172015-79-1

Usage

Chemical Properties

Off-White to Tan Solid

InChI:InChI=1/C11H12ClN5O.ClH/c12-9-8-10(16-11(13)15-9)17(5-14-8)7-2-1-6(3-7)4-18;/h1-2,5-7,18H,3-4H2,(H2,13,15,16);1H/t6-,7+;/m1./s1

Synthetic route

(1R,4S)-1-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-4-(hydroxymethyl)-2-cyclopentene (171887-04-0) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
With hydrogenchloride; orthoformic acid triethyl ester In water for 4h; Cyclization;	92%
With hydrogenchloride; orthoformic acid triethyl ester In water at 0 - 10℃; for 1h; Concentration; Temperature;	76%
With hydrogenchloride; orthoformic acid triethyl ester In ethanol at 0 - 10℃; for 10h;	72.2%

orthoformic acid triethyl ester (122-51-0) + (1R,4S)-1-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-4-(hydroxymethyl)-2-cyclopentene (171887-04-0) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; industrial methylated spirit; water at 0 - 25℃; Product distribution / selectivity;	82%
With hydrogenchloride In industrial methylated spirit; water at 0 - 25℃; Product distribution / selectivity;	81%

(-)-2-azabicyclo[2.2.1]hept-5-en-3-one (79200-56-9) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.264 g / tetrahydrofuran; H2O / 18 h / 20 - 60 °C 2: 90.5 percent / LiAlH4 / tetrahydrofuran / 19.5 h / 0 °C / Heating 3: 83 percent / Et3N / ethanol / 7 h / Heating 4: 92 percent / triethylorthoformate; HCl / H2O / 4 h View Scheme

(1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene (136522-35-5) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / Et3N / ethanol / 7 h / Heating 2: 92 percent / triethylorthoformate; HCl / H2O / 4 h View Scheme

N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (171887-03-9) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / Et3N / ethanol / 7 h / Heating 2: 92 percent / triethylorthoformate; HCl / H2O / 4 h View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / ethanol / 0.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 75 - 80 °C / Inert atmosphere 2.1: orthoformic acid triethyl ester; hydrogenchloride / ethanol / 10 h / 0 - 10 °C View Scheme

2-amino-5-{[(dimethylamino)methylene]amino}-4,6-dichloropyrimidine (171887-02-8) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 72 percent / aq. phosphate buffer / 4 h / pH 3.2 / Heating 2: 83 percent / Et3N / ethanol / 7 h / Heating 3: 92 percent / triethylorthoformate; HCl / H2O / 4 h View Scheme

(-)-(1S, 4R)-4-amino-2-cyclopentene-1-carboxylic acid methanesulfonate → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 90.5 percent / LiAlH4 / tetrahydrofuran / 19.5 h / 0 °C / Heating 2: 83 percent / Et3N / ethanol / 7 h / Heating 3: 92 percent / triethylorthoformate; HCl / H2O / 4 h View Scheme

(1S,4R)-4-amino-2-cyclopentene-1-methanol tartrate salt + 4,6-dichloro-2,5-diformamido-pyrimidine (116477-30-6) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1)

Conditions	Yield
Stage #1: (1S,4R)-4-amino-2-cyclopentene-1-methanol tartrate salt With sodium carbonate In ethanol for 0.5h; Stage #2: 4,6-dichloro-2,5-diformamido-pyrimidine In ethanol for 3h; Heating / reflux; Stage #3: With hydrogenchloride; orthoformic acid triethyl ester more than 3 stages;

Cyclopropylamine (765-30-0) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → abacavir (136470-78-5)

Conditions	Yield
In methanol at 70℃; for 12h; Substitution;	90%
Stage #1: (1S,cis)-4-(2-amino-6-chloro-9-H-purin-9-yl)-2-cyclopentene-1-methanol hydrochloride With triethylamine In water Stage #2: Cyclopropylamine In water at 70 - 75℃; Concentration; Solvent; Temperature;	90%
In isopropyl alcohol at 90 - 95℃; for 12h; sealed reactor;
In ethanol at 25 - 78℃; for 6h;
With sodium carbonate In ethanol at 70 - 80℃;	25 g

pyrographite (7440-44-0) + Cyclopropylamine (765-30-0) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → abacavir (136470-78-5)

Conditions	Yield
With sodium hydroxide In acetone	90%

(1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-((1R,4S)-4-(hydroxymethyl)cyclopentyl-2-enylamino)-9H-purin-9-yl)cyclopent-2-enyl) methanol

Conditions	Yield
With sodium carbonate In ethanol at 75 - 80℃; for 6h; Solvent; Reagent/catalyst; Inert atmosphere;	87.1%

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1R,cis)-3-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-1-cyclopentane-1-methanol

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / methanol / 12 h / 70 °C 2: 98 percent / H2 / Pd-C / ethanol / 1.5 h / 2585.74 Torr View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1S,4R)-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol (136522-33-3)

Conditions	Yield
With ammonia In water at 10 - 15℃; for 1h; pH=7 - 7.5;

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrobromide (1280727-16-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 6 h / 25 - 78 °C 2: hydrogen bromide / ethanol; water / 0.75 h / 25 - 30 °C View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol malonate (1280629-49-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 6 h / 25 - 78 °C 2: ethanol / 0.75 h / 25 - 70 °C View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol maleate (1280629-56-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 6 h / 25 - 78 °C 2: ethanol / 0.25 h / 25 - 30 °C View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol monooxalate (1280629-52-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 6 h / 25 - 78 °C 2: ethanol; water / 2.25 h / 0 - 75 °C View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol dihydrobromide

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 6 h / 25 - 78 °C 2: hydrogen bromide / ethanol; water / 0.75 h / 25 - 30 °C View Scheme

Reaxys ID: 32100528 + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → Reaxys ID: 32100526

di-tert-butyl diisopropylphosphoramide (137348-86-8) + 3-chloro-benzenecarboperoxoic acid (937-14-4) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methyl di-tert-butyl phosphate

Conditions	Yield
Stage #1: di-tert-butyl diisopropylphosphoramide; ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride With 1H-tetrazole In dichloromethane at 20℃; for 1h; Stage #2: 3-chloro-benzenecarboperoxoic acid In dichloromethane at -40 - -10℃; for 2.33333h;	161 mg

2-methoxyethylamine (109-85-3) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-((2-methoxyethyl)amino)-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol

Conditions	Yield
In tetrahydrofuran; ethanol at 120℃; for 0.75h; Microwave irradiation;	81 mg

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → carbovir (120443-30-3)

Conditions	Yield
With sodium hydroxide In water at 130℃; for 1h; Microwave irradiation;	55 mg

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → 2-(((1S,4R)-4-(2-amino-6-methoxy-9H-purin-9-yl)cyclopent-2-en-1-yl)methoxy)-4H-benzo[d][1,3,2]dioxaphosphinine 2-oxide

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / 6 h / 20 °C 2: 1-methyl-1H-imidazole / acetonitrile / 0.5 h / 20 °C / Inert atmosphere View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methyl dihydrogen phosphate hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1H-tetrazole / dichloromethane / 1 h / 20 °C 1.2: 2.33 h / -40 - -10 °C 2.1: hydrogenchloride / ethyl acetate / 3 h / 20 °C View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-methoxy-9H-purin-9-yl)cyclopent-2-en-1-yl)methyl dihydrogen phosphate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1H-tetrazole / dichloromethane / 1 h / 20 °C 1.2: 2.33 h / -40 - -10 °C 2.1: hydrogenchloride / ethyl acetate / 3 h / 20 °C 3.1: methanol / 2.5 h / 50 - 60 °C / Microwave irradiation View Scheme

((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-mercapto-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol

Conditions	Yield
With sodium hydrogensulfide In ethanol; water at 20℃; for 18h;	11 mg

methyl ((4-bromophenoxy)(4-nitrophenoxy)phosphoryl)-L-alaninate + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → methyl ((((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methoxy)(4-bromophenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; Inert atmosphere;	7.16 mg

sodium methylate (124-41-4) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-methoxy-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol (190951-74-7)

Conditions	Yield
With methanol at 20℃; for 6h;	0.47 g

dimethyl amine (124-40-3) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → ((1S,4R)-4-(2-amino-6-(dimethylamino)-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol

Conditions	Yield
In ethanol; water at 20℃; for 1h;	20 mg

methylamine (74-89-5) + ((1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol hydrochloride (172015-79-1) → (+/-)-cis-4-(2-Amino-6-methylamino-9H-purin-9-yl)-2-cyclopentene-1-methanol

Conditions	Yield
In tetrahydrofuran; ethanol at 120℃; for 1h; Microwave irradiation;	13 mg

Upstream product

• 116477-30-6 4,6-dichloro-2,5-diformamido-pyrimidine 
• 122-51-0 orthoformic acid triethyl ester 
• 171887-04-0 (1R,4S)-1-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-4-(hydroxymethyl)-2-cyclopentene 
• 171887-02-8 2-amino-5-{[(dimethylamino)methylene]amino}-4,6-dichloropyrimidine 
• 171887-03-9 N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide 
• 136522-35-5 (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene 
• 79200-56-9 (-)-2-azabicyclo[2.2.1]hept-5-en-3-one 

Downstream Products

• 136470-78-5 abacavir 
• 124752-25-6 (1α,4α)-4-(2,6-Diamino-9H-purin-9-yl)-2-cyclopentenyl-carbinol 
• 136522-33-3 (1S,4R)-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol 

Relevant academic research and scientific papers

Abacavir intermediate and method for purifying same

The invention discloses an abacavir intermediate and a method for purifying the same. The method includes heating mixtures with abacavir intermediate crude products, purified water and water-soluble organic solvents until the abacavir intermediate crude products are completely dissolved so as to obtain mixed liquid; carrying out cooling and crystallization treatment on the mixed liquid; carrying out filtering and drying treatment after crystallization treatment is carried out so as to obtain abacavir intermediate pure products. A structural formula of the abacavir intermediate is shown as a formula IV. The abacavir intermediate and the method have the advantage that the method is easy and convenient to implement and is suitable for industrial production.

PROCESS FOR THE PREPARATION OF AMINO ALCOHOL DERIVATIVES OR SALTS THEREOF

The present invention relates to a process for the preparation of amino alcohol derivatives or salts thereof. In particular the present invention relates to process for the preparation of amino alcohol derivatives or salts thereof which may be used as intermediates in the preparation of HIV reverse transcriptase inhibitors, more preferably Carbovir and Abacavir. The present invention more specifically relates to a process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula IIIa. The present invention also specifically relates to process for the preparation of Abacavir sulfate of Formula II using compound of Formula IIIa prepared according to the process of the present invention.

Process for the preparation of abacavir

A process for the preparation of Abacavir of formula 1 and its sulfate salt comprising the reaction of a compound of formula 6 with cyclopropyl amine.

Process for the synthesis of chloropurine intermediates

The present invention relates to a process for the preparation of a carbocyclic purine nucleoside analogue of formula (I), its salts and pharmaceutically acceptable derivatives thereof which comprises hydrolysing a compound of formula (IV) wherein P is a protecting group, in the presence of an acid, condensing the product of formula (V) formed in situ in the presence of a base with a compound of formula (VI) followed by in situ ring closure of the resulting intermediate.

An efficient, scalable synthesis of the HIV reverse transcriptase inhibitor Ziagen (1592U89)

Ziagen, (1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol, was synthesized from (1S,4R)-azabicyclo[2.2.1]hept- 5-en-3-one by efficient processes which bypass problematic steps in earlier routes. 2-Amino-4,6-dichloro-5-formamidopyrimidine is a key intermediate which makes possible an efficient construction of the purine from a chiral cyclopentenyl precursor.