[ CAS No. 120511-84-4 ] {[proInfo.proName]}

Name: 120511-84-4|2,2'-(5-(Bromomethyl)-1,3-phenylene)bis(2-methylpropanenitrile)|95%
Brand: Ambeed
SKU: A136077
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2D 3D

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Quality Control of [ 120511-84-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 120511-84-4 ]

SDS Specification

Alternatived Products of [ 120511-84-4 ]

Product Details of [ 120511-84-4 ]

CAS No. :	120511-84-4	MDL No. :	MFCD07782114
Formula :	C₁₅H₁₇BrN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IHXHGCDOJLOZML-UHFFFAOYSA-N
M.W :	305.21	Pubchem ID :	11522359
Synonyms :

Calculated chemistry of [ 120511-84-4 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.47
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	77.32
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) :	-5.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.79
Log Po/w (XLOGP3) :	3.65
Log Po/w (WLOGP) :	4.03
Log Po/w (MLOGP) :	3.12
Log Po/w (SILICOS-IT) :	4.44
Consensus Log Po/w :	3.61

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.08
Solubility :	0.0254 mg/ml ; 0.0000831 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.34
Solubility :	0.014 mg/ml ; 0.0000459 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.46
Solubility :	0.00106 mg/ml ; 0.00000348 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.28

Safety of [ 120511-84-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H312-H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 120511-84-4 ]

* 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 [ 120511-84-4 ]
Downstream synthetic route of [ 120511-84-4 ]

[ 120511-84-4 ] Synthesis Path-Upstream 1~2

1
[ 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

2
[ 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

[ 120511-84-4 ] Synthesis Path-Downstream 1~14

1
[ 120511-84-4 ]
[ 41253-21-8 ]
[ 876514-43-1 ]

Yield	Reaction Conditions	Operation in experiment
		3,5-bis(2-cyanoprop-2-yl)benzylbromide (1.4 g, 0.0046 mmol) was dissolved in DMF (30 ml), 1,2,4-triazole sodium salt (0.5 g, 5.4 mmol) and potassium carbonate (1.4 g, 10 mmol) were added therein. The reaction was stirred overnight at room temperature. Toluene (40 ml), followed by water (40 ml), were added to the reaction mixture and the two layers were separated. The organic phase was washed with water (3×15 ml) and acidified with 48% HBr concentrated solution (1 ml, 2 eq) until white crystals were obtained. The crystals were filtered off and washed with toluene. The hydrobromide salt was converted to the base form by treatment with concentrated sodium carbonate solution (40 ml), followed by extraction of free anastrozole with toluene (2×50 ml). The organic layers were combined and washed with water (50 ml) and dried over magnesium sulfate, concentrated and cooled. Free anastrozole was obtained by filtration as white crystals (1 g) in 74.7% yield.

Reference： [1]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 9

2
[ 120511-84-4 ]
[ 41253-21-8 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
34%		e) Preparation of 2,2'-[5-(1H-1,2,4-triazole-1-yl-methyl)-1,3-phenylene]di(2-methyl propionitrile) (1)A mixture of 2,2'-(5-bromomethyl-1,3-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 0-5 C. (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).f) Purification of Anastrozole by Column Chromatography and CrystallizationThis residue was purified through column chromatography by using silica gel column and ethylacetate-hexane (740 ml: 950 ml) as eluent. The solid (2.0 g) obtained was recrystallized using a mixture of acetone-water (12 ml: 20 ml) or ethylacetate-hexane mixture (9 ml to 18 ml) to obtain 2,2'-[5-(1H-1,2,4-triazole-1-ylmethyl)-1,3-phenylene]di(2-methyl propionitrile) (1). [Yield: 34.0%, purity, 99.9%].
34%	In N,N-dimethyl-formamide; at 20℃; for 1h;	To 1.5 kg of crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 (purity > 80%, about 3 mol) in 7.5 1 DMF 0.275 kg 1,2,4-triazole sodium (3 mol) were added. The mixture was stirred at room temperature for 1 hr. After completion, 10 1 ethyl acetate and 25 1 water were added. The mixture was stirred for about 10 minutes and then phase separated. To the aqueous layer 5 1 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 10 1 water twice. The organic layer was concentrated to dryness to obtain the crude anastrozole 6 (90 %, purity > 60%). The crude product was purified by flash column chromatography (silica) using ethyl acetate as eluent (purity > 98%). Finally, the pre-purified anastrozole was re-crystallised from ethyl acetate/cyclohexane (1:2) to obtain 6 with a purity of more than 99.9%. Yield 34 %.
34%	In N,N-dimethyl-formamide; at 20℃; for 1h;	To 1.5 kg of crude alpha,alpha,alpha',alpha'-tetramethyl-5-bromomethyl-1,3-benzene-diacetonitrile 5 (purity >80%, about 3 mol) in 7.5 l_DMF 0.275 kg 1,2,4-triazole sodium (3 mol) were added. The mixture was stirred at room temperature for 1 hr. After completion, 10 l ethyl acetate and 25 l water were added. The mixture was stirred for about 10 minutes and then phase separated. To the aqueous layer 5 l 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 10 l water twice. The organic layer was concentrated to dryness to obtain the crude anastrozole 6 (90%, purity>60%). The crude product was purified by flash column chromatography (silica) using ethyl acetate as eluent (purity>98%). Finally, the pre-purified anastrozole was re-crystallised from ethyl acetate/cyclohexane (1:2) to obtain 6 with a purity of more than 99.9%. Yield 34%.

	In DMF (N,N-dimethyl-formamide); at 25℃; for 4h;Heating / reflux;Product distribution / selectivity;	(ii) Preparation of crude anastrozole of formula-I; Into a 10L, three-necked RB flask was charged l.4kg of above crude compound of formula-V and 7L of anhydrous DMF. The reaction mass was stirred for 30min and added 0.65kg of solid sodium triazole (prepared by reaction of molar quantities of 1,2,4- IH-triazole and sodium hydroxide in isopropanol at reflux temperature and isolated by filtering of the reaction mass at room temperature) in lots keeping the temperature below 25 C. The reaction mass was maintained under stirring at this temperature for 4hr. HPLC of the reaction mass indicated the absence of starting material. The reaction mass was transferred into a 50L flask containing 21L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 3L and 1 x 1L). Toluene layers were combined and . washed with water (2 x 2L). Toluene was distilled of from the filtrate under vaccum to get 1.2kg of crude anastrozole.; Example 3; Preparation of pure anastrozole of the formula-I; (i) Preparation of crude anastrozole; Into a 1L, three-necked RB flask was charged 45g of anhydrous sodium triazole and 250ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 25 C. Bromo compound of formula-V (100g, prepared according to the process given in EP 0296749, example 1) was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.6L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled of from the filtrate under vaccum to get 95g of crude anastrozole.; Example 4; Preparation of pure anastrozole of the formula-I; (i) Preparation of crude anastrozole; Into a 1L, three-necked RB flask was charged 60g of sodium triazole monohydrate and 400ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 25 C. Bromo compound of formula-V (100g, prepared according to the process given in EP 0296749, example 1) was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.6L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled of from the filtrate under vaccum to get 96g of crude anastrozole.
	In DMF (N,N-dimethyl-formamide); toluene; at 20℃;Heating / reflux;Product distribution / selectivity;	(ii) Preparation of crude anastrozole; Into a 1 L, three-necked RB flask was charged 60g of sodium triazole monohydrate (prepared by reaction of molar quantities of 1,2,4-IH-triazole and sodium hydroxide in isopropanol at reflux temperature and isolated by filtering of the reaction mass at room temperature) and 200ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 20 C. A solution of the above bromo compound of formula-V (140g) in toluene (200ml) was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.5L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled of from the filtrate under vaccum to get 130g of crude anastrozole.
		First, 3.8 g of 1,2,4-triazole were dissolved in 8 ml of NMP at 2O0C. Then,2.2 g of NaOH and 22 ml of NMP were added in portions over 1 hour, maintaining the temperature at less than 350C. The solution was stirred for 2 hours at 20C, and 7.8 g of Na2SO4 were then added. After filtration of the solid, the resulting solution was transferred to a dropping funnel, and added over 75 minutes to a solution of 14 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,alpha',alpha' tetramethyl (having a purity of 81.8%, containing: 3,5-bis(2-cyanoisopropyl)toluene 4.0%, l,l-dibromo-3,5-bis(2- cyanoisopropyl)toluene 10.7%, and other impurities 3.5% ) in 20 ml of NMP, cooled to -3O0C. At the end of the addition, the suspension was stirred at -300C for 18 hours, and monitored via HPLC. When the concentration of starting material is less than 0.5 percent, an amount of acetic acid sufficient to give a pH of about 6.5 to about 7.0 is added (an HPLC analysis of the crude reaction mixture showed: residual starting material 0.4%, Anastrozole 68.9%, Isoanastrozole 5.5%, 3,5-bis (2-cyanoisopropyl)toluene 7.5%, 1,1-dibromomethyl- 3,5-bis(2-cyanoisopropyl)benzene, and 15.4%, and other impurities 2.3%.). The mixture is then allowed to warm slowly to 200C, filtered, and 37 ml of toluene, 75 ml of heptane, and 37 ml of water are added. The biphasic system is stirred vigorously for 30 minutes, and the organic layer is then separated. Water, toluene, and heptane in amounts of 25 ml, 25 ml, and 50 ml, respectively, are added to the aqueous phase, and the system is stirred for 30 minutes before the organic phase is separated. Then, 10 ml of toluene and 20 ml of heptane are added to the aqueous phase, and the system is stirred for 30 minutes before the organic phase is separated. Toluene and water, 99 ml and 400 ml, respectively, are added to the aqueous phase, and the resulting biphasic system is stirred for 1 hour. The organic layer is separated and washed 3 times with a mixture of MeOH and water (3 ml and 21 ml, respectively). The final organic phase is concentrated to 45 ml under reduced pressure at 400C, and 45 ml of heptane are added dropwise over 1 hour. The resulting suspension is cooled to 00C, stirred for 1 hour, and filtered. The crude solid is dissolved in toluene (40 ml) at 4O0C, and heptane (40 ml) is slowly added under stirring. The suspension is cooled to 00C, stirred for 1 hour, EPO <DP n="18"/>and filtered. The solid is driejd at 55C under reduced pressure until constant weight is achieved, yielding 5.8 g of product with a purity as follows: Anastrozole 98.45%, Isoanastrozole 0.09%, 3,5-bis (2-cyanoisopropyl)toluene 0.06%, l-bromo-3,5-bis (2- cyanoisopropyl)toluene 0.11%, l,l-dibromo-3,5-bis(2-cyanoisopropyl)toluene 0.07%, other impurities 1.22% are by HPLC.
	In N,N-dimethyl acetamide; at 57.5℃; for 36h;	EXAMPLE 2; Preparation of 1,3-benezenediacetonitrile, alpha,alpha,alpha',alpha'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl) (Formula I) 2 Kg of 2-[3-bromomethyl-5-cyano-dimethyl-methyl)-phenyl]-2-methyl-propionitrile and 10 L of N,N-dimethylacetamide were charged in a clean dry reactor followed by stirring for 10 minutes. 0.861 Kg of sodium triazole was charged under nitrogen pressure and the temperature raised to 57.5 C. The obtained solution was maintained for 36 hours at 57.5 C. and then cooled to about 25 C. followed by quenching the reaction by charging the solution to 30 L of water. The resultant reaction solution was extracted with 3×20 L of ethyl acetate followed by separation of organic and aqueous layers. The combined organic layer was distilled at 26.2 C. under a vacuum of -0.6 Kg/cm2 to afford a residue, the and the obtained residue was dissolved in 20 L of toluene followed by treatment with 2×2 L of 2N aqueous hydrochloric acid solution and with 2×8 L of water. The aqueous layer was separated and treated with 4×10 L of toluene and the obtained aqueous layer was charged into sodium bicarbonate solution, which was prepared by the dissolution of 4.7 Kg of sodium bicarbonate in 45 L of water. The obtained solution was stirred for 10 minutes and then extracted with 2×20 L of dichloromethane. A silica gel bed in a stainless steel column filter (2.05 cm diameter and 5.75 cm height) was prepared with 6.4 Kg of 230-400 mesh silica gel and the bed was washed with 4 L of ethyl acetate. The dichloromethane solution from above was passed through the silica gel bed and then the bed was washed with 38 L of ethyl acetate. The combined solution and washing was concentrated at 24.7 C. under a vacuum of -0.6 Kg/cm2 and cooled to 30 C. followed by dissolution of the residue in 1.4 L of isopropyl alcohol. The obtained solution was stirred for 10 minutes at 30 C. and 7 L of water were charged. The obtained suspension was stirred for 3 hours followed by filtration through a Nutsche filter and washing the obtained solid with a solution of 0.25 L of isopropyl alcohol and 1 L of water. The resultant solid was dried at 48 C. under vacuum of 690 mm Hg for 3 hours to afford 0.470 Kg of the title compound having a water content by Karl Fischer of 0.13% w/w.
	In N,N-dimethyl-formamide; at 25℃;Product distribution / selectivity;	(i) Preparation of crude anastrozole Into a IL, three-necked RB flask was charged 54g of sodium triazole monohydrate and 500ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 25 C. (2,2'-[5-Bromomethyl)-l,3-phenylene]di(2-methylpropio-nitrile was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3 L flask containing 1.6L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled off from the filtrate under vacuum to get 98g of crude anastrozole.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.75h;Product distribution / selectivity;	EXAMPLE 3; Preparation of crude Anustrozole:Tupsilon the title compound of example 2 (50g) in dry DMF (250ml), anhydrous potassium carbonate (26g) and triazole sodium salt (232 g) are added and the mixture stirred at room 25 temperature for 45 min. Worked up the reaction mixture by adding water ( 1500 ml) and extraction with toluene (3 x 300ml). Combined toluene layer is washed with water (1 x300ml), washed toluene layer is dried over anhydous sodium sulphate, fitered and evaporated toluene to obtain crude anastrozole (4Og) having isomeric impurity 0.5%. EXAMPLE 4Preparation of crude Anastrozole:To the title compound of example 2 (500g) in dry DMF (250ml), anhydrous potassium carbonate (26Og) and triazole sodium salt (2320 g) are added and the mixture stirred at room iemperature for 45 min. Worked up the reaction mixture by adding water ( 15000 ml) and <n="7"/>extraction with toluene (3 x 3000ml). Combined toluene layer is washed with water ( 1 3000ml), washed toluene layer is dried over anhydrous sodium sulphate, filtered and evaporated toluene to obtain crude anastrozole (45Og) having isomeric impurity 0.5%. EXAMPLE 5 Preparation of crude Anastrozole:To the title compound of example 2 (5Og) in dry DMF (250ml) anhydrous potassium carbonate (26g) and triazole sodium salt (232 g) are added and the mixture stirred at room temperature for 45 min. Worked up the reaction mixture by adding water (750 ml) and extracting with toluene (3 x 300ml). Combined toluene layer is washed with water ( 1 x300ml).The washed toluene layer is dried over anhydrous sodium sulphate, filtered and evaporated toluene to obtain crude anastrozole (42g) having isomeric impurity 4.52%.EXAMPLE 6Preparation of crude Anastrozole: To the title compound of example 2 (5Og) in dry DMF (250ml) anhydrous potassium carbonate (26g) and triazole sodium salt (232 g) are added and the mixture stirred at room temperature for 45 min. Worked up the reaction mixture by adding water (950 ml) and extracting with toluene (3 x 300ml). Combined toluene layer is washed with water ( 1 x30ml).The washed toluene layer is dried over anhydrous sodium sulphate, filtered and evaporated toluene to obtaincrude anastrozole (42g) having isomeric impurity 2.6%.EXAMPLE7Preparation of crude Anastrozole:To the title compound of example 2 (5Og) in dry DMF (250ml) anhydrous potassium carbonate (26g) and triazole sodium salt (232 g) are added and the mixture stirred at room temperature for 45 min. Worked up the reaction mixture by adding water (2500 ml) and extracting with toluene (3 x 300ml). Combined toluene layer is washed with water ( 1 .300ml).The washed toluene layer is dried over anhydrous sodium sulphate, filtered and evaporated toluene to obtain crude anastrozole (42g) having isomeric impurity 3.2%.
	at 0 - 25℃;	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: US2008/207915,2008,A1 .Location in patent: Page/Page column 5-6
[2]Patent: EP1705168,2006,A1 .Location in patent: Example 5
[3]Patent: US2006/217569,2006,A1 .Location in patent: Page/Page column 4; Fig. 1
[4]Organic and Biomolecular Chemistry,2007,vol. 5,p. 2940 - 2952
[5]Patent: WO2005/105762,2005,A1 .Location in patent: Page/Page column 8; 10-12
[6]Patent: WO2005/105762,2005,A1 .Location in patent: Page/Page column 9-10
[7]Patent: WO2006/108155,2006,A2 .Location in patent: Page/Page column 16-17
[8]Patent: US2007/100148,2007,A1 .Location in patent: Page/Page column 5
[9]Patent: WO2007/39919,2007,A1 .Location in patent: Page/Page column 4
[10]Patent: WO2007/105231,2007,A1 .Location in patent: Page/Page column 5-6
[11]Patent: WO2014/184754,2014,A1 .Location in patent: Page/Page column 4; 5; 6

3
[ 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%

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[30]Patent: WO2014/184754,2014,A1 .Location in patent: Page/Page column 4

Yield	Reaction Conditions	Operation in experiment
54 - 78%	Purification / work up;	Into a 250 ml flask equipped with a mechanical stirrer and a reflux condenser crude 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (28.6 g) was added and refluxed in ethanol (60 ml) until complete dissolution. The temperature was allowed to cool to room temperature, then the flask was put in ice-cold water for two hours. The crystals were filtered, washed with cold ethanol (10 ml) and dried at 50 C. for 4 hours, to give the product (20 g, 70% yield) (Purity as determined by HPLC: 97.1%). Example 18 Crystallization of 3,5-bis(2-cyanoprop-2-yl)benzylbromide from isopropyl acetate Into a 250 ml flask equipped with mechanical stirrer and reflux condenser crude 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (52.8 g) was added and refluxed in isopropyl acetate (120 ml) until complete dissolution. The temperature was allowed to cool to room temperature, then the flask was put in ice-cold water for two hours. The crystals were filtered and washed with cold isopropyl acetate (20 ml) and dried at 50 C. for 4 hours to obtain 28.6 g in 54% Yield (Purity as determined by HPLC: 95%). Example 19 Crystallization of 3,5-bis(2-cyanoprop-2-yl)benzylbromide from ethyl acetate Into a 250 ml flask equipped with a mechanical stirrer and a reflux condenser, crude 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (12.4 g) was added and refluxed in ethyl acetate (15 ml) until complete dissolution. The temperature was allowed to cool to room temperature, then the flask was put in ice-cold water for two hours. The crystals were filtered, washed with cold ethyl acetate (4 ml) and dried at 50 C. for 4 hours, to obtain the product (7.1 g, 57% yield, purity as determined by HPLC: 86.2%). Example 20 Precipitation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide from a mixture of dichloromethane and cyclohexane Into a 500 ml flask, crude 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (20 g) was added and dissolved in dichloromethane (20 ml), under very gentle warming to 30 C., until a clear solution was obtained. The solution was allowed to cool to room temperature, then cyclohexane was added (100 ml), and the solution was mixed for 4 hours. The precipitate was filtered, washed with cyclohexane (20 ml), and dried at 50 C. for 4 hours to obtain the product (15.8 g, 79% yield, purity as determined by HPLC: 89.1%). Example 21 Precipitation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide from a mixture of dichloromethane and heptane Into a 500 ml flask, crude 3,5-bis(2-cyanoprop-2-yl)benzylbromide (20 g) was added and dissolved in dichloromethane (20 ml) under very gentle warming to 30 C., until a clear solution was obtained. The solution was allowed to cool to room temperature, then heptane was added (100 ml), and the solution was mixed for 4 hours. The precipitate was filtered, washed with heptane (20 ml), and dried at 50 C. for 4 hours to obtain the product (15.6 g, 78% yield, purity as determined by HPLC: 88%)
	In n-heptane; isopropyl alcohol; at 25 - 60℃; for 1.5h;Purification / work up;	Purification:Isopropyl alcohol (400 ml) and n-heptane (5 Itrs.) were charged to the above material, the contents were heated to 50-550C, maintained for 30 minutes, cooled to 25-3O0C, stirred for 1 hour at 25-3O0C, filtered, washed with n-heptane (200ml) and dried under vacuum at 35- 4O0C to give 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (1.1 kg, 110 % yield (w/w), 81.6 mol% yield, 96% HPLC purity). Purification :To the above material, isopropyl alcohol (240 ml) and n-heptane (240 ml) were charged, the contents were heated to 55-6O0C for dissolution then allowed to cool to 40-440C, filtered, washed with n-heptane (25 ml) and dried under vacuum at 35-4O0C to give 3,5-bis (2-cyanoprop-2-yl)benzyl bromide (81 g, 60 mol% yield, 95 % HPLC purity).

5
[ 120511-84-4 ]
[ 41253-21-8 ]
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		3,5-bis(2-cyanoprop-2-yl)benzylbromide (7.14 g, 0.023 mole) was dissolved in DMF (150 ml), then 1,2,4-triazole sodium salt (2.4 g, 0.028 mole) and potassium carbonate (7 g, 0.051 mol) were added therein. The reaction was stirred at room temperature overnight. Toluene (200 ml), followed by water (200 ml), were added to the reaction mixture and the two layers were separated. The organic phase was washed with water (3×50 ml) and then with saturated sodium chloride solution (200 ml), then it was acidified with 32% HCl concentrated solution (4.5 ml, 2 eq) until white crystals were obtained. The crystals were filtered off and washed with toluene. Anastrozole hydrochloride was obtained as a white-yellowish solid (6.4 g) in 84% yield. The hydrochloride salt was converted to the base form by treatment with concentrated sodium carbonate solution (40 ml), followed by extraction of free anastrozole with toluene (2×50 ml). The organic layers were combined and washed with water (50 ml) and dried over magnesium sulfate, concentrated and cooled. The final product was isolated by filtration as white crystals. Free anastrozole was obtained (4.65 g) in 69.5% yield.

Reference： [1]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 9

6
[ 120511-84-4 ]
[ 41253-21-8 ]
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride [ No CAS ]
2,2'-[5-(4H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methyl-propionitrile) hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		3,5-bis(2-cyanoprop-2-yl)benzylbromide (14 g, 0.046 mole) was dissolved in DMF (200 ml), 1,2,4-triazole sodium salt (3.48 g, 0.037 mole) and potassium carbonate (6.97 g, 0.050 mole) were added therein The reaction was stirred for 4 hours at room temperature. After reaction completion (as determined by complete disappearance of 3,5-bis(2-cyanoprop-2-yl)benzylbromide by HPLC), DMF was evaporated under reduced pressure (80% of the original volume of DMF) to obtain an oily residue. Toluene (200 ml) was added and the salts and excess un-reacted triazole were removed by filtration. The toluene solution was washed with 1N aqueous acidic solution of sodium sulfate and sulfuric acid, pH 1.2 (80 ml) and phases were separated. The process was repeated additional two times. Part of the solvent was then distilled out under reduced pressure and the remaining toluene solution was saturated with gaseous HCl, which was bubbled into the solution for a period of about 15 minutes until white crystals were obtained. The crystals were filtered off and washed with toluene. The anastrozole hydrochloride salt was suspended in toluene (120 ml) and filtered. Ethyl acetate (120 ml) was added followed by water (100 ml) and sodium carbonate (68 g) and the mixture was stirred for 15 minutes. The phases were separated and the organic phase was washed with water (100 ml). Cyclohexane (3.5 volumes) was added and white crystals were obtained. Free anastrozole was obtained by filtration as white crystals (4.39 g) in 50% yield. Purity: 99.5% by HPLC (content of isoanastrozole: <0.1%).

Reference： [1]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 9-10

7
[ 288-88-0 ]
[ 120511-84-4 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium tert-butylate; In toluene; at 9 - 21℃; for 4.5h;	A) Employing toluene in a ratio of approx. 9 : 1 (v/m) relative to compound of formula I' A solution of I' (Z = Br, 328.9 g, 1.0 mol) in toluene (1.32 L) was added to a stirred mixture of K2CO3 (179.7 g, 1.3 eq.), 1,2,4-triazole (72.5 g, 1.05 eq.), PEG 600 (30.0 g, 0.05 eq.), and toluene (1.65 L) at 40 - 45 C. After stirring for 3 h at 44 - 45 C, the mixture (II' : III' = 8:1, calcd.) was filtered and the residue (III', approx. 41 g, 14 %, purity: 81.2 %), was washed with warm toluene (0.5 L). The filter residue was washed with water and dissolved in warm methanol (500 mL). The resulting solution was evaporated to dryness to give 40.9 g (13.9 %) of isomer III' (81.2 %, HPLC). The filtrate was washed with water, obtaining 3.56 L of a solution of compound II'. HPLC: 89.4 % of compound II', 3.5 % of isomer III' (3.5 %), corresponding to an isomeric ratio of approx. 26:1 (II' : III'). Yield: (91.3 %, calcd.).; E) Employing 2.2 eq of KtOBu [0070] Similar to example 1, item A) but stirring at 9 - 21 C for 4.5 h. Yield: quantitative. HPLC: 75.16 % of compound II', 3.05 % of isomer III', corresponding to an isomeric ratio of approx. 25:1 (II' : III').
82%	With tetrabutylammomium bromide; potassium hydroxide; In water; toluene; at 75 - 80℃; for 2h;	Intermediate 3, 5-Bis [(2, 2-dimethyl) cyanomethyl] -bromomethylbenzene 50g(0.16mol), 1,2,4- Triazole 12.4g(0.18mol), 10% aqueous potassium hydroxide solution200 g (0.357 mol), TBAB 2g, toluene 400ml were sequentially added into reaction flask then stirred and heated to reflux at 75-80 C and continue the stirring for 2 hours. After completion of the reaction, the mixture was allowed to stand to separate layers. The organic layer was separated, the organic layer was washed twice with 200 mL of waterand dried over anhydrous magnesium sulfate and filtered. The filtrate at 60-65 C, carried out vacuum concentration, recrystallization with isopropyl alcohol to obtain a white solid crystals 38. 4g, yield 82%.
47%	With tetrabutylammomium bromide; potassium carbonate; potassium hydroxide; In toluene; at 85 - 90℃; for 5h;	Example 3; Preparation of 2,2'-[5-(1H-1,2,4-triazol-1-yl-methyl)-1,3-phenylene]-di(2-methyl propionitrile), compound of formula (I) [ANASTROZOLE]Toluene (1000 ml), 1,2,4-triazole (27 g), potassium carbonate (110 g), powdered potassium hydroxide (20 g), tetrabutyl ammonium bromide (7 g) and 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (100 g) were charged, heated to 85-90 C. and maintained for 5 hours. After reaction completion, the mass was cooled to 20-25 C., water (500 ml) was charged and the toluene layer was separated, the aqueous layer was extracted using toluene (300 ml), the toluene layer was combined, washed using water (500 ml) and the toluene layer dried over sodium sulphate. The toluene layer was concentrated under vacuum to residue at 50-55 C., isopropyl alcohol (18.8 ml) was charged followed by n-heptane (450 ml), the contents were stirred for 1 hour at 25-30 C., the contents were chilled to 0-5 C., maintained for 45 minutes, and the resulting material was filtered and washed with n-heptane (25 ml).

	With lithium tert-butoxide; In isopropyl alcohol; at 20℃; for 12h;Product distribution / selectivity;	3,5-bis(2-cyanoprop-2-yl)benzylbromide (10 g, 0.032 mole) was dissolved in isopropyl alcohol (150 ml), and 1,2,4-triazole (2.5 g, 0.036 mole) and lithium tert-butoxide (3.05 g, 0.038 mole) were added therein The reaction was stirred for 12 hours at room temperature under nitrogen. After reaction completion (as determined by complete disappearance of 3,5-bis(2-cyanoprop-2-yl)benzylbromide by HPLC), the solvent was evaporated under reduced pressure and a solid was obtained. Toluene (30 ml) was added to the solid and reflux was applied for two hours, after which time the solution was immediately filtered and the solvent was evaporated under reduced pressure to obtain a solid. The solid residue, which was obtained on the sinter after the hot filtration, was washed with hot toluene (30 ml), and the solution was added to the solid that was obtained by evaporation. The suspension was refluxed for additional one hour, after which time the solution was evaporated under reduced pressure to obtain crude anastrozole having purity of 99.1% by HPLC.
	With potassium hydroxide; tetrabutylammomium bromide; potassium carbonate; In toluene; at 85 - 90℃; for 5h;	Example 3; Preparation of 2,2'-[5-(1H-1,2,4-triazol-1-yl-methyl)-1J3-phenylene]-di(2-methyl propionitrile), compound of formula (I) [ANASTROZOLE]Toluene (1000 ml), 1,2,4-triazole (27 g), potassium carbonate (110 g), powdered potassium hydroxide (20 g), tetrabutyl ammonium bromide (7 g) and 3,5-bis(2-cyanoprop- 2-yl) benzyl bromide (100 g) were charged, heated to 85-9O0C and maintained for 5 hours. After reaction completion, the mass was cooled to 20-250C, water (500 ml) was charged and the toluene layer was separated, the aqueous layer was extracted using toluene (300 ml), the toluene layer was combined, washed using water (500 ml) and the toluene layer dried over sodium sulphate. The toluene layer was concentrated under vacuum to residue at 50-550C, isopropyl alcohol (18.8 ml) was charged followed by n-heptane (450 ml), the contents were stirred for 1 hour at 25-3O0C, the contents were chilled to 0-50C, maintained for 45 minutes, and the resulting material was filtered and washed with n-heptane (25 ml).
	With potassium carbonate; In toluene; at 40 - 45℃;Product distribution / selectivity;	L) Employing PEG 400. 0.075 eg.Similar to example 1 , item D) and stirring at 40 - 45 C for 4 h Yield: 50.91 g (86.8 %). HPLC: 89.3 % of compound II', 2.42 % of isomer III', corresponding to an isomeric ratio of approx. 37: 1 (II' : III'

Reference： [1]Patent: EP2343278,2011,A1 .Location in patent: Paragraph 0070
[2]Patent: CN103554041,2016,B .Location in patent: Paragraph 0014; 0017-0018
[3]Patent: US2010/99887,2010,A1 .Location in patent: Page/Page column 7
[4]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 10
[5]Patent: WO2008/47104,2008,A1 .Location in patent: Page/Page column 17
[6]Patent: WO2011/83079,2011,A1 .Location in patent: Page/Page column 25

8
[ 288-88-0 ]
[ 120511-84-4 ]
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methylpropionitrile) hydrochloride [ No CAS ]
2,2'-[5-(4H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]-di(2-methyl-propionitrile) hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		3,5-bis(2-cyanoprop-2-yl)benzylbromide (100 g, 0.322 mole) was dissolved in a mixture of DMF (150 ml) and isopropyl alcohol (850 ml) and 1,2,4-triazole (25 g, 0.362 mole) and potassium carbonate (50 g, 0.357 mole) were added therein. The reaction was stirred for 20 hours at room temperature under nitrogen. After reaction completion (as determined by complete disappearance of 3,5-bis(2-cyanoprop-2-yl)benzylbromide by HPLC), the solvent was evaporated under reduced pressure (about 80% of the original volume) to obtain an oily residue. Toluene (1000 ml) was added followed by 1N aqueous acidic solution of sodium sulfate and sulfuric acid, pH 1.2 (500 ml) and stirring was applied for about 10 minutes. The phases were separated and the aqueous phase was extracted with toluene (400 ml). The phases were separated and the two organic layers were combined, washed with 1N aqueous acidic solution of sodium sulfate and sulfuric acid, pH 1.2 (350 ml) and again the phases were separated. The organic layer was washed with 1N aqueous acidic solution of sodium sulfate and sulfuric acid, pH 1.2 (250 ml) and again phases were separated. A sample was withdrawn from the organic layer and injected to HPLC. The content of isoanastrozole was less than 0.05%. Part of the solvent was then distilled out under reduced pressure and the remaining toluene solution was saturated with gaseous HCl, which was bubbled into the solution for a period of about 1.5 hr at a rate of 20 g/hr and then at a rate of 5 g/hr for about half an hour. The crystals were filtered off and washed with toluene. The anastrozole hydrochloride salt was washed first with toluene (100 ml) and then 3 times with ethyl acetate (800 ml) and filtered to obtain 75 g product in 70.7% yield. Ethyl acetate (300 ml) was added followed by water (450 ml) and sodium carbonate (50 g) and the mixture was stirred for about 20 minutes. The phases were separated and the organic phase was washed with water (225 ml). Cyclohexane (300 ml) was added and white crystals were obtained. Free anastrozole was obtained having purity of 99.7% by HPLC (content of isoanastrozole: <0.05%).

Reference： [1]Patent: US2006/35950,2006,A1 .Location in patent: Page/Page column 3; 10

9
[ 584-13-4 ]
[ 120511-84-4 ]
4-amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl]-4H-1,2,4-triazolium bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.0%	In acetonitrile; for 12h;Reflux;	1) 30 g of 5-bromomethyl-alpha, alpha, alpha ', alpha'-tetramethyl-1,3-benzenediacetonitrile was added successively to a glass reactor, 4-amino-1,2,4-triazole, acetonitrile 80 ml, heated to reflux under stirring, after 12 h, cooling, crystallization at 0 deg. 8h. Filtration, dried, to give 35.58 g of intermediate I, yield 93.0%;
65%	In isopropyl alcohol; at 0 - 85℃; for 10 - 10.5h;	3,5-bis(1-cyano-1-methylethyl) benzyl bromide obtained in Step IV (600 g, 1.965 mol) was heated with 4-amino-1,2,4-triazole (247.9 g, 2.948 mol) in isopropanol (4.5 L) for 7 to 7.5 hours at 80 C. to 85 C. The reaction mass was gradually cooled to 20 C. to 25 C. The reaction mass was stirred for 1 hour. The reaction mass was further cooled to 0 C. to 5 C., stirred for 2 hours, filtered, and washed with dichloromethane (2×500 ml). The reaction mass was sucked dry. The dried cake was further dried at 40 C. to 45 C. under vacuum to obtained 2,2'-[5-(4-amino-1,2,4-triazolium-1-ylmethyl)-1,3-phenylene]di(2-methylpropio-nitrile)bromide (497.5 g, 65.0% yield). MP-198-203 C. IR (In cm-1, KBr): 3204, 3116, 3080, 2987, 2229, 1643, 1607, 1565, 1469, 1438, 1196, 1004 H1NMR (in CDCl3,delta (ppm)]: 10.31 (1H,s),9.20 (1H,s),7.66-7.63 (3H,s),6.984 (2H,s),5.657 (2H,s),1.71 ( 12H,s). M+[309] (free base)
	In isopropyl alcohol; at 20 - 85℃;	Example-2 4-Amino-1-[3,5-bis-(1-cyano-1-methylethyl)benzyl]-1H-[1,2,4]triazolium bromide (8) (Q. A.-Salt) Isopropanol (1.5 L), 3,5-bis-(1-cyano-1-methylethyl)benzylbromide (2) (100 g) and 4-amino-1,2,4-triazole (22.5 g) were charged in a flask at room temperature. The reaction mass was heated at 80-85 C. for next 5 hours. The reaction mass was further cooled down to room temperature and stirred for next one hour at 25-35 C. The precipitated solid QA-salt was filtered and washed with fresh isopropanol (100 mL*2). The Q.A.-salt was dried at 60-70 C. till LOD is less than 1.0%, giving solid product (74.4 g). m.p.: 198-200 C.

In isopropyl alcohol; at 80 - 85℃; for 5h;

Example - 2 4-Amino-1-[3,5-bis-(1-cyano-1-methylethyl)benzyl]-1H-[1,2,4]triazolium bromide (8) (Q. A.-Salt); Isopropanol (1.5 L), 3,5-bis-(1-cyano-1-methylethyl)benzylbromide (2) (100 g) and 4-amino-1,2,4-triazole (22.5 g) were charged in a flask at room temperature. The reaction mass was heated at 80 - 85 C for next 5 hours. The reaction mass was further cooled down to room temperature and stirred for next one hour at 25 - 35 C. The precipitated solid QA-salt was filtered and washed with fresh isopropanol (100 mL x 2). The Q.A.-salt was dried at 60 - 70 C till LOD is less than 1.0 %, giving solid product (74.4 g). m.p.: 198 - 200 C.

Reference： [1]Patent: CN106083748,2016,A .Location in patent: Paragraph 0034
[2]Patent: US2006/189670,2006,A1 .Location in patent: Page/Page column 5; 7
[3]Patent: US2009/221837,2009,A1 .Location in patent: Page/Page column 4
[4]Patent: EP2397472,2011,A1 .Location in patent: Page/Page column 5
[5]Organic Process Research and Development,2013,vol. 17,p. 557 - 567

10
[ 120511-84-4 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
		First, 144.7 g of 1,2,4-triazole were dissolved in 1900 ml of NMP at 2O0C, and84 g of NaOH were added in portions over 1 hour, while maintaining the temperature at less than 350C. The solution was stirred for 18 hours at 20C, and then cooled to -22C. A solution of 355 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,alpha',alpha' tetramethyl (having a purity of 85.6%, containing: 3,5-bis(2-cyanoisopropyl)toluene 5.5%, 1,1-dibromo- 3,5-bis(2-cyanoisopropyl)toluene 7.83%, and other impurities 3.5% ) in 800 ml of NMP was slowly added over 6 hours, while maintaining the temperature below -200C. [00037] At the end of the addition, the suspension was stirred for 18 hours at -2O0C, during which the reaction was monitored via HPLC. When the amount of starting material was less than 0.5 percent, acetic acid was added in an amount sufficient to provide a pH of about 6.5 to about 7. (An HPLC analysis of the crude reaction mixture showed: residual starting material 0.44%, Anastrozole 78.7%, Isoanastrozole 5.5%, 3,5-bis (2- cyanoisopropyl)toluene 11.6%, l,l-dibromomethyl-3,5-bis(2-cyanoisopropyl)benzene 3.5%, and 0.3% other impurities.) The mixture was slowly allowed to warm to 200C, then 1 1 of toluene, 2 1 of heptane, and 1700 ml of water were added. The biphasic system was stirred vigorously for 30 minutes, and the organic layer was then separated. Water in an amount of 1100 ml, 760 ml of toluene, and 1500 ml of heptane were added to the aqueous phase, and the system was stirred for 30 minutes before the organic phase was separated. Then 2.5 1 of toluene and 10 1 of water were added to the aqueous portion, and the biphasic system was stirred for 1 hour. The organic layer was separated and washed three times with a mixture of 300 ml of MeOH and 2100 ml of water. The final organic phase was concentrated under reduced pressure to a final volume of 1500 ml at 400C, and 1500 ml of heptane was added dropwise over a period of 1 hour. The suspension was cooled to 00C, stirred for 1 hour, and filtered. The crude solid was dissolved in 1000 ml of 2-propanol at 500C, and 400 ml of heptane was slowly added under stirring.[00038] The solution was cooled to 00C, stirred for 1 hour, and filtered. The solid was dried at 55C under reduced pressure until constant weight was achieved, producing 204 g of product with a purity as follows: Anastrozole 99.75%, Isoanastrozole 0.05%, 3,5-bis (2- EPO <DP n="17"/>cyanoisopropyl)toluene 0.06%, other impurities 0.13% area by HPLC, and with a melting point of 85C, measured by DSC.[00039] 1H NMR data for anastrozole (CDCl3, 297K): delta (ppm): 8.15 (s, IH; triazole C3H); 7.91 (s, IH5 triazole Ci H); 7.47 (t, IH, phenyl C4 H); 7.27 (d, 2H, phenyl C2-6 H); 5.34(s, 2H, benzylic CH2); 1.64 (s, 12 H, CH3). Example 7: Synthesis of Anastrozole (alternative work-up)[00041] First, 14.9 g of 1,2,4-triazole were dissolved in 40 ml of NMP at 2O0C, and8.64 g of NaOH in 180 ml of NMP were added, while maintaining the temperature at less than 35C. The mixture was stirred for 55 hours at 200C, and then cooled to -260C. A solution of 37 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,alpha',alpha' tetramethyl in 73 ml of NMP was added over 6 hours. At the end of the addition, the suspension was stirred for 20 hours at -26C, and the reaction was monitored with HPLC. When the concentration of starting material was less than 0.5 percent, an amount of acetic acid sufficient to give a pH of about 6.5 to about 7 was added. The mixture was allowed to warm slowly to 2O0C, and 135 ml of toluene, 270 ml of heptane, and 194 ml of water were added. The biphasic system was stirred vigorously for 30 minutes, and the organic layer was separated. Then 140 ml of toluene and 270 ml of heptane were added to the aqueous phase obtained above, and the system was stirred for 30 minutes, the organic phase was separated, and 100 ml of water, 70 ml of toluene, and 135 ml of heptane were added to the aqueous phase obtained above. The system was then stirred for 30 minutes, and the organic phase was separated. Water in an amount of 1750 ml was added to the aqueous phase, and the product was extracted with toluene 4 times with a total volume of toluene of 530 ml. The organic phases were combined and washed with 130 ml of a 10 percent by weight solution of tartaric acid 2 times. The final organic phase was concentrated to 154 ml under reduced pressure at 400C, and 155 ml of heptane were added dropwise over 1 hour. The suspension was cooled to O0C, stirred for 1 hour, and filtered. The crude solid obtained can be crystallized as described in example 5. Example 8: Synthesis of Anastrozole[00042] First, 14.9 g of 1 ,2,4-triazole were dissolved in 40 ml of NMP at 200C, and8.64 g NaOH in 180 ml of NMP were added, while maintaining the temperature at less than 350C. The mixture was stirred for 55 hours at 200C, and then cooled to -26C. A solution of 37 g of crude l,3-benzenediacetonitrile-5-(bromomethyl)-alpha,alpha,...

Reference： [1]Patent: WO2006/108155,2006,A2 .Location in patent: Page/Page column 15-19

11
[ 120511-84-4 ]
[ 33016-47-6 ]
[ 120512-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In methanol; chloroform; water; acetonitrile;	A mixture of 4-formyl-1-tritylimidazole (0.5 g), 2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropiononitrile) and acetonitrile (2 ml) was heated under reflux for 30 h. The reaction mixture was treated with acetic acid (8 ml) and water (2 ml) and the mixture was then heated at 90 for 1 h. The mixture was diluted with water (20 ml) and washed with ether, the aqueous phase was basified with sodium carbonate, and the mixture was extracted three times with ethyl acetate. The combined extracts were dried and evaporated to dryness, and the residue was purified by flash chromatography using methanol (2% by volume) in chloroform as eluant, to give 2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]di(2-methylpropiononitrile), mp 108-111.

Reference： [1]Patent: US4935437,1990,A

12
[ 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

Yield	Reaction Conditions	Operation in experiment
	In n-heptane; isopropyl alcohol; at 50 - 55℃; for 0.5h;Purification / work up;	Purification:Isopropyl alcohol (400 ml) and n-heptane (5 ltrs.) were charged to the above material, the contents were heated to 50-55 C., maintained for 30 minutes, cooled to 25-30 C., stirred for 1 hour at 25-30 C., filtered, washed with n-heptane (200m1) and dried under vacuum at 35-40 C. to give 3,5-bis(2-cyanoprop-2-yl)benzyl bromide (1.1 kg, 110% yield (w/w), 81.6 mol % yield, 96% HPLC purity).

14
[ 288-88-0 ]
[ 120511-84-4 ]
[ 120511-92-4 ]
[ 120511-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; for 2h;Reflux;Product distribution / selectivity;	D) Employing DMF as the solventA solution of Gamma (Z = Br, 7.23 g, 23.7 mmol) in dimethylformamide (20 mL) was added to a stirred mixture of K2C03 (4.9 g, 1.5 eq.), 1 ,2,4-triazole (1.8 g, 1.1 eq.) and dimethylformamide (20 mL) at 2 - 3 C. After heating to ambient temperature over a period of 2 h and stirring for 2 h at 22 - 25 C, potable water (130 mL) was added and the mixture was extracted twice with ethyl acetate (50 mL). The organic phase was washed three times with potable water (40 mL), dried over sodium sulphate and evaporated to dryness to yield 6.7 g (89.5 %) of an isomeric mixture of compounds Iota and III' (9.7 : 1 ).
	With potassium carbonate; In toluene; at 9 - 21℃; for 4.5h;	A) Employing toluene in a ratio of approx. 9 : 1 (v/m) relative to compound of formula I' A solution of I' (Z = Br, 328.9 g, 1.0 mol) in toluene (1.32 L) was added to a stirred mixture of K2CO3 (179.7 g, 1.3 eq.), 1,2,4-triazole (72.5 g, 1.05 eq.), PEG 600 (30.0 g, 0.05 eq.), and toluene (1.65 L) at 40 - 45 C. After stirring for 3 h at 44 - 45 C, the mixture (II' : III' = 8:1, calcd.) was filtered and the residue (III', approx. 41 g, 14 %, purity: 81.2 %), was washed with warm toluene (0.5 L). The filter residue was washed with water and dissolved in warm methanol (500 mL). The resulting solution was evaporated to dryness to give 40.9 g (13.9 %) of isomer III' (81.2 %, HPLC). The filtrate was washed with water, obtaining 3.56 L of a solution of compound II'. HPLC: 89.4 % of compound II', 3.5 % of isomer III' (3.5 %), corresponding to an isomeric ratio of approx. 26:1 (II' : III'). Yield: (91.3 %, calcd.).; B) Employing toluene in a ratio of approx. 3 : 1 (v/m) relative to compound of formula I' [0066] Similar to example 1, item A). Yield: 42.14 g (71.8 %) HPLC: 78.1 % of compound II', 7.16 % of isomer III', corresponding to an isomeric ratio of approx. 11:1 (II' : III').

Reference： [1]Patent: WO2011/83079,2011,A1 .Location in patent: Page/Page column 23-24
[2]Patent: EP2343278,2011,A1 .Location in patent: Paragraph 0066

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Code	Phrase
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P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
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Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
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H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Code	Phrase
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H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
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H319	Causes serious eye irritation
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H361d	Suspected of damaging the unborn child
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H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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[ 120511-84-4 ] Synthesis Path-Upstream 1~2

[ 120511-84-4 ] Synthesis Path-Downstream 1~14

Pharmaceutical Intermediates of [ 120511-84-4 ]

Anastrozole Intermediates

Related Functional Groups of [ 120511-84-4 ]

Aryls

Bromides

Benzyl Bromides

Nitriles

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[ 120511-84-4 ]

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[ 120511-84-4 ]