170729-80-3

Basic information

• Product Name: Aprepitant
• Synonyms: aprepitant;5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,;5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, Emend;5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one;Emend;MK-0869;Aprepitant(MK-0869);ONO 7436
• CAS NO: 170729-80-3
• Molecular Formula: C₂₃H₂₁F₇N₄O₃
• Molecular Weight: 534.4266624
• EINECS: 1806241-263-5
• Product Categories: Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical intermediate;Aprepitant;Inhibitors
• Mol File: 170729-80-3.mol

Chemical Properties

• Melting Point: 244-246°C
• Appearance: off-white to light yellow cyrstalline solid
• Density: 1.51 g/cm³
• Refractive Index: 1.564
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (>25 mg/ml)
• PKA: 8.06±0.20(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Aprepitant(CAS DataBase Reference)
• NIST Chemistry Reference: Aprepitant(170729-80-3)
• EPA Substance Registry System: Aprepitant(170729-80-3)

Safety Data

• Hazardous Substances Data: 170729-80-3(Hazardous Substances Data)

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. The above information is edited by the lookchem of Dai Xiongfeng.

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.

Originator

Merck (US)

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.

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

Synthetic route

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one (252742-72-6) + (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine 4-methylbenzenesulfonate → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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 + [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride → aprepitant (170729-80-3)

Conditions	Yield
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 → aprepitant (170729-80-3)

Conditions	Yield
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) + [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride → aprepitant (170729-80-3)

Conditions	Yield
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) + [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine (171338-27-5) → aprepitant (170729-80-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;	68%

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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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 + N-methoxycarbonyl-2-chloroacetamidrazone → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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 → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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 → aprepitant (170729-80-3)

Conditions

Yield

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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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 → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

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

C25H27F7N4O4 → aprepitant (170729-80-3)

Conditions	Yield
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) → aprepitant (170729-80-3)

Conditions	Yield
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) + aprepitant (170729-80-3) → Fosaprepitant dimeglumine

Conditions	Yield
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) + aprepitant (170729-80-3) → [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)

Conditions	Yield
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) + aprepitant (170729-80-3) → [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)

Conditions	Yield
With triethylamine In tetrachloromethane; dichloromethane at 0 - 10℃; Reagent/catalyst; Solvent;	92.4%

Dimethyl phosphite (868-85-9) + aprepitant (170729-80-3) → C25H26F7N4O6P

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tert-butyl methyl ether at 0 - 30℃;	90.6%

phosphonic acid diethyl ester (762-04-9) + aprepitant (170729-80-3) → C27H30F7N4O6P

Conditions	Yield
With dmap In chloroform at 0 - 20℃;	90.4%

dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate (990-91-0) + aprepitant (170729-80-3) → dibenzyl fosaprepitant

Conditions	Yield
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) → fosaprepitant

Conditions	Yield
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 + aprepitant (170729-80-3) → C49H42F7N4O6P

Conditions	Yield
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) + aprepitant (170729-80-3) → C31H30F7N4O6P

Conditions	Yield
With triethylamine In tetrachloromethane; dichloromethane at 0 - 10℃; Reagent/catalyst; Solvent;	81.1%

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

aprepitant (170729-80-3) → 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	Yield
With magnesium; acetic acid In water; dimethyl sulfoxide at 20℃; for 2h; regioselective reaction;	41%

dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate (990-91-0) + aprepitant (170729-80-3) → [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) + C44H41F7N4O9P2

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 0.75h; phosphorylation;	A 39% B 5 % Chromat.

aprepitant (170729-80-3) → 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-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

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

Upstream product

• 24021-90-7 5-hydroxymethyl-2,4-dihydro[1,2,4]triazol-3-one 
• 171338-27-5 [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine 
• 171482-05-6 [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 
• 1765-93-1 4-fluoroboronic acid 
• 1185503-03-0 4-benzyl-3-(4-fluorophenyl)morpholin-2-ol 
• 1185503-15-4 (+/-)-trans-4-benzyl-2-[2-(3,5-bis-trifluoromethylphenyl)ethoxy]-3-(4-fluorophenyl)morphine 
• 1185503-10-9 (2S,3R)-4-benzyl-3-(4-fluorophenyl)morpholin-2-ol 
• 1349902-81-3 C₂₇H₃₁F₇N₄O₄ 
• 472968-70-0 (2R,3R)-2-[(R)-1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluoro-phenyl)-4-((R)-1-phenyl-ethyl)-morpholine 
• 380499-06-9 (2R,3R)-2-[(1R)-1-(3,5-bis-trifluoro-methylphenyl)ethoxy]-3-(4-fluorophenyl)morpholine 
• 380499-07-0 (2R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-5,6-dihydro-2H-1,4-oxazine 
• 472968-69-7 2,2,2-Trichloro-acetimidic acid (2R,3R)-3-(4-fluoro-phenyl)-4-((R)-1-phenyl-ethyl)-morpholin-2-yl ester 
• 472968-68-6 (2S,3R)-3-(4-fluorophenyl)-4-[(1R)-1-phenylethyl]-2-morpholinol 
• 287930-75-0 (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one 

Downstream Products

• 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 

Relevant articles and documents

Preparation method of NK1 receptor antagonist

The invention discloses a preparation method of an NK1 receptor antagonist. According to the invention, chiral resolution adopts a mixed solvent, CaCl2 is added for a reaction in an alkaline environment, CaCl2 does not participate in the reaction but needs to be added in advance for better devitrification, water is added for quenching after the reaction is finished, and CaCl2 is dissolved at the same time, so devitrification efficiency is further improved; and then 5-hydroxymethyl-2,4-dihydro-[1,2,4]triazin-3-one is used as a raw material for synthesis of aprepitant under the catalysis of DBU at room temperature.

Intermediates for preparing aprepitant, and preparation method and application thereof

The invention belongs to the technical field of compounds and synthesis thereof, and provides intermediates for preparing aprepitant, and a preparation method and an application thereof. The inventionprovides the aprepitant preparation intermediate represented by formula I and the aprepitant preparation intermediate represented by formula II. The aprepitant is prepared from the two intermediatesthrough condensation and reduction reactions. Compared with existing methods for preparing aprepitant, the method of the invention has the advantages of avoiding of the disadvantages of complex reaction process, multiple transition states and multiple byproducts in the intermediate preparation process and the disadvantage of complex quality control, simple synthesis process of aprepitant, enhancement of the safety and process controllability of industrial production, high yield, no pollution, easily available raw materials, simplicity in industrial operation, low energy consumption, low cost,safety and environment friendliness, and is suitable for industrial application.

Preparation process of aprepitant

The invention discloses a preparation process of aprepitant. The process comprises the steps as follows: Step 1, a compound A and a compound B are firstly added to a mixed solvent of N,N-dimethylformamide and triethylamine to be stirred and dissolved to obtain a mixed solution; Step2, adding lithium diisopropylamide to the mixed solution in a nitrogen atmosphere and performing uniform mixing; Step3, dropwise adding a diethyl sulfate xylene solution under conditions of nitrogen shielding and stirring; Step 4, after addition, conducting a stirring reaction at 30-35 DEG C for 12-15 h under shielding of nitrogen; Step 5, separating and purifying a reaction product in Step 4 to obtain a final aprepitant product. By process improvement and formula optimization, the aprepitant synthesis processhas the characteristics of mild reaction condition, low cost and the like and is suitable for large-scale industrial production; the synthesized aprepitant product has low impurity content and high purity, and the yield of aprepitant is greatly increased.

Method for preparing intermediate of the Fosaprepitant

The invention discloses a method for preparing an intermediate of the Fosaprepitant, and specifically relates to a new method for preparing a drug 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one, i.e., Aprepitant. The method comprises the steps of: synthesizing a compound (IV) in the presence of a condensation system, and then performing cyclization on the compound (IV) at 139 DEG C or below to obtain the target compound (I). The preparation method is green, environmentally friendly and efficient and has easy industrialization.

Efficient aprepitant preparation process

The invention discloses an efficient aprepitant preparation process. The preparation process comprises the steps that firstly, a 2R-[1R-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy)-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl group-2-aminohydrazonyl)-morpholine is prepared from a (2R,3S)-2-[(1R)-1-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy]-3-(4-fluorophenyl)-morpholine hydrochloride; an aprepitant crude is prepared from the 2R-[1R-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy)-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl group-2-aminohydrazonyl)-morpholine; then the aprepitant crude is refined and an aprepitant finished product is obtained. According to the efficient aprepitant preparation process, the prepared aprepitant has the advantages of high recovery rate, good efficacy, low cost of the whole process, safety and no pollution.

A kind of preparation method of dimethyl luck Sha Pitan cyclophosphadenosine

The invention relates to a method for preparing fosaprepitant. The fosaprepitant is shown as a formula (I). The method comprises steps 1, 2, 3 and 4, finally, a compound shown as the formula (I) is obtained through hydrogenation reduction; in the step 1, a compound in a formula (II) reacts with a Grignard reagent to generate a compound shown as a formula (III) in the presence of palladium carbon and ammonium formate. The method for preparing is simple in production step, has high reaction yield and less side products, is easy in control of the reaction conditions and is suitable for medical industrial production.

PREPARATION METHOD OF 5-[[2(R)-[1(R)-[3,5-BIS(TRIFLUOROMETHYL) PHENYL]ETHOXY]-3(S)-4-FLUOROPHENYL-4-MORPHOLINYL]METHYL]-1,2-DIHYDRO-3H-1,2,4-TRIAZOLE-3-ONE

Disclosed is a synthesis method of a compound of formula 1,5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxyl]-3(S)-4-fluorophenyl-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one (i.e. aprepitant), which comprises cyclizing a compound of formula 4 in a solvent, wherein R is C1-C5 alkyl. The intermediate for preparing aprepitant is also disclosed. The present method is especially suitable for industrial production of aprepitant.

AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT

The present invention provides a process for the preparation of 5-[[(2R,3S)-2-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro- 3H-1,2,4-triazol-3-one (Aprepitant) comprising condensation of 2-(R)-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(S)-(4-fluorophenyl)morpholine hydrochloride salt with 2-(2-chloro-1-iminoethyl)hydrazinecarboxylic acid methyl ester to obtain the reaction mixture containing 2-[2-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4- fluorophenyl)-4-morpholinyl]-1-iminoethyl]hydrazinecarboxylic acid methyl ester, which is in-situ cyclized in the presence of dimethylsulfoxide and a polar protic solvent at a low temperature to yield aprepitant having purity ≥ 99.5%.

A METHOD OF PREPARING 3- ( ( (2R, 3S) -2- ( (R) -1- (3, 5 -BIS (TRIFLUOROMETHYL) PHENYL) ETHOXY) -3 - (4 - FLUOROPHENYL) MORPHOLINO) METHYL) - 1H- 1, 2, 4 -TRIAZOL- 5 (4H) -ONE (APREPITANT) IN POLYMORPH FORM I OR II

The present solution relates to a method of preparing aprepitant of formula (1) in the desired crystalline form II or I, wherein the intermediate of formula (12) is extracted with a water immiscible high-boiling solvent selected from an alcohol, ester or ketone and, after washing with water and/or brine, the solution is heated up to the boiling point of the given solvent, which results in cyclization to aprepitant, and, after cooling, the produced aprepitant is isolated.

Synthesis of all enantiomerically pure diastereomers of aprepitant

Syntheses of all eight enantiomerically pure diastereomers of aprepitant and assignment of absolute configuration at newly generated stereocenters by NMR and X-ray crystallographic analysis were achieved. Copyrigh