[ CAS No. 120511-72-0 ] {[proInfo.proName]}

Name: 120511-72-0|2,2'-(5-Methyl-1,3-phenylene)bis(2-methylpropanenitrile)|98%
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Quality Control of [ 120511-72-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 120511-72-0 ]

CAS No. :	120511-72-0	MDL No. :	MFCD08062446
Formula :	C₁₅H₁₈N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SJECEXNMZXMXNE-UHFFFAOYSA-N
M.W :	226.32	Pubchem ID :	16005484
Synonyms :

Calculated chemistry of [ 120511-72-0 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.47
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	69.45
TPSA :	47.58 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) :	-5.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.51
Log Po/w (XLOGP3) :	3.46
Log Po/w (WLOGP) :	3.6
Log Po/w (MLOGP) :	2.75
Log Po/w (SILICOS-IT) :	3.87
Consensus Log Po/w :	3.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.55
Solubility :	0.0635 mg/ml ; 0.00028 mol/l
Class :	Soluble
Log S (Ali) :	-4.14
Solubility :	0.0164 mg/ml ; 0.0000723 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.61
Solubility :	0.00556 mg/ml ; 0.0000245 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 120511-72-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 120511-72-0 ]

* 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 [ 120511-72-0 ]
Downstream synthetic route of [ 120511-72-0 ]

[ 120511-72-0 ] Synthesis Path-Upstream 1~6

1
[ 120511-74-2 ]
[ 74-88-4 ]
[ 120511-72-0 ]

Yield	Reaction Conditions	Operation in experiment
70.3%	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3 - 3.5 h;	A mixture of 3,5-bis(cyanomethyl)toluene obtained in Step II (800 g, 4.70 mol), methyl iodide (2935.2 g, 20.68 mol) and dimethylformamide (11.20 L) was cooled to 0° C. to 5° C. Sodium hydride (60percent) dispersion in oil (864.2 g, 36.0 mol) was added in portions over 1 to 1.5 hours. The mixture was then allowed to warm to room temperature and stirred for 2 to 2.5 hours. The reaction was monitored by TLC (n-Hexane:EtOAc-7.5:2.5). After completion of reaction as determined by TLC, excess sodium hydride was decomposed by adding ethyl acetate. The reaction mass was diluted with water and extracted with dichloromethane (3*5 L). The organic layers were combined and washed with brine (5 L). The organic layer was charcoalized at room temperature for 1 hour and concentrated to dryness at 40° C. to 45° C. The residue obtained was dissolved in carbon tetrachloride (2400 ml) at 70° C. to 75° C. and gradually cooled to 10° C. to 15° C. The reaction mass was stirred for 1 hour. The solution was further cooled to -5° C. to 0° C. and stirred for 3 hours. Next, the stirred solution was filtered, washed with chilled carbon tetrachloride (500 ml), and dried at 40° C. to 45° C. under vacuum to obtain 3,5-bis(1-cyano-1-methylethyl)toluene (748.0 g, 70.3percent yield).
67%	With sodium hydride In N,N-dimethyl-formamide at 0 - 15℃; for 6 h;	c) Preparation of 2,2'-(5-Methyl-l,3-phenylene)di(2-methylpropiononitrile) (II)A solution of 2,2'-(5-methyl-l,3-phenylene)diacetonitrile (VI) (5 gm, 0.029 moles) in N₅N- dimethylformamide (100 ml) was stirred under nitrogen. To this, methyl iodide (18.1 gm, 0.127 moles) was added in a one lot at 0-5°C. 60percent sodium hydride (5.29gm, 0.22 moles) was added in a small portion at a time at 0-10⁰C to the reaction mixture for 1.5 hour. The reaction mixture was stirred for 30 min at 10-15⁰C and further stirred for 4 hour. The reaction mixture was poured into the ice-water and solid obtained was filtered. The filtrate was extracted with ethyl acetate. The solid was dissolved in the ethyl acetate extract and washed twice with water. The ethyl acetate layer was separated and concentrated to give a residue. The residue obtained was crystallized from EPO <DP n="15"/>ethyl acetate-hexane (20 ml : 10 ml) to give a solid 2,2'-(5-methyl-l,3-phenylene)di(2- methylpropiononitrile) (II). [Yield: 67 percent, m.p. 126-127°C]
67%	With sodium hydride In N,N-dimethyl-formamide at 0 - 15℃; for 6 h;	c) Preparation of 2,2'-(5-Methyl-1,3-phenylene)di(2-methylpropiononitrile) (II) A solution of 2,2'-(5-methyl-1,3-phenylene)diacetonitrile (VI) (5 gm, 0.029 moles) in N,N-dimethylformamide (100 ml) was stirred under nitrogen. To this, methyl iodide (18.1 gm, 0.127 moles) was added in a one lot at 0-5° C. 60percent sodium hydride (5.29 gm, 0.22 moles) was added in a small portion at a time at 0-10° C. to the reaction mixture for 1.5 hour. The reaction mixture was stirred for 30 min at 10-15° C. and further stirred for 4 hour. The reaction mixture was poured into the ice-water and solid obtained was filtered. The filtrate was extracted with ethyl acetate. The solid was dissolved in the ethyl acetate extract and washed twice with water. The ethyl acetate layer was separated and concentrated to give a residue. The residue obtained was crystallized from ethyl acetate-hexane (20 ml: 10 ml) to give a solid 2,2'-(5-methyl-1,3-phenylene)di(2-methylpropiononitrile) (II). [Yield: 67percent, m.p. 126-127° C.]

60%	Stage #1: With sodium hydride In N,N-dimethyl-formamide Stage #2: at 10 - 35℃; for 4 h;	NaH (1.25 kg; 49.5mol, 5.5 meq) was added to a solution of 1.53 kg 5-methyl-1,3-benzenediacetonitrile 3 (9 mol) in 20 1 DMF. The mixture was stirred and cooled to about 10 °C. A solution of 2,8 1 methyl iodide (45 mol, 5 meq) in 7 1 DMF was added slowly into the cooled mixture. During the addition, the temperature of the reaction mixture was controlled such that 35 °C were not exceeded. After the addition, the mixture was stirred for about 4 hours at room temperature. To the stirred solution 25 1 of H₂O and 25 1 ethyl acetate were added. The mixture was stirred for about 10 minutes and then phase separated. To the aqueous layer another 25 1 of ethyl acetate were added. The mixture was stirred for about 10 minutes and then phase separated. The aqueous layer was discarded, and the organic layers were combined. The combined organic layers were washed with 25 1 H₂O three times. The organic layer was concentrated to dryness to obtain crude α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4. The crude product was purified via crystallisation from 2-propanol to obtain purified 4 in a yield of 60 percent.
60%	Stage #1: With sodium hydride In N,N-dimethyl-formamide at 10℃; Stage #2: at 10 - 35℃; for 4 h;	NaH (1.25 kg; 49.5 mol, 5.5 meq) was added to a solution of 1.53 kg 5-methyl-1,3-benzenediacetonitrile 3 (9 mol) in 20 l DMF. The mixture was stirred and cooled to about 10° C. A solution of 2.8 methyl iodide (45 mol, 5 meq) in 7 l DMF was added slowly into the cooled mixture. During the addition, the temperature of the reaction mixture was controlled such that 35° C. were not exceeded. After the addition, the mixture was stirred for about 4 hours at room temperature. To the stirred solution 25 l of H₂O and 25 l ethyl acetate were added. The mixture was stirred for about 10 minutes and then phase separated. To the aqueous layer another 25 l of ethyl acetate were added. The mixture was stirred for about 10 minutes and then phase separated. The aqueous layer was discarded, and the organic layers were combined. The combined organic layers were washed with 25 l H₂O three times. The organic layer was concentrated to dryness to obtain crude α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4. The crude product was purified via crystallisation from 2-propanol to obtain purified 4 in a yield of 60percent.

Reference： [1] Organic and Biomolecular Chemistry, 2007, vol. 5, # 18, p. 2940 - 2952
[2] Patent: WO2006/836, 2006, A1, . Location in patent: Page/Page column 2; 9-10; 14; Figure 2
[3] Patent: US2006/189670, 2006, A1, . Location in patent: Page/Page column 5-7
[4] Patent: WO2007/39913, 2007, A1, . Location in patent: Page/Page column 13-14
[5] Patent: US2008/207915, 2008, A1, . Location in patent: Page/Page column 5
[6] Patent: EP1705168, 2006, A1, . Location in patent: Example 3
[7] Patent: US2006/217569, 2006, A1, . Location in patent: Page/Page column 4; Fig. 1

2
[ 74-88-4 ]
[ 120511-72-0 ]

Reference： [1] Patent: WO2007/105231, 2007, A1, . Location in patent: Page/Page column 5

3
[ 120511-74-2 ]
[ 80-48-8 ]
[ 120511-72-0 ]

Reference： [1] Organic Preparations and Procedures International, 2008, vol. 40, # 5, p. 487 - 489

4
[ 1611-92-3 ]
[ 851233-80-2 ]
[ 120511-72-0 ]

Reference： [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474

5
[ 120511-84-4 ]
[ 41253-21-8 ]
[ 120511-72-0 ]
[ 120511-92-4 ]
[ 120511-73-1 ]

Reference： [1] Patent: WO2009/10991, 2009, A2, . Location in patent: Page/Page column 9; 10; 11; 11-12; 12; 13

6
[ 120511-72-0 ]
[ 120511-84-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2 - 2.5 h; Heating / reflux	A mixture of 3,5-bis(1-cyano-1-methylethyl)toluene obtained in Step III (600 g, 2.65 mol), N-bromosuccinimide (519 g, 2.916 mol), benzoyl peroxide (17 g, 0.053 mol) and carbon tetrachloride (4.5 L) was refluxed for 2 to 2.5 hours. The reaction mass was cooled and filtered. The filtrate was concentrated to dryness at 40° C. to 45° C. The solid obtained was dissolved in 2-propanol (2 L) at 75° C. to 80° C. and gradually cooled to 10° C. to 15° C. The reaction mass was stirred for 1 hour. The reaction mass was further cooled -5° C. to 0° C., stirred for 2 hours, filtered, and washed with chilled 2-propanol (200 ml). The cake was washed with n-hexane and sucked dry. The cake was then dried at 40° C. to 45° C. under vacuum to obtained 3,5-bis(1-cyano-1-methylethyl)benzyl bromide (700.2 g, 87.0percent yield).
85%	With N-Bromosuccinimide In dichloromethane for 4 h; UV-irradiation; Heating / reflux	Into a 500 ml flask equipped with a reflux condenser 3,5-bis(2-cyanoprop-2-yl)toluene (20 g, 0.088 mole) was added and dissolved in dichloromethane (200 ml). N-bromosuccinimide (15.8 go 0.089 mole) was then added in several portions. UV light was applied (λ=370 nm) with the aid of a UV lamp. The mixture was heated under reflux for 4 hours and then cooled to room temperature. The solids were filtered out, and the solution was washed, first with water (80 ml), followed by NaOH 0.5N (80 ml), 2percent solution of sodium metabisulfite (80 ml) and once more with water. The layers were then separated, the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain white crystals (24.6 g, 85percent yield). (Purity as determined by HPLC: 87percent)
85%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 75 - 80℃; for 3 h;	a, a, a ', a', 5-pentamethyl-1,3-Benzenediacetonitrile 50g(0.22mol), acetonitrile 500ml , AIBN 1.0g added into reaction flask, then added NBS 205g(0.25mol), stirred and heated to reflux at 75-80 ° C and continue the stirring for 3 hours. After the completion of the reaction, carried out vacuum concentration under 60 ° C, cold to room temperature, then added 250ml of dichloromethane , then sequentially washed with 50 mL of 10percent sodium sulfite solution, 50 mL of 10percent sodium carbonate solution, 50 mL of 10percent sodium chloride solution and 50 mL of water,then dried over anhydrous sodium sulfate, and concentrated at 35-40 ° C. Added 30 mL of isopropanol and 490 mL of n-hexane, heated to 50-55 ° C, incubate for 30 min, slowly cool to 25-30 ° C, stirred for 1 h, carried out filtration and washed with 25 mL n-hexane to obtain 57 g of solid crystals, 85. 0percent, purity 92percent.

80%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) In cyclohexane at 25 - 85℃;	Example-1 3,5-bis-(1-cyano-1-meltylethyl)benzylbromide (2) In a 5 L R. B. Flask, fitted with double surface condenser and thermometer pocket on a water bath cyclohexane (1.5 L), 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile) (1) (50 g), 2,2-Azo-bis(isobutyronitrile) (AIBN) (2 g) and 1,3-dibromo-5,5-dimethylhydantoin (130 g) were charged at 25-35° C. The reaction mixture was heated at 80-85° C. with vigorous stirring for 4 hours. The reaction mass was cooled to 25-35° C. and washed with water (500 mL*2) followed by washing with 2percent aqueous solution of sodium thiosulphate (500 mL). Cyclohexane layer was separated and distilled under vacuum at 50-55° C. to get residue, which was crystallized from cyclohexane (250 mL) and further dried at 55-60° C. for 3 hours, to get crude product 52 gm, which on crystallization from methanol gave product (37 gm). HPLC-purity shows 3,5-bis-(1-cyano-1-methylethyl)benzylbromide (2) as product >80percent, contaminated with unreacted 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile) (1) <15percent and dibrominated by-product 3,5-bis(1-cyano-1-methylethyl)-α,α-dibromotoluene (3) <5percent.
74%	With N-Bromosuccinimide; dibenzoyl peroxide In 1,1,2-ethylene-trichloride for 2 - 3 h; Heating / reflux	d) Preparation of 2,2'-(5-BromomethyI-l,3-phenylene)di(2-methyl propionitrile) (HI; wherein X = Br)A mixture of 2,2-(5-methyl-l,3-phenylene)di(2-methylpropionitrile) (H) (4 gm, 0.0176 moles), N- bromosuccinimide (3.3 gm, 0.018 moles) and benzoyl peroxide (0.4 gm) in 1,1,2- ethylenetrichloride (40 ml) was refluxed for 2-3 hour. Reaction mixture was cooled gradually to room temperature and filtered. The mother liquor was concentrated under vacuum to give yellowish oily residue. The residue obtained was crystallized from hexane to give a solid 2,2'-(5- bromomethyl-l,3-phenylene)di(2-methylpropionitrile) (HI b), which was used without further purification for next step. [Yield: 74 percent]
74%	With N-Bromosuccinimide; dibenzoyl peroxide In 1,1,2-ethylenetrichloride for 2 - 3 h; Heating / reflux	d) Preparation of 2,2'-(5-Bromomethyl-1,3-phenylene)di(2-methyl propionitrile) (III; wherein X=Br) A mixture of 2,2-(5-methyl-1,3-phenylene)di(2-methylpropionitrile) (II) (4 gm, 0.0176 moles), N-bromosuccinimide (3.3 gm, 0.018 moles) and benzoyl peroxide (0.4 gm) in 1,1,2-ethylenetrichloride (40 ml) was refluxed for 2-3 hour. Reaction mixture was cooled gradually to room temperature and filtered. The mother liquor was concentrated under vacuum to give yellowish oily residue. The residue obtained was crystallized from hexane to give a solid 2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropionitrile) (IIIb), which was used without further purification for next step. [Yield: 74percent]
71.2%	With N-Bromosuccinimide In dichloromethane for 9 h; Heating / reflux	Example 14 Preparation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide in dichloromethane in the presence of benzoyl peroxide Into a 1000 ml flask equipped with a reflux condenser 3,5-bis(2-cyanoprop-2-yl)toluene (40 g, 0.177 mole) was added and dissolved in dichloromethane (400 ml). N-bromosuccinimide (31.4 g, 0.176 mole) was then added in a number of portions, followed by addition of benzoyl peroxide (0.79 g, 0.003 mole). The mixture was refluxed for 5 hours, additional N-bromo succinimide was added (6.4 g, 0.04 mole), and the reaction mixture was refluxed for further 4 hours. A sample was withdrawn and analysed by HPLC (content of 3,5-bis(2-cyanoprop-2-yl)toluene was less than 2.5percent). The reaction mixture was then cooled to room temperature. The solids were filtered out and the solution was washed first with water (150 ml), followed by NaOH 0.5N (150 ml), and a 2percent solution of sodium metabisulfite (150 ml). The layers were separated, the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain white crystals (38.4 g, 0.126 mole, 71.2percent yield).
81.0 %Chromat.	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 3 h; Heating / reflux	To 1.13 kg of α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-di-acetonitrile 4 (5 mol) in 6 1 of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4 x 250 mm, 5 μm (Merck, Lot L 552433); detection: UV = 210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water = 1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 1 of ethyl acetate and 20 1 of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude α,α,α',α'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81 percent and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2. Table 2 Bromination of α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 solvent/ bromination agentProduct 5 [percent]¹⁾ Unreacted Educt 4 [percent]¹⁾ Side products [percent]¹⁾ CCl₄/ NBS²⁾ 70.0 2.9 27.1 Cyclohexane/ NBS 64.4 29.7 3.8 Acetonitile /NBS 81.0 1.1 17.6¹⁾ determined by HPLC²⁾ comparative example
64.4 %Chromat.	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In cyclohexane for 3 h; Heating / reflux	To 1.13 kg of α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-di-acetonitrile 4 (5 mol) in 6 1 of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4 x 250 mm, 5 μm (Merck, Lot L 552433); detection: UV = 210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water = 1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 1 of ethyl acetate and 20 1 of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude α,α,α',α'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81 percent and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2. Table 2 Bromination of α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 solvent/ bromination agentProduct 5 [percent]¹⁾ Unreacted Educt 4 [percent]¹⁾ Side products [percent]¹⁾ CCl₄/ NBS²⁾ 70.0 2.9 27.1 Cyclohexane/ NBS 64.4 29.7 3.8 Acetonitile /NBS 81.0 1.1 17.6¹⁾ determined by HPLC²⁾ comparative example
70.0 %Chromat.	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3 h; Heating / reflux	To 1.13 kg of α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-di-acetonitrile 4 (5 mol) in 6 1 of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4 x 250 mm, 5 μm (Merck, Lot L 552433); detection: UV = 210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water = 1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 1 of ethyl acetate and 20 1 of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude α,α,α',α'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81 percent and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2. Table 2 Bromination of α,α,α',α'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 solvent/ bromination agentProduct 5 [percent]¹⁾ Unreacted Educt 4 [percent]¹⁾ Side products [percent]¹⁾ CCl₄/ NBS²⁾ 70.0 2.9 27.1 Cyclohexane/ NBS 64.4 29.7 3.8 Acetonitile /NBS 81.0 1.1 17.6¹⁾ determined by HPLC²⁾ comparative example

Reference： [1] Patent: US2006/189670, 2006, A1, . Location in patent: Page/Page column 5; 7
[2] Patent: US2006/35950, 2006, A1, . Location in patent: Page/Page column 3; 11
[3] Patent: CN103554041, 2016, B, . Location in patent: Paragraph 0014-0016
[4] Patent: US2009/221837, 2009, A1, . Location in patent: Page/Page column 4
[5] Patent: WO2007/39913, 2007, A1, . Location in patent: Page/Page column 14
[6] Patent: US2008/207915, 2008, A1, . Location in patent: Page/Page column 5
[7] Patent: US2006/35950, 2006, A1, . Location in patent: Page/Page column 3; 11
[8] Organic and Biomolecular Chemistry, 2007, vol. 5, # 18, p. 2940 - 2952
[9] Patent: WO2005/105762, 2005, A1, . Location in patent: Page/Page column 7-8
[10] Patent: WO2005/105762, 2005, A1, . Location in patent: Page/Page column 9
[11] Patent: US2006/35950, 2006, A1, . Location in patent: Page/Page column 3; 11-12
[12] Patent: US2006/35950, 2006, A1, . Location in patent: Page/Page column 3; 12
[13] Patent: WO2006/108155, 2006, A2, . Location in patent: Page/Page column 13
[14] Patent: WO2006/108155, 2006, A2, . Location in patent: Page/Page column 13-14
[15] Patent: WO2006/108155, 2006, A2, . Location in patent: Page/Page column 14-15
[16] Patent: WO2006/108155, 2006, A2, . Location in patent: Page/Page column 14
[17] Patent: US2007/100148, 2007, A1, . Location in patent: Page/Page column 5
[18] Patent: WO2007/105231, 2007, A1, . Location in patent: Page/Page column 5
[19] Patent: WO2008/47104, 2008, A1, . Location in patent: Page/Page column 15-16
[20] Patent: WO2008/47104, 2008, A1, . Location in patent: Page/Page column 16-17
[21] Patent: US2010/99887, 2010, A1, . Location in patent: Page/Page column 6
[22] Patent: EP1705168, 2006, A1, . Location in patent: Example 4
[23] Patent: EP1705168, 2006, A1, . Location in patent: Example 4
[24] Patent: EP1705168, 2006, A1, . Location in patent: Example 4
[25] Patent: US2006/217569, 2006, A1, . Location in patent: Page/Page column 4; Fig. 1
[26] Patent: US2006/217569, 2006, A1, . Location in patent: Page/Page column 4; Fig. 1
[27] Patent: US2006/217569, 2006, A1, . Location in patent: Page/Page column 4; Fig. 1
[28] Patent: EP2397472, 2011, A1, . Location in patent: Page/Page column 5
[29] Organic Process Research and Development, 2013, vol. 17, # 3, p. 557 - 567
[30] Patent: WO2014/184754, 2014, A1, . Location in patent: Page/Page column 4

[ 120511-72-0 ] Synthesis Path-Downstream 1~9

1
[ 120511-72-0 ]
[ 120511-84-4 ]

Yield	Reaction Conditions	Operation in experiment
87.0%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2 - 2.5h;Heating / reflux;	A mixture of 3,5-bis(1-cyano-1-methylethyl)toluene obtained in Step III (600 g, 2.65 mol), N-bromosuccinimide (519 g, 2.916 mol), benzoyl peroxide (17 g, 0.053 mol) and carbon tetrachloride (4.5 L) was refluxed for 2 to 2.5 hours. The reaction mass was cooled and filtered. The filtrate was concentrated to dryness at 40 C. to 45 C. The solid obtained was dissolved in 2-propanol (2 L) at 75 C. to 80 C. and gradually cooled to 10 C. to 15 C. The reaction mass was stirred for 1 hour. The reaction mass was further cooled -5 C. to 0 C., stirred for 2 hours, filtered, and washed with chilled 2-propanol (200 ml). The cake was washed with n-hexane and sucked dry. The cake was then dried at 40 C. to 45 C. under vacuum to obtained 3,5-bis(1-cyano-1-methylethyl)benzyl bromide (700.2 g, 87.0% yield).
85%	With N-Bromosuccinimide; In dichloromethane; for 4h;UV-irradiation; Heating / reflux;Product distribution / selectivity;	Into a 500 ml flask equipped with a reflux condenser 3,5-bis(2-cyanoprop-2-yl)toluene (20 g, 0.088 mole) was added and dissolved in dichloromethane (200 ml). N-bromosuccinimide (15.8 go 0.089 mole) was then added in several portions. UV light was applied (lambda=370 nm) with the aid of a UV lamp. The mixture was heated under reflux for 4 hours and then cooled to room temperature. The solids were filtered out, and the solution was washed, first with water (80 ml), followed by NaOH 0.5N (80 ml), 2% solution of sodium metabisulfite (80 ml) and once more with water. The layers were then separated, the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain white crystals (24.6 g, 85% yield). (Purity as determined by HPLC: 87%)
85%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 75 - 80℃; for 3h;	a, a, a ', a', 5-pentamethyl-1,3-Benzenediacetonitrile 50g(0.22mol), acetonitrile 500ml , AIBN 1.0g added into reaction flask, then added NBS 205g(0.25mol), stirred and heated to reflux at 75-80 C and continue the stirring for 3 hours. After the completion of the reaction, carried out vacuum concentration under 60 C, cold to room temperature, then added 250ml of dichloromethane , then sequentially washed with 50 mL of 10% sodium sulfite solution, 50 mL of 10% sodium carbonate solution, 50 mL of 10% sodium chloride solution and 50 mL of water,then dried over anhydrous sodium sulfate, and concentrated at 35-40 C. Added 30 mL of isopropanol and 490 mL of n-hexane, heated to 50-55 C, incubate for 30 min, slowly cool to 25-30 C, stirred for 1 h, carried out filtration and washed with 25 mL n-hexane to obtain 57 g of solid crystals, 85. 0%, purity 92%.

> 80%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile); In cyclohexane; at 25 - 85℃;	Example-1 3,5-bis-(1-cyano-1-meltylethyl)benzylbromide (2) In a 5 L R. B. Flask, fitted with double surface condenser and thermometer pocket on a water bath cyclohexane (1.5 L), 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile) (1) (50 g), 2,2-Azo-bis(isobutyronitrile) (AIBN) (2 g) and 1,3-dibromo-5,5-dimethylhydantoin (130 g) were charged at 25-35 C. The reaction mixture was heated at 80-85 C. with vigorous stirring for 4 hours. The reaction mass was cooled to 25-35 C. and washed with water (500 mL*2) followed by washing with 2% aqueous solution of sodium thiosulphate (500 mL). Cyclohexane layer was separated and distilled under vacuum at 50-55 C. to get residue, which was crystallized from cyclohexane (250 mL) and further dried at 55-60 C. for 3 hours, to get crude product 52 gm, which on crystallization from methanol gave product (37 gm). HPLC-purity shows 3,5-bis-(1-cyano-1-methylethyl)benzylbromide (2) as product >80%, contaminated with unreacted 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile) (1) <15% and dibrominated by-product 3,5-bis(1-cyano-1-methylethyl)-alpha,alpha-dibromotoluene (3) <5%.
74%	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,1,2-ethylene-trichloride; for 2 - 3h;Heating / reflux;	d) Preparation of 2,2'-(5-BromomethyI-l,3-phenylene)di(2-methyl propionitrile) (HI; wherein X = Br)A mixture of 2,2-(5-methyl-l,3-phenylene)di(2-methylpropionitrile) (H) (4 gm, 0.0176 moles), N- bromosuccinimide (3.3 gm, 0.018 moles) and benzoyl peroxide (0.4 gm) in 1,1,2- ethylenetrichloride (40 ml) was refluxed for 2-3 hour. Reaction mixture was cooled gradually to room temperature and filtered. The mother liquor was concentrated under vacuum to give yellowish oily residue. The residue obtained was crystallized from hexane to give a solid 2,2'-(5- bromomethyl-l,3-phenylene)di(2-methylpropionitrile) (HI b), which was used without further purification for next step. [Yield: 74 %]
74%	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,1,2-ethylenetrichloride; for 2 - 3h;Heating / reflux;	d) Preparation of 2,2'-(5-Bromomethyl-1,3-phenylene)di(2-methyl propionitrile) (III; wherein X=Br) A mixture of 2,2-(5-methyl-1,3-phenylene)di(2-methylpropionitrile) (II) (4 gm, 0.0176 moles), N-bromosuccinimide (3.3 gm, 0.018 moles) and benzoyl peroxide (0.4 gm) in 1,1,2-ethylenetrichloride (40 ml) was refluxed for 2-3 hour. Reaction mixture was cooled gradually to room temperature and filtered. The mother liquor was concentrated under vacuum to give yellowish oily residue. The residue obtained was crystallized from hexane to give a solid 2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropionitrile) (IIIb), which was used without further purification for next step. [Yield: 74%]
71.2%	With N-Bromosuccinimide;dibenzoyl peroxide; In dichloromethane; for 9h;Heating / reflux;Product distribution / selectivity;	Example 14 Preparation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide in dichloromethane in the presence of benzoyl peroxide Into a 1000 ml flask equipped with a reflux condenser 3,5-bis(2-cyanoprop-2-yl)toluene (40 g, 0.177 mole) was added and dissolved in dichloromethane (400 ml). N-bromosuccinimide (31.4 g, 0.176 mole) was then added in a number of portions, followed by addition of benzoyl peroxide (0.79 g, 0.003 mole). The mixture was refluxed for 5 hours, additional N-bromo succinimide was added (6.4 g, 0.04 mole), and the reaction mixture was refluxed for further 4 hours. A sample was withdrawn and analysed by HPLC (content of 3,5-bis(2-cyanoprop-2-yl)toluene was less than 2.5%). The reaction mixture was then cooled to room temperature. The solids were filtered out and the solution was washed first with water (150 ml), followed by NaOH 0.5N (150 ml), and a 2% solution of sodium metabisulfite (150 ml). The layers were separated, the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain white crystals (38.4 g, 0.126 mole, 71.2% yield).
	With N-Bromosuccinimide; 3-chloro-benzenecarboperoxoic acid; In chloroform; for 3h;Heating / reflux;Product distribution / selectivity;	Example 1; Preparation of pure anastrozole of the formula-I; (i) Preparation of a, a, a', alpha'-tetramethyl-5-bromomethyl-1,3-benzenediacetonitrile of formula-V; Into a SOL glass flask was charged 12L of chloroform and 1.0kg of 5, a, a, a', a'- pentamethyl-1,3-benzenediacetonitrile of formula-IV. The reaction mass was heated to reflux temperature and charged 0.8kg. of N-bromosuccinimide and 10g of m- chlorobenzoylperoxide. The reaction mass was maintained at reflux temperature for 3 hr. HPLC of the reaction mass indicated 90% of conversion. The reaction mass was cooled to 25 C and charged 7L of water. The reaction mass was stirred for 30min and separated the water layer. Organic layer was washed with water (2 x 7L). Activated carbon (0.2Kg) and sodium sulfate (0.5Kg) were added to the organic layer and filtered Chloroform was distilled of from the filtrate to get 1.4kg of crude compound of formula-V. Purity by HPLC was >85%.
	With N-Bromosuccinimide; 3-chloro-benzenecarboperoxoic acid; In tetrachloromethane; for 10h;Heating / reflux;Product distribution / selectivity;	Example 2; Preparation of pure anastrozole of the formula-I; (i) Preparation of a, a, a', a'-tetramethyl-5-bromomethyl-1, 3-benzenediacetonitrile of formula-V; Into a 2L, three-necked RB flask was charged 1L of carbon tetrachloride and 100g of 5,a, a, a', a'-pentamethyl-1, 3-benzenediacetonitrile of formula-IV. The reaction mass was heated to reflux temperature and charged 80g of N-bromosuccinimide and lg of m- chlorobenzoylperoxide. The reaction mass was maintained at reflux temperature for 10 hr. HPLC of the reaction mass indicated >90% of conversion. The reaction mass was cooled to 25 C and filtered the insoluble succinamide. Solvent was distilled of from the filtrate to get 140g of crude compound of formula-V. Purity by HPLC was >85%.
	With N-Bromosuccinimide;dibenzoyl peroxide; In acetone; for 4h;Heating / reflux;Product distribution / selectivity;	Example 15 Preparation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide in acetone Into a 100 ml flask equipped with a reflux condenser, 3,5-bis(2-cyanoprop-2-yl)toluene (2 g, 0.0088 mole) was added and dissolved in acetone (20 ml). N-bromosuccinimide (1.92 g, 0.0108 mole) was then added as a single portion, followed by addition of benzoyl peroxide (0.2 g, 0.0008 mole). The mixture was heated under reflux for 4 hours and then cooled to room temperature. The solids were filtered out, and the solution was washed first with water (10 ml), followed by NaOH 0.5N (10 ml) and a 2% solution of sodium metabisulfite (10 ml). The layers were separated, the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the product as a solid. 3,5-bis(2-cyanoprop-2-yl)benzylbromide content according to the HPLC chromatogram was 72%
	With N-Bromosuccinimide; In acetonitrile; for 4h;Heating / reflux;Product distribution / selectivity;	Example 16 Preparation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide in acetonitrile Into a 100 ml flask equipped with a reflux condenser, 3,5-bis(2-cyanoprop-2-yl)toluene (2 g, 0.0088 mole) was added and dissolved in acetonitrile (20 ml). N-bromo succinimide (1.6 g, 0.09 mole) was then added, the mixture was heated under reflux for 4 hours, and then cooled to room temperature. The solids were filtered out and the solution was washed first with water (10 ml), followed by NaOH 0.5N (10 ml), and a 2% solution of sodium metabisulfite (10 ml). The layers were separated, the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the product as a solid. 3,5-bis(2-cyanoprop-2-yl)benzylbromide content according to the HPLC chromatogram was 80.6%.
		Fifty grams of 3,5-bis (2-cyanoisopropyl)toluene was dissolved in 350 ml of acetonitrile, and 41.1 g of N-bromosuccinimide was added. The resulting suspension was heated to 50C for 30 minutes, until completely dissolved. Then, 0.5 g of 2,2'-azobis(2- methylpropionitrile) was added, and the reaction was heated to 70C for about 8 hours. The solution was then allowed to cool to about 200C, and 350 ml of a 5 percent by weight solution of sodium metabisulphite in water was added in 30 min under vigorous stirring. Toluene was then added in an amount of 350 ml, and the biphasic system was stirred for 30 minutes. The organic layer was separated and washed with 200 ml of water containing 5 percent by weight sodium carbonate before removal of the organic solvent under reduced pressure, until a total volume of 120 ml was achieved.[00031] The slurry thus obtained was then heated to 500C, and 350 ml of heptane was slowly added over a period of 30 minutes, rising the temperature to 70C. The suspension was then allowed to cool to 200C, and was filtered on a sintered glass funnel. Drying under reduced pressure yielded 54 g of crude l-bromomethyl-3,5-bis (2-cyanoisopropyl)toluene_in 85 percent purity, based on HPLC area percent.[00032] IH NMR data for l-bromo-3,5-bis (2-cyanoisopropyl)toluene: delta (ppm): 7.48-7.44 (m, 3H; phenyl ring H); 4.50 (s, 2H, CH2Br); 1.75 (s, 6H, isopropyl CH3).
		First, 1.13 g of 3,5-bis (2-cyanoisopropyl)toluene was dissolved in 7.5 ml of dichloromethane, and 0.94 g of N-bromosuccinimide was added. The resulting suspension was stirred at 200C for 30 minutes, until complete dissolution was achieved. Then, 16 mg of 2,2'-azobis(2-methylpropionitrile) is added, and the reaction was heated to 400C for about 8 hours. The solution was then allowed to cool to 200C, and poured into 10 ml of a 5 percent by weight solution of sodium metabisulphite in water with vigorous stirring. Toluene in an EPO <DP n="15"/>amount of 7.5 ml was then added, and the biphasic system was stirred for 30 minutes. The organic layer was separated, and the organic solvent was removed until final volume of 2 ml is obtained. 10 ml of heptane was slowly added over a period of 30 minutes, rising the temperature to 7O0C. The suspension was then allowed to cool to 20C, and was filtered on a sintered glass funnel. Drying under reduced pressure yields 1.5 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,alpha',alpha' tetramethyl in 80 percent purity, based on HPLC area percent.
		10 g of 3,5-bis (2-cyanoisopropyl)toluene were dissolved in 48 ml of chlorobenzene, and 8.26 g of N-bromosuccinimide was added. The suspension was then stirred at 900C for 30 minutes. Then, 4 mg of 2,2'-azobis(2-methylpropionitrile) were added and a complete dissolution was achieved, and the reaction was heated to 950C for 8 hours. The solution was then allowed to cool to 20C, and poured into 50 ml of a 5 percent by weight solution of sodium metabisulphite in water with vigorous stirring. Toluene (20 ml) was then added, and the biphasic system was stirred for 30 minutes. The organic layer was separated and the organic solvent was removed. Toluene (22 ml) was added and the slurry was heated to 500C, and 10 ml of heptane was slowly added over a period of 30 minutes, rising the temperature to 700C. The suspension was then allowed to cool to 200C, and was EPO <DP n="16"/>filtered on a sintered glass funnel. Drying under reduced pressure yielded 4 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,alpha',alpha' tetramethyl in 86 percent purity, based on HPLC area percent.
		First, 0.3 g of 3,5-bis (2-cyanoisopropyl)toluene was dissolved in 7 ml of acetonitrile, and 0.1 g of l,3-dibromo-5,5-dimethylhydantoin is added. The suspension was then stirred at 20C for 30 minutes, until complete dissolution was achieved. Then, 4 mg of 2,2'-azobis(2-methylpropionitrile) was added, and the reaction was heated to 70C for 8 hours. The solution was then allowed to cool to 200C, and poured into 7 ml of a 5 percent by weight solution of sodium metabisulphite in water with vigorous stirring. Toluene (7.5 ml) was then added, and the biphasic system was stirred for 30 minutes. The organic layer was separated and the organic solvent was removed until final volume of 1 ml is obtained. Then, the solution was heated to 500C, and 10 ml of heptane was slowly added over a period of 30 minutes, rising the temperature to 7O0C. The suspension was then allowed to cool to 2O0C, and was filtered on a sintered glass funnel. Drying under reduced pressure yielded 0.3 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,alpha',alpha' tetramethyl in 86 percent purity, based on HPLC area percent.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane; at 3 - 40.5℃; for 31.33h;	EXAMPLE 1; Preparation of 2-[3-bromomethyl-5-cyano-dimethyl-methyl)-phenyl]-2-methyl-propionitrile (Formula II) 1.5 Kg of 2-2'-(5-methyl-1,3-phenylene) di-(2-methylpropiononitrile) and 30 L of dichloromethane were charged into a glass flask followed by stirring for 10 minutes. 1.2 Kg of N-bromosuccinimide was charged followed by charging of 0.022 Kg of azobis(isobutyronitrile) and the reaction solution was stirred for 10 minutes. The resultant reaction mixture was heated to about 40.5 C. for 6 hours followed by cooling to 3 C. The reaction mixture was stirred for about for 30 minutes at 3 C. followed by filtering. The resultant filtrate was taken into a clean and dry glass flask followed by charging of 0.35 Kg of N-bromosuccinimide, 0.022 Kg of azobis(isobutyronitrile) and 2 L of dichloromethane. The resultant reaction mass was stirred for 10 minutes and heated to about 40.5 C. for 24 hours. The reaction mass was cooled to about 3.7 C. for 30 minutes followed by filtering. The resultant filtrate was washed with sodium bisulphite solution (7.5 L of water and 0.75 Kg of sodium bisulphate) followed by separation of the organic layer and distilling at 40 C. under a vacuum of 600 mm Hg. The obtained wet residue was dissolved in 2.25 L of dichloromethane and stirred for 10 minutes, followed by charging of 16 L of n-hexane. The resultant suspension was stirred for 30 minutes followed by filtering the separated solid and washing the solid with 2 L of n-hexane. The solid obtained was suction dried for 2 hours to afford 1.6 Kg of title compound.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; at 10 - 20℃; for 3h;Heating / reflux;	EXAMPLE 2; Preparation of ?.,?.,a' 'a' ' - tetra methyl 5- bromomethyl- 1,3-Benz.en acetonitrile of formula(III):In a 3-necked flask, charge chlorobenzene (200ml) alpha,alpha,alpha'alpha' - pentamethyl - 1 ,3 Benzene 1 5 diacetonitrile of formula (II), followed by N- bromo succinimide (98.5 g) and AIBN (2.Og) the reaction mixture heated to reflux for an hour. Cool the reaction mixture to room temperature and maintain 10 to 1 5C for 2 hr. Filter the mass and dry the cake. To the dried cake, charge DM water ( 1090 ml) stir at room temperature for 2h. Filter and dry the residue under vacuum at 45 to 500C to obtain the title compound.
	With N-Bromosuccinimide; sulfuric acid; dibenzoyl peroxide; In acetonitrile; at 50 - 80℃; for 4h;Product distribution / selectivity;	Example 1; 20 Preparation of 3,5-bis (2-cyanoprop-2-yl) benzyl bromide, compound of formula(lll)Acetonitrile (about 10 Its), 3,5-bis(2-cyanoprop-2-yl)toluene (1.0 kg), benzoyl peroxide (23 g) and sulphuric acid (10 g) were charged and heated to 50-550C. To this N- bromosuccinimide (1000 g) was added over a period of 3 hours, maintained for 30 5 minutes, then the term perature was slowly raised to reflux (75-8O0C) and maintained for 1 hour. After reaction completion, the mass was cooled to 25-3O0C, water (25 ml) was added and concentrated under vacuum to a residue at a temperature less than 6O0C. The contents were cooled to 25-3O0C, methylene choride (2500 ml) was charged, chilled to 10- 150C, the insolubles were filtered and washed with chilled methylene chloride (150 ml). 0 The combined methylene chloride layer was washed with 10% sodium sulphite solution <n="17"/>(300 ml), followed by washing with 10% sodium bicarbonate solution (300 ml) and 10% sodium chloride solution (300 ml). The methylene chloride layer was finally washed with water (300ml), dried over sodium sulphate and concentrated to a residue under vacuum at 35-4O0C. To this residue charged isopropyl alcohol followed by n-heptane, heated to 50- 550C, maintained for 30 minutes then slowly cooled to 25-3O0C and stirred for 1 hour. The material so obtained was filtered, washed with n-heptane (250 ml).
	With N-Bromosuccinimide; acetic acid; dibenzoyl peroxide; In acetonitrile; at 75 - 80℃; for 6.5h;Product distribution / selectivity;	Example 2; Preparation of 3,5-bis (2-cyanoprop-2-yl)benzylbromide, compound of formula (III)Acetonitrile(1300 ml), 3,5-bis(2-cyanoprop-2-yl) toluene (100 g), benzoyl peroxide (2.3 g) and acetic acid (1.2 ml) were heated to 50-550C. To this, N-bromosuccinimide (100 g) was added over a period of 3 hours, maintained for 30 minutes, then the temperature was slowly raised to reflux (75-8O0C) and maintained for 3 hours. After reaction completion, the mass was cooled to 25-3O0C, water (2.5 ml) was added and concentrated under vacuum to residue at a temperature lower than 6O0C. The contents were cooled to 25-3O0C, methylene chloride (250 ml) was charged, chilled to 10-150C, and the insolubles were filtered and washed with chilled methylene chloride (15 ml). The combined methylene chloride layer was washed with 10% sodium sulphite solution (30 ml), followed by a wash with 10% sodium bicarbonate solution (30 ml) and 10% sodium chloride solution (30 ml).The methylene chloride layer was finally washed with water (30 ml), dried over sodium sulphate and concentrated to residue at 35-4O0C. To this residue, isopropyl alcohol (30 ml) <n="18"/>and n-heptane (490 ml) were charged, heated to 50-550C, maintained for 30 minutes, slowly cooled to 25-3O0C and stirred for 1 hour. The material so obtained was filtered and washed with n-heptane (25 ml).
	With N-Bromosuccinimide; sulfuric acid; dibenzoyl peroxide; In acetonitrile; at 50 - 80℃; for 4.5h;Product distribution / selectivity;	Example 1; Preparation of 3,5-bis(2-cyanoprop-2-yl)benzyl bromide, compound of formula(III)Acetonitrile (about 10 lts), 3,5-bis(2-cyanoprop-2-yl)toluene (1.0 kg), benzoyl peroxide (23 g) and sulphuric acid (10 g) were charged and heated to 50-55 C. To this N-bromosuccinimide (1000 g) was added over a period of 3 hours, maintained for 30 minutes, then the temperature was slowly raised to reflux (75-80 C.) and maintained for 1 hour. After reaction completion, the mass was cooled to 25-30 C., water (25 ml) was added and concentrated under vacuum to a residue at a temperature less than 60 C. The contents were cooled to 25-30 C., methylene choride (2500 ml) was charged, chilled to 10-15 C., the insolubles were filtered and washed with chilled methylene chloride (150 ml). The combined methylene chloride layer was washed with 10% sodium sulphite solution (300 ml), followed by washing with 10% sodium bicarbonate solution (300 ml) and 10% sodium chloride solution (300 ml). The methylene chloride layer was finally washed with water (300 ml), dried over sodium sulphate and concentrated to a residue under vacuum at 35-40 C. To this residue charged isopropyl alcohol followed by n-heptane, heated to 50-55 C., maintained for 30 minutes then slowly cooled to 25-30 C. and stirred for 1 hour. The material so obtained was filtered, washed with n-heptane (250 ml).
81.0%Chromat.	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; for 3h;Heating / reflux;Product distribution / selectivity;	To 1.13 kg of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-di-acetonitrile 4 (5 mol) in 6 1 of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4 x 250 mm, 5 mum (Merck, Lot L 552433); detection: UV = 210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water = 1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 1 of ethyl acetate and 20 1 of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81 % and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2. Table 2 Bromination of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 solvent/ bromination agentProduct 5 [%]1) Unreacted Educt 4 [%]1) Side products [%]1) CCl4/ NBS2) 70.0 2.9 27.1 Cyclohexane/ NBS 64.4 29.7 3.8 Acetonitile /NBS 81.0 1.1 17.61) determined by HPLC2) comparative example
64.4%Chromat.	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In cyclohexane; for 3h;Heating / reflux;Product distribution / selectivity;	To 1.13 kg of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-di-acetonitrile 4 (5 mol) in 6 1 of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4 x 250 mm, 5 mum (Merck, Lot L 552433); detection: UV = 210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water = 1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 1 of ethyl acetate and 20 1 of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81 % and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2. Table 2 Bromination of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 solvent/ bromination agentProduct 5 [%]1) Unreacted Educt 4 [%]1) Side products [%]1) CCl4/ NBS2) 70.0 2.9 27.1 Cyclohexane/ NBS 64.4 29.7 3.8 Acetonitile /NBS 81.0 1.1 17.61) determined by HPLC2) comparative example
70.0%Chromat.	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Heating / reflux;Product distribution / selectivity;	To 1.13 kg of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-di-acetonitrile 4 (5 mol) in 6 1 of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4 x 250 mm, 5 mum (Merck, Lot L 552433); detection: UV = 210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water = 1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 1 of ethyl acetate and 20 1 of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81 % and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2. Table 2 Bromination of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 solvent/ bromination agentProduct 5 [%]1) Unreacted Educt 4 [%]1) Side products [%]1) CCl4/ NBS2) 70.0 2.9 27.1 Cyclohexane/ NBS 64.4 29.7 3.8 Acetonitile /NBS 81.0 1.1 17.61) determined by HPLC2) comparative example
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; for 3h;Heating / reflux;Product distribution / selectivity;	To 1.13 kg of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 (5 mol) in 6 l of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4×250 mm, 5 mum (Merck, Lot L 552433); detection: UV=210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water=1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 l of ethyl acetate and 20 l of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81% and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In cyclohexane; for 3h;Heating / reflux;Product distribution / selectivity;	To 1.13 kg of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 (5 mol) in 6 l of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4×250 mm, 5 mum (Merck, Lot L 552433); detection: UV=210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water=1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 l of ethyl acetate and 20 l of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81% and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Heating / reflux;Product distribution / selectivity;	To 1.13 kg of alpha,alpha,alpha',alpha'-tetramethyl-5-methyl-1,3-benzene-diacetonitrile 4 (5 mol) in 6 l of acetonitrile, 1.0 kg NBS (6 mol, 1.2 meq) and 0.125 kg AIBN (0.75 mol, 0.015 meq) were added. The mixture was stirred and kept at reflux for 3 hours. The reaction progress was monitored by HPLC (column: RP-18, 4×250 mm, 5 mum (Merck, Lot L 552433); detection: UV=210 nm; flow rate: 1 ml/min; mobile phase: acetonitrile/water=1:1), the results of the analysis at the end of the reaction are shown in Table 2. After completion, the solvent was evaporated under reduced pressure. To the residue 20 l of ethyl acetate and 20 l of water were added. The mixture was stirred for about 10 minutes and then phases were separated. The organic layer was washed with water three times and concentrated to dryness. Crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 was obtained quantitatively with a purity of about 81% and was used directly without further purification. The above process was repeated but using cyclohexane and carbon tetrachloride, respectively, instead of acetonitrile as the solvent. The reaction mixtures were analysed by HPLC as described above. The results are also shown in Table 2.
	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione;2,2'-azobis(isobutyronitrile); In cyclohexane; at 25 - 85℃; for 4h;	Example -1 3,5-bis-(1-cyano-1-methylethyl)benzylbromide (2); In a 5 L R. B. Flask, fitted with double surface condenser and thermometer pocket on a water bath cyclohexane (1.5 L), 2,2-(5-methyl-1,3-phenylene)-bis(2-methylpropionitrile) (1) (50 g), 2,2-Azo-bis(isobutyronitrile) (AIBN) (2 g) and 1,3-dibromo-5,5-dimethylhydantoin (130 g) were charged at 25 - 35 C. The reaction mixture was heated at 80 - 85 C with vigorous stirring for 4 hours. The reaction mass was cooled to 25 - 35 C and washed with water (500 mL x 2) followed by washing with 2% aqueous solution of sodium thiosulphate (500 mL). Cyclohexane layer was separated and distilled under vacuum at 50-55 C to get residue, which was crystallised from cyclohexane (250 mL) and further dried at 55 - 60 C for 3 hours, to get crude product 52 gm, which on crystallization from methanol gave product (37 gm). HPLC-purity shows 3,5-bis-(1-cyano-1-methylethyl)benzyibromide (2) as product >80%, contaminated with unreacted 2,2-(5-methyl-,3-phenylene)-bis(2-methylpropionitrile) (1) <15 % and dibrominated by-product 3,5-bis(1-cyano-1-methylethyl)-alpha,alpha-dibromotoluene (3) < 5%.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); at 65 - 75℃;	10.0 g of [COMPOUND 1] and 100 ml of tert-butyl acetate are loaded in a flask. The resulting suspension is kept under stirring at ambient temperature.8.30 g of N-bromosuccinimide (NBS) followed by 220 mg of catalyst azobisisobutyronitrile (AIBN) are then added. At this point, the resulting mixture is heated and kept at a temperature of 65-75C for 2-4 hours.The reaction quenching is performed by lowering first the temperature of the reaction mixture to 30-40C and then adding 50 ml of a 5% solution of sodium metabisulphite.At this point the organic rich phase is separated from thewater phase and then washed with distilled water.80 ml of dimethylformamide (DMF) are added to the rich solution, after the latter has been concentrated in a vacuum. The solution thus obtained is re-distilled to eliminate theresidual t-butylacetate solvent. 4.47 g sodium 1,2,4-triazole are added to the same solution, after the latter has been brought to a temperature of 0-25C (preferably 5-10C). The reaction mixture thus obtained is kept under stirring for 1-2 hours.The reaction is quenched by the addition of 100 ml toluene and 125 ml distilled water. After separation of the phases, the rich organic phase is treated with a. water solution HC1 0.lM.After separation of the phases, 1 g of carbon is added to the resulting organic phase and it is kept under stirring at ambient temperature.After filtering, the clarified organic phase is extractedtwice with 100 ml of HC1 2M. The rich water phase, containinghigh purity dissolved anastrozole, is lastly back-washed with toluene.Maintaining a temperature below 15C, a solution of NaOF{ at30 by weight is added to the rich acid solution in 60-90minutes until pH 1 is reached. The mixture is then left in crystallization break at 0-5C for 2 hours. A solution of NaOI-{ 0.5 M is then added until a pH of between 2.5 and 3.5 is obtained. The resulting suspension is then left in break at0-5C for a further 2 hours. A last quantity of NaOH 0.5 M solution is then added until a final pH of between 5 and 7 is reached, followed by a last break atThe product is lastly filtered, washed with distilled waterand then dried in a vacuum at a temperature of 50C.In this way 6.3-6.6 g of pharmaceutical grade anastrozole are obtained from 10 g of commercial grade ANA-3.In particular, the product has:anhydrous titre: 99.16% ÷ 101.10%; KF<0 .1%;total impurities: 0.21% ÷ 0.26%

Reference： [1]Patent: US2006/189670,2006,A1 .Location in patent: Page/Page column 5; 7
[2]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 11
[3]Patent: CN103554041,2016,B .Location in patent: Paragraph 0014-0016
[4]Patent: US2009/221837,2009,A1 .Location in patent: Page/Page column 4
[5]Patent: WO2007/39913,2007,A1 .Location in patent: Page/Page column 14
[6]Patent: US2008/207915,2008,A1 .Location in patent: Page/Page column 5
[7]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 11
[8]Organic and Biomolecular Chemistry,2007,vol. 5,p. 2940 - 2952
[9]Patent: WO2005/105762,2005,A1 .Location in patent: Page/Page column 7-8
[10]Patent: WO2005/105762,2005,A1 .Location in patent: Page/Page column 9
[11]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 11-12
[12]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 12
[13]Patent: WO2006/108155,2006,A2 .Location in patent: Page/Page column 13
[14]Patent: WO2006/108155,2006,A2 .Location in patent: Page/Page column 13-14
[15]Patent: WO2006/108155,2006,A2 .Location in patent: Page/Page column 14-15
[16]Patent: WO2006/108155,2006,A2 .Location in patent: Page/Page column 14
[17]Patent: US2007/100148,2007,A1 .Location in patent: Page/Page column 5
[18]Patent: WO2007/105231,2007,A1 .Location in patent: Page/Page column 5
[19]Patent: WO2008/47104,2008,A1 .Location in patent: Page/Page column 15-16
[20]Patent: WO2008/47104,2008,A1 .Location in patent: Page/Page column 16-17
[21]Patent: US2010/99887,2010,A1 .Location in patent: Page/Page column 6
[22]Patent: EP1705168,2006,A1 .Location in patent: Example 4
[23]Patent: EP1705168,2006,A1 .Location in patent: Example 4
[24]Patent: EP1705168,2006,A1 .Location in patent: Example 4
[25]Patent: US2006/217569,2006,A1 .Location in patent: Page/Page column 4; Fig. 1
[26]Patent: US2006/217569,2006,A1 .Location in patent: Page/Page column 4; Fig. 1
[27]Patent: US2006/217569,2006,A1 .Location in patent: Page/Page column 4; Fig. 1
[28]Patent: EP2397472,2011,A1 .Location in patent: Page/Page column 5
[29]Organic Process Research and Development,2013,vol. 17,p. 557 - 567
[30]Patent: WO2014/184754,2014,A1 .Location in patent: Page/Page column 4

2
[ 120511-72-0 ]
[ 41253-21-8 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; dibenzoyl peroxide; In N-methyl-acetamide; tetrachloromethane; water;	EXAMPLE 1 A mixture of 2,2'-(5-methyl-1,3-phenylene)di(2-methylpropiononitrile), (2.26 g), N-bromosuccinimide (1.78 g), benzoyl peroxide (0.05 g) and carbon tetrachloride (50 ml) was heated under reflux for 2 h, cooled and filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in dimethylformamide (20 ml), <strong>[41253-21-8]sodium triazole</strong> (1.8 g) was added, and the mixture was stirred at room temperature for 18 h. Water (100 ml) was added, and the mixture was extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluding with ethyl acetate, to give 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp 81-82 after crystallisation from ethyl acetate/cyclohexane.
		e) Preparation of 2,2'-[5-(lH-l,2,4-triazoIe-l-yl -methyl)-l,3-phenylene] di (2-methyl propionitrile) (I).A mixture of 2,2'-(5-bromomethyl-l,3-phenylene)di(2-methylpropionitrile) (V) (4 gm, 0.013 moles) and 1,2,4-triazole sodium salt (2.40 gm, 0.026 moles) in N,N-dimethylformamide (28 ml) was heated under stirring at 45-50 C for 4 hour. The reaction mixture was cooled, poured into the ice-water and extracted with ethyl acetate. The ethyl acetate layer was separated and concentrated to give a residue. This residue was diluted with water, acidified with concentrated hydrochloric acid (adjusted the pH tol-2). The reaction mixture was heated at 50 C and subsequently filtered the hot solution. The mother liquor was treated with ammonia solution at 0- 50C (adjusted the pH to 8-9) and extracted with ethyl acetate. The ethyl acetate layer was separated and concentrated to obtain a residue (3.0 g).

Reference： [1]Patent: US4935437,1990,A
[2]Patent: WO2007/39913,2007,A1 .Location in patent: Page/Page column 14

Yield	Reaction Conditions	Operation in experiment
	In di-isopropyl ether; toluene at 30 - 35℃; for 0.5 - 2h; Heating / reflux;	2; 4; 6; 8; 10; 12 Example 2Purification of AnastrozoleTo a clear solution of crude product (4.0 g) in toluene (30 ml), silica gel (100-200 mesh, 2.5 g) was added and stirred for 30 minutes. Thereafter silica gel was filtered off and toluene was evaporated to get residue. The resulting residue was further taken in diisopropylether (100 ml) and re fluxed, thereafter stirred at 30-350C for 2 hours. The reaction mixture was filtered to get crystalline residue. The HPLC purity was as follows: anastrozole : 93.44%; isoanastrozole : 4.28%; Compound of formula Il : 0.50%. Yield: 2.0 gTo a clear solution of crystalline residue (2.0 g) in toluene (20 ml), silica gel (100-200 mesh, 1.0 g) was added, stirred for 30 minutes and filtered to remove silica gel. From the resulting filtrate toluene was evaporated to get solid residue. Solid residue was further dissolved in ethanol (3.6 ml) and stirred to get a clear solution. The reaction mixture was cooled and filtered to get the crystalline anastrozole. Yield: 1.0 g. The HPLC purity was as follows: anastrozole: 99.93%; isoanastrozole: 0.02%;Compound of formula II: Not detected. Example 4Purification of AnastrozoleTo a clear solution of crude anastrozole (78 g) obtained from example 3 in toluene(720 ml), silica gel (100-200 mesh, 36 g) was added and stirred for 30 minutes. Silica gel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. The solid residue was rcfluxed with diisopropyl ether then reaction mixture was cooled down to 30-350C and further stirred for 2.5 hours. The reaction mixture was filtered to get crystalline residue. The HPLC purity was as follows:- anastrozole : 96.56%; isoanastrozole : 1.2%; Compound of formula II : 0.06%. Yield: 56.Og.To a clear solution of crystalline residue (56 g) in toluene (560 ml), silica gel (100-200 mesh, 17.Og) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered out and toluene was removed by evaporation under reduced pressure. The resulting residue was dissolved in ethanol (100 ml) and stirred to get clear solution, which was cooled to 0-5°C and filtered to get crystals of pure anastrozole. Yield: 27.0 g The HPLC purity was as follows: anastrozole: 99.97%; isoanastrozole: 0.01%; Compound of formula II: Not detected. Example 6Purification of AnastrozoleTo a clear solution of crude anastrozole (74.4 g) obtained from example 5 in toluene (687ml) , silica gel (100-200 mesh, 34.3 g) was added and stirred for 30 minutes. Silica gel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. Solid residue was further refluxed with diisopropyl ether, thereafter cooled down to 30-350C and stirred for 2.0 hours. The reaction mixture was filtered to get crystalline product. The HPLC purity was as follows: anastrozole: 96.5%; isoanastrozole : 1.2%; Compound of formula II : 0.06%. Yield: 45.Og. To a clear solution of crystalline product (45g) in toluene (450 ml), silica gel (100-200 mesh , 13.5 g) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered off and toluene was removed by evaporation under reduced pressure. The resulting residue was further dissolved in ethanol (80.0 ml) and stirred to get clear solution. The reaction mixture was cooled to 0-50C and filtered to get pure anastrozole. The HPLC purity was as follows: anastrozole: 99.86%; isoanastrozole: 0.02%; Compound of formula II: 0.01%. Yield: 25.5g. Example 8Purification of AnastrozoleTo a clear solution of crude anastrozole (83.3 g) obtained from example 7 in toluene (714 ml), silica gel (100-200 mesh, 35.7 g) was added and stirred for 30 minutes. Silica gel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. The solid residue was further refluxed with diisopropyl ether thereafter cooled down to 30-350C and stirred for 2.0 hours. The reaction mixture was filtered to get crystalline product. The HPLC purity was as' follows: anastrozole: 88.62%; isoanastrozole: 4.39%; Compound of formula II : 0.75%. Yield: 39.23g. To a clear solution of crystalline product (39.23 g) in toluene (400 ml), silica gel (100-200 mesh, 12.Og) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered out and toluene was removed by evaporation under reduced pressure. The resulting residue was further dissolved in ethanol (72 ml) and stirred to get clear solution. The reaction mixture was cooled to 0-- 50C and filtered to get pure anastrozole. The HPLC purity was as follows: anastrozole: 99.82%; isoanastrozole: 0.04 %; Compound of formula II: Not detected. Yield: 24.5g. Example 10Purification of AnastrozoleTo a clear solution of crude anastrozole (16g) obtained from example 9 in toluenc(60ml) ,silica gel (100-200 mesh, 5.0 g) was added and stirred for 30 minutes. Silica gel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. The solid residue was further refluxed with diisopropyl ether thereafter cooled down to 30-350C and stirred for 2.0 hours. The solution was filtered to get crystalline residue (7.Og).To a clear solution of crystalline residue (7.Og) in toluene (40 ml ), silica gel (100-200 mesh ,2.0 g) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered out and toluene was removed by evaporation under reduced pressure.The resulting residue was further dissolved in ethyl acetate (7.0 ml) at 40-450C and stirred to get clear solution. To this clear solution cyclohexane (14ml) was added at 40-450C then cooled down to 20-250C and further stirred for 2.0 hours. The reaction mixture was further cooled to 5-1O0C and stirred for 2.0 hours then filtered to get pure anastrozole. Yield: 4.Og. HPLC purity was as follows: anastrozole: 99.94%; isoanastrozole: 0.01%; Compound of formula II: Not detected. Example 12Purification of AnastrozoleTo a clear solution of crude anastrozole (94.Og) obtained from example 11 in toluene (564ml), silica gel (100-200 mesh, 28.2 g) was added and stirred for 30 minutes. Silica gel was filtered off and the filtrate was evaporated under reduced pressure to get solid residue. The solid residue was further refluxed with diisopropyl ether thereafter cooled down to 30-350C and stirred for 2.0 hours. The solution was filtered to get crystalline residue (60.Og). The HPLC purity was as anastrozole: 98.06%; isoanastrozole: 1.33%; Compound of formula II : 0.56%.To a clear solution of crystalline residue (60.Og) in toluene (600ml) silica gel (100-200 mesh,18.0g) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered off and toluene was removed by evaporation under reduced pressure. The resulting residue is further dissolved in ethanol (120ml) and stirred to get a clear solution. The solution was cooled down to 0 to 50C and Filtered to get crystalline anastrozole (36g). The HPLC purity was as follows: anastrozole: 99.02%; isoanastrozole: 0.44%; Compound of formula II : 0.24%.To a clear solution of crystalline anastrozole (36g) in toluene (360ml), silica gel (100- 200 mesh,10.8g) was added and the reaction mass was stirred for 30 minutes. Silica gel was filtered off and the filtrate was evaporated under reduced pressure. The resulting residue is recrystallized in ethanol(72 ml) to get highly pure anastrozole. Yield: 23.4g. HPLC purity was as follows: anastrozole: 99.76%; isoanastrozole: 0.1 1%;Compound of formula II: Not detected.

4
[ 120511-84-4 ]
[ 41253-21-8 ]
[ 120511-72-0 ]
[ 120511-92-4 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at -10 - -5℃; for 0.75h;Product distribution / selectivity;	Example 1Preparation of AnastrozoleTo a cooled suspension of 1,2,4- triazole sodium (7.5 g; 0.0824 moles) in N1N -dimelhylformamidc (40 ml), a solution of 2,2'-(5-bromomethyl-l,3-phenylene)-di-(2-methyl propionitrile) (10.0 g; 0.033 moles) inN.N-dimethylformamide (25 ml) was added.. The reaction mixture was stirred at -5 to -1O0C for 45 minutes then quenched with demineralized water (260 ml) and thereafter stirred for 2 hours at 10-150C. The precipitated product was filtered, washed with water and dried to get the title compound. The HPLC purity was as follows: anastrozole: 89.35%; isoanastrozole: 7.14%; 2,2'-(5-methyl-l,3-phenylene)-di-(2 -methyl propionitrile) of formula II : 0.54%. Example 3Preparation of AnastrozoleTo a cooled suspension of 1,2,4-triazole sodium (90.Og; 0.988 moles) in N,N-dimethylformamide (480 ml), a solution of 2,2 -(5-bromomethyl-l,3-phenylene)-di-(2 -methyl propionitrilc) (120 g; 0.394 moles) in N,N-dimethylformamide (300ml) was added. The reaction mixture was stirred at -5 to -1O0C for 45 minutes then quenched with demineralized water (3.1L) and stirred for 3 to 4 hours at 10-150C. The precipitated solid product, thus obtained, was filtered, washed with water and dried to get the title compound (78g). The HPLC purity was as follows: anastrozole: 83.28%; isoanastrozole : 1.85%; Compound of formula II: 7.8%. Example 5Preparation of AnastrozoleTo a cooled suspension of 1 ,2,4-triazole sodium (88.5g; 0.972 moles) in MN-dimethylformamide (472 ml), a solution of 2,2 -(5-bromomethyl-l,3-phenylene)-di-(2-methyl propionilrile) (118 g; 0.387 moles) in N.N-dimethylformamide (295ml) was added. The reaction mixture was stirred at -5 to -1O0C for 45 minutes then quenched with demineralized water (3.0L) and stirred for 2 hours at 10-150C.The precipitated solid product, thus obtained, was filtered, washed with water and dried to get the title compound (74.4 g). The HPLC purity was as follows: anastrozole: 84.35%; isoanastrozolc: 1.38%; Compound of formula II: 8.66%. Example 7Preparation of AnastrozoleTo a cooled suspension of 1 ,2,4-triazole sodium (89.17g; 0.979 moles) in nu,nu-dimethylformamide (298.0 ml), a solution of 2,2 -(5-bromomethyI-l,3-phenylene)-di-(2 -methyl propionitrile) (1 18.9 g; 0.389 moles) in N,N-dimethylformamide (298ml) was added. The reaction mixture was stirred at - 5 to -1O0C for 45 minutes then quenched with demineralized water (3.1L) and stirred for 2 hours at 10-150C. <n="14"/>The precipitated solid product, thus obtained, was filtered, washed with water and dried to g'ctUfteu* title compound (83.3 g). The HPLC purity was as follows: anastrozole: 79.34%; isoanastrozole: 4.7%; Compound of formula II: 6.78%. Example 9Preparation of AnastrozoleTo a cooled suspension of 1 ,2,4-triazole sodium (15.9g; 0.175moles) in N,N-dimethylformamide(53.0 ml), a solution of 2,2 -(5-bromomethyl-l,3-phenylene)-di-(2 -methyl propionitrile) (20 g;0.065 moles) in N,N-dimethylformamide (50ml) was added. The reaction mixture was stirred at -5 to -1O0C for 45 minutes then quenched with demineralized water (520 ml) and stirred for 2 hours at10-150C.The precipitated solid product, thus obtained, was filtered, washed with water and dried to get the title compound ( 16.0 g) . HPLC purity was as folio ws : anastrozole: 87.34%; isoanastrozole: 3.23%;Compound of formula II: 7.83%. Example 11Preparation of AnastrozoleTo a cooled suspension of 1,2,4-triazole sodium (96g; 1.05moles) in JV,N-dimethylformamide (512 ml), a solution of 2,2 -(5-bromomethyl-l,3-phenylene)-di-(2 -methyl propionitrile) (128 g; 0.42 moles) in N, /V-dimethylformamide (320ml) was added. The reaction mixture was stirred at -5 to - 100C for 45 minutes then quenched with demineralized water (3.3L) and stirred for 2 hours at 10-150C.The precipitated solid product, thus obtained, was filtered, washed with water and dried to get the title compound (94.Og). The HPLC purity was as follows: anastrozole: 89.06%, isoanastrozole: 1.99%; Compound of formula II: 7.78%.

Reference： [1]Patent: WO2009/10991,2009,A2 .Location in patent: Page/Page column 9; 10; 11; 11-12; 12; 13

5
[ 120511-72-0 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / 2,2'-azobis(isobutyronitrile) / cyclohexane / 4 h / 25 - 85 °C 2.1: isopropyl alcohol / 5 h / 80 - 85 °C 3.1: hydrogenchloride; sodium nitrite / water / 8 h / -5 - 20 °C 3.2: 4 h / 5 - 25 °C
	Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; acetic acid; 2,2'-azobis(isobutyronitrile) / acetonitrile / 6.5 h / 65 °C / Reflux; Industrial scale 2.1: 3 h / Reflux; Industrial scale 3.1: hydrogenchloride; sodium nitrite / acetonitrile; water / 4 h / 15 - 22 °C / Industrial scale 3.2: 0.5 h / 20 °C / Industrial scale 3.3: 12 h / 12 °C / Industrial scale

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - EP2397472, 2011, A1
[2]Adlington, Neil K.; Black, Simon N; Adshead, David L [Organic Process Research and Development, 2013, vol. 17, # 3, p. 557 - 567]

6
[ 22426-30-8 ]
3,5-bis(trifluoromethanesulfonate)toluene [ No CAS ]
[ 120511-72-0 ]

Yield	Reaction Conditions	Operation in experiment
78.8%	With copper(l) iodide; bathophenanthroline; potassium tert-butylate; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Inert atmosphere; Reflux;	Add xylene (50 mL) to a three-necked flask.Add 3,5-bis(trifluoromethanesulfonate) toluene (II) (7.77 g, 0.02 mol), <strong>[22426-30-8]2-methyl-2-cyanopropionic acid</strong> (III) (4.61 g, 0.04) under nitrogen atmosphere. Mol),Potassium tert-butoxide (9.02 g, 0.08 mol), CuI (0.38 g, 0.002 mol)And 4,7-diphenyl-1,10-phenanthroline (0.67 g, 0.002 mol).The temperature was raised to reflux for 48 hours. The mixture was cooled to room temperature, and a solid was slowly evaporated, and the solid was extracted with ethyl acetate (30mL). OrganicThe phases were washed successively with 5% aqueous hydrochloric acid (100 mL) and saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfateFiltration and concentration of the filtrate under reduced pressure.Filtration and drying gave a white solid product (3.57 g, yield: 78.8%).

Reference： [1]Patent: CN109096146,2018,A .Location in patent: Paragraph 0040-0041

7
[ 22426-30-8 ]
[ 49617-79-0 ]
[ 120511-72-0 ]

Yield	Reaction Conditions	Operation in experiment
83.9%	With 1,10-Phenanthroline; copper (I) acetate; caesium carbonate; In dimethyl sulfoxide; at 140℃; for 10h;Inert atmosphere; Large scale;	Add dimethyl sulfoxide (50 L) to a three-necked flask and add 3,5-diiodotoluene (II) under nitrogen atmosphere.(6.88 kg, 20 mol), <strong>[22426-30-8]2-methyl-2-cyanopropionic acid</strong> (III) (4.61 kg, 40 mol), cesium carbonate (4.00 kg, 400 mol),CuOAc (0.49 kg, 4 mol) and 1,10-phenanthroline (1.46 kg, 8 mol). The temperature was raised to 140 C and the reaction was carried out for 10 hours. Cool down to the roomWarm, slowly add water to precipitate solids, solids are dissolved by heating with ethanol (20L), decolorized by activated carbon, cooled and recrystallized, filtered and dried.To an off-white solid product (3.8 kg, yield: 83.9%).

Reference： [1]Patent: CN109096146,2018,A .Location in patent: Paragraph 0032; 0033; 0038; 0039; 0042; 0043

8
[ 22426-30-8 ]
[ 1611-92-3 ]
[ 120511-72-0 ]

Yield	Reaction Conditions	Operation in experiment
81.1%	With [2,2]bipyridinyl; copper(l) iodide; In N,N-dimethyl-formamide; at 150℃; for 12h;Inert atmosphere;	N,N-dimethylformamide (50 mL) was added to a three-necked flask, and 3,5-dibromotoluene was added under nitrogen atmosphere.(II) (5.0 g, 0.02 mol), <strong>[22426-30-8]2-methyl-2-cyanopropionic acid</strong> (III) (5.76 g, 0.05 mol), potassium phosphate (17.14 g,0.08 mol), CuI (0.38 g, 0.002 mol) and 2,2'-bipyridine (0.32 g, 0.002 mol). Warming up to 150 C reflux reaction12 hours. After cooling to room temperature, the solid was slowly added with water, and the solid was dissolved by heating with ethanol (20 mL), and the activated carbon was decolorized and then cooled.Recrystallization, filtration and drying gave an off-white solid product (3.67: 81.1%).

Reference： [1]Patent: CN109096146,2018,A .Location in patent: Paragraph 0034-0037

9
[ 120511-73-1 ]
[ 120511-72-0 ]
2-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-isopropylphenyl)-2-methylpropanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 47% 2: 26%	With tetraethylammonium perchlorate; triethylamine In dimethyl sulfoxide at 20℃; for 9h; Electrolysis; Green chemistry;

Reference： [1]Huang, Binbin; Guo, Lin; Xia, Wujiong [Green Chemistry, 2021, vol. 23, # 5, p. 2095 - 2103]

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tert-Butyl hydrazinecarboxylate

[ 120511-84-4 ]

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[ 13578-51-3 ]

1-Tosyl-1H-1,2,4-triazole

[ 584-13-4 ]

4H-1,2,4-Triazol-4-amine

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[ 120511-72-0 ] Synthesis Path-Upstream 1~6

[ 120511-72-0 ] Synthesis Path-Downstream 1~9

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[ 120511-72-0 ]