[ CAS No. 344329-76-6 ] {[proInfo.proName]}

Name: 344329-76-6|Tetrahydro-2H-pyran-4-carboxamide|97%
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Quality Control of [ 344329-76-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 344329-76-6 ]

CAS No. :	344329-76-6	MDL No. :	MFCD08235066
Formula :	C₆H₁₁NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DGOYLVBDCVINQZ-UHFFFAOYSA-N
M.W :	129.16	Pubchem ID :	13197203
Synonyms :

Calculated chemistry of [ 344329-76-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	32.83
TPSA :	52.32 Å²

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) :	-7.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.07
Log Po/w (XLOGP3) :	-0.55
Log Po/w (WLOGP) :	-0.1
Log Po/w (MLOGP) :	-0.41
Log Po/w (SILICOS-IT) :	0.54
Consensus Log Po/w :	0.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.23
Solubility :	76.4 mg/ml ; 0.591 mol/l
Class :	Very soluble
Log S (Ali) :	-0.08
Solubility :	108.0 mg/ml ; 0.833 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.33
Solubility :	60.6 mg/ml ; 0.469 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

Safety of [ 344329-76-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 344329-76-6 ]

* 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 [ 344329-76-6 ]
Downstream synthetic route of [ 344329-76-6 ]

[ 344329-76-6 ] Synthesis Path-Upstream 1~7

1
[ 344329-76-6 ]
[ 38041-19-9 ]

Yield	Reaction Conditions	Operation in experiment
91.8%	With sodium hypobromide; sodium hydroxide In water at 5 - 50℃; for 3 h;	(2) cooling the 4-formamide tetrahydropyran mixed solution prepared in the step 1 to a temperature of 5 ° C, adding a NaOH solution,After stirring uniformly, NaBrO solution was added dropwise thereto. After the completion of the dropwise addition, the reaction was continued at this temperature for 2 hours, and then the temperature was raised to 50 ° C for 1 hour, then cooled to room temperature, extracted with dichloromethane, and the organic phase was combined. After dichloromethane was removed by pressure distillation, recrystallization was carried out to obtain 4-aminotetrahydropyran.Preferably, the molar volume ratio of tetrahydropyran-4-carboxylic acid to water in the step (1) is 5 mol/L.The concentration of ammonia water in the step (1) is 13 mol/L; the amount of tetrahydropyran-4-carboxylic acid and ammonia in the step (1)The molar volume ratio is 10:1 mol/L.The mass concentration of the NaOH solution in the step (2) is 40percent, the 4-formamide tetrahydropyran mixed solution and the NaOH solutionThe volume-to-volume ratio was 7:1; the mass concentration of the NaBrO solution in the step (2) was 15percent.The molar ratio of tetrahydropyran-4-carboxylic acid to NaBrO was 1:1.5.The obtained 4-aminotetrahydropyran had a purity of 99.2percent and a product yield of 91.8percent.
73.7%	With sodium hypochlorite In water at 0 - 5℃; for 3 h; Reflux	Three-neck flask equipped with mechanical stirrer, thermometer, dropping funnel, 250ml of water was added to the flask, stirring was added 4-cyano-tetrahydropyran 111.14g (1mole), cooled to 0 ~ 5 ° C, was added at a concentration of 10 minutes 13.8percent sodium hydroxide solution, a total of 290 g (1 mole), temperature controlled at 0 ~ 10 ° C, after each addition incubated for 15 to 20 minutes, all the alkali was added, stirred for 1 to 3 hours, the reaction was complete by gas detecting material, controlling the temperature of 0 ~ 5 ° C, was slowly added to a concentration of 10percent sodium hypochlorite solution 1116.6g (1.5mole), plus Bi, 0 ~ 5 ° C for 1 hour, heated at reflux temperature for 2 hours to complete the reaction intermediate vapor detection, water cooling to 10 ~ 40 ° C, with 500ml dichloromethane and 50ml methanol solvent mixture and extracted 3 times, the combined extracts were recovered by distillation of methylene chloride, methylene chloride was distilled off to make, distillation to give 4-amino-tetrahydropyran 75.3 g, with a purity of 99.1percent, a yield of 73.7percent.

Reference： [1] Patent: CN108003122, 2018, A, . Location in patent: Paragraph 0021; 0029; 0034; 0034; 0037; 0038; 0039-0041
[2] Patent: CN102993144, 2016, B, . Location in patent: Paragraph 0014; 0015
[3] Helvetica Chimica Acta, 1943, vol. 26, p. 1132,1134

2
[ 344329-76-6 ]
[ 130290-79-8 ]

Reference： [1] Patent: WO2004/58759, 2004, A1, . Location in patent: Page 284
[2] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 88
[3] Patent: WO2007/75468, 2007, A1, . Location in patent: Page/Page column 111

3
[ 344329-76-6 ]
[ 4295-99-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	for 4 h; Reflux; Inert atmosphere	Thionyl chloride (10.0 mL, 137 mmol) was added to oxane-4-carboxamide (3.0 g, 23 mmol) and thereaction mixture was refluxed for 4 h, after which the reaction mixture was poured over ice andbasified to pH 14 with NaOH (50percent). The aqueous solution was extracted with EtOAc (3 × 50 mL),dried (Na2SO4) and concentrated in vacuo to give the product as a pale yellow oil (2.4 g, 94percent). Theproduct obtained did not require any further purification.IR νmax 2961, 2932, 2851, 2240, 1468, 1446, 1390, 1242, 1125, 1066, 1011 cm−1;1H-NMR (CDCl3, 500 MHz): 3.91 (2H, ddd, J 11.9, 6.3, 3.6, 2×2-HA), 3.61 (2H, ddd, J 11.9, 7.8, 3.3,2×2-HB), 2.91–2.85 (1H, m, 4-H), 1.99–1.92 (2H, m, 2×3-HA), 1.91–1.84 (2H, m, 2×3-HB);13C-NMR (CDCl3, 75 MHz): 121.2, 65.6, 28.9, 25.3;HRMS (ESI+): Calculated for C6H10NO ([M+H]+): 112.0756. Found: 112.0754, Δ –1.8 ppm.
90%	With thionyl chloride In benzene for 4 h; Heating / reflux	A suspension of tetrahydro-2H-pyran-4-carboxamide (4.90 g, 37.9 mmol) in benzene (10 ml) was treated with thionyl chloride (5 ml) and the resulting mixture was stirred at reflux for 4 hours. The cooled mixture was poured onto ice and basified with 50percent potassium hydroxide. The aqueous fraction was saturated with salt and extracted with ethyl acetate. The organic fraction was then dried over anhydrous magnesium sulfate and concentrated. Distillation under reduced pressure gave 3.80 g (90percent yield) of the title nitrile as a clear oil: bp 80-90° C./15 torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.91 (4H, m, 2.x.CH₂), 2.89 (1H, m, CH), 3.62 (2H, m, OCH₂), 3.92 (2H, m, OCH₂).

Reference： [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 11, p. 2629 - 2635
[2] Patent: US2007/111984, 2007, A1, . Location in patent: Page/Page column 45
[3] Journal of the American Chemical Society, 1943, vol. 65, p. 370
[4] Patent: US2009/253679, 2009, A1, . Location in patent: Page/Page column 54-55

4
[ 110238-91-0 ]
[ 344329-76-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With ammonia In water at 20℃; for 18 h;	A mixture of methyl tetrahydro-2/-/-pyran-4-carboxylate (7 g , 48.6 mmol) and 30percent aqueous ammonia (20 mL) was stirred in a closed bottle at r.t. for 18 h. The ammonia excess was removed under reduced pressure and the residue was crystallized from ethanol affording 5.6 g (89percent) of tetrahydro-2/-/-pyran-4-carboxamide. ¹H NMR (401 MHz, DMSO-d₆) δ ppm 7.21 (br. s., 1 H), 6.73 (br. s., 1 H), 3.90 - 3.80 (m, 2 H), 3.30 -3.23 (m, 2H), 2.36 - 2.24 (m, 1 H), 1.66 - 1.47 (m, 4 H)
89%	With ammonia In water at 20℃; for 18 h; Sealed tube	Tetrahydro-2H-pyran-4-carboxamide A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (7 g, 48.6 mmol) and 30percent aqueous ammonia (20 mL) was stirred in a closed bottle at r.t. for 18 h. The ammonia excess was removed under reduced pressure and the residue was crystallized from ethanol affording 5.6 g (89percent) of tetrahydro-2H-pyran-4-carboxamide. ¹H NMR (401 MHz, DMSO-d₆) δ ppm 7.21 (br. s., 1H), 6.73 (br. s., 1H), 3.90-3.80 (m, 2H), 3.30-3.23 (m, 2H), 2.36-2.24 (m, 1H), 1.66-1.47 (m, 4H)
78%	With ammonia In water at 22℃; for 18 h;	A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (7.0 g, 48.6 mmol) and concentrated ammonia (20 ml) was stirred at 22° C. for 18 h. The excess ammonia was then removed under reduced pressure and the residue was crystallized from ethanol to give 4.94 g (78percent yield) of the title amide as white crystals: mp 179-181° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.81 (4H, m, 2.x.CH₂), 2.42 (1H, m, CH), 3.44 (2H, m, OCH₂), 4.04 (2H, m, OCH₂), 5.55 and 5.8 (2.x.1H, broad, NH₂).

74.6%	With ammonia In water at 20℃; for 43.5 h;	Production Example 2; Tetrahydro-2H-pyran-4-carboxamide; To methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) was added concentrated ammonia water (50 mL), and the reaction mixture was stirred at room temperature for 43.5 hours. Thereafter, the reaction mixture was cooled in an ice water bath, and the precipitate was filtrated. Then, the precipitate was dried at 40° C. under reduced pressure, to obtain 33.4 g of a title compound (yield: 74.6percent). ¹H NMR (400 MHz, DMSO-d₆) δ 1.45-1.62 (m, 4H), 2.28 (tt, J=11.1, 4.4 Hz, 1H) 3.26 (ddd, J=11.4, 11.4, 2.7 Hz, 2H), 3.82 (br d, J=11.4 Hz, 2H), 6.74 (br s, 1H), 7.21 (br s, 1H)
74.6%	With ammonia In water at 20℃; for 43.5 h;	[0511] Concentrated aqueous ammonia (50 mL) was added to methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) and the reaction mixture was stirred for 43.5 hours at room temperature. The reaction mixture was then cooled in an ice water bath, after which the precipitate was filtered out and dried under reduced pressure at 40° C. to afford 33.4 g of the title compound (74.6percent yield). [0512] 1H NMR (400 MHz, DMSO-d6) δ 1.45-1.62 (m, 4H), 2.28 (tt, J=11.1, 4.4 Hz, 1H), 3.26 (ddd, J=11.4, 11.4, 2.7 Hz, 2H), 3.82 (br d, J=11.4 Hz, 2H), 6.74 (br s, 1H), 7.21 (br s, 1H).
69%	for 48 h; Inert atmosphere	Methyl tetrahydro-2H-pyran-4-carboxylate (10 g, 69 mmol) was stirred in ammonium hydroxide(35percent, 500 mL) for 2 d. The reaction mixture was concentrated in vacuo. The white residual solid wasrecrystallized from ethanol to give oxane-4-carboxamide (6.1 g, 69 percent) as colourless plates.1H-NMR (CDCl3, 500 MHz): 3.86 (2H, dt, J 11.4, 3.3, 2×2-HA), 3.38–3.29 (2H, m, 2×2-HB), 2.43–2.31(1H, m, 4-H), 1.71–1.56 (4H, m, 2×3-H2);13C-NMR (CDCl3, 75 MHz): 180.3, 68.3, 42.5, 30.4;HRMS (ESI+): Calculated for C6H11NaNO ([M+Na]+): 152.0682. Found: 152.0678, Δ –2.6 ppm.

Reference： [1] Patent: WO2012/113774, 2012, A1, . Location in patent: Page/Page column 41-42
[2] Patent: US2013/324551, 2013, A1, . Location in patent: Paragraph 0326; 0327
[3] ChemMedChem, 2015, vol. 10, # 2, p. 276 - 295
[4] Patent: WO2015/62486, 2015, A1, . Location in patent: Paragraph 00325
[5] Patent: US2007/111984, 2007, A1, . Location in patent: Page/Page column 45
[6] Patent: US2007/191613, 2007, A1, . Location in patent: Page/Page column 9
[7] Patent: US2004/224974, 2004, A1, . Location in patent: Page 57
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 11, p. 2629 - 2635
[9] Journal of the Chemical Society, 1930, p. 2525,2529
[10] Patent: WO2004/58759, 2004, A1, . Location in patent: Page 283-284
[11] Patent: WO2005/20999, 2005, A1, . Location in patent: Page/Page column 248
[12] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 88
[13] Patent: WO2007/75468, 2007, A1, . Location in patent: Page/Page column 111

5
[ 5337-03-1 ]
[ 344329-76-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With triethylamine; isobutyl chloroformate In chloroform at 0℃; for 2 h; Inert atmosphere Stage #2: With ammonia In chloroform for 0.25 h; Inert atmosphere	Intermediate 30 oxane-4-carboxamide To a stirred solution of oxane-4-carboxylic acid (800 mg, 6.15 mmol) in chloroform (5 mL) were added triethylamine (1.28 mL, 9.22 mmol) and isobutyl chloro formate (884 μ, 7.37 mmol) dropwise at 0°C under argon. The reaction mixture was stirred at 0°C for 2 h and then ammonia gas was passed through the solution for 15 min. The reaction mixture was concentrated. The residue was dissolved in propan-2-ol/chloroform (1 :4, 25 mL) and washed with water, 5percent aHC03(aq) and then 1M HCl_(aq). The organic phase was dried (Na₂SC>4), filtered and concentrated. The crude product was purified by trituration in DCM to afford the title compound as a white solid (1.20 g, 91percent); ^{FontWeight="Bold" FontSize="10"}H NMR (400 MHz, DMSO-i/₆) δ 1.44 - 1.63 (m, 4H), 2.23 - 2.34 (m, 1H), 3.27 (td, 2H), 3.82 (ddd, 2H), 6.75 (s, 1H), 7.22 (s, 1H).
46%	Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0℃; for 1 h; Inert atmosphere Stage #2: With ammonium hydroxide In acetonitrile at 20℃;	Example B5 A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h. Ammonium hydroxide (˜15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight. The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2*). The combined organics were washed with brine, dried over Na₂SO₄ and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46percent) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).
46%	Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0℃; for 1 h; Inert atmosphere Stage #2: With ammonium hydroxide In acetonitrile at 20℃;	Example B5 A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h. Ammonium hydroxide (˜15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight. The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2*). The combined organics were washed with brine, dried over Na₂SO₄ and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46percent) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).

Reference： [1] Patent: WO2015/177367, 2015, A1, . Location in patent: Page/Page column 71; 72
[2] Patent: US2014/275016, 2014, A1, . Location in patent: Paragraph 0254
[3] Patent: US2014/275080, 2014, A1, . Location in patent: Paragraph 0358
[4] Journal of the Chemical Society, 1930, p. 2525,2529
[5] Journal of the Chemical Society, 1930, p. 2525,2529
[6] Patent: WO2015/62486, 2015, A1,
[7] Patent: CN108003122, 2018, A, . Location in patent: Paragraph 0020; 0028; 0034; 0035; 0036; 0044; 0052

6
[ 40191-32-0 ]
[ 344329-76-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With ammonia In water at 0℃; for 6 h;	Example 6Synthesis of tetrahydropyran-4-carboxylic acid amide; In a vessel made of a glass, having an inner volume of 100 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 6.30 g (38.5 mmol) of tetrahydropyran-4-carboxylic acid chloride synthesized in the same method as in Example 5 and 20 g (329 mmol) of 28percent by weight aqueous ammonia, and the mixture was reacted at 0° C. for 6 hours under stirring. After completion of the reaction, the reaction mixture was filtered, and the obtained filtrate was dried to obtain 4.84 g (Isolation yield; 62percent) of tetrahydropyran-4-carboxylic acid amide was white crystals.Physical properties of the tetrahydropyran-4-carboxylic acid amide were as follows.¹H-NMR (CDCl₃, δ (ppm)); 1.46 to 1.62 (4H, m), 2.26 to 2.52 (1H, m), 3.28 to 3.34 (2H, m), 3.81 to 3.87 (2H, m), 6.77 to 7.24 (2H, d)CI-MS (m/e); 130 (M+1)

Reference： [1] Patent: US2008/306287, 2008, A1, . Location in patent: Page/Page column 6
[2] Journal of the Chemical Society, 1930, p. 2525,2529
[3] Journal of the Chemical Society, 1930, p. 2525,2529

7
[ 4295-99-2 ]
[ 344329-76-6 ]

Reference： [1] Patent: CN102993144, 2016, B, . Location in patent: Paragraph 0014; 0015

[ 344329-76-6 ] Synthesis Path-Downstream 1~88

1
[ 5337-03-1 ]
[ 344329-76-6 ]

Yield	Reaction Conditions	Operation in experiment
91%		Intermediate 30 oxane-4-carboxamide To a stirred solution of oxane-4-carboxylic acid (800 mg, 6.15 mmol) in chloroform (5 mL) were added triethylamine (1.28 mL, 9.22 mmol) and isobutyl chloro formate (884 mu, 7.37 mmol) dropwise at 0°C under argon. The reaction mixture was stirred at 0°C for 2 h and then ammonia gas was passed through the solution for 15 min. The reaction mixture was concentrated. The residue was dissolved in propan-2-ol/chloroform (1 :4, 25 mL) and washed with water, 5percent aHC03(aq) and then 1M HCl(aq). The organic phase was dried (Na2SC>4), filtered and concentrated. The crude product was purified by trituration in DCM to afford the title compound as a white solid (1.20 g, 91percent); FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6) delta 1.44 - 1.63 (m, 4H), 2.23 - 2.34 (m, 1H), 3.27 (td, 2H), 3.82 (ddd, 2H), 6.75 (s, 1H), 7.22 (s, 1H).
46%		Example B5 A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h. Ammonium hydroxide (?15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight. The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2*). The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).
46%		Example B5 A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h. Ammonium hydroxide (?15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight. The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2*). The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).

With ammonium hydroxide; In water; at 60℃; for 2h;

(1) tetrahydropyran-4-carboxylic acid is dissolved in water, heated to a temperature of 60 ° C, and ammonia water is added dropwise thereto under stirring.After the completion of the dropwise addition, the stirring reaction was continued for 2 hours, and after the completion of the reaction, the mixture was cooled to room temperature to obtain a 4-formamide tetrahydropyran mixed solution;

Reference： [1]Patent: WO2015/177367,2015,A1 .Location in patent: Page/Page column 71; 72
[2]Patent: US2014/275016,2014,A1 .Location in patent: Paragraph 0254
[3]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0358
[4]Journal of the Chemical Society,1930,p. 2525,2529
[5]Journal of the Chemical Society,1930,p. 2525,2529
[6]Patent: WO2015/62486,2015,A1
[7]Patent: CN108003122,2018,A .Location in patent: Paragraph 0020; 0028; 0034; 0035; 0036; 0044; 0052

2
[ 344329-76-6 ]
[ 130290-79-8 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 6h;Heating / reflux;	A solution of <strong>[344329-76-6]tetrahydropyran-4-carboxamide</strong> (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0 °C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in six portions over a period of ten minutes. The reaction flask was purged with nitrogen between the additions. When the reaction mixture was no longer bubbling, it was heated at reflux for six hours. The reaction was then cooled to 0 °C, and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15percent aqueous sodium hydroxide (10 mL), and water (30 mL) were sequentially added. The organic fraction was decanted off, and the remaining gray solid was washed with chloroform. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide C- (tetrahydropyran-4-yl) methylamine.
		Preparation 111; C- (Tetrahvdro-pyran)-metvlamine; In a 2L flask, charge <strong>[344329-76-6]tetrahydro-pyran-4-carboxylic acid amide</strong> (51g, 0. 395mol) and THF (1. 3L) and cool the reaction in an ice-bath. Add LAH (30g, 0.791) portion-wise. Stir the reaction at 10°C for 16 hours and quench by the drop-wise addition of DI water (30ml), 15percent NaOH (30ml), and DI water (90mol). Stir the reaction at ambient temperature for 16 hours. Filter the salts and concentrate the filtrate under vacuum to give 36.79g clear oil of the title compound.
		A solution of tetrahydro-2Hr-pyran-4-carboxamide (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0 0C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in six portions over a period of ten minutes. The reaction flask was purged with nitrogen between the additions. When the reaction mixture was no longer bubbling, it was heated at reflux for six hours. The reaction was then cooled to 0 0C, and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15percent aqueous sodium hydroxide (10 mL), and water (30 mL) were sequentially added. The organic fraction was decanted off, and the remaining gray solid was washed with chloroform. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tetrahydro- 2H-pyran-4-ylmethy lamine .

Reference： [1]Patent: WO2004/58759,2004,A1 .Location in patent: Page 284
[2]Patent: WO2005/66126,2005,A1 .Location in patent: Page/Page column 88
[3]Patent: WO2007/75468,2007,A1 .Location in patent: Page/Page column 111

3
[ 344329-76-6 ]
[ 685886-92-4 ]
N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-pyrane-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.6%		Production Example 3; N-(2-Ethyl-[1,5-a]pyridine-3-yl)<strong>[344329-76-6]tetrahydro-2H-pyran-4-carboxamide</strong>; A mixture of 2-ethyl-3-iodopyrazolo[1,5-a]pyridine (350 g, 1.29 mol), <strong>[344329-76-6]tetrahydro-2H-pyran-4-carboxamide</strong> (249 g, 1.93 mmol), copper iodide (49.0 g, 258 mmol), tripotassium phosphate (hydrate) (546 g, 2.57 mol), 1,2-cyclohexanediamine (mixture of cis and trans) (58.7 g, 514 mmol) and xylene (3500 mL) was stirred for 6 hours at an outer temperature of 120° C. (oil bath). Heating was stopped, and when the inner temperature of the reaction mixture reached 61.5° C., hot water (3500 mL) of 58° C. was added to the reaction mixture, and the mixture was stirred overnight under the same condition. To the reaction mixture was added 28percent ammonia water (1050 mL) and the mixture was stirred for 1 hour, and a precipitate was filtrated. The precipitate was washed with water (1750 mL) and ethyl acetate (1050 mL), and air-dried at 60° C. overnight, to obtain 280 g of a title compound (6:1 mixture of main conformer:sub conformer) (yield: 79.6percent). Main Conformer: 1H NMR (400 MHz, CDCl3) delta 1.33 (t, J=7.7 Hz, 3H), 1.88-2.05 (m, 4H), 2.57-2.67 (m, 1H), 2.75 (q, J=7.7 Hz, 2H), 3.50 (ddd, J=11.4, 11.4, 2.9 Hz, 2H), 4.09 (ddd, J=11.4, 4.0, 2.6 Hz, 2H), 6.68 (ddd, J=6.8, 6.8, 1.3 Hz, 1H), 6.82 (br s, 1H), 7.07 (ddd, J=9.0, 6.8, 1.3 Hz, 1H), 7.29 (br d, J=9.0 Hz, 1H) 8.30 (d, J=6.8 Hz, 1H). Sub Conformer: 1H NMR (400 MHz, CDCl3) delta 1.34 (t, J=7.7 Hz, 3H), 1.40-1.50 (m, 2H), 1.88-2.05 (m, 2H), 2.37-2.48 (m, 1H), 2.78 (q, J=7.7 Hz, 2H), 3.14 (ddd, J=11.9, 11.9, 1.8 Hz, 2H), 3.84-3.92 (m, 2H), 6.56 (br s, 1H), 6.80 (ddd, J=6.8, 6.8, 1.3 Hz, 1H), 7.20 (br dd, J=9.0, 6.8 Hz, 1H), 7.34 (br d, J=9.0 Hz, 1H), 8.39 (d, J=6.8 Hz, 1H).
79.6%		[0514] A mixture of 2-ethyl-3-iodopyrazolo[1,5-a]pyridine (350 g, 1.29 mol), tetrahydro-2H-4-pyrancarboxamide (249 g, 1.93 mol), copper iodide (49.0 g, 258 mmol), tripotassium phosphate (hydrate) (546 g, 2.57 mol), 1,2-cyclohexanediamine (mixture of cis and trans) (58.7 g, 514 mmol) and xylene (3500 mL) was stirred while heating at an external temperature of 120° C. (oil bath). The reaction mixture was heated and stirred for 6 hours, and then heating was terminated and upon reaching an internal temperature of 61.5° C., hot water (58° C., 3500 mL) was added to the reaction mixture and stirring was continued overnight. After adding 28percent aqueous ammonia (1050 mL) to the reaction mixture and stirring for 1 hour, the precipitate was filtered out and washed with water (1750 mL) and ethyl acetate (1050 mL) and then dried under aeration at 60° C. overnight to afford 280 g of the title compound (major conformer:minor conformer=6:1) (79.6percent yield). [0515] Major Conformer [0516] 1H NMR (400 MHz, CDCl3) delta 1.33 (t, J=7.7 Hz, 3H), 1.88-2.05 (m, 4H), 2.57-2.67 (m, 1H), 2.75 (q, J=7.7 Hz, 2H), 3.50 (ddd, J=11.4, 11.4, 2.9 Hz, 2H), 4.09 (ddd, J=11.4, 4.0, 2.6 Hz, 2H), 6.68 (ddd, J=6.8, 6.8, 1.3 Hz, 1H), 6.82 (br s, 1H), 7.07 (ddd, J=9.0, 6.8, 1.3 Hz, 1H), 7.29 (br d, J=9.0 Hz, 1H), 8.30 (d, J=6.8 Hz, 1H). [0517] Minor Conformer [0518] 1H NMR (400 MHz, CDCl3) delta 1.34 (t, J=7.7 Hz, 3H), 1.40-1.50 (m, 2H), 1.88-2.05 (m, 2H), 2.37-2.48 (m, 1H), 2.78 (q, J=7.7 Hz, 2H), 3.14 (ddd, J=11.9, 11.9, 1.8 Hz, 2H), 3.84-3.92 (m, 2H), 6.56 (br s, 1H), 6.80 (ddd, J=6.8, 6.8, 1.3 Hz, 1H), 7.20 (br dd, J=9.0, 6.8 Hz, 1H), 7.34 (br d, J=9.0 Hz, 1H), 8.39 (d, J=6.8 Hz, 1H).
78%	With copper(l) iodide; potassium phosphate monohydrate; 2,2-Dimethyl-1,3-diaminopropane; In 5,5-dimethyl-1,3-cyclohexadiene; at 125℃; for 18h;Inert atmosphere;	2-ethyl-3-iodopyrazolo[1,5-a]pyridine 2.0 g (7.36mmol), <strong>[344329-76-6]tetrahydro-2H-pyrane-4-carboxamide</strong> 1.43 g (11.1mmol, 1.5eq), cuprous iodide (1.47mmol, 0.2eq) 0.28 g, 2,2-dimethyl-1,3-propanediamine (0.6eq) 0.452 g, potassium triphosphate (K3 PO4 ·NH2 O) and 20 ml of xylene(10vol) under a nitrogen atmosphere (14.7mmol, 2.0eq) 3.39 g, 125 degrees temperature in heated, stirred for 18 hours. In the slowly cooled to a temperature of 95, 95 degrees 30 minutes after stirring, the temperature is slowly cooled within the 55 degree. 20 ml water (10vol) is added, the heating is stopped and gradual cooling to room temperature. In addition to the water temperature is sufficiently lowered from 6 ml of concentrated ammonia (3vol) ([35 degrees), for about 1 hour with stirring. The resulting suspension was filtered, washed with 12 ml of water (6vol), the resulting solid was returned to the reaction vessel, 12 ml of water, concentrated ammonia water added was stirred 0.5 hour to about 2 ml (1vol). The resulting suspension was filtered again, the resulting solid was 10 ml water (5vol), followed by 6 ml of ethyl acetate was washed (3vol). The filtration product was dried under reduced pressure, 1.56 g of the subject compound is a white solid, 78percent yield was obtained.

Reference： [1]Patent: US2007/191613,2007,A1 .Location in patent: Page/Page column 9
[2]Patent: US2004/224974,2004,A1 .Location in patent: Page 58
[3]Patent: JP2017/100995,2017,A .Location in patent: Paragraph 0020

5
[ 344329-76-6 ]
[ 88571-77-1 ]

Yield	Reaction Conditions	Operation in experiment
59.3%	With Lawessons reagent; In tetrahydrofuran; at 60℃; for 14h;Inert atmosphere;	Compound 67 (3 g, 23.23 mmol) , Lawson's reagent (4.7 g, 11.61 mmol) was added to a round bottom flask containing 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and stirred at 60 for 14 h. LCMS monitoring, after the reaction was completed, quenched with saturated sodium bicarbonate solution (100 mL) , extracted with EtOAc (200 mL × 2) , and the combined extracts were washed with saturated aqueous sodium chloride (50 mL) , dried with anhydrous Na 2SO 4, concentrated under reduced pressure, and then purified by column chromatography (eluent: dichloromethane/methanol, 10/1, v/v) , obtained 2 g of a white soild, yield: 59.3%. 1HNMR (400 MHz, DMSO-d 6) : delta ppm 1.55-1.59 (m, 2H) , 1.70-1.81 (m, 2H) , 2.68-2.76 (m, 1H) , 3.30-3.34 (m, 2H) , 3.86-3.90 (m, 2H) , 9.10 (s, 1H) , 9.40 (s, 1H) . LCMS: Rt = 1.01 min, MS Calcd.: 145.2, MS Found: 145.9 [M+H]
54%	With Lawessons reagent; In tetrahydrofuran; for 4h;Reflux;	Tetrahydro-2/-/-pyran-4-carboxamide (2 g, 15.5 mmol) was suspended in dry THF (20 ml_) and Lawesson's reagent (3.13 g, 7.75mmol) was added. After refluxing for 4 h the mixture was poured into a saturated NaHC03 aqueous solution (200 ml_) and then extracted with diethylether (4 x 100 ml_). The organic layer was dried over Na2S04 and evaporated to dryness, affording 1.2 g (54%) of the title compound.HPLC: Rt: min 2.791H NMR (401 MHz, DMSO-d6) delta ppm 9.37 (br. s., 1 H), 9.08 (br. s., 1 H), 3.87 (dd, J = 4.0, 11.0 Hz, 2 H), 3.37 -3.23 (m, 2 H), 2.78 - 2.67 (m, 1 H), 1.75 (dq, J = 4.5, 12.5 Hz, 2 H), 1.63 - 1.52 (m, 2 H)HRMS (ESI) calcd for Ci6HnNOS [M+H]+ 146.0634, found 146.0634.
54%	With Lawessons reagent; In tetrahydrofuran; for 4h;Reflux;	Tetrahydro-2H-pyran-4-carbothioamide, cmpd. of formula 8 [R1=tetrahydropyran-4-yl] Tetrahydro-2H-pyran-4-carboxamide (2 g, 15.5 mmol) was suspended in dry THF (20 mL) and Lawesson's reagent (3.13 g, 7.75 mmol) was added. After refluxing for 4 h the mixture was poured into a saturated NaHCO3 aqueous solution (200 mL) and then extracted with diethylether (4*100 mL). The organic layer was dried over Na2SO4 and evaporated to dryness, affording 1.2 g (54%) of the title compound. HPLC: Rt: min 2.79 1H NMR (401 MHz, DMSO-d6) delta ppm 9.37 (br. s., 1H), 9.08 (br. s., 1H), 3.87 (dd, J=4.0, 11.0 Hz, 2H), 3.37-3.23 (m, 2H), 2.78-2.67 (m, 1H), 1.75 (dq, J=4.5, 12.5 Hz, 2H), 1.63-1.52 (m, 2H) HRMS (ESI) calcd for C16H11NOS [M+H]+ 146.0634. found 146.0634.

43.8%	With Lawessons reagent; In tetrahydrofuran; for 6h;Inert atmosphere; Reflux;	A solution of <strong>[344329-76-6]tetrahydro-2H-pyran-4-carboxamide</strong> (9.47 g, 73.3 mmol) and Lawesson's reagent (14.83 g, 36.7 mmol) in THF (98 mL) was heated to reflux for 6 h. The reaction was cooled to room temperature, poured into saturated aqueous NaHCO3 (200 mL) and extracted with diethyl ether (4 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residual solid was triturated with 1 : 1 EtOAc:hexanes (100 mL) and filtered to collect the solid. The filtrate was concentrated and re- subjected to trituration and filtration using the same conditions. The combined solids were dried under vacuum to afford tetrahydro-2A -pyran-4- carbothioamide. 4.91 g (32.1 mmol, 43.8 % yield) as a white solid 1H NMR (400 MHz, CDCb) delta ppm 7.49 (br. s., 1 H), 6.84 (br. s., 1 H), 3.94 - 4.32 (m, 2 H), 3.31 - 3.62 (m, 2 H), 2.52 - 3.03 (m, 1 H), 1.81 - 1.93 (m, 4 H).
43.8%	With Lawessons reagent; In tetrahydrofuran; for 6h;Reflux;	Intermediate 4: Tetrahydro-2H-pyran-4-carbothioamide; A solution of <strong>[344329-76-6]tetrahydro-2H-pyran-4-carboxamide</strong> (9.47 g, 73.3 mmol) and Lawesson's reagent (14.83 g, 36.7 mmol) in THF (98 mL) was heated to reflux for 6 h. The reaction was cooled to rt, poured into saturated aqueous NaHCO3 (200 mL) and extracted with diethyl ether (4×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residual solid was triturated with 1:1 EtOAc:hexanes (100 mL) and filtered to collect the solid. The filtrate was concentrated and re-subjected to trituration and filtration using the same conditions. The combined solids were dried under vacuum to afford tetrahydro-2H-pyran-4-carbothioamide (4.91 g, 32.1 mmol, 43.8% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.49 (br. s., 1H), 6.84 (br. s., 1H), 3.94-4.32 (m, 2H), 3.31-3.62 (m, 2H), 2.52-3.03 (m, 1H), 1.81-1.93 (m, 4H).

Reference： [1]Patent: WO2019/206049,2019,A1 .Location in patent: Page/Page column 110-111
[2]Patent: WO2012/113774,2012,A1 .Location in patent: Page/Page column 42
[3]Patent: US2013/324551,2013,A1 .Location in patent: Paragraph 0328; 0329; 0330; 0331
[4]ChemMedChem,2015,vol. 10,p. 276 - 295
[5]Patent: WO2011/59610,2011,A1 .Location in patent: Page/Page column 106-107
[6]Patent: US2009/298815,2009,A1 .Location in patent: Page/Page column 49
[7]Patent: WO2007/40208,2007,A1 .Location in patent: Page/Page column 79

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[ 1394939-41-3 ]

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[2]Patent: US2013/324551,2013,A1
[3]ChemMedChem,2015,vol. 10,p. 276 - 295

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[ 1394939-46-8 ]

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[2]Patent: US2013/324551,2013,A1
[3]ChemMedChem,2015,vol. 10,p. 276 - 295

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[ 1394939-52-6 ]

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[2]ChemMedChem,2015,vol. 10,p. 276 - 295

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[ 1394938-45-4 ]

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[2]Patent: US2013/324551,2013,A1
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[ 1394938-46-5 ]

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[2]ChemMedChem,2015,vol. 10,p. 276 - 295

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[ 1394939-57-1 ]

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[2]Patent: US2013/324551,2013,A1
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[ 1394938-61-4 ]

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[2]Patent: US2013/324551,2013,A1
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[ 1394939-75-3 ]

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[ 1394939-77-5 ]

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[ 1394938-55-6 ]

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[ 1394939-80-0 ]

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[ 1394939-82-2 ]

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[ 1394938-56-7 ]
[ 1394939-84-4 ]

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[ 1394939-88-8 ]

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[2]Patent: US2013/324551,2013,A1
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[2]Patent: US2013/324551,2013,A1
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[2]Patent: US2013/324551,2013,A1
[3]ChemMedChem,2015,vol. 10,p. 276 - 295

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[2]Patent: US2013/324551,2013,A1
[3]ChemMedChem,2015,vol. 10,p. 276 - 295

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[2]Patent: US2013/324551,2013,A1
[3]ChemMedChem,2015,vol. 10,p. 276 - 295

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[ 1195768-37-6 ]

Reference： [1]Patent: WO2011/59610,2011,A1
[2]Patent: US2009/298815,2009,A1

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[2]Patent: US2009/298815,2009,A1

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