162515-68-6

Basic information

• Product Name: 2-[1-(Mercaptomethyl)cyclopropyl]acetic acid
• Synonyms: 2-[1-(MERCAPTOMETHYL)CYCLOPROPYL]ACETIC ACID;1-(MERCAPTOMETHYL)-CYCLOPROPANEACETIC ACID;1-(MERCAPTOMETHYL)CYCLOPROPYL ACETIC ACID;Montelukast Intermdiates;Montelukast Sodium - 2-[1-(mercaptomethyl)cyclopropyl]acetic acid;1-(MERCAPTOMETHYL)CYCLOPROPYL ACETIC ACID 98+%;Montelukast intermediate;1-(Mercaptomethyl)-Cyclopropyl
• CAS NO: 162515-68-6
• Molecular Formula: C₆H₁₀O₂S
• Molecular Weight: 146.21
• EINECS: 420-240-3
• Product Categories: Carboxylic Acids;Organic acids;(intermediate of montelukast);Metal Isotopes;Sulfur & Selenium Compounds;Carboxylic Acids;Ring Systems;Pharmaceutical intermediates;Indoles
• Mol File: 162515-68-6.mol
• Article Data: 10

Chemical Properties

• Melting Point: 42-45°C
• Boiling Point: 290.1 °C at 760 mmHg
• Flash Point: 110 °C
• Appearance: Off-white/Crystalline
• Density: 1.229 g/cm³
• Vapor Pressure: 0.001mmHg at 25°C
• Refractive Index: 1.538
• Storage Temp.: -20°C Freezer
• Solubility: soluble in Methanol
• PKA: 4.76±0.10(Predicted)
• Sensitive: Stench
• CAS DataBase Reference: 2-[1-(Mercaptomethyl)cyclopropyl]acetic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 2-[1-(Mercaptomethyl)cyclopropyl]acetic acid(162515-68-6)
• EPA Substance Registry System: 2-[1-(Mercaptomethyl)cyclopropyl]acetic acid(162515-68-6)

Safety Data

• Hazard Codes: Xi,N,C
• Statements: 21/22-34-43-51/53-20/21/22
• Safety Statements: 22-26-36/37/39-45-61
• RIDADR: 3261
• HazardClass: 8
• PackingGroup: III
• Hazardous Substances Data: 162515-68-6(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

An intermediate of Montelukast

InChI:InChI=1/C6H10O2S/c7-5(8)3-6(4-9)1-2-6/h9H,1-4H2,(H,7,8)

Synthetic route

2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester (152922-73-1) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
With water; potassium hydroxide at 0 - 20℃; for 3h;	93%
Stage #1: 2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester With methanol; sodium hydroxide; water at 70 - 80℃; for 2h; Stage #2: With hydrogenchloride; water at 40℃; pH=3.0 - ~ 4.0;

C6H9ClO2 (1314940-03-8) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Stage #1: C6H9ClO2 With thiourea In water for 3h; Reflux; Stage #2: With sodium hydroxide In water for 2h; Reflux;	91.6%

1-(isothiuroniummethyl)cyclopropaneacetonitrile hydrobromide → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
With sodium hydroxide Reflux;	91.4%
Stage #1: 1-(isothiuroniummethyl)cyclopropaneacetonitrile hydrobromide With sodium hydroxide; water for 14h; Heating / reflux; Stage #2: With formic acid In water at -5 - 5℃; pH=3.5 - 4.0;	76.7%

C15H19NO2S (1015076-74-0) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Stage #1: C15H19NO2S With potassium hydroxide; water at 120℃; for 14h; Stage #2: With hydrogenchloride; water In diethyl ether Product distribution / selectivity;	80%
With water In tetrahydrofuran at 80℃; Product distribution / selectivity;	50%

1-(Acetylthiomethyl)cyclopropaneacetonitrile (152922-72-0) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
With hydrogenchloride; sodium hydroxide In toluene	11.99 g (82%)

1-bromomethylcyclopropyl acetic acid methyl ester (855473-50-6) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: copper(l) iodide / N,N-dimethyl-formamide / 50 - 60 °C 2: potassium carbonate; methanol / 6 h / Reflux 3: phosphorus tribromide / dichloromethane / 0 - 10 °C 4: acetonitrile / Reflux 5: sodium hydroxide / Reflux View Scheme

1-cyanomethylcyclopropyl acetic acid methyl ester → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate; methanol / 6 h / Reflux 2: phosphorus tribromide / dichloromethane / 0 - 10 °C 3: acetonitrile / Reflux 4: sodium hydroxide / Reflux View Scheme

1-(hydroxymethyl)cyclopropaneacetonitrile (152922-71-9) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus tribromide / dichloromethane / 0 - 10 °C 2: acetonitrile / Reflux 3: sodium hydroxide / Reflux View Scheme

[1-(hydroxymethyl)cyclopropyl]methanol (39590-81-3) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sulphate-doped anatase / tetrahydrofuran / 45 - 55 °C 2.1: isobutyric acid sodium salt / tetrahydrofuran / 10 - 20 °C / Inert atmosphere 2.2: 0.5 h 3.1: phosphorus tribromide / dichloromethane / 0 - 20 °C 4.1: copper(l) iodide / N,N-dimethyl-formamide / 50 - 60 °C 5.1: potassium carbonate; methanol / 6 h / Reflux 6.1: phosphorus tribromide / dichloromethane / 0 - 10 °C 7.1: acetonitrile / Reflux 8.1: sodium hydroxide / Reflux View Scheme

6-bromomethyl-5,7-dioxaspiro[2.5]octane → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: isobutyric acid sodium salt / tetrahydrofuran / 10 - 20 °C / Inert atmosphere 1.2: 0.5 h 2.1: phosphorus tribromide / dichloromethane / 0 - 20 °C 3.1: copper(l) iodide / N,N-dimethyl-formamide / 50 - 60 °C 4.1: potassium carbonate; methanol / 6 h / Reflux 5.1: phosphorus tribromide / dichloromethane / 0 - 10 °C 6.1: acetonitrile / Reflux 7.1: sodium hydroxide / Reflux View Scheme

1-hydroxymethylcyclopropylacetic acid methyl ester (142148-13-8) → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: phosphorus tribromide / dichloromethane / 0 - 20 °C 2: copper(l) iodide / N,N-dimethyl-formamide / 50 - 60 °C 3: potassium carbonate; methanol / 6 h / Reflux 4: phosphorus tribromide / dichloromethane / 0 - 10 °C 5: acetonitrile / Reflux 6: sodium hydroxide / Reflux View Scheme

C14H18O3 → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium borohydride / tetrahydrofuran / 2 h / 20 °C 2.1: pyridine; triphenylphosphine; tetrachloromethane / 18 h / 75 °C 3.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 4.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 5.1: thiourea / water / 3 h / Reflux 5.2: 2 h / Reflux View Scheme

C14H20O3 → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine; triphenylphosphine; tetrachloromethane / 18 h / 75 °C 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 3.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 4.1: thiourea / water / 3 h / Reflux 4.2: 2 h / Reflux View Scheme

C14H19ClO2 → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 2.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 3.1: thiourea / water / 3 h / Reflux 3.2: 2 h / Reflux View Scheme

C6H11ClO → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 2.1: thiourea / water / 3 h / Reflux 2.2: 2 h / Reflux View Scheme

C13H15ClO2 → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / 5 h / 20 °C 2.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 3.1: thiourea / water / 3 h / Reflux 3.2: 2 h / Reflux View Scheme

C9H19ClOSi → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / methanol / 2 h / 20 °C 2.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 3.1: thiourea / water / 3 h / Reflux 3.2: 2 h / Reflux View Scheme

C13H17ClO → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; hydrogen / methanol / 6 h / 20 °C / 20686.5 Torr / Autoclave 2.1: trifluoroacetic acid; sodium nitrite / 5 h / 20 °C / Cooling with ice 3.1: thiourea / water / 3 h / Reflux 3.2: 2 h / Reflux View Scheme

C12H11NOS → 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6)

Conditions	Yield
With sodium hydroxide In methanol; water at 90℃; for 8h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	7.84 g

2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-diphenylphosphatoxypropyl)phenyl)-2-propanol + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → cyclopentyl 3-{2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl}-1-methyl-1H-indol-5-ylcarbamate (142522-28-9)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0 - 20℃; Reagent/catalyst; Solvent;	98.8%

1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → C6H9(2)HO2

Conditions	Yield
With di-tert-butyl peroxide; water-d2; ethydiphenylphosphine oxide In dichloromethane at 20℃; for 10h; Irradiation; Green chemistry;	97%

C28H20ClNO3 (1402070-72-7) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → {1-[({(1R)-1-{3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]phenyl}-3-[2-(methoxycarbonyl)phenyl]-3-oxopropyl}sulfanyl)methyl]cyclopropyl}acetic acid

Conditions	Yield
With C38H54FeN2O2(1+)*Cl(1-) In 1,2-dichloro-ethane at -5℃; for 39h;	96%

C28H20ClNO3 + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → {1-[({(1R)-1-{3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]phenyl}-3-[2-(methoxycarbonyl)phenyl]-3-oxopropyl}sulfanyl)methyl]cyclopropyl}acetic acid

Conditions	Yield
With C38H54ClFeN2O2 In 1,2-dichloro-ethane at -5℃; for 39h; enantioselective reaction;	96%

2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-diphenylphosphatoxypropyl)phenyl)-2-propanol + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → montelukast (158966-92-8)

Conditions

Yield

Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With 3-ethyl-1-methyl-1H-imidazol-3-ium bromide In dimethyl sulfoxide at 10℃; for 0.0833333h; Stage #2: With potassium tert-butylate In dimethyl sulfoxide at 10℃; for 0.166667h; Stage #3: 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-diphenylphosphatoxypropyl)phenyl)-2-propanol In dimethyl sulfoxide at 15 - 17℃; for 1h; Product distribution / selectivity;

93%

C70H109FN12O15 + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → C76H119FN12O17S

Conditions	Yield
In methanol; N,N-dimethyl-formamide at 20℃; for 4h;	93%

1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 3-methylenepentanoic acid (21962-25-4)

Conditions	Yield
With di-tert-butyl peroxide; triethyl phosphite In N,N-dimethyl-formamide	92%
With di-tert-butyl peroxide; triethyl phosphite In acetonitrile at 25℃; for 6h; Irradiation;	92%

(S)-2-(2-(3-(3-bromophenyl)-3-chloropropyl)phenyl)propan-2-ol (1021952-71-5) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → (R)-2-(1-((1-(3-bromophenyl)-3-(2-(methoxycarbonyl)phenyl)propylthio)methyl)cyclopropyl)acetic acid (1015076-82-0)

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium t-butanolate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (S)-2-(2-(3-(3-bromophenyl)-3-chloropropyl)phenyl)propan-2-ol In N,N-dimethyl-formamide at 20℃; for 48.5h; Stage #3: With tartaric acid In water; ethyl acetate; N,N-dimethyl-formamide pH=7; Product distribution / selectivity;	87.5%

C13H6F4INO + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 2-(1-(((2-fluoro-5-((3,4,5-trifluorophenyl)carbamoyl)phenyl)thio)methyl)cyclopropyl)acetic acid

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 102℃; for 13h; Inert atmosphere; Sealed tube;	86%

N-cyclohexyl-cyclohexanamine (101-83-7) + 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol (807638-71-7) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt (577953-88-9)

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium t-butanolate In toluene at -3 - 10℃; for 1h; Inert atmosphere; Stage #2: 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol In tetrahydrofuran; toluene at -5 - 15℃; Stage #3: N-cyclohexyl-cyclohexanamine In tetrahydrofuran; ethyl acetate; toluene at 10 - 15℃; for 1h;	85.45%
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With n-butyllithium In tetrahydrofuran at -12.5℃; for 0.666667h; Stage #2: 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol In tetrahydrofuran at -2℃; for 3.5h; Stage #3: N-cyclohexyl-cyclohexanamine In isopropyl alcohol; acetonitrile at 29℃; for 15.5h; Product distribution / selectivity;

C68H103F2N11O15 + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → C74H113F2N11O17S

Conditions	Yield
In methanol; N,N-dimethyl-formamide at 20℃; for 4h;	81%

C67H101F2N11O14 + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → C73H111F2N11O16S

Conditions	Yield
In N,N-dimethyl-formamide; acetonitrile at 20℃; for 4h;	77%

(S,E)-1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propan-1-ol (287930-77-2) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → montelukast (158966-92-8)

Conditions	Yield
Stage #1: (S,E)-1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propan-1-ol With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -15 - -10℃; Inert atmosphere; Stage #2: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium methylate In tetrahydrofuran; methanol; 4-methyl-2-pentanone at -15 - 20℃;	68.55%
Stage #1: (S,E)-1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propan-1-ol With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -15 - -10℃; Inert atmosphere; Stage #2: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium methylate In tetrahydrofuran; methanol; 4-methyl-2-pentanone at -15 - 20℃;

(S)-2-(2-(3-(3-bromophenyl)-3-chloropropyl)phenyl)propan-2-ol (1021952-71-5) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → (1-{1-(R)-(3-bromophenyl)-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid (1015076-80-8)

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium t-butanolate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (S)-2-(2-(3-(3-bromophenyl)-3-chloropropyl)phenyl)propan-2-ol In N,N-dimethyl-formamide at 20℃; for 48.5h; Stage #3: With tartaric acid In water; ethyl acetate; N,N-dimethyl-formamide pH=7; Product distribution / selectivity;	67.8%

1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) + Methanesulfonic acid (S)-1-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[3-iodo-5-(3-trifluoromethyl-3H-diazirin-3-yl)-phenyl]-propyl ester → (1-{(R)-1-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[3-iodo-5-(3-trifluoromethyl-3H-diazirin-3-yl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With n-butyllithium In tetrahydrofuran; hexane at -22 - 0℃; for 0.25h; Metallation; Stage #2: Methanesulfonic acid (S)-1-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[3-iodo-5-(3-trifluoromethyl-3H-diazirin-3-yl)-phenyl]-propyl ester In tetrahydrofuran; hexane at -22 - 0℃; for 2h; Substitution;	66%

(S)-methyl 2-(3-(3-bromophenyl)-3-methylsulfonyloxypropyl)benzoate (1015076-81-9) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → (R)-2-(1-((1-(3-bromophenyl)-3-(2-(methoxycarbonyl)phenyl)propylthio)methyl)cyclopropyl)acetic acid (1015076-82-0)

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium methylate In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: (S)-methyl 2-(3-(3-bromophenyl)-3-methylsulfonyloxypropyl)benzoate In tetrahydrofuran at -15 - 10℃; for 6.5h; Inert atmosphere;	61.1%

methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl)ethenyl]phenyl]-3-chloropropyl]benzoate (880769-25-5) + N-cyclohexyl-cyclohexanamine (101-83-7) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 2-(3(R)-(1-carboxymethyl-cyclopropylmethylsulfanyl)-3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-propyl)-benzoic acid methyl ester dicyclohexyl-amine

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium hydride In N,N-dimethyl-formamide at -5 - 0℃; for 2h; Stage #2: methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl)ethenyl]phenyl]-3-chloropropyl]benzoate In N,N-dimethyl-formamide at -5 - 0℃; for 25h; Stage #3: N-cyclohexyl-cyclohexanamine In ethyl acetate at 20 - 25℃; for 37.5h;	52.8%

methyl 2-[(3S)-[3-[(2E)-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-chloropropyl]benzoate + N-cyclohexyl-cyclohexanamine (101-83-7) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 2-(3(R)-(1-carboxymethyl-cyclopropylmethylsulfanyl)-3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-propyl)-benzoic acid methyl ester dicyclohexyl-amine

Conditions	Yield
Stage #1: methyl 2-[(3S)-[3-[(2E)-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-chloropropyl]benzoate; 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium hydride In N,N-dimethyl-formamide at -5 - 0℃; Inert atmosphere; Stage #2: N-cyclohexyl-cyclohexanamine In ethyl acetate at 20 - 45℃;	52.8%

2-(2-(3(S)-chloro-3-(3-(2-(7-chloro-2-quinolinyl)-(E)ethenyl)phenyl)propyl)phenyl)-2-propanol (880769-28-8) + N-cyclohexyl-cyclohexanamine (101-83-7) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt (577953-88-9)

Conditions	Yield
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium hydride In N,N-dimethyl-formamide at -5℃; for 1h; Stage #2: 2-(2-(3(S)-chloro-3-(3-(2-(7-chloro-2-quinolinyl)-(E)ethenyl)phenyl)propyl)phenyl)-2-propanol In N,N-dimethyl-formamide at -5 - 0℃; for 13h; Stage #3: N-cyclohexyl-cyclohexanamine In ethyl acetate at 20 - 22℃; for 1.75h;	40.5%
Stage #1: 2-(2-(3(S)-chloro-3-(3-(2-(7-chloro-2-quinolinyl)-(E)ethenyl)phenyl)propyl)phenyl)-2-propanol; 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium hydride In N,N-dimethyl-formamide at -5 - 0℃; Inert atmosphere; Stage #2: N-cyclohexyl-cyclohexanamine In ethyl acetate at 20 - 45℃; Product distribution / selectivity;	40.5%

benzylidene phenylamine (538-51-2) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → 6,7-diphenyl-5-thia-7-azaspiro[2.6]nonan-8-one

Conditions	Yield
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In 2-methyltetrahydrofuran at 20℃; Inert atmosphere; Cooling;	24%

C73H112FN13O17 + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → C79H122FN13O19S

Conditions	Yield
In methanol; N,N-dimethyl-formamide at 20℃; for 15h;	17%

[1-[(R)-1-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsulfanylmethyl]cyclopropyl]acetic acid dicyclohexylamine salt (1197374-12-1) + 1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) → C41H44ClNO4S2 (1351973-24-4)

Conditions	Yield
With sodium methylate In methanol; N,N-dimethyl-formamide at 25 - 45℃; for 26h;	12.4%

1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) + Methanesulfonic acid (S)-1-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-2-methoxymethoxy-1-methyl-ethyl)-phenyl]-propyl ester (186353-01-5) → (1-{(R)-1-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-2-methoxymethoxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid (184764-27-0)

Conditions	Yield
With n-butyllithium 1.) THF, 0 deg C, 30 min, 2.) THF, -15 deg C, overnight; Yield given. Multistep reaction;

1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) + Butane-1-sulfonic acid (S)-1-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-2-((S)-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-ethyl ester (184764-00-9) → {1-[(R)-1-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-2-((S)-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-ethylsulfanylmethyl]-cyclopropyl}-acetic acid

Conditions	Yield
With n-butyllithium 1.) THF, 0 deg C, 15 min, 2.) THF, 4 deg C, 16 h; Yield given. Multistep reaction;

1-(sulfanylmethyl)cyclopropaneacetic acid (162515-68-6) + Butane-1-sulfonic acid (S)-1-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-2-((R)-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-ethyl ester (184764-64-5) → {1-[(R)-1-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-2-((R)-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-ethylsulfanylmethyl]-cyclopropyl}-acetic acid

Conditions	Yield
With n-butyllithium 1.) THF, 0 deg C, 15 min, 2.) THF, 4 deg C, 16 h; Yield given. Multistep reaction;

Upstream product

• 152922-72-0 1-(Acetylthiomethyl)cyclopropaneacetonitrile 
• 1314940-03-8 C₆H₉ClO₂ 
• 142148-13-8 1-hydroxymethylcyclopropylacetic acid methyl ester 
• 39590-81-3 [1-(hydroxymethyl)cyclopropyl]methanol 
• 152922-71-9 1-(hydroxymethyl)cyclopropaneacetonitrile 
• 855473-50-6 1-bromomethylcyclopropyl acetic acid methyl ester 
• 1015076-74-0 C₁₅H₁₉NO₂S 
• 152922-73-1 2-[1-(mercaptomethyl)cyclopropyl]acetic acid methyl ester 

Downstream Products

• 851755-56-1 [R,E]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(methoxycarbonyl)phenyl]propyl]thio]methyl]-cyclopropane acetic acid 
• 1015076-82-0 (R)-2-(1-((1-(3-bromophenyl)-3-(2-(methoxycarbonyl)phenyl)propylthio)methyl)cyclopropyl)acetic acid 
• 1312993-47-7 Montelukast L-ephedrine salt 
• 1380816-64-7 montelukast 1-(1-naphthyl)ethylamine salt 
• 1351973-24-4 C₄₁H₄₄ClNO₄S₂ 
• 158966-92-8 montelukast 
• 169954-94-3 dicyclohexylamine 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)methyl)cyclopropanyl acetate 
• 945934-73-6 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetic acid cyclohexylamine salt 
• 1006038-82-9 2-[1-[1(R)-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(methoxycarbonyl)phenyl]propylsulfanylmethyl]cyclopropyl]acetic acid isopropyl amine salt 
• 151767-02-1 Montelukast sodium 
• 168214-67-3 C₂₉H₂₆ClNO 
• 168214-68-4 2-[2-((E)-3-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-allyl)-phenyl]-propan-2-ol 
• 577953-88-9 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid dicyclohexylamine salt 

Relevant articles and documents

Preparation method of montelukast sodium side chain

The invention discloses a preparation method of a montelukast sodium side chain, and high-quality montelukast sodium side chain 1- (mercaptomethyl) cyclopropylacetic acid (MLM) is obtained. Accordingto the process, 1-bromo-cyclopropylacetonitrile (MLM-5) is taken as a raw material and reacts with thioacetic acid under an alkaline condition to generate benzoic acid (1-acetonitrile cyclopropyl) methyl mercaptide (MLM-6), and an alkaline hydrolysis reaction is directly performed without treatment, so that the product 1-(mercaptomethyl) cyclopropylacetic acid (MLM) is obtained. The process is simple to operate, cheap in used materials, mild in reaction condition, low in wastewater ammonia nitrogen and easy to biochemically treat, and the product yield and purity are greatly improved.

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