125995-03-1

Basic information

• Product Name: Atorvastatin lactone
• Synonyms: 1-[2-[[(2R)-Tetrahydro-4β-hydroxy-6-oxo-2H-pyran]-2α-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4,N-diphenyl-1H-pyrrole-3-carboxamide;Atorvastatin Related Compound H (20 mg) (5-(4-Fluorophenyl)-1-{2-[(2R, 4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide);Atorvastatin EPIMp H (USP RCH);Atorvastatin EP IMpurity H;Diepoxide Atorvastatin Lactone Diepoxide;Atorvastatin Calcium Impurity D;Atorvastatin Impurity H;(RS) Atorvastatin Lactone
• CAS NO: 125995-03-1
• Molecular Formula: C₃₃H₃₃FN₂O₄
• Molecular Weight: 540.63
• Product Categories: Inhibitors;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 125995-03-1.mol
• Article Data: 21

Chemical Properties

• Melting Point: 103-106°C
• Boiling Point: 674.8 °C at 760 mmHg
• Flash Point: 361.9 °C
• Appearance: slightly yellow solid
• Density: 1.24 g/cm³
• Vapor Pressure: 3.92E-19mmHg at 25°C
• Refractive Index: 1.616
• Storage Temp.: -20°C Freezer, Under Inert Atmosphere
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 13.39±0.40(Predicted)
• Merck: 14,864
• CAS DataBase Reference: Atorvastatin lactone(CAS DataBase Reference)
• NIST Chemistry Reference: Atorvastatin lactone(125995-03-1)
• EPA Substance Registry System: Atorvastatin lactone(125995-03-1)

Safety Data

• Hazardous Substances Data: 125995-03-1(Hazardous Substances Data)

Usage

Chemical Properties

Slightly Yellow Solid

Uses

Different sources of media describe the Uses of 125995-03-1 differently. You can refer to the following data:
1. Atorvastatin intermediate as inhibitor of MAP kinase and/or HMG-CoA reductase for the treatment of inflammation
2. Atorvastatin Lactone (Atorvastatin EP Impurity H) is an intermediate of Atorvastatin, a inhibitor of MAP kinase and/or HMG-CoA reductase for the treatment of inflammation.

InChI:InChI=1/C33H33FN2O4/c1-21(2)31-30(33(39)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-27-19-26(37)20-28(38)40-27/h3-16,21,26-27,37H,17-20H2,1-2H3,(H,35,39)/t26-,27-/m1/s1

Synthetic route

pentan-1-ol (71-41-0) + lipitor (134523-03-8) → pentyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 96% B n/a

1-[2-((2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (842163-03-5) → atorvastatin lactone (125995-03-1)

Conditions	Yield
With manganese(IV) oxide In acetone at 25℃; for 24h;	95%
With Dess-Martin periodane In dichloromethane at 20℃; for 2.5h;

2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid (581772-29-4) → atorvastatin lactone (125995-03-1)

Conditions	Yield
With camphor-10-sulfonic acid In tetrahydrofuran at 20℃; for 3h;	90%

lipitor (134523-03-8) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Stage #1: lipitor With hydrogenchloride In water; ethyl acetate at 4 - 20℃; Stage #2: In toluene for 2.5h; Reflux; Dean-Stark;	88%
With hydrogenchloride In water at 20℃; for 2h;	55%
Stage #1: lipitor With hydrogenchloride In dichloromethane; water Stage #2: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Cooling with ice;	2.78 g

(3R,5R)-methyl 3,5-bis((tert-butyldimethylsilyl)oxy)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)heptanoate → atorvastatin lactone (125995-03-1)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 20℃; stereoselective reaction;	75%

2-methyl-propan-1-ol (78-83-1) + lipitor (134523-03-8) → isobutyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 74% B n/a

propan-1-ol (71-23-8) + lipitor (134523-03-8) → propyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 70% B n/a

n-heptan1ol (111-70-6) + lipitor (134523-03-8) → heptyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 68% B n/a

lipitor (134523-03-8) + hexan-1-ol (111-27-3) → hexyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 66% B n/a

lipitor (134523-03-8) + nonyl alcohol (143-08-8) → nonyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 66% B n/a

lipitor (134523-03-8) → (S)-5-(4-fluorophenyl)-2-isopropyl-1-(2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide (442851-50-5) + atorvastatin lactone (125995-03-1)

Conditions	Yield
With hydrogenchloride In water for 4h; Reflux;	A 14% B 65%

lipitor (134523-03-8) + isopropyl alcohol (67-63-0) → (3R,5R)-isopropyl 7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate (1035205-25-4) + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 54% B n/a

atorvastatin (134523-00-5) → atorvastatin lactone (125995-03-1)

Conditions	Yield
In toluene at 60℃; for 40h;	46%
hydrogenchloride In toluene	n/a
In toluene for 4h; Product distribution / selectivity; Heating / reflux;
In hexane for 6h; Heating;	3.9 g

2,2-dimethyl-propanol-1 (75-84-3) + lipitor (134523-03-8) → neopentyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 44% B n/a

1,1-dimethylethyl (R)-7-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-5-hydroxy-3-oxo-1-heptanoate (134394-98-2) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Yield given. Multistep reaction;

(+/-)-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-<2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-6-yl)ethyl>-1H-pyrrole-3-carboxamide (110862-39-0, 125995-03-1, 134523-07-2) → atorvastatin lactone (125995-03-1) + (-)-(4S)-trans-2-(4-fluorophenyl)-5-(1-methylethyl)-N,3-diphenyl-1-<(tetrahydro-4-hydroxy-2-oxo-2H-pyran-6-yl)ethyl>-1H-pyrrole-4-carboxamide (134523-07-2)

Conditions	Yield
Yield given. Yields of byproduct given;

methanol (67-56-1) + atorvastatin (134523-00-5) → atorvastatin lactone (125995-03-1) + (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (345891-62-5)

Conditions	Yield
With phosphoric acid In acetonitrile at 80℃; for 3h;	A 15.2 mg B 6.9 mg

ethyl α-bromo-4-fluorobenzeneacetate → atorvastatin lactone (125995-03-1)

Conditions

Yield

Multi-step reaction with 9 steps 1: 82.5 percent / triethylamine / acetonitrile / Ambient temperature 2: triethylamine / CH2Cl2 / 1 h / 0 °C 3: NaOH / methanol; H2O / 2 h / Heating 4: 43 percent / acetic anhydride / 4 h / 90 °C 5: 1.) concd. HCl, 2.) p-TSA, H2O / 1.) ethanol, reflux, 24 h, 2.) acetone, reflux, 2 d 6: 1.) sodium hydride, n-butyllithium / 1.) THF, hexane, 0 deg C, 30 min, 2.)a) -78 deg C, 30 min, b) 0 deg C, 1 h 7: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 8: toluene / 6 h / Heating View Scheme

ethyl 3-(4-cyanophenyl)propiolate (143952-58-3) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 4 steps 2: 73.9 g / methanol; tetrahydrofuran / 0 °C 3: 73 g / diisopropylamine, n-butyllithium / tetrahydrofuran; hexane / 4 h / -70 °C View Scheme

ethyl α-<<2-(1,3-dioxolan-2-yl)ethyl>amino>-4-fluorobenzeneacetate → atorvastatin lactone (125995-03-1)

Conditions

Yield

Multi-step reaction with 8 steps 1: triethylamine / CH2Cl2 / 1 h / 0 °C 2: NaOH / methanol; H2O / 2 h / Heating 3: 43 percent / acetic anhydride / 4 h / 90 °C 4: 1.) concd. HCl, 2.) p-TSA, H2O / 1.) ethanol, reflux, 24 h, 2.) acetone, reflux, 2 d 5: 1.) sodium hydride, n-butyllithium / 1.) THF, hexane, 0 deg C, 30 min, 2.)a) -78 deg C, 30 min, b) 0 deg C, 1 h 6: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 7: toluene / 6 h / Heating View Scheme

α-<<2-(1,3-dioxolan-2-yl)ethyl>(2-methyl-1-oxopropyl)amino>-4-fluorobenzeneacetic acid (110862-44-7) → atorvastatin lactone (125995-03-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 43 percent / acetic anhydride / 4 h / 90 °C 2: 1.) concd. HCl, 2.) p-TSA, H2O / 1.) ethanol, reflux, 24 h, 2.) acetone, reflux, 2 d 3: 1.) sodium hydride, n-butyllithium / 1.) THF, hexane, 0 deg C, 30 min, 2.)a) -78 deg C, 30 min, b) 0 deg C, 1 h 4: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 5: toluene / 6 h / Heating View Scheme

α-<<2-(1,3-dioxolan-2-yl)ethyl>(2-methyl-1-oxopropyl)amino>-4-fluorobenzeneacetic acid, ethyl ester (110862-43-6) → atorvastatin lactone (125995-03-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: NaOH / methanol; H2O / 2 h / Heating 2: 43 percent / acetic anhydride / 4 h / 90 °C 3: 1.) concd. HCl, 2.) p-TSA, H2O / 1.) ethanol, reflux, 24 h, 2.) acetone, reflux, 2 d 4: 1.) sodium hydride, n-butyllithium / 1.) THF, hexane, 0 deg C, 30 min, 2.)a) -78 deg C, 30 min, b) 0 deg C, 1 h 5: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 6: toluene / 6 h / Heating View Scheme

5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide (110862-46-9) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) sodium hydride, n-butyllithium / 1.) THF, hexane, 0 deg C, 30 min, 2.)a) -78 deg C, 30 min, b) 0 deg C, 1 h 2: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 3: toluene / 6 h / Heating View Scheme

1-<2-(1,3-dioxolan-2-yl)ethyl>-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide (110862-45-8) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) concd. HCl, 2.) p-TSA, H2O / 1.) ethanol, reflux, 24 h, 2.) acetone, reflux, 2 d 2: 1.) sodium hydride, n-butyllithium / 1.) THF, hexane, 0 deg C, 30 min, 2.)a) -78 deg C, 30 min, b) 0 deg C, 1 h 3: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 4: toluene / 6 h / Heating View Scheme

methyl (R)-(+)-5-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-3-hydroxy-1-pentanoate (134394-97-1) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 73 g / diisopropylamine, n-butyllithium / tetrahydrofuran; hexane / 4 h / -70 °C View Scheme

(R*,R*)-3,5-dihydroxy-7-<(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-1-heptanoic acid (125971-63-3) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene / 6 h / Heating View Scheme

methyl 7-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-5-hydroxy-3-oxo-1-heptanoate (110862-47-0) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) tributylborane, sodium borohydride, 2.) 3 N NaOH, 30percent H2O2 / 1.) THF, a) RT, b) 0 deg C, 3 h, 2.) RT 2: toluene / 6 h / Heating View Scheme

*,S*)>-5-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-3-hydroxy-1-pentanoic acid, 2-hydroxy-1,2,2-triphenylethyl ester (134394-96-0) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 73.9 g / methanol; tetrahydrofuran / 0 °C 2: 73 g / diisopropylamine, n-butyllithium / tetrahydrofuran; hexane / 4 h / -70 °C View Scheme

[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid; ammonium salt (340266-37-7) → atorvastatin lactone (125995-03-1)

Conditions	Yield
In toluene for 12h; Heating / reflux;

atorvastatin lactone (125995-03-1) → 1-((3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-7H-pyrrole-3-carboxamide (1174332-81-0)

Conditions	Yield
With hydroxylamine In tetrahydrofuran; water for 48h;	99%
With magnesium(II) bromide; hydroxylamine hydrochloride; sodium hydrogencarbonate In tetrahydrofuran; methanol at 20℃; for 20h;	51%

atorvastatin lactone (125995-03-1) + tetraethyl 3-aminopropylidene-1,1-bisphosphonate (141473-49-6) → tetraethyl (3R,5R)-3-N-(7-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoyl)aminopropane-1,1-bisphosphonate (1040395-59-2)

Conditions	Yield
In tetrahydrofuran at 60℃; for 48h;	96.3%

atorvastatin lactone (125995-03-1) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: atorvastatin lactone With calcium hydroxide In tetrahydrofuran; water at 45 - 50℃; for 2h; Stage #2: In dichloromethane; di-isopropyl ether at 10 - 15℃; for 0.25h; Product distribution / selectivity;	95.1%
Stage #1: atorvastatin lactone With sodium hydroxide In methanol; water at 25 - 50℃; for 2h; Stage #2: With hydrogenchloride In water pH=7.8 - 8.2; Stage #3: With calcium acetate In methanol; water at 25 - 30℃; Product distribution / selectivity;	92.21%
Stage #1: atorvastatin lactone With calcium hydroxide In tetrahydrofuran; water at 45 - 50℃; for 2h; Stage #2: In methanol at 40 - 45℃; Product distribution / selectivity;	91.82%

atorvastatin lactone (125995-03-1) → 1-[2-((2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (842163-03-5)

Conditions	Yield
Stage #1: atorvastatin lactone With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 1h; Stage #2: With water; rochelle salt In dichloromethane; toluene at 20℃; Product distribution / selectivity;	95%

calcium acetate hydrate (114460-21-8) + atorvastatin lactone (125995-03-1) → 2C33H36FN2O5(1-)*Ca(2+)

Conditions	Yield
Stage #1: atorvastatin lactone With sodium hydroxide In methanol; tert-butyl methyl ether; water at 50℃; for 2h; Stage #2: calcium acetate hydrate In water at 30 - 50℃; for 4.5h; Heating;	94%

atorvastatin lactone (125995-03-1) + tert-butyldimethylsilyl chloride (18162-48-6) → (2R,4R)-1-{2-[4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2-pyranyl]-ethyl}-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (842162-99-6)

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide	92%

strontium hydroxide (1311-10-0) + strontium(II) acetate (543-94-2) + atorvastatin lactone (125995-03-1) → [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate strontium pentahydrate

Conditions	Yield
Stage #1: strontium hydroxide; atorvastatin lactone With water In tert-butyl methyl ether; acetone at 20℃; for 3.5h; Stage #2: strontium(II) acetate With water In acetone at 50℃; for 10h; Product distribution / selectivity;	85%

atorvastatin lactone (125995-03-1) → [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate strontium

Conditions	Yield
Stage #1: atorvastatin lactone With strontium hydroxide In tert-butyl methyl ether; water; acetone at 20℃; Stage #2: With strontium(II) acetate In water; acetone at 50℃; Product distribution / selectivity;	85%

strontium hydroxide (1311-10-0) + strontium(II) acetate (543-94-2) + atorvastatin lactone (125995-03-1) → [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate strontium

Conditions	Yield
Stage #1: strontium hydroxide; atorvastatin lactone In methanol; tert-butyl methyl ether; water at 20℃; for 3.5h; Stage #2: strontium(II) acetate In methanol; tert-butyl methyl ether; water at 50℃; for 19h;	77%

atorvastatin lactone (125995-03-1) + calcium chloride → atorvastatin calcium

Conditions	Yield
Stage #1: atorvastatin lactone With methanol; sodium hydroxide; water Stage #2: calcium chloride In water	77%

atorvastatin lactone (125995-03-1) + (R)-2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (103129-81-3) → (R)-3-ethyl-5-methyl-2-{[2-({7-[(3-anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoyl}amino)ethoxy]methyl}-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate

Conditions	Yield
In ethanol for 18h; Heating / reflux;	76%

atorvastatin lactone (125995-03-1) → (2R,4R)-1-{2-[4-(tert-Butyldimethylsilyloxy)-6-oxotetrahydro-2-pyranyl]-ethyl}-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide

Conditions	Yield
With 1H-imidazole; tert-butyldimethylsilyl chloride In DMF (N,N-dimethyl-formamide) at 20℃; for 6h;	73%

atorvastatin lactone (125995-03-1) → 1-((3R,5R)-7-amino-3,5-dihydroxy-7-oxoheptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide

Conditions	Yield
With ammonia In methanol at 20℃; for 24h;	71%

atorvastatin lactone (125995-03-1) + amlodipine (103129-82-4) → (S)-3-ethyl-5-methyl-2-{[2-({7-[(3-anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoyl}amino)ethoxy]methyl}-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate

Conditions	Yield
In ethanol for 18h; Heating / reflux;	64%

atorvastatin lactone (125995-03-1) + tetraethyl (aminomethylene)bis(phosphonate) (80474-99-3) → tetraethyl [(3R,5R)-(7-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoyl)aminomethylene]bisphosphonate (1040395-64-9)

Conditions	Yield
In tetrahydrofuran at 60℃; for 48h;	62.3%

Upstream product

• 581772-29-4 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 
• 134523-03-8 lipitor 
• 143-08-8 nonyl alcohol 
• 75-84-3 2,2-dimethyl-propanol-1 
• 111-70-6 n-heptan1ol 
• 111-27-3 hexan-1-ol 
• 71-41-0 pentan-1-ol 
• 78-83-1 2-methyl-propan-1-ol 
• 71-23-8 propan-1-ol 
• 67-63-0 isopropyl alcohol 
• 134523-02-7 atorvastatin potassium 
• 119146-87-1 (3R,5R)-methyl 3,5-bis((tert-butyldimethylsilyl)oxy)-7-hydroxyheptanoate 
• 134395-00-9 (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester 
• 125971-95-1 tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate 

Downstream Products

• 134523-07-2 (-)-(4S)-trans-2-(4-fluorophenyl)-5-(1-methylethyl)-N,3-diphenyl-1-<(tetrahydro-4-hydroxy-2-oxo-2H-pyran-6-yl)ethyl>-1H-pyrrole-4-carboxamide 
• 134523-02-7 atorvastatin potassium 
• 134523-01-6 atorvastatin sodium 
• 1040395-64-9 tetraethyl [(3R,5R)-(7-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoyl)aminomethylene]bisphosphonate 
• 1040395-59-2 tetraethyl (3R,5R)-3-N-(7-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoyl)aminopropane-1,1-bisphosphonate 
• 1174332-81-0 1-((3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-7H-pyrrole-3-carboxamide 

Relevant articles and documents

Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids

Atorvastatin calcium (Lipitor, Sortis) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be sensitive to acid treatment, but only little data has been published on the structures of the degradation products. Here we report the identification of two novel degradation products of atorvastatin, which are formed only under drastic acidic conditions. While treatment with conc. sulfuric acid led to a loss of the carboxanilide residue (accompanied by an expectable lactonization/dehydration process in the side chain), treatment with conc. aqueous hydrochloric acid gave a complex, bridged molecule under C–C-bond formation of the lactone moiety with the pyrrole, migration of the isopropyl group and loss of the carboxanilide residue. The novel degradation products were characterized by NMR spectroscopy, HRMS data and X-ray crystal structure analysis.

Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases

1. We investigated the structure-activity relationship of 31 kinds of synthesized atorvastatin esters, thioesters, amides and lactone, selected as prodrug models, for metabolic activation by microsomes and hydrolases. 2. The susceptibility to human carboxylesterase 1 (hCES1) was influenced not only by the size of the acyl group and alkoxy group but also by the degree of steric crowding around the alkoxy group. 3. The susceptibility to human carboxylesterase 2 (hCES2) increased with a decrease in electron density around the alkoxy group of the substrate. 4. Lactone was specifically hydrolyzed by paraoxonase 3 (PON3). 5. These findings should be useful in prodrug design for controlling metabolic activation.

Multi-substituted pyrroles he the sandbank contains the fluorine derivative and use thereof

The invention belongs to the field of pharmaceutical chemistry, provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor and particularly provides a polysubstituted pyrimidine statin fluorinated modifier containing a 3-fluoro-caprolactone fragment and 1-fluoro-3-hydroxy pentanoic acid formed after the ring opening of lactone and salts or esters thereof, wherein the polysubstituted pyrimidine statin fluorinated modifier has a structural formula described by a formula shown in the description or a formula shown in the description or a formula shown in the description. Proven by tests, the compound has the effect of inhibiting the activity of the HMG-coA reductase and can serve as a new-generation potential HMG-CoA reductase inhibitor.