[ CAS No. 105-60-2 ] {[proInfo.proName]}

Name: 105-60-2|Azepan-2-one|99%
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Quality Control of [ 105-60-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 105-60-2 ]

Product Details of [ 105-60-2 ]

CAS No. :	105-60-2	MDL No. :	MFCD00006936
Formula :	C₆H₁₁NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JBKVHLHDHHXQEQ-UHFFFAOYSA-N
M.W :	113.16	Pubchem ID :	7768
Synonyms :

Calculated chemistry of [ 105-60-2 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.76
TPSA :	29.1 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) :	-7.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.47
Log Po/w (XLOGP3) :	-0.1
Log Po/w (WLOGP) :	0.3
Log Po/w (MLOGP) :	0.47
Log Po/w (SILICOS-IT) :	1.55
Consensus Log Po/w :	0.74

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.48
Solubility :	37.6 mg/ml ; 0.332 mol/l
Class :	Very soluble
Log S (Ali) :	-0.06
Solubility :	98.9 mg/ml ; 0.874 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.43
Solubility :	4.21 mg/ml ; 0.0372 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.01

Safety of [ 105-60-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P312-P332+P313-P337+P313-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H302+H332-H313-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 105-60-2 ]

* 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 [ 105-60-2 ]
Downstream synthetic route of [ 105-60-2 ]

[ 105-60-2 ] Synthesis Path-Upstream 1~23

1
[ 105-60-2 ]
[ 420-37-1 ]
[ 2525-16-8 ]

Reference： [1] Organic Preparations and Procedures International, 1992, vol. 24, # 2, p. 147 - 158
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2651 - 2653
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4359 - 4362
[4] Patent: US6046211, 2000, A,
[5] Patent: US5854234, 1998, A,
[6] Journal of the American Chemical Society, 2009, vol. 131, p. 8714 - 8718
[7] Patent: WO2010/68520, 2010, A2, . Location in patent: Page/Page column 29

2
[ 105-60-2 ]
[ 77-78-1 ]
[ 2525-16-8 ]

Reference： [1] Arkivoc, 2016, vol. 2016, # 5, p. 118 - 141
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6307 - 6315
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 21, p. 7647 - 7663
[4] Journal of the Indian Chemical Society, 1988, vol. 65, p. 800 - 802
[5] Journal of Medicinal Chemistry, 1987, vol. 30, # 8, p. 1433 - 1454
[6] European Journal of Medicinal Chemistry, 2002, vol. 37, # 5, p. 419 - 425
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3018 - 3033

3
[ 67-56-1 ]
[ 100-64-1 ]
[ 105-60-2 ]
[ 2525-16-8 ]

Reference： [1] Patent: US6344557, 2002, B1, . Location in patent: Page column 7
[2] Patent: US6344557, 2002, B1, . Location in patent: Page column 7-8

4
[ 105-60-2 ]
[ 77-78-1 ]
[ 2525-16-8 ]
[ 2556-73-2 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 2115,2116[2] Org.Synth.Coll.Vol., 1963, vol. IV, p. 588

5
[ 105-60-2 ]
[ 2525-16-8 ]

Reference： [1] Patent: WO2004/60376, 2004, A1, . Location in patent: Page/Page column 95

6
[ 105-60-2 ]
[ 77-78-1 ]
[ 71-43-2 ]
[ 2525-16-8 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 2115,2116[2] Org.Synth.Coll.Vol., 1963, vol. IV, p. 588

7
[ 105-60-2 ]
[ 74-86-2 ]
[ 2235-00-9 ]

Reference： [1] Patent: US2317804, 1940, ,
[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1952, p. 690,692; engl. Ausg. S. 633, 634
[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1957, p. 1457,1461; engl. Ausg. S. 1478, 1481
[4] Sint. org. Soedin., 1952, vol. 2, p. 44; dtsch. Ausg. S. 47[5] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1952, p. 682,685; engl. Ausg. S. 626, 629
[6] Journal of Molecular Structure, 1989, vol. 192, p. 141 - 152
[7] Patent: US6384216, 2002, B1, . Location in patent: Page column 7
[8] Patent: US2009/131657, 2009, A1, . Location in patent: Page/Page column 7-8
[9] Patent: US2806847, 1955, ,
[10] Patent: US2806848, 1956, ,

8
[ 151455-49-1 ]
[ 105-60-2 ]
[ 2235-00-9 ]

Reference： [1] Gazzetta Chimica Italiana, 1993, vol. 123, # 8, p. 457 - 462
[2] Gazzetta Chimica Italiana, 1993, vol. 123, # 8, p. 457 - 462

9
[ 105-60-2 ]
[ 2235-00-9 ]

Reference： [1] Gazzetta Chimica Italiana, 1993, vol. 123, # 8, p. 457 - 462

10
[ 105-60-2 ]
[ 54-95-5 ]

Reference： [1] Patent: DE855711, 1950, ,
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 2605

11
[ 105-60-2 ]
[ 143-15-7 ]
[ 59227-89-3 ]

Yield	Reaction Conditions	Operation in experiment
99.6%	With sodium hydroxide In water; toluene	EXAMPLE 1 A 1l reactor is charged with 34 g (0.3 mole) of azacycloheptane-2-one, 112 g (0.45 mole) of dodecyl bromide, 300 g of toluene, 3.4 g (3.3 mole percent based on the azacycloheptane-2-one) of crystalline tetrabutylammonium hydrogensulfate (TBAHS) and 90 g (2.25 moles) of flaky sodium hydroxide. This heterogeneous mixture was stirred at 50° C. for 10 hours. After the mixture was cooled to 40° C., 135 g of water was added to the mixture, followed by stirring at 40° C. for 30 minutes. The oil layer was separated and the oil layer thus obtained was subjected to distillation, giving 84.0 g of 1-dodecylazacycloheptane-2-one having a boiling point of 195° to 200° C./3 mmHg (yield of 99.6percent based on the azacycloheptane-2-one), and also 0.8 g of dodecyl ether (yield of 1.0percent based on the dodecyl bromide).
95%	With sodium hydroxide In toluene	EXAMPLE 3 A 1l reactor was charged with 57 g (0.5 mole) of azacycloheptane-2-one, 125 g (0.5 mole) of dodecyl bromide, 182 g of toluene, 3.2 g (2 mole percent) of crystalline tetrabutylammonium bromide (TBAB) and 60 g (1.5 moles) of flaky sodium hydroxide. This heterogeneous mixture was stirred at 50° C. for 10 hours. The same aftertreatment as in Example 1 was repeated, giving 133.5 g of 1-dodecylazacycloheptane-2-one (yield of 95.0percent) and 0.7 g of dodecyl ether (yield of 0.8percent)
92.8%	With sodium hydroxide; tetrabutylammomium bromide; potassium carbonate In cyclohexane	EXAMPLE 1 Preparation of 1-n-dodecylazacycloheptan-2-one at a bath temperature of 55° C. 117 g of caprolactam (1.033 mole), 10 g of tetrabutylammonium bromide (0.03 mole), 100 g of anhydrous potassium carbonate (0.7 mole, dried for 2 hrs at 120 C.), 100 g of pulverized sodium hydroxide (2.5 mole), and 1 L of cyclohexane were placed in a flask equipped with a funnel, reflux condenser and a mechanical stirrer. To this mixture were added dropwise a solution of 250 ml of 1-bromododecane (1.033 mole) and 250 ml of cyclohexane with vigorous stirring over one-half hour at a bath temperature of 55° C. The stirring was continued; in the meanwhile thin-layer chromatography was used to monitor the course of the reaction, and it was found that the reaction was completed after 7 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was washed with water (3*500 ml) to remove remaining caprolactam. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was evaporated using a rotary film evaporator to remove cyclohexane (which can be used again), and the residue was distilled at reduced pressure to yield 270 g of colorless, odorless, transparent liquid product (yield: 92.8percent), b,p.200-201 C/0.7 mmHg.

Reference： [1] Patent: US4812566, 1989, A,
[2] Patent: US4812566, 1989, A,
[3] Patent: US4973688, 1990, A,
[4] JAOCS, Journal of the American Oil Chemists' Society, 1996, vol. 73, # 7, p. 847 - 850
[5] Journal of Pharmaceutical Sciences, 1993, vol. 82, # 2, p. 214 - 219
[6] Journal of Pharmaceutical Sciences, 1989, vol. 78, # 9, p. 738 - 741

12
[ 105-60-2 ]
[ 143-15-7 ]
[ 59227-89-3 ]

Reference： [1] Patent: US4310525, 1982, A,

13
[ 105-60-2 ]
[ 1634-04-4 ]
[ 143-15-7 ]
[ 59227-89-3 ]

Reference： [1] Patent: US5986092, 1999, A,

14
[ 105-60-2 ]
[ 143-15-7 ]
[ 59227-89-3 ]

Reference： [1] Patent: US4525199, 1985, A,

15
[ 105-60-2 ]
[ 59227-89-3 ]

Reference： [1] Journal of Organic Chemistry, 1953, vol. 18, p. 1087,1088

16
[ 105-60-2 ]
[ 24566-95-8 ]

Reference： [1] Synthetic Communications, 1993, vol. 23, # 22, p. 3191 - 3194

17
[ 105-60-2 ]
[ 4048-33-3 ]

Yield	Reaction Conditions	Operation in experiment
92 %Spectr.	With sodium 2-methyl-2-adamantoxide; dichlorobis(dicyclohexylphosphinomethylpyridine)-ruthenium (II); hydrogen; sodium hydride In toluene; mineral oil at 160℃; for 24 h; Inert atmosphere; Autoclave	General procedure: Under a continuous Ar flow, 2-methyl-2-adamantanol (16.6 mg, 0.1 mmol), NaH (60percent oil dispersion, 4.0 mg, 0.1 mmol), anhydrous toluene (1.5 mL) and a magnetic stirring bar were placed in a dried Teflon tube (21 mL capacity). The Teflon tube was stoppered with a rubber septum, and the mixture was stirred at room temperature for 2 h under Ar. After removing the septum, under a continuous Ar flow, to the mixture was added RUPCY (7.50 mg, 0.01 mmol) and N-benzylbenzamide (105.6 mg, 0.5 mmol). The Teflon tube was quickly inserted into an autoclave and the inside of the autoclave was purged several times with hydrogen gas (>5 MPa). The autoclave was pressurized with an 8 MPa of hydrogen gas at 25°C, and heated at 160°C for 24 h under stirring (800 rpm). The autoclave was cooled to room temperature in an ice–water (0°C) bath,and the reaction mixture was quenched with NH4Cl (5.3 mg, 0.1 mmol). The organic phase was removed in vacuo (ca. 100 mmHg, 40 °C). The residue was diluted with CDCl₃, and analyzed by 1H NMR. The yields of benzyl alcohol (92percent) and benzylamine (92percent) were calculated based on the integral ratio among the signals of these compounds with respect to an internal standard (1,1,2,2-tetrachloroethane). Afterward, the reaction mixture was purified by column chromatography on silica gel (silica gel (ca. 100 g) was pretreated with Et₃N (small amount)–Et₂O/hexane (vol percent: 2/3), eluent; Et₂O/hexane = 2/3, then EtOAc/Et₃N = 100/1) to give N-benzylbenzamide (7.7 mg, 0.036 mmol, 7percent), benzyl alcohol (47.4 mg, 0.438 mmol, 88percent) and benzylamine (44.1 mg, 0.4187 mmol, 82percent).
90 %Spectr.	With sodium 2-methyl-2-adamantoxide; C₂₄H₃₈Cl₂N₂P₂Ru; hydrogen In toluene at 130 - 160℃; for 44 h; Autoclave; Sealed tube	1) Preactivation of Catalyst In an argon gas atmosphere, a stirrer, a ruthenium complex (Compound 2b; RUPIP2) (0.0067 mmol, 3.98 mg) and sodium-2-methyl-2-adamantoxide (0.067 mmol, 12.6 mg) were placed in a dried fluororesin tube (30 mL). Thereafter, the tube containing this compound was rapidly inserted into an autoclave, and toluene (2.0 mL) was added in an argon atmosphere. Subsequently, the autoclave was hermetically sealed while being grounded, and hydrogen gas was introduced into the autoclave from a hydrogen compressed gas cylinder connected via a stainless-steel pipe, thereby substituting the inside of the autoclave with hydrogen gas. More specifically, 1-MPa hydrogen gas pressure was applied inside the autoclave, and then the hydrogen gas pressure was removed through a leak valve. This operation (substitution and desubstitution) was repeated 10 times. Finally, the hydrogen gas inside the autoclave was set to 1 MPa, and a reaction was performed for 5 hours using a constant-temperature bath at 160° C. (2) Hydrogenation Reaction of Substrate (0285) After the reaction was completed, the autoclave was cooled to substantially room temperature by being immersed in an icy bath. Then, the leak valve of the autoclave was opened and the hydrogen gas inside the autoclave was released into the air. Subsequently, in an argon gas atmosphere, the reaction solution (1.5 mL) was obtained from the autoclave using a gas-tight syringe, and placed in another autoclave (a stirrer, and N-benzylbenzamide (0.5 mmol, 105.63 mg) were placed in a dried fluororesin tube (30 mL) in an argon gas atmosphere; thereafter, the tube containing this compound was rapidly inserted into an autoclave, and the inside of the autoclave was substituted with argon). Subsequently, the autoclave was hermetically sealed while being grounded, and hydrogen gas was introduced into the autoclave from a hydrogen compressed gas cylinder connected via a stainless-steel pipe, thereby substituting the inside of the autoclave with hydrogen gas. More specifically, 1-MPa hydrogen gas pressure was applied inside the autoclave, and then the hydrogen gas pressure was removed through a leak valve. This operation (substitution and desubstitution) was repeated 10 times. Finally, the hydrogen gas inside the autoclave was set to 1 MPa, and a reaction was performed for 24 hours using a constant-temperature bath at 110° C. For ¹H NMR analysis, an internal standard substance (mesitylene) was added to the solution. Based on the hydrogen atom amount of the internal standard substance, the yield of the reaction product was calculated. The results of the analysis showed that the yields of benzyl alcohol and benzylamine were both 86percent (corresponding to Entry 8 in Table 2 described later). A hydrogenation reaction was performed in the same manner as in Reaction Example A5, except that the conditions specified in Table 2 were used. Tables 2 and 3 show the results.

Reference： [1] Chemical Communications, 2014, vol. 50, # 76, p. 11211 - 11213
[2] Canadian Journal of Chemistry, 1958, vol. 36, p. 147,149
[3] Angewandte Chemie - International Edition, 2011, vol. 50, # 44, p. 10377 - 10380
[4] Tetrahedron Letters, 2013, vol. 54, # 21, p. 2674 - 2678
[5] Patent: US9463451, 2016, B2, . Location in patent: Page/Page column 46-50
[6] ChemCatChem, 2017, vol. 9, # 22, p. 4275 - 4281
[7] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2559 - 2565

18
[ 105-60-2 ]
[ 4224-70-8 ]

Reference： [1] Tetrahedron, Supplement, 1966, vol. 8, p. 313 - 319
[2] Journal of Organic Chemistry USSR (English Translation), 1966, vol. 2, # 11, p. 1990 - 1992[3] Zhurnal Organicheskoi Khimii, 1966, vol. 2, # 11, p. 2028 - 2031
[4] Patent: CN106632474, 2017, A,

19
[ 105-60-2 ]
[ 64-17-5 ]
[ 25542-62-5 ]

Reference： [1] Chemische Berichte, 1954, vol. 87, p. 356,362

20
[ 105-60-2 ]
[ 6404-29-1 ]

Reference： [1] Synlett, 2018, vol. 29, # 13, p. 1786 - 1790

21
[ 105-60-2 ]
[ 501-53-1 ]
[ 1947-00-8 ]

Reference： [1] Patent: US2014/39219, 2014, A1, . Location in patent: Paragraph 0051; 0052

22
[ 105-60-2 ]
[ 3633-17-8 ]

Reference： [1] Synthetic Communications, 1988, vol. 18, # 4, p. 1625 - 1636

23
[ 105-60-2 ]
[ 50889-29-7 ]

Reference： [1] Patent: CN106632474, 2017, A,

[ 105-60-2 ] Synthesis Path-Downstream 1~87

1
[ 123-91-1 ]
[ 105-60-2 ]
[ 100-85-6 ]
[ 107-13-1 ]
[ 7336-15-4 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 2115,2116
Org.Synth.Coll.Vol.,1963,vol. IV,p. 588

2
[ 105-60-2 ]
[ 108-24-7 ]
[ 1888-91-1 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 2115,2116
Org.Synth.Coll.Vol.,1963,vol. IV,p. 588
[2]Pharmaceutical Chemistry Journal,1988,vol. 22,p. 401 - 402
Khimiko-Farmatsevticheskii Zhurnal,1988,vol. 22,p. 591 - 592

3
[ 105-60-2 ]
[ 75-36-5 ]
[ 1888-91-1 ]

Reference： [1]Journal of the American Chemical Society,1958,vol. 80,p. 5880,5884

4
[ 105-60-2 ]
[ 107-13-1 ]
[ 7336-15-4 ]

Reference： [1]Synthetic Communications,1993,vol. 23,p. 3191 - 3194
[2]Journal of the American Chemical Society,1948,vol. 70,p. 2115,2116
Org.Synth.Coll.Vol.,1963,vol. IV,p. 588

5
[ 105-60-2 ]
[ 56987-35-0 ]

Yield	Reaction Conditions	Operation in experiment
76%		3-Piperidin-l-yl-l,5,6,7-tetrahydroazepin-2-one (1).; To a solution of epsilon- caprolactam (15.2 g, 133 mmol) in CHC13 (400 mL) cooled to 0-5 C was added PC15 (55.2 g, 265 mmol) over the course of 30 min, followed by addition of anhydrous Znl2 (1.53 g, 4.79 mmol) under N2. The reaction mixture was slowly allowed to reach room temperature as Br2 (42.4 g, 265 mmol) was added dropwise over the course of 30 min. The mixture was stirred at room temperature for 6 h and then poured into ice-water (300 mL). The aqueous layer was extracted with CHCI3 (3 x 100 mL) and the combined organic layers were washed with 0.50 M aq. NaHS03 (3 x 200 mL) and brine (1 x 400 mL), dried (MgS04) and concentrated to yield a yellow solid residue. The solid was suspended in water, filtered, and washed with water and Et20 to give 3,3-dibromoazepan-2-one (27.5 g, 76%) as a white solid: 1H NMR(CDC13, 600 MHz) delta 6.91 (bs, 1 H), 3.39 (app dd, 2 H, J= 10.3, 5.8 Hz), 2.77-2.72 (m, 2 H), 2.02-1.94 (m, 2 H), 1.73-1.67 (m, 2 H); 13C NMR (CDC13, 150 MHz) delta 168.7, 69.7, 46.2, 42.8, 28.6, 28.5; HRMS (ESI) m/z calcd for C6H9Br2NONa (M+Na) 291.8949, found291.8973.
	With phosphorus pentachloride; bromine;zinc(II) chloride; In chloroform;	A. Preparation of 3,3-Dibromoazacycloheptan-2-one To a cold solution of 45.2 g (0.4 mol) of caprolactam in CHCl3 was added 166.0 g (0.8 mol) of PCl5, keeping the temperature less than 5 C. The mixture was brought to room temperature, 2.0 g of ZnCl2 was added, and finally 128 g (0.8 mol) of bromine was added dropwise. After stirring the mixture for 5 hours at room temperature, the solvent and excess bromine was removed by vacuum distillation. The residue was poured into ice water and extracted with CH2 Cl2. The combined organic extracts were washed with sat. Na2 S2 O5, dried over MgSO4, and concentrated in vacuo to give a crude solid. Washing the solid with CH2 Cl2 /toluene yielded the product as a white powder; mp 156-159 C.
23 g	With phosphorus pentachloride; bromine; zinc(II) iodide; In dichloromethane; at 20℃; for 1h;Cooling with ice; Inert atmosphere;	11.3 g of the caprolactam was dissolved in 200 ml of methylene chloride,41.6 g of phosphorus pentachloride was added portionwise under ice-cooling, and the reaction was continued for 10 minutes after the completion of the addition. 1 g of zinc iodide was added under a nitrogen atmosphere,The reaction was allowed to proceed to room temperature for 1 hour. A solution of bromine in dichloromethane (32 g of bromine in 100 ml of dichloromethane) was then added dropwise,After completion of the addition, the mixture was stirred overnight. The ice bath was cooled to 0 to 5 degrees,The reaction was carefully poured into 500 ml of ice water,Extracted with dichloromethane for 5 times,Dried over anhydrous sodium sulfate,After concentration, a mixed solvent of petroleum ether and ethyl acetate was added,Precipitation of solid,Filtration gave 23 g of solid,Directly used in the next step reaction. 13.5 g of 3,3-dibromoheptalactam was dissolved in 70 ml of dry DMF,4 g of lithium chloride were added successively,7 grams of lithium carbonate,After heating to 130 C for 8 hours,DMF was distilled off,Purification by column afforded 7.1 g of a white solid,Yield 75%

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 4133 - 4141
[2]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 1545 - 1552
[3]Patent: WO2012/78859,2012,A2 .Location in patent: Page/Page column 30; 46
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 6678 - 6696
[5]Journal of the American Chemical Society,1958,vol. 80,p. 6233,6237
[6]Patent: US4755535,1988,A
[7]Patent: CN105367495,2016,A .Location in patent: Paragraph 0116; 0117; 0118; 0119

6
[ 105-60-2 ]
[ 59227-89-3 ]

Reference： [1]Journal of Organic Chemistry,1953,vol. 18,p. 1087,1088

7
[ 105-60-2 ]
[ 4224-62-8 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1952,vol. 576,p. 232

8
[ 105-60-2 ]
[ 60-32-2 ]

Yield	Reaction Conditions	Operation in experiment
99.4%	With dodecatungstosilic acid; water at 75℃; for 6h; Large scale;	1; 1.1; 1.2; 1.3; 1.4; 1.5; 2; 3; 4; 5; 6; 7; 8; 9; 10 Example 1. Preparation of aminocaproic acid General procedure: 1) Hydrolysis, neutralizationWeigh 150kg of caprolactam and 600kg of purified water into a 2000L reactor and stir to dissolve.150kg of concentrated sulfuric acid was slowly added dropwise from the high-level tank with stirring, the jacket steam was heated to 75°C, and the reaction was carried out for 15 hours.After the reaction is completed, close the steam valve, open the cooling water valve, cool to about 50, add sodium hydroxide to adjust the pH of the solution to 7-8, add activated carbon to decolorize for 15 minutes, filter, wash the filter with an appropriate amount of purified water, and concentrate to remove about 450kg Water, reduce the temperature to -10 ~ -5 , filter to remove solids, the filtrate is supplemented with 300kg of water, and is referred to as filter washing solution;2) Resin adsorption and elutionOpen the resin column feed valve, pump the filtrate and washing solution obtained in step 1) into the cation resin exchange column and the anion resin exchange column in sequence, and control the flow rate to 300L/hour for adsorption. When the chemical solution flows out, collect no calcium ions and acid radicals The effluent of ions is recorded as exchange fluid;Then open the resin column purification water valve, wash the cation resin exchange column and the anion resin exchange column with purified water, combine the obtained washing liquid and exchange liquid, and record it as the solution to be crystallized, to be concentrated and crystallized.The cation resin exchange column used in this step is D113 weak acid cation resin exchange column; the anion resin column used is D301 weakly basic anion resin exchange column;The dosage ratio of the filter washing solution to the filler in the cation resin exchange column is 1L: 4kg;The dosage ratio of the filter washing solution to the filler in the anion resin exchange column is 1L: 4kg;In the adsorption step, the clarified solution is driven into an ion exchange resin to collect the exchange solution.In the washing step, the detergent is purified water, and the dosage and the feed ratio of caprolactam are 1L: 14kg.The collection standard of the exchange fluid is 2-9.3) CrystallizationAbsorb the solution to be cleaned in step 2) into a clean 1000L reaction pot, turn on the jacket to heat, heat up and concentrate to dryness, add ethanol while hot, stir to precipitate crystals, cool for more than 6 hours, filter, filter cake washed with ethanol and spin dry Wet crude aminocaproic acid was weighed.4) RefinedPut the wet crude aminocaproic acid product into a 1000L reaction pot, add 6 times the amount of mixed liquid composed of purified water and absolute ethanol in a volume ratio of 1:3, turn on the jacket and heat up to about 70 to dissolve, add activated carbon Decolorize for half an hour, filter while hot, the filtrate is concentrated to near dryness under reduced pressure, crystals are precipitated by adding 700kg of ethanol, cooled for more than 6 hours, filtered, and the crystals are washed with about 50kg of ethanol, and dried to obtain the aminocaproic acid middle product.The middle product is recrystallized according to this method, and the crystal is washed with 50 kg of ethanol. After spin-drying, the aminocaproic acid refined product is obtained, which is to be dried.5) DryLay the aminocaproic acid refined product in a stainless steel baking tray, send it to the oven, and set the temperature to 60 for drying.After drying, the finished product of aminocaproic acid is obtained, which is packaged and stored after cooling.According to the above production process, the maximum feeding scale is 300kg caprolactam, and the final yield of aminocaproic acid is 99.2% relative to caprolactam; the purity is 98.8%;
98.5%	With water; sodium hydroxide at 120℃; for 11h;	1-11; 1-8 Add 5.0g of caprolactam, 2.1g of sodium hydroxide and 25g of demineralized water to a 100mL reaction flask, increase the pressure to 0.2MPa, increase the temperature to 120°C, and carry out the alkaline hydrolysis reaction for 1 hour. Cool the material after alkaline hydrolysis in step to room temperature, and neutralize it to pH=7.7±0.1 with hydrochloric acid with a concentration of 20wt%. Pressurize the neutralized material in step to pass through a reverse osmosis device for desalination treatment, with the chloride ion content in the effluent ≤10mg/L as the end point. Desalination of the materials instep is first decolorized with activated carbon and filtered. The filtrate is concentrated under reduced pressure at 50-65°C to benearly dry, and ethanol is added while it is hot, stirred for crystallization, cooled, and filtered to obtain crude 6-aminocaproic acid. Then the crude product was recrystallized with ethanol +water (7:1) mixed solvent, cooled, filtered, and dried to obtain 5.71 g of 6-aminocaproic acid product with a yield of 98.5% and a purity (HPLC) of 99.3%.
88.1%	Stage #1: caprolactam With acetic acid In water; acetone at 120℃; for 12h; Stage #2: With ethylamine at 15℃; for 12h;	1; 2; 3; 4; 5; 6; 7 Example 6 After diluting 10.0 mL of glacial acetic acid with 30.0 mL of desalted water,After adding 10.0 g of caprolactam and stirring at 120 ° C for 12 hours, water was distilled off under reduced pressure.Add 50 mL of acetone to the reaction system and stir vigorously until the solid is completely dissolved.Then, 13.5 mL of ethylamine was slowly added dropwise at 15 ° C, and stirring was continued for 12 hours after the completion of the dropwise addition.After filtration, the filter cake was washed with 30 mL of acetone for 4 times, filtered, and then dried under vacuum at 50 ° C for 12 hours to give a white powdery solid, yield 88.1%. The pH of the product was tested to be 7.80 as described in Example 1. The product purity was determined to be 99.1% according to the method described in Example 1. The collected acetone filtrate can be recovered by atmospheric distillation, and the recovery rate is 95.0%;After adding 50 mL of 10% NaOH to the residue, the ethylamine was recovered by atmospheric distillation, and the recovery was 85.4%.

	With water at 100℃; different time of hydrolysis;
	With sulfuric acid at 25℃; variation of the concenntration of sulfuric acid; ΔH (excit.), ΔS (excit.); 24.72 percent H2SO4;
	With sulfuric acid; water at 94℃; effective rate constants for hydrolysis at different temperatures; further temperatures;
	With water; oxalic acid
	With water; toluene-4-sulfonic acid
	With kieselguhr; phosphoric acid; water
	With water und einem sauren Ionenaustauscher;
	With water at 250℃; unter Druck;
	With ammonium hydroxide at 80℃; unter Druck;
	With barium dihydroxide; water
	With hydrogenchloride Hydrolysis_.Isolierung aus dem erhaltenen Hydrochlorid;
	With hydrogenchloride Darst_.;
	With piperidine
	With sodium hydroxide
	In sulfuric acid at 25℃; ΔH(excit.), ΔS(excit.);
	With Flavobacterium aquatile strain ZJB-09211 In water at 30℃; Microbiological reaction;
	With hydrogenchloride; water Reflux;	5.a (a) Preparation of 6-amino-hexanoic acid benzyl ester 5 g of ε-caprolactam was dissolved in 10% HCl (20 g) and heated to reflux until the starting material was reacted completely. The pH of the mixture was adjusted to 7.6 by adding 10% NaOH(aq). The mixture was concentrated at 55° C. and then recrystallized in methanol to obtain aminocaproic acid containing inorganic salts.
	With sodium hydroxide for 5h; Reflux;	1 Example 1 The present embodiment provides a process for the preparation of 6-brominated triphenylphosphonium orthohexanoic acid, which comprises the steps of: Hydrolysis reaction: 500ml bottle into the 220g caprolactam, 140g sodium hydroxide, heated to reflux reaction for 5 hours, the reaction completed, add 230 water diluted to get the hydrolyzate To the 1000ml bottle, add 353g hydrolyzate, drop 230g 30% industrial hydrochloric acid to adjust the pH to 4, pour out. Diazotization reaction: in 1000ml bottle by adding 150g water, 100g sodium nitrite, stirring dissolved, down to -5 ° C, at -5 ° C ~ 0 ° C dropping good pH hydrolyzate, 35min drop finished , Add drop at -5 ° C ~ 0 ° C for 5 hours, then add 42g 30% of industrial hydrochloric acid, heated to reflux 13min to starch potassium iodide test paper unchanged blue, pH = 1, down to 25 ° C, transferred to Separate the funnel, divide the water layer below, and separate the upper reservoir. Bromination reaction: Add 200 g of the upper layer to the 1000 ml bottle, 500 g of 48% hydrobromic acid, start stirring, add 94 g of concentrated sulfuric acid, raise the temperature to 70 ° C for 3.5 hours, drop to 45 °, transfer to the separatory funnel, Out of the upper oil about 360g (by 50% content into the next step reaction). The lower layer of acid water was added to a 30% solution with a pH of 7% (96% of caustic soda). 4, 6-brominated triphenylphosphonium n-hexanoic acid synthesis: 1000ml bottle by adding 180g of the previous bromine oil, 370g toluene, 136g triphenyl phosphorus, temperature reflux reaction 3 hours, cooling and crude crude. efined: by the crude: methanol (m: m) = 1: 0.6 all dissolved, then add 5 times the crude amount of ethyl acetate, stir, add 13% times the crude activated carbon, filter, the filtrate plus 6 times In the crude amount of ethyl acetate will be finished all the finished product, filtered and dried finished product, the mother liquor washed away after the methanol off the water recovery of ethyl acetate.
277 g	With potassium hydroxide In water; isopropyl alcohol at 25 - 95℃; for 10.5h;	3; 4; 5 Example-5: Process for the preparation of pure 6-aminohexanoic acid Caprolactam (500 gms) was added to freshly prepared aqueous potassium hydroxide solution (280 gms of potassium hydroxide dissolved in 450 ml of water) at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 10 hrs at same temperature. Isopropanol (2.5 Lt) and charcoal (25 gms) were added to the reaction mixture at 25-30°C and stirred for 30 min at same temperature. Filtered the reaction mixture through hy-flow bed and washed with isopropanol. Mixture of acetic acid (425 ml) and isopropanol (500 ml) solution was added to the obtained filtrate to neutralized the pH. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs. Filtered the precipitated solid, washed with isopropanol and then dried under reduced pressure for 6 hrs. Water (525 ml) and isopropanol (1255 ml) were added to the obtained material at 25-30°C and stirred for 10 min. Heated the reaction mixture to 65-70°C and stirred for 30 min. Filtered the reaction mixture and washed with pre-heated isopropanol. Cooled the filtrate to 25-30°C and slowly added isopropanol and stirred for 8 hrs. Filtered the precipitated solid, washed with isopropanol and then dried to afford title compound. (Yield: 277 gms, caprolactam impurity: not detected, dimer impurity: 0.02%, purity: 99.98% by HPLC).
	With C₁₅₀H₁₄₉BF₁₅N₄O₉Zn In toluene

Reference： [1]Current Patent Assignee: JIANGSU YONGAN PHARMACEUTICAL - CN111100025, 2020, A Location in patent: Paragraph 0026-0068
[2]Current Patent Assignee: CHANGZHOU LANLING PHARMACEUTICAL CO LTD - CN112500304, 2021, A Location in patent: Paragraph 0027-0036
[3]Current Patent Assignee: CANGZHOU XUYANG CHEMICAL - CN109369430, 2019, A Location in patent: Paragraph 0027-0062
[4]Yasnitskii, B. G.; Dol'berg, E. B.; Spivak, A. L. [Pharmaceutical Chemistry Journal, 1980, vol. 14, # 1, p. 60 - 63][Khimiko-Farmatsevticheskii Zhurnal, 1980, vol. 14, # 1, p. 73 - 75]
[5]Wan, Peter; Modro, Tomasz A.; Yates, Keith [Canadian Journal of Chemistry, 1980, vol. 58, p. 2423 - 2432]
[6]Vinnik, M. I.; Moiseev, Yu. V. [Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 1983, vol. 32, # 4, p. 708 - 716][Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1983, # 4, p. 777 - 786]
[7]Current Patent Assignee: PHRIX WERKE AG - DE922104, 1951, C Current Patent Assignee: PHRIX WERKE AG - DE837697, 1942, C [DRP/DRBP Org.Chem.][DRP/DRBP Org.Chem.]
[8]Hall et al. [Journal of the American Chemical Society, 1958, vol. 80, p. 6420,6421]
[9]Current Patent Assignee: BASF SE - DE820440, 1948, C [DRP/DRBP Org.Chem.][DRP/DRBP Org.Chem.]
[10]Current Patent Assignee: TK Industrial Solutions (in: Thyssenkrupp); THYSSENKRUPP AG - DE1011429, 1955, B Current Patent Assignee: BASF SE - DE820440, 1948, C [DRP/DRBP Org.Chem.][DRP/DRBP Org.Chem.]
[11]Current Patent Assignee: BASF SE - US2453234, 1947, A
[12]Galat; Mallin [Journal of the American Chemical Society, 1946, vol. 68, p. 2730]
[13]Current Patent Assignee: DUPONT DE NEMOURS INC - US2327119, 1941, A
[14]Meyers; Miller [Organic Syntheses, 1952, vol. 32, p. 13]
[15]Eck [Organic Syntheses, 1937, vol. 17, p. 7]
[16]Current Patent Assignee: BASF SE - DE820439, 1948, C [DRP/DRBP Org.Chem.][DRP/DRBP Org.Chem.]
[17]Schpitalnyi; Jablotschnik [Zhurnal Obshchei Khimii, 1958, vol. 28, p. 3282,3284;engl.Ausg.S.3307]
[18]Cox, Robin A. [Canadian Journal of Chemistry, 1998, vol. 76, # 6, p. 649 - 656]
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[20]Current Patent Assignee: SUNNY PHARMTECH - US2014/39219, 2014, A1 Location in patent: Paragraph 0056; 0056
[21]Current Patent Assignee: HUANGSHI LIFUDA MEDICINE CHEMICAL - CN106632474, 2017, A Location in patent: Paragraph 0048-0055; 0056-0063; 0064-0071; 0072-0079
[22]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2020/31201, 2020, A1 Location in patent: Paragraph 10-11
[23]Ikeuchi, Takuro; Kudo, Ryota; Yoshii, Tatsuya; Kobayashi, Nagao; Kitazawa, Yu; Kimura, Mutsumi [European Journal of Inorganic Chemistry, 2020, vol. 2020, # 7, p. 622 - 625]

9
[ 60-32-2 ]
[ 105-60-2 ]

Yield	Reaction Conditions	Operation in experiment
99.1%	In toluene for 20h; Heating;
99.1%	In toluene for 20h; Heating; other catalyst, other solvent;
95%	With di(n-butyl)tin oxide In xylene for 12h; Heating;

94%	In water at 315℃; for 0.416667h; Inert atmosphere;	2 Comparative example A Fermentation broth was obtained from a fermentation process with E. Coli for production of a commercial enzyme. Biomass was removed from the broth by microfiltration. Bio-polymers, including the target product, then were removed by ultrafiltration. By adding 6-ACA to the remaining fermentation broth, a model fermentation broth for a 6-ACA fermentation process was prepared, wherein 6-ACA is obtained at a titer of 150 g/l. The total carbohydrate content in this mixture was 6.3 g/l (i.e. the carbohydrate to 6-ACA weight ratio was 0.042). The resulting product mixture was concentrated under vacuum in a forced circulation evaporator at 40 °C. The concentrated mixture contained 48.3 wt.% water, 42.1 wt.% 6-ACA, 1 .8 wt.% carbohydrates and 7.8 wt.% of other broth components (organic acids, inorganic ions, etc.). 1 Kilogram of the thus obtained concentrated product mixture was fed to a 2 liter stirred tank reactor. The reactor was closed and the contents were inertized by flushing with nitrogen. The reactor pressure controller in the vapour exit line in top of the reactor was kept at 1 .2 MPa during the entire experiment. After starting the stirrer at 1000 r.p.m. the reactor contents were gradually heated up during approximatey 25 minutes to about 315 °C, using electric wall heating. During this period the water present in product mixture gradually evaporated and was condensed in a vapour cooler present in the vapour exit line. The recovered condensate fraction was weighed and analysed using HPLC for 6-ACA, CAP and the linear and cyclic oligomers thereof. When the reactor content reached the target temperature of about 315 °C a water feed was started and controlled at a rate of between 400 and 800 g/hr. This water was fed via a feed pipe beneath the stirrer where steam was formed in situ when the water came in contact with the hot reactor contents. Steam and steam-stripped products left the reactor via the vapour exit line at the top of the reactor. The condensed fractions were weighed and analysed by HPLC for content of CAP, 6-ACA and the linear and cyclic oligomers thereof. In this way it took approx. 5 hours to complete the reaction. The caprolactam yield obtained in this experiment was 67 mol% (calculated as the total of caprolactam analysed in the recovered product condensates relative to the overall amount of 6-ACA that was fed to the reactor originally).; Example 1A fermentation broth was prepared in a similar way as described in comparative example A, with the only difference that the original fermentation was prolonged for sufficient time so as to obtain a lower residual carbohydrate content in the fermentation broth. In this way a similar model fermentation mixture was prepared as in comparative example A, but now the carbohydrate concentration of this model broth was 1 ,3 g/l and the carbohydrate to 6-ACA weight ratio was 0.0087. Using the same procedure for 6- ACA conversion to caprolactam as described in comparative example A, the caprolactam yield finally obtained was 85 mol%.; Example 2Example 1 was repeated, with the difference that the residual carbohydrateconcentration in the finally obtained model fermentation broth was even further reduced to 0.3 g/l (by prolonging the fermentation time); the carbohydrate to 6-ACA weight ratio was thereby reduced to 0.0020. Using the same procedure for 6-ACA conversion to caprolactam as described in comparative example A, the caprolactam yield finally obtained was 94 mol%.
93%	With 3,4,5-trifluorophenylboronic acid In xylene for 22h; Heating;
93.6%		3 EXAMPLE 3 After completion of the salt-forming reaction, the reaction product mixture was concentrated to about 100 ml, transferred to another reactor and heated and distilled in the same manner as in Example 1 to obtain 36.9 g of a light yellow distillate (reaction temperature: 340°-360° C., time required for distillation: 2.5 hours). As a result of analyzing this distillate by gas chromatography it was found that 86.4% and 7.6% of ε-amino caproic acid were converted into ASB and ε-caprolactam. The yield of ASB was 93.6%.
89.6%	With silica gel In toluene for 20h; Heating;
86%	With tris(2,2,2-trifluoroethyl) borate In acetonitrile at 100℃; for 5h; Sealed tube;
82%	With aluminum oxide In toluene for 20h; Heating;
81%	With triethyl gallium In toluene for 5h; Heating;
66%	With cyclase from transaminase from Citrobacter freundii In aq. buffer at 30℃; for 24h; Enzymatic reaction;
62%	With titanium tetrakis(trimethylsilanolate) at 120℃; for 26h; Ionic liquid; Inert atmosphere;
60%	With Candida antarctica lipase B In toluene at 90℃; for 120h; Inert atmosphere; Green chemistry;	(a) Synthesis of lactams in dilute systems: A mixture of 6-aminocaproic acid (100 mg), N435 (100 mg), and dry toluene (5 mL) was stirred for 72-120 h, at 90 C under an N2 atmosphere. After cooling to room temperature, the toluene was removed by rotary evaporation. CHCl3 (20 mL) was added to the residue to extract the lactam product. After filtration and evaporation of the CHCl3, the remaining product (e-caprolactam) was purified using short path distillation (Kugelrohr); yielding a white crystalline product (60%); mp 68.68 C (Lit. 68- 71 C).
35%	With titanium(IV) isopropylate In 1,2-dichloro-ethane for 26h; Heating;
5%	With H-BEA In toluene for 3h; Dean-Stark; Heating;	5 Example 5: Caprolactam Caprolactam was prepared using 6-aminohexanoic acid (1 g) in 10 ml of toluene, in the presence of H-BEA (Si/AI2: 25) (0,5 g), using an oil bath at a temperature of 130°C. A Dean-Stark trap was used for removal of water from the reaction mixture. After 3 h of reaction, the yield was 5%.
	With 1,4-dioxane at 220 - 230℃; unter Druck;
	With di(n-butyl)tin oxide In xylene for 20h; Heating; Yield given;
	at 210 - 220℃;
	Multi-step reaction with 3 steps 1: 95 percent / N₃Tf; CuSO₄; K₂CO₃ / CH₂Cl₂; methanol; H₂O 2: 100 percent / N,N'-dicyclohexylcarbodiimide / CH₂Cl₂ / 0 °C 3: 84 percent / 1,4-diazabicyclo[2.2.2]octane / tetrahydrofuran; H₂O / 70 °C
	at 185℃; for 2h; Dean-Stark;	7 Manufacture of ε-caprolactam 3.95 g of the aminocaproic acid obtained in Example 5 was dissolved in 120 g of tetra-EG (reagent manufactured by Wako Pure Chemical Industries, Ltd.), and heated at 185 ° C for 2 hours in a 300 mL round bottom flask fitted with a Dean-Stark tube. After the reaction, the reaction mixture was distilled under reduced pressure at 135 ° C under 100 Pa. When the obtained sample was analyzed by 1 H-NMR, it was confirmed that aminocaproic acid could be quantitatively converted to ε-caprolactam. Further, the obtained ε-caprolactam was subjected to the above HPLC as well as analysis by 1 H-NMR revealed no peaks derived from 7-methyl-ε-caprolactam and 3-methyl-ε-caprolactam.
	With Streptomyces aizunensis ORF₂₇; ATP; coenzyme A; magnesium chloride In aq. buffer at 25℃; Enzymatic reaction; chemoselective reaction;	1 Product analysis of in vitro ORF27 lactam formation. [00100] To compare formation of various lactams by ORF27, a reaction mixture containing 57 µM of ORF27, 5 mM ω-amino fatty acids substrates, 1 mM ATP or ADP, 0.5mM CoASH and 1 mM Mg(Cl)2 in 100 mM HEPES (pH=8) was incubated at 25°C. The reactions were quenched by addition of methanol to a final concentration of 50% (v/v) at multiple time points (0 min, 15 min, 1 h, 2 h, 4 h and 19 h). The resulting quenched reactions were kept at 4°C and filtered through 10 K Amicon Ultra-0.5 mL Centrifugal Filters (0061) (Millipore) at 8000 ×g for 30min. The filtered solutions were analyzed for lactams and nucleotides using HPLC-MS. Control reactions were carried out without enzyme, without substrate, without ATP, without CoASH or without MgCl2 (supplying additional 0.2 mM EDTA to chelate Mg2+ ions from purified protein stock). Caprolactam, valerolactam and butyrolactam, AMP, ADP and ATP were purchased as standards from Sigma-Aldrich. The pH dependence of ORF27-catalyzed butrylactam formation was determined using an end- point assay, and the amount of butyrolactam was determined using the HPLC-MS method described above.
100 %Chromat.	With phosphoric acid In water at 261℃; for 3.75h; Flow reactor; Large scale;	9 Example 4 (three step process, with catalyst 4.0 wt. % on the total mass in the cyclization reactor) Step (i). General procedure: The following materials are introduced in a pilot reactor made of stainless steel, having a volumetric capacity of 170 liters and provided with outer jacket (unit R1): - 6ACA, powder: 25 kg (80% by weight on the total mass); - water: 6.25 kg (20% by weight on the total mass). The reactor is then heated adiabatically, starting from room temperature and atmospheric pressure, to reach the following conditions, i.e. maintenance conditions: - pressure: 8.3 bar; - liquid temperature: 185°C; - vapor temperature: 189°C. The mixture was kept on these conditions for a maintenance time of 30 minutes, and then all the material was transferred to a cyclization reactor in step (ii) in the same manner and with the same effects explained in the previous example 2a. Step (ii). The cyclization reactor R2 made of stainless steel, having a volumetric capacity of 190 liters and an outer jacket for thermal oil circulation was prepared and brought to the working conditions. The stirring inside the reactor is guaranteed by the continuous feeding of the superheated steam through the special distributor located at the bottom. The reactor was fed with the initial load of caprolactam solution composed of caprolactam, oligomers and water and with phosphoric acid in the amount of 4.0 wt.% based on the total mass in the cyclization reactor (see Table 4 which presents schematic mass balance calculation at the end of Example 4). The liquid catalyst H3PO4 with concentration of 75% in water was is fed into the cyclization reactor from time to time (when the chemical analysis indicated that the concentration of the catalyst inside the reactor fell below 2 wt. %), to guarantee its presence in the reacting mixture all the time during the trial. The reactor was heated to T=266°C, at atmospheric pressure, by the action of the oil in the outer jacket and of the superheated steam (in this example the main supply of heat is the thermal oil). The mixture form step (i) is fed into the cyclization reactor. The flash of the water causes a short initial temperature decrease down to 208°C, followed by the increase given by the heating up to 268°C, while the overheated steam is continuously fed at constant rate of 40 l/h to the reactor. The 6ACA then undergoes the cyclization reaction, with the production of CPL; the polymerization to oligomers can occur as a side reaction. As soon as the CPL is formed it is stripped away by the superheated steam to step (iii). Step (iii). The vapors as mixture of water steam and caprolactam coming from the cyclization reaction of 6ACA are continuously sent to a packed bed rectification column C1 made of stainless steel, with condenser (without any recovery of the heat in the pilot unit) and without boiler as there the heat for rectification is recovered from the energy delivered in the previous step. As cooling and condensation medium some liquid water is fed to the high part of the column. From the top of the column the water steam at 100-102°C practically without any caprolactam is sent to condensate in a condenser, from the bottom of the column a concentrate caprolactam water solution at 1 10-1 15°C is collected and stored into a storage vessel. In the pilot unit the rectification-condensation column is the same as described in example 2a. The oligomers remained are unloaded from the bottom of the cyclization reactor at the end of the trial. The total balance, considering the difference between the inputs and the outputs, is the following: caprolactam: +24,8 kg; oligomers: -3,2 kg 6ACA: -25 kg (equivalent to 21.6 kg of caprolactam). From the mass balance the following parameters are calculated: - 6ACA conversion: 100%; - 6ACA to CPL yield: 100%. - Oligomers: 0% The quality of the final raw CPL is similar to those of the traditional raw caprolactam. In particular: GC purity (% area): 99.8%; GC peaks: 8 (CPL + 6 lights and 1 heavies); Visual aspect: CPL solution transparent

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[21]Current Patent Assignee: UNITIKA LTD - JP6030397, 2016, B2 Location in patent: Paragraph 0060
[22]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2017/214159, 2017, A1 Location in patent: Paragraph 0015; 00100
[23]Current Patent Assignee: GENOMATICA, INC.; AQUAFIN HOLDING S.P.A. - WO2020/136547, 2020, A1 Location in patent: Page/Page column 23-51

10
[ 105-60-2 ]
[ 24237-39-6 ]
[ 57394-71-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate In 1,2-dichloro-ethane Heating;

Reference： [1]Lalezari,I.; Iabari-Sahbari,M.H. [Journal of Heterocyclic Chemistry, 1978, vol. 15, p. 873 - 875]

11
[ 105-60-2 ]
[ 928-50-7 ]
[ 87850-88-2 ]

Reference： [1]Canadian Journal of Chemistry,1983,vol. 61,p. 2016 - 2021

12
[ 105-60-2 ]
[ 4906-22-3 ]
[ 2417-04-1 ]
[ 117709-75-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 5959 - 5960

13
[ 105-60-2 ]
[ 2475-80-1 ]
[ 60811-49-6 ]

Reference： [1]Chemistry of Natural Compounds,1986,vol. 22,p. 435 - 438
Khimiya Prirodnykh Soedinenii,1986,vol. 22,p. 465 - 469

14
[ 105-60-2 ]
[ 60110-37-4 ]
[ 3219-55-4 ]
[ 115539-45-2 ]
[ 78877-71-1 ]
[ 75995-62-9 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 43 - 48

15
[ 105-60-2 ]
[ 2547-66-2 ]
[ 85517-53-9 ]

Reference： [1]Archiv der Pharmazie,1983,vol. 316,p. 251 - 256

16
[ 105-60-2 ]
[ 10504-60-6 ]
C₇H₁₃NO*BF₄^(1-)*H⁽¹⁺⁾ [ No CAS ]

Reference： [1]Tetrahedron,1983,vol. 39,p. 433 - 442

17
[ 105-60-2 ]
[ 143-15-7 ]
[ 59227-89-3 ]

Yield	Reaction Conditions	Operation in experiment
99.6%	With sodium hydroxide; In water; toluene;	EXAMPLE 1 A 1l reactor is charged with 34 g (0.3 mole) of azacycloheptane-2-one, 112 g (0.45 mole) of dodecyl bromide, 300 g of toluene, 3.4 g (3.3 mole percent based on the azacycloheptane-2-one) of crystalline tetrabutylammonium hydrogensulfate (TBAHS) and 90 g (2.25 moles) of flaky sodium hydroxide. This heterogeneous mixture was stirred at 50° C. for 10 hours. After the mixture was cooled to 40° C., 135 g of water was added to the mixture, followed by stirring at 40° C. for 30 minutes. The oil layer was separated and the oil layer thus obtained was subjected to distillation, giving 84.0 g of 1-dodecylazacycloheptane-2-one having a boiling point of 195° to 200° C./3 mmHg (yield of 99.6percent based on the azacycloheptane-2-one), and also 0.8 g of dodecyl ether (yield of 1.0percent based on the dodecyl bromide).
95.0%	With sodium hydroxide; In toluene;	EXAMPLE 3 A 1l reactor was charged with 57 g (0.5 mole) of azacycloheptane-2-one, 125 g (0.5 mole) of dodecyl bromide, 182 g of toluene, 3.2 g (2 mole percent) of crystalline tetrabutylammonium bromide (TBAB) and 60 g (1.5 moles) of flaky sodium hydroxide. This heterogeneous mixture was stirred at 50° C. for 10 hours. The same aftertreatment as in Example 1 was repeated, giving 133.5 g of 1-dodecylazacycloheptane-2-one (yield of 95.0percent) and 0.7 g of dodecyl ether (yield of 0.8percent)
92.8%	With sodium hydroxide; tetrabutylammomium bromide; potassium carbonate; In cyclohexane;	EXAMPLE 1 Preparation of 1-n-dodecylazacycloheptan-2-one at a bath temperature of 55° C. 117 g of caprolactam (1.033 mole), 10 g of tetrabutylammonium bromide (0.03 mole), 100 g of anhydrous potassium carbonate (0.7 mole, dried for 2 hrs at 120 C.), 100 g of pulverized sodium hydroxide (2.5 mole), and 1 L of cyclohexane were placed in a flask equipped with a funnel, reflux condenser and a mechanical stirrer. To this mixture were added dropwise a solution of 250 ml of 1-bromododecane (1.033 mole) and 250 ml of cyclohexane with vigorous stirring over one-half hour at a bath temperature of 55° C. The stirring was continued; in the meanwhile thin-layer chromatography was used to monitor the course of the reaction, and it was found that the reaction was completed after 7 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was washed with water (3*500 ml) to remove remaining caprolactam. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was evaporated using a rotary film evaporator to remove cyclohexane (which can be used again), and the residue was distilled at reduced pressure to yield 270 g of colorless, odorless, transparent liquid product (yield: 92.8percent), b,p.200-201 C/0.7 mmHg.

Reference： [1]Patent: US4812566,1989,A
[2]Patent: US4812566,1989,A
[3]Patent: US4973688,1990,A
[4]Journal of the American Oil Chemists' Society,1996,vol. 73,p. 847 - 850
[5]Journal of Pharmaceutical Sciences,1993,vol. 82,p. 214 - 219
[6]Journal of Pharmaceutical Sciences,1989,vol. 78,p. 738 - 741

18
[ 105-60-2 ]
[ 2362-10-9 ]
[ 82878-54-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium carbonate at 140℃; for 5h;

Reference： [1]Khananashvili, L. M.; Akhobadze, D. Sh.; Dzhaniashvili, L. K.; Lomtatidze, Z. Sh. [Pharmaceutical Chemistry Journal, 1982, vol. 16, # 5, p. 365 - 367][Khimiko-Farmatsevticheskii Zhurnal, 1982, vol. 16, # 5, p. 560 - 562]

19
[ 105-60-2 ]
[ 81528-48-5 ]
[ 120079-58-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1989,vol. 37,p. 2122 - 2131

20
[ 105-60-2 ]
[ 77-78-1 ]
[ 2525-16-8 ]

Reference： [1]Arkivoc,2016,vol. 2016,p. 118 - 141
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 6307 - 6315
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 7647 - 7663
[4]Journal of the Indian Chemical Society,1988,vol. 65,p. 800 - 802
[5]Journal of Medicinal Chemistry,1987,vol. 30,p. 1433 - 1454
[6]European Journal of Medicinal Chemistry,2002,vol. 37,p. 419 - 425
[7]Journal of Medicinal Chemistry,2016,vol. 59,p. 3018 - 3033

21
[ 105-60-2 ]
[ 76575-71-8 ]
[ 120079-45-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1989,vol. 37,p. 2122 - 2131

22
[ 105-60-2 ]
[ 112176-22-4 ]
[ 4224-62-8 ]

Reference： [1]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1987,vol. 36,p. 327 - 330
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1987,p. 367 - 371

23
[ 1888-91-1 ]
[ 105-60-2 ]
[ 57-08-9 ]

Reference： [1]Pharmaceutical Chemistry Journal,1980,vol. 14,p. 60 - 63
Khimiko-Farmatsevticheskii Zhurnal,1980,vol. 14,p. 73 - 75

24
[ 1888-91-1 ]
[ 105-60-2 ]
[ 57-08-9 ]
[ 60-32-2 ]

Reference： [1]Pharmaceutical Chemistry Journal,1980,vol. 14,p. 60 - 63
Khimiko-Farmatsevticheskii Zhurnal,1980,vol. 14,p. 73 - 75

25
[ 21911-84-2 ]
[ 80096-41-9 ]
[ 105-60-2 ]
[ 4903-40-6 ]
[ 13532-18-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1981,vol. 29,p. 2525 - 2530
[2]Chemical and pharmaceutical bulletin,1981,vol. 29,p. 2525 - 2530

26
[ 1888-91-1 ]
[ 105-60-2 ]
[ 463-51-4 ]

Reference： [1]International Journal of Chemical Kinetics,1995,vol. 27,p. 843 - 848

27
[ 7203-96-5 ]
[ 1600-27-7 ]
[ 105-60-2 ]
[ 1888-91-1 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 14463 - 14480

28
[ 7203-96-5 ]
[ 563-63-3 ]
[ 105-60-2 ]
[ 1888-91-1 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 14463 - 14480

29
[ 105-60-2 ]
[ 420-37-1 ]
[ 2525-16-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 257 2-(2-butynyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine STR263 The product of EXAMPLE 256 is reacted with trimethyloxonium tetrafluoroborate by the method of
		EXAMPLE 257 2-(2-butynyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine STR263 The product of EXAMPLE 256 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
	In dichloromethane;	Step 1: Preparation of (E)-7-methoxy-3,4,5,6-tetrahydro-2H-azepine: To a solution of azepan-2-one (1.13 g, 10.0 mmol) in DCM (10 mL) in a 40 mL screw cap vial was added freshly prepared trimethyloxonium tetrafluoroborate (1.57 g, 10.59 mmol). The resulting suspension was shaken overnight. The reaction was quenched by the addition of saturated aqueous NaHCtheta3 (5 ml) (caution: vigorous CO2 evolution). More aqueous sodium hydrogen carbonate was added until the aqueous layer reached pH 8. The organic layer was removed and the aqueous layer extracted with DCM (5mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield (E)-7-methoxy-3,4,5,6-tetrahydro-2H- azepine (1.2 g, 95 %) as a clear oil. LCMS (+ESI) m/z 128.2 [M+H]+. 1H-NMR (CDCl3) delta 3.60 (s, 3H), 3.45 (m, 2H), 2.40 (m, 2H), 1.80 (m, 2H), 1.60-1.50 (m, 4H). [00145]

Reference： [1]Organic Preparations and Procedures International,1992,vol. 24,p. 147 - 158
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2651 - 2653
[3]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4359 - 4362
[4]Patent: US6046211,2000,A
[5]Patent: US5854234,1998,A
[6]Journal of the American Chemical Society,2009,vol. 131,p. 8714 - 8718
[7]Patent: WO2010/68520,2010,A2 .Location in patent: Page/Page column 29

30
[ 105-60-2 ]
[ 7647-01-0 ]
[ 7732-18-5 ]
NaNO₂ [ No CAS ]
[ 1577-22-6 ]
[ 4224-62-8 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1952,vol. 576,p. 232

31
[ 105-60-2 ]
[ 1779-05-1 ]
[ 744-45-6 ]
polybenzimidazole, softening point 345-350 deg C; monomers: 3,3,,4,4-tetraaminodiphenylmethane; diphenyl isophthalate; ε-caprolactam [ No CAS ]