Home Cart 0 Sign in  
X

[ CAS No. 2032-35-1 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
3d Animation Molecule Structure of 2032-35-1
Chemical Structure| 2032-35-1
Chemical Structure| 2032-35-1
Structure of 2032-35-1 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 2032-35-1 ]

Related Doc. of [ 2032-35-1 ]

Alternatived Products of [ 2032-35-1 ]

Product Details of [ 2032-35-1 ]

CAS No. :2032-35-1 MDL No. :MFCD00000214
Formula : C6H13BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :LILXDMFJXYAKMK-UHFFFAOYSA-N
M.W : 197.07 Pubchem ID :74852
Synonyms :

Calculated chemistry of [ 2032-35-1 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 5
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.0
TPSA : 18.46 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.56
Log Po/w (XLOGP3) : 1.59
Log Po/w (WLOGP) : 1.78
Log Po/w (MLOGP) : 1.53
Log Po/w (SILICOS-IT) : 1.56
Consensus Log Po/w : 1.8

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.73
Solubility : 3.64 mg/ml ; 0.0185 mol/l
Class : Very soluble
Log S (Ali) : -1.59
Solubility : 5.08 mg/ml ; 0.0258 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.25
Solubility : 1.1 mg/ml ; 0.00556 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.87

Safety of [ 2032-35-1 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P260-P264-P271-P302+P352-P304+P340+P310-P305+P351+P338 UN#:2810
Hazard Statements:H301-H315-H319-H330 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 2032-35-1 ]

* 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 [ 2032-35-1 ]
  • Downstream synthetic route of [ 2032-35-1 ]

[ 2032-35-1 ] Synthesis Path-Upstream   1~69

  • 1
  • [ 90-02-8 ]
  • [ 2032-35-1 ]
  • [ 4265-16-1 ]
Reference: [1] Patent: US4528282, 1985, A,
  • 2
  • [ 107-21-1 ]
  • [ 2032-35-1 ]
  • [ 4360-63-8 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 14, p. 1825 - 1836
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 3781,3786
[3] DRP/DRBP Org.Chem.,
[4] Patent: DE825416, 1951, ,
[5] DRP/DRBP Org.Chem.,
[6] Patent: DE825416, 1951, ,
  • 3
  • [ 2032-35-1 ]
  • [ 4360-63-8 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 1071 - 1074
  • 4
  • [ 106-45-6 ]
  • [ 2032-35-1 ]
  • [ 14315-14-1 ]
YieldReaction ConditionsOperation in experiment
2.77 g
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 15 h;
Stage #2: at 175℃; for 0.75 h;
12116] Step 112117] A mixture of 5.2 g ofbromoacetaldehyde diethylacetal and 10 ml of tetrahydrofuran was added to a mixture of 4.00 g of 4-methylbenzenethiol, 1.4 g of 60percent sodium hydride, and 35 ml of tetrahydroffiran. The reaction mixture was stirred for 15 hours at room temperature. Ten (10) ml of aqueous saturated ammonium chloride solution was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were added to a mixture of 5 g of diphosphorus pentoxide and lOg ofphosphoric acid that had been stirred for 45 minutes at 175° C., and the residue was stirred for 5 minutes. The reaction mixture was poured into ice water, and extraction was performed three times by using tert-butyl methyl ethet The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel colunm chromatography, thereby obtaining 2.77 g of 5-methylbenzo[b] thiophene
Reference: [1] Patent: US2015/282482, 2015, A1, . Location in patent: Paragraph 2116; 2117
  • 5
  • [ 110-91-8 ]
  • [ 2032-35-1 ]
  • [ 3616-59-9 ]
YieldReaction ConditionsOperation in experiment
56% at 120℃; for 16 h; Example 28 - Preparation of Cmpd 23; [0206] A useful scheme for the preparation of compounds of the type of Cmpd 23 is provided in Scheme 2 following. Scheme 2Intermediate 7 Intermediate 8Cmpd 23 Intermediate 9[0207] A detailed description of the preparation of Intermediates 7-9 and Cmpd 23 follows. Preparation of Intermediate 7Intermediate 7[0208] A mixture of 2-bromoacetaldehyde diethyl acetal (4.5 g, 22.9 mmol), morpholine (2.0 g, 22.9 mmol) and K2C03 (6.34 g, 45.9 mmol, 2 eq) was stirred at 120 °C for 16 h. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The organic layer was washed with saturated aqueous NaHC03 (50 mL), brine (50 mL), dried over Na2S04, filtered and concentrated to get crude a residue. The crude compound was purified by column chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-50percent EtOAc-hexane as the eluent to afford Intermediate 7 (2.6 g, 56percent) as a pale yellow liquid. 1H NMR: (CDC13) δ 4.64 (t, J= 5.3 Hz, 1H), 3.63-3.70 (m, 6H), 3.50-3.58 (m, 2H), 2.52-2.55 (m, 6H), 1.20 (t, J= 7.0 Hz, 6H); TLC: 60percent EtOAc in hexane: Rf: 0.50.
56% at 120℃; for 16 h; A mixture of 2-bromoacetaldehyde diethyl acetal (4.5 g, 22.9 mmol), morpholine (2.0 g, 22.9 mmol) and K2CO3 (6.34 g, 45.9 mmol, 2 eq) was stirred at 120°C. for 16 h. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with DCM (350 mL). The organic layer was washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to get crude a residue. The crude compound was purified by column chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-50percent EtOAc-hexane as the eluent to afford Intermediate 7 (2.6 g, 56percent) as a pale yellow liquid. 1H NMR: (CDCl3) δ 4.64 (t, J=5.3 Hz, 1H), 3.63-3.70 (m, 6H), 3.50-3.58 (m, 2H), 2.52-2.55 (m, 6H), 1.20 (t, J=7.0 Hz, 6H); TLC: 60percent EtOAcin hexane: Rf: 0.50.
14% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 5 h; Synthesis of compound 62.2. Morpholine (2.0g, 2.19mmol, l .Oeq), bromoacetaldehyde diethyl acetal (4.5g, 2.54mmol, 1.16eq) and dry K2CO3 (6.04g, 4.38mmol, 2.0 eq) were mixed in dry dimethylformamide and heated at 120 °C for 5h. After completion of reaction, reaction mixture was diluted with ethyl acetate (200ml) and washed with water (200ml x2) and then with brine (100ml). Organic layer was dried over sodium sulphate and concentrated under reduced pressure at 45°C. Crude was purified by column chromatography to afford compound 62.2 (0.650g, 14percent). 1H NMR (400 MHz, CDC13): δ 4.660-4.686 (t, 1H), 3.686-3.738 (m, 6H), 3.528-3.3.581 (m, 2H), 3.554-3.577 (t, 6H), 1.216-1.252 (t, 6H).
Reference: [1] Patent: WO2011/126903, 2011, A2, . Location in patent: Page/Page column 78
[2] Patent: US2017/326125, 2017, A1, . Location in patent: Paragraph 0297-0298
[3] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00472; 00473
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1959, vol. 248, p. 2015
[5] Organic and Biomolecular Chemistry, 2011, vol. 9, # 17, p. 5930 - 5933
  • 6
  • [ 6320-01-0 ]
  • [ 2032-35-1 ]
  • [ 17347-32-9 ]
  • [ 5118-13-8 ]
Reference: [1] Patent: US6664274, 2003, B1, . Location in patent: Page column 23; 24
  • 7
  • [ 6320-02-1 ]
  • [ 2032-35-1 ]
  • [ 1423-61-6 ]
Reference: [1] Synlett, 2004, # 8, p. 1351 - 1354
  • 8
  • [ 6320-01-0 ]
  • [ 2032-35-1 ]
  • [ 17347-32-9 ]
  • [ 5118-13-8 ]
Reference: [1] Patent: US6664274, 2003, B1, . Location in patent: Page column 23; 24
  • 9
  • [ 15570-12-4 ]
  • [ 2032-35-1 ]
  • [ 90560-10-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 7, p. 1399 - 1401
[2] Patent: EP2103620, 2009, A1, . Location in patent: Page/Page column 72-73
  • 10
  • [ 15570-12-4 ]
  • [ 96803-85-9 ]
  • [ 2032-35-1 ]
  • [ 90560-10-4 ]
YieldReaction ConditionsOperation in experiment
63% With methanesulfonic acid; trifluoroborane diethyl ether; sodium hydrogencarbonate; potassium carbonate; triethylamine In hexane; dichloromethane; acetone Example (1a)
6-methoxybenzo[b]thiophene
A mixture of 3-methoxybenzenethiol (10 ml, 11.30 g, 80 mmole), K2CO3 (11.15 g, 80 mmole) and bromoacetaldehyde diethyl acetal (12 ml, 15.72 g, 80 mmole) in acetone (100 ml) was stirred at ambient temperature for 16 hours, then filtered.
The filtrate was subsequently concentrated, in vacuo.
The residue obtained was partitioned between H2O (150 ml) and Et2O (150 ml).
The layers were separated and the aqueous phase was extracted with Et2O (150 ml).
The combined organic extracts were washed with 0.5 M KOH (aq), H2O and brine, then dried over Na2SO4 and concentrated, in vacuo, to give 20.4 g of an amber oil which was used directly in the subsequent cyclization without any further purification.
Method A: A solution of this crude 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (6.41 g, 25 mmole) in CH2Cl2 (50 ml) was added, dropwise, to a solution of boron trifluoride etherate (3.4 ml, 3.81 g, 27 mmole) in CH2Cl2 (500 ml).
The resultant solution was stirred at ambient temperature for an additional 30 minutes.
Aqueous saturated NaHCO3 (200 ml) was added and the two-phase mixture was stirred for another hour.
The layers were separated and the aqueous phase was extracted with CH2Cl2 (150 ml).
The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.3 g of a red oil which was purified by silica gel chromatography.
Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 1.62 g (39percent) of a colourless oil.
Method B: A solution of the crude 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (8.27 g, 32.3 mmole) in hexane (100 ml) was added, dropwise, to a solution of methanesulfonic acid (1.05 ml, 1.55 g, 16.1 mmole) in hexane (1000 ml) containing 16.5 g of celite (2 wt. eq.).
The resultant solution was heated at reflux for one hour.
After cooling to room temperature, the reaction was quenched by addition of Et3N (4.5 ml, 3.26 g, 32.3 mmole).
The crude reaction mixture was filtered and the filtrate was concentrated, in vacuo, to give a red oil which was purified by silica gel chromatography.
Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.35 g (63percent) of a colorless oil. 1H NMR (DMSO-d6) δ7.74 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.3 Hz), 7.52 (1H, d, J=5.3 Hz) 7.33 (1H, d, J=5.3 Hz), 6.99 (1H, dd, J=2.3, 8.7 Hz), 3.81 (3H, s). Anal. Calcd. for C9H8OS: C, 65.82; H, 4.91; S, 19.53. Found: C, 66.01; H, 5.00; S, 19.40.
Reference: [1] Patent: US2004/9965, 2004, A1,
  • 11
  • [ 4214-76-0 ]
  • [ 2032-35-1 ]
  • [ 25045-82-3 ]
YieldReaction ConditionsOperation in experiment
77.6%
Stage #1: With hydrogenchloride In ethanol at 20℃; Reflux
Stage #2: at 20℃;
In a 250 mL single-necked flask, bromoacetaldehyde diethyl acetal (42.5 g, 215.7 mmol) was dissolved in 1 mol / L HCL(120 mL) and ethanol (20 mL), stirred at room temperature for 30 min, heated to reflux, stirred until the solution was clear, cooled to room temperature,Add NaHCO3 adjusted to near neutral,2-Amino-5-nitropyridine (15.0 g, 107.8 mmol) was added and reacted at room temperatureovernight. The reaction was completed, extracted with ethyl acetate (100mL × 3), the organic phase was collected and the solvent was evaporated to dryness under reduced pressure. The residue was passed through a silica gel column (PE:EA = 2: 1) to give 13.7 g of 6-nitroimidazo [1,2-a] pyridine yellow-brown crystals in a yield of 77.6percent.
Reference: [1] Patent: CN107129496, 2017, A, . Location in patent: Paragraph 0026-0028; 0014-0016; 0020-0022
  • 12
  • [ 1074-82-4 ]
  • [ 2032-35-1 ]
  • [ 78902-09-7 ]
YieldReaction ConditionsOperation in experiment
70% With cetyltributylphosphonium bromide In toluene at 111℃; for 24 h; Inert atmosphere Potassium phthalimide (5 g,26.5mmol), bromoacetal (4.1 mL, 26.5mmol), and hexadecyltributylphosphoniumbromide (13.8 g, 26.5mmol) wereheated together in toluene (200mL) for 24 h at 111 °C under N2 atmosphere.The product was then filtered, and the filtratewas concentrated on a rotary evaporator to give yellow oil.Column chromatography using hexane : ether (1 : 1) allowedobtaining the desired compound. Yield 70percent; Elementalanalysis calculated for C14H17NO4 (263.29): C 63.8, H 6.4, N 5.3; found: C 64.6, H 6.5, N 5.3. 1H NMR (300MHz,CDCl3): δ7.8–7.6 (m, 4H), 4.79 (t, 1H), 3.75 (d, 2H), 3.62–3.42 (m, 4H), 1.06 (t, 6H). ES-MS: m/z 264. IR: ν(C-O-C)2800, ](C=O) 1721 cm−1.
64% at 150℃; for 4 h; intermediate 395 H-Isoindole- l ,3(2H)-dionc, potassium salt (1 : 1) (50 g, 221.9 mmol ) and 2-bromo- 1 , 1 - diethoxy-ethane (54.7 g, 277.4 mmol ) in DMF were stirred at 1 50 °C for 4 hours. The DMF was removed under reduced pressure. The residue was purified by column chromatography (elution: petroleum ether/ ethyl acetate ratio 5/ 1 ) to afford intermediate 395 (40 g, yield: 64percent) as a white solid.
Reference: [1] Russian Journal of General Chemistry, 2007, vol. 77, # 1, p. 98 - 102
[2] Journal of Chemistry, 2015, vol. 2015,
[3] Patent: WO2017/32840, 2017, A1, . Location in patent: Page/Page column 264; 265
[4] Journal of Pharmacy and Pharmacology, 1952, vol. 4, p. 693,705
  • 13
  • [ 136918-14-4 ]
  • [ 2032-35-1 ]
  • [ 78902-09-7 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 10, p. 747 - 751
  • 14
  • [ 504-02-9 ]
  • [ 2032-35-1 ]
  • [ 16806-93-2 ]
Reference: [1] Synthetic Communications, 1986, vol. 16, # 13, p. 1635 - 1640
  • 15
  • [ 2032-35-1 ]
  • [ 2678-54-8 ]
YieldReaction ConditionsOperation in experiment
72% for 0.1 - 0.183333 h; Cooling with ice Preparation B
1,1-diethoxyethene
The equipment set-up is as follows:
a 50-ml flask provided with a distillation set (column ˜20 cm; condenser ˜20 cm, distillation thermometer).
20 g of 2-bromo-1,1-diethoxyethane (101.25 mmol) are quickly added (1 minute) to potassium tert-butoxide (102 mmol; 11.4 g) cooled in an ice bath.
Very dense white smoke is formed.
When the reaction is complete (5-10 minutes), the reaction mixture is heated to 120-130° C. (hot-plate reading), and the tert-butanol generated during the reaction is distilled off at atmospheric pressure.
When all the tert-butanol has been distilled off, a water-jet pump is connected to the distillation set.
In this way, the expected product is distilled off in vacuo in a few seconds.
8.5 g of a colourless liquid containing traces of tert-butanol are obtained.
Yield=72percent
1H NMR (CDCl3): δ=3.78 (q; 4H); 3.03 (s; 2H); 1.25 (t; 6H).
59% With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at -10℃; for 12 h; -10 ° C, 2-Bromo-1,1-diethoxyethane(1-1) (50 mL, 0.32 mol M || l-At-BuOK (80 g, 1.02 mol) and 18-C-6 THF (500 mL) was added dropwise. After the addition was completed, the reaction was incubated for 12 hours. The THF was removed by distillation under atmospheric pressure and the residue was distilled off under reduced pressure to obtain 22 g of 1,1-diethoxyethylene (1-2) as a colorless oil. Yield 59percent.
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1989, vol. 59, # 10.2, p. 2055 - 2060[2] Zhurnal Obshchei Khimii, 1989, vol. 59, # 10, p. 2293 - 2299
[3] Patent: US8859763, 2014, B1, . Location in patent: Page/Page column 5; 6
[4] Patent: CN104496857, 2016, B, . Location in patent: Paragraph 0179; 0182-0184
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3618 - 3625
[6] Journal of the American Chemical Society, 1936, vol. 58, p. 531
[7] Journal of the American Chemical Society, 1940, vol. 62, p. 964,968, 971
[8] Canadian Journal of Chemistry, 2000, vol. 78, # 9, p. 1194 - 1203
[9] Journal of Medicinal Chemistry, 2000, vol. 43, # 5, p. 829 - 842
[10] Journal of the American Chemical Society, 1936, vol. 58, p. 531
[11] Org.Synth.Coll.Vol.III&lt;1955&gt;506,
  • 16
  • [ 2032-35-1 ]
  • [ 67856-69-3 ]
  • [ 645-36-3 ]
Reference: [1] Journal of the American Chemical Society, 1929, vol. 51, p. 3613
[2] Journal of the American Chemical Society, 1927, vol. 49, p. 2518
[3] Chemische Berichte, 1929, vol. 62, p. 1314
  • 17
  • [ 2032-35-1 ]
  • [ 625-77-4 ]
  • [ 645-36-3 ]
Reference: [1] Journal of the American Chemical Society, 1929, vol. 51, p. 3613
[2] Journal of the American Chemical Society, 1927, vol. 49, p. 2518
  • 18
  • [ 2032-35-1 ]
  • [ 645-36-3 ]
Reference: [1] Chemische Berichte, 1929, vol. 62, p. 1314
[2] Journal of the American Chemical Society, 1942, vol. 64, p. 785
[3] Organic Syntheses, 1944, vol. 24, p. 3
  • 19
  • [ 7664-41-7 ]
  • [ 2032-35-1 ]
  • [ 67856-69-3 ]
  • [ 645-36-3 ]
Reference: [1] Journal of the American Chemical Society, 1929, vol. 51, p. 3613
[2] Chemische Berichte, 1929, vol. 62, p. 1314
  • 20
  • [ 100643-27-4 ]
  • [ 2032-35-1 ]
  • [ 7355-55-7 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With hydrogenchloride In water at 90℃; for 0.5 h;
Stage #2: With sodium acetate In water at 0 - 80℃; for 3.5 h;
To a suspension of bromoacetaldehyde diethyl acetal (10.4 mL,68.98 mmol) in water (35 mL) was added concentrated hydrochloric acid (1.5 mL). The reaction mixture was stirred at 90 °C. After 30 min,the solution was cooled to room temperature, and sodium acetate(6.8 g, 82.75 mmol) was added. The mixture solution was added to a suspension of 2,6-diamino-4-pyrimidinone (10.0 g, 79.29 mmol) and sodium acetate (3.5 g, 42.82 mmol) in water (75 mL). The reaction mixture was stirred at 80 °C. After 2 h, the mixture was stirred at 0 °Cfor 90 min. The precipitate was filtered off, and washed with a little amount of cold water and acetone to afford the title product (11.9 g,quantitative yield); 1H NMR (300 MHz, DMSO‑d6) δ 10.97 (s, 1H),10.23 (s, 1H), 6.61–6.60 (m, 1H), 6.18–6.17 (m, 1H), 6.05 (s, 2H).
74%
Stage #1: With hydrogenchloride In water at 90℃; for 0.5 h;
Stage #2: With sodium acetate In water at 0 - 80℃; for 3.5 h;
Step one: After adding Sm-1 (27.3 g, 138 mmol) to 70 mL of water, an additional 3.0 mL of concentrated hydrochloric acid was added and stirred at 90 ° C for 0.5 h. After cooling to room temperature, sodium acetate (13.6 g, 165 mmol) (7.0 g, 85.4 mmol) was dissolved in 150 mL of water and stirred for 2 h at 80 ° C. The mixture was stirred at 0 ° C for 1.5 h, filtered, and washed with ice-water (20.0 g, 159 mmol) and sodium acetate And acetone, and dried to give 15.4 g of a yield of 74percent.
74%
Stage #1: With hydrogenchloride In water at 90℃; for 0.5 h;
Stage #2: With sodium acetate In water at 80℃; for 2 h;
After Sm-1 (27.3 g, 138 mmol) was added to 70 mL of water, 3.0 mL of concentrated hydrochloric acid was added and the mixture was stirred at 90 ° C. for 0.5 h.After cooling to room temperature, sodium acetate (13.6 g, 165 mmol) was added and stirred,Sm-2 (20.0 g, 159 mmol) and sodium acetate (7.0 g, 85.4 mmol) were dissolved in 150 mL of water and added to the reaction. After stirring for 2 h at 80 ° C the reaction mixture was shifted to zero degrees Celsius for 1.5 h, filtered, Water and acetone, pumping dry 15.4g, yield 74percent.
42%
Stage #1: With hydrogenchloride In water at 90℃; for 0.5 h;
Stage #2: With sodium acetate In water at 80℃; for 2 h;
Bromoacetaldehyde diethyl acetal (1.1 mL, 0.91 equiv) was suspended in water (4.0 mL) and cone, hydrochloric acid (0.15 mL) was added. The mixture was stirred at 90 °C until a clear solution was formed (approximately 30 min). The solution was cooled to room temperature and sodium acetate (0.71 g) was added. This mixture was added to a suspension of 2,6-diamino- 4-pyrimidinone (1.0 g, 7.93 mmol, 1.00 equiv) and sodium acetate (0.35 g) in water (10 mL). The resulting mixture was stirred at 80 °C for 2 h. During this period the suspension first dissolved partially, before a white solid gradually precipitated. The obtained suspension was stirred at 0 °C for 90 min. The precipitate was collected and washed with a small amount of cold water and acetone. Drying in vacuo yielded 2-amino-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (0.5 g, 42 percent) as white solid.

Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 21, p. 5596 - 5611
[2] European Journal of Organic Chemistry, 2010, # 34, p. 6517 - 6519
[3] Patent: CN103601779, 2016, B, . Location in patent: Paragraph 0057; 0058; 0059
[4] Patent: CN104292117, 2016, B, . Location in patent: Paragraph 0476; 0499-0501
[5] Patent: WO2014/11911, 2014, A2, . Location in patent: Paragraph 00252; 00253; 00254
  • 21
  • [ 24241-18-7 ]
  • [ 2032-35-1 ]
  • [ 63744-22-9 ]
YieldReaction ConditionsOperation in experiment
100% at 20℃; for 19 h; Reflux Intermediate Example 1 -1 : Preparation of 6,8-dibromo-imidazo[ 1 ,2-a]pyrazineTo a stirred suspension of 2-amino-3,5-dibrompyrazine (427 g, 1688mmol) in water (6.4 L) / THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C to yield 6,8-dibromo-imidazo[1 ,2-a]pyrazine as an off-white solid (500 g, 107percent with residual MeOH): 1 H-NMR (300 MHz, d6-DMSO): δ =9.02 (s, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H) ppm. UPLC-MS: RT = 0.80 min; m/z 277.9 [MH+]; required MW = 276.9.
76% at 120℃; for 16 h; 3,5-dibromo-pyrazin-2-ylamine (10.4g, 41.12 mmol), and bromoacetaldehyde diethyl acetal (9.8 ml, 62.51mmol) then dissolved in a mixed solvent of tetrahydrofuran (14 ml) and distilled water (140 ml), and the mixture was stirred for 4 hours at 120°C , in addition stirred at room temperature for 12 hours to.Saturated aqueous sodium hydrogen carbonate solution to the reaction solution was neutralized by addition.The resulting solid was filtered, washed with distilled water and dried to give the title compound (8.7g, 76percent).
500 g at 20℃; for 19 h; Inert atmosphere; Reflux To a stirred suspension of 2-amino-3,5-dibrompyrazine (427 g, 1688mmol) in water (6.4 L) / THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C to yield 6,8-dibromo-imidazo[1 ,2-a]pyrazine as an off-white solid (500 g, 107percent with residual MeOH): 1H-NMR (300 MHz, d6-DMSO): δ =9.02 (s, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H) ppm. UPLC-MS: RT = 0.80 min; m/z 277.9 [MH+]; required MW = 276.9.
Reference: [1] Patent: WO2012/80236, 2012, A1, . Location in patent: Page/Page column 63
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6991 - 6995
[3] Patent: KR2015/113801, 2015, A, . Location in patent: Paragraph 0140-0143
[4] Patent: WO2004/72080, 2004, A1, . Location in patent: Page 45
[5] Patent: WO2005/14599, 2005, A1, . Location in patent: Page/Page column 44-45
[6] Patent: WO2012/80228, 2012, A1, . Location in patent: Page/Page column 42
[7] Patent: WO2012/80229, 2012, A1, . Location in patent: Page/Page column 44-45
[8] Patent: WO2012/80230, 2012, A1, . Location in patent: Page/Page column 44
[9] Patent: US2013/281460, 2013, A1, . Location in patent: Paragraph 0267-0268
[10] Patent: US2013/267527, 2013, A1, . Location in patent: Paragraph 0242-0243
[11] Patent: WO2014/20041, 2014, A1, . Location in patent: Page/Page column 130-131
  • 22
  • [ 603-35-0 ]
  • [ 2032-35-1 ]
  • [ 2136-75-6 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1964, vol. 73, p. 921 - 943
  • 23
  • [ 109-12-6 ]
  • [ 2032-35-1 ]
  • [ 274-95-3 ]
YieldReaction ConditionsOperation in experiment
5 g With hydrogen bromide In ethanol; water for 18 h; Reflux In a 250 ml three-neck round bottom flask, 2-aminopyrimidine (5 g),Bromoacetaldehyde diethyl acetal (20.7 g), 48percent aqueous solution of bromic acid (5 ml)Ethanol (50 ml) was added and the mixture was refluxed with stirring for 18 hours. The reaction solution was cooled to room temperature Silica gel was adsorbed. Through column separation using dichloromethane and methanol5 g of the title compound was obtained.
Reference: [1] Patent: KR2017/126059, 2017, A, . Location in patent: Paragraph 0069; 0072; 0073; 0076; 0077
  • 24
  • [ 5049-61-6 ]
  • [ 2032-35-1 ]
  • [ 274-79-3 ]
YieldReaction ConditionsOperation in experiment
94% With hydrogen bromide In ethanol; water at 70 - 80℃; for 17 h; To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48percent, 26.5 ml).
The mixture was heated at 70-80° C. for 17 hours.
The mixture was then cooled to rt (room temperature), then a mixture of 1N NaOH (200 ml) and 20percent IPA/DCM (isopropyl alcohol/Dichloromethane) was added to the reaction mixture.
The combined organic layer was dried over sodium sulfate and concentrated to afford 5.9 g of brown solid of imidazo[1,2-a]pyrazine (yield 94percent).
1H-NMR (400 MHz, DMSO-d6) δ 9.05 (m, 1H), 8.60 (dd, 1H), 8.13 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H).
MS m/z 120 [M++1].
24.01% With hydrogen bromide In ethanol for 24 h; Reflux 2-Pyrazinamine (9.51 g, 100 mmol) was dissolved in ethanol (300 ml) and 2-bromo- 1 ,1-bis(ethyloxy)ethane (21.06 ml, 140 mmol) was added. 48percent hydrobromic acid (33.3 ml) was added and the mixture heated at reflux for 24 hr. The solution was concentrated in vacuo to a crude solid that was basified with 10percent ammonia-ice (300ml). The solution was extracted in to ethyl acetate (3 x 300ml), the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid, (4.76g). The solid was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100percent [25percent 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1 ,2-a]pyrazine (2.86 g, 24.01 mmol, 24.01 percent yield).).1H NMR (CDCI3, 400 MHZ) d 9.11 (s, 1 H), 8.10 (d, 1 H, J = 4.8 Hz, 7.88 (d, 1 H. 4.8 Hz, 7.83 (s, 1 H), 7.71 (s, 1 H)
Reference: [1] Patent: US2004/220189, 2004, A1, . Location in patent: Page 21
[2] Patent: WO2010/125101, 2010, A1, . Location in patent: Page/Page column 50
  • 25
  • [ 1072-97-5 ]
  • [ 2032-35-1 ]
  • [ 6188-23-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8713 - 8722
[2] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1556 - 1567
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 9, p. 2245 - 2248
  • 26
  • [ 1603-40-3 ]
  • [ 2032-35-1 ]
  • [ 874-10-2 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogen bromide In ethanol; water at 90℃; for 26 h; 2-amino-3-methylpyridine (10 g, 92.5 mmol) and 2-bromo-1,1-diethoxyethane (36.4 g, 185 mmol) were dissolved in ethanol (100 mL) Then, 48percent aqueous hydrogen bromide solution (9 mL) was slowly added dropwise to the reaction solution. After the reaction system was heated to 90 ° C for 26 hours, LC-MS detection reaction has ended, And then cooled to room temperature. The first reaction in the system of ethanol decompression distillation, The excess hydrobromic acid in the reaction was neutralized with excess saturated sodium bicarbonate water (100 mL) and sodium bicarbonate solids (15 g). The remaining mixture was extracted with ethyl acetate (200 mL x 3) All organic phases were then mixed and washed once with deionized water (100 mL) and saturated brine (100 mL) Dried over anhydrous sodium sulfate, Press the steam to remove the solvent. The remaining mixture was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-10percent), To give 8-methyl-imidazo [1,2-a] pyridine (12 g, yield 98percent).
Reference: [1] Patent: CN106279160, 2017, A, . Location in patent: Paragraph 0259; 0263; 0264; 0265
[2] Bulletin of the Chemical Society of Japan, 1999, vol. 72, # 6, p. 1327 - 1334
  • 27
  • [ 5469-69-2 ]
  • [ 2032-35-1 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With hydrogen bromide In isopropyl alcohol for 1.5 h; Reflux
Stage #2: for 2 h; Reflux
Preparation of 6-chloroimidazo[1,2-b]pyridazine
Bromoacetaldehyde diethylacetal (13.7 g, 69.5 mmol, 1.8 equiv) was added to hydrobromic acid (4.0 mL) and heated to reflux for 1.5 h.
The reaction mixture was cooled to rt then poured into a reaction flask containing excess sodium bicarbonate in isopropanol.
The solution was stirred for 3 min and then filtered.
To the mother liquor was added 3-amino-6-chloropyridazine (5.0 g, 38.6 mmol, 1.0 equiv) and heated to reflux for 2 h.
The reaction mixture was quenched with water and extracted with ethyl acetate.
Purification using column chromatography gave 5.1 g of the brown solid, 86percent: 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.74 (s, 1H), 7.01 (d, J=9.3 Hz, 1H).
85%
Stage #1: With hydrogen bromide In water at 20 - 110℃; for 0.75 h;
Stage #2: at 0 - 130℃;
PREPARATION 1; 3-Bromo-6-chloroimidazo[1,2-b]pyridazine a) 6-Chloroimidazo[1,2-o]pyridazineHydrobromic acid (48percent solution in water, 1.8 mL, 15.47 mmol) was added to a solution of 2-bromo-1 ,1-diethoxyethane (1 1.6 mL, 77.1 1 mmol) in water (18 mL) at ambient temperature and the resulting mixture was heated at 110 °C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and the solvent evaporated to obtain a colorless oil, which was added to a suspension at 0 °C of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 °C overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85percent) as a beige solid.LRMS (m/z): 154 (M+1)+.1H-NMR δ (300 MHz, CDCI3): 7.08 (d, 1 H), 7.81 (s, 1 H), 7.88 - 7.99 (m, 2H).
85%
Stage #1: With hydrogen bromide In water at 110℃; for 0.75 h;
Stage #2: at 0 - 130℃;
PREPARATION 1 3-Bromo-6-chloroimidazo[1,2-b]pyridazine; a) 6-Chloroimidazo[1,2-b]pyridazine Aqueous hydrobromic acid (1.8 mL of a 48percent solution in water, 15.47 mmol) was added to a solution of 2-bromo-1,1-diethoxyethane (11.6 mL, 77.11 mmol) in water (18 mL) at room temperature and the resulting mixture was heated at 110 C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and evaporated to obtain a colorless oil, which was added to a suspension at 0 C of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 C overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85percent) as a beige solid. LRMS (m/z): 154 (M+1)+. 1H-NMR δ (300 MHz, CDCl3): 7.08 (d, 1H), 7.81 (s, 1H), 7.88 -7.99 (m, 2H).
59%
Stage #1: for 1.5 h; Reflux
Stage #2: With sodium hydrogencarbonate In isopropyl alcohol for 2 h; Reflux
Example 15 -1 Synthesis of 6-chloro-imidazo[1,2-b]pyridazine
A Solution of 48percent HBr (25.2ml) was added to bromoacetaldehyde diethyl acetal (104 g, 0.618 mol) and the resultant mixture was heated to reflux for 1.5 hrs.
The reaction mixture was then poured into a suspension of NaHCO3 (20.0 g) in isopropyl alcohol (800 ml).
The solution was filtered and 3-amino-6-chloropyridazine (40.0 g, 0.309 mol) was added to the filtrate and the mixture heated at reflux for 2 hours.
The mixture was cooled, evaporated to dryness, dissolved in ethyl acetate (1 L), washed with a saturated aqueous solution of NaHCO3 (500 ml), followed by brine (500 ml).
The organic layer was then dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (gradient elution with hexane and ethyl acetate 0 to 100percent) to give 28.0 g (59percent) of 6-chloro-imidazo[1,2-b]pyridazine 1*a as a brown solid. 1H-NMR (400 MHz, DMSO-d6): 8.35 (1H, d, J = 0.9 Hz), 8.23 (1 H, d, J = 9.5 Hz), 7.86 (1 H, d, J = 1.1 Hz), 7.36 (1 H, d, J = 9.5 Hz). LCMS-ESI (m/z); found 154.0 [M+H]+.

Reference: [1] Patent: US2014/256733, 2014, A1, . Location in patent: Paragraph 0227-0229
[2] Patent: WO2012/69202, 2012, A1, . Location in patent: Page/Page column 46
[3] Patent: EP2463289, 2012, A1, . Location in patent: Page/Page column 17-18
[4] Patent: EP2818471, 2014, A1, . Location in patent: Paragraph 0117; 0118
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2789 - 2798
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 21, p. 8839 - 8848
[7] MedChemComm, 2018, vol. 9, # 10, p. 1733 - 1745
  • 28
  • [ 1453176-84-5 ]
  • [ 2032-35-1 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
57% With hydrogen bromide In ethanol at 90℃; [0191] Step 1. 6-Chloro-imidazo [1 ,2-bl pyridazine. A solution of 6-chloro- 1 ,2-diazinan-3- amine (10 g, 73.75 mmol, 1.00 equiv), 2-bromo-1,1-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr (40percent, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5percent aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/21/1) to give 6.5 g (57percent) of the title compound as a yellow solid. ‘H NMR (300 MHz, CDC13) ö 7.95 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.05 (d, J = 9.3 Hz, 1H).
Reference: [1] Patent: WO2013/130935, 2013, A1, . Location in patent: Paragraph 0191
  • 29
  • [ 2032-35-1 ]
  • [ 7400-06-8 ]
Reference: [1] Archiv der Pharmazie, 2018, vol. 351, # 8,
  • 30
  • [ 2032-35-1 ]
  • [ 7400-05-7 ]
Reference: [1] European Journal of Organic Chemistry, 1998, # 5, p. 827 - 835
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6770 - 6789
  • 31
  • [ 108-05-4 ]
  • [ 64-17-5 ]
  • [ 2032-35-1 ]
Reference: [1] Patent: US2330570, 1940, ,
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 1705
[3] Org.Synth.Coll.Vol., 1955, vol. III, p. 123
[4] Patent: CN103214421, 2016, B, . Location in patent: Paragraph 0018; 0019; 0020; 0021
[5] Patent: US2411826, 1943, ,
  • 32
  • [ 105-57-7 ]
  • [ 2032-35-1 ]
Reference: [1] Carbohydrate Research, 1981, vol. 95, p. 117 - 122
[2] Polish Journal of Chemistry, 1980, vol. 54, # 4, p. 777 - 780
[3] Journal of the American Chemical Society, 1942, vol. 64, p. 1964
[4] Chemische Berichte, 1872, vol. 5, p. 150
[5] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 23, p. 113
[6] Journal of the American Chemical Society, 1927, vol. 49, p. 2518
[7] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1905, vol. 140, p. 794[8] Bulletin de la Societe Chimique de France, 1907, vol. &lt;4&gt;1, p. 75
[9] Chemische Berichte, 1902, vol. 35, p. 3388 Anm.1
[10] Chemische Berichte, 1892, vol. 25, p. 2553
[11] Journal of the American Chemical Society, 1951, vol. 73, p. 973
[12] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 23, p. 114
  • 33
  • [ 108-05-4 ]
  • [ 2032-35-1 ]
Reference: [1] Journal of the American Chemical Society, 1944, vol. 66, p. 651
[2] Patent: US5116402, 1992, A,
  • 34
  • [ 64-17-5 ]
  • [ 109-92-2 ]
  • [ 2032-35-1 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1963, p. 470 - 472
[2] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, p. 1846 - 1849[3] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 10, p. 2089 - 2093
  • 35
  • [ 89125-30-4 ]
  • [ 2032-35-1 ]
Reference: [1] Anales de la Real Sociedad Espanola de Fisica y Quimica, 1918, vol. 16, p. 336
  • 36
  • [ 123-63-7 ]
  • [ 2032-35-1 ]
Reference: [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1905, vol. 140, p. 795[2] Bulletin de la Societe Chimique de France, 1907, vol. &lt;4&gt; 1, p. 73
[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1953, vol. 236, p. 292
  • 37
  • [ 64-17-5 ]
  • [ 123-63-7 ]
  • [ 2032-35-1 ]
Reference: [1] Journal of the Chemical Society, 1937, p. 1057,1063
[2] Helvetica Chimica Acta, 1947, vol. 30, p. 189,198
  • 38
  • [ 2983-26-8 ]
  • [ 2032-35-1 ]
Reference: [1] Chemische Berichte, 1953, vol. 86, p. 1318,1322
  • 39
  • [ 109-92-2 ]
  • [ 2032-35-1 ]
Reference: [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1953, vol. 236, p. 1968
  • 40
  • [ 2983-26-8 ]
  • [ 74-96-4 ]
  • [ 64-17-5 ]
  • [ 23521-49-5 ]
  • [ 16339-88-1 ]
  • [ 2032-35-1 ]
  • [ 927-80-0 ]
Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 19, p. 3577 - 3581
  • 41
  • [ 89125-30-4 ]
  • [ 141-52-6 ]
  • [ 2032-35-1 ]
Reference: [1] Anales de la Real Sociedad Espanola de Fisica y Quimica, 1918, vol. 16, p. 336
  • 42
  • [ 105-57-7 ]
  • [ 7726-95-6 ]
  • [ 2032-35-1 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 23, p. 114
  • 43
  • [ 2983-26-8 ]
  • [ 141-52-6 ]
  • [ 2032-35-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 106
[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 106
  • 44
  • [ 64-17-5 ]
  • [ 2032-35-1 ]
Reference: [1] Chemische Berichte, 1925, vol. 58, p. 1719[2] Chemische Berichte, 1926, vol. 59, p. 2534
  • 45
  • [ 64-17-5 ]
  • [ 74-96-4 ]
  • [ 105-36-2 ]
  • [ 2032-35-1 ]
  • [ 17157-48-1 ]
Reference: [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1905, vol. 140, p. 1693[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1906, vol. 143, p. 683
[3] Bulletin de la Societe Chimique de France, 1907, vol. &lt;4&gt;1, p. 67
  • 46
  • [ 2032-35-1 ]
  • [ 621-63-6 ]
Reference: [1] Journal of the American Chemical Society, 1936, vol. 58, p. 531
[2] Annales de Chimie (Cachan, France), 1949, vol. &lt;12&gt;4, p. 828
[3] Chemische Berichte, 1872, vol. 5, p. 150
[4] Journal of the American Chemical Society, 1927, vol. 49, p. 2518
[5] Journal of the American Chemical Society, 1936, vol. 58, p. 531
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 6391
  • 47
  • [ 64-17-5 ]
  • [ 2032-35-1 ]
  • [ 621-63-6 ]
Reference: [1] Chemische Berichte, 1872, vol. 5, p. 150
  • 48
  • [ 2032-35-1 ]
  • [ 122-52-1 ]
  • [ 2041-14-7 ]
Reference: [1] Synthetic Communications, 1978, vol. 8, p. 335 - 343
  • 49
  • [ 150-76-5 ]
  • [ 2032-35-1 ]
  • [ 13196-10-6 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2013, vol. 61, # 10, p. 997 - 1001
  • 50
  • [ 23145-07-5 ]
  • [ 106-41-2 ]
  • [ 2032-35-1 ]
  • [ 10035-16-2 ]
Reference: [1] Patent: US4664693, 1987, A,
  • 51
  • [ 124-40-3 ]
  • [ 2032-35-1 ]
  • [ 3616-56-6 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1945, vol. &lt;5&gt; 12, p. 845,858
[2] Bulletin de la Societe Chimique de France, 1965, p. 2175 - 2182
  • 52
  • [ 105-56-6 ]
  • [ 2032-35-1 ]
  • [ 52133-67-2 ]
YieldReaction ConditionsOperation in experiment
78% at 145℃; for 4 h; Method AI: Ethyl 2-cyano-4,4-diethoxybutanoate (xlii-a):_ 2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq.) was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq.), K2CO3 (2.8 g, 20 mmol, 1.0 eq.) and NaI (200 mg, 1.3 mmol, 0.06 eq.), as described in J. Chem. Soc., 1960, 131-138. The reaction mixture was refluxed for 4 h at 145° C. After cooling, the reaction mixture was purified by chromatography on silica gel (eluted with petroleum ether/ethyl acetate (80:1→40:1→40:1) to give 3.57 g of xlii-a as a colorless oil (78percent). 1H NMR (400 MHz, CDCl3): δ 4.70 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.78-3.64 (m, 3H), 3.62-3.45 (m, 2H), 2.35-2.14 (m, 2H), 1.34 (q, J=7.2 Hz, 3H), 1.25-1.16 (m, 6H).
78% at 145℃; for 4 h; As described in J. Chem. Soc., 1960, 131-138,2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq)Was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq), K 2 CO 3 (2.8 g, 20 mmol, 1.0 eq) and NaI (200 mg, 1.3 mmol, 0.06 eq) .The reaction mixture was refluxed at 145 ° C. for 4 hours.After cooling, the reaction mixture was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (80: 1 → 40: 1 → 10: 1)) to give 3.57 g of xlii-a as a colorless oil I got it (78percent).
74% at 145℃; for 4.5 h; Inert atmosphere To a dry 3-necked round bottomed flask fitted with a condenser was added 11.3 g (81.5 mmol) of oven dried K2CO3 and 0.82 g (5.5 mmol) of NaI. The solids were placed under high vacuum for an hour to ensure dryness. The flask was refilled with argon and 44.0 mL (0.413 mol) of ethyl cyanoacetate was added followed by 13.0 mL (83.8 mmol) of bromoacetal. The yellow mixture was heated to 145°C for 4.5 hours and was then cooled to room temperature. The mixture was dissolved in 100 mL of water and 100 mL of diethyl ether. The organic layer was separated and the aqueous layer was extracted with an additional 100 mL of ether. The organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography (9:1 Hex/EtOAc) to give 14.2 g (62.0 mmol, 74percent yield) of a light yellow oil. (Rf: 0.53; 1:1 Hex/EtOAc). 1H-NMR (CDCl3, 600 MHz): σ 1.18 - 1.22 (m, 6H), 1.31 (t, 3H, J = 7.2 Hz), 2.16 - 2.21 (m, 1H), 2.24 - 2.29 (m, 1H), 3.49 - 3.55 (m, 2H), 3.64 - 3.71 (m, 3H), 4.24 (q, 2H, J = 7.2 Hz), 4.68 (t, 1H, J = 5.4 Hz). 13C-NMR (CDCl3, 150 Mz): σ 14.1, 15.3, 33.7, 62.8, 62.9, 100.1, 116.5, 166.0. HRMS (FAB): expected for C11H20NO4 (M+H)+: 230.13868. Found: 230.13861. IR(neat): vmax 2989, 1774 cm-1.
70% With sodium methylate In N,N-dimethyl-formamide at 90℃; for 4 h; The synthesis of target compound 3 (Scheme 1C), started with the synthesis of a reported method for compound i.’3 2-Bromo-i,i-diethoxyethane (compound 10) was reacted with ethyl2-cyanoacetate to obtain compound 1 lwhich was cyclized to compound 12 using acetamidine hydrochloride under basic conditions. Chlorination of compound 12 using POC13 provided compound 13 in 80percent yield. Displacement of the chloride of compound 13 with 4-methoxy-N- methyl aniline (compound 14) and catalytic amounts of HC1 in isopropanol, provided compound1. Methylation of compound 1 with Mel under basic conditions afforded compound 3 in 85percent yield. The synthesis of target compound 5 (Scheme 1C), involved N-formylation of 4-methoxy- 2-methylanline (compound 15) to afford compound 16 in 70percent yield. LAH reduction of compound 16 provided substituted aniline compound 17. Displacement of the chloride of compound 13 with anilines (compounds 15 and 17) and catalytic amounts of HC1 in isopropanol provided compounds 4 and 5 (75percent and 70percent respectively).
63% Reflux Example A1; Preparation of 4-chloro-5-iodopyrrolo[2,3-d]pyrimidine in Accordance with the Following Reaction Scheme; (a) 130 ml (860 mmol) of bromoacetaldehyde diethyl acetal are refluxed for 10 h with ethyl cyanoacetate (430 ml, 4.04 mol), sodium iodide (8.1 g; 54.04 mmol) and potassium carbonate (115.9 g; 839 mmol). After cooling to room temperature (RT), the batch is stirred with 800 ml of water, the aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated. Chromatography gives 124.99 g (63percent) of a colourless liquid ethyl 2-cyano-4,4-diethoxybutyrate.
60%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; benzene at -10 - 20℃; for 1 h;
Stage #2: at 100℃; for 2 h;
To a suspension of NaH (60percent dispersion in mineral oil, 1.62 g, 40.5 mmol) in DMF (35 mL) and benzene (12 mL) was added ethyl cyanoacetate (4.7 mL, 44.2 mmol) dropwise at -10 0C. After stirring for 1 hour at room temperature, 2-bromo-1 ,1-diethoxyethane (5.6 mL, 0.82 equiv.) was added and the reaction mixture was heated at 100 0C for 2 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was condensed, and water was added. The mixture was extracted with ether. The extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (20percent EtOAc/hexanes). The desired product was obtained as colorless oil (5 g, 60percent). MS: (M + Na)/z = 252.
60%
Stage #1: With sodium ethanolate; sodium iodide In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 90℃; for 4 h;
Take a 500 mL two-necked flask and ethyl cyanoacetate (50 g, 0.44 mol) in anhydrous DMF(N, N-dimethylformamide) (300 mL) was added sodium ethoxide (36 g, 0.528 mol, 1.2 eq.) And sodium iodide (catalytic amount) at room temperature Stirring for 30min,2-Bromo-1,1-diethoxyethane was added(66.5 mL, 0.44 mol, 1 equiv)The temperature was raised to 90 ° C and stirred for 4 h. Cooled to room temperature, evaporated under reduced pressure to remove most of the DMF, add EA (ethyl acetate), stirring 10min, filter, take the filtrate to add saturation Salt water extraction. The organic phase was collected, dried, dried and dried (PE: EA = 12: 1, i.e., the volume ratio of petroleum ether: ethyl acetate was12) was obtained as a pale yellow oily product (61.3 g) in 60percent yield.
57% at 140 - 150℃; 2-Cyano-4,4-diethoxy-butyric acid ethyl ester (4).; Bromoacetaldehyde diethylacetal (3, 541 g, 2.75 mol) was added to a suspension of powdered potassium carbonate (379.6 g, 2.75 mol, 1.0 equiv) and sodium iodide (33 g, 0.22 mol, 0.08 equiv) in ethyl cyanoacetate(2, 1.55 Kg, 13.75 mol, 5.0 equiv). Upon addition of the aldehyde to the reaction mixture, the resulting solution turned yellow. The reaction mixture was slowly heated to 140-150° C. collecting the volatile material in a Dean Stark trap. This material was discarded. Fairly vigorous gas evolution was observed to begin at 140° C. The reaction was monitored by G.C. and was observed to be near completion at 90 minutes. Heating was continued for an additional 45 minutes when gas evolution was observed to have ceased. The reaction mixture was then cooled to room temperature and partitioned between 4 L water and 2 L methyl tent-butyl ether (MTBE). The layers were separated and the aqueous layer was extracted with an additional 2 L of MTBE. The aqueous layer was checked for product by G.C. then discarded. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by fractional distillation (91-105° C. (at) 0.53-0.65 mm/Hg) to afford 2-cyano-4,4-diethoxy-butyric acid ethyl ester (4, 359.4 g, 630.5 g theoretical, 57percent) as a oil. For 4: 1H NMR (DMSO-d6, 300 MHz) δ ppm 4.60 (t, 1H, J=5.6 Hz), 4.15 (m, 3H), 3.59 (m, 2H), 3.45 (m,1H), 2.11 (t, 2H, J=6.2 Hz), 1.22 (t, 3H, J=6.9 Hz), 1.10 (dt, 6H, J=7.1, 6.9 Hz).
51% for 24 h; Reflux Preparation of intermediate compound (87) a. A mixture of ethyl cyanoacetate 81 (227.97 g, 2015.52 mmol), bromo acetaldehyde diethyl ether (80) (80 g, 405.94 mmol), potassium carbonate (55.99 g, 405.13 mmol) and sodium iodide (4 g, 26.67 mmol) was refluxed for 20 h (CO2 evolution was observed during the reaction). The reaction mixture was stirred at reflux for additional 4 h after the evolution of CO2 has ceased. The reaction was cooled to room temperature, diluted with water (400 mL) and diethyl ether (400 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (250 mL). The ether layers were combined washed with water (2 x 100 mL), brine (200 mL), dried, filtered and concentrated in vacuum. The product obtained was distilled under vacuum to furnish ethyl-2- cyano-4, 4-diethoxybutanoate (82) (47.5 g, 51.0 percent) as a colorless oil; B.P: 103 °C/1 mm Hg. 1HNMR (300 MHz, DMSO) δ 4.61 (t, J= 5.7, IH), 4.24 - 4.08 (m, 3H), 3.67 - 3.54 (m, 2H), 3.53 - 3.40 (m, 2H), 2.12 (t, J= 6.0, 2H), 1.23 (t, J= 7.1, 3H), 1.11 (td, J= 4.9, 7.0, 6H); IR (neat): 3482, 2980, 2901, 2361, 2252, 1749, 1446, 1374, 1262, 1218, 1128, 1062 and 857 cm"1; MS (ES"): 263.6 (M + 35); Analysis: CaIc for CnHi9NO4.0.25 H2O: C, 56.51; H, 8.40; N, 5.99; Found: C, 56.71; H, 8.16; N, 5.96.
29.2% for 12 h; Reflux Step 5:
Preparation of ethyl 2-cyano-4,4-diethoxybutanoate
A mixture of ethyl 2-cyanoacetate (1000 g, 8.84 mol), 2-bromo-1,1-diethoxyethane (400 g, 2.03 mol), KI (33.4 g, 0.201 mol) and K2CO3 (280 g, 2.03 mol) was heated to reflux for 12 hrs.
The reaction mixture was diluted with CH2Cl2 (1000 mL) and the resulting precipitate was filtered off and the filtrate was washed with brine and dried over anhydrous Na2SO4.
The solvent was removed in vacuo and the residue distilled to give the title compound (136 g, 29.2percent yield) as a light yellow oil that was used as is in the next step.

Reference: [1] Patent: US2015/307477, 2015, A1, . Location in patent: Paragraph 1563
[2] Patent: JP6121658, 2017, B2, . Location in patent: Paragraph 1270; 1271
[3] Archiv der Pharmazie, 2018, vol. 351, # 8,
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 4064 - 4067
[5] Organic Letters, 2017, vol. 19, # 9, p. 2214 - 2217
[6] Patent: WO2016/22890, 2016, A1, . Location in patent: Page/Page column 50
[7] Russian Journal of Bioorganic Chemistry, 1995, vol. 21, # 11, p. 756 - 761[8] Bioorganicheskaya Khimiya, 1995, vol. 21, # 11, p. 874 - 880
[9] Patent: US2010/160356, 2010, A1, . Location in patent: Page/Page column 33
[10] Patent: WO2009/9740, 2009, A1, . Location in patent: Page/Page column 71
[11] Patent: CN107033206, 2017, A, . Location in patent: Paragraph 0091; 0093; 0094; 0095
[12] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 100
[13] Patent: WO2010/14930, 2010, A2, . Location in patent: Page/Page column 59-60
[14] Patent: US2013/79324, 2013, A1, . Location in patent: Paragraph 0835; 0836
[15] Journal of the Chemical Society, 1960, p. 131 - 138
[16] European Journal of Organic Chemistry, 1998, # 5, p. 827 - 835
[17] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
[18] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 8116 - 8128
[19] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6770 - 6789
  • 53
  • [ 105-56-6 ]
  • [ 2032-35-1 ]
  • [ 52133-67-2 ]
YieldReaction ConditionsOperation in experiment
38% With potassium carbonate In dimethyl sulfoxide at 70 - 80℃; for 15 h; General procedure: Halo acetal 2a or 2b, 0.25 mol, was added with stirring to a mixture of 0.25 mol of the corresponding CH acid and 28 g (0.2 mol) of calcined potassium carbonate in 100 mL of DMSO. The mixture was stirred for 15 h at 70– 80°C (in the reactions with 2a), or at 100–120°C (2b), cooled, and treated with water and diethyl ether (2 100 mL). The combined extracts were dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure.
Reference: [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1390 - 1393[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1390 - 1393,4
  • 54
  • [ 6937-03-7 ]
  • [ 2032-35-1 ]
  • [ 86718-01-6 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With hydrogenchloride In water at 80℃; for 4 h;
Stage #2: With sodium hydrogencarbonate In water at 20℃;
Stage #3: at 20℃;
A mixture of 2-bromo-1 ,1-diethoxyethane (6.20ml, 41.2mmol) and HCI 35percent (0.82ml, 26.8mmol) in water (68ml) was stirred for 2.5h, then heated at 800C and stirred at this temperature for 1.5h. The mixture was cooled down to 2O0C and NaHCO3 (4.49g, 53.45mmol) was added in four portions. Finally, methyl 2-aminoisonicotinate (5g, 32.86mmol) was added and the reaction mixture stirred at room temperature overnight. The solid formed was filtered, washed with water and dried in the vacuum oven to give 5.15g of the title compound as a brown solid (yield=89percent).LRMS: m/z 177 (M+1 )+ Retention time: 1.46min (method A)1H NMR (200 MHz, CHCI3) ppm 3.97(s, 3H), 7.27(s,1 H), 7.42(d, J=6Hz, 1 H), 7.70(s, 1 H), 7.80(s,1 H), 8.19(d, J=6Hz, 1 H), 8.37(s,1 H) Yield 89percent
85.7%
Stage #1: With hydrogen bromide In water at 80℃; for 1.5 h;
Stage #2: With sodium hydrogencarbonate In methanol; water at 40 - 80℃;
Preparation of compound 24a: imidazo[1,2-a]pyridine-7-carboxylic acid methyl esterTo a solution of 2-Bromo-1 ,1 -diethoxy-ethane (18.62 g, 0.095 mol) in H2O (80 ml) was added aq. HBr (2 ml). The resulting mixture was heated to 80 0C for 1.5 h and then was cooled to 40 0C. Then a solution of 2-Amino-isonicotinic acid methyl ester(9.61 g, 0.063 mol) and NaHCO3 (6.615 g, 0.0788 mol) in CH3OH/ H2O (3:1 400 ml) was added dropwise to the above mixture. The resulting mixture was heated to 80 0C for 18 h. The mixture was concentrated and cooled to room temperature, and the solid was collected by filtration and dried in vacuo which gave the title compound 24a as a yellow solid (9.5 g, 85.7percent).
82.3% With sodium bicarbonate; hydrogen bromide In di-isopropyl ether; water EXAMPLE V
A mixture of 1.31 parts of 2-bromo-1,1-diethoxyethane, 10 parts of water and 1.5 parts of a hydrobromic acid solution 48percent in water was stirred and refluxed for 1 hour.
The mixture was poured onto 50 parts of water and the whole was neutralized with potassium carbonate.
Then there were added successively 5 parts of sodium hydrogen carbonate and 3 parts of methyl 2-amino-4-pyridinecarboxylate.
The reaction mixture was stirred and heated for 15 minutes at 55° C. in an oil-bath.
After 30 minutes, gas-evolution had ceased and the mixture was cooled.
The product was extracted with dichloromethane.
The extract was dried, filtered and evaporated.
The residue was stirred in 2,2'-oxybispropane.
The product was filtered off and dried, yielding 2.9 parts (82.3percent) of methyl imidazo-[1,2-a]pyridine-7-carboxylate; mp. 143.2° C. (intermediate 13).
Reference: [1] Patent: WO2010/43377, 2010, A1, . Location in patent: Page/Page column 53-54
[2] Patent: WO2010/16005, 2010, A1, . Location in patent: Page/Page column 118
[3] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1556 - 1567
[4] Patent: US4962115, 1990, A,
  • 55
  • [ 5345-47-1 ]
  • [ 2032-35-1 ]
  • [ 133427-08-4 ]
Reference: [1] Patent: WO2009/23253, 2009, A2, . Location in patent: Page/Page column 51
  • 56
  • [ 6320-02-1 ]
  • [ 2032-35-1 ]
  • [ 137105-52-3 ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5 h; To a suspension of K2CO3 (8.186 g, 59.23 mmol) in DMF (70 mL) was added 2-bromothiophenol, 3.27 (7.00 g, 37.02 mmol) followed by 2-bromoacetaldehyde diethyl acetal (7.821 g, 40.72 mmol). The reaction was stirred at room temperature for 5 hours and then partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was isolated and washed with water (5 × 50 mL). The combined aqueous layers were extracted with EtOAc (100 mL) and the combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by short-path vacuum-distillation and the fraction collected at 130 – 140 °C (0.2 mmHg) contained the title compound (10.42 g, 92percent) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.51 (dd, J = 7.9, 1.3 Hz, 1H), 7.34 (dd, J = 7.9, 1.5 Hz, 1H), 7.26 – 7.20 (m, 1H), 7.04 – 6.97 (m, 1H), 4.69 (t, J = 5.5 Hz), 3.69 (dq, J = 9.2, 7.0 Hz, 2H), 3.56 (dq, J = 9.2, 7.0 Hz, 2H), 3.14 (d, J = 5.5 Hz, 2H), 1.20 (t, J = 7.0 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 137.7, 133.0, 128.8, 127.7, 126.8, 123.8, 101.63, 62.4, 37.0, 15.5
85% With potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide Preparation of 2-(2-Bromophenylthio)acetaldehyde Diethyl Acetal
Scheme I, step A:
A 500 mL round bottom flask was charged with anhydrous DMF (100 mL), 2-bromothiophenol (10.0 g, 52.88 mmol), potassium carbonate (11.0 g, 79.59 mmol) and bromoacetaldehyde diethyl acetal (8.35 mL, 55.5 mmol).
The reaction was stirred at room temperature for 5 hours.
Water (50 mL) and ethyl acetate (100 mL) were then added with mixing.
The layers were separated and the organic layer was washed with water (5*50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-bromophenylthio)acetaldehyde diethyl acetal (13.78 g, 85percent).
85% With potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide Preparation of 2-(2-Bromophenylthio)acetaldehyde Diethyl Acetal
Scheme I, step A:
A 500 mL round bottom flask was charged with anhydrous DMF (100 mL), 2-bromothiophenol (10.0 g, 52.88 mmol), potassium carbonate (11.0 g, 79.59 mmol) and bromoacetaldehyde diethyl acetal (8.35 mL, 55.5 mmol).
The reaction was stirred at room temperature for 5 hours.
Water (50 mL) and ethyl acetate (100 mL) were then added with mixing.
The layers were separated and the organic layer was washed with water (5*50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-bromophenylthio) acetaldehyde diethyl acetal (13.78 g, 85percent).
85% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 5 h; SchemeI,
stepA:
A 500 mL round bottom flask was charged with anhydrous DMF (100 mL), 2-bromothiophenol (10.0 g, 52.88 mmol), potassium carbonate (11.0 g, 79.59 mmol) and bromoacetaldehyde diethyl acetal (8.35 mL, 55.5 mmol). The reaction was stirred at room temperature for 5 hours. Water (50 mL) and ethyl acetate (100 mL) were then added with mixing. The layers were separated and the organic layer was washed with water (5.x.50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-bromophenylthio) acetaldehyde diethyl acetal (13.78 g, 85percent).
15.6 g
Stage #1: With potassium carbonate In acetone at 0℃;
Stage #2: at 25℃; for 18 h;
To a stirred suspension of K2CO3 (9.56 g, 69.17 mmoi) in acetone (40 mL) was added 2- bromothiophenol (10.0 g, 53.21 mmoi) at 0 °C and stirred the reaction mixture at same temperature for 20-3 0 mm. then added bromoacetaidehyde diethylacetal (11.5 g, 58.33 mmoi) drop-wise and stirred the reaction mass at 25 °C for 18 h. The reaction was monitor by tic and after compietion of reaction voiatiies were remove under reduce pressure to get concentrated mass which was diiuted with water, extracted with ethyi acetate (3 x 150 mL), combined organic iayers were washed with water then brine, dried over anhydrous sodium suifate, concentrated under reduced pressure to give crude mass which was purified by coiumn chromatography on siiica gei using 5percent ethyi acetate/hexane mixture as eiuent to afford (2-bromophenyi)(2,2-diethoxyethyi)suifane (15.6 g) as paie yeiiow oii. ‘H-NMR (400 MHz, CDCi3): ö 7.49 (d, J 7.8 Hz, 1H), 7.32 (d, J 7.8 Hz, 1H), 7.21 (t, J= 7.6 Hz, 1H), 6.98 (t, J= 7.6 Hz, 1H), 4.67 (t, J= 5.5 Hz, 1H), 3.65 (q, J 6.9 Hz, 2H), 3.52 (q, J= 6.8 Hz, 2H), 3.12 (d, J 6.0 Hz, 2H), 1.17 (t, J 6.9 Hz, 6H).

Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 35, p. 12303 - 12307
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
[3] Patent: US6436964, 2002, B1,
[4] Patent: US6465453, 2002, B1,
[5] Patent: US6353008, 2002, B1, . Location in patent: Page column 25-26
[6] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1982, p. 1489 - 1492
[7] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 21, p. 2599 - 2604
[8] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 216
[9] Patent: WO2014/181247, 2014, A1, . Location in patent: Page/Page column 26-27
  • 57
  • [ 1072-97-5 ]
  • [ 2032-35-1 ]
  • [ 69214-09-1 ]
YieldReaction ConditionsOperation in experiment
59%
Stage #1: With hydrogenchloride In 1,4-dioxane; water for 0.5 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; water for 24 h; Heating / reflux
Method 32
5-Bromoimidazo[1,2a]pyridine
A solution of bromoacetaldehyde diethylacetyl (50ml, 0.332mol) in dioxane (143ml), water (85ml) and conc. hydrochloric acid (5ml) was heated at reflux for 30 minutes and the mixture allowed to cool.
Sodium hydrogen carbonate (53g) was added followed by a solution of 5-bromo-2-aminopyridine (30g, 0.174mol) in dioxane (230ml) and water (85ml) and the mixture was heated at reflux for 24 hours.
The mixture was allowed to cool, poured into water and acidified with 2M hydrochloric acid.
The mixture was washed with ethyl acetate and the aqueous layer was basified with 2M aqueous sodium hydroxide solution.
The aqueous mixture was extracted with ethyl acetate.
The extracts were combined, dried and the volatiles removed by evaporation.
The residue was purified by chromatography eluding with hexane/ethyl acetate (50:50) in creasing in polarity to (25:50) to give the title compound 20g (59percent). NMR: 7.30 (dd, 1H), 7.54 (d, 1H), 7.59 (s, 1H), 7.90 (s, 1H), 8.89 (s, 1H); m/z: 197 [MH]+.
Reference: [1] Patent: EP1214318, 2003, B1, . Location in patent: Page/Page column 38
  • 58
  • [ 36052-26-3 ]
  • [ 2032-35-1 ]
  • [ 88047-55-6 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1159 - 1164
  • 59
  • [ 33332-29-5 ]
  • [ 2032-35-1 ]
  • [ 76537-23-0 ]
YieldReaction ConditionsOperation in experiment
49.75% With hydrogen bromide In isopropyl alcohol at 80℃; compound 5-a (2.6g, 20mmol), 2- bromo-1,1-diethoxyethane (12.0g, 60.89mmol) was dissolved in 30ml isopropanol was then added a solution of hydrogen bromide (10.5g, 62.22mmol), 80 deg. C stirred overnight. Completion of the reaction, cooled to room temperature, adjusted to pH 8 sodium hydrogen carbonate, extracted with dichloromethane, the combined organic phases separated, concentrated under reduced pressure to give a crude product which, by Combi-flash chromatography [DCM: MeOH = 90: 10 ~ 70: 30 ] to give a brown solid compound 16-b (2.3g), was used directly in the next reaction. Yield: 49.75percent, purity 96.63percent.
Reference: [1] Patent: CN105524068, 2016, A, . Location in patent: Paragraph 0286; 0287
[2] Journal of Medicinal Chemistry, 1983, vol. 26, # 3, p. 357 - 363
  • 60
  • [ 3167-49-5 ]
  • [ 2032-35-1 ]
  • [ 139022-25-6 ]
YieldReaction ConditionsOperation in experiment
59%
Stage #1: at 90℃; for 2 h;
Stage #2: With sodium hydrogencarbonate In water at 20 - 60℃; for 0.5 h;
[1148] A mixture of bromoacetaldehyde diethylacetal (8.0 ml, 52.5 mmol), H2O (60 ml), and conc. HCl (2.6 ml) is heated to 90° C. with an oil bath for 2 h. 6-aminonicotinic acid (2.5 g, 18.1 mmol) and sodium bicarbonate (4.3 g, 50.7 mmol) are added to the solution at rt, followed by heating the resulting mixture to 60° C. with an oil bath for 30 min. Upon cooling to rt a white ppt. is formed. The resulting off white solid is recrystallized from H2O/EtOH/Et2O to afford white crystals (2.3 g, 10.6 mmol, 59percent) for imidazo[1,2-a]pyridine-6-carboxylic acid. HRMS (FAB) calcd for C8H6N2O2+H 163.0508, found 163.0492.
Reference: [1] Patent: US2003/236264, 2003, A1, . Location in patent: Page 52
  • 61
  • [ 2032-35-1 ]
  • [ 147460-41-1 ]
  • [ 253429-31-1 ]
Reference: [1] Synlett, 2004, # 8, p. 1351 - 1354
  • 62
  • [ 6863-73-6 ]
  • [ 2032-35-1 ]
  • [ 69214-33-1 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: With hydrogen bromide In water for 1 h; Reflux
Stage #2: With hydrogen bromide In 1,2-dimethoxyethane; water for 3 h; Reflux
To a 48percent aqueous hydrogen bromide solution (0.893 mL) and water (9 mL), 2-bromo-1,1-diethoxyethane (5.98 mL, 38.5 mmol) was added, and stirred for one hour while heating under reflux. To the reaction solution, water and ethyl ether were added to separate phases. The water phase was extracted with ethyl ether and organic phases were combined, dried over magnesium sulfate, filtrated and concentrated under reduced pressure. To the resultant residue and a dimethoxyethane (22 mL) solution of 3-chloropyrazine-2-amine (2.0 g, 15.4), a 48percent aqueous hydrogen bromide solution (0.3 mL) was added, stirred for 3 hours while heating under reflux. The resultant solid substance was obtained by filtration and washed with ether to obtain 8-chloroimidazo[1,2-a]pyrazine (2.07 g, 88percent) as a black solid substance.MS (ESI) m/z=154 (M+H)+.
75%
Stage #1: With hydrogen bromide In water for 1 h; Reflux
Stage #2: With hydrogen bromide In 1,2-dimethoxyethane for 1 h; Reflux
Stage #3: With sodium hydrogencarbonate In water
8-Chloroimidazor 1 ,2-alpyrazine[00237] 2-Bromo-l,l-diethoxyethane (6.21 mL, 0.041 mmol) was added to a mixture of 48percent HBr (aq.) solution (1.64 mL) and water (20 mL) and the resulting mixture was stirred under reflux for 1 hour. The reaction mixture was then allowed to cool and washed with brine (2 x 30 mL), dried (MgSO4) and carefully concentrated in vacuo. The resulting oil was dissolved in 1 ,2-dimethoxoethane (20 mL) and added to a suspension of 2-amino-3 -chloro- pyrazine (2.142 g, 0.016 mmol) in 1 ,2-dimethoxoethane (30 mL). 48 percent HBr (aq.) solution (0.313 mL) was then added and the resulting mixture was stirred under reflux for 1 hour. Upon cooling a precipitate formed which was collected by filtration and washed with diethyl ether to give the crude HBr salt. This was dissolved in NaHCO3 (aq.) and extracted into DCM. Drying of the organic layer (MgSO4) followed by concentration in vacuo provided the title compound (1.9 g, 75percent) as a yellow/pale brown solid. 1H NMR (d6-DMSO): 8.68-8.64 (IH, br m), 8.30-8.26 (IH, br m), 7.88-7.85 (IH, br m), 7.75-7.70 (IH, br m).
70%
Stage #1: With hydrogen bromide In water for 2 h; Reflux
Stage #2: With sodium hydrogencarbonate In water; isopropyl alcohol for 0.5 h;
Stage #3: at 85℃; for 4 h;
Bromoacetaldehyde diethyl acetal (17.4 ml, 115.8 mmol) was added dropwise to a 48percent aqueous solution of hydrobromic acid (4.45 ml, 38.6 mmol) at RT. The mixture was stirred at reflux temperature for 2 h. and then poured onto a suspension of sodium hydrogen carbonate (74.5 g, 0.88 mol) in isopropanol (220 ml). The mixture was stirred for a further 30 min. and then filtered off. 3-Chloro-pyrazin-2-ylamine (5 g, 38.6 mmol) was added to the filtrate and the mixture was stirred at 85 °C for 4 h. The solvent was evaporated in vacuo and the crude product suspended in a saturated solution of sodium hydrogen carbonate and extracted with DCM. The organic layer was dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was precipitated from Et20 to yield intermediate 3 (4.1 g, 70percent) as a brown solid which was used in the next step without further purification.
70%
Stage #1: With hydrogen bromide In water for 2 h; Reflux
Stage #2: With sodium hydrogencarbonate In water; isopropyl alcohol for 0.5 h;
Example A3
8-Chloro-imidazo[1,2-a]pyrazine
Bromoacetaldehyde diethyl acetal (17.4 ml, 115.8 mmol) was added dropwise to a 48percent aqueous solution of hydrobromic acid (4.45 ml, 38.6 mmol) at RT.
The mixture was stirred at reflux temperature for 2 h. and then poured onto a suspension of sodium hydrogen carbonate (74.5 g, 0.88 mol) in isopropanol (220 ml).
The mixture was stirred for a further 30 min. and then filtered off. 3-Chloro-pyrazin-2-ylamine (5 g, 38.6 mmol) was added to the filtrate and the mixture was stirred at 85° C. for 4 h.
The solvent was evaporated in vacuo and the crude product suspended in a saturated solution of sodium hydrogen carbonate and extracted with DCM.
The organic layer was dried (Na2SO4), filtered and the solvents evaporated in vacuo.
The crude product was precipitated from Et2O to yield intermediate 3 (4.1 g, 70percent) as a brown solid which was used in the next step without further purification.

Reference: [1] Patent: US2012/59162, 2012, A1, . Location in patent: Page/Page column 38-39
[2] Patent: WO2010/69684, 2010, A1, . Location in patent: Page/Page column 96
[3] Patent: WO2011/110545, 2011, A1, . Location in patent: Page/Page column 73
[4] Patent: US2012/329792, 2012, A1, . Location in patent: Page/Page column 33
[5] Patent: WO2009/12482, 2009, A2, . Location in patent: Page/Page column 90
[6] Patent: WO2010/88518, 2010, A2, . Location in patent: Page/Page column 55
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4196 - 4212
  • 63
  • [ 628322-77-0 ]
  • [ 2032-35-1 ]
  • [ 139022-26-7 ]
Reference: [1] Patent: WO2003/99816, 2003, A1, . Location in patent: Page 43-44
[2] Patent: WO2003/99817, 2003, A1, . Location in patent: Page 36
  • 64
  • [ 38875-53-5 ]
  • [ 2032-35-1 ]
  • [ 676371-00-9 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With hydrogenchloride In 1,4-dioxane; water for 0.5 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 14 h; Heating / reflux
To a soln of [BROMOACETALDEHYDE] diethyl acetal (2.37 mL, 15.4 [MMOL)] in [DIOXANE/H20] (2: 1/15 mL) at rt was added conc. [HCI] (0.3 mL) and the mixture was refluxed for 30 min. The mixture was cooled to rt whereupon [NAHCO3] (2.6 g, 30.8 [MMOL)] was carefully added followed by dropwise addition of diamino derivative (1.5 g, 7.7 [MMOL)] in [DIOXANE/H20] (2: [1/15] mL). The resultant mixture was stirred at reflux for 14 h and was cooled to rt. The mixture was diluted with 1 M [NAOH] (30 mL) and was extracted with [CH2CI2] (3 x 35 mL). The organic layers were combined, washed with brine [(1] x 20 mL), dried [(NA2SO4),] filtered and concentrated under reduced pressure to afford 1.5 g (92percent) of the desired compound [[M +] H = 214. [0].]
Reference: [1] Patent: WO2004/26867, 2004, A2, . Location in patent: Page 32-33
  • 65
  • [ 1072-97-5 ]
  • [ 2032-35-1 ]
  • [ 865156-68-9 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With hydrogen bromide In ethanol at 80℃; for 16 h;
Stage #2: With sodium hydroxide In ethanol; water
A suspension of 2-amino-5-bromopyrimidine (3.0 g, 17.2 mmol), bromoacetaldehyde diethyl acetal (3.2 mL, 20.7 mmol) and 48percent HBr (1.7 mL) in EtOH was heated was heated to 80 0C in a sealed tube for 16 h. After cooling to rt, the reaction was adjusted to pH ~12 with 6N NaOH and the resultant precipitate was collected by filtration, rinsed with water followed by hexanes and dried to a constant weight to give 2.12 g (62percent) of 6-bromoimidazo[l,2-α]pyrimidine as a white solid. MS(ES)+ m/e 199.7 [M+H]+.
Reference: [1] Patent: WO2008/14219, 2008, A2, . Location in patent: Page/Page column 48
  • 66
  • [ 7752-82-1 ]
  • [ 2032-35-1 ]
  • [ 865156-68-9 ]
YieldReaction ConditionsOperation in experiment
20 g
Stage #1: With hydrogen bromide In water at 20℃; for 1.5 h; Cooling with ice
Stage #2: at 85℃; for 0.583333 h; Cooling with ice
Under ice cooling, water (20 mL), hydrobromic acid (content 48percent, 20 mL) and bromoacetaldehyde diethyl acetal (45 mL) was added to, and stirred for 1 hour 30 minutes at room temperature. After stirring the reaction solution with ice-cold vigorously was added sodium hydrogen carbonate (31 g), the reaction solution was filtered. To the filtrate, ethanol (122 ml) and 2-amino-5-bromopyrimidine (21 g) was added and stirred for 35 min at 85 ° C. To the reaction solution was ice-cooled, water (244 mL) was added, was neutralized with sodium hydroxide solution of 4M, and stirred for 30 minutes. Collected by filtration resulting suspension, water (60 mL), followed by n- washed with hexane (60 mL), to give after drying the title compound (20 g) as a solid.
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8713 - 8722
[2] Patent: JP2016/132660, 2016, A, . Location in patent: Paragraph 0098-0099
  • 67
  • [ 957230-70-5 ]
  • [ 2032-35-1 ]
  • [ 957344-74-0 ]
YieldReaction ConditionsOperation in experiment
2.75 g at 120℃; for 4 h; 3,6-dibromopyrazin-2-ylamine (4.0 g, 15.80 mmol) and bromoacetaldehyde diethyl acetal (3.7 mL, 24.00mmol) and tetrahydrofuran (5.3 mL) eere dissolved in distilled water (53 mL), the mixture was stirred for 4 hours at 120°C .Saturated aqueous sodium hydrogen carbonate solution to the reaction solution was neutralized by addition. The resulting solid was filtered and washed with distilled water and dried to give the title compound (2.75 g).
Reference: [1] Patent: US2009/286798, 2009, A1, . Location in patent: Page/Page column 27
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2266 - 2270
[3] Patent: KR2015/113801, 2015, A, . Location in patent: Paragraph 0127-0130
  • 68
  • [ 59489-71-3 ]
  • [ 2032-35-1 ]
  • [ 912773-24-1 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With hydrogen bromide In water; isopropyl alcohol at 140℃; for 1.5 h; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In water; isopropyl alcohol for 0.166667 h;
Stage #3: for 2 h; Reflux
Example 17-7
Synthesis of 6-bromoimidazo[1,2-a]pyrazine
A mixture of bromoacetaldehyde diethylacetal (19.7 g, 0.1 M) and 48percent hydrobromic acid (4 ml) was heated to 140 °C under nitrogen for 1.5 hours.
The resulting mixture was poured onto a stirred suspension of sodium bicarbonate (40 g) in propan-2-ol (200 ml) and the resulting suspension was stirred for 10 minutes and then filtered. 5-Bromo-pyrazine-2-ylamine 12* (8.65 g, 0.05 M) was added to the filtrate and the resulting solution was heated at reflux for two hours.
The solvent was evaporated in vacuo to give dark brown viscous material.
The residue was treated with saturated sodium bicarbonate (150 ml) and extracted twice with dichloromethane (500 ml).
The combined extracts were dried and evaporated in vacuo to give a brown oil, which was purified by flash chromatography with ethyl acetate as eluant to give 7.0 g of the desired product 16* as a light brown solid (Yield 71percent).
1H-NMR (400 MHz, CDCl3): δ = 7.71 (s, 1 H, Ar), 7.85 (s, 1 H, ArH), 8.30 (s, 1 H, ArH), 8.92 (s, 1 H, ArH).
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8713 - 8722
[2] Patent: EP2818471, 2014, A1, . Location in patent: Paragraph 0189; 0190
  • 69
  • [ 88497-27-2 ]
  • [ 2032-35-1 ]
  • [ 1159977-65-7 ]
YieldReaction ConditionsOperation in experiment
100% at 80℃; for 16 h; To a solution of 6-bromopyridazin-3-amine (3.48 g, 20 mmol) in EtOH/H2O (5/1, 180 mL) was added 2-bromo-1,1-diethoxyethane (11.8 g, 60 mmol), followed by p-toluenesulphonic acid (20.6 mg, 0.12 mmol). The mixture was stirred at 80° C. for 16 hours and then concentrated in vacuo. The resulted solid was washed with H2O (4 mL), collected by filtration, and dried in a vacuum oven overnight at 40° C. to give the title compound as a gray solid (3.9 g, 100percent). MS (ESI, pos. ion) m/z: 198.1 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 8.71 (d, J=9.6 Hz, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.33 (d, J=1.9 Hz, 1H), 7.97 (d, J=9.6 Hz, 1H).
Reference: [1] Patent: US2014/134133, 2014, A1, . Location in patent: Paragraph 0288
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 2032-35-1 ]

Aliphatic Chain Hydrocarbons

Chemical Structure| 7252-83-7

[ 7252-83-7 ]

2-Bromo-1,1-dimethoxyethane

Similarity: 0.90

Chemical Structure| 3400-55-3

[ 3400-55-3 ]

2-Bromopriopionaldehydediethylacetal

Similarity: 0.80

Chemical Structure| 33170-72-8

[ 33170-72-8 ]

2-Bromo-1,1-dimethoxypropane

Similarity: 0.72

Chemical Structure| 126-38-5

[ 126-38-5 ]

1-Bromo-2,2-dimethoxypropane

Similarity: 0.69

Chemical Structure| 22094-18-4

[ 22094-18-4 ]

1,3-Dibromo-2,2-dimethoxypropane

Similarity: 0.67

Bromides

Chemical Structure| 4360-63-8

[ 4360-63-8 ]

2-Bromomethyl-1,3-dioxolane

Similarity: 0.91

Chemical Structure| 7252-83-7

[ 7252-83-7 ]

2-Bromo-1,1-dimethoxyethane

Similarity: 0.90

Chemical Structure| 3400-55-3

[ 3400-55-3 ]

2-Bromopriopionaldehydediethylacetal

Similarity: 0.80

Chemical Structure| 33170-72-8

[ 33170-72-8 ]

2-Bromo-1,1-dimethoxypropane

Similarity: 0.72

Chemical Structure| 17739-45-6

[ 17739-45-6 ]

2-(2-Bromoethoxy)tetrahydro-2H-pyran

Similarity: 0.70

Ethers

Chemical Structure| 7252-83-7

[ 7252-83-7 ]

2-Bromo-1,1-dimethoxyethane

Similarity: 0.90

Chemical Structure| 33170-72-8

[ 33170-72-8 ]

2-Bromo-1,1-dimethoxypropane

Similarity: 0.72

Chemical Structure| 17739-45-6

[ 17739-45-6 ]

2-(2-Bromoethoxy)tetrahydro-2H-pyran

Similarity: 0.70

Chemical Structure| 126-38-5

[ 126-38-5 ]

1-Bromo-2,2-dimethoxypropane

Similarity: 0.69

Chemical Structure| 22094-18-4

[ 22094-18-4 ]

1,3-Dibromo-2,2-dimethoxypropane

Similarity: 0.67