834153-87-6

Basic information

• Product Name: elagolix
• Synonyms: elagolix;4-[[(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]butanoic acid;NBI 56418;Butanoic acid, 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-;Cefiderocol;4-({(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phenylethyl}amino)butanoic acid;4-[[(1R)-2-[5-(2-FLUORO-3-METHOXYPHENYL)-3-[[2-FLUORO-6-(TRIFLUOROMETHYL)PHENYL]METHYL]-4-METHYL-2,6-DIOXOPYRIMIDIN-1-YL]-1-PHENYLETHYL]AMINO]BUTANOIC ACID
• CAS NO: 834153-87-6
• Molecular Formula: C₃₂H₃₀F₅N₃O₅
• Molecular Weight: 631.595
• Mol File: 834153-87-6.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 728.6±70.0 °C(Predicted)
• Appearance: /
• Density: 1.350
• PKA: 4.40±0.10(Predicted)
• CAS DataBase Reference: elagolix(CAS DataBase Reference)
• NIST Chemistry Reference: elagolix(834153-87-6)
• EPA Substance Registry System: elagolix(834153-87-6)

Safety Data

• Hazardous Substances Data: 834153-87-6(Hazardous Substances Data)

Usage

Overview

Elagolix (Orilissa) is a gonadotropin-releasing hormone that is indicated for pain associated with endometriosis.Elagolix combined with estradiol/norrthindrome (Oriahnn) is indicated for heavy menstrual bleeding. The medication was under investigation for the treatment of prostate cancer and enlarged prostate in men as well, but development for these conditions was discontinued. Elagolix is taken by mouth once or twice per day.It can be taken for up to 6 to 24 months, depending on the dosage.Side effects of elagolix include menopausal-like symptoms such as hot flashes, night sweats, insomnia, amenorrhea, mood changes, anxiety, and decreased bone density, among others. Elagolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic hormone gonadotropin-releasing hormone (GnRH).[1] By blocking the GnRHR, it dose-dependently suppresses the gonadal production and hence circulating levels of sex hormones such as estradiol, progesterone, and testosterone. Elagolix is a short-acting GnRH antagonist, and can be used to achieve either partial or more substantial suppression of sex hormone levels. Reduced estrogen levels in the endometrium are responsible for the efficacy of elagolix in the treatment of endometriosis.

Pharmacodynamics

Elagolix acts as a potent and selective competitive antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic peptide hormone gonadotropin-releasing hormone (GnRH).As such, it is a GnRH antagonist.The affinity (KD) of elagolix for the GnRHR is 54 pM.By blocking the GnRHR in the pituitary gland, elagolix suppresses the GnRH-induced secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, and thereby decreases the production of sex hormones by the gonads. In women, elagolix dose-dependently suppresses the production of ovarian hormones including estradiol, progesterone, and testosterone, and thereby decreases the circulating levels of these hormones. In men, GnRH modulators suppress the testicular production of testosterone and estradiol, decreasing the circulating levels of these hormones similarly. Unlike previous GnRH agonists and antagonists, referred to collectively as GnRH analogues, elagolix is a non-peptide and small-molecule compound that can be taken orally. Estrogens like estradiol stimulate the growth of the endometrium, and thereby aggravate symptoms of endometriosis.By suppressing estrogen production and levels, elagolix decreases the growth of the endometrium and decreases endometriosis symptoms such as pelvic pain. Elagolix is a short-acting GnRH antagonist, with a terminal half-life of typically about 4 to 6 hours.Because of the short duration of elagolix in the body, the activation of the GnRHR by GnRH is not fully blocked throughout the day with once-daily administration of elagolix. As a result, gonadotropin and sex hormone levels are only partially suppressed when elagolix is taken once per day.In addition, the degree of suppression can be dose-dependently adjusted as needed, for instance with higher-dose twice-daily administration to achieve greater hormonal suppression.Because of its short duration in the body, the effects of elagolix are rapidly reversible upon discontinuation. In addition, due to its partial and incomplete suppression of estradiol levels, the side effects of elagolix, such as hot flashes and decreased BMD, are lower than with first-generation GnRH modulators.

Side effects

The side effects of elagolix are in general similar to menopausal symptoms.The most common side effects of elagolix (incidence ≥10%) are hot flashes, night sweats, headaches, nausea, and amenorrhea (cessation of menstruation). The next most frequent side effects of elagolix (incidence ≥5%) are insomnia, anxiety, arthralgia (joint pain), depression, and mood changes.Less common side effects of elagolix (incidence ≥3% and <5%) include decreased sex drive, diarrhea, abdominal pain, weight gain, dizziness, constipation, and irritability. Other common side effects of elagolix include decreased bone mineral density (BMD) and changes in the blood lipid profile. Rare but serious adverse effects that were observed during elagolix therapy in clinical trials included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%), though it is unknown if these were due to elagolix.Other serious adverse effects of elagolix may include bone loss, miscarriage, suicidality, and elevated liver enzymes.Elagolix was discontinued due to side effects by 5 to 10% of women in clinical trials, with the most common reasons being hot flashes or night sweats, nausea, and decreased BMD. Elagolix dose- and duration-dependently decreases BMD in premenopausal women with long-term therapy. After 6 months of treatment with elagolix, lumbar spine BMD was decreased by 0.3 to 1.3% with 150 mg once per day and by 2.5 to 3.1% with 200 mg twice per day.The decrease in BMD during elagolix therapy may not be fully reversible with discontinuation, as only partial recovery was observed 12 months after discontinuation of therapy. The cause of the decrease in BMD with elagolix is estrogen deficiency, and is analogous to that associated with postmenopause.The consequences of the effects of elagolix on BMD are unknown, but may be an increase in the risk of bone loss and fractures.This is why the duration of use of elagolix should be limited. In women with risk factors for bone loss and osteoporosis, such as a history of low-trauma fracture, assessment of BMD may be considered. Elagolix should not be used in premenopausal women with known osteoporosis.Supplementation with calcium and/or vitamin D during treatment with elagolix has not been studied, but may be beneficial for helping to maintain bone health.

Contraindications

Contraindications of elagolix include pregnancy, known osteoporosis, severe hepatic impairment, and concomitant use with strong organic anion-transporting polypeptide (OATP) 1B1 inhibitors such as ciclosporin and gemfibrozil.Elagolix may increase the risk of miscarriage in early pregnancy.Women should avoid pregnancy while taking elagolix, for instance by using birth control, and should discontinue the medication if they become or wish to become pregnant. Elagolix should not be used in women with osteoporosis because it may increase the risk of further bone loss. Severe hepatic impairment is associated with 7-fold increased exposure to elagolix, which may increase the risk of bone loss. In women with moderate hepatic impairment, which is associated with 3-fold increased exposure to elagolix, the medication at 200 mg twice per day should not be used, while 150 mg once per day should be used for no more than 6 months.OATP1B1 inhibitors are likely to greatly increase exposure to elagolix similarly to moderate to severe hepatic impairment.Combined birth control is not contraindicated with elagolix, but because of the estrogen component, is expected to decrease the effectiveness of elagolix in the treatment of endometriosis, and hence is not recommended.Other forms of birth control, such as non-hormonal birth control, can be used instead. Elagolix is not contraindicated in women who are breastfeeding, but it is unknown whether the medication is excreted in breast milk or if it has adverse effects on milk production or the breastfed child.The use of elagolix in women who are breastfeeding should be considered carefully, weighing both benefits and risks.

Description

Elagolix is a gonadotropin-releasing hormone(GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis. Elagolix is an orally administered,nonpeptide small molecule gonadotropin-releasing hormone(GnRH) receptor antagonist that inhibits endogenousGnRH signaling by binding competitively to GnRH receptors in the pituitary gland.Elagolix results in dose-dependent suppression of luteinizing hormone(LH) and follicle-stimulating hormone(FSH) leading to decreased blood leveis of the ovarian sex hormones, estradiol and progesterone.Elagolix causes a dose-dependent decrease in bone mineral density (BMD).BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment.As milk production is dependent on at least minimal levels of estrogen, this product may reduce milk production.

Uses

Elagolix has a potential role for treating uterine bleeding associated to uterine myomas. Elagolix is also used in the methods for treatment of estrogen-dependent disorders including gonadotropin-releasing hormone (GnRH) antagonists in combination with add-back therapy.

Preparation

Elagolix was a gonadotropin-releasing hormone antagonist. It was approved in 2018 by FDA via priority review for clinical treatment of endometriosis. Based on retrosynthetic analysis, five reported synthesis routes of elagolix were summarized. They were compared and evaluated in terms of step numbers, total yields, costs, synthetic conditions and manufacturing safety. At last, the synthetic method of d6-elagolix was introduced. This review would be beneficial to the future process researches of elagolix and its deuterium analogues.Recent Progress in the Synthesis of ElagolixDiscovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor

Synthetic route

4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidine-1-yl]-1-phenylethylamino)butyric acid ethyl ester (832720-84-0) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Stage #1: ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)butanoate With sodium hydroxide; water In ethanol at 35℃; for 2h; Stage #2: With hydrogenchloride In water at 10 - 22℃; for 17h; pH=6.1;	91%
With water; sodium hydroxide In ethanol at 35℃;	86%
With water; sodium hydroxide In ethanol at 50℃; for 2h;	83.59%

(R)-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2-(2-oxopyrrolidin-1-yl)-2-phenylethyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
With water; sodium hydroxide In ethanol at 55 - 60℃;	89%

ethyl (R)-4-((tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1-(2H)-yl)-1-phenylethyl)amino)butyrate → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
With water; potassium carbonate In tetrahydrofuran at 50℃; for 6h; Solvent; Temperature;	82%

3-[(2R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-pyrimidinedione trifluoroacetate (830346-50-4) + Succinic semialdehyde (692-29-5) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 25℃; for 18h; Reagent/catalyst; Solvent; Temperature;	65%

methyl (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (1092070-97-7) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
With water; lithium hydroxide In methanol at 45℃;

3-[(2R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-pyrimidinedione trifluoroacetate (830346-50-4) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 2: sodium hydroxide; water / ethanol / 35 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 2: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 2: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione (1150560-59-0) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 55 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 3: sodium hydroxide; water / ethanol / 35 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 3: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 3: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-5-iodo-6-methylpyrimidine-2,4(1H,3H)-dione (1150560-54-5) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium hydroxide; tri tert-butylphosphoniumtetrafluoroborate / acetone; water / 0.83 h / 15 - 45 °C 2: potassium carbonate / N,N-dimethyl-formamide / 55 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 4: sodium hydroxide; water / ethanol / 35 °C View Scheme

(2-fluoro-3-methoxyphenyl)boronic acid (352303-67-4) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium hydroxide; tri tert-butylphosphoniumtetrafluoroborate / acetone; water / 0.83 h / 15 - 45 °C 2: potassium carbonate / N,N-dimethyl-formamide / 55 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 4: sodium hydroxide; water / ethanol / 35 °C View Scheme
Multi-step reaction with 7 steps 1.1: methanol; water / 24 h / 70 °C 2.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 2.2: 1 h / 80 °C / Inert atmosphere 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 4.1: toluene / 4 h / Reflux 4.2: 2 h / Reflux 5.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 7.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 7 steps 1.1: methanol; water / 24 h / 70 °C 2.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 2.2: 1 h / 80 °C / Inert atmosphere 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 4.1: toluene / 4 h / Reflux 4.2: 2 h / Reflux 5.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 7.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 7 steps 1.1: methanol; water / 24 h / 70 °C 2.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 2.2: 1 h / 80 °C / Inert atmosphere 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 4.1: toluene / 4 h / Reflux 4.2: 2 h / Reflux 5.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 7.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 7 steps 1.1: methanol; water / 24 h / 70 °C 2.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 2.2: 1 h / 80 °C / Inert atmosphere 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 4.1: toluene / 4 h / Reflux 4.2: 2 h / Reflux 5.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 7.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

(S)-(+)-<2-<(methylsulfonyl)oxy>-1-phenylethyl>carbamic acid 1,1-dimethylethyl ester (110143-62-9) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 55 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 3: sodium hydroxide; water / ethanol / 35 °C View Scheme

(2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid (2900-27-8) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 10 °C 2: potassium carbonate / N,N-dimethyl-formamide / 55 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 52 °C 4: sodium hydroxide; water / ethanol / 35 °C View Scheme

2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid ethyl ester → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene / 105 - 110 °C 1.2: 105 - 110 °C 2.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 90 - 100 °C 3.1: sodium hydroxide; water / ethanol / 55 - 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

5-bromo-6-methyluracil (15018-56-1) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 75 - 85 °C 2: iron(III)-acetylacetonate; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 0 - 45 °C 3: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 90 - 100 °C 4: sodium hydroxide; water / ethanol / 55 - 60 °C View Scheme

1-(bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene (239087-08-2) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 75 - 85 °C 2: iron(III)-acetylacetonate; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 0 - 45 °C 3: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 90 - 100 °C 4: sodium hydroxide; water / ethanol / 55 - 60 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: iron(III)-acetylacetonate; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 0 - 45 °C 2: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 90 - 100 °C 3: sodium hydroxide; water / ethanol / 55 - 60 °C View Scheme

1-bromo-2-fluoro-3-methoxybenzene (295376-21-5) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate; L-proline; copper(l) iodide / dimethyl sulfoxide / 45 - 50 °C / Inert atmosphere 2.1: toluene / 105 - 110 °C 2.2: 105 - 110 °C 3.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 90 - 100 °C 4.1: sodium hydroxide; water / ethanol / 55 - 60 °C View Scheme

2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid tert-butyl ester → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid benzyl ester → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid methyl ester → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

(2-fluoro-6-(trifluoromethyl) phenyl)methanamine (239087-06-0) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 3 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 3 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 3 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

2-fluoro-6-(trifluoromethyl)benzaldehyde (60611-24-7) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydroxylamine hydrochloride; sodium hydroxide / water; ethanol / 1 h 1.2: 2 h 2.1: hydrogenchloride / water / 3 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydroxylamine hydrochloride; sodium hydroxide / water; ethanol / 1 h 1.2: 2 h 2.1: hydrogenchloride / water / 3 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydroxylamine hydrochloride; sodium hydroxide / water; ethanol / 1 h 1.2: 2 h 2.1: hydrogenchloride / water / 3 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}urea (830346-46-8) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 1.2: 2 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 4.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

potassium 2-fluoro-3-methoxy-phenyl-1-trifluoroborate → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 1.2: 1 h / 80 °C / Inert atmosphere 2.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 1.2: 1 h / 80 °C / Inert atmosphere 2.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 1.2: 1 h / 80 °C / Inert atmosphere 2.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: tetra(n-butyl)ammonium hydroxide / water / 0.03 h / Inert atmosphere 1.2: 1 h / 80 °C / Inert atmosphere 2.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

5-(2-fluoro-3-methoxyphenyl)-2,2,6-trimethyl-4H-1,3-dioxin-4-one → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: 5,5-dimethyl-1,3-cyclohexadiene / 6 h / Reflux 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

2-fluoro-1-iodo-3-methoxybenzene (1080673-30-8) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 2.1: toluene / 4 h / Reflux 2.2: 2 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

1-fluoro-2-methoxybenzene (321-28-8) → 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h / -78 °C 2.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h / -78 °C 2.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h / -78 °C 2.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h / -78 °C 2.1: copper(l) iodide; 4R-4-hydroxyproline; caesium carbonate / dimethyl sulfoxide / 96 h / 60 °C / Heating 3.1: toluene / 4 h / Reflux 3.2: 2 h / Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 7 h / 100 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 60 °C 6.1: sodium hydroxide; water / ethanol / 2 h / 50 °C View Scheme

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → elagolix phosphoric acid salt

Conditions	Yield
With phosphoric acid In ethyl acetate at 0 - 10℃;	93.6%
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 60 °C 2: phosphoric acid / water / 25 °C View Scheme

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → (R)-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2-(2-oxopyrrolidin-1-yl)-2-phenylethyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione

Conditions	Yield
With dmap; di-tert-butyl dicarbonate In acetonitrile	92%
Stage #1: 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid With triethylamine In dichloromethane at 20℃; for 1h; Stage #2: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 24h;	64.8%
In butanone at 25℃; for 168h;	93.03 %Chromat.
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 60 °C 2: butanone / 168 h / 25 °C View Scheme

formaldehyd (50-00-0) + 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethyl-N-methylamino}butyric acid

Conditions	Yield
With borane pyridine complex In methanol at 20℃;
With borane pyridine In methanol

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate

Conditions	Yield
With Dowex MSC-1	1.58 g

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → sodium 3-[2(R)-{hydroxycarbonylpropylamino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-((2H3)-methyl)-3H-pyrimidine-2,4-dione

Conditions	Yield
With water-d2; sodium carbonate for 15h; Reflux;

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → 3-[2(R)-{hydroxycarbonylpropylamino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-((2H3)-methyl)-3H-pyrimidine-2,4-dione

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate; water-d2 / 15 h / Reflux 2: sodium carbonate; water-d2 / 15 h / Reflux View Scheme

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → elagolix hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 60 °C 2: hydrogenchloride / water / 25 °C View Scheme

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → elagolix hydrobromide

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 60 °C 2: hydrogen bromide / water / 25 °C View Scheme

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → elagolix nitrate

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 60 °C 2: nitric acid / water / 25 °C View Scheme

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → elagolix, sulfuric acid salt

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 60 °C 2: sulfuric acid / water / 25 °C View Scheme
With sulfuric acid In acetonitrile at 27℃; Solvent; Temperature;

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → C32H29F5N3O5(1-)*K(1+)

Conditions	Yield
With potassium hydroxide In water at 60℃; for 1h;	3.7 g

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) → 2C32H29F5N3O5(1-)*Ca(2+)

Conditions	Yield
With calcium acetate In water at 60℃; for 1h;	3.5 g

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) + Pamoic acid (130-85-8) → elagolix pamoic acid salt (1:1)

Conditions	Yield
In methanol at 25 - 60℃; for 19h;	1.5 g

4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid (834153-87-6) + benzenesulfonic acid (98-11-3) → elagolix benzenesulfonic acid salt

Conditions	Yield
In methanol at 20 - 60℃; for 26h;	1.1 g

Upstream product

• 830346-50-4 3-[(2R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-pyrimidinedione trifluoroacetate 
• 692-29-5 Succinic semialdehyde 
• 321-28-8 1-fluoro-2-methoxybenzene 
• 1080673-30-8 2-fluoro-1-iodo-3-methoxybenzene 
• 830346-46-8 N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}urea 
• 60611-24-7 2-fluoro-6-(trifluoromethyl)benzaldehyde 
• 239087-06-0 (2-fluoro-6-(trifluoromethyl) phenyl)methanamine 
• 295376-21-5 2-fluoro-3-methoxy-1-bromobenzene 
• 830346-48-0 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione 
• 239087-08-2 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene 
• 15018-56-1 5-bromo-6-methyluracil 
• 2900-27-8 (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid 
• 110143-62-9 (S)-(+)-<2-<(methylsulfonyl)oxy>-1-phenylethyl>carbamic acid 1,1-dimethylethyl ester 
• 352303-67-4 (2-fluoro-3-methoxyphenyl)boronic acid 

Relevant articles and documents

Preparation method of Elagolix

The invention discloses a preparation method of Elagolix. The method is characterized in that (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-diketone as shown in the formula II and 4-oxobutyric acid as shown in the formula V are subjected to a reductive amination reaction, and Elagolix as shown in the formula I is obtained; the formulas are defined in the description. The method has the advantages that a target product can be obtained through a one-step reaction, the synthetic route is greatly shortened, and the preparation process is simplified; the route has fewer side reactions, introduction of impurities is reduced, subsequent passivating treatment can be easy and convenient, and the purity of the target product is effectively improved.

Method for preparing agomelatine intermediate (by machine translation)

The invention relates to a method for preparing an intermediate of agomelatine. The method is simple and convenient to E8 operate, mild E8 in condition and very suitable for industrial production C. (by machine translation)

Elagolix synthesis method

The invention provides an elagolix synthesis method. The elagolix synthesis method comprises enabling a compound 5 and a compound 10 to participate in a condensation reaction to finish N-alkylation reaction to obtain a compound 11, and then implementing alkaline hydrolysis to obtain elagolix 12. The invention further discloses two synthesis methods of the compound 5: the method I comprises enabling a 5-bromine-6-methylpyrimidine-2,4(1H,3H)-diketone compound 1 and a 2-(brooethyl)-1-fluorin-3-(trifluoromethyl) benzene compound 2 to have a condensation reaction to obtain an intermediate 3, and then having a coupling reaction; the method II comprises enabling 1-halide-3-fluorin-2-anisole and acetoacetate 7 to have a coupling reaction to obtain a compound 8, and then having a condensation cyclization reaction with a compound 9; the improvements greatly shorten the route steps, the route efficiency is improved, the use of a noble metal catalyst is avoided, and the process cost is greatly lowered. The operation of the route is simple, the total yield is high, the purity of an obtained product is also relatively high, and the method is suitable for the enlarged production.