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170729-80-3 Usage

Anti-Vomiting drug during chemotherapy

Aprepitant is a neurokinin-1 (NK-1) receptor antagonist and belongs to the treating agents of vomiting during chemotherapy of cancer. It was first successfully developed by Merck Company (German). In March 2003, the US Food and Drug Administration approved it for being used in the treatment of chemotherapy vomiting. This product has a high selective affinity to human beings while has a low affinity to serotonin, dopamine and glucocorticoid receptor affinity. Aprepitant, when combined with 5-HT3 receptor inhibitors (such as ondansetron hydrochloride) and the corticosteroid dexamethasone, can further alleviate the cisplatin-induced acute and (or) delayed emesis. Applying this drug alone can have some preventive effect. Substance P, a kind of tachykinin (neurokinin), is mainly distributed in the neurons of central and peripheral nervous system. It is related with a lot of features such as vomiting, depression, inflammatory pain and other inflammatory diseases. The role of substance P is mediated by NK-1 receptor which is a kind of G protein receptor coupled with phosphoinositide signaling pathway. The drug has blocking effect on the NK-1 receptor through direct binding to this receptor, thus further obtaining the treatment of substance P-mediated diseases. Aprepitant can selectively prevent the binding of substance P with NK-1 receptor in the central nervous system to take antiemetic effect. Therefore, it can be used for treating the nausea and vomiting caused by the moderately and highly emetogenic chemotherapy.

Dose and usage

When being used for treating the chemotherapy-induced nausea and vomiting, aprepitant is often used in combination with ondansetron (only at the first day of administration) and dexamethasone. Detailed as follows: At 30 min before chemotherapy, intravenously inject 32 mg of ondansetron, taking 12 mg of dexamethasone; at the morning of 2~4d, take 8 mg of dexamethasone again. For nausea and vomiting induced by chemotherapy, use a initial dose of 125mg at the first day, administer at 1 hour before chemotherapy; the first 2~3d, daily 80mg; administer at 1 h before chemotherapy; for treating severe depression (with anxiety) administer 300mg each time, qd. However, the efficacy is still not clear. The above instruction doesn’t need dose adjustment for different gender or races. For patients of renal insufficiency, there is no need for dose adjustment; for mild to moderate liver dysfunction, there is no need to adjust the dose as well; we are currently still lack of pharmacokinetic data when severe liver damage happens. It is also not necessary for the elderly to adjust the dose. There is also no need for dose adjustment to patients who are undergoing hemodialysis due to advanced renal disease.

Side effects

Gastrointestinal reaction: when used for the prevention of chemotherapy-induced emesis, aprepitant may cause diarrhea, but clear relationship is still lacking. Central nervous system: the drug can cause drowsiness and weakness (or lack thereof), but statistical significance was not obvious. Genitourinary system: when aprepitant is applied for the treatment of severe depression, sexual dysfunction can occur. Respiratory system: the drug is used for the prevention of chemotherapy-induced emesis, can also cause hiccups. But the clinical significance is not clear. Skin: occasionally History-Johnson syndrome, urticaria and angioedema can occur. Liver: when aprepitant is used for the prevention of chemotherapy-induced emesis, it can cause the increase of serum aminotransferase, but the clinical significance is unclear. No cases of liver toxicity had been reported.

Uses

Antineoplastic drug.

Description

Aprepitant is an antiemetic chemical compound that belongs to “substance P” antagonists (SPA) with its effect being blocking the neurokinin 1(Nk1) receptor. It is used for the prevention of acute and delayedchemotherapy-induced nausea and vomiting(CINV) and for prevention ofpostoperative nausea and vomiting. It can also be used for the treatment of cyclic vomiting syndrome and late-stage chemotherapy induced vomiting occurring during cancer treatment. Aprepitant alleviates the case of vomiting in patients through balking the signals released by Nk1 receptors. Nk1 is a G-protein-coupled receptor with its ligand being substance P (SP). The high concentration of SP is required for the vomiting reflex. Aprepitant blocks the process of SP-NK1 signaling in activating the vomiting reflex.

Chemical Properties

Off-White to Light Yellow Cyrstalline Solid

Originator

Merck (US)

Uses

A novel selective neurokinin-1 (NK-1) receptor antagonist. In vitro studies using human liver microsomes indicate that Aprepitant is metabolised primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1. Antiemetic.

Uses

anticholinergic

Definition

ChEBI: A morpholine-based antiemetic, which is or the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/ eurokinin 1 (NK1) receptors.

Brand name

Emend (Merck).

Clinical Use

Aprepitant, a substance P (neurokinin-1 [NK-1]) receptor antagonist used for the treatment of chemotherapy-induced nausea and vomiting, was launched in the US and was later approved in the European Union. It is a non-peptide analog having a trisubstituted morpholine with three chiral centers. Two syntheses have been described. In six steps p-fluorophenylacetic acid is converted to 4-benzyl-3-pfluorophenyl- 2-oxomorpholine with a resolution step setting the S-stereochemistry. This intermediate is converted in six steps to aprepitant, with two of the steps utilizing a chiral induction strategy to set the new centers based upon the chiral 2- oxomorpholine intermediate. SAR efforts leading to aprepitant included engineering in potency for NK-1, decreasing affinity for L-type calcium ion channels, most importantly by decreasing the basicity of the core heterocycle. In vitro, it binds with very high affinity (90 pM) to the hNK1 in transfected CHO cells. It is described as an inverse agonist of hNK-1 receptor, with slow dissociation rate under some conditions. In ferrets dosed orally or intravenously prior to emetogen challenge (cisplatin, apomorphine or morphine), retching and vomiting was reduced. Its antiemetic effect is enhanced with the dosing of dexamethasone and it is effective against both the acute and delayed phase of cisplatin-induced emesis. Cisplatin-induced emesis clinical studies showed that aprepitant (125 mg p.o.) in combination with ondansetron (32 mg i.v.) and dexamethasone (20 mg p.o.) therapeutically followed by repeat dosing (days 2–5) of aprepitant (80 mg) dexamethasone (20 mg) provided acute (8 h) and delayed phase (days 2–7) no vomiting rates of 83 and 70%, respectively. L-758298, a prodrug of aprepitant, was not as effective as ondansetron (32 mg i.v.) in reducing acute phase vomiting, but was superior in reducing vomiting in the delayed phase. The terminal half-life range of aprepitant is 9–13 h and the bioavailability is about 65%. It is highly protein bound (95%) and has a Vdss of 70 L. It is a moderate CYP3A4 inhibitor, thus several drugs cleared by CYP3A4 should not be used concurrently. It is also an inducer of CYP2C9 thus potentially modulating the PK of drugs cleared by CYP2C9. Most side effects were mild to moderate, with fatigue, asthenia, diarrhea, and hiccups.

Chemical Synthesis

Several variations to the synthesis of aprepitant (II) have been published by the Merck group. The latest optimized synthesis utilizing a novel crystallization-induced diastereoselective synthesis of aprepitant is highlighted in the Scheme. The synthetic approach entailed (1) the synthesis and coupling of the key pieces, N-benzyl lactam lactol 13 and sec-phenethyl alcohol 7, to provide lactam acetal 14, (2) stereoselective elaboration to the key intermediate 14, and (3) conversion to the final compound via either intramolecular cyclization or intermolecular coupling with triazolinone chloride 24. The intermediate secphenethyl alcohol 7 was synthesized in 97% yield and 95% e.e. (improved to 99% e.e. after recrystallization) via the enantioselective borane reduction of ketone 6 in the presence of 2 mol % of (S)-oxazaborolidine catalyst 8. The optimized conditions involved the slow addition of ketone 6 to a solution containing catalyst 8 and BH3·PhNEt2 complex in MTBE at –10 to 0°C. The synthesis of lactam 12 was done by reacting N-benzylethanolamine (9) with slight excess of aqueous glyoxylic acid (10, 2.3 equivalent of 50% aqueous solution) in refluxing THF. Adjustment of the solvent composition from predominantly THF to predominantly water resulted in the crystallization of lactam 12 directly from 11 in the reaction mixture in 76% yield. Lactam 12 was treated with trifluoroacetic anhydride (1 equiv) to give trifluoroacetate 13, which was reacted in situ with chiral alcohol 7 in the presence of BF3·OEt2 to give, after workup, a 55:45 mixture of the acetals 14 and 15 in 95-98% overall yield. To obtain the desired diastereomer from the 55:45 mixture of 14 and 15, an optimized crystallization sequence was developed. To a solution of the crude mixture in heptane, 3,7-dimethyl-3-octanol (17) (0.9 equiv) was added, cooled to –10 to –5°C and, after seeding the mixture with pure 14, potassium salt of 3,7-dimethyl-3-octanol (16) (0.3 equiv) was added to initiate the crystallization-induced epimerization of 15 to 14. After 5 hr, the mixture was transformed into a 96:4 mixture from which 14 was isolated in 83-85% yield and >99% e.e. Under an optimized condition, the lactam 1 4 was reacted with 4- fluorophenylmagnesium bromide (18) (1.3 equiv) in THF at ambient temperature followed by methanol quench and addition of p-toluenesulfonic acid (1.8-2.2 equiv). Immediate hydrogenation of this mixture in the presence of 5% Pd/C gave the addition product 19, which was isolated as hydrochloride salt in 91% yield. Under these conditions, no cleavage of the benzylic ether group was seen, even after extended hydrogenation periods. Elaboration to aprepitant (II) was done by the initial alkylation of 19 in the presence of a base with amidrazone chloride 20, which was prepared from chloroacetonitrile, to give the intermediate 21. Thermolysis of 21 in toluene provided aprepitant (II) in 85% overall yield. Alternatively, the hydrochloride salt 19 has also been alkylated directly with the triazolinone chloride 24 to give aprepitant (II).

Drug interactions

Potentially hazardous interactions with other drugs Antidepressants: avoid with St John’s wort. Antipsychotics: avoid with pimozide. Avanafil: possibly increases avanafil concentration. Cytotoxics: possibly increases bosutinib concentration - avoid or reduce bosutinib dose; possibly increases ibrutinib concentration - reduce ibrutinib dose. Oestrogens and progestogens: may cause contraceptive failure. Ulipristal: possibly reduces contraceptive effect - avoid.

Metabolism

Aprepitant undergoes extensive metabolism. Following a single IV 100mg dose of [14C]fosaprepitant, a prodrug for aprepitant, aprepitant accounts for approximately 19% of the radioactivity in plasma over 72 hours. 12 metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant, primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19, occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine (57%) and via biliary excretion in faeces (45%).

References

Curran, Monique P., and D. M. Robinson. "Aprepitant."Drugs69.13(2009):1853-1878. Sant P. Chawla M.D. ? ?, et al. "Establishing the dose of the oral NK 1, antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting." Cancer 97.9(2003):2290-2300. Warr, D. G., et al. "Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy." Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology23.12(2005):2822-30. https://en.wikipedia.org/wiki/Aprepitant
InChI:InChI=1/C23H21F7N4O3/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)37-20-19(13-2-4-17(24)5-3-13)34(6-7-36-20)11-18-31-21(35)33-32-18/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H2,31,32,33,35)/t12-,19+,20-/m1/s1

170729-80-3 Well-known Company Product Price

Brand (Code)Product description CAS number Packaging Price Detail
USP (1041904)  Aprepitant  United States Pharmacopeia (USP) Reference Standard 170729-80-3 1041904-150MG 6,426.81CNY Detail

170729-80-3SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 10, 2017

Revision Date: Aug 10, 2017

1.Identification

1.1 GHS Product identifier

Product name aprepitant

1.2 Other means of identification

Product number -
Other names Aprepitant

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:170729-80-3 SDS

170729-80-3Synthetic route

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one
252742-72-6

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one

(2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine 4-methylbenzenesulfonate

(2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine 4-methylbenzenesulfonate

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With potassium carbonate In water; N,N-dimethyl-formamide at 0℃; for 3h;99%
2-[2-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]-1-iminoethyl]hydrazinecarboxylic acid methyl ester
219821-37-1

2-[2-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]-1-iminoethyl]hydrazinecarboxylic acid methyl ester

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
In 5,5-dimethyl-1,3-cyclohexadiene for 3h; Reflux;98.4%
In 5,5-dimethyl-1,3-cyclohexadiene at 130 - 139℃; for 4h; Temperature;97.7%
In acetonitrile at 120 - 125℃;60.4%
C3H4BrN3O

C3H4BrN3O

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With diethyl sulfate; triethylamine; lithium diisopropyl amide In dimethylsulfoxide-d6; 5,5-dimethyl-1,3-cyclohexadiene at 33℃; for 14h; Temperature; Inert atmosphere;97.9%
C23H21F7N4O4

C23H21F7N4O4

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With triethylsilane; boron trifluoride diethyl etherate In acetonitrile at 0 - 35℃; for 5h;94%
3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one
252742-72-6

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With potassium carbonate In N,N-dimethyl-formamide at 0 - 10℃; for 4h;92%
3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one
252742-72-6

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine
171338-27-5

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;68%
N'-(1-amino-2-chloroethylidene)hydrazinecarboxylic acid methyl ester

N'-(1-amino-2-chloroethylidene)hydrazinecarboxylic acid methyl ester

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine
171338-27-5

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Stage #1: N'-(1-amino-2-chloroethylidene)hydrazinecarboxylic acid methyl ester; [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 3h;
Stage #2: In acetonitrile at 110℃; under 1125.11 Torr; for 55h; Product distribution / selectivity;
53%
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluorophenyl-4-2-(N-methylcarboxyactamidrazono)morpholine
219821-37-1

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluorophenyl-4-2-(N-methylcarboxyactamidrazono)morpholine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With pyrographite In methanol at 60℃; for 1h;0.96 kg
In toluene at 140℃; for 3h;
at 135 - 137℃; for 2h;
(2R,3S)-4-benzyl-2-[1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine p-toluenesulfonate salt

(2R,3S)-4-benzyl-2-[1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine p-toluenesulfonate salt

N-methoxycarbonyl-2-chloroacetamidrazone

N-methoxycarbonyl-2-chloroacetamidrazone

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With potassium carbonate In dimethyl sulfoxide at 20 - 23℃; for 1.5h; Product distribution / selectivity;
3,5-bis(trifluoromethyl)phenyl methyl ketone
30071-93-3

3,5-bis(trifluoromethyl)phenyl methyl ketone

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C
2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 5 steps
1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C
2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
4: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
5: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 4 steps
1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C
2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol
368-63-8, 68120-60-5, 127852-28-2

(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 4 steps
1: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
3: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
4: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 3 steps
1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
4-benzyl-morpholine-2,3-dione
110843-90-8

4-benzyl-morpholine-2,3-dione

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C
2: acetonitrile / 5 - 34 °C
3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 6 steps
1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C
2: acetonitrile / 5 - 34 °C
3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
5: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
6: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 5 steps
1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C
2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C
3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
N-Benzylethanolamine
104-63-2

N-Benzylethanolamine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating
2: acetonitrile / 5 - 34 °C
3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 6 steps
1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating
2: acetonitrile / 5 - 34 °C
3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
5: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
6: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 5 steps
1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating
2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C
3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
2: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 2 steps
1: potassium carbonate / N,N-dimethyl-formamide / 10 - 20 °C
2: potassium hydroxide / ethanol; water / 0.2 h / 90 - 100 °C
View Scheme
Multi-step reaction with 2 steps
1: potassium carbonate / N,N-dimethyl-formamide / 10 - 20 °C
2: potassium hydroxide / ethanol; water / 0.2 h / 90 - 100 °C
View Scheme
Multi-step reaction with 2 steps
1: potassium carbonate; N-benzyl-N,N,N-triethylammonium chloride / 5,5-dimethyl-1,3-cyclohexadiene; dimethyl sulfoxide / 20 - 25 °C / Inert atmosphere
2: 5,5-dimethyl-1,3-cyclohexadiene / 2 h / 135 - 141 °C / Inert atmosphere
View Scheme
4-benzyl-2-hydroxy-morpholin-3-one
287930-73-8

4-benzyl-2-hydroxy-morpholin-3-one

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: acetonitrile / 5 - 34 °C
2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 5 steps
1: acetonitrile / 5 - 34 °C
2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
4: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
5: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 4 steps
1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C
2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
trifluoro-acetic acid 4-benzyl-3-oxo-morpholin-2-yl ester
502537-07-7

trifluoro-acetic acid 4-benzyl-3-oxo-morpholin-2-yl ester

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 4 steps
1: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
3: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
4: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
2,2,2-trichloro-acetimidic acid 4-benzyl-3-oxo-morpholin-2-yl ester
502536-97-2

2,2,2-trichloro-acetimidic acid 4-benzyl-3-oxo-morpholin-2-yl ester

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
2: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 3 steps
1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 4 steps
1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
3: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
4: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 5 steps
1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C
2: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C
3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
4: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
5: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
(2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one
327623-36-9

(2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 4 steps
1: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C
2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
3: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
4: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one
287930-75-0

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
View Scheme
Multi-step reaction with 3 steps
1: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
2: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C
3: 0.96 kg / Darco / methanol / 1 h / 60 °C
View Scheme
Multi-step reaction with 4 steps
1.1: 5%-palladium/activated carbon; hydrogen / methanol; water / 4.5 h / 50 - 60 °C / 26252.6 Torr
2.1: sodium hydroxide / acetonitrile / 2.5 h / 30 - 40 °C
3.1: tetrahydrofuran / 1 h / 15 - 25 °C
3.2: 1 h / 20 - 65 °C
4.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 5 h / 0 - 35 °C
View Scheme
(2S,3R)-3-(4-fluorophenyl)-4-[(1R)-1-phenylethyl]-2-morpholinol
472968-68-6

(2S,3R)-3-(4-fluorophenyl)-4-[(1R)-1-phenylethyl]-2-morpholinol

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: K2CO3 / toluene / 5 h / 20 °C
2: 14.3 g / BF3*Et2O / tetrahydrofuran / 1 h / -20 °C
3: TsOH*H2O; hydrogen / 5percent Pd/C / ethanol; toluene / 3 h / 30 °C / 2068.65 Torr
4: NCS; K2CO3 / dimethylformamide / 0.5 h / 0 °C
5: DBU / dimethylformamide / 3 h / 0 - 20 °C
6: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
(3R)-[3-(4-fluorophenyl)]-4-[(1R)-1-phenylethyl]-2-morpholinone

(3R)-[3-(4-fluorophenyl)]-4-[(1R)-1-phenylethyl]-2-morpholinone

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 8 steps
1: DIBALH / toluene; tetrahydrofuran / 0.5 h / -20 °C
2: K2CO3 / toluene / 5 h / 20 °C
3: 14.3 g / BF3*Et2O / tetrahydrofuran / 1 h / -20 °C
4: TsOH*H2O; hydrogen / 5percent Pd/C / ethanol; toluene / 3 h / 30 °C / 2068.65 Torr
5: NCS; K2CO3 / dimethylformamide / 0.5 h / 0 °C
6: DBU / dimethylformamide / 3 h / 0 - 20 °C
7: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
2,2,2-Trichloro-acetimidic acid (2R,3R)-3-(4-fluoro-phenyl)-4-((R)-1-phenyl-ethyl)-morpholin-2-yl ester
472968-69-7

2,2,2-Trichloro-acetimidic acid (2R,3R)-3-(4-fluoro-phenyl)-4-((R)-1-phenyl-ethyl)-morpholin-2-yl ester

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: 14.3 g / BF3*Et2O / tetrahydrofuran / 1 h / -20 °C
2: TsOH*H2O; hydrogen / 5percent Pd/C / ethanol; toluene / 3 h / 30 °C / 2068.65 Torr
3: NCS; K2CO3 / dimethylformamide / 0.5 h / 0 °C
4: DBU / dimethylformamide / 3 h / 0 - 20 °C
5: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
(2R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-5,6-dihydro-2H-1,4-oxazine
380499-07-0

(2R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-5,6-dihydro-2H-1,4-oxazine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
Multi-step reaction with 2 steps
1.1: potassium formate / palladium on carbon / ethanol; water / 2 h / 20 °C
2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h / 20 °C
2.2: 55 h / 110 °C / 1125.11 Torr
View Scheme
(2R,3R)-2-[(1R)-1-(3,5-bis-trifluoro-methylphenyl)ethoxy]-3-(4-fluorophenyl)morpholine
380499-06-9

(2R,3R)-2-[(1R)-1-(3,5-bis-trifluoro-methylphenyl)ethoxy]-3-(4-fluorophenyl)morpholine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: NCS; K2CO3 / dimethylformamide / 0.5 h / 0 °C
2: DBU / dimethylformamide / 3 h / 0 - 20 °C
3: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
Multi-step reaction with 3 steps
1.1: sodium hypochlorite; potassium carbonate / acetonitrile / 0.25 h
1.2: 14 h / 20 °C
2.1: potassium formate / palladium on carbon / ethanol; water / 2 h / 20 °C
3.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C
View Scheme
Multi-step reaction with 3 steps
1.1: sodium hypochlorite; potassium carbonate / acetonitrile / 0.25 h
1.2: 14 h / 20 °C
2.1: potassium formate / palladium on carbon / ethanol; water / 2 h / 20 °C
3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h / 20 °C
3.2: 55 h / 110 °C / 1125.11 Torr
View Scheme
(2R,3R)-2-[(R)-1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-4-chloro-3-(4-fluoro-phenyl)-morpholine

(2R,3R)-2-[(R)-1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-4-chloro-3-(4-fluoro-phenyl)-morpholine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: DBU / dimethylformamide / 3 h / 0 - 20 °C
2: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
(2R,3R)-2-[(R)-1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-4-((R)-1-phenyl-ethyl)-morpholine
472968-70-0

(2R,3R)-2-[(R)-1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-4-((R)-1-phenyl-ethyl)-morpholine

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: TsOH*H2O; hydrogen / 5percent Pd/C / ethanol; toluene / 3 h / 30 °C / 2068.65 Torr
2: NCS; K2CO3 / dimethylformamide / 0.5 h / 0 °C
3: DBU / dimethylformamide / 3 h / 0 - 20 °C
4: hydrogen / 5percent Pd/C / dimethylformamide; ethanol / 2 h / 20 °C / 2068.65 Torr
View Scheme
C27H31F7N4O4
1349902-81-3

C27H31F7N4O4

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With potassium hydroxide In ethanol; water at 90 - 100℃; for 1h; Reagent/catalyst; Solvent; Large scale;
C25H27F7N4O4

C25H27F7N4O4

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
With potassium hydroxide In ethanol; water at 90 - 100℃; for 0.2h;
(2S,3R)-4-benzyl-3-(4-fluorophenyl)morpholin-2-ol
1185503-10-9

(2S,3R)-4-benzyl-3-(4-fluorophenyl)morpholin-2-ol

aprepitant
170729-80-3

aprepitant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: boron trifluoride diethyl etherate / toluene / 1 h / -10 °C
2.1: hydrogen; toluene-4-sulfonic acid / palladium 10% on activated carbon / methanol / 16 h / 20 °C
3.1: sodium hypochlorite; potassium carbonate / acetonitrile / 0.25 h
3.2: 14 h / 20 °C
4.1: potassium formate / palladium on carbon / ethanol; water / 2 h / 20 °C
5.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C
View Scheme
Multi-step reaction with 5 steps
1.1: boron trifluoride diethyl etherate / toluene / 1 h / -10 °C
2.1: hydrogen; toluene-4-sulfonic acid / palladium 10% on activated carbon / methanol / 16 h / 20 °C
3.1: sodium hypochlorite; potassium carbonate / acetonitrile / 0.25 h
3.2: 14 h / 20 °C
4.1: potassium formate / palladium on carbon / ethanol; water / 2 h / 20 °C
5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h / 20 °C
5.2: 55 h / 110 °C / 1125.11 Torr
View Scheme
1-deoxy-1-(methylamino)-D-glucitol
6284-40-8

1-deoxy-1-(methylamino)-D-glucitol

aprepitant
170729-80-3

aprepitant

Fosaprepitant dimeglumine

Fosaprepitant dimeglumine

Conditions
ConditionsYield
Stage #1: aprepitant With dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate; sodium hexamethyldisilazane In tetrahydrofuran at -3℃; for 2h;
Stage #2: 1-deoxy-1-(methylamino)-D-glucitol With palladium 10% on activated carbon; hydrogen In methanol; water for 4h;
98%
dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate
990-91-0

dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate

aprepitant
170729-80-3

aprepitant

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester
265121-01-5

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester

Conditions
ConditionsYield
With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h; Temperature; Inert atmosphere;93.6%
With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h; Temperature; Inert atmosphere;93.6%
With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.25h; phosphorylation;90%
Dibenzyl phosphite
17176-77-1

Dibenzyl phosphite

aprepitant
170729-80-3

aprepitant

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester
265121-01-5

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester

Conditions
ConditionsYield
With triethylamine In tetrachloromethane; dichloromethane at 0 - 10℃; Reagent/catalyst; Solvent;92.4%
Dimethyl phosphite
868-85-9

Dimethyl phosphite

aprepitant
170729-80-3

aprepitant

C25H26F7N4O6P

C25H26F7N4O6P

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine In tert-butyl methyl ether at 0 - 30℃;90.6%
phosphonic acid diethyl ester
762-04-9

phosphonic acid diethyl ester

aprepitant
170729-80-3

aprepitant

C27H30F7N4O6P

C27H30F7N4O6P

Conditions
ConditionsYield
With dmap In chloroform at 0 - 20℃;90.4%
dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate
990-91-0

dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate

aprepitant
170729-80-3

aprepitant

dibenzyl fosaprepitant

dibenzyl fosaprepitant

Conditions
ConditionsYield
Stage #1: aprepitant With lithium hydroxide monohydrate In 1-methyl-pyrrolidin-2-one at 20℃; for 0.5h;
Stage #2: dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate In 1-methyl-pyrrolidin-2-one at 25 - 30℃; for 0.5h; Quantum yield;
87.4%
aprepitant
170729-80-3

aprepitant

fosaprepitant

fosaprepitant

Conditions
ConditionsYield
With dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate; sodium hexamethyldisilazane In tetrahydrofuran at -3℃; for 2h;86.7%
Multi-step reaction with 3 steps
1: sodium hexamethyldisilazane / tetrahydrofuran / 3.5 h / -20 °C
2: hydrogen / palladium 10% on activated carbon / methanol / 1 h / 5171.62 Torr
3: hydrogenchloride / water; methanol / 0.08 h / 0 - 5 °C / pH 1
View Scheme
Multi-step reaction with 2 steps
1: sodium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere
2: borane pyridine; methanol / 2 h / 20 °C / Inert atmosphere
View Scheme
C26H22ClO3P

C26H22ClO3P

aprepitant
170729-80-3

aprepitant

C49H42F7N4O6P

C49H42F7N4O6P

Conditions
ConditionsYield
Stage #1: aprepitant With sodium hexamethyldisilazane In tetrahydrofuran at -5 - 5℃; for 0.5h; Inert atmosphere; Cooling with ice;
Stage #2: C26H22ClO3P In tetrahydrofuran at 5 - 20℃; for 1h; Solvent;
82%
benzyl methyl phosphonate
53148-24-6

benzyl methyl phosphonate

aprepitant
170729-80-3

aprepitant

C31H30F7N4O6P

C31H30F7N4O6P

Conditions
ConditionsYield
With triethylamine In tetrachloromethane; dichloromethane at 0 - 10℃; Reagent/catalyst; Solvent;81.1%
aprepitant
170729-80-3

aprepitant

5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl-d)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl-d)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Conditions
ConditionsYield
With deuteroacetic acid; magnesium In dimethylsulfoxide-d6; d(4)-methanol; water-d2 at 20℃; for 2h; regioselective reaction;43%
aprepitant
170729-80-3

aprepitant

5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Conditions
ConditionsYield
With magnesium; acetic acid In water; dimethyl sulfoxide at 20℃; for 2h; regioselective reaction;41%
dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate
990-91-0

dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate

aprepitant
170729-80-3

aprepitant

A

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester
265121-01-5

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester

B

C44H41F7N4O9P2

C44H41F7N4O9P2

Conditions
ConditionsYield
With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 0.75h; phosphorylation;A 39%
B 5 % Chromat.
aprepitant
170729-80-3

aprepitant

A

5-(((2R,3S)-2-((R)-1-(3-(fluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

5-(((2R,3S)-2-((R)-1-(3-(fluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

B

5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Conditions
ConditionsYield
With magnesium; acetic acid In water; dimethyl sulfoxide at 20℃; for 5h; regioselective reaction;A 16%
B 22%
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