FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A Process For Producing P-Nitro Benzyl Thienamycin Solvate

2. APPLICANT
NAME : Frichem Private Limited
NATIONALITY : IN
ADDRESS : 12, Concord, Bullock Road, Band Stand, Bandra West, Mumbai-400 050,
India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention generally relates to solvation process involved in the production of chemicals, and active pharmaceutical ingredients (APIs). In particular, the present invention relates to short path isothermal solvation (SPIS) process for isolation of a solvate for production of Imipenem.
Background of the Invention
Conventional methods of heat transfer for transferring heat of solvation include non isothermal modes. The commonly used non isothermal modes are, reactor jacket through which a heating media is circulated to the reaction mass or by internal coil that directly introduces heat into the reaction mass or both. However, these conventional heat transfer/reactor systems have limitations" of heat transfer area & heat transfer fluid media temperature and thereby a limited heat transfer rate. In addition, the reactor system develops different temperatures and energy profiles across the reaction mass in batch reactor due to non isothermal mode of heating.
The heat of reaction and heat transfer rate are critical parameters in the solvation processes and non compliance of these parameters results in poor yield and quality of product causing further problems in downstream operations.
Existing industrial scale-up methods for production of intermediates such as p-nitro benzyl thienamycin solvate (PNBTS) involve conventional methods and have associated disadvantages such as insufficient heat transfer area available to heat large quantity of reaction mass leading to reduced quantity and yield of the product due to short heating time (e.g. less than 15 minutes) for temperatures from -65°C to -5°C.
EP 1 395 587, assigned to Ranbaxy Laboratories Limited, discloses a process for preparation of imipenem. Said patent identifies the need for the development of a process for the preparation of imipenem which is convenient to operate on an industrial scale, employs readily and commercially available raw materials and reagents and which process gives substantially pure product in good yield. However, said patent discloses the use of catalytic amount of dialkylaminopyridine to prevent the formation of impurity.

US Patent No. 7,507,814 to Bae et al., also discloses a process for preparation of imipenem. Said patent addresses the need of achieving good quality and yield by providing a process for preparing imipenem using an amine-protected thienamycin compound.
The above prior art references do not disclose or suggest the below mentioned aspect of problem solving.
The reaction chemistry for producing PNBTS dictates rapid heating (5-10 minutes) for optimum isolation, yield and quality. With the existing methods dictated by conventional engineering practice, it is nearly impossible to raise the temperature in such a short time due to the equipment limitations in indirect non-isothermal heating. The constraints include, but not limited to, limiting heat transfer area (HTA) and inadequate heat transfer coefficients (HTC) for indirect heating through reactor jacket. Due to the limitations of indirect heating and l/3rd to l/4th of the required HTC, the precipitation occurs at around -25 to -30°C leading to poor yield/quality, longer filtration time, and inefficient drying operation. Due to the poor yield/quality, the batch might require frequent complete reprocessing or partial repulping.
The heating provided through reactor jacket or internal coil by non isothermal heating media results in different temperatures and energy profiles across the reaction mass, and finally leads to inferior quality and yield reduction of the product. Due to inferior quality of product as stated above, the product has sticky and non uniform particle size distribution (PSD) nature, takes a long time in filtration, and needs more filtration equipments. Moreover, material exposure time of the product is also increased thus affecting its nature. Another aspect of inferior quality of product is that the product has large amount of trapped NMP (N-Methyl pyrrolidine) between solids crystals. Filtered solids again require re-pulping operation with solvent to remove excess NMP from the solids. Further, due to inferior quality of the product, it takes longer time for drying operation. Due to the shortcomings mentioned above, at least the solvation step of production becomes a bottleneck and reduces overall plant production capacity of the product.

Therefore, there is well felt need to devise a method for solvation that addresses at least the above mentioned shortcomings in the prior art.
Summary of the Invention
The present invention provides a process for producing p-nitro benzyl thienamycin solvate, by short path isothermal solvation (SPIS), wherein the desired temperature is achieved rapidly.
The present invention provides a process for producing p-nitro benzyl thienamycin solvate, by short path isothermal solvation (SPIS). The short path isothermal solvation is achieved by preparing a hot non-interfering organic solvent/fluid/gas to act as a heat source, adding said heat source to a reaction mass containing the solvate, and mixing the resultant with high shear to ensure turbulent mixing to achieve the desired temperature in short time to precipitate the solvate. The solvate is then isolated.
In the process of the present invention, the solvent/fluid/gas used as heat source is selected from acetone, isopropanol, dichloromethane, nitrogen, argon or air.
In the process of the present invention, the temperature of the reaction mass before the addition of heat source is -55 to -65CC. The desired temperature at which p-nitro benzyl thienamycin solvate is precipitated is -5 to 0°C.
In the process of the present invention, the volume of heat source is about 10-40 times the volume of reaction mass, preferably, 20 times. The temperature of the heat source while adding to the reaction mass is in the range of 30-50°C, preferably about 40°C.
In the process of the present invention, the desired temperature is achieved in 5 to 10 minutes.
The product obtained by the process of the present invention is of high quality and the product is obtained in high yield. The yield of p-nitro benzyl thienamycin solvate achieved by the process of the present invention is 1.256 to 1.366. The p-nitro benzyl thienamycin solvate obtained by the process of the present invention has a narrow particle size distribution.

Detailed Description of the Invention
The present invention discloses a Short Path Isothermal Solvation (SPIS) process for providing the heat of solvation during production of various intermediates/solvates such as p-nitro benzyl thienamycin solvate (PNBTS). The process is used for large scale economic production of various solvates such as PNBTS which are in turn used for producing pharmaceutical/active pharmaceutical ingredients.
The SPIS process is a method of providing heat of reaction instantaneously and directly to a reaction mass in an isothermal mode. Certain thermodynamically controlled reactions require large heat transfer area for solvation reaction to take place within very short time. In such reactions, heat of reaction and heat transfer rate are critical parameters for good quality and better yield of product (solvate) and can be readily achieved by SPIS process.
A typical Short Path Isothermal Solvation (SPIS) process involves isolation of product as a solvate by subjecting the solvate to addition of non-interfering organic solvents or inert fluids (insoluble in the product) as a heat source to provide the heat of reaction rapidly. In other words, the solvation occurs in isothermal heat transfer mode under continuous high shear mixing by intensive agitation.
A process for isolation of a chemical compound by Short Path Isothermal Solvation (SPIS) is disclosed. In an embodiment, the process includes a step of preparing a hot non interfering organic solvent/fluid/gas to act as heat source. Subsequently, the heat source is added or activated to reaction mass which acts as heat sink. The process also includes ensuring the condition of high shear mixing to ensure turbulent mixing. The product is isolated in solvate form at desired temperature within specified time limit followed by a smooth solid-liquid separation and drying.
The present invention further discloses a method of producing Imipenem, a well known antibiotic using the solvate produced according to the present invention.
Jmipenem is a well known antibiotic in the literature and industry. P-nitro benzyl thienamycin solvate is an important intermediate compound in the production of


chemicals, active pharmaceutical ingredients (APIs) like Imipenem. The structure of the above mentioned compound is described below:
in which R1 is p-nitrobenzyl and X is —S—CH2—CH2—NH2. This compound is derived as a product by reacting cysteamine hydrochloride with the above structure where R1 is p-nitrobenzyl and X is diphenylphosphate. The aforesaid reaction is carried out at a temperature of -65°C and the product is isolated from the reaction mass by rapid heating according to the isothermal process of the invention. Lab experiments and further trials have indicated that rapid heating ensures better quality product with respect to the nature of the material in hygroscopicity and yield. Hence, for successful scale-up and large-scale production of the product, complete control over rapid heating becomes essential.
In the proposed technology of SPIS, the heat of solvation is supplied by using the hot solvent as a heat source for direct addition and the mixed reaction mass as the heat sink in a dynamically mixed system.
In various other embodiments, hot solvents, ultrasonic energy, microwave energy, UV energy, hot nitrogen or hot air, hot inert fluid/gas, electrical energy, can be used as direct input to reaction mass as isothermal mode of heating. For example, isolation using isopropanol can be carried out by adding equivalent enthalpy of solvation in isothermal heating mode at a temperature of 40°C.
The SPIS process brings down the temperature of the reaction mass to -5 to 0°C from -55 to -65°C in about 5 minutes as opposed to the 45-60 minutes by conventional engineering practices involving indirect heating.
Therefore, the primary focus of product isolation at the large-scale will be on providing the heat of solvation to the reaction mass as quickly as possible to bring its temperature to about-5 to 0°C.

The invention is further described by the following illustrative but non-limiting examples:
Example 1
Process Development Laboratory Trials and Results:

Sr.
No Experi ment No Parameter Yield Assay
NLT
95% Purity NLT 95% NMP
14.5-19.0
%w/w
1 23A Reaction mass dumped into 10x IPA at 50°C 1.224 95.9 95.95 16.5
2 23B Reaction mass dumped into 15x IPA at 40°C 1.24 96.7 95.93 16
3 23C Reaction mass dumped into 10x IPA at 30°C 1.225 98 96.07 16.1
4 24A l0x IPA at 50°C dumped into reaction mass 1.24 97.1 98.58 16.4
5 24B 15x IPA at 50°C dumped into reaction mass 1.25 95.5 98.36 16.5
6 24C 20x IPA at 40°C dumped into reaction mass 1.295 96.6 98.33 16.5
7 25 15x IPA at 45°C dumped into reaction mass 1.23 96.5 97.54 23.3
8 26 15x IPA at 45°C dumped into reaction mass 1.235 99 96.78 17.5
9 27 15x IPA at 45°C dumped into reaction mass 1.232 99.7 97.48 19
10 28 20x IPA at 40°C dumped into reaction mass 1.286 99.3 97.26 17.0
11 29 20x IPA at 40°C dumped into reaction mass 1.282 99.3 97.59 17.5
12 30 20x IPA at 40°C dumped into reaction mass 1.283 98.3 97.95 17.6

IPA - Isopropanol Alcohol
Example 2
Plant-Scale Trials and Results:

Sr.No Batch No Batch
Size (Kg.) Dry Wt.
(Kg.) Yield Assay
NLT
95% Purity NLT
95% NMP
14.5-19.0
%w/w
Before
process
change IPM-IV(PNBT-
S)/041/10 30 34.94 1.165 OK OK OK
1 IPM-IV(PNBT-
S)/069/10 25 31.41 1.256 96.10 95.63 18.40
2 IPM-IV(PNBT-S)/070/10 25 30.94 1.238 96.80 96.13 17.90
3 IPM-IV(PNBT-S)/075/10 25 33.05 1.322 97.70 97.86 18.70
4 IPM-IV(PNBT-
S)/076/10 25 32.73 1.309 96.00 96.24 18.80
5 IPM-IV(PNBT-S)/077/10 25 30.8 1.232 95.20 97.98 15.20
6 IPM-IV(PNBT-S)/078/10 25 33.18 1.327 97.50 96.85 17.60
7 IPM-IV(PNBT-S)/079/10 25 34.14 1.366 97.40 96.00 18.80
IPM-IV means P-nitro benzyl thienamycin solvate
The above experiments are based on the reasoning and logic that the total heat of solvation can either be supplied by high volume, low temperature; or low volume, high temperature.
The optimized conditions obtained from the experimentation were IPA 20 volumes the batch size at a temperature of 40°C.

For the heating to be isothermal the reaction mass has to be continuously mixed turbulently with intensive agitation. As expected, the product precipitation time came down to 10 minutes, product yield and quality showed dramatic improvement. Also, the infrastructure footprint of the process came down due to the possibility of centrifuging the product for isolation as opposed to filtration earlier.
The advantages of the process of the present invention as compared to the process where short path isothermal solvation or rapid heating is not done, is provided below:

S.No Process with slow heating Process with rapid heating (Short Path Isothermal Solvation)

Material/Solvate starts precipitating out below -20°C, "which result into following drawbacks: Material/Solvate starts precipitating out at higher tempreature, which result into following augmentation:
1 slummy material results into free flow material
2 slow filtration results into fast filtration
3 inconsistency in NMP content in the product (19-25%), majority on higher side results into lower NMP content in the product (15-19%)
4 longer drying time results into lesser drying time
5 reduction in plant capacity enhancement in plant capacity
6 inconsistency in yield (0.95-1.2%) and quality consistency in yield (1.25 -1.35%) and quality
The advantages of the proposed SPIS technology over existing processes were observed after the successful plant-scale implementation of the proposed technology. The advantages include highest observed plant-scale product yield of 1.36 (with direct isothermal heat addition) showed a great positive departure from the previous yield of 1.13-1.18 thereby recording a dramatic improvement of 20.88%.
Filtration and drying time using the SPIS process is reduced by 75% due to better solids product nature. In addition, the narrow particle size distribution (PSD) due to the rapid

isothermal precipitation has far-reaching impact on the repeatability and consistency of the product quality. The SPIS process also demonstrated savings in operational time, energy, man power, and money because of elimination of re-pulping operation to remove excess NMP. The disclosed SPIS process demonstrated operational time cycle reduction of about 24-28 hrs. The total operating cost reduction is about 40% of the original cost involved in the stage. The plant capacity enhancement is around 200% in the same commercial set up.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We Claim:
1. A process for producing p-nitro benzyl thienamycin solvate, the process
comprising the step of short path isothermal solvation, wherein the short path isothermal
solvation is achieved by:
(a) preparing a hot non-interfering organic solvent/fluid/gas to act as a heat source,
(b) adding said heat source to a reaction mass containing the solvate,
(c) mixing the resultant of step (b) with high shear to ensure turbulent mixing to achieve the desired temperature to precipitate the solvate, and
(d) isolating the solvate.

2. The process as claimed in claim 1, wherein the solvent/fluid/gas used as heat source is acetone, isopropanol, dichloromethane, nitrogen, argon or air.
3. The process as claimed in claim 1, wherein the temperature of the reaction mass before the addition of heat source is -55 to -65°C.
4. The process as claimed in claim 1, wherein the desired temperature achieved in step (c) is -5 to 0°C.
5. The process as claimed in claim 1, wherein the volume of heat source is about 20 times the volume of reaction mass.
6. The process as claimed in claim 1, wherein the temperature of the heat source is about 40°C.
7. The process as claimed in claim 1, wherein the desired temperature is achieved in 5 to 10 minutes.
8. The process as claimed in claim 1, wherein the yield of p-nitro benzyl thienamycin solvate is 1.25 to 1.36.
9. The process as claimed in claim 1, wherein the p-nitro benzyl thienamycin solvate has a narrow particle size distribution.
10. P-nitro benzyl thienamycin solvate obtained by the process as claimed in any of the preceding claims for use in the production of imipenem.