122111-03-9

Basic information

• Product Name: Gemcitabine hydrochloride
• Synonyms: 2’,2’-difluorodeoxycytidinemonohydrochloride;2’-deoxy-2’,2’-difluorocytidinemonohydrochloride;2’-deoxy-2’,2’-difluoro-cytidinmonohydrochloride;gemzar;ly188011;ly188011hydrochloride;2',2'-DIFLUORO-2'-DEOXYCYTIDINE;2'-DEOXY-2',2'-DIFLUOROCYTIDINE
• CAS NO: 122111-03-9
• Molecular Formula: C₉H₁₁F₂N₃O₄*ClH
• Molecular Weight: 299.66
• EINECS: 1308068-626-2
• Product Categories: Active Pharmaceutical Ingredients;API;Antineoplastic;Bases & Related Reagents;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Antineoplastic drug, difluorine nucleoside analog;Anti-cancer&immunity;Inhibitors
• Mol File: 122111-03-9.mol

Chemical Properties

• Melting Point: >250°C dec.
• Boiling Point: 482.7 °C at 760 mmHg
• Flash Point: 245.7 °C
• Appearance: White crystalline granular, odorless
• Density: ==
• Vapor Pressure: 2.41E-11mmHg at 25°C
• Storage Temp.: Desiccate at +4°C
• Solubility: H2O: ≥10mg/mL
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20° for up to 1 month.
• Merck: 14,4386
• CAS DataBase Reference: Gemcitabine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Gemcitabine hydrochloride(122111-03-9)
• EPA Substance Registry System: Gemcitabine hydrochloride(122111-03-9)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 21-36/38-46-62-63
• Safety Statements: 25-26-36/37-53
• WGK Germany: 3
• RTECS: HA3840000
• Hazardous Substances Data: 122111-03-9(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Gemcitabine hydrochloride is used as an antineoplastic agent for the treatment of various carcinomas, including non-small cell lung cancer, pancreatic cancer, bladder cancer, and breast cancer. It is a pro-drug that is phosphorylated intracellularly by deoxycytidine kinase to its active forms, the diand triphosphates, which bind to DNA competitively. This insertion inhibits processes required for DNA synthesis and metabolism, essential functions for both cell replication and repair. Gemcitabine also displays self-potentiating mechanisms that increase the concentration and prolong the retention of its active nucleotides in tumor cells.
Used in Combination Therapy:
Gemcitabine hydrochloride is used in combination with other anticancer agents, such as cisplatin and carboplatin, to enhance the therapeutic effects and synergistic activity against various solid tumors. The combination of gemcitabine with cisplatin has shown an increased efficiency for NSCLC treatment, while the combination with carboplatin has demonstrated mutual coordination and additive effects, leading to higher curative outcomes. This approach is particularly beneficial for patients with advanced NSCLC, as carboplatin has lower toxicity, especially in terms of gastrointestinal reactions, bone marrow suppression, and toxic reactions of the kidney and nerve endings.
Used in Pharmaceutical Industry:
Gemcitabine hydrochloride is used as an active pharmaceutical ingredient in the development of antineoplastic drugs. Its unique properties and synergistic effects with other chemotherapeutic agents make it a valuable component in the formulation of cancer treatments. The main manufacturers of gemcitabine hydrochloride include Jiangsu Stockhausen Pharmaceutical Co., Ltd., and Harbin, Yu Heng Pharmaceutical Company, which supply the drug to the pharmaceutical industry for the production of life-saving medications.

Content Determination

According to the efficient chromatography (Chinese Pharmacopoeia Edition 2000 Part two Appendix VD) determination. Chromatography conditions and system suitability test Use octadecylsilane bonded silica as a filler and ammonium acetate buffer (ammonium acetate 3.85g, add water 800ml to dissolve and glacial acetic acid to adjust the pH to 5.7, adding water to 1000ml)-methanol (90:10) as mobile phase, detecting the wavelength of 268nm. The theoretical plate number calculated according to the peak of gemcitabine hydrochloride should not be less than 2000 and the resolution between the peaks of gemcitabine hydrochloride and cytosine should be greater than 2.0. Measurements Take this product about 25mg, weigh it accurately, and put it into a 25ml volumetric flask, dissolved in water and diluted to the scale. Precisely measure this solution 5ml and put the solution into 50ml volumetric flask, diluted with water to the mark. Shake well and use this solution as the test solution. Precisely measure 20μl injection fluid into chromatography and record the chromatograms; Take another appropriate amount of gemcitabine hydrochloride and dry it to constant weight under the temperature of 105℃, using the processed product as the reference. Operate the reference with the same method mentioned above, and calculate it by peak area on the basis of the external standard method. The above information is edited by the lookchem of Bai Linlin.

Distinguish

1.Take appropriate amount of gemcitabine hydrochloride, make into solution containing the 10μg per ml by adding water and measure it according to the spectrophotometric method (Chinese Pharmacopoeia Edition 2000 Part 2 Appendix Ⅳ A). It has the maximum absorption at the wavelength of 269nm, and the minimum absorption at the wavelength of 249nm. 2.In the chromatogram recorded in content determination, the retention time of the major peak in the test solution should correspond to that in the reference solution. 3.The infrared absorption spectrum should be consistent with the reference standard spectrum. 4.Identification reaction that aqueous solution is chloride. (Chinese Pharmacopoeia Edition 2000 Part two Appendix III)

Adverse reactions and side effects

The effect of bone marrow suppression. Symptoms such as anemia, leucopenia and thrombocytopenia will appear. Approximately 66% of patients have liver aminotransferase abnormalities, which mostly are mild, non-progressive damage. About 33% of patients experience nausea and vomiting. About 50% of patients have the symptoms of mild proteinuria and hematuria. There are some cases of unexplained renal failure. About 25% of patients have skin rash, 10% patients with itching. Less than 1% of patients experience bronchial spasms. Gemcitabine hydrochloride has significant cytotoxic activity on cultured human and mouse tumors, whose antitumor activity is associated with the administration. For example, daily dosing can lead to death of the animal, but the anti-cancer activity is very small; and when giving the drug every 3-4 days at a time, drug dose is non-lethal dose and has good anti-tumor activities on many tumors.

Originator

Lilly (U.S.A.)

Biological Activity

Deoxycytidine analog that inhibits DNA synthesis. Metabolized to form gemcitabine triphosphate (dFdCTP) and gemcitabine diphosphate (dFdCDP). dFdCTD inhibits ribonucleotide reductase causing a reduction in cellular nucleotides. dFdCTP is incorporated in DNA resulting in DNA strand termination. Displays antitumor activity in vitro and in vivo .

Biochem/physiol Actions

Gemcitabine is a widely used antitumor agents in both clinics and research labs. It is an antineoplastic agent and antimetabolite.

Veterinary Drugs and Treatments

Very limited clinical use and research performed with this drug to date have demonstrated limited clinical efficacy. However, it potentially may be useful as a radiosensitizer for non-resectable tumors, as part of combination protocols, or as a single agent for tumors not amenable to more accepted therapies. Follow research reports for the most up-to-date information. In humans, gemcitabine has shown some efficacy in treating pancreatic carcinoma, small-cell lung carcinoma, lymphoma, bladder and other soft tissue carcinomas.

References

1) Mini et al. (2006), Cellular Pharmacology of Gemcitabine; Ann. Oncol. 17 v7 2) Heinemann et al. (1995), Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism; Semin. Oncol. 22 11 3) Heinemann et al. (1992), Cellular elimination of 2′,2′-difluorodeoxycytidine 5’triphosphate: a mechanism of self-potentiation; Cancer Res. 52 533 4) Pourquier et al. (2002), Gemcitabine (2′,2′-difluoro-2′-deoxycytidine), an antimetabolite that poisons topoisomerase I; Clin.Cancer Res. 8 2499

InChI:InChI=1/C9H11F2N3O4.ClH/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17;/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17);1H

Synthetic route

gemcitabine (95058-81-4) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 20 - 70℃;	93.4%
With hydrogenchloride In water; acetone at 20℃; for 2h; Product distribution / selectivity;	91.5%
With hydrogenchloride In isopropyl alcohol at 0 - 5℃; for 2h; pH=2;	90%

β-2'-deoxy-2',2'-difluorocytidine hemihydrate → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In water; acetone at 20℃; for 2h; Product distribution / selectivity;	91.9%
With hydrogenchloride In water; acetone at 20℃; for 2h; Product distribution / selectivity;	91.9%

β-2'-deoxy-2',2'-difluorocytidine dihydrate → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In water; acetone at 20℃; for 2h; Product distribution / selectivity;	91.5%
With hydrogenchloride In water; acetone at 20℃; for 2h; Product distribution / selectivity;	91.5%

(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate (1445381-44-1) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate With ammonia In methanol at 20℃; for 6h; Inert atmosphere; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; pH=2; Heating;	90%
With sodium methylate In methanol at 20℃; for 4h; Reagent/catalyst;	90%
Stage #1: (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate With ammonium hydroxide In methanol at 20℃; for 16h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃;	78%

C18H33F2N3O4Si2 → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In ethanol; water; acetone at 0 - 5℃; Green chemistry; Industrial scale;	88%

3′,5′-O-bis(tert-butoxycarbonyl)-gemcitabine (250698-52-3) → gemcitabine hydrochloride (122111-03-9) + 5'-O-(tert-butoxycarbonyl)gemcitabine

Conditions	Yield
With sodium carbonate In methanol at 24℃; for 4h; Hydrolysis;	A 10% B 85%

3',5'-di-O-benzoyl-β-2'-deoxy-2',2'-difluorocytidine → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: 3',5'-di-O-benzoyl-β-2'-deoxy-2',2'-difluorocytidine With ammonium hydroxide; water In methanol for 6h; Reflux; Stage #2: With hydrogenchloride In methanol; water at 20℃; for 12h; pH=3;	85%

N-1-acetyl-2-deoxy-2,2-difluorocytidine 3,5-dicinnamonate → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: N-1-acetyl-2-deoxy-2,2-difluorocytidine 3,5-dicinnamonate With ammonia In methanol Stage #2: With hydrogenchloride In water	80%

C30H21Cl2F2N3O7 → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: C30H21Cl2F2N3O7 With ammonium hydroxide In methanol at 20℃; for 16h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃;	79%

(2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxyoxolan-3-yl benzoate (1173824-58-2) + 4-(N-trimethylsilylacetamido)-2-trimethylsiloxypyrimidine (18027-23-1) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: (2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxyoxolan-3-yl benzoate With triethylamine In tetrahydrofuran at 0 - 5℃; Stage #2: 4-(N-trimethylsilylacetamido)-2-trimethylsiloxypyrimidine With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0 - 5℃; Stage #3: In methanol at 40℃;	50.5%

α/β-1-(2-oxo-4-amino-1H-pyrimidin-1-yl)-2-desoxy-2,2'-difluororibose hydrochloride (951314-37-7) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
In water; isopropyl alcohol at 25℃; for 2h; Purification / work up; Resolution of anomeric mixture;

2’-deoxy-2’,2’-difluoro-cytidine (103882-84-4) → 2'-deoxy-2',2'-difluorocytidine hydrochloride (122111-05-1) + gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at -4 - 60℃; for 6.5h;

C26H24F2N4O8 → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: C26H24F2N4O8 With ammonia; water In methanol at 20℃; for 24h; Stage #2: With hydrogenchloride In water at 0 - 5℃; for 4h; Product distribution / selectivity;	n/a

C26H24F2N4O8 → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: C26H24F2N4O8 With ammonia; water In methanol at 20℃; for 24h; Stage #2: With hydrogenchloride In water at 0 - 5℃; for 4h; Product distribution / selectivity;	n/a

2’-deoxy-2’,2’-difluoro-cytidine (103882-84-4) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; water at 10 - 68℃; for 1.5h; Product distribution / selectivity;
With hydrogenchloride In 1,2-dimethoxyethane; water at 10 - 68℃; for 1.5h; Product distribution / selectivity;

3',5'-dicinnamoyl-2'-deoxy-2',2'-difluorocytidine → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Stage #1: 3',5'-dicinnamoyl-2'-deoxy-2',2'-difluorocytidine With methanol; ammonia at 20℃; for 4 - 6h; Stage #2: With hydrogenchloride In dichloromethane; water Product distribution / selectivity;

4-N-Acetylcytosine (14631-20-0) + 3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-1-O-methanesulfonyl-D-erythro-pentofuranose (134877-42-2, 134877-43-3, 122111-11-9) → 2'-deoxy-2',2'-difluorocytidine hydrochloride (122111-05-1) + gemcitabine hydrochloride (122111-03-9)

Conditions

Yield

Stage #1: 4-N-Acetylcytosine With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In 1,2-dichloro-ethane for 3h; Heating / reflux; Stage #2: 3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-1-O-methanesulfonyl-D-erythro-pentofuranose With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20 - 75℃; for 14 - 16h; Heating / reflux; Stage #3: With hydrogenchloride In water; 1,2-dichloro-ethane

gemcitabine → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
With hydrogenchloride In methanol; water; ethyl acetate at 20℃; Product distribution / selectivity;

C23H19F2N3O8*ClH → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / methanol / 3 h / 20 °C / pH Ca. 7 / Reflux 2.1: ammonium hydroxide; water / methanol / 6 h / Reflux 2.2: 12 h / 20 °C / pH 3 View Scheme

C26H27F2N3O8Si → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene; water / 3 h / 20 - 70 °C 2.1: triethylamine / methanol / 3 h / 20 °C / pH Ca. 7 / Reflux 3.1: ammonium hydroxide; water / methanol / 6 h / Reflux 3.2: 12 h / 20 °C / pH 3 View Scheme

(2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxyoxolan-3-yl benzoate (1173824-58-2) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 5 - 20 °C 2: 3 h / 120 °C / Heating 3: sodium t-butanolate / methanol / 2 h / 20 °C 4: hydrogenchloride / isopropyl alcohol; water / 20 - 70 °C View Scheme

2-deoxy-2,2-difluoro-D-erythro-pentofuranose-3,5-diphenylmethyl ester-1-methanesulfonate (134877-42-2) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 3 h / 120 °C / Heating 2: sodium t-butanolate / methanol / 2 h / 20 °C 3: hydrogenchloride / isopropyl alcohol; water / 20 - 70 °C View Scheme

3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-1-O-methanesulfonyl-D-erythro-pentofuranose (134877-42-2, 134877-43-3, 122111-11-9) → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: ethanol / 50 - 60 °C 2: 3 h / 120 °C / Heating 3: sodium t-butanolate / methanol / 2 h / 20 °C 4: hydrogenchloride / isopropyl alcohol; water / 20 - 70 °C View Scheme

(erytro) ethyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-difluoro-3-hydroxy propionate (95058-92-7) → gemcitabine hydrochloride (122111-03-9)

Conditions

Yield

Multi-step reaction with 4 steps 1: 1H-imidazole / tetrahydrofuran / 4 h / 0 - 20 °C / Inert atmosphere; Industrial scale 2: diisobutylaluminium hydride / toluene; methanol / -50 - -20 °C / Inert atmosphere; Industrial scale 3: binaphthol phosphonate / N,N-dimethyl-formamide / 10 h / 20 °C / Industrial scale 4: hydrogenchloride / water; acetone; ethanol / 0 - 5 °C / Green chemistry; Industrial scale View Scheme

C16H30F2O5Si → gemcitabine hydrochloride (122111-03-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: diisobutylaluminium hydride / toluene; methanol / -50 - -20 °C / Inert atmosphere; Industrial scale 2: binaphthol phosphonate / N,N-dimethyl-formamide / 10 h / 20 °C / Industrial scale 3: hydrogenchloride / water; acetone; ethanol / 0 - 5 °C / Green chemistry; Industrial scale View Scheme

gemcitabine hydrochloride (122111-03-9) + Allyl chloroformate (2937-50-0) → 4-allyloxycarbonylamino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one (688008-78-8)

Conditions	Yield
Stage #1: gemcitabine hydrochloride With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In 1,4-dioxane for 2h; Heating; Stage #2: Allyl chloroformate With 1-methyl-1H-imidazole In dichloromethane at 20℃; for 4h; Stage #3: With triethylamine In methanol at 20℃; Further stages.;	99%
Stage #1: gemcitabine hydrochloride With pyridine; chloro-trimethyl-silane at 0℃; for 2h; Stage #2: Allyl chloroformate at 0 - 45℃;	70%

tert-butyldimethylsilyl chloride (18162-48-6) + gemcitabine hydrochloride (122111-03-9) → 4-amino-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (688009-09-8)

Conditions	Yield
at 20℃;	98.5%
With 1H-imidazole; triethylamine In N,N-dimethyl-formamide at 25℃; for 24h;	95%
With 1H-imidazole; triethylamine at 20℃; for 24h; Inert atmosphere;	91%
With 1-methyl-1H-imidazole; iodine In tetrahydrofuran; pyridine at 20℃;	64%
With 1H-imidazole In dichloromethane at 20℃;

tert-butyldimethylsilyl chloride (18162-48-6) + gemcitabine hydrochloride (122111-03-9) → 4-amino-1-((2R,4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-4-hydroxytetrahydrofuran-2-yl)pyrimidin-2(1H)-one (1151528-36-7)

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 25℃; for 15h;	98%
With 1H-imidazole In N,N-dimethyl-formamide at 20 - 25℃; for 2h;	93%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 12h;	92%

gemcitabine hydrochloride (122111-03-9) + p-toluenesulfonyl chloride (98-59-9) → N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-methylbenzenesulfonamide (1519060-68-4)

Conditions	Yield
Stage #1: gemcitabine hydrochloride With pyridine; chloro-trimethyl-silane at 20℃; for 2h; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride at 20 - 60℃; for 20h; Inert atmosphere;	96%
Stage #1: gemcitabine hydrochloride With pyridine; chloro-trimethyl-silane Stage #2: p-toluenesulfonyl chloride Stage #3: With ammonia In methanol

di-tert-butyl dicarbonate (24424-99-5) + gemcitabine hydrochloride (122111-03-9) → (2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl tert-butyl carbonate (250698-51-2)

Conditions	Yield
With sodium carbonate In 1,4-dioxane; water at 20℃; for 50h;	95%
With sodium carbonate In 1,4-dioxane; water at 20℃; for 48h;	87%
With sodium carbonate In 1,4-dioxane; water at 20℃; for 48h;	87%

gemcitabine hydrochloride (122111-03-9) → Deoxydifluorouridine (114248-23-6)

Conditions	Yield
With acetic acid; sodium nitrite In water at 20℃; for 48h;	95%
Multi-step reaction with 3 steps 1: pyridine / 15 h / 25 °C 2: acetic acid / water / 14 h / Reflux 3: ammonia / methanol / 15 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: pyridine / 15 h / 25 °C 2: acetic acid / water / 14 h / Reflux 3: ammonia / methanol / 15 h / 20 °C View Scheme

benzoyl chloride (98-88-4) + gemcitabine hydrochloride (122111-03-9) → (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate (1445381-44-1)

Conditions	Yield
With pyridine at 0 - 20℃; for 12h; Temperature; Inert atmosphere;	93.5%
With pyridine at 0 - 20℃; Inert atmosphere;	93.5%
With pyridine at 0 - 20℃; Inert atmosphere;	93.5%

trityl chloride (76-83-5) + gemcitabine hydrochloride (122111-03-9) → 5'-Tr-gemcytabine

Conditions	Yield
With pyridine In water at 30℃; for 22h; Inert atmosphere;	91.2%

di-tert-butyl dicarbonate (24424-99-5) + gemcitabine hydrochloride (122111-03-9) → 3′,5′-O-bis(tert-butoxycarbonyl)-gemcitabine (250698-52-3)

Conditions	Yield
With potassium hydroxide In 1,4-dioxane at 24℃; Substitution;	90%
With potassium hydroxide In 1,4-dioxane at 22℃; for 2h; Inert atmosphere;	71%
With potassium hydroxide In 1,4-dioxane; water at 4 - 22℃; for 1h; Inert atmosphere;	71%

benzoyl chloride (98-88-4) + gemcitabine hydrochloride (122111-03-9) → N4-benzoyl-2'-deoxy-2',2'-difluorocytidine (142816-70-4)

Conditions	Yield
Stage #1: gemcitabine hydrochloride With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane for 2.5h; Reflux; Stage #2: benzoyl chloride With 1-methyl-1H-imidazole In dichloromethane at 20℃; for 3h; Stage #3: With triethylamine In methanol; dichloromethane at 20℃; for 1.5h;	83%
Stage #1: gemcitabine hydrochloride With pyridine; chloro-trimethyl-silane at 0 - 20℃; for 0.5h; Stage #2: benzoyl chloride at 0 - 20℃;	76%

3-(N-methacryloylglycyl-DL-phenylalanylleucylglycyl)thiazolidine-2-thione + gemcitabine hydrochloride (122111-03-9) → C32H41F2N7O9

Conditions	Yield
With pyridine at 50℃; for 20h; Inert atmosphere;	80.1%

gemcitabine hydrochloride (122111-03-9) → 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-5-hydroxypyrimidine-2(1H)-one

Conditions	Yield
Stage #1: gemcitabine hydrochloride With water; bromine at 0 - 5℃; for 1h; Stage #2: With tetrabutylammomium bromide; N-ethyl-N,N-diisopropylamine In hexane at 0 - 60℃; for 1h; Reagent/catalyst; Temperature;	70.8%

gemcitabine hydrochloride (122111-03-9) + 11-azidoundecanoic acid (118162-45-1) → 4-N-(11-azidoundecanoyl)-2'-deoxy-2',2'-difluorocytidine

Conditions	Yield
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	70%

C47H55N3O15 + gemcitabine hydrochloride (122111-03-9) → C53H62F2N4O19

Conditions	Yield
With pyridine In dimethyl sulfoxide at 20℃; for 24h;	68.6%

(N-(methacryloyl)glycylphenylalanylleucylglycyl)thiazolidine-2-thione (831242-05-8) + gemcitabine hydrochloride (122111-03-9) → N-methacyloylglycylphenylalanylleucylglycyl-gemcitabine (1334238-76-4)

Conditions	Yield
With pyridine at 50℃; for 12h; Inert atmosphere;	66.1%
With pyridine at 50℃; for 12h; Inert atmosphere;	66.1%

10-undecenoic acid (112-38-9) + gemcitabine hydrochloride (122111-03-9) → 4-N-(10-undecenoyl)-2'-deoxy-2',2'-difluorocytidine (1519060-51-5)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide; N,N-dimethyl-formamide at 20 - 65℃; Inert atmosphere;	66%

gemcitabine hydrochloride (122111-03-9) + N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid (59-05-2) → C29H31F2N11O8

Conditions	Yield
Stage #1: N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: gemcitabine hydrochloride With triethylamine In N,N-dimethyl-formamide at 20℃; for 48h;	65%

3-(tert-butyloxycarbonylamino)propionic acid (3303-84-2) + gemcitabine hydrochloride (122111-03-9) → 4-N-[3-N-(tert-butoxycarbonyl)-3-aminopropanoyl]-2′-deoxy-2′,2′-difluorocytidine

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide; N,N-dimethyl-formamide Inert atmosphere; Heating;	65%

12-hydroxydodecanoic acid (505-95-3) + 4-Nitrophenyl chloroformate (7693-46-1) + gemcitabine hydrochloride (122111-03-9) → C22H33F2N3O8

Conditions	Yield
Stage #1: 12-hydroxydodecanoic acid; 4-Nitrophenyl chloroformate With pyridine; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 5h; Stage #2: gemcitabine hydrochloride With triethylamine In N,N-dimethyl-formamide for 24h;	64.3%

3-(tritylthio) propanoic acid (27144-18-9) + gemcitabine hydrochloride (122111-03-9) → C31H29F2N3O5S

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 25℃; for 18h; Inert atmosphere;	63%
Stage #1: 3-(tritylthio) propanoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: gemcitabine hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 0.408333h;	45%

hex-5-ynoic acid (53293-00-8) + gemcitabine hydrochloride (122111-03-9) → 4-N-(hexynoyl)gemcitabine

Conditions	Yield
Stage #1: gemcitabine hydrochloride With pyridine; chloro-trimethyl-silane In acetonitrile at 0 - 20℃; for 4h; Stage #2: hex-5-ynoic acid With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In acetonitrile at 60℃; for 18h; Stage #3: With ethanol at 45℃; for 4h;	63%

Upstream product

• 250698-52-3 3′,5′-O-bis(tert-butoxycarbonyl)-gemcitabine 
• 951314-37-7 α/β-1-(2-oxo-4-amino-1H-pyrimidin-1-yl)-2-desoxy-2,2'-difluororibose hydrochloride 
• 103882-84-4 2’-deoxy-2’,2’-difluoro-cytidine 
• 95058-81-4 gemcitabine 
• 14631-20-0 4-N-Acetylcytosine 
• 134877-42-2 3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-1-O-methanesulfonyl-D-erythro-pentofuranose 
• 1173824-58-2 (2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxyoxolan-3-yl benzoate 
• 18027-23-1 4-(N-trimethylsilylacetamido)-2-trimethylsiloxypyrimidine 
• 1445381-44-1 (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate 
• 134877-42-2 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-3,5-diphenylmethyl ester-1-methanesulfonate 
• 95058-92-7 (erytro) ethyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-difluoro-3-hydroxy propionate 

Downstream Products

• 114248-23-6 Deoxydifluorouridine 
• 95058-85-8 α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose 
• 250698-60-3 4-N-5'-O-bis(tert-butoxycarbonyl)-3'-O-[2-[2-[N-(1-methylpropyl),N-[1-(2-chlorophenyl)-isoquinoline-3-carbonyl]amino]ethylaminocarbonyl]ethylcarbonyl]gemcitabine 
• 250698-59-0 3'-O-5'-O-bis(tert-butoxycarbonyl)-4-N-[2-[2-[N-(1-methylpropyl),N-[1-(2-chlorophenyl)-isoquinoline-3-carbonyl]amino]ethylaminocarbonyl]ethylcarbonyl]gemcitabine 
• 250698-61-4 4-N-3'-O-bis(tert-butoxycarbonyl)-5'-O-[2-[2-[N-(1-methylpropyl),N-[1-(2-chlorophenyl)-isoquinoline-3-carbonyl]amino]ethylaminocarbonyl]ethylcarbonyl]gemcitabine 
• 95058-81-4 gemcitabine 
• 892128-60-8 N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2-propylpentanamide 
• 1330703-36-0 C₆₁H₆₆F₂N₄O₂₀ 
• 138685-83-3 4-(benzyloxycarbonylamino)-1-(2-deoxy-2,2-difluoro-β-D-erythro-pentofuranosyl)pyrimidin-2(1H)-one 
• 1254062-21-9 4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f] [1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one 
• 1334238-76-4 N-methacyloylglycylphenylalanylleucylglycyl-gemcitabine 
• 1188923-02-5 dodecyl 2-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)benzoate 
• 688009-09-8 4-amino-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-tetrahydrofuran-2-yl)pyrimidin-2(1H)-one 
• 1445381-44-1 (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate 

Relevant articles and documents

Synthesis and in vitro cytotoxic activity on human anaplastic thyroid cancer cells of lipoamino acid conjugates of gemcitabine

Lipophilic derivatives of the antitumor drug gemcitabine (GEM) with the potential for improving drug loading in lipid-based colloidal carriers, like liposomes or lipid nanoparticles, are described. GEM free base was conjugated to lipoamino acids bearing an alkyl side chain of different length, by either a carbodiimide-assisted or an ethylchloroformiate-assisted coupling reaction, to obtain N4-acyl GEM derivatives. These compounds retained the same in vitro cell growth inhibitory activity of the parent drug against two lines of human anaplastic thyroid cancer cells. Stability studies suggested that the observed activity was due mainly to intact derivatives and not to released GEM. Accordingly, these amphiphilic derivatives can be proposed in a further step for the encapsulation in liposomes or lipid nanocarriers, to achieve as a final goal an improvement of the pharmacokinetics and therapeutic activity of GEM.

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Preparation method of cytidine

The invention provides a preparation method of cytidine 1, which comprises the following steps: (1) carrying out a condensation reaction on a compound 6 and a compound 7 in the presence of stannic chloride to generate a compound 8; (2) removing an alpha-isomer and other reaction impurities in the compound 8 to obtain the beta-isomer compound 8; and (3) carrying out a deprotection reaction on the beta-isomer compound 8 in the presence of an alcohol solvent, and then carrying out a salt forming reaction with hydrochloric acid to obtain a compound 1. The nucleoside compound 8 can be obtained withhigh beta-stereoselectivity starting from a cheap raw material 7 with a mixed anomeric carbon configuration, especially the raw material 7a, and a slightly excessive basic group 6, especially the basic group 6a; the trace alpha-compound 8 isomer impurities can be removed from the nucleoside compound 8 through a simple pulping method; and subsequently, deprotection and salifying reactions for beta-compound 8 have high yield, so that the method can reduce the production cost of the compound 1.

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Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine

The invention relates to a preparation method for a compound represented by a formula (I) shown in the description, i.e., a key intermediate sulfonated saccharide of Gemcitabine. The final product is prepared through subjecting a compound represented by a formula (II) shown in the description to sodium borohydride reduction, hydroxyl protection and resolution. The method is simple in process, high in yield and high in product purity and has no need of harsh reaction conditions, thereby being very suitable for industrial production.

PROCESS FOR THE PREPARATION OF GEMCITABINE HYDROCHLORIDE

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A gemcitabine hydrochloride method for the preparation of

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Novel and Highly Stereoselective Process for Preparing Gemcitabine and Intermediates Thereof

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