Crystalline Sitagliptin Hydrochloride Process Without Ether Isolation
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Solution Overview
Problem
Existing processes for preparing sitagliptin hydrochloride monohydrate are not suitable for industrial production and often use hazardous solvents like diethyl ether, posing safety and handling challenges.
Innovation Solution
A process involving the deprotection of Boc-sitagliptin with hydrochloric acid or hydrogen chloride in ethanol, followed by drying to form anhydrous sitagliptin hydrochloride and then hydrating under controlled humidity to produce crystalline sitagliptin hydrochloride monohydrate, using environmentally friendly solvents like ethanol and water.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If diethyl ether is used as solvent in the crystallization process, then crystalline sitagliptin hydrochloride monohydrate can be obtained, but the process becomes hazardous due to high volatility and flammability
Solution Approach 1:
The patent changes the solvent parameter from diethyl ether to ethanol, fundamentally altering the chemical properties of the system. Ethanol maintains the ability to produce crystalline sitagliptin hydrochloride monohydrate while eliminating the safety hazards associated with diethyl ether's high volatility and flammability.
Solution Approach 2:
The patent replaces expensive and hazardous diethyl ether with cheaper and safer ethanol. Ethanol is less volatile, non-flammable under normal conditions, and more environmentally friendly, making it suitable for industrial-scale production while maintaining product quality.
2Manufacturing precision
If multiple solvents and complex crystallization steps are used, then crystalline sitagliptin hydrochloride can be obtained, but the process complexity increases
Solution Approach 1:
The patent extracts and eliminates unnecessary process steps from the conventional multi-step procedure. By using ethanol as the sole solvent for both dissolution and crystallization, the patent removes the need for separate solvent exchange steps and complex crystallization protocols, simplifying the overall process while maintaining crystal form control.
Solution Approach 2:
Ethanol serves multiple functions in the patent: it acts as the dissolution solvent, the crystallization solvent, and the washing solvent. This multi-functionality eliminates the need for multiple different solvents and reduces the number of process steps required to obtain crystalline sitagliptin hydrochloride monohydrate.
3Manufacturing precision
If hazardous solvents are used in the process, then the desired crystalline product can be obtained, but environmental and safety concerns arise
Solution Approach 1:
The patent changes the chemical parameter of the solvent from hazardous diethyl ether to safe ethanol. This fundamental parameter change maintains the ability to produce pure crystalline sitagliptin hydrochloride monohydrate while eliminating toxicity and environmental harm, making the process suitable for industrial application.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process achieves high purity sitagliptin hydrochloride monohydrate with low impurity content, suitable for industrial production, and avoids the use of toxic solvents, ensuring safety and efficiency.
Implementation Method 1
deprotecting compound of formula (II) with a solution of hydrochloric acid or hydrogen chloride in a solvent
Implementation Method 2
drying the crystalline solid product obtained in step a)
Implementation Method 3
hydrating the product obtained in step b) to obtain crystalline sitagliptin hydrochloride monohydrate
Data Source
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AI summary
The present invention relates to a process for preparing crystalline sitagliptin hydrochloride monohydrate, compound of formula (IV) from compound of formula (II), Boc sitagliptin, without the need of isolating sitagliptin free base.