[ CAS No. 3399-22-2 ] {[proInfo.proName]}

Name: 3399-22-2|Dimethyl trans-1,4-Cyclohexanedicarboxylate|96%
Brand: Ambeed
SKU: A185390
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Quality Control of [ 3399-22-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 3399-22-2 ]

Product Details of [ 3399-22-2 ]

CAS No. :	3399-22-2	MDL No. :	MFCD00063917
Formula :	C₁₀H₁₆O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LNGAGQAGYITKCW-UHFFFAOYSA-N
M.W :	200.23	Pubchem ID :	7198
Synonyms :

Calculated chemistry of [ 3399-22-2 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.64
TPSA :	52.6 Å²

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) :	-6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.5
Log Po/w (XLOGP3) :	1.15
Log Po/w (WLOGP) :	1.14
Log Po/w (MLOGP) :	1.16
Log Po/w (SILICOS-IT) :	1.3
Consensus Log Po/w :	1.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.54
Solubility :	5.75 mg/ml ; 0.0287 mol/l
Class :	Very soluble
Log S (Ali) :	-1.85
Solubility :	2.83 mg/ml ; 0.0142 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.24
Solubility :	11.4 mg/ml ; 0.057 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.5

Safety of [ 3399-22-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P273	UN#:	N/A
Hazard Statements:	H315-H412	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 3399-22-2 ]

* 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 [ 3399-22-2 ]
Downstream synthetic route of [ 3399-22-2 ]

[ 3399-22-2 ] Synthesis Path-Upstream 1~6

1
[ 3399-22-2 ]
[ 15177-67-0 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium hydroxide In methanol for 5 h; Reflux	Example 129:frans-4-(Methoxycarbonyl)cvclohexanecarboxylic acidThe compound of example 129 was prepared according to the procedure described in Journal of Medicinal Chemistry, Eng, 2004, 47, 9, 2318-25.Dimethyl trans- 1 ,4-cyclohexanedicarboxylate (1 g) was dissolved in methanol (12 mL) and heated to reflux for 10-15 min. KOH (0.329 g) in methanol (5 mL) was added dropwise and the reaction mixture was stirred under reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated to dryness. Water was added and dilute HCI solution was added till a solid was precipitated. The solid was filtered and washed with water. The solid was dried to afford the title compound. Yield: 0.550 g (58 percent); ¹H NMR (DMSO-de, 300MHz): δ 12.07 (bs, 1 H), 3.58 (s, 3H), 2.30 (m, 1 H), 2.16 (m, 1 H), 1 .9 (m, 4H), 1 .37 (m, 4H); MS: m/z 185 (M-1 ).
58%	for 6 h; Reflux	Fourneckedflask (1l), and was added and stirred methanol 1000ml trans1,4cyclohexanedicarboxylic acid dimethyl ester (5-8-1)100.0g (500mmol). After the addition of potassium hydroxide 16.8g (300mmol), wasreaction for 6 hours under reflux. After cooling, water 500ml was added to the reaction solution was concentrated residue. Itadded until the diluted hydrochloric acid to pH 2, and filtered the precipitated crystal. After washing the crystals with water anddried under reduced pressure. Compound (582)was obtained 54.0g (58.0percent yield).
55%	With barium(II) hydroxide In methanol; water at 20℃; for 24 h;	REFERENCE SYNTHETIC EXAMPLE 14 trans-4-(Methoxycarbonyl)cyclohexane carboxylic acid To a solution of dimethyl trans-cyclohexane-1,4-dicarboxylate (60.4 g, 0.302 mol) in methanol (500 mL), barium hydroxide (28.4 g, 0.166 mol) and water (125 mL) were added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and hexane (500 mL) and water (1,200 mL) were added to it. The aqueous layer was separated, washed with hexane (500 mL), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (400 mL) three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was mixed with chloroform, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane to obtain the title compound as a white solid (30.9 g, yield: 55percent).

Reference： [1] Patent: WO2012/29032, 2012, A2, . Location in patent: Example 129
[2] Patent: JP5822098, 2015, B1, . Location in patent: Paragraph 0133; 0134
[3] Patent: EP2955181, 2015, A1, . Location in patent: Paragraph 0171; 0172
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325
[5] Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287
[6] Patent: EP1582521, 2005, A1, . Location in patent: Page/Page column 116
[7] Patent: EP1772454, 2007, A1, . Location in patent: Page/Page column 55
[8] Patent: US2003/144290, 2003, A1,

2
[ 619-82-9 ]
[ 15177-67-0 ]
[ 3399-22-2 ]

Reference： [1] Helvetica Chimica Acta, 1938, vol. 21, p. 141

3
[ 3399-22-2 ]
[ 619-82-9 ]
[ 15177-67-0 ]

Reference： [1] Helvetica Chimica Acta, 1938, vol. 21, p. 141

4
[ 94-60-0 ]
[ 3399-22-2 ]
[ 3399-21-1 ]

Yield	Reaction Conditions	Operation in experiment
80 % de	With pyridine In methanol at 40℃; for 2 h;	(1) Isomerization reaction: 0.5 mol, 100.1 g of a compound (I-b) having a trans/cis isomer ratio of 3/7 to 5/5 in a 200 g methanol solution system at a temperature of 40 ° C,After the isomerization reaction under the catalytic condition of 15 g of pyridine for 2 h, a methanol solution of the compound (II-b) having a trans/cis isomer ratio of 9/1 was obtained;

Reference： [1] Patent: CN108129307, 2018, A, . Location in patent: Paragraph 0029; 0034; 0037; 0039

5
[ 79368-45-9 ]
[ 149-73-5 ]
[ 18448-47-0 ]
[ 6493-77-2 ]
[ 3399-22-2 ]
[ 3399-21-1 ]
[ 79368-46-0 ]

Reference： [1] Liebigs Annalen der Chemie, 1981, # 8, p. 1394 - 1406

6
[ 3399-22-2 ]
[ 1467-84-1 ]

Reference： [1] Patent: EP2955181, 2015, A1,

[ 3399-22-2 ] Synthesis Path-Downstream 1~105

1
[ 67-56-1 ]
[ 619-82-9 ]
[ 3399-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	ultraviolettes Licht;
	With sulfuric acid
	With hydrogenchloride

With thionyl chloride at -30 - 20℃; for 18.5h;

A.1.1 Reference Example A1 (1) To methanol (1500 mL) was added dropwise thionyl chloride (254 mL) at -30 °C over a period of 1 hour. After stirring the mixture at room temperature for 30 minutes, thereto was added trans-cyclohexane-1,4-dicarboxylic acid (500.0 g) and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with chloroform. The solution was washed with an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The resultant residue was crystallized from n-hexane and the crystals were collected by filtration and dried to give dimethyl trans-cyclohexane-1,4-dicarboxylate (545.0 g). MS(APCI)m/z; 201 [M+H]+

Reference： [1]Stoermer; Ladewig [Chemische Berichte, 1914, vol. 47, p. 1805]
[2]Inukai,T.; Kojima,T. [Journal of Organic Chemistry, 1971, vol. 36, p. 924 - 928]
[3]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]
[4]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP1772454, 2007, A1 Location in patent: Page/Page column 55

2
[ 3399-22-2 ]
[ 3236-48-4 ]
[ 3236-47-3 ]

Reference： [1]Chemische Berichte,1938,vol. 71,p. 759,760, 764

3
[ 3399-22-2 ]
[ 15177-67-0 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium hydroxide; In methanol; for 5h;Reflux;	Example 129:frans-4-(Methoxycarbonyl)cvclohexanecarboxylic acidThe compound of example 129 was prepared according to the procedure described in Journal of Medicinal Chemistry, Eng, 2004, 47, 9, 2318-25.Dimethyl trans- 1 ,4-cyclohexanedicarboxylate (1 g) was dissolved in methanol (12 mL) and heated to reflux for 10-15 min. KOH (0.329 g) in methanol (5 mL) was added dropwise and the reaction mixture was stirred under reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated to dryness. Water was added and dilute HCI solution was added till a solid was precipitated. The solid was filtered and washed with water. The solid was dried to afford the title compound. Yield: 0.550 g (58 %); 1H NMR (DMSO-de, 300MHz): delta 12.07 (bs, 1 H), 3.58 (s, 3H), 2.30 (m, 1 H), 2.16 (m, 1 H), 1 .9 (m, 4H), 1 .37 (m, 4H); MS: m/z 185 (M-1 ).
58%	With methanol; potassium hydroxide; for 6h;Reflux;	Fourneckedflask (1l), and was added and stirred methanol 1000ml trans1,4cyclohexanedicarboxylic acid dimethyl ester (5-8-1)100.0g (500mmol). After the addition of potassium hydroxide 16.8g (300mmol), wasreaction for 6 hours under reflux. After cooling, water 500ml was added to the reaction solution was concentrated residue. Itadded until the diluted hydrochloric acid to pH 2, and filtered the precipitated crystal. After washing the crystals with water anddried under reduced pressure. Compound (582)was obtained 54.0g (58.0% yield).
55%	With barium(II) hydroxide; In methanol; water; at 20℃; for 24h;	REFERENCE SYNTHETIC EXAMPLE 14 trans-4-(Methoxycarbonyl)cyclohexane carboxylic acid To a solution of dimethyl trans-cyclohexane-1,4-dicarboxylate (60.4 g, 0.302 mol) in methanol (500 mL), barium hydroxide (28.4 g, 0.166 mol) and water (125 mL) were added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and hexane (500 mL) and water (1,200 mL) were added to it. The aqueous layer was separated, washed with hexane (500 mL), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (400 mL) three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was mixed with chloroform, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane to obtain the title compound as a white solid (30.9 g, yield: 55%).

		(2) Dimethyl trans-cyclohexane-1,4-dicarboxylate (150.0 g) obtained in (1) above is dissolved in tetrahydrofuran (1500 ml), and to the solution is added dropwise a mixed solution of 28 % sodium methoxide/methanol (149 g) and water (13.2 g) under ice-cooling. The reaction solution is warmed to room temperature, stirred for 3.5 hours, and thereto is poured n-hexane (1500 ml) and the mixture is filtered to collect the precipitates. The resulting solid is added to a mixture of conc. hydrochloric acid (50 ml), water (450 ml) and chloroform (1000 ml) under ice-cooling, and the mixture is stirred at room temperature for 20 minutes.
		(2) To a solution of dimethyl trans-cyclohexane-1,4-dicarboxylate obtained in the above step (1) (150.0 g) in tetrahydrofuran (1500 mL) was added dropwise a mixture of 28 % sodium methoxide/methanol solution (149 g) and water (13.2 g) under ice-cooling and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added n-hexane (1500 mL) and the precipitates were collected by filtration. The precipitates was added to a mixture of conc.HCl (50 mL), water (450 mL) and chloroform (1000 mL) under ice-cooling and the mixture was stirred at room temperature for 20 minutes. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant residue was crystallized from n-hexane and the precipitated crystals were collected by filtration and dried to give monomethyl trans-cyclohexane-1,4-dicarboxylate (106.0 g). MS(ESI)m/z; 185 [M-H]-
	With potassium hydroxide; In methanol; water;	A. trans-Cyclohexane-1,4-dicarboxylic acid dimethyl ester (34.2 g, 0.171 mol) was dissolved in 400 mL of anhydrous methanol and the solution brought to reflux. Slowly (dropwise), a solution of KOH (11.2 g, 0.171 mol, 85% purity) in dry methanol was added to the refluxing solution. The solution continued to reflux for 5 hours, and was then cooled and concentrated under reduced pressure to give a white solid. Water was added to dissolve most of the solid, and the aqueous mixture was washed with ether (3) in a separatory funnel. The aqueous layer was brought to pH ~6, the resulting white precipitate was collected via filtration and washed (1) with a small amount of water. Air drying afforded trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester as a white solid.

Reference： [1]Patent: WO2012/29032,2012,A2 .Location in patent: Example 129
[2]Patent: JP5822098,2015,B1 .Location in patent: Paragraph 0133; 0134
[3]Patent: EP2955181,2015,A1 .Location in patent: Paragraph 0171; 0172
[4]Journal of Medicinal Chemistry,2004,vol. 47,p. 2318 - 2325
[5]Journal of Physical Chemistry,1993,vol. 97,p. 9280 - 9287
[6]Patent: EP1582521,2005,A1 .Location in patent: Page/Page column 116
[7]Patent: EP1772454,2007,A1 .Location in patent: Page/Page column 55
[8]Patent: US2003/144290,2003,A1

4
[ 79368-45-9 ]
[ 149-73-5 ]
[ 18448-47-0 ]
[ 6493-77-2 ]
[ 3399-22-2 ]
[ 3399-21-1 ]
[ 79368-46-0 ]

Reference： [1]Liebigs Annalen der Chemie,1981,p. 1394 - 1406

5
[ 120-61-6 ]
[ 64-19-7 ]
platinum [ No CAS ]
[ 3399-22-2 ]
[ 3399-21-1 ]

Reference： [1]Helvetica Chimica Acta,1938,vol. 21,p. 141

6
[ 908094-01-9 ]
[ 3399-22-2 ]

Reference： [1]Fieser et al. [Journal of the American Chemical Society, 1948, vol. 70, p. 3177]

7
[ 908094-01-9 ]
trans-Cyclohex-2-ene-1,4-dicarboxylic acid [ No CAS ]
[ 3399-22-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: diazomethane; trans-Cyclohex-2-ene-1,4-dicarboxylic acid In diethyl ether at 0℃; Stage #2: With hydrogen In ethyl acetate at 20℃; Further stages.;

Reference： [1]Takimoto; Mori [Journal of the American Chemical Society, 2001, vol. 123, # 12, p. 2895 - 2896]

8
[ 3399-22-2 ]
[ 688311-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

9
[ 3399-22-2 ]
[ 871501-93-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / Heating

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

10
[ 3399-22-2 ]
4-[2-(3-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclohexanecarboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

11
[ 3399-22-2 ]
[ 688311-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

12
[ 3399-22-2 ]
[ 688311-49-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

13
[ 3399-22-2 ]
[ 871502-09-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / Heating 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

14
[ 3399-22-2 ]
4-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-oxo-propyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / Heating 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 6: oxalyl chloride; DMSO; TEA / CH₂Cl₂

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

15
[ 3399-22-2 ]
[ 688311-48-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

16
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1- / dimethylformamide / 16 h / 20 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

17
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1- / dimethylformamide / 20 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

18
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1- / dimethylformamide / 20 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

19
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-amino-ethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1- / dimethylformamide / 20 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

20
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid N'-acetyl-hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^(1-); triethylamine / dimethylformamide / 1.5 h / 60 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

21
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-hydroxy-propyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

22
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (2-hydroxy-propyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

23
[ 3399-22-2 ]
4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarboxylic acid (3-hydroxy-propyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: benzotriazol-1-yloxytris(dimethylamino)phosphoniumPF₆^1-; Et₃N / dimethylformamide

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

24
[ 3399-22-2 ]
N-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexanecarbonyl}-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 51 percent / KOH / methanol / 5 h / Heating 2: benzotriazol-1-yloxytris(dimethylamino)phosphonium*PF₆^1-; triethylamine / dimethylformamide / 80 °C 3: NH₄OAc; HOAc / 16 h / Heating 4: aq. LiOH / tetrahydrofuran / 20 °C 5: DMAP; EDCI / CH₂Cl₂ / 20 °C

Reference： [1]Blum, Charles A.; Zheng, Xiaozhang; De Lombaert, Stéphane [Journal of Medicinal Chemistry, 2004, vol. 47, # 9, p. 2318 - 2325]

25
[ 1165952-91-9 ]
[ 3399-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: Ni(cod)2; DBU / tetrahydrofuran / 7 h / 0 °C / 760.05 Torr 1.2: 50 percent / Me₂Zn / tetrahydrofuran / 2 h / 0 °C 2.1: diethyl ether / 0 °C 2.2: 100 percent / H₂ / Pd/C / ethyl acetate / 20 °C

Reference： [1]Takimoto; Mori [Journal of the American Chemical Society, 2001, vol. 123, # 12, p. 2895 - 2896]

26
[ 3399-22-2 ]
[ 183996-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: NaOH 2: thionyl chloride
	Multi-step reaction with 3 steps 1: potassium hydroxide / methanol / 20 h / 0 °C / Reflux 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C 3: tetrahydrofuran / 1 h / 20 °C

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]
[2]Jin, Fangfang; Hu, Qiyue; Fei, Hongbo; Lv, Hejun; Wang, Shenglan; Gui, Bin; Zhang, Junzhen; Tu, Wangyang; Zhang, Yun; Zhang, Lei; Wan, Hong; Zhang, Limin; Hu, Bin; Yang, Fanglong; Bai, Chang; He, Feng; Zhang, Lianshan; Tao, Weikang [ACS Medicinal Chemistry Letters, 2021, vol. 12, # 2, p. 195 - 201]

27
[ 3399-22-2 ]
1-[4-(3-Pyren-1-yl-propyl)-cyclohexyl]-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C 6: Huang-Minlon process 7: thionyl chloride

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

28
[ 3399-22-2 ]
trans-4-(1-pyrenyl-n-propyl)cyclohexanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C 6: Huang-Minlon process

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

29
[ 3399-22-2 ]
trans-4-(1-pyrenyl-n-propyl)cyclohexanecarboxylic acid chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C 6: Huang-Minlon process 7: thionyl chloride

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

30
[ 3399-22-2 ]
4-(3-Pyren-1-yl-propionyl)-cyclohexanecarboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

31
[ 3399-22-2 ]
(E)-3-(4-Dimethylamino-phenyl)-1-[4-(3-pyren-1-yl-propyl)-cyclohexyl]-propenone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C 6: Huang-Minlon process 7: thionyl chloride 9: NaOH / ethanol

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

32
[ 3399-22-2 ]
3-(4-Dimethylamino-phenyl)-1-[4-(3-pyren-1-yl-propyl)-cyclohexyl]-propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C 6: Huang-Minlon process 7: thionyl chloride 9: NaOH / ethanol 10: H₂ / Pd/C

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

33
[ 3399-22-2 ]
trans-1-(1-pyrenyl-n-propyl)-4-(4-N,N-dimethylamino)phenylcyclohexane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1: NaOH 2: thionyl chloride 5: H₂ / Pd/C 6: Huang-Minlon process 7: thionyl chloride 9: NaOH / ethanol 10: H₂ / Pd/C 11: Huang-Minlon process

Reference： [1]Werner, Udo; Kuehnle, Wolfgang; Staerk, Hubert [Journal of Physical Chemistry, 1993, vol. 97, # 37, p. 9280 - 9287]

34
[ 619-82-9 ]
[ 3399-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methanol With dichlorosulfoxide at -30 - 20℃; for 1.5h; Stage #2: trans-1,4-cyclohexanedicarboxylic acid at 20℃; for 17h;	1.1 Reference Example 1: (1) Thionyl chloride (254 ml) is added dropwise to methanol (1500 ml) under cooling to -30°C over a period of about an hour. After the addition, the reaction mixture is stirred at room temperature for 0.5 hours, and thereto is added trans-cyclohexane-1,4-dicarboxylic acid (500.0 g), and the mixture is stirred at room temperature for 17 hours. The reaction solution is concentrated under reduced pressure. The residue is diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is crystallized from n-hexane. The product is collected by filtration and dried to give dimethyl trans-cyclohexane-1,4-dicarboxylate (545.0 g). APCI-MS M/Z:201[M+H]+.
	Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 4 h / 0 - 35 °C 2: triethylamine; diazomethyl-trimethyl-silane / acetonitrile / 0 - 35 °C / Cooling with ice 3: triethylamine; benzoic acid silver salt / methanol / 0 - 35 °C

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP1582521, 2005, A1 Location in patent: Page/Page column 116
[2]Current Patent Assignee: EMERGENT BIOSOLUTIONS INC - WO2022/11211, 2022, A1

35
[ 3399-22-2 ]
[ 3236-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	Step 2 trans-1,4-Bis(hydroxymethyl)cyclohexane Under argon stream, a suspension of 2.96 g of lithium aluminum hydride in 100 mL of anhydrous tetrahydrofuran was treated dropwise with a solution of 3.9 g of trans-1,4-cyclohexanedicarboxylic acid dimethyl ester in anhydrous tetrahydrofuran at -20° C., and stirred for 2.5 hours. The reaction solution was combined with ice water to complete the reaction, and the insolubles were filtered off through Celite. After drying over magnesium sulfate, the residue was concentrated to obtain 2.80 g of the desirable compound.
	With copper chromium; hydrogen; at 210℃; under 152940.0 Torr;	To produce cyclohexane dimethanol, a fixed-bed continuous reactor as shown in Figure 1 was used. The fixed-bed continuous-reaction equipment includes a raw material storage container for storing raw materials, a pump for supplying high-pressure raw material and hydrogen, a fixed-bed continuous reactor filled with copper chromium (CuCr) catalyst, and a separator for separating cyclohexanedimethanol and hydrogen. By this fixed-bed continuous reaction equipment to use the hydrogenation the proportion of trans isomers is 20percent by mole of dimethyl 1,4-cyclohexane dicarboxylate under the conditions described in Table 1 was produced 1,4-cyclohexanedimethanol. 1,4- dimethylcyclohexanedicarboxylate in which the rate of the trans isomer was 60 mole percent was hydrogenated at the Comparative Example 1 and same condition and the cyclohexane dimethanol was produced.

Reference： [1]Patent: US2003/119855,2003,A1
[2]Patent: KR2017/60349,2017,A .Location in patent: Paragraph 0037; 0042-0043; 0053

36
[ 3399-22-2 ]
methyl 4-(2-(4-nitrophenyl)-2-oxoethylcarbamoyl)cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide / methanol / 5 h / Reflux 2: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 16 h / 60 °C

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - WO2012/29032, 2012, A2

37
[ 3399-22-2 ]
[ 1363365-18-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium hydroxide / methanol / 5 h / Reflux 2: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 16 h / 60 °C 3: trichlorophosphate / acetonitrile / 5 h / Reflux

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - WO2012/29032, 2012, A2

38
[ 3399-22-2 ]
[ 1363365-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium hydroxide / methanol / 5 h / Reflux 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 2.2: 8 h / 20 °C 2.3: 16 h / Reflux

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - WO2012/29032, 2012, A2

39
[ 3399-22-2 ]
dimethyl 1-methylcyclohexane-1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 1.2: 2 h / 20 °C 2.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1

40
[ 3399-22-2 ]
(1s,4s)-4-(tert-butoxycarbonyl)-1-fluorocyclohexanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 1.2: 2 h / 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 0.25 h / 20 °C 3.1: dmap; <i>tert</i>-butyl alcohol / 15 h / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1

41
[ 3399-22-2 ]
(1s,4s)-1-fluorocyclohexane-1,4-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 0.67 h / -78 °C 1.2: 2 h / 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 0.25 h / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1

42
[ 3399-22-2 ]
(1r,4r)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: dimethyl 1,4-cyclohexanedicarboxylate With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.666667h; Stage #2: With N-fluorobis(benzenesulfon)imide In tetrahydrofuran at 20℃; for 2h;	A Step A: (1r,4r)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate Step A: (1r,4r)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate A 2.5 M hexanes solution of butyllithium (4.07 mL, 10.16 mmol) was added to another solution of diisopropylamine (1.448 mL, 10.16 mmol) in tetrahydrofuran (30 mL) at -78° C. and stirred at 0° C. for 30 min. The mixture was cooled down to -78° C. and added a solution of (1r,4r)-dimethyl cyclohexane-1,4-dicarboxylate (1.85 g, 9.24 mmol) in tetrahydrofuran (15 mL) dropwise over 10 min. The resultant mixture was stirred at -78° C. for 30 min and added a solution of N-fluorobenzenesulfonimide (3.06 g, 9.70 mmol) in tetrahydrofuran (15 mL). The mixture was warmed up to room temperature and stirred for 2 h. After quenching with saturated ammonium chloride (20 mL), the mixture was diluted with ethyl acetate (300 mL), washed with water (30 mL), brine (30 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. Silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes, gave the desired (1r,4r)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate as the first eluent off the column (940 mg, 47% yield, major isomer). 1H NMR (400 MHz, CDCl3) δ ppm 3.74 (s, 3H), 3.67 (s, 3H), 2.60 (t, J=4.7 Hz, 1H), 2.15-1.72 (m, 8H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1 Location in patent: Paragraph 0220-0221

43
[ 3399-22-2 ]
(1s,4s)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	Stage #1: dimethyl 1,4-cyclohexanedicarboxylate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.666667h; Stage #2: With N-fluorobis(benzenesulfon)imide In tetrahydrofuran; hexane at 20℃; for 2h;	A Step A: (1s,4s)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate Step A: (1s,4s)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate A 2.5 M hexanes solution of butyllithium (4.07 mL, 10.16 mmol) was added to another solution of diisopropylamine (1.448 mL, 10.16 mmol) in tetrahydrofuran (30 mL) at -78° C. and stirred at 0° C. for 30 min. The mixture was cooled down to -78° C. and added a solution of (1r,4r)-dimethyl cyclohexane-1,4-dicarboxylate (1.85 g, 9.24 mmol) in tetrahydrofuran (15 mL) dropwise over 10 min. The resultant mixture was stirred at -78° C. for 30 min and added a solution of N-fluorobenzenesulfonimide (3.06 g, 9.70 mmol) in tetrahydrofuran (15 mL). The mixture was warmed up to room temperature and stirred for 2 h. After quenching with saturated ammonium chloride (20 mL), the mixture was diluted with ethyl acetate (300 mL), washed with water (30 mL), brine (30 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. Silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes, gave the desired (1s,4s)-dimethyl 1-fluorocyclohexane-1,4-dicarboxylate as the second eluent off the column (330 mg, 16% yield, minor isomer). 1H NMR (400 MHz, CDCl3) δ ppm 3.76 (s, 3H), 3.66 (s, 3H), 2.44-2.29 (m, 1H), 2.26-1.73 (m, 8H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1 Location in patent: Paragraph 0206-0207

44
[ 3399-22-2 ]
(1r,4r)-1-fluorocyclohexane-1,4-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 0.67 h / -78 °C 1.2: 2 h / 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 15 h / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1

45
[ 3399-22-2 ]
[ 74-88-4 ]
(1s,4s)-dimethyl 1-methylcyclohexane-1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: dimethyl 1,4-cyclohexanedicarboxylate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.666667h; Stage #2: methyl iodide In tetrahydrofuran; hexane at 20℃; for 2h;	A Step A: Step A: (1s,4s)-dimethyl 1-methylcyclohexane-1,4-dicarboxylate A 2.5 M hexanes solution of butyllithium (3.78 mL, 9.44 mmol) was added to another solution of diisopropylamine (1.345 mL, 9.44 mmol) in tetrahydrofuran (30 mL) at -78° C. and stirred at 0° C. for 30 min. The mixture was cooled down to -78° C. and added a solution of (1r,4r)-dimethyl cyclohexane-1,4-dicarboxylate (1.80 g, 8.99 mmol) in tetrahydrofuran (10 mL) dropwise over 10 min. The resultant mixture was stirred at -78° C. for 30 min and added iodomethane (0.562 mL, 8.99 mmol). The mixture was warmed up to room temperature and stirred for 2 h. After quenching with saturated ammonium chloride (5 mL), the mixture was diluted with ethyl acetate (300 mL), washed with water (30 mL), brine (30 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. Silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, gave the desired (1s,4s)-dimethyl 1-methylcyclohexane-1,4-dicarboxylate (1.51 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.74-3.57 (m, 6H), 2.35-2.16 (m, 2H), 1.95-1.82 (m, 2H), 1.80-1.71 (m, 1H), 1.67-1.59 (m, 1H), 1.55-1.38 (m, 2H), 1.23-1.18 (m, 1H), 1.16 (s, 3H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/191483, 2015, A1 Location in patent: Paragraph 0197-0198

46
[ 619-82-9 ]
[ 74-88-4 ]
[ 3399-22-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;	13 REFERENCE SYNTHETIC EXAMPLE 13 Dimethyl trans-cyclohexane-1,4-dicarboxylate REFERENCE SYNTHETIC EXAMPLE 13 Dimethyl trans-cyclohexane-1,4-dicarboxylate To a solution of trans-cyclohexane-1,4-dicarboxylic acid (25.9 g, 0.151 mol) in N,N-dimethylformamide (125 mL), methyl iodide (64.7 g, 0.456 mol) and potassium carbonate (63.4 g, 0.459 mol) were added, and the mixture was stirred at room temperature for 1 day. To the reaction mixture, diethyl ether (600 mL) and water (500 mL) were added. The organic layer was separated, washed with water (500 mL) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue, followed by stirring at ice bath temperature, and the residue was collected by filtration and washed with ice-cold hexane to obtain the title compound as a white solid (21.0 g, yield: 70%).

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION - EP2955181, 2015, A1 Location in patent: Paragraph 0169; 0170

47
[ 3399-22-2 ]
(trans-4-[(benzyloxy)carbonyl]amino}cyclohexyl)methyl 4-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: barium(II) hydroxide / water; methanol / 24 h / 20 °C 2.1: triethylamine; diphenyl phosphoryl azide / toluene / 3.5 h / 110 °C 2.2: 6.16 h / 110 °C 3.1: sodium hydroxide; water / methanol / 3 h / 20 °C 4.1: borane-THF / tetrahydrofuran / 24 h / 20 °C 5.1: triethylamine / dichloromethane / 0.17 h / 20 °C 5.2: 24 h