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (3.x.100 mL), washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 1percent MeOH/DCM to afford Int-5 (1.6 g, 28percent). Mass (m/z): 244 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 8.51 (t, J=5 Hz, 2H), 7.71 (s, 1H), 7.63-7.55 (m, 2H), 7.34 (t, J=7 Hz, 1H), 6.94 (t, J=7 Hz, 1H), 2.43 (s, 3H). To a stirred mixture of 5-bromo 2-aminopyrimidine (8 g, 45.97 mmol) in MeOH-CH3CN (200 mL) in a steel bomb were added Pd(CH3CN)2Cl (2.38 g, 9.19 mmol), racemic-BINAP (5.7 g, 9.19 mmol), DIPEA (10.4 mL, 53.7 mmol) at room temperature and then closed the steel vessel tightly. Then CO gas (100 psi) was purged into the steel bomb and the stirring was continued at 120° C. for 45 hours. The reaction mixture was allowed to room temperature. The reaction mixture was filtered through a pad of celite. The celite pad was washed with excess of methanol and the filtrate was concentrated under vacuum. The crude material was purified by column chromatography eluting with 0.75percent MeOH/DCM to afford Int-6 (5 g, 71percent) as solid. Mass (m/z): 154 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 8.65 (s, 3H), 7.49 (brs, 2H), 3.58 (s, 3H) To a stirred mixture of Int-5 (3 g, 2.34 mmol) and Int-6 (1.8 g, 12.34 mmol) in 1,4-dioxane (90 mL) were added Pd(OAc)2 (279 mg, 1.23 mmol) and Xanthpos (710 mg, 1.23 mmol) followed by cesium carbonate (6 g, 18.5 mmol) at room temperature. The resulting mixture was degassed and stirred at reflux temperature for 30 hours. The reaction mixture was cooled to room temperature and then stirred for 15 minutes. The precipitated solids were filtered off, washed with water (2.x.10 mL) and dried under vacuum. The crude material was purified by column chromatography eluting with 1.5percent MeOH/DCM to afford Int-7 (0.6 g, 13.6percent) as solid. Mass (m/z): 361.2 [M++1]. 1H NMR (500 MHz, dmso-d6): δ 10.76 (brs, 1H), 8.97 (s, 2H), 8.56 (d, J=7, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 7.58 (d, J=9.5 Hz 1H), 7.34-7.29 (m, 2H), 6.99 (t, J=76 Hz, 1H), 3.84 (s, 3H), 2.46 (s, 3H). To a stirred solution of Int-7 (0.5 g, 1.38 mmol) in MeOH-CH3CN (1:2, 25 mL) was added aqueous NH2OH solution (15 mL) at 0° C. After being stirred for 20 minutes at the same temperature, NaOH (0.44 g, 11.10 mmol) in water (1 mL) was added drop wise to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 days. The volatiles were concentrated under vacuum and the obtained residue was diluted with water and neutralized to about pH 7 with 2 N HCl at 0° C. The precipitated solids were filtered off, washed with water (2.x.10 mL) and dried under vacuum to afford the title compound (0.4 g, 80percent) as off-white solid. Mass (m/z): 362.1 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 11.2 (bs, 1H), 10.5 (s, 1H), 9.12 (bs, 1H), 8.84 (s, 2H), 8.57 (d, J=7.0 Hz, 1H), 8.45 (d, J=5.0 Hz, 1H), 8.38 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.25 (d, J=4.0 Hz, 1H), 6.98 (d, J=7.0 Hz, 1H), 2.49 (s, 3H). 13C NMR (125 MHz, dmso-d6): δ 160.7, 157.1, 153.0, 148.7, 144.5, 142.3, 137.9, 125.2, 123.9, 118.8, 118.2, 117.0, 116.6, 112.7, 112.4, 14.3.
Reference: [1] Patent: US2010/29638, 2010, A1, . Location in patent: Page/Page column 123-124
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2692 - 2703
  • 5
  • [ 50-01-1 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
61.5% at 100℃; for 1 h; Step f:
2-Amino-pyrimidine-5-carboxylic acid methyl ester (Compound 207)
To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300 mL) was added compound 206 (80 g, 0.40 mol).
The resulting mixture was heated at 100° C. for 1 h.
The reaction mixture was filtered before cooled.
The filter cake was washed with 50 mL of DMF and the combined filtrate was concentrated to leave a residue which was suspended in cold EtOH and washed with cold EtOH (50 mL) to afford the compound 207 (38 g, 61.5percent) as a yellow solid. LCMS (m/z): 154.2 [M+1]+, 195.1[M+42]+. 1H NMR (400 MHz, CD3OD): δ 3.88 (s, 3H), 8.77 (s, 2H).
61.5% at 100℃; for 1 h; To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300 mL) was added compound 206 (80 g, 0.40 mol). The resulting mixture was heated at 100 °C for 1 h.The reaction mixture was filtered before cooled. The filter cake was washed with 50 mLof DMF and the combined filtrate was concentrated to leave a residue which wassuspended in cold EtOH and washed with cold EtOH (50 mL) to afford the compound 207(38 g, 61.5percent) as a yellow solid. LCMS (m/z): 154.2 [M+if, i95.i[M+42f. ‘HNMR(400 MHz, CD3OD): ö 3.88 (s, 3H), 8.77 (s, 2H).
50% at 100℃; for 1 h; Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37 g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 0C for 1 h, then was cooled to rt and diluted with water. Methyl 2-aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1H NMR (DMSO-Gf6) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).
50% at 100℃; for 1 h; Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37 g, 7.8 mmol) was diluted in DM F (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 °C for 1 h, then was cooled to rt and diluted with water. Methyl 2-aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1 H NMR (DMSO-cfe) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H
50% at 100℃; for 1 h; Preparation of 2-aminopyrimidine-5-carboxylicSodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1 -olate was prepared as described by Zhichkin (Zhichkin et a/., 2002).Sodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1 -olate (1.37 g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 °C for 1 h, then was cooled to rt and diluted with water. Methyl 2- aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1H NM (DMSO-cfe) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).
50% at 100℃; for 1 h; Intermediate APreparation of 2-aminopyrimidine-5-carboxylic acidSodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1-olate was prepared as described by Zhichkin (Zhichkin et al., 2002).Sodium (1 Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1 -en-1 -olate (1.37 g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride (640 mg, 6.7 mmol) was added. The mixture was stirred at 100 °C for 1 h, then was cooled to rt and diluted with water. Methyl 2- aminopyrimidine-5-carboxylate precipitated as a light yellow solid, which was isolated by vacuum filtration (510 mg, 50percent): 1H NMR (DMSO-cfe) δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCI. 2-Aminopyrimidine-5- carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90percent): 1 H NMR (DMSO-d6) δ: 12.73 (1 H, br s), 8.63 (2H, s), 7.44 (2H, br s).
63 g at 100℃; for 3 h; Inert atmosphere The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 1 00 °C under N2 for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 percent yield for 2 steps).

Reference: [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 35
[2] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 28
[3] Patent: WO2008/70150, 2008, A1, . Location in patent: Page/Page column 59
[4] Patent: WO2012/62748, 2012, A1, . Location in patent: Page/Page column 53
[5] Patent: WO2012/62743, 2012, A1, . Location in patent: Page/Page column 57
[6] Patent: WO2012/62745, 2012, A1, . Location in patent: Page/Page column 58
[7] ChemMedChem, 2016, p. 1517 - 1530
[8] Patent: WO2013/127266, 2013, A1, . Location in patent: Page/Page column 131
[9] Patent: WO2013/130943, 2013, A1, . Location in patent: Paragraph 0183
  • 6
  • [ 7424-91-1 ]
  • [ 107-31-3 ]
  • [ 50-01-1 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 50℃; for 4 h;
Stage #2: at 100℃; for 3 h; Inert atmosphere
Methyl 3,3-dimethoxypropanoate ( 1 00 g, 675 mmol) and methyl formate (8 1 g, 1 350 mmol) were dissolved in anhydrous THF (450 mL). Sodium hydride (60percent dispersion; 32.4 g, 8 1 0 mmol, 1 .2 eq.) was then added slowly in portions at 0 °C. The reaction mixture was stirred at rt for 1 h, then was heated at 50 °C for 3 h. During this period, H2 evolution was observed. After cooling to rt, the solvent was then removed under reduced pressure to give the crude product which was directly used in the next step without further purification. The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 1 00 °C under Ni for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 percent yield for 2 steps).
61%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 50℃; for 4 h;
Stage #2: at 100℃; for 3 h; Inert atmosphere
Methyl 3,3-dimethoxypropanoate ( 1 00 g, 675 mmol) and methyl formate (8 1 g, 1 350 mmol) were dissolved in anhydrous THF (450 mL). Sodium hydride (60percent dispersion; 32.4 g, 8 1 0 mmol, 1 .2 eq.) was then added slowly in portions at 0 °C. The reaction mixture was stirred at rt for 1 h, then was heated at 50 °C for 3 h. During this period, H2 evolution was observed. After cooling to rt, the solvent was then removed under reduced pressure to give the crude product which was directly used in the next step without further purification. The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 1 00 °C under N2 for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 percent yield for 2 steps).
Reference: [1] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 82
[2] Patent: WO2013/127268, 2013, A1, . Location in patent: Page/Page column 60
  • 7
  • [ 50-01-1 ]
  • [ 308348-93-8 ]
YieldReaction ConditionsOperation in experiment
30% at 100℃; for 1 h; Synthesized by the method described in Synthesis, 2002,6,720; 3,3-dimethoxy-2-methoxy-carbonyl-propen-1-ol sodium salt (3.0g) and guanidine hydrochloride was dissolved in DMF (24mL). The mixture was stirred for 1 hour at 100°C. After cooling to room temperature,Was filtered off and water was added to the precipitated solid,After drying under reduced pressure,To give the title compound 720mg (30percent).
Reference: [1] Patent: JP5851663, 2016, B1, . Location in patent: Paragraph 0171
  • 8
  • [ 308348-93-8 ]
  • [ 1032568-63-0 ]
Reference: [1] ChemMedChem, 2016, p. 1517 - 1530
  • 9
  • [ 308348-93-8 ]
  • [ 944896-64-4 ]
Reference: [1] Patent: WO2013/127266, 2013, A1,
[2] Patent: WO2013/127267, 2013, A1,
[3] Patent: WO2013/127269, 2013, A1,
[4] Patent: WO2013/127268, 2013, A1,
[5] Patent: WO2013/130935, 2013, A1,
[6] Patent: WO2013/130943, 2013, A1,
  • 10
  • [ 308348-93-8 ]
  • [ 1339928-25-4 ]
Reference: [1] Patent: US9249156, 2016, B2,
[2] Patent: WO2018/85342, 2018, A1,
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[ 308348-93-8 ]

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Chemical Structure| 57401-76-0

[ 57401-76-0 ]

Ethyl 2-aminopyrimidine-5-carboxylate

Similarity: 0.97

Chemical Structure| 15400-53-0

[ 15400-53-0 ]

Ethyl 2-amino-4-hydroxypyrimidine-5-carboxylate

Similarity: 0.86

Chemical Structure| 81633-29-6

[ 81633-29-6 ]

Ethyl 2-amino-4-methylpyrimidine-5-carboxylate

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Chemical Structure| 15400-54-1

[ 15400-54-1 ]

Ethyl 2,4-diaminopyrimidine-5-carboxylate

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Chemical Structure| 4774-35-0

[ 4774-35-0 ]

Methyl 4-hydroxypyrimidine-5-carboxylate

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Amines

Chemical Structure| 57401-76-0

[ 57401-76-0 ]

Ethyl 2-aminopyrimidine-5-carboxylate

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Chemical Structure| 3167-50-8

[ 3167-50-8 ]

2-Aminopyrimidine-5-carboxylic acid

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Chemical Structure| 15400-53-0

[ 15400-53-0 ]

Ethyl 2-amino-4-hydroxypyrimidine-5-carboxylate

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Chemical Structure| 81633-29-6

[ 81633-29-6 ]

Ethyl 2-amino-4-methylpyrimidine-5-carboxylate

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Chemical Structure| 5388-21-6

[ 5388-21-6 ]

2-(Methylamino)pyrimidine-5-carboxylic acid

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Related Parent Nucleus of
[ 308348-93-8 ]

Pyrimidines

Chemical Structure| 57401-76-0

[ 57401-76-0 ]

Ethyl 2-aminopyrimidine-5-carboxylate

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Chemical Structure| 3167-50-8

[ 3167-50-8 ]

2-Aminopyrimidine-5-carboxylic acid

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Chemical Structure| 15400-53-0

[ 15400-53-0 ]

Ethyl 2-amino-4-hydroxypyrimidine-5-carboxylate

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Chemical Structure| 81633-29-6

[ 81633-29-6 ]

Ethyl 2-amino-4-methylpyrimidine-5-carboxylate

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Chemical Structure| 5388-21-6

[ 5388-21-6 ]

2-(Methylamino)pyrimidine-5-carboxylic acid

Similarity: 0.85